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NZ623298B2 - Pesticidal compositions and processes related thereto - Google Patents
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NZ623298B2 - Pesticidal compositions and processes related thereto - Google Patents

Pesticidal compositions and processes related thereto Download PDF

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Publication number
NZ623298B2
NZ623298B2 NZ623298A NZ62329812A NZ623298B2 NZ 623298 B2 NZ623298 B2 NZ 623298B2 NZ 623298 A NZ623298 A NZ 623298A NZ 62329812 A NZ62329812 A NZ 62329812A NZ 623298 B2 NZ623298 B2 NZ 623298B2
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NZ
New Zealand
Prior art keywords
methyl
sodium
ethyl
mmol
composition according
Prior art date
Application number
NZ623298A
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NZ623298A (en
Inventor
Ann M Buysse
David A Demeter
Negar Garizi
Ricky Hunter
Timothy C Johnson
Daniel Knueppel
Asako Kubota
Paul Renee Leplae
Christian T Lowe
Noormohamed M Niyaz
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Dow Agrosciences Llc
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Priority claimed from PCT/US2012/061508 external-priority patent/WO2013062981A1/en
Publication of NZ623298A publication Critical patent/NZ623298A/en
Publication of NZ623298B2 publication Critical patent/NZ623298B2/en

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/647—Triazoles; Hydrogenated triazoles
    • A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/76—1,3-Oxazoles; Hydrogenated 1,3-oxazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/18—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing a —O—CO—N< group, or a thio analogue thereof, directly attached to a heterocyclic or cycloaliphatic ring
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/36—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing the group >N—CO—N< directly attached to at least one heterocyclic ring; Thio analogues thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N53/00—Biocides, pest repellants or attractants, or plant growth regulators containing cyclopropane carboxylic acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

Disclosed are aminopyrazoles compounds of formula (I), wherein the substituents are as defined in the specification. Also disclosed is the use of compounds of formula (I) as pesticides. An example of a compound of formula (I) is: N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-(methylthio)-N-(prop-2-yn-1-yl)propanamide op-2-yn-1-yl)propanamide

Description

wo 2013/062981 2012/061508 PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO CROSS-REFERENCE TO RELATED APPLICATIONS This Application claims priority from U.S. provisional application 611551585 filed on October 26, 2011. The entire content of this provisional application is hereby incorporated by reference into this Application.
FIELD OF THE DISCLOSURE This disclosure is related to the field of processes to produce molecules that are useful as pesticides (e.g., acaricides, insecticides, molluscicides, and nematicides), such les, and processes of using such molecules to control pests.
BACKGROUND Pests cause millions of human deaths around the world each year. rmore, there are more than ten nd 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 all kinds of e 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 resistance to pesticides in current use. Hundreds of pest species are resistant to one or more pesticides. The development of resistance to some of the older pesticides, such as DDT, the carbamates, and the organophosphates, is well known. But ance has even developed to some of the newer pesticides.
Therefore, for many reasons, including the above reasons, a need exists for new pesticides.
DEFINITIONS The examples given in the tions are generally non-exhaustive and must not be construed as limiting the invention disclosed in this nt. It is tood that a substituent should comply with chemical bonding rules and steric compatibility constraints in wo 2013/062981 relation to the particular molecule to which it is attached.
"Alkenyl" means an acyclic, unsaturated (at least one -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, xy, butenyloxy, pentenyloxy, loxy. y" means an alkyl r consisting of a carbon-oxygen single bond, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, oxy, and tert-butoxy.
"Alkyl" means an c, saturated, branched or ched, substituent consisting of carbon and hydrogen, for example, methyl, ethyl, kyl which represents n-propyl and isopropyl), kyl 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. y)" where the ipts "x" and "y" are integers such as 1, 2, or 3, means the range of carbon atoms for a substituent- for example, (C1-C4)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, norbornenyl, bicyclo[2.2.2]octenyl, tetrahydronaphthyl, hexahydronaphthyl, and dronaphthyl.
"Cycloalkenyloxy" means a cycloalkenyl further consisting of a -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, ropyl, cyclobutyl, cyclopentyl, norbornyl, bicyclo[2.2.2]octyl, and decahydronaphthyl.
"Cycloalkoxy" means a cycloalkyl further ting of a carbon-oxygen single bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, norbornyloxy, and wo 2013/062981 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, oromethoxy, 2,2-difluoropropoxy, chloromethoxy, trichloromethoxy, 1,1 ,2,2- tetrafluoroethoxy, and pentafluoroethoxy.
"Haloalkyl" means an alkyl further consisting of, from one to the maximum possible number of, cal or different, halos, for example, fluoromethyl, trifluoromethyl, 2,2- difluoropropyl, chloromethyl, trichloromethyl, and 1,1 etrafluoroethyl.
"Heterocyclyl" means a cyclic substituent that may be fully saturated, partially unsaturated, or fully unsaturated, where the cyclic structure contains at least one carbon and at least one atom, where said heteroatom is nitrogen, sulfur, or . In the case of sulfur, that atom can be in other oxidation states such as a sulfoxide and sulfone. Examples of aromatic heterocyclyls e, 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, l, triazinyl, and triazolyl. Examples of fully ted heterocyclyls include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, yl, tetrahydrofuranyl, ydrothienyl and tetrahydropyranyl. Examples of partially rated heterocyclyls include, but are not limited to, 1,2,3,4-tetrahydroquinolinyl, 4,5-dihydro-oxazolyl, 4,5- dihydro-1H-pyrazolyl, 4,5-dihydro-isoxazolyl, and 2,3-dihydro-[1,3,4]-oxadiazolyl.
Additional examples include the following thietanyl thietany1-dioxide. wo 2013/062981 DETAILED DESCRIPTION This document ses molecules having the following formula ("Formula One"): wherein (a) A is either X~ attachment bond II h Rl~N AI or R2 N= In another embodiment of this invention A is A1.
In another embodiment of this ion A is A2.
In r embodiment of this invention Rl is H.
In another embodiment of this invention R2 is H.
In another embodiment of this invention R3 is selected from H, or substituted or unsubstituted C1-C6 alkyl.
In another embodiment of this invention R3 is selected from H or CH3.
In another embodiment of the invention when A is A1 then A1 is A11.
In another ment of the invention when A is A 1, and A1 is A11, then R4 is selected from H, or substituted or unsubstituted C1-C6 alkyl, or tuted or unsubstituted wo 2013/062981 C6-C2o aryl.
In another embodiment of the invention when A is A1, and A 1 is A11 then R4 is selected from CH3, CH(CH3h, or phenyl.
In another embodiment of the invention when A is A1, and A1 is A12, then R4 is In another embodiment of this invention when A is A2 then R4 is selected from H, or tuted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted CrC10 cycloalkyl, substituted or unsubstituted C6-C20 aryl, wherein each said R4, which is substituted, has one or more tuents selected from F, Cl, Br, or I.
In r embodiment of this invention when A is A2 then R4 isH or C1-C6 alkyl.
In another embodiment of this invention when A is A2 then R4 is H, CH3, CH2CH3, CH=CH2, ropyl, CH2Cl, CF3, or phenyl.
In r embodiment of this invention when A is A2 then R4 is Cl.
In another embodiment of this invention R5 isH, F, Cl, Br, I, or substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy.
In another embodiment of this invention R5 is H, OCH2CH3, F, Cl, Br, or CH3.
In another embodiment of this invention, when A is A1 then R6 is substituted or unsubstituted C1-C6 alkyl.
In another embodiment of this invention when A is A2 then R6 is selected from is substituted or unsubstituted C1-C6 alkyl, substituted or tituted C2-C6 alkenyl, substituted or unsubstituted CrC10 cycloalkyl, C(=X1)R9, C(=X1)X2R9, R9X2R9, CI-C6 alkyl)S(O)n(C1-C6 alkyl), (C1-C6 alkyl)OC(=O)(C6-C2o aryl), (C1-C6 alkyl)OC(=O)(C1-C6 alkyl), or R9X2C(=X1)X2R9.
In another embodiment of this invention when A is A2 then R6 and R8 are connected in a cyclic arrangement, where optionally such arrangement can have one or more heteroatoms selected from 0, S, or, N, in the cyclic structure connecting R6 and R8.
In another embodiment of this invention R6 is C1-C6 alkyl, or C1-C6alkyl-phenyl.
In r embodiment of this invention R6 is H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2phenyl, CH2CH(CH3)2, lopropyl, C(=O)CH2CH2SCH3, C(=O)OC(CH3)3, CH2CH=CH2, C(=O)OCH2CH3, C(=O)CH(CH3)CH2SCH3, cyclopropyl, CD3, CH20C(=O)phenyl, H3, C(=O)CH(CH3)2, CH20C(=O)CH(CH3)2, CH20C(=O)CH3, C(=O)phenyl, CH20CH3, CH20C(=O)CH20CH2CH3, CH2CH20CH3, wo 2013/062981 CH20C(=0)0CH(CH3)2, 0CH20CH3, CH2CH20CH3, CH2CH20C(=O)CH3, CH2CN.
In another embodiment of this invention R6 is methyl or ethyl.
In another embodiment of this invention R7 is 0 or S.
In another embodiment of this invention R8 is selected from tuted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, tuted or unsubstituted CrC10 cycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted CrC20 heterocyclyl, R9C(=Xl)OR9, SR9, S(0)0 0R9, R9S(0)0 R9, or R9S(O)n(NZ)R9.
In another embodiment of this invention R8 is CH(CH3)CH2SCH3, CH(CH3h, C(CH3)2CH2SCH3, CH2CH2SCH3, CH2CF3, CH2CH2C(=O)OCH3, N(H)(CH2CH2SCH3), 2SCH3, CH(CH2SCH3)(CH2phenyl), thiazolyl, oxazolyl, isothiazolyl, substitutedfuranyl , CH3, C(CH3)3, phenyl, CH2CH20CH3, pyridyl, CH2CH(CH3)SCH3, )3, 2CH2SCH3, CH(CH3)CH(CH3)SCH3, )CF3, CH2CH2-thienyl, CH(CH3)SCF3,CH2CH2Cl, CH2CH2CH2CF3, S(=O)CH3, CH(CH3)CH2S( =O)CH3, S(=OhCH3, CH(CH3)CH2S(=OhCH3, NCH2CH3, N(H)(CH2CH2CH3), C(CH3)=C(H)(CH3), N(H)(CH2CH=CH2), CH2CH(CF3)SCH3, CH(CF3)CH2SCH3, thietanyl, CH2CH(CF3)2, CH2CH2CF(OCF3)CF3, CH2CH2CF(CF3)CF3, CF(CH3)2, CH(CH3)phenyl-Cl, CH(CH3)phenyl-F, CH(CH3)phenyl-OCF3, CH2N(CH3)(S(=OhN(CH3)2, CH(CH3)0CH2CH2SCH3, )0CH2CH20CH3, OCH3, CH(CH3)SCH3, CH2SCH3, N(H)CH3, CH(Br)CH2Br, CH2CH2SCH2CH2CF3, CH2CH2SH, CH2CH2SC(phenyl)3, CH2N(CH3)S(0)2CH3, CH(SCH3)(C(=O)CH2SCH3), CH2S(O)CH3, CH2CH(cyclopropyl)SCH3, or CH(CH3)CH2SCD3.
In another embodiment of this invention R8 is selected from (substituted or unsubstituted CrC6 alkyl)-S(0) 0 -(substituted or unsubstituted CrC6 alkyl) wherein said substituents on said substituted alkyls are selected from F, Cl, Br, I, CN, N02, N(R9)S(O)nR9, OR9, S(O)n0R9, R9S(O)nR9, 9, C6-C2o aryl, or C1-C2o heterocyclyl, (each of which that can be substituted, may ally be substituted with R9).
In another embodiment of this invention X is CRn1 where Rn1is H or halo.
In another embodiment of this invention X is CRn1 where Rn1is H or F.
In another embodiment of this invention Xl is 0.
In another embodiment of this invention X2 is 0.
In another embodiment of this invention Rll is substituted or unsubstituted C1-C6 wo 2013/062981 alkylC::CR12.
In another embodiment of this invention R11 is CH2C::CH.
In another embodiment R11 is ably CH2C::CH and R8 is preferably (substituted or unsubstituted C1-C6 alkyl)-S(0)0 -(substituted or unsubstituted C1-C6 alkyl) wherein said substituents on said substituted alkyls are selected from F, Cl, Br, I.
In another embodiment R11 is preferably CH2C::CH and R8 is preferably (unsubstituted C1-C6 alkyl)-S(0)0 -(substituted C1-C6 alkyl) wherein said substituents on said substituted alkyls are selected from F, Cl, Br, I.
In another embodiment R11 is preferably CH2C::CH and R8 is preferably (unsubstituted C1-C2 alkyl)-S(0)0 tituted C1-C3 alkyl) wherein said substituents on said substituted alkyls are F.
The molecules of a One will generally have 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 red if the molecular mass is from about 140 s to about 600 Daltons.
The following schemes illustrate ches to generating aminopyrazoles. In step a of Scheme I, treatment of a 3-acetopyridine or a 5-acetopyrimidine of Formula II, wherein R1, R2, R3 and X are as previously defined, with carbon disulfide and iodomethane in the presence of a base such as sodium hydride and in a solvent such as dimethyl sulfoxide provides the compound of a III. In step b of Scheme I, the nd of Formula III can be d with an amine or amine hydrochloride, in the presence of a base, such as triethylamine, in a solvent such as ethyl alcohol to afford the compound of Formula IV, wherein R1, R2, R3, R6 and X are as usly defined. The compound of Formula IV can be transformed into the aminopyrazole of Formula Va where R5 = H as in step c of Scheme I and as in Peruncheralathan, S. et al. J. Org. Chern. 2005, 70, 9644-9647, by reaction with a hydrazine, such as methylhydrazine, in a polar protic solvent such as ethyl alcohol. wo 2013/062981 Scheme I xY x:X'(sR o s/ a b Xw,HN R~N~ A ~ Rs I _)l 5 ~6 R3 R 1 N R3 R 1 N R3 IT Ill IV Rr-ZX ~~ Another approach to aminopyrazoles is illustrated in Scheme II. In step a, the e of Formula VI wherein X, R1, R2 and R3 are as previously defined and R5 is hydrogen, is condensed as in Dhananjay, B. Kendre et al. J. Het Chern 2008, 45, (5), 1281-86 with hydrazine of Formula VII, such as methylhydrazine to give a mixture of yrazoles of Formula Vb, wherein R5 and R6 =H, both of whose components were isolated.
Scheme II R2 0 R2 R4 H ~ I a )lbX X ~ / H2N....... 'H R~~ N R 1 N N R6 VI VII Vb ation of aminopyrazoles such as those of Formula XIIa is demonstrated in Scheme III. The compound of Formula X in step a and as in Cristau, Henri-Jean et al. Eur. J.
Org. Chern. 2004, 695-709 can be prepared through the N-arylation of a pyrazole of Formula wo 2013/062981 IX with an appropriate aryl halide of Formula VIlla where Q is bromo in the presence of a base such as cesium carbonate, a copper catalyst such as copper (II) oxide and a ligand such as salicylaldoxime in a polar aprotic solvent such as acetonitrile. Compounds of a IX, as shown in Scheme III, wherein R4 = Cl and R5 =H, can be ed as in Pelcman, B. et al Al. Nitration of the pyridylpyrazole of Formula X as in step b of Scheme III and as in Khan, Misbanul Ain et al. J. Heterocyclic Chern. 1981, 18, 9-14 by reaction with nitric acid and ic acid gave compounds of Formula Xla. Reduction of the nitro functionality of compounds of Formula Xla in the ce of hydrogen with a catalyst such as 5% Pd/C in a polar aprotic solvent such as tetrahydrofuran gave the amine of Formula XIIa, as shown in step c in Scheme III. Reduction of the nitro functionality of compounds of Formula Xla, wherein R1, R2, R3, R4 and X are as usly defined and R5 =H, in the presence of hydrogen with a st such as 10% Pd/C in a polar protic solvent such as ethanol gave the amine of Formula XIIa, wherein R5 =H, as well as the amine of Formula XIIa, wherein R5 = OEt, as shown in step d of Scheme III. Compounds of Formula Xla, wherein R1, R2, R3, R5 and X are as previously defined and R4 = Cl, can be reduced in the presence of a reducing agent such as iron in a mixture of polar protic solvents such as acetic acid, water, and ethanol to give amines of Formula XIIa, wherein R1, R2, R3, R5 and X are as previously defined R4 = Cl, as shown in step e of Scheme III. Compounds of Formula Xla, wherein R1, R2, R3, R5 and X are as usly defined and R4 = Cl, can be allowed to react under Suzuki coupling conditions with a boronic acid such as phenylboronic acid in the presence of a catalyst such as palladium tetrakis, a base such as 2M aqueous potassium ate, and in a mixed solvent system such as ethanol and toluene to provide crosscoupled pyrazoles of Formula Xlb, as shown in step f of Scheme III. wo 2013/062981 Scheme III x:):o R4 R2 Rs R, R--0 :XN~~ + a ~N.o # R 4 N 3 H ~ R, R 1 N R3 VIlla IX X c, d ore XI a XIIa In step a of Scheme IV, the compounds of Formula XIIb can be treated with ylorthoformate and an acid such as trifluoroacetic acid. Subsequent addition of a reducing agent such as sodium borohydride in a polar protic solvent such as ethanol gave a compound of Formula XIIIa, wherein R6 =methyl.
In step b of Scheme IV, the compound of Formula XIIb can be d with acetone in a t such as isopropyl acetate, an acid such as trifluoroacetic acid and sodium triacetoxyborohydride to give compounds of Formula XIIIa, wherein R6 =isopropyl.
In step c of Scheme IV, the compounds of Formula XIIb can be acylated with an acid chloride such as acetyl chloride in a polar aprotic solvent such as dichloromethane using the wo 2013/062981 2012/061508 conditions described in Scheme V. Reduction of the amide with a reducing agent such as lithium um hydride in a polar aprotic solvent such tetrahydrofuran gives compounds of Formula XIIIa, wherein R6 = ethyl.
Alternatively, in step d of Scheme IV, the compounds of Formula XIIb can be treated with benzotriazole and an aldehyde in ethanol followed by reduction using, for e, sodium borohydride, to afford compounds of Formula XIIIa. In step e of Scheme IV, the compounds of Formula XIIb can be treated with an aldehyde such as naldehyde and sodium triacetoxyborohydride in a polar aprotic solvent such as dichloromethane to give compounds of Formula XIIIa, wherein R6 =propyl. As in step f, acylation of compounds of Formula XIIIa in Scheme IV using the conditions bed in Scheme IX affords nds of Formula Ia, wherein Rl, R2, R3, R4, R5, R6, R8 and X are as previously defined.
Scheme IV a or b or c or d or e x~Z}{ ~--~ 6 R 1 N R3 XIIIa XIIb Ia In step a of Scheme V, the compounds of Formula Vc, wherein Rl, R2, R3, R4, R5 and R6 and X are as previously defined, can be treated with an acid chloride of Formula XIV, in the presence of a base such as triethylamine or N,N-dimethylaminopyridine in a polar aprotic solvent such as dichloroethane (DCE) to yield nds of Formula Ib, wherein R8 is as previously defined. Additionally, when R6 = H the 2° amide may be subsequently wo 2013/062981 alkylated in step b of Scheme V with an alkyl halide such as iodoethane, in the presence of a base such as sodium hydride and a polar aprotic solvent such as N,N-dimethylformamide (DMF) to yield the desired compounds of Formula lb. The acid chlorides used in the acylation reactions herein are either commercially available or can be synthesized by those skilled in the art.
Scheme V X ~ a or a, b R~~ N)-Rs N \ Vc XIV Ib In step a of Scheme VI and as in Sammelson et al. Bioorg. Med. Chern. 2004, 12, 3345-3355, the yrazoles of Formula Vd, wherein Rl, R2, R3, R4, R6 and X are as previously defined and R5 =H, can be halogenated with a n source such as N- chlorosuccinimide or N-bromosuccinimide in a polar aprotic t such as acetonitrile to provide the stituted pyrazole. In step b, acylation of this compound using the conditions bed in Scheme V affords the compound of FormulaIc, wherein Rl, R2, R3, R4, R5, R6, R8 and X are as previously defined.
Scheme VI X ~ X ~ R~~ R~~ N N Vd Ic In step a of Scheme VII, ureas and carbamates are made from the aminopyrazoles of Formula Ve. Compounds of Formula Ve, wherein X, Rl, R2, R3, R4, R5 and R6 are as previously defined are allowed to react with phosgene to provide the ediate carbamoyl wo 2013/062981 chloride which is subsequently treated with an amine, as shown in step b, or l, as shown in step c, respectively, to generate a urea of Formula Id or a carbamate of Formula Ie, respectively, wherein R9 is as previously defined.
Scheme VII R2 0 )_Cl b/ XV \c R2 0 R2 0 )_ "R9 )_ X ~ N N X ~ 0 R9 R~N--:; \ \ R~~ N R6 H \ R3 R3 Id Te In step a of Scheme VIII, compounds of Formula Xllc, wherein X, Rl, R2, R3, R4 and R5 are as previously defined, can be treated with di-tert-butyl dicarbonate (Boc20) and a base such as triethylamine in a polar aprotic solvent such as dichloromethane (DCM) to yield compounds of a XVIa. Treatment of the carbamate functionality with an alkyl halide such as iodomethane or hydride in the presence of a base such as sodium hydride and in a polar aprotic t such as DMF yields carbamates of Formula XVII, as shown in step b of Scheme VIII, wherein R6 is as previously defined, except where R6 is hydrogen. The wo 2013/062981 Boc-group can be removed under conditions that are well-known in the art, such as under acidic conditions such as trifluoroacetic acid (TFA) in a polar aprotic solvent like dichloromethane to give compounds of Formula XIIIb as in step c.
Scheme VIII a b Xllc XVIa XVII Xlllb In steps a, band c of Scheme IX, compounds of Formula XIIIc, wherein X, R1, R2, R3, R4, R5 and R6 are as previously defined, can be treated with a compound of Formula XVIII, wherein R8 is as previously defined and RlO is either OH, OR9 or O(C=O)OR9, to yield compounds of Formula Id. When RlO = OH, compounds of Formula XIIIc can be converted to compounds of Formula Id in the presence of a ng reagent such as 1-(3- dimethylaminopropyl)ethylcarbodiimide hydrochloride (EDC. HCl) and a base such as N,N-dimethylaminopyridine (DMAP) in a polar aprotic solvent such as dichloroethane (DCE), as shown in step a. When RlO = OR9, compounds of Formula XIIIc can be converted to compounds of a Id in the ce of 2,3 ,4,6,7,8-hexahydro-1H-pyrimido[1,2- a]pyrimidine in a polar aprotic solvent such as 1,4-dioxane under elevated temperature, as shown in step b. When RlO = O(C=O)OR9, nds of Formula XIIIc can be converted to compounds of Formula Id in a polar aprotic t such as dichloromethane (DCM), as shown in step c. ion of amides of Formula Id, when R6 = H, with an acid chloride in wo 2013/062981 the presence of a base such as diisopropyl ethylamine in a polar aprotic t such as dichloroethane (DCE) yields imides of Formula Ie, as shown in step d. Furthermore, alkylation of amides of Formula Id, when R6 =H, with an alkyl halide in the presence of a base such as sodium hydride in a polar aprotic t such as N,N-dimethylformamide (DMF) yields alkylated amides of Formula Ie, as shown in step e. Halogenation of compounds of Formula Id, wherein Rl, R2, R3, R4, R6, R8 and X are as previously defined and R5 =H, with a halogen source such as N-bromosuccinimide in a polar aprotic solvent such as DCE or a halogen source such as N-chlorosuccinimide in a polar aprotic solvent such as DCE or acetonitrile or a halogen source such as Selectfluor® in a mixture of polar aprotic ts such as acetonitrile and DMF give halogenated pyrazoles of Formula Ie, wherein R5 =halogen, as shown in stepf of Scheme IX. Amides of Formula Id can be converted to thioamides of Formula If in the ce of a thionating agent such as Lawesson's t in a polar aprotic solvent such as dichloroethane (DCE), as shown in step g.
Scheme IX a orb or c Xlllc XVIII Id Ie If In step a of Scheme X, compounds of Formula XIIId, n X, Rl, R2, R3, R4, R5 and R6 are as previously defined, can be treated with compounds of Formula XIX, wherein wo 2013/062981 R8 is as previously defined, in a polar aprotic solvent such as dichloroethane (DCE) to yield compounds of Formula XX. Additionally, when R6 =Hand R8 contains a halogen, compounds of Formula XX can be treated with a base, such as sodium hydride, in a polar aprotic solvent, such as THF, to yield compounds of Formula XXI, where m is an integer selected from 1, 2, 3, 4, 5, or 6, as shown in step b of Scheme X.
Scheme X [0, S] + a XIIId XIX XX Oxidation of the sulfide to the sulfoxide or sulfone is accomplished as in Scheme XI where (-S-) can be any sulfide previously defined within the scope of R8 of this invention.
The sulfide of Formula XXIIa, wherein X, R1, R2, R3, R4, R5 and R6 are as previously defined, is treated with an oxidant such as sodium ate ydrate in a polar protic solvent such as glacial acetic acid to give the ide of Formula XXIII as in step a of Scheme XI. atively, the sulfide of Formula XXIIa can be oxidized with an oxidant such as hydrogen peroxide in a polar protic solvent such as uoroisopropanol to give the sulfoxide of Formula XXIII as in step d of Scheme XI. The sulfoxide of Formula XXIII can be further oxidized to the sulfone of Formula XXIV by sodium perborate tetrahydrate in a polar protic solvent such as glacial acetic acid as in step c of Scheme XI. Alternatively, the sulfone of Formula XXIV can be generated in a one-step procedure from the e of Formula XXIIa by using the aforementioned conditions with >2 equivalents of sodium wo 2013/062981 perborate tetrahydrate, as in step b of Scheme XI.
Scheme XI a ord XXIIa XXIII XXIV Oxidation of the sulfide to the imine is accomplished as in Scheme XII where (-S-) can be any sulfide previously defined within the scope of R8 of this ion. The sulfide of Formula XXIIb, wherein X, Rl, R2, R3, R4, R5 and R6 are as previously defined, is ed as in step a with iodobenzene diacetate in the presence of cyanamide in a polar aprotic t such as methylene chloride (DCM) to give the sulfilimine of the Formula XXV. The sulfilimine of Formula XXV may be further oxidized to the sulfoximine of Formula XXVI with an oxidant such as meta-Chloroperoxybenzoic acid ("mCPBA") in the presence of a base such as potassium carbonate in a protic polar solvent system such as ethanol and water as in step b of Scheme XII. wo 2013/062981 Scheme XII XXlib XXV XXVI Iodination of the pyrazole of Formula Xb as in step a of Scheme XIII and as in Potapov, A. et al. Russ. J. Org. Chern. 2006, 42, 1368-1373 was accomplished by reaction with an iodinating agent such as iodine in the presence of acids such as iodic acid and sulfuric acid in a polar protic solvent such as acetic acid gives compounds of Formula XXVII. In step b of Scheme XIII and as in Wang, D. et al. Adv. Synth. Catal. 2009, 351, 1722-1726, yrazoles of Formula XIIIe can be prepared from iodopyrazoles of Formula XXVII through cross coupling reactions with an appropriate amine in the presence of a base such as cesium carbonate, a copper st such as copper (I) e, and a ligand such as 1- (5,6,7,8-tetrahydroquinolinyl)ethanone in a polar aprotic solvent such as DMSO. wo 2013/062981 Scheme XIII Xb XXVII b x2vZi-\'R4 ~~,~ 6 R 1 N R3 XIIIe In step a of the Scheme XIV, compounds of the formula XXIX, n R4 is Cl, R5 isH and x- represents cr, can be prepared according to the methods described in Acta.
Pharm. Suec. 22, 147-156 (1985) by Tolf, Bo-Ragnar and Dahlbom, R. In a similar manner, compounds of the a XXIX, wherein R4 is Br, x- represents Br-and R5 is as defined previously, can be prepared by treating compounds of the Formula XXVIII with hydrogen gas in the presence of a metal catalyst such as 5% Pd on alumina and a solution of 50% aqueous HBr in a solvent such as ethanol. Alternatively, in step a of Scheme XIV, nds of the Formula XXIX, wherein R4 is Cl or Br, x- represents cr or Br- and R5 is as defined previously, can be ed by treating compounds of the Formula XXVIII, wherein R5 is as defined usly, with a hydrosilane such as triethyl silane in the presence of a metal catalyst such as 5% Pd on alumina and an acid such as HCl or HBr, respectively, in a solvent such as ethanol.
In step b of the Scheme XIV, compounds of the Formula XXX, wherein R4 is Cl or Brand R5 is as defined previously, can be prepared by treating the compounds of the Formula XXIX, wherein R4 is Cl or Br, X represents Cr or Br- and R5 is as defined previously, with di-tert-butyl onate (Boc20) in the presence of a mixture of solvents such as THF and water and a base such as sodium bicarbonate.
In step c of the Scheme XIV, compounds of the Formula XVIa, wherein X, R1, R2, wo 2013/062981 R3 and R5 are as defined previously and R4 is Cl or Br can be obtained by treating nds of the Formula XXX, wherein R4 is Cl or Brand R5 is as defined previously, with compounds of the Formula VIIIb, wherein X, Rl, R2 and R3 are as defined previously and Q is bromo or iodo, in the presence of a catalytic amount of copper salt such as CuCb, an ethane-1,2-diamine derivative such as N\N2-dimethylethane-1,2-diamine and a base such as K3P04 in a polar aprotic solvent such as acetonitrile at a suitable temperature.
The Boc-group of compounds of Formula XVIa can be removed under conditions that are well-known in the art such as under acidic conditions such as TFA in a polar aprotic t such as dichloromethane to give compounds of Formula XIId, as shown in step d of Scheme XIV.
Scheme XIV N:{-pI N"~- a b HN j b- - - XXVIII XXIX XXX XIId wo 2013/062981 Bromopyrazoles of a XXXI, wherein Rl, R2, R3, R5, R8 and X are as previously d, can be allowed to react under Suzuki coupling conditions with a boronic ester such as vinylboronic acid pinacol ester or cyclopropylboronic acid pinacol ester in the ce of a catalyst such as palladium tetrakis, a base such as 2 M aqueous potassium carbonate, and in a mixed solvent system such as ethanol and toluene to provide compounds of Formula XXXII, as shown in step a of Scheme XV.
Scheme XV XXXI XXXII The vinyl group of nds of Formula XXXIII, wherein Rl, R2, R3, R5, R6, R8 and X are as previously defined, can be reduced in the presence of en with a catalyst such as 10% Pd/C in a polar protic solvent such methanol to give compounds of Formula XXXIV, as shown in step a of Scheme XVI. Oxidation of the vinyl group of nds of Formula XXXIII using an oxidant such as osmium tetroxide in the presence of sodium periodate in mixture of a polar protic solvent such as water and a polar aprotic solvent such as THF gave compounds of Formula XXXV, as shown in step b of Scheme XVI. Reduction of the aldehyde of compounds of Formula XXXV, as shown in step c of Scheme XVI, with a reducing agent such as sodium borohydride in a polar protic solvent such as methanol gave the ponding alcohol of Formula XXXVI. Treatment of compounds of Formula XXXVI with a chlorinating agent such as thionyl chloride in a polar aprotic solvent such as dichloromethane gave compounds of Formula XXXVII, as shown in step d of Scheme XVI. wo 2013/062981 Scheme XVI ---+ XXXlll XXXIV ---+ XXXV XXXVII In step a of Scheme XVII, an a,B-unsaturated acid XXXVIII can be treated with a nucleophile such as sodium thoxide in a polar protic solvent such as methanol to give acid XXXIX. wo 2013/062981 Scheme XVII 0 0 SMe HO~CF3 a I XXXIX In Step a of the Scheme XVIII, treatment of the compounds of Formula Ig, where A is A2, R7 is 0 and R8 is tert-butoxy with a reagent such as propargyl bromide in the presence of a base such as sodium hydride and in a polar aprotic solvent such as DMF yields compounds of Formula Ih, wherein R6 =Rll.
Scheme XVIII Ig Ih Sulfonamide compounds of Formula Ii, n (-N) can be any amine defined within the scope of R8 of this invention, can be prepared through steps a, b, and c illustrated in Scheme XIX. In step a, acylation of compounds of Formula XIIIf according to methods described in Scheme IX affords compounds of Formula XXXX, wherein Rl, R2, R3, R4, R5, R9, X, and where R6 = Rll are as previously d. Removal of the Boc group of compounds of Formula XXXX, depicted in step b, can be achieved using the conditions described in Scheme XIV to give compounds of Formula XXXXI, wherein Rl, R2, R3, R4, R5, R9, X, and where R6 = Rll are as previously defined. Compounds of a XXXXI can be treated with sulfonyl chlorides of Formula XXXXII such as methanesulfonyl chloride in the presence of a base such as diisopropylethylamine in a polar c solvent such as dichloromethane to give compounds of Formula Ii, as shown in step c of Scheme XIX wo 2013/062981 Scheme XIX Xlllf xxxx .R9 c II - XXXXI XXXXII Ii 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 es.
Starting materials, reagents, and solvents that were obtained from cial sources were used without further cation. ous 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. Molecules 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 molecule, the molecule is named using conventional naming rules. All NMR shifts are in ppm (o) and were recorded at 300, 400 or 600 MHz unless otherwise stated.
Example 1, Step 1: Preparation of 3,3-bis-methylsulfanylpyridinyl-propenone To a emperature suspension of sodium hydride (NaH, 60% suspension in mineral oil; wo 2013/062981 4.13 g, 86 mmol) in dry dimethyl sulfoxide (DMSO, 60 mL) under an atmosphere of nitrogen (N2) was added ylpyridine (5.00 g, 41.3 mmol) dropwise over 30 minutes (min). The mixture was stirred for an additional 30 minutes at the same temperature. Carbon disulfide (CS2; 3.27 g, 43 mmol) was added dropwise with vigorous stirring ed by iodomethane (12.21 g, 86 mmol) dropwise over a period of 45 min. Stirring was continued for an additional18 hours (h) under N2. The reaction was ed with cold water (H20, 50 mL).
The dark solid was filtered and washed with ice-cold ethyl alcohol (EtOH) until the washings were colorless. The off-white solid product was dried under vacuum at 60 oc to provide 3,3- bis-methylsulfanylpyridinyl-propenone as a brown solid (4.8 g, 51%): 1H NMR (300 MHz, CDCb) 8 9.13 (d, J = 1.8 Hz, lH), 8.72 (dd, J = 4.8, 1.6 Hz, lH), 8.23 (ddd, J =7.9, 2, 2Hz, lH), 7.40 (dd, J = 7.9, 4.8 Hz, lH), 6.73 (s, lH), 2.58 (d, J = 9.4 Hz, 6H); MS m/z 226.2 (M+l). 1-(5-fluoropyridinyl)-3,3-bis(methylthio)propenone was ed as described in Example 1, Step 1: mp 150-152 oc; 1H NMR (400 MHz, CDCb) o8.93 (t, J = 1.6 Hz, lH), 8.58(d, J =2.8 Hz, 1H),7.94 (ddd, J = 8.9, 2.8, 1.7 Hz, lH), 6.69 (s, lH), 2.60 (s, 3H), 2.57 (s, 3H).
Example 1, Step 2: Preparation of (Z)methylaminomethylsulfanylpyridinyl- propenone A solution of 3,3-bis-methylsulfanylpyridinyl-propenone (18.6 g, 82.5 mmol) in absolute l (400 mL) under N2 was treated with methylamine hloride (27.86 g, 412 mmol) followed by triethylamine (Et3N; 58.5 mL, 412 mmol). The mixture was heated to reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The solid residue was dissolved in ethyl acetate (EtOAc; 150 mL). The solution was washed with H20 (2 x 50 mL) and brine (50 mL), dried over Na2S04., concentrated under reduced re and purified by silica gel chromatography eluting with 10% EtOAc in petroleum wo 2013/062981 ether to yield (Z)methylaminomethylsulfanylpyridinyl-propenone as a pale yellow solid (8.6 g, 50%): 1H NMR (300 MHz, CDCh) 811.8 (br s, 1H), 9.06 (s, 1H); 8.67 (d, J = 3.9 Hz, 1H), 8.26 (d, J = 8.0 Hz 1H), 7.46 (dd, J = 7.6, 4.9 Hz 1H), 5.62 (s, 1H), 3.10 (d, J = 5.2 Hz, 3H), 2.52 (s, 3H); MS (mlz) 209.2 [M+1].
(Z)(ethylamino)-3(methylthio)(pyridinyl)propenone was prepared as described in Example 1, Step 2: 1H NMR (400 MHz, CDCb) 8 11.81 (bs, 1H), 9.04 (dd, J = 2.2, 0.7 Hz, 1H), 8.64 (dd, J = 4.8, 1.7 Hz, 1H), 8.29-7.98 (m, 1H), 7.35 (ddd, J =7.9, 4.8, 0.9 Hz, 1H), 3.45 (q, J =7.2, 5.6 Hz, 2H), 2.50 (s, 3H), 1.35 (t, J =7.2 Hz, 3H).
(Z)(cyclopropylmethyl)amino-3(methylthio)(pyridinyl)propenone was prepared as bed in Example 1, Step 2: 1H NMR (400 MHz, CDCh) 8 9.00 (s, 1H), 9.05 (dd, J = 2.2, 0.7 Hz, 1H), 8.64 (dd, J = 4.8, 1.7 Hz, 1H), 8.16 (dt, J =7.9, 2.0 Hz, 1H), 7.35 (ddd, J = 7.9, 4.8, 0.8 Hz, 1H), 5.62 (s, 1H), 3.27 (dd, J = 7.0, 5.5 Hz, 2H), 2.50 (s, 3H), 1.20 - 1.07 (m, 1H), 0. 73 - 0.49 (m, 2H), 0.41 - 0.17 (m, 2H).
Example 1, Step 3: Preparation of methyl-(2-methylpyridinpyrazolyl)-amine ~~-H A solution of (Z)methylaminomethylsulfanylpyridinyl-propenone (3.00 g, 14 mmol) and methylhydrazine (729 mg, 15.4 mmol) in absolute EtOH (64 mL) was d at reflux for 18 h under N2, cooled to room temperature and evaporated under d pressure.
The residue was dissolved in EtOAc (50 mL), and the organic layer was washed with H20 (2 x 30 mL) and brine (30 mL), dried over Na2S04, concentrated under reduced pressure and purified using silica gel chromatography eluting with a gradient of 0-1% EtOH in EtOAc to yield two regioisomers in a 1:2 ratio, with the major regioisomer as a brown solid (1.0 g, 27%): 1H NMR (300 MHz, CDCb) 8 8.97 (d, J = 1.3 Hz, 1H), 8.51 (dd, J = 3.6, 1.0 Hz, 1H), 8.07 (ddd, J = 5.9, 1.4, 1.4 Hz, 1H), 7.30 (dd, J = 5.9, 3.6 Hz, 1H), 5.82 (s, 1H), 3.69 (s, 3H), 2.93 (s, 3H); MS (mlz) 188.6 [M+1]. wo 2013/062981 1-Ethyl-N-methyl(pyridinyl)-1H-pyrazolamine was prepared as described in Example 1, Step 3: ESIMS m/z 204 ([M+2H]).
N-ethylmethyl(pyridinyl)-1H-pyrazolamine was prepared as described in Example 1, Step 3: ESIMS m/z 203 ([M+H]).
N-methylphenyl(pyridinyl)-1H-pyrazolamine was prepared as described in Example 1, Step 3: ESIMS m/z 252 ([M+2H]). lopropylmethyl)methyl(pyridinyl)-1H-pyrazolamine was prepared as described in Example 1, Step 3: ESIMS m/z 230 ([M+2H]). 1-Isopropyl-N-methylpyridinyl)-1H-pyrazolamine was prepared as described in Example 1, Step 3: 1H NMR (300 MHz, CDCb) o8.53 (s, 1H), 8.06-7.90 (m, J =7.2 Hz, 2H), 7.13 (dd, J = 7.9, 5.6 Hz, 1H), 5.33 (s, 1H), 3.70 (bs, 1H), 3.65 (dt, J = 13.2, 6.6 Hz, 1H), 2.31 (s, 3H), 0.88 (d, J = 6.6 Hz, 6H); ESIMS m/z 217 ([M+H]). 3-(5-Fluoropyridinyl)-N, 1-dimethyl-1H-pyrazolamine was ed as described in Example 1, Step 3: 1H NMR (300 MHz, CDCb) o8.28 (s, 1H), 7.87 (t, J = 1.3 Hz, 1H), 7.60 (m, 1H), 6.66 (s, 1H), 5.28 (bs, 2H), 3.12 (s, 3H), 2.34 (s, 3H); ESIMS m/z 206 ([M+H]) Example 2: Preparation of (4-chloromethylpyridinyl-2H-pyrazolyl)-methylamine ~)_.H l!..Nd II ~ A e of methyl-(2-methylpyridinyl-2H-pyrazolyl)-amine (0.35 g, 1.8 mmol) and N-chlorosuccinimide (0.273 g, 2 mmol) was combined in acetonitrile (3 mL), stirred at room temperature for 30 minutes, concentrated under reduced pressure and purified using wo 2013/062981 2012/061508 silica gel chromatography eluting with a gradient of EtOAc in hexanes to yield the title compound as a yellow oil (0.096 g, 23%): IR (thin film) 1581.6 cm-1; 1H NMR (400 MHz, CDCb) 8 9.12 (d, J = 1.5 Hz, 1H), 8.57 (dd, J = 4.8, 1.3 Hz, 1H), 8.15 (ddd, J =7.8, 2.0, 2.0 Hz, 1H), 7.33 (dd, J = 8.1, 5.1 Hz, 1H), 3.80 (s, 3H), 2.91 (d, J = 5.8 Hz, 3H); ESIMS (mlz) 225.6 [M+2].
The reaction also gave 4-chloromethylpyridinyl-2H-pyrazolylamine as a green gum (0.046 g, 13%): IR (thin film) 1720.5 cm-1.; 1H NMR (CDCb, 400 MHz) 8 9.13 (br s, 1H), 8.57 (br s, 1H), 8.16 (dt, J = 8.0, 2.0 Hz, 1H), 7.33 (dd, J =7.8, 4.8 Hz, 1H), 3.76 (s, 3H); ESIMS (mlz) 207.0 [M-1].
Example 3: ation of 2,N-dimethyl-N-(2-methylpyridinyl-2H-pyrazolyl)- 3-methylsulfanyl-propionamide (Compound 1) To a solution of methyl-(2-methylpyridinyl-2H-pyrazolyl)-amine (150 mg, 0.8 mmol) under N2 in ice-cold dichloroethane (DCE; 2 mL) was added dropwise via pipette a solution of 2-methylmethylsulfanyl-propionylchloride (146 mg, 0.9 mmol) in DCE (1.5 mL). After stirring for 10 minutes (min), a solution of 4-N,N-dimethylaminopyridine (DMAP; 107 mg, 0.9 mmol) in DCE (2 mL) was added dropwise. The ice bath was removed after 30 min, and the mixture was stirred at room temperature for 90 min and then at reflux for 14 h. The mixture was concentrated under reduced re and was purified by silica gel chromatography eluting with a gradient of EtOAc in hexane. The product, methyl-N- (2-methylpyridinyl-2H-pyrazolyl)methylsulfanyl-propionamide, was isolated as a yellow semi-solid (44 mg, 24%): 1H NMR (400 MHz, CDCb) 8 9.00 (s, 1H), 8.58 (s, 1H), 8.08 (br d, J =7.0 Hz, 1H), 7.35 (br dd, J = 7.3, 4.8 Hz, 1H), 6.58 (br s, 0.5 H), 6.49 (br s, 0.5 H), 3.89-3.79 (m, 3H), 3.25 (s, 3H), 2.96-2.80 (m, 1H), 2.42-2.40 (m, 1H), 2.02-1.99 (m, 3H), 2.62 (m, 1H), 1.15 (d, J = 6.0 Hz, 3H); MS (mlz) 305.0 [M+1]. wo 2013/062981 Compounds 2-6,9-10, 12, 24-33, 477, 487,509,520,556-557, 562-568 were made from the appropriate amines in ance with the procedures disclosed in Example 3.
Example 4: Preparation of 1-methyl(2-methylpyridinyl-2H-pyrazolyl)(2- methylsulfanyl-ethyl)-urea (Compound 7) To a solution of methyl-(2-methylpyridinyl-2H-pyrazolyl)-amine (150 mg, 0.8 mmol) in ice-cold DCE (2 mL) under N2 was added a solution of phosgene in toluene (20%, 0.43 mL, 0.88 mmol). The ice bath was removed after 30 min, and the mixture was stirred at room temperature for 1 h and at reflux for 2 h. The mixture was cooled to room temperature and then more phosgene (0.86 mL, 1.76 mmol) was added. The mixture was d at reflux for 90 min and then cooled in an ice bath. To this was added a solution of 2- methylthioethylamine (80 mg, 0.88 mmol) in DCE (2 mL). The ice bath was removed after min, and the reaction mixture was stirred at reflux for 14 h, cooled, and diluted with DCE (30 mL). The d reaction mixture was washed with saturated NaHC03 (20 mL), dried over MgS04, adsorbed onto silica gel and purified using silica gel chromatography eluting with a gradient of methanol in dichloromethane to afford 1-methyl(2-methylpyridin pyrazolyl)(2-methylsulfanyl-ethyl)-urea as a yellow gum (14 mg, 6%): 1H NMR (400 MHz, CDCb) 8 8.99 (d, J = 1.5 Hz, 1H), 8.57 (dd, J = 4.8, 1.5 Hz, 1H), 8.08 (ddd, J = 8.1, 2.1, 2.1 Hz, 1H), 7.34 (dd, J =7.9, 4.8 Hz, 1H), 6.52 (s, 1H), 4.88 (br t, J = 5.5 Hz, 1H), 3.80 (s, 3H), 3.41 (q, J = 6.3 Hz, 2H), 3.24 (s, 3H), 2.61 (t, J = 6.3, 2H), 2.06 (s, 3H); ESIMS (mlz) 292.2 [M+2].
Compound 8 was made in accordance with the procedures disclosed in Example 4 using 2-(methylthio)ethanol in place of 2-methylthioethylamine.
