WO2009025983A2 - Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives - Google Patents

Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives Download PDF

Info

Publication number
WO2009025983A2
WO2009025983A2 PCT/US2008/072074 US2008072074W WO2009025983A2 WO 2009025983 A2 WO2009025983 A2 WO 2009025983A2 US 2008072074 W US2008072074 W US 2008072074W WO 2009025983 A2 WO2009025983 A2 WO 2009025983A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
optionally substituted
halogen
nhch
ring
Prior art date
Application number
PCT/US2008/072074
Other languages
French (fr)
Other versions
WO2009025983A3 (en
WO2009025983A4 (en
Inventor
Gary David Annis
Brenton Todd Smith
Original Assignee
E. I. Du Pont De Nemours And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to KR1020157017534A priority Critical patent/KR20150082693A/en
Priority to MX2013011829A priority patent/MX337588B/en
Priority to RU2010109881/04A priority patent/RU2536039C2/en
Priority to EP08797091.9A priority patent/EP2176244B1/en
Priority to JP2010521081A priority patent/JP5965102B2/en
Priority to ES08797091.9T priority patent/ES2587386T3/en
Priority to MX2010001773A priority patent/MX2010001773A/en
Application filed by E. I. Du Pont De Nemours And Company filed Critical E. I. Du Pont De Nemours And Company
Priority to CA2693067A priority patent/CA2693067C/en
Priority to AU2008289321A priority patent/AU2008289321B2/en
Priority to BRPI0814153A priority patent/BRPI0814153B8/en
Priority to US12/679,382 priority patent/US8217180B2/en
Priority to CN200880103362A priority patent/CN101855215A/en
Publication of WO2009025983A2 publication Critical patent/WO2009025983A2/en
Publication of WO2009025983A3 publication Critical patent/WO2009025983A3/en
Publication of WO2009025983A4 publication Critical patent/WO2009025983A4/en
Priority to IL203174A priority patent/IL203174A/en
Priority to ZA2010/00214A priority patent/ZA201000214B/en
Priority to HK10109984.7A priority patent/HK1143373A1/en
Priority to US13/544,113 priority patent/US8513431B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/835—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups having unsaturation outside an aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/38—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/007—Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention pertains to a method for the preparation of 5-haloalkyl-4,5- dihydroisoxazole derivatives.
  • the present invention also relates to novel enones useful as starting materials for the aforedescribed method.
  • the present invention relates to a method for preparing a compound of Formula 1
  • R 1 is CHX 2 , CX 3 , CX 2 CHX 2 or CX 2 CX 3 ; each X is independently Cl or F; Z is optionally substituted phenyl;
  • Q a is phenyl substituted with one Q 1 and optionally substituted with one to four substituents independently selected from R 3 ;
  • Q 1 is a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfmyl, C 1 -C 6 haloalkylsulfmyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfony
  • each R 7 is independently a phenyl ring or a pyridinyl ring, each ring optionally substituted with one or more substituents independently selected from R 8 ; each R 8 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy,
  • each Q 2 is independently a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfmyl, C 1 -C 6 haloalkylsulfmyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, C 1 -C 6 alkylamino, C
  • each R 10 is independently H; or C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl; each R 11 is independently H; or C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl, C 4 -C 7 cycloalkylalkyl, C 2 -C 7 alkylcarbonyl, C 2 -C alkoxycarbonyl, C 1 -C 6 alkylsulfonyl or C 1 -C 6 haloalkylsulf
  • R 1 , Q and Z are as previously defined for Formula 1, with hydroxylamine in the presence of a base.
  • the present invention also relates to novel compounds of Formula 2, useful as starting materials for the aforedescribed method.
  • compositions, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.
  • Ratios are generally recited herein as single numbers, which are relative to the number
  • a ratio of 4 means 4 : 1.
  • equivalent ratio refers to the number of equivalents of one component (e.g., of a base) relative to another component added to a reaction mixture, recognizing that some compounds may provide two or more equivalents per mole.
  • alkyl used either alone or in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, /-propyl, or the different butyl, pentyl or hexyl isomers.
  • Alkenyl includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers.
  • Alkenyl also includes polyenes such as 1 ,2-propadienyl and 2,4-hexadienyl.
  • Alkynyl includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers.
  • Alkynyl can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
  • Alkoxy includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers.
  • Alkylthio includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers.
  • Alkylsulfmyl includes both enantiomers of an alkylsulf ⁇ nyl group.
  • alkylsulfonyl examples include CH 3 SO 2 -, CH 3 CH 2 SO 2 -, CH 3 CH 2 CH 2 SO 2 -, (CH 3 ) 2 CHSO 2 -, and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers.
  • Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • alkylcycloalkyl denotes alkyl substitution on a cycloalkyl moiety and includes, for example, ethylcyclopropyl, /-propylcyclobutyl, 3-methylcyclopentyl and 4-methylcyclohexyl.
  • cycloalkylalkyl denotes cycloalkyl substitution on an alkyl moiety. Examples of “cycloalkylalkyl” include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups.
  • halogen either alone or in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, or when used in descriptions such as “alkyl substituted with halogen” said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” or “alkyl substituted with halogen” include F 3 C-, ClCH 2 -, CF 3 CH 2 - and CF 3 CCl 2 -.
  • haloalkoxy and haloalkylthio are defined analogously to the term “haloalkyl".
  • haloalkoxy include CF 3 O-, CCl 3 CH 2 O-, HCF 2 CH 2 CH 2 O- and CF 3 CH 2 O-.
  • haloalkylthio include CCl 3 S-, CF 3 S-, CCl 3 CH 2 S- and ClCH 2 CH 2 CH 2 S-.
  • haloalkylsulfmyl include CF 3 S(O)-, CCl 3 S(O)-, CF 3 CH 2 S(O)- and CF 3 CF 2 S(O)-.
  • haloalkylsulfonyl include CF 3 SO 2 -, CCl 3 SO 2 -, CF 3 CH 2 SO 2 - and CF 3 CF 2 SO 2 -.
  • Alkylcarbonyl denotes a straight-chain or branched alkyl moieties bonded to a
  • alkylcarbonyl examples include CH 3 C(O)-, CH 3 CH 2 CH 2 C(O)- and (CH 3 ) 2 CHC(O)-.
  • CpC j The total number of carbon atoms in a substituent group is indicated by the "CpC j " prefix where i and j are numbers from 1 to 7.
  • C 1 -C 4 alkylsulfonyl designates methylsulfonyl through butylsulfonyl.
  • said substituents are independently selected from the group of defined substituents, e.g., (R v ) r in U-I of Exhibit 1 wherein v is 0, 1, 2, 3, 4 or 5.
  • substituents on rings in Exhibits 1 and 2 Q-A and Q-B respectively, each may substitute any available carbon or nitrogen ring member(s) of the rings.
  • a variable group is shown to be optionally attached to a position, for example (R v ) r wherein v may be 0, then hydrogen may be at the position even if not recited in the variable group definition.
  • one or more positions on a group are said to be "not substituted” or "unsubstituted"
  • hydrogen atoms are attached to take up any free valency.
  • heterocyclic ring denotes a ring in which at least one atom forming the ring backbone is not carbon, e.g., nitrogen, oxygen or sulfur. Typically a heterocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs. Unless otherwise indicated, a heterocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring.
  • unsaturated heterocyclic ring relates to both partially and fully unsaturated rings. When a fully unsaturated heterocyclic ring satisfies H ⁇ ckel's rule, then said ring is also called a "heteroaromatic ring” or "aromatic heterocyclic ring”.
  • heterocyclic rings can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
  • an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.
  • An optionally substituted group also may have no substituents. Therefore the phrase “optionally substituted with one or more substituents” means that the number of substituents may vary from zero up to the number of available positions for substitution. Similarly the phrase “optionally substituted with 1-5 substituents” means that the number of substituents may vary from zero up to the number of available position but not exceeding 5.
  • Each X is independently Cl or F.
  • CHX 2 could be CHCl 2 CHCF 2 or CHClF.
  • Q 1 or Q 2 When Q 1 or Q 2 is a nitrogen-containing heterocyclic ring it may be attached to the remainder of Formula 1 though any available carbon or nitrogen ring atom, unless otherwise described.
  • Q 1 and Q 2 can be (among others) phenyl optionally substituted with one or more substituents selected from a group of substituents as defined in the Summary of Invention.
  • An example of phenyl optionally substituted with one to five substituents is the ring illustrated as U-I in Exhibit 1, wherein R v is the optional substituents as defined in the Summary of the Invention for Q 1 and Q 2 and r is an integer from 0 to 5.
  • Q 1 and Q 2 can be a 5- or 6-membered heterocyclic ring, which may be saturated or unsaturated, optionally substituted with one or more substituents selected from a group of substituents as defined in the Summary of Invention.
  • Examples of a 5- or 6-membered aromatic unsaturated heterocyclic ring optionally substituted with one or more substituents include the rings U-2 through U-61 illustrated in Exhibit 1 wherein R v is any substituent as defined in the Summary of the Invention for Q 1 and Q 2 and r is an integer from 0 to 4, limited by the number of available positions on each U group.
  • U-29, U-30, U-36, U-37, U-38, U-39, U-40, U-41, U-42 and U-43 have only one available position, for these U groups r is limited to the integers 0 or 1, and r being 0 means that the U group is unsubstituted and a hydrogen is present at the position indicated by (R v ) r .
  • Q 1 or Q 2 is a 5- or 6-membered saturated or non-aromatic unsaturated heterocyclic ring optionally substituted with one or more substituents selected from the group of substituents as defined in the Summary of Invention for Q 1 and Q 2
  • one or two carbon ring members of the heterocycle can optionally be in the oxidized form of a carbonyl moiety.
  • Examples of a 5- or 6-membered saturated or non-aromatic unsaturated heterocyclic ring include the rings G-I through G-35 as illustrated in Exhibit 2. Note that when the attachment point on the G group is illustrated as floating, the G group can be attached to the remainder of Formula 1 through any available carbon or nitrogen of the G group by replacement of a hydrogen atom. The optional substituents corresponding to R v can be attached to any available carbon or nitrogen by replacing a hydrogen atom.
  • r is typically an integer from 0 to 4, limited by the number of available positions on each G group.
  • Q 1 and Q 2 comprise a ring selected from G-28 through G-35
  • G 2 is selected from O, S or N.
  • G 2 is N, the nitrogen atom can complete its valence by substitution with either H or the substituents corresponding to R v as defined in the Summary of Invention for Q 1 and Q 2 .
  • Embodiment 1 The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein
  • Z is phenyl optionally substituted with one to five substituents independently selected from R 2 (i.e.
  • n O, 1, 2, 3, 4 or 5
  • each R 2 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy,
  • Embodiment IA The method of Embodiment 1 wherein Z is phenyl substituted with one to three substituents independently selected from R 2 , said substituents attached at the 3-, 4- or 5-positions of the phenyl ring.
  • Embodiment IB The method of Embodiment 1 wherein Z is phenyl substituted with one to three substituents independently selected from R 2 , said substituents attached at the 3-, 4- or 5-positions of the phenyl ring.
  • each R 2 is independently F, Cl, Br, C 1 -C 6 alkyl, C 1 -C 6 fiuoroalkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkoxy, C 1 -C 6 alkylthio or C 1 -C 6 fluoroalkylthio.
  • Embodiment 1C The method of Embodiment 1 or IA wherein each R 2 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or -CN.
  • Embodiment ID The method of Embodiment 1C wherein each R 2 is independently halogen or C 1 -C 6 haloalkyl.
  • Embodiment IE The method of Embodiment 1C wherein each R 2 is independently halogen or CF 3 .
  • Embodiment IF The method of Embodiment IE wherein each R 2 is independently F,
  • Embodiment IG The method of Embodiment IA wherein Z is
  • R 2a is halogen, C 1 -C 2 haloalkyl or C 1 -C 2 haloalkoxy;
  • R 2b is H, halogen or cyano; and
  • R 2c is H, halogen or CF 3 .
  • Embodiment IH The method of Embodiment IG wherein R 2a is CF 3 or halogen; and
  • R 2c is H, CF 3 or halogen.
  • Embodiment II The method of Embodiment IH wherein R 2a is CF 3 .
  • Embodiment IJ The method of any one of Embodiments IG through II wherein R 2 ⁇ is
  • Embodiment IK The method of any one of Embodiments IG through IJ wherein R 2c is CF 3 or halogen.
  • Embodiment IL The method of Embodiment IK wherein R 2c is CF 3 , F, Cl or Br.
  • Embodiment IM The method of Embodiment IL wherein R 2c is F, Cl or Br.
  • Embodiment IN The method of Embodiment IL wherein R 2c is CF 3 , Cl or Br.
  • Embodiment 10. The method of Embodiment IN wherein R 2c is Cl or Br.
  • Embodiment IP The method of Embodiment IO wherein R 2 ⁇ is H and R 2c is Cl.
  • Embodiment IQ The method of Embodiment 10 wherein R 2 ⁇ is H and R 2c is Br.
  • Embodiment 2 The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base, or the method of any one of Embodiments 1 through IQ, wherein Qb is 1-naphthalenyl optionally substituted with one to four substituents independently selected from R 3 .
  • Embodiment 2A The method of Embodiment 2 wherein Q is Q a .
  • Embodiment 2B The method of Embodiment 2 wherein Q is Qb.
  • Embodiment 2E The method of Embodiment 2 wherein each R 4 is independently H or
  • Embodiment 2F The method of Embodiment 2 wherein each R 5 is independently H; or C 1 -C 6 alkyl optionally substituted with one or more substituents independently selected from R 6 .
  • Embodiment 2G The method of Embodiment 2 wherein each R 6 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 2 -C 7 alkoxycarbonyl, C 2 -C 7 alkylaminocarbonyl, C 3 -C9 dialkylaminocarbonyl, C 2 -C 7 haloalkylaminocarbonyl, C 3 -C9 halodialkylaminocarbonyl or -CN; or Q 2 .
  • Embodiments 2H The method of Embodiment 2 wherein each Q 2 is a pyridinyl ring optionally substituted with one to four halogen.
  • Embodiments 21 The method of Embodiment 2 wherein each Q a is a phenyl substituted with one Q 1 at the para position and optionally substituted with one to three substituents independently selected from R 3 at the other positions on the phenyl ring.
  • Embodiment 2J The method of Embodiment 21 wherein Q 1 is an optionally substituted
  • Embodiment 2K The method of Embodiment 2 J wherein R 3 is Me or -CN at a meta position of the phenyl ring.
  • Embodiment 2L The method of Embodiment 2B wherein
  • R 3 is C(O)N(R 4 )R 5 or C(O)OR 5 .
  • Embodiment 2M The method of Embodiment 2L wherein
  • R 4 is H, C 2 -C7 alkylcarbonyl or C 2 -C7 alkoxycarbonyl.
  • Embodiment 2N The method of Embodiment 2M wherein R 4 is H.
  • Embodiment 20 The method of any one of Embodiments 2L through 2N wherein
  • R 3 is C(O)N(R 4 )R 5 or C(O)OR 5a ;
  • R 5 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, each substituted with one substituent independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfmyl, C 1 -C 6 alkylsulfonyl, C 2 -C7 alkylaminocarbonyl, C 3 -C9 dialkylaminocarbonyl, C 2 -C7 haloalkylaminocarbonyl and C 3 -C9 halodialkylaminocarbonyl; and
  • R 5a is C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each optionally substituted with one or more substituents independently selected from halogen, C 1 -C 2 alkoxy and phenyl optionally substituted with up to 5 substituents selected from halogen and C 1 -C 3 alkyl.
  • Embodiment 2P The method of any one of Embodiments 2L through 20 wherein
  • R 5a is C 1 -C 6 alkyl optionally substituted with phenyl.
  • Embodiment 2Q The method of any one of Embodiments 2L through 2P wherein
  • R 3 is C(O)N(R 4 )R 5 .
  • Embodiment 2R The method of any one of Embodiments 2L through 2N wherein
  • R 3 is C(O)OR 5 .
  • Embodiment 2S The method of any one of Embodiments 20 through 2P wherein
  • R 3 is C(O)OR 5a .
  • Embodiment 3 The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base, or the method of any one of Embodiments 1 through IQ and 2 through 2S, wherein in Formulae 1 and 2 R 1 is CF 3 .
