OA19157A - Pesticidal Compositions and Processes Related Thereto - Google Patents

Pesticidal Compositions and Processes Related Thereto Download PDF

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OA19157A
OA19157A OA1201300532 OA19157A OA 19157 A OA19157 A OA 19157A OA 1201300532 OA1201300532 OA 1201300532 OA 19157 A OA19157 A OA 19157A
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alkyl
halo
substituted
alkoxy
heterocyclyl
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OA1201300532
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Akshay PATNY
Dan ERNICH
Ramadevi SANAM
William C. Lo
Gerald B. Watson
Gary D. Gustafson
Adiraj MANDALESWARAN
Rambabu GUNDLA
Beth Lorsbach
James E. Hunter
Hemant Joshi
Pravin S. IYER
William K. Brewster
Michael R. Loso
Thomas C. Sparks
Debra L. Camper
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Dow Agrosciences Llc
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Publication of OA19157A publication Critical patent/OA19157A/en

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Abstract

This document discloses molecules having the following formula ("Formula One"): and processes associated therewith.

Description

PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO
CROSS REFERENCES TO RELATED APPLICATIONS
This Application claims priority from U.S. provisional application 61/500,685 filed on June 24, 2011 the entire content of this provisional application is hereby incorporated by référencé into this Application. This Application also claims priority from U.S. provisional application 61/540,056 filed on September 28, 2011 the entire content of this provisional application is also hereby incorporated by référencé into this Application. This Application also claims priority from U.S. provisional application 61/601,077 filed on February 21,2012 the entire content of this provisional application is also hereby incorporated by référencé into this Application. This Application also claims priority from U.S. provisional application 61/645,267 filed on May 10, 2012 the entire content of this provisional application is also hereby incorporated by référencé into this Application.
FIELD OF THE DISCLOSURE
The invention disclosed in this document is related to the field of processes to produce molécules that are useful as pesticides (e.g., acaricides, insecticides, molluscicides, and nematicides), such molécules, and processes of using such molécules to control pests.
BACKGROUND OF THE DISCLOSURE
Pests cause millions of human deaths around the world each year. Furthermore, there are more than ten thousand species of pests that cause losses in agriculture. The world-wide agricultural losses amount to billions of U.S. dollars each year.
Termites cause damage to ail kinds of private and public structures. The world-wide termite damage losses amount to billions of U.S. dollars each year.
Stored food pests eat and adulterate stored food. The world-wide stored food losses amount to billions of U.S. dollars each year, but more importantly, deprive people of needed food.
There is an acute need for new pesticides. Certain pests are developing résistance to pesticides in current use. Hundreds of pest species are résistant to one or more pesticides. The development of résistance to some ofthe older pesticides, such as DDT, the carbamates, and the organophosphates, is well known. But résistance has even developed to some ofthe newer pesticides, for example, imidacloprid.
Therefore, for many reasons, including the above reasons, a need exists for new pesticides.
DEFINITIONS
The examples given in the définitions are generally non-exhaustive and must not be construed as limiting the invention disclosed in this document. It is understood that a substituent should comply with chemical bonding rules and steric compatibility constraints in relation to the particular molécule to which it is attached.
“Alkenyl” means an acyclic, unsaturated (at least one carbon-carbon double bond), branched or unbranched, substituent consisting of carbon and hydrogen, for example, vinyl, allyl, butenyl, pentenyl, and hexenyl.
“Alkenyloxy” means an alkenyl further consisting of a carbon-oxygen single bond, for example, allyloxy, 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, (C3)alkyl which represents n-propyl and isopropyl), (C4)alkyl which represents n-butyl, sec-butyl, isobutyl, 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 biphenyl.
“(Cx-Cy)” where the subscripts “x” and “y” are integers such as 1,2, or 3, means the range of carbon atoms for a substituent - for example, (CrC^alkyl means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl, each individually.
“Cycloalkenyl” means a monocyclic or polycyclic, unsaturated (at least one carbon-carbon double bond) substituent consisting of carbon and hydrogen, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbomenyl, bicyclo[2.2.2]octenyl, tetrahydronaphthyl, hexahydronaphthyl, and octahydronaphthyl.
“Cycloalkenyloxy” means a cycloalkenyl further consisting of a carbon-oxygen single bond, for example, cyclobutenyloxy, cyclopentenyloxy, norbornenyloxy, and bicyclo[2.2.2]octenyloxy.
“Cycloalkyl” means a monocyclic or polycyclic, saturated substituent consisting of carbon and hydrogen, for example, cyclopropyl, cyclobutyl, cyclopentyl, norbornyl, bicyclo[2.2.2]octyl, and decahydronaphthyl.
“Cycloalkoxy” means a cycloalkyl further consisting of a carbon-oxygen single bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, norbornyloxy, and bicyclo[2.2.2]octyloxy.
“Halo” means fluoro, chloro, bromo, and iodo.
“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, partially unsaturated, orfully unsaturated, where the cyclic structure contains at least one carbon and at least one heteroatom, where said heteroatom is nitrogen, sulfur, or oxygen. In the case of sulfur, that atom can be in other oxidation states such as a sulfoxide and sulfone. Examples of aromatic heterocyclyls include, but are not limited to, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolinyl, thiazolyl, thienyl, triazinyl, and triazolyl. Examples of fully saturated heterocyclyls include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl and tetrahydropyranyl. Examples of partially unsaturated heterocyclyls include, but are not limited to, 1,2,3,4-tetrahydroquinolinyl, 4,5dihydro-oxazolyl, 4,5-dihydro-1/-/-pyrazolyl, 4,5-dihydro-isoxazolyl, and 2,3-dihydro-[1,3,4]oxadiazolyl.
Additional examples include the following
thietanyl thietanyl-oxidethietanyl-dioxide.
DETAILED DESCRIPTION OF THE DISCLOSURE
This document discloses molécules having the following formula (“Formula One”):
Formula One wherein:
(a) R1 is selected from (1) H, F, Cl, Br, I, CN, NO2, (Ci-C8)alkyl, halo(Ci-C8)alkyl, (CrC^alkoxy, halofCr C8)alkoxy, SfCrC^alkyl, SihalofCrCeJalkyl), S(O)(CrC8)alkyl, SiOMhaloiCi-CeJalkyl), S(O)2(Cr C8)alkyl, StO^haloiCrCejalkyl), N(R14)(R15), (2) substituted (CrCsJalkyl, wherein said substituted (C^C^alkyl has one or more substituents selected from CN and NO2, (3) substituted halo(Ci-C8)alkyl, wherein said substituted halo^-Csjalkyl, has one or more substituents selected from CN and NO2, (4) substituted (CrCsJalkoxy, wherein said substituted (Ci-C8)alkoxy has one or more substituents selected from CN and NO2, and (5) substituted halo(Ci-C8)alkoxy, wherein said substituted halo(Ci-C8)alkoxy has one or more substituents selected from CN and NO2;
(b) R2 is selected from (1) H, F, Cl, Br, I, CN, NO2, (Ci-C8)alkyl, halo(Ci-C8)alkyl, (C-i-CsJalkoxy, halo(Cr C8)alkoxy, S(CrC8)alkyl, SfhalofC^C^alkyl), S(O)(CrC8)alkyl, S(O)(halo(C.rC8)alkyl), S(O)2(CiC8)alkyl, S(O)2(halo(Ci-C8)alkyl), N(R14)(R15), (2) substituted (CrC8)alkyl, wherein said substituted (CrCsjalkyl has one or more substituents selected from CN and NO2, (3) substituted halofCrCsIalkyl, wherein said substituted halo(C-i-C8)alkyl, has one or more substituents selected from CN and NO2, (4) substituted (CrCsJalkoxy, wherein said substituted (CTCsjalkoxy has one or more substituents selected from CN and NO2, and (5) substituted halofCvCslalkoxy, wherein said substituted halo(Ci-C8)alkoxy has one or more substituents selected from CN and NO2;
(c) R3 is selected from (1) H, F, Cl, Br, I, CN, NO2, (CrC8)alkyl, halo(CrC8)alkyl, (C^C^alkoxy, halo(Cr C8)alkoxy, S(CrC8)alkyl, S(halo(CrC8)alkyl), SiOXCrC^alkyl, SiOXhalo^-C^alkyl), S(O)2(Cr C8)alkyl, SiOMhaloiCrCeJalkyl), N(R14)(R15), (2) substituted (CrC8)alkyl, wherein said substituted (Ci-C8)alkyl has one or more substituents selected from CN and NO2, (3) substituted haloiC^CsJalkyl, wherein said substituted halo(Ci-C8)alkyl, has one or more substituents selected from CN and NO2, (4) substituted (Ct-C8)alkoxy, wherein said substituted (C-i-C8)alkoxy has one or more substituents selected from CN and NO2, and (5) substituted halofCrCeJalkoxy, wherein said substituted haloiCrCsJalkoxy has one or more substituents selected from CN and NO2;
(d) R4 is selected from (1) H, F, Cl, Br, I, CN, NO2, (CrC^alkyl, halo(Ci-C8)alkyl, (CrCejalkoxy, halo(Cr C8)alkoxy, S^-C^lkyl, SfhaloiCrC^alkyl), SiOjiC^Cslalkyl, SiOXhaloiCvCfOalkyl), 8(Ο)2(^C8)alkyl, S(O)2(halo(Ci-C8)alkyl), N(R14)(R15), (2) substituted (Ci-C8)alkyl, wherein said substituted (CrCajalkyl has one or more substituents selected from CN and NO2, (3) substituted halo(Ci-C8)alkyl, wherein said substituted halolC^Csjalkyl, has one or more substituents selected from CN and NO2, (4) substituted (Ci-CsJalkoxy, wherein said substituted (C-rCsjalkoxy has one or more substituents selected from CN and NO2, and (5) substituted halofCvCsIalkoxy, wherein said substituted halo^-CsJalkoxy has one or more substituents selected from CN and NO2;
(e) R5 is selected from (1) H, F, Cl, Br, I, CN, NO2, (C^Csjalkyl, halofCrCfOalkyl, (CrQOalkoxy, halo(C.r C8)alkoxy, S(CrC8)alkyl, S(halo(C,-C8)alkyl), SfOXCrCaJalkyl, SfOXhaloiCrCeJalkyl), S(O)2(Cr C8)alkyl, SiOMhaloiCrCgjalkyl), N(R14)(R15), (2) substituted (CrCejalkyl, wherein said substituted (Ci-CsJalkyl has one or more substituents selected from CN and NO2, (3) substituted halofCvCelalkyl, wherein said substituted halofCvCgjalkyl, has one or more substituents selected from CN and NO2) (4) substituted (Ci-C8)alkoxy, wherein said substituted (C-i-Csjalkoxy has one or more substituents selected from CN and NO2, and (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(Ci-C8)alkoxy has one or more substituents selected from CN and NO2;
(f) R6 is a (C-i-CeJhaloalkyl;
(g) R7 is selected from H, F, Cl, Br, I, OH, (Ci-C8)alkoxy, and halofC^Cgjalkoxy;
(h) R8 is selected from H, (CTCeJalkyl, halofC-i-Cgjalkyl, OR14, and N(R14)(R15);
(i) R9 is selected from H, F, Cl, Br, I, (CrC8)alkyl, halofCrCsjalkyl, (Ci-C^alkoxy, halo(Ci-C8)alkoxy, OR14, and N(R14)(R15);
(j) R10 is selected from (1) (u), H, F, Cl, Br, I, CN, NO2, (Ci-C8)alkyl, halo(Ci-C8)alkyl, (Ci-C8)alkoxy, halotCrCsJaIkoxy, cyclo(C3-C6)alkyl, S(C-i-C8)alkyl, SfhalofC^Cgjalkyl), S(OXCrC8)alkyl, S(OXhalo(CrC8)alkyl), SiOMCrC^alkyl, SfOMhaloiCrCOalkyl), NR14R15, C(=O)H, C(=O)N(R14)(R15), CN(R14)(R15X=NOH), (C=O)O(CrC8)alkyl, (C=O)OH, heterocyclyl, (C2C8)alkenyl, halo(C2-C8)alkenyl, (C2-C8)alkynyl, (2) substituted (C-t-CeJalkyl, wherein said substituted (C-i-C8)alkyl has one or more substituents selected from OH, (Ci-C8)alkoxy, StCi-CsJalkyl, S(OXCi-C8)alkyl, S(O)2(CiC8)alkyl, NR14R15, and (3) substituted haloiCi-CeJalkyl, wherein said substituted halojC^Cajalkyl, has one or more substituents selected from (C^CgJalkoxy, SfCvCgJalkyl, SCOXC^Cejalkyl, S(O)2(Cr C8)alkyl, and N(R14)(R15);
(k) R11 is selected from (u), substituted (CrC8)alkyl, C(=O)OH, C(=O)O(C1-C8)alkyl,
C(=O)(substituted- (CrC8)alkyl), C(=O)O(substituted (C^alkyl), C(=O)N(R14)(R15), C(=O)heterocyclyl, C(=O)(substituted heterocyclyl), C(=S)N(R14)(R15), C(=S)heterocyclyl, C(=S)(substituted heterocyclyl), (Ci-C8)alkylN(R11a)(C(=X11)R11b), N(11a)(11d), ON(11c)(11d), halo(Ci-C8)alkyl, (Ci-C8)alkyl, (CrCeJalkylNiHXheterocyclyl), (Ci-C8)alkyl(N(R15))(0=0)0(^C8)alkyl, (CrCeJalkyKRUXRIS), N(H)N(H)(heterocyclyl), B(OH)2, (Cr C8)alkylN(R11 a)(C(=X11 )R14), (C.i-C8)alkylN(R11 a)(C(=X11 )N(R14)(R15)), (Cp C8)alkylN(R11a)(C(=X11)OR14), substituted or unsubstituted heterocyclyl, C(=O)N(R14)(N(R16)(R17), C(=O)N(R14)((C1-C8)alkylC(=O)N(R14)N(R14)(R15)), C(=O)N(R14)((C1-C8)alkylC(=O)N(R14)(R15)), C(=S)N(R14)((C1-C8)alkylC(=S)N(R14)(R15)), C(=S)N(R14)((C1-C8)alkylC(=O)N(R14)(R15)), C(=O)N(R14)((C1-C8)alkylC(=S)N(R14)(R15)), C(=O)N(R14)((C1-C8)alkylC(=O)(R15), (1) wherein each said substituted (Ci-C8)alkyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, wherein each said substituted aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (CvCeJalkyl, halo(C-|-C8)alkyl, (CpCsJalkoxy, halo(C-i-C8)alkoxy, SfCpC^alkyl, SfhalofC-i-Cajalkyl), NffCrCsjalkylE (wherein each (CpCsjalkyl is independently selected), and oxo, (2) wherein each said substituted heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (CpCgjalkyl, halolCpCsjalkyl, (C-|-C8)alkoxy, halo(Ci-C8)alkoxy, S(Ci-C8)alkyl, SfhalojCpCejalkyl), N((Ci-C8)alkyl)2 (wherein each (C!-C8)alkyl is independently selected), C(=O)(C1-C8)alkyl, C(=O)(C3-C6)cycloalkyl, S(=O)2(CrC8)alkyl, NR14R15, and oxo, (3) wherein R11a is selected from H, (CpCejalkyl, and (CpC^alkyl-heterocyclyl, R14, C(X11)R14, (CrC8)alkylR14 (4) wherein R11b is selected from (CrC8)alkyl, cyclo(C3-C6)alkyl, halo(Cp C8)alkyl, heterocyclyl, substituted-heterocyclyl (where said substituents are one or more of F, Cl, Br, I, CN, NO2, (CrC8)alkyl, halo(CrC8)alkyl, (CrC8)alkoxy, halo(Ci-C8)alkoxy, SCCpCeJalkyl, S(halo(Ci-C8)alkyl), N((Ci-C8)alkyl)2 (wherein each (Ci-C8)alkyl is independently selected), and oxo), (CrCejalkylSfCrCejalkyl, (CrCgjalkylSCOXCvCgJalkyl, (C1-C8)alkylS(O)2(Ci-C8)alkyl, N(R11 c)(R11 d), O(Ci-C8)alkyl, Oheterocyclyl, O-substituted-heterocyclyl (where said substituents are one or more of F, Cl, Br, I, CN, NO2, (Ci-C8)alkyl, halo(Ci-C8)alkyl, (Ci-C8)alkoxy, halo(Ci-C8)alkoxy, S/C^Csjalkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C^Csjalkyl is independently selected), and oxo), C(=O)OR11d, C(=O)N(R11c)(R11d), C(=O)(R11d)aryl, substituted aryl (where said substituents are one or more of F, Cl, Br, I, CN, NO2, (CrC8)alkyl, haloiC^CfOalkyl, (C^Cgjalkoxy, haloiCrCgjalkoxy, S^-Crialkyl, SihaloiCi-Csjalkyl), Ν((0τ C8)alkyl)2 (wherein each (CrC8)alkyl is independently selected), (5) wherein X11 is O or S, (6) wherein R11c is selected from H, (7) wherein R11d is selected from H, (C^CsJalkyl, (C^Cajalkenyl, halo/C-r C8)alkyl, heterocyclyl, substituted-heterocyclyl (where said substituents are one or more of F, Cl, Br, I, CN, NO2, (Ci-Csjalkyl, halo(C1-C8)alkyl, (C^Csjalkoxy, halo^-Csjalkoxy, SiCi-CeJalkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (C-i-Csjalkyl is independently selected), and oxo), N(H)(C(=O)cyclo(C3-C6)alkyl), N(H)(C(=O)halo(C1-C8)alkyl), (8) wherein optionally R11 c and R11 d along with N form a 5, 6, 7, or 8 membered ring that may optionally further contain 1,2, or 3, additional heteroatoms selected from O, N, or S, in the ring;
(l) R12 is selected from (v), H, F, Cl, Br, I, CN, (CrCeJalkyl, haloiCi-Csjalkyl, (Cr C8)alkoxy, halo^-rCsjalkoxy, and cyclo(C3-C6)alkyl;
(m) R13 is selected from (v), H, F, Cl, Br, I, CN, (CrCeJalkyl, haloiC-i-Crialkyl, (C-]C8)alkoxy, and haloiCTCsjalkoxy;
(n) each R14 is independently selected from H, (CrC8)alkyl, (C-i-C8)alkenyl, substituted (CrCeJalkyl, halo/C^Cejalkyl, substituted haloiC-i-Cejalkyl), (C-|-C8)alkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (CT-Cajalkyl-aryl, (Ci-C8)alkyl-(substituted-aryl), O-(Ci-C8)alkyl-aryl, O-(Ci-C8)alkyl(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C-i-Cgjalkyl-heterocyclyl, (CrCajalkyl(substituted-heterocyclyl), O-iCrCajalkyl-heterocyclyl, 0-(CrC8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (CrC8)alkyl-C(=O)N(R16)(R17), C(=O)(C1-C8)alkyl, C(=O)(halo(Cr C8)alkyl),C(=O)(C3-C6)cycloalkyl, (Ci-C8)alkyl-C(=O)O(C1-C8)alkyl, C(=O)H wherein each said substituted (CrCsjalkyl has one or more substituents selected from CN, and NO2, wherein each said substituted halo/CvCsjalkyl), has one or more substituents selected from CN, and NO2, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (Ci-C8)alkyl, halotCvCsjalkyl, (C^Csjalkoxy, halo(C1-C8)alkoxy, SfCrCaJalkyl,
S(halo(Ci-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (Ci-C8)alkyl is independently selected), and oxo, and wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (CrCsJalkyl, halo^-Crfalkyl, (C^Csjalkoxy, halo(Ci-C8)alkoxy, (C3C6)cycloalkyl S(C1-C8)alkyl, S(halo(Ci-C8)alkyl), NfiC-rCrfalkyl^ (wherein each (Ci-C8)alkyl is independently selected), heterocyclyl, C(=O)(C1-C8)alkyl, C(=O)O(Ci-C8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, Cl, Br, I, CN, and NO2);
(o) each R15 is independently selected from H, (Ci-C8)alkyl, (Ci-C8)alkenyl, substituted (C-|-C8)alkyl, haloiCrCrfalkyl, substituted hakXCrCrfalkyl), (CrCrfalkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C-rCrfalkyi-aryl, (C-i-Cejalkylrfsubstituted-aryl), OrfCrCrfalkyl-aryl, O-(C1-C8)alkyl(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (Ci-Csjalkyl-heterocyclyl, (Ci-C8)alkyl(substituted-heterocyclyl), OrfCrCrfalkyl-heterocyclyl, O-(C1-C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (CrCfOalkyl-CiOJNiRieXR-R), C(=O)(C.|-C8)alkyl, C^OXhaloiCrC^alkyl), C(=O)(C3-C6)cycloalkyl, (C1-C8)alkyl-C(=O)O(C1-C8)alkyl, C(=O)H wherein each said substituted (C^Csjalkyl has one or more substituents selected from CN, and NO2, wherein each said substituted haloiCi-Crfalkyl), has one or more substituents selected from CN, and NO2, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (CrCejalkyl, haloiC-rCrfalkyl, (CrCrfalkoxy, halo(C1-C8)alkoxy, S(CrC8)alkyl, SihaloiCrCrfalkyl), N((C-i-C8)alkyl)2 (wherein each (CrCrfalkyl is independently selected), and oxo, and wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (CrCeJalkyl, halo(Ci-C8)alkyl, (C^Crfalkoxy, halo(Ci-C8)alkoxy, (C3C6)cycloalkyl S(CrC8)alkyl, S(halo(CrC8)alkyl), N((Ci-C8)alkyl)2 (wherein each (CrCrfalkyl is independently selected), heterocyclyl, C(=O)(Ci-C8)alkyl, C(=O)O(C1-C8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, Cl, Br, I, CN, and NO2);
(p) each R16 is independently selected from H, (CrC8)alkyl, substitutedXCj-Csjalkyl, halo(CrC8)alkyl, substituted-halo(Ci-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (Ci-C8)alkylaryl, (C.|-C8)alkyl-(substituted-aryl), O-(Ci-C8)alkyl-aryl, O-iCrCeJalkyl-isubstituted-aryl), heterocyclyl, substituted-heterocyclyl, (Ci-C8)alkyl-heterocyclyl, (Ci-C8)alkyl-(substitutedheterocyclyl), O-(Ci-C8)alkyl-heterocyclyl, O-(Ci-C8)alkyl-(substituted-heterocyclyl), O-(C1-C8)alkyl wherein each said substituted (C-i-C8)alkyl has one or more substituents selected from CN, and NO2, wherein each said substituted halo(Ci-C8)alkyl), has one or more substituents selected from CN, and NO2, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (Ci-C8)alkyl, haloiCTCsjalkyl, (C^Csjalkoxy, halotCi-CsJalkoxy, StCi-Csjalkyl, S(halo(C1-C8)alkyl), N^C^Csjalkylk (wherein each (G-C^alkyl is independently selected), and oxo, and wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (CrC^alkyl, halo^-Csjalkyl, (C^Csjalkoxy, halo(C1-C8)alkoxy, δ(^C8)alkyl, S(halo(C-i-C8)alkyl), N((CrC8)alkyl)2 (wherein each (C-|-C8)alkyl is independently selected), and oxo;
(q) each R17 is independently selected from H, (CrC8)alkyl, substituted-(C1-C8)alkyl, halotCrCejalkyl, substituted-halotCrCsjalkyl, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (Ci-C8)alkylaryl, (CrCsjalkyl-tsubstituted-aryl), O-tCj-Cejalkyl-aryl, O-ÏC-i-Cgjalkyl-tsubstituted-aryl), heterocyclyl, substituted-heterocyclyl, (G-CeJalkyl-heterocyclyl, (C-i-C8)alkyl-(substitutedheterocyclyl), O-(C1-C8)alkyl-heterocyclyl, O-(C1-C8)alkyl-(substituted-heterocyclyl), O-(C1-C8)alkyl wherein each said substituted (C-|-C8)alkyl has one or more substituents selected from CN, and NO2, wherein each said substituted halolG-Csjalkyl), has one or more substituents selected from CN, and NO2, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (Ci-CeJalkyl, halotC^Csjalkyl, (C^Csjalkoxy, halotCrCelalkoxy, StCrCsjalkyl, S(halo(Ci-C8)alkyl), N((Ci-C8)alkyl)2 (wherein each (CrC8)alkyl is independently selected), and oxo, and wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (Ci-C8)alkyl, halo(Ci-C8)alkyl, (Ci-Csjalkoxy, halo(Ci-C8)alkoxy, SfCr C8)alkyl, S(halo(C1-C8)alkyl), NftC^Csjalkyl);, (wherein each (CvCelalkyl is independently selected), and oxo;
(r) X1 is selected from N and CR12;
(s) X2 is selected from N, CR9, and CR13;
(t) X3 is selected from N and CR9;
(u) R10 and R11 together form a linkage containing 3 to 4 atoms selected from C, N, O, and S, wherein said linkage connects back to the ring to form a 5 to 6 member saturated or unsaturated cyclic ring, wherein said linkage has at least one substituent X4 wherein X4 is selected from F, Cl, Br, I, R14, N(R14)(R15), N(R14)(C(=O)R14), N(R14)(C(=S)R14),
N(R14)(C(=O)N(R14)(R14)), N(R14)(C(=S)N(R14)(R14)), N(R14)(C(=O)N(R14)((0^8)3^0^)), N(R14)(C(=S)N(R14)((C1-C8)alkenyl)), oxo, C^OXCrCtOalkylNiRUXRU), (0,C8)alkylC(=O)N(R14)R(15), wherein each R14 is independently selected; and (v) R12 and R13 together form a linkage containing 3 to 4 atoms selected from C, N, O, and S, wherein said linkage connects back to the ring to form a 5 to 6 member saturated or unsaturated cyclic ring, wherein said linkage has at least one substituent X4 wherein X4 is selected from R14, N(R14)(R15), N(R14)(C(=O)R14), N(R14)(C(=S)R14),
N(R14)(C(=O)N(R14)(R14)), N(R14)(C(=S)N(R14)(R14)), N(R14)(C(=O)N(R14)((^8)3^^)), N(R14)(C(=S)N(R14)((C1-C8)alkenyl)), wherein each R14 is independently selected.
In another embodiment of this invention R1 may be selected from any combination of one or more of the following - H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
In another embodiment of this invention R2 may be selected from any combination of one or more of the following - H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
In another embodiment of this invention R3 may be selected from any combination of one or more of the following - H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
In another embodiment of this invention R4 may be selected from any combination of one or more ofthe following - H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
In another embodiment of this invention R5 may be selected from any combination of one or more of the following - H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
In another embodiment of this invention R2 and R4 are selected from F, Cl, Br, I, CN, and NO2 and R1, R3, and R5 are H.
In another embodiment of this invention R2, R3, and R4 are selected from F, Cl, Br, I, CN, and NO2 and R1, and R5 are H.
In another embodiment of this invention R2, R3, and R4 are independently selected from F and Cl and R1and R5 are H.
In another embodiment of this invention R1 is selected from Cl and H.
In another embodiment of this invention R2 is selected from CF3, CH3, Cl, F, andH.
In another embodiment of this invention R3 is selected from OCH3, CH3, F, Cl, orH.
In another embodiment of this invention R4 is selected from CF3, CH3, Cl, F, andH.
In another embodiment of this invention R5 is selected from F, Cl, and H.
In another embodiment of this invention R6 may be selected from any combination of one or more ofthe following - halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, and halo(C8)alkyl.
In another embodiment of this invention R6 is trifluoromethyl.
In another embodiment of this invention R7 may be selected from any combination of one or more ofthe following - H, F, Cl, Br, and I.
In another embodiment of this invention R7 is selected from H, OCH3, and OH.
In another embodiment of this invention R8 may be selected from any combination of one or more of the following - H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, and halo(C8)alkyl.
In another embodiment of this invention R8 is selected from CH3 and H.
In another embodiment of this invention R9 may be selected from any combination of one or more of the following - H, F, Cl, Br, I, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
In another embodiment of this invention R10 may be selected from any combination of one or more of the following - H, F, Cl, Br, I, CN, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, halo(C8)alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
In another embodiment of this invention R10 may be selected from any combination of one or more of the following - H, Cl, Br, CH3, and CF3.
In another embodiment of this invention R10 is selected from Br, C(=NOH)NH2, C(=O)H, C(=O)NH2, C(=O)OCH2CH3i C(=O)OH, CF3, CH2CH3, CH2OH, CH3, Cl, CN, F, H, NH2, NHC(=O)H, NHCH3, NO2i OCH3i OCHF2i and pyridyl.
In another embodiment of this invention R11 may be selected from any combination of one or more of the following - C(=O)(substituted- (Ci-C8)alkyl), C(=O)N(R14)(R15), C(=O)heterocyclyl, and C(=O)(substituted-heterocyclyl).
In another embodiment of this invention R11 is C(=O)morpholinyL
In another embodiment of this invention R11 may be selected from any combination of CH2N(H)C(=O)CH3, CH2N(H)C(=O)cyclopropyl, CH2N(H)C(=O)CH2CF3, CH2N(H)C(=O)CH2CH3, CH2N(H)C(=O)C(CH3)3, CH2N(H)C(=O)(chloropyridyl), CH2N(H)C(=0)CH2(chloropyridyl), CH2N(H)C(=O)CH2CH2SCH3, N(H)C(=O)(pyridyl), CH2N(CH2pyridyl)C(=O)cyclopropyl, CH2N(H)C(=O)N(H)(CH2CH3), CH2N(H)C(=O)morpholinyl, CH2N(H)C(=O)N(H)(pyridyl), CH2N(H)C(=O)NH2, CH2N(H)C(=O)NH(CH2CH3), CH2N(H)C(=O)NH(CH2CHCH2),
CH2N(H)C(=O)OC(CH3)3, CH2N(H)C(=O)O(chlorophenyl), CH2N(H)C(=O)(C=O)OCH3, CH2N(H)C(=O)(C=O)N(H)CH2CF3, CH2N(H)(pyridyl), N(H)N(H)C(=O)cyclopropyl, N(H)N(H)C(=O)CH2CF3, ON(H)C(=O)cyclopropyl, and ON(H)C(=O)CH2CF3.
In another embodiment of this invention R11 may be selected from any combination of
1.2.4- triazolyl, 1,2,4-triazolyl-C(=O)cyclopropyl, 1,2,4-triazolyl-C(=O)CH3, 1,2,- methyltriazolyl,
1.2.4- triazolyl-N(C(=O)cyclopropyl)2, 1,2,4-triazolylN(H)(C(=O)cyclopropyl), 1,2,4-triazolylNH2,
1.2.4- triazolyl-NO2, 1,2,4-triazolylS(O)2CH3,1,2,4-triazolylSCH3, C(=O)(morpholinyl), C(=O)N(CH3)(CH3), C(=O)N(H)(CH(CH3)chloropyridinyl), C(=O)N(H)(CH2C(=O)N(CH3)(CH2CF3)), C(=O)N(H)(CH2-benzothiazolyl), C(=O)N(H)(CH2C(=O)N(H)(CH2CF3)), C(=O)N(H)(CH2C(=O)N(H)(CH2CH=CH2)), C(=O)N(H)(CH2C(=O)N(H)(cyclopropyl)), C(=O)N(H)(CH2C(=O)N(H)(N(CH3)2)), C(=O)N(H)(CH2C(=O)N(H)(OCH3)), C(=O)N(H)(CH2C(=O)N(H)(thietanyl)), C(=O)N(H)(CH2C(=O)N(H)(thietanyl-dioxide)) C(=O)N(H)(CH2C(=O)OC(CH3)3), C(=O)N(H)(CH2C(=S)N(H)(CH2CF3)), C(=O)N(H)(CH2CF3), C(=O)N(H)(CH2CH2-chloropyridinyl)
C(=O)N(H)(CH2-furanyl), C(=O)N(H)(CH2-methylimidazolyl) C(=O)N(H)(CH2-cyclopropyloxadiazolyl), C(=O)N(H)(CH2-phenyl), C(=O)N(H)(CH2trifluoromethylphenyl), C(=O)N(H)(CH2-fluorophenyl), C(=O)N(H)(CH2-pyrazinyl), C(=O)N(H)(CH2trifluoromethylpyridinyl), C(=O)N(H)(CH2-chloropyridinyl), C(=O)N(H)(CH2-pyridinyl-NO2), C(=O)N(H)(CH2-pyridinyl-OCH3), C(=O)N(H)(CH2-pyrimidinyl), 0(=0)N(H)(CH2-tetrahydrofuranyl), C(=O)N(H)(CH2-chlorothiazolyl), C(=O)N(H)(CH3), C(=O)NH2, C(=O)N(H)(N(CH3)(fluorophenyl)), C(=O)N(H)(N(H)(fluorophenyl)), C(=O)N(H)(OCH2-chloropyridinyl), C(=O)N(H)(piperidinyl), C(=O)N(H)(piperidinylC(=O)CH2CF3), C(=O)N(H)(piperidinyl-CH2CN), C(=O)N(H)(piperidinylC(=O)CH3), C(=O)N(H)(piperidinylCH2CH2OH), C(=O)N(H)(piperidinyloxetanyl), C(=O)N(H)(chloropyridinyl), C(=O)N(H)(CH2-tetrahydropyranyl), C(=O)N(H)(thietanyl), C(=O)N(H)(thietanyl-dioxide), C(=O)N(H)(thietanyl-oxide), C(=O)N(H)(CH2-pyrazinyl) C(=O)pyrrolidinyl-oxo, C(=S)N(H)(CH2C(=O)N(H)(CH2CF3)), C(=S)N(H)(CH2C(=S)N(H)(CH2CF3)), C(=S)N(H)(CH2-chloropyridinyl), CH2N(CH2-pyridinyl)(C(=O)-cyclopropyl), CH2N(H)(C(=O)C(=O)N(H)(CH2CF3), CH2N(H)(C(=O)C(=O)OCH3), CH2N(H)(C(=O)C(CH3)3), CH2N(H)(C(=O)-CH2- chloropyridinyl), CH2N(H)(C(=O)CH2CF3), CH2N(H)(C(=O)CH2CH2S(O)2CH3), CH2N(H)(C(=O)CH2CH2SCH3), CH2N(H)(C(=O)CH2CH3), CH2N(H)(C(=0)-cyclopropyl), CH2N(H)(C(=O)morpholinyl), CH2N(H)(C(=O)N(CH3)2, CH2N(H)(C(=O)N(H)(CH2CH3)),
CH2N(H)(C(=O)N(H)(pyridinyl)), CH2N(H)(C(=O)OC(CH3)3), CH2N(H)(C(=0)0-chlorophenyl), CH2N(H)(C(=O)-pyridinyl), CH2N(H)(C(=O)-chloropyridinyl), CH2N(H)(C(=S)cyclopropyl), CH2N(H)(C(=S)N(H)(CH2CH=CH2)), CH2N(H)(C(=S)N(H)(CH2CH3)), CH2N(H)(pyridinyl), N(H)(N(H)(C(=O)CH2CF3), N(H)(N(H)(C(=O)cyclopropyl), ON(H)(C(=O)CH2CF3), and ON(H)(C(=O)cyclopropyl).
In another embodiment of this invention R12 may be selected from any combination of one or more of the following - H, F, Cl, Br, I, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
In another embodiment of this invention R12 is selected from CH3, and H.
In another embodiment of this invention R13 may be selected from any combination of one or more of the following - H, F, Cl, Br, I, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy.
In another embodiment of this invention R13 is selected from CH3, Cl and H.
In another embodiment of this invention R12-R13 are a hydrocarbyl linkage containing CH=CHCH=CH.
In another embodiment of this invention R14 may be selected from any combination of one or more of the following - H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl-(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethylaryl, O-(C3)alkyl-aryl, O-(C4)alkyl-aryl, O-(C5)alkyl-aryl, O-(C6)alkyl-aryl, O-(C7)alkyl-aryl, O(C8)alkyl-aryl, O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl), O-(C3)alkyl-(substituted-aryl), O-(C4)alkyl-(substituted-aryl), O-(C5)alkyl-(substituted-aryl), O-(C6)alkyl-(substituted-aryl), O(C7)alkyl-(substituted-aryl), O-(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkylheterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl-(substitutedheterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl15 (substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O-(C3)alkylheterocyclyl, O-(C4)alkyl-heterocyclyl, O-(C5)alkyl-heterocyclyl, O-(C6)alkyl-heterocyclyl, O(C7)alkyl-heterocyclyl, O-(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl(substituted-heterocyclyl), O-(C3)alkyl-(substituted-heterocyclyl), O-(C4)alkyl-(substitutedheterocyclyl), O-(C5)alkyl-(substituted-heterocyclyl), O-(C6)alkyl-(substituted-heterocyclyl), O(C7)alkyl-(substituted-heterocyclyl), O-(C8)alkyl-(substituted-heterocyclyl), methylC(=O)N(R16)(R17), ethyl-C(=O)N(R16)(R17), (C3)alkyl-C(=O)N(R16)(R17), (C4)alkylC(=O)N(R16)(R17), (C5)alkyl-C(=O)N(R16)(R17), (C6)alkyl-C(=O)N(R16)(R17), (C7)alkylC(=O)N(R16)(R17), and (C8)alkyl-C(=O)N(R16)(R17).
In another embodiment of this invention R14 may be selected from any combination of one or more of the following - H, CH3, CH2CF3, CH2-halopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH2-phenyl, CH2-pyridyl, thietanyl-dioxide, CH2-halothiazolyl, C((CH3)2)-pyridyl, N(H)(halophenyl), CH2-pyrimidinyl, CH2-tetrahydrofuranyl, CH2-furanyl,
O-CH2-halopyridyl, and CH2C(=O)N(H)(CH2CF3).
In another embodiment of this invention R15 may be selected from any combination of one or more ofthe following - H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl-(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethylaryl, O-(C3)alkyl-aryl, O-(C4)alkyl-aryl, O-(C5)alkyl-aryl, O-(C6)alkyl-aryl, O-(C7)alkyl-aryl, O(C8)alkyl-aryl, O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl), O-(C3)alkyl-(substituted-aryl), O-(C4)alkyl-(substituted-aryl), O-(C5)alkyl-(substituted-aryl), O-(C6)alkyl-(substituted-aryl), O(C7)alkyl-(substituted-aryl), O-(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkylheterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl-(substitutedheterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O-(C3)alkylheterocyclyl, O-(C4)alkyl-heterocyclyl, O-(C5)alkyl-heterocyclyl, O-(C6)alkyl-heterocyclyl, O(C7)alkyl-heterocyclyl, O-(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl16 (substituted-heterocyclyl), O-(C3)alkyl-(substituted-heterocyclyl), O-(C4)alkyl-(substitutedheterocyclyl), O-(C5)alkyl-(substituted-heterocyclyl), O-(C6)alkyl-(substituted-heterocyclyl), O(C7)alkyl-(substituted-heterocyclyl), O-(C8)alkyl-(substituted-heterocyclyl), methylC(=O)N(R16)(R17), ethyl-C(=O)N(R16)(R17), (C3)alkyl-C(=O)N(R16)(R17), (C4)alkylC(=O)N(R16)(R17), (C5)alkyl-C(=O)N(R16)(R17), (C6)alkyl-C(=O)N(R16)(R17), (C7)alkylC(=O)N(R16)(R17), and (C8)alkyl-C(=O)N(R16)(R17).
In another embodiment of this invention R15 may be selected from any combination of one or more ofthe following - H, CH3, CH2CF3, CH2-halopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH2-phenyl, CH2-pyridyl, thietanyl-dioxide, CH2-halothiazolyl, C((CH3)2)-pyridyl, N(H)(halophenyl), CH2-pyrimidinyl, CH2-tetrahydrofuranyl, CH2-furanyl,
O-CH2-halopyridyl, and CH2C(=O)N(H)(CH2CF3).
In another embodiment of this invention R16 may be selected from any combination of one or more ofthe following - H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl-(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethylaryl, O-(C3)alkyl-aryl, O-(C4)alkyl-aryl, O-(C5)alkyl-aryl, O-(C6)alkyl-aryl, O-(C7)alkyl-aryl, O(C8)alkyl-aryl, O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl), O-(C3)alkyl-(substituted-aryl), O-(C4)alkyl-(substituted-aryl), O-(C5)alkyl-(siibstituted-aryl), O-(C6)alkyl-(substituted-aryl), O(C7)alkyl-(substituted-aryl), O-(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkylheterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl-(substitutedheterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O-(C3)alkylheterocyclyl, 0-(C4)alkyl-heterocyclyl, O-(C5)alkyl-heterocyclyl, O-(C6)alkyl-heterocyclyl, O(C7)alkyl-heterocyclyl, O-(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl(substituted-heterocyclyl), O-(C3)alkyl-(substituted-heterocyclyl), O-(C4)alkyl-(substitutedheterocyclyl), O-(C5)alkyl-(substituted-heterocyclyl), O-(C6)alkyl-(substituted-heterocyclyl), O(C7)alkyl-(substituted-heterocyclyl), and O-(C8)alkyl-(substituted-heterocyclyl).
In another embodiment of this invention R16 may be seiected from any combination of one or more of the following - H, CH2CF3, cyclopropyl, thietanyl, thietanyl dioxide, and halophenyl.
In another embodiment of this invention R17 may be seiected from any combination of one or more of the following - H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkyl-aryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl-(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl-(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl(substituted-aryl), (C7)alkyl-(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethylaryl, O-(C3)alkyl-aryl, O-(C4)alkyl-aryl, O-(C5)alkyl-aryl, O-(C6)alkyl-aryl, O-(C7)alkyl-aryl, O(C8)alkyl-aryl, O-methyl-(substituted-aryl), O-ethyl-(substituted-aryl), O-(C3)alkyl-(substituted-aryl), O-(C4)alkyl-(substituted-aryl), O-(C5)alkyl-(substituted-aryl), O-(C6)alkyl-(substituted-aryl), O(C7)alkyl-(substituted-aryl), O-(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethyl-heterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkyl-heterocyclyl, (C7)alkylheterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substituted-heterocyclyl), ethyl-(substitutedheterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl(substituted-heterocyclyl), (C6)alkyl-(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substituted-heterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O-(C3)alkylheterocyclyl, O-(C4)alkyl-heterocyclyl, O-(C5)alkyl-heterocyclyl, O-(C6)alkyl-heterocyclyl, O(C7)alkyl-heterocyclyl, O-(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl(substituted-heterocyclyl), O-(C3)alkyl-(substituted-heterocyclyl), O-(C4)alkyl-(substitutedheterocyclyl), O-(C5)alkyl-(substituted-heterocyclyl), O-(C6)alkyl-(substituted-heterocyclyl), O(C7)alkyl-(substituted-heterocyclyl), and O-(C8)alkyl-(substituted-heterocyclyl).
In another embodiment of this invention R17 may be seiected from any combination of one or more of the following - H, CH2CF3, cyclopropyl, thietanyl, thietanyl dioxide, and halophenyl.
In another embodiment of this invention X1 is CR12, X2 is CR13, and X3 is CR9.
In another embodiment of this invention when R10 and R11 form a linkage said linkage is seiected from (a) - (I).
X4
where * indicates attachment back to the ring, (Note while the structures are drawn this way, they can be flipped from bottom to top thereby rotating the structure 180 degrees) (note hydrogens for carbons atoms are implied and not shown)
In another embodiment of this invention a heterocyclyl has preferably about 6 to 10 atoms in the ring structure, more preferably, 6 to 8 atoms.
The molécules of Formula One will generally hâve a molecular mass of about 100 Daltons to about 1200 Daltons. However, it is generally preferred if the molecular mass is from about 120 Daltons to about 900 Daltons, and it is even more generally preferred if the molecular mass is from about 140 Daltons to about 600 Daltons.
The benzyl alcohol of Formula IV, wherein R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, can be synthesized in two ways. One way, disclosed in step a of Scheme I, is 10 by treatment of the ketone of Formula II, wherein R1, R2, R3, R4, R5, and R6 are as previously disclosed, with a reducing agent, such as sodium borohydride (NaBH^, under basic conditions, such as aqueous sodium hydroxide (NaOH), in a polar protic solvent, such as methyl alcohol (CH3OH) at 0 °C. Alternatively, an aldéhyde of Formula III, wherein R1, R2, R3, R4, R5, and R7 are as previously disclosed, is allowed to react with trifluorotrimethylsilane in the presence of a catalytic amount of tetrabutylammonium fluoride in a polar aprotic solvent, such as tetrahydrofuran (THF), as in step b of Scheme I. The compound of Formula IV can be transformed into the compound of Formula V, wherein Y is selected from Br, Cl or I, and R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, by reaction with a halogenating reagent, such as /V-bromosuccinimide and triethyl phosphite in a non-reactive solvent, such as dichloromethane (CH2CI2) at reflux température to provide Y = Br, or such as thionyl chloride and pyridine in a hydrocarbon solvent, such as toluene at reflux température to provide Y = Cl, as in step c of Scheme I.
Scheme I
R5 O
R2
III
Formation of the styrene coupling partners can be accomplished as in Schemes II, III IV and V.
In Scheme II, a vinylbenzoic acid of Formula VI, wherein R11 is (C=O)OH and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, can be converted in two steps to the vinylbenzamide of Formula VIla, wherein R11 is (C=O)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, and X are as previously disclosed. As in step d of Scheme II, the benzoic acid of Formula VI is treated with oxalyl chloride in the presence of a catalytic amount of N,Ndimethylformamide (DMF) in a non-reactive solvent such as CH2CI2 to form the acid chloride, which is subsequently allowed to react with an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed, in the presence of a base, such as triethylamine, in a polar aprotic solvent, such as THF, to provide the vinyl benzamide of Formula VIIa, wherein R11 is (C=O)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, as in step e of Scheme II.
Scheme II
d,e
Vlla ln Schemes III and IV, a halobenzoic acid of Formula VIII, wherein R18 is Br or I, R11 is (C=O)OH and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed can be converted to a vinylbenzoic acid ester of Formula VIIb 1 or Formula VIIb2, wherein R18 is Br or I, R11 is (¢=0)0((^-06 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. In step fof Scheme III, the halobenzoic acid of Formula VIII, wherein R18 is Br, is treated with a base, such as n-butyllithium (n-BuLi), and DMF in a polar, aprotic solvent, such as THF, at a température of about -78 °C. The resulting formyl benzoic acid is allowed to react with an acid, such as sulfuric acid (H2SO4), in the presence of an alcohol, such as ethyl alcohol (EtOH), as in step g, to provide the formyl benzoic acid ethyl ester of Formula IX, wherein R11 is (0=0)0(0^06 alkyl), and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The vinyl benzoic acid ester of Formula Vllbl is accessed via reaction ofthe compounds of Formula IX, with a base, such as potassium carbonate (K2CO3), and methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, at ambient température, as in step h of Scheme III.
Scheme III
VIII
RIO
RH
Vllbl ln step i of Scheme IV, the halobenzoic acid of Formula VIII, wherein R18 is Br, R11 is (C=0)0H, and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, is treated with 21 di-terf-butyl bicarbonate in the presence of a base, such as triethylamine (Et3N) and a catalytic amount of 4-(dimethylamino)pyridine (DMAP) in a polar aprotic solvent, such as THF, at ambient température. The resulting benzoic acid tert-butyl ester is allowed to react with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such a tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4), and a base, such as K2CO3, in a non-reactive solvent such as toluene at reflux température, as in step j, to provide the vinyl benzoic acid ester of Formula Vllb2, wherein R11 is (C=O)O(Ci-C6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.
Scheme IV
RIO
Rll
VIII
VIIb2
In step k of Scheme V, the vinyl benzoic acid ester of Formula VIIb2, wherein R10 is Br, R11 is (0=0)0(0^06 alkyl), and R8, R9, R12, R13, X1, X2, and X3 are as previously defined, can be further transformed into the corresponding vinyl benzoic acid ester of Formula VIIb3, wherein R10 is CN, R11 is (C=0)0(C1-C6 alkyl), and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with copper(l) cyanide (CuCN) in a polar aprotic solvent, such as DMF, at 140 °C.
VIIb2
VIIb3
Coupling ofthe compounds of Formula V with the compounds of Formula Vlla, Vllbl, Vllb2 and VIIb3 can be accomplished as in Schemes VI, VII, and VIII. In step / of Scheme VI, a compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzamide of Formula Vlla, wherein R11 is (C=O)N(R14)(R15), and R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of copper(l) chloride (CuCI) and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a température of about 180 °C to provide the molécules of Formula One, wherein R11 is (C=O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1,X2, and X3 are as previously disclosed.
Scheme VI
In step / of Scheme VII, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoic acid ester of Formula Vllbl, wherein R11 is (C=O)O(Ci-C6 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCI and 2,2-bipyridyl in a solvent, such as 1,2dichlorobenzene, at a température of about 180 °C to provide the compounds of Formula Xa, wherein R11 is (C=O)O(Ci-C6 alkyl), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula Xa are then converted to the molécules of Formula One, wherein R11 is (C=O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, by either a two-step process as disclosed in steps m and n or in one step as disclosed in step o. In step m of Scheme VII, the ester of Formula Xa is saponified to the corresponding acid under acidic conditions, such as about 11 Normal (N) hydrochloric acid (HCl), in a polar aprotic solvent, such as 1,4-dioxane, at about 100 °C. The acid is subsequently coupled to an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed, with 1-hydroxybenzotriazole hydrate (HOBt*H2O) and A/-(3dimethylaminopropyl)-A/’-ethyl-carbodiimide hydrochloride (EDC’HCI) in the presence of a base, such as /V,/V-diisopropylethylamine (DIEA), and in a polar aprotic solvent, such as DMF, to give the molécules of Formula One, wherein R11 is (C=O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed. Alternatively, the ester of Formula Xa is allowed to react with an amine (HN(R14)(R15)) in the presence of a solution of trimethylaluminum in toluene in a non-reactive solvent, such as CH2CI2, at ambient température, as in step o of Scheme VII, to access the molécules of Formula One, wherein R11 is (C=O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed.
Scheme VII
m, n or o
Formula One
In step / of Scheme VIII, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoic acid ester of Formula Vllb2 or VIIb3, wherein R11 is (0=0)0(0^06 alkyl), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCI and 2,2-bipyridyl in a solvent, such as 1,2dichlorobenzene, at a température of about 180 °C to provide the compounds of Formula Xb, wherein R11 is (C=O)OH, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1,
X2, and X3 are as previously disclosed. The compounds of Formula Xb are then converted to the molécules of Formula One, wherein R11 is (C=O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed, in one step as disclosed in step n. In step n of Scheme VII, the acid of Formula Xb is coupled to an amine (HN(R14)(R15)), wherein R14 and R15 are as previously disclosed, with HOBt*H2O and EDC’HCI in the presence of a base, such as DIEA, and in a polar aprotic solvent, such as DMF, to give the molécules of Formula One, wherein R11 is (C=O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, X1, X2, and X3 are as previously disclosed.
Scheme VIII
R4
R3
R3
VIIb2 or VIIb3
Xb
R5 R6 R8
I UR7
R4
R3
X3
R2
RIO
X2 'XI RH
Formula One
In step j of Scheme IX, the halobenzoketone of Formula Vlllb, wherein R18 is Br, R10 and R11 togetherform a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5- or 6-membered cyclic ring, and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, is allowed to react with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh3)4, and a base, such as K2CO3, in a non-reactive solvent such as toluene at reflux température, to provide the vinyl benzoketone of Formula VIIb4, wherein R10 and R11 togetherform a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5- or 6-membered ring, and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed.
Scheme IX
R8
XI Rll
Vlllb
RIO
X2
XI Rll
VIIb4
In step / of Scheme X, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the vinylbenzoketone of Formula Vllb4 as previously disclosed, wherein R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCI and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a température of about 180 °C to provide the compounds of Formula Xc, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5or6-membered ring, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula Xc are then converted to the molécules of Formula Xd, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an oxime [(C=N)(OH)] substituent and with the ring carbon atoms form a 5- or 6-membered ring,, and R1, R2,
R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, in step p. In step p of Scheme X, the ketone of Formula Xc is allowed to react with hydroxylamine hydrochloride in the presence of sodium acetate and in a polar protic solvent, such as EtOH, at a température of about 78 °C, to give the molécules of Formula Xd as previously disclosed.
Scheme X
The compounds of Formula Xc are also converted to the molécules of Formula Xe, wherein R10 and R11 together form a linkage, having 3-4 carbon atoms and an amine substituent and with the ring carbon atoms form a 5- or 6-membered ring, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, as demonstrated in step q of Scheme XI.
The ketone of Formula Xc is allowed to react with ammonium acetate in the presence of sodium cyanoborohydride and in a polar protic solvent, such as CH3OH, at a température of about 65 °C, to give the molécules of Formula Xe.
Scheme XI
The compounds of Formula Xe are converted to the molécules of Formula One, wherein
R10 and R11 togetherform a linkage as previously disclosed in (u), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously, in one step as disclosed in steps r or s. In step r of Scheme XII, the amine of Formula Xe is allowed to react with an isocyanate in a polar, aprotic solvent such as diethyl ether at ambient température to provide the molécules of Formula 10 One as previously disclosed. In step s of Scheme XII, the amine of Formula Xe is coupled to an acid with HOBt*H2O and EDC’HCI in the presence of a base, such as DIEA, in a non-reactive solvent, such as CH2CI2, to give the molécules of Formula One, as previously disclosed.
Xe
Formula One | ln step t of Scheme XIII, the vinyl benzyl chloride of Formula Xla, wherein R11 is 2CH2CI and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously defined, can be transformed into the corresponding phthalimide-protected benzyl amine of Formula Xlla, wherein R11 is CH2N(Phthalimide), and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 70 °C.
Scheme XIII
R8 R8
RIO _X3 .RIO _^\\ T
RH X2x6r11
Xla Xlla
In step u of Scheme XIV, the 4-methylbenzonitrile of Formula XIlia, wherein R11 is CH3 and R9, R10, R12, R13, X1, X2, and X3 are as previously defined, can be transformed into the corresponding benzyl bromide of Formula XlVa, wherein R11 is CH2Br and R8, R9, R10, R12, R13,
X1, X2, and X3 are as previously disclosed, by reaction with /V-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) in a non-reactive solvent, such as carbon tetrachloride at 77 °C. The nitrile group (CN) of Formula XlVa can be reduced to the corresponding aldéhyde of Formula XVa, wherein R11 is CH2Br and R9, R10, R12, R13, X1, X2, and X3 are as previously defined via reaction with diisobutylaluminum hydride (DIBAL-H) in an aprotic solvent, such as toluene, at 0 °C, followed by quenching with 1.0 M hydrochloric acid (HCl) as in step v of Scheme XIV. The compound of Formula XVa can be further transformed to the corresponding phthalimide-protected benzyl amine of Formula XVIa, wherein R11 is CH2N(Phthalimide) and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 60 °C as in step f of Scheme XIV. In step ivof Scheme XIV, the aldéhyde of Formula XVIa can be converted to the olefin of Formula XIIb, wherein R11 is CH2N(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, in the presence of a base, such as K2CO3, at ambient température.
Scheme XIV
RIO
Rll
RIO
Rll
H
RIO
Rll
XlIIa XlVa XVa
RIO
Rll
XVIa
R8
RIO
Rll
Xllb
The aldéhyde of Formula XVa, wherein R11 is CH2Br and R9, R10, R12, R13, X1, X2, and X3 are as previously defined, can be reacted with a nucleophile, such as 2-aminopyridine, in a polar aprotic solvent, such as A/,A/-dimethylacetamide (DMA), in the presence of a base, such as K2CO3, at ambient température to provide the compound of Formula XVII, wherein R11 is CH2NH(2-pyridine) and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, as in step x of Scheme XV. In step wof Scheme XV, the compound of Formula XVII can be converted to the olefin of Formula XVIII, wherein R11 is CH2NH(2-pyridine) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.
Scheme XV
H HR8
0^X3 RIO x O^XVRIO „R!0 X2x6rh X2xiÀrh X2xiÀrh
XVa XVIIXVIII
In a two-step, one-pot reaction as in steps y and z of Scheme XVI, the compound of Formula XIX can be reacted with the compounds of Formula XX, wherein R10 and R11 are Cl, X1 is N, and R9, R13, X2, and X3 are as previously disclosed, in the presence of a base, such as sodium hydride (NaH), and a polar aprotic solvent, such as DMF, at ambient température to provide the compounds of Formula XXI, wherein R10 is Cl, R11 is (CH)NH2CO2CH2CH3, X1 is N, and R9, R13, X2, and X3 are as previously defined. Hydrolysis and décarboxylation ofthe compounds of Formula XXI can be accomplished by reaction under acidic conditions, such as with 3 N HCl, at reflux température, to afford the compounds of Formula XXII, wherein R10 is Cl, R11 is
CH2NH2*HCI, X1 is N, and R9, R13, X2, and X3 are as previously disclosed, as in step aa in Scheme XVI. The compounds of Formula XXII can be further transformed to the corresponding phthalimide-protected benzyl amines of Formula XXIila, wherein R10 is Cl, R11 is CH2N(Phthalimide), X1 is N, and R9, R13, X1, X2, and X3 are as previously disclosed, by reaction with phthalic anhydride in the presence of a base, such as Et3N, and an aprotic solvent, such as toluene, at reflux température as in step ab of Scheme XVI. The bromide of Formula XXIila can be converted to the olefin of Formula Xllc, wherein R10 is Cl, R11 is CH2N(Phthalimide), X1 is N, and R8, R9, R13, X2 and X3 are as previously disclosed, by reaction with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh3)4, and a base, such as K2CO3, in a non-reactive solvent such as toluene at reflux température, as in step ac of Scheme XVI.
Scheme XVI
XIX
Br X3 .RIO
T y, z
XI Rll
RIO
Rll αα
XX XXI
RIO
RH
XXII ab
RIO
Rll ac
R8
RIO
Rll
XIIc
XXIila
In step u of Scheme XVII, the 4-methylnaphthonitrile of Formula XI II b, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a
6-membered aromatic ring, R11 is CH3, and R12, R13, X1 and X2 are as previously defined, can be transformed into the corresponding naphthyl bromide of Formula XlVb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6membered aromatic ring, R11 is CH2Br, and R12, R13, X1 and X2 are as previously disclosed, by reaction with /V-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) in a non-reactive solvent, such as carbon tetrachloride at 77 °C. The nitrile group (CN) of Formula XlVb can be reduced to the corresponding aldéhyde of Formula XVb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring (or if desired a non-aromatic ring), R11 is CH2Br, and R12, R13, X1 and X2 are as previously defined via reaction with diisobutylaluminum hydride (DIBAL-H) in an aprotic solvent, such as toluene, at 0 °C, followed by quenching with 1.0 M HCl as in step v of Scheme XVII. The compound of Formula XVb can be further transformed to the corresponding phthalimide-protected benzyl amine of Formula XVIb, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(Phthalimide), and R12, R13, X1 and X2 are as previously disclosed, by reaction with potassium phthalimide in a polar aprotic solvent, such as DMF, at 60 °C as in step f of Scheme XVII. In step w of Scheme XVII, the aldéhyde of Formula XVIb can be converted to the olefin of Formula Xlld, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(Phthalimide), and R8, R12, R13, X1 and X2 are as previously disclosed, by reaction with methyl triphenyl phosphonium bromide in a polar aprotic solvent, such as 1,4-dioxane, in the presence of a base, such as K2CO3, at ambient température.
Scheme XVII
H
NC. _X3 .RIO NC..X3 ^R10 Y ^X3 T10
Ύ Y \ Ύ Y v r 0 7i Y X2xYrh X2xiÀrh X2x6rh
XHIb XlVbXVb
HR8 , o^WR1° „ ~ X2xYrii X2xYrh
XVIbXlld
The compound of Formula XXIV, wherein R11 is NHNH2*HCI and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, can be transformed into the corresponding phthalimideprotected hydrazine of Formula XXV, wherein R11 is NHN(Phthalimide) and R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with phthalic anhydride in glacial acetic acid at reflux température as in step ad of Scheme XVIII. The bromide of Formula XXV can be converted to the olefin of Formula XIle, wherein R11 is NHN(Phthalimide) and R8, R9, R10, R13, X1, X2 and X3 are as previously disclosed, by reaction with vinyl boronic anhydride pyridine complex in the presence of a palladium catalyst, such as Pd(PPh3)4, and a base, such as K2CO3, in a polar aprotic solvent such as 1,2-dimethoxyethane at 150 °C under microwave conditions, as in step ae of Scheme XVIII.
Scheme XVIII
RIO
RH
XXIV ad
RIO
RH ae
R8
RIO
RH
Xlle
In step af of Scheme XIX, the compound of Formula XXVI, wherein R11 is B(OH)2, and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react with 2hydroxyisoindoline-1,3-dione in the presence of CuCI and pyridine in a solvent, such as 1,2dichlorobenzene, at ambient température to provide the compound of Formula XIIf, wherein R11 is ON(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.
Scheme XIX
R8
RIO
Rll
XXVI af
R8
RIO
Rll
Xllf
In step / of Scheme XX, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIla, wherein R11 is CH2N(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCI and 2,2-bipyridyl in a solvent, such as 1,2dichlorobenzene, at a température of about 180 °C to provide the corresponding compounds of Formula XXVIIa, wherein R11 is CH2N(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIa is removed as in step ag of Scheme XX by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 °C to provide the compounds of Formula XXVIIIa, wherein R11 is CH2NH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIa can be transformed into the compounds of Formula One, wherein R11 is CH2N(C=O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by acylation with an anhydride, such as acetic anhydride, and a base, such as Et3N, in a non-reactive solvent such as
CH2CI2 at 0 °C as in step ahi of Scheme XX.
Scheme XX
XXVIIIa
R5 R6 R8 X3^ R1 o ïï ï I R3^Y^R1 XI RH
R2
XXVIIa
R5 R6 R8
RIO
TT T X
R3^y^Rl XI RH
R2
Formula One
In step / of Scheme XXI, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIb, wherein R11 is CH2N(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCI and 2,2-bipyridyl in a solvent, such as 1,2dichlorobenzene, at a température of about 180 °C to provide the corresponding compounds of Formula XXVIIb, wherein R11 is CH2N(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIb is removed as in step ag of Scheme XXI by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 °C to provide the compounds of Formula XXVIIIb, wherein R11 is CH2NH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C=O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt»H2O, EDC’HCI and a base, such as DIEA, in a polar aprotic solvent, such as DMF, as in step ah2a of Scheme XXI.
In another embodiment, the compounds of Formula XXVIIIb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C=S)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with a thioacid in the presence of HOBt*H2O, EDC’HCI and a base, such as DIEA, in a polar aprotic solvent, such as DMF, as in step ah2 of Scheme XXI.
In another embodiment, the compounds of Formula XXVIIlb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C=O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, in two steps. The first step (step ah3a of Scheme XXI) involves reaction with an aldéhyde in a polar protic solvent such as methyl alcohol, followed by reaction with sodium borohydride. The second step (step ah3b of Scheme XXI) involves acylation with an acid chloride, such as cyclopropylcarbonyl chloride, and a base, such as Et3N, in a non-reactive solvent such as CH2CI2 at ambient température of Scheme XXI.
In another embodiment, the compounds of Formula XXVIIlb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C=O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an isocyanate (step ah of Scheme XXI) or a carbamoyl chloride (step a/2 of Scheme XXI) in the presence of a base such as Et3N and in a non-reactive solvent such as CH2CI2 at 0 °C.
In another embodiment, the compounds of Formula XXVIIlb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C=S)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an isothiocyanate in the presence of a base such as Et3N and in a non-reactive solvent such as CH2CI2 at 0 °C, as in steps aj of Scheme XXI.
In another embodiment, the compounds of Formula XXVIIlb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C=O)O(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with a dicarbonate, such as di-terfrbutyl dicarbonate in the presence of a base such as Et3N and in a non-reactive solvent such as CH2CI2 at ambient température, as in steps ak of Scheme XXI.
In yet another embodiment, the compounds of Formula XXVIIlb can be transformed into the compounds of Formula One, wherein R11 is CH2N(C=O)(C=O)O(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with a chlorooxalic acid ester, such as 2-chloro-2-oxoacetate in the presence of a base such as Et3N and in a non-reactive solvent such as CH2CI2 at 0 °C, as in steps al of Scheme XXI.
Scheme XXI
XXVIIIb
R5
R4
R3 R6R7R8
X3 RH)
RI
R2
XXVIIb X2x iKi i variety of steps see discussion
R5
R4
R3 R6R7R8
X3 Rio
RI X2xArh
Formula One
In step I of Scheme XXII, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIle, wherein R10 is Cl, R11 is CH2N(Phthalimide), X1 is N, and R8, R9, R12, R13, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCI and 2,2-bipyridyl in a solvent, such as 1,2dichlorobenzene, at a température of about 180 °C to provide the corresponding compounds of Formula XXVIIc, wherein R10 is Cl, R11 is CH2N(Phthalimide), X1 is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIc is removed as in step ag of Scheme XXII by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 °C to provide the compounds of Formula XXVIIIc, wherein R10 is Cl, R11 is CH2NH2, X1 is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIc can be transformed into the compounds of Formula One, wherein R10 is Cl, R11 is CH2N(C=O)(R14), X1 is N, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt*H2O, EDC*HCI and a base, such as DIEA, in a polar aprotic solvent, such as CH2CI2, as in step ah2b of Scheme XXII.
Scheme XXII
XXVIIIc
R5 R6 R8
Rio
L1 A X
R3^y^Rl XI Rll R2
XXVIIc
R5 R6 R8 R4vA^AzxtRiO ïï X2 X
R3^y^RI XI Rll
R2
Formula One
In step / of Scheme XXIII, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula Xlld, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 65 membered aromatic ring (or if desired a non-aromatic ring), R11 is CH2N(Phthalimide) and R8, R9, R12, R13, X1 and X2 are as previously disclosed, are allowed to react in the presence of CuCI and
2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a température of about 180 °C to provide the corresponding compounds of Formula XXVIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, 10 R11 is CH2N(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1 and X2 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIId is removed as in step ag of Scheme XXIII by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 °C to provide the compounds of Formula XXVIIId, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 615 membered aromatic ring, R11 is CH2NH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1 and X2 are as previously disclosed. The compounds of Formula XXVIIId can be transformed into the compounds of Formula One, wherein X3 is CR9, R10 and X3 together form a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(C=O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1 and X2 are as previously disclosed, by reaction with an acid in the presence of HOBt*H2O, EDOHCI and a base, such as DIEA, in a polar aprotic solvent, such as CH2CI2, as in step ah2b of Scheme XXIII.
In another embodiment, the compounds of Formula XXVIIId can be transformed into the compounds of Formula One, wherein X3 is CR9, R10 and X3 togetherform a linkage having 4 carbon atoms and with the ring carbon atoms form a 6-membered aromatic ring, R11 is CH2N(C=O)N(R14)(R15) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1 and X2 are as previously disclosed, by reaction with an isocyanate in the presence of a base such as Et3N and in a non-reactive solvent such as CH2CI2 at 0 °C as in step a/\ of Scheme XXIII.
Scheme XXIII
R8
X3 RIO vo A
Xl'Rll
R5
R4
R3 R6R7R8
X3 Rio
RI
R2
XXVIId
Y? oL
XI Rll ag
Xlld
R5
R4
R3 R6R7R8
X3 Rio
XXVIIId
XI Rll
RI
R2 ah2b or aij
R5
R4
R3 R6R7R8
X3 Rio
RI
R2
Y?
XI Rll
Formula One
In step / of Scheme XXIV, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIle, wherein R11 is NHN(Phthalimide) and R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCI and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a température of about 180 °C to provide the corresponding compounds of Formula XXVIIe, wherein R11 is NHN(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIe is removed as in step ag of Scheme XXIV by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 °C to provide the compounds of Formula XXVIIIe, wherein R11 is NHNH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIe can be transformed into the compounds of Formula One, wherein R11 is NHN(C=O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt*H2O, EDC*HCI and a base, such as DIEA, in a polar aprotic solvent, such as CH2CI2, as in step ah2b of Scheme XXIV.
Scheme XXIV
R8
X3 RIO
Xi Rll
R2
Xlle ag
R4
R3
X3 RIO
Xl'Rll
R2
XXVIIIe
XXVIIe
R5 R6 R8 ah2b R4^AA^VX3^R1O
- Il ΐ I R3^y^Rl XI Rll
R2
Formula One
In step I of Scheme XXV, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XIIf, wherein R11 is ON(Phthalimide) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCI and 2,2-bipyridyl in a solvent, such as 1,2dichlorobenzene, at a température of about 180 °C to provide the corresponding compounds of Formula XXVIIf, wherein R11 is ON(Phthalimide) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The phthalimide protecting group in the compounds of Formula XXVIIf is removed as in step ag of Scheme XXV by reaction with hydrazine hydrate in a polar protic solvent such as EtOH at 90 °C to provide the compounds of Formula XXVIIIf, wherein R11 is ONH2 and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed. The compounds of Formula XXVIIIf can be transformed into the compounds of Formula One, wherein R11 is ON(C=O)(R14) and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, by reaction with an acid in the presence of HOBt*H2O, EDC»HCI and a base, such as DIEA, in a polar aprotic solvent, such as CH2CI2, as in step ah2b of Scheme XXV.
Scheme XXV
XXVIIIf
R5 R6 R8 R4^X^^A^X3 RIO TT II
R3^Y^Rl XI Rll R2
XXVIIf
R5 R6 R8
Ύ J2 X
RT^^^RI XI Rll R2
Formula One
In step/of Scheme XXVI, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XVIII, wherein R11 is CH2NH(2-pyridine) and R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCI and 2,2-bipyridyl in a solvent, such as 1,2dichlorobenzene, at a température of about 180 °C to provide the corresponding compounds of Formula One, wherein R11 is CH2NH(2-pyridine), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, X1, X2, and X3 are as previously disclosed.
The compounds of Formula One can be further elaborated by standard methods. For example, when R11 contains a thioether, the thioether can be oxidized to the sulfone by treatment with oxone in the presence of an acetone:water mixture at ambient température. When R11 contains an oxalate ester, the compound of Formula One can be transformed into the corresponding oxalamide by reaction with an amine hydrochloride and a solution of trimethylaluminum in toluene in a non-reactive solvent such as CH2CI2.
Scheme XXVI
R8
X3 RIO X2xArh
R5
R3 R6R7R8 / R4
X3 RIO
RI
R2
Formula One X2xÎ^R11
XVIII
In Scheme XXVII, a fluorobenzaldéhyde of Formula XXIX, wherein R10, X1, X2, and X3 are as previously disclosed can be converted to a (1,2,4-triazol-1-yl)benzaldehyde of Formula XXX, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1 -yl group, and R10, X1, X2, and X3 are as previously disclosed by reaction with a substituted or unsubstituted 1,2,4-triazole in the presence of a base, such as potassium carbonate, in a solvent such as DMF as in step aj. In step ak, the (1,2,4-triazol-1-yl)benzaldehyde of Formula XXX is converted to a (1,2,4-triazol-1-yl)vinyl benzene of Formula XXXIa wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1 -yl group, and R8, R10, X1, X2, and X3 are as previously disclosed by reaction with triphenyl phosphonium bromide in the presence of a base, such as potassium carbonate, in an aprotic solvent, such as 1,4-dioxane.
Scheme XXVII
RIO
RH
XXIX XXX XXXIa
In Scheme XXVIII, a bromofluorobenzene of Formula XXXII, wherein R10, X1, X2, and X3 are as previously disclosed can be converted to a (1,2,4-triazol-1-yl)vinylbenzene of Formula XXXIb, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R8, R10, X1, X2, and X3 are as previously disclosed in two steps. In step al, the bromofluorobenzene is reacted with a substituted or unsubstituted 1,2,4-triazole in the presence of a base, such as potassium carbonate, in a solvent such as DMF to generate the (1,2,4-triazol-1-yl)bromobenzene. In step cl, the (1,2,4-triazol-1-yl)bromobenzene is reacted with vinyl boronic anhydride pyridine complex in the presence of a catalyst, such as Pd (PPh3)4, and a base, such as potassium carbonate in a solvent such as toluene.
Scheme XXVIII
al, cl
RIO
Rll
ΧΧΧΠ XXXIb
Coupling of the compounds of Formula V with compounds of Formula XXXIa and XXXIb can be accomplished as in Schemes XXIX. In step /, a compound of Formula V, wherein Y is Br, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and a vinylbenzene of Formula XXXIa or XXXIb, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1-yl group, and R8, R9, R10, 5 X1, X2, and X3 are as previously disclosed, are allowed to react in the presence of CuCI and 2,2bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a température of about 180 °C to provide the molécules of Formula One, wherein R11 is a substituted or unsubstituted 1,2,4-triazol-1 -yl group, and R1, R2, R3, R4, R5, R6, R7, R8, R10, X1, X2, and X3 are as previously disclosed.
Scheme XXIX
In Scheme XXX, compounds of Formula XXXIII wherein R11 is a 3-nitro-1,2,4-triazol-1-yl group, and R1, R2, R3, R4, R5, R6, R7, R8, R10, X1, X2, and X3 are as previously disclosed can be converted to compounds of Formula One, wherein R11 is a 3-amido-1,2,4-triazol-1 -yl group, and R1, R2, R3, R4, R5, R6, R7, R8, R10, X1, X2, and X3 are as previously disclosed by a two step process. In step am, the 3-nitro-1,2,4-triazol-1-yl group is reduced to a 3-amino-1,2,4-triazol-1-yl group in the presence of zinc dust and ammonium chloride in a protic solvent, such as methanol. In step an, the 3-amino-1,2,4-triazol-1-yl group is acylated with an acid chloride, such as cyclopropylcarbonyl chloride or acetyl chloride, in the presence of a base, such as triethylamine, in a solvent such as dichloromethane.