Example 5: ation of 1-methyl(pyridinyl)-1H-pyrazolamine and 1-methyl- wo 2013/062981 3-(pyridinyl)-1H-pyrazolamine To ethanol (8.53 ml) was added 3-(pyridinyl)propanenitrile (0.82 g, 5.61 mmol) and methylhydrazine (0.25 g, 5.61 mmol) and stirred at reflux for 2 hours. The reaction was cooled to room temperature and concentrated to dryness. The crude material was purified by silica gel chromatography by eluting with 0-20% MeOH I dichloromethane to yield two products methyl(pyridinyl)-1H-pyrazolamine (0.060 g; 6.14%): 1H NMR (300 MHz, CDCb) 8 8.72 (s, 1H), 8.53 (d, 1H), 7.76-7.63 (m, 1H), 7.43-7.33 (m, 1H), 5.75 (s, 1H), .57 (m, 5H) and 1-methyl(pyridinyl)-1H-pyrazolamine (0.150 g, .35%): 1H NMR (300 MHz, CDCb) o8.88 (s, 1H), 8.48 (d, 1H), 7.99 (d, 1H), 7.38-7.07 (m, 1H), 585 (s, 1H), 3.80-3.59 (m, 5H).
Example 6, Step 1: Preparation of 3-pyrazolyl-pyridine To a solution of 3-bromopyridine (5 g, 0.031 mol) in 50 ml of acetonitrile were added pyrazole (2.6 g, 0.038 mol), Cs2C03 (16.5 g, 0.050 mol), Cu20 (0.226 g, 0.0016 mol), and laldoxime (0.867 g, 0.006 mol) under N2 atmosphere. The on mass was refluxed for 24 hrs at 80 °C. The reaction mass was concentrated and the crude was purified by column chromatography using ethyl acetate and hexane (1:1) to afford the pyrazolyl pyridine as a dark brown liquid (2 g, 43 %): 1H NMR (400 MHz, CDCb) 8 8.99 (d, J =2.8 Hz, 1H), 8.48 (dd, J = 4.8, 1.2 Hz, 1H), 8.11-8.08 (m, 1H), 7.99 (d, J = 1.2 Hz, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.38-7.35 (m, 1H), 6.53 (t, J = 1.2 Hz, 1H); MS (mlz) 146 [M+1]. 3-(3-chloro-1H-pyrazolyl)pyridine was prepared as in Example 6, Step 1: mp 98-106 oc; wo 2013/062981 1H NMR (400 MHz, CDCb) o8.93 (d, J = 2.6 Hz, 1H), 8.57 (dd, J = 4.8, 1.4 Hz, 1H), 8.03 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 7.90 (d, J =2.5 Hz, 1H), 7.42 (ddd, J = 8.3, 4.8, 0.7 Hz, 1H), 6.46 (d, J =2.5 Hz, 1H); 13C (DMSO-d6) 148, 142, 140, 136, 131, 126, 125, 108. 2-methyl(3-methyl-1H-pyrazolyl)pyridine was prepared as in Example 6, Step 1: 1H NMR (400 MHz, CDCb) o8.53 (d, J = 4.7 Hz, 1H), 7.67 (d, J =7.9 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.27- 7.19 (m, 1H), 6.27 (d, J = 1.4 Hz, 1H), 2.53 (s, 3H), 2.38 (s, 3H).
Trifluoromethyl)-1H-pyrazolyl)pyridine was prepared from the appropriate starting materials as described in Example 6, Step 1.: mp 59.0-61.0 oc; 1H NMR (400 MHz, CDCl3) o9.00 (s, 1H), 8.70-8.59 (m, 1H), 8.11 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 8.05-7.98 (m, 1H), 7.46 (dd, J = 8.3, 4.8 Hz, 1H), 6.79 (d, J =2.4 Hz, 1H); ElMS m/z 213. 3-Fluoro(3-methyl-1H-pyrazolyl)pyridine was prepared from the appropriate starting materials as described in Example 6, Step 1: mp 70.0-72.0 oc; 1H NMR (400 MHz, CDCl3) o 8.76- 8.73 (m, 1H), 8.37- 8.33 (m, 1H), 7.88- 7.85 (m, 1H), 7.84- 7.79 (m, 1H), 6.34- 6.29 (m, 1H), 2.37 (s, 3H); ElMS m/z 177. 3-(3-Chloro-1H-pyrazolyl)fluoropyridine was prepared from the riate starting materials as described in Example 6, Step 1: mp 2.0 oc; 1H NMR (400 MHz, CDCb) o 8.75 (d, J = 1.8 Hz, 1H), 8.43 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 2.6 Hz, 1H), 7.84 (dt, J = 9.3, 2.4 Hz, 1H), 6.48 (d, J =2.6 Hz, 1H); ElMS m/z 198. 3-(3-methyl-1H-pyrazolyl)pyridine was ed as described in Example 6, Step 1: 1H NMR (400 MHz, CDCb) o8.94 (bs, 1H), 8.51 (d, J = 3.9 Hz, 1H), 8.02 (ddd, J = 8.3, 2.6, 1.5 Hz, 1H), 7.90-7.79 (m, 1H), 7.39 (dd, J = 8.2, 5.1 Hz, 1H), 6.30 (d, J =2.4 Hz, 1H), 2.39 (s, 3H). 3-(5-methyl-1H-pyrazolyl)pyridine was prepared as in Example 6, Step 1: 1H NMR (400 MHz, CDCb) o8.77 (d, J =2.5 Hz, 1H), 8.65 (dd, J = 4.8, 1.5 Hz, 1H), 7.84 (ddd, J = 8.2, 2.5, 1.5 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.44 (ddd, J = 8.2, 4.8, 0.7 Hz, 1H), 6.225 (dd, J = 1.6, 0.7 Hz, 1H), 2.40 (s, 3H). wo 62981 Example 6, Step 2: Preparation of itro-pyrazolyl)-pyridine u"~NO, 3-Pyrazolyl-pyridine (2 g, 0.032 mol) was dissolved in concentrated H2S04 (32 mL 0.598 mmol.) and cooled to -5 °C using an ice bath. To the reaction mass, a 1: 1 mixture of concentrated HN03 (30 mL, 0.673 mmol) and concentrated H2S04 (30ml, 15 Vol.) was added dropwise over a period of 30 min. Cooling was discontinued and the reaction e was stirred at room temperature overnight. After the reaction was complete, the e was poured over crushed ice and neutralized with saturated NaHC03, filtered, washed with water and dried to furnish the nitro pyrazole as pale yellow solid (1.8 g, 68%): 1H NMR (400 MHz, DMSO-d6) 8 9.03 (d, J =2.8 Hz, 1H); 8.70 (dd, J = 4.8, 1.6 Hz, 1H), 8.69 (s, 1H), 8.33 (s, 1H), 8.11 - 8.08 (m, 1H), 7.51 (dd, J = 8.4, 4.8 Hz, 1H); MS (mlz) 191 [M+1]. 3-(3-chloronitro-1H-pyrazolyl)pyridine was prepared as in Example 6, Step 2: mp 139- 142 oc, 1H NMR (400 MHz, CDCb) o9.01 (d, J =2.0 Hz, 1H), 8.73 (d, J =4.9 Hz, 2H), 8.08 (ddd, J = 8.3, 2.5, 1.3 Hz, 1H), 7.52 (dd, J = 8.3, 4.8 Hz, 1H), ElMS m/z 224. 3-(5-methylnitro-1H-pyrazolyl)pyridine was prepared as in Example 6, Step 2: 1H NMR (400 MHz, CDCb) o8.81-8.71 (m, 2H), 8.32 (s, 1H), 7.83 (ddd, J = 8.2, 2.5, 1.6 Hz, 1H), 7.54 (dd, J = 8.2, 4.8 Hz, 1H), 2.72(s, 3H). 2-methyl(3-methylnitro-1H-pyrazolyl)pyridine was prepared as in Example 6, Step 2: 1H NMR (400 MHz, d 6-DMSO) o14.01 (s, 1H), 9.37 (d, J =4.0 Hz, 1H), 8.69 (t, J = 17.3 Hz, 1H), 8.21 (dd, J =7.7, 4.8 Hz, 1H), 2.29 (s, 3H), 2.20 (s, 3H); .13C 154, 150, 146, 135, 134.9, 134.8, 134.3, 122, 21, 14; ElMS m/z 218. 3-(3-methylnitro-1H-pyrazolyl)pyridine was prepared as in Example 6, Step 2: mp 122 -124 oc; 1H NMR (400 MHz, CDCb) o9.01 (d, J =2.5 Hz, 1H), 8.77-8.56 (m, 2H), 8.07 wo 2013/062981 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 7.56-7.37 (m, 1H), 2.66 (s, 3H); ElMS m/z 208. 3-Fluoro(3-methylnitro-1H-pyrazolyl)pyridine was prepared from the appropriate ng material as described in Example 6, Step 2: mp 90.0-92.0 oc; 1H NMR (400 MHz, CDCl3) o8.82 (d, J = 2.0 Hz, 1H), 8.69 (s, 1H), 8.54 (d, J = 2.5 Hz, 1H), 7.89 (dt, J = 8.9, 2.4 Hz, 1H), 2.66 (s, 3H); ElMS m/z 222. 3-(4-Nitro(trifluoromethyl)-1H-pyrazolyl)pyridine was prepared from the appropriate starting material as described in Example 6, Step 2: mp 121.0-123.0 oc; 1H NMR (400 MHz, CDCl3) o9.04 (d, J =2.5 Hz, 1H), 8.79 (s, 1H), 8.77 (d, J = 0.9 Hz, 1H), 8.13 (ddd, J = 8.3, 2.7, 1.4 Hz, 1H), 7.55 (dt, J = 10.8, 5.4 Hz, 1H); ElMS m/z 258. 3-(3-Chloronitro-1H-pyrazolyl)fluoropyridine was ed from the appropriate starting material as described in Example 6, Step 2: mp 109.5-111.0 oc; 1H NMR (400 MHz, CDCb) o8.83 (d, J = 2.1 Hz, 1H), 8.75 (s, 1H), 8.60 (d, J =2.4 Hz, 1H), 7.89 (dt, J = 8.6, 2.4 Hz, 1H); ElMS m/z 242. 3-(3-Bromonitro-1H-pyrazolyl)pyridine was prepared from the appropriate starting material as described in Example 6, Step 2: mp 139.0-141.0 oc; 1H NMR (400 MHz, CDCb) o9.01 (d, J = 2.5 Hz, 1H), 8.73 (dd, J = 4.7, 1.1 Hz, 1H), 8.71 (s, 1H), 8.15-8.00 (m, 1H), 7.52 (dd, J = 8.3, 4.8 Hz, 1H); ESlMS m/z 271 ([M+2t). e 6, Step 3: Preparation of 1-pyridinyl-lH-pyrazolylamine To a solution of 3-(4-nitro-pyrazolyl)-pyridine (1.8 g, 0.009 mol) in dry THF (18 ml) was added 5% Pd/C (180 mg) under nitrogen atmosphere. The e was then stirred under hydrogen atmosphere until the reaction was complete. The reaction mixture was filtered through a pad of , and concentrated to dryness to give an impure dark brown solid (1.76 g): 1H NMR (400 MHz, DMSO-d6) o8.89 (dd, J = 2.8. 0.4 Hz, 1H); 8.48 (dd, J = 4.8, 1.2 Hz, wo 2013/062981 2012/061508 1H), 7.99-7.96 (m, 1H), 7.54 (d, J = 1.2 Hz, 1H), 7.45 (d, J =0.4 Hz, 1H), 7.38-7.35 (m, 1H), 4.81 (bs 1H); ESIMS (mlz) 161 [M+l]. -methyl(pyridinyl)-1H-pyrazolamine was ed as in Example 6, Step 3: 1H NMR (400 MHz, CDCb) o8.74 (d, J =2.3 Hz, 1H), 8.63-8.50 (m, 1H), 7.81 (ddd, J = 8.2, 2.5, 1.5 Hz, 1H), 7.46-7.33 (m, 2H), 2.64 (bs, 1H),, 2.29 (s, 3H); 13C (DMSO-d 6) 147, 144, 137, 133, 130, 129, 124, 123, 10; ElMS m/z 174 3-methyl(pyrimidinyl)-1H-pyrazolamine was prepared as in Example 6, Step 3: mp 211-215 oc; 1H NMR (400 MHz, CDCb) o9.10-8.87 (m, 3H), 7.51 (s, 1H), 3.24 (bs, 2H), 2.29 (s, 3H); ESIMS m/z 176 ([M+H]). 3-chloro(pyrimidinyl)-1H-pyrazolamine was prepared as in Example 6, Step 3: mp 146-148 oc; 1H NMR (400 MHz, CDCb) o9.07 (s, 1H), 9.02 (s, 2H), 7.52 (s, 1H), 3.45 (s, 2H); ESIMS m/z 196 ([M+H]).
Example 7: Preparation of methyl-(1-pyridinyl-lH-pyrazolyl)-amine N~ H r('YN..._r-N~ ll..J MethodA: To a 25 ml round bottom flask containing dinyl-1H-pyrazolylamine (1.76 g, 0.011 mol) in ethanol (26.4 ml) was added benzotriazole (1.31 g, 0.011 mol). The reaction was cooled to 0 °C- 10° C and formaldehyde (0.36 mL, 0.0121 mol) was added slowly and kept for 30 min at this temperature. The reaction was filtered and concentrated to dryness.
The crude material (2.56 g, 0.009 mol) was dissolved in dry tetrahydrofuran (25.6 mL), cooled to 0 ° C and sodium dride (0.326 g, 0.00882 mol.) was added over 15 min. The reaction was warmed to room temperature and stirred for 2 hours. The reaction was poured into water and extracted using dichloromethane, the organic layer was dried over anhydrous Na2S04 and concentrated to dryness. Purified the crude al by silica gel chromatography eluting with 20% methanol I chloroform to afford the d product as a brown solid (0.610 wo 2013/062981 g, 32 %): 1H NMR (400 MHz, d ) 8 8.92 (d, J =2.4 Hz, 1H), 8.47 (dd, J = 4.8, 1.6 Hz, 1H), 8.01-7.98 (m, 1H), 7.45 (s, 1H), 7.30 (s, 1H), 7.37 (dd, J = 8.0, 4.4 Hz, 1H), 2.84 (s, 3H); ESIMS m/z 175 ([M+1]).
Method B: 1-pyridinyl-1H-pyrazolylamine (1.0 g, 6.2 mmol) was dissolved in triethyl orthoformate (5 ml, 30 mmol) and to that was added trifluoroacetic acid (3-4 drops). The reaction mixture was refluxed at l20°C for 3 hours and was then concentrated. The crude was dissolved in ethanol (5 ml), cooled to ooc and treated with sodium borohydride (0.6 g, 15.7 mmol). After warming to room temperature, the mixture was refluxed for 3 hours. The e was concentrated and the residue was suspended between water and diethyl ether.
The diethyl ether layer was separated and concentrated to dryness. The crude material was purified by silica gel chromatography, eluting with 5% methanol I chloroform to afford the desired product as a pale yellow solid (0.3 g, 27%): mp 65- 67 oc; 1H NMR (300 MHz, CDCb) o8.91 (bs, 1H), 8.46 (d, J = 4.5 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.43 (s, 1H), 7.41 (s, 1H), 7.36 (dd, J = 8.3, 4.7 Hz, 1H), 2.86 (d, J = 12.4 Hz, 3H); ESIMS m/z 175 ([M+1]).
Example 8: ation of (1-pyridinyl-lH-pyrazolyl)-amine a"--r;N~ H N Method A: To 1-pyridinyl-1H-pyrazolylamine (0.5 g, 3.12 mmol) in dichloromethane (5 ml) was added acetyl chloride (0.28 g, 3.75 mmol) followed by DMAP (0.57 g, 4.68 mmol) and stirred at room ature for 3 hours. The reaction mixture was concentrated and purified by silica gel column chromatography. The recovered material was dissolved in tetrahydrofuran (5ml) and lithium aluminum hydride (0.23 g, 6.25 mmol) was added and stirred at room temperature for 12 hours. The reaction was quenched with saturated Na2S04 and filtered through . The filtrate was collected and concentrated to dryness. The crude al was purified by silica gel column chromatography eluting with 0-5% methanol I wo 2013/062981 chloroform and resubjected to silica gel chromatography, eluting with 0-100% ethyl acetate I hexanes) to give the desired product (0.080 g, 14%): 1H NMR (400 MHz, CDCb) o8.90 (d, J = 2.7 Hz, 1H), 8.46 (dd, J = 4.7, 1.3 Hz, 1H), 7.98 (ddd, J = 8.3, 2.6, 1.5 Hz, 1H), 7.41 (dt, J = 13.3, 6.6 Hz, 2H), 7.36 (ddd, J = 8.3, 4. 7, 0.7 Hz, 1H), 3.10 (q, J = 7.1 Hz, 2H), 1.27 (t, 3H).
MethodE: To a solution of tert-butyl ethyl(1-(pyridinyl)-1H-pyrazolyl)carbamate (3.4 g, 11.79 mmol) in dichloromethane (4.54 ml) was added trifluoroacetic acid (9 ml), and the reaction e was stirred for 1 hour at room temperature. Toluene was added and the reaction was concentrated to near dryness. The reaction was poured into a separatory funnel and carefully quenched with saturated aqueous NaHC03 and extracted with dichloroethane. The organic layer was dried (MgS04), filtered and concentrated to s. The crude product was purified by silica gel chromatography (0-10% MeOH I dichloromethane) to give the desired product as a pale yellow oil (2.10 g, 95%): 1H NMR (400 MHz, CDCb) o8.90 (dd, J = 1.8, 0.8 Hz, 1H), 8.51- 8.39 (m, 1H), 7.97 (ddt, J = 8.3, 2.7, 1.3 Hz, 1H), 7.41 (d, J =0.8 Hz, 2H), 7.38-7.30 (m, 1H), 3.21-2.93 (m, 2H), 1.34- 1.19 (m, 3H). 3-chloro-N-ethyl(pyridinyl)-1H-pyrazolamine was prepared as bed in Example 8, Method B: 1H NMR (400 MHz, CDCb) o8.87 (d, J = 2.5 Hz, 1H), 8.47 (dd, J = 4.7, 1.2 Hz, 1H), 7.96 (ddd, J = 8.4, 2.6, 1.4 Hz, 1H), 7.38- 7.32 (m, 2H), 3.11 (q, J = 7.1 Hz, 2H), 2.97 (bs, 1H), 1.31 (t, J =7.1 Hz, 3H). 3-chloro-N-methyl(pyridinyl)-1H-pyrazolamine was prepared as in e 8, Method B: mp 108-118 C; 1H NMR (400 MHz, CDCb) o8.88 (d, J = 2.4 Hz, 1H), 8.48 (dd, J = 4.7, 1.4 Hz, 1H), 7.96 (ddd, J = 8.3, 2.7, 1.4 Hz, 1H), 7.41- 7.29 (m, 2H), 2.87 (s, 3H); ElMS m/z 208.
N,3-dimethyl(pyridinyl)-1H-pyrazolamine was prepared as in Example 8, Method B: 1H NMR (400 MHz, CDCb) o9.03- 8.73 (m, 1H), 8.41 (dd, J = 4.7, 1.4 Hz, 1H), 7.95 (ddd, J = 8.4, 2.7, 1.4 Hz, 1H), 7.42- 7.27 (m, 2H), 2.85 (s, 4H), 2.25 (s, 3H); ElMS m/z 189 3-chloro-N-(cylopropylmethyl)(pyridinyl)-1H-pyrazolamine was prepared as in wo 2013/062981 Example 8, Method B: 1H NMR (400 MHz, CDCb) o8.86 (d, J = 2.5 Hz, 1H), 8.47 (dd, J = 4.7, 1.4 Hz, 1H), 8.03- 7.89 (m, 1H), 7.40- 7.29 (m, 2H), 3.21 (s, 1H), 2.91 (d, J =4.4 Hz, 2H), 1.18 - 1.02 (m, 1H), 0.65 - 0.45 (m, 2H), 0.41 - 0.12 (m, 2H). 3-chloro-N-propyl(pyridinyl)-1H-pyrazolamine was prepared as in Example 8, Method B: 1H NMR (400 MHz, CDCb) o8.86 (d, J =2.6 Hz, 1H), 8.47 (dd, J = 4.7, 1.4 Hz, 1H), 8.01 - 7.89 (m, 1H), 7.42- 7.27 (m, 2H), 3.23- 2.84 (m, 3H), 1.77- 1.59 (m, 2H), 1.03 (t, J =7.4 Hz, 3H). 1-(5-Fluoropyridinyl)-N,3-dimethyl-1H-pyrazolamine was prepared from the appropriate Boc-amine as described in Example 8, Method B: mp 142.0-143.5 oc; 1H NMR (400 MHz, CDCb) o8.67 (s, 1H), 8.26 (d, J = 2.3 Hz, 1H), 7.73 (dt, J = 10.0, 2.4 Hz, 1H), 7.27 (s, 1H), 2.92- 2.81 (m, 4H), 2.24 (s, 3H); ESIMS m/z 207 ([M+Ht).
N-ethyl(5-fluoropyridinyl)methyl-1H-pyrazolamine was prepared from the appropriate Boc-amine as described in Example 8, Method B: mp 85.0-86.0 oc; 1H NMR (400 MHz, CDCb) o8.66 (s, 1H), 8.25 (d, J = 2.5 Hz, 1H), 7.72 (dt, J = 10.0, 2.3 Hz, 1H), 7.27 (s, 1H), 3.07 (q, J =7.1 Hz, 2H), 2.71 (s, 1H), 2.25 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); ESIMS m/z 221 ). 3-Methyl-N-propyl(pyridinyl)-1H-pyrazolamine was prepared from the appropriate Boc-amine as described in Example 8, Method B: mp 65.0-67.0 oc; 1H NMR (400 MHz, CDCl3) o8.86 (d, J = 2.4 Hz, 1H), 8.40 (dd, J = 4.7, 1.4 Hz, 1H), 7.94 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 7.35-7.28 (m, 2H), 3.00 (t, J =7.1 Hz, 2H), 2.26 (s, 3H), 1.76- 1.58 (m, 2H), 1.03 (t, J =7.4 Hz, 3H); ESIMS m/z 217 ([M+Ht).
N-(cyclopropylmethyl)methyl(pyridinyl)-1H-pyrazolamine was prepared from the riate Boc-amine as described in Example 8, Method B: mp 73.0-75.0 oc; 1H NMR (400 MHz, CDCl3) o8.86 (d, J =2.4 Hz, 1H), 8.40 (dd, J = 4.7, 1.3 Hz, 1H), 7.94 (ddd, J = 8.3, 2.6, 1.5 Hz, 1H), 7.35- 7.28 (m, 2H), 2.87 (d, J = 6.9 Hz, 2H), 2.75 (s, 1H), 2.28 (s, 3H), 1.22- 1.05 (m, 1H), 0.63- 0.56 (m, 2H), 0.26 (q, J = 4.7 Hz, 2H); ESIMS m/z 229 ([M+Ht). wo 2013/062981 N-isopropylmethyl(pyridinyl)-1H-pyrazolamine was prepared from the appropriate Boc-amine as described in Example 8, Method B: lR (thin film) 3303 cm-1; 1H NMR (400 MHz, CDCl3) o8.86 (d, J = 2.3 Hz, 1H), 8.41 (dd, J = 4.7, 1.4 Hz, 1H), 7.94 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 7.36- 7.28 (m, 2H), 3.30 (hept, J =6.3 Hz, 1H), 2.25 (s, 3H), 1.24 (d, J = 6.3 Hz, 6H); ElMS m/z 216.
-Ethoxy(5-fluoropyridinyl)-N,3-dimethyl-1H-pyrazolamine was prepared from the appropriate Boc-amine as described in Example 8, Method B: lR (thin film) 3340 cm-1; 1H NMR (400 MHz, CDCb) o8.91 (s, 1H), 8.31 (d, J =2.5 Hz, 1H), 7.88- 7.80 (m, 1H), 4.24 (q, J =7.1 Hz, 2H), 2.79 (s, 3H), 2.24 (s, 3H), 1.36 (t, J =7.1 Hz, 3H); ElMS m/z 250.
-Bromo-N-methyl(pyridinyl)-1H-pyrazolamine was ed from the appropriate Boc-amine as described in Example 8, Method B: mp 77.0-79.0 oc; 1H NMR (400 MHz, CDCb) o8.90 (d, J =2.0 Hz, 1H), 8.63 (d, J = 3.9 Hz, 1H), 7.93 (ddd, J = 8.2, 2.4, 1.5 Hz, 1H), 7.51 (s, 1H), 7.43 (dd, J = 8.2, 4.8 Hz, 1H), 4.49 (s, 1H), 2.91 (s, 3H); ESlMS m/z 255 ([M+2t).
-Fluoro-N,3-dimethyl(pyridinyl)-1H-pyrazolamine was prepared from the appropriate ine as described in Example 8, Method B: 1H NMR (400 MHz, CDCb) o 8.91 (t, J = 2.1 Hz, 1H), 8.50 (dd, J = 4.8, 1.5 Hz, 1H), 7.93 (ddt, J = 8.3, 2.8, 1.5 Hz, 1H), 7.37 (ddd, J = 8.3, 4.8, 0.7 Hz, 1H), 2.86 (d, J = 1.6 Hz, 3H), 2.43 (s, 2H), 2.24 (s, 3H); ElMS m/z 206.
-Broma-N, 3-dimethyl(pyridinyl)-1H-pyrazolamine was prepared from the appropriate Boc-amine as bed in Example 8, Method B: 1H NMR (400 MHz, CDCb) o 8.86 (dd, J = 2.5, 0.5 Hz, 1H), 8.59 (dd, J = 4.8, 1.5 Hz, 1H), 7.88 (ddd, J = 8.2, 2.6, 1.5 Hz, 1H), 7.40 (ddd, J = 8.2, 4.8, 0.7 Hz, 1H), 2.85 (s, 3H), 2.69 (s, 1H), 2.35 (s, 3H); ESlMS m/z 268 ). 5-Chloro-N,3-dimethyl(pyridinyl)-1H-pyrazolamine was prepared from the appropriate Boc-amine as described in Example 8, Method B: 1H NMR (400 MHz, CDCb) o 8.87 (d, J = 2.3 Hz, 1H), 8.59 (dd, J = 4.8, 1.3 Hz, 1H), 7.90 (ddd, J = 8.2, 2.6, 1.5 Hz, 1H), 7.40 (ddd, J = 8.2, 4.8, 0.6 Hz, 1H), 2.87 (s, 3H), 2.45-2.19 (m, 4H); ElMS m/z 223. wo 2013/062981 3-Chloro(5-fluoropyridinyl)-N-methyl-1H-pyrazolamine was prepared from the appropriate Boc-amine as described in Example 8, Method B: mp 119.0 oc; 1H NMR (400 MHz, CDCb) o8.68 (d, J = 1.1 Hz, 1H), 8.33 (d, J =2.5 Hz, 1H), 7.75 (dt, J = 9.6, 2.4 Hz, 1H), 7.31 (s, 1H), 3.14 (s, 1H), 2.87 (s, 3H); ESIMS m/z 227 ([Mt). 3-Chloro-N-ethyl(5-fluoropyridinyl)-1H-pyrazolamine amine was prepared from the appropriate Boc-amine as described in Example 8, Method B: 1H NMR (400 MHz, CDCb) o 8.70-8.63 (m, 1H), 8.32 (d, J =2.4 Hz, 1H), 7.74 (dt, J = 9.7, 2.4 Hz, 1H), 7.31 (s, 1H), 3.11 (q, J =7.2 Hz, 2H), 1.31 (t, J =7.1 Hz, 3H). luoropyridinyl)-N-methylvinyl-1H-pyrazolamine was prepared from the appropriate Boc-amine as bed in Example 8, Method B: 105.0-107.0 oc; 1H NMR (400 MHz, CDCb) o8.72 (s, 1H), 8.31 (d, J =2.5 Hz, 1H), 7.81 (dt, J = 9.8, 2.4 Hz, 1H), 7.33 (s, 1H), 6. 75 (dd, J = 18.0, 11.6 Hz, 1H), 5.83 (dd, J = 18.0, 1.1 Hz, 1H), 5.46 (dd, J = 11.6, 1.1 Hz, 1H), 2.86 (s, 3H); ESIMS m/z 219 ([M+Ht). 3-Cyclopropyl(5-fluoropyridinyl)-N-methyl-1H-pyrazolamine was prepared from the riate Boc-amine as described in Example 8, Method B: mp 118.0-119.5 oc; 1H NMR (400 MHz, CDCb) o8.66- 8.58 (m, 1H), 8.23 (d, J =2.5 Hz, 1H), 7.75- 7.68 (m, 1H), 7.25 (s, 1H), 3.09 (s, 1H), 2.86 (s, 3H), 1.78- 1.63 (m, 1H), 0.99- 0.90 (m, 4H); ESIMS m/z 233 ([M+Ht). 3-Chloro(pyridinyl)-1H-pyrazolamine was prepared from the appropriate Boc-amine as described in Example 8, Method B: mp 137.9-139.9 C; 1H NMR (400 MHz, CDCb) o8.84 (d, J =2.4 Hz, 1H), 8.50 (dd, J = 4.7, 1.4 Hz, 1H), 7.95 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 7.52 (s, 1H), 7.37 (ddd, J = 8.4, 4.7, 0.7 Hz, 1H), 3.18 (s, 2H); ESIMS m/z 196 ([M+Ht). 2-((3-Chloro(pyridinyl)-1H-pyrazolyl)amino)acetonitrile was prepared from tert- butyl (3-chloro(pyridinyl)-1H-pyrazolyl)(cyanomethyl)carbamate as in Example 8, Method B: mp 141-143 oc; 1H NMR (300 MHz, CDCb) o8.91 (d, J =2.7 Hz, 1H), 8.54 (dd, J = 5.1, 1.8 Hz, 1H), 7.97 (m, 1H), 7.62 (s, 1H), 7.38 (dd, J = 12.0, 7.5 Hz, 1H), 4.97 (d, J = 6.9 Hz, 2H), 3.52 (m, 1H); ElMS m/z 235 ([M+1t). wo 2013/062981 Ndimethyl(pyrimidinyl)-1H-pyrazolamine was prepared as in Example 8, Method B: mp 139-143 oc; 1H NMR (400 MHz, CDCb) o9.02 (s, 2H), 9.00 (s, 1H), 7.30 (s, 1H), 2.87 (d, J = 11.5 Hz, 3H), 2.27 (s, 3H); ESIMS m/z 190 ([M+H]). 3-chloro-N-methyl(pyrimidinyl)1-1H-pyrazolamine was prepared as in Example 8, Method B: mp 111-114 oc; 1H NMR (400 MHz, CDCb) o9.09- 9.04 (m, 1H), 9.02 (s, 2H), 7.30 (s, 1H), 3.14 (bs, 1H), 2.88 (s, 3H); ESIMS m/z 196 ([M+H]). 1-(5-Fluoropyridyl)methyl-N-(trideuteriomethyl)pyrazolamine was prepared from compound 380 using the ure as described in Example 8, method B: mp 146-148 °C; 1H NMR (400 MHz, CDCb) o8.67 (s, 1H), 8.25 (d, J =2.5 Hz, 1H), 7.73 (dt, J = 10.0, 2.3 Hz, 1H), 7.27 (s, 1H), 2.87 (s, 1H), 2.24 (s, 3H); ESIMS m/z 210 ([M+Ht); IR (Thin film) 1599 em.-1 3-Chloro(3-pyridyl)-N-(trideuteriomethyl)pyrazolamine was prepared from compound 381 using the procedure as described in e 8, method B: mp 104-106 °C; 1H NMR (400 MHz, CDCb) o8.87 (d, J = 1.9 Hz, 1H), 8.47 (d, J =4.7 Hz, 1H), 8.00- 7.90 (m, 1H), 7.40-7.30 (m, 2H), 3.10 (s, 1H); ESIMS m/z 212 ([M+Ht); IR (Thin film) 1579 cm-1. 3-Chloro-N-(cyclopropylmethyl)(pyridinyl)-1H-pyrazolamine was prepared from compound 361 using the procedure as described in Example 8, method B: mp 82-83 °C; 1H NMR (400 MHz, CDCb) o8.86 (d, J =2.5 Hz, 1H), 8.47 (dd, J =4.7, 1.3 Hz, 1H), 7.95 (ddd, J = 8.4, 2.7, 1.5 Hz, 1H), 7.38-7.32 (m, 2H), 3.22 (s, 1H), 2.90 (d, J = 6.9 Hz, 2H), 1.23- 1.06 (m, 1H), 0.65-0.53 (m, 2H), 0.31-0.19 (m, 2H).; ESIMS m/z 249 ); 3-Chloro-N-propyl(pyridinyl)-1H-pyrazolamine was prepared from compound 360 using the procedure as described in Example 8, method B: mp 92-94 °C; 1H NMR (400 MHz, CDCb) o8.86 (d, J =2.6 Hz, 1H), 8.47 (dd, J = 4.7, 1.4 Hz, 1H), 7.95 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 7.35 (ddd, J = 8.4, 4.7, 0.6 Hz, 1H), 7.33 (s, 1H), 3.22- 2.94 (m, 3H), 1.75- 1.52 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H); ESIMS m/z 237 ([M+Ht). e 9: Preparation of isopropyl-(1-pyridinyl-lH-pyrazolyl)-amine wo 2013/062981 dinyl-1H-pyrazolylamine (0.6 g, 3.7 mmol) was dissolved in isopropyl acetate (8.5 ml). To the mixture, acetone (0.261 g, 4.5 mmol), trifluoroacetic acid (0.855 g, 7.5 mmol) and sodium triacetoxyborohydride (0.945 g, 4.5 mmol) were added. The reaction was stirred under nitrogen at room temperature for 4.5 hours and then quenched with 10% sodium hydroxide solution until the pH reached - 9. The layers were separated, and the aqueous phase was ted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate and concentrated to dryness. The crude material was purified by silica gel chromatography (gradient elution of 5% methanol I romethane) to give the title compound as an off white solid (0.35 g, 46%): mp 105-107 oc; 1H NMR (300 MHz, CDCb) o8.82 (d, J =2.2 Hz, 1H), 8.63 (dd, J = 4.8, 1.5 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 8.03 (d, J =2.7 Hz, 1H), 7.94- 7.77 (m, 1H), 7.38 (dt, J = 15.2, 7.6 Hz, 1H), 6.99 (t, 1H), 3.72 (m, 1H), 1.30 (t, J = 10.0 . ESIMS 214 m/z (M+1).
Example 10: ation of propyl-(1-pyridinyl-1H-pyrazolyl-amine To 1-pyridinyl-1H-pyrazolylamine (0.5 g, 3.12 mmol) in dichloromethane (5 ml) was added propionaldehyde (0.18 g, 3.12 mmol) and sodium triacetoxy borohydride (0.99 g, 4.68 mmol) and stirred at room temperature for 16 hours. The reaction was taken up in dichloromethane and was washed with water and brine. The organic layer was dried (MgS04), filtered and trated to dryness. The crude material was purified by silica gel chromatography eluting with 0-5% MeOH I Dichloromethane and resubjected in 0-100% ethylacetate I hexanes) to give the title compound as a dark oil (0.05 g, 7%): 1H NMR (300 MHz, CDCb) o8.92 (d, J =2.6 Hz, 1H), 8.48 (dd, J = 4.7, 1.4 Hz, 1H), 8.00 (ddd, J = 8.3, wo 2013/062981 2012/061508 2.7, 1.5 Hz, 1H), 7.47-7.40 (m, 2H), 7.37 (dd, J = 8.3, 4.7 Hz, 1H), 3.04 (t, J =7.1 Hz, 3H), 1.92- 1.46 (m, 2H), 1.03 (t, J =7.4 Hz, 3H).
Example 11: Preparation of N-methyl-N-(1-pyridinyl-1H-pyrazolyl)- isobutyramide und 42) A solution of isobutyryl chloride (0.138 g, 1.3 mmol) in dichloroethane (1 mL) was pipetted at a dropwise rate into an ice-cold suspension ofmethyl-(1-pyridinyl-1H-pyrazolyl)- amine (0.15 g, 0.86 mmol) in dichloroethane (5 mL), stirred for 10 minutes and then treated at a dropwise rate with a solution of 4-N,N-dimethylaminopyridine (0.11 g, 0.9 mmol) in dichloroethane (1.5 mL). The cooling bath was d after 30 minutes, stirred under nitrogen at room temperature for 14 hours, diluted with dichloroethane (40 mL), washed with water (30 mL), brine (10 mL), dried over MgS04 and purified by ed phase column chromatography to give a yellowish gum (0.114 g, 54%) 1H NMR (300 MHz, CDCb) o9.01- 8.93(m, 1H), 8.67 (s, 0.4H), 8.61 (d, J =4.2 Hz, 0.6H), 8.54 (d, 0.4H), 8.08-8.02 (m, 1H), 7.96 (s, 0.6H), 7.80 (s, 0.4H), 7.70 (s, 0.6H), 7.47-7.37 (m, 1H), 3.49 (s, 1.2H), 3.26 (s, 2.8H), 3.06-2.98 (m, 0.4H), 2.86-2.70 (m, 0.6H), 1.25 (d, J = 6.1 Hz, 2.4H), 1.09 (d, J = 6.6 Hz, 3.6H). ESIMS m/z 245 ).
Compounds 32-41, 43-52, 54-56, 59-61, 66,73 -75,77-79,82-85, 93- 100, 113, 117-129, 131-134, 139-140, 142-144, 148, 160, 163, 173-175, 184-186, 197-198,202,208,215-217,252-253, 277, 282-285,287-290,314-316,347, 350-351, 353-355, 365-367, 370, 388, 395, 399-403, 407,409,415-418,444-449,452-454, 462-463, 465, 467-469, 496-498, 7,512, 525-527,569, 577, 581, 591 and 592 were made from the appropriate amines in accordance with the procedures disclosed in Example 11.
Example 12: Preparation of 4,4,4-trifluoromethyl-N-(1-(pyridinyl)-1H-pyrazol wo 2013/062981 yl)butanamide (Compound 65) To a solution of 1-(pyridinyl)-1H-pyrazolamine (0.150 g, 0.93 mmol) in dichloroethane (1.8 ml) was added 4,4,4-trifluoromethylbutanoic acid (0.14 g, 0.93 mmol) and 4-N,N- ylaminopyridine (0.23 g, 1.87 mmol) followed by imethylaminopropyl) ethylcarbodiimide hloride (0.36 g, 1.87 mmol). The reaction stirred at room temperature overnight. The reaction mixture was concentrated and the crude product was purified by silica gel tography eluting with 0-5% MeOH I dichloromethane to give a white solid (0.15 g, 55%); mp 5°C; 1H NMR (400 MHz, CDCb) o9.00 (d, J =2.4 Hz, 1H), 8.62- 8.47 (m, 2H), 8.01 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 7.68 (s, 1H), 7.53 (bs, 1H), 7.40 (ddd, J = 8.3, 4.8, 0.6 Hz, 1H), 2.92- 2.61 (m, 2H), 2.32- 2.05 (m, 1H), 1.38 (d, J = 6.6 Hz, 3H); ESIMS m/z 300 ([M+2]).
Compounds 53, 58, 62-63, 72, 76, 80-81, 107- 108, 136-138, 147, 151-159, 164-168, 176-179, 187-196, 201, 203-207, 209-214, 220, 224-249, 251, 259-275, 286, 292-296, 303-313, 323-326, 341-344,356-359, 371,378-379, 382, 384,419- 426, 439-443, 455,458-461,464,466,476, 486, 490-493, 505, 508, 517,528-529, 536 -537,539-541,544-545, 549-554, 572-577,578, 579 and 580 were prepared from the appropriate amines in accordance with the procedures disclosed in Example 12.
Example 13: Preparation of tert-butyl1-(pyridinyl)-1H-pyrazolylcarbamate (Compound 57) wo 2013/062981 Method A: To a solution of 1-(pyridinyl)-1H-pyrazolamine (3 g, 18.73 mmol) in dichloromethane (33.4 ml) was added triethylamine (3.13 ml, 7.68 mmol) and BOC-anhydride (4.5 g, 20.60 mmol). The resulting solution was stirred at room temperature overnight. The on mixture was partitioned between ethyl acetate and water. The organic portion was dried (MgS04), filtered and trated to dryness. The crude product was purified by silica gel chromatography eluting with 0-100% ethyl acetate I s to yield a white solid (2.0 g, 41 %); mp 108-112 oc; 1H NMR (400 MHz, CDCb) o9.02 (d, J =2.2 Hz, 1H), 8.51 (t, J = 8.7 Hz, 1H), 8.37 (s, 1H), 8.30 (s, 1H), 7.98 (ddd, J = 8.3, 2.4, 1.3 Hz, 1H), 7.68 (s, 1H), 7.36 (dd, J = 8.2, 4.8 Hz, 1H), 1.52 (s, 9H); ESIMS m/z 261 ([M+1]).
Compounds 64 and 130 were prepared in accordance with the procedures disclosed in Example 13, Method A.
Method B: To a solution of 1-(pyridinyl)-1H-pyrazolamine (0.1 g, 0.624 mmol) and di-tert-butyl onate (0.161 ml, 0.693 mmol) in tetrahydrofuran (1.890 ml) and water (0.568 ml) was added dropwise saturated aqueous sodium bicarbonate (0.572 ml, 0.687 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water and ted with ethyl e. The combined organic phases were concentrate to give tert-butyl 1- (pyridinyl)-1H-pyrazolylcarbamate (135 mg, 0.519 mmol, 83 %), for which the analytical data was consistent with that reported in Example 13, Method A.
Compounds 150, 172,223, and 317 were prepared in accordance with the procedures disclosed in Example 13, Method B. Compounds 172 and 317 were also prepared in accordance with the procedures disclosed in Example 17. These compounds, as well as, certain other compounds, were made by alternative methods further illustrating certain embodiments.
Example 14: Preparation of utyl (1-(pyridinyl)-1H-pyrazol yl)carbamate (Compound 67) wo 2013/062981 To a solution of tert-butyl1-(pyridinyl)-1H-pyrazolylcarbamate (1.6 g, 6.15 mmol) in DMF (30.7 ml) at ooc was added sodium hydride (0.34 g, 8.61 mmol, 60% dispersion in mineral oil) in one portion and the suspension was stirred for 30 minutes. The ice bath was removed and stirred for an additional30 minutes. Iodomethane (0.46 ml, 7.38 mmol) was added in one portion and stirred overnight at room temperature. Water and ethyl acetate were added and the resulting biphasic mixture was separated. The aqueous layer was extracted one time with ethyl acetate. The combined organic ts were washed with brine, dried (MgS04), filtered and concentrated to dryness. The crude t was ed by silica gel chromatography eluting with 0-35% ethyl acetate I hexanes to yield a light yellow semi-solid (0.85 g, 50%): IR (KBr) 1703 cm-1; 1H NMR(400 MHz, CDCb) o8.98 (s, 1H), 8.52 (d, J = 3.8 Hz, 1H), 8.32 (s, 0.5H), 8.13- 7.97 (m, 1H), 7.84 (s, 0.5H), 7.74 (s, 1H), 7.39 (dd, J = 8.0, 4.8 Hz, 1H), 3.30 (s, 3H), 1.56 (s, 9H); ESIMS m/z 275 ([M+H]).
Compounds 68,86-92, 105 -106, 114-116, 141, 149, 161-162, 199-200, 254, 258, 291,332,352,360-361,380-381,414,430-431,450,457, 474-475, 485, 488,510- 511, 515, 523, and 590 were prepared from the appropriate amides in accordance with the ures disclosed in Example 14. utyl methyl(3-methyl(pyridinyl)-1H-pyrazolyl)carbamate was prepared as in Example 14: 1H NMR (400 MHz, CDCb) o8.91 (d, J =2.5 Hz, 1H), 8.51 (dd, J = 4.7, 1.3 Hz, 1H), 8.00 (ddd, J =8.3, 2.4, 1.4 Hz, 1H), 7.83 (s, 1H), 7.38 (dd, J = 8.3, 4.7 Hz, 1H), 3.20 (s, 3H), 2.22 (s, 3H), 1.60 - 1.30 (m, 9H).
Example 15: Preparation of l-N-(1-methyl(pyridinyl)-1H-pyrazol yl)isobutyramide (Compound 23) wo 2013/062981 N-~ O ~AN~ ZNd ~ ) To a on of N-(1-methyl(pyridineyl)-1H-pyrazolyl)isobutyramide (0.08 g, 0.33 mmol) in DMF (0.66 ml) at ooc was added sodium hydride (0.016 g, 0.39 mmol, 60% dispersion in mineral oil) in one portion and the suspension was stirred for 30 minutes. The ice bath was removed and stirred for an additional 30 minutes. Iodoethane (0.06 g, 0.39 mmol) was added in one portion and stirred overnight at room temperature. Water and ethyl acetate were added and the resulting biphasic mixture was separated. The aqueous layer was extracted one time with ethyl acetate. The ed organic extracts were washed with brine, dried (MgS04), filtered and concentrated to s. The crude product was purified by silica gel chromatography to give the title compound as a clear oil (27.5 mg, 30%): 1H NMR (300 MHz, CDCb) o9.00 (bs, 1H), 8.57 (s, 1H), 8.09 (dd, J =7.9 Hz, 1H), 7.34 (dd, 1H), 6.48 (s, 1H), 4.00 (m, 1H), 3.76 (s, 3H), 3.36 (m, 1H), 2.33 (m, 1H), 1.17 (t, J =7.1 Hz, 3H), 1.08 (t, J = 6.7 Hz, 6H); ESIMS m/z 273 (M+H).
Compound 22 was prepared in accordance with the ures disclosed in Example 15.
Example 16: Preparation of 5-bromo-lH-pyrazolamine, HBr A mixture of 4-nitro-1H-pyrazole (10 g, 88 mmol) and 5% ium on Al20 3 (1 g) in a mixture of ethanol (150 mL) and 50% aqueous HBr (50 mL) was shaken in a Par apparatus under hydrogen (10 psi) for 36 h. The mixture was filtered and the catalyst washed with ethanol. The filtrate was concentrated in vacuo to give a white solid. This solid was suspended in 10 mL of ethanol. After ng the flask for 5 min, ether was added to complete the crystallization. The solid was filtered, was washed with ether and dried under wo 2013/062981 high vacuum to afford 5-bromo-1H-pyrazolamine, HBr (18.1 g, 84% yield) as a white solid: mp 248 oc dec; 1H NMR (400 MHz, DMSO-d6) o11.47 (s, 1H), 10.00 (s, 1H), 7.79 (s, 1H).