  • Embodiment 4 The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein the contact occurs in a temperature range of from about 0 to about 150 0 C.
  • Embodiment 4A The method of Embodiment 4 wherein the temperature range is from about 15 to about 40 0 C.
  • Embodiment 5A The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein the hydroxylamine is derived from a hydroxylamine salt.
  • Embodiment 5 A The method of Embodiment 5 wherein the hydroxylamine salt is a hydroxylamine salt of a mineral acid.
  • Embodiment 5B The method of Embodiment 5 A wherein the hydroxylamine salt is a hydroxylamine salt of hydrochloric acid, sulfuric acid, phosphoric acid, or a mixture thereof.
  • Embodiment 6 The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein the molar ratio of hydroxylamine to the compound of Formula 2 is at least about 1.
  • Embodiment 6A The method of Embodiment 6 wherein the molar ratio of hydroxylamine to the compound of Formula 2 is at least about 1.2.
  • Embodiment 6B The method of Embodiment 6 A wherein the molar ratio of hydroxylamine to the compound of Formula 2 is at least about 1.5.
  • Embodiment 6C The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein the molar ratio of hydroxylamine to the compound of Formula 2 is no more than about 3.
  • the method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein the base comprises one or more compounds selected from organic bases, hydroxide bases, alkoxide bases and carbonate bases.
  • Embodiment 7A The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein the base comprises one or more compounds selected from amine bases, alkali metal hydroxide bases, alkali metal alkoxide bases and alkali metal carbonate bases.
  • Embodiment 7AA The method of Embodiment 7 wherein the base comprises an alkali metal carbonate.
  • Embodiment 7B The method of Embodiment 7AA wherein the base comprises sodium carbonate, potassium carbonate or a mixture thereof.
  • Embodiment 7C The method of Embodiment 7B wherein the base comprises sodium carbonate.
  • Embodiment 7D The method of Embodiment 7 wherein the base comprises an alkali metal hydroxide.
  • Embodiment 7E The method of Embodiment 7D wherein the base comprises sodium hydroxide, potassium hydroxide or a mixture thereof.
  • Embodiment 8 The method of the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein the base in excess of the amount needed to neutralize hydroxylamine salts is in an equivalent ratio of at least about 1 to the compound of Formula 2.
  • Embodiment 8 A The method of Embodiment 8 wherein the ratio is no more than about
  • Embodiment 9 The method of the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein the compound of Formula 2, hydroxylamine and base are contacted in the presence of a suitable solvent.
  • the suitable solvent comprises a solvent selected from alcohols, ethers, amides, nitriles, halogenated hydrocarbons and aromatic hydrocarbons (including mixtures thereof).
  • Embodiment 9B The method of Embodiment 9 A wherein the suitable solvent comprises isopropanol.
  • R 1 is CHX 2 , CX 3 , CX 2 CHX 2 or CX 2 CX 3 ; each X is independently Cl or F; Z is optionally substituted phenyl; Q is Q a or Q b ;
  • Q a is phenyl substituted with one Q 1 and optionally substituted with one to four substituents independently selected from R 3 ;
  • Q 1 is a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulf
  • Qb is optionally substituted 1-naphthalenyl; each R 3 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 3 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl,
  • each R 4 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl, C 4 -C 7 cycloalkylalkyl, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxycarbonyl; each R 5 is independently H; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R 6 ; each R 6 is independently halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyny
  • each Q 2 is independently a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylsulf ⁇ nyl, C 1 -C 6 haloalkylsulf ⁇ nyl,
  • each R 9 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl, C 4 -C 7 cycloalkylalkyl, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxycarbonyl; each R 10 is independently H; or C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C
  • Embodiment 1OA A compound of Embodiment 10 wherein Z is phenyl optionally substituted with one to five substituents independently selected from R 2 ; and each R 2 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, -CN or -NO 2 .
  • Embodiment 1OB A compound of Embodiment 1OA wherein Z is phenyl substituted with one to three substituents independently selected from R 2 , said substituents attached at the 3-, 4- or 5-positions of the phenyl ring.
  • Embodiment 1OC A compound of Embodiment 1OA or 1OB wherein each R 2 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or CN.
  • Embodiment 1OD A compound of Embodiment 1OC wherein each R 2 is independently halogen or C 1 -C 6 haloalkyl.
  • Embodiment 1OE A compound of Embodiment 1OD wherein each R 2 is independently halogen or CF 3 .
  • Embodiment 1OF A compound of Embodiment 1OE wherein each R 2 is independently
  • Embodiment 11 A compound of Embodiment 10 wherein Qb is 1-naphthalenyl optionally substituted with one to four substituents independently selected from R 3 .
  • Embodiment 1 IA A compound of Embodiment 11 wherein Q is Q a .
  • Embodiment 1 IB A compound of Embodiment 11 wherein Q is Qj 5 .
  • Embodiment 1 IE A compound of Embodiment 11 wherein each R 4 is independently H or C 1 -C 6 alkyl.
  • Embodiment 1 IF.
  • Embodiment 1 IG A compound of Embodiment 11 wherein each R 6 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 2 -C 7 alkoxycarbonyl,
  • Embodiment 1 IH A compound of Embodiment 11 wherein each Q 2 is a pyridinyl ring optionally substituted with one to four halogen.
  • Embodiment 1 II A compound of Embodiment 11 wherein each Q a is a phenyl substituted with one Q 1 at the para position and optionally substituted with one to three substituents independently selected from R 3 at the other positions on the phenyl ring.
  • Embodiment 1 IJ A compound of Embodiment 111 wherein Q 1 is an optionally substituted 1-triazolyl or 1-pyrazolyl ring.
  • Embodiment 1 IK A compound of Embodiment 1 IJ wherein R 3 is Me or CN at a meta position of the phenyl ring.
  • Embodiment 12 A compound of Embodiment 10 wherein R 1 is CF 3 .
  • Embodiment 13 The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein Z is phenyl optionally substituted with one to five substituents independently selected from R 2 .
  • Embodiment 13 a The method of Embodiment 13 wherein Z is phenyl substituted with one to three substituents independently selected from R 2 , said substituents attached at the 3-, 4- or 5-positions (i.e. meta or para) of the phenyl ring.
  • Embodiment 13b The method of Embodiment 13a wherein each R 2 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 - C 6 alkylthio, C 1 -C 6 halo alky lthio, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, -CN or -NO 2 .
  • Embodiment 13c The method of Embodiment 13b wherein each R 2 is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy or -CN.
  • Embodiment 14 The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein R 1 is CF 3 .
  • Embodiment 15 The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein Q is Q a .
  • Embodiment 15 a The method of Embodiment 15 wherein Q a is phenyl substituted with one Q 1 attached at the 4-position of the phenyl ring, said phenyl ring further optionally substituted with one or two substituents independently selected from R 3
  • Embodiment 15b The method of Embodiment 15a wherein Q 1 is a 5-membered heteroaromatic ring optionally substituted with one or two substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -CN,
  • Embodiment 15d The method of Embodiment 15a wherein each R 3 is independently halogen, C 1 -C 6 alkyl or -CN.
  • Embodiment 15e The method of Embodiment 15d wherein one R 3 is Cl, CH 3 or -CN and is attached at the 3-position of the phenyl ring (i.e. adjacent to Q 1 ).
  • Embodiment 15d The method of
  • Embodiment 15b or 15c wherein R 4 is H.
  • Embodiment 15g The method of Embodiment 15b or 15c wherein R 5 is H; or C 1 -C 3 alkyl, cyclopropyl or cyclopropylmethyl, each optionally substituted with halogen and further optionally substituted with 1 or 2 CH 3 .
  • Embodiment 16 The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein Q is Qj 5 .
  • Embodiment 16a The method of Embodiment 16 wherein Qb is 1-naphthalenyl substituted with one or two substituents independently selected from R 3
  • n 1 or 2
  • Embodiment 16b The method of Embodiment 16 wherein Qb is 1-naphthalenyl substituted with one R 3 attached at the 4-position of the naphthalene ring
  • Embodiment 16e The method of Embodiment 16c or 16d wherein each R 4 is independently H, C 1 -C 6 alkyl, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxy carbonyl.
  • Embodiment 16f The method of Embodiment 16c or 16d wherein each R 4 is independently H, C 1 -C 6 alkyl, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxy carbonyl.
  • each R 5 is independently C 1 -C 6 alkyl substituted with one substituent selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfmyl, C 1 -C 6 alkylsulfonyl, C 2 -C 7 alkylaminocarbonyl, C 3 -C9 dialkylaminocarbonyl, C 2 -C 7 haloalkylaminocarbonyl, C 3 -C9 halodialkylaminocarbonyl and Q 2 .
  • Embodiment 16g The method of Embodiment 16c or 16d wherein each R 5 is independently C 1 -C 2 alkyl substituted with C 2 -C 7 haloalkylaminocarbonyl.
  • Embodiment 16h The method of Embodiment 16f wherein Q 2 is a pyridinyl ring optionally substituted with one to four halogen.
  • Embodiment 16i The method of Embodiment 16c wherein R 11 is H, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 7 alkylcarbonyl, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 alkylsulfonyl or C 1 -C 6 haloalkylsulfonyl.
  • Embodiment 17 A compound of Formula 2 as described in the Summary of the Invention wherein R 1 is CHX 2 , CX 3 , CX 2 CHX 2 or CX 2 CX 3 ; each X is independently Cl or F;
  • Z is optionally substituted phenyl
  • Q a is phenyl substituted with one Q 1 and optionally substituted with one to four substituents independently selected from R 3 ;
  • Qb is optionally substituted 1-naphthalenyl; each R 3 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkynyl, C 3 -C 6 haloalkynyl, C 3 -C 6 cycloalkyl,
  • each R 4 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl, C 4 -C 7 cycloalkylalkyl, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxycarbonyl; each R 5 is independently H; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl or C ⁇ C 7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R 6 .
  • each R 6 is independently halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyny
  • each R 7 is independently a phenyl ring or a pyridinyl ring, each ring optionally substituted with one or more
  • each Q 2 is independently a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring
  • each R 9 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 alkylcycloalkyl, C 4 -C 7 cycloalkylalkyl, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxycarbonyl; each R 10 is independently H; or C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C
  • Embodiment 17a A compound of Embodiment 17 wherein Z is phenyl optionally substituted with one to five substituents independently selected from R 2 .
  • Embodiment 17b A compound of Embodiment 17a wherein Z is phenyl substituted with one to three substituents independently selected from R 2 , said substituents attached at the 3-, 4- or 5-positions (i.e. meta or para) of the phenyl ring.
  • Embodiment 17c Embodiment 17c.
  • each R 2 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 - C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, -CN or -NO 2 .
  • Embodiment 17d A compound of Embodiment 17c wherein each R 2 is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy or -CN.
  • Embodiment 18. A compound of Formula 2 wherein R 1 is CF 3 .
  • Embodiment 19. A compound of Formula 2 wherein Q is Q a .
  • Embodiment 19a A compound of Embodiment 19 wherein Q a is phenyl substituted with one Q 1 attached at the 4-position of the phenyl ring, said phenyl ring further optionally substituted with one or two substituents independently selected from R 3
  • Embodiment 19b A compound of Embodiment 19a wherein Q 1 is a 5-membered heteroaromatic ring optionally substituted with one or two substituents independently selected from halogen, C j -C 6 alkyl, C ⁇ -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, Q-C 6 alkoxy, Q-C 6 haloalkoxy, -CN,
  • Embodiment 19d A compound of Embodiment 19a wherein each R 3 is independently halogen, C 1 -C 6 alkyl or -CN.
  • Embodiment 19e A compound of Embodiment 19d wherein one R 3 is Cl, CH 3 or -CN and is attached at the 3-position of the phenyl ring (i.e. adjacent to Q 1 ).
  • Embodiment 19d A compound of
  • Embodiment 19b or 19c wherein R 4 is H.
  • Embodiment 19g A compound of Embodiment 19b or 19c wherein R 5 is H; or Q-C 3 alkyl, cyclopropyl or cyclopropylmethyl, each optionally substituted with halogen and further optionally substituted with 1 or 2 CH 3 .
  • Embodiment 20 A compound of Formula 2 wherein Q is Q ⁇ .
  • Embodiment 20a A compound of Embodiment 20 wherein Q ⁇ is 1-naphthalenyl substituted with one or two substituents independently selected from R 3
  • n 1 or 2
  • Embodiment 20b A compound of Embodiment 20 wherein Qb is 1-naphthalenyl substituted with one R 3 attached at the 4-position of the naphthalene ring (i.e.
  • Embodiment 2Oe A compound of Embodiment 20c or 16d wherein each R 4 is independently H, C 1 -C 6 alkyl, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxy carbonyl.
  • Embodiment 2Of A compound of Embodiment 20c or 16d wherein each R 4 is independently H, C 1 -C 6 alkyl, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxy carbonyl.
  • each R 5 is independently C 1 -C 6 alkyl substituted with one substituent selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfmyl, C 1 -C 6 alkylsulfonyl, C 2 -C 7 alkylaminocarbonyl, C 3 -C9 dialkylaminocarbonyl, C 2 -C 7 haloalkylaminocarbonyl, C 3 -C9 halodialkylaminocarbonyl and Q 2 .
  • Embodiment 2Og A compound of Embodiment 20c or 2Od wherein each R 5 is independently C 1 -C 2 alkyl substituted with C 2 -C 7 haloalkylaminocarbonyl.
  • Embodiment 2Oh A compound of Embodiment 2Of wherein Q 2 is a pyridinyl ring optionally substituted with one to four halogen.
  • Embodiment 2Oi A compound of Embodiment 20c wherein R 11 is H, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 7 alkylcarbonyl, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 alkylsulfonyl or C 1 -C 6 haloalkylsulfonyl.
  • Embodiments of this invention can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 and Formula 2 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1 or Formula 2.
  • Embodiment A The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein
  • Z is phenyl optionally substituted with one to five substituents independently selected from R 2 ; each R 2 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, -CN or -NO 2 ; and
  • Qb is 1-naphthalenyl optionally substituted with one to four substituents independently selected from R 3 .
  • Embodiment B The method of Embodiment A wherein Q is Q a .
  • Embodiment C The method of Embodiment A wherein Q is Qb.
  • Embodiment D The method of Embodiment B or C wherein in Formulae 1 and 2 R 1 is
  • each R 4 is independently H or C 1 -C 6 alkyl
  • each R 5 is independently H; or C 1 -C 6 alkyl optionally substituted with one or more substituents independently selected from R 6
  • each R 6 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio,
  • Embodiment El The method of Embodiment C or D wherein
  • R 2a is halogen, C 1 -C 2 haloalkyl or C 1 -C 2 haloalkoxy;
  • R 2 b is H, halogen or cyano
  • R 2c is H, halogen or CF 3 ;
  • R 3 is C(O)N(R 4 )R 5 or C(O)OR 5a ;
  • R 4 is H, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxycarbonyl;
  • R 5 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, each substituted with one substituent independently selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfmyl, C 1 -C 6 alkylsulfonyl, C 2 -C 7 alkylaminocarbonyl, C 3 -C9 dialkylaminocarbonyl, C 2 -C7 haloalkylaminocarbonyl and C 3 -C9 halodialkylaminocarbonyl; and R 5a is C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each optionally substituted with one or more substituents independently selected from halogen, C 1 -C 2 alkoxy and phenyl optionally substituted with up to 5 substituents selected from halogen and C 1 -C 3 alky
  • Embodiment E2 The method of Embodiment El wherein R 3 is C(O)N(R 4 )R 5 .
  • Embodiment E3. The method of Embodiment El wherein R 3 is C(O)OR 5a .
  • Embodiment F The method of Embodiment El wherein R 3 is C(O)OR 5a .
  • Embodiment G A compound of Embodiment F wherein Q is Q a .
  • Embodiment H A compound of Embodiment F wherein Q is Qb.
  • Embodiment I A compound of Embodiment G or H wherein R 1 is CF 3 .
  • Embodiment J A compound of Embodiment J.