Scheme XXX
In step ao of Scheme XXXI, a bromophenyl methyl ketone of Formula XXXIV wherein R10, X1, X2, and X3 are as previously disclosed is converted to an phenyl methyl ketone ofthe Formula
XXXV wherein R11 is a 1,2,4-triazol-1 -yl group, and R10, X1, X2, and X3 are as previously disclosed by treatment with 1,2,4-triazole in the presence of a base, such as césium carbonate, and a catalyst, such as copper iodide, in a solvent, such as DMF. In step ap, the 1,2,4triazolylacetophenone of Formula XXXV is converted to the trimethylsilyl enol ether of Formula
XXXVI by treatment with trimethylsilyl triflluoromethanesulfonate in the presence of a base, such as triethylamine, in an aprotic solvent, such as dichloromethane. In step aq, the silyl enol ether is reacted with a compound of Formula V, wherein Y is Br, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed in the presence of CuCI and 2,2-bipyridyl in a solvent, such as 1,2dichlorobenzene at a température of about 180 °C to generate a ketone ofthe Formula XXXVII, wherein R11 is a 1,2,4-triazol-1 -yl group, and R1, R2, R3, R4, R5, R6, R7, R10, X1, X2, and X3 are as previously disclosed. In step ar, the ketone ofthe Formula XXXVII is treated with méthylmagnésium bromide in an aprotic solvent, such as THF to generate the tertiary alcohol. The tertiary alcohol then undergoes an élimination reaction when treated with a catalytic amount of ptoluenesulfonic acid in a solvent, such as toluene, when heated to a température to allow azeotropic removal of water to produce compounds of Formula One wherein R11 is a 1,2,4-triazol-
1-yl group, R8 is methyl, and R1, R2, R3, R4, R5, R6, R7, R10, X1, X2, and X3 are as previously disclosed, as in step as.
Scheme XXXI
XXXIV
XXXVI
XXXVI
Formula One
In Scheme XXXII, a compound of Formula XXXVIII, wherein R10 and R11 togetherform a linkage, having 3-4 carbon atoms and an oxo substituent and with the ring carbon atoms form a 5or 6-membered cyclic ring, and R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously 5 disclosed is converted to a molécule of Formula One, wherein R10 and R11 togetherform a linkage, having 3-4 carbon atoms and an alkylamine substituent with the ring carbon atoms form a 5- or 6-membered cyclic ring and R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, by treatment with an alkylamine, such as 3,3,3-trifluoropropylamine, in the presence of a reducing agent, such as sodium cyanoborohydride, in a solvent, such as DCE.
Scheme XXXII
XXXVIII
Formula One
In Scheme XXXIII, a compound of Formula XXXIX, wherein X1, X2, and X3 are as previously disclosed is converted to a molécule of Formula XL, wherein X1, X2, and X3 are as previously disclosed, by treatment with a reducing agent, such as sodium cyanoborohydride, in a solvent, such as acetic acid, as in step au. In step av, the nitrogen atom is protected with a tertbutyloxycarbonyl (BOC) group by reaction with di-ferf-butyl dicarbonate in the presence of a catalyst, such as DMAP, in a solvent, such as acetonitrile. The bromide of Formula XL can be converted to the olefin of Formula XLI, wherein R8, X1, X2 and X3 are as previously disclosed, by reaction with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as PdCI2(dppf), and a base, such as K2CO3, in a polar aprotic solvent such as DMSO at 100 °C, as in step aw.
Scheme XXXIII
au
av,aw
XLI
XXXIX XL
In Scheme XXXIV, a compound of Formula XXXIX, wherein X1, X2, and X3 are as previously disclosed is converted to a molécule of Formula XLII, wherein X1, X2, and X3 are as previously disclosed in two steps. In step ax, the olefin is formed by treatment of the bromide with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as PdCI2, and a ligand, such as triphenylphosphine, and a base, such as Cs2CO3, in a solvent mixture such as THF/H2O. In step ay, the nitrogen atom is protected with a tert-butyloxycarbonyl (BOC) group by reaction with diferf-butyl dicarbonate in the presence of a catalyst, such as DMAP, in a solvent, such as acetonitrile.
Scheme XXXIV
ax,ay
xxxix xlii
In step / of Scheme XXXV, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compounds of Formula XLI or XLII, wherein R8, X1, X2 and X3 are as previously disclosed, are allowed to react in the presence of CuCI and 2,25 bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a température of about 150 °C to provide the corresponding compounds of Formula XLIIIa orXLIIIb, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed.
Scheme XXXV
In Scheme XXXVI, a compound of Formula XLIIIa, wherein R1, R2, R3, R4, R5, R6, R7, R8, 10 X1, X2, and X3 are as previously disclosed is converted to a molécule of Formula XLIV, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed by treatment with trifluoroacetic acid, in a solvent such as dichloromethane, as in step az. Compounds of the Formula XLIV can then be transformed into compounds of the Formula XLV wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, in two steps. In step ba, the indoline is treated with sodium nitrite (NaNO2), in an acid, such as concentrated HCl, at a température around 5 °C, to form the nitrosoindole. In step bb, the nitrosoindole is reacted with ammonium chloride in the presence of zinc powder in a protic solvent, such as methanol. In step bc, compounds of the Formula XLV are transformed into compounds of the Formula XLVI, wherein X4 is N(R14)(C(=O)R14) and R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, by treatment with and acid, such as 3,3,3-trifluoropropanoic acid, PyBOP, and a base, such as DIEA, in a polar aprotic solvent, such as dichloromethane.
XLIIIa XLIV
In Scheme XXXVII, a compound of Formula XLIIIb, wherein R1, R2, R3, R4, R5, R6, R7,
R8, X1, X2, and X3 are as previously disclosed is converted to an indole of Formula XLVII, wherein
R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed by treatment with trifluoroacetic acid, in a solvent such as dichloromethane, as in step bd. Compounds ofthe Formula XLVII can be transformed into compounds ofthe Formula XLVIII wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, by reaction with 4-nitrophenyl-2-((tert10 butoxycarbonyl)amino)acetate in the presence of potassium fluoride and a crown ether, such as 18crown-6-ether, in a solvent, such as acetonitrile, as in step be. Compounds of the Formula XLVIII can be transformed into compounds ofthe Formula XLIX, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed in two steps. In step bf, the Boc group is removed by treatment with trifluoroacetic acid, in a solvent such as dichloromethane. ln step bg, the amine is treated with 3,3,3-trifluoropropanoic acid, PyBOP, and a base, such as DIEA, in a polar aprotic solvent, such as dichloromethane.
In Scheme XXXVIII, a compound of Formula L, wherein X1, X2, and X3 are as previously disclosed is converted to a compound of the Formula Ll, wherein X1, X2, and X3 are as previously disclosed by treatment with copper (II) sulfate pentahydrate and Zn powder in a base, such as sodium hydroxide as in step bh. Compounds of the Formula Ll can be transformed into compounds of the Formula LH wherein X1, X2, and X3 are as previously disclosed, by reaction with hydrazine, in a solvent such as water, at a température around 95 °C, as in step bi. In step bj, the olefin of the Formula LUI wherein X1, X2, and X3 are as previously disclosed is formed by treatment of the bromide with potassium vinyl trifluoroborate in the presence of a palladium catalyst, such as
PdCI2(dppf), and a base, such as K2CO3, in a solvent mixture such as DMSO. Compounds of the Formula LIV, wherein X1, X2, and X3 are as previously disclosed, can be formed from compounds of the Formula LUI by reaction with ethyl bromoacetate, in the presence of a base, such as Cs2CO3, in a solvent, such as DMF.
Scheme XXXVIII
LUI
LIV
In step I of Scheme XXXIX, the compound of Formula V, wherein Y, R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed, and the compound of Formula LIV, wherein R8, X1, X2 and X3 are as previously disclosed, are allowed to react in the presence of CuCI and 2,2-bipyridyl in a solvent, such as 1,2-dichlorobenzene, at a température of about 180 °C to provide the corresponding compound of Formula LV, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed. The compound of Formula LV can be further transformed into a compound ofthe Formula LVI, wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, and X3 are as previously disclosed, in two steps. In step bl, the ester is hydrolyzed to the acid in the presence of HCl and acetic acid, at a température of about 100 °C. In step bm, the acid is treated with an amine, such as 2,2,2-trifluoroethylamine, PyBOP, and a base, such as DIEA, in a polar aprotic solvent, such as dichloromethane.
Scheme XXXIX
In step bn of Scheme XL, carboxylic acids ofthe Formula LVII, wherein R11 is C(=O)OH and R8, R10, X1, X2, and X3 are as previously disclosed and compounds ofthe Formula V, wherein Y is Br and R1, R2, R3, R4, R5, R6, and R7 are as previously disclosed are allowed to 5 react in the presence of CuCI and 2,2-bipyridyl in a solvent, such as A/-methyl pyrrolidine, at a température of about 150 °C to afford compounds of Formula LVIII, wherein R11 is (C=O)OH and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X1, X2, and X3 are as previously disclosed. Compounds ofthe Formula LVIII can be further transformed to the corresponding benzamides of Formula LIX, wherein R11 is (C=O)N(R14)(R15), and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X1, X2, and X3 10 are as previously disclosed, by treatment with an amine, such as 2-amino-/V-(2,2,2trifluoroethyl)acetamide, PyBOP, and a base, such as DIEA, in a polar aprotic solvent, such as dichloromethane, as in step bo.
Scheme XL
LIX
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 a Thomas Hoover Unimelt capillary melting point apparatus or an OptiMelt Automated Melting Point System from Stanford Research Systems and are uncorrected. Molécules are given their known names, named according to naming programs within ISIS Draw, ChemDraw, or ACD Name Pro. If such programs are unable to name a molécule, the molécule is named using conventional naming rules. 1H NMR spectral data are in ppm (δ) and were recorded at 300, 400, or 600 MHz, and 13C NMR spectral data are in ppm (O) and were recorded at 75, 100, or 150 MHz, unless otherwise stated.
Example 1: Préparation of 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (AH)
Step 1 Method A. 1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanol (AI2). To a stirred solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (procured from Rieke Metals, UK; 5.0 grams (g), 20.5 millimoles (mmol)) in methyl alcohol (CH3OH; 100 milliliters (mL)) at 0 °C were added sodium borohydride (NaBH4; 3.33 g, 92.5 mL) and 1 Normal (N) aqueous sodium hydroxide solution (NaOH; 10 mL). The reaction mixture was warmed to 25 °C and stirred for 2 hours (h). After the reaction was deemed complété by thin layer chromatography (TLC), saturated (satd) aqueous (aq) ammonium chloride (NH4CI) solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was diluted with diethyl ether (Et2O) and washed with water (H2O; 3 x 50 mL). The organic layer was dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure to afford the title compound as a liquid (4.0 g, 79%): 1H NMR (400 MHz, CDCI3) δ 7.41 (m, 3H), 5.00 (m, 2H), 2.74 (s, 1H); ESIMS m/z 242.97 ([M-H]-).
Step 1 Method B. 1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanol (AI2). To a stirred solution of 3,5-dichlorobenzaldehyde (10 g, 57 mmol) in tetrahydrofuran (THF; 250 mL) were added trifluoromethyltrimethylsilane (9.79 g, 69.2 mmol) and a catalytic amount of tetrabutylammonium fluoride (TBAF). The reaction mixture was stirred at 25 °C for 8 h. After the reaction was deemed complété by TLC, the reaction mixture was diluted with 3 N hydrochloric acid (HCl) and then was stirred for 16 h. The reaction mixture was diluted with H2O and was extracted with ethyl acetate (EtOAc; 3 x). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a liquid (8.41 g, 60%).
The following compounds were made in accordance with the procedures disclosed in Step 1 Method B of Example 1 above.
2,2,2-Trifluoro-1-(3,4,5-trichlorophenyl)ethanol (AI3)
The product was isolated as a pale yellow liquid (500 mg, 65%): 1H NMR (400 MHz, CDCI3) δ 7.45 (s, 2H), 5.00 (m, 1H), 2.80 (s, 1H); ESIMS m/z 278 ([M+H]+); IR (thin film) 3420, 1133, 718 cm'1.
-(3,5-Dichloro-4-fluorophenyl)-2,2,2-trifluoroethanol (AI4)
The product was isolated as a pale yellow liquid (500 mg, 65%): 1H NMR (400 MHz, CDCI3) δ 7.41 (s, 2H), 5.00 (m, 1H), 2.80 (s, 1H); ESIMS m/z 262 ([M+H]+); IR (thin film) 3420, 1133, 718 cm'1.
-(3,4-Dichlorophenyl)-2,2,2-trifluoroethanol (AI5)
OH
The product was isolated as a pale yellow liquid (500 mg, 65%): 1H NMR (400 MHz, CDCI3) δ 7.60 (s, 1 H), 7.51 (m, 1 H), 7.35 (m, 1 H), 5.01 (m, 1 H), 2.60 (s, 1 H); EIMS m/z 244 ([M]+).
Step 2.1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (AI1). To a stirred solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanol (4.0 g, 16.3 mmol) in dichloromethane (CH2CI2; 50 mL), were added /V-bromosuccinimide (NBS; 2.9 g, 16.3 mmol) and triphenyl phosphite (5.06 g,
16.3 mmol), and the résultant reaction mixture was heated at reflux for 18 h. After the reaction was deemed complété by TLC, the reaction mixture was cooled to 25 °C and was concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 100% pentane) afforded the title compound as a liquid (2.0 g, 40%): 1H NMR (400 MHz, CDCI3) δ
7.41 (s, 3H), 5.00 (m, 1H); EIMS m/z 306 ([M]+).
The following compounds were made in accordance with the procedures disclosed in Step 2 of Example 1.
5-(1-Bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (AI6)
The product was isolated as a colorless oil (300 mg, 60%): 1H NMR (400 MHz, CDCI3) δ
7.59 (s, 2H), 5.00 (m, 1H); EIMS m/z 340.00 ([M]+).
5-(1-Bromo-2,2,2-trifluoroethyI)-1,3-dichloro-2-fluorobenzene (AI7)
The product was isolated as a colorless oil (320 mg, 60%): 1H NMR (400 MHz, CDCI3) δ
7.45 (s, 2H), 5.00 (m, 2H); EIMS m/z 324.00 ([M]+).
4-(1-Bromo-2,2,2-trifluoroethyl)-1,2-dichlorobenzene (AI8)
The product was isolated as a colorless oil (300 mg, 60%): 1H NMR (400 MHz, CDCI3) δ 7.63 (s, 1H), 7.51 (m, 1H), 7.35 (m, 1H), 5.01 (m, 1H); EIMS m/z 306.00 ([M]+).
Example 2: Préparation of AFmethyl-4-vinylbenzamide (AI9)
O
Step 1.4-Vinylbenzoyl chloride (AI10). To a stirred solution of 4-vinylbenzoic acid (1 g,
6.75 mmol) in CH2CI2 (20 mL) at 0 °C were added a catalytic amount of /V,A/-dimethylformamide (DMF) and oxalyl chloride (1.27 g, 10.12 mmol) dropwise overa period of 15 minutes (min). The reaction mixture was stirred at 25 °C for 6 h. After the reaction was deemed complété by TLC, the reaction mixture was concentrated under reduced pressure to give the crude acid chloride.
Step 2. W-Methyl-4-vinylbenzamide (AI9). To 1 M /V-methylamine in THF (13.5 mL, 13.5 mmol) at 0 °C were added triethylamine (Et3N; 1.34 mL, 10.12 mmol) and the acid chloride from Step 1 above in THF (10 mL), and the reaction mixture was stirred at 25 °C for 3 h. After the reaction was deemed complété by TLC, the reaction mixture was quenched with water and then was extracted with EtOAc (3x). The combined EtOAc layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (650 mg, 60%): 1H NMR (400 MHz, CDCI3) δ 7.76 (d, J = 8.0 Hz, 2H), 7.45 ( d, J = 8.0 Hz, 2H),
6.79 (m, 1H), 6.20 (brs,1H), 5.82 (d, J= 17.6 Hz, 1H), 5.39 (d, J =10.8 Hz, 1H); ESIMS m/z 161.95 ([M+H]+).
The following compounds were made in accordance with the procedures disclosed in accordance with Example 2.
The product was isolated as an off-white solid (650 mg, 60%): 1H NMR (400 MHz, CDCI3) δ
7.42 (m, 4H), 6.71 (m, 1H), 5.80 (d, J= 17.6 Hz, 1H), 5.31 (d, J = 10.8 Hz, 1H), 3.05 (s, 3H), 3.00 (s, 3H); ESIMS m/z 176.01 ([M+Hf).
/V-(2,2,3-trifluoromethyl)-4-vinylbenzamide (AI12)
The product was isolated as an off-white solid (900 mg, 60%): 1H NMR (400 MHz, CDCI3) δ
7.76 (d, J= 8.0 Hz, 2H), 7.45 ( d, J= 8.0 Hz, 2H), 6.79 (m, 1H), 6.20 (brs,1H), 5.82 (d, J= 17.6 Hz,
1H), 5.39 (d, J= 10.8 Hz, 1H), 4.19 (m, 2H); ESIMS m/z 230.06 ([M+H]+).
Morpholino(4-vinylphenyl)methanone (AI13)
O
The product was isolated as a white solid (850 mg, 60%): ESIMS m/z 218.12 ([M+H]+).
Example 3: Préparation of ethyl 2-methyl-4-vinylbenzoate (AI14)
O
Step 1. 4-Formyl-2-methylbenzoic acid (AI15). To a stirred solution of 4-bromo-2methylbenzoic acid (10 g, 46.4 mmol) in dry THF (360 mL) at -78 °C was added n-butyllithium (nBuLi, 1.6 M solution in hexane; 58.17 mL, 93.0 mmol) and DMF (8 mL). The reaction mixture was stirred at -78 °C for 1 h then was warmed to 25 °C and stirred for 1 h. The reaction mixture was quenched with 1 N HCl solution and extracted with EtOAc. The combined EtOAc extracts were washed with brine and dried over Na2SO4 and concentrated under reduced pressure. The residue was washed with n-hexane to afford the title compound as a solid (3.0 g, 40%): mp 196-198 °C; 1H NMR (400 MHz, DMSO-d6) δ 13.32 (brs, 1H), 10.05 (s, 1H), 7.98 (m, 1H), 7.84 (m, 2H), 2.61 (s, 3H); ESIMS m/z 163.00 ([M-H]’).
Step 2. Ethyl 4-formyl-2-methylbenzoate (AI16). To a stirred solution of 4-formyl-2methylbenzoic acid (3 g, 18.2 mmol) in ethyl alcohol (EtOH; 30 mL) was added sulfuric acid (H2SO4, x M; 2 mL), and the reaction mixture was heated at 80 °C for 18 h. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with H2O. The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a solid (2.8 g, 80%): 1H NMR (400 MHz, CDCI3) δ 10.05 (s, 1H), 8.04 (m, 1H), 7.75 (m, 2H), 4.43 (m, 2H), 2.65 (s, 3H), 1.42 (m, 3H).
Step 3. ethyl 2-methyl-4-vinylbenzoate (Al 14). To a stirred solution of ethyl 4-formyl-2methylbenzoate (2.8 g, 4 mmol) in 1,4-dioxane (20 mL) were added potassium carbonate (K2CO3; 3.01 g, 21.87 mmol) and methyltriphenyl phosphonium bromide (7.8 g, 21.87 mmol) at25 °C. Then the reaction mixture was heated at 100 °C for 18 h. After the reaction was deemed complété by TLC, the reaction mixture was cooled to 25 °C and filtered, and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 25-30% EtOAc in n-Hexane) to afford the title compound as a solid (2.0 g, 72%): 1H NMR (400 MHz, CDCI3) δ 7.86 (m, 1H), 7.27 (m, 2H), 6.68 (dd, J =17.6, 10.8 Hz , 1H), 5.84 (d, J = 17.6 Hz, 1 H), 5.39 (d, J = 10.8 Hz, 1 H), 4.39 (m, 2H), 2.60 (s, 3H), 1.40 (m, 3H); ESIMS m/z
191.10 ([M-H]’); IR (thin film) 2980, 1716, 1257 cm’1.
Example 4: Préparation of iert-butyl 2-chloro-4-vinylbenzoate (AI17)
Cl
Step 1. tert-Butyl 4-bromo-2-chlorobenzoate (AI18). To a stirred solution of 4-bromo-2chlorobenzoic acid (5 g, 21.37 mmol) in THF (30 mL) was added di-tert-butyl dicarbonate (25.5 g, 25.58 mmol), Et3N (3.2 g, 31.98 mmol) and 4-(dimethylamino)pyridine (DMAP; 0.78 g, 6.398 mmol), and the reaction mixture was stirred at 25 °C for 18 h. The reaction mixture was diluted with EtOAc and washed with H2O. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 2-3% EtOAc in n-hexane) to afford the title compound as a liquid (3.2 g, 51%): 1H NMR (400 MHz, CDCI3) □ 7.62 (m, 2H), 7.44 (d, J= 8.4 Hz, 1H), 1.59 (s, 9H); ESIMS m/z 290.10 ([M+H]+); IR(thin film) 1728 cm'1.
The following compounds were made in accordance with the procedures disclosed in Step 1 of Example 4.
tert-Butyl 2-bromo-4-iodobenzoate (AI19)
Br
The product was isolated as a colorless oil (1.2 g, 50%): 1H NMR (400 MHz, CDCI3) □ 8.01 (s, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.41 (d, J= 8.0 Hz, 1H), 1.59 (s, 9H); ESIMS m/z 382.10 ([M+H]+); IR(thinfilm) 1727 cm'1.
tert-Butyl 4-bromo-2-(trifluoromethyl)benzoate(AI20)
Br
The product was isolated as a colorless oil (1 g, 52%): 1H NMR (400 MHz, CDCI3) □ 7.85 (s, 1H), 7.73 (d, J =8.4 Hz, 1H), 7.62 (d, J =8.4 Hz, 1H), 1.57 (s, 9H); ESIMS m/z 324.10 ([M+H]+); IR (thin film) 1725 cm-1.
Step 2. tert-butyl 2-chloro-4-vinylbenzoate (AI17). To a stirred solution of tert-butyl 4bromo-2-chlorobenzoate (1.6 g, 5.50 mmol) in toluene (20 mL) was added tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4; (0.31 mg, 0.27 mmol), K2CO3 (2.27 g, 16.5 mmol) and vinylboronic anhydride pyridine complex (2.0 g, 8.3 mmol) and the reaction mixture was heated to reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 5—6% EtOAc in n-hexane) afforded the title compound as a liquid (0.6 g, 46%): 1H NMR (400 MHz, CDCI3) □ 7.72 (d, J= 8.1 Hz, 1H), 7.44 (m, 1 H), 7.31 ( d, J = 8.0 Hz, 1 H), 6.69 (dd, J =17.6, 10.8 Hz , 1 H), 5.85 (d, J = 17.6 Hz, 1 H), 5.40 (d, J= 10.8 Hz, 1H), 1.60 (s, 9H); ESIMS m/z 238.95 ([M+H]+); IR (thin film) 2931, 1725, 1134 cm’1.
The following compounds were made in accordance with the procedures disclosed in Step 2 of Example 4.
tert-Butyl 2-bromo-4-vinylbenzoate (AI21)
ο
The product was isolated as a colorless oil (1g, 52%): 1H NMR (400 MHz, CDCI3) □ 7.68 (m, 2H), 7.36 ( d, J = 8.0 Hz, 1 H), 6.68 (dd, J =17.6, 10.8 Hz , 1 H), 5.84 (d, J = 17.6 Hz, 1 H), 5.39 (d, J= 10.8 Hz, 1H), 1.60 (s, 9H); ESIMS m/z 282.10 ([M+H]+); IR (thin film) 2978, 1724, 1130 cm’1.
tert-Butyl 2-(trifluoromethyl)-4-vinylbenzoate (AI22)
O
The product was isolated as a colorless oil (1.2 g, 50%): 1H NMR (400 MHz, CDCI3) □ 7.71 (d, J = 6.4 Hz, 2H), 7.59 (d, J = 7.6 Hz, 1 H), 6.77 (dd, J = 17.6, 10.8 Hz , 1 H), 5.89 (d, J = 17.6 Hz, 1H), 5.44 (d, J= 10.8 Hz, 1H), 1.58 (s, 9H); ESIMS m/z 272.20 ([M+H]+); IR (thin film) 2982, 1727, 1159 cm'1.
Example 5: Préparation of tert-butyl 2-cyano-4-vinylbenzoate (AI23)
O
To a stirred solution of tert-butyl 2-bromo-4-vinylbenzoate (0.5 g, 1.77 mmol) in DMF (20 mL) was added copper(l) cyanide (CuCN; 0.23 g, 2.65 mmol), and the reaction mixture was heated at 140 °C for 3 h. The reaction mixture was cooled to 25 °C, diluted with H2O, and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 15% EtOAc in n-hexane) to afford the title compound as a white solid (0.3 g, 72%): mp 51-53 °C; 1H NMR (400 MHz, CDCI3) □ 8.03 (s, 1 H), 7.77 (s, 1 H), 7.64 (d, J = 8.4 Hz, 1 H), 6.75 (dd, J= 17.6, 10.8 Hz , 1H), 5.93 (d, J= 17.6 Hz, 1H), 5.51 (d, J= 10.8 Hz, 1H), 1.65 (s, 9H); ESIMS m/z 229.84 ([M+H]+); IR (thin film) 2370, 1709, 1142 cm’1.
Example 6: Préparation of ethyl 2-bromo-4-iodobenzoate (AI46)
O
To a stirred solution of 4-iodo-2-bromobenzoic acid (5 g, 15.29 mmol) in ethyl alcohol (EtOH; 100 mL) was added sulfuric acid (H2SO4; 5 mL), and the reaction mixture was heated at 80 °C for 18 h. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was diluted with EtOAc (2x100 mL) and washed with H2O (100 mL). The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the compound as a pale yellow solid (5 g, 92%): 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 1.2 Hz, 1 H), 7.71 (d, J = 7.6 Hz, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 4.41 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H).
The following compounds were made in accordance with the procedures disclosed in Example 6.
Ethyl 4-bromo-2-chlorobenzoate (AI47)
The title compound was isolated as an off-white solid (2.0 g, 80 %): 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 1.2 Hz, 1 H), 7.79 (d, J = 7.6 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 1 H), 4.65 (q, J =
7.2 Hz, 2H), 1.56 (t, J= 7.2 Hz, 3H).
Ethyl 4-bromo-2-methylbenzoate (AI48)
The title compound was isolated as a pale yellow liquid (3.0 g, 83%): 1H NMR (400 MHz,
CDCI3) δ 7.79 (d, J = 8.4 Hz, 1 H), 7.41 (s, 1 H), 7.39 (d, J = 8.4 Hz, 1 H), 4.42 (q, J = 7.2 Hz, 2H),
2.60 (s, 3H), 1.40 (t, J= 7.2 Hz, 3H)ESIMS m/z 229.11 ([M+H]+); IR (thin film) 1725 cm’1.
Ethyl 4-bromo-2-fluorolbenzoate (AI49)
The title compound was isolated as a colorless liquid (9.0 g, 79%): 1H NMR (400 MHz, DMSO-d6) δ 7.84 (t, J = 8.4 Hz, 1 H), 7.76 (d, J = 2.0 Hz, 1 H), 7.58 (d, J = 1.6 Hz, 1 H), 4.34 (q, J =
7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H); ESIMS m/z 246.99 ([M+H]+), IR (thin film) 1734 cm’1.
Example 7: Préparation of ethyl 4-bromo-2-ethylbenzoate (Al50)
To a stirred solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.17 mmol) in THF (16 mL), was added 1.0 M ethyl magnésium bromide in THF (32 mL, 32.0 mmol) dropwise at 0°C and the résultant reaction mixture was stirred at RT for 18h. The reaction mixture was quenched with 2 N HCl and extracted with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude 4-bromo-2-ethylbenzoic acid as a colorless liquid that was used in the next step without purification (0.4 g): 1H NMR (400 MHz, CDCI3) δ 7.64 (d, J = 8.4 Hz, 1 H), 7.47 (m, 1 H), 7.43 (m, 1 H), 2.95 (q, J = 4.0 Hz, 2H), 1.32 (t, J = 4.0 Hz, 3H); ESIMS m/z 228.97 ([M+H]+).
The title compound was synthesized from 4-bromo-2-ethylbenzoic acid in accordance to the procedure in Example 6, isolated as a colorless liquid (0.15 g, 68%): 1H NMR (400 MHz, DMSOd6)ô 7.90 (d, J = 8.4 Hz, 1 H), 7.47 (m, 2H), 4.40 (q, J = 7.2 Hz, 2H), 3.06 (q, J = 7.6 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.6 Hz, 3H); ESIMS m/z 226.96 ([M-H]'); IR (thin film) 3443, 1686, 568 cm'1.
Example 8: Préparation of ethyl 2-bromo-4-vinylbenzoate (AI51)
O
To a stirred solution of ethyl 2-bromo-4-iodobenzoate (5 g, 14.3 mmol) in THF/water (100 mL, 9:1) was added potassium vinyltrifluoroborate (1.89 g, 14.3 mmol), Cs2CO3 (18.27 g, 56.07 mmol) and triphenylphosphine (0.22 g, 0.85 mmol) and the reaction mixture was degassed with argon for 20 min, then charged with PdCI2 (0.05 g,0.28 mmol). The reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to RT and filtered through a celite bed and washed with ethyl acetate. The filtrate was again extracted with ethyl acetate and the combined organic layers washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% ethyl acetate/ petroleum ether) to afford the title compound as a light brown gummy material (2 g, 56%): 1H NMR (400 MHz, CDCI3) δ 7.78 (d, J = 8.4 Hz, 1H), 7.71 (d, J= 1.2 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.69 (dd, J= 17.6, 10.8 Hz, 1H), 5.86 (d, J= 17.6 Hz, 1 H), 5.42 (d, J = 11.2 Hz, 1 H), 4.42 (q, J = 7.2Hz, 2H), 1.43 (t, J = 3.6 Hz, 3H); ESIMS m/z 255.18 ([M+H]+); IR (thin film) 1729 cm'1.
The following compounds were made in accordance with the procedures disclosed in Example 8.
Ethyl 2-methyl-4-vinylbenzoate (AI52)
O
The title compound was isolated as a colorless liquid (0.8 g, 80 %): 1H NMR (400 MHz, CDCI3) δ 7.89 (d, J= 8.4 Hz, 1H), 7.27 (m, 2H), 6.79 (dd, J= 17.6, 10.8 Hz, 1H), 5.86 (d, J = 17.6 Hz, 1 H), 5.42 (d, J = 11.2 Hz, 1 H), 4.42 (q, J = 7.2 Hz, 2H), 2.60 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H); ESIMS m/z 191.10 ([M+H]+); IR (thin film) 1717, 1257 cm'1.
Ethyl 2-fluoro-4-vinylbenzoate (Al53)
O
The title compound was isolated as a pale yellow liquid (2.0 g, 50 %): 1H NMR (400 MHz, DMSO-de) δ 7.87 (t, J = 8.0 Hz, 1H), 7.51(d, J= 16.0 Hz, 1H), 7.48 (d, J= 16.0 Hz, 1H), 6.82 (dd, J = 17.6, 10.8 Hz, 1H), 6.09 (d, J = 17.6 Hz, 1H), 5.50 (d, J= 10.8 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H),
1.35 (t, J = 7.2 Hz, 3H); ESIMS m/z 195.19 ([M+H]+); IR (thin film) 1728 cm'1.
Example 9: Préparation of ethyl 2-chloro-4-vinylbenzoate (AI54)
Cl
To a stirred solution of ethyl 2-chloro-4-bromobenzoate (2 g, 7.63 mmol) in dimethylsulfoxide (20 mL) was added potassium vinyltrifluoroborate (3.06 g, 22.9 mmol) and potassium carbonate (3.16 g, 22.9 mmol). The reaction mixture was degassed with argon for 30 min. Bistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride (0.27 g, 0.38 mmol) was added and the reaction mixture was heated to 80 °C for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2 x 50 mL), washed with brine, dried over
Na2SO4 and concentrated under reduced pressure to obtain the compound as brown gummy material (1.1 g, 69%): 1H NMR (400 MHz, CDCI3) δ 7.81 (d, J =8.4 Hz, 1H), 7.46 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.70 (dd, J= 17.6, 11.2 Hz, 1H), 5.87 (d, J= 17.6 Hz, 1H), 5.42 (d, J= 10.8 Hz, 1H),
4.41 (q, J = 7.2 Hz,2H), 1.43 (t, J = 7.2 Hz, 3H); ESIMS m/z 211.22 ([M+H]+); IR (thin film) 1729, 886 cm'1.
The following compounds were made in accordance with the procedures disclosed in Example 9.
Ethyl 2-ethyl-4-vinylbenzoate (AI55)
O
The title compound was isolated as a color less liquid (1.0 g, 66 %): 1H NMR (300 MHz, CDCI3) δ 7.85 (m, 1H), 7.29 (m, 2H), 6.76 (d, J= 10.8 Hz, 1H), 5.86 (d, J= 17.6 Hz, 1H), 5.36 (d, J = 10.5 Hz, 1 H), 4.41 (q, J = 7.2 Hz, 2H), 3.10 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H); ESIMS m/z 205.26 ([M+H]+); IR (thin film) 1720, 1607, 1263 cm’1.
Methyl 2-methoxy-4-vinylbenzoate (Al56)
The title compound was isolated as a pale yellow liquid (1.2 g, 75 %): 1H NMR (400 MHz, CDCI3) δ 7.79 (d, J = 8.0 Hz, 1 H), 7.04 (d, J = 1.2 Hz, 1 H), 6.97 (s, 1 H), 6.74 (dd, J = 11.2, 11.2 Hz, 1H), 5.86 (d, J= 17.6 Hz, 1H), 5.39 (d, J = 17.6 Hz, 1H) 3.93 (s, 3H), 3.91 (s, 3H). ESIMS m/z
193.18 ([M+H]+); IR (thin film) 1732 cm'1,
Example 10: Préparation of (E)-ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2methylbenzoate (AI24)
CF
Cl
Cl
To a stirred solution of ethyl 2-methyl-4-vinylbenzoate (2.0 g, 10.5 mmol) in 1,2dichlorobenzene (25 mL) were added 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (6.44 g, 21.0 mmol), copper(l) chloride (CuCI; 208 mg, 21 mmol) and 2,2bipyridyl (0.65 g, 4.1 mmol). The reaction mixture was degassed with argon for 30 min and then stirred at 180 °C for 24 h. After the reaction was deemed complété by TLC, the reaction mixture was cooled to 25 °C and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; eluting with 25-30% EtOAc in petroleum ether) afforded the title compound as a solid (1.7 g, 40%): 1H NMR (400 MHz, CDCI3) □ 7.91 (d, J = 8.0 Hz, 1H), 7.37 (m, 1H), 7.27-7.24 (m, 4H), 6.59 (d, J= 16.0 Hz, 1H), 6.59 (dd, J= 16.0, 8.0 Hz, 1H), 4.38 (q, J= 7.2 Hz, 2H), 4.08 (m, 1H), 2.62 (s, 3H), 1.42 (t, J= 7.2 Hz, 3H); ESIMS m/z 415.06 ([M-H] ); IR (thin film) 1717, 1255, 1114 cm'1.
Compounds AI25, AI57-AI68 and AC1-AC5 (Table 1) were made in accordance with the procedures disclosed in Example 10.
(E)-Ethyl 4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)-benzoic acid (AI25)
Cl O
The product was isolated as a pale brown gummy liquid (500 mg, 40%): 1H NMR (400 MHz, CDCI3) □ 7.79 (d, J = 8.0 Hz, 1 H), , 7.71 (m, 1 H), 7.61 (d, J = 7.6 Hz, 1 H),7.42 (s, 2H), 6.70 (d, J = 16.0 Hz, 1H), 6.57 (dd, J =16.0, 8.0 Hz, 1H), 4.42 (q, J =7.2 Hz, 2H), 4.19 (m, 1H), 1.40 (t, J = 7.6 Hz, 3H),; ESIMS m/z 502.99 ([M-H]'); IR (thin film) 1730, 1201, 1120, 749 cm’1.
(E)-Ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluorobenzoate (AI57)
Cl o 1H NMR (400 MHz, CDCI3) δ 7.38 (s, 1H), 7.26 (s, 3H), 7.21 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 11.6 Hz, 1H), 6.59 (d, J = 16.0 Hz, 1H), 6.47 (dd, J = ,16.0, 8.0 Hz, 1H), 4.41 (q, J = 6.8 Hz, 2H),
4.18 (m, 1H), 1.41 (t, J= 6.8 Hz, 3H); ESIMS m/z 419.33 ([M-H] ); IR (thin film) 1723, 1115, 802 cm 1 (E)-Ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1 -enyl)-2-bromobenzoate (AI58)
1H NMR (400 MHz, CDCI3) δ 7.79 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.38 (m, 2H), 7.26 (m, 2H), 6.56 (d, J= 16.0 Hz, 1H), 6.45 (dd, J= 16.0, 7.6 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 4.39 (m, 1H), 1.42 (t, J= 7.2 Hz, 3H); ESIMS m/z 481.22 ([M-H] ); IR (thin film) 1727, 1114, 801, 685 cm'1.
(E)-Ethyl 2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-1-enyl)benzoate (AI59)
1H NMR (400 MHz, CDCI3) δ 7.79 (d, J = 8.0 Hz, 1 H), 7.67 (d, J = 1.6 Hz, 1 H), 7.40 (s, 2H),
7.36 (d, J= 1.6 Hz, 1H), 6.56 (d, J= 16.0 Hz, 1H), 6.44 (dd, J= 16.0, 7.6 Hz, 1H), 4.42 (q, J = 6.8 Hz, 2H), 4.15 (m, 1H), 1.42 (t, J= 6.8 Hz, 3H); ESIMS m/z 514.74 ([M-H]); IR (thin film) 1726, 1115, 808,620 cm’1.
(E)-Ethyl 2-methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-1-enyl)benzoate (AI60)
Cl O
The title compound was isolated as a light brown gummy material: 1H NMR (400 MHz, CDCI3) δ 7.90 (d, J = 8.8 Hz, 1 H), 7.34 (d, J = 6.0 Hz, 2H), 7.25 (d, J = 7.2 Hz, 2H), 6.59 (d, J = 16.0 Hz, 1H), 6.42 (dd, J= 16.0, 8.0 Hz, 1H), 4.38 (q, J= 7.2 Hz, 2H), 4.19 (m, 1H), 2.63 (s, 3H),
1.41 (t, J =7.2 Hz, 3H).
(E)-Ethyl 2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-1-enyl)benzoate (AI61)
1H NMR (400 MHz, CDCI3) δ 7.87 (d, J = 8.0 Hz, 1 H), 7.46 (d, J = 1.6 Hz, 1 H), 7.40 (s, 2H),
7.31 (d, J= 1.6 Hz, 1H), 6.57 (d, J= 16.0 Hz, 1H), 6.44 (dd, J= 16.0 Hz,, 8.0 Hz, 1H), 4.42 (q, J =
6.8 Hz, 2H), 4.15 (m, 1H), 1.42 (t, J= 6.8 Hz, 3H); ESIMS m/z 470.73 ([M-H]’); IR (thin film) 1726, 1115, 809, 3072 cm’1.
(E)-Ethyl 4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzoate (Al 62)
The title compound was isolated as a pale brown liquid (1.0 g, 46.3 %): 1H NMR (400 MHz, CDCI3) δ 7.79 (d, J= 8.0 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J= 7.6 Hz, 1H), 7.41 (s, 2H) 6.65 (d, J = 16.0 Hz, 1H), 6.49 (dd, J= 16.0, 8.0 Hz, 1H), 4.42 (q, J= 7.6 Hz, 2H), 4.15 (m, 1H), 1.42 (t, J= 7.6 Hz, 3H); ESIMS m/z 502.99 ([M-H]’); IR (thin film) 1730, 1202, 1120, 750 cm’1.
(£)-Ethyl 2-chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (Al63)
Cl O 1H NMR (400 MHz, CDCI3) δ 7.85 (d, J = 6.0 Hz, 1 H), 7.46 (d, J = 1.8 Hz, 2H), 7.34 (m, 1 H),
7.24 (m, 1H), 6.57 (d, J =16.2 Hz, 1 H), 6.45 (dd, J = 16.2, 7.2 Hz, 1 H), 4.43 (q, J = 7.2 Hz, 2H),
4.13 (m, 1H), 1.41 (t, J= 7.2 Hz, 3H); ESIMS m/z 455.0 ([M+H]+); IR (thin film) 1728, 1115, 817 cm’ (E)-Ethyl 2-fluoro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (A164)
1H NMR (400 MHz, CDCI3) δ 7.93 (t, J= 7.6 Hz, 1H), 7.34 (d, J= 5.6 Hz, 2H), 7.21 (d, J = 8.0 Hz, 1H), 7.16 (d, J= 11.6 Hz, 1H), 6.59 (d, J= 16.0 Hz, 1H), 6.49 (dd, J= 16.0, 7.6 Hz, 1H),
4.42 (q, J= 7.6 Hz, 2H), 4.13 (m, 1H), 1.41 (t, J= 7.6 Hz, 3H); ESIMS m/z 436.81 ([M-H]’); IR (thin film) 1725 cm’1.
(E)-Ethyl 2-bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI65)
Cl ο 1H NMR (400 MHz, CDCI3) δ 7.94 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.36 (m, 3H), 6.56 (d, J = 15.6 Hz, 1H), 6.44 (dd, J= 15.6, 8.0 Hz, 1H), 4.42 (q, J=6.8Hz, 2H), 4.10 (m, 1H), 1.42 (t, J =
6.8 Hz, 3H); ESIMS m/z 498.74 ([M-H]'); IR (thin film) 1726, 1114, 820, 623 cm’1.
(E)-Ethyl 2-methyl-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (Al66)
Cl O
The title compound was isolated as a brown semi-solid: 1H NMR (400 MHz, CDCI3) δ 7.90 (d, J = 8.8 Hz, 1 H), 7.34 (d, J = 6.0 Hz, 2H), 7.25 (d, J = 7.2 Hz, 2H), 6.59 (d, J = 16.0 Hz, 1 H), 6.42 (dd, J = 16.0 Hz, 8.0 Hz, 1H), 4.38 (q, J= 7.2 Hz, 2H), 4.19 (m, 1H), 2.63 (s, 3H), 1.41 (t, J=7.2 Hz, 3H); ESIMS m/z 432.90 ([M-H]’); IR (thin film) 1715 cm’1.
(E)-Methyl 2-methoxy-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI67)
Cl O 1H NMR (400 MHz, CDCI3) δ 7.80 (d, J = 8.4 Hz, 1 H), 7.35 (d, J = 6.0 Hz, 2H), 7.03 (d, J =
1.2 Hz, 1H), 6.92 (s, 1H), 6.59 (d, J = 15.6 Hz, 1H), 6.42 (dd, J= 15.6, 8.0 Hz, 1H), 4.13 (m, 1H), 3.93 (s, 3H), 3.88 (s, 3H); ESIMS m/z 437.29 ([M+H]+); IR (thin film) 1724 cm’1.
(E)-Ethyl 2-ethyl-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoate (AI68)
Cl o 1H NMR (400 MHz, CDCI3) δ 7.85 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 9.6 Hz, 2H), 7.26 (m,
1H), 7.24 (m, 1H), 6.60 (d, J= 15.6 Hz, 1H), 6.42 (dd, J = 15.6, 8.0 Hz, 1H), 4.38 (q, J = 7.2 Hz,
2H), 4.14 (m, 1H), 3.01 (q, J = 7.6 Hz 2H), 1.41 (t, J = 7.2 Hz, 3H), 1.26 (t, J =7.6 Hz, 3H); ESIMS m/z 447.05 ([M-H]); IR (thin film) 1715, 1115, 817 cm’1.
Example 11: Préparation of (E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2methylbenzoic acid (AI32)
To a stirred solution of (E)-ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2methylbenzoate (1.7 g, 4.0 mmol) in 1,4-dioxane (10 mL) was added 11 N HCl (30 mL), and the reaction mixture was heated at 100 °C for 48 h. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was diluted with H2O and extracted with chloroform (CHCI3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure, and the crude compound was washed with n-hexane to afford the title compound as a white solid (0.7 g, 50%): mp 142-143 °C; 1H NMR (400 MHz, DMSO-d6) □ 12.62 (br s, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.66 (s, 3H), 7.52-7.44 (m, 2H), 6.89 (dd, J = 16.0, 8.0 Hz, 1 H), 6.78-6.74 (d, J= 16.0 Hz, 1H), 4.84 (m, 1H), 2.50 (s, 3H); ESIMS m/z 387.05 ([M-H]’); IR (thin film) 3448, 1701, 1109, 777 cm’1.
The following compounds were made in accordance with the procedures disclosed in Example 11.
(E)-2-Methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI26)
Cl o
The product was isolated as a pale brown gummy liquid (1 g, 46%); 1H NMR (400 MHz, CDCI3) □ 7.97 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.65 (m, 1H), 7.41 (s, 2H), 6.68 (d, J = 16.0 Hz, 1H), 6.53 (dd, J= 16.0, 8.0 Hz, 1H), 4.16 (m, 1H), 2.50 (s, 3H); ESIMS m/z 422.67 ([M-H]’). (E)-2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1 -enyl)benzoic acid (AI27)
The product was isolated as an off-white semi-solid (1 g, 45%): 1H NMR (400 MHz, CDCI3) □ 7.99 (d, J = 8.4 Hz, 1 H), 7.50 (m, 1 H), 7.40 (s, 1 H), 7.36 (m, 2H), 6.59 (d, J = 15.6 Hz, 1 H), 6.48 (dd, J = 15.6, 7.6 Hz, 1H), 4.14 (m, 1H); ESIMS m/z 442.72 ([M-H]’); IR (thin film) 3472, 1704, 1113, 808 cm’1.
(£)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1 -enyl)benzoic acid (AI28)
The product was isolated as a brown solid (1 g, 45%): mp 70-71 °C; 1H NMR (400 MHz,
CDCI3) □ 7.99 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.40 (m, 3H), 6.58 (d, J= 16.0 Hz, 1H), 6.48 (dd, J = 16.0, 8.0 Hz, 1H), 4.14 (m, 1H); ESIMS m/z 484.75 ([M-H]’); IR (thin film) 3468, 1700 cm’1.
(E)-2-Cyano-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI29)
The product was isolated as an off-white solid (500 mg, 45%): mp 100-101 °C; 1H NMR (400 MHz, CDCI3) □ 7.90 (s, 1 H), 7.85 (d, J = 7.6 Hz, 1 H), 7.72 (d, J = 8.0 Hz, 1 H), 7.65 (br s, 1 H),
7.42 (s, 2H), 6.73 (d, J= 16.0 Hz, 1H), 6.58 (dd, J= 16.0, 8.0 Hz, 1H), 4.19 (m, 1H); ESIMS m/z 431.93 ([M-H]’).
£)-4-(3-(3,4-Dichlorophenyl)-4,4,4-trifluorobut-1 -enyl)-2-methylbenzoic acid (AI30)
The product was isolated as a pale brown liquid (500 mg, 46%): 1H NMR (400 MHz, CDCI3) □ 8.03 (m, 1H), 7.49 (m, 2H), 7.29 (m, 1H), 7.22 (m, 2H), 6.73 (d, J = 16.0 Hz, 1H), 6.58 (dd, J =
16.0, 7.8 Hz, 1H), 4.16 (m, 1H), 2.64 (s, 3H); ESIMS m/z 386.84 ([M-H]); IR (thin film) 3428, 1690, 1113, 780 cm’1.
(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid (AI31)
The product was isolated as a white solid (500 mg, 50%): mp 91-93°C; 1H NMR (400 MHz, CDCI3) □ 8.02 (d, J= 8.0 Hz, 1H), 7.35 (d, J= 5.6 Hz, 1H), 7.30 (m, 3H), 6.61 (d, J= 16.0 Hz, 1H),
6.48 (dd, J= 16.0, 8.0 Hz, 1H), 4.13 (m, 1H), 2.65 (s, 3H); ESIMS m/z 406.87 ([M-H] ).
(E)-4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzoic acid (AI33)
The product was isolated as a white solid (500 mg, 45%): mp 142-143 °C; 1H NMR (400
MHz, CDCh) □ 7.97 (d, J= 8.0 Hz, 1H), 7.77 (s, 1H), 7.65 (m, 1H), 7.41 (s, 2H), 6.68 (d, J = 16.0
Hz, 1H), 6.53 (dd, J= 16.0, 8.0 Hz, 1H), 4.16 (m, 1H); ESIMS m/z 474.87 ([M-H]’).
(E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (AI69)
The title compound was isolated as a brown solid (0.8 g, 28%): 1H NMR (400 MHz, CDCI3) δ 13.42 (br, 1H), 7.98 (d, J= 1.5 Hz, 1H), 7.94 (m, 2H), 7.75 (d, J= 8.1 Hz, 1H), 7.65 (m, 1H), 7.06 (dd, J = 15.9, 9.0 Hz, 1 H), 6.80 (d, J = 15.9 Hz, 1 H), 4.91 (m, 1 H); ESIMS m/z 484.75 ([M-H] ); IR (thin film) 3469, 1700 cm·1.
(E)-2-Bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluo robut-1-enyl)benzoic acid (AI70)
Cl
F
OH
Cl
O
The title compound was isolated as a yellow liquid (0.3 g, crude): 1H NMR (300 MHz, CDCI3) δ 7.79 (d, J= 8.1 Hz, 1H), 7.67 (s, 1H), 7.34 (m, 3H), 6.56 (d, J = 15.9 Hz, 1H), 6.45 (dd, J = 15.9, 7.6 Hz, 1H), 4.43 (m, 1H); ESIMS m/z 471.0 ([M-H]').
(£)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-ethyIbenzoic acid (AI71)
CF
Cl
OH
Cl
The title compound was isolated as a brown gummy material (0.2 g, crude): 1H NMR (300 MHz, DMSO-d6) δ 12.5 (br, 1H), 7.85 (d, J= 6.3 Hz, 2H), 7.75 (d, J= 8.1 Hz, 1H), 7.52 (m, 2H), 6.96 (dd, J = 8.7, 8.7 Hz, 1 H), 6.78 (d, J = 15.6 Hz, 1 H), 4.80 (m, 1 H), 4.06 (q, J = 7.2 Hz, 2H), 1.33 (t, J= 7.2 Hz, 3H); ESIMS m/z 419.06 ([M-H]’).
(£)-2-Chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoic acid (AI72)
CF
Cl
OH
Cl
The title compound was isolated as a yellow liquid (0.7 g, 95%): 1H NMR (300 MHz, CDCI3) δ 7.85 (d, J= 6.0 Hz, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.41 (s, 3H), 6.57 (d, J = 16.0 Hz, 1H), 6.45 (dd, J= 16.0, 8.0 Hz, 1H), 4.16 (m, 1H); ESIMS m/z 455.0 ([M+H]+); IR (thin film) 1728, 1115, 817 cm'1.
(£)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid (AI73)
CF
Cl
OH
Cl
The title compound was isolated as a light brown gummy material (0.7 g, 38%): mp 91-93 °C; 1H NMR (400 MHz, CDCI3) δ 8.02 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 5.6 Hz, 1H), 7.30 (m, 3H),
6.10 (d, J = 16.0 Hz, 1H), 6.46 (dd, J= 16.0, 8.0 Hz, 1H), 4.03 (m, 1H), 2.65 (s, 3H); ESIMS m/z
406.87 ([M-H]’).
(£)-4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluorobenzoic acid (AI74)
ÇF3
Cl O
The title compound was isolated as a light brown liquid (0.3 g, crude): ESIMS m/z 393.15 ([M-H]-).
(E)-2-Bromo-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)benzoic acid (AI75)
ÇF3
Br
Cl O
The title compound was isolated as a light brown liquid (0.35 g, crude): ESIMS m/z 451.91 ([M-H]').
Prophetically, compounds AI34, AI36-AI41, AI44-AI45 (Table 1) could be made in accordance with the procedures disclosed in Example 10, or Examples 10 and 11.
Example 12: Préparation of (£)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylA/-(2,2,2-trifluoroethyl)benzamide (AC6)
To a stirred solution of (£)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2methylbenzoic acid in DMF was added 2,2,2-trifluoroethylamine, 1-hydroxybenzotriazole hydrate (HOBt«H2O), /V-(3-dimethylaminopropyl)-Af-ethylcarbodiimide hydrochloride (EDOHCI) and N,Ndiisopropylethylamine (DIEA), and the reaction mixture was stirred at 25 °C for 18 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with hexane:EtOAc afforded a white semisolid (110 mg, 50%): 1H NMR (400 MHz, CDCI3) 7.40 (m, 2H), 7.26 (m, 3H), 6.56 (d, J = 16.0 Hz, 1H), 6.48 (dd, J= 16.0, 8.0 Hz, 1H), 5.82 (brs, 1H), 4.08 (m, 3H), 2.52 (s, 3H); ESIMS m/z 468.40 ([Μ-H] ); IR (thin film) 1657, 1113, 804 cm'1.
Compounds AC7-AC38, AC40-AC58, AC110-AC112, AC117, and AC118 (Table 1) were made in accordance with the procedures disclosed in Example 12.
Example 13: Préparation of 4-((E)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methyl/V-((pyrimidin-5-yl)methyl)benzamide (AC39)
Cl O
To a stirred solution of (pyrimidin-5-yl)methanamine (0.15 g, 1.43 mmol) in CH2CI2 (10 mL) was added drop wise trimethylaluminum (2 M solution in toluene; 0.71 mL, 1.43 mmol), and the reaction mixture was stirred at 25 °C for 30 min. A solution of ethyl 4-((E)-3-(3,5-dichlorophenyl)-
4,4,4-trifluorobut-1-enyl)-2-methylbenzoate (0.3 g, 0.71 mmol) in CH2CI2 was added drop wise to the reaction mixture at 25 °C. The reaction mixture was stirred at reflux for 18 h, cooled to 25 °C, quenched with 0.5 N HCl solution (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 40% EtOAc in n-hexane) to afford the title compound (0.18 g, 55%): mp 141-144 °C;
1H (400 MHz, CDCI3) δ 9.19 (s, 1H), 8.79 (s, 2H), 7.37 (m, 2H), 7.23 (m, 2H),7.21 (m, 1H), 6.57 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 7.6 Hz1H), 6.21 (m, 1H), 4.65 (s, 2H), 4.11 (m, 1H), 2.46 (s, 3H); ESIMS m/z 477.83 ([M-H]’).
Example 14: Préparation of (E)-2-chloro-W-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4(4j4)4-trifluoro-3-(3,4,5-trichlorophenyi)but-1-en-1-yl)benzamide (AC64)
ÇF3 TT XXAa Cl O H
To a stirred solution of glycine amide (0.15 g, 0.58 mmol) in CH2CI2 (5 mL) was added trimethylaluminum (2 M solution in toluene; 1.45 mL, 2.91 mmol) dropwise, and the reaction mixture was stirred at 28 °C for 30 min. A solution of (E)-ethyl 2-chloro-4-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-enyl)benzoate (0.3 g, 0.58 mmol) in ΟΗ2ΟΙ2 (5 mL) was added drop wise to the reaction mixture at 28 °C. The reaction mixture was stirred at reflux for 18 h, cooled to 25 °C, quenched with 1N HCl solution (50 mL) and extracted with CH2CI2 (2 x 50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 40% EtOAc in n-hexane) to afford the title compound as yellow solid (0.15 g, 50%): mp 83-85 °C; 1H NMR (400 MHz, CDCI3) δ 7.72 (d, J = 8.0 Hz, 1 H), 7.44 (s, 1 H), 7.40 (s, 2H), 7.36 (d, J = 6.8 Hz, 1 H), 7.05 (t, J = 5.2 Hz, 1 H), 6.70 (t, J = 5.2 Hz, 1 H), 6.57 (d, J = 15.6 Hz, 1 H), 6.44 (dd, J = 15.6, 8.0 Hz, 1H), 4.23 (d, J= 5.6 Hz, 2H), 4.15 (m, 1H), 4.01 (m, 2H); ESIMS m/z 580.72 ([M-H]').
Compounds AC59-AC75 (Table 1) were made in accordance with the procedures disclosed in Example 14.
Example 15: Préparation of(E)-2-bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-
1-en-1-yl)-A/-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide (AC79)
To a stirred solution of (E)-2-bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1enyl)benzoic acid (300 mg, 0.638 mmol) in DCM (5.0 mL) was added 2-amino-A/-(2,2,2trifluoroethyl)acetamide (172. mg, 0.638 mmol) followed by benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (364.5 mg, 0.701 mmol) and DIPEA (0.32 mL, 1.914 mmol), and the résultant reaction mixture was stirred at RT for 18 h. The reaction mixture was diluted with water and extracted with DCM. The combined DCM layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 40% ethyl acetate/ petroleum ether) afforded the title compound as an off-white solid (121 mg, 31 %): 1H NMR (400 MHz, CDCI3) δ 8.69 (t, J = 6.0 Hz, 1 H), 8.58 (t, J = 6.0 Hz, 1 H), 7.92 (s, 1 H), 7.87 (d, J = 6.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1 H),
7.45 (d, J = 8.4 Hz, 1 H), 7.0 (m, 1 H), 6.76 (d, J = 15.6 Hz, 1 H), 4.83 (t, J = 8.0 Hz, 1 H), 3.98 (m, 4H); ESIMS m/z 610.97 ([M+H]+); IR (thin film) 3303, 1658, 1166, 817 cm’1.
Compounds AC76-AC80, AC96-AC102, and AC113 (Table 1) were made in accordance with the procedures disclosed in Example 15.
Example 16: Préparation of (£)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yI)-A/-(1,1dioxidothietan-3-yl)-2-fluorobenzamide (AC83)
To a stirred solution of (£)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluoro-/V(thietan-3-yl)benzamide (100 mg, 0.2159 mmol) in acetone/ water (1:1,5.0 mL) was added oxone (266 mg, 0.4319 mmol) and the résultant reaction mixture was stirred at RT for 4h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/ pet ether) afforded the title compound as a off white solid (70.0 mg, 66 %): 1H NMR (400 MHz, CDCI3) δ 8.07 (t, J= 8.4 Hz, 1H), 7.39 (t, J= 1.6 Hz, 1H), 7.31 (d, J= 1.2 Hz, 1H), 7.26 (m, 2H), 7.23 (m, 2H), 7.19 (d, J =
1.6 Hz, 1 H), 6.60 (d, J = 16.8 Hz, 1 H), 6.49 (dd, J = 16.8, 7.6 Hz, 1 H), 4.90 (m, 1 H), 4.64 (m, 2H),
4.14 (m, 2H),; ESIMS m/z 493.83 ([M-H] ); IR (thin film) 1527, 1113, 801, 1167, 1321 cm’1.
Compounds AC81-AC87 (Table 1) were made in accordance with the procedures disclosed in Example 16.
Example 17: Préparation of (E)-A/-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-4-(3-(3,5dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-methylbenzamide (AC89)
Cl O
A solution of (E)-/V-(2-(2-(cyclopropanecarbonyl)hydrazinyl)-2-oxoethyl)-4-(3-(3,5dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzamide (200 mg, 0.379 mmol) in POCI3 (2.0 mL) was stirred at RT for 10 min, then the résultant reaction mixture was heated to 50 °C for 1h. The reaction mixture was quenched with ice water at 0 °C and extracted with ethyl acetate. The combined ethyl acetate layer was washed with saturated NaHCO3 solution and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 50% ethyl acetate/ pet ether) afforded the title compound as a light brown gummy material (70.0 mg, 36 %): 1H NMR (400 MHz, CDCI3) δ 7.43 (m,
2H), 7.27 (m, 2H), 7.23 (m, 2H), 6.58 (d, J= 16.0 Hz, 1H), 6.41 (dd, J= 16.0, 7.6 Hz, 1H), 4.79 (d, J= 5.6 Hz, 2H), 4.14 (m, 1H), 2.48 (s, 3H), 2.18 (m, 1H), 1.16 (m, 4H); ESIMS m/z 509.89 ([M+H]+); IR (thin film) 1666, 1166, 1112, 800 cm1.
Example 18: Préparation of (E)-2-bromo-/V-(2-thioxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzothioamide (AC90)
ÇF3
ΪΎ II I H H d'y
Cl s H
To a stirred solution of (E)-2-bromo-/V-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (400 mg, 0.638 mmol) in 5 mL of THF at RT was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson’s reagent) (336 mg, 0.830 mmol) in one portion. The resulting reaction mixture was stirred for 18 h. TLC showed the reaction was not complété, therefore additional Lawesson’s reagent (168 mg, 0.415 mmol) was added and reaction stirred for 48 h. After the reaction was deemed complété by TLC, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 230-400 mesh; eluting with 20% EtOAc in hexanes) afforded the title compound as a yellow glassy oil (188 mg, 44.7%):
1H NMR (400 MHz, CDCI3) δ 8.34 (m, 1H), 8.27 (m, 1H), 7.60 (d, J= 1.6 Hz, 1H), 7.49 (d, J =8.0 Hz, 2H), 7.40 (s, 2H), 7.36 (dd, J = 8.2, 1.7 Hz, 1 H), 6.53 (d, J = 16.0 Hz, 1 H), 6.38 (dd, J = 15.9,
7.9 Hz, 1 H), 4.89 (d, J = 8.4, 5.5 Hz, 2H), 4.48 (qd, J = 9.0, 6.0 Hz, 2H), 4.11 (m, 1 H); ESIMS m/z
656.9 ([M-H]’).
Example 19: Préparation of (E)-2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-
1-yl)phenylthioamido)-/V-(2,2,2-trifluoroethyl)acetamide (AC91)
To a stirred solution of(E)-2-bromo-/V-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (400 mg, 0.638mmol) in 5 mL of THF at RT was added Lawesson’s reagent (64.5 mg, 0.160 mmol) in one portion. The resulting reaction mixture was stirred for 18 h, after which time, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 230-400 mesh; eluting with 20% EtOAc in hexanes) afforded the title compounds as a yellow oil (18.5 mg, 4.51%): 1H NMR (400 MHz, CDCI3) δ 8.18 (t, J = 5.0 Hz, 1 H), 7.58 (d, J = 1.6 Hz, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.40 (s, 2H), 7.34 (dd, J = 8.1, 1.6 Hz, 1H), 6.52 (m, 2H), 6.37 (dd, J = 15.9, 7.9 Hz, 1H), 4.54 (d, J=4.9Hz, 2H), 4.12 (m, 1H), 3.99 (qd, J= 8.9, 6.5 Hz, 2H); ESIMS m/z 640.9 ([M-H]’).
The following compound was made in accordance with the procedures disclosed in Example 19.
(E)-2-bromo-N-(2-thioxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-en-1-yl)benzamide (AC92)
The product was isolated as a colorless oil (17.9 mg, 4.36%):
1H NMR (400 MHz, CDCI3) δ 9.16 (d, J= 6.1 Hz, 1H), 7.65 (d, J= 1.6 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1 H), 7.41 (m, 3H), 7.21 (t, J = 5.6 Hz, 1 H), 6.55 (d, J = 15.9 Hz, 1 H), 6.41 (dd, J = 15.9, 7.8 Hz, 1H), 4.59 (d, J= 5.6 Hz, 2H), 4.45 (qd, J = 9.0, 6.0 Hz, 2H), 4.12 (q, J= 7.2 Hz, 1H); ESIMS m/z
640.9 ([M-H]').
Example 106: Préparation of ethyl (Z) 2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-
1-en-1-yl)benzoate (AI76)
Cl
The title compound was made in accordance with the procedure disclosed in Example 88 and was isolated as a yellow viscous oil (416 mg, 23%):
1H NMR (400 MHz, CDCI3) δ 7.80 (d, J = 8.0 Hz, 1 H), 7.40 (d, J = 1.7 Hz, 1 H), 7.35 (s, 2H), 7.12 (dd, J= 8.0, 1.7 Hz, 1H), 6.86 (d, J= 11.4 Hz, 1H), 6.23-5.91 (m, 1H), 4.42 (q, J= 7.1 Hz, 2H), 4.33 - 4.10 (m, 1 H), 1.42 (t, J = 7.2 Hz, 3H); 19F NMR (376 MHz, CDCI3) δ -69.34 (d, J = 8.3 Hz); EIMS m/z 514.10 ([M]’); IR (thin film) 2983, 1727, 1247, 1204, 1116 cm·1.
Example 107 : Préparation of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-
1-yl)benzoic acid (AI77)
To a stirred solution of (Z)-ethyl 2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-
1-yl)benzoate (360 mg, 0.70 mmol) in CH3CN (1.0 mL) was added iodotrimethylsilane (0.28 mL, 2.8 mmol). The reaction mixture was heated to reflux for 20 h, allowed to cool to ambient température and partitioned between CH2CI2and aq. 10 % Na2S2O3. Organic phase was washed once with aq. 10% Na2S2O3 and dried over MgSO4 and concentrated in vacuo. Passing the material through a silica plug with 10% EtOAc in hexanes, followed by 20% MeOH in CH2CI2 ) as the eluting solvents afforded the title compound as a yellow foam (143 mg, 42%): mp 54-64°C; 1H NMR (400 MHz, CDCI3) δ 11.36 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.30 (s, 2H), 7.14 (d, J= 7.9 Hz, 1H),
6.85 (d, J = 11.4 Hz, 1 H), 6.15 (t, J = 10.9 Hz, 1 H), 4.36 - 4.09 (m, 1 H);19F NMR (376 MHz, CDCI3) δ -69.30.
Example 108 : Préparation of (Z)-2-bromo-A/-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-4- (4)4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC95)
Cl
To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added DCI (82 mg, 0.51 mmol). The mixture was heated in a 50 °C oil bath for 1.5 h, treated with 2-amino-/V-(2,2,2trifluoroethyl)acetamide hydrochloride (109 mg, .057 mmol) and the resuiting mixture heated to reflux for 8 h. After cooling to ambient température, the mixture was taken up in Et2O and washed twice with aq. 5% NaHSO4 (2X) and once with sat. NaCI (1X). After dying over MgSO4, concentration in vacuo and purification by medium pressure chromatography on silica with EtOAc/Hexanes as the eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61 °C: 1H NMR (400 MHz, CDCI3) δ 7.58 (d, J =7.9 Hz, 1H), 7.44 - 7.29 (m, 3H), 7.14 (dd, J = 7.9, 1.6 Hz, 1 H), 6.86 (d, J = 11.4 Hz, 1 H), 6.76 (t, J = 5.9 Hz, 1 H), 6.59 (br s, 1 H), 6.21 - 6.04 (m, 1 H), 4.23 (d, J = 5.5 Hz, 1 H), 3.98 (qd, J = 9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDCI3) δ -69.31, 72.3; EIMS m/z 626.9 ([M+1 ]+).
Example 109a: Préparation of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-en-1-yl)benzamide (AC114)
(E)-tert-Butyl 4-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1enyl)benzamido)piperidine-1-carboxylate (0.75 g, 1.11 mmol) was added to dioxane HCl (10 mL) at 0 °C and was stirred for 18 h. The reaction mixture was concentrated under reduced pressure and triturated with diethylether to afford the compound as a light brown solid (0.6 g, 88%).
Example 109b: Préparation of (E)-A/-(1-acetylpiperidin-4-yl)-2-bromo-4-(4,4,4-trifluoro-3(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC103)
O
To a stirred solution of (E)-2-bromo-/V-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol) in DCM (10.0 mL) was added triethylamine (0.046 mL, 0.35 mmol) and stirred for 10 min. Then acetyl chloride (0.014, 0.18 mmol) was added and stirred for 16 h at RT. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution and brine solution. The combined DCM layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was washed with 5% diethyl ether / n-pentane to afford the title compound as a white solid (0.054 g, 50%).
Example 110: Préparation of (E^-bromo-A-ÎM^-trifluoro-S-fSAS-trichlorophenyObut-l-en- l-ylF/V-fl-fS.S.S-trifluoropropanoyOpiperidin^-yObenzamide (AC104)
To a stirred solution of 3,3,3-trifluoropropanoic acid (0.02g, 0.16 mmol) in DCM (10.0 mL), (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol), PYBOP (0.09 g, 0.17 mmol), and DIPEA (0.06 g, 0.48 mmol) were added at RT. The reaction mixture was stirred at RT for 5 h. The reaction mixture was diluted with DCM. The combined DCM layer was washed with 3N HCl and saturated NaHCO3 solution, the separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% methanol in DCM) to afford the title compound as a off white gummy material (0.035 g, 29.%).
Example 111: Préparation of(E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-
1-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide (AC105)
To a stirred solution of (E)-2-bromo-/V-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol) in THF (5.0 mL) was added triethylamine (0.06 mL, 0.64 mmol) and stirred for 10 min. Then 2,2,2-trifluoroethyl triflluoromethanesulfonate (0.03, 0.16 mmol) was added and stirred for 16 h at RT. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a brown solid (0.05 g, 44%).
Example 112: Préparation of (E)-2-bromo-/V-(1-methylpiperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5· trichlorophenyl)but-1-en-1-yl)benzamide (AC106)
A solution of (E)-2-bromo-A/-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1enyl)benzamide (0.1 g, 0.16 mmol), formaldéhyde (30% in water) (0.1 mL, 0.16 mmol) and acetic acid (0.01 mL) in methanol (5.0 mL) was stirred at RT for 30 min. After that NaBH3CN (0.01 g, 0.16 mmol) was added at 0°C and the reaction was stirred for 8 h at RT. The solvent was removed under reduced pressure to obtain residue which was diluted with ethyl acetate and washed with saturated aq. NaHCO3 solution and brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue, which was triturated with diethyl ether/ pentane to afford the title compound as a pale yellow gummy material (0.06 g, 59%).
Example 113: Préparation of((E)-2-bromo-/V-(1-(cyanomethyl)piperidin-4-yl)-4-(4,4,4-trifluoro-
3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC107)
To a stirred solution of (E)-2-bromo-A/-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-enyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added triethylamine (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2bromoacetonitrile (0.07, 0.65 mmol) was added and the reaction was stirred for 8 h at RT. The reaction mixture was diluted with ethyl acetate and washed with saturated brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (0.125 g, 46.8%).
Example 114: Préparation of (E)-2-bromo-A/-(1-(oxetan-3-yl)piperidin-4-yl)-4-(4,4,4-trifluoro-3(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC108)
A solution of (E)-2-bromo-/V-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1enyl)benzamide (0.2 g, 0.35 mmol), oxetan-3-one (0.027 g, 0.38 mmol) and acetic acid (0.01 mL) in methanol (5.0 mL) was stirred at RT for 30 min. After that NaBH3CN (0.022 g, 0.35 mmol) was added at 0 °C slowly lot wise over the period of 10 min and the reaction was stirred for 8 h at RT. The solvent was removed under reduced pressure to obtain a residue which was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a residue, which was triturated with diethyl ether/ pentane to afford the title compound as an off-white solid (0.05 g, 23%).
Example 115: Préparation of (E)-2-bromo-/V-(1-(2-hydroxyethyl)piperidin-4-yl)-4-(4,4,4trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzamide (AC109)
To a stirred solution of (E)-2-bromo-A/-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-enyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added triethylamine (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-chloroethanol (0.05, 0.65 mmol) was added and the reaction was stirred for 8 h at RT. The reaction mixture was diluted with ethyl acetate and washed with saturated brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (0.09 g, 34%).
Example 116: Préparation of(H)-2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1en-1-yl)benzamido)acetic acid (AI78)
Το a stirred solution of (E)-tert-butyl 2-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-enyl)benzamido)acetate (440 mg, 0.734 mmol) in DCM (36.0 ml), was added TFA (4.0 mL) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure to obtain residue which was washed with n-pentane to afford the title compound as an off-white solid (310 mg, 78%): 1H NMR (400 MHz, CDCI3) δ 13.0 (s, 1H),
8.75 (t, J = 5.7 Hz, 1 H), 7.93 (m, 2H), 7.62 (d, J = 7.5 Hz, 1 H), 7.40 (d, J = 8.1 Hz, 1 H), 6.96 (dd, J = 15.3, 9.3 Hz, 1 H), 6.78 (d, J = 15.3 Hz, 1 H), 4.83 (m, 1 H), 3.90 (d, J = 5.7 Hz, 2H); ESIMS m/z 543.61 ([M+H]+); IR (thin film) 3429, 1635, 1114, 772 cm'1.
Example 117: Préparation of (E)-/V-((6-chloropyridin-3-yl)methyl)-4-(3-(3,5-dichlorophenyl)-
4,4,4-trifluorobut-1-en-1-yl)-2-methylbenzothioamide (AC115)
To the stirred solution of (E)-A/-((6-chloropyridin-3-yl)methyl)-4-(3-(3,5-dichlorophenyl)-4,4,4trifluorobut-1-enyl)-2-methylbenzamide (0.06 g, 0.117 mmol) in toluene (3 mL) was added Lawesson’s reagent (0.14 g, 0.351 mmol) and the reaction was irradiated at 100 C for 1 h, then cooled to RT and concentrated under reduced pressure to provide crude compound. The crude product was purified by préparative HPLC to afford the product as yellow color solid (0.03 g, 49%).
Example 118: Préparation of (£)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1 -en-1yl)-A/-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-2-(trifluoromethoxy)benzamide (AC116)
Step 1. 2-(Trifluoromethoxy)-4-vinylbenzoic acid (AI79): To a stirred solution of 4-bromo-
2-(trifluoromethoxy)benzoic acid (1 g, 3.67 mmol) in DMSO (20 mL) was added potassium vinyltrifluoroborate (1.47 g, 11.02 mmol) and potassium carbonate (1.52 g, 11.02 mmol). The reaction mixture was degassed with argon for 30 min.
Bistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride (0.13 g, 0.18 mmol) was added and the reaction mixture was heated to 80 °C for 1 h. The reaction mixture was diluted with water (100mL), extracted with ethyl acetate (2 x 50 mL), washed with brine, and dried over Na2SO4. Concentration under reduced pressure furnished the crude compound which was purified by flash column chromatography to afford the product as pale yellow gummy material (0.4 g, 47%); 1H NMR (400 MHz, CDCI3) δ 8.05 (d, J = 8.1 Hz, 1 H), 7.44 (d, J = 1.8 Hz, 1 H), 7.35 (s, 1 H), 6.78 (dd, J =17.4.1, 11.1 Hz, 1H), 5.92 (d, J= 17.4 Hz, 1H), 5.51 (d, J= 10.8 Hz, 1H); ESIMS m/z 232.97 ([M+H]+).