Example 17: ation of utyl (3-chloro(pyridinyl)-1H-pyrazol yl)carbamate (Compound 172) Example 17, Step 1: Preparation of 3-chloro-1H-pyrazolamine hloride Into a 2 L three-necked round bottom flask affixed with an overhead stirrer, a ature probe, an addition funnel, and a nitrogen inlet were added ethanol (600 mL) and 4-nitro-1H- pyrazole (50.6 g, 447 mmol). To this solution was added, in one portion, cone. HCl (368 mL) (note: rapid exotherm from 15 octo 39 OC) and the resulting mixture was purged with nitrogen for 5 minutes. Palladium on alumina (5%w/w) (2,6 g, Alfa, black solid) was added to the mixture and d at room temperature while triethylsilane (208 g, 1789 mmol) was added drop-wise over 4 h. The reaction, which started to slowly exotherm from 35 oc to 55 oc over 2.0 h, was stirred for a total of 16 hand vacuum filtered through a plug of Celite® to give a biphasic mixture. The mixture was transferred to a separatory funnel, the bottom aqueous layer was collected and rotary ated (60 oc, 50 mmHg) to dryness with the aid of acetonitrile (3 x 350 mL). The resulting yellow solid was suspended in acetonitrile (150 mL) and allowed to stand for 2 h at room temperature followed by 1 h at 0 oc in the refrigerator. The solids were filtered and washed with acetonitrile (100 mL) to afford the titled compound 3-chloro-1H-pyrazolamine hydrochloride (84 g, 97% yield, 80% purity) as a white solid: mp 190-193 oc; 1H NMR (400 MHz, DMSO-d6) o10.46 -10.24 ( bs, 2H), 8.03 (s, 0.54H), 7.75 (s, 0.46H), 5.95 (bs, 1H)); R (101 MHz, DMSO) o128.24, 125.97, 116.71. wo 2013/062981 Example 17, Step 2: ation of tert-butyl (3-chloro-1H-pyrazolyl)carbamate Into a 2 L round bottom flask was added 3-chloro-1H-pyrazolamine hydrochloride (100 g, 649 mmol) and THF (500 mL). To this mixture were added di-tert-butyldicarbonate (156 g, 714 mmol) followed by sodium bicarbonate (120 g, 1429 mmol) and water (50.0 ml). The mixture was stirred for 16 h, diluted with water (500 mL) and ethyl acetate (500 mL) and transferred to a tory funnel. This gave three ; bottom- a white gelatinous precipitate, middle- light yellow aqueous, top- auburn c. The phases were separated collecting the white gelatinous precipitate and the aqueous layer together. The aqueous was extracted with ethyl acetate (2 x 200 mL) and the ethyl acetate extracts were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and rotary evaporated to give an auburn thick oil (160 g.). The thick oil was suspended in hexane (1000 mL) and stirred at 55 oc for 2 h. This gave a light brown suspension. The e was cooled to 0 oc and the solid collected by vacuum filtration and rinsed with hexane (2 x 10 mL). The sample was air dried to constant mass to afford (3-chloro-1H-pyrazolyl)carbamate (102.97 g, 72% yield, 80% purity) as a light brown solid: mp 137-138 oc; 1H NMR (400 MHz, CDCb) o10.69 (s, 1H), 7.91 (s, 1H), 1.52 (s, 9H).
Example 17, Step 3: Preparation of tert-butyl (3-chloro(pyridinyl)-1H-pyrazol yl)carbamate und 172) Cl 0 )L_ N::::{ ~0 U NJ-NH'-'::::...-:; To a dry 2 L round bottom flask equipped with mechanical stirrer, nitrogen inlet, wo 2013/062981 thermometer, and reflux condenser was charged the 3-iodopyridine (113.0 g, 551 mmol), (3- chloro-1H-pyrazolyl)carbamate (100 g, 459 mmol), potassium phosphate (powdered in a mortar and pestle) (195g, 919 mmol), and copper chloride (3.09, 22.97 mmol). Acetonitrile (1 L) followed by N\N2-dimethylethane-1,2-diamine were added and the e was heated to 81 °C for 4 hours. The mixture was cooled to room temperature and filtered through a bed of Celite®. The filtrate was transferred to a 4 L eyer flask equipped with mechanical stirrer and diluted with water until the total volume was about 4 L. The mixture was stirred for 30 minutes at room temperature and the resulting solid was collected by vacuum filtration. The solid was washed with water and washed with water and oven dried for l days in vacuo at 40 °C to a nt weight to give tert-butyl (3-chloro(pyridinyl)-1H- pyrazolyl)carbamate (117.8 g, 87% yield, 80% purity) as a tan solid: mp 140-143 °C; 1H NMR (400 MHz, CDCb) o8.96 (s, 1H), 8.53 (dd, J =4.7, 1.2 Hz, 1H), 8.36 (s, 1H), 7.98 (ddd, J = 8.3, 2.7, 1.4 Hz, 1H), 7.38 (dd, J = 8.3, 4.8 Hz, 1H), 6.37 (s, 1H), 1.54 (s, 9H); ESIMS (mlz) 338 ([M-t-But), 220 ([M-O-t-BuD.
Compound 172 was also prepared in accordance with the procedures sed in Example 13. Compound 317 was prepared in accordance with the procedures disclosed in Example 17 from tert-butyl (3-bromo-1H-pyrazolyl)carbamate and also in accordance with the procedures disclosed in Example 13.
Example 18: Preparation of 3-(3-methyl-1H-pyrazolyl)pyridine and 3-(5-methyl-1H- pyrazolyl)pyridine To a solution of 3-methyl-1H-pyrazole (10.99 g, 134 mmol) in methylformamide (100 ml) at 0 oc was added sodium hydride (3.71 g, 154 mmol, 60% dispersion). The reaction was stirred at 0 oc for 2 hours. ropyridine (10.0 g, 103 mmol) was added, and the reaction was stirred at 100 oc overnight. The reaction was cooled to room temperature and water was added slowly. The mixture was extracted with dichloromethane and the combined organic wo 2013/062981 phases were washed with brine, concentrated and chromatographed (0-100% ethyl acetate I hexanes) to afford ethyl-1H-pyrazolyl)pyridine (8.4g, 52.77 mmol, 51.2 %) and 3- (5-methyl-1H-pyrazolyl)pyridine (1.0 g, 6%). Analytical data of both products is consistent with that reported under Example 6, Step 1. 3-(3-Bromo-1H-pyrazolyl)pyridine was prepared from 3-fluoropyridine and 3- bromopyrazole, which was made as in W02008130021, as described e 18: mp 89.5- 92.5 oc; 1H NMR (400 MHz, CDCl3) o8.94 (d, J =2.4 Hz, 1H), 8.62- 8.49 (m, 1H), 8.03 (ddd, J = 8.3, 2.7, 1.4 Hz, 1H), 7.87 (d, J = 2.5 Hz, 1H), 7.42 (dd, J =8.2, 4.7 Hz, 1H), 6.54 (d, J =2.5 Hz, 1H); ESIMS m/z 224 ([Mt).
Example 19, Preparation of ro(5-fluoropyridinyl)-1H-pyrazolamine To a stirred on of 5-chloro-1H-pyrazolamine, HCl (2 g, 12.99 mmol) and cesium carbonate (8.89 g, 27.3 mmol) in DMF (13 mL) was added 3,5-difluoropyridine (1.794 g, .58 mmol) and the e heated at 70 oc for 12 h. The mixture was cooled to room temperature and filtered. The solids were washed with copious amount of ethyl acetate. The filtrates was washed with brine, dried over anhydrous MgS04 and concentrated in vacuo to give a brown solid. This solid was dissolved in ethyl acetate and the resulting solution was saturated with hexanes to precipitate 3-chloro(5-fluoropyridinyl)-1H-pyrazolamine (2.31g, 10.32 mmol, 79% yield) as a brown solid: 1H NMR (400 MHz, DMSO-d6) o8.89- 8.82 (m, 1H), 8.45 (d, J = 2.5 Hz, 1H), 8.07 (d, J = 10.4 Hz, 1H), 7.94 (s, 1H), 4.51 (s, 2H); ElMS (mlz) 213 ([M+1]+). 3-Bromo(5-fluoropyridinyl)-1H-pyrazolamine was prepared from the corresponding pyrazole as described in Example 19: mp 164-165 oc; 1H NMR (400 MHz, CDCb) o8.65 (d, J = 1.7 Hz, 1H), 8.36 (d, J = 2.5 Hz, 1H), 7.76 (dd, J = 5.9, 3.6 Hz, 1H), 7.48 (s, 1H), 3.22 (s, wo 2013/062981 2H). 13C NMR (101 MHz, CDCb) o160.87, 158.30, 135.36, 135.13, 134.39, 134.35, 131.16, , 114.02, 112.77, 112.54; ElMS (mlz) 258 ([M+1]+). e 20: Preparation of 1-(5-fluoropyridinyl)methyl-1H-pyrazolamine To a solution of 3-fluoro(3-methylnitro-1H-pyrazolyl)pyridine (3.133 g, 14.10 mmol) in ethanol (28.2 ml) was added ethyl acetate until all of the starting material went into solution. The solution was degassed and 10% palladium on carbon (0.750 g, 0.705 mmol) was added and the reaction was stirred in a parr hydrogenator at 40 psi for 3 hours. The on was filtered h celite with ethyl acetate and concentrated to give 1-(5- fluoropyridinyl)methyl-1H-pyrazolamine (2.000 g, 10.41 mmol, 73.8 %) as a brown solid: mp 136.0-138.0 oc; 1H NMR (400 MHz, CDCl3) o8.67 - 8.59 (m, 1H), 8.27 (d, J = 2.5 Hz, 1H), 7.73 (dt, J = 9.9, 2.3 Hz, 1H), 7.45 (s, 1H), 3.01 (s, 2H), 2.28 (s, 3H); ElMS m/z 192. 1-(Pyridinyl)(trifluoromethyl)-1H-pyrazolamine was prepared from the appropriate nitropyrazole as described in Example 20: mp 112.5-115.0 oc; 1H NMR (400 MHz, CDCl3) o8.89 (d, J =2.4 Hz, 1H), 8.57 (dd, J = 4.7, 1.4 Hz, 1H), 8.03 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 7.56 (d, J =0.7 Hz, 1H), 7.41 (ddd, J = 8.3, 4.8, 0.7 Hz, 1H), 3.47- 3.31 (m, 2H); ElMS m/z 228.
Example 21: Preparation of 3-chloro(pyridinyl)-1H-pyrazolamine wo 2013/062981 To 3-(3-chloronitro-1H-pyrazolyl)pyridine (0.95 g, 4,23 mmol) in acetic acid (8.46 mL), ethanol (8.46 mL) and water (4.23 mL) was added iron powder (1.18 g, 21.15 mmol) and the reaction was stirred at room temperature for 30 minutes. To this was added carefully 2M KOH and extracted with ethyl acetate. The ethyl acetate layers were combined, dried (MgS04), filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (0-10% methanol I dichloromethane) to give the desired t as a white solid (0.66 g, 80%): 1H NMR (400 MHz, CDCb) o8.84 (d, J =2.6 Hz, 1H), 8.49 (dd, J = 4.7, 1.4 Hz, 1H), 7.95 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 7.53 (s, 1H), 7.37 (ddd, J = 8.4, 4.7, 0.6 Hz, 1H), 3.17 (bs, 2H). 3-methyl(2-methylpyridinyl)-1H-pyrazolamine was prepared as described in Example 21: 1H NMR (400 MHz, CDCb) o8.48 (dd, J = 4.8, 1.6 Hz, 1H), 7.62 (dd, J = 8.0, 1.6 Hz, 1H), .18 (m, 2H), 2.91 (bs, 2H), 2.55 (s, 3H), 2.28 (s, 3H); ElMS m/z 188. 3-Phenyl(pyridinyl)-1H-pyrazolamine was prepared from the appropriate nitropyrazole as described in Example 21: lR (thin film) 3324 cm-1; 1H NMR (400 MHz, CDCb) o8.94 (d, J =2.2 Hz, 1H), 8.47 (dd, J = 4.7, 1.4 Hz, 1H), 8.07 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 7.87- 7.80 (m, 2H), 7.60 (s, 1H), 7.50- 7.44 (m, 2H), 7.40- 7.34 (m, 2H), 3.86 (s, 2H); ElMS m/z 236. 3-Chloro(5-fluoropyridinyl)-1H-pyrazolamine was prepared from the appropriate nitropyrazole as described in Example 21: mp 149.0-151.0 oc; 1H NMR (400 MHz, CDCb) o 8.65 (d, J = 1.6 Hz, 1H), 8.35 (d, J =2.4 Hz, 1H), 7.75 (dt, J = 9.5, 2.4 Hz, 1H), 7.51 (s, 1H), 3.21 (s, 2H); ESlMS m/z 213 ([Mt). 3-Bromo(pyridinyl)-1H-pyrazolamine was prepared from the riate nitropyrazole as described in Example 21: mp 143.0-146.0 oc; 1H NMR (400 MHz, CDCb) o 8.85 (d, J =2.4 Hz, 1H), 8.50 (dd, J = 4.7, 1.4 Hz, 1H), 7.96 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 7.49 (s, 1H), 7.37 (ddd, J = 8.4, 4.7, 0.7 Hz, 1H), 3.21 (s, 2H); ESlMS m/z 241 ([M+2t).
Example 22: ation of tert-butyl (5-methyl(pyridinyl)-1H-pyrazol bamate (Compound 281) wo 2013/062981 N~}-o I /J NH ll..J To a solution of (E)-tert-butyl1-(dimethylamino)oxobutenylcarbamate (0.59 g, 2.58 mmol) in ethanol (2.5 mL) was added 3-hydrazinylpyridine, 2HC1 (0.470 g, 2.58 mmol). The reaction e was stirred at ambient temperature for 16 hours. The on mixture was concentrated and purified using silica gel chromatography (0-100% ethyl acetate I hexanes) to yield the title nd as an orange foam (0.235 g, 30%): IR (thin film) 3268, 2978 and 1698 cm-1; 1H NMR (400 MHz, CDCb) o8.75 (dd, J = 2.5, 0.5 Hz, 1H), 8.62 (dd, J = 4.8, 1.5 Hz, 1H), 7.82 (ddd, J = 8.2, 2.6, 1.5 Hz, 1H), 7.78 (s, 1H), 7.43 (ddd, J = 8.1, 4.8, 0.6 Hz, 1H), 6.04 (s, 1H), 2.29 (s, 3H), 1.52 (s, 9H); ESIMS m/z 275 ), 273 ([M-HD.
Example 23: Preparation of tert-butyl1-(5-fluoropyridinyl)methyl-1H-pyrazol ylcarbamate (Compound 111) and tert-butyl5-ethoxy(5-fluoropyridinyl)methyl- 1H-pyrazolylcarbamate (Compound 112) i o,_0}.c_ N I N F'-r(YN H ~--J 0 N \ To a solution of3-fluoro(3-methylnitro-1H-pyrazolyl)pyridine (3.133 g, 14.10 mmol) in ethanol (28.2 ml) was added ethyl acetate until all of the starting material went into solution. The solution was degassed and 10% palladium on carbon (0.750 g, 0.705 mmol) was added and the reaction was stirred in a parr hydrogenator at 40 psi for 3 hours. The solution was filtered through celite with ethyl acetate and the solvent was removed under d pressure. The residue was dissolved in ydrofuran (32.0 ml) and water (9.61 ml). Di-tert-butyl dicarbonate (2.52 g, 11.55 mmol) was added followed by saturated aqueous sodium bicarbonate (9.54 ml, 11.45 mmol). The reaction was stirred at room temperature overnight, diluted with water and extracted with ethyl acetate. The combined organic phases wo 2013/062981 were concentrated and chromatographed (0-100% ethyl acetate I hexanes) to give tert-butyl 1-(5-fluoropyridinyl)methyl-1H-pyrazolylcarbamate (1.673 g, 5.72 mmol, 41.0 %) as a yellow solid and the tert-butyl5-ethoxy(5-fluoropyridinyl)methyl-1H-pyrazol- 4-ylcarbamate (0.250 g, 0.74 mmol, 5.2 %) as a brown oil: utyl luoropyridinyl)methyl-1H-pyrazolylcarbamate (Compound 111): mp 131.5-133.0 oc; 1H NMR (400 MHz, CDCb) o8.75 (s, 1H), 8.32 (d, 1 = 2.5 Hz, 1H), 8.28 (s, 1H), 7.77 (dt, 1 = 9.7, 2.4 Hz, 1H), 6.15 (s, 1H), 2.29 (s, 3H), 1.54 (s, 9H); ESIMS m/z 293 tert-Butyl 5-ethoxy(5-fluoropyridinyl)methyl-1H-pyrazolylcarbamate (Compound 112): IR (thin film) 1698 cm-1; 1H NMR (400 MHz, CDCb) o8.88 (s, 1H), 8.34 (d, 1 =2.5 Hz, 1H), 7.83 (d, 1 = 9.9 Hz, 1H), 5.99 (s, 1H), 4.37 (q, 1 =7.0 Hz, 2H), 2.17 (s, 3H), 1.50 (s, 9H), 1.37 (t, 1 =7.1 Hz, 3H); ESIMS m/z 337 ([M+Ht).
Example 24: Preparation of Bis tert-t-butyl (1-(pyridinyl)-lH-pyrazolyl)carbamate (Compound 595) To a solution of tert-butyl (1-(pyridinyl)-JH-pyrazolyl)carbamate (2.00 g, 7.68 mmol) in dry THF (21.95 mL) at 0 oc was added 60% sodium hydride (0.33 g, 8.45 mmol) in one portion and stirred at that temperature for 30 minutes. To this was then added hydride (1.84 g, 8.45 mmol) in one portion and stirred for 5 minutes at 0 oc. The water bath was removed and the reaction was warmed to room temperature and stirred at additional 30 minutes. The reaction was quenched with water and extracted with ethyl acetate. The ethyl acetate layers were combined, dried ), filtered and concentrated to dryness. The crude material was purified by silica gel chromatography (0-100% ethyl acetate I hexanes) to give the desired product as a white solid (2.0 g, 72%): 1H NMR (400 MHz, CDCb) o9.12- 8.86 (m, 1H), 8.55 (dd, 1 = 4.7, 1.4 Hz, 1H), 8.04 (ddd, 1 = 8.3, 2.7, 1.5 Hz, 1H), 8.01 (d, 1 = 0.5 wo 2013/062981 Hz, lH), 7.84- 7.65 (m, lH), 7.41 (ddd, J = 8.3, 4.8, 0.7 Hz, lH), 1.51 (s, 18H).
Example 25: Preparation of 3-chloro(pyridinyl)-1H-pyrazolamine (Compound 516) To tert-butyl oro(pyridinyl)-lH-pyrazolyl)carbamate (2 g, 6.79 mmol) in dichloromethane (6.79 ml) was added trifluoroacetic acid (6.79 ml) and the mixture was left ng at room temperature for 2 hours. e (12 mL) was added and the reaction was concentrated to near dryness. The mixture was poured into a separatory funnel containing saturated aqueous sodium bicarbonated and was extracted with dichloromethane. The combined organic layers were concentrated to give 3-chloro(pyridinyl)-lH-pyrazol amine (0.954g, 4.90 mmol, 72.2 %) as a white solid: mp 137.9-139.9 oc; 1H NMR (400 MHz, CDCb) o8.84 (d, J =2.4 Hz, lH), 8.50 (dd, J = 4.7, 1.4 Hz, lH), 7.95 (ddd, J = 8.3, 2.7, 1.5 Hz, lH), 7.52 (s, lH), 7.37 (ddd, J = 8.4, 4.7, 0.7 Hz, lH), 3.18 (s, 2H); ESIMS m/z 196 ([M+Ht).
Example 26: Preparation of N-allyl(5-fluoropyridinyl)methyl-1H-pyrazol amine hloride FyyNfNH.HCI ~NJ ~ To a solution of tert-butyl allyl(l-(5-fluoropyridinyl)methyl-lH-pyrazolyl)carbamate (908 mg, 2.73 mmol) in dioxane (5 mL) was added HCl (1M in ether) (13.65 mL, 13.65 mmol) and the mixture stirred at room temperature for 48 h. The resulting white solid was filtered, washed with ether and dried under vacuum to give N-allyl(5-fluoropyridinyl)- wo 2013/062981 2012/061508 3-methyl-1H-pyrazolamine, HCl (688 mg, 94% yield) as a white solid: mp 189-190 oc; 1H NMR (400 MHz, CDCb) o8.79-8.68 (m, 1H), .26 (m, 1H), 8.23 (s, 1H), 7.98- 7.86 (m, 1H), 5.86-5.68 (m, 1H), 5.28-5.17 (m, 1H), 5.17-5.03 (m, 1H), 3.59 (d, J = 6.2 Hz, 2H), 2.11 (s, 3H); ElMS (mlz) 233 ([M+1]+).
N-Allylchloro(pyridinyl)-1H-pyrazolamine, HCl was prepared as described in Example 26 from tert-butyl allyl(3-chloro(pyridinyl)-1H-pyrazolyl)carbamate: mp 172-174 oc; 1H NMR (400 MHz, CDCl3) o9.20 (d, J =2.5 Hz, 1H), 8.65 (dd, J =5.3, 1.1 Hz, 1H), 8.61 (ddd, J = 8.6, 2.5, 1.1 Hz, 1H), 8.24 (s, 1H), 7.93 (dd, J = 8.6, 5.3 Hz, 1H), 3.66 (dt, J = 5.5, 1.3 Hz, 2H); ElMS (mlz) 235 ([M+1]+).
N-Allylmethyl(pyridinyl)-1H-pyrazolamine, HCl was prepared as described in Example 26 from tert-butyl allyl(3-methyl(pyridinyl)-1H-pyrazolyl): mp 195-197 oc; 1H NMR (400 MHz, DMSO-d6) o9.12 (d, J =2.4 Hz, 1H), 8.58 (dd, J = 5.0, 1.2 Hz, 1H), 8.48 (s, 1H), 8.43 (d, J = 9.7 Hz, 1H), 7.77 (dd, J = 8.4, 5.0 Hz, 1H), 6.04- 5.92 (m, 1H), .44 (dd, J = 17.2, 1.4 Hz, 1H), 5.32 (d, J = 9.4 Hz, 1H), 3.81 (d, J = 6.2 Hz, 2H); ElMS (mlz) 249 +). 3-Bromo(5-fluoropyridinyl)-N-methyl-1H-pyrazolamine, HCl was ed as described in Example 26 from tert-butyl3-bromo(5-fluoropyridinyl)-1H-pyrazol yl(methyl)carbamate: mp 167-168 oc; 1H NMR (400 MHz, CDCb) o8.93 (s, 1H), 8.50 (d, J =2.5 Hz, 1H), 8.23 (s, 1H), 8.14 (dt, J = 10.4, 2.3 Hz, 1H), 2. 73 (s, 3H). 3-Bromo-N-methyl(pyridinyl)-1H-pyrazolamine, HCl was prepared as described in Example 26 from tert-butyl (3-bromo(pyridinyl)-1H-pyrazolyl)(methyl)carbamate (160 mg, 0.45 mmol) in dioxane (1 mL) was added 4M HCl: mp. 226-228 oc; 1H NMR (400 MHz, DMSO-d6) o9.26- 9.06 (d, J =2.6 Hz, 1H), 8.69- 8.54 (m, 1H), 8.54- 8.39 (d, J = 8.0 Hz, 1H), 8.33 - 8.14 (s, 1H), 7.90 - 7.72 (m, 1H), 2.82 - 2.67 (s, 3H); ElMS (mlz) 253 +), 255 ([M+2H]+). 3-Bromo-N-ethyl(pyridinyl)-1H-pyrazolamine, HCl was prepared as described in Example 26 from 3-bromo-N-ethyl(pyridinyl)-1H-pyrazolamine, HCl: mp 216-217 wo 2013/062981 oc; 1H NMR (400 MHz, DMSO-d6) - 10.05 (s, 3H), 9.28- 9.20 (d, J =2.5 Hz, 1H), 8.74- 8.67 (m, 1H), 8.67- 8.56 (m, 3H), 7.96- 7.84 (m, 1H), 3.21- 3.14 (m, 2H), 1.29- 1.22 (m, 3H); ElMS (mlz) 267 ([M+1]+). 3-Chloro-N-(2-methoxyethyl)(pyridinyl)-1H-pyrazolamine, HCl was prepared as described in Example 26 from tert-butyl (3-chloro(pyridinyl)-1H-pyrazolyl)(2- methoxyethyl)carbamate, HCl: mp 157-158 °C; 1H NMR (400 MHz, DMSO) o9.22- 9.14 (d, J =2.5 Hz, 1H), 8.70- 8.65 (s, 1H), 8.65 - 8.59 (m, 1H), 8.38 - 8.33 (m, 1H), 8.00- 7.89 (m, 1H), 3.59- 3.50 (t, J = 5.8 Hz, 2H), 3.32- 3.27 (s, 3H), 3.22- 3.14 (m, 2H); ElMS (mlz) 253 ([M+1]+). e 27: Preparation of 3-chloro-N-ethyl(pyridinyl)-lH-pyrazolamine hydrochloride N-===(_CI ()')NJ-NH2HCI N Into a 500 mL three-necked round bottom flask equipped with a magnetic stir bar was added a solution of tert-butyl (3-chloro(pyridinyl)-1H-pyrazolyl)(ethyl)carbamate (21 g, 65.1 mmol) in 1.4-dioxane (35 mL). This pale yellow solution was placed into an ice bath and cooled to 1 oc. A solution of 4M HCl in dioxane (65 mL, 260 mmol) was added in one n. After stirring for 20 s, the ice bath was removed and the suspension was stirred further at ambient temperature for 16 hours. The reaction was diluted with 200 mL of ethyl ether and the solid was filtered and washed with ether and placed in a vacuum oven at 40 oc for 18 hours. The title compound was isolated as a pale yellow solid (18.2 g, 95%): 1H NMR (400 MHz, MeOD) o9.52 (d, J =2.5 Hz, 1H), 9.17 (s, 1H), 9.14 (ddd, J = 8.7, 2.5, 1.1 Hz, 1H), 8.93 (ddd, J = 5.7, 1.1, 0.6 Hz, 1H), 8.31 (ddd, J = 8.7, 5.7, 0.5 Hz, 1H), 3.58 (q, J = 7.3 Hz, 2H), 1.48 (t, J = 7.3 Hz, 3H); ESIMS m/z 223 ([M+Ht). 3-Chloro-N-methyl(pyridinyl)-1H-pyrazoleamine, 2HC1 was prepared as described in Example 27: 1H NMR (400 MHz, MeOD) o9.28 (d, J =2.5 Hz, 1H), 8.86 (ddd, J = 8.7, wo 2013/062981 2.5, 1.2 Hz, 1H), 8.79-8.75 (m, 1H), 8.62 (s, 1H), 8.19 (ddd, J = 8.7, 5.6, 0.5 Hz, 1H), 3.06 (s, 3H); 13C NMR (101 MHz, MeOD) 2, 139.58, 137.76, 134.58, 134.11, 129.33, 127.55, 122.14, ; ESIMS m/z 209 ([M+Ht).
Example 28: Preparation of 3-(4-nitrophenyl-1H-pyrazolyl)pyridine To a suspension of phenylboronic acid (0.546 g, 4.47 mmol) in toluene (6.63 ml) was added 3-(3-chloronitro-1H-pyrazolyl)pyridine (0.335 g, 1.492 mmol) followed by ethanol (3.31 ml) and 2M aqueous potassium carbonate (1.492 ml, 2.98 mmol). The solution was degassed by applying vacuum and then purging with nitrogen (3 times). To the reaction mixture was added palladium tetrakis (0.086 g, 0.075 mmol) and the flask was heated at 110 oc under nitrogen for 16 hours. The aqueous layer was removed and the organic layer was concentrated. The crude t was purified via silica gel tography (0-100% ethyl acetate I hexanes) to give 3-(4-nitrophenyl-1H-pyrazolyl)pyridine (499 mg, 1.874 mmol, 80 %) as a yellow solid: mp 144.0-146.0 oc; 1H NMR (400 MHz, CDCl3) o9.09 (d, J =2.3 Hz, 1H), 8.82 (s, 1H), 8.71 (dd, J = 4.8, 1.4 Hz, 1H), 8.16 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 7.82- 7.74 (m, 2H), 7.55- 7.48 (m, 4H); ElMS m/z 266. e 29: Preparation of 5-bromo(pyridinyl)-1H-pyrazol yl(methyl)carbamate (Compound 110) N~~oI N ~N~ \ fl ...J Br To tert-butyl methyl(1-(pyridinyl)-1H-pyrazolyl)carbamate (0.200 g, 0.729 mmol) in wo 2013/062981 2012/061508 roethane (3.65 ml) was added 1-bromopyrrolidine-2,5-dione (0.260 g, 1.458 mmol) and the reaction was stirred overnight at 50°C. The reaction was concentrated, diluted with dichloromethane, and washed with water and saturated aqueous sodium thiosulfate. The organic phase was concentrated to give tert-butyl 5-bromo(pyridinyl)-1H-pyrazol yl(methyl)carbamate (256 mg, 0.725 mmol, 99%) as a brown oil: IR (thin film) 1697 cm-1; 1H NMR (400 MHz, CDCb) o8.89 (s, 1H), 8.68 (d, J = 4.1 Hz, 1H), 7.93 (ddd, J = 8.2, 2.5, 1.5 Hz, 1H), 7.69 (s, 1H), 7.46 (dd, J = 8.1, 4.8 Hz, 1H), 3.22 (s, 3H), 1.44 (s, 9H); ESIMS mlz 352 ([M-Hn.
Example 30: Preparation of Bis tert-t-butyl oro(pyridinyl)-1H-pyrazol yl)carbamate (Compound 109) To bis t-butyl ridinyl)-1H-pyrazolyl)carbamate (1.30 g, 3.61 mmol) in acetonitrile (21.22 mL) was added N-chlorosuccinimide (0.96 g, 7.21 mmol) and the reaction was stirred at 45 oc for 48 hours. The reaction was cooled to room temperature and poured into water and extracted with dichloromethane. The dichloromethane layers were combined, poured through a phase separator to remove water and concentrated to dryness. The crude material was ed by silica gel chromatography (0-60% ethyl acetate I hexanes) to give the desired product as a yellow solid (0.90 g, 63%): mp 109-115 oc; 1H NMR (400 MHz, CDCb) o8.90 (d, J = 2.3 Hz, 1H), 8.68 (dd, J = 4.8, 1.5 Hz, 1H), 7.94 (ddd, J = 8.2, 2.5, 1.5 Hz, 1H), 7.70 (s, 1H), 7.47 (dtd, J = 11.0, 5.6, 5.5, 4.8 Hz, 1H), 1.49 (s, 18H); ESIMS m/z 395 ([M+Ht). tert-Butyl oromethyl(pyridinyl)-1H-pyrazolyl)(methyl)carbamate was prepared from the appropriate pyrazole in dichloroethane as the solvent as described in Example 30: ESIMS m/z 324 ([M+Ht). wo 2013/062981 nds 110 (see also procedure in Example 29) and 146 were prepared from the appropriate pyrazoles using N-bromosuccinimide in accordance with the procedures disclosed in Example 30. tert-Butyl 5-bromomethyl(pyridinyl)-1H-pyrazolyl(methyl)carbamate was prepared from the riate pyrazole in dichloroethane as described in Example 30: 1H NMR (400 MHz, CDCb) o8.88 (d, 1 = 2.3 Hz, 1H), 8.69- 8.60 (m, 1H), 7.96- 7.86 (m, 1H), 7.48- 7.39 (m, 1H), 3.18 (s, 3H), 2.26 (s, 3H), 1.60- 1.36 (m, 9H); ESIMS m/z 368 ([M+Ht).
Example 31: Preparation of bis utyl (5-fluoro(pyridinyl)-1H-pyrazol bamate (Compound 135) N~)\-o ~N'( }-o l!__N_J F 0 )\:-- To a solution ofbis tert-t-butyl (1-(pyridinyl)-1H-pyrazolyl)carbamate (0.075 g, 0.208 mmol) in DMF (0.416 ml) and acetonitrile (0.416 ml) was added Selecfluor® (0.184 g, 0.520 mmol). The on was stirred at room temperature for one week. The reaction was trated, saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The combined organic phases were concentrated and chromatographed (0-100% ethy1acetate I hexanes) to give bis tert-buty1 (5-fluoro(pyridin- 3-yl)-1H-pyrazolyl)carbamate (16 mg, 0.042 mmol, 20.32 %) as an off-white solid: 1H NMR (400 MHz, CDCb) o8.97 (t, 1 =2.0 Hz, 1H), 8.61 (dd, 1 = 4.8, 1.4 Hz, 1H), 7.99 (ddt, 1 = 8.3, 2.6, 1.3 Hz, 1H), 7.57 (d, 1 =2.5 Hz, 1H), 7.44 (ddd, 1 = 8.3, 4.8, 0.6 Hz, 1H), 1.50 (s, 18H); ESIMS m/z 379 ([M+Ht). tert-Butyl (5-fluoromethyl(pyridinyl)-1H-pyrazolyl)(methyl)carbamate was prepared as described in Example 31: 1H NMR (400 MHz, CDCb) o8.94 (s, 1H), 8.57 (d, 1 = 4.2 Hz, 1H), 7.96 (d, 1 =7.7 Hz, 1H), 7.41 (dd, 1 = 7.9, 4.7 Hz, 1H), 3.17 (s, 3H), 2.23 (s, 3H), 1.58- 1.40 (m, 9H); ESIMS m/z 307 ([M+Ht). wo 2013/062981 Example 32: Preparation of N-cyclopropylmethyl(pyridinyl)-1H-pyrazol amine Example 32, Step 1: Preparation of 3-(4-iodomethyl-1H-pyrazolyl)pyridine r('YN ;; I ll..) To a e of 3-(3-methyl-1H-pyrazolyl)pyridine (6.7 g, 42.1 mmol), iodic acid (2.96 g, 16.84 mmol), and diiodine (8.55 g, 33.7 mmol) in acetic acid (60.1 ml) was added concentrated sulfur acid (3.74 ml, 21.04 mmol). The reaction mixture heated to 70 oc for 30 minutes. The reaction mixture was poured onto ice with sodium lfate and was extracted with diethyl ether. The combined organic phases were washed with saturated aqueous sodium bicarbonate. The organic phases were then dried with magnesium sulfate, filtered and concentrated in vacuo. The solid residue was ved in dichloromethane , applied to a 80g silica gel column, and eluted with 0-80% acetone in hexanes to afford 3-(4-iodomethyl- azolyl)pyridine (11.3 g, 35.7 mmol, 85 %) as a white solid: mp 131 oc; 1H NMR (400 MHz, CDCb) o8.95-8.85 (m, 1H), 8.52 (dd, J = 4.8, 1.4 Hz, 1H), 8.00-7.94 (m, 1H), 7.91 (s, 1H), 7.38 (ddd, J = 8.3, 4.8, 0.7 Hz, 1H), 2.34 (s, 3H); ElMS m/z 285.
Example 32, Step 2: Preparation of N-cyclopropylmethyl(pyridinyl)-1H- pyrazolamine uNJ. NJ-NH To a solution of3-(4-iodomethyl-1H-pyrazolyl)pyridine (2.0 g, 7.02 mmol) in dimethylsulfoxide (7.02 ml) was added 1-(5,6,7,8-tetrahydroquinolinyl)ethanone (0.246 g, wo 2013/062981 1.403 mmol), cyclopropanamine (0.486 ml, 7.02 mmol), cesium carbonate (6.86 g, 21.05 mmol) and copper(!) bromide (0.101 g, 0.702 mmol). The reaction mixture was stirred at 35 oc for 2 days. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organics were washed with brine, concentrated and chromatographed (0-100% ethyl acetate I hexanes) to give N-cyclopropylmethyl (pyridinyl)-1H-pyrazolamine (269 mg, 1.255 mmol, 17.90 %) as a yellow solid: mp 104.0-107.0 oc; 1H NMR (400 MHz, CDCb) o8.89 (dd, 1 = 2.7, 0.5 Hz, 1H), 8.41 (dd, 1 = 4.7, 1.4 Hz, 1H), 7.96 (ddd, 1 = 8.3, 2.7, 1.5 Hz, 1H), 7.51 (s, 1H), 7.33 (ddd, 1 = 8.3, 4.7, 0.7 Hz, 1H), 3.42 (s, 1H), 2.53 - 2.42 (m, 1H), 2.22 (s, 3H), 0.72- 0.65 (m, 2H), 0.60 - 0.53 (m, 2H); ESIMS m/z 215 ([M+Ht). 3-Methyl-N-(3-(methylthio)propyl)(pyridinyl)-1H-pyrazolamine was ed as described in Example 32: IR (thin film) 3298 cm-1; 1H NMR (400 MHz, CDCb) o8.87 (d, 1 =2.3 Hz, 1H), 8.40 (dd, 1 = 4.7, 1.4 Hz, 1H), 7.93 (ddd, 1 = 8.3, 2.7, 1.5 Hz, 1H), 7.35 (s, 1H), 7.34- 7.29 (m, 1H), 3.16 (t, 1 = 6.8 Hz, 2H), 2.89 (s, 1H), 2.64 (t, 1 =7.0 Hz, 2H), 2.25 (s, 3H), 2.13 (s, 3H), 1.95 (p, 1 = 6.9 Hz, 2H); ESIMS m/z 263 ). yl-N-(2-methyl(methylthio)propyl)(pyridinyl)-1H-pyrazolamine was prepared as described in Example 32: IR (thin film) 3325 cm-1; 1H NMR (400 MHz, CDCb) o8.86 (d, 1 = 2.5 Hz, 1H), 8.40 (dd, 1 = 4.7, 1.2 Hz, 1H), 7.93 (ddd, 1 = 8.3, 2.7, 1.5 Hz, 1H), 7.35 (s, 1H), 7.32 (ddd, 1 = 8.3, 4.7, 0.5 Hz, 1H), 3.12 (dd, 1 = 11.5, 6.1 Hz, 1H), 2.94 (dd, 1 = 11.9, 6.6 Hz, 1H), 2.62 (dd, 1 = 12.9, 6.9 Hz, 1H), 2.52 (dd, 1 = 12.9, 6.2 Hz, 1H), 2.26 (s, 3H), 2.14 (s, 3H), 2.12- 2.02 (m, 1H), 1.11 (d, 1 = 6.8 Hz, 3H); ElMS m/z 276. wo 62981 Example 33: Preparation of tert-butyl (3-cyclopropyl(5-fluoropyridinyl)-1H- pyrazolyl)carbamate und 434) and tert-butyl (1-(5-fluoropyridinyl)-1H- pyrazolyl)carbamate (Compound 489) NJ>0~~-- o)L_ N~ ~0 FuN-'-NH FUN.__r-NH I~ I~ .....:: .....:: N N To a suspension of 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.087 g, 6.47 mmol) in toluene (13.69 ml) was added tert-butyl (3-bromo(5-fluoropyridinyl)-1H- pyrazolyl)carbamate (1.1 g, 3.08 mmol) followed by ethanol (6.84 ml) and 2M aqueous potassium carbonate (3.08 mL, 6.16 mmol). The solution was degassed by applying vacuum and then purging with en (3 times). To the reaction mixture was added palladium tetrakis (0.178 g, 0.154 mmol) and the flask was heated at 100 oc under nitrogen for 36 hours. Water (5 mL) was added and the e was extracted with ethyl acetate. The combined organics were concentrated and chromatographed (0-100% ethyl acetate I hexanes) to give tert-butyl lopropyl(5-fluoropyridinyl)-1H-pyrazolyl)carbamate (705 mg, 2.215 mmol, 71.9% yield) as a yellow solid and tert-butyl (1-(5-fluoropyridinyl)-1H- pyrazolyl)carbamate (242 mg, 0.870 mmol, 28.2% yield) as a yellow solid. tert-Butyl (3-cyclopropyl(5-fluoropyridinyl)-1H-pyrazolyl)carbamate: mp 156.5- 158.0; 1H NMR (400 MHz, CDC13) o8.73 (s, 1H), 8.30 (d, J =2.5 Hz, 1H), 8.27 (s, 1H), 7.76 (dt, J = 9.8, 2.4 Hz, 1H), 6.43 (s, 1H), 1.55 (s, 9H), 1.01-0.91 (m, 4H); ESIMS m/z 319 ([M+Ht). (1-(5-Fluoropyridinyl)-1H-pyrazolyl)carbamate: mp 121.0-123.0 oc; 1H NMR (300 MHz, CDC13) o8.78 (s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 7.81 (d, J = 9.6 Hz, 1H), 7.59 (s, 1H), 6.44 (s, 1H), 1.53 (s, 9H). ESIMS m/z 278 ([Mt). wo 2013/062981 Compounds 340 and 404 were prepared as described in Example 33.
Example 34: Preparation of tert-butyl (3-ethyl(5-fluoropyridinyl)-1H-pyrazol yl)(methyl)carbamate (Compound 408) To a N2-purged solution of utyl (1-(5-fluoropyridinyl)vinyl-1H-pyrazol yl)(methyl)carbamate (0.730 g, 2.293 mmol) in methanol (15.29 ml) was added 10% palladium on carbon (0.036 g, 0.339 mmol). The reaction was purged with hydrogen and run under 80 psi of hydrogen at room temperature for 60 hours. The reaction gave less than 20% conversion. The on mixture was filtered through , concentrated, and redissolved in ethyl e ( 4 mL) and transferred to a bomb. The reaction was heated at 50 oc at 600 psi of hydrogen for 20 hours. The reaction was only 50% complete. Methanol (1 mL) and 10% palladium on carbon (36 mg) were added, and the reaction was heated at 80 oc at 650 psi of hydrogen for 20 hours. The reaction was filtered through celite and concentrated to give tert- butyl (3-ethyl(5-fluoropyridinyl)-1H-pyrazolyl)(methyl)carbamate (616 mg, 1.923 mmol, 84% yield) as yellow oil: IR (thin film) 1692 cm-1; 1H NMR (300 MHz, CDCb) o 8.71 (t, J = 1.4 Hz, 1H), 8.35 (d, J =2.6 Hz, 1H), 7.83 (dt, J = 9.5, 2.3 Hz, 2H), 3.18 (s, 3H), 2.65 (q, J =7.5 Hz, 2H), 1.44 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H); ElMS m/z 320. e 35: Preparation of N-(1-(5-fluoropyridinyl)formyl-1H-pyrazol yl)isobutyramide (Compound 560) •y"",J)-~>L-{ N wo 2013/062981 To a solution of N-(1-(5-fluoropyridinyl)vinyl-1H-pyrazolyl)isobutyramide (0.706 g, 2.57 mmol) in tetrahydrofuran (12.87 ml) and water (12.87 ml) was added osmium tetroxide (0.164 ml, 0.026 mmol). After 10 minutes at room temperature, sodium periodate (1.101 g, .15 mmol) was added in ns over 3 s and the resulting solution was stirred at room temperature. After 18 hours, the solution was poured into 10 mL water and was extracted with 3 x 10 mL dichloromethane. The combined organic layers were dried, concentrated and chromatographed (0-100% ethyl e I hexanes) to give N-(1-(5- fluoropyridinyl)formyl-1H-pyrazolyl)isobutyramide (626 mg, 2.266 mmol, 88% yield) as a yellow solid: mp 140.0-142.0 oc; 1H NMR (300 MHz, CDCb) o10.12 (s, 1H), 9.14 (s, 1H), 8.90 (d, J =2.0 Hz, 1H), 8.82 (s, 1H), 8.51 (d, J =2.5 Hz, 1H), 7.92 (dt, J = 9.2, 2.4 Hz, 1H), 2.65 (dt, J = 13.8, 6.9 Hz, 1H), 1.31 (d, J = 6.9 Hz, 6H); ESIMS m/z 277 ([M+Ht).
Compound 369 was ed in accordance with the ures sed in Example 35.
Example 36: Preparation of N-(1-(5-fluoropyridinyl)(hydroxymethyl)-1H-pyrazol- 4-yl)isobutyramide (Compound 435) and N-(1-(5-fluoropyridinyl)-1H-pyrazol yl)isobutyramide (Compound 436) HO 0 Fy~):)_~Yy FyyZ)-~~ ~..) t.) N To a solution of N-(1-(5-fluoropyridinyl)formyl-1H-pyrazolyl)isobutyramide (0.315 g, 1.140 mmol) in methanol (5.70 ml) at 0 oc was added sodium borohydride (0.086 g, 2.280 mmol). The reaction was stirred at 0 oc for 2 hours, and room temperature for 20 hours. 0.5 M HCl was added, the reaction was neutralized with saturated aqueous sodium bicarbonate, and the mixture was extracted with dichloromethane. The organic phases were concentrated and chromatographed (0-100% ethyl acetate I hexanes) to give N-(1-(5-fluoropyridinyl) (hydroxymethyl)-1H-pyrazolyl)isobutyramide (180 mg, 0.647 mmol, 56.7 %) as a white wo 2013/062981 solid and N-(1-(5-fluoropyridinyl)-1H-pyrazolyl)isobutyramide (9 mg, 0.036 mmol, 3.18 %) as a white solid.
N-(1-(5-Fluoropyridinyl)(hydroxymethyl)-1H-pyrazolyl)isobutyramide: mp 144.0- 146.0 oc; 1H NMR (400 MHz, CDCb) o8.74 (d, J = 1.1 Hz, 1H), 8.64 (s, 1H), 8.37-8.29 (m, 2H), 7.74 (dt, J = 9.5, 2.3 Hz, 1H), 4.95 (d, J = 3.0 Hz, 2H), 3.21- 3.06 (m, 1H), 2.63- 2.48 (m, 1H), 1.26 (d, J = 6.9 Hz, 6H); ESIMS m/z 279 ([M+Ht).
N-(1-(5-Fluoropyridinyl)-1H-pyrazolyl)isobutyramide: IR (thin film) 1659 cm-1; 1H NMR (400 MHz, CDCb) o8.79 (d, J = 1.2 Hz, 1H), 8.60 (s, 1H), 8.38 (d, J =2.5 Hz, 1H), 7.81 (dt, J = 9.5, 2.3 Hz, 1H), 7.68 (s, 1H), 7.54 (s, 1H), 2.63- 2.51 (m, 1H), 1.28 (d, J = 6.9 Hz, 6H); ESIMS mlz 249 ([M+Ht).
Example 37: ation of N-(3-(chloromethyl)(5-fluoropyridinyl)-1H-pyrazol yl)isobutyramide (Compound 561) FyyZ~~ly To a solution of N-(1-(5-fluoropyridinyl)(hydroxymethyl)-1H-pyrazol yl)isobutyramide (0.100 g, 0.359 mmol) in dichloromethane ( 3.59 ml) was added thionyl chloride (0.157 ml, 2.151 mmol). The reaction was stirred at room temperature for 2 hours.