  • each R 2 is independently halogen or C 1 -C 6 haloalkyl
  • each R 4 is independently H or C 1 -C 6 alkyl
  • each R 5 is independently H; or C 1 -C 6 alkyl optionally substituted with one or more substituents independently selected from R 6
  • each R 6 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio,
  • Embodiment AA The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein
  • Z is phenyl optionally substituted with one to five substituents independently selected from R 2 ; and each R 2 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, -CN or -NO 2 .
  • Embodiment BB The method of Embodiment AA wherein R 1 is CF 3 ;
  • Z is phenyl substituted with one to three substituents independently selected from R 2 , said substituents attached at the 3-, 4- or 5-positions (i.e. meta or para) of the phenyl ring; and each R 2 is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy or -CN.
  • Embodiment CC The method of Embodiment BB wherein Q is Q a .
  • Embodiment DD The method of Embodiment CC wherein
  • Q a is phenyl substituted with one Q 1 attached at the 4-position of the phenyl ring, said phenyl ring further optionally substituted with one or two substituents independently selected from R 3 ;
  • Q 1 is a 5-membered heteroaromatic ring optionally substituted with one or two substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl,
  • each R 3 is independently halogen, C 1 -C 6 alkyl or -CN.
  • Embodiment EE The method of Embodiment DD wherein
  • R 4 is H
  • R 5 is H; or C 1 -C 3 alkyl, cyclopropyl or cyclopropylmethyl, each optionally substituted with halogen and further optionally substituted with 1 or 2 CH 3 .
  • Embodiment FF The method of Embodiment BB wherein
  • Embodiment GG The method of Embodiment FF wherein Qb is 1-naphthalenyl substituted with one or two substituents independently selected from R 3 .
  • R 5 is C 1 -C 6 alkyl substituted with one substituent selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulf ⁇ nyl, C 1 -C 6 alkylsulfonyl, C 2 -C 7 alkylaminocarbonyl, C 3 -C9 dialkylaminocarbonyl, C 2 -C 7 haloalkylaminocarbonyl, C 3 -C9 halodialkylaminocarbonyl and Q 2 ;
  • Q 2 is a pyridinyl ring optionally substituted with one to four halogen; and
  • R 1 * is H, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 7 alkylcarbonyl, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 alkylsulfonyl or C ⁇ C 6
  • R 5 is C 1 -C 2 alkyl substituted with C 2 -C 7 haloalkylaminocarbonyl.
  • Embodiment JJ A compound of Formula 2 wherein
  • Z is phenyl optionally substituted with one to five substituents independently selected from R 2 ; each R 2 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 haloalkylthio, C 1 -C 6 alkylamino, C 2 -C 6 dialkylamino, -CN or -NO 2 ; and
  • R 1 and Q are as defined in the Summary of the Invention.
  • Embodiment KK A compound of Embodiment JJ wherein R 1 is CF 3 ;
  • Z is phenyl substituted with one to three substituents independently selected from R 2 , said substituents attached at the 3-, 4- or 5-positions (i.e. meta or para) of the phenyl ring; and each R 2 is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy or -CN.
  • Embodiment LL A compound of Embodiment KK wherein
  • Q is Q a .
  • Embodiment MM A compound of Embodiment LL wherein Q a is phenyl substituted with one Q 1 attached at the 4-position of the phenyl ring, said phenyl ring further optionally substituted with one or two substituents independently selected from R 3 ;
  • Q 1 is a 5-membered heteroaromatic ring optionally substituted with one or two substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl,
  • R 4 is H; and R 5 is H; or C 1 -C 3 alkyl, cyclopropyl or cyclopropylmethyl, each optionally substituted with halogen and further optionally substituted with 1 or 2 CH 3 .
  • Embodiment OO A compound of Embodiment KK wherein Q is Q b .
  • Embodiment PP A compound of Embodiment OO wherein Qb is 1-naphthalenyl substituted with one or two substituents independently selected from R 3 .
  • Embodiment QQ A compound of Embodiment PP wherein one R 3 is halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, -N(R 4 )R 5 ,
  • each R 4 is independently H, C 1 -C 6 alkyl, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxycarbonyl;
  • R 5 is C 1 -C 6 alkyl substituted with one substituent selected from hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 2 -C 7 alkylaminocarbonyl, C 3 -Cg dialkylaminocarbonyl, C 2 -C 7 haloalkylaminocarbonyl, C 3 -Cg halodialkylaminocarbonyl and Q 2 ;
  • Embodiment RR A compound of Embodiment QQ wherein
  • Qb is 1-naphthalenyl substituted with one R 3 attached at the 4-position of the naphthalene ring;
  • R 4 is H;
  • R 5 is C 1 -C 2 alkyl substituted with C 2 -C7 haloalkylaminocarbonyl.
  • a compound of Formula 2 is contacted with hydroxylamine and a base to form a 5-haloalkyl-4,5- dihydroisoxazole compound of Formula 1.
  • Hydroxylamine can be generated from a mineral acid salt such as hydroxylamine sulfate or hydroxylamine chloride by treatment with a base in a suitable solvent, or can be obtained commercially as 50% aqueous solution.
  • a mineral acid salt of hydroxylamine is typically contacted with a base.
  • the base is contacted in an amount in excess of the amount needed to convert the hydroxylamine mineral acid salt to hydroxylamine. Base is not consumed in the reaction of Scheme 1, and appears to act as a catalyst for the desired cyclization.
  • Formula 2 can be used. To ensure the cost-effective, complete, and expeditious conversion of the enone of Formula 2 to the isoxazole of Formula 1, in a manner suitable for large-scale production, between about one and about two molar equivalents of hydroxylamine relative to the enone of Formula 2 is typically found to be most suitable.
  • Suitable bases can include, but are not limited to, alkali metal alkoxides such as sodium methoxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, and organic bases.
  • Preferred organic bases are amine bases having at least one pair of free electrons available for protonation such as pyridine, triethylamine or NJV- diisopropylethylamine.
  • Weaker bases such as pyridine can be used, but stronger bases which efficiently deprotonate hydroxylamine, such as an alkali metal alkoxide or an alkali metal hydroxide, typically provide better results.
  • water is an especially useful solvent for deprotonating hydroxylamine, as well as forming hydroxylamine from its salts
  • bases compatible with water are of particular note. Examples of strong bases that are soluble and compatible with water are alkali metal hydroxides.
  • Sodium hydroxide is preferred, because it is inexpensive and works well for deprotonating hydroxylamine, thereby forming the sodium salt of hydroxylamine in aqueous solution.
  • Alkali metal alkoxides are frequently used in solution in a lower alkanol, often the alkanol corresponding to the alkoxide.
  • the method of Scheme 1 is conducted in the presence of a suitable solvent.
  • the solvent should be inert to the base and hydroxylamine, and should be capable of dissolving the enone of Formula 2.
  • Suitable organic solvents include alcohols, ethers, nitriles or aromatic hydrocarbons.
  • Water-miscible solvents such as alcohols (e.g., methanol, isopropanol), ethers (e.g., tetrahydrofuran) or nitriles (e.g., acetonitrile) work well with alkali metal hydroxide bases.
  • Solvents which are non-nucleophilic e.g., ethers and nitriles
  • the most preferred solvents are tetrahydrofuran and acetonitrile.
  • Water is particularly useful as a co-solvent, because mineral acid salts of hydroxylamine and alkali metal hydroxide bases such as sodium hydroxide are particularly soluble in water. The rapid generation of hydroxylamine from its mineral acid salt and subsequent deprotonation of hydroxylamine facilitated by water, and the solubility and stability of the deprotonated species in water are especially desirable.
  • the other solvent is typically a water-miscible solvent such as tetrahydrofuran or acetonitrile.
  • water-miscible solvent such as tetrahydrofuran or acetonitrile.
  • Other highly polar, hydroxylic solvents such as lower alkanols (e.g., methanol, ethanol) are also particularly useful as co-solvents, because like water they readily dissolve mineral acid salts of hydroxylamine and alkali metal hydroxides.
  • Lower alkanols can give better results than water as a co-solvent when the other solvent is not water-miscible, e.g., tert-butyl methyl ether.
  • the base added is often an alkali metal alkoxide instead of an alkali metal hydroxide.
  • the hydroxylamine, the base and the enone of Formula 2 can be contacted in a variety of ways in the method of Scheme 1.
  • a mixture formed from hydroxylamine and the base typically in a solvent such as water
  • the enone of Formula 2 typically in a solvent such as tetrahydrofuran or acetonitrile.
  • the hydroxylamine and the base can be concurrently added separately to the enone of Formula 2.
  • the enone of Formula 2 (typically in a solvent such as tetrahydrofuran or acetonitrile) can be added to a mixture formed from the hydroxylamine and the base (typically in a solvent such as water).
  • solvents for example, methanol with tert-butyl methyl ether instead of water with tetrahydrofuran or acetonitrile.
  • the method of Scheme 1 can be conducted at a reaction temperature between about 0 and 150 0 C, or most conveniently between 20 and 40 0 C.
  • the product of Formula 1 is isolated by the usual methods known to those skilled in the art including extraction and crystallization.
  • This method involves portion-wise addition of a dehydrating agent such as thionyl chloride to a mixture of a compound of Formula 3 and a base in an organic solvent such as toluene to provide a compound of Formula 2.
  • a dehydrating agent such as thionyl chloride
  • a base such as toluene
  • organic solvent such as toluene
  • Bases useful in the method of Scheme 2 include amine bases such as pyridine. About three molar equivalents of pyridine relative to the compound of Formula 3 is typically necessary to achieve the conversion of the compound of Formula 3 to the compound of Formula 2.
  • the method of Scheme 2 is generally conducted using a reaction temperature in the range of about 50 to about 80 0 C, more commonly in the range of about 60 to about 65 0 C.
  • the product can be isolated by the usual methods known to one skilled in the art such as extraction and crystallization.
  • compounds of Formula 2 can also be prepared from addition- elimination reactions of organometallic reagents such as Grignard reagents of Formula 4 with ⁇ -enamines or ⁇ -haloenones of Formula 5.
  • organometallic reagents such as Grignard reagents of Formula 4 with ⁇ -enamines or ⁇ -haloenones of Formula 5.
  • the reaction can be run in a variety of solvents including tetrahydrofuran, diethyl ether, dioxane or methylene chloride, and optimum temperatures range from about -78 0 C to the refluxing temperature of the solvent.
  • solvents including tetrahydrofuran, diethyl ether, dioxane or methylene chloride
  • optimum temperatures range from about -78 0 C to the refluxing temperature of the solvent.
  • General procedures for additions of Grignard reagents to enamines and haloenones are well documented in the chemical literature; see for example, Jeong et al., Journal of Fluorine Chemistry 2004, 125, 1629-1638, as well as references cited within.
  • the method of Scheme 3 is illustrated in Reference Example 1 , Step B.
  • a compound of Formula 2 can be formed by condensation of a ketone of Formula 6 with a phosphonate compound of Formula 7 according to the Wadsworth-Emmons modification of the Wittig Reaction.
  • R is, for example, methyl or ethyl
  • the phosphonate compound of Formula 7 is deprotonated with a base such as pyridine, triethylamine, NaH, NaHC ⁇ 3 or lithium diisopropylamide (LDA) in a solvent such as tetrahydrofuran, diethyl ether, dioxane or methylene chloride to form a ylid intermediate, and the ketone of Formula 6 is added to provide the compound of Formula 2.
  • Optimum temperatures range from about 0 0 C to the refluxing temperature of the solvent.
  • the general reaction conditions of the Wittig Reaction are well documented in the chemical literature. For example, see Dull et al., J. Org. Chem. 1967, 32, 1622-1623.
  • ketones can be combined under acidic, or more commonly basic conditions, to provide compounds of Formula 3.
  • the aldol condensation has been extensively reviewed (e.g., Organic Reactions, 1968, 16, 1), and wide range of conditions have been used to achieve this transformation. This reaction is illustrated in Scheme 5.
  • a compound of Formula 3 wherein R 1 is CF 3 can be prepared by addition of a non-nucleophilic base such as lithium hydride (Sosnovskikh et al, J. Org. Chem. USSR (Eng.
  • reaction conditions can be used to prepare compounds of Formula 2 directly from compounds of Formula 6 and compounds of Formula 8.
  • suitable conditions such as treatment with a mixture comprising potassium carbonate and acetonitrile at about 82 0 C, can be used to prepare compounds of Formula 2.
  • Compounds of Formula 2 can also be prepared directly from compounds of Formula 6 and compounds of Formula 8 by treatment with calcium hydroxide in N, ⁇ /-dimethylformamide and tert-butyl methyl ether, and then heating the mixture to reflux with azeotropic removal of water. These reactions are usually conducted at temperatures ranging from about 25 0 C to the boiling point of the solvent(s).
  • the reaction is conducted using a base such as lithium diisopropylamide or lithium bis(trimethylsilyl)amide, which may react with compounds of Formula 6 wherein R 1 is CF 3 (Gosselin et al., Organic Letters 2005, 7, 355), the order of addition of the components of the reaction becomes important.
  • the most preferred order of addition is the metered addition of a ketone of Formula 8 to a base such as lithium diisopropylamide at about -78 0 C in a solvent such as tetrahydrofuran.
  • the enolate formed can then be contacted with a compound of Formula 6 at about -78 0 C to afford the desired compound of Formula 3.
  • the product can be isolated by methods well known to one skilled in the art such as extraction, crystallization, etc.
  • Ketones of Formula 6 and Formula 8 can be prepared by numerous methods described in the general literature.
  • R 2 , R 4 and R 5 are as defined in the Summary of the Invention.
  • routes are possible for the preparation of compounds of Formula Ia from compounds of Formula 1.
  • one such method involves the aminocarbonylation of a compound of Formula Ib with an appropriately substituted amine compound of Formula 9 wherein R 2 , R 4 and R 5 are defined in the Summary of the Invention.
  • the reaction is typically carried out with an aryl bromide of Formula Ib in the presence of a palladium catalyst under a CO atmosphere.
  • the palladium catalyst used for the present method typically comprises palladium in a formal oxidation state of either 0 (i.e. Pd(O)) or 2 (i.e. Pd(II)).
  • Pd(O) i.e.
  • Pd(II) i.e. Pd(II)
  • a wide variety of such palladium-containing compounds and complexes are useful as catalysts for the present method.
  • Examples of palladium-containing compounds and complexes useful as catalysts in the method of Scheme 6 include PdCl 2 (PPh 3 ) 2 (bis(triphenylphosphine)palladium(II) dichloride), Pd(PPh 3 ) 4
  • the method of Scheme 6 is generally conducted in a liquid phase, and therefore to be most effective the palladium catalyst preferably has good solubility in the liquid phase.
  • Useful solvents include, for example, ethers such as 1,2- dimethoxyethane, amides such as 7V,iV-dimethylacetamide, and non-halogenated aromatic hydrocarbons such as toluene.
  • the method of Scheme 6 can be conducted over a wide range of temperatures, ranging from about 25 to about 150 0 C. Of note are temperatures from about 60 to about 110 0 C, which typically provide fast reaction rates and high product yields.
  • the general methods and procedures for aminocarbonylation with an aryl bromide and an amine are well known in the literature; see, for example, H. Horino et al., Synthesis 1989, 715; and J. J. Li, G. W. Gribble, editors, Palladium in Heterocyclic Chemistry: A Guide for the Synthetic Chemist, 2000.
  • This reaction is generally carried out in the presence of a dehydrating coupling reagent such as dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-propanephosphonic acid cyclic anhydride or carbonyl diimidazole in the presence of a base such as triethylamine, pyridine, 4-(dimethylamino)pyridine or JV,jV-diisopropylethylamine in an anhydrous aprotic solvent such as dichloromethane or tetrahydrofuran at a temperature typically between 25 and 70 0 C.
  • a dehydrating coupling reagent such as dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-propanephosphonic acid cyclic anhydride or carbonyl diimidazole
  • R is methyl or ethyl
  • an ester of Formula Id is converted to a corresponding carboxylic acid of Formula Ic by general procedures well known in the art. For example, treatment of a methyl or ethyl ester of Formula Id with aqueous lithium hydroxide in tetrahydrofuran, followed by acidification yields the corresponding carboxylic acid of
  • Step B Preparation of l-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4- trifluoro-2-buten- 1 -one To a stirred solution of diisopropylamine (11.1 mL, 83.3 mmol) in tetrahydrofuran
  • Step A the title product of Step A) (5.0 g, 19.4 mmol) in tetrahydrofuran (20 mL) was added to the reaction mixture at -78 0 C, which was then warmed to 0 0 C. Water (25 mL) was added to the mixture, which was then stirred for 1 hour at 0 0 C.