Step 2. (£)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2(trifluoromethoxy)benzoic acid (AI80): To a stirred solution of 2-(trifluoromethoxy)-4-vinylbenzoic acid (0.356 g, 1.53 mmol) in 1N methyl pyrrolidine (5.0 mL) was added 1-(1-bromo-2,2,2trifluoroethyl)-3,5-dichloro 4-fluorobenzene (1.0 g, 3.07 mmol), copper(l) chloride (CuCI; 0.03 g, 0.307 mmol) and 2,2 bipyridyl (0.095 g, 0.614 mmol). The reaction mixture was stirred at 150 °C for 1 h. After the reaction was complété by TLC, the reaction mixture was diluted with water (1 OOmL) and extracted with ethyl acetate (2X 50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the crude compound which was purified by flash column chromatography to afford the product as pale yellow gummy material (0.3 g, 21%): 1H NMR (400 MHz, CDCI3) δ 8.08 (d, J= 8.0 Hz, 1H), 7.45 (d, J= 1.6 Hz, 1H), 7.35 (s, 3H), 6.63 (d, J= 16.0 Hz, 1H), 6.50 (dd, J= 16.0, 8.0 Hz, 1H), 4.15 (m, 1H); ESIMS m/z 474.81 ([M-H]).
Step 3. (£)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-A/-(2-oxo-2(2,2,2-trifluoroethylamino)ethyl)-2-(trifluoromethoxy)benzamide (AC116) : A mixture of (£)-4(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-(trifluoromethoxy)benzoic acid (0.25 g, 0.52 mmol), 2-amino-/V-(2,2,2-trifluoroethyl)acetamide (0.158 g, 0.62 mmol), PyBOP (0.40 g, 0.78 mmol) and DIPEA (0.134 g, 1.04 mmol) in DCM (10.0 mL) were stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with DCM. The combined DCM layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 20% ethyl acetate/ pet ether) afforded the title compound as a pale yellow gummy material (0.15 g, 47 %).
Example 20: Préparation of 5-vinyl-2,3-dihydro-1H-inden-1-one (BI1)
Το a stirred solution of 5-bromo-2,3-dihydro-1H-inden-1-one (5 g, 23.7 mmol) in toluene were added vinylboronic anhydride pyridine complex (8.55 g, 35.54 mmol), Pd(PPh3)4 (0.1 g, 0.094 mmol), K2CO3 (22.88 g, 165.83 mmol). The résultant reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to 25 °C and filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with H2O and brine. The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (SiO2, 5% EtOAc in petroleum ether) afforded the title compound as a solid (1.8 g, 48%): 1H NMR (400 MHz, CDCI3) δ 7.74 (d, J = 7.2 Hz, 1 H), 7.49 (br s, 1 H), 7.44 (d, J = 7.2 Hz, 1 H), 6.82 (m, 1 H), 5.90 (d, J = 7.4 Hz, 1H), 5.42 (d, J = 6.4 Hz, 1H), 3.20 (m, 2H), 2.70 (m, 2H); ESIMS m/z 159.06 ([M+H]’).
The following compound was made in accordance with the procedures disclosed in Example 20.
6-Vinyl-3,4-dihydronaphthalen-1 (2H)-one (BI2)
O
The product was isolated as an off-white solid (5 g, 48%): 1H NMR (400 MHz, DMSO-d6) δ
7.85 (d, J = 8.4 Hz, 1 H), 7.48 (m, 2H), 6.82 (m, 1 H), 6.02 (d, J = 7.4 Hz, 1 H), 5.44 (d, J = 6.4 Hz, 1H), 2.95 (m, 2H), 2.60 (m, 2H), 2.00 (m, 2H); ESIMS m/z 173.14 ([M-H]’); IR (thin film) 1681 cm'1.
Example 21: Préparation of(E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3dihydro-1H-inden-1-one (BI3)
5-(1-Bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (4 g, 11.7 mmol), 5-vinyl-2,3-dihydro1/-/-inden-1-one (0.92 g, 5.8 mmol), CuCI (0.115 g, 1.171 mmol) and 2,2-bipyridyl (0.053 g, 0.34 mmol) in 1,2-dichlorobenzene (25 mL) were heated at 180 °C for 16 h. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 5% EtOAc in petroleum ether) to afford the title compound as a liquid (1.28 g, 25%): 1H NMR (400 MHz, CDCI3) δ 7.76 (d, J = 7.4 Hz, 1H), 7.52 (m, 3H), 6.68 (d, J = 7.4 Hz, 1H), 6.52 (m, 1H), 4.18 (m, 1H), 3.18 (m, 2H), 2.75 (m, 2H); ESIMS m/z 419.14 ([M+H] ); IR (thin film) 1708.94, 1113.60, 807.77 cm’1.
The following compound was made in accordance with the procedures disclosed in Example 21.
(E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2,3-dihydro-1H-inden-1-one (BI4)
CF
Cl
Cl
The product was isolated as a brown semi-solid (1.2 g, 16%): 1H NMR (400 MHz, CDCI3) δ
7.76 (d, J =7.4 Hz, 1 H), 7.54 (m, 3H), 7.30 (s, 1 H), 6.68 (d, J =7.4 Hz, 1 H), 6.52 (m, 1H), 4.18 (m, 1H), 3.18 (m, 2H), 2.75 (m, 2H); ESIMS m/z 400.84 ([M-H] ); IR (thin film) 815, 1113, 1709 cm’1.
(£-)-6-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyi)-3,4-dihydronaphthalen-1(2H)-one (BI5)
CF
Cl
The product was isolated as a pale yellow semi solid (1.2 g, 30%): 1H NMR (400 MHz, CDCI3) δ 8.20 (d, J = 8.0 Hz, 1H), 7.42 (s, 2H), 7.35 (m, 1H), 7.24 (m, 2H), 6.62 (d, J = 16 Hz, 1H),
6.46 (m, 1H), 4.18 (m, 1H), 2.95 (m, 2H), 2.65 (m, 2H), 2.19 (m, 2H); ESIMS m/z 432.94 ([M-H]’); IR (thin film) 1680, 1113, 808 cm’1.
Example 22: Préparation of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-
2-fluoro-2,3-dihydro-1H-inden-1-one (BI6)
CF
Cl
Cl
To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2,3dihydro-1H-inden-1-one (0.5 g, 1.24 mmol) in acetonitrile (20 mL), was added Selectfluor® (0.52 g,
1.48 mmol) and the reaction was heated to reflux température for 16 h. The reaction mixture was cooled to room température, concentrated under reduced pressure and diluted with DCM. The solution was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by flash column chromatography (SiO2,100-200 mesh; 15% EtOAc in petroleum ether) to afford the title compound as a pale yellow semi solid (0.1g, 24%): 1H NMR (400 MHz, CDCh) δ 7.80 (m, 1H), 7.48 (m, 2H),
7.32 (m, 2H), 6.65 (d, J= 16.0 Hz, 1H), 6.54 (dd, J = 16.0, 8.0 Hz, 1H), 5.38 (m, 1H), 4.18 (m, 1H), 3.62 (m, 1H), 3.32 (m, 1H); ESIMS m/z 419.06 ([M-H] ); IR (thin film) 1728, 1114, 817 cm’1.
Example 23: Préparation of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)· A/-(3,3,3-trifluoropropyl)-2,3-dihydro-1H-inden-1-amine (BC10)
f3c
To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2,3dihydro-1H-inden-1-one (0.15 g, 0.35 mmol) in DCE (10 mL), was added trifluoropropyl amine (0.048 g, 0.42 mmol) and sodium cyanoborohydride (0.055 g, 0.875 mmol) in cooling and the reaction mixture was stirred at room température for 16 h. The reaction mixture was diluted with DCE, was washed with water and brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the crude compound, which was purified by flash column chromatography (SiO2, 100-200 mesh; 10-15% EtOAc in petroleum ether) to afford the title compound as a colorless gummy material (0.042g, 24%): 1H NMR (400 MHz, CDCI3) δ 7.38-7.20 (m, 5H), 6.62 (d, J = 16.0 Hz, 1H), 6.34 (dd, J = 16.0, 8.0 Hz, 1H), 5.83 (br, 1H), 5.52 (m, 1H), 4.12 (m, 1 H), 3.02 (m, 3H), 2.82 (m, 1 H), 2.50 (m, 2H), 1.82 (m, 1 H), 1.42 (m, 1 H); ESIMS m/z 497.98 ([M-H] ); IR (thin film) 3027, 1654, 815 cm’1.
Example 24: Préparation of 6-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-3,4dihydronaphthalen-1(2H)-one oxime (BI5a)
To a stirred solution of ((E)-6-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-3,4dihydronaphthalen-1 (2H)-one (0.4 g, 0.92 mmol) in EtOH (50 mL) were added hydroxylamine hydrochloride (0.128 g, 1.85 mmol) and sodium acetate (0.23 g, 2.77 mmol), and the reaction mixture was heated at reflux for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H2O and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude compound, which was purified by flash column chromatography (SiO2, 100-200 mesh; 10-15% EtOAc in petroleum ether). The title compound was isolated as a solid (0.3 g, 73%): mp 155-158 °C; 1H NMR (400 MHz, CDCI3) δ 7.89 (d, J = 8.4 Hz, 1H), 7.41 (s, 2H), 7.24 (m, 1H), 7.17 (m, 1H), 6.57 (d, J=16Hz, 1H), 6.46 (dd, J=16.0, 8.0 Hz, 1H), 4.13 (m, 1H), 2.82 (m, 4H), 2.04 (m, 2H); ESIMS m/z 445.95 ([M-H]').
Example 25: Préparation of(E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3dihydro-1H-inden-1-amine (BI5b)
CF
Cl
Cl
To a stirred solution of (E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro1/7-inden-1-one (1 g, 2.39 mmol) in CH3OH (10 mL) were added ammonium acetate (1.84 g, 23.9 mmol) and sodium cyanoborohydride (NaCNBH3; 0.44 g, 7.17 mmol,) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H2O and extracted with EtOAc . The combined organic extracts were washed with H2O and saturated aqueous sodium bicarbonate (satd aq NaHCO3) solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound as a liquid (500 mg, crude): 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 2H), 7.40 (s, 1H), 7.30 (s, 2H), 6.71 (s, 2H), 4.78 (m, 1 H), 4.2 (m, 1 H), 2.80 (m, 1 H), 2.73 (m, 1 H), 1.60 (m, 2H); ESIMS m/z 419.02 ([M+H]+); IR (thin film) 2924, 1552, 1112, 807 cm'1.
The following compound was made in accordance with the procedures disclosed in Example 25.
(E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2,3-dihydro-1H-inden-1amine (BI7)
The product was isolated as a light brown gummy material, taken as such to the next step (0.15 g, crude compound): ESIMS m/z 401.97 ([M-H]‘).
(£)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-fluoro-2,3-dihydro-1Hinden-1-amine (BI8)
The product was isolated as a light brown gummy material, taken as such to the next step 10 (0.15 g, crude compound): ESIMS m/z 420.15 ([M-H] ).
(£)-6-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-1,2,3,4-tetrahydronaphthalen-1amine (BI9)
The product was isolated as a pale yellow liquid (500 mg crude).
Example 26: Préparation of (£)-1-methyl-3-(5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)-but-1enyl)-2,3-dihydro-1H-inden-1-yl)thiourea (BC1)
To a stirred solution of (5)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro1H-inden-1-amine (0.1 g, 0.23 mmol) in Et2O (5 mL) was added methylisothiocyanate (0.026 g, 0.35 mmol), and the mixture was stirred for 2 h at 25 °C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (SIO2, 20% EtOAc in petroleum ether). The title compound was isolated as a liquid (65 mg, 50%): 1H NMR (400 MHz, CDCI3) δ 7.39 (s, 2H), 7.25 - 7.18 (m, 3H), 6.58 (d, J = 16.0 Hz, 1H), 6.30 (dd, J = 16.0, 8.4 Hz, 1 H), 5.91 - 5.70 (br, 2H), 4.05 (m, 1 H), 3.05 - 2.80 (m, 6H), 2.70 (m, 1 H), 1.81 (m, 1 H); ESIMS m/z 492.17 ([M+H]+); IR (thin film) 3211, 1569,1113, 806 cm’1.
Compounds BC2 - BC3 in Table 1 were made in accordance with the procedures disclosed in Example 26.
Example 27: Préparation of (E)-3,3,3-trifluoro-/V-(5-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-enyl)-2,3-dihydro-1W-inden-1-yl)propanamide (BC4)
F
To a stirred solution of (5)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro1/-/-inden-1-amine (0.1 g, 0.23 mmol) in CH2CI2 (10 mL) were added trifluoropropionic acid (0.044 g, 0.34 mmol), EDC’HCI (0.038 g, 0.35 mmol), HOBt«H2O (0.07 g, 0.46 mmol) and DIEA (0.074 g, 0.57 mmol), and the reaction mixture was stirred for 16 h at 25 °C. The reaction mixture was diluted with CH2CI2 and washed with H2O. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO2, 15% EtOAc in petroleum ether) to afford the title compound as a liquid (65 mg, 65%): 1H NMR (400 MHz, CDCI3) δ 7.39 (s, 2H), 7.25-7.20 (m, 3H), 6.34 (d, J = 16.0 Hz, 1H), 6.30 (dd, J = 16.0, 8.0 Hz, 1H), 5.81 (br, 1H), 5.48 (m, 1H), 4.10 (m, 1H), 3.10 (m, 2H), 2.86-3.07 (m, 2H), 2.86 (m, 1H), 1.81 (m, 1H); ESIMS m/z 529.02 ([M+H]+); IR (thin film) 3283, 1652, 1241, 811 cm'1.
Compounds BC5 - BC9, BC11 in Table 1 were made in accordance with the procedures disclosed in Example 27.
Example 28: Préparation of tert-butyl 5-vinylindoline-1-carboxylate (BI10)
Step 1. 5-Bromo-indoline (BI11): To 5-Bromo-1 H-indole (2.5 g, 12.82 mmol) in acetic acid (10.0 mL), NaCNBH3 (2.38 g, 38.46 mmol) was added portion wise at 10 °C over the period of 20 min. After that the reaction mixture was stirred at RT for 3 h. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated NaHCO3, water and brine solution. The combined ether layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford title compound as a pale yellow semi-solid (1.8 g, 71%).
Step 2. tert-Butyl-5-bromoindoline-1-carboxylate (BI12): To a stirred solution of 5bromo-indoline (3.0 g , 15mmol) in acetonitrile (100 ml), was added DMAP (0.185 g , 1.522 mmol) and di-ferf-butyl dicarbonate (3.98 g, 18.3 mmol) and the reaction was stirred at RT for 16 h. The reaction mixture was concentrated on reduced pressure to obtain a residue which was diluted with diethyl ether and washed with water and brine solution (2X). The combined ether layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product as a off-white solid, which was used in the next step without further purification (3.0 g).
Step 3. fert-Butyl-5-vinylindoline-1-carboxylate (BI10): A stirred solution of tert-butyl-5bromoindoline-1-carboxylate (2.0 g, 6.73 mmol), potassium vinyl trifluoroborate (2.6 g, 20.20 mmol) and K2CO3(2.78 g, 20.2 mmol) in DMSO (50.0 mL) was degassed with argon for 20 min at RT. PdCI2(dppf) (0.49 g, 0.67mmol) was added at RT, then the reaction mixture was heated to 100 °C for 3 h. The reaction mixture was cooled to RT and filtered through a celite bed under vacuum and washed with diethyl ether. The reaction mixture was extracted with diethyl ether. The combined diethyl ether layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% ethyl acetate/ petroleum ether) to afford the title compound as a off-white solid (1.2 g, 73%): Mp 85.5 -88.6 °C; 1H NMR (400 MHz, CDCI3) δ 7.23 (m, 3H), 6.69 (dd, J= 17.4, 10.8 Hz, 1H), 5.64 (d, J= 10.5 Hz, 1H), 5.13 (d, J= 10.5 Hz, 1H), 4.00 (t, J= 9.0 Hz, 2H), 3.10 (t, J= 9.0 Hz, 2H), 1.55 (bs, 9H).
Example 29: Préparation of (E)-tert-butyl 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-
1-en-1-yl)indoline-1-carboxylate (BI13)
To a stirred solution of tert-butyl-5-vinylindoline-1-carboxylate (1.28 g, 5.23mmol) in1,2dichlorobenzene (10.0 mL), was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2fluorobenzene (3.4 g ,10 mmol), CuCI (103 mg, 1.05 mmol) and 2,2-bipyridyl (0.326 g, 2.092 mmol) and the résultant reaction mixture was degassed with argon for 30 min and heated to 150 °C for 1
h. The reaction mixture was cooled to RT and filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/ petroleum ether) to afford the title compound as a pale yellow gummy solid (0.3 g, 61%): 1H NMR (400 MHz, CDCI3) δ 7.34 (d, J = 6.0 Hz, 2H), 7.22 (s, 2H), 7.16 (d, J= 8.4 Hz, 1H), 6.52 (d, J =16.0 Hz, 1H), 6.21 (dd, J =16.0, 7.6 Hz, 1H), 4.07 (m, 3H), 3.10 (t, J =8.4 Hz, 2H), 1.55 (s, 9H); ESIMS m/z 433.79 ([M-H]); IR (thin film) 1168, 858 cm’1.
Example 30: Préparation of (£)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1yl)indolin-1-amine (BI14)
Step 1. (£)- 5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline (BI15)
To a stirred solution of (£)-iert-butyl-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1enyl)indoline-1-carboxylate (0.2 g, 0.4 mmol) in DCM (10.0 mL) was added TFA (0.6 mL) and the reaction was stirred at RT for 2 h. The reaction mixture was diluted with DCM, washed with saturated aq NaHCO3, water and brine solution. The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product as a light brown gummy material which was used in the next step without further purification (0.12 g): 1H NMR (400 MHz, CDCI3) δ 7.33 (d, J= 6.4 Hz, 2H), 7.21 (s, 1H), 7.02 (d, J= 8.0 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.49 (d, J= 15.6 Hz, 1H), 6.21(dd, J = 15.6, 8.4 Hz, 1H), 4.07 (m, 1H), 3.61 (t, J =
8.4 Hz, 2H), 3.05 (t, J= 8.4 Hz, 2H); ESIMS m/z 389.89 ([M+H]+); IR (thin film) 3385, 1112,816 cm’ 1
Step 2. 5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-nitrosoindoline (BI16): Το (E)- 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline (0.2 g, 0.5 mmol) in concentrated HCl (5.0 ml) at 5 °C, was added slowly NaNO2 in water and the reaction was allowed to stir at RT for 2 h. The reaction mixture was diluted with DCM, and the DCM layer washed with water and brine solution. The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product as a pale yellow solid that was used in the next step without further purification (0.2 g): 1H NMR (400 MHz, CDCI3) δ 7.33 (d, J = 8.4 Hz, 1H), 7.39 (m, 4H), 6.61 (d, J= 16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.4 Hz, 1H), 4.07 (m, 3H),
3.23 (t, J= 8.4 Hz, 2H); ESIMS m/z 418.82 ([M+H]+); IR (thin film) 1488, 1112, 860 cm’1.
Step 3. (£)-5-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)indolin-1amine (BI14): Το (E)- 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-nitrosoindoline (0.1 g, 0.2 mmol) in methanol(10.0 mL) was added zinc powder (77.5 mg) and NH4CI (36.9 mg, 0.69 mmol) in water (2.0 mL). The reaction mixture was stirred at RT for 3 h. The reaction mixture was diluted with DCM and the DCM layer was washed with water and brine solution. The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography (SiO2,100200 mesh; eluting with 2% ethyl acetate/ petroleum ether) to afford the title compound as a light brown gummy material (0.08 g): ESIMS m/z 404.86 ([M+H]+).
Example 31: Préparation of (E)-N-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1yl)indolin-1-yl)-3,3,3-trifluoropropanamide (BC12)
CF
Cl cf3
To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1enyl)indoline-1-amine (0.1 g, 0.247 mmol) in DCM (10.0 ml) was added 3,3,3-trifluoropropanoic acid (0.038 g, 0.297 mmol), PyBOP (0.192 g, 0.370 mmol) and DIEA (0.047 g, 0.370 mmol) and the reaction was stirred at RT for 18 h. The reaction mixture was diluted with DCM, and the separated DCM layer dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 20-25% ethyl acetate/ petroleum ether) to afford the title compound as a light brown gummy material (0.12 g, 33%): 1H NMR (400 MHz, CDCI3) δ 7.32, (d, J= 6.0 Hz, 2H) 7.28 (m, 1H), 7.20 (d,
J = 8.0, 1H), 7.14 (d, J= 8.8, 1H ), 6.70 (d, J= 8.0 Hz, 1H), 6.60 (m, 2H), 4.15 (m, 1H), 3.85 (m, 1H), 3.65 (m, 1H), 3.46 (m, 2H), 3.19 (m, 2H); ESIMS m/z 514.86 ([M+H]+); IR (thin film) 3428, 1112, 857 cm'1.
Example 32: Préparation of tert-butyl-5-vinyl-1H-indole-1-carboxylate (BI17)
Step 1. 5-Vinyl-1H-indole (BI18): A mixture of 5-bromo-1H-indole (2.5 g, 12.82 mmol), potassium vinyltrifluoroborate (2.57 g ,19.2 mmol), Cs2CO3 (12.53 g, 38.46 mmol) and triphenylphosphine (201 mg, 0.769 mmol) in THF/water (9:1, 75 ml) was degassed with argon for 20 min, then charged with PdCI2(45.3 mg,0.256 mmol). The reaction mixture was heated to reflux for 16 h, then cooled to RT, filtered through celite bed and washed with ethyl acetate. The filtrate was again extracted with ethyl acetate, and the combined organic layer washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/ petroleum ether) to afford the title compound as a light brown gummy material (1.5 g, 83%): 1H NMR (400 MHz, CDCI3) δ 8.20 (br, 1H), 7.68 (s, 1H), 7.45 (s, 2H), 7.21 (m, 1H), 6.90 (dd, J =16.0,10.8 Hz, 1H), 6.55 (m, 1H), 5.75 (d, J= 10.5 Hz, 1H), 5.21 (d, J= 10.5 Hz, 1H); ESIMS m/z 142.05 ([M-H]').
Step 2. iert-Butyl-5-vinyl-1H-indole-1-carboxylate (BI17): To a stirred solution of 5vinyl-1 H-indole (0.7 g, 4.89 mmol) in acetonitrile (20 ml) was added DMAP (59.65 mg, 0.489 mmol) and di-tert-butyl dicarbonate (1.38 g, 6.36 mmol), and the reaction was stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure to obtain a residue which was diluted with DCM and washed with water and brine solution. The combined DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/ petroleum ether) to afford the title compound as an off-white semi-solid (0.7 g, 59%): 1H NMR (400 MHz, CDCI3) δ 8.15 (d, J= 8.0 Hz, 1H), 7.60 (s, 2H), 7.30 (d, J= 8.4 Hz, 1H), 7.21 (m, 1H), 6.90 (dd, J =16.0, 10.8 Hz, 1H), 6.59 (s, 1H), 5.75 (d, J= 10.5 Hz, 1H), 5.21 (d, J=10.5 Hz, 1H), 1.65 (s, 9H); ESIMS m/z 242.10 ([M-H]’); IR (thin film) 1630 cm’1.
Example 33: Préparation of (E)-fert-butyl 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut1 -en-1 -yl)-1 H-indole-1 -carboxylate (BI19)
To a stirred solution of tert-butyl 5-vinyl-1/-/-indole-1-carboxylate (0.65 g, 2.67 mmol), in 1,2dichlorobenzene (10.0 mL) was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (1.74 g, 5.37 mmol), CuCI (53 mg, 0.537 mmol) and 2,2-bipyridyl (167 mg, 1.07 mmol). The résultant reaction mixture was degassed with argon for 30 min and heated to 150 °C for 2 h. The reaction mixture was cooled to RT and filtered, and the filtrate concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/ petroleum ether) to afford the title compound as a light brown gummy material (0.25 g, 10%): 1H NMR (400 MHz, CDCI3) δ 8.20 (d, J = 8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H), 6.69 (d, J= 16.0 Hz, 1H), 6.55 (d, J=10.5 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 1.65 (s, 9H); ESIMS m/z 485.91 ([M-H] ); IR (thin film) 1165, 854 cm'1.
Example 34: Préparation of (£)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)1H-indole (BI20)
To a stirred solution of (E)-tert-butyl 5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1enyl)-1H-indole-1-carboxylate (0.2 g, 0.40 mmol) in DCM (10.0 mL) was added TFA (70 mg, 0.61 mmol) and the reaction was stirred at RT for 2 h. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water and brine solution. The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound as a light brown solid (0.2 g, 97%): mp 132.9-138.8 °C; 1H NMR (400 MHz, CDCI3) δ 11.19 (br, 1H), 8.20 (d, J= 8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H), 6.69 (d, J= 16.0 Hz, 1H), 6.55 (d, J= 10.5 Hz, 1H), 6.36 (dd, J =16.0, 8.0 Hz, 1H), 4.82 (m, 1H); ESIMS m/z 387.98 ([M+Hf).
Example 35: Préparation of 4-nitrophenyl 2-((tert-butoxycarbonyl)amino)acetate (BI21)
To a stirred solution of 4-nitrophenol (1.0 g, 7.19 mmol) in DCM (20.0 mL) was added ΛΖ-Boc glycine (1.38 g, 7.91 mmol) and EDCHCI (2.05 g,10.785 mmol) and the reaction was stirred at RT for 24 h. The reaction mixture was diluted with DCM and washed with water and saturated brine solution. The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound as a light brown gummy material that was used in the next step without further purification (1.1 g): 1H NMR (400 MHz, CDCI3) δ 8.29 (d, J = 9.2 Hz, 2H),
7.33 (d, J= 8.8 Hz, 2H), 5.07 (br, 1H), 4.20 (s, 2H), 1.47 (s, 9H); ESIMS m/z 296.27 ([M+H]+).
Example 36: Préparation of (E)-tert-butyl (2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4trifluorobut-1-en-1-yl)-1H-indol-1-yl)-2-oxoethyl)carbamate (BI22)
To a stirred solution of (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1Hindole (0.1 g, 0.258 mmol) in acetonitrile (5.0 mL) was added 4-nitrophenyl 2-{tertbutoxycarbonylamino) acetate (0.114 g, 0.387 mmol), potassium fluoride (0.03 g, 0.516 mmol), 18crown-6-ether (0.075 g, 0.283 mmol) and DIEA (0.0332 g, 0.258 mmol) and the reaction was stirred at RT for 16 h. The reaction mixture was concentrated to obtain a residue which was diluted with DCM and washed with water and brine solution. The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude title compound as a light brown gummy material which was used in the next step without further purification (0.1 g): ESIMS m/z 545.23 ([M+H]+).
Example 37: Préparation of (E)-/V-(2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1en-1 -yl)-1 H-indol-1-yl)-2-oxoethyl)-3,3,3-trifluoropropanamide (BC13)
Step 1. (£)-2-amino-1 -(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1 -enyl)-1Hindol-1-yl)ethanone (BI23): To a stirred solution of (E)-tert-butyl 2-(5-(3-(3,5-dichloro-4fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1/7-indol-1-yl)-2-oxoethylcarbamate (0.05 g, 0.09 mmol) in DCM (5.0 mL) was added TFA (0.01 mL) and the reaction was stirred at RT for 16 h. The reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution, water and brine solution. The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude title compound which was used in the next step without further purification (50 mg).
Step 2. (Ê)-N-(2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-1Hindol-1-yl)-2-oxoethyl)-3,3,3-trifluoropropanamide (BC13): To a stirred solution of (E)-2amino-1 -(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1 -enyl)-1 H-indol-1 -yl) ethanone (0.04 g, 0.09 mmol) in DCM (5.0 ml) was added 3,3,3-trifluoropropanoic acid (17.5 mg, 0.136 mmol), PyBOP (70 mg, 0.135 mmol) and DIEA (29 mg, 0.225 mmol) and the reaction was stirred at RT for 16 h. The reaction mixture was diluted with DCM, and the DCM layer was washed with water and saturated brine solution .The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography (SiO2, 100-200 mesh; 10% ethyl acetate/ petroleum ether) to afford the title compound as an off-white solid (30 mg, 60%); mp 121-126 °C; 1H NMR (400 MHz, CDCI3) δ 8.33 (br, 1 H), 7.59 (s, 1 H), 7.45 (m, 4H), 6.72 (d, J = 3.6 Hz, 3H), 6.39 (m, 1H ), 4.71 (t, J = 7.2 Hz, 2H), 4.15 (m, 1H), 3.51 (m, 1H), 3.28 (m, 1H); ESIMS m/z 553.06 ([M-H] ).
Example 38: Préparation of ethyl 2-(1-oxo-6-vinylphthalazin-2(1H)-yl)acetate (BI24)
O
Step 1. 5-Bromo-3-hydroxyisoindoline-1-one (BI25): A mixture of Zn powder (1.73 g, 26.154 mmol), copper (II) sulfate pentahydrate (0.02 g ,0.08 mmol) and 2M aq NaOH (27 mL) were cooled to 0 °C. 5-Bromoisoindoline-1,3-dione (5 g, 22mmol) was added at the same température over the period of 30 min. The reaction mixture was stirred at 0 °C for 30 min and 3 h at RT. The reaction mixture was filtered and the filtrate was neutralized with concentrated HCl. The reaction mixture was diluted with éthanol and extracted with ethyl acetate. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude title compound as a brown solid, which was used in the next step without further purification (1.3 g): mp 258-261 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (br, 1H), 7.81 (m, 2H), 7.69 (m, 1H), 6.44 (m, 1H), 5.88 (d, J = 9.3 Hz, 1H); ESIMS m/z 225.83 ([M-H] ); IR (thin film) 1684, 3246,606 cm’1.
Step 2. 6-Bromophthalazine-1(2H)-one (BI26): To a stirred solution of 5-bromo-3hydroxyisoindoline-1-one (1.0 g, 4.40 mmol) in water, was added hydrazine hydrate (0.45 g , 8.80 mmol) and heated to 95°C for 5 h. The reaction mixture was cooled to RT, filtered and washed with 95 diethyl ether and pentane (1:1) to afford the title compound as a white solid that was used in the next step without further purification (0.5 g): ESIMS m/z 225.15 ([M+H]+).
Step 3. 6-vinylphthalazine-1(2H)-one (BI27): A solution of 6-bromophthalazine-1(2/-/)one (0.25 g, 1.11 mmol), potassium vinyl trifluoroborate (0.446 g, 3.33 mmol) and K2CO3(0.46 g,
3.33 mmol) in DMSO (2 mL) was degassed with argon for 20 min at RT. PdCI2(dppf) (0.04 g, 0.055 mmol) was added at RT, and the reaction mixture was heated to 80 °C for 2 h. The reaction mixture was cooled to RT and filtered through celite bed under vacuum and washed with ethyl acetate. The reaction mixture was extracted with ethyl acetate and the combined ethyl acetate layer dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 50% ethyl acetate/ petroleum ether) to afford the title compound as a brown solid (0.12 g, 63%): 1H NMR (400 MHz, DMSO-d6) δ 13.61 (br, 1H), 8.33 (m, 1H), 8.19 (m, 1H), 8.01 (m, 2H), 6.97 (m, 1H), 6.15 (m, 1H), 5.56 (d, J = 10.8 Hz, 1H); ESIMS m/z 172.93 ([M+H]+); IR (thin film) 1748, 1655, 3241 cm’1.
Step 4. Ethyl-2-(1-oxo-6-vinylphthalazine-2(1H)-yl acetate (BI24): To a stirred solution of 6-vinylphthalazine-1(2/-/)-one (0.5 g, 2.90 mmol) in DMF (5.0 mL) was added Cs2CO3 (0.94 g, 2.90 mmol) and the reaction was stirred for 10 min. Ethyl bromoacetate (0.48 g,2.90 mmol) was added to the reaction mixture at RT and the reaction was stirred for 8 h at RT. The reaction mixture was diluted and extracted with ethyl acetate, and the ethyl acetate layer was washed with water and brine solution (2X). The separated ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 25% ethyl acetate/ petroleum ether) to afford the title compound as a brown solid (0.34 g, 45%): 1H NMR (400 MHz, DMSO-d6) δ 8.45 (m, 1H), 8.24 (m, 1H), 8.04 (m, 2H), 7.01 (m, 1H), 6.17 (d, J =2.1 Hz, 1H), 5.56 (d, J = 10.8 Hz, 1H), 4.92 (s, 2H),
4.19 (m, 2H), 1.23 (m, 3H). ESIMS m/z 259.10 ([M+H]+); IR (thin film) 1750, 1660 cm’1.
Example 39: Préparation of (E)-ethyl 2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1en-1-yl)-1-oxophthalazin-2(1 H)-yl)acetate (BI28)
Cl O
To a stirred solution of ethyl-2-(1-oxo-6-vinylphthalazine-2(1/-/)-yl acetate (0.07 g, 0.27 mmol) in 1,2-dichlorobenzene (1.0 mL) was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro2fluorobenzene (0.17 g, 0.54 mmol), CuCI (0.005 g, 0.05 mmol) and 2,2-bipyridyl (0.016 g, 0.10 96 mmol) and the résultant reaction mixture was degassed with argon for 30 min and heated to 180 °C for 12 h. The reaction mixture was cooled to RT and filtered and the filtrated was concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100200 mesh; 10-15% ethyl acetate/ petroleum ether) to afford the title compound as a brown solid (40 mg, 29%): 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 8.4 Hz, 1H), 7.84 (d, J= 1.5 Hz, 1H), 7.65 (s, 1H), 7.37 (d, J= 6.3 Hz, 2H), 6.76 (d, J= 16.0 Hz, 1H), 6.59 (dd, J =16.0, 8.0 Hz, 1H), 4.96 (s, 2H), 4.29 (m, 3H), 1.31 (t, J = 7.2 Hz, 3H); ESIMS m/z 503.0 ([M+H]+); IR (thin film) 1660, 1114, 817 cm·1.
Example 40: Préparation of (£)-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1yl)-1-oxophthalazin-2(1H)-yl)acetic acid (BI29)
Cl o
A solution of (E)-ethyl-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1oxophthalazin-2(1H)-yl) acetate (0.04 g, 0.07mmol) in HCl (0.5 mL) and acetic acid (0.5 mL) was heated to 100 °C for 3 h. The solvent was removed under reduced pressure and the residue diluted with water. The aqueous layer was extracted with ethyl acetate and the separated ethyl acetate layer dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was triturated with diethyl ether-pentane mixture to afford the title compound as a brown solid (0.03 g): 1H NMR (400 MHz, DMSO-d6) δ 13.0 (br s, 1H), 8.43 (m, 1H),
8.23 (d, J = 8.1 Hz, 1H), 8.14 (m, 2H), 7.91 (m, 2H), 7.16 (dd, J =16.0, 8.0 Hz, 1H), 6.99 (d, J = 16.0 Hz, 1H), 4.96 (m, 3H),; ESIMS m/z 473.0 ([M-H] ); IR (thin film) 1629, 1168, 817 cm’1.
Example 41: Préparation of(£)-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1yl)-1-oxophthalazin-2(1H)-yl)-N-(2,2,2-trifluoroethyl)acetamide (BC14)
To a stirred solution of (£)-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1oxophthalazin-2(1/-/)-yl)acetic acid (0.15 g, 0.31 mmol) in DCM (20.0 ml) was added 2,2,2,trifluoroethanamine (0.03 g, 0.31 mmol), PyBOP (0.17 g, 0.34 mmol) and DIEA (0.15 ml, 0.93 mmol) at RT, and the reaction was stirred for 18 h. The reaction mixture was diluted with DCM and washed with 3N HCl (2 x 20 mL), NaHCO3 (2 x 20 mL) and brine solution (2x).The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 20-25% ethyl acetate/ petroleum ether) to afford the title compound as a brown solid (0.11 g): mp 172-175 °C; 1H NMR (400 MHz, CDCI3) δ 8.83 (t, J = 6.6 Hz, 1H), 8.42 (t, J = 14.7 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.13 (t, J =6.3 Hz, 1H), 7.98-7.86 (m, 2H), 7.16-7.07 (m, 1H), 7.01 -6.93 (m, 1 H), 4.96 - 4.81 (m, 3H), 4.00 - 3.88 (m, 2H); ESIMS m/z 554.0 ([M-H]').
Example 42: Préparation of 2-(4-vinylbenzyl)isoindoline-1,3-dione (CI1)
O
To a stirred solution of 1-(chloromethyl)-4-vinylbenzene (10 g, 66 mmol) in DMF (100 mL) was added potassium phthalimide (13.3 g, 72.1 mmol), and the résultant reaction mixture was heated at 70 °C for 16 h. The reaction mixture was diluted with H2O and extracted with CHCI3. The combined CHCI3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Recrystallization from CH3OH afforded the title compound as an off-white solid (8 g, 46%): 1H NMR (400 MHz, CDCI3) δ 7.83 (m, 2H), 7.71 (m, 2H), 7.39 (m, 4H), 6.65 (dd, J= 17.6,
10.8 Hz, 1 H), 5.72 (d, J = 17.6 Hz, 1 H), 5.21 (d, J = 10.8 Hz , 1 H), 4.82 (s, 2H); GCMS m/z 263.2 ([M]+); IR (thin film) 3420, 1133, 718 cm’1.
Example 43: Préparation of (£)-2-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1yl)benzyl)isoindoline-1,3-dione (CI2)
CF
Cl
Using the procedure of Example 10 with 2-(4-vinylbenzyl)isoindoline-1,3-dione and 1-(1bromoethyl)-3,5-dichlorobenzene as the starting materials, the title compound was isolated as an off-white solid (0.3 g, 40-50%): mp 142-145 °C; 1H NMR (400 MHz, CDCI3) δ 7.86 (m, 2H), 7.74 (m, 2H ), 7.42 (m, 2H), 7.36 (m,3H), 7.27 (m, 2H), 6.58 (d, J= 16.0 Hz, 1H), 6.32 (dd, J= 16.0, 8.0 Hz, 1H), 4.82 (s, 2H), 4.05 (m, 1H); ESIMS m/z 488.17 ([M-H]’).
The following compound was made in accordance with the procedures disclosed in Example 43.
(£)-2-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)isoindoline-1,3-dione (CI3)
The title compound was isolated as an off white solid (0.3 g, 56%): mp 145-146 °C; 1H NMR (400 MHz, CDCI3) δ 7.86 (m, 2H), 7.74 ( m, 2H ), 7.42-7.31 (m, 6H), , 6.58 (d, J = 16.0 Hz, 1H), 6.53 (dd, J= 16.0, 8.0 Hz, 1H), 4.82 (s, 2H), 4.05 (m, 1H); ESIMS m/z 522.2 ([M-H]'); IR (thin film) 1716, 1110, 712 cm’1.
Prophetically, compounds CI4-CI5 (Table 1) could be made in accordance with the procedures disclosed in Example 43.
Example 44: Préparation of (E)-(4-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-
To a stirred solution of (£)-2-(4-(3-(3,5-dichlorophenyl)but-1-en-1-yl)benzyl)-isoindoline-1,3dione (1.2 g, 2.45 mmol) in EtOH was added hydrazine hydrate (0.61 g, 12 mmol), and the résultant reaction mixture was heated at 90 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2CI2, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the crude title compound as a gummy liquid (0.9 g) which was used without further purification.
The following compounds were made in accordance with the procedures disclosed in Example 44.
(E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)methanamine (CI7)
The title compound was isolated and used without further purification.
Prophetically, compounds CI8-CI9 (Table 1) could be made in accordance with the procedures disclosed in Example 44.
Example 45: Préparation of 4-(bromomethyl)-3-chlorobenzonitrile (CI10)
To a stirred solution of 3-chloro-4-methylbenzonitrile (5 g, 25.4 mmol) in carbon tetrachloride (CCI4; 50 mL) under an argon atmosphère was added NBS (5.16 g, 29 mmol), and the mixture was degassed for 30 min. To this was added azobisisobutyronitrile (AIBN; 0.3 g, 1.8 mmol), and the résultant reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient température, washed with H2O, and extracted with CH2CI2. The combined CH2CI2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in nHexane) to afford the title compound as a white solid (4.8 g, 68%): mp 87-88 °C; 1H NMR (400 MHz, CDCI3) δ 7.71 (s, 1H), 7.59 ( s, 2H ), 4.60 (s, 2H); ESIMS m/z 229.77 ([M+H]+); IR (thin film) 2235, 752, 621 cm’1.
The following compounds were made in accordance with the procedures disclosed in Example 45.
4-(Bromomethyl)-3-(trifluoromethyl)benzonitrile (CI11)
NC OHCF 3 ^Br
The title compound was isolated as an off-white gummy material (5 g, 66%): 1H NMR (400 MHz, CDCI3) δ 7.96 (s, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 4.62 (s, 2H); ESIMS m/z 262.11 ([M-H] ); IR (thin film) 2236, 1132, 617 cm’1.
3-Bromo-4-(bromomethyl)benzonitrile (CI12)
100
NC / V-Br
Y Br
The title compound was isolated as an off-white solid(5 g, 67%): mp 82-83 °C; 1H NMR (400 MHz, CDCI3) δ 7.90 (s, 1H), 7.61 (m, 2H ), 4.62 (s, 2H); EIMS m/z 272.90; IR (thin film) 2229, 618 cm'1.
4-(Bromomethyl)-3-fluorobenzonitrile (CI13)
NC
Br
The title compound was isolated as an off-white solid (2 g, 60%): mp 79-81 °C; 1H NMR (400 MHz, CDCI3) δ 7.54 (t, J = 8.0 Hz, 1 H), 7.48 (dd, J = 8.0 Hz, 8.0, 1 H), 7.38 (dd, J = 5 Hz, 1H ),
4.5 (s, 2H); EIMS m/z 215.
Example 46: Préparation of 4-(bromomethyl)-3-chlorobenzaldehyde (CI14)
Cl
Br
To a stirred solution of 4-(bromomethyl)-3-chlorobenzonitrile (4.8 g, 17 mmol) in toluene (50 mL) at 0 °C was added dropwise diisobutylaluminum hydride (DIBAL-H, 1.0 M solution in toluene;
23.9 mL), and the reaction mixture was stirred at 0 °C for 1 h. 10 M HCl in H2O (5 mL) was added until the reaction mixture turned to a white slurry and then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with CHCI3. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in nHexane) to afford the title compound as a white solid (3.8 g, 80%): mp 64-66 °C; 1H NMR (400 MHz, CDCI3) δ 10.00 (s, 1 H), 7.92 (s, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.64 (d, J = 8.0 Hz, 1 H), 4.60 (s, 2H); ESIMS m/z 232.78 ([M+H]+).
The following compounds were made in accordance with the procedures disclosed in Example 46.
101
4-(Bromomethyl)-3-(trifluoromethyl)benzaldehyde (CH 5)
The title compound was isolated as a pale yellow low-melting solid (5 g, 60%): 1H NMR (400 MHz, CDCI3) δ 10.09 (s, 1H), 8.19 (s, 1H), 8.09 (m, 1H), 7.81 (m, 1H), 4.61 (s, 2H); ESIMS m/z 265.04 ([M-H]’); IR (thin film) 1709, 1126, 649 cm'1.
3-Bromo-4-(bromomethyl)benzaldehyde (CI16)
The title compound was isolated as a pale yellow solid (5 g, 62%): mp 94-95 °C; 1H NMR (400 MHz, CDCI3) δ 9.96 (s, 1H), 8.05 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H),
4.60 (s, 2H); EIMS m/z 275.90.
4-(Bromomethyl)-3-fluorobenzaldehyde (CI17)
The title compound was isolated as an off-white solid (5 g, 61%): mp 43-45 °C; 1H NMR (400 MHz, CDCI3)Ô9.1 (s, 1H), 7.54 (t, J = 8 Hz, 1H), 7.48 (d, J=8Hz, 1H), 7.38 (d, J=5Hz, 1H ), 4.5 (s, 2H); EIMS m/z 216.
Example 47: Préparation of 3-chloro-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (CI18)
To a stirred solution of 4-(bromomethyl)-3-chlorobenzaldehyde (3.8 g, 14 mmol) in DMF (40 mL) was added potassium pthalimide (3.54 g, 19.14 mmol), and the mixture was heated at 60°C for
h. The reaction mixture was cooled to ambient température and diluted with H2O (100 mL). The
102 solid obtained was separated by filtration and dried under vacuum to afford the title compound as a white solid (2.8 g, 60%): mp 123-126 °C; 1H NMR (400 MHz, CDCI3) δ 9.95 (s, 1H), 8.21 (s, 1H),
7.91 (m, 3H), 7.80 (m, 2H), 7.20 (m, 1 H), 5.05 (s, 2H); ESIMS m/z 298.03 ([M-H]').
The following compounds were made in accordance with the procedures disclosed in
Example 47.
4-((1,3-Dioxoisoindolin-2-yl)-3-(trifluoromethyl)benzaldehyde (CI19)
The title compound was isolated as an off white solid (1 g, 62%): mp 142-143 °C; 1H NMR (400 MHz, CDCI3) δ 10.05 (s, 1H), 8.15 (s, 1H), 7.91 (m, 2H), 7.80 (m, 3H), 7.27 (m, 1H), 5.19 (s, 10 2H); ESIMS m/z 332.03 ([M-H] ).
3-Bromo-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (CI20)
The title compound was isolated as an off-white solid (0.5 g, 64%): mp 159-161 °C; 1H
NMR (400 MHz, CDCI3) δ 9.95 (s, 1H), 8.21 (s, 1H), 7.91 (m, 3H), 7.80 (m, 2H), 7.20 (m, 1H), 5.05 (s, 2H); ESIMS m/z 314.00 ([M-CHO] ).
4-((1,3-Dioxoisoindolin-2-yl)-3-fluorobenzaldehyde (CI21)
103
The title compound was isolated as a white solid (2 g, 60%): mp 154-156 °C; 1H NMR (400 MHz, CDCI3) δ 9.95 (s, 1H), 7.9 (m, 2H), 7.75 (m, 2H), 7.6 (m, 2H), 7.5 (t, J = 7.6 Hz, 1H), 5.05 (s, 2H); EIMS m/z 283.1.
Example 48: Préparation of 2-(2-chloro-4-vinylbenzyl)isoindoline-1,3-dione (CI22)
Cl
To a stirred solution of 3-chloro-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (2.8 g, 8.2 mmol) in 1,4-dioxane (30 mL) were added K2CO3 (1.68 g, 12.24 mmol) and methyl triphenyl phosphonium bromide (4.37 g, 12.24 mmol) at ambient température. Then the résultant reaction mixture was heated at 100 °C for 18 h. After the reaction was deemed complété by TLC, the reaction mixture was cooled to ambient température and filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 20% EtOAc in n-Hexane) to afford the title compound as a white solid (1.94 g, 70%): mp 141-143 °C; 1H NMR (400 MHz, CDCI3) δ 7.85 (m, 2H), 7.70 (m, 2H), 7.41 (m, 1H), 7.21 (m, 2H), 6.71 (dd, J = 17.6, 10.8 Hz, 1H), 5.72 (d, J = 17.6 Hz, 1H), 5.23 (d, J= 10.8 Hz, 1H), 4.92 (s, 2H); ESIMS m/z 298.10 ([M-H] ).
The following compounds were made in accordance with the procedures disclosed in Example 48.
2-(2-(Trifluoromethyl)-4-vinylbenzyl)isoindoline-1,3-dione (CI23)
The title compound was isolated as a light brown solid (0.5 g, 60%): mp 134-135 °C; 1H NMR (400 MHz, CDCI3) δ 7.92 (m, 2H), 7.80 (m, 2H), 7.71 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.65 (m, 1 H), 5.80 (d, J =17.8 Hz, 1 H), 5.19 (d, J = 10.8 Hz, 1H), 5.09 (s, 2H); ESIMS m/z 332.10 ([M+H]+).
104
2-(2-Bromo-4-vinylbenzyl)isoindoline-1,3-dione (CI24)
The title compound was isolated as a off white solid (0.5 g, 62%); mp 126-128 °C; 1H NMR (400 MHz, CDCI3) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.62 (s, 1H), 7.21 (m, 1H), 7.16 (d, J= 8.0 Hz, 1H), 5 6.62 (m, 1H), 5.72 (d, J= 17.8 Hz, 1H), 5.15 (d, J= 10.8 Hz, 1H), 4.95 (s, 2H); EIMS m/z 341.10.
2-(2-Fluoro-4-vinylbenzyl)isoindoline-1,3-dione (C125)
The title compound was isolated as a white solid (0.5 g, 61%); mp 140-142 °C; 1H NMR (400 MHz, CDCI3) δ 7.85 (m, 2H), 7.72 (m, 2H), 7.25 (m, 1H), 7.11 (m, 2H), 6.63 (m, 1H), 5.80 (d, J 10 = 17.6 Hz, 1H), 5.28 (d, J= 10.8 Hz, 1H), 4.92 (s, 2H); EIMS m/z 282.08.
Example 49: Préparation of (E)-2-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1yl)benzyl)isoindoline-1,3-dione (CI26)
To a stirred solution of 2-(2-chloro-4-vinylbenzyl)isoindoline-1,3-dione (2.0 g, 6.51 mmol) in
1,2-dichlorobenzene (25 mL) were added 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (3.48 g, 11.36 mmol), CuCI (112 mg, 1.13 mmol) and 2,2- bipyridyl (0.35 g). The résultant reaction mixture was degassed with argon for 30 min and then was stirred at 180 °C for 24 h. After the reaction was deemed complété by TLC, the reaction mixture was cooled to ambient température
105 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in n-hexane) to afford the title compound as solid (1.3 g, 50%): mp 141—143 °C; 1H NMR (400 MHz, CDCI3) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.42 (m, 2H), 7.24 (m, 2H), 7.20 (m, 2H), 6.54 (d, J= 16.0 Hz, 1H), 6.34 (dd, J= 16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.10 (m, 1H); ESIMS m/z 524.07 ([M+H]+).
The following compounds were made in accordance with the procedures disclosed in Example 49.
(E)-2-(2-Chloro-4T(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)isoindoline-1,3dione (CI27)
The title compound was isolated as a pale white solid (0.2 g, 55%); mp 128-129 °C; 1H
NMR (400 MHz, CDCI3) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.42 (m, 3H), 7.22 (m, 2H), 6.52 (d, J= 16.0 Hz, 1 H), 6.32 (dd, J = 16.0, 8.0 Hz, 1 H), 5.00 (s, 2H), 4.05 (m, 1 H); ESIMS m/z 557.99 ([M+H]+).
(E)-2-(2-Chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1yl)benzyl)isoindoline-1,3-dione (CI28)
The title compound was isolated as a off white solid (0.2 g, 54%): mp 177-180 °C; 1H NMR (400 MHz, CDCI3) δ 7.90 (m, 2H), 7.77 (m, 2H), 7.42 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.21 (m, 2H), 6.52 (d, J = 16.0 Hz, 1H), 6.32 (dd, J= 16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.05 (m, 1H); ESIMS m/z 540.08 ([M-H]’); IR (thin film) 1716 cm'1.
106 (E)-2-(2-Chloro-4-(3-(3,4-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3dione (CI29)
The title compound was isolated as an off-white solid (0.2 g, 59%): 1H NMR (400 MHz, CDCI3) δ 7.89 (m, 2H), 7.76 (m, 2H), 7.47 (m, 3H), 7.21 ( m, 3H), 6.50 (d, J= 16.0 Hz, 1H), 6.32 (dd, J= 16.0, 7.6 Hz, 1H), 4.97 (s, 2H), 4.11 (m, 1H); ESIMS m/z 522.27 ([M-H] ); IR (thin film) 3064, 1717, 1111, 715 cm'1.
(Ê)-2-(4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromethyl)benzyl)isoindoline-1,3-dione (CI30)
The title compound was isolated as an off-white solid (0.2 g, 54%): mp 141-142 °C; 1H NMR (400 MHz, CDCI3) 7.94 (m, 2H), 7.80 (m, 2H), 7.69 (s, 1H), 7.44 ( m, 1H), 7.38 (m, 1H), 7.24 (m, 2H), 7.19( m, 1H ), 6.60 (d, J= 16.0 Hz, 1H), 6.39 (dd, J= 16.0, 7.6 Hz, 1H), 5.10 (s, 2H), 4.11 (m, 1H); ESIMS m/z 556.00 ([M-H]').
(£)-2-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzyl)isoindoline-1,3-dione (CI31)
107
The title compound was isolated as an off-white solid (0.2 g, 56%): mp 130-132 °C; 1H
NMR (400 MHz, CDCI3) δ 7.94 (m, 2H), 7.80 (m, 2H), 7.69 (s, 1H), 7.44 (m, 3H), 7.19 (m, 1H), 6.61 (d, J= 16.0 Hz, 1H), 6.38 (dd, J= 16.0, 7.6 Hz, 1H), 5.10 (s, 2H), 4.12 (m, 1H); ESIMS m/z 589.57 5 ([M-2H]·).
(E)-2-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-isoindoline-
1,3-dione (CI32)
The title compound was isolated as a pale yellow solid (0.2 g, 55%): mp 160-162 °C; 1H
NMR (400 MHz, CDCI3) δ 7.92 (m, 2H), 7.80 (m, 2H), 7.62 (s, 1H), 7.39 (s, 2H), 7.24 (m, 1H), 7.16 (m, 1H), 6.52 (d, J= 16.0 Hz, 1H), 6.32 (dd, J= 16.0, 8.0 Hz, 1H), 4.98 (s, 2H), 4.12 (m, 1H); ESIMS m/z 599.78 ([M-H]’).
(E)-2-(2-Fluoro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-isoindoline-1,3dione (CI33)
108
The title compound was isolated as an off-white solid (0.2 g, 55%): mp 72-74 °C; 1H NMR (400 MHz, CDCI3) δ 7.88 (m, 2H), 7.74 (m, 2H), 7.38 (s, 2H), 7.34 (m, 1H), 7.18 (m, 2H), 6.54 (d, J = 16.0 Hz, 1H), 6.32 (dd, J= 16.0, 8.0 Hz, 1H), 4.91 (s, 2H), 4.08 (m, 1H); ESIMS m/z 539.89 ([ΜΗ]); IR (thin film)1773 cm’1.
Prophetically, compounds CI34-CI41 (Table 1) could be made in accordance with the procedures disclosed in Example 49.
Example 50: Préparation of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-
To a stirred solution of (E)-2-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1yl)benzyl)isoindoline-1,3-dione (0.4 g, 0.76 mmol) in EtOH was added hydrazine hydrate (0.38 g,
7.6 mmol), and the résultant reaction mixture was heated at 80 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2CI2, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a gummy liquid (0.3 g), which was carried on to the next step without further purification.
The following compounds were made in accordance with the procedures disclosed in Example 50.
(E)-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-methanamine (CI43)
The product obtained in this reaction was carried on to the next step without further purification.
(E)-(2-Chloro-4-(3-(3,4-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)-methanamine (CI44)
109
The product obtained in this reaction was carried on to the next step without further purification.: 1H NMR (400 MHz, CDCI3) δ 7.48 (d, J = 8.4 Hz, 2H), 7.39 (m, 2H), 7.23 (m, 2H), 6.52 (d, J= 16.0 Hz, 1H), 6.38 (dd, J= 16.0, 7.6 Hz, 1H), 4.12 (m, 1H), 3.90 (s, 2H); ESIMS m/z 391.90 ([M-H] ); IR (thin film) 3370, 3280, 1111,817 cm·1.
(E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-y!)-2-(trifluoromethyl)phenyl)methanamine (CI45)
The title compound was isolated as a gummy material. The product obtained in this reaction was carried on to the next step without further purification.
(E)-(2-Bromo-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)-methanamine (CI46)
The title compound was isolated as a gummy material: The product obtained in this reaction was carried on to the next step without further purification.
(E)-(2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-iTiethanamine (CI47)
The title compound was isolated as a gummy material. The product obtained in this reaction was carried on to the next step without further purification.
110 (E)-(2-Fluoro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)phenyl)-methanamine (CI48)
The title compound was isolated as a gummy material: 1H NMR (400 MHz, CDCI3) δ 7.40 (s, 2H), 7.33 (t, J= 7.6 Hz, 1H), 7.13 (m, 2H), 6.56 (d, J= 16.0 Hz, 1H), 6.33 (dd, J = 16.0, 7.6 Hz, 1H), 4.08 (m, 1H), 3.90 (s, 2H); ESIMS m/z 413.84 ([M+H]+); IR (thin film) 3368, 3274, 1114, 808 cm’1.
Prophetically, compounds CI49-CI57 (Table 1) could be made in accordance with the procedures disclosed in Example 50.
Example 51: Préparation of 3-chloro-4-((pyridin-2-ylamino)methyl)benzaldehyde (CI58)
To a stirred solution of 4-(bromomethyl)-3-chlorobenzaldehyde (2 g, 9 mmol) in N,Ndimethylacetamide (DMA; 20 mL) was added K2CO3 (2.36 g, 17.16 mmol) and 2-aminopyridine (0.84 g, 8.58 mmol), and the reaction mixture was stirred at ambient température for 4 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 100-200 mesh; 20% EtOAc in n-Hexane) to afford the title compound as off-white solid (1.05 g, 50%): mp 122-123 °C; 1H NMR (400 MHz, CDCI3) δ 9.94 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.72 (d, J=4.8 Hz, 1H), 7.62 (d, J= 5.7 Hz, 1H), 7.4 (m, 1 H), 6.64 (d, J = 3.9 Hz, 1 H), 6.38 (d, J = 6.3 Hz, 1 H), 5.04 (br s, 1 H), 4.71 (s, 2H); ESIMS m/z 246.97 ([M+H]+).
Example 52: Préparation of /V-(2-chloro-4-vinylbenzyl)pyridin-2-amine (Cl59)
111
To a stirred solution of 3-chloro-4-((pyridin-2-ylamino)methyl)benzaldehyde (1 g, 4. mmol) in
1,4-dioxane (20 mL) were added K2CO3 (0.84 g, 6.09 mmol) and methyl triphenyl phosphonium bromide (2.17 g, 6.09 mmol) at ambient température. Then the résultant reaction mixture was heated at 100 °C for 18 h. After the reaction was deemed complété by TLC, the reaction mixture was cooled to ambient température and filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 10% EtOAc in n-Hexane) to afford the title compound as a white solid (0.5 g, 50%): mp 119-121 °C; 1H NMR (400 MHz, CDCI3) δ 8.12 (s, 1H), 7.42 - 7.40 (m, 3H), 7.26 (s, 1H), 6.66 (m, 2H), 6.36 (d, J =
6.3 Hz, 1H), 5.75 (d, J= 13.2 Hz, 1H), 4.92 (brs, 1H), 4.60 (s, 2H); ESIMS m/z 245.05 ([M+H]+).
Example 53: Préparation of ethyl 2-amino-2-(5-bromo-3-chloropyridin-2-yl)acetate (CI60)
Ethyl 2-(diphenylmethyleneamino)acetate (10.2 g, 38.2 mmol) was added to sodium hydride (NaH; 3.18 g, 133.52 mmol) in DMF (50 mL) at 0 °C, and the mixture was stirred for 30 min. To this was added 5-bromo-2,3-dichloropyridine (12.9 g, 57.23 mmol), and the reaction mixture was stirred for 3 h at ambient température. The reaction mixture was quenched with 2 N HCl solution and then stirred for 4 h at ambient température. The mixture was extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (20-30% EtOAc in hexane) afforded the title compound as a liquid (1.3 g, 20%): 1H NMR (400 MHz, CDCI3) δ 8.52 (s, 1H), 7.89 (s, 1H ), 5.09 (s1 H), 4.23 (m, 2H), 2.27 (br s, 2H), 1.26 (m, 3H); ESIMS m/z 293.05 ([M+H]+); IR (thin film) 3381,3306, 1742, 759, 523 cm’1.
Example 54: Préparation of (5-bromo-3-chloropyridin-2-yl)methanamine hydrochloride (CI61)
L A ^NH2 «HCl
A stirred solution of ethyl 2-amino-2-(5-bromo-3-chloropyridin-2-yl)acetate (0.5 g, 1.7 mmol) in 3 N HCl (25 mL) was heated at reflux for 4 h. The reaction mixture was washed with diethyl ether and H2O. The combined ether layer was concentrated under reduced pressure to afford the title compound as an off-white solid (400 mg, 65%): 1H NMR (400 MHz, CDCI3) δ 8.78 (s, 1H), 8.70 (br s, 2H), 8.45 (s, 1 H), 4.56 (m, 2H); ESIMS m/z 221.15 ([M+H]+).
112
Example 55: Préparation of 2-((5-bromo-3-chloropyridin-2-yl)methyl)isoindoline-1,3-dione (CI62)
To a stirred solution of (5-bromo-3-chloropyridin-2-yl)methanamine hydrochloride (0.3 g, 1.4 mmol) in toluene (40 mL) was added Et3N (0.41 g, 4.08 mmol) and phthalic anhydride (0.24 g, 1.63 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H2O and extracted with EtOAc . The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (2030% EtOAc in hexane) to afford the title compound as a white solid (0.25 g, 65%): 1H NMR (400 MHz, CDCI3) δ 8.78 (s, 1H), 8.45 (s, 1H), 7.88 (m, 2H), 7.74 ( m, 2H), 4.56 (m, 2H); ESIMS m/z 349 ([M-H]); IR (thin film) 3307, 1665, 1114,813 cm·1.
Example 56: Préparation of 2-((3-chloro-5-vinylpyridin-2-yl)methyl)isoindoline-1,3-dione (CI63)
To a stirred solution of 2-((5-bromo-3-chloropyridin-2-yl)methyl)isoindoline-1,3-dione (0.23 g, 0.65 mmol) in toluene (10 mL) were added Pd(PPh3)4 (3.7 mg, 0.003 mmol), K2CO3 (0.269 g, 1.95 mmol) and vinyl boronic anhydride pyridine complex (0.78 g, 3.28 mmol), and the reaction mixture was heated at reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (20-30% EtOAc in hexane) afforded the title compound as an off-white solid (0.2 g, 65%): 1H NMR (400 MHz, CDCI3) δ 8.30 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.72 (m, 1H), 6.63 (m, 1H), 5.79 (d, J = 16.0 Hz, 1H), 5.39 (d, J = 16.0 Hz, 1H), 5.12 (s, 2H); ESIMS m/z 299.20 ([M+H]+).
113
Example 57: Préparation of (E)-2-((3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichloro-phenyl)but-1 en-1 -yl)pyridin-2-yl)methyl)isoindoline-1,3-dione (CI64)
To a stirred solution of 2-((3-chloro-5-vinylpyridin-2-yl)methyl)isoindoline-1,3-dione (0.35 g,
1.17 mmol) in 1,2-dichlorobenzene (10 mL) were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3trichlorobenzene (0.8 g, 2.3 mmol), CuCI (23 mg, 0.12 mmol), 2,2-bipyridyl (0.073 g, 0.234 mmol), and the reaction mixture was heated at 180 °C for 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (20-30% EtOAc in hexane) to afford the title compound as a liquid (0.4 g, 50%): mp 79-82 °C; 1H NMR (400 MHz, CDCI3) δ 8.27 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.36 (s, 2H), 6.51 (d, J= 15.6 Hz, 1H), 6.32 (dd, J= 15.6, 8.0 Hz, 1H), 5.30 (s, 2H), 4.13 (m, 1H); ESIMS m/z 559 ([M+H]+).
Example 58: Préparation of (E)-(3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1yl)pyridin-2-yl)methanamine (CI65)
To a stirred solution of (E)-2-((3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1yl)pyridin-2-yl)methyl)isoindoline-1,3-dione (200 mg, 0.358 mmol) in EtOH (5 mL) was added hydrazine hydrate (89.6 mg, 1.79 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in CH2CI2. The organic layer was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (100 mg). The product obtained in this reaction was carried on to the next step without further purification.
Example 59: Préparation of 4-(bromomethyl)-1-naphthonitrile (CI66)
114
CN
Br
To a stirred solution of 4-methyl-1-naphthonitrile (5 g, 30 mmol) in CCI4 (50 mL) under argon atmosphère was added NBS (6.06 g, 34.09 mmol), and the reaction mixture was degassed for 30 min. AIBN (0.3 g, 2.1 mmol) was added, and the résultant reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient température, diluted with H2O and extracted with CH2CI2 (3 x 100 mL). The combined CH2CI2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 52%): mp 131-133 °C; 1H NMR (400 MHz, CDCI3) δ 8.33 (m, 1H), 8.24 (m, 1H), 7.88 (d, J= 8.0 Hz, 1H), 7.78 (m, 2H), 7.62 (d, J= 8.0 Hz, 1H), 4.95 (s, 2H); ESIMS m/z 245.92 ([M+H]+); IR (thin film) 2217 cm’1.
Example 60: Préparation of 4-(bromomethyl)-1-naphthaldehyde (CI67)
Br
To a stirred solution of 4-(bromomethyl)-1 -naphthonitrile (8 g, 33mmol) in toluene (100 mL) at 0 °C was added dropwise DIBAL-H (1.0 M solution in toluene; 43 mL), and the reaction mixture was stirred at 0 °C for 1 h. 3 N HCl in H2O (50 mL) was added to the mixture until it became a white slurry and then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with EtOAc (3 x100 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in petroleum ether) afforded the title compound as a white solid (7 g, 88%): mp 115-116 °C; 1H NMR (400 MHz, CDCI3) δ 10.41 (s, 1 H), 9.35 (m, 1 H), 8.22 (m, 1 H),
7.90 (d, J= 8.0 Hz, 1H), 7.75 (m, 3H), 4.95 (s, 2H); ESIMS m/z 248.88 ([M+H]+).
Example 61: Préparation of 4-((1,3-dioxoisoindolin-2-yl)methyl)-1-naphthaldehyde (CI68)
115
To a stirred solution of 4-(bromomethyl)-1-naphthaldehyde (7 g, 28. mmol) in DMF (100 mL) was added potassium phthalimide (7.3 g, 39.5 mmol), and the mixture was heated at 85 °C for 2 h. The reaction mixture was cooled to ambient température and diluted with H2O (100 mL). The obtained solid was separated by filtration and dried under vacuum to afford the title compound as a white solid (8.8 g, 98%): mp 190-192 °C; 1H NMR (400 MHz, CDCI3) δ 10.39 (s, 1H), 9.25 (m, 1H),
8.41 (m, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 7.95 (m, 4H), 7.80 (m, 4H), 7.61 (m, 4H), 5.39 (s, 2H); ESIMS m/z 316.09 ([M+H]+); IR (thin film) 1708 cm’1.
Example 62: Préparation of 2-((4-vinylnaphthalen-1-yl)methyl) isoindoline-1,3-dione (CI69)
To a stirred solution of 4-((1,3-dioxoisoindolin-2-yl)methyl)-1-naphthaldehyde (9 g, 28.5 mmol) in 1,4-dioxane (100 mL) were added K2CO3 (6 g, 42.8 mmol) and methyl triphenyl phosphonium bromide (15.3 g, 35.7 mmol) at ambient température. The reaction mixture was heated at 100 °C for 14 h and then was cooled to ambient température. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 20% EtOAc in petroleum ether) afforded the title compound as a white solid (6 g, 67%): mp 146-147 °C; 1H NMR (400 MHz, CDCI3) δ 8.35 (m, 2H), 7.95 (m, 4H), 7.65 (m, 4H), 7.39 (m, 1H), 5.81 (m, 1H), 5.45 (m, 1H), 5.21 (s, 2H); ESIMS m/z 314.13 ([M+H]+).
Example 63: Préparation of (E)-2-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1yl)naphthalen-1-yl)methyl)isoindoline-1,3-dione (CI70)
116
ÇF3
Cl
Cl
To a stirred solution of 2-((4-vinylnaphthalen-1-yl)methyl)isoindoline-1,3-dione (1.5 g, 4.79 mmol) in 1,2-dichlorobenzene (15 mL) were added 1-(1-bromo-2,2,2-trifluoroethyl)-3,4,5trichlorobenzene (3.2 g, 9.5 mmol), CuCI (24 mg, 0.24 mmol) and 2,2-bipyridyl (0.149 g, 0.95 mmol), and the résultant reaction mixture was degassed with argon for 30 min and then stirred at 180 °C for 14 h. After the reaction was deemed complété by TLC, the reaction mixture was cooled to ambient température and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) afforded the title compound as an off-white solid (1.5 g, 56%): mp 158-160 °C; 1H NMR (400 MHz, CDCI3) δ 8.40 (m, 1H), 7.89 (m, 2H), 7.74 (m, 2H), 7.64 (m, 2H), 7.58 (m, 2H), 7.46 (s, 2H), 7.36 (m, 2H), 6.31 (m, 1H), 5.30 (s, 2H), 4.21 (m, 1H); ESIMS m/z 572.08 ([M-H] ).
Example 64: Préparation of (£)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1yl)naphthalen-1 -yl)methanamine (CI71 )
ÇF3
Cl
Cl
To a stirred solution of (£)-2-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1yl)naphthalen-1-yl)methyl)isoindoline-1,3-dione (0.4 g, 0.7 mmol) in EtOH was added hydrazine hydrate (0.18 g, 3.5 mmol), and the résultant reaction mixture was heated at 80 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2CI2, and the solution was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The title compound was isolated as a gummy liquid (150 mg, 50%). The product obtained in this reaction was carried on to the next step without further purification.
Example 65: Préparation of 2-((4-bromophenyl)amino)isoindoline-1,3-dione (CI72)
117
Br
NH
To a stirred solution of (4-bromophenyl)hydrazine hydrochloride (0.5 g, 2.2 mmol) in glacial acetic acid (8 mL) was added phthalic anhydride (0.398 g, 2.690 mmol), and the reaction mixture was stirred at 130 °C for 1 h under a nitrogen atmosphère. The reaction mixture was quenched with satd aq. NaHCO3 solution and filtered to give a solid. Purification by column chromatography (SiO2, 0-10% EtOAc in petroleum ether) afforded the title compound as a solid (60 mg, 84%): mp 205206 °C; 1H NMR (400 MHz, CDCI3) δ 8.71 (s, 1H), 7.99 (m, 4H), 7.32 (d, J= 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H); ESIMS m/z 314.95 ([M-H]).
Example 66: Préparation of 2-((4-vinylphenyl)amino)isoindoline-1,3-dione (CI73)
NH
To a solution of 2-(4-bromophenylamino)isoindoline-1,3-dione (2 g, 6. mmol) in 1,2dimethoxyethane (20 mL) and H2O (4 mL) were added vinyl boronic anhydride pyridine complex (4.57 g, 18.98 mmol) and K2CO3 (1.3 g, 9.5 mmol) followed by Pd(PPh3)4 (0.219 g, 0.189 mmol). The résultant reaction mixture was heated at 150 °C in a microwave for 30 min and then was concentrated under reduced pressure. Purification by column chromatography (SiO2, 15% EtOAc in petroleum ether) afforded the title compound as a solid (200 mg, 13%): mp 174-176 °C; 1H NMR (400 MHz, CDCI3) δ 8.65 (s, 1H), 7.94 (m, 4H), 7.29 (d, J= 8.4 Hz, 2H), 6.72 (d, J= 8.4 Hz, 2H),
6.61 (m, 1 H), 5.61 (d, J = 17.6 Hz, 1 H), 5.05 (d, J = 11.2 Hz, 1 H); ESIMS m/z 263.18 ([M-H]’).
Example 67: Préparation of (E)-2-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1yl)phenyl)amino)isoindoline-1,3-dione (CI74)
CF
Cl
Cl
Cl
118
To a stirred solution of 2-(4-vinylphenylamino)isoindoline-1,3-dione (0.3 g, 1.1 mmol) in 1,2dichlorobenzene (5 mL) were added CuCI (0.022 g, 0.273 mmol), 2,2-bipyridyl (0.07 g, 0.46 mmol) and 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.77 g, 2.27 mmol). The reaction mixture was degassed with argon for 30 min and was heated at 180 °C for 2 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, 0-30% EtOAc in petroleum ether) to afford the title compound as a solid (450 mg, 75%); mp 187-189 °C; 1H NMR (400 MHz, CDCI3) δ 8.75 (s, 1H), 7.96 (m, 4H), 7.82 (s, 2H), 7.37 (d, J = 8.8 Hz, 1 H), 6.73 (d, J = 8.4 Hz, 2H), 6.61 (m, 2H), 6.58 (m, 1 H), 4.59 (m, 1 H); ESIMS m/z 523.05 ([M-H]).
Example 68: Préparation of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1yl)phenyl)hydrazine (CI75)
To a stirred solution of (E)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1enyl)phenylamino)isoindoline-1,3-dione (0.16 g, 0.31 mmol) in EtOH (5 mL), was added hydrazine hydrate (0.076 g, 1.52 mmol), and the reaction mixture was heated at 85 °C for 1 h. The reaction mixture was cooled to ambient température and filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a solid (0.08 g, 66%) which was carried on to the next step without further purification.
Example 69: Préparation of 2-(4-vinylphenoxy)isoindoline-1,3-dione (CI76)
To a stirred solution of 4-vinylphenylboronic acid (2 g, 13 mmol), 2-hydroxyisoindoline-1,3dione (3.63 g, 24.53 mmol), and CuCI (1.214 g 12.26 mmol) in 1,2-dichloroethane (50 mL) was added pyridine (1.065 g, 13.48 mmol), and the résultant reaction mixture was stirred at ambient température for 48 h. The reaction mixture was diluted with H2O and extracted with CHCI3. The combined CHCI3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced
119 pressure. Purification by flash column chromatography (SiO2; 20% EtOAc in petroleum ether) afforded the title compound as a white solid (2 g, 63%): mp 129-131 °C; 1H NMR (400 MHz, CDCI3) δ 7.93 (d, J = 2.0 Hz, 2H), 7.82 (d, J = 3.2 Hz, 2H), 7.38 (d, J = 2.0 Hz, 2H), 7.14 (d, J = 2.0 Hz, 2H), 6.70 (m, 1H), 5.83 (d, J= 16.0 Hz, 1H), 5.22 (d, J= 10.8 Hz, 1H); ESIMS m/z 266.12 ([M+H]+).