Saturated aqueous sodium bicarbonate was added, and the e was extracted with dichloromethane. The combined c phases were washed with brine and concentrated to give N-(3-(chloromethyl)(5-fluoropyridinyl)-1H-pyrazolyl)isobutyramide (100 mg, 0.337 mmol, 94% yield) as a white solid: mp 172.0-177.0 oc; 1H NMR (400 MHz, CDCb) o 8.79 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 7.80 (dt, J = 9.4, 2.3 Hz, 1H), 7.42 (s, 1H), 4.77 (s, 2H), 2.63 (hept, J = 6.9 Hz, 1H), 1.30 (d, J = 6.9 Hz, 6H); ESIMS mlz 298 ([M+Ht). wo 2013/062981 Example 38: Preparation of N-(3-chloro(pyridinyl)-1H-pyrazolyl)-N-ethyl methoxyacetamide (Compound 512) (see also Example 11) erNf)c1 o o- N::::( }----/ To a solution of 3-chloro-N-ethyl(pyridinyl)-1H-pyrazolamine, 2HC1 (0.130 g, 0.502 mmol) and in DCM (2.508 ml) was added N-ethyl-N-isopropylpropanamine (0.257 ml, 1.505 mmol) followed by 2-methoxyacetyl chloride (0.109 g, 1.003 mmol) and the reaction mixture was stirred at ambient ature for 16 hours. The reaction was quenched by the on of saturated sodium bicarbonate. The organic layer was extracted with DCM. The organic layer was dried over sodium sulfate, ed, concentrated and purified using silica gel chromatography (0-100% ethyl acetate I hexanes) to yield the title compound as a pale yellow oil (0.12 g, 77%): IR (thin film) 3514,3091,2978, 1676 cm-1; 1H NMR (400 MHz, CDCb) o8.96 (d, J =2.4 Hz, 1H), 8.63 (d, J = 3.8 Hz, 1H), 8.09- 8.03 (m, 1H), 7.99 (s, 1H), 7.47 (dd, J = 8.3, 4.8 Hz, 1H), 3.88 (s, 2H), 3.77- 3.65 (m, 2H), 3.40 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H); ESIMS m/z 295 ([M+Ht).
Compounds 71, 478, 481, 483 - 484, and 543 were prepared in accordance with the procedures disclosed in Example 38.
Example 39: Preparation of N-(3-chloro(5-fluoropyridinyl)-1H-pyrazolyl)-N- ethylmethyl(methylthio)butanamide und 182) and (Z)-N-(3-chloro(5- fluoropyridinyl)-1H-pyrazolyl)-N-ethylmethylbutenamide (Compound 183) Cl q\ }_ I~ ) ....: N To a solution 2-methyl(methylthio)butanoic acid (0.154 g, 1.039 mmol) in wo 2013/062981 dichloromethane (1 mL) at room temperature was added 1 drop of dimethylformamide.
Oxalyl dichloride (0.178 ml, 2.078 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was redissolved in dichloromethane (1 mL) and the solvent was removed under reduced pressure. The residue was redissolved in dichloromethane (0.5 mL) and the solution was added to a solution of 3-chloro-N-ethyl(5-fluoropyridinyl)-1H-pyrazolamine (0.100 g, 0.416 mmol) and 4-dimethylaminopyridine (0.254 g, 2.078 mmol) in dichloromethane (1.5 mL) and stirred at room ature overnight. The solvent was removed under reduced pressure and the residue was purify by chromatography (0-100% ethyl acetate I hexanes) to give N-(3-chloro(5-fluoropyridinyl)-1H-pyrazolyl)-N-ethylmethyl (methylthio)butanamide (34 mg, 0.092 mmol, 22.06 %) as a faint yellow oil and (Z)-N-(3- (5-fluoropyridinyl)-1H-pyrazolyl)-N-ethylmethylbutenamide (38 mg, 0.118 mmol, 28.3 % yield) as a yellow oil. hloro(5-fluoropyridinyl)-1H-pyrazolyl)-N-ethylmethyl (methylthio)butanamide: IR (thin film) 1633 cm-1; 1H NMR (400 MHz, CDCb) o8.79 (d, 1 = 2.0 Hz, 0.66H), 8.77 (d, 1 =2.0 Hz, , 8.50 (d, 1 =2.6 Hz, , 8.49 (d, 1 =2.5 Hz, , 8.08 (s, 0.66H), 7.95 (s, 0.33H), 7.92- 7.81 (m, 1H), 4.03- 3.46 (m, 2H), 3.03 - 2.78 (m, 1H), 2.59- 2.33 (m, 1H), 2.04 (s, 2H), 2.02 (s, 1H), 1.32 (d, 1 = 6.7 Hz, 1H), 1.27 (d, 1 = 6.2 Hz, 1H), 1.23 (d, 1 = 6.9 Hz, 2H), 1.18- 1.12 (m, 5H); ESIMS m/z 371 ([Mt).
(Z)-N-(3-Chloro(5-fluoropyridinyl)-1H-pyrazoly1)-N-ethylmethylbutenamide: 1H NMR (400 MHz, CDCb) o8.73 (d, 1 =2.0 Hz, 1H), 8.46 (d, 1 =2.4 Hz, 1H), 7.87 (d, 1 = 4.9 Hz, 1H), 7.84 (dt, 1= 9.2, 2.4 Hz, 1H), 5.93-5.76 (m, 1H), 3.73 (q, 1= 7.1 Hz, 2H), 1.72 (s, 3H), 1.58 (dd, 1 = 6.9, 0.9 Hz, 3H), 1.17 (t, 1 =7.1 Hz, 3H); ESIMS m/z 323 ([Mt).
Compounds 70, 180 - 181, 389 - 392, 397 - 398, 405 - 406, 427 - 429, 432, 456, 482, 521 - 522, 532 - 534, 555, and 589 were prepared from the corresponding intermediates and starting materials in accordance with the procedures disclosed in Example 39. wo 2013/062981 Example 40: Preparation of N-(3-chloro(pyridinyl)-1H-pyrazolyl)-N-methyl (methylthio)acetamide (Compound 337) N:}- }-Ic1 o s- I N r(YN ~ \ ll..J To an ice cold solution of 2-(methylthio)acetic acid (0.092 g, 0.863 mmol) in DCM (2 mL) was added N-ethyl-N-isopropylpropanamine (0.111 g, 0.863 mmol) followed by isobutyl chlorofonnate (0.099 ml, 0.767 mmol). ng was continued for 10 minutes. Next, the mixed anhydride was added to a solution of 3-chloro-N-methyl(pyridinyl)-1H-pyrazol- 4-amine (0.08 g, 0.383 mmol) in DCM (0.66 mL) and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated and purified using reverse phase C-18 column chromatography % CH3CN I H20) to yield the title compound as a pale yellow oil (0.075 g, 66%): 1H NMR (400 MHz, CDCb) o8.95 (d, J = 2.5 Hz, 1H), 8.62 (dd, J = 4.8, 1.4 Hz, 1H), 8.13 (s, 1H), 8.04 (ddd, J = 8.3, 2.7, 1.4 Hz, 1H), 7.50-7.43 (m, 1H), 3.26 (s, 3H), 3.12 (s, 2H), 2.24 (s, 3H); 13C NMR (101 MHz, CDCb) o 170.00, , 140.15, 140.03, 135.68, , 126.42, 125.33, 124.15, 37.16, 34.94, 16.22; ESIMS m/z 297 ([M+Ht).
Compounds 335, 336, and 542 were prepared in accordance with the procedures disclosed in Example 40. e 41, Preparation of N-(3-chloro(pyridinyl)-1H-pyrazolyl)-N-ethyl methyloxobutanamide (Compound 499) To a solution of 3-chloro-N-ethyl(pyridinyl)-1H-pyrazolamine, HCl (259 mg, 1 wo 2013/062981 mmol) and ethyl2-methyloxobutanoate (144 mg, 1.000 mmol) in dioxane (1 mL) was added 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine (181 mg, 1.30 mmol) and the mixture was heated in a microwave (CEM Discover) at 150 oc for 1.5 h, with external IR- sensor temperature monitoring from the bottom of the vessel. LCMS (ELSD) indicated a 40% conversion to the desired product. The mixture was diluted with ethyl acetate (50 ML) and saturated s NH4Cl (15 mL), and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL) and the combined c phase was washed with brine, dried over MgS04 and concentrated in vacuo to give an oily residue. This residue was purified on silica gel eluting with es of ethyl acetate and hexanes to give N-(3-chloro- 1-(pyridinyl)-1H-pyrazolyl)-N-ethylmethyloxobutanamide (37 mg, 11 %yield, 96% purity) as a colorless oil: 1H NMR (400 MHz, CDCb) o9.02- 8.92 (dd, J = 2.6, 0.8 Hz, 1H), 8.68- 8.60 (dd, J = 4.8, 1.5 Hz, 1H), 8.09- 7.98 (m, 1H), 7.96- 7.87 (s, 1H), 3.87- 3.58 (d, J = 3.0 Hz, 2H), 3.49- 3.38 (m, 1H), 2.16- 2.08 (s, 3H), 1.39- 1.32 (d, J = 7.0 Hz, 3H), 1.22- 1.13 (m, 3H); ElMS (mlz) 321 ([M+1t), 319 ([M-1D.
Example 42: Preparation of N-(3-chloro(pyridinyl)-lH-pyrazolyl)-N- yclopropanecarboxamide (Compound 538) To a solution of 3-chloro-N-ethyl(pyridinyl)-1H-pyrazolamine monohydrochloride (0.10 g, 0.0.38 mmol) in dichloroethane (0. 75 ml) was added cyclopropanecarboxylic acid (0.03 g, 0.38 mmol) and 4-N,N-dimethylaminopyridine (0.14 g, 1.15 mmol) ed by 1- (3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (0.14 g, 0. 77 mmol). The reaction was d at room temperature overnight. The reaction mixture was concentrated to dryness and the crude t was purified by reverse phase silica gel chromatography eluting with 0-50% acetonitrile I water to give a white solid (0.03 g, 25%); mp 111-119 oc; 1H NMR (400 MHz, CDCb) o8.96 (d, J = 2.5 Hz, 1H), 8.63-8.59 (m, 1H), 8.06 (ddd, J = 8.3, 2.6, 1.4 Hz, 1H), 8.01 (s, 1H), 7.46 (dd, J = 8.3, 4.7 Hz, 1H), 3.73 (q, J =7.2 Hz, 2H), 1.46 (ddd, J = 12.6, 8.1, 4.7 Hz, 1H), 1.16 (t, J =7.2 Hz, 3H), 1.04 (t, J = 3.7 Hz, 2H), 0.71 wo 2013/062981 (dd, J =7.7, 3.0 Hz, 2H); ESIMS m/z 291 ([M+H]).
Compounds 69, 516, 524, 546, 558 - 559, 582-588, 593, and 594 were prepared from the appropriate acids in accordance with the procedures disclosed in Example 42.
Example 43: Preparation of hloro(pyridinyl)-1H-pyrazolyl)methyl (methylthio)-N-(3-(methylthio)propanoyl)propanamide (Compound 407) To a solution of hloro(pyridinyl)-1H-pyrazolyl)(methylthio)propanamide (0.216 g, 0.728 mmol) in DCE (2.91 ml) in a 10 mL vial was added 2-methyl (methylthio)propanoyl chloride (0.244 g, 1.601 mmol). The vial was capped and placed in a Biotage Initiator microwave reactor for 3 hours at 100 °C, with external IR-sensor temperature monitoring from the side of the vessel. The crude mixture was concentrated and purified using e phase C-18 column chromatography (0-100% acetonitrile I water) to yield the title compound as a pale yellow oil (67 mg, 22%): IR (thin film) 2916 and 1714 cm- 1; 1H NMR (300 MHz, CDCb) o8.96- 8.92 (d, J =2.7 Hz, 1H), 8.64- 8.59 (dd, J = 4.9, 1.4 Hz, 1H), 8.07- 7.99 (m, 2H), 7.50- 7.40 (dd, J = 8.4, 4.8 Hz, 1H), 3.39- 3.28 (m, 1H), 3.10- 2.99 (td, J = 7.2, 3.9 Hz, 2H), 2.96- 2.86 (dd, J = 13.2, 8.7 Hz, 1H), 2.86- 2.79 (t, J =7.3 Hz, 2H), 2.58- 2.48 (dd, J = 13.1, 5.8 Hz, 1H), 2.14- 2.12 (s, 3H), 2.09- 2.06 (s, 3H), 1.30- 1.26 (d, J = 6.9 Hz, 3H); ESIMS m/z 413 ([M+Ht). wo 2013/062981 2012/061508 Compounds 383, 410,433, 437, 451, 470,530 and 531 were prepared in accordance with the procedures disclosed in Example 43.
Example 44: Preparation of N-[3-chloro(3-pyridyl)pyrazolyl]-2,2-dideuterio-N- ethylmethylsulfanyl-propanamide und 393) Cl o I erNNI)-~sN) DD To a 7 mL vial was added 3-chloro-N-ethyl(pyridinyl)-1H-pyrazolamine (111 mg, 0.5 mmol), 2,2-dideuteriomethylsulfanyl-propanoic acid (58.0 mg, 0.475 mmol) and followed by DCM (Volume: 2 mL). The solution was stirred at 0 oc. Then the solution of DCC (0.500 mL, 0.500 mmol, l.OM in DCM) was added. The solution was allowed to warm up to 25 °C slowly and d at 25 °C overnight. White precipitate formed during the reaction. The crude reaction mixture was filtered through a cotton plug and purified by silica gel chromatography (0-100% EtOAc I hexane) to [3-chloro(3-pyridyl)pyrazol yl]-2,2-dideuterio-N-ethylmethylsulfanyl-propanamide (97 mg, 0.297 mmol, 59.4 % yield) as a colorless oil: 1H NMR (400 MHz, CDCb) o8.96 (d, J = 2.4 Hz, 1H), 8.63 (dd, J = 4.6, 0.9 Hz, 1H), 8.06 (ddd, J = 8.4, 2.7, 1.4 Hz, 1H), 7.98 (s, 1H), 7.52- 7.40 (m, 1H), 3.72 (q, J =7.2 Hz, 2H), 2.78 (s, 2H), 2.06 (s, 3H), 1.17 (t, J =7.2 Hz, 3H); ESIMS m/z 327 ([M+Ht); IR (Thin film) 1652 cm-1. nds 394, 396, and 471 - 473 were prepared from the corresponding intermediates and starting materials in accordance with the procedures disclosed in Example wo 2013/062981 Example 45: Preparation of 1-ethyl(3-methyl(pyridinyl)-1H-pyrazolyl)urea (Compound 145) To a solution of 3-methyl(pyridinyl)-1H-pyrazolamine (0.1 g, 0.574 mmol) in DCM (5.74 ml) was added ethyl nate (0.041 g, 0.574 mmol) and the reaction mixture was stirred at ambient temperature for 40 minutes. The reaction e had turned from a clear solution to a suspension with white solid material. The reaction mixture was trated and purified using silica gel chromatography (0-20% MeOH I DCM) to yield the title compound as a white solid (0.135 g, 95%): mp 0 oc; 1H NMR (400 MHz, CDCb) o 8.94 (d, J = 2.3 Hz, 1H), 8.48- 8.37 (m, 1H), 8.32 (s, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.52 (br s, 1H), 7.41 - 7.25 (m, 1H), 5.79 (br s, 1H), 3.33 - 3.23 (m, 2H), 2.29 (d, J =2.9 Hz, 3H), 1.16 (dd, J = 8.7, 5.7 Hz, 3H); ESIMS m/z 246 ([M+Ht), 244 ([M-HD.
Compounds 169-171, 221- 222, 255- 257, 278-280,297-302, 318- 322,334, 345, 348, 375- 377, 385- 387, and 411- 413 were prepared in accordance with the procedures sed in Example 45.
Example 46: Preparation of 3-butyl(3-chloro(pyridinyl)-1H-pyrazolyl) ethylurea (Compound 500) Nj-CIO ~}-NH I N UN~) To a solution of 3-chloro-N-ethyl(pyridinyl)-1H-pyrazolamine, 2HC1 (0.130 g, 0.502 mmol) in DCE (1.25 ml) was added N-ethyl-N-isopropylpropaneamine (0.21 mL, 1.255 mmol) followed by 1-isocyanatobutane (0.109 g, 1.104 mmol) and the reaction mixture was wo 2013/062981 stirred at ambient temperature for 16 hours. The reaction mixture was trated and purified using silica gel chromatography (0-20% MeOH I DCM) to yield the title compound as a beige solid (0.131 g, 77%): IR (thin film) 3326,2959,2931, 1648 cm-1; 1H NMR (400 MHz, CDCb) o8.95 (s, 1H), 8.62 (d, J =4.0 Hz, 1H), 8.08- 8.01 (m, 1H), 7.97 (s, 1H), 7.46 (dd, J = 8.3, 4.7 Hz, 1H), 4.42-4.32 (m, 1H), 3.74-3.61 (m, 2H), 3.27-3.15 (m, 2H), 1.49- 1.37 (m, 2H), 1.37- 1.22 (m, 2H), 1.19- 1.12 (m, 3H), 0.94-0.84 (m, 3H); ESIMS m/z 322 ([M+Ht).
Compounds 479 - 480, 501 - 504, 513, 518 and 519 were prepared according to Example 46.
Example 47: Preparation of 1-(3-chloro(pyridinyl)-1H-pyrazolyl)imidazolidin- 2-one und 374) To a on of 1-(3-chloro(pyridinyl)-1H-pyrazolyl)(2-chloroethyl)urea (0.1 g, 0.333 mmol) in THF (6.66 ml) was added sodium hydride (8.00 mg, 0.333 mmol) and the reaction mixture was stirred at ambient temperature for 30 minutes. The reaction was quenched by the addition of a solution of saturated ammonium chloride and the t was extracted with ethyl e (2x). The combined c layers were dried over sodium sulfate, filtered and concentrated. The product was a beige solid which was pure and did not need any further purification (63 mg, 72%): mp 167-170 oc; 1H NMR (400 MHz, CDCb) o 8.96 (d, J =2.2 Hz, 1H), 8.56 (dd, J = 4.7, 1.4 Hz, 1H), 8.33 (s, 1H), 7.99 (ddd, J = 8.3, 2.7, 1.4 Hz, 1H), 7.40 (ddd, J = 8.3, 4.8, 0.7 Hz, 1H), 5.00 (s, 1H), 4.14- 4.07 (m, 2H), 3.68- 3.58 (m, 2H); ESIMS m/z 264 ([M+Ht).
Compound 349 was prepared in accordance with the procedures disclosed in Example 47. wo 2013/062981 e 48: ation of S-tert-butyl (3-chloro(pyridinyl)-1H-pyrazol yl)(ethyl)carbamothioate (Compound 514) To a solution of 3-chloro-N-ethyl(pyridinyl)-1H-pyrazolamine, 2HC1 (0.13 g, 0.502 mmol) in DCM (2.508 ml) was added N-ethyl-N-isopropylpropanamine (0.257 ml, 1.505 mmol) followed by S-tert-butyl carbonochloridothioate (0.153 g, 1.003 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction was quenched by the addition of saturated sodium bicarbonate. The organic layer was extracted with DCM. The organic layer was dried over sodium sulfate, filtered, concentrated and purified using silica gel column chromatography (0-100% ethyl acetate I s) to yield the title compound as a white solid (132 mg, 78%): mp 91-93 oc; 1H NMR (400 MHz, CDCb) o8.96 (d, J = 2.5 Hz, 1H), 8.60 (dd, J = 4.7, 1.4 Hz, 1H), 8.08- 8.03 (m, 1H), 7.97 (s, 1H), 7.47- 7.41 (m, 1H), 3.69 (q, J = 7.2 Hz, 2H), 1.47 (s, 9H), 1.21 - 1.13 (m, 3H); ESIMS m/z 339 ([M+Ht).
Compounds 333, 338, 339, 346, 368 and 373 were prepared in accordance with the procedures sed in Example 48.
Example 49: Preparation of N-(3-chloro(pyridinyl)-1H-pyrazolyl)-N-ethyl (methio)propanethioamide (Compound 364) To a microwave reaction vessel was added N-(3-chloro(pyridinyl)-1H-pyrazolyl)-N- ethylmethyl(methio)propanamide (0.07 g, 0.22 mmol) in dichloroethane (1.87 mL) and Lawesson'sreagent (0.05 g, 0.12 mmol). The vessel was capped and heated in a Biotage wo 2013/062981 Initiator microwave reactor for 15 minutes at 130 °C, with al IR-sensor temperature monitoring from the side of the . The reaction was concentrated to dryness and the crude material was purified by silica gel chromatography (0-80% acetonitrile I water) to give the desired product as a yellow oil (0.33 g, 44%): IR (thin film) 1436 cm-1; 1H NMR (400 MHz, CDCb) o8.97 (d, J =2.5 Hz, 1H), 8.77- 8.52 (m, 1H), 8.11 - 7.89 (m, 2H), 7.60- 7.38 (m, 1H), 4.62 (bs, 1H), 4.02 (bs, 1H), 3.21 - 2.46 (m, 3H), 2.01 (s, 3H), 1.35- 1.15 (m, 6H); ESIMS m/z 355 ([M+Ht).
Compounds 372, 438 and 548 were prepared in accordance with the ures disclosed in Example 49.
Example 50: Preparation of N-(3-chloro(pyridinyl)-lH-pyrazolyl)-N-ethyl-4,4,4- oro(methylsulfinyl)butanamide (Compound 570) Cl q, 3 )__ / a,\-f-)N :::=( 'j---/ ~~" N To a 20 mL vial was added N-(3-chloro(pyridinyl)-1H-pyrazolyl)-N-ethyl-4,4,4- trifluoro(methylthio)butanamide (82 mg, 0.209 mmol) and hexafluoroisopropanol (1.5 mL). Hydrogen peroxide (0.054 mL, 0.626 mmol, 35% solution in water) was added in one portion and the solution was stirred at room temperature. After 3 hours the reaction was quenched with saturated sodium sulfite solution and extracted with EtOAc (3 x 20 mL). The ed organic layers were dried over sodium sulfate, concentrated and purified by tography (0-10% MeOH I DCM) to give N-(3-chloro(pyridinyl)-1H-pyrazol yl)-N-ethyl-4,4,4-trifluoro(methylsulfinyl) butanamide (76 mg, 0.186 mmol, 89 % yield) as white semi-solid: 1H NMR (400 MHz, CDCb) o8.98 (d, J = 2.3 Hz, 1H), 8.63 (td, J = 4.8, 2.4 Hz, 1H), 8.14- 8.01 (m, 2H), 7.46 (ddd, J = 8.3, 4.8, 0.7 Hz, 1H), 4.26 (dd, J = 17.2, 8.4 Hz, 1H), 3.89- 3.61 (m, 2H), 3.01 (dd, J = 17.6, 8.2 Hz, 1H), 2.77 (s, 2H), 2.48 (dd, J = 17.7, 3.3 Hz, 1H), 1.19 (t, J = 7.2 Hz, 3H) (only one isomer shown); ESIMS m/z 409 ([M+Ht); IR (Thin film) 1652 cm-1. wo 2013/062981 Compound 571 was prepared from the corresponding intermediates and starting materials in accordance with the procedures disclosed in Example 50. e 51: ation of N-(3-chloro(pyridinyl)-lH-pyrazolyl)-N-ethyl (methylsulfinyl)propanamide und 362) To N-(3-chloro(pyridinyl)-1H-pyrazolyl)-N-ethyl(methylthio)propanamide (0.08 g, 0.24 mmol) in glacial acetic acid (0.82 mL) was added sodium perborate tetrahydrate (0.05 g, , 0.25 mmol), and the mixture was heated at 60 oc for 1 hour. The reaction mixture was carefully poured into a separatory funnel containing saturated aqueous NaHC03 resulting in gas evolution. When the gas evolution had ceased, ethyl acetate was added and the layers were separated. The s layer was extracted twice with ethyl acetate, and all the organic layers were combined, dried over MgS04, filtered and concentrated under reduced pressure.
The crude material was purified by silica gel chromatography (0-10% ol I romethane) to give the desired product as a clear oil (0.03 g, 40%): IR (thin film) 1655 cm-1; 1H NMR (400 MHz, CDC13) o8.95 (t, J = 9.2 Hz, 1H), 8.63 (dd, J = 4.7, 1.4 Hz, 1H), 8.20- 7.86 (m, 2H), 7.59- 7.33 (m, 1H), 3.73 (ddt, J = 20.5, 13.4, 6.8 Hz, 2H), 3.23 - 3.06 (m, 1H), 2.94- 2.81 (m, 1H), 2.74- 2.62 (m, 2H), 2.59 (s, 3H), 1.25- 1.07 (m, 3H); ESIMS m/z 341 ([M+Ht).
Compounds 101 - 102, 218, 328, 330, and 494 were prepared from the appropriate sulfides in accordance with the procedures disclosed in Example 51. wo 2013/062981 Example 52: Preparation of N-(3-chloro(pyridinyl)-1H-pyrazolyl)-N-ethyl (methylsulfonyl)propanamide und 363) N:)_ )\-/~~0Cl 0 II/ I N 0 UN~) To N-(3-chloro(pyridinyl)-1H-pyrazolyl)-N-ethyl(methylthio)propanamide (0.08 g, 0.25 mmol) in glacial acetic acid (0.85 mL) was added sodium perborate tetrahydrate (0.11 g, 0.52 mmol), and the mixture was heated at 60 oc for 1 hour. The reaction mixture was carefully poured into a separatory funnel containing ted aqueous NaHC03 resulting in gas evolution. When the gas evolution had ceased, ethyl acetate was added and the layers were separated. The aqueous layer was extracted twice with ethyl acetate, and all the organic layers were combined, dried over MgS04, filtered and concentrated under reduced re.
The crude product was purified by silica gel column chromatography (0 to 10% methanol I dichloromethane) to give the desired product as a clear oil (0.04, 47%): (thin film) 1661 cm-1; 1H NMR (400 MHz, CDCb) o8.95 (t, J = 11.5 Hz, 1H), 8.64 (dd, J = 4.8, 1.4 Hz, 1H), 8.17- 7.96 (m, 2H), 7.59- 7.39 (m, 1H), 3.73 (d, J = 7.0 Hz, 2H), 3.44 (dd, J =22.5, 15.7 Hz, 2H), 2.96 (s, 3H), 2.71 (t, J = 6.9 Hz, 2H), 1.18 (dd, J = 8.8, 5.5 Hz, 3H); ESIMS m/z 357 ([M+Ht).
Compounds 103, 104, 219, 329, 331 and 495 were prepared from the appropriate sulfides in accordance with the procedures disclosed in e 52.
Example 53: Preparation of N-(3-methyl(3-fluoropyridinyl)-1H-pyrazolyl)N- 2-methyl-(3-oxido-A.4-sulfanylidenecyanamide)(methyl)propanamide (Compound 250) wo 2013/062981 To a solution of N-ethyl-N-(1-(5-fluoropyridinyl)methyl-1H-pyrazolyl)methyl (methylthio)propanamide (0.30 g, 0.89 mmol) in dichloromethane (3.57 mL) at 0 oc was added cyanamide (0.07 g, 1.78 mmol) and iodobenzenediacetate (0.31 g, 0.98 mmol) and subsequently stirred at room temperature for 1 hour. The reaction was concentrated to dryness and the crude material was purified by silica gel column chromatography (10% methanol I ethyl acetate) to give the d sulfilamine as a light yellow solid (0.28 g, 85%).
To a solution of70% mCPBA (0.25 g, 1.13 mmol) in ethanol (4.19 mL) at 0 oc was added a solution of potassium carbonate (0.31 g, 2.26 mmol) in water (4.19 mL) and stirred for 20 minutes after which a solution of sulfilamine (0.28 g, 0. 75 mmol) in ethanol (4.19 mL) was added in one portion. The reaction was stirred for 1 hour at 0 °C. The excess mCPBA was quenched with 10% sodium thiosulfite and the reaction was concentrated to s. The residue was purified by silica gel tography (0-10% ol I dichloromethane) to give the desired product as a clear oil (0.16 g, 56%): IR (thin film) 1649 cm-1; 1H NMR (400 MHz, CDCb) o8.80 (dd, J =43.8, 10.1 Hz, 1H), 8.51-8.36 (m, 1H), 8.11 (d, J = 38.7 Hz, 1H), 7.96-7.77 (m, 1H), 4.32-3.92 (m, 2H), 3.49- 3.11 (m, 6H), 2.32 (s, 3H), 1.27- 1.05 (m, 6H); ESIMS m/z 393 ([M+Ht).
Example 54: Preparation of N-ethyl-4,4,4-trifluoromethoxy-N-(3-methyl(pyridin- 3-yl)-lH-pyrazolyl)(trifluoromethyl)butanamide (Compound 276) To a solution of N-ethyl-4,4,4-trifluorohydroxy-N-(3-methyl(pyridinyl)-1H-pyrazol- 3-(trifluoromethyl)butanamide (184 mg, 0.448 mmol) in DMF (3 mL) stirring at 0 oc was added sodium hydride (26.9 mg, 0.673 mmol). The solution was stirred at 0 oc for 0.5 hour. Then iodomethane (0.034 mL, 0.538 mmol) was added and ice bath was removed and the mixture was stirred at 25 oc overnight. Reaction was worked up by slow addition of water and further diluted with 20 mL of water, then extracted with 4x20 mL of EtOAc. The combined organic layers were washed with water, dried over Na2S04 and concentrated. Silica wo 2013/062981 Gel chromatography (0-100% EtOAc I hexane) gave N-ethyl-4,4,4-trifluoromethoxy-N-(3- methyl(pyridinyl)-1H-pyrazolyl)(trifluoromethyl)butanamide (52 mg, 0.123 mmol, 27.3% yield) as a white solid: mp = 83-86 °C; 1H NMR (400 MHz, CDCb) o8.94 (d, J = 2.5 Hz, 1H), 8.59 (dd, J = 4.7, 1.3 Hz, 1H), 8.01 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 7.85 (s, 1H), 7.44 (ddd, J = 8.3, 4.8, 0.6 Hz, 1H), 4.00 (brs, 1H), 3.73 (s, 3H), 3.39 (brs, 1H), 2.86 (s, 2H), 2.26 (s, 3H), 1.16 (t, J =7.1 Hz, 3H); ESIMS m/z 425 ([M+Ht); IR (Thin film) 1664 Compound 327 was prepared from the corresponding intermediates and starting materials in accordance with the procedures disclosed in Example 54. e 55, Step 1: Preparation of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(3- chloro(pyridinyl)-1H-pyrazolyl)methyl(methylthio)propanamide A solution of N-(3-chloro(pyridinyl)-1H-pyrazolyl)methyl (methylthio)propanamide (0.150 g, 0.483 mmol) in N,N-dimethylformamide (2.413 ml) was cooled to 0 oc. Sodium hydride (0.039 g, 0.965 mmol, 60% dispersion) was added at and the reaction was stirred at 0 oc for 30 minutes. (2-Bromoethoxy)(tert-butyl)dimethylsilane (0.231 g, 0.965 mmol) was added, the ice bath was removed, and the reaction was stirred at room ature for 2 hours. The reaction was heated at 65 oc for 1.5 hours and then cooled to room temperature. Brine was added and the e was extracted with dichloromethane. The combined organic phases were trated and chromatographed (0-100% ethyl acetate I hexanes) to give N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(3-chloro(pyridinyl)-1H- pyrazolyl)methyl(methylthio)propanamide (0.120g, 0.243 mmol, 50.4 %) as an orange oil: IR (thin film) 1669 cm-1; 1H NMR (400 MHz, CDCb) o8.88 (d, J =2.5 Hz, 1H), 8.55 (dd, J = 4.7, 1.4 Hz, 1H), 8.05 (s, 1H), 7.98 (ddd, J = 8.3, 2.6, 1.4 Hz, 1H), 7.41 (ddd, J =8.4, 4.8, 0.5 Hz, 1H), 4.35-3.06 (m, 4H), 2.86-2.73 (m, 1H), 2.73-2.59 (m, 1H), 2.41 wo 2013/062981 (dd, J = 12.8, 5.7 Hz, 1H), 1.94 (s, 3H), 1.11 (d, J = 6.7 Hz, 3H), 0.80 (s, 9H), 0.00 (s, 3H),- 0.01 (s, 3H); ESIMS m/z 470 ([M+Ht).
Example 55, Step 2: Preparation of N-(3-chloro(pyridinyl)-1H-pyrazolyl)-N-(2- hydroxyethyl)methyl(methylthio)propanamide und 535) To a solution of (tert-butyldimethylsilyl)oxy)ethyl)-N-(3-chloro(pyridinyl)-1H- lyl)methyl(methylthio)propanamide (0.180 g, 0.384 mmol) in tetrahydrofuran (1.54 ml) was added tetrabutylammonium fluoride (0.201 g, 0.767 mmol) and the reaction was stirred at room temperature for 2 hours. Brine was added and the mixture was extracted with ethyl acetate. The combined organic phases were concentrated and chromatographed (0- 100% water I acetonitrile) to give N-(3-chloro(pyridinyl)-1H-pyrazolyl)-N-(2- hydroxyethyl)methyl(methylthio)propanamide as a white oil g, 0.217 mmol, 56.5 %): IR (thin film) 3423, 1654 cm-1; 1H NMR (400 MHz, CDCb) o9.00 (d, J =2.5 Hz, 1H), 8.62 (dd, J = 4.7, 1.2 Hz, 1H), 8.25 (s, 1H), 8.07 (ddd, J = 8.3, 2.4, 1.3 Hz, 1H), 7.47 (dd, J = 8.3, 4.7 Hz, 1H), 4.47-3.70 (m, 3H), 3.65-3.09 (m, 2H), 2.91-2.68 (m, 2H), 2.48 (dd, J = 12.4, 5.0 Hz, 1H), 2.01 (s, 3H), 1.18 (d, J = 6.5 Hz, 3H); ESIMS m/z 356 ([M+Ht).
Example 56: Preparation of 2-(N-(3-chloro(pyridinyl)-1H-pyrazolyl)methyl- 3-(methylthio)propanamido)ethyl acetate (Compound 547) To a solution of N-(3-chloro(pyridinyl)-1H-pyrazolyl)-N-(2-hydroxyethyl)methyl- wo 2013/062981 hylthio)propanamide (0.045 g, 0.127 mmol) in dichloromethane (1.27 ml) was added N,N-dimethylpyridinamine (0.023 g, 0.190 mmol) and triethylamine (0.019 g, 0.190 mmol) followed by acetyl chloride (0.015 g, 0.190 mmol). The on was stirred at room temperature ght. Water was added and the e was extracted with dichloromethane. The combined organic phases were concentrated and chromatographed (0- 100% ethyl acetate I hexanes) to give 2-(N-(3-chloro(pyridinyl)-1H-pyrazolyl) methyl(methylthio)propanamido)ethyl acetate as a yellow oil (0.015 g, 0.034 mmol, 26.8 %): IR (thin film) 1739, 1669 cm-1; 1H NMR (400 MHz, CDCb) o8.97 (d, J = 2.3 Hz, 1H), 8.64 (dd, J = 4.7, 1.4 Hz, 1H), 8.15 (s, 1H), 8.04 (ddd, J = 8.3, 2.7, 1.4 Hz, 1H), 7.47 (ddd, J =8.3, 4.8, 0.7 Hz, 1H), 4.50-3.40 (m, 4H), 2.84 (dd, J = 12.7, 8.9 Hz, 1H), 2.78-2.63 (m, 1H), 2.46 (dd, J = 12.7, 5.4 Hz, 1H), 2.03 (s, 3H), 2.01 (s, 3H), 1.16 (d, J = 6.6 Hz, 3H); ESIMS m/z 398 ([M+Ht).
Example 57: Preparation of 2,2-dideuteriomethylsulfanyl-propanoic acid HOYSMe To a 100 mL round bottom flask was added 3-(methylthio)propanoic acid (3 g, 24.96 mmol), followed by D20 (23 mL) and KOD (8.53 mL, 100 mmol) (40% wt solution in D20), the solution was heated to reflux overnight. NMR showed ca. 95% D at alpha-position. The on was cooled down and quenched with concentrated HCl until pH<2. White precipitate appeared in aqueous layer upon acidifying. Reaction mixture was ted with 3 x 50 mL EtOAc, the combined organic layers were dried over Na2S04 , concentrated in vacuo to almost dryness. 100 mL hexane was added and the solution was concentrated again to give 2,2-dideuteriomethylsulfanyl-propanoic acid as a colorless oil (2.539 g, 20.78 mmol, 83%): IR (Thin film) 3430, 1704 cm-1; 1H NMR (400 MHz, CDCb) o2.76 (s, 2H), 2.14 (s, 3H); 13C NMR (101 MHz, CDCb) o178.28, 38.14-28.55(m), 28.55, 15.51; ElMS m/z 122.. 2-Deuteriomethylmethylsulfanyl-propanoic acid was prepared as described in Example 57 to afford a colorless oil (3.62 g, 26.8 mmol, 60.9 %): IR (Thin film) 2975, 1701 cm-1; 1H NMR (400 MHz, CDCb) o11.39- 10.41 (brs, 1H), 2.88- 2.79 (d, J = 13.3 Hz, 1H), 2.61- wo 62981 2.53 (d, J = 13.3 Hz, 1H), 2.16- 2.09 (s, 3H), 1.32- 1.25 (s, 3H); 13 C NMR (101 MHz, CDCb) o181.74,39.74-39.02 (m), 37.16, 16.50, 16.03; ElMS m/z 135. e 58: Preparation of 2-methyl(trideuteriomethylsulfanyl)propanoic acid To a 50 mL round bottom flask was added 3-mercaptomethylpropanoic acid (5 g, 41.6 mmol), followed by MeOH (15 mL), the solution was stirred at 25 oc. Potassium ide (5.14 g, 92 mmol) was added slowly as the reaction is exothermic. lodomethane-d3 (6.63 g, 45.8 mmol) was added slowly and then the reaction mixture was heated at 65 oc overnight.
The reaction was worked up by addition of 2 N HCl until the mixture was acidic. It was then extracted with EtOAc (4x50 mL) and the combined organic layers were dried over Na2S04, concentrated and purified with flash chromatography, eluted with 0-80% EtOAc I hexane to give 2-methyl(trideuteriomethylsulfanyl)propanoic acid (4.534 g, 33.0 mmol, 79 %) as colorless oil: lR (Thin film) 3446, 1704 cm-1; 1H NMR (400 MHz, CDCb) o2.84 (dd, J = 13.0, 7.1 Hz, 1H), 2.80-2.66 (m, 1H), 2.57 (dd, J = 13.0, 6.6 Hz, 1H), 1.30 (d, J =7.0 Hz, 3H); ElMS m/z 137.
Example 59: ation of 2-hydroxy(methylthio)propanoic acid HOYSMe Sodium methanethiolate (4.50 g, 64.2 mmol) was added at 25 octo a solution of 3-chloro hydroxypropanoic acid (2 g, 16.06 mmol) in MeOH (120 mL). The reaction mixture was heated at reflux for 8 hours, then cooled to 25 °C. The precipitate was d by filtration and the filtrate was evaporated. The residue was acidified to pH 2 with 2 N HCl, extracted with EtOAc (3 x 30 mL), combined organic layers were dried with Na2S04, concentrated to give 2-hydroxy(methylthio)propanoic acid as a white solid, (1.898 g, 13.94 mmol, 87% yield): mp 55-59 °C; lR (Thin film) 2927, 1698 cm-1; 1H NMR (400 MHz, CDCb) o6.33 (s, wo 2013/062981 3H), 4.48 (dd, J = 6.3, 4.2 Hz, 1H), 3.02 (dd, J = 14.2, 4.2 Hz, 1H), 2.90 (dd, J = 14.2, 6.3 Hz, 1H), 2.20 (s, 3H); ElMS m/z 136.
Example 60: Preparation of 2-methoxy(methylthio)propanoic acid HOYSMe To a stirred solution of sodium hydride (0.176 g, 4.41 mmol) in DMF (5 mL) was added a solution of oxy(methylthio)propanoic acid (0.25 g, 1.836 mmol) in 1 mL DMF at 25 °C and d for 10 min. Vigorous bubbling was observed upon addition of NaH. Then iodomethane (0.126 mL, 2.020 mmol) was added and the solution was stirred at 25 °C overnight. The reaction was quenched by addition of 2 N HCl, extracted with 3 x 10 mL of EtOAc, the combined organic layers were washed with water (2 x 20 mL), concentrated and purified by column chromatography, eluted with 0-100% EtOAc I hexane, gave 2-methoxy- 3-(methylthio)propanoic acid (126 mg, 0.839 mmol, 45.7% yield) as colorless oil: 1H NMR (400 MHz, CDCb) o9.10 (s, 1H), 4.03 (dd, J = 6.9, 4.4 Hz, 1H), 3.51 (s, 3H), 2.98- 2.93 (m, 1H), 2.86 (dd, J = 14.1, 6.9 Hz, 1H), 2.21 (s, 3H); ElMS m/z 150. e 61: Preparation of 2-(acetylthiomethyl)-3,3,3-trifluoropropanoic acid 0 0 HoYs~ To a 50 mL round bottom flask was added 2-(trifluoromethyl)acrylic acid (6 g, 42.8 mmol), followed by thioacetic acid (4.59 ml, 64.3 mmol). The reaction was slightly exothermic. The mixture was then stirred at 25 °C overnight. NMR showed some starting material (-30%).
One more equiv of etic acid was added and the mixture was heated at 95 °C for 1 hour, then allowed to cool to room ature. Mixture was purified by vacuum distillation at 2.1- 2.5 mm Hg, fraction distilled at 80-85 °C was mostly thioacetic acid, fraction distilled at 100- 110 °C was almost pure product, contaminated by a nonpolar impurity (by TLC). It was again wo 2013/062981 purified by flash chromatography (0-20% MeOH I DCM), to give 2-(acetylthiomethyl)-3,3,3- oropropanoic acid (7.78 g, 36.0 mmol, 84% yield) as colorless oil, which solidified under high vacuum to give a white solid: mp 28-30 °C; 1H NMR (400 MHz, CDCb) o7.52 (brs, 1H), 3.44 (dt, J = 7.5, 3.5 Hz, 2H), 3.20 (dd, J = 14.9, 11.1 Hz, 1H), 2.38 (s, 3H); Be NMR (101 MHz, CDCb) o194.79, , 123.44 (q, J = 281.6 Hz), 50.47 (q, J = 27.9 Hz), .44, 24.69 (q, J = 2.6 Hz); 19F NMR (376 MHz, CDCb) o-67.82.
Example 62: Preparation of 3,3,3-trifluoro(methylthiomethyl)propanoic acid HoJYs/0 CF3 To a solution of 2-(acetylthiomethyl)-3,3,3-trifluoropropanoic acid (649 mg, 3 mmol) in MeOH (5 mL) stirring at 25 °C was added pellets of potassium hydroxide (421 mg, 7.50 mmol) in four portions over 5 minutes. Reaction was exothermic. Then Mel was added in once, the reaction mixture was then heated at 65 °C for 18 hours. The reaction was then cooled down and quenched with 2N HCl until , and the aqueous layer extracted with chloroform (4 x 20 mL). Combined c layer was dried, concentrated in vacuo, ed with flash chromatography (0-20% MeOH I DCM), to give 3,3,3-trifluoro (methylthiomethyl)propanoic acid (410 mg, 2.179 mmol, 72.6 % yield) as a light yellow oil: 1H NMR (400 MHz, CDCb) o10.95 (s, 1H), 3.49- 3.37 (m, 1H), 3.02 (dd, J = 13.8, 10.8 Hz, 1H), 2.90 (dd, J = 13.8, 4.0 Hz, 1H), 2.18 (s, 3H); BC NMR (101 MHz, CDCb) o172.04 (q, J = 2.8 Hz), 123.55 (q, J = 281.2 Hz), 50.89 (q, J = 27.5 Hz), 29.62 (q, J = 2.3 Hz), 15.85; 19F NMR (376 MHz, CDCb) o-67.98.
Example 63: Preparation of 3-(methylthio)pentanoic acid S,S-dimethyl carbonodithioate (1.467 g, 12.00 mmol) was added with vigorous stirring to a solution of (E)-pentenoic acid (2.002 g, 20 mmol) in 30% KOH solution (prepared from wo 62981 potassium hydroxide (3.87 g, 69 mmol) and Water (10 mL)). The reaction mixture was slowly heated to 90°C over a period of 20-30 min. Heating was continued for 3 hours before the reaction was cooled down to 25 °C and quenched slowly with HCl. The mixture was then extracted with DCM (3 x 30 mL), combined organic layer dried and concentrated to give 3- (methylthio)pentanoic acid (2.7g, 18.22 mmol, 91 %yield) as light orange oil: lR (Thin film) 2975, 1701 cm-1; 1H NMR (400 MHz, CDCb) o2.92 (qd, 1 = 7.3, 5.6 Hz, lH), 2.63 (d, 1 = 7.2 Hz, 2H), 2.08 (s, 3H), 1.75- 1.51 (m, 2H), 1.03 (t, 1 = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCb) o178.14, 43.95, 39.78, 27.04, 12.95, 11.29; ElMS m/z 148. 4-methyl(methylthio)pentanoic acid was ed as described in Example 63 and isolated as a colorless oil: lR (Thin film) 2960, 1704 cm-1; 1H NMR (400 MHz, CDCb) o2.88 (ddd, 1 = 9.1, 5.4, 4.7 Hz, lH), 2.68 (dd, 1= 16.0, 5.5 Hz, lH), 2.55 (dd, 1= 16.0, 9.1 Hz, lH), 2.13 (s, 3H), 2.01- 1.90 (m, lH), 1.03 (d, 1 = 6.8 Hz, 3H), 0.99 (d, 1 = 6.8 Hz, 3H); ElMS m/z 162.
Example 64: ation of ethyll-(hydroxymethyl)cyclopropanecarboxylate H0¥0~ A 1M solution of lithium aluminum tri-tert-butoxyhydride in tetrahydrofuran (70.90 mL, 70.90 mmol) was added to a stirred solution of diethyl cyclopropane-1,1 '-dicarboxylate (6 g, 32.20 mmol) in ydrofuran (129 mL) at 23 oc. The resulting on was heated to 65 oc and stirred for 24 h. The cooled reaction mixture was diluted with a 10% solution of sodium bisulfate (275 mL) and extracted with ethyl acetate. The combined organic layers were dried (MgS04), filtered, and concentrated to dryness to give the desired product as a pale yellow oil (4.60, 91 %): 1H NMR (300 MHz, CDCb) o4.16 (q, 1 =7Hz, 2H), 3.62 (s, 2H), 2.60 (br s, lH), 1.22-1.30 (m, 5H), 0.87 (dd, 1 = 7, 4Hz, 2H). wo 2013/062981 Example 65: Preparation of ethyl 1- ((methylsulfonyloxy)methyl)cyclopropanecarboxylate Triethylamine (5.57 mL, 40.00 mmol) and methanesulfonyl de (2.85 mL, 36.60 mmol) were sequentially added to a stirred solution of ethyl 1- (hydroxymethyl)cyclopropanecarboxylate (4.80 g, 33.30 mmol) in dichloromethane (83 mL) at 23 oc. The resulting bright yellow solution was d at 23 oc for 20 h. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried (MgS04), filtered, and concentrated to dryness to give the desired product as a brown oil (6.92 g, 94%): 1H NMR (300 MHz, CDCb) o4.33 (s, 2H), 4.16 (q, J =7Hz, 2H), 3.08 (s, 3H), 1.43 (dd, J = 7, 4Hz, 2H), 1.26 (t, J =7Hz, 3H), 1.04 (dd, J = 7, 4Hz, 2H).