  • Step A Preparation of l-(4-bromo-l-naphthalenyl)-3-(3,5-dichlorophenyl)-4,4,4- trifluoro-3 -hydroxy- 1 -butanone
  • Lithium diisopropylamide (Aldrich Chemical Company, 2M in tetrahydrofuran/ ethylbenzene, 4 mL, 7.94 mmol) was added to tetrahydrofuran (4 mL) at -78 0 C.
  • a solution of l-(4-bromo-l-naphthalenyl)ethanone (1.8 g, 7.22 mmol) in tetrahydrofuran (4 mL) was added dropwise to the mixture. When the addition was complete the mixture was stirred for 30 min at -78 0 C.
  • Step B Preparation of l-(4-bromo-l-naphthalenyl)-3-(3,5-dichlorophenyl)-4,4,4- trifluoro-2-buten- 1 -one
  • Step A Preparation of l-(3-bromo-4-fluorophenyl)-3-(3,5-dichlorophenyl)-4,4,4- trifluoro-3 -hydroxy- 1 -butanone
  • Lithium diisopropylamide (Aldrich Chemical Company, 2M in tetrahydrofuran/ ethylbenzene 10.18 mL, 20.36 mmol) was added to tetrahydrofuran (8 mL) at -78 0 C.
  • a solution of l-(3-bromo-4-fluorophenyl)ethanone (4.01 g, 18.47 mmol) in tetrahydrofuran (8 mL) was added dropwise to the mixture. When the addition was complete the mixture was stirred at -78 0 C for 30 min.
  • Step B Preparation of l-(3-bromo-4-fluorophenyl)-3-(3,5-dichlorophenyl)-4,4,4- trifluoro-2-buten-l-one
  • Aqueous sodium hydroxide (50%, 1.36 g, 17.0 mmol) was added to a solution of hydroxylamine sulfate (0.70 g, 4.26 mmol) in water (8 mL).
  • hydroxylamine sulfate (0.70 g, 4.26 mmol)
  • water 8 mL
  • Step B 1.8 g, 4.07 mmol
  • tetrahydrofuran 20 mL
  • the mixture was stirred for 20 min.
  • the mixture was poured into water (150 mL), and the resulting mixture was extracted with ethyl acetate (2 x 100 mL). The combined extracts were dried and evaporated.
  • Triethylamine 14.20 g, 0.14 mol
  • 1 ,2-dichloroethane 80 mL
  • the solvent was removed under reduced pressure, and the residue was dissolved in hot acetonitrile (50 mL).
  • the mixture was then cooled to 25 0 C, and water (40 mL) was added dropwise.
  • the mixture was further cooled to 0 0 C and filtered.
  • the isolated solid was washed with water (100 mL) and dried overnight in a vacuum oven (approximately 16-33 kPa at 50 0 C) to provide the title product as an off-white solid (37 g, 75% yield) melting at 169-169 0 C.
  • Step C Preparation of 4-[3-[3-chloro-5-(trifluoromethyl)phenyl]-4,4,4-trifluoro-l- oxo-2-buten-l-yl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-l- naphthalenecarboxamide
  • a mixture of the product of Synthesis Example 7, Step B (10.00 g, 28.38 mmol), l-[3- chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethanone (9.00 g, 32.5 mmol), calcium hydroxide (1.05 g, 14.2 mmol), ⁇ /, ⁇ /-dimethylformamide (20 mL) and tert-butyl methyl ether (32 mL) was placed in a thermometer-equipped reaction vessel.
  • the reaction vessel was connected to a ten-plate Oldershaw column, the output of which was condensed and fed into a decanter initially filled with tert-butyl methyl ether. A nitrogen atmosphere was maintained in the apparatus. The upper part of the decanter was connected to return condensate to the fifth plate of the Oldershaw column. This arrangement ensured that wet (containing dissolved water) tert-butyl methyl ether was not returned from the decanter to the reaction vessel. A drain valve at the bottom of the decanter allowed removing tert-butyl methyl ether in addition to water from the decanter. The reaction mixture was heated to distill the tert-butyl methyl ether/water azeotrope.
  • the decanter trap contained an amount of tert-butyl methyl ether sufficient to dissolve all of the water formed by the reaction, the condensate in the trap did not separate into layers containing predominately water and predominately tert-butyl methyl ether. Because the reaction mixture initially contained mostly tert-butyl methyl ether, the mixture boiled at a temperature not much exceeding the normal boiling point of tert-butyl methyl ether (e.g., about 65-70 0 C). The reaction proceeded relatively slowly at this temperature, so condensate was gradually drained from the decanter trap to remove tert-butyl methyl ether.
  • tert-butyl methyl ether As the concentration of tert-butyl methyl ether decreased in the reaction mixture, the temperature of the boiling mixture increased. Tert-butyl methyl ether was removed by draining the decanter until the temperature of the boiling reaction mixture reached about 85 0 C. To maintain this temperature, tert-butyl methyl ether was added as needed to compensate for loss of solvent from the apparatus. The total time from the start of heating the reaction mixture to stopping distillation, not including a shutdown period overnight, was about 6 h.
  • Step D Preparation of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5- (trifluoromethyl)-3-isoxazolyl]- ⁇ f-[2-oxo-2-[(2,2,2- trifluoroethyl)amino]ethyl]- 1 -naphthalenecarboxamide
  • Aqueous sodium hydroxide (50%, 3.04 g, 38.0 mmol) was added dropwise to a stirred solution of hydroxylamine sulphate (1.48 g, 9.02 mmol) in water (28 mL) at 25 0 C. After this addition was complete the product of Synthesis Example 7, Step C (10.00 g, 16.33 mmol) in tetrahydrofuran (60 mL) was added dropwise over 40 min. After the addition was complete the mixture was stirred further for 30 min. The solvent was removed under reduced pressure and IN hydrochloric acid (100 mL) was added. The mixture was extracted with ether (2 x 100 mL) and the combined extracts were dried and evaporated.
  • the decanter trap contained an amount of tert- butyl methyl ether sufficient to dissolve all of the water formed by the reaction, the condensate in the trap did not separate into layers containing predominately water and predominately tert-butyl methyl ether.
  • Tert-butyl methyl ether was removed by gradually draining the decanter trap until the reaction temperature was 85 0 C. To maintain this temperature, tert-butyl methyl ether was added as needed to compensate for loss of solvent from the apparatus. The total time from the start of heating the reaction mixture to stopping distillation was about 4.5 h.
  • Aqueous sodium hydroxide (50%, 2.08 g, 25.5 mmol) was added dropwise to a stirred solution of hydroxylamine sulfate (1.07 g, 6.52 mmol) in water (20 mL) at 25 0 C. After this addition was complete the product of Synthesis Example 8, Step A (5 g, 10.27 mmol) in tetrahydrofuran (20 mL) was added dropwise over 40 min. After the addition was complete the mixture was stirred further for 30 min. The organic phase was separated and added to hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate (2 x 20 mL). The organic solvent was evaporated under reduced pressure.
  • Et means ethyl
  • Me means methyl
  • CN means cyano
  • Ph means phenyl
  • Py means pyridinyl
  • c-Pr means cyclopropyl
  • z-Pr means isopropyl
  • t-Bu means tertiary butyl
  • SMe means methylthio
  • SO 2 means sulfonyl
  • Thz means thiazole.
  • Concatenations of groups are abbreviated similarly; for example, "SO 2 Me” means methylsulfonyl.
  • R 2a is CL
  • R 2b is H
  • R 2c is Cl
  • R 2a is CL
  • R 2b is CL
  • R 2c is Cl
  • R 2a is CL
  • R 2b is F
  • R 2c is Cl R! si
  • R 2a is Br
  • R 2b is H
  • R 2c is Br
  • R 2a is CF
  • R 2b is H
  • R 2c is H
  • R 2a is CF 3 .
  • R 2b is H.
  • R 2c is F
  • R 2a is CF, R 2b is H, R 2c is Cl s! s! s!
  • R 2a is CF, R 2b is H, R 2c is Br s! s! s!
  • R 2a is CF 3 .
  • R 2b is H.
  • R 2c is CF 3
  • R 2a is 0CF, R 2b is H, R 2c is Cl s! s! s!
  • R 2a is OCHoCF, R 2b is H .
  • R 2c is F s! s! s!
  • R 2a is OCH 2 CF 2 .
  • R 2b is H.
  • R 2c is Cl
  • R 2a is OCH 2 CF 2 .
  • R 2b is H.
  • R 2c is Br
  • R 2a is CL
  • R 2b is H.
  • R 2 ⁇ is Cl s!
  • R 2a is CL
  • R 2b is CL
  • R 2c is Cl s!
  • R 2a is CL
  • R 2b is F
  • R 2c is Cl
  • R 2a is Br
  • R 2b is H
  • R 2c is Br si Ei Ei
  • R 2a is CF 2 .
  • R 2b is H.
  • R 2c is H
  • R 2a is CF, R 2b is H, R 2c is F s! s! s!
  • R 2a is CF, R 2b is H, R 2c is Cl s! s! s!
  • R 2a is CF 3 .
  • R 2b is H.
  • R 2c is Br
  • R 2a is CF
  • R 2b is H
  • R 2c is CF, s! s! s!
  • R 2a is 0CF, R 2b is H, R 2c is Cl s! s! s!
  • R 2a is OCH 2 CF 2 .
  • R 2b is H.
  • R 2c is F
  • R 2a is OCHoCF, R 2b is H .
  • R 2c is Cl s! s! s!
  • R 2a is OCHoCF, R 2b is H .
  • R 2c is Br s! s! s!
  • R 1 is CFoCL
  • R 2 is Cl s! s! s!
  • R 1 is CF 2 CF 2 H.
  • R 2 is Cl s!
  • R 1 is CCl 2 F.
  • R 2 is Cl s!

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Disclosed is a method for preparing a compound of Formula: (1); wherein R1 is CHX2, CX3, CX2CHX2 or CX2CX3; each X is independently Cl or F; Z is optionally substituted phenyl; and Q is phenyl or 1-naphthalenyl, each optionally substituted as defined in the disclosure; comprising contacting a compound of Formula: (2).

Description

TITLE
METHOD FOR PREPARING 5-HALOALKYL-^S-DIHYDROISOXAZOLE
DERIVATIVES
FIELD OF THE INVENTION The present invention pertains to a method for the preparation of 5-haloalkyl-4,5- dihydroisoxazole derivatives. The present invention also relates to novel enones useful as starting materials for the aforedescribed method.
SUMMARY OF THE INVENTION
The present invention relates to a method for preparing a compound of Formula 1
Figure imgf000002_0001
1 wherein
R1 is CHX2, CX3, CX2CHX2 or CX2CX3; each X is independently Cl or F; Z is optionally substituted phenyl;
Figure imgf000002_0002
Qa is phenyl substituted with one Q1 and optionally substituted with one to four substituents independently selected from R3; Q1 is a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfmyl, C1-C6 haloalkylsulfmyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, -CN, -NO2, -N(R4)R5, -C(=W)N(R4)R5, -C(=O)OR5 and R7; Qb is optionally substituted 1-naphthalenyl; each R3 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C2-C7 alkylcarbonyl, C2-C7 haloalkylcarbonyl, C1-C6 haloalkylthio, C1-C6 alkylsulfmyl, C1-C6 haloalkylsulfmyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, -N(R4)R5, -C(=W)N(R4)R5, -C(=W)0R5, -CN, -OR11 or -NO2; or a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfmyl, C1-C6 haloalkylsulfϊnyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, -CN, -NO2, -N(R4)R5, -C(=W)N(R4)R5, -C(=O)OR5 and R7; each R4 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; each R5 is independently H; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R6; each R6 is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfmyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl,
C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-Cg halodialkylaminocarbonyl, -OH, -NH2, -CN or -NO2; or Q2; each R7 is independently a phenyl ring or a pyridinyl ring, each ring optionally substituted with one or more substituents independently selected from R8; each R8 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy,
C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfmyl, C1-C6 haloalkylsulfmyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-C7 dialkylaminocarbonyl, -OH, -NH2,
-C(=O)OH, -CN or -NO2; each Q2 is independently a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfmyl, C1-C6 haloalkylsulfmyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, -CN, -NO2, -C(=W)N(R9)R10 and -Q=O)OR1 °; each R9 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl,
C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; each R10 is independently H; or C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl; each R11 is independently H; or C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl, C2-C alkoxycarbonyl, C1-C6 alkylsulfonyl or C1-C6 haloalkylsulfonyl; and each W is independently O or S; comprising contacting a compound of Formula 2
R1 O
wherein R1, Q and Z are as previously defined for Formula 1, with hydroxylamine in the presence of a base.
The present invention also relates to novel compounds of Formula 2, useful as starting materials for the aforedescribed method.
DETAILS OF THE INVENTION
As used herein, the terms "comprises," "comprising," "includes," "including," "has,"
"having" or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.
Further, unless expressly stated to the contrary, "or" refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
Also, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore "a" or "an" should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.
Ratios are generally recited herein as single numbers, which are relative to the number
1; for example, a ratio of 4 means 4 : 1. The term "equivalent ratio" refers to the number of equivalents of one component (e.g., of a base) relative to another component added to a reaction mixture, recognizing that some compounds may provide two or more equivalents per mole.
In the present disclosure and claims, the radical "SO2"means sulfonyl, "-CN" means cyano, "-NO2" means nitro, and "-OH" means hydroxyl.
In the above recitations, the term "alkyl", used either alone or in compound words such as "alkylthio" or "haloalkyl" includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, /-propyl, or the different butyl, pentyl or hexyl isomers. "Alkenyl" includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. "Alkenyl" also includes polyenes such as 1 ,2-propadienyl and 2,4-hexadienyl. "Alkynyl" includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. "Alkynyl" can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
"Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. "Alkylthio" includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. "Alkylsulfmyl" includes both enantiomers of an alkylsulfϊnyl group. Examples of "alkylsulfmyl" include CH3S(=O)-, CH3CH2S(=O)-, CH3CH2CH2S(=O)-, (CH3)2CHS(=O)- and the different butylsulfinyl, pentylsulfmyl and hexylsulfinyl isomers. Examples of "alkylsulfonyl" include CH3SO2-, CH3CH2SO2-, CH3CH2CH2SO2-, (CH3)2CHSO2-, and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers.
"Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "alkylcycloalkyl" denotes alkyl substitution on a cycloalkyl moiety and includes, for example, ethylcyclopropyl, /-propylcyclobutyl, 3-methylcyclopentyl and 4-methylcyclohexyl. The term "cycloalkylalkyl" denotes cycloalkyl substitution on an alkyl moiety. Examples of "cycloalkylalkyl" include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups.
The term "halogen", either alone or in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen" includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as "haloalkyl", or when used in descriptions such as "alkyl substituted with halogen" said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "haloalkyl" or "alkyl substituted with halogen" include F3C-, ClCH2-, CF3CH2- and CF3CCl2-. The terms "haloalkoxy" and "haloalkylthio" and the like, are defined analogously to the term "haloalkyl". Examples of "haloalkoxy" include CF3O-, CCl3CH2O-, HCF2CH2CH2O- and CF3CH2O-. Examples of "haloalkylthio" include CCl3S-, CF3S-, CCl3CH2S- and ClCH2CH2CH2S-. Examples of "haloalkylsulfmyl" include CF3S(O)-, CCl3S(O)-, CF3CH2S(O)- and CF3CF2S(O)-. Examples of
"haloalkylsulfonyl" include CF3SO2-, CCl3SO2-, CF3CH2SO2- and CF3CF2SO2-. "Alkylcarbonyl" denotes a straight-chain or branched alkyl moieties bonded to a
C(O) moiety. Examples of "alkylcarbonyl" include CH3C(O)-, CH3CH2CH2C(O)- and (CH3)2CHC(O)-. Examples of "alkoxycarbonyl" include CH3OC(O)-, CH3CH2OC(O)-, CH3CH2CH2OC(=O)-, (CH3)2CHOC(=O)- and the different butoxy-, pentoxy-, or hexoxycarbonyl isomers.