Example 70: Préparation of (£)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1yl)phenoxy)isoindoline-1,3-dione (C177)
To a stirred solution of 2-(4-vinylphenoxy)isoindoline-1,3-dione (0.3g, 1.1 mmol) in 1,2dichlorobenzene (10 mL) was added 1-(1-bromoethyl)-3,4,5-trichlorobenzene (769 mg, 2.26 mmol), CuCI (22 mg, 0.22mmol) and 2,2-bipyridyl (35 mg, 0.44 mmol), and the résultant reaction mixture was degassed with argon for 30 min and heated to 180 °C for 24 h. The reaction mixture was cooled to ambient température and filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 100-200 mesh; 20% EtOAc in petroleum ether) to afford the title compound as a solid (0.29 g, 50%): 1H NMR (400 MHz, CDCI3) δ 7.90 (m, 1H), 7.62 (m, 2H), 7.50 (m, 1H), 7.40 (s, 2H), 7.12 (s, 1H), 6.90 (m, 2H), 6.60 (m, 2H), 6.20 (m,1H), 4.08 (m, 1H); ESIMS m/z 524.09 ([M-H] ).
Example 71: Préparation of (£)-0-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1yl)phenyl)hydroxylamine (CI78)
To a stirred solution of (£)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1enyl)phenoxy)isoindoline-1,3-dione (0.2 g, 0.4 mmol) in EtOH was added hydrazine hydrate (0.1 g,
1.9 mmol), and the résultant reaction mixture was heated at 90 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2CI2. washed with brine, dried over Na2SO4and concentrated under reduced pressure to afford the crude title compound as a gummy liquid (0.08 g, 53%): 1H NMR (400 MHz, CDCI3) δ 7.40 (s, 2H), 6.98 (s, 1H), 6.82 (s, 2H),
6.48 (m, 1 H), 6.20 (m, 1 H), 5.02 (s, 1 H), 4.08 (m, 1 H); ESIMS m/z 394.94 ([M-H]').
120
Example 72: Préparation of (E)-/V-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1enyl)benzyl)acetamide (CC1)
ÇF3
Cl
Cl
To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1yl)phenyl)methanamine (0.3 g, 0.8 mmol) in DCM (10 mL) was added acetic anhydride (0.12 mL,
1.14 mmol), and TEA (0.217 mL, 1.52 mmol), and the résultant reaction mixture was stirred at ambient température for 6 h. The reaction mixture was diluted with H2O and extracted with DCM. The combined DCM layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 30-50% ethyl acetate in hexane) afforded the title compound as a off-white solid (0.2 g, 60%) mp 107-109 °C; 1H NMR (400 MHz, CDCI3) δ 7.37 (m, 3H), 7.28 (m, 4H), 6.60 (d, J = 16.0 Hz, 1H), 6.36 (dd, J = 16.0, 8.0 Hz, 1H), 5.75 (brs, 1 H), 4.46 (d, J=6 Hz, 2H), 4.01 (m, 1H), 2.11 (s, 3H); ESIMS m/z 402.00 ([M+H]+).
Compounds CC2 - CC6 in Table 1 were made in accordance with the procedures disclosed in Example 72. In addition, compound DC56 in Table 1 was made from compound DC55 in accordance with the procedures disclosed in Example 72.
Example 73: Préparation of (E)-A/-(2-chloro-4-(3-(3,5-diçhlorophenyl)-4,4,4-trifluorobut-1-en-
1-yl)benzyl)acetamide (CC7)
CF
Cl
To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1yl)phenyl)methanamine (0.3 g, 0.8 mmol) in DMF (5 mL) was added 2,2,2-trifluoro-propanoic acid (97 mg, 0.76 mmol), HOBt»H2O (174 mg, 1.14 mmol) and EDC’HCI (217 mg, 1.14 mmol) and DIEA (196 mg, 1.52 mmol), and the résultant reaction mixture was stirred at ambient température for 18 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; ethyl acetate in hexane (30-50% afforded the title compound as a off-white solid (0.2 g, 60%): mp 127-128 °C; 1H NMR (400 MHz, CDCI3) δ
121
7.42 (m, 4H), 7.24 (m, 2H), 6.53 (d, J= 16.0 Hz, 1H), 6.36 (dd, J= 16.0, 8.0 Hz, 1H), 5.86 (brs, 1H), 4.51 (d, J= 6.0 Hz, 2H), 4.05 (m, 1H), 2.02 (s, 3H); ESIMS m/z 436.03 ([M+H]+).
Compounds CC8 - CC28 in Table 1 were made in accordance with the procedures disclosed in Example 73.
Example 74: Préparation of (5)-A/-(pyridin-2-ylmethyl)-A/-(4-(4,4,4-tnfluoro-3-(3,4,5trichlorophenyl)but-1-enyl)-2-(trifluoromethyl)benzy!)cyclopropanecarboxamide (CC29)
CF
Cl
Cl
Step 1 : (E)-1-(Pyridin-2-yl)-/V-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2(trifluoromethyl)benzyl)methanamine. (5)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1 -en-1 yl)-2-(trifluoromethyl)phenyl)methanamine (0.46 g, 1 mmol) was dissolved in CH3OH (3 mL). To this was added pyridine-2-carbaldehyde (0.107 g, 1 mmol). The reaction mixture was stirred for 1 h. After 1 h, NaBH4 (0.076 g, 2 mmol) was added and left at ambient température for 3 h. The reaction mixture was concentrated to give an oily residue. Purification by flash column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a pale yellow liquid (0.22 g, 40%): 1H NMR (400 MHz, CDCI3) □ 8.58 (d, J= 4.8 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J = 16.0 Hz, 1H), 6.38 (dd, J = 16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 4.02 (s, 2H), 3.96 (s, 2H); ESIMS m/z 552.95 ([M+H]+); IR (thin film) 3338, 1114, 808 cm’1.
Step 2: (E)-A/-(Pyridin-2-ylmethyl)-N-(4-(4,4)4-trifluoro-3-(3,4,5-trichlorophenyl)but-1enyl)-2-(trifluoromethyl)benzyl)cyclopropanecarboxamide. (5z)-1-(Pyridin-2-yl)-A/-(4-(4,4,4trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzyl)methanamine (0.27 g, 0.05 mmol) was taken up in CH2CI2 (3 mL). To this was added Et3N (0.14 mL, 0.1 mmol). The reaction mixture was stirred for 10 min. After 10 min, the reaction mixture was cooled to 0 °C, and cyclopropylcarbonyl chloride (0.08 mL, 0.075 mmol) was added. The reaction mixture was stirred at ambient température for 1 h and then was washed with H2O and satd aq NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and evaporated to obtain pale yellow gummy material (0.15 g, 50%): 1H NMR (400 MHz, CDCI3) □ 8.58 (d, J= 4.6 Hz, 1H), 7.74 (m, 1H), 7.62
122 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J= 16.0 Hz, 1 H), 6.38 (dd, J = 16.0, 8.0 Hz, 1H), 5.02 (s, 1H), 4.8 (s, 1H), 4.8 (d, J = 10 Hz, 2H), 4.10 (m, 1H), 1.8 (m, 1H), 1.2 (m, 2H), 0.6 (m, 2H); ESIMS m/z 620.86 ([M-H] ); IR (thin film) 1645, 1115, 808 cm’1.
Example 75: Préparation of (E)-A/-(2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1en-1-yl)benzyl)-3-(methylsulfonyl)propanamide (CC30)
(E)-/V-(2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-3(methylthio)propanamide (0.15 g, 0.28 mmol) was treated with oxone (0.175 g, 0.569 mmol) in 1:1 acetone:water (20mL) for 4 h at ambient température. The acetone was evaporated to obtain a white solid (0.095 g, 60%): mp 101-104 °C; 1H NMR (400 MHz, CDCI3) δ 7.41 (m, 4H), 7.24 (m, 1H), 6.53 (d, J= 16.0 Hz, 1H), 6.35 (dd, J= 16.0, 8.0 Hz, 1H), 6.12 (brs, 1H), 4.53 (m, 2H), 4.10 (m, 1H), 3.42 (m, 2H), 2.91 (s, 3H), 2.78 (m, 2H); ESIMS m/z 559.75 ([M-H] ).
Example 76: Préparation of (E)-1-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1yl)benzyl)-3-ethylurea (CC31)
To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2CI2 (5 mL) at 0 °C were added Et3N (0.141 mL, 1 mmol) and ethylisocyanate (0.053 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0 °C. The reaction mixture was diluted with CH2CI2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.141 g, 60%): mp 177-178 °C; 1H NMR (400 MHz, CDCI3) δ 7.58 (m, 2H), 7.41 (m, 3H),
7.24 (m, 1H), 6.53 (d, J= 16.0 Hz, 1H), 6.35 (dd, J= 16.0, 8.0 Hz, 1H), 4.70 (brs, 1H), 4.43 (s, 2H), 4.08 (m, 1H), 3.21 (m, 2H), 1.25 (m, 3H); ESIMS m/z 463 ([M-H]’).
Compounds CC32 - CC35 in Table 1 were made in accordance with the procedures disclosed in Example 76.
123
Example 77: Préparation of (E)-3-(2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en1 -yl)benzyl)-1,1 -dimethylurea (CC36)
Cl O
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2CI2 (5 mL) at 0 °C were added Et3N (0.141 mL, 1 mmol) and /V;A/-dimethylcarbamoyl chloride (0.08 g, 0.075 mmol), and the reaction mixture was stirred for 1 h at 0 °C. The reaction mixture was diluted with CH2CI2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.15 g, 60%): 1H NMR (400 MHz, CDCI3) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J= 16.0 Hz, 1H), 6.34 (dd, J= 16.0, 8.0 Hz, 1H), 4.97 (brs, 1H), 4.38 (d, J= 6.0 Hz, 2H), 4.10 (m, 1H), 2.9 (s, 3H), 2.7 (s, 3H); ESIMS m/z 497 ([M-H] ); IR (thin film) 3350, 1705, 1114, 808 cm’1.
Example 78: Préparation of (E)-1-(2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-
1-yl)benzyl)-3-ethylthiourea (CC37)
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2CI2 (5 mL) at 0 °C were added Et3N (0.141 mL, 1 mmol) and ethyl isothicyanate (0.053 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0 °C. The reaction mixture was diluted with CH2CI2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.14 g, 60%): mp 88-91 °C; 1H NMR (400 MHz, CDCI3) δ 7.49 (d, J= 8 Hz, 1H), 7.41 (d, J =
7.2 Hz, 2H), 7.26 (m, 2H), 6.50 (d, J = 16 Hz, 1 H), 6.35 (dd, J = 16.0, 8.0 Hz, 1 H), 6.0 (br s, 1 H), 5.73 (br s, 1 H), 4.80 (br s, 2H), 4.09 (m, 1 H), 1.23 (m, 3H); ESIMS m/z 515.01 ([M+H]+).
Compound CC38 in Table 1 was made in accordance with the procedures disclosed in Example 78.
124
Example 79: Préparation of (E)-tert-butyl (2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4trifluorobut-1-en-1-yl)benzyl)-3-ethylurea (CC39)
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1yl)phenyl)methanamine (0.2 g, 0.5 mmol in CH2CI2 (5 mL) at 0 °C were added Et3N (0.141 mL, 1 mmol) and di-ferf-butyl dicarbonate (0.163 mL, 0.75 mmol), and the reaction mixture was stirred for 4 h at ambient température. The reaction mixture was diluted with CH2CI2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 10-20% EtOAc in hexane) afforded the title compound as a white solid (0.147 g, 60%): 1H NMR (400 MHz, CDCI3) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J= 16.0 Hz, 1H), 6.34 (dd, J= 16.0, 8.0 Hz, 1H), 4.97 (brs, 1H), 4.38 (d, J = 6.0 Hz, 2H), 4.10 (m, 1H), 1.53 (s, 9H); ESIMS m/z 526.09 ([M-H] ); IR (thin film) 3350, 1705, 1114, 808 cm’1.
Compound CC40 in Table 1 was made in accordance with the procedures disclosed in Example 79.
Example 80: Préparation of (E)-methyl 2-((2-chloro-4-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-en-1-yl)benzyl)amino)-2-oxoacetate (CC41)
Cl O
To a stirred solution of (£)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2CI2 (5 mL) at 0 °C were added Et3N (0.141 mL, 1 mmol) and methyl 2-chloro-2-oxoacetate (0.09 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0 °C. The reaction mixture was diluted with CH2CI2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20% EtOAc in hexane) afforded the title compound as a solid (0.12 g, 50%): 1H NMR (400 MHz, CDCI3) δ 7.48 (m, 1H). 7.43 (m, 3H), 7.38 (m, 1H),
7.23 (s, 1H), 6.55 (d, J= 16.0 Hz, 1H), 6.36 (dd, J= 16.0, 8.0 Hz, 1H), 4.60 (d, J = 4.4 Hz, 2H),
4.18 (m, 1H), 3.85 (s, 3H); ESIMS m/z 512.22 ([M-H]’); IR (thin film) 1740, 1701, 1114, 808 cm’1.
125
Example 81: Préparation of (E)-/V1-(2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1en-1-yl)benzyl)-A/2-(2,2,2-trifluoroethyl)oxalamide (CC42)
To a stirred solution of 2,2,2-trifluoroethylamine hydrochloride (0.1 g, 0.77 mmol) in CH2CI2 (10 mL) was added dropwise trimethylaluminum (2 M solution in toluene; 0.39 mL, 0.77 mmol), and the reaction mixture was stirred at 25 °C for 30 min. A solution of (E)-methyl 2-((2-chloro-4-(4,4,4trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzyl)-2-oxoacetate (0.2 g, 0.38 mmol) in CH2CI2 (5 mL) was added dropwise to the reaction mixture at 25 °C. The reaction mixture was stirred at reflux for 18 h, cooled to 25 °C, quenched with 0.5 N HCl solution (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; 20%-40% EtOAc in n-hexane) to afford the title compound (0.13 g, 60%): mp 161-163 °C; 1H NMR (400 MHz, DMSO-cfe) δ 9.45 (br s, 2H), 7.90 (s, 2H), 7.75 (s, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 6.93 (m, 1H), 6.75 (m, 1H), 4.80 (m, 1H), 4.40 (s, 2H), 3.90 (s, 2H); ESIMS m/z 578.96 ([Μ-H]’).
Example 82: Préparation of (E)-/V-(2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1en-1 -yl)benzyl)pyridin-2-amine (CC43)
To a stirred solution of /V-(2-chloro-4-vinylbenzyl)pyridin-2-amine (0.3 g, 1.22 mmol) in 1,2dichlorobenzene (5 mL) were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.83 g, 2.44 mmol), CuCI (24 mg, 0.24 mmol) and 2,2-bipyridyl (76 mg, 0.48 mmol). The résultant reaction mixture was degassed with argon for 30 min and then stirred at 180 °C for 24 h. After the reaction was deemed complété by TLC, the reaction mixture was cooled to ambient température and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 15% EtOAc in n-hexane) afforded the title compound as an off-white solid (0.2 g, 35%): mp 140-142 °C; 1H NMR (400 MHz, CDCI3) δ 8.11 (d, J = 4.0 Hz, 1H),
126
7.40 (m, 5H), 7.22 (m, 1H), 6.61 (m, 2H), 6.35 (m, 2H), 4.94 (brs, 1H), 4.61 (d, J = 6.4 Hz, 2H),
4.11 (m, 1H); ESIMS m/z 505.39 ([M+H]+).
Example 83: Préparation of (E)-/V-((3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)-but-1en-1-yl)pyridin-2-yl)methyl)-3,3,3-trifluoropropanamide (CC44)
To a stirred solution of (E)-(3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1yl)pyridin-2-yl)methanamine (0.1 g, 0.2 mmol) in CH2CI2 (5 mL) were added 3,3,3-trifluoropropanoic acid (45 mg, 0.350 mmol), EDOHCI (67 mg, 0.350 mmol), HOBt»H2O (71 mg, 0.467 mmol) and DIEA (60.2 mg, 0.467 mmol), and the reaction mixture was stirred at ambient température for 18 h. The reaction mixture was diluted with CH2CI2 and washed with H2O. The combined CH2CI2 layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in petroleum ether) afforded the title compound as a pale yellow liquid (30 mg, 35%): 1H NMR (400 MHz, CDCI3) δ 8.41 (s, 1H), 7.77 (s, 1H), 7.47 (brs, 1H), 7.40 (s, 2H), 6.58 (d, J= 16.0 Hz, 1H), 6.45 (dd, J= 16.0, 8.0 Hz, 1H), 4.68 (d, J = 4.0 Hz, 2H), 4.14 (m, 1H), 3.24 (q, J= 10.8 Hz, 2H); ESIMS m/z 536.88 ([ΜΗ]’); IR (thin film) 3320, 1674, 1114, 808.
Compound CC45 in Table 1 was made in accordance with the procedures disclosed in Example 83.
Example 84: Préparation of (E)-3,3,3-trifluoro-/V-((4-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)propanamide (CC46)
To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1yl)naphthalen-1-yl)methanamine (0.1 g, 0.22 mmol) in CH2CI2 (8 mL) were added 3,3,3trifluoropropanoic acid (0.032 g, 0.24 mmol), HOBt*H2O (52 mg, 0.33 mmol), EDC’HCI (0.065 g, 0.33 mmol) and DIEA (0.044 g, 0.45 mmol), and the résultant reaction mixture was stirred at ambient température for 18 h. The reaction mixture was diluted with H2O and extracted with EtOAc
127 (3 x30 mL). The combined EtOAc layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in n-hexane) afforded the title compound as a gummy material (60 mg, 50%): mp 151-153 °C; 1H NMR (400 MHz, CDCI3) δ 8.06 (m, 1H), 7.61 (m, 4H), 7.48 (s, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.38 (m, 1H), 6.42 (m, 1H), 5.92 (brs, 1H), 4.92 (m, 2H), 4.24 (m, 1H), 3.12 (m,2H); ESIMS m/z 554.04 ([M-H] ).
Compounds CC47 - CC48 in Table 1 were made in accordance with the procedures disclosed in Example 84.
Example 85: Préparation of (E)-1-ethyl-3-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-
1-yl)naphthalen-1-yl)methyl)urea (CC49)
To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1yl)naphthalen-1-yl)methanamine (0.1 g, 0.22 mmol) in CH2CI2 at 0 °C were added Et3N (0.064 mL, 0.44 mmol) and ethylisocyanate (0.023 mL, 0.33 mmol), and the reaction mixture was stirred for 1 h at 0 °C. The reaction mixture was diluted with CH2CI2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30% EtOAc in hexane) afforded the title compound as a solid (0.07 g, 60%): mp 84-87 °C; 1H NMR (400 MHz, CDCI3) δ 8.06 (m, 1H), 7.98 (m, 1H), 7.61 (m, 3H), 7.48 (s, 2H), 7.44 (d, J= 8.0 Hz, 1H), 7.38 (m, 2H), 6.42 (m, 1H), 4.92 (s, 2H), 4.6 (brs, 1 H), 4.24 (m, 1 H), 3.21 (m, 2H), 1.2 (t, J = 4.6 Hz, 3H); ESIMS m/z 515.33 ([M+H]+).
Example 86: Préparation of (£)-/^-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1yl)phenyl)cyclopropanecarbohydrazide (CC50)
To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1yl)phenyl)hydrazine (0.1 g, 0. 3 mmol) in CH2CI2 (10 mL) was added DIEA (65 mg, 0.51 mmol), HOBt»H2O (59 mg, 0.38 mmol), EDC»HCI (73 mg, 0.38 mmol) and cyclopropanecarbonyl chloride
128 (0.024 g, 0.28 mmol), and the reaction mixture was stirred at ambient température for 1 h. The reaction mixture was diluted with satd aq NaHCO3 solution and extracted with CH2CI2. The combined CH2CI2 layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 5-25% EtOAc in petroleum ether) afforded the title compound as a solid (65 mg, 55%): mp 138-140 °C; 1H NMR (400 MHz, CDCI3) δ 9.81 (s, 1H), 7.90 (s, 1H), 7.84 (s, 2H), 7.34 (d, J= 8.4 Hz, 2H), 6.65 (d, J =
15.6 Hz, 1 H), 6.61 (m, 1 H), 6.57 (s, 1 H), 6.48 (dd, J = 15.6, 8.8 Hz, 1 H), 4.74 (m, 1 H), 1.64 (m, 1 H), 0.75 (m, 4H); ESIMS m/z 461.32 ([M-H]’).
Compound CC51 in Table 1 was made in accordance with the procedures disclosed in Example 86.
Example 87: Préparation of (E)-/V-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1yl)phenoxy)cyclopropanecarboxamide (CC52)
To a stirred solution of (E)-O-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1yl)phenyl)hydroxylamine (0.15 g, 0.38 mmol) in CH2CI2 (5 mL) was added EDC’HCI (0.109 g, 0.569 mmol), HOBt*H2O (0.087 g, 0.569 mmol), DIEA (0.097 g, 0.758 mmol) and cyclopropanecarboxylic acid (0.049 g, 0.569 mmol). The résultant reaction mixture was stirred at ambient température for 18 h. The reaction mixture was diluted with H2O and extracted with CHCI3 (35 mL) The combined CHCI3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2; 20% EtOAc in hexane) afforded the title compound as a brown liquid (0.06 g, 34%); 1H NMR (400 MHz, CDCI3) δ 7.40 (s, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 6.85 (m, 1H), 6.45 (m, 1H), 6.65 (m, 1H), 6.20 (m, 1H), 5.55 (s, 1H), 4.08 (m, 1H),
1.90 (m, 1H), 1.30-1.10 (m, 4H); ESIMS m/z 464.87 ([M-H]').
Compound CC53 in Table 1 was made in accordance with the procedures disclosed in Example 87.
Example 88: Préparation of (Z)-3,3,3-trifluoro-/V-(4-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-en-1-yl)benzyl)propanamide (CC54)
129
A silicon borate vial was charged with (E)-3,3,3-trifluoro-/V-(4-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-en-1-yl)benzyl)propanamide (133 mg, 0.269 mmol) and dimethyl sulfoxide (DMSO; 10 mL). The mixture was placed within 0.6 to 1 meter (m) of a bank of eight 115 watt Sylvania FR48T12/350BL/VHO/180 Fluorescent Tube Black Lights and four 115 watt Sylvania (daylight) F48T12/D/VHO Straight T12 Fluorescent Tube Lights for 72 h. The mixture was concentrated in vacuo and purified by reverse phase chromatography to give the title compound as a colorless oil (11 mg, 8%): 1H NMR (300 MHz, CDCI3) δ 7.28 (s, 2H), 7.25 (m, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 11.4 Hz, 1 H), 6.07 (br s, 1 H), 6.01 (m, 1 H), 4.51 (d, J = 5.8 Hz, 2H), 4.34 (m, 1H), 3.12 (q, J =7.5 Hz, 2H); 13C NMR (101 MHz, CDCI3) δ 162.44, 137.20, 135.38, 135.23, 134.82, 134.68, 131.71, 129.00, 128.80, 128.69, 128.10, 127.96, 122.63,76.70, 47.33 (q, J = 28 Hz), 43.59, 42.12 (q, J= 30 Hz); ESIMS m/z 504 ([M+H]+).
Compounds DC46, AC93. AC94 in Table 1 were made in accordance with the procedures disclosed in Example 88.
Example 89: Préparation of 1-(1-bromo-2,2,2-trifluoroethyl)-3-chlorobenzene (DI2)
ÇF3
OH
Cl
DU
ÇF3
Br
Cl
DI2
The title compound was synthesized in two steps via 1-(3-chlorophenyl)-2,2,2trifluoroethanol (DI1, prepared as in Step 1, Method B in Example 1); isolated as a colorless viscous oil (1.5 g, 75%): 1H NMR (400 MHz, CDCI3) δ 7.50 (s, 1H), 7.42-7.35 (m, 3H), 5.02 (m, 1H),
2.65 (br s, 1H)) and Step 2 in Example 1 and isolated (0.14 g, 22%): 1H NMR (400 MHz, CDCI3) δ 7.50 (br s, 1H), 7,42-7.35 (m, 3H), 5.07 (m, 1H).
The following compounds were made in accordance with the procedures disclosed in Example 89.
(1-Bromo-2,2,2-trifluoroethyl)benzene (DI4)
130
ÇF3
ΌΗ
cf3 ABr
DI3
DI4
2,2,2-Trifluoro-1-phenylethanol (DI3) was isolated (10 g, 80%): 1H NMR (300 MHz, CDCI3) δ 7.48 (m, 2H), 7.40 (m, 3H), 5.02 (m, 1H), 2.65 (d, J =7.1 Hz, 1H). The title compound (DI4) was isolated as a liquid (8.0 g, 60%): 1H NMR (400 MHz, CDCI3) δ 7.50 (m, 2H), 7.40 (m, 3H), 5.00 (q, J =7.5 Hz, 1H).
1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dimethylbenzene (DI20)
ÇF3
OH
DI19
1-(3,5-Dimethylphenyl)-2,2,2-trifluoroethanol (DI19) was isolated an off white solid : 1H NMR (400 MHz, CDCI3) δ 7.05 (s, 2H), 7.02 (s, 1H), 4.95 (m, 1H), 2.32 (s, 6H); ESIMS m/z 204 ([M] ). The title compound (DI20) was isolated (3.0 g, 51%).
1-(1-Bromo-2,2,2-trifluoroethyl)-2,4-dichlorobenzene (DI22)
1-(2,4-Dichlorophenyl)-2,2,2-trifluoroethanol (DI21) was isolated as an off white powder (5.3 g, 61%): mp 49-51 °C; 1H NMR (400 MHz, CDCI3) δ 7.62-7.66 (d, 1H), 7.42-7.44 (d, 1H), 7.32-7.36 (d, 1H), 5.6 (m, 1H), 2.7 (s, 1H); ESIMS m/z 244 ([M]+). The title compound (DI22) was isolated (3.2 g, 50%): 1H NMR (400 MHz, CDCI3) δ 7.62-7.72 (m, 1H), 7.4-7.42 (m, 1H), 7.3-7.38 (m, 1H), 5.7-5.8 (m, 1H).
1-(1-Bromo-2,2,2-trifluoroethyl)-2,3-dichlorobenzene (DI24)
131
DI23
1-(2,3-Dichlorophenyl)-2,2,2-trifluoroethanol (DI23) was isolated as a pale yellow oil (5.2 g, 60%): 1H NMR (400 MHz, CDCI3) δ 7.62-7.64 (d, 1H), 7.52-7.54 (m, 1H), 7.29-7.33 (t, 1H), 5.6-5.76 (m, 1H), 2.7 (s, 1H); ESIMS m/z 243.9 ([M]+). The title compound (DI24) was isolated as an oil (8.7 g, 60%): 1H NMR (400 MHz, CDCI3) δ 7.62-7.71 (m, 1H), 7.44-7.52 (m, 1H), 7.27-7.3 (s, 1H), 5.81-
5.91 (m, 1H).
2-(1-Bromo-2,2,2-trifluoroethyl)-1,4-dichlorobenzene (DI26)
Cl
DI26
1-(2,5-Dichlorophenyl)-2,2,2-trifluoroethanol (DI25) was isolated as a yellow oil (4.1 g, 60%): 1H NMR (400 MHz, CDCI3) δ 7.68-7.7 (s, 1H), 7.3-7.37 (m, 2H), 5.51-5.6 (m, 1H), 2.7 (s, 1H); ESIMS m/z 244 ([M]+)). The title compound (DI26) was isolated (3.0 g, 60%): 1H NMR (400 MHz, CDCI3) δ 7.7-7.78 (m, 1H), 7.3-7.4 (m, 2H), 5.7-5.8 (m, 1H).
1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-bis(trifluoromethyl)benzene (DI28)
1-(3,5-Bis(trifluoromethyl)phenyl)-2,2,2-trifluoroethanol (DI27) was isolated (3.8 g, 60%): 1H NMR (400 MHz, CDCI3) δ 7.98 (m, 3H), 5.25 (m, 1H), 3.2 (br, 1H); ESIMS m/z 312.2 ([M]+). The title compound (D128) was prepared and carried on crude.
1-(1-Bromo-2,2,2-trifluoroethyl)-2,3,5-trichlorobenzene (DI30)
132
0129
2,2,2-Trifluoro-1-(2,3,5-trichlorophenyl)ethanol (DI29) was isolated as a white solid (4.0 g, 60%): mp 113-115 °C; 1H NMR (400 MHz, CDCI3) δ 7.62 (d, 1H), 7.50 (d, 1H), 5.60-5.70 (m, 1H),
2.75 (s, 1H); ESIMS m/z 278.0 ([M+]). The title compound (DI30) was isolated (2.9 g, 60%): 1H
NMR (400 MHz, CDCI3) δ 7.70 (d, 1 H), 7.50 (d, 1 H), 5.72-5.82 (m, 1 H).
1-(1-Bromo-2,2,2-trifluoroethyl)-3-chloro-5-(trifluoromethyl)benzene (DI32)
1-(3-Chloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethanol (DI31) was isolated as a pale yellowoil (2.0 g, 50%): 1H NMR (400 MHz, CDCI3) δ 7.51 (m, 3H), 5.08 (m, 1H), 2.81 (s, 1H);
ESIMS m/z 278.1 ([M]+). The title compound (DI32) was isolated oil (2.0 g, 40%): ESIMS m/z 342 ([MF).
5-(1 -Bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-methoxybenzene (DI34)
1-(3,5-Dichloro-4-methoxyphenyl)-2,2,2-trifluoroethanol (DI33) was isolated as an off white solid (0.8 g, 60%); mp 92-95 °C: 1H NMR (400 MHz, CDCI3) δ 7.41 (s, 2H), 5.00 (m, 1 H), 3.89 (s, 3H), 2.64 (m, 1H); ESIMS m/z 274 ([M]+). The title compound (DI34) was isolated as a colorless liquid (0.6 g, 57%).
Example 90: Préparation of 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-difluorobenzene (DI36)
133
The title compound was synthesized in two steps via 1-(3,5-difluorophenyl)-2,2,2trifluoroethanol (DI35, prepared as in Step 1, Method A in Example 1; isolated as a colorless oil (0.2 g, 75%): 1H NMR (400 MHz, CDCI3) δ 7.05 (m, 2H), 6.88 (m, 1H), 5.06 (m, 1H), 2.66 (s, 1H); ESIMS m/z 212 ([M]+) and Step 2 in Example 1 and isolated (3.2 g, 50%); 1H NMR (400 MHz, CDCI3) δ 7.05 (m, 2H), 6.86 (m, 1H), 5.03 (q, J= 7.4 Hz, 1H).
The following compounds were made in accordance with the procedures disclosed in Example 90.
-(1 -Bromo-2,2,2-trifluoroethyl)-4-chlorobenzene (DI38)
DI37
DI38
1-(4-Chlorophenyl)-2,2,2-trifluoroethanol (DI37) was isolated as a colorless oil (5.0 g, 99%): 1H NMR (400 MHz, CDCI3) δ 7.44-7.38 (m, 4H), 5.05 (m, 1H), 2.55 (s, 1H); ESIMS m/z 210 ([M]+). The title compound (DI38) was isolated (3.0 g, 46 %): 1H NMR (400 MHz, CDCI3) δ 7.45 (d, J = 8.2 Hz, 2H), 7.37 (d, J= 8.2 Hz, 2H), 5.10 (q, J = 7.2 Hz, 1H).
-(1 -Bromo-2,2,2-trifluoroethyl)-4-methoxybenzene (0140)
2,2,2-Trifluoro-1-(4-methoxyphenyl)ethanol (DI39) was isolated as a pale yellow liquid: 1H NMR (400 MHz, CDCI3) δ 7.41 (d, J = 8.8 Hz, 2H), 6.95 (m, J = 8.8 Hz, 2H), 5.00 (m, 1 H), 3.82 (s, 3H), 2.44 (s, 1H); ESIMS m/z 206.1 ([M]+). The title compound (DI40) was isolated (3.8 g, 62%).
1-(1-Bromo-2,2,2-trifluoroethyl)-4-fluorobenzene (DI42)
134
2,2,2-Trifluoro-1-(4-fluorophenyl)ethanol (DI41) was isolated as a colorless oil (5 g, 99%): 1H NMR (400 MHz, CDCI3) δ 7.48-7.45 (m, 2H), 7.13-7.07 (m, 2H), 5.06 (m, 1H), 2.53 (s, 1H); ESIMS m/z 194 ([M]+). The title compound (DI42) was prepared and carried on as crude intermediate.
1-(1-Bromo-2,2,2-trifluoroethyl)-4-methylbenzene (DI44)
DI43 DI44
2,2,2-Trifluoro-1-(p-tolyl)ethanol (DI43) was isolated as colorless oil (5.0 g, 99%); 1H NMR (400 MHz, CDCI3) δ 7.37 (d, J = 8.0 Hz, 2H), 7.23 (d, J =8.0 Hz, 2H), 5.02 (m, 1H), 2.46 (m, 1H),
2.37 (s, 3H); ESIMS m/z 190 ([M]+). The title compound (DI44) was isolated (3.0 g, 45%).
1-(1-bromo-2,2,2-trifluoroethyl)-3-fluorobenzene (DI46)
DI45 DI46
2,2,2-Trifluoro-1-(3-fluorophenyl)ethanol (DI45) was isolated as a colorless viscous oil (2.8 g, 93%); 1H NMR (400 MHz, CDCI3) δ 7.41 (m, 1H), 7.25 (m, 2H), 7.14 (m, 1H), 5.06 (m, 1H), 2.60 (s, 1H); ESIMS m/z 194 ([M]+). The title compound (DI46) was isolated (2.0 g, 61%).
1-(1-Bromo-2,2,2-trifluoroethyl)-2-fluorobenzene (DI48)
DI47
DI48
135
2,2,2-Trifluoro-1-(2-fluorophenyl)ethanol (DI47) was isolated as a colorless oil (2.5 g, 99%): 1H NMR (400 MHz, CDCI3) δ 7.40 (m, 1H), 7.43 (m,1H), 7.24 (m, 1H), 7.13 (m, 1H), 5.42 (m, 1H),
2.65 (s, 1H); ESIMS m/z 194 ([M]+). The title compound (DI48) was isolated (2.0 g, 61%): 1H NMR (400 MHz, CDCI3) δ 7.61 (m, 1H), 7.40 (m, 1H), 7.23 (m, 1H), 7.10 (m, 1H), 5.40 (m, 1H); GCMS m/z 255 ([M-H]’).
Example 91: Préparation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI5)
To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4- triazole (6.67 g, 96.7 mmol) and the résultant reaction mixture was stirred at 120 °C for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc (3 x100 mL). The combined EtOAc layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65%): mp 145-149 °C: 1H NMR (400 MHz, CDCI3) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J = 8.0 Hz, 2H), 7.92 (d, J= 8.0 Hz, 2H); ESIMS m/z 173.9 ([M+Hf).
The following compound was made in accordance with the procedures disclosed in Example 91.
5-Formyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (DI49)
O
The title compound was isolated (2.8 g, 60%); 1H NMR (400 MHz, CDCI3) δ 10.10 (s, 1H), 8.98 (s, 1H), 8.35 (s, 1H), 8.30 (d, 1H), 8.22 (s, 1H), 8.07 (d, 1H); IR (thin film) 3433, 3120, 1702, 1599, 1510 cm·1.
2-Chloro-4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI50)
136
\^Ν
The title compound was isolated as an off white solid (3.0 g, 40%): mp 149-151 °C; 1H NMR (400 MHz, CDCI3) δ 10.05 (s, 1H), 8.74 (s, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.90 (m, 2H) ; ESIMS m/z 208.10 ([M+H]+).
5-Methyl-4-(1 H-1,2,4-triazol-1 -yl)benzaldehyde (DI51 )
The title compound was isolated as a white solid (0.5 g, 74 %): mp 109-111 °C; 1H NMR (400 MHz, D6-DMSO) δ 10.06 (s, 1H), 9.00 (s, 1H), 8.30 (s, 1H), 7.99 (s, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.69 (d, J= 9.2 Hz, 1H), 2.30 (s, 3H); ESIMS m/z 188.13 ([M+H]+).
Example 92: Préparation of 5-formyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)benzonitrile (DI52)
To a stirring solution of 2-fluoro-5-formylbenzonitrile (0.5 g, 3.3 mmol) in DMF (25 mL) were added K2CO3 (0.68 g, 4.95 mmol) and 3-nitro-1,2,4 triazole (0.45 g, 4.2 mmol) and the résultant reaction mixture was stirred at RT for 14 h. After completion of reaction (TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined EtOAc layer was washed with water and brine then dried over Na2SO4 and concentrated under reduced pressure to afforded the title compound as a pale yellow solid (0.36 g, 45%); mp 170-172 °C; 1H NMR (300 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.61 (s, 1H), 8.69 (s, 1H), 8.45 (d, J = 9.3 Hz, 1H), 8.23 (d, J = 9.3 Hz, 1H); ESIMS m/z 242.3 ([M-H] ); IR (thin film) 2238, 1705, 1551, 1314 cm·1.
Example 93: Préparation of 4-(3-methyl-1H-1,2,4-triazol-1-yl)benzaldehyde (DI53)
137
To a stirring solution of 4-fluorobenzaldehyde (5.0 g, 40.32 mmol) in DMF (50 mL), were added K2CO3 (3.34 g, 40.32 mmol) and 3-methyl-1,2,4-trizole (3.34 g, 40.32 mmol) and the résultant reaction mixture was stirred at RT for 4 h. After completion ofthe reaction (TLC), the reaction mixture was diluted with water and extracted with EtOAc (3x). The combined EtOAc layer was washed with water and brine then dried over Na2SO4 and concentrated under reduced pressure to afforded the title compound as a white solid (4.1 g, 60%): mp 125-128°C; 1H NMR (400 MHz, CDCI3) δ 10.05 (s, 1H), 8.76 (s, 1H), 8.02 (d, 2H), 7.85 (d, 2H), 2.50 (s, 3H); ESIMS m/z 188.04 ([M+H]+).
The following compound was made in accordance with the procedures disclosed in Example 93.
4-(1H-1,2,4-triazol-1-yl)-3-(trifluoromethyl)benzaldehyde (DI54)
The title compound was isolated as white solid (1.05 g, 60%); mp 81-83 °C; 1H NMR (400 MHz, CDCI3) δ 10.15 (s, 1H), 8.43 (s, 1H), 8.37 (s, 1H), 8.25 (d, J= 7.2 Hz, 1H), 8.18 (s, 1H), 7.79 (d, J = 7.2 Hz, 1 H); ESIMS m/z 241.0 ([M]+).
4-(3-nitro-1 Η-Ί ,2,4-triazol-1 -yl)benzaldehyde (DI55)
The title compound was isolated as pale yellow solid (0.10 g, 23%): mp 159-161 °C; 1H
NMR (400 MHz, CDCI3) δ 10.10 (s, 1H), 8.89 (s, 1H), 8.15 (m, 2H), 8.00 (m, 2H); ESIMS m/z
217.11 ([M-H]').
138
3-bromo-4-(1 H-1,2,4-triazol-1 -yl)benzaldehyde (DI56)
The title compound was isolated as white solid (3.2 g, 51%): mp 126-128 °C; 1H NMR (400 MHz, CDCI3) δ 10.04 (s, 1H), 8.69 (s, 1H), 8.27 (Μ, 1H, 8.18 (s, 1H) 7.99 (d, J = 9.2 Hz, 1H), 7.76 (d, J= 9.2 Hz, 1H); ESIMS m/z 250.9 ([M]+).
5-formyl-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile (DI57)
O
The title compound was isolated as white solid (0.13 g, 30%): mp 147-149 °C; 1H NMR (400 MHz, CDCI3) δ 10.07 (s, 1 H), 8.89 (s, 1 H), 8.32 (d, J = 1.8 Hz, 1 H), 8.24 (dd, J = 8.6, 1.3 Hz, 1 H), 8.06 (d, J = 8.6 Hz, 1H), 2.54 (s, 3H); ESIMS m/z 213.09 ([M+H]+); IR (thin film) 2239, 1697 cm'1.
3-nitro-4-(1 /7-1,2,4-triazol-1 -yl)benzaldehyde (DI58)
The title compound was isolated as pale yellow solid (3.0 g, 60 %): mp 116-118 °C; 1H NMR (400 MHz, CDCI3) δ 10.15 (s, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 8.26 (d, J = 6.9 Hz, 1H), 8.16 (s, 1H), 7.83 (d, J= 6.9 Hz, 1H); ESIMS m/z 219.00 ([M+H]+).
Example 94: Préparation of 1-(4-vinylphenyl)-1H-1,2,4-triazole (DI59)
To a stirred solution of 4-[1,2,4]triazol-1-yl-benzaldehyde (9.0 g, 52 mmol) in 1,4-dioxane (100 mL), were added K2CO3 (10.76 g, 78 mmol) and methyl triphenyl phosphonium bromide (22.2
139 g, 62.4 mmol) at room température. The résultant reaction mixture was heated to 70 °C for 18 h. After completion ofthe reaction (TLC), the reaction mixture was cooled to room température and filtered and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) to afforded the title compound as a white solid (5.6 g, 63%): ESIMS m/z 172.09 ([M+H]+).
The following compound was made in accordance with the procedures disclosed in Example 94.
1-(2-Methyl-4-vinylphenyl)-1H-1,2,4-triazole (DI60)
The title compound was isolated as an off white solid (1.5 g, 76%): 1H NMR (400 MHz, CDCI3) δ 8.25 (s, 1H), 8.11 (s, 1H), 7.35 (m, 2H), 7.27 (d, J =8.7 Hz, 1H), 6.74 (m, 1H), 5.82 (d, J = 17.3 Hz, 1H), 5.36 (d, J= 10.0 Hz, 1H), 2.25 (s, 3H); ESIMS m/z 186.14 ([M+H]+).
2-(1H-1,2,4-Triazol-1-yl)-5-vinylbenzonitrile (DI61)
The title compound was isolated as an off-white solid (1.40 g, 71%): mp 126-129 °C; 1H NMR (400 MHz, CDCI3) δ 8.76 (s, 1H), 8.18 (s, 1H), 7.82-7.84 (m, 1H), 7.72-7.80 (m, 2H), 6.70-
6.80 (dd, J= 17.6, 10.8 Hz, 1H), 5.90-5.95 (d, J= 17.6 Hz, 1H), 5.50-5.70 (d, J= 10.8 Hz, 1H); ESIMS m/z 197.03 ([M+H]+).
Example 95: Préparation of 2-(3-nitro-1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI62)
O2N
To a stirred solution of 5-formyl-2-(3-nitro-1/-/-1,2,4-triazol-1-yl)benzonitrile (0.36 g, 1.49 mmol) in 1,4-dioxane (25 mL), were added K2CO3 (0.3 g, 2.2 mmol) and methyl triphenyl phosphonium bromide (0.63 g, 1.79 mmol). The résultant reaction mixture was heated to 100 °C for 18 h. After completion ofthe reaction (TLC), the reaction mixture was cooled to room température
140 and filtered and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) to afford the title compound as a solid (0.25 g, 70%); mp 103-105 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H),
8.34 (m, 1H), 7.98 (d, J= 7.8 Hz, 1H), 7.68 (d, J= 7.8 Hz, 1H), 6.87 (m, 1H), 6.20 (d, J = 15.7 Hz, 1H), 5.56 (d, J= 11.8 Hz, 1H); ESIMS m/z 240.27 ([M-H]’); IR (thin film) 2240, 1514, 1312 cm’1.
The following compound was made in accordance with the procedures disclosed in Example 95.
1-(3-chloro-4-vinylphenyl)-1 H-1,2,4-triazole (DI63)
The title compound was isolated as an off-white solid (2.3 g, 80%); mp 134-137 °C; 1H NMR (400 MHz, CDCI3) δ 8.56 (s, 1H), 8.11 (s, 1H), 7.76 (s, 1 H), 7.70 (d, J =9.0 Hz, 1H), 7.57 (d, J =9.0 Hz, 1H), 7.10 (m, 1H), 5.80 (d, J= 17.2 Hz, 1H), 5.47 (d, J = 12.4 Hz, 1H); ESIMS m/z 206.04 ([M+H]+.
3-methyl-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI64)
The title compound was isolated as a white solid (0.6 g, 60%): mp 109-111 °C; 1H NMR (400 MHz, CDCI3) δ 8.42 (s, 1H), 7.40-7.60 (m, 4H), 6.70-7.00 (dd, J= 17.6, 10.8 Hz, 1H), 5.80 (d, J = 17.6 Hz, 1H), 5.30 (d, J = 17.6 Hz,1H), 2.50 (s, 3H); ESIMS m/z 186.20 ([M+H]+).
-(2-(trifluoromethyl)-4-vinylphenyl)-1 H-1,2,4-triazole (DI65)
FoC
The title compound was isolated as a colorless oil (0.6 g, 60%): 1H NMR (400 MHz, CDCI3) δ 8.32 (s, 1H), 8.14 (s, 1H), 7.84 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.50 (d, J= 7.6 Hz, 1H), 6.70-
6.90 (dd, J= 17.6, 10.8 Hz, 1H), 5.90-6.00 (d, J= 17.6 Hz, 1H), 5.50-5.80 (d, J= 10.8 Hz 1H); ESIMS m/z 240.16 ([M+H]+).
3-nitro-1-(4-vinylphenyl)-1 H-1,2,4-triazole (DI66)
141
The title compound was isolated as a pale yellow solid (61 mg, 20%): mp 137-139 °C; 1H NMR (400 MHz, CDCI3) δ 8.60 (s, 1H), 7.68 (d, J= 7.7 Hz, 2H),7.60 (d, J= 8.3 Hz, 2H), 6.77 (dd, J = 17.7, 10.8, 1 H), 5.87 (d, J = 17.7 Hz, 1 H), 5.42 (d, J = 10.8 Hz, 1 H); ESIMS m/z 217.28 ([M+H]+).
-(2-bromo-4-vinylphenyl)-1 H-1,2,4-triazole (DI67)
The title compound was isolated as a white solid (1.2 g, 40%): mp 75-77 °C; 1H NMR (400
MHz, CDCI3) δ 8.48 (s, 1H), 8.12 (s, 1H), 7.75 (s, 1H) 7.42 (s, 2H), 6.70 (m, 1H), 5.83 (d, J= 18 Hz, 1H), 5.42 (d, J= 12 Hz, 1H); ESIMS m/z 249.1 ([M]+).
2-(3-methyl-1 H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI68)
The title compound was isolated as an off-white solid (0.6 g, 60%): mp 96-97 °C; 1H NMR (400 MHz, CDCI3) δ 8.66 (s, 1H), 7.80 (s, 1H), 7.74 (m, 2H), 6.73 (dd, J= 17.6 Hz, 10.8 Hz, 1H), 5.88 (d, J= 17.6 Hz, 1H), 5.49 (d, J = 10.8 Hz, 1H), 2.52 (s, 3H); ESIMS m/z 211.10 ([M+H]+); IR (thin film) 2229 cm’1.
-(2-nitro-4-vinylphenyl)-1 H-1,2,4-triazole (DI69)
The title compound was isolated as a yellow solid (1.78 g, 60%): mp 102-104 °C; 1H NMR (400 MHz, CDCI3) δ 8.40 (s, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.72-7.76 (d, J= 8.0 Hz, 1H), 7.52-7.56
142 (d, J = 17.6 Hz, 1H), 6.70-6.82 (dd, J= 17.6, 10.8 Hz, 1H), 5.85-6.00 (d, J = 17.6 Hz, 1H), 5.505.60 (d, J = 10.8, Hz 1H); ESIMS m/z 217.0 ([M+H]+).
Example 96: Préparation of 3-methyl-2-(1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI70)
Step 1. 5-Bromo-2-fluoro-3-methylbenzaldehyde: To a stirred solution of di-isopropyl amine (4.01 g, 39.88 mmol) in THF (20 mL) was added n-butyl lithium (1.6 M in hexane) (19.9 mL,
31.91 mmol) at -78 °C slowly dropwise over the period of 10 min, the reaction mixture was stirred at -78°C for 30 min. A solution of 4-bromo-1-fluoro-2-methylbenzene (5.0 g, 26.6 mmol) in THF (30.0 mL) was added at -78°C, and the reaction mixture was stirred for 1h at the same température. DMF (5.0 mL) was added and stirred at -78°C for another 30 min. The reaction was monitored by TLC; then the reaction mixture was quenched with 1N HCl solution (aq) at 0°C. The aqueous layer was extracted with diethyl ether, washed with water and saturated brine solution. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 5% ethyl acetate/ pet ether) to afford the title compound as a white solid (3.6 g, 64 %); mp 48-50°C: 1H NMR (400 MHz, CDCI3) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J = 17.6,
10.8 Hz, 1H), 5.92 (dd, J = 17.6, 10.8 Hz, 1H), 5.52 (d, J = 17.6 Hz, 1H), 2.21 (s, 3H); ESIMS m/z 211.35 ([M-H] ).
Step 2. ((E)-5-Bromo-2-fluoro-3-methylbenzaldehyde oxime: To a stirred solution of 5bromo-2-fluoro-3-methylbenzaldehyde (3.5 g, 16.2 mmol) in éthanol (50.0 mL) were added sodium acetate (2.0 g, 24.3 mmol) and hydroxylamine hydrochloride (1.69 g, 24.3 mmol) at RT. The reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated on rotavapourto obtain crude compound, which was washed with water filtered and dried under vacuum to afford the title compound as a white solid: mp 126-127 °C; 1H NMR (400 MHz, CDCI3) δ 8.32 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.51 (s, 1H), 7.34 (d, J = 2.4 Hz, 1H), 2.25 (s, 3H); ESIMS m/z 232.10 ([M+H]+).
Step 3. 5-Bromo-2-fluoro-3-methylbenzonitrile: A stirred solution of (E)-5-bromo-2-fluoro-
3-methylbenzaldehyde oxime (0.5 g, 2.2 mmol) in acetic anhydride (5.0 mL) was heated to reflux for 18 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound as a light brown gummy material (0.4 g, crude): ESIMS m/z 213.82 ([M+H]+).
143
Step 4. 5-Bromo-3-methyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (DI71) : To a stirred solution of 5-bromo-2-fluoro-3-methylbenzonitrile (1.0 g, 47.716 mmol), in DMF (10.0 mL) was added potassium carbonate (1.95 g, 14.14 mmol) followed by 1/-/-1,2,4-triazole (0.811 g, 9.433 mmol) at RT. The reaction mixture was heated to 140 °C for 18 h. The reaction mixture was cooled to RT, diluted with water and extracted with ethyl acetate (2 x 100 mL). The combined ethyl acetate layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/ pet ether) to afford the title compound as a pink solid (0.6 g, 49 %): 1H NMR (400 MHz, CDCI3) δ 8.39 (s, 1H), 8.23 (s, 1H), 7.91 (d, J = 2.4 Hz, 2H), 2.21 (s, 3H), ESIMS m/z 262.57 ([M+H]+); IR (thin film) 2231, 554 cm’1.
Step 5. 3-Methyl-2-(1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (DI70) : A mixture of 5bromo-3-methyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.6 g, 2.3 mmol), potassium carbonate (0.95 g, 6.87 mmol), vinyl boronic anhydride (0.82 g, 3.43 mmol) and triphenylphosphine (0.13 g, 0.114 mmol) in toluene (20.0 mL) were stirred and degassed with argon for 30 min. The reaction mixture was heated to reflux for 18 h. The reaction mixture was cooled to RT, diluted with water and extracted with ethyl acetate (2 x 100 mL). The combined ethyl acetate layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound that was purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/ pet ether) to afford the title compound as a pink solid (0.25 g, 52 %): 1H NMR (400 MHz, CDCI3) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J= 17.6, 10.8 Hz, 1H), 5.92 (d, J = 17.6, 1 H), 5.52 (d, J = 10.8 Hz, 1 H), 2.21 (s, 3H), ESIMS m/z 211.35 ([M+H]+); IR (thin film) 2236, 1511 cm’1.
The following compound was made in accordance with the procedures disclosed in Steps 4 and 5 of Example 96.
1-(2-fluoro-4-vinylphenyl)-1H-1,2,4-triazole (DI72)
1-(4-Bromo-2-fluorophenyl)-1H-1,2,4-triazole (DI73) was isolated as a pale yellow solid (3.0 g, 75%): mp 113-116 °C; 1H NMR (400 MHz, CDCI3) δ 8.69 (s, 1H), 8.13 (m, 2H), 7.50 (m, 1H),
7.21 (m, 1 H); ESIMS m/z 241.93 ([M]+). The title compound (DI72) was isolated as a yellow solid (1.0 g, 71%): mp 67-70 °C; 1H NMR (400 MHz, CDCI3) δ 8.67 (s, 1H), 8.13 (s, 1H), 7.94 (m, 1H),
144
7.41 (m, 1H), 7.24 (s, 1H), 6.75 (dd, J= 17.6, 10.8 Hz, 1H ), 5.81 (d, J= 17.6 Hz, 1H), 5.37 (d, J =
10.8 Hz, 1H); ESIMS m/z 190.00 ([M+H]+).
Example 119: Préparation of 1-(1-(4-vinylphenyl)-1H-1,2,4-triazol-5-yl)ethanone (DI78) ,0 \=^N
To a stirred solution of 1-(4-vinyl-phenyl)-1/-/-[1,2,4]triazole (1 g, 5.8 mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at -78 °C and stirred for 30 min. To this A/-methoxy-/V-methyl acetamide in THF (0.66 g, 6.4 mmol) was added and the résultant reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with a saturated aqueous NH4CI solution and extracted with EtOAc (3 x50 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (280 mg, 23%): mp 97-98 °C; 1H NMR (400 MHz, CDCI3) δ 8.10 (s, 1H), 7.50 (d, 2H), 7.38 (d, 2H), 6.68 (dd, 1H), 5.85 (d, 1H), 5.38 (d, 1H), 2.75 (s, 3H); ESIMS m/z 214.14 ([M+Hf).
Example 120: Préparation of cyclopropyl(1-(4-vinylphenyl)-1H-1,2,4-triazol-5-yl)methanone (DI79)
To a stirred solution of 1 -(4-vinyl-phenyl)-1 /-/-[1,2,4]triazole (1 g, 5.8 mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at -78 °C and stirred for 30 min. To this N-methoxy Nmethylcyclopropoxide in THF (0.82 g, 6.4 mmol) was added and the résultant reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with a saturated aqueous NH4CI solution and extracted with EtOAc (3 x25 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2,100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (420 mg, 30%): mp 90-91 °C; 1H NMR (400 MHz, CDCI3) δ 8.12 (s, 1H), 7.50 (d, J = 7.8 Hz, 2H), 7.38 (d, J= 7.8 Hz, 2H), 6.75 (dd, J= 16.3, 10.7 Hz, 1H), 5.81 (d, J =
16.3 Hz, 1H), 5.35 (d, J= 10.7 Hz, 1H), 3.22 (m, 1H), 1.27(m, 2H), 1.18 (m, 2H); ESIMS m/z
240.18 ([M+H]+); IR (thin film) 2922, 1630 cm'1.
145
Example 121: Préparation of 5-(methylthio)-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI80)
To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8 mmol) in 50 mL of THF, was added n-BuLi (0.41 g, 6.4 mmol) at -78 °C and stirred for 30 min. To this dimethyldisulfide in THF (0.6 g, 6.43 mmol) was added and the résultant reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with a saturated aqueous NH4CI solution and extracted with EtOAc (3 x 25 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (0.6 g, 48%): mp 68-70 °C; 1H NMR (400 MHz, CDCI3) δ 7.96 (s, 1H), 7.05 (m, 4H),
6.75 (dd, J= 16.4, 10.7 Hz, 1H), 5.81 (d, J= 16.4 Hz, 1H), 5.35 (d, J= 10.7 Hz, 1H), 2.73 (s, 3H); ESIMS m/z 218.09 ([M+H]+).
Example 122: Préparation of 5-methyl-1-(4-vinylphenyl)-1H-1,2,4-triazole (DI81)
To a stirred solution of 1-(4-vinyl-phenyl)-1/-/-[1,2,4]triazole (0.5 g, 2.9 mmol) in 10 mL of THF, was added n-BuLi (0.22 g, 3.5 mmol) at -78 °C and stirred for 30 min. To this methyl iodide in THF (0.50 g, 3.5 mmol) was added and the résultant reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with a saturated aqueous NH4CI solution and extracted with EtOAc (3 x 25 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) afford the title compound as a pale brown liquid (250 mg, 46%): 1H NMR (400 MHz, CDCI3) δ 7.93 (s, 1H), 7.55 (d, J = 9 Hz, 2H),
7.42 (d, J= 9 Hz, 2H), 6.76 (dd, J= 18, 11 Hz, 1H), 5.83 (d, J = 18 Hz, 1H), 5.38 (d, J= 11 Hz, 1H), 2.55 (s, 3H); ESIMS m/z 186.13 ([M+H]+); IR (thin film) 1517, 1386, 1182, 847 cm'1.
Example 97: Préparation of (E)-1-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1yl)phenyl)-1 H-1,2,4-triazole (DC1 )
146
To a stirred solution of 1-(1-bromo-2,2,2-trifluoro-ethyl)-3,5-dichloro-benzene (2.0 g, 6.51 mmol) in 1,2-dichlorobenzene (25 mL), were added 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (2.22 g, 13.0 mmol), CuCI (64 mg, 0.65 mmol) and 2,2 -bipyridyl (0.2 g, 1.3 mmol). The résultant reaction mixture was degassed with argon for 30 min, then stirred at 180 °C for 24 h. After completion of reaction (TLC), the reaction mixture was cooled to RT and filtered and the filtrate concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) afforded the title compound as an off-white solid (0.8 g, 32%): mp 93-97 °C; 1H NMR (300 MHz, CDCI3) δ 8.56 (s, 1 H), 8.11 (s, 1 H), 7.68 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.38 (t, J = 1.8 Hz, 1 H), 7.29 (s, 2H), 6.62 (d, J = 15.6 Hz, 1 H), 6.42 (dd, J = 15.6, 8.2 Hz, 1H), 4.15 (m, 1H); ESIMS m/z 398.05 ([M+H]+).
Compounds DC2-DC37, DC44, DC45, DC47-49, DC50, DC51, DC54, DC58, DC60, DC62, and DC63-DC67 in Table 1 were made in accordance with the procedures disclosed in Example 97.
Example 98: Préparation of (E)-2-(3-nitro-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-en-1-yl)benzonitrile (DC40)
To a stirred solution of 2-(3-nitro-1/-/-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (0.9 g, 3.7 mmol) in 1,2- dichlorobenzene (10 mL), were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3trichlorobenzene (2.5 g, 7.5 mmol), CuCI (73 mg, 0.74 mmol) and 2,2-bipyridyl (0.23 g, 1.49 mmol) and the résultant reaction mixture was degassed with argon for 30 min and then stirred at 180°C for 14 h. After completion of the reaction (TLC), the reaction mixture was cooled to RT and filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh, 25-30% EtOAc in Pet ether) afforded the title compound as a off white solid (0.9 g, 50%): mp 70-73 °C; 1H NMR (300 MHz, CDCI3) δ 8.86 (s, 1H), 7.88 (m, 3H), 7.44 (s, 2H), 6.67 (d, J= 16.0 Hz, 1H), 6.56 (dd, J= 16.0, 7.6 Hz, 1H), 4.19 (m, 1H); ESIMS m/z 436.11 ([M-2H] ).
147
Example 99: Préparation of (E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-en-1-yl)benzonitrile (DC41)
To a stirred solution of (E)-2-(3-nitro-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-enyl)benzonitrile (0.6 g, 1.2 mmol) in MeOH (10 mL), were added Zn dust (0.39g, 5.98 mmol) and sat. aq NH4CI solution (5 mL) and the résultant reaction mixture was stirred at RT for 2 h. After completion ofthe reaction (TLC), the reaction mass was concentrated under reduced pressure. The reaction mass was diluted with DCM, filtered through a celite bed, and the obtained filtrate concentrated under reduced pressure to afford the title compound as a solid (0.5 g, 89%): mp 72-75 °C; 1H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.26 (s, 1H), 8.01 (d, J = 8.4 Hz, 1 H), 7.91 (s, 2H), 7.77 (d, J = 8.4 Hz, 1 H), 6.42 (dd, J = 15.6, 9.2 Hz, 1 H), 6.83 (d, J = 15.6 Hz, 1H), 5.87 (s, 2H), 4.89 (m, 1H); ESIMS m/z 469.95 ([M-H] ).
Compound DC38 in Table 1 was made in accordance with the procedures disclosed in Example 99. Also, compound DC55 in Table 1 was made from compound DC54 in accordance with the procedures disclosed in Example 99, with the exception of using ammonium formate in place of ammonium chloride.
Example 100: Préparation of(E)-A/-(1-(2-cyano-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but1-en-1-yl)phenyl)-1H-1,2,4-triazol-3-yl)-N-(cyclopropanecarbonyl)cyclopropanecarboxamide (DC42)
To a stirred solution of (E)-2-(3-amino-1/-/-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-enyl)benzonitrile (0.1 g, 0.21 mmol) in DCM at RT, was added cyclopropylcarbonyl chloride (0.045 g, 0.42 mmol) and the reaction mixture was stirred for 2 h at RT. The reaction mixture was diluted with DCM and washed with water and brine and dried over Na2SO4. Concentration under reduced pressure and purification by préparative HPLC afforded the title compound as a solid (0.09g, 79%): mp 104-107 °C; 1H NMR (300 MHz, CDCI3) δ 8.78 (s, 2H), 148
7.83 (s, 1H), 7.80 (m, 2H), 7.42 (s, 2H), 6.65 (d, J= 16.4 Hz, 1H), 6.51 (dd, J= 7.6, 8.0 Hz, 1H),
4.17 (m, 1H), 2.16 (m, 2H), 1.25 (m, 4H), 1.00 (m, 4H); ESIMS m/z 609.98,([M+H]+); IR (thin film) 2234, 1714, 1114, 807 cm'1.
Example 101: Préparation of (E)-A/-(1-(2-cyano-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but1 -en-1 -yl)phenyl)-1 H-1,2,4-triazol-3-yl)cyclopropanecarboxamide (DC43)
To a stirred solution of (E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5trichlorophenyl)but-1-enyl)benzonitrile (0.15 g,0.31 mmol) in DCM at 0 °C, were added triethylamine (0.1 g, 1 mmol) and cyclopropylcarbonyl chloride (0.04 g, 0.38mmol) and the reaction mixture was stirred for 1 h at 0 °C. The reaction mixture was diluted with DCM and washed with water and brine and dried over Na2SO4. Concentration under reduced pressure and purification by column chromatography (SiO2, 100-200 mesh) afforded the title compound as a solid (66 mg, 34%): mp 109-112 °C; 1H NMR (300 MHz, DMSO-de) δ 10.94 (brs, 1H), 8.36 (s, 1H), 8.08 (m, J = 8.4 Hz, 1H), 7.91 (s, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.13 (dd, J = 15.6, 9.2 Hz, 1H),6.87 (d, J=15.6 Hz, 1H), 4.92 (m, 1H), 1.99 (brs, 1H), 0.82 (s, 4H); ESIMS m/z 540.04 ([M+H]+); IR (thin film) 3233, 2233, 1699, 1114, 807cm’1.
Compound DC39 in Table 1 was made in accordance with the procedures disclosed in Example 101.
Example 102: Préparation of 1-(4-(1 H-1,2,4-triazol-1-yl)phenyl)ethanone (DI74)
O
To a stirred solution of 4-bromoacetophenone (10 g, 50 mmol) in DMF (100 mL), were added 1,2,4-triazole (5 g, 75mmol), Cs2CO3 (32.6 g, 100.5 mmol) and Cul (1.4 g, 10.1 mmol) and the résultant reaction mixture was refluxed for 48 h. After completion of the reaction (by TLC), the reaction mixture was cooled to RT and diluted with water (200 mL) and extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure. Purification by washing with diethyl ether afforded the title compound as a solid
149 (5 g, 96%): 1H NMR (400 MHz, CDCI3) δ 8.71 (s, 1H), 8.16, (s, 1H), 8.13 (d, J = 8.6 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H), 2.66 (s, 3H); ESIMS m/z 186.02 ([M-H] ).
Example 103: Préparation of 1-(4-(1 H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4trifluorobutan-1-one (DI75):
Step 1.1 -(4-(1 -(trimethylsilyloxy)vinyI)phenyl)-1H-1,2,4-triazole (DI76) To a stirred solution of 1-(4-(1 H-1,2,4-triazol-1-yl)phenyl)ethanone (4.5 g, 24.0 mmol) in DCM at 0 °C, were added TEA (3.7 g, 36.1 mmol) and trimethylsilyl triflluoromethanesulfonate (8 g, 36 mmol) and the résultant reaction mixture was stirred for 1 h. The reaction mixture was quenched with a mixture of sat aq sodium bicarbonate solution and ether. The ether layer and was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (5.5 g) which was taken directly to next step.
Step 2.1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobutan-1one (DI75): To a stirred solution of 1-(4-(1-(trimethylsilyloxy)vinyl)phenyl)-1H-1,2,4-triazole (6g, 23 mmol) and 1-(1-bromo-2,2,2-trifluoro-ethyl)-3,5-dichlorobenzene (7.1 g, 34.7 mmol) in 1,2dichlorobenzene (30 mL) was degassed with argon. To this CuCI (0.23g, 2.31 mmol) and 2,2bipyridyl (0.73g, 4.63 mmol) was added to the above reaction mixture and the résultant reaction mixture was heated to 180 °C for 18 h. After completion of the reaction (by TLC), the reaction mixture was absorbed onto silica gel and purified by column chromatography (SIO2; 10% EtOAc in petroleum ether) to afford title compound as a solid (3 g, 31%); 1H NMR (400 MHz, CDCI3) δ 8.67 (s, 1H), 8.15 (s, 1H), 8.10 (d, J= 8.3 Hz, 2H), 7.82 (d, J = 8.3 Hz, 2H), 7.33 (m, 1H), 7.30 (m, 2H),
4.20 (m, 1H), 3.63 (m, 2H); ESIMS m/z 412. 14 ([M-H]').
Example 104: Préparation of 2-(4-(1 H-1,2,4-triazoI-1-yl)phenyl)-4-(3,5-dichlorophenyl)-5,5,5trifluoropentan-2-ol (DI77)
150
To a solution of 1-(4-(1/-/-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4trifluorobutan-1-one (300 mg, 0.726 mmol ) in THF cooled to 0 °C was added méthylmagnésium bromide (450 mg, 5 mmol) drop wise. The reaction was stirred for 3 h at 0 °C, then the reaction mixture was quenched with sat aq NH4CI solution and extracted with ethyl acetate. The combined EtOAc layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20%-25% EtOAc in petroleum ether) afforded the title compound as a solid (100 mg, 32%): 1H NMR (400 MHz, CDCI3) δ two diastereoisomers 8.58 (s, 1H, minor), 8.48 (s, 1H, major), 8.13 (s, 1H, minor), 8.09 (s, 1H, major), 7.70 (d, J = 9.0 Hz, 2H, minor), 7.53 (d, J = 9.0 Hz, 2H, minor), 7.40 (d, J = 9.0 Hz, 2H, major), 7.31 (m, 1H, minor), 7.27 (d, J= 9.0 Hz, 2H, major), 7.20 (m, 2H, minor), 7.01 (m, 1H, major), 6.75 (m, 2H, major), 350 (m, 1H), 2.50 (m, 2H), 1.56 (s, 3H, major), 1.54 (s, 3H, minor); ESIMS m/z 430.05 ([M+H]+).
Example 105: Préparation of (E)-1 -(4-(4-(3,5-dichlorophenyl)-5,5,5-trifluoropent-2-en-2yl)phenyl)-1 H-1,2,4-triazole (DC68)
CF
Cl
To a solution of 2-(4-(1 H-1,2,4-triazol-1-yl)phenyl)-4-(3,5-dichlorophenyl)-5,5,5trifluoropentan-2-ol (100 mg, 0.233 mmol) in toluene was added a catalytic amount of ptoluenesulfonic acid (PTSA) and the water was removed by azeotropic distillation over the course of 12 h. The reaction mixture was cooled to room température and dissolved in ethyl acetate. The solution was washed with sat aq NaHCO3 solution and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20%-25% EtOAc in petroleum ether) afforded the title compound as a solid (30 mg, 31%).
Example 123: Préparation of (£)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-
1,2,4-triazol-1-yl)benzaldehyde (DC52)
CF
Cl
151
To a stirred solution of (£)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1/-/-1,2,4triazol-1-yl)benzonitrile (0.3 g, 0.71 mmol) in toluene (10 mL) at -78 °C was added dropwise diisobutylaluminum hydride (DIBAL-H, 1.0 M solution in toluene; 0.85 mL), and the reaction mixture was stirred at -78 °C for 20 min. The reaction mixture was quenched with the addition of 1 N HCl solution, then the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 50% EtOAc/ Pet ether) to afford the title compound as a yellow oil.
Compound DC53 in Table 1 was made in accordance with the procedures disclosed in Example 123.
Example 124: Préparation of(E)-5-(3-(3,5-dich1orophenyl)-4,4,4-trifluorobut-1-en-1-yl)-A/methyl-2-(1H-1,2,4-triazol-1-yl)aniline (DC57)
Cl
To a stirred solution of (£)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1/-/-1,2,4triazol-1-yl)aniline (0.3 g, 0.7 mmol) in DCM (10 mL) was added triethylamine (0.155 mL, 1.09 mmol) and methyl iodide (0.124 g, 0.873 mmol). The reaction was stirred at RT for 18 h. The DCM layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 50% EtOAc/ Pet ether) to afford the title compound as a yellow semi-solid (0.07 g, 70%).
Example 125: Préparation of (£)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-
1,2,4-triazol-1-yl)benzoic acid (DC61)
CF
Cl
A solution of (£)-ethyl 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4triazol-1-yl)benzoate (0.2 g, 0.4 mmol) in 6 N HCl (10 mL) was stirred at 100 °C for 18 h. The reaction was cooled to RT, resulting in a white solid precipitate. The precipitate was filtered to afford the title compound as a white solid (0.12 g, 60%).
152
Example 126: Préparation of(Z)-5-((£)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-A/’hydroxy-2-(1 H-1,2,4-triazol-1-yl)benzimidamide (DC59)
A solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1/-/-1,2,4-triazol-1yl)benzonitrile (0.3 g, 0.71 mmol), sodium acetate (0.087 g, 1.065 mmol) and hydroxylammonium chloride (0.072 g, 1.065 mmol) in 9:1 ethanol/water mixture (10 mL) was stirred at 70 °C for 8 h. The reaction was cooled to RT, and the éthanol was evaporated. The residue was dissolved in water and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off white solid.
Example 127: Préparation of (£)-1-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-methoxybut-1en-1 -yl)phenyl)-1 H-1,2,4-triazole (DC70)
Step 1. (£)-3-(4-(1 H-1,2,4-triazol-1-yl)phenyl)-1-(3,5-dichlorophenyl)prop-2-en-1-one: To a solution of 1-(3,5-dichlorophenyl)ethanone (0.5 g, 2.6 mmol) in éthanol (20 mL) was added 4(1H-1,2,4-triazol-1-yl)benzaldehyde (0.46 g, 2.65 mmol) and the reaction was cooled to 0 °C. Sodium hydroxide (0.22 g, 5.29 mmol) in water (10 mL) was then added and the reaction was allowed to stir for 2 h at 0 °C. The reaction was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (0.149 g, 17%): ); ESIMS m/z 430.05 ([M+H]+) 344.08
Step 2. (£)-4-(4-(1 H-1,2,4-triazol-1 -yl)phenyl)-2-(3,5-dichlorophenyl)-1,1,1 -trifluorobut-
3-en-2-ol (DC69): To a solution of (£)-3-(4-(1/-/-1,2,4-triazol-1-yl)phenyl)-1-(3,5dichlorophenyl)prop-2-en-1-one (1 g, 3 mmol) in THF (150 mL) was added trifluoromethyltrimethylsilane (0.517 g, 3.644 mmol) and tetra-n-butylammonium fluoride (TBAF) (1.0 M, 1 mL) at 0 °C. The reaction was slowly warmed to RT and allowed to stir for 2 h. The reaction was then cooled to 0 °C and 5 M HCl solution was added and the reaction was stirred for
153 an additional 4 h at RT. The reaction was extracted with DCM and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 25% EtOAc/ hexanes) to afford the title compound as an off-white solid (0.3 g, 25%).
Step 3. (£)-1-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-methoxybut-1-en-1-yI)phenyl)1W-1,2,4-triazole (DC70): To a solution of (E)-4-(4-(1/-/-1,2,4-triazol-1-yl)phenyl)-2-(3,5dichlorophenyl)-1,1,1-trifluorobut-3-en-2-ol (0.15 g, 0.36 mmol) in THF (5 mL) was added NaH (60%, 10 mg, 0.44 mmol) at 0 °C. The reaction was allowed to stir at 0 °C for 30 min, then methyl iodide (61 mg, 0.44 mmol) was added slowly and the reaction was warmed to RT and allowed to stir for 4 h. The reaction was quenched with aq NH4CI solution and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (55 mg, 35%).
Example A: BlOASSAYS ON Beet Armyworm (“BAW”) AND CORN EARWORM (“CEW”)
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 concern upon asparagus, cotton, corn, soybeans, tobacco, alfalfa, sugar beets, peppers, tomatoes, potatoes, onions, peas, sunflowers, and citrus, among other plants. CEW is known to attack corn and tomatoes, but it also attacks artichoke, asparagus, cabbage, cantaloupe, collards, cowpeas, cucumbers, eggplant, lettuce, lima beans, melon, okra, peas, peppers, potatoes, pumpkin, 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, molécules that control these pests are useful in controlling other pests.
Certain molécules disclosed in this document were tested against BAW and CEW using procedures described in the following examples, ln the reporting ofthe results, the “BAW & CEW Rating Table” was used (See Table Section).