Example 66: Preparation of ethyll-(methylthiomethyl)cyclopropanecarboxylate 'sY.o~ Sodium methanethiolate (4.36 g, 62.30 mmol) was added to a stirred solution of ethyl 1- ((methylsulfonyloxy)methyl) cyclopropanecarboxylate (6.92 g, 31.10 mmol) in N,N- ylformamide (62.30 mL) at 23 oc. The resulting brown suspension was stirred at 23 oc for 18 h. The reaction mixture was diluted with water and extracted with diethyl ether.
The combined c layers were dried (MgS04), filtered, and trated by rotary evaporation to afford the title compound as a brown oil (5.43 g, 100%): 1H NMR (300 MHz, CDCb) o4.14 (q, J =7Hz, 2H), 2.83 (s, 2H), 2.16 (s, 3H), 1.31 (dd, J = 7, 4Hz, 2H), 1.25 (t, J =7Hz, 3H), 0.89 (dd, J = 7, 4Hz, 2H). wo 2013/062981 Example 67: Preparation of 1-(methylthiomethyl)cyclopropanecarboxylic acid 'sYoH0 A 50% on of sodium hydroxide (12.63 mL, 243 mmol) was added to a stirred solution of ethyl1-(methylthiomethyl)cyclopropanecarboxylate (5.43 g, 31.20 mmol) in absolute ethanol (62.30 mL) at 23 °C. The resulting solution was stirred at 23 oc for 20 h. The reaction mixture was diluted with a 0.5 M solution of sodium hydroxide and washed with dichloromethane. The aqueous layer was acidified to pH::::::1 with concentrated hydrochloric acid and extracted with romethane. The combined organic layers were dried (Na2S04), filtered, and concentrated and concentrated to s to give the desired product as a light brown oil (2.10 g, 46%): 1H NMR (300 MHz, CDCb) o2.82 (s, 2H), 2.17 (s, 3H), 1.41 (dd, J =7, 4Hz, 2H), 0.99 (dd, J =7, 4Hz, 2H).
Example 68: Preparation of 2,2-dimethyl(methylthio)propanoic acid 's¥oH0 methyl(methylthio)propanoic acid can be ed as demonstrated in the literature (reference Musker, W. K.; et al. J. Org. Chern. 1996, 51, 1026-1029). Sodium methanethiolate (1.0 g, 14 mmol, 2.0 equiv) was added to a stirred solution of 3-chloro-2,2- dimethylpropanoic acid (1.0 g, 7.2 mmol, 1.0 equiv) in N,N-dimethylformamide (3.7 mL) at 0 oc. The resulting brown suspension was allowed to warm to 23 oc and d for 24 h. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (300 mL) and washed with diethyl ether (3 x 75 mL). The aqueous layer was acidified to ::1 with concentrated hydrochloric acid and extracted with l ether (3 x 75 mL). The combined organic layers were dried (sodium sulfate), gravity filtered, and concentrated to afford a colorless oil (1.2 g, 99% crude yield). 1H NMR (300 MHz, CDCb) o2.76 (s, 2H), 2.16 (s, 3H), 1.30 (s, 6H). wo 2013/062981 Example 69: Preparation of 4,4,4-trifluoro(methylthio)butanoic acid To a 100 mL round bottom flask was added (E)-4,4,4-trifluorobutenoic acid (8 g, 57.1 mmol) and Methanol (24 mL), the solution was stirred in a water bath, then sodium methanethiolate (10.01 g, 143 mmol) was added in three portions. Vigorous bubbling was observed, the mixture was stirred at 25 °C overnight, NMR showed no more starting material.
To the on mixture was added 2 N HCl until acidic. The mixture was extracted with chloroform (5 x 50 mL), combined organic layer was dried over Na2S04, concentrated in vacuo and further dried under high vacuum until there was no weight loss to give 4,4,4- trifluoro(methylthio)butanoic acid (10.68 g, 56.8 mmol, 99 % yield) as a colorless oil: 1H NMR (400 MHz, CDCb) o10.88 (s, 1H), 3.53 (dqd, J = 10.5, 8.3, 4.0 Hz, 1H), 2.96 (dd, J = 16.9, 4.0 Hz, 1H), 2.65 (dd, J = 16.9, 10.4 Hz, 1H), 2.29 (s, 3H); 13C NMR (101 MHz, CDCb) o175.78 (s), 126.61 (q, lc-F= 278.8 Hz), 44.99 (q, lc-F = 30.3Hz), 34.12 (d, lc-F = 1.7 Hz), 15.95 (s); ElMS m/z 162.
Example 70: ation of 3-methylmethylsulfanyl-butyric acid 3-methylmethylsulfanyl-butyric acid was made using the procedures disclosed in J.Chem Soc Perkin 1, 1992, 10, 1215-21.
Example 71: ation of 3-methylsulfanyl-butyric acid H...oDs./ 3-Methylsulfanyl-butyric acid was made using the ures disclosed in tic Comm., 1985, 15 (7), 623-32. wo 2013/062981 Example 72: Preparation of tetrahydro-thiophenecarboxylic acid Tetrahydro-thiophenecarboxylic acid was made using the ures disclosed in Heterocycles, 2007, 74, 9.
Example 73: Preparation of 2-methylmethylsulfanyl-butyric acid o1I ls H- -1 2-Methylmethylsulfanyl-butyric acid was made as described in J.Chem Soc Perkin 1, 1992, 10, 1215-21.
Example 74: Preparation of (1S,2S)(methylthio)cyclopropanecarboxylic acid (1S,2S)(Methylthio)cyclopropanecarboxylic acid was made using the procedures disclosed in Synthetic Comm., 2003, 33 (5); 801-807.
Example 75: Preparation of 2-(2-(methylthio)ethoxy)propanoic acid HoAy0~s/ wo 2013/062981 Methylthio)ethoxy)propanoic acid was made as described in Al.
Example 76: ation of 2-((tetrahydrofuranyl)oxy)propanoic acid 2-((Tetrahydrofuranyl)oxy)propanoic acid was made as described in Example 77: Preparation of tert-butyll-(5-fluoropyridinyl)methyl-lH-pyrazol pynyl)carbamate (Compound 601) To an ice cold solution of tert-butyl1-(5-fluoropyridinyl)methyl-1H-pyrazol ylcarbamate (1200 mg, 4.11 mmol) in dry N,N-dimethylformamide (DMF; 4 mL) under nitrogen was added 60% wt sodium hydride (197 mg, 4.93 mmol) and the mixture stirred for minutes (min). 3-Bromopropyne (733 mg, 6.16 mmol) was then added and the mixture was stirred for additional 0.5 hour (h) at 0- 5 °C. The mixture was allowed to warm to ambient ature and then stirred for additional 3 h. The brown on mixture was poured into saturated aqueous ammonium chloride (NH Cl; 20 mL), and diluted with ethyl acetate (EtOAc; 50 mL). The organic phase was separated and the aqueous phase extracted with EtOAc (20 mL). The combined organic phase was washed with brine, dried over anhydrous magnesium sulfate (MgS0 ), filtered, and trated in vacuo to give a brown oil. This oil was purified on silica gel eluting with mixtures of hexanes and EtOAc to give the title compound as a light yellow solid (1103 mg, 81 %): mp 81-82 oc; 1H NMR (400 MHz, CDCb) o8.73 (s, 1H), 8.37 (d, J = 2.5 Hz, 1H), 7.99 (s, 1H), 7.83 (dt, J = 9.5, 2.2 Hz, 1H), 4.31 (s, 2H), 2.29 (t, J = 2.4 Hz, 1H), 2.27 (s, 3H), 1.45 (s, 9H); ESIMS m/z 229.84 ([Mt). wo 2013/062981 Compounds 596 and 606 were prepared in accordance with the procedure disclosed in Example 77 from the corresponding amine.
Example 78: Preparation of 1-(5-fluoropyridinyl)methyl-N-(propynyl)-lH- pyrazolamine, hydrochloride FyyNfNH.HCI ~N) ~\ To a solution of tert-butyl 1-(5-fluoropyridinyl)methyl-1H-pyrazolyl(prop ynyl)carbamate (1.03 g, 3.11 mmol) in dioxane (5 mL) was added 4 molar (M) en chloride (HCl; 3.9 mL, 15.5 mmol) in diethyl ether (Et20). The mixture was stirred at room temperature for 48 h and the resulting white solid was filtered, washed with Et20 and dried under vacuum to give the title nd as a white solid (741 mg, 89%): mp 167-168 oc; 1H NMR (400 MHz, DMSO d6) o8.92-8.85 (m, 1H), 8.42 (d, J =2.5 Hz, 1H), 8.15 (s, 1H), 8.12-8.02 (m, 1H), 3.85 (d, J =2.5 Hz, 2H), 3.27-3.19 (m, 1H), 2.22 (s, 3H); ESIMS m/z 230.4 ([Mt). 3-Chloro-N-(propynyl)(pyridinyl)-1H-pyrazolamine, hydrochloride was ed in accordance with the procedure disclosed in Example 78 from nd 606: mp 180-182 oc; 1H NMR (400 MHz, CDCl3) o9.22 (d, J =2.5 Hz, 1H), 8.67 (dd, J = 5.3, 1.0 Hz, 1H), 8.64 (ddd, J = 8.6, 2.6, 1.2 Hz, 1H), 8.32 (s, 1H), 7.96 (dd, J = 8.6, 5.3 Hz, 1H), 3.81 (d, J = 2.4 Hz, 2H), 3.15 (t, J = 2.4 Hz, 1H); ESIMS m/z 234 ([M+2t). 3-Methyl-N-(propynyl)(pyridinyl)-1H-pyrazolamine, hydrochloride was prepared in accordance with the procedure disclosed in Example 78 from Compound 596: mp 161-163 °C; 1H NMR (400 MHz, DMSO-d6) o8.46 (s, 1H), 8.05 (s, 1H), 7.83 (d, J = 5.9 Hz, 1H), 7.57 (s, 1H), 7.29 (dd, J = 8.8, 5.6 Hz, 1H), 3.27 (d, J = 2.5 Hz, 2H), 3.21 (t, J = 1.2Hz, 1H), 1.52 (s, 3H); ElMS m/z 213.1 ([M]+). wo 2013/062981 Example 79: Preparation of N-(1-(5-fluoropyridinyl)methyl-1H-pyrazolyl) lthio)-N-(propynyl)propanamide (Compound 605) To a stirred solution of 1-(5-fluoropyridinyl)methyl-N-(propynyl)-1H-pyrazol amine, HCl (100 mg, 0.38 mmol) and N,N-dimethylpyridinamine (DMAP; 115 mg, 0.94 mmol) in CH2Cl2 (DCM; 2 mL) was added 2-methyl(methylthio)propanoyl chloride (69 mg, 0.45 mmol), and the mixture stirred at room temperature for 24 h. The mixture was concentrated in vacuo to give a brown oil which was purified on silica gel eluting with mixtures of EtOAc and hexanes to give the title compound as a colorless oil (80 mg, 61%): 1H NMR (400 MHz, CDCb) o8.76 (d, J = 1.6 Hz, 1H), 8.44 (d, J =2.5 Hz, 1H), 8.05 (s, 1H), 7.86 (dt, J = 9.3, 2.3 Hz,1H), 4.45 (s, 2H), 2.79 (t, J =7.3 Hz, 2H), 2.43 (t, J =7.3 Hz, 2H), 2.30 (s, 3H), 2.25 (t, J =2.5 Hz, 1H), 2.06 (s, 3H); ESIMS m/z 333.6 ([M+Ht). nds 598, 599, 600,602, 603, 607, 608 and 610 were prepared in accordance with the procedure disclosed in e 79 from the ponding amines.
Example 80: Preparation of N-(3-chloro(pyridinyl)-1H-pyrazolyl)-4,4,4- trifluoro(methylthio)-N-(propynyl)butanamide (Compound 613) N,_ Q, '}--/ SFC 3 Cl )__ / UN/)I N'- To a 7 mL vial was added 3-chloro-N-(propynyl)(pyridinyl)-1H-pyrazolamine (140 mg, 0.6 mmol), N,N-dimethylpyridinamine (249 mg, 2.040 mmol), N1- ((ethylimino)methylene)-N3,N3-dimethylpropane-1 ,3-diamine hydrochloride (276 mg, 1.440 mmol) followed by 4,4,4-trifluoro(methylthio)butanoic acid (158 mg, 0.840 mmol) and wo 2013/062981 DCE (1.2 mL). The solution was stirred at 25 °C for 18 hours, the crude on mixture was concentrated and purified with silica gel chromatography (0-100% EtOAc I hexane) to give the title nd as a brown oil (237 mg, 0.588 mmol, 98%): (IR thin film) 1674 cm-1; 1H NMR (400 MHz, CDCb) o8.97 (d, J = 2.6 Hz, 1H), 8.64 (dd, J = 4.7, 1.3 Hz, 1H), 8.13 (s, 1H), 8.07 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 7.48 (ddd, J = 8.3, 4.8, 0.5 Hz, 1H), 4.39 (s, 2H), 3.76 (dqd, J = 17.2, 8.6, 3.6 Hz, 1H), 2.67 (dd, J = 16.6, 3.6 Hz, 1H), 2.46 (dd, J = 16.5, 9.9 Hz, 1H), 2.29 (d, J =2.5 Hz, 4H); ESIMS m/z 403 ([M+Ht). tert-Butyl (2-((3-chloro(pyridinyl)-1H-pyrazolyl)(propynyl)amino) oxoethyl)(methyl)carbamate was prepared as described in e 80: IR (thin film) 1696 cm-1; 1H NMR (400 MHz, CDCb) o8.96 (bs, 1H), 8.63 (dd, J =4.9 Hz, 1H), 8.21- 7.86 (m, 2H), 7.46 (dd, J = 8.3, 4.8 Hz, 1H), 4.65- 4.30 (m, 2H).4.02- 3.70 (bs, 2H), 3.06- 2.79 (m, 3H), 2.25(bs, 1H), 1.44(s, 9H); ESIMS m/z 404 ([M+Ht).
Compounds 597, 604, 609,614-616, 619, 624,626, and 627 were prepared in accordance with the procedure disclosed in Example 80. Compound 625 was prepared from Compound 624 using the methodology described in US 20120053146 Al.
Example 81: Preparation of 3-chloro-N-(propynyl)(pyridinyl)-1H-pyrazol amine To a solution of tert-butyl (3-chloro(pyridinyl)-1H-pyrazolyl)(propyn yl)carbamate (2.2 g, 6.61 mmol) in dichloromethane (DCM; 8.3 ml) was added 2,2,2- oroacetic acid (12.06 g, 106 mmol) and the reaction mixture was stirred at ambient temperature for 1 h. The reaction was ed by the addition of saturated sodium bicarbonate 3l. The organic layer was extracted with DCM (2 x 20 mL). The organic layers were combined and dried over sodium sulfate (Na2S04), filtered and concentrated to afford the title compound as a beige solid (1.5 g, 6.12 mmol, 93%): 1H NMR (400 MHz, wo 62981 CDCb) o8.89 (d, J = 2.3 Hz, 1H), 8.50 (dd, J = 4.7, 1.4 Hz, 1H), 8.01- 7.93 (m, 1H), 7.54 (s, 1H), 7.37 (ddd, J = 8.3, 4.8, 0.7 Hz, 1H), 3.90 (s, 2H), 3.38 (s, 1H), 2.44- 2.09 (m, 1H); ESIMS m/z 233 ([M+Ht).
Example 82: Preparation of N-(3-chloro(pyridinyl)-1H-pyrazolyl) (methylthio)-N-(propynyl)propanamide (Compound 611) Cl o s- ri'YZ)-N~ ~N~ ) To a on of 2-(methylthio )propanoic acid (0.36 g, 3.00 mmol) in DCM (3 mL) was added oxalyl dichloride (0.29 ml, 3.31 mmol) followed by one drop of DMF. The reaction e was stirred for 30 min before all of the solvent was evaporated. The resulting e was dissolved in DCM (2 mL) and the solution was added to a pre-stirred on of 3- chloro-N-(propynyl)(pyridinyl)-1H-pyrazolamine (0.35 g, 1.50 mmol) and N- ethyl-N-isopropylpropanamine (0.57 ml, 3.31 mmol) in DCM (5.5 mL). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated and the residue was purified using silica gel chromatography (0-100% EtOAc I hexanes) to afford the title nd as a yellow oil (432 mg, 1.23 mmol, 85%): 1H NMR (400 MHz, CDCb) o8.97 (d, J =2.5 Hz, 1H), 8.66- 8.60 (m, 1H), 8.25 (s, 1H), 8.08- 8.01 (m, 1H), 7.49 - 7.42 (m, 1H), 4.86 (s, 1H), 4.29- 3.97 (m, 1H), 3.31 (d, J = 6.5 Hz, 1H), 2.30- 2.24 (m, 1H), 2.09 (s, 3H), 1.46 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCb) o171.30, 148.66, 140.71, 140.18, 135.71, 127.87, 126.35, 124.11, 122.12, 78.53, 72.92, 53.39, 37.97, 16.42, 11.07; ESIMS m/z 335 ([M+Ht).
Compounds 612 and 622 were prepared in accordance with the procedure disclosed in Example 82.
Example 83: Preparation of N-(3-chloro(pyridinyl)-1H-pyrazolyl) (methylsulfinyl)-N-(propynyl)propanamide (Compound 617) wo 2013/062981 To a solution of N-(3-chloro(pyridinyl)-1H-pyrazolyl)(methylthio)-N-(propyn- ropanamide (0.1 g, 0.30 mmol) in hexafluoroisoproanol (2.0 ml) was added hydrogen peroxide (35 wt %, 0.08 ml, 0.90 mmol) and the reaction mixture was stirred vigorously at ambient temperature. The reaction was complete after 1 h. The reaction was ed with saturated sodium e solution and the organic layer was ted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2S04, filtered and concentrated. The residue was purified using silica gel tography (0-20% methanol (MeOH) I DCM) to afford the title compound as an off-white foam (82 mg, 0.21 mmol, 78 %): 1H NMR (400 MHz, CDCb) o8.98 (s, 1H), 8.65 (d, J =4.6 Hz, 1H), 8.23 (s, 1H), 8.11- 7.97 (m, 1H), 7.51 - 7.41 (m, 1H), 4.88 (br s, 1H), 4.14 (br s, 1H), 2.64 (s, 1.2H), 2.55 (s, 1.8H), 2.33- 2.27 (m, 1H), 1.47 (d, J = 6.8 Hz, 3H), 1.42 (br s, 1H); 13C NMR (101 MHz, CDCb) o168.11, 148.95, 148.78, 140.45, 140.33, 140.20, 135.56, 126.54, 124.10, 121.68, 121.58, 121.48, 77.69, 73.49, 38.60; ESIMS m/z 351 ([M+Ht). e 84: Preparation of N-(3-chloro(pyridinyl)-1H-pyrazolyl) (methylsulfonyl)-N-(propynyl)propanamide (Compound 618) To a solution of N-(3-chloro(pyridinyl)-1H-pyrazolyl)(methylthio)-N-(propyn- 1-yl)propanamide (0.10 g, 0.30 mmol) and acetic acid (2.0 ml) was added sodium perborate tetrahydrate (0.11 g, 0.74 mmol) and the vial was heated to 65 oc for 2 h. The reaction mixture was cooled to ambient temperature and neutralized with saturated NaHC03. The aqueous layer was extracted with EtOAc (3x). The organic layers were combined, dried over wo 2013/062981 Na2S04, filtered and concentrated. The e was purified using silica gel tography (0-20% MeOH I DCM) to afford the title compound as a yellow foam (84 mg, 0.21 mmol, 73%): 1H NMR (400 MHz, CDCb) o9.00 (s, 1H), 8.65 (s, 1H), 8.29 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.54- 7.39 (m, 1H), 4.89 (d, J = 16.9 Hz, 1H), 4.20- 4.08 (m, 1H), 4.07- 3.92 (m, 1H), 3.01 (s, 3H), 2.34- 2.29 (m, 1H), 1.67 (d, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCb) 0 166.97, , 148.77, 140.43, 140.24, 135.58, 129.36, 126.64, 124.14, 121.34, 73.80, 60.91, 38.78, 36.29, 13.97; ESIMS m/z 367 ([M+Ht).
Compounds 620 and 621 were prepared in accordance with the procedure sed in Example 84.
Example 85: Preparation of N-(3-chloro(pyridinyl)-1H-pyrazolyl) (methylamino)-N-(propynyl)acetamide To a solution of tert-butyl (2-((3-chloro(pyridinyl)-1H-pyrazolyl)(propyn yl)amino)oxoethyl)(methyl)carbamate (0.47 g, 1.16 mmol) in DCM (1.16 ml) was added 2,2,2-trifluoroacetic acid (1.16 ml) and the reaction mixture was stirred at ambient temperature for 1 h. To the mixture was added toluene and then the reaction was concentrated to dryness. The oil was redissolved in DCM and saturated NaHC03 on was added. The phases were separated and the aqueous phase was extracted with DCM. The organic layers were combined, the t evaporated, and the residue purified using silica gel chromatography (0-15% MeOH I DCM) to afford the title compound as yellow oil (0.258 g, 0.849 mmol, 73%): IR (thin film) 1696 cm-1; 1H NMR (400 MHz, CDCb) o8.98 (d, J =2.6 Hz, 1H), 8.64 (dd, J = 4.7, 1.3 Hz, 1H), 8.19 (s, 1H), 8.06 (ddd, J = 8.3, 2.6, 1.4 Hz, 1H), 7.47 (dd, J = 8.3, 4.7 Hz, 1H), 4.48 (s, 2H), 3.49 (s, 2H), 2.49 (s, 3H), 2.28 (t, J =2.5 Hz, 1H); ESIMS m/z 304 ([M+Ht). wo 2013/062981 Example 86: ation of N-(3-chloro(pyridinyl)-1H-pyrazolyl)(N- methylmethylsulfonamido)-N-(propynyl)acetamide (Compound 623) To a solution of N-(3-chloro(pyridinyl)-1H-pyrazolyl)(methylamino)-N-(prop ynyl)acetamide (0.100 g, 0.329 mmol) in DCM (0.65 ml) was added methanesulfonyl de (0.057 g, 0.494 mmol) ed by diisopropylethylamine (0.11 ml, 0.658 mmol) and the reaction was stirred at room temperature for 24 h. The reaction mixture was poured into a solution of saturated NaHC03 and subsequently extracted with DCM. The organic layers were combined and concentrated, and the residue was purified using silica gel chromatography (50-100% EtOAc I hexanes) to afford the title compound as a yellow solid (0.091 g, 0.238 mmol, 72%): (IR thin film) 1678 cm-1; 1H NMR (400 MHz, CDCb) o8.97 (d, J =2.6 Hz, 1H), 8.65 (dd, J = 4.8, 1.3 Hz, 1H), 8.15 (s, 1H), 8.04 (ddd, J = 8.3, 2.7, 1.4 Hz, 1H), 7.48 (dd, J = 8.4, 4.7 Hz, 1H), 3.77 (hept, J = 6.9 Hz, 2H), 3.05 (s, 2H), 3.01 (s, 3H), 2.87 (s, 3H), 2.31 (t, J = 2.5 Hz, 1H); ESIMS m/z 382 ).
Example 87: Preparation of 3-((3,3,3-trifluoropropyl)thio)propanoic acid J_/-s HO 3-Mercaptopropanoic acid (3.2 g, 30.1 mmol) was dissolved in MeOH (20 mL) and stirred at RT. ed potassium hydroxide (3.72 g, 66.3 mmol) was added to the solution, followed by 3-bromo-1,1,1-trifluoropropane (6.14 g, 34.7 mmol). The solution was then stirred at 65 oc for 3 h and then it was quenched with 1N HCl until the pH of the solution was acidic. The mixture was extracted with DCM (3 x 30 mL), the combined organic phases were dried, concentrated and purified by silica gel chromatography (0-50% EtOAc I hexane) to give 3- wo 2013/062981 ((3,3,3-trifluoropropyl)thio)propanoic acid (5.5 g, 27.2 mmol, 90% yield) as ess oil mixed with some white sion: IR (Thin film) 2936, 1708 cm-1; 1H NMR (300 MHz, CDCb) o2.86- 2.78 (m, 2H), 2.78- 2.58 (m, 4H), 2.52- 2.25 (m, 2H); ElMS m/z 202.
Example 88: ation of N-(3-methyl(pyridinyl)-1H-pyrazolyl)-N-(prop ynyl)((3,3,3-trifluoropropyl)thio)propanamide (Compound 627) In a 4mL vial was added 3-methyl-N-(propynyl)(pyridinyl)-1H-pyrazolamine hydrochloride (120 mg, 0.482 mmol) and DMAP (59 mg, 0.482 mmol) with dry Et20 ( 1.6 mL). The solution was stirred at room temperature for 1 h. Then additional DMAP (200 mg, 1.639 mmol) was added. The solution was cooled to 0 oc under N2 and dicyclohexylcarbodiimide (DCC; 239 mg, 1.158 mmol) was added. The solution was allowed to warm up to room temperature slowly and stirred ght. White precipitate formed during the reaction. The crude reaction mixture was filtered and purified by silica gel chromatography (0-90% EtOAc I hexane) to give N-(3-methyl(pyridinyl)-1H-pyrazol- 4-yl)-N-(propynyl)((3,3,3-trifluoropropyl)thio)propanamide (113 mg, 0.269 mmol, 55.7% yield) as a yellow viscous oil: IR (Thin film) 3293, 1663 cm-1; 1H NMR (400 MHz, CDCb) o8.96 (d, J =2.6 Hz, 1H), 8.58 (dd, J = 4.8, 1.5 Hz, 1H), 8.04 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 8.01 (s, 1H), 7.44 (dd, J = 8.3, 4.9 Hz, 1H), 4.45 (s, 2H), 2.84 (t, J =7.1 Hz, 2H), 2.72-2.60 (m, 2H), 2.44 (t, J =7.1 Hz, 2H), 2.41-2.32 (m, 2H), 2.31 (s, 3H), 2.26 (t, J = 2.4 Hz, 1H); ESIMS m/z 397 ([M+Ht).
Example A: BIOASSAYS ON GREEN PEACH APHID ("GPA") (Myzus persicae) (MYZUPE).
GPA is the most significant aphid pest of peach trees, causing decreased , ling 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 wo 2013/062981 other food crops. GPA attacks such plants as broccoli, k, cabbage, carrot, lower, daikon, eggplant, green beans, lettuce, macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress, and zucchini, among other . GPA also attacks many ornamental crops such as carnation, nthemum, flowering white e, poinsettia, and roses.
GPA has developed resistance to many pesticides.
Certain molecules disclosed in this document were tested against GPA using procedures described in the following example. In the reporting of the results, "Table 3: GPA (MYZUPE) and sweetpotato whitefly-crawler (BEMITA) Rating Table" was used (See Table Section).
Cabbage seedlings grown in 3-inch pots, with 2-3 small (3-5 em) true leaves, were used as test substrate. The seedlings were infested with 20-50 GPA ess 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) t, forming stock solutions of 1000 ppm test compound. The stock solutions were diluted 5X with 0.025% Tween 20 in H20 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 for three days at approximately 25 oc and ambient relative humidity (RH) prior to grading. Evaluation was conducted by counting the number of live aphids per plant under a microscope. Percent l was measured by using Abbott's correction formula (W.S. Abbott, "A Method of Computing the Effectiveness of an Insecticide" J. Econ. Entomol. 18 , pp.265-267) as follows.
Corrected % Control =100 * (X - Y) I X where X= No. of live aphids on solvent check plants and Y =No. of live aphids on treated plants The results are ted in the table entitled "Table 4. Biological Data for GPA (MYZUPE) and sweetpotato whitefly-crawler (BEMITA)" (See Table Section). e B: Insecticidal test for sweetpotato whitefly-crawler (Bemisia tabaci) (BEMITA) in foliar spray assay Cotton plants grown in 3-inch pots, with 1 small (3-5 em) true leaf, were used as test wo 2013/062981 2012/061508 substrate. The plants were placed in a room with ly adults. Adults were allowed to deposit eggs for 2-3 days. After a 2-3 day egg-laying period, plants were taken from the adult whitefly room. Adults were blown off leaves using a hand-held Devilbiss sprayer (23 psi).
Plants with egg infestation (100-300 eggs per plant) were placed in a holding room for 5-6 days at 82 oF and 50% RH for egg hatch and crawler stage to develop. Four cotton plants were used for each treatment. Compounds (2 mg) were dissolved in 1 mL of acetone solvent, forming stock solutions of 2000 ppm. The stock solutions were diluted lOX with 0.025% Tween 20 in H20 to obtain a test solution at 200 ppm. A hand-held Devilbiss sprayer was used for spraying a solution to both sides of cotton leaf until runoff. nce plants (solvent check) were d with the diluent only. Treated plants were held in a holding room for 8-9 days at approximately 82°F and 50% RH prior to grading. Evaluation was conducted by counting the number of live nymphs per plant under a microscope. Insecticidal activity was measured by using Abbott's tion formula and presented in "Table 4. ical Data for GPA (MYZUPE) and sweetpotato ly-crawler (BEMITA)" (see column "BEMITA"): ted % Control = 100 * (X - Y) I X where X = No. of live nymphs on solvent check plants Y = No. of live nymphs on treated plants IDALLY ACCEPTABLE ACID ADDITION SALTS, SALT TIVES, SOLVATES, ESTER DERIVATIVES, POLYMORPHS, ISOTOPES AND RADIONUCLIDES Molecules of Formula One may be formulated into pesticidally acceptable acid addition salts. By way of a miting example, an amine function can form salts with hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic, succinic, ic, lactic, ic, 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 magnesium.
Molecules of Formula One may be formulated into salt derivatives. By way of a nonlimiting example, a salt derivative can be prepared by contacting a free base with a sufficient wo 2013/062981 2012/061508 amount of the desired acid to produce a salt. A free base may be regenerated by treating the salt 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 salt..
Molecules of Formula One may be ated into stable complexes with a solvent, such that the complex s intact after the non-complexed solvent is removed. These complexes are often referred to as "solvates." However, it is particularly ble to form stable hydrates with water as the solvent.
Molecules of Formula One may be made into ester derivatives. These ester derivatives can then be applied in the same manner as the invention disclosed in this document is applied.
Molecules 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 molecule can have vastly different physical properties and biological performances.
Molecules of Formula One may be made with different es. Of particular importance are molecules having 2H (also known as deuterium) in place of 1H.
Molecules of Formula One may be made with different radionuclides. Of particular importance are molecules having 14C.
STEREOISOMERS les of Formula One may exist as one or more stereoisomers. Thus, certain molecules 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 isomers may be obtained by known selective synthetic procedures, by conventional synthetic procedures using resolved starting materials, or by conventional resolution procedures. n les disclosed in this nt can exist as two or more isomers.
The various isomers include geometric isomers, diastereomers, and omers. Thus, the molecules disclosed in this document include geometric 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 wo 2013/062981 present disclosure are drawn in only one ric form for clarity, but are intended to represent all geometric forms of the molecule.
COMBINATIONS Molecules of Formula One may also be used in combination (such as, in a compositional mixture, or a aneous or sequential application) with one or more compounds having acaricidal, algicidal, avicidal, bactericidal, fungicidal, herbicidal, insecticidal, molluscicidal, nematicidal, rodenticidal, or virucidal properties. Additionally, the molecules of a One may also be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with nds that are antifeedants, bird repellents, chemosterilants, herbicide safeners, insect attractants, insect repellents, mammal repellents, mating disrupters, plant tors, plant growth regulators, or synergists.
Examples of such compounds in the above groups that may be used with the Molecules of Formula One are- (3-ethoxypropyl)mercury bromide, 1,2-dichloropropane, 1,3- dichloropropene, 1-methylcyclopropene, 1-naphthol, 2-(octylthio)ethanol, 2,3 ,5-triiodobenzoic acid, 2,3,6-TBA, 2,3,6-TBA-dimethylammonium, 2,3,6-TBA-lithium, 2,3,6- TBA-potassium, 2,3,6-TEA-sodium, 2,4,5-T, 2,4,5-Tbutoxypropyl, Tethylhexyl, 2,4,5-Tbutoxypropyl, 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-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-Dbutoxypropyl, 2,4-D- 2-ethylhexyl, 2,4-Dbutoxypropyl, 2,4-D-ammonium, 2,4-DB, 2,4-DB-butyl, 2,4-DB- dimethylammonium, 2,4-DB-isoctyl, 2,4-DB-potassium, 2,4-DB-sodium, 2,4-D-butotyl, 2,4- D-butyl, 2,4-D-diethylammonium, 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, triethylammonium, tris(2- hydroxypropyl)ammonium, 2,4-D-trolamine, 2iP, 2-methoxyethylmercury chloride, 2- phenylphenol, 3,4-DA, 3,4-DB, , 4-aminopyridine, 4-CPA, 4-CPA-potassium, 4-CPA- sodium, 4-CPB, 4-CPP, 4-hydroxyphenethyl alcohol, 8-hydroxyquinoline e, 8- phenylmercurioxyquinoline, abamectin, abscisic acid, ACC, acephate, acequinocyl, acetamiprid, on, hlor, acetophos, acetoprole, zolar, acibenzolar-S-methyl, acifluorfen, acifluorfen-methyl, acifluorfen-sodium, fen, acrep, acrinathrin, acrolein, wo 2013/062981 acrylonitrile, acypetacs, acypetacs-copper, acypetacs-zinc, alachlor, alanycarb, albendazole, rb, aldimorph, carb, aldrin, allethrin, allicin, allidochlor, allosamidin, alloxydim, alloxydim-sodium, allyl l, allyxycarb, alorac, alpha-cypermethrin, alpha-endosulfan, ametoctradin, dione, ametryn, amibuzin, amicarbazone, amicarthiazol, amidithion, amidoflumet, amidosulfuron, aminocarb, aminocyclopyrachlor, aminocyclopyrachlor-methyl, yclopyrachlor-potassium, aminopyralid, yralid-potassium, aminopyralid-tris(2- hydroxypropyl)ammonium, amiprofos-methyl, amiprophos, amisulbrom, amiton, amiton oxalate, amitraz, amitrole, ammonium sulfamate, ammonium a-naphthaleneacetate, amobam, ampropylfos, anabasine, ancymidol, anilazine, anilofos, on, anthraquinone, antu, apholate, aramite, arsenous oxide, asomate, aspirin, asulam, asulam-potassium, asulamsodium , athidathion, n, atrazine, ungin, aviglycine, aviglycine hloride, azaconazole, azadirachtin, azafenidin, azamethiphos, azimsulfuron, azinphos-ethyl, azinphosmethyl , aziprotryne, azithiram, azobenzene, azocyclotin, ate, azoxystrobin, bachmedesh, barban, barium hexafluorosilicate, barium polysulfide, in, BCPC, beflubutamid, benalaxyl, benalaxyl-M, benazolin, benazolin-dimethylammonium, benazolinethyl , benazolin-potassium, bencarbazone, benclothiaz, bendiocarb, ralin, benfuracarb, benfuresate, nil, benomyl, benoxacor, benoxafos, benquinox, bensulfuron, bensulfuron-methyl, bensulide, bensultap, bentaluron, bentazone, bentazone-sodium, benthiavalicarb, benthiavalicarb-isopropyl, benthiazole, bentranil, benzadox, benzadox- ammonium, benzalkonium de, benzamacril, benzamacril-isobutyl, benzamorf, ndizone, 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, fos-sodium, binapacryl, bingqingxiao, bioallethrin, bioethanomethrin, biopermethrin, methrin, yl, bisazir, bismerthiazol, bispyribac, bispyribac-sodium, bistrifluron, bitertanol, bithionol, bixafen, blasticidin-S, borax, Bordeaux mixture, boric acid, boscalid, brassinolide, brassinolide-ethyl, omin, brodifacoum, brofenvalerate, brofluthrinate, bromacil, bromacil-lithium, bromacil-sodium, bromadiolone, bromethalin, bromethrin, nvinfos, 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, wo 2013/062981 ezin, Burgundy mixture, busulfan, rb, butachlor, butafenacil, butamifos, butathiofos, butenachlor, butethrin, buthidazole, buthiobate, buthiuron, butocarboxim, butonate, ronoxyl, butoxycarboxim, butralin, ydim, buturon, butylamine, te, cacodylic acid, cadusafos, trole, calcium te, calcium chlorate, m cyanamide, m polysulfide, calvinphos, cambendichlor, camphechlor, r, captafol, captan, carbamorph, carbanolate, yl, carbasulam, dazim, 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, mben, mben-ammonium, chloramben-diolamine, chloramben-methyl, chloramben-methylammonium, mben-sodium, chloramine phosphorus, chloramphenicol, chloraniformethan, chloranil, chloranocry1, chlorantraniliprole, chlorazifop, chlorazifop-propargyl, zine, 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, ropham, chlorpyrifos, chlorpyrifos-methyl, chlorquinox, chlorsulfuron, chlorthal, chlorthal-dimethyl, chlorthal-monomethyl, chlorthiamid, chlorthiophos, linate, choline chloride, chromafenozide, cinerin I, cinerin II, cinerins, cinidon-ethyl, cinmethylin, cinosulfuron, ciobutide, cisanilide, cismethrin, clethodim, climbazole, cliodinate, clodinafop, clodinafop-propargyl, ocarb, clofencet, clofencet-potassium, clofentezine, clofibric acid, clofop, clofop-isobutyl, clomazone, clomeprop, cloprop, xydim, clopyralid, clopyralid-methy1, clopyralid-olamine, clopyralid-potassium, clopyralid-tris(2- hydroxypropyl)ammonium, cloquintocet, cloquintocet-mexyl, cloransulam, cloransulammethyl , closantel, clothianidin, clotrimazole, cloxyfonac, cloxyfonac-sodium, CMA, wo 2013/062981 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, uryl, hos, coumatetralyl, coumithoate, coumoxystrobin, CPMC, CPMF, CPPC, credazine, cresol, crimidine, crotamiton, crotoxyphos, crufomate, cryolite, cue-lure, cufraneb, cumyluron, am, cuprous oxide, curcumenol, cyanamide, cyanatryn, cyanazine, enphos, cyanophos, cyanthoate, cyantraniliprole, cyazofamid, cybutryne, cyclafuramid, cyclanilide, cyclethrin, cycloate, cycloheximide, rate, cycloprothrin, cyclosulfamuron, 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, ulfamide, cyromazine, cythioate, daimuron, dalapon, dalapon-calcium, dalapon-magnesium, n-sodium, daminozide, dayoutong, dazomet, dazomet-sodium, DBCP, d-camphor, DCIP, DCPTA, DDT, debacarb, decafentin, decarbofuran, dehydroacetic acid, delachlor, deltamethrin, demephion, demephion-0, demephion-S, demeton, demeton-methyl, demeton-0, n methyl, demeton-S, demeton-S-methyl, demeton-S-methylsulphon, desmedipham, desmetryn, d-fanshiluquebingjuzhi, diafenthiuron, os, di-allate, diamidafos, aceous earth, diazinon, dibutyl phthalate, dibutyl succinate, dicamba, dicamba- diglycolamine, dicamba-dimethylammonium, a-diolamine, dicambaisopropylammonium , dicamba-methyl, dicamba-olamine, dicamba-potassium, asodium , dicamba-trolamine, dicapthon, dichlobenil, dichlofenthion, fluanid, dichlone, dichloralurea, dichlorbenzuron, rflurenol, dichlorflurenol-methyl, dichlormate, dichlormid, dichlorophen, dichlorprop, dichlorpropethylhexyl, dichlorprop-butotyl, dichlorprop-dimethy!ammonium, dichlorprop-ethyIammonium, dichlorprop-isocty1, dichlorprop-methyl, dichlorprop-P, dichlorprop-Pethylhexyl, dichlorprop-P- dimethylammonium, dichlorprop-potassium, dichlorprop-sodium, dichlorvos, dichlozoline, diclobutrazol, diclocymet, diclofop, diclofop-methyl, diclomezine, ezine-sodium, dicloran, diclosulam, dicofol, dicoumarol, dicresyl, dicrotophos, anil, dicyclonon, in, dienochlor, diethamquat, diethamquat dichloride, diethatyl, tyl-ethyl, diethofencarb, dietholate, diethyl pyrocarbonate, diethyltoluamide, difenacoum, difenoconazole, difenopenten, difenopenten-ethyl, difenoxuron, difenzoquat, difenzoquat metilsulfate, difethialone, diflovidazin, diflubenzuron, diflufenican, diflufenzopyr, wo 2013/062981 diflufenzopyr-sodium, etorim, lac, dikegulac-sodium, dilor, dimatif, uthrin, dimefox, dimefuron, dimepiperate, dimetachlone, n, dimethacarb, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimethipin, dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate, dimethyl phthalate, dimethylvinphos, dimetilan, dimexano, dimidazon, dimoxystrobin, dinex, dinex-diclexine, dingjunezuo, nazole, diniconazole-M, dinitramine, dinobuton, dinocap, dinocap-4, dinocap-6, on, dinofenate, dinopenton, dinoprop, dinosam, dinoseb, dinoseb e, dinoseb-ammonium, dinoseb-diolamine, dinoseb-sodium, dinoseb-trolamine, dinosulfon, dinotefuran, rb, dinoterb e, dinoterbon, diofenolan, dioxabenzofos, dioxacarb, dioxathion, inone, diphacinone-sodium, diphenamid, diphenyl sulfone, diphenylamine, dipropalin, dipropetryn, dipyrithione, diquat, diquat dibromide, disparlure, disul, disulfiram, disulfoton, disul-sodium, ditalimfos, dithianon, dithicrofos, ether, dithiopyr, diuron, dlimonene , 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, erone, edifenphos, eglinazine, eglinazine-ethyl, emamectin, tin benzoate, EMPC, empenthrin, endosulfan, al, endothal-diammonium, endothaldipotassium , endothal-disodium, endothion, endrin, enestroburin, EPN, epocholeone, epofenonane, epoxiconazole, eprinomectin, epronaz, EPTC, erbon, ergocalciferol, erlujixiancaoan, esdepallethrine, esfenvalerate, esprocarb, etacelasil, etaconazole, s, etem, ethaboxam, ethachlor, ethalfluralin, ethametsulfuron, ethametsulfuron-methyl, ethaprochlor, ethephon, ethidimuron, ethiofencarb, ethiolate, ethion, ethiozin, ethiprole, ethirimol, ethoate-methyl, ethofumesate, ethohexadiol, ethoprophos, ethoxyfen, ethoxyfenethyl , ethoxyquin, ethoxysulfuron, ethychlozate, ethyl formate, ethyl a-naphthaleneacetate, ethyl-DDD, ethylene, ethylene dibromide, ethylene dichloride, ethylene oxide, ethylicin, ethylmercury 2,3-dihydroxypropyl tide, ethylmercury acetate, ethylmercury bromide, ethylmercury chloride, ethylmercury phosphate, etinofen, etnipromid, etobenzanid, etofenprox, ole, etridiazole, etrimfos, eugenol, EXD, famoxadone, famphur, fenamidone, fenaminosulf, fenamiphos, fenapanil, fenarimol, fenasulam, fenazaflor, fenazaquin, fenbuconazole, fenbutatin oxide, orazole, fenchlorazole-ethyl, orphos, rim, fenethacarb, fenfluthrin, fenfuram, fenhexamid, fenitropan, fenitrothion, fenjuntong, fenobucarb, fenoprop, opbutoxypropyl, fenopropbutomety1 , fenoprop-butoty1, fenoprop-buty1, fenoprop-isocty1, fenoprop-methy1, fenoprop- wo 2013/062981 potassium, fenothiocarb, fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P, fenoxaprop-P-ethyl, fenoxasulfone, carb, fenpiclonil, fenpirithrin, fenpropathrin, fenpropidin, fenpropimorph, fenpyrazamine, fenpyroximate, fenridazon, fenridazonpotassium , fenridazon-propyl, 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- pyl, flamprop-M-methyl, flazasulfuron, flocoumafen, flometoquin, flonicamid, florasulam, fluacrypyrim, fluazifop, fluazifop-butyl, fluazifop-methyl, fop-P, fluazifop- P-butyl, nam, fluazolate, ron, diamide, flubenzimine, flucarbazone, flucarbazone-sodium, flucetosulfuron, fluchloralin, flucofuron, loxuron, flucythrinate, fludioxonil, fluenetil, fluensulfone, flufenacet, flufenerim, flufenican, flufenoxuron, flufenprox, pyr, flufenpyr-ethyl, role, 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, sulfuron-methyl, flupyrsulfuronmethyl-sodium , fluquinconazole, ole, flurenol, flurenol-butyl, flurenol-methyl, fluridone, hloridone, fluroxypyr, fluroxypyr-butometyl, fluroxypyr-meptyl, flurprimidol, flursulamid, flurtamone, flusilazole, flusulfamide, fluthiacet, fluthiacet-methyl, flutianil, flutolanil, flutriafol, fluvalinate, fluxapyroxad, fluxofenim, folpet, fen, fomesafen-sodium, fonofos, ulfuron, forchlorfenuron, formaldehyde, formetanate, anate hydrochloride, formothion, formparanate, formparanate hydrochloride, fosamine, fosamine-ammonium, fosetyl, l-aluminium, fosmethilan, fospirate, azate, fosthietan, lin, fuberidazole, fucaojing, fucaomi, funaihecaoling, fuphenthiourea, furalane, furalaxyl, furamethrin, furametpyr, iocarb, banil, 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, wo 2013/062981 griseofulvin, guazatine, guazatine acetates, halacrinate, halfenprox, halofenozide, halosafen, halosulfuron, halosulfuron-methyl, haloxydine, haloxyfop, haloxyfop-etotyl, haloxyfopmethyl , haloxyfop-P, haloxyfop-P-etotyl, haloxyfop-P-methyl, fop-sodium, HCH, hemel, hempa, HEOD, heptachlor, heptenophos, heptopargil, heterophos, hexachloroacetone, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, hexaflumuron, hexaflurate, hexalure, hexamide, hexazinone, hexylthiofos, hexythiazox, HHDN, holosulf, iwo, huangcaoling, huanjunzuo, hydramethylnon, hydrargaphen, hydrated lime, en e, hydroprene, zol, hyquincarb, IAA, IBA, icaridin, imazalil, imazalil nitrate, il sulfate, imazamethabenz, imazamethabenz-methyl, imazamox, imazamox- ammonium, imazapic, imazapic-ammonium, imazapyr, imazapyr-isopropylammonium, imazaquin, imazaquin-ammonium, imazaquin-methyl, imazaquin-sodium, imazethapyr, imazethapyr-ammonium, imazosulfuron, imibenconazole, imicyafos, imidacloprid, imidaclothiz, iminoctadine, iminoctadine triacetate, iminoctadine trialbesilate, imiprothrin, fide, indanofan, indaziflam, indoxacarb, , iodobonil, iodocarb, iodomethane, iodosulfuron, iodosulfuron-methyl, iodosulfuron-methyl-sodium, iofensulfuron, iofensulfuron-sodium, ioxynil, ioxynil octanoate, ioxynil-lithium, ioxynil-sodium, ipazine, ipconazole, arbazone, iprobenfos, one, iprovalicarb, iprymidam, ipsdienol, ipsenol, IPSP, isamidofos, isazofos, zan, isocarbamid, isocarbophos, isocil, isodrin, isofenphos, isofenphos-methyl, isolan, hiozin, isonoruron, isopolinate, isoprocarb, palin, isoprothiolane, isoproturon, azam, isopyrimol, isothioate, isotianil, isouron, isovaledione, isoxaben, isoxachlortole, isoxadifen, isoxadifen-ethyl, isoxaflutole, yrifop, isoxathion, ivermectin, izopamfos, japonilure, japothrins, jasmolin I, jasmolin II, jasmonic acid, jiahuangchongzong, jiajizengxiaolin, jiaxiangjunzhi, jiecaowan, jiecaoxi, jodfenphos, juvenile hormone I, juvenile hormone II, juvenile hormone III, kadethrin, karbutilate, karetazan, karetazan-potassium, kasugamycin, kasugamycin hydrochloride, kejunlin, n, iradox, ketospiradox-potassium, kinetin, kinoprene, kresoximmethyl , kuicaoxi, lactofen, lambda-cyhalothrin, latilure, lead arsenate, lenacil, lepimectin, leptophos, lindane, lineatin, linuron, lirimfos, litlure, looplure, lufenuron, lvdingjunzhi, lvxiancaolin, lythidathion, MAA, malathion, maleic hydrazide, malonoben, maltodextrin, MAMA, mancopper, mancozeb, mandipropamid, maneb, matrine, mazidox, MCPA, MCPA- 2-ethylhexyl, MCPA-butotyl, MCPA-butyl, MCPA-dimethylammonium, iolamine, MCPA-ethyl, MCPA-isobutyl, MCPA-isoctyl, MCPA-isopropyl, ethyl, MCPA- e, MCPA-potassium, MCPA-sodium, MCPA-thioethyl, MCPA-trolamine, MCPB, wo 2013/062981 thyl, MCPB-methyl, MCPB-sodium, mebenil, mecarbam, mecarbinzid, mecarphon, op, mecopropethylhexyl, mecoprop-dimethylammonium, mecoprop-diolamine, mecoprop-ethadyl, mecoprop-isoctyl, mecoprop-methyl, mecoprop-P, mecoprop-P ethylhexyl, mecoprop-P-dimethylammonium, mecoprop-P-isobutyl, mecoprop-potassium, 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, mepronil, meptyldinocap, mercuric de, mercuric oxide, mercurous de, merphos, mesoprazine, lfuron, mesosulfuron-methyl, mesotrione, mesulfen, mesulfenfos, metaflumizone, metalaxyl, metalaxyl-M, metaldehyde, metam, metam-ammonium, metamifop, tron, metam-potassium, metam-sodium, metazachlor, metazosulfuron, metazoxolon, metconazole, metepa, metflurazon, methabenzthiazuron, methacrifos, propalin, 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 ocyanate, methylacetophos, methylchloroform, dymron, methylene chloride, methylmercury benzoate, methylmercury diamide, methylmercury pentachlorophenoxide, methylneodecanamide, metiram, metobenzuron, metobromuron, metofluthrin, chlor, metolcarb, metominostrobin, metosulam, metoxadiazone, metoxuron, metrafenone, uzin, metsulfovax, furon, furon-methyl, mevinphos, mexacarbate, mieshuan, ectin, milbemycin oxime, milneb, mipafox, mirex, MNAF, moguchun, molinate, molosultap, monalide, monisouron, monochloroacetic acid, monocrotophos, nuron, monosulfuron, monosulfuron-ester, monuron, monuron TCA, morfamquat, morfamquat dichloride, moroxydine, moroxydine hydrochloride, morphothion, morzid, moxidectin, MSMA, muscalure, myclobutanil, myclozolin, N-(ethylmercury)-ptoluenesulphonanilide , nabam, ofos, naled, naphthalene, naphthaleneacetamide, alic ide, 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, wo 2013/062981 nornicotine, noruron, novaluron, noviflumuron, nuarimol, OCH, octachlorodipropyl ether, inone, 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, para-dichlorobenzene, parafluron, paraquat, paraquat dichloride, paraquat dimetilsulfate, parathion, parathion-methyl, parinol, pebulate, pefurazoate, pelargonic acid, azole, pencycuron, pendimethalin, penflufen, penfluron, penoxsulam, pentachlorophenol, pentanochlor, penthiopyrad, pentmethrin, pentoxazone, perfluidone, hrin, pethoxamid, phenamacril, phenazine oxide, phenisopham, phenkapton, phenmedipham, phenmedipham-ethyl, phenobenzuron, phenothrin, oxide, phenthoate, phenylmercuriurea, phenylmercury acetate, phenylmercury de, mercury derivative of pyrocatechol, phenylmercury nitrate, phenylmercury late, phorate, etim, phosalone, phosdiphen, phosfolan, lan-methyl, phosglycin, phosmet, phosnichlor, phosphamidon, phosphine, phosphocarb, phosphorus, phostin, phoxim, phoxim-methyl, phthalide, picloram, picloramethylhexyl, picloram-isoctyl, piclorammethy1 , picloram-olamine, picloram-potassium, picloram-triethy!ammonium, picloram-tris(2- hydroxypropyl)ammonium, picolinafen, picoxystrobin, pindone, pindone-sodium, pinoxaden, piperalin, nyl butoxide, nyl cyclonene, piperophos, piproctanyl, piproctanyl e, piprotal, pirimetaphos, pirimicarb, pirimioxyphos, pirimiphos-ethyl, pirimiphosmethyl , plifenate, polycarbamate, polyoxins, orim, polyoxorim-zinc, polythialan, potassium arsenite, potassium azide, potassium cyanate, potassium gibberellate, potassium naphthenate, potassium polysulfide, potassium thiocyanate, potassium a-naphthaleneacetate, pp'-DDT, prallethrin, precocene I, precocene II, precocene III, pretilachlor, primidophos, ulfuron, ulfuron-methyl, probenazole, prochloraz, oraz-manganese, proclonol, procyazine, procymidone, prodiamine, ofos, profluazol, profluralin, profluthrin, profoxydim, proglinazine, proglinazine-ethyl, prohexadione, prohexadione- calcium, rojasmon, promacyl, promecarb, prometon, ryn, promurit, propachlor, propamidine, propamidine dihydrochloride, propamocarb, propamocarb hydrochloride, propanil, propaphos, propaquizafop, propargite, proparthrin, propazine, propetamphos, m, propiconazole, propineb, propisochlor, propoxur, propoxycarbazone, wo 2013/062981 propoxycarbazone-sodium, propyl isome, propyrisulfuron, propyzamide, proquinazid, prosuler, prosulfalin, prosulfocarb, prosulfuron, prothidathion, ocarb, prothiocarb hydrochloride, prothioconazole, prothiofos, prothoate, protrifenbute, proxan, proxan-sodium, prynachlor, pydanon, pymetrozine, pyracarbolid, pyraclofos, pyraclonil, pyraclostrobin, pyraflufen, pyraflufen-ethyl, uprole, pyramat, pyrametostrobin, pyraoxystrobin, lfotole, lynate, pyrazophos, sulfuron, pyrazosulfuron-ethyl, pyrazothion, pyrazoxyfen, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyribambenz-isopropyl, pyribambenz-propyl, pyribencarb, pyribenzoxim, pyributicarb, pyriclor, pyridaben, pyridafol, pyridalyl, phenthion, pyridate, pyridinitril, pyrifenox, pyrifluquinazon, pyriftalid, pyrimethanil, pyrimidifen, pyriminobac, pyriminobac-methyl, pyrimisulfan, pyrimitate, pyrinuron, pyriofenone, pyriprole, pyripropanol, pyriproxyfen, pyrithiobac, iobacsodium , pyrolan, pyroquilon, pyroxasulfone, pyroxsulam, chlor, pyroxyfur, quassia, quinacetol, quinacetol sulfate, phos, quinalphos-methyl, quinazamid, quinclorac, quinconazole, quinmerac, lamine, quinonamid, quinothion, quinoxyfen, quintiofos, quintozene, quizalofop, quizalofop-ethyl, quizalofop-P, quizalofop-P-ethyl, quizalofop-P- tefuryl, quwenzhi, quyingding, rabenzazole, rafoxanide, rebemide, resmethrin, rhodethanil, rhodojaponin-III, ribavirin, rimsulfuron, rotenone, ryania, saflufenacil, saijunmao, saisentong, salicylanilide, sanguinarine, santonin, schradan, scilliroside, sebuthylazine, secbumeton, ne, selamectin, semiamitraz, semiamitraz chloride, sesamex, lin, 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 acetate, sodium hexafluorosilicate, sodium naphthenate, sodium orthophenylphenoxide, sodium pentachlorophenoxide, sodium polysulfide, sodium thiocyanate, sodium a-naphthaleneacetate, sophamide, oram, spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine, streptomycin, streptomycin sesquisulfate, strychnine, sulcatol, uron, sulcofuron-sodium, sulcotrione, sulfallate, sulfentrazone, sulfiram, sulfluramid, sulfometuron, sulfometuron-methyl, ulfuron, sulfotep, sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid, sulfuryl de, sulglycapin, sulprofos, sultropen, swep, tau-fluvalinate, tavron, arb, TCA, TCA-ammonium, TCA- calcium, TCA-ethadyl, TCA-magnesium, TCA-sodium, TDE, nazole, tebufenozide, tebufenpyrad, tebufloquin, tebupirimfos, tebutam, tebuthiuron, tecloftalam, tecnazene, tecoram, teflubenzuron, tefluthrin, tefuryltrione, tembotrione, temephos, tepa, TEPP, tepraloxydim, terallethrin, il, arb, terbuchlor, terbufos, terbumeton, wo 2013/062981 terbuthylazine, terbutryn, tetcyclacis, tetrachloroethane, hlorvinphos, tetraconazole, tetradifon, tetrafluron, tetramethrin, tetramethylfluthrin, tetramine, tetranactin, tetrasul, thallium sulfate, thenylchlor, theta-cypermethrin, thiabendazole, thiacloprid, fluor, thoxam, thiapronil, thiazafluron, thiazopyr, thicrofos, thicyofen, thidiazimin, thidiazuron, thiencarbazone, thiencarbazone-methyl, thifensulfuron, thifensulfuron-methyl, thifluzamide, thiobencarb, thiocarboxime, thiochlorfenphim, thiocyclam, thiocyclam hydrochloride, clam e, thiodiazole-copper, carb, thiofanox, thiofluoximate, thiohempa, thiomersal, thiometon, thionazin, thiophanate, thiophanate-methyl, thioquinox, thiosemicarbazide, ltap, thiosultap-diammonium, thiosultap-disodium, thiosultap- monosodium, thiotepa, , thuringiensin, tiadinil, tiaojiean, tiocarbazil, tioclorim, tioxymid, tirpate, tolclofos-methyl, tolfenpyrad, luanid, tolylmercury acetate, topramezone, tralkoxydim, tralocythrin, tralomethrin, tralopyril, transfluthrin, transpermethrin, tretamine, triacontanol, triadimefon, triadimenol, triafamone, tri-allate, phos, triapenthenol, triarathene, mol, triasulfuron, mate, triazbutil, triaziflam, triazophos, triazoxide, tribenuron, tribenuron-methyl, tribufos, yltin 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, sime, triforine, trihydroxytriazine, trimedlure, trimethacarb, trimeturon, trinexapac, trinexapac-ethyl, triprene, tripropindan, triptolide, tritac, triticonazole, tritosulfuron, trunc-call, uniconazole, azole-P, urbacide, uredepa, valerate, validamycin, valifenalate, valone, thion, vangard, vaniliprole, vernolate, vinclozolin, warfarin, warfarin-potassium, warfarin-sodium, xiaochongliulin, xinjunan, xiwojunan, XMC, xylachlor, xylenols, xylylcarb, ing, zarilamid, , zengxiaoan, zeta-cypermethrin, zinc naphthenate, zinc phosphide, zinc thiazole, zineb, ziram, zolaprofos, zoxamide, zuomihuanglong, a-chlorohydrin, a-ecdysone, a-multistriatin, and a-naphthaleneacetic acid.