The total number of carbon atoms in a substituent group is indicated by the "CpCj" prefix where i and j are numbers from 1 to 7. For example, C1-C4 alkylsulfonyl designates methylsulfonyl through butylsulfonyl.
When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can exceed 1, said substituents (when they exceed 1) are independently selected from the group of defined substituents, e.g., (Rv)r in U-I of Exhibit 1 wherein v is 0, 1, 2, 3, 4 or 5. As (Rv)r are optional substituents on rings in Exhibits 1 and 2, Q-A and Q-B respectively, each may substitute any available carbon or nitrogen ring member(s) of the rings. When a variable group is shown to be optionally attached to a position, for example (Rv)r wherein v may be 0, then hydrogen may be at the position even if not recited in the variable group definition. When one or more positions on a group are said to be "not substituted" or "unsubstituted", then hydrogen atoms are attached to take up any free valency.
The term "heterocyclic ring" denotes a ring in which at least one atom forming the ring backbone is not carbon, e.g., nitrogen, oxygen or sulfur. Typically a heterocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs. Unless otherwise indicated, a heterocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. The term "unsaturated heterocyclic ring" relates to both partially and fully unsaturated rings. When a fully unsaturated heterocyclic ring satisfies Hϋckel's rule, then said ring is also called a "heteroaromatic ring" or "aromatic heterocyclic ring". Unless otherwise indicated, heterocyclic rings can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen. A "heterocyclic ring" may optionally contain ring members selected from the group C(=O), C(=S), S(=O) and SO2. The term "ring member" refers to any atom or other moiety (e.g., C(=O), C(=S), S(=O) or SO2) forming the backbone of a ring.
"Aromatic" indicates that each of the ring atoms is essentially in the same plane and has a/?-orbital perpendicular to the ring plane, and in which (4p + 2) π electrons, where p is a positive integer, are associated with the ring to comply with Hϋckel's rule.
As is generally known in the art, the chemical name "pyridyl" is synonymous with "pyridinyl".
The term "optionally substituted" is used herein interchangeably with the phrase "substituted or unsubstituted" or with the term "(un)substituted". Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other. An optionally substituted group also may have no substituents. Therefore the phrase "optionally substituted with one or more substituents" means that the number of substituents may vary from zero up to the number of available positions for substitution. Similarly the phrase "optionally substituted with 1-5 substituents" means that the number of substituents may vary from zero up to the number of available position but not exceeding 5.
Each X is independently Cl or F. Thus, for example, CHX2 could be CHCl2 CHCF2 or CHClF.
When Q1 or Q2 is a nitrogen-containing heterocyclic ring it may be attached to the remainder of Formula 1 though any available carbon or nitrogen ring atom, unless otherwise described. As noted above, Q1 and Q2 can be (among others) phenyl optionally substituted with one or more substituents selected from a group of substituents as defined in the Summary of Invention. An example of phenyl optionally substituted with one to five substituents is the ring illustrated as U-I in Exhibit 1, wherein Rv is the optional substituents as defined in the Summary of the Invention for Q1 and Q2 and r is an integer from 0 to 5.
As noted above, Q1 and Q2 can be a 5- or 6-membered heterocyclic ring, which may be saturated or unsaturated, optionally substituted with one or more substituents selected from a group of substituents as defined in the Summary of Invention. Examples of a 5- or 6-membered aromatic unsaturated heterocyclic ring optionally substituted with one or more substituents include the rings U-2 through U-61 illustrated in Exhibit 1 wherein Rv is any substituent as defined in the Summary of the Invention for Q1 and Q2 and r is an integer from 0 to 4, limited by the number of available positions on each U group. As U-29, U-30, U-36, U-37, U-38, U-39, U-40, U-41, U-42 and U-43 have only one available position, for these U groups r is limited to the integers 0 or 1, and r being 0 means that the U group is unsubstituted and a hydrogen is present at the position indicated by (Rv)r.
Exhibit 1
Figure imgf000007_0001
U-I U-2 U-3 U-4 U-5
Figure imgf000007_0002
Figure imgf000008_0001
U-16 U-17 U-18 U-19 U-20
Figure imgf000008_0002
U-21 U-22 U-23 U-24 U-25
Figure imgf000008_0003
U-26 U-27 U-28 U-29 U-30
Figure imgf000008_0004
U-31 U-32 U-33 U-34 U-35
Figure imgf000008_0005
U-36 U-37 U-38 U-39 U-40
Figure imgf000008_0006
Figure imgf000008_0007
Figure imgf000008_0008
U-54 U-55
Figure imgf000009_0001
U-56 U-57 U-58 U-59 U-60
Figure imgf000009_0002
U-61
Note that when Q1 or Q2 is a 5- or 6-membered saturated or non-aromatic unsaturated heterocyclic ring optionally substituted with one or more substituents selected from the group of substituents as defined in the Summary of Invention for Q1 and Q2, one or two carbon ring members of the heterocycle can optionally be in the oxidized form of a carbonyl moiety.
Examples of a 5- or 6-membered saturated or non-aromatic unsaturated heterocyclic ring include the rings G-I through G-35 as illustrated in Exhibit 2. Note that when the attachment point on the G group is illustrated as floating, the G group can be attached to the remainder of Formula 1 through any available carbon or nitrogen of the G group by replacement of a hydrogen atom. The optional substituents corresponding to Rv can be attached to any available carbon or nitrogen by replacing a hydrogen atom. For these G rings, r is typically an integer from 0 to 4, limited by the number of available positions on each G group.
Note that when Q1 and Q2 comprise a ring selected from G-28 through G-35, G2 is selected from O, S or N. Note that when G2 is N, the nitrogen atom can complete its valence by substitution with either H or the substituents corresponding to Rv as defined in the Summary of Invention for Q1 and Q2.
Exhibit 2
Figure imgf000009_0003
G-I G-2 G-3 G-4 G-5
Figure imgf000009_0004
G-6 G-7 G-8 G-9 G-IO
Figure imgf000010_0001
G-I l G-12 G-13 G-14 G-15
Figure imgf000010_0002
G-16 G-17 G-18 G-19 G-20
Figure imgf000010_0003
G-21 G-22 G-23 G-24 G-25
Figure imgf000010_0004
G-31 G-32 G-33 G-34 G-35
Embodiments of the present invention include:
Embodiment 1. The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein
Z is phenyl optionally substituted with one to five substituents independently selected from R2 (i.e.
3 2
Figure imgf000010_0005
wherein n is O, 1, 2, 3, 4 or 5); and each R2 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy,
C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino, C2-C6 dialkylamino, -CN or -NO2. Embodiment IA. The method of Embodiment 1 wherein Z is phenyl substituted with one to three substituents independently selected from R2, said substituents attached at the 3-, 4- or 5-positions of the phenyl ring. Embodiment IB. The method of Embodiment 1 or IA wherein each R2 is independently F, Cl, Br, C1-C6 alkyl, C1-C6 fiuoroalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, C1-C6 alkylthio or C1-C6 fluoroalkylthio. Embodiment 1C. The method of Embodiment 1 or IA wherein each R2 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl or -CN. Embodiment ID. The method of Embodiment 1C wherein each R2 is independently halogen or C1-C6 haloalkyl.
Embodiment IE. The method of Embodiment 1C wherein each R2 is independently halogen or CF3. Embodiment IF. The method of Embodiment IE wherein each R2 is independently F,
Cl Or CF3. Embodiment IG. The method of Embodiment IA wherein Z is
Figure imgf000011_0001
R2a is halogen, C1-C2 haloalkyl or C1-C2 haloalkoxy; R2b is H, halogen or cyano; and R2c is H, halogen or CF3. Embodiment IH. The method of Embodiment IG wherein R2a is CF3 or halogen; and
R2c is H, CF3 or halogen. Embodiment II. The method of Embodiment IH wherein R2a is CF3.
Embodiment IJ. The method of any one of Embodiments IG through II wherein R2^ is
H. Embodiment IK. The method of any one of Embodiments IG through IJ wherein R2c is CF3 or halogen. Embodiment IL. The method of Embodiment IK wherein R2c is CF3, F, Cl or Br.
Embodiment IM. The method of Embodiment IL wherein R2c is F, Cl or Br. Embodiment IN. The method of Embodiment IL wherein R2c is CF3, Cl or Br. Embodiment 10. The method of Embodiment IN wherein R2c is Cl or Br. Embodiment IP. The method of Embodiment IO wherein R2^ is H and R2c is Cl. Embodiment IQ. The method of Embodiment 10 wherein R2^ is H and R2c is Br.
Embodiment 2. The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base, or the method of any one of Embodiments 1 through IQ, wherein Qb is 1-naphthalenyl optionally substituted with one to four substituents independently selected from R3. Embodiment 2A. The method of Embodiment 2 wherein Q is Qa.
Embodiment 2B. The method of Embodiment 2 wherein Q is Qb. Embodiment 2C. The method of Embodiment 2 wherein each R3 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C(=W)N(R4)R5, -C(=W)0R5, -CN or -OR1 !; or a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -CN, -C(=W)N(R4)R5 and -C(=O)OR5. Embodiment 2D. The method of Embodiment 2 wherein each R3 is independently halogen, -C(=W)N(R4)R5, -C(=W)0R5, -CN or -OR11. Embodiment 2E. The method of Embodiment 2 wherein each R4 is independently H or
C1-C6 alkyl.
Embodiment 2F. The method of Embodiment 2 wherein each R5 is independently H; or C1-C6 alkyl optionally substituted with one or more substituents independently selected from R6. Embodiment 2G. The method of Embodiment 2 wherein each R6 is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 halodialkylaminocarbonyl or -CN; or Q2. Embodiments 2H. The method of Embodiment 2 wherein each Q2 is a pyridinyl ring optionally substituted with one to four halogen.
Embodiments 21. The method of Embodiment 2 wherein each Qa is a phenyl substituted with one Q1 at the para position and optionally substituted with one to three substituents independently selected from R3 at the other positions on the phenyl ring. Embodiment 2J. The method of Embodiment 21 wherein Q1 is an optionally substituted
1-triazolyl or 1-pyrazolyl ring. Embodiment 2K. The method of Embodiment 2 J wherein R3 is Me or -CN at a meta position of the phenyl ring. Embodiment 2L. The method of Embodiment 2B wherein
Figure imgf000013_0001
R3 is C(O)N(R4)R5 or C(O)OR5. Embodiment 2M. The method of Embodiment 2L wherein
R4 is H, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl. Embodiment 2N. The method of Embodiment 2M wherein R4 is H. Embodiment 20. The method of any one of Embodiments 2L through 2N wherein
R3 is C(O)N(R4)R5 or C(O)OR5a; R5 is C1-C6 alkyl or C1-C6 haloalkyl, each substituted with one substituent independently selected from hydroxy, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfmyl, C1-C6 alkylsulfonyl, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylaminocarbonyl and C3-C9 halodialkylaminocarbonyl; and
R5a is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, each optionally substituted with one or more substituents independently selected from halogen, C1-C2 alkoxy and phenyl optionally substituted with up to 5 substituents selected from halogen and C1-C3 alkyl.
Embodiment 2P. The method of any one of Embodiments 2L through 20 wherein
R5a is C1-C6 alkyl optionally substituted with phenyl. Embodiment 2Q. The method of any one of Embodiments 2L through 2P wherein
R3 is C(O)N(R4)R5. Embodiment 2R. The method of any one of Embodiments 2L through 2N wherein
R3 is C(O)OR5. Embodiment 2S. The method of any one of Embodiments 20 through 2P wherein
R3 is C(O)OR5a.
Embodiment 3. The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base, or the method of any one of Embodiments 1 through IQ and 2 through 2S, wherein in Formulae 1 and 2 R1 is CF3.
Embodiment 4. The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein the contact occurs in a temperature range of from about 0 to about 150 0C. Embodiment 4A. The method of Embodiment 4 wherein the temperature range is from about 15 to about 40 0C. Embodiment 5. The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein the hydroxylamine is derived from a hydroxylamine salt. Embodiment 5 A. The method of Embodiment 5 wherein the hydroxylamine salt is a hydroxylamine salt of a mineral acid.
Embodiment 5B. The method of Embodiment 5 A wherein the hydroxylamine salt is a hydroxylamine salt of hydrochloric acid, sulfuric acid, phosphoric acid, or a mixture thereof. Embodiment 6. The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein the molar ratio of hydroxylamine to the compound of Formula 2 is at least about 1.
Embodiment 6A. The method of Embodiment 6 wherein the molar ratio of hydroxylamine to the compound of Formula 2 is at least about 1.2. Embodiment 6B. The method of Embodiment 6 A wherein the molar ratio of hydroxylamine to the compound of Formula 2 is at least about 1.5. Embodiment 6C. The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein the molar ratio of hydroxylamine to the compound of Formula 2 is no more than about 3. Embodiment 7. The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein the base comprises one or more compounds selected from organic bases, hydroxide bases, alkoxide bases and carbonate bases.
Embodiment 7A. The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein the base comprises one or more compounds selected from amine bases, alkali metal hydroxide bases, alkali metal alkoxide bases and alkali metal carbonate bases.
Embodiment 7AA. The method of Embodiment 7 wherein the base comprises an alkali metal carbonate.
Embodiment 7B. The method of Embodiment 7AA wherein the base comprises sodium carbonate, potassium carbonate or a mixture thereof. Embodiment 7C. The method of Embodiment 7B wherein the base comprises sodium carbonate. Embodiment 7D. The method of Embodiment 7 wherein the base comprises an alkali metal hydroxide. Embodiment 7E. The method of Embodiment 7D wherein the base comprises sodium hydroxide, potassium hydroxide or a mixture thereof.
Embodiment 8. The method of the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein the base in excess of the amount needed to neutralize hydroxylamine salts is in an equivalent ratio of at least about 1 to the compound of Formula 2. Embodiment 8 A. The method of Embodiment 8 wherein the ratio is no more than about
5.
Embodiment 9. The method of the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein the compound of Formula 2, hydroxylamine and base are contacted in the presence of a suitable solvent. Embodiment 9A. The method of Embodiment 9 wherein the suitable solvent comprises a solvent selected from alcohols, ethers, amides, nitriles, halogenated hydrocarbons and aromatic hydrocarbons (including mixtures thereof).
Embodiment 9B. The method of Embodiment 9 A wherein the suitable solvent comprises isopropanol. Embodiment 9C. The method of Embodiment 9 A wherein the suitable solvent further comprises water. Embodiment 10. A compound of Formula 2 as described in the Summary of the
Invention wherein
R1 is CHX2, CX3, CX2CHX2 or CX2CX3; each X is independently Cl or F; Z is optionally substituted phenyl; Q is Qa or Qb;
Qa is phenyl substituted with one Q1 and optionally substituted with one to four substituents independently selected from R3; Q1 is a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, -CN, -NO2, -N(R4)R5, -C(=W)N(R4)R5, -C(=O)OR5 and R7;
Qb is optionally substituted 1-naphthalenyl; each R3 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C6 cycloalkyl,
C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C2-C7 alkylcarbonyl, C2-C7 haloalkylcarbonyl, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, -N(R4)R5, -C(=W)N(R4)R5, -C(=W)0R5, -CN, -OR11 or -NO2; or a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, -CN, -NO2, -N(R4)R5,
-C(=W)N(R4)R5, -C(=O)OR5 and R7; each R4 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; each R5 is independently H; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R6; each R6 is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, C2-Cg dialkylamino, C3-C6 cycloalkylamino, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-Cg halodialkylaminocarbonyl, -OH, -NH2, -CN or -NO2; or QΛ each R7 is independently a phenyl ring or a pyridinyl ring, each ring optionally substituted with one or more substituents independently selected from R8; each R8 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy,
C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl,
C2-C7 alkylaminocarbonyl, C3-C7 dialkylaminocarbonyl, -OH, -NH2, -C(=O)OH, -CN or -NO2; each Q2 is independently a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfϊnyl, C1-C6 haloalkylsulfϊnyl,
C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, -CN, -NO2, -C(=W)N(R9)R10 and -C(=O)OR10; each R9 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; each R10 is independently H; or C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl; each R11 is independently H; or C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C1-C6 alkylsulfonyl or C1-C6 haloalkylsulfonyl; and each W is independently O or S.