Bioassays ON BAW (Spodoptera exigua)
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) ofthe diet tray that had been previouslyfilled with 1 mL of artificial diet to which 50 pg/cm2 ofthe test compound (dissolved in 50 pL of 90:10 acetone-water mixture) had been applied (to each of eight wells) and then allowed to dry. Trays were covered with a clear self-adhesive 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 154 averaged. The results are indicated in the table entitled “Table 3: Assay Results” (See Table Section).
Bioassays ON CEW (Helicoverpa 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) ofthe diettray that had been previously filled with 1 mL of artificial diet to which 50 pg /cm2 ofthe test compound (dissolved in 50 pL of 90:10 acetone-water mixture) had been applied (to each of eight wells) and then allowed to dry. Trays were covered with a clear self-adhesive 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 3: Assay Results” (See Table Section).
Example B: Bioassays on Green Peach Aphid (“GPA”) {Myzus persicae).
GPA is the most significant aphid pest of peach trees, causing decreased growth, shriveling of the leaves, 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 leafroll virus to members of the nightshade/potato family Solanaceae, and various mosaic viruses to many other food crops. GPA attacks such plants as broccoli, burdock, cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce, macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress, and zucchini, among other plants. GPA also attacks many ornamental crops such as carnation, chrysanthemum, flowering white cabbage, poinsettia, and roses. GPA has developed résistance to many pesticides.
Certain molécules disclosed in this document were tested against GPA using procedures described in the following example. In the reporting of the results, the “GPA Rating Table” was used (See Table Section).
Cabbage seedlings grown in 3-inch pots, with 2-3 small (3-5 cm) true leaves, were used as test substrate. The seedlings were infested with 20-50 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 in 2 mL of acetone/methanol (1:1) solvent, forming stock solutions of 1000 ppm test compound. The stock solutions were diluted 5X with 0.025% Tween 20 in 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 leaves until runoff. Reference plants (solvent check) were sprayed with the diluent only containing 20% by volume of acetone/methanol (1:1) solvent. Treated plants were held in a holding room forthree days at approximately 25 °C and ambient relative humidity (RH) prior to grading. Evaluation was conducted by counting the number 155 of live aphids 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. Entomol. 18 (1925), pp.265-267) as follows.
Corrected % Control = 100 * (X - Y) / X where
X = No. of live aphids on solvent check plants and
Y = No. of live aphids on treated plants
The results are indicated in the table entitled “Table 3: Assay Results” (See Table Section).
PESTICIDALLY ACCEPTABLE ACID ADDITION SALTS, SALT DERIVATIVES, SOLVATES, ESTER DERIVATIVES, POLYMORPHS, ISOTOPES AND RADIONUCLIDES
Molécules of Formula One may be formulated into pesticidally acceptable acid addition salts. By way of a non-limiting example, an amine function can form salts with hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic, benzenesulfonic, methanesulfonic, ethanesulfonic, hydroxymethanesulfonic, and hydroxyethanesulfonic acids. Additionally, by way of a non-limiting example, an acid function can form salts including those derived from alkali or alkaline earth metals and those derived from ammonia and amines. Examples of preferred cations include sodium, potassium, and magnésium.
Molécules of Formula One may be formulated into sait dérivatives. By way of a non-limiting example, a sait dérivative can be prepared by contacting a free base with a sufficient amount of the desired acid to produce a sait. A free base may be regenerated by treating the sait with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide (NaOH), potassium carbonate, ammonia, and sodium bicarbonate. As an example, in many cases, a pesticide, such as
2,4-D, is made more water-soluble by converting it to its dimethylamine sait..
Molécules of Formula One may be formulated into stable complexes with a solvent, such that the complex remains intact after the non-complexed solvent is removed. These complexes are often referred to as solvatés.” However, it is particularly désirable to form stable hydrates with water as the solvent.
Molécules of Formula One may be made into ester dérivatives. These ester dérivatives can then be applied in the same manner as the invention disclosed in this document is applied.
156
Molécules of Formula One may be made as various crystal polymorphs. Polymorphism is important in the development of agrochemicals since different crystal polymorphs or structures of the same molécule can hâve vastly different physical properties and biological performances.
Molécules of Formula One may be made with different isotopes. Of particular importance are molécules having 2H (also known as deuterium) in place of 1H.
Molécules of Formula One may be made with different radionuclides. Of particular importance are molécules having 14C.
STEREOISOMERS
Molécules of Formula One may exist as one or more stereoisomers. Thus, certain molécules can be produced as racemic mixtures. It will be appreciated by those skilled in the art that one stereoisomer may be more active than the other stereoisomers. Individual stereoisomers may be obtained by known sélective synthetic procedures, by conventional synthetic procedures using resolved starting materials, or by conventional resolution procedures. Certain molécules disclosed in this document can exist as two or more isomers. The various isomers include géométrie isomers, diastereomers, and enantiomers. Thus, the molécules disclosed in this document include géométrie isomers, racemic mixtures, individual stereoisomers, and optically active mixtures. It will be appreciated by those skilled in the art that one isomer may be more active than the others. The structures disclosed in the présent disclosure are drawn in only one géométrie form for clarity, 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 acaricidal, algicidal, avicidal, bactericidal, fungicidal, herbicidal, insecticidal, molluscicidal, nematicidal, rodenticidal, or virucidal 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 repellents, chemosterilants, herbicide safeners, insect attractants, insect repellents, mammal repellents, mating disrupters, plant activators, plant growth regulators, or synergists. Examples of such compounds in the above groups that may be used with the Molécules of Formula One are - (3-ethoxypropyl)mercury bromide, 1,2-dichloropropane, 1,3-dichloropropene, 1-methylcyclopropene, 1-naphthol, 2(octylthio)ethanol, 2,3,5-tri-iodobenzoic acid, 2,3,6-TBA, 2,3,6-TBA-dimethylammonium, 2,3,6-TBAlithium, 2,3,6-TBA-potassium, 2,3,6-TBA-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,
157
2.4.5- T-isobutyl, 2,4,5-T-isoctyl, 2,4,5-T-isopropyl, 2,4,5-T-methyl, 2,4,5-T-pentyl, 2,4,5-T-sodium,
2.4.5- T-triethylammonium, 2,4,5-T-trolamine, 2,4-D, 2,4-D-2-butoxypropyl, 2,4-D-2-ethylhexyl, 2,4D-3-butoxypropyl, 2,4-D-ammonium, 2,4-DB, 2,4-DB-butyl, 2,4-DB-dimethylammonium, 2,4-DBisoctyl, 2,4-DB-potassium, 2,4-DB-sodium, 2,4-D-butotyl, 2,4-D-butyl, 2,4-D-diethylammonium, 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-isoctyl, 2,4-D-isopropyl, 2,4-D-isopropylammonium,
2.4- D-lithium, 2,4-D-meptyl, 2,4-D-methyl, 2,4-D-octyl, 2,4-D-pentyl, 2,4-D-potassium, 2,4-D-propyl,
2.4- D-sodium, 2,4-D-tefuryl, 2,4-D-tetradecylammonium, 2,4-D-triethylammonium, 2,4-D-tris(2hydroxypropyl)ammonium, 2,4-D-trolamine, 2iP, 2-methoxyethylmercury chloride, 2-phenylphenol,
3.4- DA, 3,4-DB, 3,4-DP, 4-aminopyridine, 4-CPA, 4-CPA-potassium, 4-CPA-sodium, 4-CPB, 4CPP, 4-hydroxyphenethyl alcohol, 8-hydroxyquinoline sulfate, 8-phenylmercurioxyquinoline, abamectin, abscisic acid, ACC, acephate, acequinocyl, acetamiprid, acethion, acetochlor, acetophos, acetoprole, acibenzolar, acibenzolar-S-methyl, acifluorfen, acifluorfen-methyl, acifluorfen-sodium, aclonifen, acrep, acrinathrin, acrolein, acrylonitrile, acypetacs, acypetacscopper, acypetacs-zinc, alachlor, alanycarb, albendazole, aldicarb, aldimorph, aldoxycarb, aldrin, allethrin, allicin, allidochlor, allosamidin, alloxydim, alloxydim-sodium, allyl alcohol, allyxycarb, alorac, a/pfta-cypermethrin, a/pha-endosulfan, ametoctradin, ametridione, ametryn, amibuzin, amicarbazone, amicarthiazol, amidithion, amidoflumet, amidosulfuron, aminocarb, aminocyclopyrachlor, aminocyclopyrachlor-methyl, aminocyclopyrachlor-potassium, aminopyralid, aminopyralid-potassium, aminopyralid-tris(2-hydroxypropyl)ammonium, amiprofos-methyl, amiprophos, amisulbrom, amiton, amiton oxalate, amitraz, amitrole, ammonium sulfamate, ammonium α-naphthaleneacetate, amobam, ampropylfos, anabasine, ancymidol, anilazine, anilofos, anisuron, anthraquinone, antu, apholate, aramite, arsenous oxide, asomate, aspirin, asulam, asulam-potassium, asulam-sodium, athidathion, atraton, atrazine, aureofungin, aviglycine, aviglycine hydrochloride, azaconazole, azadirachtin, azafenidin, azamethiphos, azimsulfuron, azinphos-ethyl, azinphos-methyl, aziprotryne, azithiram, azobenzene, azocyclotin, azothoate, azoxystrobin, bachmedesh, barban, barium hexafluorosilicate, barium polysulfide, barthrin, BCPC, beflubutamid, benalaxyl, benalaxyl-M, benazolin, benazolin-dimethylammonium, benazolin-ethyl, benazolin-potassium, bencarbazone, benclothiaz, bendiocarb, benfluralin, benfuracarb, benfuresate, benodanil, benomyl, benoxacor, benoxafos, benquinox, bensulfuron, bensulfuronmethyl, bensulide, bensultap, bentaluron, bentazone, bentazone-sodium, benthiavalicarb, benthiavalicarb-isopropyl, benthiazole, bentranil, benzadox, benzadox-ammonium, benzalkonium chloride, benzamacril, benzamacril-isobutyl, benzamorf, benzfendizone, benzipram, benzobicyclon, benzofenap, benzofluor, benzohydroxamic acid, benzoximate, benzoylprop, benzoylprop-ethyl,
158 benzthiazuron, benzyl benzoate, benzyladenine, berberine, berberine chloride, befa-cyfluthrin, befa-cypermethrin, bethoxazin, bicyclopyrone, bifenazate, bifenox, bifenthrin, bifujunzhi, bilanafos, bilanafos-sodium, binapacryl, bingqingxiao, bioallethrin, bioethanomethrin, biopermethrin, bioresmethrin, biphenyl, bisazir, bismerthiazol, bispyribac, bispyribac-sodium, bistrifluron, bitertanol, bithionol, bixafen, blasticidin-S, borax, Bordeaux mixture, boric acid, boscalid, brassinolide, brassinolide-ethyl, brevicomin, brodifacoum, brofenvalerate, brofluthrinate, bromacil, bromacillithium, bromacil-sodium, bromadiolone, bromethalin, bromethrin, bromfenvinfos, bromoacetamide, bromobonil, bromobutide, bromocyclen, bromo-DDT, bromofenoxim, bromophos, bromophos-ethyl, bromopropylate, bromothalonil, bromoxynil, bromoxynil butyrate, bromoxynil heptanoate, bromoxynil octanoate, bromoxynil-potassium, brompyrazon, bromuconazole, bronopol, bucarpolate, bufencarb, buminafos, bupirimate, buprofezin, Burgundy mixture, busulfan, butacarb, butachlor, butafenacil, butamifos, butathiofos, butenachlor, butethrin, buthidazole, buthiobate, buthiuron, butocarboxim, butonate, butopyronoxyl, butoxycarboxim, butralin, butroxydim, buturon, butylamine, butylate, cacodylic acid, cadusafos, cafenstrole, calcium arsenate, calcium chlorate, calcium cyanamide, calcium polysulfide, calvinphos, cambendichlor, camphechlor, camphor, captafol, captan, carbamorph, carbanolate, carbaryl, carbasulam, carbendazim, carbendazim benzenesulfonate, carbendazim sulfite, carbetamide, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, carboxazole, carboxide, carboxin, carfentrazone, carfentrazone-ethyl, carpropamid, cartap, cartap hydrochloride, carvacrol, carvone, CDEA, celiocidin, CEPC, ceralure, Cheshunt mixture, chinomethionat, chitosan, chlobenthiazone, chlomethoxyfen, chloralose, chloramben, chloramben-ammonium, chloramben-diolamine, chloramben-methyl, chloramben-methylammonium, chloramben-sodium, chloramine phosphorus, chloramphenicol, chloraniformethan, chloranil, chloranocryl, chlorantraniliprole, chlorazifop, chlorazifop-propargyl, chlorazine, chlorbenside, chlorbenzuron, chlorbicyclen, chlorbromuron, chlorbufam, chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride, chlorempenthrin, chlorethoxyfos, chloreturon, chlorfenac, chlorfenac-ammonium, chlorfenac-sodium, chlorfenapyr, chlorfenazole, chlorfenethol, chlorfenprop, chlorfenson, chlorfensulphide, chlorfenvinphos, chlorfluazuron, chlorflurazole, chlorfluren, chlorfluren-methyl, chlorflurenol, chlorflurenol-methyl, chloridazon, chlorimuron, chlorimuron-ethyl, chlormephos, chlormequat, chlormequat chloride, chlornidine, chlornitrofen, chlorobenzilate, chlorodinitronaphthalenes, chloroform, chloromebuform, chloromethiuron, chloroneb, chlorophacinone, chlorophacinone-sodium, chloropicrin, chloropon, chloropropylate, chlorothalonil, chlorotoluron, chloroxuron, chloroxynil, chlorphonium, chlorphonium chloride, chlorphoxim, chlorprazophos, chlorprocarb, chlorpropham, chlorpyrifos, chlorpyrifosmethyl, chlorquinox, chlorsulfuron, chlorthal, chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid,
159 chlorthiophos, chlozolinate, choline chloride, chromafenozide, cinerin I, cinerin II, cinerins, cinidonethyl, cinmethylin, cinosulfuron, ciobutide, cisanilide, cismethrin, clethodim, climbazole, cliodinate, clodinafop, clodinafop-propargyl, cloethocarb, clofencet, clofencet-potassium, clofentezine, clofibric acid, clofop, clofop-isobutyl, clomazone, clomeprop, cloprop, cloproxydim, clopyralid, clopyralidmethyl, clopyralid-olamine, clopyralid-potassium, clopyralid-tris(2-hydroxypropyl)ammonium, cloquintocet, cloquintocet-mexyl, cloransulam, cloransulam-methyl, closantel, clothianidin, clotrimazole, cloxyfonac, cloxyfonac-sodium, CMA, codlelure, colophonate, copper acetate, copper acetoarsenite, copper arsenate, copper carbonate, basic, copper hydroxide, copper naphthenate, copper oleate, copper oxychloride, copper silicate, copper sulfate, copper zinc chromate, coumachlor, coumafuryl, coumaphos, coumatetralyl, coumithoate, coumoxystrobin, CPMC, CPMF, CPPC, credazine, cresol, crimidine, crotamiton, crotoxyphos, crufomate, cryolite, cue-lure, cufraneb, cumyluron, cuprobam, cuprous oxide, curcumenol, cyanamide, cyanatryn, cyanazine, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyazofamid, cybutryne, cyclafuramid, cyclanilide, cyclethrin, cycloate, cycloheximide, cycloprate, cycloprothrin, cyclosulfamuron, cycloxaprid, cycloxydim, cycluron, cyenopyrafen, cyflufenamid, cyflumetofen, cyfluthrin, cyhalofop, cyhalofop-butyl, cyhalothrin, cyhexatin, cymiazole, cymiazole hydrochloride, cymoxanil, cyometrinil, cypendazole, cypermethrin, cyperquat, cyperquat chloride, cyphenothrin, cyprazine, cyprazole, cyproconazole, cyprodinil, cyprofuram, cypromid, cyprosulfamide, cyromazine, cythioate, daimuron, dalapon, dalapon-calcium, dalapon-magnesium, dalapon-sodium, daminozide, dayoutong, dazomet, dazomet-sodium, DBCP, d-camphor, DCIP, DCPTA, DDT, debacarb, decafentin, decarbofuran, dehydroacetic acid, delachlor, deltamethrin, demephion, demephion-O, demephionS, demeton, demeton-methyl, demeton-O, demeton-O-methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulphon, desmedipham, desmetryn, d-fanshiluquebingjuzhi, diafenthiuron, dialifos, di-allate, diamidafos, diatomaceous earth, diazinon, dibutyl phthalate, dibutyl succinate, dicamba, dicamba-diglycolamine, dicamba-dimethylammonium, dicamba-diolamine, dicambaisopropylammonium, dicamba-methyl, dicamba-olamine, dicamba-potassium, dicamba-sodium, dicamba-trolamine, dicapthon, dichlobenil, dichlofenthion, dichlofluanid, dichlone, dichloralurea, dichlorbenzuron, dichlorflurenol, dichlorflurenol-methyl, dichlormate, dichlormid, dichlorophen, dichlorprop, dichlorprop-2-ethylhexyl, dichlorprop-butotyl, dichlorprop-dimethylammonium, dichlorprop-ethylammonium, dichlorprop-isoctyl, dichlorprop-methyl, dichlorprop-P, dichlorprop-P-2ethylhexyl, dichlorprop-P-dimethylammonium, dichlorprop-potassium, dichlorprop-sodium, dichlorvos, dichlozoline, diclobutrazol, diclocymet, diclofop, diclofop-methyl, diclomezine, diclomezine-sodium, dicloran, diclosulam, dicofol, dicoumarol, dicresyl, dicrotophos, dicyclanil, dicyclonon, dieldrin, dienochlor, diethamquat, diethamquat dichloride, diethatyl, diethatyl-ethyl,
160 diethofencarb, dietholate, diethyl pyrocarbonate, diethyltoluamide, difenacoum, difenoconazole, difenopenten, difenopenten-ethyl, difenoxuron, difenzoquat, difenzoquat metilsulfate, difethialone, diflovidazin, diflubenzuron, diflufenican, diflufenzopyr, diflufenzopyr-sodium, diflumetorim, dikegulac, dikegulac-sodium, dilor, dimatif, dimefluthrin, dimefox, dimefuron, dimepiperate, dimetachlone, dimetan, dimethacarb, dimethachlor, dimethametryn, dimethenamid, dimethenamidP, dimethipin, dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate, dimethyl phthalate, dimethylvinphos, dimetilan, dimexano, dimidazon, dimoxystrobin, dinex, dinex-diclexine, dingjunezuo, diniconazole, diniconazole-M, dinitramine, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, dinofenate, dinopenton, dinoprop, dinosam, dinoseb, dinoseb acetate, dinosebammonium, dinoseb-diolamine, dinoseb-sodium, dinoseb-trolamine, dinosulfon, dinotefuran, dinoterb, dinoterb acetate, dinoterbon, diofenolan, dioxabenzofos, dioxacarb, dioxathion, diphacinone, diphacinone-sodium, diphenamid, diphenyl sulfone, diphenylamine, dipropalin, dipropetryn, dipyrithione, diquat, diquat dibromide, disparlure, disul, disulfiram, disulfoton, disulsodium, ditalimfos, dithianon, dithicrofos, dithioether, dithiopyr, diuron, d-limonene, DMPA, DNOC, DNOC-ammonium, DNOC-potassium, DNOC-sodium, dodemorph, dodemorph acetate, dodemorph benzoate, dodicin, dodicin hydrochloride, dodicin-sodium, dodine, dofenapyn, dominicalure, doramectin, drazoxolon, DSMA, dufulin, EBEP, EBP, ecdysterone, edifenphos, eglinazine, eglinazine-ethyl, emamectin, emamectin benzoate, EMPC, empenthrin, endosulfan, endothal, endothal-diammonium, endothal-dipotassium, endothal-disodium, endothion, endrin, enestroburin, EPN, epocholeone, epofenonane, epoxiconazole, eprinomectin, epronaz, EPTC, erbon, ergocalciferol, erlujixiancaoan, esdépalléthrine, esfenvalerate, esprocarb, etacelasil, etaconazole, etaphos, etem, ethaboxam, ethachlor, ethalfluralin, ethametsulfuron, ethametsulfuronmethyl, ethaprochlor, ethephon, ethidimuron, ethiofencarb, ethiolate, ethion, ethiozin, ethiprole, ethirimol, 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, ethylicin, ethylmercury 2,3dihydroxypropyl mercaptide, ethylmercury acetate, ethylmercury bromide, ethylmercury chloride, ethylmercury phosphate, etinofen, etnipromid, etobenzanid, etofenprox, etoxazole, etridiazole, etrimfos, eugenol, EXD, famoxadone, famphur, fenamidone, fenaminosulf, fenamiphos, fenapanil, fenarimol, fenasulam, fenazaflor, fenazaquin, fenbuconazole, fenbutatin oxide, fenchlorazole, fenchlorazole-ethyl, fenchlorphos, fenclorim, fenethacarb, fenfluthrin, fenfuram, fenhexamid, fenitropan, fenitrothion, fenjuntong, fenobucarb, fenoprop, fenoprop-3-butoxypropyl, fenopropbutometyl, fenoprop-butotyl, fenoprop-butyl, fenoprop-isoctyl, fenoprop-methyl, fenoproppotassium, fenothiocarb, fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P,
161 fenoxaprop-P-ethyl, fenoxasulfone, fenoxycarb, fenpiclonil, fenpirithrin, fenpropathrin, fenpropidin, fenpropimorph, fenpyrazamine, fenpyroximate, fenridazon, fenridazon-potassium, fenridazonpropyl, fenson, fensulfothion, fenteracol, fenthiaprop, fenthiaprop-ethyl, fenthion, fenthion-ethyl, fentin, fentin acetate, fentin chloride, fentin hydroxide, 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, flometoquin, flonicamid, florasulam, fluacrypyrim, fluazifop, fluazifop-butyl, fluazifopmethyl, fluazifop-P, fluazifop-P-butyl, fluazinam, fluazolate, fluazuron, flubendiamide, flubenzimine, flucarbazone, flucarbazone-sodium, flucetosulfuron, fluchloralin, flucofuron, flucycloxuron, flucythrinate, fludioxonil, fluenetil, fluensulfone, flufenacet, flufenerim, flufenican, flufenoxuron, flufenprox, flufenpyr, flufenpyr-ethyl, flufiprole, flumethrin, flumetover, flumetralin, flumetsulam, flumezin, flumiclorac, flumiclorac-pentyl, flumioxazin, flumipropyn, flumorph, fluometuron, fluopicolide, fluopyram, fluorbenside, fluoridamid, fluoroacetamide, fluorodifen, fluoroglycofen, fluoroglycofen-ethyl, fluoroimide, fluoromidine, fluoronitrofen, fluothiuron, fluotrimazole, fluoxastrobin, flupoxam, flupropacil, flupropadine, flupropanate, flupropanate-sodium, flupyradifurone, flupyrsulfuron, flupyrsulfuron-methyl, flupyrsulfuron-methyl-sodium, fluquinconazole, flurazole, flurenol, flurenol-butyl, flurenol-methyl, fluridone, flurochloridone, fluroxypyr, fluroxypyr-butometyl, fluroxypyr-meptyl, flurprimidol, flursulamid, flurtamone, flusilazole, flusulfamide, fluthiacet, fluthiacet-methyl, flutianil, flutolanil, flutriafol, fluvalinate, fluxapyroxad, fluxofenim, folpet, fomesafen, fomesafen-sodium, fonofos, foramsulfuron, forchlorfenuron, formaldéhyde, formetanate, formetanate hydrochloride, formothion, formparanate, formparanate hydrochloride, fosamine, fosamine-ammonium, fosetyl, fosetyl-aluminium, fosmethilan, fospirate, fosthiazate, fosthietan, frontalin, fuberidazole, fucaojing, fucaomi, funaihecaoling, fuphenthiourea, furalane, furalaxyl, furamethrin, furametpyr, furathiocarb, furcarbanil, furconazole, furconazole-cis, furethrin, furfural, furilazole, furmecyclox, furophanate, furyloxyfen, gamma-cyhalothrin, gammaHCH, genit, gibberellic acid, gibberellins, gliftor, glufosinate, glufosinate-ammonium, glufosinate-P, glufosinate-P-ammonium, glufosinate-P-sodium, glyodin, glyoxime, glyphosate, glyphosatediammonium, glyphosate-dimethylammonium, glyphosate-isopropylammonium, glyphosatemonoammonium, glyphosate-potassium, glyphosate-sesquisodium, glyphosate-trimesium, glyphosine, gossyplure, grandlure, griseofulvin, guazatine, guazatine acétates, halacrinate, halfenprox, halofenozide, halosafen, halosulfuron, halosulfuron-methyl, haloxydine, haloxyfop, haloxyfop-etotyl, haloxyfop-methyl, haloxyfop-P, haloxyfop-P-etotyl, haloxyfop-P-methyl, haloxyfopsodium, HCH, hemel, hempa, HEOD, heptachlor, heptenophos, heptopargil, heterophos, hexachloroacetone, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole,
162 hexaflumuron, hexaflurate, hexalure, hexamide, hexazinone, hexylthiofos, hexythiazox, HHDN, holosulf, huancaiwo, huangcaoling, huanjunzuo, hydramethylnon, hydrargaphen, hydrated lime, hydrogen cyanide, hydroprene, hymexazol, hyquincarb, IAA, IBA, icaridin, imazalil, imazalil nitrate, imazalil sulfate, imazamethabenz, imazamethabenz-methyl, imazamox, imazamox-ammonium, imazapic, imazapic-ammonium, imazapyr, imazapyr-isopropylammonium, imazaquin, imazaquinammonium, imazaquin-methyl, imazaquin-sodium, imazethapyr, imazethapyr-ammonium, imazosulfuron, imibenconazole, imicyafos, imidacloprid, imidaclothiz, iminoctadine, iminoctadine triacetate, iminoctadine trialbesilate, imiprothrin, inabenfide, indanofan, indaziflam, indoxacarb, inezin, iodobonil, iodocarb, iodomethane, iodosulfuron, iodosulfuron-methyl, iodosulfuron-methylsodium, iofensulfuron, iofensulfuron-sodium, ioxynil, ioxynil octanoate, ioxynil-lithium, ioxynilsodium, ipazine, ipconazole, ipfencarbazone, iprobenfos, iprodione, iprovalicarb, iprymidam, ipsdienol, ipsenol, IPSP, isamidofos, isazofos, isobenzan, isocarbamid, isocarbophos, isocil, isodrin, isofenphos, isofenphos-methyl, isolan, isomethiozin, isonoruron, isopolinate, isoprocarb, isopropalin, isoprothiolane, isoproturon, isopyrazam, isopyrimol, isothioate, isotianil, isouron, isovaledione, isoxaben, isoxachlortole, isoxadifen, isoxadifen-ethyl, isoxaflutole, isoxapyrifop, isoxathion, ivermectin, izopamfos, japonilure, japothrins, jasmolin I, jasmolin II, jasmonic acid, jiahuangchongzong, jiajizengxiaolin, jiaxiangjunzhi, jiecaowan, jiecaoxi, jodfenphos, juvénile hormone I, juvénile hormone II, juvénile hormone III, kadethrin, karbutilate, karetazan, karetazanpotassium, kasugamycin, kasugamycin hydrochloride, kejunlin, kelevan, ketospiradox, ketospiradox-potassium, kinetin, kinoprene, kresoxim-methyl, kuicaoxi, lactofen, lambdacyhalothrin, latilure, lead arsenate, lenacil, lepimectin, leptophos, lindane, lineatin, linuron, lirimfos, litlure, looplure, lufenuron, Ivdingjunzhi, Ivxiancaolin, lythidathion, MAA, malathion, maleic hydrazide, malonoben, maltodextrin, ΜΑΜΑ, mancopper, mancozeb, mandipropamid, maneb, matrine, mazidox, MCPA, MCPA-2-ethylhexyl, MCPA-butotyl, MCPA-butyl, MCPAdimethylammonium, MCPA-diolamine, MCPA-ethyl, MCPA-isobutyl, MCPA-isoctyl, MCPAisopropyl, MCPA-methyl, MCPA-olamine, MCPA-potassium, MCPA-sodium, MCPA-thioethyl, MCPA-trolamine, MCPB, MCPB-ethyl, MCPB-methyl, MCPB-sodium, mebenil, mecarbam, mecarbinzid, mecarphon, mecoprop, mecoprop-2-ethylhexyl, mecoprop-dimethylammonium, mecoprop-diolamine, mecoprop-ethadyl, mecoprop-isoctyl, mecoprop-methyl, mecoprop-P, mecoprop-P-2-ethylhexyl, mecoprop-P-dimethylammonium, mecoprop-P-isobutyl, mecoproppotassium, mecoprop-P-potassium, mecoprop-sodium, mecoprop-trolamine, medimeform, medinoterb, medinoterb acetate, medlure, mefenacet, mefenpyr, mefenpyr-diethyl, mefluidide, mefluidide-diolamine, mefluidide-potassium, megatomoic acid, menazon, mepanipyrim, meperfluthrin, mephenate, mephosfolan, mepiquat, mepiquat chloride, mepiquat pentaborate,
163 mepronil, meptyldinocap, mercuric chloride, mercuric oxide, mercurous chloride, merphos, mesoprazine, mesosulfuron, mesosulfuron-methyl, mesotrione, mesulfen, mesulfenfos, metaflumizone, metalaxyl, metalaxyl-M, metaldehyde, metam, metam-ammonium, metamifop, metamitron, metam-potassium, metam-sodium, metazachlor, metazosulfuron, metazoxolon, metconazole, metepa, metflurazon, methabenzthiazuron, methacrifos, methalpropalin, methamidophos, methasulfocarb, methazole, methfuroxam, methidathion, methiobencarb, methiocarb, methiopyrisulfuron, methiotepa, methiozolin, methiuron, methocrotophos, methometon, methomyl, methoprene, methoprotryne, methoquin-butyl, methothrin, methoxychlor, methoxyfenozide, methoxyphenone, methyl apholate, methyl bromide, methyl eugenol, methyl iodide, methyl isothiocyanate, methylacetophos, methylchloroform, methyldymron, methylene chloride, methylmercury benzoate, methylmercury dicyandiamide, methylmercury pentachlorophenoxide, methylneodecanamide, metiram, metobenzuron, metobromuron, metofluthrin, metolachlor, metolcarb, metominostrobin, metosulam, metoxadiazone, metoxuron, metrafenone, metribuzin, metsulfovax, metsulfuron, metsulfuron-methyl, mevinphos, mexacarbate, mieshuan, milbemectin, milbemycin oxime, milneb, mipafox, mirex, MNAF, moguchun, molinate, molosultap, monalide, monisouron, monochloroacetic acid, monocrotophos, monolinuron, monosulfuron, monosulfuron-ester, monuron, monuron TCA, morfamquat, morfamquat dichloride, moroxydine, moroxydine hydrochloride, morphothion, morzid, moxidectin, MSMA, muscalure, myclobutanil, myclozolin, N-(ethylmercury)-p-toluenesulphonanilide, nabam, naftalofos, naled, naphthalene, naphthaleneacetamide, naphthalic anhydride, naphthoxyacetic acids, naproanilide, napropamide, naptalam, naptalam-sodium, natamycin, neburon, niclosamide, niclosamide-olamine, nicosulfuron, nicotine, nifluridide, nipyraclofen, nitenpyram, nithiazine, nitralin, nitrapyrin, nitrilacarb, nitrofen, nitrofluorfen, nitrostyrene, nitrothal-isopropyl, norbormide, norflurazon, nornicotine, noruron, novaluron, noviflumuron, nuarimol, OCH, octachlorodipropyl ether, octhilinone, ofurace, omethoate, orbencarb, orfralure, ortho-dichlorobenzene, orthosulfamuron, oryctalure, orysastrobin, oryzalin, osthol, ostramone, oxabetrinil, oxadiargyl, oxadiazon, oxadixyl, oxamate, oxamyl, oxapyrazon, oxapyrazon-dimolamine, oxapyrazon-sodium, oxasulfuron, oxaziclomefone, oxinecopper, oxolinic acid, oxpoconazole, oxpoconazole fumarate, oxycarboxin, oxydemeton-methyl, oxydeprofos, oxydisulfoton, oxyfluorfen, oxymatrine, oxytetracycline, oxytetracycline hydrochloride, paclobutrazol, paichongding, para-dichlorobenzene, parafluron, paraquat, paraquat dichloride, paraquat dimetilsulfate, parathion, parathion-methyl, parinol, pebulate, pefurazoate, pelargonic acid, penconazole, pencycuron, pendimethalin, penflufen, penfluron, penoxsulam, pentachlorophenol, pentanochlor, penthiopyrad, pentmethrin, pentoxazone, perfluidone, permethrin, pethoxamid, phenamacril, phenazine oxide, phenisopham, phenkapton,
164 phenmedipham, phenmedipham-ethyl, phenobenzuron, phenothrin, phenproxide, phenthoate, phenylmercuriurea, phenylmercury acetate, phenylmercury chloride, phenylmercury dérivative of pyrocatechol, phenylmercury nitrate, phenylmercury salicylate, phorate, phosacetim, phosalone, phosdiphen, phosfolan, phosfolan-methyl, phosglycin, phosmet, phosnichlor, phosphamidon, phosphine, phosphocarb, phosphorus, phostin, phoxim, phoxim-methyl, phthalide, picloram, picloram-2-ethylhexyl, picloram-isoctyl, picloram-methyl, picloram-olamine, picloram-potassium, picloram-triethylammonium, picloram-tris(2-hydroxypropyl)ammonium, picolinafen, picoxystrobin, pindone, pindone-sodium, pinoxaden, piperalin, piperonyl butoxide, piperonyl cyclonene, piperophos, piproctanyl, piproctanyl bromide, piprotal, pirimetaphos, pirimicarb, pirimioxyphos, pirimiphos-ethyl, pirimiphos-methyl, plifenate, polycarbamate, polyoxins, polyoxorim, polyoxorimzinc, polythialan, potassium arsenite, potassium azide, potassium cyanate, potassium gibberellate, 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, prodiamine, profenofos, profluazol, profluralin, profluthrin, profoxydim, proglinazine, proglinazine-ethyl, prohexadione, prohexadione-calcium, prohydrojasmon, promacyl, promecarb, prometon, prometryn, promurit, propachlor, propamidine, propamidine dihydrochloride, propamocarb, propamocarb hydrochloride, propanil, propaphos, propaquizafop, propargite, proparthrin, propazine, propetamphos, propham, propiconazole, propineb, propisochlor, propoxur, propoxycarbazone, propoxycarbazone-sodium, propyl isome, propyrisulfuron, propyzamide, proquinazid, prosuler, prosulfalin, prosulfocarb, prosulfuron, prothidathion, prothiocarb, prothiocarb hydrochloride, prothioconazole, prothiofos, prothoate, protrifenbute, proxan, proxan-sodium, prynachlor, pydanon, pymetrozine, pyracarbolid, pyraclofos, pyraclonil, pyraclostrobin, pyraflufen, pyraflufen-ethyl, pyrafluprole, pyramat, pyrametostrobin, pyraoxystrobin, pyrasulfotole, pyrazolynate, pyrazophos, pyrazosulfuron, pyrazosulfuron-ethyl, pyrazothion, pyrazoxyfen, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyribambenz-isopropyl, pyribambenz-propyl, pyribencarb, pyribenzoxim, pyributicarb, pyriclor, pyridaben, pyridafol, pyridalyl, pyridaphenthion, pyridate, pyridinitril, pyrifenox, pyrifluquinazon, pyriftalid, pyrimethanil, pyrimidifen, pyriminobac, pyriminobac-methyl, pyrimisulfan, pyrimitate, pyrinuron, pyriofenone, pyriprole, pyripropanol, pyriproxyfen, pyrithiobac, pyrithiobac-sodium, pyrolan, pyroquilon, pyroxasulfone, pyroxsulam, pyroxychlor, pyroxyfur, quassia, quinacetol, quinacetol sulfate, quinalphos, quinalphos-methyl, quinazamid, quinclorac, quinconazole, quinmerac, quinoclamine, quinonamid, quinothion, quinoxyfen, quintiofos, quintozene, quizalofop, quizalofop-ethyl, quizalofop-P, quizalofop-P-ethyl, quizalofop-P-tefuryl, quwenzhi, quyingding, rabenzazole,
165 rafoxanide, rebemide, resmethrin, rhodethanil, rhodojaponin-lll, ribavirin, rimsulfuron, rotenone, ryania, saflufenacil, saijunmao, saisentong, salicylanilide, sanguinarine, santonin, schradan, scilliroside, sebuthylazine, secbumeton, sedaxane, selamectin, semiamitraz, semiamitraz chloride, sesamex, sesamolin, sethoxydim, shuangjiaancaolin, siduron, siglure, silafluofen, silatrane, silica gel, silthiofam, simazine, simeconazole, simeton, simetryn, sintofen, SMA, S-metolachlor, sodium arsenite, sodium azide, sodium chlorate, sodium fluoride, sodium fluoroacetate, sodium hexafluorosilicate, sodium naphthenate, sodium orthophenylphenoxide, sodium pentachlorophenoxide, sodium polysulfide, sodium thiocyanate, sodium a-naphthaleneacetate, sophamide, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine, streptomycin, streptomycin sesquisulfate, strychnine, sulcatol, sulcofuron, sulcofuron-sodium, sulcotrione, sulfallate, sulfentrazone, sulfiram, sulfluramid, sulfometuron, sulfometuron-methyl, sulfosulfuron, sulfotep, sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid, sulfuryl fluoride, sulglycapin, sulprofos, sultropen, swep, tau-fluvalinate, tavron, tazimcarb, TCA, TCA-ammonium, TCA-calcium, TCA-ethadyl, TCA-magnesium, TCA-sodium, TDE, tebuconazole, tebufenozide, tebufenpyrad, tebufloquin, tebupirimfos, tebutam, tebuthiuron, tecloftalam, tecnazene, tecoram, teflubenzuron, tefluthrin, tefuryltrione, tembotrione, temephos, tepa, TEPP, tepraloxydim, terallethrin, terbacil, terbucarb, terbuchlor, terbufos, terbumeton, terbuthylazine, terbutryn, tetcyclacis, tetrachloroethane, tetrachlorvinphos, tetraconazole, tetradifon, tetrafluron, tetramethrin, tetramethylfluthrin, tetramine, tetranactin, tetrasul, thallium sulfate, thenylchlor, theta-cypermethrin, thiabendazole, thiacloprid, thiadifluor, thiamethoxam, thiapronil, thiazafluron, thiazopyr, thicrofos, thicyofen, thidiazimin, thidiazuron, thiencarbazone, thiencarbazone-methyl, thifensulfuron, thifensulfuron-methyl, thifluzamide, thiobencarb, thiocarboxime, thiochlorfenphim, thiocyclam, thiocyclam hydrochloride, thiocyclam oxalate, thiodiazole-copper, thiodicarb, thiofanox, thiofluoximate, thiohempa, thiomersal, thiometon, thionazin, thiophanate, thiophanate-methyl, thioquinox, thiosemicarbazide, thiosultap, thiosultap-diammonium, thiosultap-disodium, thiosultapmonosodium, thiotepa, thiram, thuringiensin, tiadinil, tiaojiean, tiocarbazil, tioclorim, tioxymid, tirpate, tolclofos-methyl, tolfenpyrad, tolylfluanid, tolylmercury acetate, topramezone, tralkoxydim, tralocythrin, tralomethrin, tralopyril, transfluthrin, transpermethrin, tretamine, triacontanol, triadimefon, triadimenol, triafamone, tri-allate, triamiphos, triapenthenol, triarathene, triarimol, triasulfuron, triazamate, triazbutil, triaziflam, triazophos, triazoxide, tribenuron, tribenuron-methyl, tribufos, tributyltin oxide, tricamba, trichlamide, trichlorfon, trichlormetaphos-3, trichloronat, triclopyr, triclopyr-butotyl, triclopyr-ethyl, triclopyr-triethylammonium, tricyclazole, tridemorph, tridiphane, trietazine, trifenmorph, trifenofos, trifloxystrobin, trifloxysulfuron, trifloxysulfuron-sodium, triflumizole, triflumuron, trifluralin, triflusulfuron, triflusulfuron-methyl, trifop, trifop-methyl, trifopsime, triforine,
166 trihydroxytriazine, trimedlure, trimethacarb, trimeturon, trinexapac, trinexapac-ethyl, triprene, tripropindan, triptolide, tritac, triticonazole, tritosulfuron, trunc-call, uniconazole, uniconazole-P, urbacide, uredepa, valerate, validamycin, valifenalate, valone, vamidothion, vangard, vaniliprole, vernolate, vinclozolin, warfarin, warfarin-potassium, warfarin-sodium, xiaochongliulin, xinjunan, xiwojunan, XMC, xylachlor, xylenols, xylylcarb, yishijing, zarilamid, zeatin, zengxiaoan, zetacypermethrin, zinc naphthenate, zinc phosphide, zinc thiazole, zineb, ziram, zolaprofos, zoxamide, zuomihuanglong, α-chlorohydrin, a-ecdysone, a-multistriatin, and α-naphthaleneacetic acid. For more information consult the “Compendium of Pesticide Common Names” located at http://www.alanwood.net/pesticides/index.html. Also consult “The Pesticide Manual” 14th Edition, edited by C D S Tomlin, copyright 2006 by British Crop Production Council, or its prior or more recent éditions.
BIOPESTICIDES
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 biopesticides. The term “biopesticide” is used for microbial biological pest control agents that are applied in a similar manner to chemical pesticides. Commonly these are bacterial, but there are also examples of fungal control agents, including Trichoderma spp. and Ampelomyces quisqualis (a control agent for grape powdery mildew). Bacillus subtilis are used to control plant pathogens. Weeds and rodents hâve also been controlled with microbial agents. One well-known insecticide example is Bacillus thuringiensis, a bacterial disease of Lepidoptera, Coleoptera, and Diptera. Because it has little effect on other organisms, it is considered more environmentally friendly than synthetic pesticides. Biological insecticides include products based on:
1. entomopathogenic fungi (e.g. Metarhizium anisopliae)',
2. entomopathogenic nematodes (e.g. Steinernema feltiae); and
3. entomopathogenic viruses (e.g. Cydia pomonella granulovirus).
Other examples of entomopathogenic organisms include, but are not limited to, baculoviruses, bacteria and other prokaryotic organisms, fungi, protozoa and Microsproridia. Biologically derived insecticides include, but not limited to, rotenone, veratridine, as well as microbial toxins; insect tolérant or résistant plant varieties; and organisms modified by recombinant DNA technology to either produce insecticides or to convey an insect résistant property to the genetically modified organism. In one embodiment, the molécules of Formula One may be used with one or more biopesticides in the area of seed treatments and soil amendments. The Manual of Biocontrol Agents gives a review of the available biological insecticide (and other biology-based
167 control) products. Copping L.G. (ed.) (2004). The Manual of Biocontrol Agents (formerly the Biopesticide Manual) 3rd Edition. British Crop Production Council (BCPC), Farnham, Surrey UK. OTHER ACTIVE COMPOUNDS
Molécules of Formula One may also be used in combination (such as in a compositional mixture, or a simultaneous or sequential application) with one or more of the following:
1. 3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8-oxa-1 -azaspiro[4,5]dec-3-en-2-one;
2. 3-(4’-chloro-2,4-dimethyl[1,1 ’-biphenyl]-3-yl)-4-hydroxy-8-oxa-1 -azaspiro[4,5]dec-3-en-2one;
3- 4-[[(6-chloro-3-pyridinyl)methyl]methylamino]-2(5/-/)-furanone;
4. 4-[[(6-chloro-3-pyridinyl)methyl]cyclopropylamino]-2(5H)-furanone;
5. 3-chloro-/V2-[(1S)-1-methyl-2-(methylsulfonyl)ethyl]-A/1-[2-methyl-4-[1,2,2,2-tetrafluoro-1(trifluoromethyl)ethyl]phenyl]-1,2-benzenedicarboxamide;
6. 2-cyano-A/-ethyl-4-fluoro-3-methoxy-benenesulfonamide;
7. 2-cyano-/V-ethyl-3-methoxy-benzenesulfonamide;
8. 2-cyano-3-difluoromethoxy-A/-ethyl-4-fluoro-benzenesulfonamide;
9. 2-cyano-3-fluoromethoxy-A/-ethyl-benzenesulfonamide;
10. 2-cyano-6-fluoro-3-methoxy-A/,A/-dimethyl-benzenesulfonamide;
11. 2-cyano-A/-ethyl-6-fluoro-3-methoxy-/\/-methyl-benzenesulfonamide;
12. 2-cyano-3-difluoromethoxy-A/,A/-dimethylbenzenesulfon-amide;
13. 3-(difluoromethyl)-/\/-[2-(3,3-dimethylbutyl)phenyl]-1 -methyl-1 H-pyrazole-4-carboxamide;
14. A/-ethyl-2,2-dimethylpropionamide-2-(2,6-dichloro-a,a,a-trifluoro-p-tolyl) hydrazone;
15. A/-ethyl-2,2-dichloro-1 -methylcyclopropane-carboxamide-2-(2,6-dichloro-a,a,a-trifluoro-ptolyl) hydrazone nicotine;
16. O-{(E-)-[2-(4-chloro-phenyl)-2-cyano-1 -(2-trifluoromethylphenyl)-vinyl]} S-methyl thiocarbonate;
17. (E)-N1-[(2-chloro-1,3-thiazol-5-ylmethyl)]-N2-cyano-N1-methylacetamidine;
18. 1 -(6-chloropyridin-3-ylmethyl)-7-methyl-8-nitro-1,2,3,5,6,7-hexahydro-imidazo[1,2-a]pyridin5-ol;
168
19. 4-[4-chlorophenyl-(2-butylidine-hydrazono)methyl)]phenyl mesylate; and
20. N-Ethyl-2,2-dichloro-1-methylcyclopropanecarboxamide-2-(2,6-dichloro-a/p/7a,a/p/7a,a/p/7atrifluoro-p-tolyl)hydrazone.
SYNERGISTIC MIXTURES
Molécules 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 molécules of Formula One are the same, similar, or different. Examples of modes of action include, but are not limited to: acetylcholinesterase inhibitor; sodium channel modulator; chitin biosynthesis 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; nicotinic acétylcholine receptor; Midgut membrane disrupter; oxidative phosphorylation disrupter, and ryanodine receptor (RyRs). Generally, weight ratios of the molécules of Formula One in a synergistic mixture with another compound are from about 10:1 to about 1:10, 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 émulsions, dusts, emulsifiable concentrâtes, fumigants, gels, granules, microencapsulations, seed treatments, suspension concentrâtes, suspoemulsions, tablets, water soluble liquids, water dispersible granules or dry flowables, wettable powders, and ultra low volume solutions. For further information on formulation types see “Catalogue of Pesticide Formulation Types and International Coding System” Technical Monograph n°2, 5th Edition by CropLife International (2002).
Pesticides are applied most often as aqueous suspensions or émulsions prepared from concentrated formulations of such pesticides. Such water-soluble, water-suspendable, or emulsifiable formulations are either solids, usually known as wettable powders, or water dispersible granules, or liquids usually known as emulsifiable concentrâtes, or aqueous suspensions. Wettable powders, which may be compacted to form water dispersible granules, comprise an intimate mixture ofthe pesticide, a carrier, and surfactants. The concentration of the pesticide is usually from about 10% to about 90% by weight. The carrier is usually selected from among the attapulgite clays, the montmorillonite clays, the diatomaceous earths, or the purified silicates. Effective
169 surfactants, comprising from about 0.5% to about 10% of the wettable powder, are found among sulfonated lignins, condensed naphthalenesulfonates, naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates, and non-ionic surfactants such as ethylene oxide adducts of alkyl phénols.
Emulsifiable concentrâtes of pesticides comprise a convenient concentration of a pesticide, such as from about 50 to about 500 grams per liter of liquid dissolved in a carrier that is either a water miscible solvent or a mixture of water-immiscible organic solvent and emulsifiers. Useful organic solvents include aromatics, especially xylenes and petroleum fractions, especially the highboiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, such as the terpenic solvents including rosin dérivatives, aliphatic ketones such as cyclohexanone, and complex alcohols such as 2-ethoxyethanoL Suitable emulsifiers for emulsifiable concentrâtes are selected from conventional anionic and non-ionic surfactants.
Aqueous suspensions comprise suspensions of water-insoluble pesticides dispersed in an aqueous carrier at a concentration in the range from about 5% to about 50% by weight. Suspensions are prepared by finely grinding the pesticide and 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 pesticide at the same time by preparing the aqueous mixture and homogenizing it in an implement such as a sand mill, bail mill, or piston-type homogenizer.
Pesticides may also be applied as granular compositions that are particularly useful for applications to the soil. Granular compositions usually contain from about 0.5% to about 10% by weight of the pesticide, dispersed in a carrier that comprises clay or a similar substance. Such compositions are usually prepared by dissolving the pesticide in a suitable solvent and applying it to a granular carrier which has been pre-formed to the appropriate particle size, in the range of from about 0.5 to about 3 mm. Such compositions may also be formulated by making a dough or paste of the carrier and compound and crushing and drying to obtain the desired granular particle size.
Dusts containing a pesticide are prepared by intimately mixing the pesticide in powdered form with a suitable dusty agricultural carrier, such as kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1% to about 10% of the pesticide. They can be applied as a seed dressing or as a foliage application with a dust blower machine.
170
It is equally practical to apply a pesticide in the form of a solution in an appropriate organic solvent, usually petroleum oil, such as the spray oils, which are widely used in agricultural chemistry.
Pesticides can also be applied in the form of an aérosol composition. In such compositions the pesticide is dissolved or dispersed in a carrier, which is a pressure-generating propellant mixture. The aérosol composition is packaged in a container from which the mixture is dispensed through an atomizing valve.
Pesticide baits are formed when the pesticide is mixed with food or an attractant or both. When the pests eat the bait they also consume the pesticide. Baits may take the form of granules, gels, flowable powders, liquids, or solids. They can be used in pest harborages.
Fumigants are pesticides that hâve a relatively high vapor pressure and hence can exist as a gas in sufficient concentrations to kill pests in soil or enclosed spaces. The toxicity of the fumigant is proportional to its concentration and the exposure time. They are characterized by a good capacity for diffusion and act by penetrating the pest’s respiratory System or being absorbed through the pest’s cuticle. Fumigants are applied to control stored product pests under gas proof sheets, in gas sealed rooms or buildings or in spécial chambers.
Pesticides can be microencapsulated by suspending the pesticide particles or droplets in plastic polymers of various types. By altering the chemistry of the polymer or by changing factors in the processing, microcapsules can be formed of various sizes, solubility, wall thicknesses, and degrees of penetrability. These factors govern the speed with.which the active ingrédient within is released, which in turn, affects the residual performance, speed of action, and odor of the product.
Oil solution concentrâtes are made by dissolving pesticide in a solvent that will hold the pesticide in solution. Oil solutions of a pesticide usually provide faster knockdown and kill of pests than other formulations due to the solvents themselves having pesticidal action and the dissolution of the waxy covering of the integument increasing the speed of uptake of the pesticide. Other advantages of oil solutions include better storage stability, better pénétration of crevices, and better adhesion to greasy surfaces.
Another embodiment is an oil-in-water émulsion, wherein the émulsion comprises oily globules which are each provided with a lamellar liquid crystal coating and are dispersed in an aqueous phase, wherein each oily globule comprises at least one compound which is agriculturally active, and is individually coated with a monolamellar or oligolamellar layer comprising: (1) at least one non-ionic lipophilie surface-active agent, (2) at least one non-ionic hydrophilic surface-active agent and (3) at least one ionic surface-active agent, wherein the globules having a mean particle 171 diameter of less than 800 nanometers. Further information on the embodiment is disclosed in U.S. patent publication 20070027034 published February 1,2007, having Patent Application serial number 11/495,228. Forease of use, this embodiment will be referred to as OIWE”.
For further information consult “Insect Pest Management” 2nd Edition by D. Dent, copyright CAB International (2000). Additionally, for more detailed information consult “Handbook of Pest Control - The Behavior, Life History, and Control of Household Pests” by 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, cleaning agents, and emulsifiers. A few components are described forthwith.
A wetting agent is a substance that when added to a liquid increases the spreading or pénétration power of the liquid by reducing the interfacial tension between the liquid and the surface on which it is spreading. Wetting agents are used for two main functions in agrochemical formulations: during processing and manufacture to increase the rate of wetting of powders in water to make concentrâtes for soluble liquids or suspension concentrâtes; and during mixing of a product with water in a spray tank to reduce the wetting time of wettable powders and to improve the pénétration of water into water-dispersible granules. Examples of wetting agents used in wettable powder, suspension concentrate, and water-dispersible granule formulations are: sodium lauryl sulfate; sodium dioctyl sulfosuccinate; alkyl phénol ethoxylates; and aliphatic alcohol ethoxylates.
A 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 facilitate 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 particle surface and provide a charged or steric barrier to reaggregation of particles. The most commonly used surfactants are anionic, non-ionic, or mixtures of the two types. For wettable powder formulations, the most common dispersing agents are sodium lignosulfonates. For suspension concentrâtes, very good adsorption and stabilization are obtained using polyelectrolytes, such as sodium
172 naphthalene sulfonate formaldéhyde condensâtes. Tristyrylphenol ethoxylate phosphate esters are also used. Non-ionics such as alkylarylethylene oxide condensâtes and EO-PO block copolymers are sometimes combined with anionics as dispersing agents for suspension concentrâtes. In recent years, new types of very high molecular weight polymeric surfactants hâve been developed as dispersing agents. These hâve very long hydrophobie ‘backbones’ and a large number of ethylene oxide chains forming the ‘teeth’ of a ‘comb’ surfactant. These high molecular weight polymers can give very good long-term stability to suspension concentrâtes because the hydrophobie backbones hâve many anchoring points onto the particle surfaces. Examples of dispersing agents used in agrochemical formulations are: sodium lignosulfonates; sodium naphthalene sulfonate formaldéhyde condensâtes; tristyrylphenol ethoxylate phosphate esters; aliphatic alcohol ethoxylates; alkyl ethoxylates; EO-PO block copolymers; and graft copolymers.
An emulsifying agent is a substance which stabilizes a suspension of droplets of one liquid phase in another liquid phase. Without the emulsifying agent the two liquids would separate into two immiscible liquid phases. The most commonly used emulsifier blends contain alkylphenol or aliphatic alcohol with twelve or more ethylene oxide units and the oil-soluble calcium sait of dodecylbenzenesulfonic acid. A range of hydrophile-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 solubilizing agent is a surfactant which will form micelles in water at concentrations above the critical micelle concentration. The micelles are then able to dissolve or solubilize water-insoluble materials inside the hydrophobie part of the micelle. The types of surfactants usually used for solubilization are non-ionics, sorbitan monooleates, sorbitan monooleate ethoxylates, and methyl oleate esters.
Surfactants are sometimes used, either alone or with other additives such as minerai or vegetable oils as adjuvants to spray-tank mixes to improve the biological performance of the pesticide on the target. The types of surfactants used for bioenhancement dépend generally on the nature and mode of action of the pesticide. However, they are often non-ionics such as: alkyl ethoxylates; linear aliphatic alcohol ethoxylates; aliphatic amine ethoxylates.
A carrier or diluent in an agricultural formulation is a material added to the pesticide to give a product of the required strength. Carriers are usually materials with high absorptive capacities, while diluents are usually materials with low absorptive capacities. Carriers and diluents are used in the formulation of dusts, wettable powders, granules and water-dispersible granules.
173
Organic solvents are used mainly in the formulation of emulsifiable concentrâtes, oil-inwater émulsions, suspoemulsions, and ultra low volume formulations, and to a lesser extent, granular formulations. Sometimes mixtures of solvents are used. The first main groups of solvents are aliphatic paraffinic oils such as kerosene or refined 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 emulsified into water. Alcohols are sometimes used as cosolvents to increase solvent power. Other solvents may include vegetable oils, seed oils, and esters of vegetable and seed oils.
Thickeners or gelling agents are used mainly in the formulation of suspension concentrâtes, émulsions and suspoemulsions to modify the rheology or flow properties of the liquid and to prevent séparation and settling of the dispersed particles or droplets. Thickening, gelling, and anti-settling agents generally fall into two categories, namely water-insoluble particulates and water-soluble polymers. It is possible to produce suspension concentrate formulations using clays and silicas. Examples of these types of materials, include, but are not limited to, montmorillonite, bentonite, magnésium aluminum silicate, and attapulgite. Water-soluble polysaccharides hâve been used as thickening-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 include, but are not limited 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, polyvinyl alcohol and polyethylene oxide. Another good anti-settling agent is xanthan gum.
Microorganisms can cause spoilage of formulated products. Therefore préservation agents are used to eliminate or reduce their effect. Examples of such agents include, but are not limited to: propionic acid and its sodium sait; sorbic acid and its sodium or potassium salts; benzoic acid and its sodium sait; p-hydroxybenzoic acid sodium sait; methyl p-hydroxybenzoate; and 1,2benzisothiazolin-3-one (BIT).
The presence of surfactants often causes water-based formulations to foam during mixing operations in production and in application through a spray tank. In order to reduce the tendency to foam, anti-foam agents are often added either during the production stage or before filling into bottles. Generally, there are two types of anti-foam agents, namely silicones and non-silicones. Silicones are usually aqueous émulsions of dimethyl polysiloxane, while the non-silicone anti-foam
174 agents are water-insoluble oils, such as octanol and nonanol, orsilica. In both cases, the function of the anti-foam agent is to displace the surfactant from the air-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 from natural 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 D.A. Knowles, copyright 1998 by Kluwer Academie Publishers. Also see “Insecticides in Agriculture and Environment - Retrospects and Prospects” by A.S. Perry, I. Yamamoto, I. Ishaaya, and R. Perry, copyright 1998 by Springer-Verlag.
PESTS
In general, the molécules of Formula One may be used to control pests e.g. beetles, earwigs, cockroaches, flies. aphids, scales, whiteflies, leafhoppers, ants, wasps, termites, moths, butterflies, lice, grasshoppers, locusts, crickets, fleas, thrips, bristletails, mites, ticks, nematodes, and symphylans.
In another embodiment, the molécules of Formula One may be used to control pests in the Phyla Nematoda and/or Arthropoda.
In another embodiment, the molécules of Formula One may be used to control pests in the Subphyla Chelicerata, Myriapoda, and/or Hexapoda.
In another embodiment, the molécules of Formula One may be used to control pests in the Classes of Arachnida, Symphyla, and/or Insecta.
In another embodiment, the molécules of Formula One may be used to control pests of the Order Anoplura. A non-exhaustive list of particular généra includes, but is not limited to, Haematopinus spp., Hoplopleura spp., Linognathus spp., Pediculus spp., and Polyplax spp. A nonexhaustive list of particular species includes, but is not limited to, Haematopinus asini, Haematopinus suis, Linognathus setosus, Linognathus ovillus, Pediculus humanus capitis, Pediculus humanus humanus, and Pthirus pubis.
In another embodiment, the molécules of Formula One may be used to control pests in the Order Coleoptera. A non-exhaustive list of particular généra includes, but is not limited to, Acanthoscelides spp., Agriotes spp., Anthonomus spp., Apion spp., Apogonia spp., Aulacophora spp., Bruchus spp., Cerostema spp., Cerotoma spp., Ceutorhynchus spp., Chaetocnema spp., Colaspis spp., Ctenicera spp., Curculio spp., Cyclocephala spp., Diabrotica spp., Hypera spp., Ips
175 spp., Lyctus spp., Megascelis spp., Meligethes spp., Otïorhynchus spp., Pantomorus spp., Phyllophaga spp., Phyllotreta spp., Rhizotrogus spp., Rhynchites spp., Rhynchophorus spp., Scolytus spp., Sphenophorus spp., Sitophilus spp., and Tribolium spp. A non-exhaustive list of particular species includes, but is not limited to, Acanthoscelides obtectus, Agrilus planipennis, Anoplophora glabripennis, Anthonomus grandis, Ataenius spretulus, Atomaria linearis, Bothynoderes punctiventris, Bruchus pisorum, Callosobruchus maculatus, Carpophilus hemipterus, Cassida vittata, Cerotoma trifurcata, Ceutorhynchus assimilis, Ceutorhynchus napi, Conoderus scalaris, Conoderus stigmosus, Conotrachelus nénuphar, Cotinis nitida, Crioceris asparagi, Cryptolestes ferrugineus, Cryptolestes pusillus, Cryptolestes turcicus, Cylindrocopturus adspersus, Deporaus marginatus, Dermestes lardarius, Dermestes maculatus, Epilachna varivestis, Faustinus cubae, Hylobius pales, Hypera postica, Hypothenemus hampei, Lasioderma serricorne, Leptinotarsa decemlineata, Liogenys fuscus, Liogenys suturalis, Lissorhoptrus oryzophilus, Maecolaspis joliveti, Melanotus commuais, Meligethes aeneus, Melolontha melolontha, Oberea brevis, Oberea linearis, Oryctes rhinocéros, Oryzaephilus mercator, Oryzaephilus surinamensis, Ouléma melanopus, Ouléma oryzae, Phyllophaga cuyabana, Popillia japonica, Prostephanus truncatus, Rhyzopertha dominica,, Sitona lineatus, Sitophilus granarius, Sitophilus oryzae, Sitophilus zeamais, Stegobium paniceum, Tribolium castaneum, Tribolium confusum, Trogoderma variabile, and Zabrus tenebrioides.
In another embodiment, the molécules 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 Blattaria. A non-exhaustive list of particular species includes, but is not limited to, Blattella germanica, Blatta orientalis, Parcoblatta pennsylvanica, Periplaneta americana, Periplaneta australasiae, Periplaneta brunnea, Periplaneta fuliginosa, Pycnoscelus surinamensis, and Supella longipalpa.
In another embodiment, the molécules of Formula One may be used to control pests of the Order Diptera. A non-exhaustive list of particular généra includes, but is not limited to, Aedes spp., Agromyza spp., Anastrepha spp., Anopheles spp., Bactrocera spp., Ceratitis spp., Chrysops spp., Cochliomyia spp., Contarinia spp., Culex spp., Dasineura spp., Délia spp., Drosophila spp., Fannia spp., Hylemyia spp., Liriomyza spp., Musca spp., Phorbia spp., Tabanus spp., and Tipula spp. A non-exhaustive list of particular species includes, but is not limited to, Agromyza frontella, Anastrepha suspensa, Anastrepha ludens, Anastrepha obliqa, Bactrocera cucurbitae, Bactrocera dorsalis, Bactrocera invadens, Bactrocera zonata, Ceratitis capitata, Dasineura brassicae, Délia
176 platura, Fannia canicularis, Fannia scalaris, Gasterophilus intestinalis, Gracillia perseae, Haematobia irritans, Hypoderma lineatum, Liriomyza brassicae, Melophagus ovinus, Musca autumnalis, Musca domestica, Oestrus ovis, Oscinella frit, Pegomya betae, Psila rosae, Rhagoletis cerasi, Rhagoletis pomonella, Rhagoletis mendax, Sitodiplosis mosellana, and Stomoxys calcitrans.
In another embodiment, the molécules of Formula One may be used to control pests of the Order Hemiptera. A non-exhaustive list of particular généra includes, but is not limited to, Adelges spp., Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Ceroplastes spp., Chionaspis spp., Chrysomphalus spp., Coccus spp., Empoasca spp., Lepidosaphes spp., Lagynotomus spp., Lygus spp., Macrosiphum spp., Nephotettix spp., Nezara spp., Philaenus spp., Phytocoris spp., Piezodorus spp., Planococcus spp., Pseudococcus spp., Rhopalosiphum spp., Saissetia spp., Therioaphis spp., Toumeyella spp., Toxoptera spp., Trialeurodes spp., Triatoma spp. and Unaspis spp. A non-exhaustive list of particular species includes, but is not limited to, Acrosternum hilare, Acyrthosiphon pisum, Aleyrodes proletella, Aleurodicus dispersus, Aleurothrixus floccosus, Amrasca biguttula biguttula, Aonidiella aurantii, Aphis gossypii, Aphis glycines, Aphis pomi, Aulacorthum solani, Bemisia argentifolii, Bemisia tabaci, Blissus leucopterus, Brachycorynella asparagi, Brevennia rehi, Brevicoryne brassicae, Calocoris norvegicus, Ceroplastes rubens, Cimex hemipterus, Cimex lectularius, Dagbertus fasciatus, Dichelops furcatus, Diuraphis noxia, Diaphorina citri, Dysaphis plantaginea, Dysdercus suturellus, Edessa meditabunda, Eriosoma lanigerum, Eurygaster maura, Euschistus héros, Euschistus servus, Helopeltis antonii, Helopeltis theivora, Icerya purchasi, Idioscopus nitidulus, Laodelphax striatellus, Leptocorisa oratorius, Leptocorisa varicornis, Lygus hesperus, Maconellicoccus hirsutus, Macrosiphum euphorbiae, Macrosiphum granarium, Macrosiphum rosae, Macrosteles quadrilineatus, Mahanarva frimbiolata, Metopolophium dirhodum, Midis longicornis, Myzus persicae, Nephotettix cindipes, Neurocolpus longirostris, Nezara viridula, Nilaparvata lugens, Parlatoria pergandii, Parlatoria ziziphi, Peregrinus maidis, Phylloxéra vitifoliae, Physokermes piceae,, Phytocoris californicus, Phytocoris relatives, Piezodorus guildinii, Poecilocapsus lineatus, Psallus vaccinicola, Pseudacysta perseae, Pseudococcus brevipes, Quadraspidiotus perniciosus, Rhopalosiphum maidis, Rhopalosiphum padi, Saissetia oleae, Scaptocoris castanea, Schizaphis graminum, Sitobion avenae, Sogatella furcifera, Trialeurodes vaporariorum, Trialeurodes abutiloneus, Unaspis yanonensis, and Zulia entrerriana.
In another embodiment, the molécules 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,
177
Acromyrmex spp., Atta spp., Camponotus spp., Diprion spp., Formica spp., Monomorium spp., Neodiprion spp., Pogonomyrmex spp., Polistes spp., Solenopsis spp., Vespula spp., and Xylocopa spp. A non-exhaustive list of particular species includes, but is not limited to, Athalia rosae, Atta texana, Iridomyrmex humilis, Monomorium minimum, Monomorium pharaonis, Solenopsis invicta, Solenopsis geminata, Solenopsis molesta, Solenopsis richtery, Solenopsis xyloni, and Tapinoma sessile.
In another embodiment, the molécules of Formula One may be used to control pests ofthe Order Isoptera. A non-exhaustive list of particular généra includes, but is not limited to, Coptotermes spp., Cornitermesspp., Cryptotermes spp., Heterotermes spp., Kalotermes spp., Incisitermes spp., Macrotermes spp., Marginitermes spp., Microcerotermes spp., Procornitermes spp., Reticulitermes spp., Schedorhinotermes spp., and Zootermopsis spp. A non-exhaustive list of particular species includes, but is not limited to, Coptotermes curvignathus, Coptotermes frenchi, Coptotermes formosanus, Heterotermes aureus, Microtermes obesi, Reticulitermes banyulensis, Reticulitermes grassei, Reticulitermes flavipes, Reticulitermes hageni, Reticulitermes hesperus, Reticulitermes santonensis, Reticulitermes speratus, Reticulitermes tibialis, and Reticulitermes virginicus.
ln another embodiment, the molécules of Formula One may be used to control pests of the Order Lepidoptera. A non-exhaustive list of particular généra includes, but is not limited to, Adoxophyes spp., Agrotis spp., Argyrotaenia spp., Cacoecia spp., Caloptilia spp., Chilo spp., Chrysodeixis spp., Colias spp., Crambus spp., Diaphania spp., Diatraea spp., Earias spp., Ephestia spp., Epimecis spp., Feltia spp., Gortyna spp., Helicoverpa spp., Heliothis spp., Indarbela spp., Lithocolletis spp., Loxagrotis spp., Malacosoma spp., Peridroma spp., Phyllonorycter spp., Pseudaletia spp., Sesamia spp., Spodoptera spp., Synanthedon spp., and Yponomeuta spp. A non-exhaustive list of particular species includes, but is not limited to, Achaea janata, Adoxophyes orana, Agrotis ipsilon, Alabama argillacea, Amorbia cuneana, Amyelois transitella, Anacamptodes defectaria, Anarsia lineatella, Anomis sabulifera, Anticarsia gemmatalis, Archips argyrospila, Archips rosana, Argyrotaenia citrana, Autographe gamma, Bonagota cranaodes, Borbo cinnara, Bucculatrix thurberiella, Capua reticulana, Carposina niponensis, Chlumetia transversa, Choristoneura rosaceana, Cnaphalocrocis medinalis, Conopomorpha cramerella, Cossus cossus, Cydia caryana, Cydia funebrana, Cydia molesta, Cydia nigricana, Cydia pomonella, Darna diducta, Diatraea saccharalis, Diatraea grandiosella, Earias insulana, Earias vittella, Ecdytolopha aurantianum, Elasmopalpus lignosellus, Ephestia cautella, Ephestia elutella, Ephestia kuehniella, Epinotia aporema, Epiphyas postvittana, Erionota thrax, Eupoecilia ambiguella, Euxoa auxiliaris,
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Grapholita molesta, Hedylepta indicata, Helicoverpa armigera, Helicoverpa zea, Heliothis virescens, Hellula undalis, Keiferia lycopersicella, Leucinodes orbonalis, Leucoptera coffeella, Leucoptera malifoliella, Lobesia botrana, Loxagrotis albicosta, Lymantria dispar, Lyonetia clerkella, Mahasena corbetti, Mamestra brassicae, Maruca testulalis, Metisa plana, Mythimna unipuncta, Neoleucinodes elegantalis, Nymphula depunctalis, Operophtera brumata, Ostrinia nubilalis, Oxydia vesulia, Pandemis cerasana, Pandemis heparana, Papilio demodocus, Pectinophora gossypiella, Peridroma saucia, Perileucoptera coffeella, Phthorimaea operculella, Phyllocnistis citrella, Pieris rapae, Plathypena scabra, Plodia interpunctella, Plutella xylostella, Polychrosis viteana, Prays endocarpa, Prays oleae, Pseudaletia unipuncta, Pseudoplusia includens, Rachiplusia nu, Scirpophaga incertulas, Sesamia inferens, Sesamia nonagrioides, Setora nitens, Sitotroga cerealella, Sparganothis pilleriana, Spodoptera exigua, Spodoptera frugiperda, Spodoptera eridania, Thecla basilides, Tineola bisselliella, Trichoplusia ni, Tuta absoluta, Zeuzera coffeae, and Zeuzera pyrina.
In another embodiment, the molécules of Formula One may be used to control pests of the Order Mallophaga. A non-exhaustive list of particular généra includes, but is not limited to, Anaticola spp., Bovicola spp., Chelopistes spp., Goniodes spp., Menacanthus spp., and Trichodectes spp. A non-exhaustive list of particular species includes, but is not limited to, Bovicola bovis, Bovicola caprae, Bovicola ovis, Chelopistes meleagridis, Goniodes dissimilis, Goniodes gigas, Menacanthus stramineus, Menopon gallinae, and Trichodectes canis.
In another embodiment, the molécules of Formula One may be used to control pests of the Order Orthoptera. A non-exhaustive list of particular généra includes, but is not limited to, Melanoplus spp., and Pterophylla spp. A non-exhaustive list of particular species includes, but is not limited to, Anabrus simplex, Gryllotalpa africana, Gryllotalpa australis, Gryllotalpa brachyptera, Gryllotalpa hexadactyla, Locusta migratoria, Microcentrum retinerve, Schistocerca gregaria, and Scudderia furcata.
In another embodiment, the molécules of Formula One may be used to control pests of the Order Siphonaptera. A non-exhaustive list of particular species includes, but is not limited to, Ceratophyllus gallinae, Ceratophyllus niger, Ctenocephalides canis, Ctenocephalides 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 includes, but is not limited to, Caliothrips spp., Frankliniella spp., Scirtothrips spp., and Thrips spp. A non-exhaustive list of particular sp. includes, but is not limited to, Frankliniella fusca, Frankliniella occidentalis,
179
Frankliniella schultzei, Frankliniella williamsi, Heliothrips haemorrhoidalis, Rhipiphorothrips cruentatus, Scirtothrips citri, Scirtothrips dorsalis, and Taeniothrips rhopalantennalis, Thrips hawaiiensis, Thrips nigropilosus, Thrips orientalis, Thrips tabaci.
In anotherembodiment, the molécules of Formula One may be used to control pests ofthe Order Thysanura. A non-exhaustive list of particular généra includes, but is not limited to, Lepisma spp. and Thermobia spp.
In another embodiment, the molécules of Formula One may be used to control pests of the Order Acarina. A non-exhaustive list of particular généra includes, but is not limited to, Acarus spp., Aculops spp., Boophilus spp., Demodex spp., Dermacentor spp., Epitrimerus spp., Eriophyes spp., Ixodes spp., Oligonychus spp., Panonychus spp., Rhizoglyphus spp., and Tetranychus spp. A non-exhaustive list of particular species includes, but is not limited to, Acarapis woodi, Acarus siro, Aceria mangiferae, Aculops lycopersici, Aculus pelekassi, Aculus schlechtendali, Amblyomma americanum, Brevipalpus obovatus, Brevipalpus phoenicis, Dermacentor variabilis, Dermatophagoides pteronyssinus, Eotetranychus carpini, Notoedres cati, Oligonychus coffeae, Oligonychus ilicis, Panonychus citri, Panonychus ulmi, Phyllocoptruta oleivora, Polyphagotarsonemus latus, Rhipicephalus sanguineus, Sarcoptes scabiei, Tegolophus perseaflorae, Tetranychus urticae, and Varroa destructor.
In another embodiment, the molécules of Formula One may be used to control pest of the Order Symphyla. A non-exhaustive list of particular sp. includes, but is not limited to, Scutigerella immaculata.