For more ation consult the "COMPENDIUM OF PESTICIDE COMMON NAMES" located at http://www.a1anwood.netipesticides/index.htrn1. 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 editions. wo 2013/062981 BIOPESTICIDES Molecules 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 ial 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 myces quisqualis (a l agent for grape powdery mildew). Bacillus subtilis are used to control plant pathogens. Weeds and rodents have also been lled with microbial agents. One well-known insecticide e is Bacillus thuringiensis, a bacterial disease of Lepidoptera, Coleoptera, and Diptera. Because it has little effect on other organisms, it is ered more environmentally friendly than synthetic ides. Biological insecticides include products based on: 1. entomopathogenic fungi (e.g. Metarhizium anisopliae); 2. pathogenic nematodes (e.g. Steinernemafeltiae); 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 d insecticides include, but not limited to, rotenone, veratridine, as well as microbial toxins; insect tolerant or ant plant varieties; and sms modified by recombinant DNA technology to either produce insecticides or to convey an insect resistant property to the cally modified organism. In one embodiment, the molecules of Formula One may be used with one or more biopesticides in the area of seed treatments and soil amendments. The Manual ofBiocontrol Agents gives a review of the available biological insecticide (and other biology-based control) products. Copping L.G. (ed.) (2004). The Manual ofBiocontrol Agents (formerly the Biopesticide Manual) 3rd Edition. British Crop Production Council (BCPC), Farnham, Surrey UK.
OTHER ACTIVE COMPOUNDS Molecules of Formula One may also be used in combination (such as in a compositional mixture, or a simultaneous or sequential ation) with one or more of the ing: 1. 3-(4-chloro-2,6-dimethylphenyl)hydroxyoxaazaspiro[4,5]decenone; wo 62981 2012/061508 2. 3-(4'-chloro-2,4-dimethyl[1,1'-biphenyl]yl)hydroxyoxaazaspiro[4,5]dec- 3-enone; 3. 4-[[(6-chloropyridinyl)methyl]methylamino]-2(5H)-furanone; 4. 4-[[(6-chloropyridinyl)methyl]cyclopropylamino]-2(5H)-furanone; 5. 3-chloro-N2-[(1S)methyl(methylsulfonyl)ethyl]-N1-[2-methyl[ 1,2,2,2- tetrafluoro(trifluoromethy1)ethy1]pheny1] -1 ,2-benzenedicarboxamide; 6. 2-cyano-N-ethy1fluoro- 3-methoxy-benenesulfonamide; 7. 2-cyano-N-ethylmethoxy-benzenesulfonamide; 8. 2-cyanodifluoromethoxy-N-ethylfluoro-benzenesulfonamide; 9. 2-cyanofluoromethoxy-N-ethy1-benzenesulfonamide; . 2-cyanofluoromethoxy-N,N-dimethy1-benzenesulfonamide; 11. 2-cyano-N-ethy1fluoro- 3-methoxy-N-methy1-benzenesulfonamide; 12. 2-cyanodifluoromethoxy-N,N-dimethylbenzenesulfon-amide; 13. luoromethyl)-N-[2-(3,3-dimethylbutyl)phenyl]methyl-1H-pyrazole carboxamide; 14. N-ethy1-2,2-dimethylpropionamide(2,6-dichloro-a,a,a-trifluoro-p-toly1) hydrazone; . 1-2,2-dichloromethylcyclopropane-carboxamide(2,6-dichloro-a,a,atrifluoro-p-tolyl ) one nicotine; 16. 0-{(E-)-[2-(4-chloro-phenyl)cyano(2-trifluoromethylphenyl)-vinyl]} S-methyl thiocarbonate; 17. (E)-N1-[(2-chloro-1 azolylmethyl)]-N2-cyano-N1-methylacetamidine; 18. 1-(6-chloropyridinylmethyl)methylnitro-1 ,2,3,5,6,7-hexahydro-imidazo[1 ,2- a]pyridinol; 19. 4-[4-chloropheny1-(2-butylidine-hydrazono)methy1)]pheny1mesylate; and 20. N-Ethy1-2,2-dichloromethylcyclopropanecarboxamide(2,6-dichloro- alpha,alpha,alpha-trifluoro-p-tolyl)hydrazone.
SYNERGISTIC MIXTURES Molecules 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 molecules 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 wo 62981 antagonist; GABA and glutamate-gated de channel agonist; acetylcholine receptor t; acetylcholine receptor antagonist; MET I inhibitor; Mg-stimulated ATPase inhibitor; nicotinic choline receptor; Midgut membrane disrupter; oxidative phosphorylation disrupter, and ryanodine receptor (RyRs). Generally, weight ratios of the molecules 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 ty. Thus, pesticides are ated into, for example, baits, concentrated emulsions, dusts, fiable concentrates, fumigants, gels, granules, microencapsulations, seed treatments, sion concentrates, suspoemulsions, s, water soluble s, water dispersible granules or dry flowables, wettable powders, and ultra low volume solutions. For further information on formulation types see "Catalogue of ide Formulation Types and International Coding System" Technical Monograph n°2, 5th Edition by CropLife International (2002). ides are applied most often as aqueous suspensions or emulsions 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 y known as emulsifiable concentrates, or aqueous suspensions. Wettable powders, which may be compacted to form water dispersible granules, comprise an intimate mixture of the pesticide, a carrier, and surfactants. The concentration of the pesticide is usually from about 10% to about 90% by weight. The carrier is y selected from among the attapulgite clays, the montmorillonite clays, the diatomaceous earths, or the purified silicates. Effective surfactants, comprising from about 0.5% to about % of the wettable powder, are found among ated lignins, condensed naphthalenesulfonates, naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates, and non-ionic surfactants such as ethylene oxide adducts of alkyl s.
Emulsifiable concentrates 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 wo 2013/062981 that is either a water miscible solvent or a mixture of water-immiscible c solvent and emulsifiers. Useful organic solvents include aromatics, especially xylenes and petroleum fractions, especially the oiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, such as the ic solvents including rosin derivatives, aliphatic ketones such as cyclohexanone, and complex alcohols such as 2-ethoxyethanol. Suitable emulsifiers for emulsifiable concentrates are selected from conventional anionic and non-ionic surfactants.
Aqueous suspensions comprise sions of water-insoluble pesticides dispersed in an s carrier at a concentration in the range from about 5% to about 50% by weight. sions are ed by finely grinding the pesticide and vigorously mixing it into a carrier comprised of water and tants. Ingredients, 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, ball mill, or piston-type homogenizer.
Pesticides may also be d as granular compositions that are particularly useful for ations to the soil. Granular compositions usually contain from about 0.5% to about % 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 le 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 ng or as a foliage application with a dust blower machine.
It is equally practical to apply a pesticide in the form of a solution in an riate 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 aerosol composition. In such compositions the pesticide is dissolved or dispersed in a r, which is a pressure- wo 2013/062981 generating propellant e. The aerosol 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 es, gels, flowable powders, liquids, or solids. They can be used in pest harborages.
Fumigants are pesticides that have a relatively high vapor pressure and hence can exist as a gas in sufficient concentrations to kill pests in soil or ed spaces. The toxicity of the fumigant is proportional to its concentration and the re time. They are characterized by a good capacity for diffusion and act by penetrating the pest'srespiratory system or being absorbed through the pest'scuticle. Fumigants are applied to control stored product pests under gas proof sheets, in gas sealed rooms or buildings or in special chambers. ides can be microencapsulated by ding the pesticide particles or droplets in plastic polymers of various types. By altering the try of the polymer or by changing factors in the processing, microcapsules can be formed of s sizes, solubility, wall thicknesses, and degrees of penetrability. These factors govern the speed with which the active ingredient within is released, which in turn, affects the residual performance, speed of action, and odor of the product.
Oil on concentrates are made by dissolving pesticide in a solvent that will hold the ide 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 penetration of crevices, and better adhesion to greasy surfaces. r embodiment is an oil-in-water emulsion, wherein the emulsion 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 nic lipophilic surface-active agent, (2) at least one nonionic hydrophilic surface-active agent and (3) at least one ionic surface-active agent, wherein the globules having a mean le diameter of less than 800 ters. Further information on the embodiment is disclosed in U.S. patent publication 20070027034 published February 1, 2007, having Patent Application serial number 111495,228. For ease of use, this ment will be referred to as "OIWE". wo 2013/062981 For further ation consult t Pest Management" 2nd Edition by D. Dent, copyright CAB International . Additionally, for more detailed information consult "Handbook of Pest Control- The Behavior, Life History, and l of Household Pests" by Arnold Mallis, 9th Edition, copyright 2004 by GIE Media Inc.
OTHER FORMULATION COMPONENTS lly, when the molecules 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 ive list) wetters, spreaders, stickers, penetrants, buffers, sequestering agents, drift reduction 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 penetration power of the liquid by ng the acial 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 concentrates for soluble liquids or suspension concentrates; and during mixing of a product with water in a spray tank to reduce the wetting time of wettable powders and to improve the penetration of water into water-dispersible granules. Examples of g agents used in wettable powder, suspension concentrate, and water-dispersible granule formulations are: sodium lauryl sulfate; sodium l sulfosuccinate; alkyl phenol lates; and aliphatic l 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 emical 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, sion concentrates and water-dispersible granules. Surfactants that are used as dispersing agents have the ability to adsorb ly 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 trates, very good adsorption and stabilization are obtained using polyelectrolytes, such as sodium naphthalene sulfonate formaldehyde wo 2013/062981 condensates. Tristyrylphenol ethoxylate phosphate esters are also used. Non-ionics such as alkylarylethylene oxide condensates and EO-PO block copolymers are sometimes combined with anionics as dispersing agents for suspension concentrates. In recent years, new types of very high molecular weight polymeric surfactants have been developed as dispersing agents.
These have very long hobic ones'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 concentrates because the hydrophobic nes have many anchoring points onto the particle surfaces. Examples of dispersing agents used in agrochemical formulations are: sodium lignosulfonates; sodium naphthalene sulfonate formaldehyde condensates; tristyrylphenol ethoxylate phosphate ; aliphatic alcohol ethoxylates; alkyl lates; 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 n alkylphenol or aliphatic alcohol with twelve or more ethylene oxide units and the oilsoluble calcium salt of dodecylbenzenesulfonic acid. A range of hydrophile-lipophile balance ) values from 8 to 18 will normally provide good stable emulsions. Emulsion stability can sometimes be improved by the addition of a small amount of an EO-PO block copolymer surfactant.
A lizing 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 hydrophobic part of the micelle. The types of surfactants usually used for solubilization are non-ionics, sorbitan monooleates, sorbitan monooleate ethoxylates, and methyl oleate esters. tants are sometimes used, either alone or with other additives such as mineral or vegetable oils as nts to spray-tank mixes to improve the biological performance of the ide on the target. The types of tants used for bioenhancement depend 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; tic amine ethoxylates.
A carrier or diluent in an agricultural formulation is a material added to the pesticide to give a t of the ed strength. Carriers are usually materials with high tive capacities, while diluents are usually materials with low absorptive capacities. Carriers and wo 2013/062981 diluents are used in the formulation of dusts, wettable powders, granules and waterdispersible granules.
Organic solvents are used mainly in the formulation of emulsifiable trates, oilin-water emulsions, 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 inic 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 ClO aromatic solvents. Chlorinated arbons are useful as ents to t crystallization of pesticides when the formulation is emulsified into water. Alcohols are mes 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 sion concentrates, emulsions and suspoemulsions to modify the rheology or flow properties of the liquid and to prevent separation and settling of the dispersed particles or droplets. ning, gelling, and anti-settling agents generally fall into two categories, namely waterinsoluble particulates and water-soluble polymers. It is possible to produce sion concentrate formulations using clays and silicas. Examples of these types of materials, include, but are not limited to, montmorillonite, ite, magnesium aluminum silicate, and attapulgite. Water-soluble polysaccharides have been used as thickening-gelling agents for many years. The types of polysaccharides most commonly used are l extracts of seeds and seaweeds or are synthetic derivatives of cellulose. Examples of these types of materials include, but are not limited to, guar gum; locust bean gum; carrageenam; alginates; methyl cellulose; sodium ymethyl ose (SCMC); hydroxyethyl cellulose (HEC). Other types of anti-settling agents are based on ed starches, polyacrylates, polyvinyl alcohol and polyethylene oxide. r good anti-settling agent is xanthan gum.
Microorganisms can cause spoilage of formulated products. Therefore preservation agents are used to eliminate or reduce their effect. Examples of such agents include, but are not limited to: propionic acid and its sodium salt; sorbic acid and its sodium or potassium salts; benzoic acid and its sodium salt; p-hydroxybenzoic acid sodium salt; methyl phydroxybenzoate ; and 1,2-benzisothiazolinone (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 wo 2013/062981 the cy to foam, anti-foam agents are often added either during the tion stage or before g into bottles. Generally, there are two types of anti-foam agents, namely silicones and non-silicones. Silicones are usually aqueous emulsions of dimethyl loxane, while the non-silicone anti-foam agents are water-insoluble oils, such as octanol and nonanol, or silica. 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 biodegradable and generally derived from natural and/or sustainable sources, e.g. plant and animal sources.
Specific examples are: vegetable oils, seed oils, and esters thereof, also alkoxylated alkyl ucosides.
For further information, see "Chemistry and Technology of Agrochemical Formulations" edited by D.A. Knowles, ght 1998 by Kluwer Academic 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 molecules 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 molecules of Formula One may be used to control pests in the Phyla Nematoda and/or Arthropoda.
In r embodiment, the molecules of a One may be used to control pests in the la Chelicerata, Myriapoda, and/or Hexapoda.
In another embodiment, the molecules of Formula One may be used to l pests in the Classes of Arachnida, Symphyla, and/or Insecta.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Anoplura. A non-exhaustive list of particular genera es, but is not limited to, Haematopinus spp., Hoplopleura spp., Linognathus spp., Pediculus spp., and Polyp/ax spp. A non-exhaustive list of particular species includes, but is not limited to, Haematopinus asini, opinus suis, Linognathus setosus, Linognathus ovillus, lus humanus capitis, Pediculus humanus humanus, and Pthirus pubis. wo 2013/062981 In another embodiment, the molecules of Formula One may be used to l pests in the Order Coleoptera. A non-exhaustive list of particular genera includes, but is not d to, Acanthoscelides spp., Agriotes spp., Anthonomus spp., Apion spp., Apogonia spp., Aulacophora spp., Bruchus spp., Cerosterna spp., ma spp., Ceutorhynchus spp., Chaetocnema spp., Colaspis spp., Ctenicera spp., Curculio spp., ephala spp., Diabrotica spp., Hypera spp., Ips spp., Lyctus spp., elis spp., Meligethes spp., Otiorhynchus spp., Pantomorus spp., Phyllophaga spp., Phyllotreta spp., Rhizotrogus spp., Rhynchites spp., Rhynchophorus spp., Scolytus spp., Sphenophorus spp., Sitophilus spp., and Tribolium spp. A non-exhaustive list of particular species es, but is not d to, Acanthoscelides obtectus, Agrilus planipennis, Anoplophora glabripennis, Anthonomus grandis, us spretulus, Atomaria linearis, Bothynoderes punctiventris, Bruchus pisorum, Callosobruchus maculatus, Carpophilus hemipterus, a vittata, Cerotoma trifurcata, hynchus assimilis, Ceutorhynchus napi, Conoderus scalaris, Conoderus stigmosus, Conotrachelus nenuphar, Cotinis nitida, Crioceris asparagi, Cryptolestes ferrugineus, Cryptolestes pusillus, Cryptolestes turcicus, rocopturus adspersus, Deporaus atus, Dermestes ius, Dermestes maculatus, Epilachna varivestis, Faustinus cubae, Hylobius pales, Hypera postica, Hypothenemus hampei, Lasioderma serricorne, Leptinotarsa decemlineata, ysfuscus, Liogenys suturalis, Lissorhoptrus oryzophilus, Maecolaspis joliveti, Melanotus communis, Meligethes aeneus, Melolontha melolontha, Oberea brevis, Oberea linearis, Oryctes rhinoceros, Oryzaephilus mercator, Oryzaephilus surinamensis, Oulema melanopus, Oulema 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 molecules of Formula One may be used to control pests of the Order Dermaptera.
In another embodiment, the molecules of Formula One may be used to control pests of the Order ria. A non-exhaustive list of particular species includes, but is not limited to, Blattella germanica, Blatta orienta/is, Parcoblatta pennsylvanica, aneta ana, Periplaneta australasiae, Periplaneta brunnea, Periplanetafuliginosa, Pycnoscelus surinamensis, and Supella longipalpa.
In another embodiment, the les of Formula One may be used to control pests of the Order Diptera. A non-exhaustive list of particular genera includes, but is not limited wo 62981 to, Aedes spp., Agromyza spp., Anastrepha spp., Anopheles spp., Bactrocera spp., Ceratitis spp., Chrysops spp., omyia spp., Contarinia spp., Culex spp., Dasineura spp., Delia 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 es, but is not d to, Agromyzafrontella, Anastrepha suspensa, Anastrepha ludens, Anastrepha obliqa, Bactrocera cucurbitae, Bactrocera dorsalis, Bactrocera invadens, Bactrocera zonata, Ceratitis capitata, Dasineura brassicae, Delia platura, Fannia canicularis, Fannia scalaris, Gasterophilus inalis, Gracillia perseae, Haematobia irritans, rma lineatum, Liriomyza brassicae, Melophagus ovinus, Musca autumnalis, Musca domestica, Oestrus ovis, Oscinellafrit, Pegomya betae, Psila rosae, Rhagoletis cerasi, Rhagoletis pomonella, Rhagoletis , Sitodiplosis mosellana, and Stomoxys calcitrans.
In another embodiment, the les of Formula One may be used to control pests of the Order Hemiptera. A non-exhaustive list of particular genera includes, but is not limited to, Adelges spp., Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Ceroplastes spp., Chionaspis spp., mphalus 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, Aleurothrixusfloccosus, a ula biguttula, Aonidiella ii, Aphis gossypii, Aphis glycines, Aphis pomi, Aulacorthum , Bemisia ifolii, Bemisia tabaci, Blissus leucopterus, Brachycorynella asparagi, Brevennia rehi, Brevicoryne brassicae, ris norvegicus, Ceroplastes rubens, Cimex hemipterus, Cimex lectularius, Dagbertusfasciatus, opsfurcatus, Diuraphis noxia, Diaphorina citri, Dysaphis plantaginea, Dysdercus suturellus, Edessa meditabunda, Eriosoma lanigerum, Eurygaster maura, Euschistus heros, Euschistus servus, Helopeltis antonii, Helopeltis theivora, Icerya purchasi, Idioscopus nitidulus, Laodelphax ellus, Leptocorisa oratorius, Leptocorisa varicornis, Lygus hesperus, Maconellicoccus hirsutus, Macrosiphum biae, Macrosiphum granarium, Macrosiphum rosae, Macrosteles quadrilineatus, Mahanarvafrimbiolata, Metopolophium dirhodum, Mictis longicornis, Myzus persicae, Nephotettix cinctipes, Neurocolpus longirostris, Nezara viridula, Nilaparvata lugens, Parlatoria pergandii, oria ziziphi, Peregrinus maidis, Phylloxera vitifoliae, wo 2013/062981 Physokermes piceae, Phytocoris californicus, Phytocoris relativus, Piezodorus guildinii, Poecilocapsus lineatus, Psallus vaccinicola, Pseudacysta perseae, coccus brevipes, Quadraspidiotus perniciosus, Rhopalosiphum maidis, Rhopalosiphum padi, Saissetia oleae, Scaptocoris castanea, Schizaphis graminum, Sitobion avenae, Sogatellafurcifera, Trialeurodes vaporariorum, urodes abutiloneus, s yanonensis, and Zulia entrerriana.
In another embodiment, the molecules of Formula One may be used to l pests of the Order Hymenoptera. A non-exhaustive list of particular genera includes, but is not limited to, Acromyrmex spp., Atta spp., Camponotus spp., Diprion spp., Formica spp., rium 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 s, Monomorium minimum, Monomorium pharaonis, Solenopsis invicta, Solenopsis geminata, Solenopsis molesta, Solenopsis richtery, Solenopsis xyloni, and Tapinoma sessile.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Isoptera. A non-exhaustive list of particular genera includes, but is not limited to, Coptotermes spp., Cornitermes spp., Cryptotermes spp., Heterotermes spp., Kalotermes spp., Incisitermes spp., Macrotermes spp., Marginitermes spp., Microcerotermes spp., nitermes spp., Reticulitermes spp., rhinotermes spp., and Zootermopsis spp. A haustive list of particular species includes, but is not limited to, Coptotermes nathus, ermes i, Coptotermes formosanus, Heterotermes aureus, Microtermes obesi, Reticulitermes banyulensis, litermes grassei, litermes flavipes, Reticulitermes hageni, Reticulitermes hesperus, Reticulitermes santonensis, Reticulitermes speratus, Reticulitermes tibialis, and Reticulitermes virginicus.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Lepidoptera. A non-exhaustive list of particular genera es, but is not limited to, Adoxophyes spp., Agrotis spp., Argyrotaenia spp., ia 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., hedon 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, wo 2013/062981 Amorbia cuneana, is transitella, Anacamptodes defectaria, Anarsia lineatella, Anomis sabulifera, Anticarsia gemmatalis, s argyrospila, Archips , Argyrotaenia citrana, Autographa gamma, Bonagota cranaodes, Barbo cinnara, atrix thurberiella, Capua lana, Carposina niponensis, tia transversa, Choristoneura rosaceana, Cnaphalocrocis medina/is, Conopomorpha cramerella, Cossus cossus, Cydia a, Cydia funebrana, Cydia molesta, Cydia nigricana, Cydia lla, Darna diducta, Diatraea saccharalis, Diatraea grandiosella, Earias insulana, Earias vittella, Ecdytolopha ianum, Elasmopalpus lignosellus, Ephestia cautella, Ephestia elutella, Ephestia ella, Epinotia aporema, Epiphyas postvittana, Erionota thrax, Eupoecilia ambiguella, Euxoa auxiliaris, Grapholita molesta, Hedylepta ta, Helicoverpa armigera, Helicoverpa zea, Heliothis virescens, Hellula undalis, Keiferia rsicella, Leucinodes orbonalis, Leucoptera coffeella, Leucoptera malifoliella, Lobesia botrana, Loxagrotis albicosta, Lymantria dispar, Lyonetia clerkella, Mahasena ti, 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 lla, 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, tera eridania, Thecla basi/ides, Tineola liella, Trichoplusia ni, Tuta absoluta, Zeuzera coffeae, and Zeuzera pyrina.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Mallophaga. A non-exhaustive list of particular genera includes, but is not limited to, Anaticola spp., la spp., Chelopistes spp., Goniodes spp., Menacanthus spp., and Trichodectes spp. A non-exhaustive list of ular species includes, but is not limited to, Bovicola bovis, Bovicola caprae, Bovicola ovis, Chelopistes meleagridis, Goniodes dissimilis, Goniodes gigas, Menacanthus stramineus, Menopon ae, and Trichodectes canis.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Orthoptera. A non-exhaustive list of particular genera es, but is not limited to, Melanoplus spp., and Pterophylla spp. A non-exhaustive list of particular species wo 2013/062981 includes, but is not limited to, Anabrus simplex, Gryllotalpa africana, talpa australis, talpa brachyptera, Gryllotalpa hexadactyla, Locusta migratoria, Microcentrum retinerve, Schistocerca gregaria, and Scudderiafurcata.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Siphonaptera. A haustive list of particular species includes, but is not limited to, Ceratophyllus gallinae, Ceratophyllus niger, ephalides canis, Ctenocephalidesfelis, and Pulex irritans.
In another embodiment, the les of Formula One may be used to control pests of the Order Thysanoptera. A non-exhaustive list of particular genera es, but is not limited to, Caliothrips spp., Frankliniella spp., Scirtothrips spp., and Thrips spp. A nonexhaustive list of particular sp. includes, but is not d to, Frankliniella fusca, Frankliniella occidentalis, Frankliniella zei, Frankliniella williamsi, Heliothrips haemorrhoidalis, Rhipiphorothrips cruentatus, Scirtothrips citri, Scirtothrips dorsalis, and Taeniothrips rhopalantennalis, Thrips hawaiiensis, Thrips nigropilosus, Thrips orienta/is, Thrips tabaci.
In another embodiment, the molecules of Formula One may be used to control pests of the Order Thysanura. A non-exhaustive list of particular genera includes, but is not limited to, a spp. and Thermobia spp.
In another ment, the molecules of Formula One may be used to control pests of the Order Acarina. A non-exhaustive list of particular genera includes, but is not limited to, Acarus spp., Aculops spp., lus spp., x 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 htendali, 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 les of Formula One may be used to control pest of the Order Symphyla. A haustive list of particular sp. es, but is not limited to, Scutigerella immaculata. wo 2013/062981 2012/061508 In another embodiment, the molecules of Formula One may be used to control pests of the Phylum Nematoda. A non-exhaustive list of particular genera 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 ca, Onchocerca volvulus, olus simi/is, 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 Molecules 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 e 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 molecule of a One is applied can be any area inhabited (or maybe inhabited, or traversed by) a pest, for example: where crops, trees, fruits, cereals, fodder s, vines, turf and ornamental plants, are growing; where domesticated animals are residing; the or or exterior surfaces of buildings (such as places where grains are ), the materials of construction used in building (such as impregnated wood), and the soil around buildings. Particular crop areas to use a molecule of Formula One include areas where apples, corn, wers, cotton, ns, canola, wheat, rice, sorghum, barley, oats, potatoes, oranges, a, 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 ageous to use um sulfate with a molecule 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 come about when: pest populations are repulsed from an area; when pests are citated 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 wo 2013/062981 than 90 t. Generally, the area is not in or on a human; consequently, the locus is generally a non-human area.
The molecules of Formula One may be used in mixtures, applied simultaneously or sequentially, alone or with other compounds to e 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 molecules may be used during times when pest activity is low, such as before the plants that are growing begin to e valuable agricultural commodities. Such times e the early planting season when pest pressure is usually low.
The molecules of Formula One can be d to the foliar and fruiting portions of plants to control pests. The molecules will either come 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 molecules of Formula One can also be applied to the soil, and when applied in this manner, root and stem feeding pests can be controlled. The roots can absorb a molecule taking it up into the foliar ns of the 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 come into contact with, and/or be attracted to, the bait. Baits can also be applied to a surface of a building, (horizontal, vertical, or slant surface) where, for example, ants, termites, cockroaches, and flies, can come into contact with, and/or be attracted to, the bait.
Baits can se a molecule of Formula One.
The molecules of Formula One can be ulated inside, or placed on the e of a capsule. The size of the es can range from nanometer size (about 100-900 nanometers in diameter) to micrometer size (about 10-900 microns in diameter). e of the unique ability of the eggs of some pests to resist certain pesticides, repeated applications of the molecules of a One may be desirable 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 molecules of Formula One to a different portion of the plant. For example, control of foliar-feeding insects can be achieved by drip irrigation or furrow application, by ng the soil with for example pre- or post-planting soil drench, or by treating the seeds of a plant before planting. wo 2013/062981 Seed treatment can be d to all types of seeds, including those from which plants genetically modified to express specialized traits will ate. entative examples include those expressing ns toxic to invertebrate pests, such as Bacillus thuringiensis or other insecticidal toxins, those expressing herbicide resistance, such as "Roundup Ready" seed, or those with "stacked" foreign genes expressing insecticidal toxins, herbicide resistance, nutrition-enhancement, drought resistance, or any other beneficial traits.
Furthermore, such seed treatments with the molecules 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 molecules 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 e even better benefits.
It should be readily apparent that the molecules of Formula One may be used on, in, or around plants genetically ed to express specialized traits, such as Bacillus thuringiensis or other icidal toxins, or those expressing herbicide resistance, or those with "stacked" foreign genes expressing insecticidal toxins, herbicide resistance, ionenhancement , or any other beneficial traits.
The molecules 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 molecules of Formula One are applied, such as by oral administration in the form of, for example, tablets, capsules, , granules, by dermal application in the form of, for example, dipping, ng, pouring on, spotting on, and dusting, and by parenteral administration in the form of, for e, an injection.
The molecules 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 l would be fleas and ticks that are some to such animals. Suitable formulations are administered orally to the animals with the drinking water or feed. The dosages and ations that are suitable depend on the species.
The les of Formula One may also be used for controlling parasitic worms, especially of the intestine, in the animals listed above. wo 2013/062981 The molecules 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 have been migrating to new environments (for such pest) and fter becoming a new invasive species in such new environment. The molecules of Formula One may also be used on such new invasive species to control them in such new environment.
The les 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 molecules in such area is to benefit the plants being grown in the area. Such benefits, may e, 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 le ingredients), 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 n ingredients), and improving the tolerance to c and/or biotic stress of the plant.
Before a pesticide can be used or sold commercially, such pesticide undergoes lengthy evaluation processes by various governmental authorities (local, regional, state, national, and international). Voluminous data requirements are specified by tory authorities and must be addressed through data generation 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 determination of safety is concluded, provide the potential user or seller with t registration approval. Thereafter, in that locality where the product registration is d and supported, such user or seller may use or sell such ide.
A molecule according to Formula One can be tested to determine its efficacy against pests. Furthermore, mode of action studies can be conducted to determine if said molecule has a different mode of action than other pesticides. Thereafter, such acquired data can be disseminated, such as by the internet, to third parties.