Embodiment 1OA. A compound of Embodiment 10 wherein Z is phenyl optionally substituted with one to five substituents independently selected from R2; and each R2 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino, C2-C6 dialkylamino, -CN or -NO2.
Embodiment 1OB. A compound of Embodiment 1OA wherein Z is phenyl substituted with one to three substituents independently selected from R2, said substituents attached at the 3-, 4- or 5-positions of the phenyl ring.
Embodiment 1OC. A compound of Embodiment 1OA or 1OB wherein each R2 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl or CN. Embodiment 1OD. A compound of Embodiment 1OC wherein each R2 is independently halogen or C1-C6 haloalkyl. Embodiment 1OE. A compound of Embodiment 1OD wherein each R2 is independently halogen or CF3. Embodiment 1OF. A compound of Embodiment 1OE wherein each R2 is independently
F, Cl Or CF3.
Embodiment 11. A compound of Embodiment 10 wherein Qb is 1-naphthalenyl optionally substituted with one to four substituents independently selected from R3.
Embodiment 1 IA. A compound of Embodiment 11 wherein Q is Qa. Embodiment 1 IB. A compound of Embodiment 11 wherein Q is Qj5. Embodiment 11C. A compound of Embodiment 11 wherein each R3 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C(=W)N(R4)R5, -C(=W)OR5, -CN or -OR1 !; or a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -CN,
-C(=W)N(R4)R5 and -C(=O)OR5.
Embodiment 1 ID. A compound of Embodiment 11 wherein each R3 is independently halogen, -C(=W)N(R4)R5, -C(=W)0R5, -CN or -OR11.
Embodiment 1 IE. A compound of Embodiment 11 wherein each R4 is independently H or C1-C6 alkyl.
Embodiment 1 IF. A compound of Embodiment 11 wherein each R5 is independently H; or C1-C6 alkyl optionally substituted with one or more substituents independently selected from R6.
Embodiment 1 IG. A compound of Embodiment 11 wherein each R6 is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C2-C7 alkoxycarbonyl,
C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 halodialkylaminocarbonyl or -CN; or Q2.
Embodiment 1 IH. A compound of Embodiment 11 wherein each Q2 is a pyridinyl ring optionally substituted with one to four halogen. Embodiment 1 II. A compound of Embodiment 11 wherein each Qa is a phenyl substituted with one Q1 at the para position and optionally substituted with one to three substituents independently selected from R3 at the other positions on the phenyl ring.
Embodiment 1 IJ. A compound of Embodiment 111 wherein Q1 is an optionally substituted 1-triazolyl or 1-pyrazolyl ring.
Embodiment 1 IK. A compound of Embodiment 1 IJ wherein R3 is Me or CN at a meta position of the phenyl ring.
Embodiment 12. A compound of Embodiment 10 wherein R1 is CF3.
Embodiment 13. The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein Z is phenyl optionally substituted with one to five substituents independently selected from R2.
Embodiment 13 a. The method of Embodiment 13 wherein Z is phenyl substituted with one to three substituents independently selected from R2, said substituents attached at the 3-, 4- or 5-positions (i.e. meta or para) of the phenyl ring.
Embodiment 13b. The method of Embodiment 13a wherein each R2 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1- C6 alkylthio, C1-C6 halo alky lthio, C1-C6 alkylamino, C2-C6 dialkylamino, -CN or -NO2. Embodiment 13c. The method of Embodiment 13b wherein each R2 is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy or -CN.
Embodiment 14. The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein R1 is CF3.
Embodiment 15. The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein Q is Qa. Embodiment 15 a. The method of Embodiment 15 wherein Qa is phenyl substituted with one Q1 attached at the 4-position of the phenyl ring, said phenyl ring further optionally substituted with one or two substituents independently selected from R3
(i.e.
Figure imgf000019_0001
wherein m is 0, 1 or 2).
Embodiment 15b. The method of Embodiment 15a wherein Q1 is a 5-membered heteroaromatic ring optionally substituted with one or two substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -CN,
-C(=W)N(R4)R5 and -C(=O)OR5.
Embodiment 15c. The method of Embodiment 15b wherein Q1 is a pyrazole or triazole ring optionally substituted with one or two substituents independently selected from halogen, -CN and -C(=W)N(R4)R5. Embodiment 15d. The method of Embodiment 15a wherein each R3 is independently halogen, C1-C6 alkyl or -CN. Embodiment 15e. The method of Embodiment 15d wherein one R3 is Cl, CH3 or -CN and is attached at the 3-position of the phenyl ring (i.e. adjacent to Q1). Embodiment 15f. The method of Embodiment 15b or 15c wherein R4 is H. Embodiment 15g. The method of Embodiment 15b or 15c wherein R5 is H; or C1-C3 alkyl, cyclopropyl or cyclopropylmethyl, each optionally substituted with halogen and further optionally substituted with 1 or 2 CH3. Embodiment 16. The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein Q is Qj5. Embodiment 16a. The method of Embodiment 16 wherein Qb is 1-naphthalenyl substituted with one or two substituents independently selected from R3
Figure imgf000020_0001
(i.e. 3 wherein n is 1 or 2).
Embodiment 16b. The method of Embodiment 16 wherein Qb is 1-naphthalenyl substituted with one R3 attached at the 4-position of the naphthalene ring
(i.e.
Figure imgf000020_0002
Embodiment 16c. The method of Embodiment 16a or 16b wherein one R3 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -N(R4)R5, -C(=W)N(R4)R5, -C(=W)0R5, -CN, -OR11 or -NO2, and said R3 is attached at the 4-position of the naphthalene ring.
Embodiment 16d. The method of Embodiment 16c wherein the R3 attached at the 4-position of the naphthalene ring is -C(=O)N(R4)R5.
Embodiment 16e. The method of Embodiment 16c or 16d wherein each R4 is independently H, C1-C6 alkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxy carbonyl. Embodiment 16f. The method of Embodiment 16c or 16d wherein each R5 is independently C1-C6 alkyl substituted with one substituent selected from hydroxy, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfmyl, C1-C6 alkylsulfonyl, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 halodialkylaminocarbonyl and Q2. Embodiment 16g. The method of Embodiment 16c or 16d wherein each R5 is independently C1-C2 alkyl substituted with C2-C7 haloalkylaminocarbonyl.
Embodiment 16h. The method of Embodiment 16f wherein Q2 is a pyridinyl ring optionally substituted with one to four halogen.
Embodiment 16i. The method of Embodiment 16c wherein R11 is H, C2-C6 alkenyl, C2-C6 alkynyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C1-C6 alkylsulfonyl or C1-C6 haloalkylsulfonyl.
Embodiment 17. A compound of Formula 2 as described in the Summary of the Invention wherein R1 is CHX2, CX3, CX2CHX2 or CX2CX3; each X is independently Cl or F;
Z is optionally substituted phenyl;
Figure imgf000021_0001
Qa is phenyl substituted with one Q1 and optionally substituted with one to four substituents independently selected from R3;
Q1 is a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfmyl, C ^C6 haloalkylsulfmyl, C ^C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, -CN, -NO2, -N(R4)R5, -C(=W)N(R4)R5, -C(=O)OR5 and R7;
Qb is optionally substituted 1-naphthalenyl; each R3 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C6 cycloalkyl,
C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C2-C7 alkylcarbonyl, C2-C7 haloalkylcarbonyl, C1-C6 haloalkylthio, C1-C6 alkylsulfmyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, -N(R4)R5, -C(=W)N(R4)R5, -C(=W)0R5, -CN, -OR11 or -NO2; or a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfmyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, -CN, -NO2, -N(R4)R5,
-C(=W)N(R4)R5, -C(=O)OR5 and R7; each R4 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C 4-C7 alkylcycloalkyl, C 4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; each R5 is independently H; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C 4-C7 alkylcycloalkyl or C^C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R6. each R6 is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio,
C1-C6 alkylsulfmyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, C2-Cg dialkylamino, C3-C6 cycloalkylamino, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 halodialkylaminocarbonyl, -OH, -NH2, -CN or -NO2; or Q2; each R7 is independently a phenyl ring or a pyridinyl ring, each ring optionally substituted with one or more substituents independently selected from R8; each R8 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy,
C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-C7 dialkylaminocarbonyl, -OH, -NH2, -C(=O)OH, -CN or -NO2; each Q2 is independently a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfmyl, C1-C6 haloalkylsulfinyl,
C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, -CN, -NO2, -C(=W)N(R9)R10 and -C(=O)OR10; each R9 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; each R10 is independently H; or C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl; each R11 is independently H; or C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C1-C6 alkylsulfonyl or C1-C6 haloalkylsulfonyl; and each W is independently O or S. Embodiment 17a. A compound of Embodiment 17 wherein Z is phenyl optionally substituted with one to five substituents independently selected from R2. Embodiment 17b. A compound of Embodiment 17a wherein Z is phenyl substituted with one to three substituents independently selected from R2, said substituents attached at the 3-, 4- or 5-positions (i.e. meta or para) of the phenyl ring. Embodiment 17c. A compound of Embodiment 17b wherein each R2 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1- C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino, C2-C6 dialkylamino, -CN or -NO2.
Embodiment 17d. A compound of Embodiment 17c wherein each R2 is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy or -CN. Embodiment 18. A compound of Formula 2 wherein R1 is CF3. Embodiment 19. A compound of Formula 2 wherein Q is Qa.
Embodiment 19a. A compound of Embodiment 19 wherein Qa is phenyl substituted with one Q1 attached at the 4-position of the phenyl ring, said phenyl ring further optionally substituted with one or two substituents independently selected from R3
(i.e.
Figure imgf000023_0001
wherein m is 0, 1 or 2).
Embodiment 19b. A compound of Embodiment 19a wherein Q1 is a 5-membered heteroaromatic ring optionally substituted with one or two substituents independently selected from halogen, Cj-C6 alkyl, C^-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, Q-C6 alkoxy, Q-C6 haloalkoxy, -CN,
-C(=W)N(R4)R5 and -C(=O)OR5.
Embodiment 19c. A compound of Embodiment 19b wherein Q1 is a pyrazole or triazole ring optionally substituted with one or two substituents independently selected from halogen, -CN and -C(=W)N(R4)R5. Embodiment 19d. A compound of Embodiment 19a wherein each R3 is independently halogen, C1-C6 alkyl or -CN. Embodiment 19e. A compound of Embodiment 19d wherein one R3 is Cl, CH3 or -CN and is attached at the 3-position of the phenyl ring (i.e. adjacent to Q1). Embodiment 19f. A compound of Embodiment 19b or 19c wherein R4 is H. Embodiment 19g. A compound of Embodiment 19b or 19c wherein R5 is H; or Q-C 3 alkyl, cyclopropyl or cyclopropylmethyl, each optionally substituted with halogen and further optionally substituted with 1 or 2 CH3. Embodiment 20. A compound of Formula 2 wherein Q is Q^. Embodiment 20a. A compound of Embodiment 20 wherein Q^ is 1-naphthalenyl substituted with one or two substituents independently selected from R3
Figure imgf000023_0002
(i.e. 3 wherein n is 1 or 2).
Embodiment 20b. A compound of Embodiment 20 wherein Qb is 1-naphthalenyl substituted with one R3 attached at the 4-position of the naphthalene ring (i.e.
Figure imgf000024_0001
Embodiment 20c. A compound of Embodiment 20a or 20b wherein one R3 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -N(R4)R5, -C(=W)N(R4)R5, -C(=W)OR5, -CN, -OR11 or -NO2, and said R3 is attached at the 4-position of the naphthalene ring.
Embodiment 2Od. A compound of Embodiment 20c wherein the R3 attached at the 4-position of the naphthalene ring is -C(=O)N(R4)R5.
Embodiment 2Oe. A compound of Embodiment 20c or 16d wherein each R4 is independently H, C1-C6 alkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxy carbonyl. Embodiment 2Of. A compound of Embodiment 20c or 2Od wherein each R5 is independently C1-C6 alkyl substituted with one substituent selected from hydroxy, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfmyl, C1-C6 alkylsulfonyl, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 halodialkylaminocarbonyl and Q2. Embodiment 2Og. A compound of Embodiment 20c or 2Od wherein each R5 is independently C1-C2 alkyl substituted with C2-C7 haloalkylaminocarbonyl.
Embodiment 2Oh. A compound of Embodiment 2Of wherein Q2 is a pyridinyl ring optionally substituted with one to four halogen.
Embodiment 2Oi. A compound of Embodiment 20c wherein R11 is H, C2-C6 alkenyl, C2-C6 alkynyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C1-C6 alkylsulfonyl or C1-C6 haloalkylsulfonyl.
Embodiments of this invention, including Embodiments 1-2Oi above as well as any other embodiments described herein, can be combined in any manner, and the descriptions of variables in the embodiments pertain not only to the compounds of Formula 1 and Formula 2 but also to the starting compounds and intermediate compounds useful for preparing the compounds of Formula 1 or Formula 2.
Combinations of Embodiments 1-2Oi are illustrated by: Embodiment A. The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein
Z is phenyl optionally substituted with one to five substituents independently selected from R2; each R2 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino, C2-C6 dialkylamino, -CN or -NO2; and
Qb is 1-naphthalenyl optionally substituted with one to four substituents independently selected from R3.
Embodiment B. The method of Embodiment A wherein Q is Qa. Embodiment C. The method of Embodiment A wherein Q is Qb. Embodiment D. The method of Embodiment B or C wherein in Formulae 1 and 2 R1 is
CF3. Embodiment E. The method of Embodiment D wherein each R2 is independently halogen or C1-C6 haloalkyl; each R3 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C(=W)N(R4)R5, -C(=W)0R5, -CN or -OR11; or a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl,
-CN, -C(=W)N(R4)R5 and -C(=O)OR5; each R4 is independently H or C1-C6 alkyl; each R5 is independently H; or C1-C6 alkyl optionally substituted with one or more substituents independently selected from R6; each R6 is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio,
C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 halodialkylaminocarbonyl or -CN; or Q2; and each Q2 is a pyridinyl ring optionally substituted with one to four halogen. Embodiment El . The method of Embodiment C or D wherein
Figure imgf000025_0001
R2a is halogen, C1-C2 haloalkyl or C1-C2 haloalkoxy;
R2b is H, halogen or cyano;
R2c is H, halogen or CF3;
R3 is C(O)N(R4)R5 or C(O)OR5a; R4 is H, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; and
R5 is C1-C6 alkyl or C1-C6 haloalkyl, each substituted with one substituent independently selected from hydroxy, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfmyl, C1-C6 alkylsulfonyl, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylaminocarbonyl and C3-C9 halodialkylaminocarbonyl; and R5a is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, each optionally substituted with one or more substituents independently selected from halogen, C1-C2 alkoxy and phenyl optionally substituted with up to 5 substituents selected from halogen and C1-C3 alkyl.
Embodiment E2. The method of Embodiment El wherein R3 is C(O)N(R4)R5. Embodiment E3. The method of Embodiment El wherein R3 is C(O)OR5a. Embodiment F. A compound of Formula 2 wherein Z is phenyl optionally substituted with one to five substituents independently selected from R2; each R2 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino, C2-C6 dialkylamino, -CN or -NO2; and Qb is 1-naphthalenyl optionally substituted with one to four substituents independently selected from R3.
Embodiment G. A compound of Embodiment F wherein Q is Qa. Embodiment H. A compound of Embodiment F wherein Q is Qb. Embodiment I. A compound of Embodiment G or H wherein R1 is CF3. Embodiment J. A compound of Embodiment I wherein each R2 is independently halogen or C1-C6 haloalkyl; each R3 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C(=W)N(R4)R5, -C(=W)OR5, -CN or -OR11; or a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl,
-CN, -C(=W)N(R4)R5 and -C(=O)OR5; each R4 is independently H or C1-C6 alkyl; each R5 is independently H; or C1-C6 alkyl optionally substituted with one or more substituents independently selected from R6; each R6 is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio,
C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl, C-C7 haloalkylaminocarbonyl, C3-Cg halodialkylaminocarbonyl or -CN; or Q2; and each Q2 is a pyridinyl ring optionally substituted with one to four halogen. Embodiment K. A compound of Embodiment J wherein each R3 is independently halogen, -C(=W)N(R4)R5, -C(=W)OR5, -CN or -OR11. Embodiment AA. The method described in the Summary of the Invention for preparing a compound of Formula 1 comprising contacting a compound of Formula 2 with hydroxylamine in the presence of a base wherein
Z is phenyl optionally substituted with one to five substituents independently selected from R2; and each R2 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino, C2-C6 dialkylamino, -CN or -NO2.