In another embodiment, the molécules of Formula One may be used to control pests of the Phylum Nematoda. A non-exhaustive list of particular généra includes, but is not limited to, Aphelenchoides spp., Belonolaimus spp., Criconemella spp., Ditylenchus spp., Heterodera spp., Hirschmanniella spp., Hoplolaimus spp., Meloidogyne spp., Pratylenchus spp., and Radopholus spp. A non-exhaustive list of particular sp. includes, but is not limited to, Dirofilaria immitis, Heterodera zeae, Meloidogyne incognita, Meloidogyne javanica, Onchocerca volvulus, Radopholus similis, and Rotylenchulus reniformis.
For additional information consult “Handbook of Pest Control - The Behavior, Life History, and Control of Household Pests” by Arnold Mallis, 9th Edition, copyright 2004 by GIE Media Inc.
APPLICATIONS
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Molécules of Formula One are generally used in amounts from about 0.01 grams per hectare to about 5000 grams per hectare to provide control. Amounts from about 0.1 grams per hectare to about 500 grams per hectare are generally preferred, and amounts from about 1 gram per hectare to about 50 grams per hectare are generally more preferred.
The area to which a molécule of Formula One is applied can be any area inhabited (or maybe inhabited, ortraversed by) a pest, for example: where crops, trees, fruits, cereals, fodder species, vines, turf and ornamental plants, are growing; where domesticated animais are residing; the interior or exterior surfaces of buildings (such as places where grains are stored), the materials of construction used in building (such as impregnated wood), and the soil around buildings. Particular crop areas to use a molécule of Formula One include areas where apples, corn, sunflowers, cotton, soybeans, canola, wheat, rice, sorghum, barley, oats, potatoes, oranges, alfalfa, lettuce, strawberries, tomatoes, peppers, crucifers, pears, tobacco, almonds, sugar beets, beans and other valuable crops are growing or the seeds thereof are going to be planted. It is also advantageous to use 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 incapacitated 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-methylcyclopropene (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 include the early 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 pesticide when eating leaf, fruit mass, or extracting sap, that contains the pesticide. The molécules of Formula One can also be applied to the soil, and when applied in this manner,
181 root and stem feeding pests can be controlled. The roots can absorb a molécule taking it up into the foliar portions ofthe plant to control above ground chewing and sap feeding pests.
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 also be applied to a surface of a building, (horizontal, vertical, orslant surface) where, for example, ants, termites, cockroaches, and flies, can corne into contact with, and/or be attracted to, the bait. Baits can comprise a molécule of Formula One.
The molécules of Formula One can be encapsulated inside, or placed on the surface of a capsule. The size ofthe capsules can range from nanometer size (about 100-900 nanometers in diameter) to micrometer size (about 10-900 microns in diameter).
Because of the unique ability of the eggs of some pests to resist certain pesticides, repeated applications ofthe molécules of Formula One may be désirable to control newly emerged larvae.
Systemic movement of pesticides in plants may be utilized to control pests on one portion of the plant by applying (for example by spraying an area) the molécules of Formula One to a different portion ofthe plant. For example, control of foliar-feeding insects can be achieved by drip irrigation or furrow application, by treating the soil with for example pre- or post-planting soil drench, or by treating the seeds of a plant before planting.
Seed treatment can be applied to ail types of seeds, including those from which plants genetically modified to express specialized traits will germinate. Représentative examples include those expressing proteins toxic to invertebrate pests, such as Bacillus thuringiensis or other insecticidal toxins, those expressing herbicide résistance, such as “Roundup Ready” seed, or those with “stacked” foreign genes expressing insecticidal toxins, herbicide résistance, nutritionenhancement, drought résistance, or any other bénéficiai traits. Furthermore, such seed treatments with the molécules of Formula One may further enhance the ability of a plant to better withstand stressful growing conditions. This results in a healthier, more vigorous plant, which can lead to higher yields at harvest time. Generally, about 1 gram of the molécules of Formula One to about 500 grams per 100,000 seeds is expected to provide good benefits, amounts from about 10 grams to about 100 grams per 100,000 seeds is expected to provide better benefits, and amounts from about 25 grams to about 75 grams per 100,000 seeds is expected to provide even better benefits.
It should be readily apparent that the molécules of Formula One may be used on, in, or around plants genetically modified to express specialized traits, such as Bacillus thuringiensis or other insecticidal toxins, or those expressing herbicide résistance, or those with “stacked” foreign 182 genes expressing insecticidal toxins, herbicide résistance, nutrition-enhancement, or any other bénéficiai traits.
The molécules of Formula One may be used for controlling endoparasites and ectoparasites in the veterinary medicine sector or in the field of non-human animal keeping. The molécules of Formula One are applied, such as by oral administration in the form of, for example, tablets, capsules, drinks, granules, by dermal application in the form of, for example, dipping, spraying, pouring on, spotting on, and 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 species.
The molécules of Formula One may also be used for controlling parasitic worms, especially of the intestine, in the animais listed 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 world hâve been migrating to new environments (for such pest) and thereafter becoming a new invasive species in such new environment. The molécules of Formula One may also be used on such new invasive species to control them in such new environment.
The molécules of Formula One may also be used in an area where plants, such as crops, are growing {e.g. pre-planting, planting, pre-harvesting) and where there are low levels (even no actual presence) of pests that can commercially damage such plants. The use of such molécules in such area is to benefit the plants being grown in the area. Such benefits, may include, but are not limited to, improving the health of a plant, improving the yield of a plant (e.g. increased biomass and/or increased content of valuable ingrédients), improving the vigor of a plant {e.g. improved plant growth and/or greener leaves), improving the quality of a plant (e.g. improved content or composition of certain ingrédients), and improving the tolérance to abiotic and/or biotic stress of the plant.
Before a pesticide can be used or sold commercially, such pesticide undergoes lengthy évaluation processes by various governmental authorities (local, régional, state, national, and
183 international). Voluminous data requirements are specified by regulatory authorities and must be addressed through data génération and submission by the product registrant or by a third party on the product registrant's behalf, often using a computer with a connection to the World Wide Web. These governmental authorities then review such data and if a détermination of safety is concluded, provide the potential user or seller with product registration approval. Thereafter, in that locality where the product registration is granted and supported, such user or seller may use or sell such pesticide.
A molécule according to Formula One can be tested to détermine its éfficacy against pests. Furthermore, mode of action studies can be conducted to détermine if said molécule has a different 10 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 convenience only and must not be used to interpret any portion hereof.
184
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 in this bioassay D
Table 1: Structures for Compounds
Compound Number Structure
AI34 ÇF3 Cl o
AI36 ÇF3 Cl 0
185
AI37 ÇF3 \^γΟΗ Cl 0
AI38 ÇF3 C1U ΜγΟΗ 0
Al 39 ÇF3 ciaJ UÇoh 0
Al 40 ÇF3 ClxrOir«. O
AI41 ÇF3 O
AI44 ÇF3 ci^^A^\^^cf3 P^X^^OC^OH F γ Π Cl 0
AI45 ÇF3 F^Ç* 1OC.OH F γ Π Cl O
186
AC1 ÇF3 Il I II I H Cl 0
AC2 ÇF3 U LA^nh, Cl 0
AC3 ÇF3 ÇTOrt Cl 0
AC4 ÇF3 cix^^A^-^/-^. Il Ί II 1 H AA^N^CF3 Cl 0
AC5 ÇF3 XA ULO Cl o
AC6 ÇF3 CK Il 1 II 1 H v/yN^CFs Cl o
AC7 ÇF3 Il Ί II Ί H 1 H iAÿJ \ΑζΝΑ^ν Cl 0
187
AC8 cf3 Cl 0 ο
AC9 cf3 Cl 0 F
AC10 ÇF3 I | Il 1 H ^ynv\ Cl 0
AC11 cf3 <:ιχΧ'ΌςΒ..ΰ Cl 0
AC12 cf3 V^aX3 Cl 0
AC13 cf3 Il Ί II 1 H T ïï ->° Cl 0
AC14 cf3 Cl 0
188
AC15 ÇF3 Y ΥγΥΥ1 Cl 0
AC16 ÇF3 YY ii i H Y il UYnYY Cl o /
AC17 ÇF3 IT II 1 H 1 II YY \Αλ Y J 1 Y N Cl 0 H F
AC18 ÇF3 Yj^tTX s X j Cl 0
AC19 ÇF3 ψ ΙΧγνΧ/’ Cl 0
AC20 ÇF3 Xpl Χ^γΝ^ζ/0 Cl 0
AC21 ÇF3 cix^xA^x/^/ XJ XXx Y °^[Π ci ο ^Υέι
189
AC22 ÇF3 .n^ci Il Ί II 1 H I II ΛΑ n. AJ Cl 0
AC23 ÇF3 ci//^/A^\/^/ ]| I X 1 H JLA AA» nl _ ci^y Cl o Vs
AC24 ÇF3 XX XIXA Cl 0 H
AC25 ÇF3 Il 1 II 1 H cAH ^ν,ο Cl 0
AC26 ÇF3 aJ TX/nAAci CI^Y Cl 0
AC27 ÇF3 ü ί y i H ia ALA ΧΑχ^Νχ/ΑΑ Cl^Y Cl 0 Z
AC28 ÇF3 cix/^/L^\/^.cl /i^/Ai H 1 X Ί H 1 X Cl 0
190
AC29 ÇF3 Il 1 h i H ci^ ^SîNVA Cl o Vs
AC30 ÇF3 Clx^x/k^^x^Cl ΠΙ II Y H Cl γ Y YY „z0 Cl 0
AC31 ÇF3 Il i I i H i ii C1A^ U^nXn Cl 0
AC32 ÇF3 Il 1 Il i H ci^y γ\ Cl 0
AC33 ÇF3 Cl^^A^^^^Br Il Ί II 1 H cr γ^ ιί Ύ^->ο Cl o
AC34 ÇF3 ci^^A^^^.cf3 Ύ Ί II 1 H ci^y ya Cl 0
AC35 ÇF3 C1^^A>^^Cf 3 Il 1 II Ί H Cl^Y^ ΥΛ ZzO Cl 0 '^'o
I9l
AC36 ÇF3 C'A,CF3 ^\AI ΎΊ ΎΎH I H AA l\A NL A>. N cF^-f Cl 0
AC37 ÇF3 ci^^A^a^^/ ^^ci I | II Ί H Γ II TJ kA\ T/k/N 0
AC38 ÇF3 T η T η h \ T F j Π Cl 0
AC39 ÇF3 Τη || T h Γ il Cl 0
AC40 ÇF3 c‘Ou^- 1 W H HN Cl U^A 0
AC41 cf3 '?%ςΐΛΰ 0 H
AC42 ÇF3 U l /=\ ΊΓ if^^ H N a kyjA 0
192
AC43 ÇF3 ï T 1 ^N\ i H 1 II π N 0
AC44 ÇF3 ci^^A a T II J H Π T Cl Μ^γΝ,Λ/Ν O 1
AC45 ÇF3 Cl\^>\ « ’CCn^JQ 0 1 F
AC46 Cp3 “X/VyB. 0
AC47 cf3 Y Yr,.sX Vo H O
AC48 ÇF3 U V/ ^C1 ci 0
193
AC49 ÇF3 JJ T Ύ η h \ X Cl 0
AC50 ÇF3 π 11 i |ίΎ h JA ci UVA; O '
AC51 CF3 JVïav„, 0 1
AC 52 CF3 -V\y?o
AC53 ÇF3 fayv^ν« α (Χ,,Ν,ίΤ 0
AC54 cf3 ni F^T ιΓΎh n? ci υγΛΑα 0
194
AC57 ÇF3 Ο 'ίγ-νθ' o τ 1Ύ H ? ci ./CF O H
AC58 ÇF3 Cl^f Τ^ΥΒΓΗ ° I ci LX^n^A0J< 0
AC59 ÇF3 YY il T |fYY h Cl 0 YAci
AC 60 VY/ja O
AC61 ÇF3 w. α ·ΟγΝ O vs
AC 62 cf3 FI θ C1 YYyN'Y^N^'CF3 O H
195
AC63 ÇF3 Cl F T H 1 h f H Cl 0
AC64 Cp3 0 H
AC65 ÇF3 ji ^\^Cl F VV H I H Cl 0
AC66 ÇF3 ci^^A. I zï K Br Cl^T iTV h ° Cl ^^YN^N^CF3 O H
AC67 cf3 VSa;^ 0
AC 68 CF3 'VuXv, O H
196
AC69 ÇF3 Ck ΥΥΊ F H ° Cl O H
AC70 ÇF3 Ck /X Il Ί 11 1 FAJ ^^ci h T Y Y h f T ci o
AC71 ÇF3 VÀX^ o vs
AC72 ÇF3 FXX F T Y η h \ h Cl o
AC75 9F3 ..JU ri^YzCF3 c H Ί H I H ci 0
AC76 CP3 y v-æ 0 Cl
197
AC77 Çf3 Π 1 F T YY H ¥ |] ci Myn^Ac| 0
AC78 ÇF3 Cl^^A ÏY1 CI^T W H 0 Cl U/A-CFj 0 H
AC79 ÇF3 ci^^A FIJ VvBr F ' T i H ? C1 ^^yNx-Tn^cf3 0 H
AC80 ÇF3 Il 1 J F t W h ? C1 ^LrN^T'N^CF3 0 H
AC81 ÇF3 il / ° Y YXsJN^° 0 H
AC82 ÇF3 ci ΧΧ/^Πγ-Λ o Y^o _
198
AC83 ÇF3 Ck Λ ci s h°
AC84 ÇF3 fXXX^f ci 0 Vs=0 0
AC85 ÇF3 ΧΧχ Cl S U%0
AC86 ÇF3 ci\^=X\ XTXu Cl θ
AC87 ÇF3 ρΧΧχ^,ρ X ULn ο Vs.o
AC89 ÇF3 c1yX^Xty » XVx Cl 0
199
AC90 ÇF3 xj xxx Cl s H
AC91 ÇF3 Il I II 1 H h ciX^ L^yn^î'n^cf3 Cl s H
AC92 ÇF3 Xj uH Cl^T^ CF3 Cl 0 H
AC93 0 Vnhhn^ C1 'M. >aL3C \=/ 0 Cl
AC94 ox V-nh C1 /F~\ '\ V-Cl yA/cF3v/ N Cl
AC95 0 Vnh o ci CF3 CF3 ( Y-Br HN^ ci-^ Y—/ \=J Cl7
AC96 ÇF3 ci^V e Y - Cl
200
AC97 ÇF3 ClBr Il T II I 1 ci-V ^T° LV° Cl Hn¥U
AC98 Çp3 ανΧ^ττνΝ0Η2 o w3 AJ 11 n a J f^X N Cl 0 H
AC99 ÇF3 ^yVaaL 0 CF 1 j La a 3 0 H
AC100 ÇF3 Cl^^A^^Br ΪΎ Il 1 H H ciA^ UïNJTrCF3 Cl O
AC101 ÇF3 clA^^LiABr A ACF3 LA^nA Cl 0
AC102 ÇF3 TJ XXfi ? CI^T '^^N CF3 F 0 H
AC103 A F Cl \Br Il 1 II 1 H Cl^A Tl Cl ο ΑΝγ/ 0
201
202
AC109 F ΪΎ II I H Cl^Y Tl Cl o
AC110 ÇF3 C1^T BrH 0 Cl ΜΧΧΑν-(Κ 0 H
AC111 ÇF3 C1 0 Cl XXJO^^^· o H
AC112 ÇF3 X ï 1 Rr C1^Y H o ! Cl VV%Ank 0 H
AC113 ÇF3 Cl\Br Ύ i il Ύ H C1-V W'-'-'n Cl 0
AC114 f-Xf H 1 II 1 h ci^T Tl Cl 0 ^NH
203
AC115 ÇF3 ΪΎ iii h Γ Y Cl s
AC116 ÇF3 (K Il II 1 h θ F XyNxXYf3 Cl 0 H
AC117 ÇF3 ci^^Y^ O /n-^ci τ il ί 1 \ Y Cl O
AC118 ÇF3 Cl^^/k li^Y h 9A ci mYnYY O
BC1 ÇF3 IJ I x> Cl^T Cl sXH NH
BC2 ÇF3 1J IX) λ NH C1 S^( NH
204
205
206
BC13 ÇF3 ci Y ^0
BC14 ÇF3 f^y ^y^x^n^cf3 Cl 0 H
CI4 ÇF3 /=x iÇUJnsî^ F γ Cl O
CI5 9F3 z=x 0
CI8 ÇF3 FXjJ LX,nh2 Cl
CI9 ÇF3 ci^^A^^^ CIJU ULnh2
CI34 ÇF3 Ύ Y Y T C1 0^0
207
208
CI39 ÇF3 IT ΊΓΤ C1 oJyo
CI40 ÇF3 jf Y TT C1
CI41 ÇF3
CI49 ÇF3 fA^ VLnh2 Cl
CI50 ÇF3 Cl\r^A^Y^/CF3 IT TTnh2 Cl
CI51 ÇF3 plyJ UVNH2 Cl
209
CI52 ÇF3 clJJ ULnh2
CI53 ÇF3 ΡΧχ UCnh2 Cl
CI54 ÇF3 clJU ULnh2
CI55 ÇF3 jj in^NH 2 Cl
CI56 ÇF3 ci^^A^x/^r FXp Ia^nh, Cl
CI57 ÇF3 C1XJ ULnh2
CC1 ÇF3 Xi il i H Cl 0
CC2 ÇF3 V^Xuça Cl o
210
CC3 ÇF3 T Y Y η h <Υ Y π Cl 0
CC4 ÇF3 Y Y Y I H <Y Cl 0
CC5 ÇF3 JTW Cl 0
CC6 ÇF3 Y Ύ Y | h JL Y TYL n Cl-^f Y^Cl; 3 Cl 0
CC7 ÇF3 Y Ύ Y Y h YY Cl 0
CC8 ÇF3 χχ^ΧΥν Cl O
CC9 ÇF3 il J U H T ^Y^CF. Cl o
2ll
CC10 cf3 Il I II I H JL Λ Y YL N Cl 0
CC11 ÇF3 c,V^xx^ Cl o
CC12 ÇF3 ci^^A^^^/Ci Il T T I H L· Cl^Y Cl o
CC13 ÇF3 H \ P JL Y L /Y N JL^ JL Cl^Y Cl 0
CC14 ÇF3 Il 1 II T H Cl^ Cl 0 ^N^C|
CC15 ÇF3 X^COça Cl o
CC16 ÇF3 ÏT 1 Jl N Cl o
212
CC17 ÇF3 jrw/ 0
CC18 ÇF3 ÏJ 1J H C1AA kANy^CF3 o
CC19 ÇF3 H T II H C1^Y Cl 0
CC20 ÇF3 ci^^A^^^^ci αθΑ Cl s
CC21 ÇF3 VAlv Cl o
CC22 ÇF3 C1IÇAIX^ Cl o
CC23 ÇF3 CI\x^A^^^/CF3 N CIJQ WVÛ Cl o
CC24 ÇF3 C1^^A^^^CF3 Il Ί II 1 H C1X^ IAn^xCF3 Cl 0
213
CC25 ÇF3 Cl Br Il I Y Y H ci-YjX k-Y^NY^cF3 Cl 0
CC26 ÇF3 γΧΧγ Cl o
CC27 ÇF3 X Y X Y h αΧχ ^^n^cf3 Cl 0
CC28 ÇF3 αιγγχ^ Cl o
CC29 ÇF3 Cl^^A^xY^r/CF3 X Y x Y rVA 6°
CC30 ÇF3 α^^Λ^^/^χι n Y Ί Y Ί H Cl j Cl 0 0
CC31 ÇF3 α^^Λ^^^^/Ci Y Ί Y Y H H T Y Cl o
214
CC32 ÇF3 CI^^J^îî^^^CF, Il I II 1 H H AA k AL N N /- C1^Y Cl O
CC33 ÇF3 Il T il T H H A L A\ N N / C!^Y Cl O
CC34 ÇF3 yy yy s O Cl O
CC35 ÇF3 Il 1 II 1 H H A M N N N γ γ % Cl O
CC36 ÇF3 Il 1 H 1 H 1 Λ 11 N N C1^Y Cl 0
CC37 ÇF3 H Ί II 1 H H JI Λ < N N / Ci^Y WV, y Cl s
CC38 ÇF3 H Ί T Ύ H H 1 J IA n N ClY Cl s
215
CC39 ÇF3 Y Y Y Y h AA < Ak N 0 /- Cl'^y Cl 0
CC40 ÇF3 Y Y Y Y h y C1H Cl 0 XJ
CC41 ÇF3 AT CY -Y ciX^ x γΑ) Cl 0
CC42 ÇF3 A J lAA Y ci^X ^^^yXXcf3 Cl O H
CC43 ÇF3 H Ί Y Ύ H C1H Cl nX
CC44 ÇF3 ci^^XX/^ci H Ί Y Y H ci^V ^n^nyXcf3 Cl 0
CC45 ÇF3 CIx^XAxZvC1 C,VUYX Cl 0
216
CC46 ÇF3 II I Th h Y^A-n^Pcf3 Cl 0
CC47 ÇF3 V ?λνΔ Cl 0
CC48 ÇF3 Cl 0
CC49 ÇF3 cIx/xAzvax „v Cl 0
CC50 ÇF3 Cl^Y Π Cl H θ
CC51 ÇF3 Cl\/^>^\x^ H Ί H Ί H CI-V LX'n'n'|Ccf3 Cl H O
CC52 ÇF3 IjU Ci-^S^ Y Cl °
217
CC53 ÇF3 Ck Il Ί II 1 H ci^f ^Ytn^cf3 Cl O
CC54 Xm h αΎ^Γ cf3^^nY^cf3 ci^ 0 Cl
DC1 ÇF3 Cl W
DC2 cf3 Cl X
DC3 CF3 (TiCLj
DC4 A3 C1JU
DC5 CF3 Oniç
218
DC6 Γ3 μ
DC7 Γ3
DC8 ÇF3 V^X N F
DC9 ÇF3 γ\/%Ζ\Α\ΖΑ Ύ J T J M M
DC10 F CF3 (TAj
DC11 CF3 L1 Xiû>
DC12 CF3 CIA/ XAnn ci W
219
DC13 Γ3 qAa-q
DC14 cf3 γΎΐ Cl W
DC15 Cl CF3 Cl An
DC16 ÇF3 V o ct3 A
DC17 ÇF3 Xp^ci ^An-N cl W
DC18 ÇF3 Cl^Y ci W
DC19 ÇF3 Αθ y cf3 An
220
DC20 ÇF3 Cl W
DC21 ÇF3 TJ ί JL NT ci A
DC22 ÇF3 T J T l NT Ύνο2 Cl M
DC23 ÇF3 νΑγ Cl /W
DC24 ÇF3 TJ T l NT T l I C1 Yi* 0
DC25 ÇF3 a ^s>n
DC26 ÇF3 YjyYn-t ci 0
221
DC27 ÇF3 cl ° 0
DC28 ÇF3 CjTf ^Tn-N Cl W
DC29 ÇF3 y% Cl W
DC30 ÇF3 f3C^^A^^^.cn TT T J xi cf3
DC31 ÇF3 c1\^Ay^^.cn TJ T J NT Cl^Y Cl W
DC32 ÇF3 ο αΐ5
DC33 ÇF3 V X/% ct3
222
DC34 ÇF3 Cl W
DC35 ÇF3 ^^N'N X\ ci W
DC36 ÇF3 V^Xv Cl Sq
DC37 ÇF3 i n vno2 Cl W
DC38 ÇF3 ci^^A^^x-^cn YjY \ΥΝ·Ν i n vnh2 Cl W
DC39 ÇF3 Cl^^^^^/CN _ Ύ J ÏT üy- ci W
DC40 ÇF3 Cl-^^J^^^^^CN Cl^f ^^N'N^n0 Cl Si
223
DC41 ÇF3 Ck Cl W
DC42 ÇF3 TT TT ci^^t ^^ν·ν^ν . ci 0
DC43 ÇF3 TT TT VA2 ci^T ^y'Vnh Cl W
DC44 ÇF3 1 T 1 T M y Υνλ Cl 1 W
DC45 ÇF3 αΥΤ Cl 1 W
DC46 Cl F^cy/=yr )=7 cf3\ Æcn Cl 3 \=< FkN 4 N
DC47 ÇF3 ν^χς5 Cl S/ _
224
DC48 ÇF3 Cl W
DC49 ÇF3 Cl jX X^nY Cl W
DC50 ÇF3 TJ XX n Cl W
DC51 ÇF3 Y Y Y Y XT Cl Yn
DC52 CF3 0 α^γΑ^/γΥ-ι YY Y i y y» Cl W
DC53 ÇF3 αγ^γΑγ|ρ^οΗ Y w ci W
DC54 ÇF3 γγγ ci W
225
DC55 ÇF3 XJ XJ N T Y ') Cl W
DC56 çf 3 V V X Cl W
DC57 ÇF3 I Cl^xAZXvNll V^X, Cl W
DC58 Çp3 0 CIXsYYfY'NH2 v Y Cl W
DC59 CF3 nh2 f| fiN k A IL X m τ ci W
DC60 CT3 0 ci^xJx-^Αθ^ ï T JT V Cl W
DC61 Çf3 0 ε1χγ^χχ^οΗ V ci
226
DC62 ÇF3 Ï^ATGÇn Cl W
DC63 ÇF3 IJ l X NT CI^Y A\-N ci W
DC64 cf3 Aa A^A Cl W
DC65 ÇF3 ï T ï X NT TjA Ά<Αν·Ν Cl W
DC66 ÇF3 XJ XX N ci^y ci Ai
DC67 ÇF3 XjX ciXXn'\ Cl W
DC68 ÇF3 1 A A, Cl Sq
227
DC69 ÇF3 t/™ Un.N Cl W
DC70 ÇF3 lÇuyQn-t Cl W
228
Table 2: Analytical Data for Compounds in Table 1.
Compound Number mp (°C) ESIMS 1H NMR(n)1 IR (cm'1)
AC1 156- 161 386.09 ([M-H]’) 7.83 (m, 2H), 7.68-7.63 (m, 5H), 6.93 (dd, J = 15.6, 8.0 Hz, 1H), 6.81 (d J=15.6 Hz, 1H,), 4.15 (m, 1H), 2.80 (s, 3H)
AC2 110- 112 374 ([M+HD 7.80 (d, J =8.4 Hz, 2H), 7.48 (d, J =8.0 Hz, 2H), 7.38 (m, 1H), 7.30 (s, 2H), 6.65 (d, J =16.0 Hz, 1H), 6.46 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H)
AC3 162- 166 402.24 ([M+HD 7.42 (m, 4H), 7.37 (t, J = 1.8 Hz, 1H), 7.28 (s, 2H), 6.63 (d, J =16.0 Hz, 1H), 6.41 (dd, J = 16.0, 8.4 Hz, 1H), 4.15 (m, 1H), 3.20 (s, 3H), 3.00 (s, 3H)
AC4 122- 126 454 ([M-H]’) 7.79 (d, J= 1.2 Hz, 2H), 7.48 (d, J =8.4 Hz, 2H), 7.38 (t, J = 1.8 Hz, 1H), 7.30 (s, 2H), 6.64 (d, J = 15.6 Hz, 1H), 6.40 (dd, J = 15.6, 8.0 Hz, 1H), 6.30 (m, 1H), 4.15 (m, 3H)
229
AC5 444.12 ([M+HD 7.67 (s, 3H), 7.64 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 6.91 (dd, J = 15.6, 8.0 Hz, 1H), 6.80 (d, J= 15.6 Hz, 1H), 4.80 (m, 1H), 3.60 (brs, 8H)
AC6 468.40 ([Μ-H]) 7.40 (m, 2H), 7.26 (m, 3H), 6.56 (d, J =16.0 Hz, 1H), 6.48 (dd, J = 16.0, 8.0 Hz, 1H), 5.82 (brs, 1H), 4.08 (m, 3H), 2.52 (s, 3H) 1657, 1113, 804
AC7 511.02 ([Μ-ΗΠ 8.39 (s, 1H), 7.74 (m, 1H), 7.39 (m, 3H), 7.24 (m, 4H), 6.58 (d, J = 16.0 Hz, 1H), 6.38 (dd, J= 16.0, 8.0 Hz, 1H), 6.16 (brs, 1H), 4.63 (m, 2H), 4.12 (m, 1H), 2.41 (s, 3H) 3276, 1645, 1111, 801
AC8 454.11 ([Μ-HD 7.39 (s, 1H), 7.22 (m, 2H), 7.19 (m, 3H), 6.53 (d, J = 16.0 Hz, 1H), 6.39-6.34 (dd, J= 16.0, 8.0 Hz, 1H), 4.22 (m, 1H), 3.95 (t, J =7.0 Hz, 2H), 2.62 (t, J = 8.0 Hz, 2H), 2.30 (s, 3H), 2.18 (m, 2H) 1748, 1112, 801
230
AC9 494.02 ([M-H]’) 7.45 (t, J =7.6 Hz, 1H), 7.36 (m, 2H), 7.21 (m, 3H), 7.15 (m, 4H), 6.56 (d, J= 16.0 Hz, 1H), 6.38 (dd, J =16.0, 8.4 Hz, 1H), 6.08 (brs, 1H), 4.68 (d, J =5.6 Hz, 2H), 4.11 (m, 1H), 2.44 (s, 3H) 3276, 1645, 1112, 801
A10 140- 143 458.00 ([M-H]’) 7.38 (t, J = 1.6 Hz, 1H), 7.34 (d, J =7.6 Hz, 1H), 7.27 (m, 2H), 7.24 (m, 2H), 6.57 (d, J =16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 6.16 (m 1 H), 5.44 (m, 1H), 4.12 (m, 1H), 3.51 (m, 2H), 3.40 (m, 2H), 2.44 (s, 3H)
AC11 476.17 ([M-H]') 7.39-7.29 (m, 9H), 7.24 (m, 2H), 6.56 (d, J = 16.0 Hz, 1H), 6.38 (dd, J = 16.0, 8.0 Hz, 1H), 5.99 (brs, 1H), 4.63 (d, J = 6.0 Hz, 1H), 4.11 (m, 1H), 2.47 (s, 3H) 3287, 1644, 1112, 801
231
AC12 479.30 ([Μ+ΗΓ) 8.63 (d, J =4.4 Hz, 1H), 7.71 (m, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.37 (m, 2H), 7.32 (m, 2H), 7.23 (m, 2H), 7.13 (m, 1H), 6.58 (d, J =16.0 Hz, 1H), 6.40 (dd, J =16.0, 8.0 Hz, 1H), 4.75 (d, J = 4.8 Hz, 2H), 4.12 (m, 1H), 2.49 (s, 3H) 3293, 1653, 1112,800
AC13 75-78 490.04 ([M-H]) 7.38 (m, 2H), 7.27 (m, 3H), 7.23 (brs, 1H), 6.58 (d, J= 16.0 Hz, 1H), 6.45 (m 1H), 6.42 (dd, J= 16.0, 8.4 Hz, 1H), 4.91 (m 1H), 4.64 (m, 2H), 4.14 (m, 1H), 4.04 (m, 2H), 2.46 (s, 3H)
AC14 480.99 ([M+2H]+) 8.63 (s, 2H), 7.76 (d, J = 8.0 Hz, 1H), 7.36 (m, 3H), 7.22 (m, 1H), 7.13 (m, 2H), 6.57 (d, J = 16.0 Hz, 1H), 6.39 (dd, J = 16.0, 8.0 Hz, 1H), 6.13 (brs, 1H), 4.66 (d, J = 5.6 Hz, 2H ), 4.11 (m, 1 H), 2.46 (s, 3H) 3293, 1645, 1113,800
232
AC15 59-61 516.86 ([M-H]') 7.45 (s, 1H), 7.37 (m, 1H), 7.34 (m, 1H), 7.26 (m, 3H), 7.22 (m, 1H), 6.57 (d, J= 16.0 Hz, 1H), 6.40 (dd, J =16.0, 8.0 Hz, 1H), 6.18 (m, 1H), 4.71 (d, J = 6.4 Hz, 2H), 4.11 (m, 1H), 2.46 (s, 3H) 3246, 1635, 1112, 801
AC16 506.93 ([M+HD 8.47 (m, 1H), 8.19 (s, 1H), 7.76 (m, 1H), 7.47 (m, 2H), 7.37 (m, 1H), 7.28 (m, 2H), 7.24 (m, 1H), 7.21 (m, 1H), 6.59 (d, J= 16.0 Hz, 1H), 6.39 (dd, J= 16.0, 8.4 Hz, 1H), 4.12 (m, 1H), 2.48 (s, 3H), 1.88 (s, 6H) 1657, 1113, 801
AC17 70-73 494.98 ([M-H]’) 7.49 (m, 2H), 7.38 (m, 1H), 7.29 (m, 4H), 7.08 (m, 3H), 6.91 (m, 1H), 6.61 (d, J= 16.0 Hz, 1H), 6.48 (m, 1H), 6.43 (dd, J= 16.0, 8.0 Hz, 1H), 4.13 (m, 1H), 2.49 (s, 3H)
233
AC18 155- 158 480.44 ([M+HD 8.73 (d, J =4.8 Hz, 2H), 7.53 (d, J =8.4 Hz, 1H), 7.37 (m, 1H), 7.27 (m, 4H), 7.23 (m, 1H), 7.11 (m, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.41 (dd, J = 16.0, 8.0 Hz, 1H), 4.90 (d, J = 4.8 Hz, 2H), 4.13 (m, 1H), 2.52 (s, 3H)
AC19 55-57 471.66 ([M+HD 7.37 (m, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.27 (m, 2H), 7.22 (m, 2H), 6.57 (d, J= 16.0 Hz, 1H), 6.39 (dd, J =16.0, 8.0 Hz, 1H), 6.10 (brs, 1H), 4.13 (m,2H), 3.94 (m, 1H), 3.79 (m, 2H), 3.35 (m, 1H), 2.45 (s, 3H), 2.14 (m, 1H), 1.71 (m, 2H), 1.65 (m, 1H).
AC 20 467.68 ([M+HD 7.37 (m, 2H), 7.27 (m, 2H), 7.23 (m, 2H), 6.57 (d, J= 16.0 Hz, 1H), 6.38 (m, 3H), 6.01 (m, 1H), 4.63 (d, J =5.6 Hz, 2H), 4.13 (m, 1H), 2.45 (s, 3H) 3437, 1664, 1265, 1114, 746
234
AC21 61-64 528.78 ([M+HD 8.44 (s, 1H), 8.18 (s, 1H), 7.83 (brs, 1H), 7.38 (m, 2H), 7.27 (m, 2H), 7.25 (m, 2H), 7.21 (m, 1H), 6.57 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 5.01 (s, 2H), 4.11 (m, 1H), 2.43 (s, 3H)
AC22 545.08 ([M-H]) 8.39 (s, 1H), 7.73 (m, 1H), 7.40 (s, 1H), 7.35 (m, 2H), 7.22 (m, 3H), 6.57 (d, J= 16.0 Hz, 1H), 6.38 (dd, J =16.0, 7.6 Hz, 1H), 6.14 (brs, 1H), 4.62 (d, J = 6.0 Hz, 2H), 4.13 (m, 1H), 2.45 (s, 3H) 3270, 1642, 1111, 809
AC23 492.35 ([M-H]') 7.42 (s, 2H), 7.36 (m, 1H), 7.24 (m, 2H), 6.59 (d, J =16.0 Hz, 1H), 6.40 (dd, J =16.0, 8.0 Hz, 1H), 6.20 (brs, 1H), 5.46 (m, 1H), 4.15 (m, 1H), 3.52 (m, 2H), 3.41 (m, 2H), 2.45 (s, 3H) 3273, 1641, 1250, 1113, 807
235
AC24 129- 132 526.98 ([M+HD 7.40 (m, 2H), 7.27 (m, 2H), 7.25 (m, 2H), 6.92 (brs, 2H), 6.60 (m, 1H), 6.48(dd, J= 16.0, 8.0 Hz, 1H), 4.19 (d, J = 5.2, 2H), 4.08 (m, 1H), 3.99 (m, 2H), 2.46 (s, 3H) 3298, 1664, 1113, 803
AC25 542.24 ([M-H]) 7.41 (m, 3H), 7.27 (m, 2H), 6.58 (d, J =15.6 Hz, 1H), 6.42 (m, 2H), 4.92 (m, 1H), 4.65 (m, 2H), 4.14 (m, 1H), 4.09 (m, 2H), 2.46 (s, 3H) 3257, 1652, 1316, 1109, 807
AC26 550.69 ([M-H]’) 7.45 (s, 1H), 7.40 (s, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.22 (m, 2H), 6.54 (d, J= 16.0 Hz, 1H), 6.38 (dd, J = 16.0, 8.0 Hz, 1H), 4.71 (d, J = 6.0 Hz, 2H), 4.11 (m, 1H), 2.46 (s, 3H) 3255, 1638, 1113, 809
AC27 541.00 ([M-H]-) 8.46 (d, J =4.0 Hz, 1H), 8.20 (s, 1H), 7.76 (m, 1H), 7.47 (m, 2H), 7.41 (s, 2H), 7.23 (m, 2H), 7.21 (m, 1 H), 6.59 (d, J = 16.0 Hz, 1H), 6.37 (dd, J= 16.0, 8.4 Hz, 1H), 4.11 (m, 1H), 2.48 (s, 3H), 1.88 (s, 6H) 1653, 1113, 809
236
AC28 65-67 564.84 ([Μ-HD 8.40 (s, 1H), 7.74 (m, 2H), 7.42 (m, 3H), 7.36 (m, 2H), 6.72 (brs, 1H), 6.52 (d, J = 16.0 Hz, 1H), 6.43 (dd, J =16.0, 8.0 Hz, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.12 (m, 1H) 3267,1650, 1112, 809
AC29 75-78 511.78 ([M-H]) 7.71 (d, J =8.4 Hz, 1H), 7.42 (m, 3H), 7.35 (m, 1H), 6.75 (brs, 1H), 6.56 (d, J =16.0 Hz, 1H), 6.43 (dd, J =16.0, 8.0 Hz, 1H), 5.49 (m, 1H), 4.14 (m, 1H), 3.50 (m, 4H)
AC30 110- 113 543.72 ([M-H]’) 7.42 (d, J =8.4 Hz, 1H), 7.44 (s, 1H), 7.40 (s, 1H), 7.38 (m, 1H), 7.06 (brs, 1H), 6.58 (d, J = 15.6 Hz, 1H), 6.45 (dd, J = 15.6, 8.0 Hz, 1H), 4.93 (m, 1H), 4.65 (m, 2H), 4.13 (m, 3H)
AC31 68-70 610.73 ([M+H]+) 8.42 (s, 1H), 7.76 (m, 1H), 7.61 (m, 2H), 7.39 (m, 4H), 6.54 -6.39 (m, 3H), 4.66 (d, J = 6.0 Hz, 2H), 4.12 (m, 1H)
237
AC32 78-80 555.89 ([M-H]') 7.61 (m, 2H), 7.40 (m, 3H), 6.54 (m, 2H), 6.40 (dd, J =16.0, 8.0 Hz, 1H), 5.46 (m, 1H), 4.14 (m, 1H), 3.50 (m, 4H)
AC33 182- 184 587.68 ([M-H]’) 7.62 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.40 (m, 3H), 6.84 (br s, 1H), 6.55 (d, J =15.6 Hz, 1H), 6.45 (dd, J = 15.6, 7.6 Hz, 1H), 4.93 (m 1H), 4.65 (m, 2H), 4.13 (m, 4H)
AC34 151— 153 545.83 ([M-H]) 7.67 (s, 1H), 7.61 (d, J = 6.0 Hz, 1H), 7.53 (m, 1H), 7.41 (s, 2H), 6.64 (d, J = 16.0 Hz, 1H), 6.40 (dd, J =16.0, 8.0 Hz, 1H), 6.18 (brs, 1H), 5.44 (m, 1H), 4.14 (m, 1H), 3.50 (m, 2H), 3.40 (m, 2H)
AC35 100- 102 577.71 ([M-H]') 7.70 (s, 1H), 7.63 (m, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.41 (s, 2H), 6.53 (d, J = 16.0 Hz, 1H), 6.49 (m, 2H), 4.93 (m, 1H), 4.64 (m, 2H), 4.13 (m, 1H), 4.03 (m, 2H) 3257, 1655, 1113, 808
238
AC36 81-83 600.83 ([Μ+ΗΓ) 8.40 (s, 1H), 7.73 (m, 2H), 7.61 (d, J =8.4 Hz, 1H), 7.52 (d, J =8.0 Hz, 1H), 7.40 (s, 2H), 7.35 (d, J =8.0 Hz, 1H), 6.63 (d, J = 16.0 Hz, 1H), 6.46 (dd, J= 16.0, 7.6 Hz, 1H), 6.14 (m, 1H), 4.63 (d, J =6.0 Hz, 2H), 4.14 (m, 1H)
AC37 512.68 ([M+HD 8.39 (s, 1H), 7.73 (m, 1H), 7.48 (m, 2H), 7.34 (d, J= 7.6 Hz, 1H), 7.24 (m, 3H), 6.55 (d, J = 16.0 Hz, 1H), 6.41 (dd, J= 16.0, 7.6 Hz, 1H), 6.12 (m, 1H), 4.62 (d, J = 6.0 Hz, 2H), 4.13 (m, 1H), 2.45 (s, 3H) 3268, 1644, 1109, 820
AC38 79-80 528.85 ([M-H]’) 8.46 (m, 1H), 7.73 (m, 1H), 7.35 (m, 4H), 7.22 (m, 2H), 6.56 (d, J = 16.0 Hz, 1H), 6.38 (dd, J = 16.0, 8.0 Hz, 1H), 4.62 (d, J = 6.0 Hz, 2H), 4.10 (m, 1H), 2.45 (s, 3H)
239
AC39 141— 144 477.83 ([M-H]') 9.19 (s, 1H), 8.79 (s, 2H), 7.37 (m, 2H), 7.23 (m, 2H), 7.21 (m, 1H), 6.57 (d, J= 16.0 Hz, 1H), 6.40 (dd, J =16.0, 7.6 Hz 1H), 6.21 (m, 1H), 4.65 (s, 2H), 4.11 (m, 1H), 2.46 (s, 3H)
AC40 69-72 484.67 ([M+Hf) 8.33 (t, J =5.6 Hz, 1H), 8.61 (m, 1H), 7.68 (m, 3H), 7.48 (m, 2H), 6.86 (dd, J= 15.6, 8.2 Hz 1H), 6.74 (d, J = 15.6 Hz, 1H), 4.44 (m, 1H), 3.76 (d, J =6.0 Hz, 2H), 2.54 (m, 1 H), 2.67 (s, 3H), 0.59 (m, 2H), 0.54 (m, 2H)
AC41 196- 199 515.00 ([M-H]’) 8.66 (d, J =7.6 Hz, 1H), 8.39 (t, J = 5.6 Hz, 1H), 7.65 (s, 3H), 7.45 (m, 3H), 6.86 (dd, J = 15.6, 8.8 Hz, 1H), 6.74 (d, J= 15.6 Hz, 1H), 5.01 (m, 1H), 4.99 (m, 1H), 3.78 (d, J = 6.0 Hz, 2H), 3.40 (m, 2H), 3.22 (m, 2H), 2.37 (m, 3H)
240
AC42 79-82 534.72 ([Μ+ΗΓ) 7.99 (d, J = 8.0 Hz, 1H), 7.89 (d, J =8.0 Hz, 1H), 7.51 (m, 2H), 7.44 (m, 2H), 7.27 (m, 4H), 6.71 (t, J =5.2 Hz, 1H), 6.59 (d, J =16.0 Hz, 1H), 6.41 (dd, J = 16.0, 8.0 Hz, 1H), 5.05 (d, J= 1.6 Hz, 2H), 4.12 (m, 1H), 2.52 (m, 3H)
AC43 481.75 ([M+HD 8.69 (s, 1H), 8.52 (s, 2H), 7.45 (d, J =7.6 Hz, 1H), 7.37 (d, J =2.0 Hz, 1H), 7.26 (m, 2H), 7.21 (m, 1H), 6.83 (s, 1H), 6.58 (d, J =16.0 Hz, 1H), 6.40 (dd, J =16.0, 8.4 Hz, 1H), 4.81 (d, J = 5.6 Hz, 2H), 4.12 (t, J = 8.4 Hz 1 H), 2.45 (s, 3H) 1663, 1608,1168, 1114, 801
241
AC44 528.01 ([M+HD 8.44 (d, J =2.4 Hz, 1H), 7.69 (d, J =2.4 Hz, 1H), 7.37 (m, 1H), 7.33 (s, 1H), 7.31 (s, 1H), 7.26 (m, 1H), 7.24 (m, 3H), 6.57 (d, J =16.0 Hz, 1H), 6.39 (dd, J = 16.0, 8.0 Hz, 1H), 5.96 (d, J = 7.2 Hz, 1H), 5.32 (t, J = 7.2 Hz, 1H), 4.11 (t, J = 8.4 Hz, 1H), 2.41 (s, 3H), 1.61 (d, J =7.2 Hz, 3H) 1640, 1166, 1112, 800
AC45 512.88 ([Μ+ΗΓ) 7.66 (s, 1H), 7.37 (d, J = 6.8 Hz, 2H), 7.26 (m, 3H), 7.18 (m, 1H), 7.11 (m, 2H), 6.99 (m, 1H), 6.57 (d, J= 15.6 Hz, 1H), 6.39 (dd, J =15.6, 8.0 Hz, 1H), 4.11 (t, J = 8.4 Hz, 1H), 3.36 (s, 3H), 2.43 (s, 3H) 1657, 1167, 1106, 800
AC46 61-64 575.93 ([M+HD 8.42 (d, J =2.0 Hz, 1H), 7.76 (d, J =2.4 Hz, 1H), 7.61 (m, 2H), 7.39 (m, 3H), 7.26 (s, 2H), 6.54 (d, J= 16.0 Hz, 1H), 6.42 (dd, J= 16.0, 7.6 Hz, 1 H), 4.65 (d, J = 6.0 Hz, 2H), 4.14 (m, 1H)
242
AC47 525.89 ([M-H]’) 10.02 (s, 1H), 9.87 (s, 1H), 8.47 (t, J = 6.0 Hz, 1H), 7.66 (s, 3H), 7.44 (s, 1H), 7.40 (d, J = 3.6 Hz, 2H), 6.86 (dd, J = 15.6, 9.2 Hz, 1H), 6.74 (d, J = 15.6 Hz, 1H), 4.82 (t, J =9.6 Hz, 2H), 3.88 (d, J =6.0 Hz, 2H), 2.36 (s, 3H), 1.63 (m, 1H), 0.76 (m, 4H) 3280, 1640
AC 48 509.96 ([M-H]') 7.37 (m, 7H), 7.34 (m, 3H), ,6.57 (d, J =16.0 Hz, 1H), 6.39 (dd, J = 16.0, 8.0 Hz, 1H), 6.01 (m, 1H), 4.60 (d, J = 6.0 Hz, 2H), 4.13 (m, 1H), 2.46 (s, 3H) 3275, 1642
AC49 518.85 ([M+HD 8.39 (d, J =2.0 Hz, 1H), 8.11 (m, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.41 (m, 3H), 7.17 (m, 3H), 6.59 (d, J = 16.0 Hz, 1H), 6.47 (dd, J =16.0, 8.0 Hz, 1H), 4.66 (d, J = 5.6 Hz, 2H), 4.14 (m, 1H) 1658, 1112, 1025, 2219
243
AC50 481.88 ([M+HD 8.72 (m, 1H), 7.67 (s, 3H), 7.46 (s, 1H), 7.40 (m, 2H), 7.08 (s, 1H), 6.82 (m, 2H), 6.55 (d, J = 7.6 Hz, 1H), 4.82 (m, 1H), 4.48 (s, 2H), 3.65 (s, 3H), 2.38 (s, 3H) 1654, 1112, 800,3069
AC51 540.83 ([M+HD 7.45 (d, J =7.6 Hz, 1H), 7.38 (m, 1H), 7.27 (m, 2H), 7.22 (m, 2H), 6.85 (m, 1H), 6.58 (d, J = 16.0 Hz, 1H), 6.40 (dd, J= 16.0, 8.0 Hz, 1H), 4.33 (m, 2H), 4.14 (m, 3H), 3.18 (s, 3H), 2.48 (s, 3H) 1652, 1571, 802, 1114, 2926
AC52 488.29 ([M-H]’) 7.33 (m, 2H), 7.25 (m, 3H), 6.56 (d, J = 15.6 Hz, 1H), 6.37 (dd, J = 15.6, 8.0 Hz, 1H), 5.61 (d, J = 8.0 Hz, 1H), 4.21 (m, 1H), 4.01 (m, 1H), 4.08 (m, 2H), 3.56 (t, J = 10.0 Hz, 2H), 2.48 (m, 2H), 2.08 (m, 2H), 1.5 (m, 3H) 1635, 11134, 813, 2927
244
AC53 532.92 ([M+HD 8.49 (d, J =2.0 Hz, 1H), 7.69 (d, J =2.4 Hz, 1H), 7.43 (d, J =8.0 Hz, 1H), 7.34 (m, 3H), 7.26 (m, 2H), 6.95 (m, 1 H), 6.58 (d, J= 16.0 Hz, 1H), 6.38 (dd, J= 16.0, 8.0 Hz, 1H), 4.72 (d, J = 5.2 Hz, 2H), 4.09 (m, 1H), 2.47 (s, 3H) 1651, 3027, 815, 1113
AC54 529.06 ([M-H]') 8.37 (d, J =5.2 Hz, 1H), 7.41 (d, J= 8.0 Hz, 1H), 7.36 (m, 3H), 7.31 (m, 1H), 7.26 (m, 2H), 6.58 (d, J= 16.0 Hz, 1H), 6.40 (dd, J= 16.0, 7.6 Hz, 1H), 5.20 (t, J =5.6 Hz, 1H), 4.63 (d, J = 6.0 Hz, 2H), 4.13 (m, 1H), 2.18 (s, 3H) 1654, 3434, 814, 1112
AC57 464.96 ([M+HD 8.69 (t, J =6.0 Hz, 1H), 8.58 (t, J = 6.0 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J = 6.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.0 (m, 1H), 6.76 (d, J =15.6 Hz, 1H), 6.76 (dd, J = 15.6, 8.0 Hz, 1H), 4.01 (m, J =8.0 Hz, 1H), 3.71 (m, 2H), 3.49 (m, 2H) 3417, 1658, 1165, 817
245
AC58 124.4- 126.9 599.76 ([M+HD 7.62 (m, 2H), 7.40 (s, 2H), 7.37 (d, J= 1.6 Hz, 1H), 6.61 (t, J =4.8 Hz, 1H), 6.55 (d, J=16.0 Hz, 1H), 6.41 (dd, J = 16.0, 7.6 Hz, 1H), 4.16 (d, J =6.0 Hz, 2H), 4.01 (m, 1H), 1.56 (s, 9H)
AC59 80-83 497.40 ([M-H]) 8.42 (d, J =2.1 Hz, 1H), 8.29 (d, J= 7.5 Hz, 1H), 7.51 (m, 2H), 7.39 (m, 1H), 7.36 (m, 4H), 7.28 (m, 1H), 6.61 (d, J = 15.9 Hz, 1H), 6.45 (dd, J=15.9, 7.8Hz1H), 4.14 (t, J = 8.4 Hz, 1H), 2.51 (s, 3H)
AC60 515.09 ([M+HD 8.52 (s, 1H), 8.39 (d, J = 1.8 Hz, 2H), 7.70 (d, J = 2.1 Hz, 1H), 7.62 (s, 1H), 7.43 (s, 1H), 7.35 (m, 3H), 6.62 (d, J = 16.2 Hz, 1H), 6.52 (dd, J = 16.2, 7.5 Hz, 1H), 4.62 (d, J = 6.3 Hz, 2H), 4.19 (m, 1H), 2.76 (s, 3H) 1668, 1589, 1167, 1113, 802
246
AC61 461.90 ([M-H]) 8.07 (t, J =8.0 Hz, 1H), 7.39 (t, J =2.0 Hz, 1H), 7.28 (d, J= 1.2 Hz, 3H), 7.17 (d, J = 1.6 Hz, 1H), 7.11 (m, 1H), 6.59 (d, J = 15.6 Hz, 1H), 6.47 (dd, J= 15.6, 7.6 Hz, 1H), 5.49 (m, 1H), 4.14 (t, J = 8.4 Hz, 1H), 3.48 (m, 4H) 1658, 1114, 801
AC62 105- 108 528.88 ([M-H]’) 8.62 (t, J =6.4 Hz, 1H), 8.46 (m, 1H), 7.73 (m, 5H), 7.48 (d, J= 7.6 Hz, 1H), 7.03 (dd, J =15.6, 9.2 Hz, 1H), 6.81 (d, J = 15.6 Hz, 1H), 4.86 (m, 1H), 3.97 (m, 4H)
AC63 77-80 594.67 ([M+HD 8.43 (s, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.60 (m, 2H), 7.38 (d, J =7.6 Hz, 1H), 7.33 (d, J=6.4 Hz, 3H), 6.54 (d, J =16.0 Hz, 1H), 6.46 (m, 1H), 6.41 (dd, J = 16.0 8.0 Hz, 1H), 4.65 (d, J = 6.0 Hz, 2H), 4.15 (m, 1H) 3257, 1653
247
AC64 83-85 580.72 ([M-H]’) 7.72 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.40 (s, 2H), 7.36 (d, J =6.8 Hz, 1H), 7.05 (t, J =5.2 Hz, 1H), 6.70 (t, J =5.2 Hz, 1H), 6.57 (d, J= 15.6 Hz, 1H), 6.44 (dd, J = 15.6, 8.0 Hz, 1H), 4.23 (d, J= 5.6 Hz, 2H), 4.15 (m, 1H), 4.01 (m, 2H)
AC65 534.72 ([M-H]’) 8.39 (d, J = 2.0 Hz, 1H), 8.12 (t, J =8.4 Hz, 1H), 7.71 (d, J =2.4 Hz, 1H), 7.34 (m, 3H), 7.26 (m, 1H), 7.11 (m, 2H), 6.59 (d, J= 16.0 Hz, 1H), 6.46 (dd, J =16.0, 8.0 Hz, 1H), 4.66 (d, J = 5.2 Hz, 2H), 4.13 (m, 1H) 1658, 1113, 817, 2925
AC66 73-75 624.61 ([M-H]') 7.88 (s, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.40 (m, 2H), 6.80 (t, J = 5.6 Hz, 1H), 6.70 (t, J =5.6 Hz, 1H), 6.56 (d, J =16.0 Hz, 1H), 6.44 (dd, J = 16.0, 8.0 Hz, 1H), 4.22 (m, 2H), 4.12 (m, 1H), 4.01 (m, 2H) _
248
AC67 479.82 ([M-H]’) 8.07 (t, J =8.0 Hz, 1H), 7.34 (d, J =6.0 Hz, 2H), 7.28 (s, 1H), 7.17(s, 2H), 6.59 (d, J = 15.6 Hz, 1H), 6.46 (dd, J = 15.6, 8.0 Hz, 1H), 5.49 (m, 1H), ,4.12(m, 1H), 3.49 (m, 4H). 3272, 1644
AC 68 90-93 546.80 ([M-H]’) 8.6 (t, J =6.4 Hz, 1H), 8.45 (m, 1H), 7.86 (d, J = 6.4 Hz, 2H), 7.75 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 12.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.03 (dd, J =15.6, 9.6 Hz, 1H), 6.80 (d, J = 15.6 Hz, 1H), 4.88 (m, 1H), 3.96 (m, 4H) 3315, 1684
AC69 542.82 ([M-H]’) 7.41 (d, J= 8.0 Hz, 1H), 7.34 (d, J =5.6 Hz, 2H), 7.26 (m, 1H), 7.23 (m, 1H), 6.81 (s, 1H), 6.57 (d, J = 15.6 Hz, 1H), 6.55 (s, 1H), 6.39 (dd, J = 15.6, 8.0 Hz, 1H), 4.18 (m, 2H), 4.13 (m, 1H), 3.97 (m, 2H), 2.46 (s, 3H) 3294, 1685
249
AC70 176- 178 545.23 ([M-H]') 8.38 (d, J =2.4 Hz, 1H), 8.22 (d, J =6.8 Hz, 2H), 7.71 (d, J =2.4 Hz, 1H), 7.35 (d, J =6.0 Hz, 2H), 7.30 (d, J =7.6 Hz, 1H), 7.15 (d, J= 1.6 Hz, 1H), 6.93 (d, J= 1.2 Hz, 1H), 6.60 (d, J = 15.6 Hz, 1H), 6.43 (dd, J= 15.6, 7.6 Hz, 1H), 4.66 (d, J = 6.0 Hz, 2H), 4.13 (m, 1H), 3.98 (s, 3H)
AC71 492.20 ([M-H]') 8.24 (d, J =7.6 Hz, 1H), 8.15 (d, J =8.4 Hz, 1H), 7.35 (d, J = 6.0 Hz, 2H), 7.13 (d,J = 1.2 Hz, 1H), 6.92 (s, 1H), 6.61 (d, J = 16.0 Hz, 1H), 6.43 (dd, J = 16.0, 7.6 Hz, 1H), 5.48 (m, 1H), 4.13 (m, 1H), 4.03 (s, 3H), 3.48 (m, 4H) 1639, 3079, 858
AC72 543.05 ([M-H]’) 8.42 (d, J =2.4 Hz, 1H), 7.75 (d, J =2.4 Hz, 1H), 7.34 (m, 4H), 7.20 (m, 2H), 6.60 (d, J =16.0 Hz, 1H), 6.36 (dd, J = 16.0, 8.0 Hz, 1H), 6.12 (t, J =5.6 Hz, 1H), 4.62 (d, J =6.0 Hz, 2H), 4.20 (m, 1H), 2.82 (m, 2H), 1.45 (t, J =5.6 Hz, 3H) 1642, 3246, 814, 1113
250
AC75 644.78 ([M+H]+) 8.72 (s, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.61 (m, 2H), 7.40 (m, 2H), 6.55 (m, 2H), 6.42 (dd, J = 16.0, 8.0 Hz, 1H), 4.76 (d, J =6.0 Hz, 2H), 4.12 (m, 1H) 3431, 1652, 1171,809
AC76 531.34 ([Μ+ΗΓ) 8.87 (t, J =6.0 Hz, 1H), 8.34 (d, J =2.1 Hz, 1H), 7.85 (d, J =6.3 Hz, 3H), 7.48 (m, 4H), 6.57 (d, J = 15.6 Hz, 1H), 6.45 (dd, J= 15.6, 9.0 Hz, 1H), 4.84 (m, 1H), 4.49 (d, J= 5.7 Hz, 2H), 2.82 (m, 2H), 2.36 (t, J =5.6 Hz , 3H) 3120, 1708, 1171
AC77 531.1 ([M+HD 8.87 (t, J =6.0 Hz, 1H), 8.34 (d, J =2.1 Hz, 1H), 7.85 (d, J =6.3 Hz, 3H), 7.48 (m, 4H), 6.57 (d, J = 15.6 Hz, 1H), 6.45 (dd, J = 15.6, 8.0 Hz, 1H), 4.84 (m, 1H), 4.49 (d, J= 5.7 Hz, 2H), 2.36 (s, 3H) 3444, 1648, 1114, 814
251
AC78 561.06 ([M+HD 8.59 (t, J =6.4 Hz, 1H), 8.47 (t, J =5.6 Hz, 1H), 7.89 (s, 2H), 7.45 (m, 3H), 6.87 (m, 1 H), 6.75 (d, J= 15.6 Hz, 1H), 4.85 (t, J =8.0 Hz 1 H), 3.98 (m, 4H), 2.58 (s, 3H) 3432, 1631, 1161, 840
AC79 610.97 ([M+Hf) 8.69 (t, J =6.0 Hz, 1H), 8.58 (t, J =6.0 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J = 6.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.0 (m, 1H), 6.76 (d, J =15.6 Hz, 1 H) 4.83 (t, J = 8.0 Hz, 1H), 3.98 (m, 4H) 3303, 1658, 1166, 817
AC 80 561.06 ([M+Hf) 7.37 (m, 3H), 7.26 (m, 1H), 7.24 (m, 1H), 6.59 (d, J= 15.6 Hz, 1H), 6.39 (dd, J= 15.6, 8.0 Hz, 1H), 4.24 (m, 4H), 3.90 (m, 1H), 2.83 (m, 2H), 1.26 (m, 3H) 3412, 1624, 1157, 825
252
AC81 9-92 546.93 ([M-H]’) 8.73 (d, J =5.6 Hz, 1H), 8.45 (t, J =6.0 Hz, 1H), 7.76 (s, 3H), 7.45 (m, 3H), 6.86 (dd, J = 16.0, 9.2 Hz, 1H), 4.83 (m, 1H), 4.56 (m, 2H), 4.51 (m, 1H), 4.10 (m, 2H), 3.85 (d, J =6.0 Hz, 2H), 2.50 (m, 3H)
AC 82 477.69 ([M+HD 7.38 (d, J = 1.8 Hz, 2H), 7.33 (s, 1H), 7.27 (s, 3H), 6.58 (d, J =16.0 Hz, 1H), 6.42 (d, J = 8.1 Hz, 1H), 6.36 (dd, J = 16.0, 7.8 Hz, 1H), 4.71 (m, 1H), 4.23 (m, 3H), 3.26 (m, 2H), 2.45 (s, 3H) 1646, 1353, 1196, 1112, 800
AC83 493.83 ([M-H]') 8.07 (t, J =8.4 Hz, 1H), 7.39 (t, J = 1.6 Hz, 1H), 7.31 (d, J= 1.2 Hz, 1H), 7.26 (m, 2H), 7.23 (m, 1H), 7.19 (d, J =1.6 Hz, 1H), 6.60 (d, J =16.8 Hz, 1H), 6.49 (dd, J = 16.8, 7.6 Hz, 1H), 4.90 (m, 1H), 4.64 (m, 2H), 4.14 (m, 2H), 4.10 (m, 1H) 1527, 1113, 801, 1167, 1321
253
AC84 511.75 ([M-H]) 8.07 (t, J =8.0 Hz, 1H), 7.34 (m, 3H), 7.19 (d, J = 13.2 Hz, 1H), 6.60 (d, J = 16.4 Hz, 1H), 6.48 (dd, J= 16.4, 8.0 Hz, 1H), 4.88 (m, 1H), 4.62 (m, 2H), 4.12 (m, 3H) 1645, 1113, 804, 3030, 1245
AC85 523.83 ([M-H]') 8.60 (d, J=6.8 Hz, 1H), 8.15 (d, J =8.4 Hz, 1H), 7.35 (d, J =6.0 Hz, 1H), 7.15 (d, J =7.2 Hz, 1H), 6.94 (s, 1H), 6.60 (d, J = 15.6 Hz, 1H), 6.44 (dd, J = 7.6, 7.6 Hz, 1H), 4.93 (m, 1H), 4.62 (m, 2H), 4.13 (m,6H) 1652, 3039, 802, 1114
AC 86 524.36 ([M+H]+) 7.35 (d, J =6.3 Hz, 3H), 7.26 (m, 2H), 7.20 (m, 1H), 6.60 (d, J=15.9 Hz, 1H), 6.47 (dd, J = 15.9, 6.6 Hz, 1H), 4.86 (m, 1H), 4.65 (m, 2H), 4.13 (m, 3H), 2.84 (q, 2.8 Hz, 2H), 1.26 (m, 3H) 3333, 1651, 815
AC 87 495.82 ([M-H]’) 8.07 (t, J =8.0 Hz, 1H), 7.52 (m, 3H), 7.19 (d, J = 13.2 Hz, 1H), 6.59 (d, J = 16.4 Hz, 1H), 6.47 (dd, J= 16.4, 8.0 Hz, 1H), 4.69 (m, 1 H), 4.23 (m, 3H), 3.29 (m, 2H) 1623, 1114, 816
254
AC89 509.89 ([M+HD 7.43 (m, 2H), 7.27 (m, 2H), 7.23 (m, 2H), 6.58 (d, J= 16.0 Hz, 1H), 6.41 (dd, J= 16.0, 7.6 Hz, 1 H), 4.79 (d, J = 5.6 Hz, 2H), 4.14 (m, 1H), 2.48 (s, 3H), 2.18 (m, 1H), 1.16 (m, 4H) 1666, 1166, 1112, 800
AC90 656.9 ([Μ-HD 8.34 (m, 1H), 8.27 (m, 1H), 7.60 (d, J =1.6 Hz, 1H), 7.49 (d, J =8.0 Hz, 2H), 7.40 (s, 2H), 7.36 (dd, J =8.2, 1.7 Hz, 1H), 6.53 (d, J =16.0 Hz, 1H), 6.38 (dd, J = 15.9, 7.9 Hz, 1 H), 4.89 (d, J =8.4 Hz, 2H), 4.48 (d, J= 9.0 Hz, 2H), 4.11 (m, 1H)
AC91 640.9 ([M-H]') 8.18 (t, J = 5.0 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.47 (d, J =8.0 Hz, 1H), 7.40 (s, 2H), 7.34 (dd, J = 8.1, 1.6 Hz, 1H), 6.52 (m, 2H), 6.37 (dd, J = 15.9, 7.9 Hz, 1 H), 4.54 (d, J =4.9 Hz, 2H), 4.12 (m, 1H), 3.99 (qd, J = 8.9, 6.5 Hz, 2H)
255
AC92 640.9 ([M-H]') 9.16 (d, J = 6.1 Hz, 1H), 7.65 (d, J =1.6 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.41 (m, 3H), 7.21 (t, J = 5.6 Hz, 1H), 6.55 (d, J = 15.9 Hz, 1H), 6.41 (dd, J = 15.9, 7.8 Hz, 1H), 4.59 (d, J =5.6 Hz, 2H), 4.45 (qd, J = 9.0, 6.0 Hz, 2H), 4.12 (q, J = 7.2 Hz, 1H)
AC93 485.5 ([M+HD 7.52-7.41 (d, J = 8.2 Hz, 1H), 7.39-7.34 (m, 1H), 7.24-7.17 (d, J =1.8 Hz, 2H), 7.02-6.92 (m, 2H), 6.90-6.83 (d, J= 11.4 Hz, 1H), 6.71 (brs, 1H), 6.17 (brs, 1H), 6.126.01 (dd, J= 11.4, 10.3 Hz, 1H), 4.44-4.38 (d, J = 4.2 Hz, 1H), 4.35-4.27 (m, 1H), 4.10-3.99 (d, J = 5.1 Hz, 2H), 2.78-2.67 (m, 1H), 2.44 (s, 3H), 0.88-0.78 (m, 2H), 0.600.45 (m, 2H) 13C NMR (O)3 169.91, 169.84, 138.23, 137.41, 136.84, 134.79, 134.69, 131.07, 128.69, 127.49, 127.43, 126.72, 126.61 (q, J = 212.10 Hz), 125.61, 123.76, 47.89 (q, J = 28.28 Hz), 43.46, 22.65, 19.97, 8.21
256
AC 94 511.6 ([MD 8.36- 8.24 (d, J =2.4 Hz, 1H), 7.75-7.64 (m, 1H), 7.38-7.24 (m, 3H), 7.24-7.09 (d, J = 1.8 Hz, 2H), 6.99-6.90 (m, 2H), 6.89-6.74 (d, J = 11.4 Hz, 1H), 6.636.43 (m, 1H), 6.145.98 (m, 1H), 4.694.51 (d, J=6.1 Hz, 2H), 4.37- 4.20 (m, 1H), 2.46 - 2.31 (s, 3H) 3262, 1607, 1247,1164, 1111
AC95 48-61 626.9 ([M+HD 7.58 (d, J = 7.9 Hz, 1H), 7.44-7.29 (m, 3H), 7.14 (dd, J= 7.9, 1.6 Hz, 1H), 6.86 (d, J = 11.4 Hz, 1H), 6.76 (t, J = 5.9 Hz, 1 H), 6.59 (br s, 1 H), 6.21 -6.04 (m, 1H), 4.23 (d, J =5.5 Hz, 1H), 3.98 (qd, J = 9.0, 6.5 Hz, 2H)
AC96 61 9.6 ([M+HD 8.83 (s, 1H), 8.06 (br, 1H), 7.90 (s, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.53 (m, 1H), 6.94 (m, 1H), 6.77 (d, J =15.3 Hz, 1H), 6.63 (d, J =9.3 Hz, 1H), 4.84 (m, 1H), 4.30 (d, J = 5.6 Hz, 2H), 2.99 (s, 6H) 1616, 1114
257
AC97 606.6 ([M+HD 8.20 (d, J =2.1 Hz, 1H), 7.73 (d, J =2.7 Hz, 1H), 7.60 (m, 2H), 7.39 (s, 2H), 7.29 (m, 1H), 6.79 (d, J =8.4 Hz, 1H), 6.55 (d, J =15.9 Hz, 1H), 6.40 (m, 2H), 4.60 (d, J =2.7 Hz, 2H), 4.13 (m, 1H), 3.95 (s, 3H) 1644, 1113
AC98 577.87 ([Μ+ΗΓ) 9.04 (t, J =6.0 Hz, 1H), 8.60 (t, J =6.6 Hz, 1H), 8.25 (s, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 6.3 Hz, 2H), 7.69 (d, J = 7.5 Hz, 1H), 7.15 (dd, J = 15.9, 9.3 Hz, 1H), 6.89 (d, J= 15.9 Hz, 1H), 4.86 (m, 1H), 3.98 (m, 4H). 1663, 1168