The headings in this nt are for convenience only and must not be used to interpret any portion hereof. wo 2013/062981 TABLE N Table 1: Compound number, appearance, and structure Compound Appearance Structure erv--CH30IN-N y CH, N s/ Yellow \ CH 1 CH 3 Gum N 3 / 0 N-N N~CH3 Yellow 2 I ~ Solid .-: bH3 CH3 erv--CH30IN-N ~ CH, N s/ Yellow \ crfH3 3 CH 3 3 Gum N wo 2013/062981 Appearance Structure / 30 N-N ~ CH3 ~ s/ 4 Yellow Oil N CH3 /CH3)l_)( v-N F ,ij N Yellow Oil I --~ \ N CH3 o-v-CH3I 0 N-N ~0-CH ~ 0 ' Yellow N CH3 wo 2013/062981 Compound ance Structure / 00 ~-N )l_ ,/'--/s_CH3 Yellow 7 N CH3 / 30 N-N )l_ ~S-CH ~~0 ' Yellow 8 N CH3 oY-CH/ 30 N-N ~ CH3 9 Beige Gum N Cl CH3 wo 62981 Compound Appearance Structure o-Y-CH/ 30 N-N ~ CH3 Colorless ~ Gum N Br CH3 / 0 N-N N~CH3 Colorless 12 I ~ Glass .-: bH3 CH3 N Br o-v--HC 3 '\ 0 N-N y CH; N s/ 18 Brown Oil bH CH3 N 3 wo 2013/062981 Compound Appearance ure o--v--H C 3 '\ 0 N-N ~ CH3 19 Yellow Oil N CH3 H 3 C \. 0 N-N NJ--(HJ Yellow Oil I ~ ~" \ CH3 .-: CH3 o--v--H C 3 '\ 0 N-N ~ CH; N s/ \ cifH3 21 Yellow Oil CH 3 N 3 wo 2013/062981 Appearance Structure 22 Clear Oil 23 Clear Oil wo 2013/062981 Appearance Structure Nu--o0 25 H C.,... r N h ~ /; H c" --N wo 2013/062981 2012/061508 Compound Appearance Structure wo 2013/062981 2012/061508 Compound Structure 33 Brown Solid wo 62981 Compound Structure Off White Solid O CH T\CH~ I \\ I 3 Off White ~N~~ CH, ' Solid Off White 36 Solid wo 2013/062981 2012/061508 Compound Appearance Structure 37 White Solid crt)---u}--0 H3C-O Off White Solid 39 White Solid wo 2013/062981 Compound Appearance ure ~f) }-0 Pale Yellow Solid l::::.. ) ..._y-H N Brown Thick Mass wo 2013/062981 2012/061508 Compound Structure Pale Yellow Solid 44 White Solid O CH3CH N- ~ I I 3 Brown ~N:>-~1\CH3 Thick Mass ~,) 3 wo 2013/062981 Compound ance Structure Pale Yellow Thick Mass N:)-.J)-/ 3 CH Pale Yellow ~N ,0 N Thick Mass ~,) ' )=o N H,c-Sr Pale Green Thick Mass wo 2013/062981 2012/061508 Compound Structure Pale Yellow Solid Brown Thick Mass Pale Yellow Thick Mass wo 2013/062981 Structure 53 White Solid 54 Clear Oil err~ N~/H3~H CH 3 wo 2013/062981 Appearance Structure White Semi Solid 56 Brown Solid 57 White Solid wo 2013/062981 Compound ance Structure 58 Clear Oil 59 White Solid 60 White Solid wo 62981 Compound Appearance Structure Light 61 Yellow Solid 62 Clear Oil Light 63 Yellow Solid UJJ--~)_{--sP'CH3 wo 62981 Compound Structure 64 White Solid 65 White Solid White Semi Solid wo 62981 Compound Structure Yellow Semi Solid H3C CH N~CloL )L-c~J 1- j 68 Clear Oil ~)~N ~ N'------ 185 White Solid p /} N~CH; u \H, F n ~HcH3 9' ~ _ij N~CH3 186 White Solid '\CH2 wo 2013/062981 2012/061508 Compound Appearance Structure Yellow Solid 188 Yellow Oil 189 Yellow Oil wo 2013/062981 2012/061508 Compound Appearance Structure 190 Yellow Oil 191 Yellow Oil 192 Yellow Oil wo 2013/062981 2012/061508 Compound Appearance Structure Yellow Solid 194 White Solid 195 White Solid wo 2013/062981 Appearance Structure 196 Tan Solid 197 White Solid 198 Tan Solid wo 62981 Compound Appearance Structure wo 62981 Compound Appearance Structure White Semi Solid 203 Yellow Oil 204 Yellow Oil wo 2013/062981 Compound ance Structure AND Enantiomer 205 Yellow Oil 206 Yellow Oil 207 White Solid wo 2013/062981 2012/061508 Compound Appearance Structure 208 White Solid 209 Yellow Oil 210 Yellow Oil wo 2013/062981 2012/061508 Compound Structure 212 Yellow Oil 213 Yellow Oil wo 62981 Compound Structure 215 Clear Oil Cream 216 Colored Solid wo 62981 Compound Structure 217 Clear Oil 218 Clear Oil 219 Clear Oil wo 2013/062981 Compound ance Structure 220 Yellow Oil 221 White Solid 222 White Solid wo 62981 Compound Appearance Structure 223 White Solid Colorless Light Yellow Oil wo 2013/062981 Compound ance Structure 226 White Solid 227 White Solid F Colorless wo 2013/062981 Compound Appearance Structure ~< F Colorless Oil CJ) CH 3 Colorless wo 62981 Compound Appearance Structure !:)_3CH ~~ F\/F 0 :-- 0/--F 232 White Solid UN~ N\ CH 3 233 White Solid 234 White Solid wo 2013/062981 2012/061508 Compound Appearance Structure Colorless 236 Colorless F F f--oH 237 White Solid wo 2013/062981 2012/061508 Compound Appearance Structure Colorless Colorless 240 White Solid wo 2013/062981 2012/061508 Compound Appearance Structure F F Colorless Oil cr~N; F N 3 CH;~r Colorless 242 u 0-N <~r Oil \_CH; r ~0 F Colorless 243 ~ ~ N Oil u )<~ \_CH; wo 2013/062981 Appearance Structure 244 White Solid 245 White Solid ~~CH ~~~ F\/F >0 ,(--' 246 Colorless ~N_j-N Oil ll~ H)3 wo 62981 Compound Appearance Structure 247 White Solid Colorless 249 White Solid wo 2013/062981 2012/061508 Compound Appearance Structure 250 Clear Oil 251 Brown Oil 252 Off White Solid wo 2013/062981 2012/061508 Compound Appearance Structure 253 Off White Solid 254 Brown Solid 255 White Solid wo 2013/062981 Compound ance Structure 256 White Solid 257 White Solid 258 Brown Oil wo 2013/062981 Appearance Structure 259 White Solid Colorless 261 White Solid wo 2013/062981 Compound Appearance Structure F F CH,~ 262 White Solid Fu)j_) FF I h. H c N 3 "1))j:N; F 263 F Oil F F I ~ H c N 3 Cll;~p Colorless 264 Fl)xj_N) 7\p Oil I ~ H,C F N - wo 2013/062981 2012/061508 Compound Structure 265 White Solid Colorless Semi-Solid Colorless wo 2013/062981 Compound ance Structure 268 White Solid 269 White Solid 270 White Solid wo 2013/062981 Compound Appearance Structure Fu)~~ OH F Colorless 271 ~F Oil I h. H c ,/' F N F F 3 F N~ N'CH 272 White Solid 3 h. R,C F F N - F Fuxj:N; ~-- \ Colorless Oil CH 3 I h. H c N 3 wo 2013/062981 Appearance Structure Colorless 275 White Solid 276 White Solid wo 2013/062981 Appearance Structure Brown 277 Amorphous Solid N~~CHf? 1- INfCH3 N H 278 White Solid erN~ 'cH3 279 White Solid wo 2013/062981 2012/061508 Compound Appearance Structure 280 White Solid 281 Orange Foam 282 Colorless wo 2013/062981 Structure Colorless Colorless 285 Clear Oil wo 2013/062981 2012/061508 Compound Appearance Structure 286 Yellow Oil 287 Yellow Oil 288 Yellow Oil wo 2013/062981 2012/061508 Compound Appearance Structure ~~/H' Dark Yellow Oil 0) h_ N S ~~sp' 290 Yellow Oil Ux )-{' N S CH 3 :5-- }-oH 3 CCl a-I3C+-CH3 291 Clear Oil UNI 0 N>-CHJ H 3 C wo 62981 Compound Appearance Structure 292 Tan Solid 293 Clear Oil 294 Yellow Oil wo 62981 Compound Appearance Structure White Semi- v~~~!1:~L) Solid L Cl00F Colorless Oil (JJ:5-N~ F N CH2 j_o}- FUN 1 cu3 N N I NH 297 White Solid I~ H wo 62981 Compound Appearance Structure 298 White Solid 299 White Solid 300 White Solid wo 62981 Compound Appearance Structure 301 White Solid 302 White Solid Colorless wo 62981 Compound Appearance Structure Light Yellow Oil 305 White Solid 306 F wo 62981 Compound Appearance Structure ,j_)--vLF Colorless Oil (::(N ) N H3C Cl O -- Colorless Oil 0)~) CH 3 ~O F Colorless 0) ) ~F 309 OH N H3C F~F wo 2013/062981 2012/061508 Compound Structure Light 310 Yellow Semi-Solid Colorless 312 White Solid wo 2013/062981 Compound ance Structure Light 313 Yellow Solid 314 Faint Yellow Oil 315 Faint Yellow Oil wo 62981 Compound Appearance Structure Faint 316 Yellow Solid 317 White Solid 318 Brown Solid wo 2013/062981 Appearance Structure 319 Brown Solid Yellow Solid Yellow Solid wo 2013/062981 2012/061508 Compound Structure Yellow Solid 323 Colorless 324 White Solid wo 2013/062981 Appearance Structure 325 White Solid Colorless 327 White Solid wo 62981 Compound Appearance Structure wo 2013/062981 Compound Appearance Structure CH 3 c1 oHs-0 -N) 0u- 331 White Foam J CH, H 3 C CH3 Nj_}-oCl 0 )L--cH3 Clear Yellow Oil UJ ~ N"----<\ N F N6- )_lH,0 I N 333 Clear Oil UN H) wo 2013/062981 2012/061508 Compound Structure N:j_Cl0~ fCH3 F 1- N 0 IN N H Light Brown Solid U 335 White Solid 336 White Solid wo 2013/062981 2012/061508 Compound Structure Pale Yellow 338 Clear Oil 339 Clear Oil wo 2013/062981 2012/061508 Compound Appearance Structure 340 White Solid 341 Yellow Oil 342 Yellow Oil wo 62981 Compound Appearance Structure CH3~F 343 Yellow Oil o)j_Ni> F UN~CJJ 3~FI // Ni> F 344 Yellow Oil en, Nj_O}--lH' Yellow I ~ N Solid UN \CH3 wo 62981 Compound Appearance Structure 346 White Solid 347 Pale Yellow C\ 0 ~C\ 348 Brown Solid r:Yx:)-fj wo 2013/062981 2012/061508 Compound Structure 349 Beige Solid Colorless 351 White Solid wo 62981 Compound Appearance Structure Yellow Solid H3-C O CH N )\-// 3 F I s 353 N N Yellow Oil U \CH N - 354 Yellow Oil wo 2013/062981 2012/061508 Compound Appearance Structure Yellow Solid 356 Yellow Oil 357 Yellow Oil wo 2013/062981 Compound ance Structure B' 00F Off-White Solid F'(J):>--'\-;?" CH 3 ~ I u ~~}--Qo Off White F N \ Solid I CH3 ~~c)L~'.313 360 White Solid OJ 2° CH 3 wo 62981 Compound Structure 362 Clear Oil 363 Clear Oil wo 2013/062981 2012/061508 Compound Structure 365 Yellow Oil 366 Yellow Oil wo 2013/062981 Appearance Structure 367 Clear Oil ~~/[ 0 ~CH; r(Yl__;---N}--s 368 White Solid ~~ H) Light Brown wo 2013/062981 2012/061508 Compound Structure Colorless Colorless 372 Yellow Oil wo 2013/062981 2012/061508 Compound Appearance Structure 373 White Solid 374 Beige Solid 375 White Solid wo 2013/062981 2012/061508 Compound Appearance Structure 376 White Solid 377 White Solid 378 White Solid wo 2013/062981 2012/061508 Compound Appearance Structure 379 White Solid 380 White Solid 381 White Solid wo 2013/062981 Compound 382 Clear Oil Pale Yellow 384 Colorless wo 2013/062981 Compound ance Structure 385 White Solid 386 White Solid 387 White Solid wo 2013/062981 Compound Appearance Structure 388 White Solid Off-White Solid wo 2013/062981 Compound Structure Colorless Cl O \/D y~ D Colorless N.__/-N/ \ S Oil U \___ CH 3 N -' Colorless wo 62981 Compound Appearance Structure Colorless 395 Pink Solid Colorless wo 2013/062981 Compound ance Structure Colorless 398 White Solid 399 White Solid wo 2013/062981 Compound ance Structure 400 Yellow Oil 401 Yellow Oil 402 Yellow Oil wo 2013/062981 Compound ance Structure 403 Yellow Oil 404 Yellow Solid 405 Colorless wo 2013/062981 Compound Appearance ure Colorless 407 Pale Yellow 408 Yellow Oil wo 2013/062981 Structure 409 White Solid 410 Orange Oil 411 Beige Solid wo 2013/062981 Compound ance Structure 412 White Solid 413 White Solid 414 Yellow Oil wo 2013/062981 Compound ance Structure :5-- H 3 C CH3 Cl 0 'I- )L 3 0) ~13CH Off-White Solid N S ) O)-/s/CH; 416 Yellow Oil F,0 N\ I """= CH3 '\O~s/CH; 417 Yellow Oil F,0 ) I CH; """= CH3 wo 2013/062981 Appearance Structure Yellow Solid 419 Yellow Oil 420 Yellow Oil wo 2013/062981 Appearance Structure H 3C Light Yellow Oil Fuo:~;J:5 I h H3C H 3 C Light Cl J:5 Yellow Oil x)--N; - 0 H C N cu,vcn,3 0 423 Light Yellow Oil FlJr)-> I ~ H3C wo 2013/062981 2012/061508 Compound Appearance Structure 424 Tan Solid 425 Colorless 426 Colorless wo 2013/062981 Structure 428 Yellow Oil 429 Yellow Oil wo 2013/062981 2012/061508 Compound Structure Light Yellow Oil 431 White Solid 432 Yellow Oil wo 2013/062981 2012/061508 Compound Appearance Structure 433 Yellow Oil 434 White Solid 435 White Solid N 0 wo 2013/062981 2012/061508 Compound Structure 436 White Solid 437 Yellow Oil 438 Yellow Oil wo 2013/062981 Compound ance Structure 439 White Solid 440 White Solid 441 Yellow Solid wo 2013/062981 Compound ance Structure 442 White Solid 443 White Solid 444 Brown Solid wo 2013/062981 Structure 446 Yellow Solid 447 Dark Oil wo 62981 Compound Structure 449 Tan Solid 450 White Oil wo 2013/062981 Structure 452 Colorless 453 White Solid wo 2013/062981 2012/061508 Compound Appearance Structure 454 White Solid 455 Colorless 456 Yellow Oil wo 2013/062981 Compound ance Structure 457 White Oil ANDEnant10mer· Br 0 /CH3 458 White Solid crx:>-~"sCH3 459 Colorless wo 2013/062981 2012/061508 Compound Structure 460 White Solid 461 Colorless 462 White Solid wo 2013/062981 2012/061508 Compound Structure 463 White Solid 464 Colorless 465 White Solid wo 2013/062981 Appearance Structure ANDEnant10mer· {'Yx:}-{_/\"'sBr 0 FH3 466 White Solid ll~~ CH3 467 Colorless Light 468 Yellow Solid wo 2013/062981 2012/061508 Compound Appearance Structure tr-N\_ )' OHS-CH3 CH3 469 White Solid U CH3 Light Yellow Oil Light Yellow Oil wo 2013/062981 Compound ance Structure Light Yellow Oil Light Purple Solid 474 Yellow Oil wo 2013/062981 Structure Light Yellow Oil 476 White Solid Off-White Solid wo 2013/062981 2012/061508 Compound Appearance Structure 478 Clear Oil 479 Beige Solid wo 62981 Compound Structure Light Yellow Oil 482 Beige Solid 483 Clear Viscous Oil wo 2013/062981 Compound Clear Viscous Oil 485 White Oil 486 Off White Solid wo 2013/062981 Compound Appearance ure Off-White Light 488 Yellow Solid 489 Yellow Solid wo 2013/062981 Compound ance Structure Light Yellow Oil Light Yellow Oil 492 White Solid wo 2013/062981 2012/061508 Compound Appearance Structure Light Orange Oil 494 Yellow Oil 495 Clear Oil wo 2013/062981 2012/061508 Compound Appearance Structure Light Yellow Oil 497 Light Yellow Oil 498 Light Yellow Oil wo 2013/062981 Compound Appearance ure Colorless 500 Beige Solid 501 White Solid wo 2013/062981 Appearance Structure Thick Yellow Oil 503 Beige Solid 504 Beige Solid wo 2013/062981 Appearance Structure Colorless Clear 506 Colorless Clear 507 Colorless wo 2013/062981 Appearance Structure Clear 508 Colorless Pale Yellow 510 Yellow Oil wo 62981 Compound Structure 511 White Oil Pale Yellow Thick Clear wo 2013/062981 Compound ance Structure 514 White Solid 515 White Oil 516 Dark Brown wo 62981 Compound Appearance Structure erNN:)_ct 0~/ I /} N 517 White Solid '-'::: 11 N:)- }---~O ~S-CH3 I /} 518 N White Solid UN ) H3 C s-cH, Cl 0 ~ - Nj_}-~ I /} 519 N White Solid UN ) H3 C wo 2013/062981 2012/061508 Compound Appearance Structure 520 Brown Gum 521 Beige Solid 522 White Solid wo 2013/062981 Structure 523 Yellow Solid 524 Light Brown Solid Faint 525 Yellow Solid wo 2013/062981 Structure Faint 526 Yellow Solid 527 Yellow Oil Light Brown wo 2013/062981 Compound Appearance ure Faint N-- 529 Yellow N Solid Fl~( \ I~ b CH 3 Cl~F 530 Clear Oil N S CIVFCH3 531 Yellow Oil ()J~J-{H3 N S CH 3 wo 62981 Compound Structure 532 White Solid 533 Orange Oil Cl O 534 Red Oil wo 62981 Compound Appearance Structure 535 White Oil 536 White Solid F F 537 Clear Oil wo 2013/062981 Appearance Structure 538 White Solid 539 Clear Oil 540 Clear Oil wo 62981 Compound Structure 541 Light Yellow Oil 542 Colorless 543 White Solid wo 2013/062981 Structure 544 White Solid 545 White Fluffy Solid wo 2013/062981 Appearance Structure 547 Yellow Oil 548 White- Yellow Oil 549 Colorless wo 2013/062981 Compound Appearance Structure Colorless 551 ess 552 Colorless wo 2013/062981 Compound Appearance Structure 554 Colorless 555 Yellow Oil wo 62981 Compound Appearance Structure II3C) Pale Yellow 556 I ,!} hs Gum \ \ I ~ CH3 CH3 )-cH 3 N-N CH 3 557 Pale Yellow I I Gum 0 N}-- wo 2013/062981 Appearance Structure Faint Yellow Oil Yellow Solid 561 White Solid N 0 wo 2013/062981 Appearance Structure 562 Brown Gum Pale Yellow 564 Pale Yellow wo 2013/062981 Appearance Structure Pale Yellow Pale Yellow 567 Off-White F Solid wo 2013/062981 Compound ance Structure Pale Yellow Colorless wo 2013/062981 I T l Compound a nee Structure uxj_'~P'N ~~ White Semi- 571 ) F F F Solid N H 3 C N- F Colorless Oil cr~:>-N\ FFF CH 3 Colorless 573 crr:>-N FFF F \__CH I I I wo 2013/062981 2012/061508 Compound Appearance Structure Nj_Cl~F Colorless F 574 ~ _o N F F Oil v ~H; Nj_Cl~F Colorless F 575 I .0 N F F Oil UN ~ uzj_0'\~113/H3 Colorless wo 2013/062981 Compound Appearance Structure Colorless 578 ess 579 Colorless wo 62981 Compound Appearance Structure Colorless 581 Colorless Solid 582 Clear Oil wo 2013/062981 Appearance Structure 0)~; ~ NH :....- 583 Brown Oil ~ h N H C Nil ~ 584 Dark Yellow Oil 0)~; N 3 J-_o~KJN ~ 585 White Solid ~ >H3C H 3 C wo 62981 Compound Appearance Structure Yellow Solid 587 Purple Solid Dark Yellow Oil wo 2013/062981 Compound ance Structure Colorless Solid 590 Brown Solid Light 591 Yellow Solid wo 2013/062981 2012/061508 Compound Appearance Structure 592 Brown Oil 593 Brown Oil Faint 594 Yellow Solid wo 2013/062981 S Compound Appearanee Structure a 3YH3 ~)-o CH3 595 White Solid UN//N N )--o'I-H3 CH 3 H 3C H3C CH 3 ~o '/-en~ N }-o 596 Brown Solid C(I N "----==_CH Colorless Oil 0):>-N"----=_CHf Colorless ~'Vs Oil cr~ '---==_CH L _j wo 2013/062981 2012/061508 Compound Appearanee Structure N~(HS Colorless Oil ()~ ,? N\ en, :::-..
N!;'HCH, 600 White Solid a~ ,'l \ CH; 1'-l;:_cJ-:~, Yellow r 601 0 Solid FUNI N\ :::-..
Colorless j:Hs Oil FUJ \ I CH, :::-.. wo 2013/062981 Compound ance Structure 603 Light Brown Solid 604 Brown Gum Light Brown Light Brown wo 2013/062981 Compound Appearanee ure Nj_'V'I . 607 Colorless Oil crJ ,'l N\ CH Nj_OHSFH3 Colorless Oil cr* ,'l N\ cu, Cl0F Colorless Oil crx:}-N'----= F N6-oHcH, Yellow Solid a* # N\ _CHCH; :::-... wo 62981 Compound Appearance Structure ~k~cn, 611 Yellow Oil ) ) 0 en, HC~~ N Cl 0 :>--~s-en, 612 Beige Solid v)J/) N F F Cl ~ CH, 613 Brown Oil JN:)__ s/ Cf N\_ Nj_ F Cl ~CH3 Colorless 614 I /) N F Oil C( \_ CH wo 2013/062981 Compound Appearance Structure CIWF 615 ess N:)_ F Oil UNI .0 N F F N ~CH 616 White Solid crxj_) /"' N HC~!J ~HLcn, 617 Off-White Foam ) ) 0 en, HC~~ N Cl 0 \\ :)__ k\\CII; Yellow Foam ) ) 0 Ci~ N HC~~ wo 2013/062981 2012/061508 Compound Appearance Structure c1 ~/err, 619 White Solid o):? s N HC7' Cl 0 \\ ~)-Js-cn, Pale Yellow 620 ~ 8 Oil v)N ::>-- 0 Cl 0 \\ )-J\\cn, Pale Yellow N 0 621 ~ Oil vII)N x:}_N~.., 622 Yellow Oil () ) s-cH3 N HC:?' wo 2013/062981 Compound Appearance Structure H 3C 0 ~)_)'VH' N '6 623 Yellow J N Solid v ) ~ /; Cl 0 ~ /, 624 White Solid s~ ())-<; ,_1 N HC N~~SII Colorless 625 u ~ /) Oil )N N HC Light 626 o-<:C~s~: Yellow Oil ~H wo 2013/062981 Compound Appearance Structure CH 3 Yellow 627 o-<:C~s~; Viscous Oil ~H Table 2: Compound number and analytical data Compound MY' IRb Mass 1HNMR 13CNMR 1HNMR (300 MHz, DMSO-d6) o 9.04 (d, J =2.4 Hz, 1H), 8.60 (s, 1H), 8.49 (dd, J = 4.7, 1.4 Hz, 1H), 8.17 ESIMS 73- (ddd, J = 8.4, 2.7, 596 m/z 312.2 75 1.4 Hz, 1H), 7.52 ([M+1t) (ddd, J = 8.4, 4.7, 0.6 Hz, 1H), 4.30 (d, J = 2.1 Hz, 2H), 3.23 (s, 1H), 2.18 (s, 3H), 1.39 (s, 6H). 1HNMR (400 13C NMR (101 MHz, CDCb) o MHz, CDCb) o 8.97 (d, J =2.5 Hz, 170.37, 148.49, 1H), 8.59 (dd, J = 148.04, , ESIMS 4.7, 1.3 Hz, 1H), 136.04, 126.23, 597 m/z 337 8.05 (ddd, J = 8.3, 125.26, 124.16, ) 2.7, 1.5 Hz, 1H), 124.01, 78.59, 8.01 (s, 1H), 7.44 72.69, 38.69, (ddd, J = 8.3, 4.8, 29.57, 29.26, 0.4 Hz, 1H), 4.44 26.69,11.14 (s, 2H), 2.61 - 2.43 wo 2013/062981 Compound MY' IRb Mass 1HNMR 13CNMR (m, 2H), 2.43 - 2.33 (m, 2H), 2.30 (s, 3H), 2.26 (t, J = 2.5 Hz, 1H). 1HNMR (400 MHz, CDC13) o 8.96 (d, J =2.4 Hz, 1H), 8.58 (dd, J = 13C NMR (101 4.7, 1.4 Hz, 1H), MHz, CDC13) o 8.04 (ddd, J = 8.3, 171.73, 148.71, 2.7, 1.5 Hz, 1H), 147.93, 140.17, ESIMS 8.01 (s, 1H), 7.43 136.09, 126.15, 598 mlz 315.1 (ddd, J = 8.3, 4.8, 125.41, , ([M+Ht) 0.5 Hz, 1H), 4.45 123.99, 78.85, (s, 2H), 2.79 (t, J = 72.51, 38.35, 7.3 Hz, 2H), 2.45 33.80, 29.57, (t, J = 7.3 Hz, 2H), 15.96, 11.20 2.31 (s, 3H), 2.24 (t, J = 2.5 Hz, 1H), 2.06 (s, 3H). 1H NMR (400 MHz, CDC13) o 8.96 (d, J =2.5 Hz, 1H), 8.58 (dd, J = 4.7, 1.4 Hz, 1H), 8.04 (ddd, J = 6.9, 2.7, 1.5 Hz, 2H), ESIMS 7.48- 7.38 (m, 1H), 599 m/z 283 4.47 (bs, 2H), 2.88 ([M-SMe+Ht) (dd, J = 12.7, 9.2 Hz, 1H), 2.77 (s, 1H), 2.44 (dd, J = 12.8, 5.1 Hz, 1H), 2.34 (s, 3H), 2.24 (s, 1H), 2.01 (s, 3H), 1.14 (d, J = 6.7 Hz, 3H). 1HNMR (400 uC NMR (101 MHz, CDCb) o MHz, CDCb) o 8.96 (d, J =2.5 Hz, 177.64, 148.89, ESIMS 1H), 8.57 (dd, J = 148.85, 147.83, 600 mlz 283.5 4.7, 1.3 Hz, 1H), 140.13, 136.13, ) 8.04 (ddd, J = 8.3, 126.06, 125.08, 2.7, 1.5 Hz, 1H), 125.02, 123.97, 8.00 (s, 1H), 7.43 79.12, 72.41, (dd, J = 8.3, 4.8 Hz, 38.23, 31.05, wo 2013/062981 MY' IRb Mass 1HNMR 13CNMR 1H), 4.43 (bs, 2H), 19.52, 11.16. 2.60 (dt, J = 13.5, 6.8 Hz, 1H), 2.29 (s, 3H), 2.23 (t, J = 2.5 Hz, 1H), 1.08 (d, J = 6.7 Hz, 6H). 1HNMR (400 MHz, CDCb) 8 8.73 (s, 1H), 8.37 (d, J = 2.5 Hz, 1H), ESIMS 81- 7.99 (s, 1H), 7.83 601 mlz 329.8 82 (dt, J = 9.5, 2.2 Hz, ([M-Ht) 1H), 4.31 (s, 2H), 2.29 (t, J = 2.4 Hz, 1H), 2.27 (s, 3H), 1.45 (s, 9H). 1HNMR (400 MHz, CDCb) 8 8.77 (d, J = 1.7 Hz, 1H), 8.43 (d, J = 2.5 Hz, 1H), 8.05 (s, 1H), 7.86 (dt, J =9.4, 2.3 Hz, 1H), ESIMS 4.49 (s, 2H), 2.88 602 mlz 347.5 (dd, J = 12.8, 9.4 ([M+Ht) Hz, 1H), 2.74 (s, 1H), 2.45 (dd, J = 12.9, 5.0 Hz,1H), 2.34 (s, 3H), 2.24 (t, J = 2.5 Hz, 1H), 2.02 (s, 3H), 1.14 (d, J = 6.8 Hz, 3H). 1HNMR (400 MHz, CDCb) 8 8.77 (d, J = 1.5 Hz, 1H), 8.43 (d, J = 2.5 Hz, 1H), 8.01 ESIMS (s, 1H), 7.86 (dt, J 603 mlz 299.5 =9.4, 2.3 Hz, 1H), ([M-Ht) 4.43 (s, 2H), 2.57 (dt, J = 13.5, 6.7 Hz, 1H), 2.29 (s, 3H), 2.23 (t, J = 2.5 Hz, 1H), 1.08 (d, J =6.7 Hz, 6H). wo 2013/062981 Compound MY' IRb Mass 1HNMR 13CNMR 1HNMR (400 MHz, eDel3) o Be NMR (101 8.77 (d, J = 1.9 Hz, MHz, eDeb) o 1H), 8.44 (t, J =4.4 170.26, 149.03, Hz, 1H), 8.03 (s, 136.33, 136.28, ESIMS 1H), 7.87 (dt, J = 136.05, 135.42, 604 mlz 353.8 9.3, 2.4 Hz, 1H), 135.29, 126.49, ([Mt) 4.44 (s, 2H), 2.56 - 125.48, 124.59, 2.42 (m, 2H), 2.36 113.48, 78.51, (dd, J = 12.7, 5.5 72.81, 38.62, Hz, 2H), 2.30 (s, 26.73, 11.13. 3H), 2.27 (s, 1H). 1H NMR (400 MHz, eDel3) o 8.76 (d, J = 1.6 Hz, 1H), 8.44 (d, J = 2.5 Hz, 1H), 8.05 ESIMS (s, 1H), 7.86 (dt, J 605 mlz 333.69 = 9.3, 2.3 Hz, 1H), ) 4.45 (s, 2H), 2.79 (t, J = 7.3 Hz, 2H), 2.43 (t, J = 7.3 Hz, 2H), 2.30 (s, 3H), 2.25 (t, J = 2.5 Hz, 1H), 2.06 (s, 3H) 1HNMR (400 MHz, eDel3) o Be NMR (101 8.94 (d, J =2.5 Hz, MHz, eDel3) o 1H), 8.58 (dd, J = 170.97, , ESIMS 4.7, 1.3 Hz, 1H), 148.02, 139.81, 606 m/z 276.8 8.07 (s, 1H), 8.05 - 136.83, 135.90, ([M-t-But) 7.92 (m, 1H), 7.42 133.69, 133.53, (dd, J = 8.3, 4.8 Hz, 126.02, 124.26, 1H), 4.36 (s, 2H), 123.96, 81.33, 2.29 (t, J = 2.4 Hz, 60.31, 28.08. 1H), 1.46 (s, 9H). 1HNMR (400 ue NMR (101 MHz, eDeb) o MHz, eDeb) o 8.96 (d, J =2.5 Hz, 175.54, 148.75, 1H), 8.64 (dd, J = 140.82, 140.16, ESIMS 4.7, 1.3 Hz, 1H), 135.66, 126.41, 607 mlz 335.1 8.12 (s, 1H), 8.06 , 122.68, ([M+Ht) (ddd, J = 8.4, 2.7, 78.61, 77.33, 1.4 Hz, 1H), 7.47 77.02, 76.70, (dd, J = 8.3, 4.8 Hz, 72.86, 37.83, 1H), 4.48 (s, 2H), 37.22, 18.11, 2.81 (t, J =7.4 Hz, 16.54. wo 62981 Compound MY' IRb Mass 1HNMR 13CNMR 2H), 2.50 (t, J = 7.4 Hz, 2H), 2.27 (t, J =2.5 Hz, 1H), 2.08 (s, 3H). 1HNMR (400 MHz, eDel3) o 8.97 (d, J = 2.5 Hz, 1H), 8.64 (dd, J = 4.7, 1.3 Hz, 1H), Be NMR (101 8.16 (s, 1H), 8.05 MHz, eDeb) o (ddd, J = 8.3, 2.7, 171.42, 148.77, 1.4 Hz, 1H), 7.47 140.68, 140.10, ESIMS (dd, J = 8.3, 4.8 Hz, 135.65, 127.00, 608 mlz 349.1 1H), 5.30 (s, 2H), 126.48, 124.14, ([M+Ht) 2.87 (dd, J = 12.8, 122.73, 78.58, 8.8 Hz, 1H), 2.75 72.91, 37.82, (d, J = 6.3 Hz, 1H), 33.86, 29.41, 2.49 (dd, J = 12.9, 15.92. .4 Hz, 1H), 2.26 (t, J = 2.5 Hz, 1H), 2.03 (s, 3H), 1.18 (d, J = 6.7 Hz, 3H). 1H NMR (400 MHz, eDel3) o Be NMR (101 8.97 (d, J =2.5 Hz, MHz, eDel3) o 1H), 8.65 (dd, J = 170.10, 148.90, 4.7, 1.3 Hz, 1H), 140.16, 139.27, ESIMS 8.22 (s, 1H) 8.12 (s, 126.82, ' 609 m/z 357.1 1H), 7.48 (dd, J = 124.14, 123.89, ([M+Ht) 7.5, 3.9 Hz, 1H), 122.29, 78.32, 4.46 (s, 2H), 2.61 - 73.09, 72.50, 2.35 (m, 4H), 2.29 38.13, 36.29, (dd, J = 4.7, 2.4 Hz, 26.71. 1H). 1HNMR (400 MHz, eDeb) o 8.96 (d, J =2.6 Hz, 1H), 8.63 (dd, J = 4.7, 1.2 Hz, 1H), ESIMS 98- 8.09 (s, 1H), 8.06 610 mlz 303.1 99 (ddd, J = 8.3, 2.7, ([M+Ht) 1.5 Hz, 1H), 7.46 (dd, J = 8.4, 4.8 Hz, 1H), 4.40 (m, 2H), 2.76- 2.44 (m, 1H), 2.24 (t, J = 2.4 Hz, wo 2013/062981 Compound MY' IRb Mass 1HNMR 13CNMR 1H), 1.57 (s, 1H), 1.11 (d, J = 6.7 Hz, 6H). 1H NMR (400 MHz, eDeb) o Be NMR (101 8.97 (d, J =2.5 Hz, MHz, eDeb) o 1H), 8.66 - 8.60 (m, 171.30, 148.66, 1H), 8.25 (s, 1H), , 140.18, ESIMS 8.08 - 8.01 (m, 1H), 135.71, 127.87, 611 m/z 335 7.49- 7.42 (m, 1H), 126.35, 124.11, ([M+Ht) 4.86 (s, 1H), 4.29 - 122.12, 78.53, 3.97 (m, 1H), 3.31 72.92, 53.39, (d, J = 6.5 Hz, 1H), 37.97, 16.42, 2.30 - 2.24 (m, 1H), 11.07. 2.09 (s, 3H), 1.46 (d, J- 6.9 Hz, 3H). 1HNMR (400 Be NMR (101 MHz, eDeb) o MHz, eDeb) o 8.96 (s, 1H), 8.63 169.20, 148.57, (d, J = 4.2 Hz, 1H), 140.58, 140.10, ESIMS 8.21 (s, 1H), 8.09 - 65- 127.82, , 612 m/z 321 8.00 (m, 1H), 7.50- 68 122.27, 99.98, ([M+Ht) 7.43 (m, 1H), 4.53 78.37, (br s, 2H), 3.12 (s, 77.23,73.07, 2H), 2.28 (t, J = 2.5 37.90, 35.01, Hz, 1H), 2.23 (s, .96. 3H). 1HNMR (400 MHz, eDeb) o 8.97 (d, J =2.6 Hz, 1H), 8.64 (dd, J = 4.7, 1.3 Hz, 1H), 8.13 (s, 1H), 8.07 (ddd, J = 8.3, 2.7, ESIMS 1.5 Hz, 1H), 7.48 613 1674 m/z 403 (ddd, J = 8.3, 4.8, ([M+Ht) 0.5 Hz, 1H), 4.39 (s, 2H), 3.76 (dqd, J = 17.2, 8.6, 3.6 Hz, 1H), 2.67 (dd, J = 16.6, 3.6 Hz, 1H), 2.46 (dd, J = 16.5, 9.9 Hz, 1H), 2.29 (d, J- 2.5 Hz, 4H).
ESIMS 1H NMR (400 614 1671 m/z 353 MHz, eDeb) o wo 2013/062981 MY' IRb Mass 1HNMR 13CNMR ([M+Ht) 8.97 (d, J = 2.5 Hz, 1H), 8.64 (dd, J = 4.7, 1.4 Hz, 1H), 8.12 (s, 1H), 8.07 (ddd, J = 8.3, 2.7, 1.4 Hz, 1H), 7.47 (ddd, J = 8.3, 4.8, 0.4 Hz, 1H), 4.47 (s, 2H), 2.48 - 2.35 (m, 2H), 2.35-2.16 (m, 3H), 1.60 (t, J = 18.4 Hz, 3H). 1H NMR (400 MHz, CDCb) o 8.97 (d, J = 2.5 Hz, 1H), 8.65 (dd, J = 4.7, 1.2 Hz, 1H), ESIMS 8.13 (s, 1H), 8.07 615 1676 m/z 407 (ddd, J = 8.3, 2.7, ([M+Ht) 1.5 Hz, 1H), 7.48 (dd, J = 8.3, 4.7 Hz, 1H), 4.47 (s, 2H), 2.58 - 2.39 (m, 4H), 2.29 (t, J = 2.5 Hz, 1H). 1HNMR (400 MHz, CDCb) o 8.97 (d, J = 2.5 Hz, 1H), 8.64 (dd, J = 4.7, 1.1 Hz, 1H), 8.17 (s, 1H), 8.06 (ddd, J = 8.3, 2.7, 1.4 Hz, 1H), 7.47 (dd, J = 8.3, 4.7 Hz, ESIMS 1H), 4.92- 4.10 (m, 616 1662 m/z 377 2H), 3.06 (ddd, J = ([M+Ht) 7.7, 6.2, 4.3 Hz, 1H), 2.45 (s, 1H), 2.44 (d, J =2.4 Hz, 1H), 2.27 (t, J = 2.5 Hz, 1H), 2.11 (s, 3H), 1.97 - 1.85 (m, 1H), 0.96 (d, J = 6.7 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H). wo 2013/062981 2012/061508 Compound MY' IRb Mass 1HNMR 13CNMR 1HNMR (400 MHz, eDeb) o 8.98 (s, 1H), 8.65 Be NMR (101 (d, J = 4.6 Hz, 1H), MHz, eDeb) o 8.23 (s, 1H), 8.11 - 168.11, 148.95, 7.97 (m, 1H), 7.51 - 148.78, 140.45, ESIMS 7.41 (m, 1H), 4.88 140.33, 140.20, 617 m/z 351 (br s, 1H), 4.14 (br 135.56, 126.54, ([M+Ht) s, 1H), 2.64 (s, 124.10, 121.68, 1.2H), 2.55 (s, 121.58, 121.48, 1.8H), 2.33 - 2.27 77.69, 73.49, (m, 1H), 1.47 (d, J 38.60. =6.8 Hz, 3H), 1,42 (br s). 1H NMR (400 MHz, eDeb) o 9.00 (s, 1H), 8.65 Be NMR (101 (s, 1H), 8.29 (s, MHz, eDeb) o 1H), 8.03 (d, J = 166.97, 166.90, ESIMS 8.0 Hz, 1H), 7.54- 148.77, 140.43, m/z 367 7.39 (m, 1H), 4.89 140.24, 135.58, ([M+Ht) (d, J = 16.9 Hz, 129.36, 126.64, 1H), 4.20 - 4.08 (m, 124.14, , 1H), 4.07 - 3.92 (m, 73.80, 60.91, 1H), 3.01 (s, 3H), 38.78, 36.29, 2.34 - 2.29 (m, 1H), 13.97. 1.67 (d, J = 7.0 Hz, 3H). 1HNMR (400 MHz, eDeb) o 8.97 (s, 1H), 8.64 (d, J = 4.2 Hz, 1H), 8.14 (s, 1H), 8.07 (ddd, J = 8.3, 2.6, 1.4 Hz, 1H), 7.47 ESIMS (dd, J = 8.3, 4.7 Hz, 109- 619 1665 mlz 375.5 1H), 4.45 (s, 2H), ([M+Ht) 2.63 - 2.46 (m, 3H), 2.27 (t, J = 2.5 Hz, 1H), 2.14 (s, 3H), 0.90- 0.73 (m, 1H), 0.66 - 0.57 (m, 1H), 0.57 - 0.44 (m, 1H), 0.42 - 0.35 (m, 1H), 0.35 - 0.23 (m, 1H). wo 2013/062981 Compound MY' IRb Mass 1HNMR 13CNMR 1HNMR (300 MHz, CDC13) o 8.97 (d, J = 2.6 Hz, 1H), 8.64 (dd, J = 4.8, 1.4 Hz, 1H), 8.23 (s, 1H), 8.03 ESIMS (ddd, J = 8.4, 2.7, 620 1673 m/z 337 1.5 Hz, 1H), 7.46 (dd, J = 8.4, 4.7 Hz, 1H), 4.52 (br s, 2H), 3.68 (br s, 2H), 2.78 (s, 3H), 2.29 (t, J = 2.5 Hz, 1H). 1HNMR (300 MHz, CDC13) o 8.98 (d, J = 2.7 Hz, 1H), 8.64 (d, J = 4.8 Hz, 1H), 8.28 (d, J = 1.0 Hz, 1H), ESIMS 8.03 (dt, J = 8.4, 621 1667 m/z 353 1.3 Hz, 1H), 7.46 ([M+Ht) (dd, J = 8.3, 4.8 Hz, 1H), 4.88 (br S, 2H), 3.97 (br s, 2H), 3.20 (s, 3H), 2.31 (dt, J = 2.4, 1.3 Hz, 1H). 1HNMR (300 MHz, CDC13) o 9.01 (s, 1H), 8.61 (s, 1H), 8.28 (s, 1H), 8.12 - 8.05 (m, 1H), 7.48- 7.41 (m, ESIMS 1749, 1H), 6.09 (s, 0.5H), 622 m/z 409 1666 4.10 (s, 1H), 3.58 ([M+Ht) (s, 0.5H), 3.37 (s, 0.5H), 3.27 (s, 1.5H), 2.30 (d, J = 1.4 Hz, 1H), 2.24 (s, 3H), 2.20 (s, 3H), 1.61 (s, 1H) 1HNMR (400 ESIMS MHz, CDCb) o 623 1678 m/z 382 8.97 (d, J = 2.6 Hz, ([M+Ht) 1H), 8.65 (dd, J = wo 2013/062981 MY' IRb Mass 1HNMR 13CNMR 4.8, 1.3 Hz, 1H), 8.. 15 (s, 1H), 8.04 (ddd, J = 8.3, 2.7, 1.4 Hz, 1H), 7.48 (dd, J = 8.4, 4.7 Hz, 1H), 3.77 (hept, J = 6.9 Hz, 2H), 3.05 (s, 2H), 3.01 (s, 3H), 2.87 (s, 3H), 2.31 (t, J = 2.5 Hz, 1H). 1HNMR (400 MHz, CDCb) o 8.94 (dd, J = 4.9, 2.7 Hz, 1H), 8.65 (dd, J = 4.8, 1.5 Hz, ESIMS 1H), 8.07 -7.98 624 mlz 563.2 (m, 1H), 7.94 (s, ([M+l]t 1H), 7.2-7.5 (m, 16H), 4.44(m, 2H), 2.64 (t, J =7.1 Hz, 2H), 2.52 (t, J = 7.3 Hz, 2H), 2.22 (s, 1H). 1HNMR (400 MHz, CDCb) o 9.01 - 8.92 (m, 1H), 8.64 (d, J = .9 Hz, 1H), 8.11 (s, 1H), 8.06 (ddd, ESIMS 3254, J = 8.3, 2.7, 1.5 Hz, mlz 321.1 3039, 1H), 7.47 (dd, J = 625 ([M+1t), 2555, 8.3, 4.8 Hz, 1H), 319.1 1685 4.56 (m, 1H), 2.93 ([M-1D (dt, J = 8.5, 6.6 Hz, 2H), 2.54 (t, J = 6.7 Hz, 2H), 2.27 (t, J =2.5 Hz, 1H), 1.71 (dt, J = 11.6, 8.4 Hz, 2H).
ESIMS 1HNMR (400 mlz 417.2 MHz, CDCb) o 3299, ([M+Ht) 8.96 (d, J =2.7 Hz, 1672 1H), 8.64 (dd, J = HRMS-FAB 4.8, 1.4 Hz, 1H), (mlz) [M+Ht 8.12 (s, 1H), 8.06 wo 2013/062981 Compound MY' IRb Mass 1HNMR 13CNMR calcd for (ddd, J = 8.3, 2.7, CnHnClF3N40S 1.5 Hz, 1H), 7.47 417.0758; found, (dd, J = 8.5, 4.8 Hz, 417.0754 1H), 4.47 (s, 2H), 2.86 (t, J = 7.2 Hz, 2H), 2.74- 2.61 (m, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.45 - 2.29 (m, 2H), 2.28 (t, J = 2.5 Hz, 1H). 1HNMR (400 MHz, CDCb) o 8.96 (d, J =2.6 Hz, 1H), 8.58 (dd, J = ESIMS 4.8, 1.5 Hz, 1H), mlz 397.3 8.04 (ddd, J = 8.3, 2.7, 1.5 Hz, 1H), 8.01 (s, 1H), 7.44 3293, HRMS-FAB 627 (dd, J = 8.3, 4.9 Hz, 1663 (mlz) [M+Ht 1H), 4.45 (s, 2H), calcd for 2.84 (t, J = 7.1 Hz, C1sH2oF3N40S, 2H), 2.72- 2.60 (m, 397.1304; found, 2H), 2.44 (t, J = 7.1 397.1322 Hz, 2H), 2.41 - 2.32 (m, 2H), 2.31 (s, 3H), 2.26 (t, J = 2.4 Hz, 1H). a (°C) b (Thin Film; cm-1) wo 2013/062981 Table 3: GPA (MYZUPE) and sweetpotato whitefly-crawler A) 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 4. Biological Data for GPA (MYZUPE) and sweetpotato whitefly-crawler (BEMITA) MYZUPE BEMITA Compound % Ctrl@ % Ctrl@ 200ppm 200ppm 596 A A 597 A B 598 A B 599 A B 600 A B 601 A A 602 A A 603 A A 604 A A 605 A A 606 A A 607 A A 608 A A 609 A A 610 A A 611 A A 612 A A 613 A A 614 A A 615 B A 616 c c 1000998969 MYZUPE BEMITA Compound % Ctrl @ °/o Ctr] @ 200 ppm 200 ppm A A A A 624 C C 625 C C 626 A A 627 A A As used herein, the term "comprise" and variations of the term, such as ising", "comprises" and "comprised", are not intended to exclude other additives, ents, integers or steps.
Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in New Zealand or any other jurisdiction wo 2013/062981 2012/061508

Claims (65)

1. A ition comprising a molecule according to "Formula One" 5 wherein (a) A is either X~ attachment bond II h Rl~N Al or R2 N=
2. A composition according to claim 1 wherein A is Al.
3. A ition according to claim 1 wherein A is A2.
4. A composition according to any one of the preceding claims wherein R1 is H.
5. A composition according to any one ofthc preceding claims wherein R2 is H.
6. A composition according to any one of the ing claims n R3 is selected from H, or tuted or unsubstituted C1—C6 alkyl.
7. A composition according to any one of the preceding claims wherein R3 is selected from H or CHg.
8. A composition according to claim 1 or 2 wherein when A is Al then Al is A1 1.
9. A composition according to any one of claims 1, 2 or 8 wherein when A is Al, and A1 is Al 1, then R4 is selected from H, or substituted or unsubstituted C1—C6 alkyl, or substituted or unsubstituted C6—C20 aryl. 30
10. A composition according to any one of claims 1, 2, 8 or 9 wherein when A is Al, and A1 is All then R4 is selected from CH3, CH(CH3)2, or .
11. A composition according to claim 1 or 2 wherein when A is Al, and A1 is A12, then 8969 R4 is CH3.
12. A ition according to claim 1 or 3 wherein when A is A2 then R4 is selected from H, substituted or unsubstituted C1—C6 alkyl, substituted or unsubstituted C2—C6 alkenyl, substituted or unsubstituted C3—C10 lkyl, substituted or unsubstituted C6—C20 aryl, wherein each said R4, which is substituted, has one or more substituents selected from F, Cl, Br, or I.
13. , A composition according to any one of claims 1, 3 or 12 wherein when A is A2 then 10 R4 is H or C1—C6 alkyl.
14. A composition according to any one of claims 1, 3 or 12 wherein when A is A2 then R4 is H, CH3, CllgCHg, CHZCHg, cyclopropyl, CHzCl, CF3, or phenyl.
15. 15. A composition according to claim 1 or 3 wherein when A is A2 then R4 is Cl.
16. A composition according to any one ofthe preceding claims wherein R5 is selected from H, F, Cl, Br, I, substituted or unsubstituted C1—C6 alkyl, substituted or unsubstituted C1- C6 alkoxy.
17. A composition ing to any one of the ing claims wherein R5 is selected from H, OCHgCHg, F, Cl, Br, or CHg.
18. A composition according to any one of the preceding claims wherein R11 is 25 CHZCECH and R8 is (substituted or unsubstituted C1—C6 alkyl)—S(O)n»(substituted or unsubstituted C1—C6 alkyl) wherein said substituents on said substituted alkyls are selected from F, Cl, Br, I.
19. A composition according to any one of the preceding claims wherein R11 is 30 CHZCECH and R8 is (unsubstituted C1—C6 -S(Oh—(substituted C1—C6 alkyl) n said substituents on said substituted alkyls are selected from F, Cl, Br, 1.