Embodiment BB. The method of Embodiment AA wherein R1 is CF3;
Z is phenyl substituted with one to three substituents independently selected from R2, said substituents attached at the 3-, 4- or 5-positions (i.e. meta or para) of the phenyl ring; and each R2 is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy or -CN.
Embodiment CC. The method of Embodiment BB wherein Q is Qa.
Embodiment DD. The method of Embodiment CC wherein
Qa is phenyl substituted with one Q1 attached at the 4-position of the phenyl ring, said phenyl ring further optionally substituted with one or two substituents independently selected from R3; Q1 is a 5-membered heteroaromatic ring optionally substituted with one or two substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl,
C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -CN, -C(=W)N(R4)R5 and -C(=O)OR5; and each R3 is independently halogen, C1-C6 alkyl or -CN.
Embodiment EE. The method of Embodiment DD wherein
Q1 is a pyrazole or triazole ring optionally substituted with one or two substituents independently selected from halogen, -CN and -C(=W)N(R4)R5; one R3 is Cl, CH3 or -CN and is attached at the 3 -position of the phenyl ring adjacent to
Q1;
R4 is H; and
R5 is H; or C1-C3 alkyl, cyclopropyl or cyclopropylmethyl, each optionally substituted with halogen and further optionally substituted with 1 or 2 CH3. Embodiment FF. The method of Embodiment BB wherein
Q is Qb. Embodiment GG. The method of Embodiment FF wherein Qb is 1-naphthalenyl substituted with one or two substituents independently selected from R3.
Embodiment HH. The method of Embodiment GG wherein one R3 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -N(R4)R5, -C(=W)N(R4)R5, -C(=W)OR5, -CN, -OR11 or -NO2, and said R3 is attached at the 4-position of the naphthalene ring; each R4 is independently H, C1-C6 alkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl;
R5 is C1-C6 alkyl substituted with one substituent selected from hydroxy, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfϊnyl, C1-C6 alkylsulfonyl, C2-C7 alkylaminocarbonyl, C3-C9 dialkylaminocarbonyl, C2-C7 haloalkylaminocarbonyl, C3-C9 halodialkylaminocarbonyl and Q2; Q2 is a pyridinyl ring optionally substituted with one to four halogen; and R1 * is H, C2-C6 alkenyl, C2-C6 alkynyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C1-C6 alkylsulfonyl or C ^C6 haloalkylsulfonyl.
Embodiment II. The method of Embodiment HH wherein Qb is 1-naphthalenyl substituted with one R3 attached at the 4-position of the naphthalene ring; R3 is -C(=O)N(R4)R5; R4 is H; and
R5 is C1-C2 alkyl substituted with C2-C7 haloalkylaminocarbonyl.
Embodiment JJ. A compound of Formula 2 wherein
Z is phenyl optionally substituted with one to five substituents independently selected from R2; each R2 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino, C2-C6 dialkylamino, -CN or -NO2; and
R1 and Q are as defined in the Summary of the Invention. Embodiment KK. A compound of Embodiment JJ wherein R1 is CF3;
Z is phenyl substituted with one to three substituents independently selected from R2, said substituents attached at the 3-, 4- or 5-positions (i.e. meta or para) of the phenyl ring; and each R2 is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy or -CN.
Embodiment LL. A compound of Embodiment KK wherein
Q is Qa.
Embodiment MM. A compound of Embodiment LL wherein Qa is phenyl substituted with one Q1 attached at the 4-position of the phenyl ring, said phenyl ring further optionally substituted with one or two substituents independently selected from R3;
Q1 is a 5-membered heteroaromatic ring optionally substituted with one or two substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl,
C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy,
-CN, -C(=W)N(R4)R5 and -C(=O)OR5; and each R3 is independently halogen, C1-C6 alkyl or -CN. Embodiment NN. A compound of Embodiment MM wherein Q1 is a pyrazole or triazole ring optionally substituted with one or two substituents independently selected from halogen, -CN and -C(=W)N(R4)R5; one R3 is Cl, CH3 or -CN and is attached at the 3 -position of the phenyl ring adjacent to
Q1;
R4 is H; and R5 is H; or C1-C3 alkyl, cyclopropyl or cyclopropylmethyl, each optionally substituted with halogen and further optionally substituted with 1 or 2 CH3. Embodiment OO. A compound of Embodiment KK wherein Q is Qb.
Embodiment PP. A compound of Embodiment OO wherein Qb is 1-naphthalenyl substituted with one or two substituents independently selected from R3.
Embodiment QQ. A compound of Embodiment PP wherein one R3 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -N(R4)R5,
-C(=W)N(R4)R5, -C(=W)0R5, -CN, -OR11 or -NO2, and said R3 is attached at the 4-position of the naphthalene ring; each R4 is independently H, C1-C6 alkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; R5 is C1-C6 alkyl substituted with one substituent selected from hydroxy, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C7 alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl, C2-C7 haloalkylaminocarbonyl, C3-Cg halodialkylaminocarbonyl and Q2; Q2 is a pyridinyl ring optionally substituted with one to four halogen; and R11 is H, C2-C6 alkenyl, C2-C6 alkynyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl,
C1-C6 alkylsulfonyl or C1-C6 haloalkylsulfonyl. Embodiment RR. A compound of Embodiment QQ wherein
Qb is 1-naphthalenyl substituted with one R3 attached at the 4-position of the naphthalene ring; R3 is -C(=O)N(R4)R5; R4 is H; and
R5 is C1-C2 alkyl substituted with C2-C7 haloalkylaminocarbonyl.
In the following Schemes 1-8 the definitions of R1, R2, R4, R5, Z, and Q in the compounds of Formulae 1 through 9 are as defined above in the Summary of the Invention and description of Embodiments unless otherwise indicated. Formulae Ia, Ib, Ic and Id are subsets of Formula 1.
Scheme 1
Figure imgf000030_0001
base solvent
As shown in Scheme 1, according to the method of this invention a compound of Formula 2 is contacted with hydroxylamine and a base to form a 5-haloalkyl-4,5- dihydroisoxazole compound of Formula 1.
Hydroxylamine can be generated from a mineral acid salt such as hydroxylamine sulfate or hydroxylamine chloride by treatment with a base in a suitable solvent, or can be obtained commercially as 50% aqueous solution. In this method before contact with an enone of Formula 2, hydroxylamine or a mineral acid salt thereof is typically contacted with a base. When a mineral acid salt of hydroxylamine is used, the base is contacted in an amount in excess of the amount needed to convert the hydroxylamine mineral acid salt to hydroxylamine. Base is not consumed in the reaction of Scheme 1, and appears to act as a catalyst for the desired cyclization. Deprotonation of the hydroxylamine with a base prior to contact with an enone of Formula 2 is necessary to obtain good yields, because in the absence of base the reaction of hydroxylamine with enones can afford products other than compounds of Formula 2. Therefore although often about one molar equivalent of base (in addition to any base used to convert a hydroxylamine mineral acid salt to hydroxylamine) is used relative to hydroxylamine, less than one molar equivalent of base can give excellent results. More than one molar equivalent (e.g., up to about 5 molar equivalents) of base relative to hydroxylamine can be used, provided that the excess base does not react with the enone of Formula 2 or the isoxazole of Formula 1. A molar excess of one to three equivalents of hydroxylamine relative to the enone of
Formula 2 can be used. To ensure the cost-effective, complete, and expeditious conversion of the enone of Formula 2 to the isoxazole of Formula 1, in a manner suitable for large-scale production, between about one and about two molar equivalents of hydroxylamine relative to the enone of Formula 2 is typically found to be most suitable. Suitable bases can include, but are not limited to, alkali metal alkoxides such as sodium methoxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, and organic bases. Preferred organic bases are amine bases having at least one pair of free electrons available for protonation such as pyridine, triethylamine or NJV- diisopropylethylamine. Weaker bases such as pyridine can be used, but stronger bases which efficiently deprotonate hydroxylamine, such as an alkali metal alkoxide or an alkali metal hydroxide, typically provide better results. Because water is an especially useful solvent for deprotonating hydroxylamine, as well as forming hydroxylamine from its salts, bases compatible with water are of particular note. Examples of strong bases that are soluble and compatible with water are alkali metal hydroxides. Sodium hydroxide is preferred, because it is inexpensive and works well for deprotonating hydroxylamine, thereby forming the sodium salt of hydroxylamine in aqueous solution. Alkali metal alkoxides are frequently used in solution in a lower alkanol, often the alkanol corresponding to the alkoxide. The method of Scheme 1 is conducted in the presence of a suitable solvent. For best results the solvent should be inert to the base and hydroxylamine, and should be capable of dissolving the enone of Formula 2. Suitable organic solvents include alcohols, ethers, nitriles or aromatic hydrocarbons. Water-miscible solvents such as alcohols (e.g., methanol, isopropanol), ethers (e.g., tetrahydrofuran) or nitriles (e.g., acetonitrile) work well with alkali metal hydroxide bases. Solvents which are non-nucleophilic (e.g., ethers and nitriles) often provide the best results. Particularly when a single solvent is used, the most preferred solvents are tetrahydrofuran and acetonitrile.
Alternatively it may be more desirable to conduct the reaction using a mixture of two solvents formed by contacting a solution of the enone of Formula 2 in a solvent such as tetrahydrofuran or acetonitrile with a solution of hydroxylamine and a base such as sodium hydroxide in a second solvent, which acts as the co-solvent in the solvent mixture. Water is particularly useful as a co-solvent, because mineral acid salts of hydroxylamine and alkali metal hydroxide bases such as sodium hydroxide are particularly soluble in water. The rapid generation of hydroxylamine from its mineral acid salt and subsequent deprotonation of hydroxylamine facilitated by water, and the solubility and stability of the deprotonated species in water are especially desirable. In large-scale production, solutions rather than slurries are preferred, because they are easier to handle and transfer in process equipment. When water is the co-solvent, the other solvent is typically a water-miscible solvent such as tetrahydrofuran or acetonitrile. Other highly polar, hydroxylic solvents such as lower alkanols (e.g., methanol, ethanol) are also particularly useful as co-solvents, because like water they readily dissolve mineral acid salts of hydroxylamine and alkali metal hydroxides. Lower alkanols can give better results than water as a co-solvent when the other solvent is not water-miscible, e.g., tert-butyl methyl ether. When a lower alkanol is used as a co-solvent, particularly with another solvent that is not water-miscible, the base added is often an alkali metal alkoxide instead of an alkali metal hydroxide.
As long as base is present to deprotonate hydroxylamine, the hydroxylamine, the base and the enone of Formula 2 can be contacted in a variety of ways in the method of Scheme 1. For example, a mixture formed from hydroxylamine and the base (typically in a solvent such as water) can be added to the enone of Formula 2 (typically in a solvent such as tetrahydrofuran or acetonitrile). Alternatively, the hydroxylamine and the base can be concurrently added separately to the enone of Formula 2. In another embodiment, the enone of Formula 2 (typically in a solvent such as tetrahydrofuran or acetonitrile) can be added to a mixture formed from the hydroxylamine and the base (typically in a solvent such as water).
In these example embodiments other combinations of solvents can be used; for example, methanol with tert-butyl methyl ether instead of water with tetrahydrofuran or acetonitrile.
The method of Scheme 1 can be conducted at a reaction temperature between about 0 and 150 0C, or most conveniently between 20 and 40 0C. The product of Formula 1 is isolated by the usual methods known to those skilled in the art including extraction and crystallization.
Scheme 2
Figure imgf000032_0001
Compounds of Formula 2 can be prepared by dehydration of compounds of Formula 3 as shown in Scheme 2 according to the general method of Sosnovskikh et al., J. Org. Chem. USSR/(Eng. Trans.), 1992, 28, 420.
This method involves portion-wise addition of a dehydrating agent such as thionyl chloride to a mixture of a compound of Formula 3 and a base in an organic solvent such as toluene to provide a compound of Formula 2. About two molar equivalents of thionyl chloride relative to the compound of Formula 3 are typically required for high levels of conversion to the compound of Formula 2.
Bases useful in the method of Scheme 2 include amine bases such as pyridine. About three molar equivalents of pyridine relative to the compound of Formula 3 is typically necessary to achieve the conversion of the compound of Formula 3 to the compound of Formula 2.
The method of Scheme 2 is generally conducted using a reaction temperature in the range of about 50 to about 80 0C, more commonly in the range of about 60 to about 65 0C. After the reaction mixture is treated with water to remove salts, the product can be isolated by the usual methods known to one skilled in the art such as extraction and crystallization.
As shown in Scheme 3, compounds of Formula 2 can also be prepared from addition- elimination reactions of organometallic reagents such as Grignard reagents of Formula 4 with β-enamines or β-haloenones of Formula 5.
Scheme 3
ZMgBr
Figure imgf000033_0001
solvent
wherein X is a secondary amine or halogen
The reaction can be run in a variety of solvents including tetrahydrofuran, diethyl ether, dioxane or methylene chloride, and optimum temperatures range from about -78 0C to the refluxing temperature of the solvent. General procedures for additions of Grignard reagents to enamines and haloenones are well documented in the chemical literature; see for example, Jeong et al., Journal of Fluorine Chemistry 2004, 125, 1629-1638, as well as references cited within. The method of Scheme 3 is illustrated in Reference Example 1 , Step B.
Alternatively, as shown in Scheme 4, a compound of Formula 2 can be formed by condensation of a ketone of Formula 6 with a phosphonate compound of Formula 7 according to the Wadsworth-Emmons modification of the Wittig Reaction.
Scheme 4
Figure imgf000033_0002
wherein R is, for example, methyl or ethyl
In this method, the phosphonate compound of Formula 7 is deprotonated with a base such as pyridine, triethylamine, NaH, NaHCθ3 or lithium diisopropylamide (LDA) in a solvent such as tetrahydrofuran, diethyl ether, dioxane or methylene chloride to form a ylid intermediate, and the ketone of Formula 6 is added to provide the compound of Formula 2. Optimum temperatures range from about 0 0C to the refluxing temperature of the solvent. The general reaction conditions of the Wittig Reaction are well documented in the chemical literature. For example, see Dull et al., J. Org. Chem. 1967, 32, 1622-1623. A wide variety of methods exist for the preparation of β-hydroxyketone compounds of
Formula 3. For example, ketones can be combined under acidic, or more commonly basic conditions, to provide compounds of Formula 3. The aldol condensation has been extensively reviewed (e.g., Organic Reactions, 1968, 16, 1), and wide range of conditions have been used to achieve this transformation. This reaction is illustrated in Scheme 5.
Scheme 5
Figure imgf000034_0001
6 8
Some of the conditions usually employed in the aldol condensadtion may be precluded by the reactivity of compounds of Formula 6 (e.g., wherein R1 is CF3) and compounds of Formula 3 (e.g., wherein R1 is CF3) with nucleophiles. A compound of Formula 3 wherein R1 is CF3 can be prepared by addition of a non-nucleophilic base such as lithium hydride (Sosnovskikh et al, J. Org. Chem. USSR (Eng. Trans.), 1992, 28, 420), or potassium carbonate to a mixture of a ketone of Formula 6 and a ketone of Formula 8 in a suitable non- nucleophilic organic solvent such as tetrahydrofuran, hexanes, toluene, or acetonitrile. Usually, more than one molar equivalent of the base relative to the ketone of Formula 8 used.
Alternatively small changes in the reaction conditions can be used to prepare compounds of Formula 2 directly from compounds of Formula 6 and compounds of Formula 8. For example suitable conditions, such as treatment with a mixture comprising potassium carbonate and acetonitrile at about 82 0C, can be used to prepare compounds of Formula 2. Compounds of Formula 2 can also be prepared directly from compounds of Formula 6 and compounds of Formula 8 by treatment with calcium hydroxide in N,Λ/-dimethylformamide and tert-butyl methyl ether, and then heating the mixture to reflux with azeotropic removal of water. These reactions are usually conducted at temperatures ranging from about 25 0C to the boiling point of the solvent(s). If the reaction is conducted using a base such as lithium diisopropylamide or lithium bis(trimethylsilyl)amide, which may react with compounds of Formula 6 wherein R1 is CF3 (Gosselin et al., Organic Letters 2005, 7, 355), the order of addition of the components of the reaction becomes important. The most preferred order of addition is the metered addition of a ketone of Formula 8 to a base such as lithium diisopropylamide at about -78 0C in a solvent such as tetrahydrofuran. The enolate formed can then be contacted with a compound of Formula 6 at about -78 0C to afford the desired compound of Formula 3. The product can be isolated by methods well known to one skilled in the art such as extraction, crystallization, etc. Ketones of Formula 6 and Formula 8 can be prepared by numerous methods described in the general literature.