AC99 574.81 ([M+HD 8.69 (t, J =6.0 Hz, 1H), 8.58 (t, J = 6.6 Hz, 1H), 7.91 (s, 1H), 7.85 (m, 1H), 7.61 (m, 2H), 7.52 (m, 2H), 6.98 (dd, J = 15.3, 9.0 Hz, 1 H), 6.76 (d, J= 15.3 Hz, 1H), 4.81 (m, 1H), 4.01 (m, 4H) 1650, 1164
258
AC 100 673.80 ([M+H]+) 8.29 (s, 1H), 8.22 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.72 (m, 1H), 7.65 (m, 2H), 7.40 (s, 2H), 7.18 (br, 1H), 6.59 (d, J = 16.0 Hz, 1H), 6.43 (dd, J =16.0, 7.6 Hz, 1H), 5.02 (d, J = 1.2 Hz, 2H), 4.12 (m, 1H) 3403, 1659
AC101 636.83 ([M+HD 7.56 (d, J =9.0 Hz, 1H), 7.39 (d, J =6.0 Hz, 2H), 7.26 (m, 2H), 6.54 (d, J = 15.9 Hz, 1H), 6.37 (dd, J =8.0, 15.9 Hz, 1H), 4.01 (m, 1H), 3.84 (m, 2H), 3.33 (m, 2H), 3.04 (m, 2H), 2.84 (m, 3H), 2.62 (m, 1H) 1637, 1113
AC 102 592.84 ([M+HD 7.60 (m, 2H), 7.32 (m, 1H), 7.03 (d, J =7.2 Hz, 2H), 6.74 (br, 1H), 6.62 (br, 1H), 6.56 (d, J = 16.2 Hz, 1H), 6.41 (dd, J = 16.2, 7.8 Hz, 1H), 4.22 (d, J =5.4 Hz, 2H), 4.14 (m, 1H), 4.01 (m, 2H) 1668, 1167
259
AC103 99.2- 105.0 612.7 ([Μ+ΗΓ) 8.40 (d, J =8.0 Hz, 1H), 7.92 (d, J =5.2 Hz, 1H), 7.59 (d, J =8.0 Hz, 1H), 7.35 (d, J =8.0 Hz, 1H), 6.99 (dd, J =16.0, 7.6 Hz, 1H), 6.76 (d, J = 16.0 Hz, 1H), 4.84 (m, 1H), 4.23 (d, J= 13.2 Hz, 1H), 3.97 (m, 1H), 3.79 (d, J =13.6 Hz, 1H), 3.16 (t, J= 11.2 Hz, 1 H), 2.77 (t, J = 11.2 Hz, 1H), 1.99 (s, 3H), 1.88 (m, 2H ), 1.45 (m, 2H) 1634, 1113, 809
AC104 680.97 ([Μ+ΗΓ) 7.60 (m, 2H), 7.40 (m 3H), 6.55 (d, J= 15.6 Hz, 1H), 6.41 (dd, J = 15.6, 7.8 Hz, 1H), 4.24 (m, 1H), 3.34 (m, 2H), 2.90 (m, 1H), 2.24 (m, 2H), 1.52(m, 2H), 1.34 (m, 4H) 3437, 1644, 1113, 807, 511
AC105 609.9 ([M+HD 7.59 (s, 1H), 7.55 (m, 1H), 7.50 (m, 1 H),7.40 (m, 2H), 6.54(d, J= 16.0 Hz, 1H), 6.50 (J = 16.0, 8.0 Hz, 1H), 4.14 (m, 2H), 3.08 (m, 4H), 2.67 (m, 2H), 2.12 (m, 2H), 1.70 (m, 2H). 3303, 1649, 1115, 2242, 809, 506
260
AC 106 584.95 ([M+HD 7.59 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.40 (s, 2H), 7.36 (d, J = 6.8 Hz, 1H), 6.54 (d, J =16.0 Hz, 1 H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 6.03 (d, J = 8.0 Hz, 1H), 4.11 (m, 2H), 3.10 (m,2H), 2.50 (m, 2H ), 2.50 (s, 3H) (m, 2H ), 1.94 (m, 2H) 3417, 1648, 1112, 805, 555
AC107 609.9 ([M+HD 8.41 (d, J =7.8 Hz, 1H), 7.90 (s, 2H), 7.62 (m, 2H), 7.51 (m, 1H), 6.92 (dd, J= 15.9, 9.0 Hz, 1H), 6.77 (d, J = 15.9 Hz, 1H), 4.81 (m, 1H), 3.73 (s, 2H), 3.31 (m, 1H), 3.28 (m, 1H), 2.82 (t, J =11.4 Hz, 2H), 2.82 (m, 2H), 2.30 (m, 2H), 1.88 (m, 2H), 1.57 (m, 2H) 3303, 1645, 1115, 2243, 810, 507
AC 108 626.9 ([M+HD 7.60 (m, 2H) 7.39 (s, 2H), 7.28 (m, 1H), 6.56 (d, J= 15.6 Hz, 1H), 6.40 (dd, J =15.6, 7.8 Hz, 1H), 5.91 (m, 1H), 4.65 (m, 2H), 4.10 (m, 1H), 4.07 (m, 2H), 3.59 (m, 1H), 2.74 (m, 2H), 2.13 (m, 4H), 2.07 (m, 1H) 3420, 1649, 1113, 809, 554
261
AC 109 614.6 ([M+HD 7.56 (m, 2H), 7.39 (s, 2H), 7.29 (s, 1H), 6.50 (d, J= 15.9 Hz, 1H), 6.41 (dd, J= 15.9, 8.0 Hz 1H), 4.09 (m, 1H), 3.88 (m, 2H), 3.49 (m, 2H), 2.92 (m, 2H), 2.81 (m, 1H), 2.74 (m, 2H), 2.25 (m, 4H) 1647, 1113
AC110 572.6 ([M+HD 11.20 (s, 1H), 8.66 (br, 1H), 7.92 (m, 3H), 7.62 (d, J =8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 6.77 (dd, J= 15.6, 9.2 Hz, 1H), 6.77 (d, J = 15.6 Hz, 1H), 4.85 (m, 1H), 3.74 (d, J= 5.2 Hz, 2H), 3.61 (s, 3H) 3412, 1690, 1114, 846, 559
AC111 582.79 ([M+HD 8.63 (t, J =6.0 Hz, 1H), 8.04 (t, J = 6.0 Hz, 1H), 7.92 (m, 3H), 7.62 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.00 (dd, J = 15.6, 8.8 Hz, 1H), 6.77 (d, J =15.6 Hz, 1H), 5.19 (d, J = 1.6 Hz, 1H), 5.01 (d, J= 1.2 Hz, 1H), 4.85 (m, 1H), 3.86 (d, J= 5.6 Hz, 2H), 3.75 (t, J =5.6 Hz, 2H) 3419, 1659, 843, 557
262
AC112 582.79 ([M+HD 8.84 (br, 1H), 8.58 (m, 1H), 8.30 (m, 1H), 7.91 (s, 2H), 7.61 (d, J =8.1 Hz, 1H), 7.42 (d, J =7.8 Hz, 1H), 7.00 (dd, J = 15.6, 9.3 Hz, 1 H), 6.77 (d, J = 15.6 Hz, 1H), 4.85 (m, 1 H), 4.11 (d, J = 5.6 Hz, 1H), 3.73 (d, J =5.6 Hz, 1H), 3.04 (s, 6H) 3399, 1662, 1114, 807, 582
AC113 626.88 ([Μ+ΗΓ) 8.48 (t, J =5.2 Hz, 1H), 8.3 (s, 1H), 7.90 (s, 2H), 7.79 (dd, J =2.0, 2.0 Hz 2H), 7.58 (d, J =8.4 Hz, 1 H) 7.46 (d, J =7.6 Hz, 1 H) 7.26 (d, J =7.6 Hz, 1H), 6.98 (m, 1H), 6.75 (d, J= 15.6 Hz, 1H), 4.85 (m, 1 H), 3.49 (d, J = 6.4 Hz, 2H) 2.87 (t, J = 6.4 Hz, 2H) 3431, 1651, 1113, 808, 554
AC114 113.7- 117.5 570.7 ([M+HD 8.77 (s, 1H), 8.58 (d, J = 7.2 Hz, 2H), 7.93 (d, J = 7.2 Hz, 2H), 7.60 (dd, J = 1.2, 0.8 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 6.99 (m, 1H), 6.77 (d, J= 16 Hz, 1H), 4.85 (m, 1H), 4.10 (m, 1H) 3.29 (m, 2H), 3.05 (m, 2H), 2.0 (m, 2H), 1.76 (m, 2H)
263
AC115 529.00 ([M+HD 8.43 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.51 (m, 1H), 7.36 (d, J =8.4 Hz, 3H), 7.21 (m, 3H), 6.55 (d, J = 15.6 Hz, 1H), 6.36 (dd, J =15.6, 8.0 Hz, 1H), 5.04 (d, J = 5.6 Hz, 2H), 4.10 (m, 1H), 2.35 (s, 3H) 1589, 3459, 801, 1110
AC116 614.87 ([Μ+ΗΓ) 7.99 (d, J =8.4 Hz, 1H), 7.46 (d, J= 1.6 Hz, 1H), 7.34 (d, J =6.4 Hz, 2H), 7.28 (m, 2H), 6.62 (m, 2H), 6.47 (dd, J =16.0, 7.2 Hz, 1H), 4.23 (m, 2H), 4.12 (m, 1H), 4.00 (m, 2H) 3424, 1657, 1165
AC117 525.42 ([Μ-H]) 8.39 (br, 1H), 7.85 (br, 1H), 7.62 (m, 3H), 7.53 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.17 (m, 1H), 6.78 (dd, J =16.0, 8.8 Hz, 1H), 6.70 (m, 1H), 4.77 (m, 1 H), 4.66 (s, 1H), 4.32 (s, 1H), 2.97 (s, 3H), 2.16 (s, 3H) 3401, 1636, 1113, 750
264
AC118 471.79 ([Μ+ΗΓ) 7.36 (d, J =8.0 Hz, 2H), 7.27 (m, 2H), 7.22 (m, 2H), 6.57 (d, J = 16.0 Hz, 1H), 6.38 (dd, J = 16.0, 8.0 Hz, 1H), 6.10 (br, 1H), 4.15 (m, 2H), 3.89 (m, 1H), 3.80 (m, 2H), 3.35 (m, 1H), 2.46 (s, 3H), 2.06 (s,1H), 1.96 (m, 2H), 1.65 (m, 1H) 3437, 1655, 1262, 1105, 802
BC1 492.17 ([M+HD 7.39 (s, 2H), 7.25-7.18 (m, 3H), 6.58 (d, J = 16.0 Hz, 1H), 6.30 (dd, J = 16.0, 8.4 Hz, 1H), 5.91 -5.70 (br, 2H), 4.05 (m, 1H), 3.05- 2.80 (m, 6H), 2.70 (m, 1H), 1.81 (m, 1H) 3211, 1569, 1113, 806
BC2 506.4 ([M+HD 8.80 (s, 1H), 8.20 (s, 1H), 7.82 (m, 3H), 7.4 (s, 2H), 6.62 (d, J =16.0 Hz, 1 H), 6.52 (dd, J = 16.0, 8.0 Hz, 1H), 4.18(m, 1H), 3.38 (m, 2H), 2.98 (m, 2H), 2.71 (m, 1H), 2.04 (m, 2H), 1.54 (s, 3H). 2923, 1542, 1033, 805
265
BC3 518.04 ([Μ-HD 7.40 (s, 2H), 7.33-7.22 (m, 3H), 6.61 (d, J = 16.0 Hz, 1H), 6.34- 6.28 (dd, J= 16.0, 8.0 Hz, 1H), 5.96-5.80 (m, 3H), 5.22 (m, 4H), 4.01 (m, 2H), 2.84-2.99 (m, 2H), 2.71 (m, 1H), 1.86 (m, 1H) 3120, 1592, 1146, 895
BC4 529.02 ([M+HD 7.39 (s, 2H), 7.25-7.20 (m, 3H), 6.34 (d, J = 16.0 Hz, 1H), 6.30 (dd, J = 16.0, 8.0 Hz, 1H), 5.81 (br, 1H), 5.48 (m, 1H), 4.10 (m, 1H), 3.10 (m, 2H), 2.86-3.07 (m, 2H), 2.86 (m, 1H), 1.81 (m, 1H); 3283, 1652, 1241, 811
BC5 544.25 ([M-H]’) 7.40 (s, 2H), 7.21 (s, 1H), 7.12 (m, 1H), 6.56 (d, J= 16.0 Hz, 1H), 6.32 (dd, J =16.0, 8.4 Hz, 1H), 5.85 (brs, 1H), 5.23 (brs, 1H), 4.12 (m, 1H), 3.18 (m, 3H), 2.80 (m, 3H), 2.08 (m, 2H), 1.83 (m, 5H), 1.25 (m, 2H), 1.01 (m, 3H), 0.78 (m, 2H) 3489, 3291, 1655, 1112, 808
266
BC6 485.96 ([M-H]’) 7.40 (s, 2H), 7.31 -7.18 (m, 3H), 6.58 (d, J = 16.0 Hz, 1H), 6.24- 6.28 (dd, J= 16.0, 8.0 Hz, 1H), 5.40 (br, 1H), 4.01 (m, 2H), 2.783.01 (m, 2H), 2.51 (s, 1H), 1.86 (m, 1H), 1.20 (m, 2H), 1.01 (m, 2H), 0.78 (m, 2H) 3429, 1114, 804
BC7 500.01 ([M-H]') 7.40 (s, 2H), 7.31 (s, 1H), 7.18 (m, 1H), 7.18 (s, 1H), 6.58 (d, J= 16.0 Hz, 1H), 6.32 (dd, J = 16.0, 8.0 Hz, 1H), 5.78 (brs, 1H), 5.21 (brs, 1H), 4.01 (m, 1H), 2.78 (m, 2H), 2.01 (m, 1H), 1.86 (m, 4H), 1.25 (m, 2H), 1.01 (m, 3H), 0.78 (m, 2H) 3296, 1115, 806
BC8 511.88 ([M-H]’) 7.38-7.20 (m, 5H), 6.62 (d, J= 16.0 Hz, 1H), 6.34 (dd, J= 16.0, 8.0 Hz, 1H), 5.83 (br, 1H), 5.52 (m, 1H), 4.12 (m, 1H), 3.12 (m,2H), 3.062.82 (m, 2H), 2.75 (m, 1H), 1.85 (m, 1H) 1657, 1113, 855
267
BC9 179- 181 556.83 ([M-H]’) 8.30 (s, 1H), 7.68 (d, J = 6.4 Hz, 1H), 7.38-7.20 (m, 5H), 6.60 (d, J = 16.0 Hz, 1 H), 6.34 (dd, J = 16.0, 8.0 Hz, 1H), 5.63 (br, 1H), 5.52 (m, 1H), 4.12 (m, 1H), 3.56 (s, 2H), 3.06-2.82 (m, 2H), 2.70 (m, 1H), 1.82 (m, 1H)
BC10 497.98 ([M-H]’) 7.38-7.20 (m, 5H), 6.62 (d, J =16.0 Hz, 1H), 6.34 (dd, J= 16.0, 8.0 Hz, 1H), 5.83 (br, 1H), 5.52 (m, 1H), 4.12 (m, 1H), 3.02 (m, 3H), 2.82 (m, 1H), 2.50 (m, 3H), 1.82 (m, 1H), 1.42 (m, 1H) 3027, 1654, 815
BC11 530.09 ([M-H]’) 7.80 (m, 1H), 7.48 (m, 2H), 7.32 6.65 (d, J = 16.0 Hz, 1H), 6.54 (dd, J = 16.0, 8.0 Hz, 1H), 5.38 (m, 1H), 4.18 (m, 1H), 3.62 (m, 1H), 3.32 (m, 1H), 2.86 (m, 1H), 1.81 (m, 1H) 1715, 1113, 816
268
BC12 514.86 ([Μ+ΗΓ) 7.32, (d, J = 6.0 Hz, 2H) 7.28 (m, 1H), 7.20 (d, J = 8.0, 1H), 7.14 (d, J = 8.8, 1H ),6.70 (d, J = 8.0 Hz, 1H), 6.60 (m, 2H), 4.15 (m, 1H), 3.85 (m, 1H), 3.65 (m, 1H), 3.46 (m, 2H), 3.19 (m, 2H); 3428, 1112, 857
BC13 121- 126 553.06 ([M-H]-) 8.33 (br, 1H), 7.59 (s, 1H), 7.45 (m, 3H), 6.72 (d, J= 3.6, 1H), 6.39 (m, 1 H), 4.71 (t, J =7.2 Hz, 2H), 4.15 (m, 2H)
BC14 172- 175 554.0 ([M-H]') 8.83 (t, J =6.6 Hz, 1H), 8.42 (t, J =14.7 Hz, 1H), 8.22 (d, J = 8.1 Hz, 1H), 8.13 (t, J = 6.3 Hz, 1H), 7.98-7.86 (m, 2H), 7.16-7.07 (m, 1H), 7.01 -6.93 (m, 1H), 4.96-4.81 (m, 3H), 4.00 - 3.88 (m, 2H)
CC1 107- 109 402.00 ([M+HD 7.37 (m, 3H), 7.28 (m, 4H), 6.60 (d, J= 16.0 Hz, 1 H), 6.36 (dd, J = 16.0, 8.0 Hz, 1H), 5.75 (brs, 1H), 4.46 (d, J=Q Hz, 2H), 4.01 (m, 1H), 2.11 (s, 3H)
269
CC2 118— 120 428.11 ([M+HD 7.37 (m, 3H), 7.28 (m, 4H), 6.60 (d, J =16.0 Hz, 1H), 6.35 (dd, J = 16.0, 8.0 Hz, 1H), 5.83 (brs, 1H), 4.46 (d, J = 6.0 Hz, 2H), 4.11 (m, 1H), 1.40 (m, 1H), 1.02 (m, 2H), 0.77 (m, 2H)
CC3 119- 122 468.20 ([M-H]’) 7.38 (m, 3H), 7.27 (m, 3H), 6.60 (d, J =16.0 Hz, 1H), 6.36 (dd, J = 16.0, 8.4 Hz, 1H), 5.00 (brs, 1H), 4.48 (d, J = 5.6 Hz, 2H), 4.11 (m, 1H), 3.15 (q,J= 10.4 Hz, 2H)
CC4 414.16 ([M-H]) 7.37 (m, 3H), 7.28 (m, 3H), 6.60 (d, J= 16.0 Hz, 1H), 6.35 (dd, J = 16.0, 8.0 Hz, 1H), 5.69 (brs, 1H), 4.46 (d, J = 6.0 Hz, 2H), 4.21 (m, 1H), 2.29 (q, J =5.8 Hz, 2H), 1.30 (t, J =7.2 Hz, 3H)
270
CC5 460.28 ([M-H]) 7.40 (m, 3H), 7.28 (m, 2H), 6.60 (d, J =15.6 Hz, 1H), 6.33 (dd, J = 15.6, 8.0 Hz, 1H), 5.84 (brs, 1H), 4.46 (d, J = 5.6 Hz, 2H), 4.10 (m, 1H), 1.36 (m, 1H), 1.02 (m, 2H), 0.77 (m, 2H)
CC6 106- 108 504.08 ([M-H]) 7.40 (m, 3H), 7.26 (m, 1H), 6.60 (d, J =16.0 Hz, 1H), 6.34 (dd, J = 16.0, 8.0 Hz, 1H), 5.96 (brs, 1H), 4.49 (d, J = 5.6 Hz, 2H), 4.10 (m, 1H), 3.15 (q, J = 10.8 Hz, 2H)
CC7 127- 128 436.03 ([M+HD 7.42 (m, 4H), 7.24 (m, 2H), 6.53 (d, J =16.0 Hz, 1H), 6.36 (dd, J = 16.0, 8.0 Hz, 1H), 5.86 (brs, 1H), 4.51 (d, J = 6.0 Hz, 2H), 4.05 (m, 1H), 2.02 (s, 3H)
271
CC8 129- 131 462.15 ([Μ+ΗΓ) 8.58 (t, J =5.6 Hz, 1H), 7.72 (m, 1H), 7.66 (m, 3H), 7.49 (d, J =8.0 Hz, 1H), 7.30 (d, J =8.0 Hz, 1H), 6.90 (dd, J =16.0, 8.0 Hz, 1H), 6.73 (d, J = 16 Hz, 1H), 4.81 (m, 1H), 4.33 (d, J =6.0 Hz, 1H), 1.64 (m, 1H), 0.68 (m, 4H)
CC9 132- 134 504.25 ([M+HD 7.41 (m, 3H), 7.26 (m, 3H), 6.54 (d, J= 16.0 Hz, 1H), 6.37 (dd, J = 16.0, 8.0 Hz, 1H), 6.13 (brs, 1H), 4.56 (d, J = 6.0 Hz, 2H), 4.11 (m, 1H), 3.13 (m,2H)
CC10 538.03 ([M+2H]+) 7.38 (m, 4H), 6.56 (d, J = 16.0 Hz, 1H), 6.38 (dd, J= 16.0, 8.0 Hz, 1H), 6.18 (m, 1H), 4.58 (m, 2H), 4.08 (m, 1H), 3.08 (m, 2H) 1651, 1112, 807
CC11 111- 112 494.12 ([M-H]’) 7.42 (m, 3H), 7.24 (m, 1H), 6.54 (d, J= 15.6 Hz, 1H), 6.34 (dd, J = 16.0, 8.0 Hz, 1H), 6.03 (m, 1H), 4.53 (d, J = 6.0 Hz, 1H), 4.10 (m, 1H), 1.39 (m, 1H), 1.00 (m, 2H), 0.77 (m, 2H)
272
CC12 76-78 510.07 ([M-H]') 7.39 (s, 4H), 7.34 (d, J = 8.0 Hz, 1H), 7.26 (m, 1H), 6.57 (d, J = 16.0 Hz, 1H), 6.35 (dd, J = 16.0, 8.0 Hz, 1H), 6.10 (brs, 1H ), 4.49 (d, J = 6.0 Hz, 2H), 4.10 (m, 1H), 1.20 (s, 9H)
CC13 73-76 563.37 ([M-H]') 8.51 (d, J= 5.2 Hz, 1H), 7.63 (s, 1H), 7.51 (m, 1H), 7.45 (m, 2H), 7.39 (s, 2H), 7.28 (m, 1H), 6.58 (m, 2H), 6.37 (dd, J = 16.0, 8.0 Hz, 1H), 4.71 (d, J =6.0 Hz, 1H), 4.11 (m, 1H)
CC14 581.45 ([M+1H]+) 8.51 (m, 1H), 8.30 (d, J = 2.4 Hz, 1H), 7.73 (m, 1H), 7.61 (s, 2H), 7.51 (s, 1H), 7.32 (m, 3H), 6.66 (d, J= 16.0 Hz, 1H), 6.56 (dd, J =16.0, 8.4 Hz, 1H), 4.50 (m, 1H), 4.45 (d, J =5.6 Hz, 1H), 3.56 (s, 2H) 3430, 1656, 1109, 806
273
CC15 480.24 ([M+HD 7.40 (m, 3H), 7.33 (m, 1H), 7.22 (m, 2H), 6.54 (d, J =15.6 Hz, 1H), 6.34 (dd, J= 16.0, 8.0 Hz, 1H), 6.03 (brs, 1H), 4.53 (d, J =6.0 Hz, 2H), 4.13 (m, 1H), 1.41 (m, 1H), 1.00 (m, 2H), 0.77 (m, 2H) 3293, 1651, 1543, 1114, 812
CC16 520.33 ([Μ-HD 7.42 (s, 1H), 7.37 (m, 3H), 7.22 (m, 1H), 6.54 (d, J =16.0 Hz, 1H), 6.36 (dd, J =16.0, 8.0 Hz, 1H), 6.19 (brs, 1H), 4.51 (d, J =6.0 Hz, 2H), 4.21 (m, 1H), 3.33 (m, 2H) 3307, 1665, 1114, 813
CC17 117- 119 459.83 ([Μ-H]') 7.51 (m, 2H), 7.39 (m, 2H), 7.24 (m, 2H), 6.52 (d, J= 15.6 Hz, 1H), 6.38 (dd, J= 15.6, 7.6 Hz, 1H), 6.02 (brs, 1H), 4.53 (d, J =6.0 Hz, 2H), 4.14 (m, 1H), 1.38 (m, 1H)), 1.00 (m, 2H), 0.77 (m, 2H) 3293, 1633, 1110, 820
274
CC18 119- 123 501.88 ([M-H]) 7.48 (m, 2H), 7.41 (s, 1H), 7.36 (d, J =8.0 Hz, 1H), 7.23 (m, 2H), 6.52 (d, J =16.0 Hz, 1H), 6.39 (dd, J =16.0, 8.0 Hz, 1H), 6.13 (brs, 1H), 4.56 (d, J =6.0 Hz, 2H), 4.15 (m, 1H), 3.13 (m, 2H) 3435, 1644, 1111,817
CC19 530 ([M+HD 7.41 (m, 2H), 7.24 (m, 1H), 6.53 (d, J =16.0 Hz, 1H), 6.35 (dd, J = 16.0, 8.0 Hz, 1H), 4.53 (m, 2H), 4.10 (m, 1H), 3.42 (m, 2H), 2.97 (s, 3H), 2.78 (m, 2H) 3435, 1644, 1111,817
CC20 512 ([M+HD 7.42 (m, 3H), 7.24 (m, 1H), 6.54 (d, J = 15.6 Hz, 1H), 6.34 (dd, J = 15.6, 8.0 Hz, 1H), 6.03 (m 1 H), 4.53 (d, J =6.0 Hz, 1H), 4.10 (m, 1H), 1.19 (m, 1H), 1.00 (m, 2H), 0.77 (m, 2H) 3293, 1633, 1110, 820
275
CC21 55-58 493.99 ([M-H]') (DMSO-d6) 8.62 (m, 1H), 7.95 (s, 1H), 7.85 (m, 1H), 7.66 (m, 3H), 7.47 (d, J =8.0 Hz, 1H), 6.98 (dd, J =16.0, 8.0 Hz, 1H), 6.84 (d, J = 16.0 Hz, 1H), 4.83 (m, 1H), 4.44 (s, 2H), 1.68 (m, 1H), 0.71 (m, 4H)
CC22 67-69 530.01 ([M+HD 8.62 (m, 1H), 7.90 (s, 3H), 7.82 (m, 1H), 7.45 (m, 1H), 6.98 (m, 1H), 6.84 (d, J= 16.0 Hz, 1H), 4.82 (m, 1H), 4.4 (s, 2H), 1.66 (m, 1H), 0.72 (m, 4H)
CC23 69-71 564.99 ([M-H]) 9.02 (brs, 1H), 8.54 (br s, 1 H), 8.26 (brs, 1H), 7.48-7.54 (m, 3H), 7.22 - 7.42 (m, 3H), 6.59-6.62 (m, 2H), 6.38-6.42 (m, 1H), 4.82 (m, 2H), 4.19 (s, 1H)
CC24 125- 127 570.26 ([M-H]') 7.64 (s, 1H), 7.54 (s, 2H), 7.46 (s, 2H), 6.62 (d, J=16.0 Hz, 1H), 6.41 (dd, J= 16.0, 8.4 Hz, 1H), 6.03 (m, 1H), 4.65 (d, J = 6.4 Hz, 2H), 4.14 (m, 1H,), 3.13 (q, J = 10.6 Hz, 2H)
276
CC25 579.86 ([M-H]') 7.60 (s, 1H), 7.40 (s, 2H), 7.37 (d, J = 8.0 Hz, 1H), 7.31 (d, J =8.0 Hz, 1H), 6.53 (d, 1H, J = 16.0 Hz), 6.35 (dd, J = 16.0, 8.0 Hz, 1H), 6.17 (brs, 1H), 4.56 (d, J = 6.4 Hz, 2H), 4.12 (m, 1H), 3.15 (q, J= 10.6 Hz, 2H) 3297, 1663, 1114, 809
CC26 129- 131 539.89 ([M+HD 7.59 (s, 1H), 7.39 (m, 2H), 7.30 (s, 1H), 6.53 (d, J= 16.0 Hz, 1H), 6.35 (dd, J =16.0, 8.0 Hz, 1H), 6.06 (brs, 1H), 4.42 (d, J =4.4 Hz, 2H), 4.12 (m, 1H), 1.35 (brs, 1H), 0.95 (br s, 2H), 0.75 (m, 2H)
CC27 519.95 ([M-H]’) 7.39 (s, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.14 (m, 2H), 6.56 (d, J = 16.0 Hz, 1H), 6.35 (dd, J = 16.0, 7.6 Hz, 1 H), 6.06 (brs, 1H), 4.52 (d, J = 16.0 Hz, 2H), 4.08 (m, 1H), 3.90 (s, 2H), 3.13 (m, 2H) 3306, 1786
277
CC28 477.93 ([M-H]') 7.39 (s, 2H), 7.35 (m, 1H), 7.14 (m, 2H), 6.55 (d, J= 15.6 Hz, 1H), 6.33 (dd, J= 15.6, 8.0 Hz, 1H), 5.93 (brs, 1H), 4.49 (d, J= 16.0 Hz, 2H), 4.10 (m, 1H), 1.36 (m, 1H), 1.00 (m, 2H), 0.77 (m, 2H) 3625, 1747
CC29 620.86 ([M-H]’) 8.58 (d, J =4.6 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J = 16.0 Hz, 1H), 6.38 (dd, J = 16.0, 8.0 Hz, 1H), 5.02 (s, 1H), 4.8 (s, 1H), 4.8 (d, J =10 Hz, 2H), 4.10 (m, 1H), 1.8 (m, 1H), 1.2 (m, 2H), 0.6 (m, 2H) 1645, 1115, 808
CC30 101- 104 559.75 ([M-H]’) 7.41 (m, 4H), 7.24 (m, 1H), 6.53 (d, J =16.0 Hz, 1H), 6.35 (dd, J = 16.0, 8.0 Hz, 1H), 6.12 (brs, 1H), 4.53 (m, 2H), 4.10 (m, 1H), 3.42 (m, 2H), 2.91 (s, 3H), 2.78 (m, 2H)
278
CC31 177- 178 463 ([M-H]') 7.58 (m, 2H), 7.41 (m, 3H), 7.24 (m, 1H), 6.53 (d, J= 16.0 Hz, 1H), 6.35 (dd, J =16.0, 8.0 Hz, 1H), 4.70 (brs, 1H), 4.43 (s, 2H), 4.08 (m, 1H), 3.21 (m, 2H), 1.25 (m, 3H);
CC32 141- 142 532.99 ([M+HD 7.66 (m, 2H), 7.54 (m, 1H), 7.41 (s, 2H), 6.62 (d, J = 16.0Hz, 1H), 6.40 (dd, J= 16.0, 8.0 Hz, 1H), 4.59 (s, 3H), 4.19 (m, 1H), 3.25 (m, 2H), 1.15 (m, 2H)
CC33 540.88 ([M-H]') 7.57 (s, 1H), 7.40 (m, 2H), 7.30 (s, 1H), 7.20 (brs, 1H), 6.53 (d, J = 16.0 Hz, 1H), 6.33 (dd, J = 16.0, 8.0 Hz, 1H), 6.06 (brs, 1H), 4.75 (br s, 1H), 4.42 (s, 2H), 4.20 (brs, 1H), 4.15 (m, 2H), 3.20 (m, 2H), 1.15 (m, 3H) 3338, 1631, 1578, 1114, 809
279
CC34 118- 120 541.40 ([M+HD 7.42 (m, 3H), 7.28 (m, 2H), 6.54 (d, J= 16.0 Hz, 1H), 6.36 (dd, J = 16.0, 8.0 Hz, 1H), 4.96 (m, 1H), 4.51 (d, J =5.6 Hz, 2H), 4.12 (m, 1H), 3.69 (t, J =4.8 Hz, 4H), 3.35 (t, J =4.8 Hz, 1H)
CC35 78-79 547.82 ([M+HD 9.95 (brs, 1H), 8.17 (d, J = 4.8 Hz, 1H), 7.61 (d, J = 6.4 Hz), 7.43 (m, 3H), 7.24 (m, 2H), 6.90 (t, J =5.6 Hz, 1H), 6.66 (d, J =8.4 Hz, 1H), 6.54 (d, J= 16.0 Hz, 1H), 6.33 (dd, J =16.0, 8.0 Hz, 1H), 4.65 (d, J = 6.0 Hz, 1H), 4.09 (m, 1H)
CC36 497 ([M-H]’) 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J= 16.0 Hz, 1H), 6.34 (dd, J = 16.0, 8.0 Hz, 1 H), 4.97 (brs, 1H), 4.38 (d, J = 6.0 Hz, 2H), 4.10 (m, 1H), 2.9 (s, 3H), 2.7 (s, 3H) 3350, 1705, 1114, 808
280
CC37 88-91 515.01 ([M+Hf) 7.49 (d, J=8Hz, 1H), 7.41 (d, J= 7.2 Hz, 2H), 7.26 (m, 2H), 6.50 (d, J = 16 Hz, 1H), 6.35 (dd, J = 16.0, 8.0 Hz, 1H), 6.0 (brs, 1H), 5.73 (br s, 1H), 4.80 (br s, 2H), 4.09 (m, 1H), 1.23 (m, 3H)
CC38 63-66 526.97 ([M+Hf) 7.48 (d, J=8Hz, 1H), 7.39 (m, 3H), 7.27 (m, 1H), 6.54 (d, J= 16 Hz, 1H), 6.33 (dd, J = 6.0, 8.0 Hz, 1H), 6.17 (brs, 1H), 5.92 (brs, 1H), 5.83 (m, 2H), 5.29 (t, J = 15.4 Hz, 2H), 4.80 (br s, 2H), 4.12 (m, 1 H), 4.02 (brs, 2H)
CC39 526.09 ([M-H]’) 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J= 16.0 Hz, 1H), 6.34 (dd, J = 16.0, 8.0 Hz, 1H), 4.97 (brs, 1H), 4.38 (d, J = 6.0 Hz, 2H), 4.10 (m, 1H), 1.53 (s, 9H) 3350, 1705, 1114, 808
281
CC40 159- 160 580.25 ([M-H]') 7.46 (m, 5H), 7.29 (m, 1H), 7.20 (m, 3H), 6.55 (d, J= 16.0 Hz, 1H), 6.37 (dd, J= 16.0, 8.0 Hz, 1H), 5.62 (brs, 1H), 4.55 (d, J =6.4 Hz, 2H), 4.11 (m, 1H)
CC41 512.22 ([M-H]’) 7.48 (m, 1H), 7.43 (m, 3H), 7.38 (m, 1H), 7.23 (s, 1H), 6.55 (d, J =16.0 Hz, 1H), 6.36 (d, J = 16.0 Hz, 1H), 4.60 (d, 2H), 4.18 (m, 1H), 3.85 (s, 3H) 1740, 1701, 1114, 808
CC42 161— 163 578.96 ([M-H]-) (DMSO-d6) 9.45 (br s, 2H), 7.90 (s, 2H), 7.75 (s, 1H), 7.46 (brs, 1H), 7.28 (brs, 1H), 6.93 (m, 1H), 6.75 (brs, 1H), 4.80 (m, 1H), 4.40 (br s, 2H), 3.90 (br s, 2H)
CC43 140- 142 505.39 ([M+HD 8.11 (d, J =4.0 Hz, 1H), 7.40 (m, 5H), 7.22 (m, 1H), 6.61 (m, 2H), 6.35 (m, 2H), 4.94 (brs, 1H) 4.61 (d, J = 6.4 Hz, 2H), 4.11 (m, 1H)
282
CC44 536.88 ([M-H]’) 8.41 (s, 1H), 7.77 (s, 1H), 7.47 (brs, 1H), 7.40 (s, 2H), 6.58 (d, J = 16.0 Hz, 1H), 6.45 (dd, J = 16.0, 8.0 Hz, 1H), 4.68 (d, J = 4.0 Hz, 2H), 4.14 (m, 1H), 3.24 (q, J = 10.8 Hz, 2H) 3320, 1674, 1114, 808
CC45 494.88 ([M-H]) 8.41 (s, 1H), 7.76 (s, 1H), 7.40 (s, 2H), 7.15 (brs, 1H), 6.58 (d, J = 16.0 Hz, 1 H), 6.44 (dd, J = 16.0, 8.0 Hz, 1H), 4.67 (d, J =4.4 Hz, 2H), 4.16 (m, 1H), 1.57 (m, 1H), 1.04 (m, 2H), 0.87 (m, 2H) 3309, 1659, 1115, 808
CC46 151— 153 554.04 ([M-H]) 8.06 (m, 1H), 7.61 (m, 4H), 7.48 (s, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.38 (m, 1H), 6.42 (m, 1H), 5.92 (brs, 1H), 4.92 (m, 2H), 4.24 (m, 1H), 3.12 (m, 2H)
CC47 478.09 ([M+HD 8.06 (m, 2H), 7.61 (m, 4H), 7.48 (s, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.38 (m, 2H), 6.42 (m, 1H), 4.92 (s, 2H), 1.36 (m, 1H), 1.00 (m, 2H), 0.77 (m, 2H) 3309, 1659, 1115, 808
283
CC48 511.05 ([M+HD 8.06 (m, 2H), 7.61 (m, 3H), 7.48 (s, 2H), 7.44 (d, J =8.0 Hz, 1H), 7.38 (m, 2H), 6.42 (m, 1H), 4.92 (s, 2H), 1.36 (m, 1H), 1.00 (m, 2H), 0.77 (m, 2H) 3309, 1659, 1115, 808
CC49 84-87 515.33 ([M+HD- 8.06 (m, 1H), 7.98 (m, 1H), 7.61 (m, 3H), 7.48 (s, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.38 (m, 2H), 6.42 (m, 1 H), 4.92 (s, 2H), 4.6 (brs, 1H), 4.24 (m, 1H), 3.21 (m, 2H), 1.2 (t, J = 4.6 Hz, 3H)
CC50 138- 140 461.32 ([M-1H]) 9.81 (s, 1H), 7.90 (s, 1H), 7.84 (s, 2H), 7.34 (d, J= 8.4 Hz, 2H), 6.65 (d, J= 15.6 Hz, 1H), 6.61 (m, 1H), 6.57 (s, 1H), 6.48 (dd, J = 15.6, 8.8 Hz, 1H), 4.74 (m, 1H), 1.64 (m, 1H), 0.75 (m, 4H);
284
CC51 149- 150 505.31 ([M-H]’) 7.56 (brs, 1H), 7.4 (s, 3H), 7.3 (m, 3H), 7.05 (brs, 1H), 6.8 (d, J=6 Hz, 2H), 6.57 (m, 2H), 6.20 (m, 2H), 4.05 (m, 1H), 3.2 (q, J =10.4 Hz, 2H)
CC52 464.87 ([M-H]’) 7.40 (s, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 6.85 (m, 1H), 6.45 (m, 1H), 6.20 (m, 1H), 5.55 (s,1H), 4.08 (m, 1H), 1.30-1.10 (m,4H), 1.90 (m,1H) 3309, 1659, 1115, 808
CC53 506 ([M+HD 7.40 (s, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 6.85 (m, 1H), 6.45 (m, 1H), 6.20 (m, 1H), 5.55 (s,1H), 4.08 (m, 1H), 3.21 (m, 2H) 3309, 1659, 1115, 808
CC54 504 ([M+HD 7.28 (s, 2H), 7.25 (m, 2H), 7.10 (d, J =8.0 Hz, 2H), 6.89 (d, J =11.4 Hz, 1H), 6.07 (brs, 1H), 6.01 (m, 1H), 4.51 (d, J = 5.8 Hz, 2H), 4.34 (m, 1H), 3.12 (q, J = 7.5 Hz, 2H)
285
DC1 93-97 398.05 ([M+HD 8.56 (s, 1H), 8.11 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.54 (d, J =8.4 Hz, 2H), 7.38 (t, J= 1.8 Hz, 1H), 7.29 (s, 2H), 6.62 (d, J = 15.6 Hz, 1H), 6.42 (dd, J= 15.6, 8.2 Hz, 1H), 4.15 (m, 1H)
DC2 363.0746 (363.075) 8.59 (s, 1H), 8.13 (s, 1H), 7.69 (d, J =8.5 Hz, 2H), 7.55 (d, J =8.5 Hz, 2H), 7.41 -7.29 (m, 4H), 6.64 (d, J= 15.7 Hz, 1H), 6.47 (dd, J = 15.9, 8.0 Hz, 1H), 4.17 (m, 1H) 3121, 1524, 1251, 1165, 1119
DC3 329.1144 (329.114) 8.56 (s, 1H), 8.11 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.40 (m, 5H), 6.61 (d, J= 15.8 Hz, 1H), 6.51 (dd, J= 15.9, 7.7 Hz, 1H), 4.18 (m, 1H) 1521, 1246, 1219, 1162, 1152,1107
DC4 364.11 ([M+HD 8.56 (s, 1H), 8.10 (s, 1H), 7.66 (d, J =2.0 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.38 (d, J =2.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 7.6 Hz, 1H), 4.15 (m, 1H) 3147, 1528, 1494, 1246, 1165,1108
286
DC5 344.25 ([M+HD 8.54 (s, 1H), 8.10 (s, 1H), 7.62 (d, J =8.3 Hz, 2H), 7.50 (d, J =8.4 Hz, 2H), 7.25 (d, J =8.3 Hz, 2H), 7.20 (d, J =8.0 Hz, 2H), 6.60 (d, J =16.0 Hz, 1H), 6.51 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H), 2.37 (s, 3H) 3122, 3047, 1523, 1252, 1160, 1107
DC6 360.28 ([M+HD 8.55 (s, 1H), 8.10 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.52 (d, J =8.8 Hz, 2H), 7.32 (d, J =8.8 Hz, 2H), 6.95 (d, J =8.8 Hz, 2H), 6.60 (d, J =16.0 Hz, 1H), 6.56 (dd, J = 16.0, 7.4 Hz, 1H), 4.15 (m, 1H), 3.82 (s, 3H) 3124, 2936, 1522, 1249, 1160
DC7 348 ([M+HD 8.55 (s, 1H), 8.10 (s, 1H), 7.62 (d, J =8.8 Hz, 2H), 7.5 (d, J = 8.4 Hz, 2H), 7.38 (m, 2H), 7.12 (m, 2H), 6.61 (d, J = 16.0 Hz, 1H), 6.40 (dd, J= 16.0, 7.6 Hz, 1H), 4.15 (m, 1H) 3141, 1512, 1246, 1118
287
DC8 366.13 ([M+Hf) 8.57 (s, 1H), 8.11 (s, 1H), 7.65 (d, J =7.2 Hz, 2H), 7.52 (d, J =8.0 Hz, 2H), 6.95 (m, 2H), 6.82 (m, 1H), 6.65 (d, J = 16.0 Hz, 1H), 6.50 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H) 3116, 1628, 1524, 1252, 1168, 1118
DC9 348.11 ([M+Hf) 8.71 (s, 1H), 8.20 (s, 1H), 7.70 (d, J =8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.40 (m, 1H), 7.19 (m, 3H), 6.60 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.4 Hz, 1H), 4.15 (m, 1H) 3115, 1525, 1248, 1174
DC10 348.11 ([M+Hf) 8.75 (s, 1H), 8.20 (s, 1H), 7.72 (d, J =8.4 Hz, 2H), 7.6 (d, J = 8.4 Hz, 2H), 7.20-7.40 (m, 4H), 6.60 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H,)> 4.60 (m, 1H) 3114, 1526, 1259, 1238, 1193, 1114
DC11 75.5- 78.5 358.14 ([M+Hf) 8.55 (s, 1H), 8.10 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.01 (s, 3H), 6.60 (d, J = 16.0 Hz, 1H), 6.51 (dd, J= 16.0, 7.8 Hz, 1H), 4.15 (m, 1H), 2.34 (s, 6H)
288
DC12 398.05 ([M+HD 8.58 (s, 1H), 8.10 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.53 (m, 4H), 7.2 (s, 1 H) 6.62 (d, J =15.6 Hz, 1H), 6.44 (dd, J = 15.6, 8.0 Hz, 1H), 4.15 (m, 1H) 3055, 2930, 1523, 1250, 1165
DC13 396.16 ([Μ+ΗΓ) 8.58 (s, 1H), 8.10 (s, 1H), 7.62 (d, J =8.4 Hz, 2H), 7.55 (m, 4H), 7.25 (m, 1H), 6.64 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 4.90 (m, 1H) 3108, 1523, 1249, 1166, 1127
DC14 398.05 ([M+HD 8.58 (s, 1H), 8.10 (s, 1H), 7.62 (d, J =8.4 Hz, 2H), 7.55 (m, 4H), 7.25 (m, 1H), 6.67 (d, J = 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 5.00 (m, 1H) 3117, 2925, 1526, 1246, 1172, 1117
DC15 397.95 ([M+HD 8.58 (s, 1H), 8.10 (s, 1H), 7.66 (d, J =8.0 Hz, 2H), 7.52 (m, 3H), 7.40 (d, J= 8.0 Hz, 1H), 7.30 (dd, J =8.4, 2.9 Hz, 1H), 6.64 (d, J= 16.0 Hz, 1H), 6.40 (dd, J = 16.0, 8.0 Hz, 1H), 4.90 (m, 1H) 3120, 1524, 1267, 1176, 1112
289
DC16 466 ([M+HD 8.61 (s, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.86 (s, 2H), 7.70 (d, J =7.0 Hz, 2H), 7.54 (d, J = 7.0 Hz, 2H), 6.67 (d, J = 16.0 Hz, 1H), 6.46 (dd, J = 16.0, 8.0 Hz, 1H), 4.35 (m, 1H)
DC17 430.06 ([M+HD 8.58 (s, 1H), 8.1 (s, 1H), 7.68 (d, J =8.4 Hz, 2H), 7.54 (d, J =8.4 Hz, 2H), 7.51 (s, 1H), 7.42 (s, 1H), 6.68 (d, J= 16.0 Hz, 1H), 6.35 (dd, J = 16.0, 8.0, Hz, 1H), 4.98 (m, 1H) 3122, 3076, 2929, 1523, 1250, 1168, 1114
DC18 92-95 429.91 ([M+HD 8.57 (s, 1H), 8.11 (s, 1H), 7.69 (d, J =8.8 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.42 (s, 2H), 6.65 (d, J =16.0 Hz, 1H), 6.40 (dd, J= 16.0, 8.0 Hz, 1H), 4.10 (m, 1H)
DC19 97-99 430.321 ([M+HD 8.58 (s, 1H), 8.12 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.64 (s, 1H), 7.59 (s, 1H), 7.55 (m, 3H), 6.60 (d, J = 16.0 Hz, 1H), 6.40 (dd, J =16.0, 8.0 Hz, 1H), 4.22 (m, 1H)
290
DC20 427.0463 (427.0466 ) 8.58 (s, 1H), 8.15 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.36 (s, 2H), 6.62 (d, J =16.0 Hz, 1H), 6.43 (dd, J= 16.0, 8.0 Hz, 1H), 4.12 (m, 1H), 3.88 (s, 3H) 2937, 1524, 1482, 1278, 1249, 1166, 1112
DC21 412.04 ([M+HD 8.42 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.40 (s, 1H), 7.22 (s, 2H), 6.60 (d, J =16.0 Hz, 1H), 6.42 (dd, J =16.0, 8.0 Hz, 1H), 4.15 (m, 1H), 2.5 (s, 3H) 3108, 1572, 1531, 1242, 1172, 1104
DC22 147- 149 441.01 ([M-H]') 8.62 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.40 (s, 1H), 7.30 (s, 2H), 6.67 (d, J= 16.0 Hz, 1H), 6.48 (dd, J= 16.0, 8.0 Hz, 1H), 4.15 (m, 1H)
DC23 412.05 ([M+HD 7.95 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.39 (s, 1H), 7.29 (s, 2H), 6.67 (d, J= 16.0 Hz, 1H), 6.45 (dd, J= 16.0, 8.0 Hz, 1H), 4.12 (m, 1H), 2.51 (s, 3H) 1112, 799
291
DC24 133- 134 440.03 ([M+HD 8.10 (s, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.42-7.38 (m, 3H), 7.28 (s, 2H), 6.67 (d, J = 16.0 Hz, 1H), 6.45 (dd, J =16.0, 8.0 Hz, 1H), 4.16 (m, 1H), 2.79 (s, 3H)
DC25 442.02 ([M-H]’) 7.97 (s, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.38 (m, 1H), 7.29 (s, 2H), 6.65 (d, J =16.0 Hz, 1H), 6.42 (dd, J =16.0, 8.0 Hz, 1H), 4.17 (m, 1H), 2.74 (s, 3H) 1167, 1114, 800
DC26 464.03 ([M-H]') 8.12 (s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.40-7.37 (m 3H), 7.28 (s, 2H), 6.66 (d, J= 16.0 Hz, 1H), 6.44 (dd, J= 16.0, 8.0 Hz, 1H), 4.14 (m, 1H), 3.22 (m, 1H), 1.09 -1.16(m, 4H) 1689, 1253, 1166, 1114, 979, 964
DC27 473.94 ([M-H]’) 8.19 (s, 1H), 7.64 (d, J = 7.2 Hz, 2H), 7.55 (d, 7.2 Hz, 2H), 7.39 (s, 1H), 7.30 (s, 2H), 6.62 (d, J = 16.0 Hz, 1 H), 6.42 (dd, J =8.0, 16.0 Hz, 1H), 4.18 (m, 1H), 3.58 (s, 3H) 1571, 1331, 1170, 1113, 764
292
DC28 421.22 ([M+HD 8.79 (s, 1H), 8.18 (s, 1H), 7.80 (m, 3H), 7.52 (m, 2H), 7.24 (m, 1H), 6.63 (d, J= 16.0 Hz, 1H), 6.54 (d, J= 16.0, 7.6 Hz, 1H), 4.19 (m, 1H) 3126, 2233, 1516, 1250, 1165, 1109
DC29 421.22 ([M+HD 8.80 (s, 1H), 8.2 (s, 1H), 7.75-7.82 (m, 3H), 7.41 (t, J=2Hz, 1H), 7.26 (m, 2H), 6.65 (d, J = 16.0 Hz, 1H), 6.52 (dd, J =16.0, 7.6 Hz, 1H), 4.16 (m, 1H) 3005, 1716, 1363, 1223
DC30 489.17 ([M+HD 8.81 (s, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.85 (m, 3H), 7.79 (m, 2H), 6.70 (d, J= 16.0 Hz, 1H), 6.58 (dd, J =16.0, 8.0 Hz, 1H), 4.35 (m, 1H) 2964, 2234, 1289, 1166, 1136
DC31 117- 118 455.27 ([M+HD 8.80 (s, 1H), 8.20 (s, 1H), 7.82 (m, 3H), 7.4 (s, 2H), 6.62 (d, J =16.0 Hz, 1H), 6.52 (dd, J = 16.0, 8.0 Hz, 1H), 4.18 (m, 1H)
293
DC32 388.0705 (388.0703 ) 8.82 (s, 1H), 8.22 (s, 1H), 7.82-7.78 (m, 3H), 7.38-7.30 (m, 3H), 6.62 (d, J = 16.1 Hz, 1H), 6.56 (dd, J= 16.1,6.8 Hz, 1H), 4.18 (m, 1H) 3126, 2234, 1520, 1280, 1164, 1112
DC33 455.22 ([M-H]) 8.80 (s, 1H), 8.20 (s, 1H), 7.82-7.80 (m, 3H), 7.70-7.50 (m, 3H), 6.65 (d, J = 16.9 Hz, 1H), 6.54 (dd, J= 16.9, 6.8 Hz, 1H), 4.25 (m, 1H) 3122, 3086, 2234, 1517, 1327, 1168, 1113
DC34 452.0412 (452.0419 ) 8.85 (s, 1H), 8.23 (brs, 1H), 7.83-7.78 (m, 3H), 7.33 (s, 2H), 6.69 (d, J = 14.9 Hz, 1H), 6.50 (dd, J = 14.9, 7.2 Hz, 1H), 4.15 (m, 1H), 3.90 (s, 3H) 3122, 2934, 2231, 1516, 1480, 1248, 1211, 1165, 1111
DC35 439.01 ([M-H]') 8.60 (s, 1H), 8.20 (s, 1H), 7.82 (m, 3H), 7.28 (m, 2H), 6.65 (d, J = 16.0 Hz, 1H), 6.48 (dd, J = 16.0, 8.0 Hz, 1H), 4.20 (m, 1H) 2233, 1518, 1250, 1169, 1035, 817
DC36 437.25 ([M+HD 8.70 (s, 1H), 7.80 (m, 3H), 7.40 (s, 1H), 7.28 (s, 2H), 6.63 (d, J =16.0 Hz, 1 H), 6.50 (dd, J = 16.0, 8.0 Hz, 1H), 4.18 (m, 1 H), 2.50 (s, 1H) 2927, 2233, 1572, 1531, 1248, 1166, 1112
294
DC37 109- 111 466.10 ([M-H]) 8.86 (s, 1H), 7.89 (m, 3H), 7.40 (s, 1H), 7.30 (s, 2H), 6.68 (d, J =16.0 Hz, 1H), 6.57 (dd, J = 16.0, 8.0 Hz, 1H), 4.18 (m, 1H)
DC38 96-98 436.11 ([M-H]') 8.58 (s, 1H), 7.75 (m, 3H), 7.40 (s, 1H), 7.28 (s, 2H), 6.61 (d, J= 16.0 Hz, 1H), 6.42 (dd, J = 16.0, 8.2 Hz, 1H), 4.40 (brs, 2H), 4.15 (m, 1H)
DC39 224- 226 480.30 ([M+HD 8.65 (s, 1H), 8.18 (brs, 1H), 7.80-7.70 (m, 3H), 7.40 (s, 1H), 7.27 (s, 2H), 7.36 (m, 1H), 7.28 (m, 2H), 6.60 (d, J = 16.8 Hz, 1H), 6.47 (m, 1H), 4.16 (m, 1H), 2.40 (brs, 3H) 3352, 2237, 1707, 1163, 841
DC40 70-73 436.11 ([M-2H]-) 8.86 (s, 1H), 7.88 (m, 3H), 7.44 (s, 2H), 6.67 (d, J= 16.0 Hz, 1H), 6.56 (dd, J= 16.0 7.6 Hz, 1H), 4.19 (m, 1H)
295
DC41 72-75 469.95 ([M-H]-) (DMSO-d6) 8.72 (s, 1H), 8.26 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.91 (s, 2H), 7.77 (d, J =8.4 Hz, 1H), 6.42 (dd, J= 15.6, 9.2 Hz, 1H), 6.83 (d, J = 15.6 Hz, 1H), 5.87 (s, 2H), 4.89 (m, 1H)
DC42 104- 107 609.98 ([M+HD 8.78 (s, 2H), 7.83 (s, 1H), 7.80 (m, 2H), 7.42 (s, 2H), 6.65 (d, J =16.4 Hz, 1H), 6.51 (dd, J = 16.4, 7.8 Hz, 1H), 4.17 (m, 1H), 4 2.16 (m, 2H), 1.25 (m, 4H), 1.00 (m, 4H), 2234, 1714, 1114, 807
DC43 109- 112 540.04 ([M+HD (DMSO-d6) 10.94 (br s, 1H), 8.36 (s, 1H), 8.08 (m, J =8.4 Hz, 1H), 7.91 (s, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.13 (dd, J = 15.6, 9.2 Hz, 1H), 6.87 (d, J= 15.6 Hz, 1H), 4.92 (m, 1H), 1.99 (brs, 1H), 0.82 (s, 4H) 3233, 2233, 1699, 1114, 807
296
DC44 435.26 [M-H]' 8.33 (s, 1H), 8.23 (s, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.41 (m, 1H), 7.28 (m, 2H), 6.62 (d, J = 16.0 Hz, 1H), 6.51 (dd, J = 16.0, 7.8 Hz, 1H), 4.16 (m, 1H), 2.20 (s, 3H) 2236,1510, 1114, 801
DC45 75-78 468.87 [M-H]' 8.36 (s, 1H), 8.23 (s, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.41 (s, 2H), 6.62 (d, J =16.4 Hz, 1H), 6.51 (dd, J= 16.4, 7.6 Hz, 1H), 4.16 (m, 1H), 2.20 (s, 3H)
DC46 411.4 ([MD 8.83 (s, 1H), 8.21 (s, 1H), 7.83 (d, J =8.5 Hz, 1H), 7.61 (d, J= 1.9 Hz, 1H), 7.52 (dd, J = 8.4, I. 9 Hz, 1H), 7.28 (d, J = 3.8 Hz, 2H), 6.93 (d, J = II. 5 Hz, 1H), 6.26- 6.20 (m, 1H), 4.22 (m, 1H) 13C NMR(Q)3 155.63, 153.27, 153.12, 143.01, 137.89, 136.25, 134.03, 133.88, 132.23, 131.23, 131.18, 129.20, 126.17, 125.04, 124.99
297
DC47 139- 141 474.16 ([M-H]') 8.51 (s, 1H), 8.14 (s, 1H), 7.75 (s, 1H), 7.5 (m, 2H), 7.4 (s, 1H), 7.30 (m, 2H), 6.60 (d, J = 16.0 Hz, 1H), 6.50 (dd,J= 16.0, 8.0 Hz, 1H), 4.15 (m, 1H)
DC48 124- 126 414.05 [M-H]’ 8.69 (s, 1H), 8.14 (s, 1H), 7.96 (d, J = 4.8 Hz, 1H), 7.39-7.27 (m, 5H), 6.95 (d, J =16.0 Hz, 1H), 6.51 (dd, J= 16.0, 7.6 Hz, 1H), 4.13 (m, 1H)
DC49 81-83 463.96 [M-H]’ 8.57 (s, 1H), 8.14 (s, 1H), 7.60 (m, 2H), 7.44 (m, 3H), 6.95 (d, J = 16.0 Hz, 1H), 6.51 (dd, J = 16.0, 7.6 Hz, 1H), 4.13 (m, 1H)
DC50 140- 143 430.07 [M-H]') 8.56 (s, 1H), 8.13 (s, 1H), 7.59 (d, J =1.2 Hz, 2H), 7.44 (m, 2H), 7.28 (m, 2H), 6.61 (d, J = 16.0 Hz, 1H), 6.47 (dd, J = 16.0, 8.0 Hz, 1H), 4.15 (m, 1H) 1110, 803
298
DC51 118- 121 464.22 ([M-H]) 8.32 (s, 1H), 8.15 (s, 1H), 7.82 (s, 1H), 7.73 (d, J =8.4 Hz, 1H), 7.53 (d, J =8.4 Hz, 1H), 7.41 (s, 1H), 7.29 (s, 2H), 6.70 (d, J= 15.6 Hz, 1H), 6.50 (dd, J =15.6, 8.0 Hz, 1H), 4.20 (m, 1H)
DC52 9.99 (s, 1H), 8.42 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.68 (m, 1H), 7.44 (m, 1H), 7.33 (m, 1H), 7.22 (s, 2H), 6.62 (d, J= 16.7 Hz, 1H), 6.45 (dd, J =16.7, 9.3 Hz, 1H), 4.10 (m, 1H) 3123, 3079, 2925, 1692, 1571, 1512, 1253, 1164, 1111
DC53 8.30 (m, 1H), 8.00 (brs, 1H), 7.75 (m, 1 H),7.68 (m, 1H), 7.55 (m, 1H), 7.36 (m, 1H), 7.28 (m, 2H), 6.70 (m, 1H), 6.58 (brs, 1H), 6.33 (m, 1H), 5.88 (m, 2H), 4.10 (m, 1H) 3250, 3043, 1683, 1116
299
DC54 56-58 441.07 ([M-H]-) 8.40 (s, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.76 (d, J =8.4 Hz, 1H), 7.59 (d, J= 8.0 Hz, 1H), 7.4 (s, 1H), 7.29 (m, 2H), 6.69 (d, J= 15.6 Hz, 1H), 6.57 (dd, J= 15.6, 7.8 Hz, 1H), 4.15 (m, 1H)
DC55 412.97 ([M+HD 8.37 (s, 1H), 8.18 (s, 1H), 7.39 (s, 1H), 7.30 (m, 2H), 7.19 (d, J =8.0 Hz, 1H), 6.90 (m, 2H), 6.55 (d, J= 15.6 Hz, 1H), 6.38 (dd, J= 15.6, 8.2 Hz, 1H), 4.20 (m, 1H), 2.50 (br s, 2H)
DC56 175- 177 453 ([M-H]') 9.59 (brs, 1H), 8.55 (s, 1H), 8.47 (s, 2H), 8.23 (s, 1H), 7.30 (m, 4H), 6.62 (d, J = 16.0 Hz, 1H), 6.40 (dd, J =16.0, 8.0 Hz, 1H), 4.15 (m, 1H), 2.20 (s, 3H)
300
DC57 426.0627 (426.0626 ) 8.33 (s, 1H), 8.16 (s, 1H), 7.38 (s, 1H), 7.29 (s, 2H), 7.15 (d, J = 7.6 Hz, 1H), 6.80 (d, J =7.6 Hz, 1H), 6.74 (m, 1H), 6.60 (d, J =15.6 Hz, 1H), 6.35 (dd, J =15.6, 8.4 Hz, 1H), 5.40 (brs, 1H), 4.15 (m, 1H), 2.90 (s, 3H) 3342, 3112, 2931, 1606, 1583, 1574, 1528, 1153
DC58 94-97 440.0424 (440.0419 (DMSO-d6) 8.76 (s, 1H), 8.16 (s, 1H), 7.90 (brs, 1H), 7.83 (s, 1H), 7.70 (d, J= 7.9 Hz, 1H), 7.71-7.67 (m, 3H), 7.58 (d, J =7.9 Hz, 1H), 7.52 (brs, 1H), 7.00 (dd, J = 15.8,8.7 Hz, 1H), 6.85 (d, J= 15.8 Hz, 1H), 4.85 (m, 1H) 3403, 3304, 3178, 1674, 1571, 1169, 1108
DC59 87-90 (DMSO-d6) 9.00 (s, 1H), 8.63 (s, 1H), 8.17 (s, 1H), 7.70-7.59 (m, 5H), 7.00 (dd, J= 16.2, 9.7 Hz, 1H), 6.85 (d, J = 16.2 Hz, 1H), 5.90 (brs 2H), 4.83 (m, 1H)
301
DC60 469.0577 (469.0572 ) 8.32 (s, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.47 (d, J =8.1 Hz, 1H), 7.40 (m, 1H), 7.28 (s, 2H), 6.62 (d, J = 16.5 Hz, 1H), 6.49 (dd, J =16.5, 7.7 Hz, 1H), 4.23-4.04 (m, 3H), 1.15 (t, J = 8.0 Hz, 3H) 2987, 1725, 1518, 1275, 1166,1113
DC61 130— 132 442.15 ([M+Hf) (DMSO-d6) 9.90 (s, 1H), 8.17 (s, 1H), 8.15 (m, 1H), 7.90 (m, 1H), 7.71 (m, 2H), 7.67 (m, 1H), 7.62 (d, J= 7.3 Hz, 1H), 7.03 (dd, J =16.5, 8.3 Hz, 1H), 6.62 (d, J = 16.5 Hz, 1H), 4.87 (m, 1H)
DC62 412.10 ([M+Hf) 8.27 (s, 1H), 8.23 (s, 1H), 7.40 (m, 3H), 7.30 (m, 3H), 6.64 (d, J = 16.0 Hz, 1H), 6.45 (dd, J = 16.0, 8.0 Hz, 1H), 4.19 (m, 1H), 2.21 (s, 3H) 1513, 1252, 1166, 1112, 801
302
DC63 446.01 ([M+HD 8.26 (s, 1H), 8.12 (s, 1H), 7.42 (s, 2H), 7.18- 7.28 (m, 3H), 6.62 (d, J = 15.6 Hz, 1H), 6.39 (dd, J= 15.6, 9.4 Hz, 1H), 4.10 (m, 1H), 2.25 (s, 3H) 2928, 2525,1249, 1169, 1114, 809
DC64 475.03 ([M+HD 8.84 (d, J =5.8 Hz, 2H), 8.33 (s, 1H), 8.20 (s, 1H), 7.75 (m, 1H), 7.60 (d, J =28.6 Hz, 1H), 7.58-7.48 (m, 3H), 7.42 (m, 1H), 7.28 (s, 2H), 6.71 (d, J = 16.9 Hz, 1H), 6.39 (dd, J= 16.9, 8.2 Hz, 1H), 4.15 (m, 1H) 1683, 1167, 650, 479
DC65 412.05 ([M+HD 8.55 (s, 1H), 8.12 (s, 1H), 7.55 (m, 3H), 7.39 (m, 1H), 7.30 (d, J= 1.6 Hz, 1H), 6.85 (d, J = 16.0 Hz, 1H), 6.41 (dd, J = 16.0, 8.0 Hz, 1H), 4.17 (m, 1H), 2.40 (s, 3H) 722,111
303
DC66 60-61 468.26 ([M+HD 8.59 (s, 1H), 8.14 (s, 1H), 7.94 (s, 1H), 7.70 (d, J =8.0 Hz, 1H), 7.61 (d, J =8.0 Hz, 1H), 7.43 (s, 2H), 7.23 (d, J= 16.0 Hz, 1H), 6.41 (dd, J = 16.0, 8.0 Hz, 1 H), 4.20 (m, 1H)
DC67 133- 134 432.30 ([M+HD 8.59 (s, 1H), 8.12 (s, 1H), 7.78 (brs, 1H), 7.71 (m, 1H), 7.62 (m, 1H), 7.39 (s, 1H), 7.32 (s, 2H), 7.03 (d, J= 16.0 Hz, 1H), 6.43 (dd, J = 16.0, 8.0 Hz, 1H), 0.21 (m, 1H) 800, 114
DC68 412.03 ([M+HD 8.71 (s, 1H), 8.18 (s, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.55 (d, J =8.0 Hz, 2H), 7.37 (s, 1H), 7.28 (m, 2H), 6.08 (d, J = 16.0 Hz, 1H), 4.26 (m, 1H), 2.05 (s, 3H)
DC69 162- 168 414.03 ([M+HD 8.56 (s, 1H), 8.11 (s, 1H), 7.70 (d, J =8.5 Hz, 2H), 7.56 (d, J =8.5 Hz, 2H), 7.54 (m, 2H), 7.40 (m, 1H), 6.91 (d, J = 16.5 Hz, 1H), 6.66 (d, J = 16.5 Hz, 1H)
304
DC70 99- 103 428.05 ([M+HD 8.58 (s, 1H), 8.13 (s, 1H), 7.73 (d, J =8.7 Hz, 2H), 7.60 (d, J =8.7 Hz, 2H), 7.46 (m, 2H), 7.42 (m, 1H), 6.85 (d, J = 16.2 Hz, 1H), 6.40 (d, J = 16.2 Hz, 1H), 3.42 (s, 3H)
11H NMR spectral data were acquired using a 400 MHz instrument in CDCI3 except where noted. HRMS data are noted observed value (theoretical value).
305
Table 3: Assays Results
Compound BAW CEW GPA
Number Rating Rating Rating
AC1 D D B
AC2 C C C
AC3 D D B
AC4 D A B
AC5 D D B
AC6 D A B
AC7 A A B
AC8 D B B
AC9 A A B
AC10 A A B
AC11 A A D
AC12 A A D
AC13 A A B
AC14 A B D
AC15 A A B
AC16 A A C
AC17 A A B
AC18 A A B
AC19 D D B
AC20 A A C
AC21 D D C
AC 22 A A D
AC23 A A B
306
Compound BAW CEW GPA
Number Rating Rating Rating
AC24 A A D
AC25 A A D
AC26 A A B
AC27 A A B
AC28 A A B
AC29 A A B
AC30 A A B
AC31 A A B
AC32 A A B
AC33 A A B
AC34 A A B
AC35 A A C
AC36 A A B
AC37 A A B
AC38 A A C
AC39 A A C
AC40 A A D
AC41 A D D
AC42 A D D
AC43 A A B
AC44 A A B
AC45 A A D
AC46 A A D
AC47 D D B
307
Compound BAW CEW GPA
Number Rating Rating Rating
AC48 A A B
AC49 A A B
AC50 A D B
AC51 A A B
AC 52 A A B
AC53 A A B
AC 54 A A B
AC57 A A B
AC 58 A A B
AC59 A A B
AC60 A A B
AC61 A A B
AC 62 A A D
AC63 A A B
AC64 A A B
AC65 A A B
AC66 A A B
AC67 A A B
AC68 A A D
AC69 A A A
AC70 D D B
AC71 A A B
AC72 A A B
AC75 A A B
308
Compound BAW CEW GPA
Number Rating Rating Rating
AC76 A A D
AC77 A A B
AC78 A A A
AC79 A A A
AC80 A A B
AC81 A D D
AC 82 A A B
AC83 A A B
AC84 A A D
AC85 A A B
AC86 A A D
AC87 A A B
AC89 A A B
AC90 A A C
AC91 A A C
AC92 A A C
AC93 A D C
AC94 D B B
AC95 A A C
AC96 D D C
AC97 D D C
AC98 A A C
AC99 A A C
AC 100 C C C
309
Compound BAW CEW GPA
Number Rating Rating Rating
AC101 D D C
AC 102 D A C
AC103 A A D
AC 104 A A B
AC105 A A D
AC 106 A A B
AC107 B A D
AC 108 B D D
AC109 D D C
AC110 A A C
AC111 A A C
AC112 A A C
AC113 B A D
AC114 A B D
AC115 A A D
AC116 C C C
AC117 A D B
AC118 A D D
BC1 A A D
BC2 A A D
BC3 A A D
BC4 A A B
BC5 A A B
BC6 A A D
310
Compound BAW CEW GPA
Number Rating Rating Rating
BC7 A A D
BC8 A A B
BC9 A A D
BC10 A A B
BC11 C C C
BC12 C C C
BC13 A A D
BC14 A D D
CC1 D D D
CC2 A A B
CC3 A A D
CC4 A B B
CC5 A A B
CC6 A A B
CC7 A A B
CC8 A A D
CC9 A A B
CC10 A A B
CC11 A A B
CC12 D D B
CC13 A A B
CC14 A D D
CC15 A A B
CC16 A A B
311
Compound BAW CEW GPA
Number Rating Rating Rating
CC17 A A B
CC18 A A B
CC19 A A B
CC20 A A D
CC21 A A D
CC22 A A B
CC23 A A B
CC24 A A D
CC25 A A B
CC26 A D B
CC27 A A D
CC28 A A D
CC29 A A B
CC30 A A D
CC31 B D C
CC32 A A B
CC33 A A B
CC34 A A B
CC35 D D D
CC36 A A D
CC37 A A D
CC38 A A D
CC39 D D B
CC40 D A D
312
Compound BAW CEW GPA
Number Rating Rating Rating
CC41 D D B
CC42 D D D
CC43 A B B
CC44 A A B
CC45 A A D
CC46 D A C
CC47 D D C
CC48 D D C
CC49 D D D
CC50 A A D
CC51 A A D
CC52 A D D
CC53 D D B
CC54 A A C
DC1 A A D
DC2 D D C
DC3 B D C
DC4 A D C
DC5 D D C
DC6 D D C
DC7 A D C
DC8 A D C
DC9 D D C
DC10 D D C
313
Compound BAW CEW GPA
Number Rating Rating Rating
DC11 A D C
DC12 A A B
DC13 A A C
DC14 D D C
DC15 D D C
DC16 A A C
DC17 A A C
DC18 A A C
DC19 A A C
DC20 A D C
DC21 D D C
DC22 D D C
DC23 D A C
DC24 D D C
DC25 D D C
DC26 D D C
DC27 D D C
DC28 A A B
DC29 A A C
DC30 A A C
DC31 A A B
DC32 D D C
DC33 A A C
DC34 A A B
314
Compound BAW CEW GPA
Number Rating Rating Rating
DC35 A A B
DC36 D D C
DC37 A A C
DC38 A A C
DC39 A A C
DC40 A A C
DC41 A A C
DC42 A A C
DC43 A A C
DC44 A A C
DC45 A A C
DC46 A A C
DC47 A A C
DC48 A A C
DC49 A A C
DC50 A A C
DC51 A A C
DC52 D D C
DC53 D A C
DC54 D D C
DC55 D D C
DC56 D D C
DC57 A A C
DC58 D D C
315
Compound BAW CEW GPA
Number Rating Rating Rating
DC59 D D C
DC60 A A C
DC61 D D C
DC62 A A C
DC63 A A C
DC64 D D C
DC65 D A C
DC66 A A C
DC67 A A C
DC68 A A C
DC69 D D C
DC70 A A C
316
ABSTRACT OF THE DISCLOSURE
This document discloses molécules having the following formula (“Formula One”):
RIO
Rll
Formula One and processes associated therewith.