20. A composition according to any one of the preceding claims wherein R11 is 1000998969 H and R8 is (unsubstituted C1~C2 alky1)-S(O)n-(substituted C1-C3 alkyl) wherein said substituents on said substituted alkyls are F.
21. A composition according to any one of the preceding claims wherein R11 is substituted or unsubstituted C1—C3 alkleECH.
22. A composition according to any one of the preceding claims wherein R11 is substituted or unsubstituted C1—C2 alkleECH. 10
23. A composition according to any one of the preceding claims wherein R11 is substituted or unsubstituted CHgCECH.
24. A composition according to any one of the preceding claims n R7 is O or S. 15
25. A composition according to any one of claims 1 to 17, or 21 to 23 wherein R8 is selected from substituted or unsubstituted C1-C6 alkyl, tuted or unsubstituted C2—C6 alkenyl, substituted or unsubstituted C3—C10 cycloalkyl, substituted or unsubstituted C6—C20 aryl, substituted or unsubstituted C1—C20 heterocyclyl, 1)OR9, SR9, S(O)nOR9, R9S(O)nR9, or R9S(O)n(NZ)R9.
26. A composition according to any one of claims 1 to 17, or 21 to 23 wherein R8 is CH(CH3)CHzSCI-13, CH(CH3)2, C(C1~l3)2CHgSCHg, SCH3, CHZCFg, CH2C1712C(:O)OCH3, N(H)(CHgCI-IZSCH3), OCHzCHzSCHg, CH(CH28C1‘13)(CH2phenyl), thiazolyl, oxazolyl, isothiazolyl, substituted—furanyl, CH3, C(CH3)3, phenyl, CHzCHgOCH3, 25 pyridyl, CH2CH(CH3)SCH3, OC(CH3)3, C(CH3)2CH28CH3, CH(CH3)CH(CH3)SCH3, CH(CH3)CF3, CHZCHz—thienyl, CH(CH3)SCF3,CH2CH2C1, CH2CH2CH2CF3, CH2CH2$(=O)CH3, CH(CH3)CHZS(=O)CH3, CH2CH28(=O)2CH3, CH(CH3)CH2S(=O)2CH3, NCHZCH3, N(H)(CH2CH2CH3), C(CH3)=C(H)(CH3), N(H)(CH2CH=CH2), CH2CH(CF3)SCH3, )CH2$CH3, thietanyl, CF3)2, CH2CH2CF(OCF3)CF3, 30 CH2CH2CF(CF3)CF3, CF(CH3)2, CH(CH3)pheny1-Cl, )pheny1—F, CH(CH3)pheny1— OCF3, CH2N(CH3)(S(=O)2N(CH3)2, CH(CH3)OCH2CH2$CH3, CH(CH3)OCH2CHZOCH3, OCH3, CH(CH3)SCH3, CHZSCHg, N(H)CH3, CH2Br, SCHZCHZCFg, CHZCHgsH, CH2CHZSC(pheny1)3, CH2N(CH3)S(O)2CH3, CH(SCH3)(C(=O)CH28CH3), 1000998969 CH2$(O)CH3, CH2CH(cyc10propyl)SCH3, or CH(CH3)CH28CD3.
27. A composition according to any one of claims 1 to 17, or 21 to 23 wherein R8 is selected from ituted or tituted C1-C6 alky1)-S(Oh—(substituted or unsubstituted C1-C6 alkyl) wherein said substituents on said substituted alkyls are selected from F, Cl, Br, 1, CN, N02, N(R9)S(O)nR9, 0R9, S(O)nOR9, R9S(O)nR9, S(O)nR9, C6-C20 aryl, or C1—C20 heterocyclyl, (each of which that can be substituted, may optionally be tuted with R9).
28. A composition according to any one of the preceding claims wherein X is CR,” where 10 Rm is H or halo.
29. A composition according to any one of the ing claims wherein X is CR.” where Rn] is 11 or F. 15
30. A composition according to any one of the preceding claims wherein X1 or X2 or both are 0.
31. A composition according to claim 1 comprising a molecule according to: “Formula One’3 A )L \1|\1 R8 wherein (a) Ais R2 If,“ attachment bond A / RS R1 N R3 (b) R1 is H; 1000998969 (c) R2 is H; (d) R3 is H; (e) R4 is F, Cl, Br, I, or unsubstituted C1—C6 alkyl; (0 R5 is H; 5 (g) R6 is R11, and R11 is H; (h) R7 is O or S; (i) R8 is substituted or unsubstituted C1—C5 alkyl, 0R9, R9S())nR9, wherein each said R8, which is substituted, has one or more substituents selected from F, Cl, Br, I, N(R9)S(O)HR9, oxo, or 9; 10 0) R9 is, each independently, H or substituted or unsubstituted C1—C6 alkyl wherein each said R9, which is substituted, has one or more substituents selected from F, Cl, Br, I, C3-C10 cycloalkyl, or C6—C20 aryl; (k) n is 0, 1 or 2; and (1) X is CRM is H, F, Cl, Br or 1.
32. A composition according to claim 1 wherein said molecule has one of the following> structures 8969 113C CI-I3 CHp >401} 8969 8969 8969 8969 8969 618 N 8969 1000998969
33. A composition according to any one of the preceding claims further comprising: (a) one or more compounds having idal, algicidal, avicidal, bactericidal, fungicidal, herbicidal, insecticidal, molluscicidal, nematicidal, rodenticidal, or Virucidal properties; or (b) one or more compounds that are antifeedants, bird ents, chemosterilants, herbicide safeners, insect attractants, insect repellents, mammal ents, mating disrupters, plant activators, plant growth regulators, or ists; or 10 (0) both (a) and (b).
34. A composition according to any one of the preceding claims wherein further sing one or more compounds selected from: (3—ethoxypropyl)mercury bromide, 1,2— dichloropropane, 1,3-dichloropropene, l-methylcyclopropene, l—naphthol, 2— 15 (octylthio)ethanol, 2,3,5-tri—iodobenzoic acid, 2,3,6-TBA, 2,3,6—TBA-dimethylammonium, 2,3,6—TBA—lithium, 2,3,6-TBA-potassium, TBA-sodiurn, 2,4,5-T, 2,4,5—T—2- butoxypropyl, 2,4,5-T-2—ethylhexyl, 2,4,5-Tbutoxypropyl, 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-T— methyl, 2,4,5-T—pentyl, 2,4,5-T-sodium, 2,4,5-T-triethylammonium, 2,4,5-T-trolamine, 2,4— 8969 D, 2,4-D—2—butoxypropyl, 2,4—Dethylhexyl, 2,4-D—3—butoxypropyl, 2,4-D—ammonium, 2,4— DB, 2,4—DB—butyl, 2,4-DB-dimethylammonium, 2,4-DB—isoetyl, 2,4—DB-potassium, 2,4-DB- sodium, 2,4-D-butotyl, 2,4—D-butyl, 2,4—D-diethylammonium, 2,4—D-dimethylammonium, 2,4~D—diolamine, 2,4-D-dodeeylammonium, 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, lithium, 2,4-D—meptyl, 2,4—D—methyl, 2,4—D—octyl, 2,4—D—perityl, 2,4-D—potassium, propyl, 2,4-D-sodium, tefuryl, 2,4-D—tetradecylammonium, 2,4—D-triethylammonium, 2,4—D-tris(2—hydroxypropyl)ammonium, 2,4—D—trolamine, 2iP, 2— methoxyethylmercury Chloride, 2-phenylphenol, 3,4—DA, 3,4—DB, 3,4—DP, 4—aminopyridine, l0 4—CPA, 4—CPA—potassium, 4~CPA-sodium, 4—CPB, 4-CPP, 4—hydroxyphenethyl alcohol, 8— hydroxyquinoline sulfate, 8—phenylmercurioxyquinoline, abamectin, ic acid, ACC, acephate, acequinocyl, acetamiprid, acethion, acetochlor, aceiophos, acetoprole, acibenzolar, acibenzolar—S—methyl, acifluorfen, acifluorfen—methyl, acilluorfen—sodium, aclonifen, acrep, acrinaihrin, acrolein, acrylonitrile, acypetacs, acypetacs—copper, acypetacs—zinc, or, 15 alanycarb, albendazole, aldicarb, aldimorph, aldoxycarb, aldrin, allethrin, alliein, chlor, allosamidin, alloxydim, alloxydim—sodium, allyl alcohol, allyxycarb, alorac, alpha— cypermcthrin, alpha—endosulfan, ametoctradin, ametridione, ametryn, amibuzin, amicarbazone, thiazol, amidithion, amidoflumet, amidosulfuron, aminocarb, aminocyclopyrachlor, aminocyclopyrachlor—mcthy1, aminocyclopyrachlor—potassium, 20 yralid, aminopyralid—potassium, aminopyralid-tris(2—hydroxypropyl)ammonium, amiprol’os—methyl, amiprophos, amisulbrom, amiton, amiton oxalate, amitraz, amitrole, ammonium sulfamate, ammonium a~naphthaleneacetate, amobam, ylfos, anabasine, dol, anilazine, ‘os, anisuron, anthraquinone, antu, apholate, aramite, arsenous oxide, asomate, aspirin, asulam, asulam—potassium, asulam—sodium, athidathion, atraton, 25 atrazine, aureofungin, aviglycine, aviglycine hydrochloride, azaconazole, azadirachtin, azafenidin, azamethiphos, azimsulfuron, azinphos—ethyl, os~methyl, aziprotryne, azithiram, azobenzene, azocyclotin, azothoate, azoxystrobin, bachmedesh, barban, barium hexafluorosilicate, barium polysulfide, barthrin, BCPC, beflubutamid, benalaxyl, benalaxyl— M, benazolin, lin-dimethylammonium, benazolin—ethyl, benazolin-potassium, 30 bencarbazone, benclothiaz, bendiocarb, benfluralin, benfuracarb, benfuresate, benodanil, benomyl, benoxacor, benoxafos, benquinox, bensulfuron, furon—methyl, bensulide, bensultap, bentaluron, one, bentazone-sodium, benthiavalicarb, benthiavalicarb— isopropyl, benthiazole, bentranil, benzadox, benzadox-ammonium, konium chloride, 1000998969 benzamacril, benzamacril-isobutyl, benzamorf, benzfendizone, benzipram, benzobicyclon, benzofenap, benzofluor, benzohydroxamic acid, benzoximate, benzoylprop, benzoylprop— ethyl, benzthiazuron, benzyl te, benzyladenine, ine, berberine chloride, beta— cyfluthrin, beta-cypermethrin, bethoxazin, bicyclopyrone, zate, bifenox, bifenthrin, bifujunzhi, bilanafos, bilanafos-sodium, binapacryl, bingqingxiao, ethrin, bioethanomethrin, biopermethrin, bioresmethrin, biphenyl, r, bismerthiazol, bispyribac, bispyribac—sodium, bistrifluron, bitertanol, bithionol, bixafen, blasticidin-S, borax, Bordeaux mixture, boric acid, boscalid, brassinolide, brassinolide-ethyl, brevicomin, brodifacoum, valerate, brofluthrinate, bromacil, bromacil—lithium, bromacil—sodium, bromadiolone, 10 halin, bromethrin, bromfenvinfos, cetamide, bromobonil, bromobutide, bromocyclen, bromo-DDT, bromofenoxim, bromophos, bromophos-ethyl, ropylate, bromothalonil, bromoxynil, bromoxynil butyrate, bromoxynil heptanoate, bromoxynil octanoate, bromoxynil—potassium, brompyrazon, bromuconazole, ol, bucarpolate, bufencarb, buminal’os, bupirimate, buprofezin, dy mixture, busulfan, butacarb, 15 butachlor, butafenacil, butamifos, butathiofos, butenachlor, butethrin, buthidazole, buthiobate, bulhiuron, butocarboxim, te, butopyronoxyl, butoxycarboxim, butralin, butroxydim, buturon, butylamine, butylatc, cacodylic acid, cadusafos, cafcnstrole, calcium arsenate, calcium chlorate, calcium ide, calcium polysulfide, calvinphos, dichlor, camphechlor, r, bl, captan, orph, carbanolate, yl, 20 carbasulam, carbcndazim, carbendazim benzenesull’onate, carbendazim sulfite, carbetamide, carbol’uran, carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan, carboxazole, carboxide, carboxin, carfentrazone, carfentrazone—ethyl, carpropamid, cartap, cartap hydrochloride, carvacrol, e, CDEA, cellocidin, CEPC, ceralure, Cheshunt mixture, chinomethionat, chitosan, chlobenthiazone, chlomethoxyfen, chloralose, 25 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 30 hydrochloride, chlorempenthrin, chlorethoxyfos, chloreturon, chlorfenac, chlorfenac- ammonium, chlorfenac—sodium, chlorfenapyr, chlorfenazole, chlorfenethol, chlorfenprop, chlorfenson, chlorfensulphide, envinphos, chlorfluazuron, chlorflurazole, chlorfluren, chlorfluren—methyl, chlorflurenol, chlorflurenol-methyl, chloridazon, chlorimuron, 8969 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, yrifos—methyl, chlorquinox, chlorsulfuron, chlorthal, chlorthal-dimethyl, chlorthal-monornethyl, chlorthiamid, chlorthiophos, chlozolinate, choline chloride, chromafenozide, cinerin I, cinerin H, cinerins, cinidon—ethyl, cinmethylin, cinosulfuron, ciobutide, Cisanilide, cismethrin, clethodim, climbazole, cliodinate, clodinafop, 10 clodinafop—propargyl, cloethocarb, clofencet, clofencet—potassium, clofentezine, clofibric acid, clofop, clofop-isobutyl, clomazone, clomeprop, cloprop, cloproxydim, clopyralid, clopyralid—methyl, clopyralid—olamine, clopyralid~potassium, clopyralid—trisQ— hydroxypropyl)ammonium, cloquintocet, cloquintocet—mexyl, cloransulam, cloransulam— methyl, closantel, clothianidin, mazole, cloxyfonac, cloxyfonac—sodium, CMA, 15 ure, colophonate, copper acetate, copper acetoarsenite, copper arsenate, copper carbonate, basic, copper hydroxide, copper naphthenate, copper oleate, copper oride, copper silicate, copper e, copper zinc chromate, coumachlor, uryl, coumaphos, coumatetralyl, coumithoate, coumoxystrobin, CPMC, CPMF, CPPC, credazine, cresol, crimidine, crotamiton, crotoxyphos, cruibmale, tc, cue—lure, cufraneb, cumyluron, 20 cuprobam, cuprous oxide, curcumenol, cyanamide, cyanatryn, cyanazine, cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyazofamid, yne, cyclafuramid, ilide, hrin, cycloate, cycloheximide, cycloprate, cycloprothrin, cyclosulfamuron, cycloxydim, cycluron, cyenopyrafen, cy’llufenamid, cyflumetofen, cyfluthrin, cyhalofop, cyhalol’op-butyl, cyhalothrin, cyhexatin, cymiazole, eymiazole hydrochloride, nil, cyometrinil, 25 azole, cypermethrin, cyperquat, cyperquat chloride, cyphenothrin, cyprazine, cyprazole, cyproconazole, cyprodinil, cyprofuram, id, cyprosulfamide, cyromazine, cythioate, on, dalapon, dalapon-calcium, n~magnesiurn, dalapon-sodium, darninozide, dayoutong, dazomet, dazomet—sodiurn, DBCP, d—camphor, DCIP, DCPTA, DDT, debacarb, ntin, decarbofuran, dehydroacetic acid, delachlor, deltamethrin, 30 ion, demephion-O, demephion-S, demeton, demeton—methyl, demeton-O, demeton—O— methyl, n-S, demeton—S-methyl, demeton—S—methylsulphon, desmedipharn, desmetryn, d—fanshiluquebingjuzhi, diafenthiuron, dialifos, di-allate, diamidafos, diatomaceous earth, diazinon, dibutyl phthalate, dibutyl succinate, a, dicamba- 1000998969 diglycolamine, dicamba—dimethylammonium, dicamba-diolamine, dicamba- isopropylammonium, dicamba—methyl, a-olamine, dicamba-potassium, dicamba— sodium, dicamba-trolamine, dicapthon, dichlobenil, dichlofenthion, dichlofluanid, dichlone, dichloralurea, dichlorbenzuron, dichlorflurenol, dichlorflurenol-methyl, rmate, rmid, dichlorophen, dichlorprop, rprop—2—ethylhexy1, dichlorprop—butotyl, diohlorprop-dimethylammonium, dichlorprop-ethylammonium, dichlorprop—isoctyl, dichlorprop-methyl, dichlorprop—P, dichlorprop—Pethy1hexy1, rprop—P— dimethylammonium, dichlorprop—potassium, dichlorprop—sodium, dichlorvos, dichlozoline, diclobutrazol, dielocymet, op, diclofop—methyl, ezine, diclomezine—sodium, 10 dicloran, diclosulam, dicofol, dicoumarol, dicresyl, dicrotophos, anil, dicyclonon, dieldrin, dienochlor, diethamquat, diethamquat dichloride, diethatyl, diethatyl—ethyl, diethofencarb, dietholate, l pyrocarbonate, diethyltoluamide, difenacoum, difenoconazole, difenopenten, difenopenten—ethyl, difenoxuron, difenzoquat, difenzoquat metilsulfate, difelhialone, diflovidazin, diflubenzuron, diflufeniean, diflufenzopyr, 15 diflufenzopyr—sodium, torim, dikegulac, lac~sodium, dilor, dimatif, dimefluthrin, dimefox, dimefuron, perate, dimetachlone, dimetan, dimethacarb, dimethachlor, dimethametryn, dimethenamid, dimethenamid—P, dimethipin, dimethirimol, dimethoate, dimethomorph, dimethrin, dimethyl carbate, dimethyl phthalate, dimethylvinphos, dimetilan, no, zon, strobin, dinex, dinex—diclexine, 20 dingjunezuo, diniconazole, diniconazole—M, dinitramine, dinobuton, dinocap, dinocap—4, dinocap—o, dinocton, dinofenate, dinopenton, dinoprop, dinosam, dinoseb, dinoseb acetate, dinoseb—ammonium, dinoseb—diolamine, dinoseb-sodium, dinoseb—trolamine, dinosulfon, dinotefin‘an, dinoterb, dinoterb acetate, dinoterbon, diofenolan, dioxabenzofos, dioxacarb, dioxathion, diphaeinone, diphacinone—sodium, diphenamid, diphenyl sulfone, diphenylamine, 25 dipropalin, dipropetryn, dipyrithione, diquat, diquat dibromide, disparlure, disul, disulfiram, disulfoton, sodium, ditalimfos, dithianon, rofos, 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, 30 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, epoxioonazole, eprinomectin, epronaz, EPTC, erbon, ergocalciferol, 1000998969 erlujixiancaoan, esde’palle’thrine, esfenvalerate, esprocarb, etacelasil, etaconazole, etaphos, etem, ethaboxam, ethachlor, ethalfluralin, ethametsulfuron, ethametsulfuron-methyl, ethaprochlor, ethephon, ethidimuron, encarb, ethiolate, ethion, ethiozin, ethiprole, ethirimol, ethoate-rnethyl, mesate, ethohexadiol, ethoprophos, ethoxyfen, ethoxyfen~ ethyl, ethoxyquin, ethoxysulfuron, ethychlozate, ethyl formate, ethyl d-naphthaleneacetate, ethyl—DDD, ethylene, ethylene dibromide, ethylene dichloride, ethylene oxide, ethylicin, ethylmercury 2,3-dihydroxypropyl mercaptide, ethylmercury acetate, ethylmercury bromide, ethylrnercury chloride, nercury phosphate, etinofen, etnipromid, etobenzanid, etofenprox, etoxazole, etridiazole, etrimfos, eugenol, EXD, famoxadone, famphur, 10 fenamidone, fenaminosulf, fenamiphos, fenapanil, fenarimol, fenasulam, fenazaflor, fenazaquin, ieiibuconazole, fenbutatin oxide, fenchlorazole, fenchlorazole—ethyl, fenchlmphos, fenclorim, fenethacarb, fenl‘luthrin, fenfuram, fenhexamid, opan, Fenitrothion, fenj untong, i‘enobucarb, lenoprop, fenoprop—3—butoxypropyl, fenoprop— butometyl, fenoprop—butotyl, fenoprop—butyl, fenoprop—isoctyl, fenoprop—methyl, fenoprop— 15 potassium, fenothiocarb, fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop—ethyl, prop—P, prop—P—ethyl, sulfone, fenoxycarb, fenpiclonil, fenpirithrin, fenpropathrin, fcnpropidin, fenpropimorph, fenpyrazamine, fenpyroximate, fenridazon, fenridazon— potassium, azon—propyl, fenson, fensulfothion, lienteracol, fenthiaprop, fenthiaprop— ethyl, fenthion, Fenthion—ethyl, , fentin acetate, fentin chloride, fentin hydroxide, 20 fentrazamide, fentril’anil, n, fenuron TCA, fenvalerate, ferbam, ferimzone, s sulfate, fipronil, flamprop, Ilamprop—isopropyl, flamprop—M, flamprop—methyl, Ilamprop—M— isopropyl, flamprop—M-methyl, llazasulfuron, flocoumafen, flometoquin, flonicamid, llorasulam, ypyrim, lluazil’op, fluazil’op—butyl, fluazifop—methyl, fluazifop—P, 'l'luazifop— P—butyl, fluazinarn, ate, fluazuron, flubendiamide, imine, flucarbazone, 25 flucarbazone—sodium, flucetosulfuron, fluchloralin, flucofuron, flucycloxuron, flucythrinate, fludioxonil, fluenetil, lfone, flufenacet, flufenerim, flufenican, flufenoxuron, flufenprox, flufenpyr, flufenpyr-ethyl, flufiprole, rin, flumetoyer, alin, flumetsulam, flumezin, flumiclorac, orac-pentyl, flumioxazin, flumipropyn, flumorph, fluometuron, olide, fluopyram, fluorbenside, fluoridarnid, fluoroacetamide, 30 fluorodifen, fluoroglycofen, fluoroglycofen-ethyl, fluoroirnide, fluoromidine, fluoronitrofen, fluothiuron, fluotrimazole, fluoxastrobin, arn, flupropacil, flupropadine, flupropanate, flupropanate-sodium, flupyradifurone, flupyrsulfuron, flupyrsulfuron-methyl, flupyrsulfuron- methyl-sodium, fluquinconazole, flurazole, flurenol, flurenol-butyl, flurenol—methyl, 1000998969 fluridone, flurochloridone, fluroxypyr, fluroxypyr—butometyl, pyr-meptyl, flurprimidol, flursulamid, flurtamone, flusilazole, flusulfamide, fluthiacet, fluthiacet—rnethyl, flutianil, flutolanil, flutriafol, fluvalinate, fluxapyroxad, fluxofenim, folpet, fomesafen, fomesafen-sodium, fonofos, ulfuron, forchlorfenuron, formaldehyde, formetanate, anate hydrochloride, formothion, formparanate, formparanate hydrochloride, fosamine, ne-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, yclox, furophanate, furyloxyfen, 10 gamma—cyhalothrin, gamma—HCH, genit, gibberellie acid, gibberellins, gliftor, glufosinate, g1ufosinate-amm0nium, inate—P, glufosinate—P~ammonium, glufosinate—P—sodium, n, glyoxime, glyphosate, sate—diammonium, glyphosatc—dimethylammonium, glyphosate—isopropylammonium, g1yphosate—monoammonium, glyphosate-potassium, glyphosate—sesquisodium, glyphosate—trimesium, glyphosine, gossyplure, grandlure, 15 griseofulvin, guazatine, guazatine acetates, inate, hall‘enprox, halofenozide, halosafen, halosult’uron, halosulfuron-methyl, haloxydine, haloxyfop, haloxyfop—etotyl, haloxyfop— methyl, haloxyfop-P, haloxyfop—P—etotyl, haloxy’l’op—P—methyl, haloxyfop—sodium, IlCH, hemel, hempa, HEOD, heptachlor, heptenophos, heptopargil, heterophos, hexachloroacetone, hexaehlorobenzene, lorobutadiene, hexaehlorophene, hexaconazole, muron, 2O hexafl urate, hexalure, hexamide, hexazinone, hiofos, hexythiazox, HHDN, holosull’, huaneaiwo, huangcaoling, huanjunzuo, hydramethylnon, hydrargaphen, hydrated lime, hydrogen cyanide, hydroprene, zol, hyquincarb, 1AA, IBA, in, imazalil, imazalil nitrate, imazalil e, imazamethabenz, imazamethabenz—methyl, imazamox, imazamox— ammonium, imazapic, ic-ammonium, imazapyr, imazapyr—isopropylammonium, 25 imazaquin, imazaquin—ammonium, imazaquin—methyl, imazaquin—sodium, imazethapyr, imazethapyr—ammonium, imazosulfuron, imibenconazole, imicyafos, imidacloprid, imidaclothiz, iminoetadine, iminoctadine triacetate, iminoctadine trialbesilate, imiprothrin, inabenfide, indanofan, indaziflam, indoxacarb, inezin, iodobonil, iodocarb, iodomethane, iodosulfuron, lfuron—methyl, iodosulfuron-methyl-sodium, iofensulfuron, 30 iofensulfuron—sodium, ioxynil, ioxynil ate, ioxynil-lithium, ioxynil~sodium, 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, 1000998969 isopropalin, isoprothiolane, isoproturon, isopyrazam, isopyrimol, isothioate, nil, isouron, isovaledione, isoxaben, isoxachlortole, isoxadifen, isoxadifen-ethyl, isoxaflutole, isoxapyrifop, isoxathion, ivermectin, izopamfos, japonilure, japothrins, jasmolin I, jasmolin ll, ic acid, ngchongzong, jiajizengxiaolin, jiaxiangjunzhi, jiecaowan, jiecaoxi, 5 jodfenphos, juvenile hormone I, juvenile hormone ll, juvenile hormone Ill, kadethrin, karbutilate, zan, karetazan—potassium, kasugamycin, kasugamycin hydrochloride, kejunlin, kelevan, ketospiradox, ketospiradox-potassium, kinetin, kinoprene, kresoxim- methyl, kuicaoxi, lactofen, lambda—cyhalothrin, latilure, lead arsenate, lenacil, lepimectin, leptophos, e, lineatin, linuron, lirimfos, litlure, re, ron, lVdingjunzhi, 10 lVXiancaolin, lythidathion, MAA, malathion, maleic hydrazide, malonoben, maltodextrin, MAMA, mancopper, mancozeb, mandipropamid, maneb, matrine, mazidox, MCPA, MCPA— 2~ethylhexyl, MCPA~butotyl, utyl, MCPA~dimethylammonium, MCPA-diolamine, MCPA—ethyl, MCPA—isobutyl, MCPA—isoctyl, sopropyl, MCPA—methyl, MCPA— olamine, MCPA~potassium, MCPA-sodium, MCPA—thioethyl, MCPA—trolamine, MCPB, 15 MCPB—cthyl, MCPB—methyl, MCPB—Sodium, mebenil, mecarbam, mecarbinzid, mecarphon, mecoprop, op—2—ethylhcxyl, mecoprop—dimethylammonium, mccoprop-diolamine, mecoprop—ethadyl, mecoprop—isoctyl, mecoprop—mcthyl, mecoprop—P, mecoprop-P—Z— ethylhexyl, mecoprop-P—dimethylammonium, mecoprop—P—isobutyl, mecoprop—potassium, mecoprop-P—potassium, mecoprop—sodium, mecoprop-trolamine, medimeform, medinoterb, 20 modinoterb acetate, medlurc, mefenacet, mefcnpyr, melenpyr—diethyl, mefluidide, mefluidide—diolamine, mefluidide—potassium, megatomoic acid, menazon, mepanipyrim, l’luthrin, mephenate, mephosfolan, mepiquat, mepiquat chloride, mepiquat pentaborate, mepronil, meptyldinocap, mercuric chloride, mercuric oxide, mercurous de, merphos, mesoprazine, mesosulfuron, mesosulfuron—methyl, mesotrione, mesulfen, enfos, 25 metaflumizone, metalaxyl, metalaxyl—M, metaldehyde, metam, metam—ammonium, metamifop, metamitron, metam—potassium, metam—sodium, metazachlor, metazosulfuron, metazoxolon, azole, metepa, metflurazon, methabenzthiazuron, methacrifos, methalpropalin, methamidophos, methasulfocarb, methazole, methfuroxam, methidathion, methiobencarb, methiocarb, pyrisulfuron, tepa, methiozolin, methiuron, 30 methocrotophos, methometon, methomyl, methoprene, methoprotryne, methoquin-butyl, methothrin, methoxychlor, methoxyfenozide, methoxyphenone, methyl apholate, methyl e, methyl eugenol, methyl iodide, methyl ocyanate, methylacetophos, methylchloroform, methyldymron, ene chloride, methylmercury benzoate, 8969 methylmercury dicyandiamide, mercury pentachlorophenoxide, methylneodecanarnide, metiram, metobenzuron, metobromuron, metofluthrin, metolachlor, metolcarb, metominostrobin, metosulam, metoxadiazone, metoxuron, metrafenone, metribuzin, metsulfovax, metsulfuron, metsulfuron-methyl, mevinphos, mexacarbate, mieshuan, milbemectin, milbemycin oxime, milneb, x, mirex, MNAF, moguchun, molinate, molosultap, monalide, monisouron, monochloroacetic acid, monocrotophos, monolinuron, monosulfuron, monosulfuron—ester, monuron, monuron TCA, morfamquat, quat dichloride, moroxydine, moroxydine hydrochloride, morphothion, morzid, moxidectin, MSMA, muscalure, utanil, olin, N—(ethylmercury)~p~ 10 toluenesulphonanilide, nabarn, ofos, naled, alene, naphthaleneacetamide, naphthalic anhydride, naphthoxyacetic acids, naproanilide, naproparnide, naptalam, naptalam-sodium, natamycin, neburon, niclosamide, amide—olamine, nicosull’uron, nicotine, nilltlridide, clofen, nitenpyram, nithiazine, nitralin, nitrapyrin, nitrilacarb, nitrol’en, nitrofluorfen, nitrostyrene, nitrothal—isopropyl, norbormide, nortlurazon, 15 nornicotine, noruron, novaluron, noviflumuron, nuarimol, OCH, octachlorodipropyl ether, octhilinone, ofurace, omethoate, orbencarb, orfralure, ortho—dichlorobenzene, orthosulfaniuron, oryctalure, orysastrobin, oryzalin, osthol, ostramone, oxabetrinil, oxadiargyl, zon, yl, oxamate, oxamyl, oxapyrazon, azon—dimolainine, oxapyrazon—sodium, oxasulfuron, oxaziclomefone, oxine—copper, oxolinic acid, 20 oxpoconazole, oxpoconazole fumarate, oxycarboxin, eton—methyl, oxydeprofos, oxydisulfoton, oxylluorfen, oxyinatrine, oxytetracycline, oxytetracycline hydrochloride, paclobutrazol, paichongding, para—dichlorobenzene, ‘luron, paraquat, paraquat dichloride, paraquat dimetilsulf’ate, parathion, parathion—methyl, l, pebulate, pefurazoate, pelargonic acid, penconazole, uron, pendimethalin, penflufen, penfluron, 25 penoxsulam, pentachlorophenol, pentanochlor, penthiopyrad, pentmethrin, pentoxazone, perfluidone, perrnethrin, pethoxamid, phenamaoril, phenazine oxide, phenisopham, phenkapton, phenmedipham, phenmedipham-ethyl, enzuron, phenothrin, phenproxide, phenthoate, phenylmercuriurea, phenylmercury acetate, phenylmercury chloride, phenylmercury derivative of pyrocatechol, phenylmercury nitrate, phenylmercury salicylate, 30 phorate, phosacetim, phosalone, phosdiphen, phosfolan, lan-methyl, phosglycin, phosmet, phosnichlor, phosphamidon, phosphine, phosphocarb, phosphorus, phostin, phoxim, phoxim-methyl, phthalide, picloram, picloram-Z—ethylhexyl, picloram—isoctyl, picloram- methyl, picloram-olarnine, picloram-potassium, piclorarn-triethylamrnonium, picloram—tris(2- 1000998969 hydroxypropyl)ammonium, picolinafen, picoxystrobin, pindone, pindone—sodium, den, piperalin, piperonyl butoxide, piperonyl cyclonene, piperophos, piproctanyl, piproctanyl bromide, al, pirimctaphos, pirimicarb, pirimioxyphos, pirimiphos—ethyl, pirimiphos— methyl, plifenate, rbamate, polyoxins, polyoxorim, polyoxorim—zinc, ialan, ium arsenite, ium azide, potassium cyanate, potassium gibberellate, potassium naphthenate, potassium polysulfide, potassium thiocyanate, potassium a-naphthaleneacetate, T, prallethrin, precocene I, precocene II, ene Ill, pretilachlor, primidophos, primisulfuron, primisulfuron—methyl, probenazole, prochloraz, prochloraz-manganese, proclonol, procyazine, procymidone, prodiamine, profenofos, profluazol, profluralin, 10 profluthrin, profoxydim, proglinazine, proglinazine—ethy], prohexadione, prohexadionc— calcium, prohydrojasmon, promacyl, promecai‘b, prometon, prometryn, promurit, propachlor, propamidinc, propamidinc dihydrochloridc, propamocarb, propamocarb hydrochloride, propanil, propaphos, propaquizafop, propargite, proparthrin, propazinc, amphos, m, propiconazolc, pi‘opineb, propisochlor, propoxur, propoxycarbazone, 15 propoxycarbazone—sodium, propyl isome, propyrisulfuron, amide, proquinazid, prosulcr, prosulfalin, prosulfocai‘b, prosulfilron, prothidathion, prothiocarb, prothiocarb hydrochloride, prothioconazolc, ofos, prothoate, protrifcnbute, proxan, proxan—sodium, prynachlor, pydanon, pymetrozinc, pyracarbolid, pyraclofos, pyraclonil, pyraclostrobin, pyraflufcn, pyraflufen-ethyl, prolc, pyramat, pyramctostrobin, pyraoxystrobin, pyrasulfotolc, pyrazolynate, pyrazophos, pyrazosulfuron, pyrazosulfuron—ethyl, pyrazothion, pyrazoxyfen, pyrcsmethrin, pyrethrin l, pyrethrin ll, pyrethrins, mbcnz—isopropyl, pyribambcnz—propyl, pyribcncarb, pyribenzoxim, pyributicarb, pyriclor, pyridabcn, pyridal‘ol, pyridalyl, pyridaphenthion, pyridate, pyridinitril, nox, pyri’lluquinazon, pyrifialid, pyrimethanil, pyrimidifen, pyriminobac, pyriminobac—methyl, pyrimisulfan, pyrimitate, 25 pyrinuron, pyriofenone, pyriprole, pyripropanol, pyriproxyfen, pyrithiobac, pyrithiobac— sodium, n, pyroquilon, pyroxasulfone, pyroxsulam, pyroxychlor, pyroxyfur, quassia, quinacetol, quinacetol sulfate, quinalphos, phos—methyl, quinazamid, quinclorac, quinconazole, quinmerac, quinoclamine, quinonamid, quinothion, quinoxyfen, quintiofos, zene, quizalofop, quizalofop-ethyl, ofop-P, quizalofop-P-ethyl, quizalofop—P- 30 l, quwenzhi, quyingding, rabenzazole, rafoxanide, rebemide, resmethrin, rhodethanil, rhodojaponin—III, ribavirin, rimsulfuron, rotenone, ryania, saflufenacil, mao, saisentong, salicylanilide, sanguinarine, santonin, schradan, scilliroside, sebuthylazine, sccbumeton, sedaxane, selamectin, semiamitraz, semiamitraz chloride, sesamex, sesamolin, sethoxydim, 1000998969 jiaancaolin, 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 hlorophenoxide, sodium polysulfide, sodium thiocyanate, sodium a—naphthaleneacetate, sophamide, spinetoram, spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine, streptomycin, streptomycin sesquisulfate, strychnine, sulcatol, sulcofuron, sulcofuron—sodium, sulcotrione, sulfallate, trazone, sulfiram, sulfluramid, sulfometuron, sulfometuron—methyl, sulfosulfuron, sulfotep, sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid, yl fluoride, sulglycapin, 10 sulprofos, sultropen, swep, tau—fluvalinate, tavron, tazimcarb, TCA, TCA—ammonium, TCA~ calcium, hadyl, TCA—magnesium, TCA—sodium, TDE, tebuconazole, tebufenozide, tebufenpyrad, tebulloqtliii, tcbupirimfos, tebutam, tebuthiuron, tecloftalam, tecnazene, tecoram, tellubenzuron, tefluthrin, tefuryltrione, tembotrione, temephos, tepa, TEPP, tepraloxydim, terallethrin, terbacil, terbucarb, terbuchlor, terbufos, eton, 15 terbuthylazine, terbutryn, tetcyclacis, tetrachloroethane, tetrachlorvinphos, tetraconazole, tctradil’on, tetrafluron, tetramethrin, tetramethyll’luthrin, ine, tetranactin, tetrasul, thallium sulfate, thenylchlor, theta—cypermethrin, thiabendazole, thiacloprid, thiadifluor, thiamethoxam, thiapronil, thiazafluron, thiazopyr, thicrofos, thicyofen, thidiazimin, zuron, thiencarbazone, thiencarbazone—methyl, thifensulfuron, thifcnsulturon—methyl, 20 thitluzamidc, thiobencarb, thiocarboxime, thiochlorfenphim, thiocyclam, thiocyclam hydrochloride, thiocyclam e, thiodiazole—copper, thiodicarb, thiofanox, thiol‘luoximate, thiohempa, rsal, thiometon, thionazin, thiophanate, thiophanate~methyl, thioquinox, thiosemicarbazide, thiosultap, ltap—diammonium, thiosultap—disodium, thiosultap— monosodium, thiotepa, thiram, thuringiensin, tiadinil, tiaojiean, tiocarbazil, tioclorim, 25 tioxymid, tirpate, tolclofos—methyl, tolfenpyrad, tolylfluanid, tolylmercury acetate, topramezone, tralkoxydim, tralocythrin, tralomethrin, yril, transfluthrin, transpermethrin, tretamine, ntanol, triadimefon, triadimenol, triafamone, tri—allate, triamiphos, triapenthenol, triarathene, mol, triasulfuron, triazamate, triazbutil, flam, triazophos, xide, tribenuron, tribenuron—methyl, tribufos, tributyltin oxide, tricamba, 30 trichlamide, orfon, trichlormetaphos-3, trichloronat, triclopyr, triclopyr—butotyl, triclopyr—ethyl, pyr-triethylammonium, tricyclazole, tridemorph, tridiphane, trietazine, trifenmorph, trifenofos, trifloxystrobin, trifloxysulfuron, trifloxysulfuron-sodium, triflumizole, triflumuron, trifluralin, triflusulfuron, triflusulfuron-methyl, trifop, trifop— 1000998969 methyl, sime, triforine, trihydroxytriazine, trimedlure, trimethacarb, trimeturon, trinexapac, apac-ethyl, triprene, pindan, triptolide, tritac, triticonazole, tritosulfuron, 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, uanglong, a—chlorohydrin, a—ecdysone, a-multistriatin, and thaleneacetic acid. 10
35. A composition according to any one of the ing claims further comprising an agriculturally acceptable carrier.
36. A composition according to any one of the preceding claims wherein said le is in the form of a pesticidally acceptable acid addition salt.
37. A composition according to any one of claims 1 to 35 n said molecule is in the form of a salt derivative.
38. A composition according to any one of claims 1 to 35 wherein said molecule is in the 20 form a hydrate.
39. A composition according to any one of the preceding claims n said molecule is a resolved stereoisomer. 25
40. A composition according to any one of the preceding claims wherein said molecule is in the form a crystal polymorph.
41. A composition according to any one of the preceding claims wherein said molecule has a 2H in place of 1H.
42. A composition according to any one of the preceding claims wherein said molecule has a 14C in place ofa 12C. 1000998969
43. A ition according to any one of the preceding claims further comprising a biopesticide.
44. A composition according to any one of the preceding claims further comprising one or more of the following compounds: (a) 3 -(4—chloro-2,6-dimethylphenyl)hydroxy-8—oxa—l -azaspiro [4,5]dec—3—en one; (b) 3—(4’ —chloro-2,4—dimethyl [l ,1 ’—biphenyl]—3 —yl)~4—hydroxy—8—oxa~ l — 10 azaspiro[4,5]dec—3~en—2—one; (c) 4— [ [(6—chloro—3 —pyridiny1)methyl]methylamino] —2(5H)—furanone; (d) 4-[[(6—chloro—3~pyridiny1)methyl]oyclopropylamino]—2(5H)—furanone; (c) 3—chloro—N2—[( l S)—l —me1hy1—2—(methylsull‘onyl)ethyl]—Nl -[2—methyl—4— [l ,2,2,2—tetrafluoro—l—(trifluoromethyl)ethyl]phenyl]—1,2—benzcnedicarboxamidc; (t) 2—cyano—N—cthyl~4—l’luoro—3 xy—benenesulfonamide; (g) 2—cyano—N—ethyl—3-methoxy—benzenesulfonamide; (h) 2—cyano—3 vdifluoromethoxy—N—ethyl-4—lluoro—bcnzenesulfonamide; 25 (i) o—3 —fluoromethoxy—N—ethyl~benzenesulfonamide; (j) 2—cyano-6—fluoro-3 -methoxy-N,N-dimethyl—benzenesulfonamide; (k) 2—cyano-N-ethylfluoro-3 —methoxy—N—methyl—benzenesulfonamide; (l) 2—cyano-3 oromethoxy—N, N—dimethylbenzenesulfon—amide; 1000998969 (m) 3 oromethyl)—N—[2-(3,3-dirnethylbutyl)phenyl]methyl-1H—pyrazole amide; (n) N—ethyl-2,2~dimethylpropionamide-Z—(Z,6-dichloro-a,cx,a—trifluoro-p—tolyl) hydrazone; (o) N—ethyl—2,2-dichloro—1~methylcyclopropane-carboxamide—Z-(Z,6-dichloro— a,a,a—trifluoro—p—tolyl) hydrazonc nicotine; 10 (p) O~ { (E-)— [2—(4-chloro—phenyl)—2—cyano— l ~(2 —trifluoromethylphenyl)~Vinyl]} S- methyl thiocarbonate; (q) (E)—N l —[(2—chloro-l ,3~thiazol—5—ylmethyl)]—N2—cyano—N l —mcthylacetamidine; 15 (r) l~(6—chloropyridin—3—ylmethyl)—7—methyl~8~nitro— l ,2,3 ,5,6,7—hcxahydro— imidazo[l ,2—afjpyridin—5—ol; (s) 4—[4—Cliloroplienyl—(2—butylidine—hydrazono)methyl)]phenyl mesylate; and 20 (t) N—Ethyl—Z,Z—dichloro— l —methylcyclopropanccarboxamide—2—(2,6—dichloro- alpha, alpha, alpha—tn fluoro-p—tolyl)hydrazone.
45. A ition according to any one ol‘thc preceding claims further comprising a compound having one or more of the following modes of action: acetylcholinesterase 25 inhibitor; sodium channel modulator; chitin biosynthesis inhibitor; GABA and glutamate- gated chloride channel nist; GABA and glutamate—gated chloride channel t; acetylcholine receptor t; acetylcholine receptor antagonist; MET I inhibitor; Mg— stimulated ATPase inhibitor; nicotinic acetylcholine receptor; Midgut membrane disrupter; oxidative phosphorylation disrupter, and ryanodine receptor (RyRs).
46. A composition according to any one of the preceding claims further comprising a seed. 1000998969
47. A composition according to any one of the preceding claims further comprising a seed that has been genetically modified to express one or more specialized traits.
48. A composition according to any one of the preceding claims wherein said composition is encapsulated inside, or placed on the surface of, a capsule.
49. A ition according to any one of the preceding claims wherein said composition is encapsulated inside, or placed on the surface of, a capsule, wherein said capsule has a diameter of about 100—900 nanometers or about 10—900 microns.
50. A process comprising applying a composition ing to any one of claims 1 to 45, to an area to control a pest, in an amount sufficient to control such pest.
51. A process according to claim 50 wherein said pest is selected from beetles, earwigs, 15 cockroaches, flies. aphids, scales, whiteflies, ppers, ants, wasps, termites, moths, butterflies, lice, grasshoppers, locusts, crickets, fleas, thrips, bristletails, mites, ticks, nematodes, and lans.
52. A process according to claim 50 n said pest is from the Phyla Nematoda or 2O Arthropoda.
53. A process ing to claim 50 wherein said pest is from the Subphyla Chelicerata, oda, or Hexapoda. 25
54. A process according to claim 50 wherein said pest is from the Class of Arachnida, Symphyla, or a.
55. A process according to claim 50 wherein said pest is from the Order Anoplura, Order Coleoptera, Order Dermaptera, Order Blattaria, Order Diptera, Order Hemiptera, Order 30 Hymenoptera, Order ra, Order Lepidoptera, Order haga, Order Orthoptera, Order Siphonaptera, Order Thysanoptera, Order Thysanura, Order Acarina, or Order Symphyla. 1000998969
56. A process according to claim 50 n said pest is MYZUPE or BEMITA.
57. A process according to any one of claims 50 to 56 n said amount is from about 0.01 grams per hectare to about 5000 grams per hectare.
58. A process according to any one of claims 50 to 57 wherein said amount is from about 0.1 grams per e to about 500 grams per hectare.
59. A process according to any one of claims 50 to 58 wherein said amount is from about 10 1 gram per hectare to about 50 grams per e.
60. A s according to any one of claims 50 to 59 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 15 beets, or beans, are growing, or the seeds thereof are going to be planted.
61. A process according to any one ofclaims 50 to 56 further comprising applying said composition to a genetically modified plant that has been genetically modified to express one or more specialized traits.
62. A process according to any one of claims 50 to 61 where said composition further se ammonium sulfate.
63. A process comprising: orally administering; or topically applying; a composition 25 according to any one of claims 1 to 49, to a non—human animal, to control endoparasites, rasites, or both.
64. A process comprising applying a composition according to any one of claims 1 to 49 to a plant to enhance the plant’s health, yield, vigor, quality, or tolerance, at a time when pest 30 activity is low.
65. A compound selected from the group consisting of: 8969 8969 8969 8969 8969 8969 8969 8969
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US201161551585P 2011-10-26 2011-10-26
US61/551,585 2011-10-26
PCT/US2012/061508 WO2013062981A1 (en) 2011-10-26 2012-10-24 Pesticidal compositions and processes related thereto

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NZ623298B2 true NZ623298B2 (en) 2016-01-06

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