Claims (15)

  1. NEW CLAIMS
    1. A composition comprising a molécule according to Formula One:
    Formula One wherein:
    (a) R1 is selected from (1) H, F, Cl, Br, I, CN, NO2, (CrCeJalkyl, halofCrCfOalkyl, (Cr C8)alkoxy, halo/CrCgjalkoxy, S(CrC8)alkyl, S(halo(C1-C8)alkyl), S(OXCi-C8)alkyl,
    10 SiOXhalofCrCeJalkyl), SiO^CrCsJalkyl, SiOHhaloiCrCeJalkyl), N(R14XR15), (2) substituted (CrC8)alkyl, wherein said substituted (C^C^alkyl has one or more substituents selected from CN and NO2, (3) substituted halo(CrC8)alkyl, wherein said substituted halo(CiC8)alkyl, has one or more substituents selected from CN and NO2,
    15 (4) substituted (Ci-C8)alkoxy, wherein said substituted (C^Csjalkoxy has one or more substituents selected from CN and NO2, and (5) substituted halo(CrC8)alkoxy, wherein said substituted halo(CiC8)alkoxy has one or more substituents selected from CN and NO2;
    (b) R2 is selected from
    20 (1) H, F, Cl, Br, I, CN, NO2, (CrC8)alkyl, halo(Ci-C8)alkyl, (Cr
    C8)alkoxy, halo(C1-C8)alkoxy, S(CrC8)alkyl, S(halo(CrC8)alkyl), S(OXCrC8)alkyl, S(OXhalo(CrC8)alkyl), S(O)2(CrC8)alkyl, S(O)2(halo(CrC8)alkyl), N(R14XR15), (2) substituted (CrC8)alkyl, wherein said substituted (C^C^alkyl has one or more substituents selected from CN and NO2,
    25 (3) substituted halo(CrC8)alkyl, wherein said substituted halo(CiC8)alkyl, has one or more substituents selected from CN and NO2, (4) substituted (Ci-C8)alkoxy, wherein said substituted (C!-C8)alkoxy has one or more substituents selected from CN and NO2, and
    318 (5) substituted halo(CrC8)alkoxy, wherein said substituted halo(CiC8)alkoxy has one or more substituents selected from CN and NO2;
    (c) R3 is selected from (1) H, F, Cl, Br, I, CN, NO2, (Ci-C8)alkyl, haloiCrCeJalkyl, (Cr C8)alkoxy, halo(C1-C8)alkoxy, S(Ci-C8)alkyl, SihaloiCrCsJalkyl), S(OXCrC8)alkyl, SiOXhaloiCrCeJalkyl), SiOHC^Cgjalkyl, SiOMhaloiCrCejalkyl), N(R14XR15), (2) substituted (CrC8)alkyl, wherein said substituted (CrC8)alkyl has one or more substituents selected from CN and NO2, (3) substituted halo(CrC8)alkyl, wherein said substituted halo(CiC8)alkyl, has one or more substituents selected from CN and NO2, (4) substituted (CrC8)alkoxy, wherein said substituted (CvCgjalkoxy has one or more substituents selected from CN and NO2, and (5) substituted halofCrCsjalkoxy, wherein said substituted halo(Cr C8)alkoxy has one or more substituents selected from CN and NO2;
    (d) R4 is selected from (1) H, F, Cl, Br, I, CN, NO2, (CrCeJalkyl, halo(CrC8)alkyl, (Cr C8)alkoxy, haloCCT-Csjalkoxy, SiCrCsjalkyl, SChalo^-CgJalkyl), S(OXCi-C8)alkyl, S(OXhalo(CrC8)alkyl), S(O)2(C1-C8)alkyl, S(O)2(halo(Ci-C8)alkyl), N(R14XR15), (2) substituted (Ci-C8)alkyl, wherein said substituted (CrC8)alkyl has one or more substituents selected from CN and NO2, (3) substituted halo(CrC8)alkyl, wherein said substituted halo(C1C8)alkyl, has one or more substituents selected from CN and NO2, (4) substituted (C-i-C8)alkoxy, wherein said substituted (CrC8)alkoxy has one or more substituents selected from CN and NO2, and (5) substituted halo(CrC8)alkoxy, wherein said substituted halo^C8)alkoxy has one or more substituents selected from CN and NO2;
    (e) R5 is selected from (1) H, F, Cl, Br, I, CN, NO2, (C1-C8)alkyl, halo(Ci-C8)alkyl, (Cr C8)alkoxy, halo(Ci-C8)alkoxy, S^-Cgjalkyl, SihaloiCrCsjalkyl), SiOXCi-CeJalkyl, S(OXhalo(CrC8)alkyl), StO^-C^alkyl, S(O)2(halo(Ci-C8)alkyl), N(R14XR15), (2) substituted (C1-C8)alkyl, wherein said substituted (CrCsjalkyl has one or more substituents selected from CN and NO2, (3) substituted haloiCrCeJalkyl, wherein said substituted halo(CT C8)alkyl, has one or more substituents selected from CN and NO2, (4) substituted (CrC8)alkoxy, wherein said substituted (Ci-C8)alkoxy has one or more substituents selected from CN and NO2, and
    3/0 (5) substituted halo(C1-C8)alkoxy, wherein said substituted halo(C!C8)alkoxy has one or more substituents selected from CN and NO2;
    (f) R6 is a (Ci-C8)haloalkyl;
    (g) R7 is selected from H, F, Cl, Br, I, OH, (Ci-C8)alkoxy, and halo(C-iC8)alkoxy;
    (h) R8 is selected from H, (Ci-C8)alkyl, halofCT-Csjalkyl, OR14, and N(R14)(R15);
    (i) R9 is selected from H, F, Cl, Br, I, (C-i-C8)alkyl, halo^-Csfolkyl, (Cr C8)alkoxy, halo(Ci-C8)alkoxy, OR14, and N(R14)(R15);
    (j) R10 is selected from (1) (u), H, F, Cl, Br, I, CN, NO2> (Ci-C8)alkyl, halo(CrC8)alkyl, (Cr C8)alkoxy, haloiCrCsjalkoxy, cyclo(C3-C6)alkyl, S(Ci-C8)alkyl, S(halo(Ci-C8)alkyl), SiOXCrCeJalkyl, S(O)(halo(Ci-C8)alkyl), SfOHCrC^alkyl, S(O)2(halo(Ci-C8)alkyl), NR14R15, C(=O)H, C(=O)N(R14)(R15), CN(R14)(R15)(=NOH), (C=O)O(CrC8)alkyl, (C=O)OH, heterocyclyl, (C2-C8)alkenyl, halo(C2-C8)alkenyl, (C2-C8)alkynyl, (2) substituted (CrC8)alkyl, wherein said substituted (CrCejalkyl has one or more substituents selected from OH, (Ci-C8)alkoxy, SfCrCsjalkyl, S(O)(Cr C8)alkyl, SiOXCrC^alkyl, NR14R15, and (3) substituted halo(C1-C8)alkyl, wherein said substituted halo(CiC8)alkyl, has one or more substituents selected from (CrC8)alkoxy, SiCi-Csjalkyl, S(O)(Ci-C8)alkyl, S(O)2(Ci-C8)alkyl, and N(R14)(R15);
    (k) R11 is selected from (u), substituted (Ci-C8)alkyl, C(=O)OH, C(=O)O(Cr C8)alkyl, C(=O)(substituted- (CrC8)alkyl), C(=O)O(substituted (Ci-C8)alkyl), C(=O)N(R14)(R15), C(=O)heterocyclyl, C(=O)(substituted heterocyclyl), C(=S)N(R14)(R15), C(=S)heterocyclyl, C(=S)(substituted heterocyclyl), (Cr C8)alkylN(R11a)(C(=X11)R11b), N(11a)(11d), ON(11c)(11d), halo(Ci-C8)alkyl, (Cr C8)alkyl, (Ci-C8)alkylN(H)(heterocyclyl), (CrC8)alkyl(N(R15))(0=0)0(0^8)3^1, (Cr C8)alkyl(R14)(R15), N(H)N(H)(heterocyclyl), B(OH)2, (CrC8)alkylN(R11a)(C(=X11)R14), (CrCejalkylNiR11 a)(C(=X11 )N(R14)(R15)), (CrCejalkylNiR11 a)(C(=X11 )0R14), substituted or unsubstituted heterocyclyl, C(=O)N(R14)(N(R16)(R17), C(=O)N(R14)((Cr C8)alkylC(=O)N(R14)N(R14)(R15)), C(=O)N(R14)((CrC8)alkylC(=O)N(R14)(R15)), C(=S)N(R14)((C1-C8)alkylC(=S)N(R14)(R15)), C(=S)N(R14)((CiC8)alky!C(=O)N(R14)(R15)), C(=O)N(R14)((CrC8)alkylC(=S)N(R14)(R15)), C(=O)N(R14)((C1-C8)alkylC(=O)(R15), (1) wherein each said substituted (CrC8)alkyl has one or more substituents selected from F, Cl, Br, I, CN, N02, aryl, substituted aryl, heterocyclyl,
    320 substituted heterocyclyl, wherein each said substituted aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C^Cejalkyl, halofCrCejalkyl, (C-i-Cajalkoxy, halo(C-iC8)alkoxy, SfCrCsjalkyl, S(halo(CrC8)alkyl), NftC^Csjalkyl);. (wherein each (CrC8)alkyl is independently selected), and oxo, (2) wherein each said substituted heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (C-i-C8)alkyl, halofC^Csjalkyl, (Cr C8)alkoxy, halo(CrC8)alkoxy, S(Ci-C8)alkyl, SfhaloiCrC^alkyl), N((CrC8)alkyl)2 (wherein each (CrC8)alkyl is independently selected), C(=O)(CrC8)alkyl, C(=O)(C3-C6)cycloalkyl, S(=O)2(C1-C8)alkyl, NR14R15, and oxo, (3) wherein R11a is selected from H, (Ci-C8)alkyl, and (CrC8)alkylheterocyclyl, R14, C(X11)R14, (C^C^alkylRU (4) wherein R11 b is selected from (CrC8)alkyl, cyclo(C3-C6)alkyl, halo(Ci-C8)alkyl, heterocyclyl, substituted-heterocyclyl (where said substituents are one or more of F, Cl, Br, I, CN, NO2, (Ci-C8)alkyl, halo(Ci-C8)alkyl, (CrC8)alkoxy, halotCr C8)alkoxy, S(Ci-C8)alkyl, SfhalofCi-Cejalkyl), NifCrCsjalkyl^ (wherein each (CrC8)alkyl is independently selected), and oxo), (C-i-CsjalkylSiCrCsjalkyl, (CrCejalkylSiOXCiC8)alkyl, (C-i-CsjalkylSfOMCrCsjalkyl, N(R11c)(R11d), O(Ci-C8)alkyl, Oheterocyclyl,
    O-substituted-heterocyclyl (where said substituents are one or more of F, Cl, Br, I, CN, NO2, (CrC8)alkyl, halofA-C^alkyl, (Ci-C8)alkoxy, halofCrCsjalkoxy, S(Ci-C8)alkyl, S(halo(Ci-C8)alkyl), NftCrCsjalkyl);? (wherein each (C^Csjalkyl is independently selected), and oxo), C(=O)OR11d, C(=O)N(R11c)(R11d), C(=O)(R11d)aryl, substituted aryl (where said substituents are one or more of F, Cl, Br, I, CN, NO2i(C1-C8)alkyl, halo(Ci-C8)alkyl, (CrCgjalkoxy, halo(C!-C8)alkoxy, SfCrCsjalkyl, SfhalofCrCsjalkyl), N((Ci-C8)alkyl)2 (wherein each (CrC8)alkyl is independently selected), (5) wherein X11 is O or S, (6) wherein R11 c is selected from H, (7) wherein R11d is selected from H, (Ci-C8)alkyl, (A-C^alkenyl, halo(Ci-C8)alkyl, heterocyclyl, substituted-heterocyclyl (where said substituents are one or more of F, Cl, Br, I, CN, NO2, (CrC^alkyl, halo(Ci-C8)alkyl, (Ci-C8)alkoxy, halo(Cr C8)alkoxy, S(CrC8)alkyl, SihalofCrCejalkyl), N((CrC8)alkyl)2 (wherein each (CrC^alkyl is independently selected), and oxo), N(H)(C(=O)cyclo(C3-C6)alkyl), N(H)(C(=0)halo(C1C8)alkyl), (8) wherein optionally R11 c and R11 d along with N form a 5, 6, 7, or 8 membered ring that may optionally further contain 1,2, or 3, additional heteroatoms selected from O, N, or S, in the ring;
    321 (l) R12 is selected from (v), H, F, Cl, Br, I, CN, (CrCeJalkyl, halo(Ci-C8)alkyl, (CvCsJalkoxy, haloiCrCsjalkoxy, and cyclo(C3-C6)alkyl;
    (m) R13 is selected from (v), H, F, Cl, Br, I, CN, (CrCeJalkyl, halo(C1-C8)alkyl, (CrCejalkoxy, and haloiCrCsjalkoxy;
    (n) each R14 is independently selected from H, (CrC8)alkyl, (C^Csjalkenyl, substituted (Ci-C8)alkyl, halo(CrC8)alkyl, substituted haloiCrCsjalkyl), (CrCsjalkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (CrCsjalkyl-aryl, (CrCsjalkyl-isubstituted-aryl), (□-(Ci-CsJalkyl-aryl, O-iCrCsjalkyl-isubstituted-aryl), heterocyclyl, substitutedheterocyclyl, (CrCsJalkyl-heterocyclyl, (Ci-C8)alkyl-(substituted-heterocyclyl), 0-(0^ C8)alkyl-heterocyclyl, O-(CrC8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (CrC8)alkylC(=O)N(R16)(R17), C^OXCrC^alkyl, C(=O)(halo(Ci-C8)alkyl),C(=O)(C3-C6)cycloalkyl, (CrC8)alkyl-C(=O)O(Ci-C8)alkyl, C(=O)H wherein each said substituted (Ci-C8)alkyl has one or more substituents selected from CN, and NO2, wherein each said substituted halo(CrC8)alkyl), has one or more substituents selected from CN, and NO2, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (Ci-C8)alkyl, halo(Ci-C8)alkyl, (CrCsjalkoxy, halo(CiC8)alkoxy, SiCrC^alkyl, S(halo(Ci-C8)alkyl), N((Ci-C8)alkyl)2 (wherein each (Ci-C8)alkyl is independently selected), and oxo, and wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (Ci-C8)alkyl, halo(CrC8)alkyl, (CrCejalkoxy, halo(CiC8)alkoxy, (C3-C6)cycloalkyl SiCrCsjalkyl, SihakXCrCejalkyl), NftCrCsjalkylk (wherein each (CrCejalkyl is independently selected), heterocyclyl, C(=O)(CrC8)alkyl, C(=O)O(CiC8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, Cl, Br, I, CN, and NO2);
    (o) each R15 is independently selected from H, (CrC8)alkyl, (C^Csjalkenyl, substituted (CrC8)alkyl, halo(Ci-C8)alkyl, substituted halo(Ci-C8)alkyl), (CrCsjalkoxy, cyclo(C3-C6)alkyl, aryl, substituted-aryl, (C^Cgjalkyl-aryl, (CrCeJalkyl-isubstituted-aryl), O-(Ci-C8)alkyl-aryl, O-(Ci-C8)alkyl-(substituted-aryl), heterocyclyl, substitutedheterocyclyl, (Ci-C8)alkyl-heterocyclyl, (CrCsjalkyHsubstituted-heterocyclyl), O-(CiC8)alkyl-heterocyclyl, O-(C1-C8)alkyl-(substituted-heterocyclyl), N(R16)(R17), (Ci-C8)alkylC(=O)N(R16)(R17), C(=O)(Ci-C8)alkyl, C(=O)(halo(C1-C8)alkyl), C(=O)(C3-C6)cycloalkyl, (C1-C8)alkyl-C(=O)O(C1-C8)alkyl, C(=O)H wherein each said substituted (CrC8)alkyl has one or more substituents selected from CN, and NO2,
    322 6 wherein each said substituted halofC! -C8)alkyl), has one or more substituents selected from CN, and NO2, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (Ci-C8)alkyl, halofCrC^alkyl, (CrCsjalkoxy, halo(CiC8)alkoxy, SfCrCsjalkyl, S(halo(C1-C8)alkyl), N((Ci-C8)alkyl)2 (wherein each (CrCejalkyl is independently selected), and oxo, and wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (CrC8)alkyl, halo(CrC8)alkyl, (Ci-C8)alkoxy, halo(C!C8)alkoxy, (C3-C6)cycloalkyl S(Ci-C8)alkyl, S(halo(C1-C8)alkyl), N((C1-C8)alkyl)2 (wherein each (CrCejalkyl is independently selected), heterocyclyl, C(=O)(C1-C8)alkyl, C(=O)O(C1C8)alkyl, and oxo, (wherein said alkyl, alkoxy, and heterocyclyl, may be further substituted with one or more of F, Cl, Br, I, CN, and NO2);
    (p) each R16 is independently selected from H, (Ci-C8)alkyl, substituted-fCr C8)alkyl, haloiCrCsjalkyl, substituted-halo(Ci-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substitutedaryl, (CrCsjalkyl-aryl, (CrC8)alkyl-(substituted-aryl), O-(CrC8)alkyl-aryl, O-(Ci-C8)alkyl(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (C^Csjalkyl-heterocyclyl, (Cr C8)alkyl-(substituted-heterocyclyl), O-(Ci-C8)alkyl-heterocyclyl, O-fC^Csjalkyl(substituted-heterocyclyl), O-(CrC8)alkyl wherein each said substituted (C^Csjalkyl has one or more substituents selected from CN, and NO2, wherein each said substituted halo(C1-C8)alkyl), has one or more substituents selected from CN, and NO2, wherein each said substituted-aryl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (CrC^alkyl, halo(Ci-C8)alkyl, (Ci-C8)alkoxy, halo(Cr C8)alkoxy, S(CrC8)alkyl, S(halo(Ci-C8)alkyl), NffC^Csjalkyl^ (wherein each (CrCsjalkyl is independently selected), and oxo, and wherein each said substituted-heterocyclyl has one or more substituents selected from F, Cl, Br, I, CN, NO2, (CrCsjalkyl, halo(Ci-C8)alkyl, (C^Cgjalkoxy, halo(Cr C8)alkoxy, SfCrCsjalkyl, SihaloiCrCgjalkyl), N((CrC8)alkyl)2 (wherein each (CrC^alkyl is independently selected), and oxo;
    (q) each R17 is independently selected from H, (CrCsjalkyl, substituted-(Cr C8)alkyl, halo(CrC8)alkyl, substituted-halo(Ci-C8)alkyl, cyclo(C3-C6)alkyl, aryl, substitutedaryl, (C-i-Cgjalkyl-aryl, (Ci-C8)alkyl-(substituted-aryl), O-fCrCsjalkyl-aryl, O-(C-|-C8)alkyl(substituted-aryl), heterocyclyl, substituted-heterocyclyl, (CTCejalkyl-heterocyclyl, (Cr C8)alkyl-(substituted-heterocyclyl), O-(CrC8)alkyl-heterocyclyl, O-(Ci-C8)alkyl(substituted-heterocyclyl), O-iCrCsjalkyl
    323 wherein each said substituted (CrCsjalkyl has one or more substituents seiected from CN, and NO2, wherein each said substituted haloiCi-Csjalkyl), has one or more substituents seiected from CN, and NO2, wherein each said substituted-aryl has one or more substituents seiected from F, Cl, Br, I, CN, NO2, (CrC8)alkyl, halo(Ci-C8)alkyl, (CrCejalkoxy, halo(Cr C8)alkoxy, SiCrC^alkyl, S(halo(CrC8)alkyl), N((C1-C8)alkyl)2 (wherein each (CrC8)alkyl is independently seiected), and oxo, and wherein each said substituted-heterocyclyl has one or more substituents seiected from F, Cl, Br, I, CN, NO2, (Ci-C8)alkyl, halo(CrC8)alkyl, (CrCsjalkoxy, halo(C-iC8)alkoxy, S(CrC8)alkyl, SihakXCrCsjalkyl), N((C1-C8)alkyl)2 (wherein each (CrCsjalkyl is independently seiected), and oxo;
    (r) X1 is seiected from N and CR12;
    (s) X2 is seiected from N, CR9, and CR13;
    (t) X3 is seiected from N and CR9;
    (u) R10 and R11 together form a linkage containing 3 to 4 atoms seiected from C, N, O, and S, wherein said linkage connects back to the ring to form a 5 to 6 member saturated or unsaturated cyclic ring, wherein said linkage has at least one substituent X4 wherein X4 is seiected from F, Cl, Br, I, R14, N(R14)(R15), N(R14)(C(=O)R14), N(R14)(C(=S)R14), N(R14)(C(=O)N(R14)(R14)),
    N(R14)(C(=S)N(R14)(R14)), N(R14)(C(=O)N(R14)((C1-C8)alkenyl)), N(R14)(C(=S)N(R14)((C1-C8)alkenyl)), oxo, C(=O)(C1-C8)alkylN(R14)(R14), (Cr C8)alkylC(=O)N(R14)R(15), wherein each R14 is independently seiected;
    (v) R12 and R13 together form a linkage containing 3 to 4 atoms seiected from C, N, O, and S, wherein said linkage connects back to the ring to form a 5 to 6 member saturated or unsaturated cyclic ring, wherein said linkage has at least one substituent X4 wherein X4 is seiected from R14, N(R14)(R15), N(R14)(C(=O)R14), N(R14)(C(=S)R14), N(R14)(C(=O)N(R14)(R14)), N(R14)(C(=S)N(R14)(R14)),
    N(R14)(C(=O)N(R14)((C1-C8)alkenyl)), N(R14)(C(=S)N(R14)((C1-C8)alkenyl)), wherein each R14 is independently seiected.
  2. 2. A molécule according to claim 1 wherein
    R1 is seiected from H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C8)alkyl, (C4)alkyl, (Cs)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy,
    324 (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy, preferably from Cl and H,
    R2 is selected from H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy, preferably from CF3, CH3, Cl, F, and H,
    R3 is selected from H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy, preferably from OCH3, CH3, F, Cl, or H,
    R4 is selected from H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy, preferably from CF3, CH3, Cl, F, and H,
    R5 is selected from H, F, Cl, Br, I, CN, NO2, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy, preferably from F, Cl, and H,
    R2 and R4 are selected from F, Cl, Br, I, CN, and NO2 and R1, R3, and R5 are H, R2, R3, and R4 are selected from F, Cl, Br, I, CN, and NO2 and R1, and R5 are H, preferably wherein R2, R3, and R4 are independently selected from F and Cl and R1and R5 are H,
    325
    R6 is selected from halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, and halo(C8)alkyl, and preferably is trifluoromethyl,
    R7 is selected from H, F, Cl, Br, I, OCH3, and OH,
    R8 is selected from H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, and halo(C8)alkyl, preferably from CH3 and H,
    R9 is selected from H, F, Cl, Br, I, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy,
    R10 is selected from Br, C(=NOH)NH2, C(=O)H, C(=O)NH2, C(=O)OCH2CH3, C(=O)OH, CF3, CH2CH3, CH2OH, CH3, Cl, CN, F, H, NH2, NHC(=O)H, NHCH3, NO2, OCH3> OCHF2, and pyridyl or from H, F, Cl, Br, I, CN, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methoxy, ethoxy, (C3)alkoxy, (C4)alkoxy, (C5)alkoxy, (C6)alkoxy, (C7)alkoxy, (C8)alkoxy, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, halo(C8)alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, preferably from H, Cl, Br, CH3, and CF3,
    R11 is selected from C(=O)(substituted- (Ci-C8)alkyl), C(=O)N(R14)(R15), C(=O)heterocyclyl, and C(=O)(substituted-heterocyclyl), and preferably is C(=O)morpholinyl, or is selected from CH2N(H)C(=O)CH3, CH2N(H)C(=0)cyclopropyl, CH2N(H)C(=O)CH2CF3, CH2N(H)C(=O)CH2CH3, CH2N(H)C(=O)C(CH3)3, CH2N(H)C(=O)(chloropyridyl), CH2N(H)C(=O)CH2(chloropyridyl), CH2N(H)C(=O)CH2CH2SCH3, N(H)C(=O)(pyridyl), CH2N(CH2pyridyl)C(=O)cyclopropyl, CH2N(H)C(=O)N(H)(CH2CH3), CH2N(H)C(=O)morpholinyl, CH2N(H)C(=O)N(H)(pyridyl), CH2N(H)C(=O)NH2, CH2N(H)C(=O)NH(CH2CH3), CH2N(H)C(=O)NH(CH2CHCH2), CH2N(H)C(=O)OC(CH3)3, CH2N(H)C(=O)O(chlorophenyl), CH2N(H)C(=O)(C=O)OCH3, CH2N(H)C(=O)(C=O)N(H)CH2CF3, CH2N(H)(pyridyl), N(H)N(H)C(=O)cyclopropyl, N(H)N(H)C(=O)CH2CF3, ON(H)C(=O)cyclopropyl, and ON(H)C(=O)CH2CF3, orfrom 1,2,4
    32S triazolyl, 1,2,4-triazolyl-C(=O)cyclopropyl, 1,2,4-triazolyl-C(=O)OH3, 1,2,- methyltriazolyl,
    1,2,4-triazolyl-N(C(=O)cyclopropyl)2, 1,2,4-triazolylN(H)(C(=O)cyclopropyl), 1,2,4triazolylNH2, 1,2,4-triazolyl-NO2, 1,2,4-triazolylS(0)2CH3, 1,2,4-triazolylSCH3, C(=O)(morpholinyl), C(=O)N(CH3)(CH3), C(=O)N(H)(CH(CH3)chloropyridinyl), C(=O)N(H)(CH2C(=O)N(CH3)(CH2CF3)), C(=O)N(H)(CH2-benzothiazolyl), C(=O)N(H)(CH2C(=O)N(H)(CH2CF3)), C(=O)N(H)(CH2C(=O)N(H)(CH2CH=CH2)), C(=0)N(H)(CH2C(=0)N(H)(cyclopropyl)), C(=O)N(H)(CH2C(=O)N(H)(N(CH3)2)), C(=O)N(H)(CH2C(=O)N(H)(OCH3)), C(=O)N(H)(CH2C(=O)N(H)(thietanyl)), C(=O)N(H)(CH2C(=O)N(H)(thietanyl-dioxide))
    C(=O)N(H)(CH2C(=O)OC(CH3)3), C(=O)N(H)(CH2C(=S)N(H)(CH2CF3)), C(=O)N(H)(CH2CF3), C(=O)N(H)(CH2CH2-chloropyridinyl) C(=O)N(H)(CH2-furanyl), C(=O)N(H)(CH2-methylimidazolyl)
    C(=O)N(H)(CH2-cyclopropyloxadiazolyl), C(=O)N(H)(CH2-phenyl), C(=O)N(H)(CH2trifluoromethylphenyl), C(=O)N(H)(CH2-fluorophenyl), C(=O)N(H)(CH2-pyrazinyl), C(=O)N(H)(CH2-trifluoromethylpyridinyl), C(=0)N(H)(CH2-chloropyridinyl), C(=O)N(H)(CH2-pyridinyl-NO2), C(=O)N(H)(CH2-pyridinyl-OCH3), C(=O)N(H)(CH2pyrimidinyl), C(=O)N(H)(CH2-tetrahydrofuranyl), C(=O)N(H)(CH2-chlorothiazolyl), C(=O)N(H)(CH3), C(=O)NH2, C(=0)N(H)(N(CH3)(fluorophenyl)), C(=O)N(H)(N(H)(fluorophenyl)), C(=0)N(H)(OCH2-chloropyridinyl), C(=O)N(H)(piperidinyl), C(=O)N(H)(piperidinylC(=O)CH2CF3), C(=O)N(H)(piperidinyl-CH2CN), C(=O)N(H)(piperidinylC(=O)CH3), C(=O)N(H)(piperidinylCH2CH2OH), C(=O)N(H)(piperidinyl-oxetanyl), C(=O)N(H)(chloropyridinyl), C(=O)N(H)(CH2tetrahydropyranyl), C(=O)N(H)(thietanyl), C(=O)N(H)(thietanyl-dioxide), C(=O)N(H)(thietanyl-oxide), C(=O)N(H)(CH2-pyrazinyl) C(=O)pyrrolidinyl-oxo, C(=S)N(H)(CH2C(=O)N(H)(CH2CF3)), C(=S)N(H)(CH2C(=S)N(H)(CH2CF3)), C(=S)N(H)(CH2-chloropyridinyl), CH2N(CH2pyridinyl)(C(=O)-cyclopropyl), CH2N(H)(C(=O)C(=O)N(H)(CH2CF3), CH2N(H)(C(=O)C(=O)OCH3), CH2N(H)(C(=O)C(CH3)3), CH2N(H)(C(=O)-CH2chloropyridinyl), CH2N(H)(C(=O)CH2CF3), CH2N(H)(C(=O)CH2CH2S(O)2CH3), CH2N(H)(O(=O)CH2CH2SCH3), CH2N(H)(C(=O)CH2CH3), CH2N(H)(C(=O)-cyclopropyl), CH2N(H)(C(=O)morpholinyl), CH2N(H)(C(=O)N(CH3)2, CH2N(H)(C(=O)N(H)(CH2CH3)), CH2N(H)(C(=O)N(H)(pyridinyl)), 0Η2Ν(Η)(0(=Ο)Ο0(0Η3)3), CH2N(H)(C(=O)Ochlorophenyl), CH2N(H)(C(=O)-pyridinyl), CH2N(H)(C(=O)-chloropyridinyl), CH2N(H)(C(=S)cyclopropyl), CH2N(H)(C(=S)N(H)(CH2CH=CH2)), CH2N(H)(C(=S)N(H)(CH2CH3)), CH2N(H)(pyridinyl), N(H)(N(H)(C(=O)CH2CF3), N(H)(N(H)(C(=O)cyclopropyl), ON(H)(C(=O)CH2CF3), and ON(H)(C(=O)cyclopropyl),
    327
    R12 is selected from H, F, Cl, Br, I, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy, preferably from CH3 and H,
    R13 is selected from H, F, Cl, Br, I, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, halomethoxy, haloethoxy, halo(C3)alkoxy, halo(C4)alkoxy, halo(C5)alkoxy, halo(C6)alkoxy, halo(C7)alkoxy, and halo(C8)alkoxy, preferably from CH3, Cl, and H,
    R12-R13 is the hydrocarbyl linkage CH=CHCH=CH,
    R14 and R15 are independently selected from H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkylaryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethyl-aryl, O-(C3)alkyl-aryl, O-(C4)alkyl-aryl, O-(C5)alkyl-aryl, O-(C6)alkyl-aryl, O-(C7)alkyl-aryl, O-(C8)alkyl-aryl, Omethyl-(substituted-aryl), O-ethyl-(substituted-aryl), O-(C3)alkyl-(substituted-aryl), O(C4)alkyl-(substituted-aryl), O-(C5)alkyl-(substituted-aryl), O-(C6)alkyl-(substituted-aryl), O(C7)alkyl-(substituted-aryl), O-(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethylheterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C8)alkylheterocyclyl, (C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substitutedheterocyclyl), ethyl-(substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl-(substituted-heterocyclyl), (C6)alkyl(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substitutedheterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O-(C3)alkyl-heterocyclyl, O(C4)alkyl-heterocyclyl, O-(C5)alkyl-heterocyclyl, O-(C6)alkyl-heterocyclyl, O-(C7)alkylheterocyclyl, O-(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl(substituted-heterocyclyl), O-(C3)alkyl-(substituted-heterocyclyl), O-(C4)alkyl-(substitutedheterocyclyl), O-(C5)alkyl-(substituted-heterocyclyl), O-(C6)alkyl-(substituted-heterocyclyl),
    328
    O-(C7)alkyl-(substituted-heterocyclyl), O-(C8)alkyl-(substituted-heterocyclyl), methylC(=O)N(R16)(R17), ethyl-C(=O)N(R16)(R17), (C3)alkyl-C(=O)N(R16)(R17), (C4)alkylC(=O)N(R16)(R17), (C5)alkyl-C(=O)N(R16)(R17), (C6)alkyl-C(=O)N(R16)(R17), (C7)alkylC(=O)N(R16)(R17), and (C8)alkyl-C(=O)N(R16)(R17), or from H, CH3, CH2CF3> CH2halopyridyl, oxo-pyrrolidinyl, halophenyl, thietanyl, CH2-phenyl, CH2-pyridyl, thietanyldioxide, CH2-halothiazolyl, C((CH3)2)-pyridyl, N(H)(halophenyl), CH2-pyrimidinyl, CH2tetrahydrofuranyl, CH2-furanyl, O-CH2-halopyridyl, and CH2C(=O)N(H)(CH2CF3),
    R16 and R17 are independently selected from H, methyl, ethyl, (C3)alkyl, (C4)alkyl, (C5)alkyl, (C6)alkyl, (C7)alkyl, (C8)alkyl, halomethyl, haloethyl, halo(C3)alkyl, halo(C4)alkyl, halo(C5)alkyl, halo(C6)alkyl, halo(C7)alkyl, halo(C8)alkyl, methyl-aryl, ethyl-aryl, (C3)alkylaryl, (C4)alkyl-aryl, (C5)alkyl-aryl, (C6)alkyl-aryl, (C7)alkyl-aryl, (C8)alkyl-aryl, methyl(substituted-aryl), ethyl-(substituted-aryl), (C3)alkyl-(substituted-aryl), (C4)alkyl(substituted-aryl), (C5)alkyl-(substituted-aryl), (C6)alkyl-(substituted-aryl), (C7)alkyl(substituted-aryl), (C8)alkyl-(substituted-aryl), O-methyl-aryl, O-ethyl-aryl, O-(C3)alkyl-aryl, O-(C4)alkyl-aryl, O-(C5)alkyl-aryl, O-(C6)alkyl-aryl, O-(C7)alkyl-aryl, O-(C8)alkyl-aryl, Omethyl-(substituted-aryl), O-ethyl-(substituted-aryl), O-(C3)aIkyl-(substituted-aryl), O(C4)alkyl-(substituted-aryl), O-(C5)alkyl-(substituted-aryl), O-(C6)alkyl-(substituted-aryl), O(C7)alkyl-(substituted-aryl), O-(C8)alkyl-(substituted-aryl), methyl-heterocyclyl, ethylheterocyclyl, (C3)alkyl-heterocyclyl, (C4)alkyl-heterocyclyl, (C5)alkyl-heterocyclyl, (C6)alkylheterocyclyl, (C7)alkyl-heterocyclyl, (C8)alkyl-heterocyclyl, methyl-(substitutedheterocyclyl), ethyl-(substituted-heterocyclyl), (C3)alkyl-(substituted-heterocyclyl), (C4)alkyl-(substituted-heterocyclyl), (C5)alkyl-(substituted-heterocyclyl), (C6)alkyl(substituted-heterocyclyl), (C7)alkyl-(substituted-heterocyclyl), (C8)alkyl-(substitutedheterocyclyl), O-methyl-heterocyclyl, O-ethyl-heterocyclyl, O-(C3)alkyl-heterocyclyl, O(C4)alkyl-heterocyclyl, O-(C5)alkyl-heterocyclyl, O-(C6)alkyl-heterocyclyl, O-(C7)alkylheterocyclyl, O-(C8)alkyl-heterocyclyl, O-methyl-(substituted-heterocyclyl), O-ethyl(substituted-heterocyclyl), O-(C3)alkyl-(substituted-heterocyclyl), O-(C4)alkyl-(substitutedheterocyclyl), O-(C5)alkyl-(substituted-heterocyclyl), O-(C6)alkyl-(substituted-heterocyclyl), 0-(C7)alkyl-(substituted-heterocyclyl), and O-(C8)alkyl-(substituted-heterocyclyl), or from H, CH2CF3, cyclopropyl, thietanyl, thietanyl dioxide, and halophenyl,
    X1 is CR12, X2 is CR13, and X3 is CR9, or
    R10 and R11 form a linkage and said linkage is selected from (a) - (I).
    329
    X4
    where * indicates attachment back to the ring, (Note while the structures are drawn this way, they can be flipped from bottom to top thereby rotating the structure 180 degrees) (note hydrogens for carbons atoms are implied and not shown)
  3. 3.
    A molécule according to claim 1 having one of the following structures
    330
  4. 4. A composition according to claim 1 further comprising:
    I. (a) one or more compounds having acaricidal, algicidal, avicidal, bactericidal,
  5. 5 fungicidal, herbicidal, insecticidal, molluscicidal, nematicidal, rodenticidal, or virucidal properties; or (b) one or more compounds that are antifeedants, bird repellents, chemosterilants, herbicide safeners, insect attractants, insect repellents, mammal repellents, mating disrupters, plant activators, plant growth regulators, or synergists; or
    10 (c) both (a) and (b);
    II. one or more compounds selected from: (3-ethoxypropyl)mercury bromide, 1,2dichloropropane, 1,3-dichloropropene, 1-methylcyclopropene, 1-naphthol, 2(octylthio)ethanol, 2,3,5-tri-iodobenzoic acid, 2,3,6-TBA, 2,3,6-TBA-dimethylammonium,
    15 2,3,6-TBA-lithium, 2,3,6-TBA-potassium, 2,3,6-TBA-sodium, 2,4,5-T, 2,4,5-T-2butoxypropyl, 2,4,5-T-2-ethylhexyl, 2,4,5-T-3-butoxypropyl, 2,4,5-TB, 2,4,5-T-butometyl,
    2,4,5-T-butotyl, 2,4,5-T-butyl, 2,4,5-T-isobutyl, 2,4,5-T-isoctyl, 2,4,5-T-isopropyl, 2,4,5-Tmethyl, 2,4,5-T-pentyl, 2,4,5-T-sodium, 2,4,5-T-triethylammonium, 2,4,5-T-trolamine, 2,4D, 2,4-D-2-butoxypropyl, 2,4-D-2-ethylhexyl, 2,4-D-3-butoxypropyl, 2,4-D-ammonium,
    20 2,4-DB, 2,4-DB-butyl, 2,4-DB-dimethylammonium, 2,4-DB-isoctyl, 2,4-DB-potassium, 2,4DB-sodium, 2,4-D-butotyl, 2,4-D-butyl, 2,4-D-diethylammonium, 2,4-Ddimethylammonium, 2,4-D-diolamine, 2,4-D-dodecylammonium, 2,4-DEB, 2,4-DEP, 2,4D-ethyl, 2,4-D-heptylammonium, 2,4-D-isobutyl, 2,4-D-isoctyl, 2,4-D-isopropyl, 2,4-Disopropylammonium, 2,4-D-lithium, 2,4-D-meptyl, 2,4-D-methyl, 2,4-D-octyl, 2,4-D-pentyl,
    25 2,4-D-potassium, 2,4-D-propyl, 2,4-D-sodium, 2,4-D-tefuryl, 2,4-D-tetradecylammonium,
    2,4-D-triethylammonium, 2,4-D-tris(2-hydroxypropyl)ammonium, 2,4-D-trolamine, 2iP, 2methoxyethylmercury chloride, 2-phenylphenol, 3,4-DA, 3,4-DB, 3,4-DP, 4-aminopyridine,
    4-CPA, 4-CPA-potassium, 4-CPA-sodium, 4-CPB, 4-CPP, 4-hydroxyphenethyl alcohol, 8hydroxyquinoline sulfate, 8-phenylmercurioxyquinoline, abamectin, abscisic acid, ACC,
    30 acephate, acequinocyl, acetamiprid, acethion, acetochlor, acetophos, acetoprole,
    331 acibenzolar, acibenzolar-S-methyl, acifluorfen, acifluorfen-methyl, acifluorfen-sodium, aclonifen, acrep, acrinathrin, acrolein, acrylonitrile, acypetacs, acypetacs-copper, acypetacs-zinc, alachlor, alanycarb, albendazole, aldicarb, aldimorph, aldoxycarb, aldrin, allethrin, allicin, allidochlor, allosamidin, alloxydim, alloxydim-sodium, allyl alcohol, allyxycarb, alorac, a/pfta-cypermethrin, a/p/ia-endosulfan, ametoctradin, ametridione, ametryn, amibuzin, amicarbazone, amicarthiazol, amidithion, amidoflumet, amidosulfuron, aminocarb, aminocyclopyrachlor, aminocyclopyrachlor-methyl, aminocyclopyrachlorpotassium, aminopyralid, aminopyralid-potassium, aminopyralid-tris(2hydroxypropyl)ammonium, amiprofos-methyl, amiprophos, amisulbrom, amiton, amiton oxalate, amitraz, amitrole, ammonium sulfamate, ammonium a-naphthaleneacetate, amobam, ampropylfos, anabasine, ancymidol, anilazine, anilofos, anisuron, anthraquinone, antu, apholate, aramite, arsenous oxide, asomate, aspirin, asulam, asulam-potassium, asulam-sodium, athidathion, atraton, atrazine, aureofungin, aviglycine, aviglycine hydrochloride, azaconazole, azadirachtin, azafenidin, azamethiphos, azimsulfuron, azinphos-ethyl, azinphos-methyl, aziprotryne, azithiram, azobenzene, azocyclotin, azothoate, azoxystrobin, bachmedesh, barban, barium hexafluorosilicate, barium polysulfide, barthrin, BCPC, beflubutamid, benalaxyl, benalaxyl-M, benazolin, benazolin-dimethylammonium, benazolin-ethyl, benazolinpotassium, bencarbazone, benclothiaz, bendiocarb, benfluralin, benfuracarb, benfuresate, benodanil, benomyl, benoxacor, benoxafos, benquinox, bensulfuron, bensulfuron-methyl, bensulide, bensultap, bentaluron, bentazone, bentazone-sodium, benthiavalicarb, benthiavalicarb-isopropyl, benthiazole, bentranil, benzadox, benzadoxammonium, benzalkonium chloride, benzamacril, benzamacril-isobutyl, benzamorf, benzfendizone, benzipram, benzobicyclon, benzofenap, benzofluor, benzohydroxamic acid, benzoximate, benzoylprop, benzoylprop-ethyl, benzthiazuron, benzyl benzoate, benzyladenine, berberine, berberine chloride, beta-cyfluthrin, beta-cypermethrin, bethoxazin, bicyclopyrone, bifenazate, bifenox, bifenthrin, bifujunzhi, bilanafos, bilanafossodium, binapacryl, bingqingxiao, bioallethrin, bioethanomethrin, biopermethrin, bioresmethrin, biphenyl, bisazir, bismerthiazol, bispyribac, bispyribac-sodium, bistrifluron, bitertanol, bithionol, bixafen, blasticidin-S, borax, Bordeaux mixture, boric acid, boscalid, brassinolide, brassinolide-ethyl, brevicomin, brodifacoum, brofenvalerate, brofluthrinate, bromacil, bromacil-lithium, bromacil-sodium, bromadiolone, bromethalin, bromethrin, bromfenvinfos, bromoacetamide, bromobonil, bromobutide, bromocyclen, bromo-DDT, bromofenoxim, bromophos, bromophos-ethyl, bromopropylate, bromothalonil, bromoxynil, bromoxynil butyrate, bromoxynil heptanoate, bromoxynil octanoate, bromoxynilpotassium, brompyrazon, bromuconazole, bronopol, bucarpolate, bufencarb, buminafos,
    332 bupirimate, buprofezin, Burgundy mixture, busulfan, butacarb, butachlor, butafenacil, butamifos, butathiofos, butenachlor, butethrin, buthidazole, buthiobate, buthiuron, butocarboxim, butonate, butopyronoxyl, butoxycarboxim, butralin, butroxydim, buturon, butylamine, butylate, cacodylic acid, cadusafos, cafenstrole, calcium arsenate, calcium chlorate, calcium cyanamide, calcium polysulfide, calvinphos, cambendichlor, camphechlor, camphor, captafol, captan, carbamorph, carbanolate, carbaryl, carbasulam, carbendazim, carbendazim benzenesulfonate, carbendazim sulfite, carbetamide, carbofuran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, carboxazole, carboxide, carboxin, carfentrazone, carfentrazone-ethyl, carpropamid, cartap, cartap hydrochloride, carvacrol, carvone, CDEA, cellocidin, CEPC, ceralure, Cheshunt mixture, chinomethionat, chitosan, chlobenthiazone, chlomethoxyfen, chloralose, chloramben, chloramben-ammonium, chloramben-diolamine, chlorambenmethyl, chloramben-methylammonium, chloramben-sodium, chloramine phosphorus, chloramphenicol, chloraniformethan, chloranil, chloranocryl, chlorantraniliprole, chlorazifop, chlorazifop-propargyl, chlorazine, chlorbenside, chlorbenzuron, chlorbicyclen, chlorbromuron, chlorbufam, chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride, chlorempenthrin, chlorethoxyfos, chloreturon, chlorfenac, chlorfenacammonium, chlorfenac-sodium, chlorfenapyr, chlorfenazole, chlorfenethol, chlorfenprop, chlorfenson, chlorfensulphide, chlorfenvinphos, chlorfluazuron, chlorflurazole, chlorfluren, chlorfluren-methyl, chlorflurenol, chlorflurenol-methyl, chloridazon, chlorimuron, chlorimuron-ethyl, chlormephos, chlormequat, chlormequat chloride, chlornidine, chlornitrofen, chlorobenzilate, chlorodinitronaphthalenes, chloroform, chloromebuform, chloromethiuron, chloroneb, chlorophacinone, chlorophacinone-sodium, chloropicrin, chloropon, chloropropylate, chlorothalonil, chlorotoluron, chloroxuron, chloroxynil, chlorphonium, chlorphonium chloride, chlorphoxim, chlorprazophos, chlorprocarb, chlorpropham, chlorpyrifos, chlorpyrifos-methyl, chlorquinox, chlorsulfuron, chlorthal, chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid, chlorthiophos, chlozolinate, choline chloride, chromafenozide, cinerin I, cinerin II, cinerins, cinidon-ethyl, cinmethylin, cinosulfuron, ciobutide, cisanilide, cismethrin, clethodim, climbazole, cliodinate, clodinafop, clodinafop-propargyl, cloethocarb, clofencet, clofencet-potassium, clofentezine, clofibric acid, clofop, clofop-isobutyl, clomazone, clomeprop, cloprop, cloproxydim, clopyralid, clopyralid-methyl, clopyralid-olamine, clopyralid-potassium, clopyralid-tris(2-hydroxypropyl)ammonium, cloquintocet, cloquintocet-mexyl, cloransulam, cloransulam-methyl, closantel, clothianidin, clotrimazole, cloxyfonac, cloxyfonac-sodium, CMA, codlelure, colophonate, copper acetate, copper acetoarsenite, copper arsenate, copper carbonate, basic, copper hydroxide, copper naphthenate, copper oleate, copper
    333 oxychloride, copper silicate, copper sulfate, copper zinc chromate, coumachlor, coumafuryl, coumaphos, coumatetralyl, coumithoate, coumoxystrobin, CPMC, CPMF, CPPC, credazine, cresol, crimidine, crotamiton, crotoxyphos, crufomate, cryolite, cuelure, cufraneb, cumyluron, cuprobam, cuprous oxide, curcumenol, cyanamide, cyanatryn,
    5 cyanazine, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyazofamid, cybutryne, cyclafuramid, cyclanilide, cyclethrin, cycloate, cycloheximide, cycloprate, cycloprothrin, cyclosulfamuron, cycloxaprid, cycloxydim, cycluron, cyenopyrafen, cyflufenamid, cyflumetofen, cyfluthrin, cyhalofop, cyhalofop-butyl, cyhalothrin, cyhexatin, cymiazole, cymiazole hydrochloride, cymoxanil, cyometrinil, cypendazole, cypermethrin,
    10 cyperquat, cyperquat chloride, cyphenothrin, cyprazine, cyprazole, cyproconazole, cyprodinil, cyprofuram, cypromid, cyprosulfamide, cyromazine, cythioate, daimuron, dalapon, dalapon-calcium, dalapon-magnesium, dalapon-sodium, daminozide, dayoutong, dazomet, dazomet-sodium, DBCP, d-camphor, DCIP, DCPTA, DDT, debacarb, decafentin, decarbofuran, dehydroacetic acid, delachlor, deltamethrin,
    15 demephion, demephion-O, demephion-S, demeton, demeton-methyl, demeton-O, demeton-O-methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulphon, desmedipham, desmetryn, d-fanshiluquebingjuzhi, diafenthiuron, dialifos, di-allate, diamidafos, diatomaceous earth, diazinon, dibutyl phthalate, dibutyl succinate, dicamba, dicamba-diglycolamine, dicamba-dimethylammonium, dicamba-diolamine, dicamba20 isopropylammonium, dicamba-methyl, dicamba-olamine, dicamba-potassium, dicambasodium, dicamba-trolamine, dicapthon, dichlobenil, dichlofenthion, dichlofluanid, dichlone, dichloralurea, dichlorbenzuron, dichlorflurenol, dichlorflurenol-methyl, dichlormate, dichlormid, dichlorophen, dichlorprop, dichlorprop-2-ethylhexyl, dichlorprop-butotyl, dichlorprop-dimethylammonium, dichlorprop-ethylammonium, dichlorprop-isoctyl,
    25 dichlorprop-methyl, dichlorprop-P, dichlorprop-P-2-ethylhexyl, dichlorprop-Pdimethylammonium, dichlorprop-potassium, dichlorprop-sodium, dichlorvos, dichlozoline, diclobutrazol, diclocymet, diclofop, diclofop-methyl, diclomezine, diclomezine-sodium, dicloran, diclosulam, dicofol, dicoumarol, dicresyl, dicrotophos, dicyclanil, dicyclonon, dieldrin, dienochlor, diethamquat, diethamquat dichloride, diethatyl, diethatyl-ethyl,
    30 diethofencarb, dietholate, diethyl pyrocarbonate, diethyltoluamide, difenacoum, difenoconazole, difenopenten, difenopenten-ethyl, difenoxuron, difenzoquat, difenzoquat metilsulfate, difethialone, diflovidazin, diflubenzuron, diflufenican, diflufenzopyr, diflufenzopyr-sodium, diflumetorim, dikegulac, dikegulac-sodium, dilor, dimatif, dimefluthrin, dimefox, dimefuron, dimepiperate, dimetachlone, dimetan, dimethacarb,
    35 dimethachlor, dirriethametryn, dimethenamid, dimethenamid-P, dimethipin, dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate, dimethyl phthalate,
    334 dimethylvinphos, dimetilan, dimexano, dimidazon, dimoxystrobin, dinex, dinex-diclexine, dingjunezuo, diniconazole, diniconazole-M, dinitramine, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton, dinofenate, dinopenton, dinoprop, dinosam, dinoseb, dinoseb acetate, dinoseb-ammonium, dinoseb-diolamine, dinoseb-sodium, dinoseb-trolamine, dinosulfon, dinotefuran, dinoterb, dinoterb acetate, dinoterbon, diofenolan, dioxabenzofos, dioxacarb, dioxathion, diphacinone, diphacinone-sodium, diphenamid, diphenyl sulfone, diphenylamine, dipropalin, dipropetryn, dipyrithione, diquat, diquat dibromide, disparlure, disul, disulfiram, disulfoton, disul-sodium, ditalimfos, dithianon, dithicrofos, dithioether, dithiopyr, diuron, d-limonene, DMPA, DNOC, DNOC-ammonium, DNOC-potassium, DNOC-sodium, dodemorph, dodemorph acetate, dodemorph benzoate, dodicin, dodicin hydrochloride, dodicin-sodium, dodine, dofenapyn, dominicalure, doramectin, drazoxolon, DSMA, dufulin, EBEP, EBP, ecdysterone, edifenphos, eglinazine, eglinazine-ethyl, emamectin, emamectin benzoate, EMPC, empenthrin, endosulfan, endothal, endothal-diammonium, endothal-dipotassium, endothal-disodium, endothion, endrin, enestroburin, EPN, epocholeone, epofenonane, epoxiconazole, eprinomectin, epronaz, EPTC, erbon, ergocalciferol, erlujixiancaoan, esdépalléthrine, esfenvalerate, esprocarb, etacelasil, etaconazole, etaphos, etem, ethaboxam, ethachlor, ethalfluralin, ethametsulfuron, ethametsulfuron-methyl, ethaprochlor, ethephon, ethidimuron, ethiofencarb, ethiolate, ethion, ethiozin, ethiprole, ethirimol, ethoate-methyl, ethofumesate, ethohexadiol, ethoprophos, ethoxyfen, ethoxyfen-ethyl, ethoxyquin, ethoxysulfuron, ethychlozate, ethyl formate, ethyl anaphthaleneacetate, ethyl-DDD, ethylene, ethylene dibromide, ethylene dichloride, ethylene oxide, ethylicin, ethylmercury 2,3-dihydroxypropyl mercaptide, ethylmercury acetate, ethylmercury bromide, ethylmercury chloride, ethylmercury phosphate, etinofen, etnipromid, etobenzanid, etofenprox, etoxazole, etridiazole, etrimfos, eugenol, EXD, famoxadone, famphur, fenamidone, fenaminosulf, fenamiphos, fenapanil, fenarimol, fenasulam, fenazaflor, fenazaquin, fenbuconazole, fenbutatin oxide, fenchlorazole, fenchlorazole-ethyl, fenchlorphos, fenclorim, fenethacarb, fenfluthrin, fenfuram, fenhexamid, fenitropan, fenitrothion, fenjuntong, fenobucarb, fenoprop, fenoprop-3butoxypropyl, fenoprop-butometyl, fenoprop-butotyl, fenoprop-butyl, fenoprop-isoctyl, fenoprop-methyl, fenoprop-potassium, fenothiocarb, fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P, fenoxaprop-P-ethyl, fenoxasulfone, fenoxycarb, fenpiclonil, fenpirithrin, fenpropathrin, fenpropidin, fenpropimorph, fenpyrazamine, fenpyroximate, fenridazon, fenridazon-potassium, fenridazon-propyl, fenson, fensulfothion, fenteracol, fenthiaprop, fenthiaprop-ethyl, fenthion, fenthion-ethyl, fentin, fentin acetate, fentin chloride, fentin hydroxide, fentrazamide, fentrifanil, fenuron, fenuron
    335
    TCA, fenvalerate, ferbam, ferimzone, ferrous sulfate, fipronil, flamprop, flampropisopropyl, flamprop-M, flamprop-methyl, flamprop-M-isopropyl, flamprop-M-methyl, flazasulfuron, flocoumafen, flometoquin, flonicamid, florasulam, fluacrypyrim, fluazifop, fluazifop-butyl, fluazifop-methyl, fluazifop-P, fluazifop-P-butyl, fluazinam, fluazolate, fluazuron, flubendiamide, flubenzimine, flucarbazone, flucarbazone-sodium, flucetosulfuron, fluchloralin, flucofuron, flucycloxuron, flucythrinate, fludioxonil, fluenetil, fluensulfone, flufenacet, flufenerim, flufenican, flufenoxuron, flufenprox, flufenpyr, flufenpyr-ethyl, flufiprole, flumethrin, flumetover, flumetralin, flumetsulam, flumezin, flumiclorac, flumiclorac-pentyl, flumioxazin, flumipropyn, flumorph, fluometuron, fluopicolide, fluopyram, fluorbenside, fluoridamid, fluoroacetamide, fluorodifen, fluoroglycofen, fluoroglycofen-ethyl, fluoroimide, fluoromidine, fluoronitrofen, fluothiuron, fluotrimazole, fluoxastrobin, flupoxam, flupropacil, flupropadine, flupropanate, flupropanate-sodium, flupyradifurone, flupyrsulfuron, flupyrsulfuron-methyl, flupyrsulfuronmethyl-sodium, fluquinconazole, flurazole, flurenol, flurenol-butyl, flurenol-methyl, fluridone, flurochloridone, fluroxypyr, fluroxypyr-butometyl, fluroxypyr-meptyl, flurprimidol, flursulamid, flurtamone, flusilazole, flusulfamide, fluthiacet, fluthiacet-methyl, flutianil, flutolanil, flutriafol, fluvalinate, fluxapyroxad, fluxofenim, folpet, fomesafen, fomesafensodium, fonofos, foramsulfuron, forchlorfenuron, formaldéhyde, formetanate, formetanate hydrochloride, formothion, formparanate, formparanate hydrochloride, fosamine, fosamine-ammonium, fosetyl, fosetyl-aluminium, fosmethilan, fospirate, fosthiazate, fosthietan, frontalin, fuberidazole, fucaojing, fucaomi, funaihecaoling, fuphenthiourea, furalane, furalaxyl, furamethrin, furametpyr, furathiocarb, furcarbanil, furconazole, furconazole-cis, furethrin, furfural, furilazole, furmecyclox, furophanate, furyloxyfen, gamma-cyhalothrin, gamma-HCH, genit, gibberellic acid, gibberellins, gliftor, glufosinate, glufosinate-ammonium, glufosinate-P, glufosinate-P-ammonium, glufosinate-P-sodium, glyodin, glyoxime, glyphosate, glyphosate-diammonium, glyphosate-dimethylammonium, glyphosate-isopropylammonium, glyphosate-monoammonium, glyphosate-potassium, glyphosate-sesquisodium, glyphosate-trimesium, glyphosine, gossyplure, grandlure, griseofulvin, guazatine, guazatine acétates, halacrinate, halfenprox, halofenozide, halosafen, halosulfuron, halosulfuron-methyl, haloxydine, haloxyfop, haloxyfop-etotyl, haloxyfop-methyl, haloxyfop-P, haloxyfop-P-etotyl, haloxyfop-P-methyl, haloxyfopsodium, HCH, hemel, hempa, HEOD, heptachlor, heptenophos, heptopargil, heterophos, hexachloroacetone, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, hexaflumuron, hexaflurate, hexalure, hexamide, hexazinone, hexylthiofos, hexythiazox, HHDN, holosulf, huancaiwo, huangcaoling, huanjunzuo, hydramethylnon, hydrargaphen, hydrated lime, hydrogen cyanide, hydroprene, hymexazol, hyquincarb,
    336
    IAA, IBA, icaridin, imazalil, imazalil nitrate, imazalil sulfate, imazamethabenz, imazamethabenz-methyl, imazamox, imazamox-ammonium, imazapic, imazapicammonium, imazapyr, imazapyr-isopropylammonium, imazaquin, imazaquin-ammonium, mazaquin-methyl, imazaquin-sodium, imazethapyr, imazethapyr-ammonium, mazosulfuron, imibenconazole, imicyafos, imidacloprid, imidaclothiz, iminoctadine, minoctadine triacetate, iminoctadine trialbesilate, imiprothrin, inabenfide, indanofan, ndaziflam, indoxacarb, inezin, iodobonil, iodocarb, iodomethane, iodosulfuron, odosulfuron-methyl, iodosulfuron-methyl-sodium, iofensulfuron, iofensulfuron-sodium, oxynil, ioxynil octanoate, ioxynil-lithium, ioxynil-sodium, ipazine, ipconazole, pfencarbazone, iprobenfos, iprodione, iprovalicarb, iprymidam, ipsdienol, ipsenol, IPSP, samidofos, isazofos, isobenzan, isocarbamid, isocarbophos, isocil, isodrin, isofenphos, sofenphos-methyl, isolan, isomethiozin, isonoruron, isopolinate, isoprocarb, isopropalin, soprothiolane, isoproturon, isopyrazam, isopyrimol, isothioate, isotianil, isouron, sovaledione, isoxaben, isoxachlortole, isoxadifen, isoxadifen-ethyl, isoxaflutole, isoxapyrifop, isoxathion, ivermectin, izopamfos, japonilure, japothrins, jasmolin I, jasmolin II, jasmonic acid, jiahuangchongzong, jiajizengxiaolin, jiaxiangjunzhi, jiecaowan, jiecaoxi, jodfenphos, juvénile hormone I, juvénile hormone II, juvénile hormone III, kadethrin, karbutilate, karetazan, karetazan-potassium, kasugamycin, kasugamycin hydrochloride, kejunlin, kelevan, ketospiradox, ketospiradox-potassium, kinetin, kinoprene, kresoximmethyl, kuicaoxi, lactofen, lambda-cyhalothrin, latilure, lead arsenate, lenacil, lepimectin, leptophos, lindane, lineatin, linuron, lirimfos, litlure, looplure, lufenuron, Ivdingjunzhi, Ivxiancaolin, lythidathion, MAA, malathion, maleic hydrazide, malonoben, maltodextrin, ΜΑΜΑ, mancopper, mancozeb, mandipropamid, maneb, matrine, mazidox, MCPA, MCPA-2-ethylhexyl, MCPA-butotyl, MCPA-butyl, MCPA-dimethylammonium, MCPAdiolamine, MCPA-ethyl, MCPA-isobutyl, MCPA-isoctyl, MCPA-isopropyl, MCPA-methyl, MCPA-olamine, MCPA-potassium, MCPA-sodium, MCPA-thioethyl, MCPA-trolamine, MCPB, MCPB-ethyl, MCPB-methyl, MCPB-sodium, mebenil, mecarbam, mecarbinzid, mecarphon, mecoprop, mecoprop-2-ethylhexyl, mecoprop-dimethylammonium, mecoprop-diolamine, mecoprop-ethadyl, mecoprop-isoctyl, mecoprop-methyl, mecopropP, mecoprop-P-2-ethylhexyl, mecoprop-P-dimethylammonium, mecoprop-P-isobutyl, mecoprop-potassium, mecoprop-P-potassium, mecoprop-sodium, mecoprop-trolamine, medimeform, medinoterb, medinoterb acetate, medlure, mefenacet, mefenpyr, mefenpyrdiethyl, mefluidide, mefluidide-diolamine, mefluidide-potassium, megatomoic acid, menazon, mepanipyrim, meperfluthrin, mephenate, mephosfolan, mepiquat, mepiquat chloride, mepiquat pentaborate, mepronil, meptyldinocap, mercuric chloride, mercuric oxide, mercurous chloride, merphos, mesoprazine, mesosulfuron, mesosulfuron-methyl,
    337 mesotrione, mesulfen, mesulfenfos, metaflumizone, metalaxyl, metalaxyl-M, metaldehyde, metam, metam-ammonium, metamifop, metamitron, metam-potassium, metam-sodium, metazachlor, metazosulfuron, metazoxolon, metconazole, metepa, metflurazon, methabenzthiazuron, methacrifos, methalpropalin, methamidophos, methasulfocarb, methazole, methfuroxam, methidathion, methiobencarb, methiocarb, methiopyrisulfuron, methiotepa, methiozolin, methiuron, methocrotophos, methometon, methomyl, methoprene, methoprotryne, methoquin-butyl, methothrin, methoxychlor, methoxyfenozide, methoxyphenone, methyl apholate, methyl bromide, methyl eugenol, methyl iodide, methyl isothiocyanate, methylacetophos, methylchloroform, methyldymron, methylene chloride, methylmercury benzoate, methylmercury dicyandiamide, methylmercury pentachlorophenoxide, methylneodecanamide, metiram, metobenzuron, metobromuron, metofluthrin, metolachlor, metolcarb, metominostrobin, metosulam, metoxadiazone, metoxuron, metrafenone, metribuzin, metsulfovax, metsulfuron, metsulfuron-methyl, mevinphos, mexacarbate, mieshuan, milbemectin, milbemycin oxime, milneb, mipafox, mirex, MNAF, moguchun, molinate, molosultap, monalide, monisouron, monochloroacetic acid, monocrotophos, monolinuron, monosulfuron, monosulfuron-ester, monuron, monuron TCA, morfamquat, morfamquat dichloride, moroxydine, moroxydine hydrochloride, morphothion, morzid, moxidectin, MSMA, muscalure, myclobutanil, myclozolin, N-(ethylmercury)-p-toluenesulphonanilide, nabam, naftalofos, naled, naphthalene, naphthaleneacetamide, naphthalic anhydride, naphthoxyacetic acids, naproanilide, napropamide, naptalam, naptalam-sodium, natamycin, neburon, niclosamide, niclosamide-olamine, nicosulfuron, nicotine, nifluridide, nipyraclofen, nitenpyram, nithiazine, nitralin, nitrapyrin, nitrilacarb, nitrofen, nitrofluorfen, nitrostyrene, nitrothal-isopropyl, norbormide, norflurazon, nornicotine, noruron, novaluron, noviflumuron, nuarimol, OCH, octachlorodipropyl ether, octhilinone, ofurace, omethoate, orbencarb, orfralure, ortho-dichlorobenzene, orthosulfamuron, oryctalure, orysastrobin, oryzalin, osthol, ostramone, oxabetrinil, oxadiargyl, oxadiazon, oxadixyl, oxamate, oxamyl, oxapyrazon, oxapyrazon-dimolamine, oxapyrazon-sodium, oxasulfuron, oxaziclomefone, oxine-copper, oxolinic acid, oxpoconazole, oxpoconazole fumarate, oxycarboxin, oxydemeton-methyl, oxydeprofos, oxydisulfoton, oxyfluorfen, oxymatrine, oxytetracycline, oxytetracycline hydrochloride, paclobutrazol, paichongding, paradichlorobenzene, parafluron, paraquat, paraquat dichloride, paraquat dimetilsulfate, parathion, parathion-methyl, parinol, pebulate, pefurazoate, pelargonic acid, penconazole, pencycuron, pendimethalin, penflufen, penfluron, penoxsulam, pentachlorophenol, pentanochlor, penthiopyrad, pentmethrin, pentoxazone, perfluidone, permethrin, pethoxamid, phenamacril, phenazine oxide, phenisopham, phenkapton,
    338 phenmedipham, phenmedipham-ethyl, phenobenzuron, phenothrin, phenproxide, phenthoate, phenylmercuriurea, phenylmercury acetate, phenylmercury chloride, phenylmercury dérivative of pyrocatechol, phenylmercury nitrate, phenylmercury salicylate, phorate, phosacetim, phosalone, phosdiphen, phosfolan, phosfolan-methyl, phosglycin, phosmet, phosnichlor, phosphamidon, phosphine, phosphocarb, phosphorus, phostin, phoxim, phoxim-methyl, phthalide, picloram, picloram-2-ethylhexyl, picloramisoctyl, picloram-methyl, picloram-olamine, picloram-potassium, picloramtriethylammonium, picloram-tris(2-hydroxypropyl)ammonium, picolinafen, picoxystrobin, pindone, pindone-sodium, pinoxaden, piperalin, piperonyl butoxide, piperonyl cyclonene, piperophos, piproctanyl, piproctanyl bromide, piprotal, pirimetaphos, pirimicarb, pirimioxyphos, pirimiphos-ethyl, pirimiphos-methyl, plifenate, polycarbamate, polyoxins, polyoxorim, polyoxorim-zinc, polythialan, potassium arsenite, potassium azide, potassium cyanate, potassium gibberellate, potassium naphthenate, potassium polysulfide, potassium thiocyanate, potassium α-naphthaleneacetate, pp'-DDT, prallethrin, precocene I, precocene II, precocene III, pretilachlor, primidophos, primisulfuron, primisulfuronmethyl, probenazole, prochloraz, prochloraz-manganese, proclonol, procyazine, procymidone, prodiamine, profenofos, profluazol, profluralin, profluthrin, profoxydim, proglinazine, proglinazine-ethyl, prohexadione, prohexadione-calcium, prohydrojasmon, promacyl, promecarb, prometon, prometryn, promurit, propachlor, propamidine, propamidine dihydrochloride, propamocarb, propamocarb hydrochloride, propanil, propaphos, propaquizafop, propargite, proparthrin, propazine, propetamphos, propham, propiconazole, propineb, propisochlor, propoxur, propoxycarbazone, propoxycarbazonesodium, propyl isome, propyrisulfuron, propyzamide, proquinazid, prosuler, prosulfalin, prosulfocarb, prosulfuron, prothidathion, prothiocarb, prothiocarb hydrochloride, prothioconazole, prothiofos, prothoate, protrifenbute, proxan, proxan-sodium, prynachlor, pydanon, pymetrozine, pyracarbolid, pyraclofos, pyraclonil, pyraclostrobin, pyraflufen, pyraflufen-ethyl, pyrafluprole, pyramat, pyrametostrobin, pyraoxystrobin, pyrasulfotole, pyrazolynate, pyrazophos, pyrazosulfuron, pyrazosulfuron-ethyl, pyrazothion, pyrazoxyfen, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyribambenz-isopropyl, pyribambenz-propyl, pyribencarb, pyribenzoxim, pyributicarb, pyriclor, pyridaben, pyridafol, pyridalyl, pyridaphenthion, pyridate, pyridinitril, pyrifenox, pyrifluquinazon, pyriftalid, pyrimethanil, pyrimidifen, pyriminobac, pyriminobac-methyl, pyrimisulfan, pyrimitate, pyrinuron, pyriofenone, pyriprole, pyripropanol, pyriproxyfen, pyrithiobac, pyrithiobac-sodium, pyrolan, pyroquilon, pyroxasulfone, pyroxsulam, pyroxychlor, pyroxyfur, quassia, quinacetol, quinacetol sulfate, quinalphos, quinalphos-methyl, quinazamid, quinclorac, quinconazole, quinmerac, quinoclamine, quinonamid, quinothion,
    339 quinoxyfen, quintiofos, quintozene, quizalofop, quizalofop-ethyl, quizalofop-P, quizalofopP-ethyl, quizalofop-P-tefuryl, quwenzhi, quyingding, rabenzazole, rafoxanide, rebemide, resmethrin, rhodethanil, rhodojaponin-lll, ribavirin, rimsulfuron, rotenone, ryania, saflufenacil, saijunmao, saisentong, salicylanilide, sanguinarine, santonin, schradan, scilliroside, sebuthylazine, secbumeton, sedaxane, selamectin, semiamitraz, semiamitraz chloride, sesamex, sesamolin, sethoxydim, shuangjiaancaolin, siduron, siglure, silafluofen, silatrane, silica gel, silthiofam, simazine, simeconazole, simeton, simetryn, sintofen, SMA, S-metolachlor, sodium arsenite, sodium azide, sodium chlorate, sodium fluoride, sodium fluoroacetate, sodium hexafluorosilicate, sodium naphthenate, sodium orthophenylphenoxide, sodium pentachlorophenoxide, sodium polysulfide, sodium thiocyanate, sodium α-naphthaleneacetate, sophamide, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine, streptomycin, streptomycin sesquisulfate, strychnine, sulcatol, sulcofuron, sulcofuron-sodium, sulcotrione, sulfallate, sulfentrazone, sulfiram, sulfluramid, sulfometuron, sulfometuron-methyl, sulfosulfuron, sulfotep, sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid, sulfuryl fluoride, sulglycapin, sulprofos, sultropen, swep, tau-fluvalinate, tavron, tazimcarb, TCA, TCAammonium, TCA-calcium, TCA-ethadyl, TCA-magnesium, TCA-sodium, TDE, tebuconazole, tebufenozide, tebufenpyrad, tebufloquin, tebupirimfos, tebutam, tebuthiuron, tecloftalam, tecnazene, tecoram, teflubenzuron, tefluthrin, tefuryltrione, tembotrione, temephos, tepa, TEPP, tepraloxydim, terallethrin, terbacil, terbucarb, terbuchlor, terbufos, terbumeton, terbuthylazine, terbutryn, tetcyclacis, tetrachloroethane, tetrachlorvinphos, tetraconazole, tetradifon, tetrafluron, tetramethrin, tetramethylfluthrin, tetramine, tetranactin, tetrasul, thallium sulfate, thenylchlor, theta-cypermethrin, thiabendazole, thiacloprid, thiadifluor, thiamethoxam, thiapronil, thiazafluron, thiazopyr, thicrofos, thicyofen, thidiazimin, thidiazuron, thiencarbazone, thiencarbazone-methyl, thifensulfuron, thifensulfuron-methyl, thifluzamide, thiobencarb, thiocarboxime, thiochlorfenphim, thiocyclam, thiocyclam hydrochloride, thiocyclam oxalate, thiodiazolecopper, thiodicarb, thiofanox, thiofluoximate, thiohempa, thiomersal, thiometon, thionazin, thiophanate, thiophanate-methyl, thioquinox, thiosemicarbazide, thiosultap, thiosultapdiammonium, thiosultap-disodium, thiosultap-monosodium, thiotepa, thiram, thuringiensin, tiadinil, tiaojiean, tiocarbazil, tioclorim, tioxymid, tirpate, tolclofos-methyl, tolfenpyrad, tolylfluanid, tolylmercury acetate, topramezone, tralkoxydim, tralocythrin, tralomethrin, tralopyril, transfluthrin, transpermethrin, tretamine, triacontanol, triadimefon, triadimenol, triafamone, tri-allate, triamiphos, triapenthenol, triarathene, triarimol, triasulfuron, triazamate, triazbutil, triaziflam, triazophos, triazoxide, tribenuron, tribenuronmethyl, tribufos, tributyltin oxide, tricamba, trichlamide, trichlorfon, trichlormetaphos-3,
    340 trichloronat, triclopyr, triclopyr-butotyl, triclopyr-ethyl, triclopyr-triethylammonium, tricyclazole, tridemorph, tridiphane, trietazine, 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, urbacide, uredepa, valerate, validamycin, valifenalate, valone, vamidothion, vangard, vaniliprole, vernolate, vinclozolin, warfarin, warfarin-potassium, warfarin-sodium, xiaochongliulin, xinjunan, xiwojunan, XMC, xylachlor, xylenols, xylylcarb, yishijing, zarilamid, zeatin, zengxiaoan, zeta-cypermethrin, zinc naphthenate, zinc phosphide, zinc thiazole, zineb, ziram, zolaprofos, zoxamide, zuomihuanglong, α-chlorohydrin, aecdysone, a-multistriatin, and α-naphthaleneacetic acid;
    III. an agriculturally acceptable carrier;
    IV. a biopesticide;
    V. one or more of the following compounds:
    (a) 3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8-oxa-1-azaspiro[4,5]dec-3-en-
    2-one;
    (b) 3-(4’-chloro-2,4-dimethyl[1,1 ’-biphenyl]-3-yl)-4-hydroxy-8-oxa-1 azaspiro[4,5]dec-3-en-2-one;
    (c) 4-[[(6-chloro-3-pyridinyl)methyl]methylamino]-2(5H)-furanone;
    (d) 4-[[(6-chloro-3-pyridinyl)methyl]cyclopropylamino]-2(5A7)-furanone;
    (e) 3-chloro-A/2-[(1 S)-1 -methyl-2-(methylsulfonyl)ethyl]-/V1 -[2-methyl-4[1,2,2,2-tetrafluoro-1 -(trifluoromethyl)ethyl]phenyl]-1,2-benzenedicarboxamide;
    (f) 2-cyano-/V-ethyl-4-fluoro-3-methoxy-benenesulfonamide;
    (g) 2-cyano-/V-ethyl-3-methoxy-benzenesulfonamide;
    (h) 2-cyano-3-difluoromethoxy-/V-ethyl-4-fluoro-benzenesulfonamide;
    (i) 2-cyano-3-fluoromethoxy-A/-ethyl-benzenesulfonamide;
    (j) 2-cyano-6-fluoro-3-methoxy-A/,A/-dimethyl-benzenesulfonamide;
    (k) 2-cyano-A/-ethyl-6-fluoro-3-methoxy-A/-methyl-benzenesulfonamide;
    (l) 2-cyano-3-difluoromethoxy-/\/,/V-dimethylbenzenesulfon-amide;
    (m) 3-(difluoromethyl)-A/-[2-(3,3-dimethylbutyl)phenyl]-1 -methyl-1 H-pyrazole-4carboxamide;
    341 (n) /V-ethyl-2,2-dimethylpropionamide-2-(2,6-dichloro-a,a,a-trifluoro-p-tolyl) hydrazone;
    (o) A/-ethyl-2,2-dichloro-1-methylcyclopropane-carboxamide-2-(2,6-dichloroα,α,α-trifluoro-p-tolyl) hydrazone nicotine;
    (p) 0-{(E-)-[2-(4-chloro-phenyl)-2-cyano-1 -(2-trifluoromethylphenyl)-vinyl]} Smethyl thiocarbonate;
    (q) (E)-N1-[(2-chloro-1,3-thiazol-5-ylmethyl)]-N2-cyano-N1-methylacetamidine;
    (r) 1-(6-chloropyridin-3-ylmethyl)-7-methyl-8-nitro-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridin-5-ol;
    (s) 4-[4-chlorophenyl-(2-butylidine-hydrazono)methyl)]phenyl mesylate; and (t) N-Ethyl-2,2-dichloro-1-methylcyclopropanecarboxamide-2-(2,6-dichloroalpha,alpha,a/p/ia-trifluoro-p-tolyl)hydrazone, or
    VI. a seed, preferably a seed that has been genetically modified to express one or more specialized traits.
    5. A composition according to claim 1 wherein said molécule is in the form of a pesticidally acceptable acid addition sait, a sait dérivative, a hydrate, an ester dérivative, or a crystal polymorph, or has a 2H in place of 1H, or a 14C in place of a 12C.
  6. 6. A composition according to claim 1 further comprising a compound having one or more of the following modes of action: acetylcholinesterase inhibitor; sodium channel modulator; chitin biosynthesis 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; nicotinic acétylcholine receptor; Midgut membrane disrupter; oxidative phosphorylation disrupter, and ryanodine receptor (RyRs).
  7. 7. A composition according to claim 1 wherein said composition is encapsulated inside, or placed on the surface of, a capsule, wherein said capsule preferably has a diameter of 100-900 nanometers or 10-900 pm [microns],
  8. 8. A process comprising applying a composition according to claim 1, to an area to control a pest, in an amount sufficient to control such pest.
    342
  9. 9. A process according to claim 8 wherein said pest is selected from beetles, earwigs, cockroaches, flies, aphids, scales, whiteflies, leafhoppers, ants, wasps, termites, moths, butterflies, lice, grasshoppers, locusts, crickets, fleas, thrips, bristletails, mites, ticks, nematodes, and symphylans, preferably from the Phyla Nematoda or Arthropoda, more preferably from the Subphyla Chelicerata, Myriapoda, or Hexapoda, even more preferably from the Class of Arachnida, Symphyla, or Insecta, still even more preferably from the Order Anoplura, Order Coleoptera, Order Dermaptera, Order Blattaria, Order Diptera, Order Hemiptera, Order Hymenoptera, Order Isoptera, Order Lepidoptera, Order Mallophaga, Order Orthoptera, Order Siphonaptera, Order Thysanoptera, Order Thysanura, Order Acarina, or Order Symphyla and most preferably is beet armyworm (BAW), corn earworm (CEW) or green peach aphid (GPA).
  10. 10. A process according to claim 8 wherein said amount is from 0.01 grams per hectare to 5000 grams per hectare, preferably from 0.1 grams per hectare to 500 grams per hectare, more preferably from 1 gram per hectare to 50 grams per hectare.
  11. 11. A process according to claim 8 wherein said area is an area where apples, corn, cotton, soybeans, canola, wheat, rice, sorghum, barley, oats, potatoes, oranges, alfalfa, lettuce, strawberries, tomatoes, peppers, crucifers, pears, tobacco, almonds, sugar beets, or beans, are growing, or the seeds thereof are going to be planted.
  12. 12. A process according to claim 8 further comprising applying said composition to a genetically modified plant that has been genetically modified to express one or more specialized traits.
  13. 13. A process according to claim 8 where said composition further comprises ammonium sulfate.
  14. 14. A composition according to claim 1 for use in controlling endoparasites, ectoparasites, or both in a non-human animal by oral administration, topical application or parenteral administration.
  15. 15. A process comprising applying a composition according to claim 1 to a plant to enhance the plant’s health, yieid, vigor, quality, or tolérance, at a time when pes* activity is low.
OA1201300532 2011-06-24 2012-06-21 Pesticidal Compositions and Processes Related Thereto OA19157A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US61/500,685 2011-06-24
US61/540,056 2011-09-28
US61/601,077 2012-02-21
US61/645,267 2012-05-10

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OA19157A true OA19157A (en) 2020-03-09

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