In another aspect of the present invention, certain compounds of Formula 1 (e.g., compounds of Formula 1 wherein Q is Q^ and Q^ is 1-naphthalenyl substituted in the 4-position with -C(=O)OR5) prepared by the method of Scheme 1, are useful for preparing compounds of Formula Ia, which are particularly useful as insecticides.
Figure imgf000035_0001
wherein R2, R4 and R5 are as defined in the Summary of the Invention. A variety of routes are possible for the preparation of compounds of Formula Ia from compounds of Formula 1. As outlined in Scheme 6, one such method involves the aminocarbonylation of a compound of Formula Ib with an appropriately substituted amine compound of Formula 9 wherein R2, R4 and R5 are defined in the Summary of the Invention.
Scheme 6
Figure imgf000035_0002
This reaction is typically carried out with an aryl bromide of Formula Ib in the presence of a palladium catalyst under a CO atmosphere. The palladium catalyst used for the present method typically comprises palladium in a formal oxidation state of either 0 (i.e. Pd(O)) or 2 (i.e. Pd(II)). A wide variety of such palladium-containing compounds and complexes are useful as catalysts for the present method. Examples of palladium-containing compounds and complexes useful as catalysts in the method of Scheme 6 include PdCl2(PPh3)2 (bis(triphenylphosphine)palladium(II) dichloride), Pd(PPh3)4
(tetrakis(triphenylphosphine)palladium(O)), Pd^HyC^ (palladium(II) acetylacetonate), Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(O)), and [l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II). The method of Scheme 6 is generally conducted in a liquid phase, and therefore to be most effective the palladium catalyst preferably has good solubility in the liquid phase. Useful solvents include, for example, ethers such as 1,2- dimethoxyethane, amides such as 7V,iV-dimethylacetamide, and non-halogenated aromatic hydrocarbons such as toluene.
The method of Scheme 6 can be conducted over a wide range of temperatures, ranging from about 25 to about 150 0C. Of note are temperatures from about 60 to about 110 0C, which typically provide fast reaction rates and high product yields. The general methods and procedures for aminocarbonylation with an aryl bromide and an amine are well known in the literature; see, for example, H. Horino et al., Synthesis 1989, 715; and J. J. Li, G. W. Gribble, editors, Palladium in Heterocyclic Chemistry: A Guide for the Synthetic Chemist, 2000.
Another method of preparing compounds of Formula Ia is shown in Scheme 7. In this method a carboxylic acid of Formula Ic is coupled with an appropriately substituted amine compound of Formula 9.
Scheme 7
Figure imgf000036_0001
This reaction is generally carried out in the presence of a dehydrating coupling reagent such as dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-propanephosphonic acid cyclic anhydride or carbonyl diimidazole in the presence of a base such as triethylamine, pyridine, 4-(dimethylamino)pyridine or JV,jV-diisopropylethylamine in an anhydrous aprotic solvent such as dichloromethane or tetrahydrofuran at a temperature typically between 25 and 70 0C.
Compounds of Formula Ic can be prepared by hydrolysis of esters of Formula Id, wherein R5 is methyl or ethyl, as shown in Scheme 8. Scheme 8
Figure imgf000037_0001
wherein R is methyl or ethyl
In the method of Scheme 8, an ester of Formula Id is converted to a corresponding carboxylic acid of Formula Ic by general procedures well known in the art. For example, treatment of a methyl or ethyl ester of Formula Id with aqueous lithium hydroxide in tetrahydrofuran, followed by acidification yields the corresponding carboxylic acid of
Formula Ic.
It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula 1 may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula 1. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula 1. One skilled in the art will also recognize that compounds of Formula 1 and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.
Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Synthesis Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Steps in the following Synthesis Examples illustrate a procedure for each step in an overall synthetic transformation, and the starting material for each step may not have necessarily been prepared by a particular preparative run whose procedure is described in other Examples or Steps. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. 1H NMR spectra are reported in ppm downfϊeld from tetramethylsilane; "s" means singlet, "d" means doublet, "t" means triplet, "q" means quartet, "ABq means AB quartet, "m" means multiplet, "dd" means doublet of doublets, "dt" means doublet of triplets and "br" means broad. The symbol "~" means approximately. LCMS refers to liquid chromatography-mass spectrometry.
SYNTHESIS EXAMPLE 1
Preparation of l-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten- 1-one
Step A: Preparation of 4-bromo-N-methoxy-N,3-dimethylbenzamide
A stirred suspension of 4-bromo-3-methylbenzoic acid (15 g, 69.0 mmol) in thionyl chloride (60 mL) was heated at reflux for 2 h and then concentrated under reduced pressure.
The residual acyl chloride was dissolved in dichloromethane (300 mL) and added to a stirred solution of Λ/,O-dimethylhydroxylamine hydrochloride (7.2 g, 72.0 mmol) and pyridine
(16.8 mL, 207.0 mmol) in dichloromethane (450 mL) at -20 0C. The reaction mixture was allowed to warm to room temperature overnight and then washed with 1 M aqueous potassium carbonate solution. The aqueous solution was extracted with dichloromethane.
The organic extracts were concentrated under reduced pressure. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes as eluent to afford the title product as a pale yellow oil (17.81 g, 69.0 mmol, 100% yield).
1H NMR (CDCl3): 7.55 (m, 2H), 7.37 (m, IH), 3.54 (s, 3H), 3.34 (s, 3H), 2.42 (s, 3H).
Step B: Preparation of l-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4- trifluoro-2-buten- 1 -one To a stirred solution of diisopropylamine (11.1 mL, 83.3 mmol) in tetrahydrofuran
(100 mL) at -78 0C was added 2.5 M /?-BuLi in hexanes (33.31 mL, 83.3 mmol). The reaction mixture was allowed to warm to 0 0C, stirred for 20 minutes, and then cooled to -78 0C. 2-Bromo-3,3,3-trifluoropropene (6.78 g, 38.7 mmol) was added to the reaction mixture, which was stirred for 30 minutes. Then a solution of 4-bromo-N-methoxy- JV,3-dimethylbenzamide (i.e. the title product of Step A) (5.0 g, 19.4 mmol) in tetrahydrofuran (20 mL) was added to the reaction mixture at -78 0C, which was then warmed to 0 0C. Water (25 mL) was added to the mixture, which was then stirred for 1 hour at 0 0C. The reaction mixture was extracted with ether and concentrated under reduced pressure, and the oily residue was purified by chromatography on silica gel to afford a mixture of 3-[bis(l-methylethyl)amino]-l-(4-bromo-3-methylphenyl)-4,4,4-trifluoro-2- buten- 1 -one and 1 -(4-bromo-3-methylphenyl)-4,4,4-trifluoro-3-(methoxymethylamino)-2- buten- 1-one (2.5:1 ratio by LCMS) (6.55 g, approx. 92% yield) as a bright orange oil. This crude mixture (3 g, approx. 8.5 mmol) was diluted with tetrahydrofuran (40 rnL) and cooled to -78 0C, and 3,5-dichlorophenylmagnesium bromide (0.5 M in tetrahydrofuran) (51 mL, 25.5 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 2 h, then quenched with an aqueous solution of saturated ammonium chloride, and extracted with diethyl ether. The organic solution was concentrated under reduced pressure, and the residual oil was purified by chromatography on silica gel using 10% ethyl acetate/hexanes as eluant to afford the title product as a yellow oil (3.24 g, 87% yield).
SYNTHESIS EXAMPLE 2 Preparation of l-(4-bromo-l -naphthalenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-l- one
Step A: Preparation of l-(4-bromo-l-naphthalenyl)-3-(3,5-dichlorophenyl)-4,4,4- trifluoro-3 -hydroxy- 1 -butanone
Lithium diisopropylamide (Aldrich Chemical Company, 2M in tetrahydrofuran/ ethylbenzene, 4 mL, 7.94 mmol) was added to tetrahydrofuran (4 mL) at -78 0C. A solution of l-(4-bromo-l-naphthalenyl)ethanone (1.8 g, 7.22 mmol) in tetrahydrofuran (4 mL) was added dropwise to the mixture. When the addition was complete the mixture was stirred for 30 min at -78 0C. Then a solution of l-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (1.75 g, 7.20 mmol) in tetrahydrofuran (4 mL) was added dropwise to the mixture at such a rate that the temperature of the reaction mixture did not exceed -55 0C. The mixture was allowed to warm to ambient temperature over 120 min. The mixture was then poured into IN hydrochloric acid (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined extracts were dried and evaporated. Chromatography on silica gel (eluted with 1 :9 ethyl acetate/ hexanes) and crystallization from hexanes gave the title product as a white solid (1.1 g, 40% yield) melting at 74.5-75 0C (after recrystallization from hexanes). IR (nujol) 3409, 1684, 1569, 1505, 1407, 1343, 1232, 1170, 1141, 1121 cm-1.
1H NMR (CDCl3) δ 8.38-8.30 (m, 2H), 7.90 (d, J=7.7 Hz, IH), 7.73-7.61 (m, 3H), 7.52 (s, 2H), 7.36 (t, J=I.8 Hz, IH), 5.86 (s, IH), 3.87 (1/2ABq, J=17.1 Hz, IH), 3.80 (1/2ABq, J=IlA Hz, IH).
Step B: Preparation of l-(4-bromo-l-naphthalenyl)-3-(3,5-dichlorophenyl)-4,4,4- trifluoro-2-buten- 1 -one
A solution of thionyl chloride (0.5 g, 4.46 mmol) in toluene (2 mL) was added dropwise to the product of Step A (1.1 g, 2.23 mmol) in toluene (10 mL) at 65 0C. The mixture was cooled to ambient temperature and then poured into IN hydrochloric acid (50 mL). The resulting mixture was extracted with ethyl acetate (2 x 25 mL). The combined extracts were dried and evaporated to give the title product as an oil (1.0 g, 95% yield).
1H NMR (CDCl3) δ 9.16-9.13 (m, ~ 0.23 H), 8.51-8.45 (m, ~ 0.77 H), 8.40-8.39 (d, ~ 0.23 H), 8.30-8.26 (m, 0.77 H), 7.91-6.99 (m, 8H). SYNTHESIS EXAMPLE 3 Preparation of l-(3-bromo-4-fluorophenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-
1-one
Step A: Preparation of l-(3-bromo-4-fluorophenyl)-3-(3,5-dichlorophenyl)-4,4,4- trifluoro-3 -hydroxy- 1 -butanone
Lithium diisopropylamide (Aldrich Chemical Company, 2M in tetrahydrofuran/ ethylbenzene 10.18 mL, 20.36 mmol) was added to tetrahydrofuran (8 mL) at -78 0C. A solution of l-(3-bromo-4-fluorophenyl)ethanone (4.01 g, 18.47 mmol) in tetrahydrofuran (8 mL) was added dropwise to the mixture. When the addition was complete the mixture was stirred at -78 0C for 30 min. Then a solution of l-(3,5-dichlorophenyl)-2,2,2- trifluoroethanone (4.50 g, 18.52 mmol) in tetrahydrofuran (8 mL) was added dropwise to the mixture so the temperature of the reaction mixture did not exceed -60 0C. After the addition was complete the mixture was stirred at -78 0C for 60 min. The mixture was allowed to warm to 0 0C and then poured into IN hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate (2 x 100 mL), and the combined extracts were dried and evaporated. Chromatography of the residue on silica gel (eluted with 1 :4 ethyl acetate/hexanes) gave the title product as a white solid (3.32 g, 39% yield) melting at 134— 135 0C (after crystallization from ethyl acetate/hexanes). IR (nujol) 3466, 1679, 1591, 1571, 1346, 1252, 1236, 1213, 1185, 1159, 1142, 1054, 825, 803 cm-1.
1H NMR (CDCl3), δ 8.16 (dd, J=6.5,2.2 Hz, IH), 7.94-7.89 (m, IH), 7.48 (s, 2H), 7.36 (s, IH), 7.26 (t, J=8.2 Hz, IH), 5.55 (s, IH), 3.80 (1/2 ABq, J=17.5 Hz, IH), 3.65 (1/2 ABq, J=17.5 Hz, IH).
Step B: Preparation of l-(3-bromo-4-fluorophenyl)-3-(3,5-dichlorophenyl)-4,4,4- trifluoro-2-buten-l-one
To a solution of thionyl chloride (0.618 g, 5.52 mmol) in toluene (1 mL) was added to a mixture of the product from Step A (1.2 g, 2.60 mmol) and pyridine (0.41 g, 5.18 mmol) in toluene (15 mL) at 60-65 0C. When the addition was complete, pyridine (0.2 g, 2.53 mmol) was added incrementally to the reaction mixture. When the addition was complete, the mixture was allowed to cool to ambient temperature and then poured into IN hydrochloric acid (100 mL). The resulting mixture was extracted with ethyl acetate (2 x 50 mL) and the combined extracts dried and evaporated to give the title product as an oil (1.12 g, 97% yield).
IR (neat) 1681, 1588, 1561, 1492, 1399, 1282, 1211, 1185, 1139, 1048, 866, 822, 806, 709 cm-1.
1H NMR (CDCl3), δ 8.21-8.18 (m, -0.18H), 8.06-8.03 (m, -0.82H), 7.92-7.88 (m,
-0.18H), 7.80-7.76(m, -0.82H), 7.49-6.81 (m, 5H). SYNTHESIS EXAMPLE 4 Preparation of 3-(4-bromo-l-naphthalenyl)-5-(3,5-dichlorophenyl)-4,5-dihydro-5-
(trifluoromethyl)isoxazole
To a solution of hydroxylamine sulfate (0.18 g, 1.10 mmol) in water (1 mL) was added a solution of sodium carbonate (0.7 g, 6.6 mmol) in water (2 mL). The resulting mixture was added to a solution of the product of Synthesis Example 2, Step B (0.7 g, 1.48 mmol) in isopropanol (11 mL). The mixture was stirred at ambient temperature overnight. A further portion of the hydroxylamine sulfate (0.18 g, 1.09 mmol), sodium carbonate (0.7 g,
6.6 mmol), and water (3 mL) mixture was prepared as before and then added to the reaction mixture. After stirring for a further 24 h the mixture was poured into water (25 mL), and the resulting mixture was extracted with ethyl acetate (2 x 25 mL). The combined extracts were dried and evaporated under reduced pressure. Chromatography of the residue on silica gel
(eluted with hexanes/ether, 9:1) gave the title product as a white solid (0.35 g, 48%) melting at 131-132 0C (after recrystallization from hexanes). IR(nujol) 1591, 1569, 1508, 1426, 1329, 1303, 1280, 1261, 1191, 1170, 1127, 1011, 898,
821, 801 cm-1.
1H NMR (CDCl3) δ 8.92-8.88 (m, IH), 8.38-8.34 (m, IH), 7.82 (d, J=7.7Hz, IH), 7.71- 7.68 (m, 2H), 7.57 (d, J=I.3 Hz, 2H), 7.46 (d, J=2 Hz, IH), 7.37 (d, J=7.7 Hz, IH), 4.27 (1/2 ABq,J=17.1 Hz, IH), 3.90 (1/2 ABq, J=18.1 Hz, IH).
SYNTHESIS EXAMPLE 5 Preparation of 3-(3-bromo-4-fluorophenyl)-5-(3,5-dichlorophenyl)-4,5-dihydro-
5 -(trifluoromethyl)isoxazole
Aqueous sodium hydroxide (50%, 1.36 g, 17.0 mmol) was added to a solution of hydroxylamine sulfate (0.70 g, 4.26 mmol) in water (8 mL). When the mixture had cooled to ambient temperature it was added to a solution of the product of Synthesis Example 3, Step B (1.8 g, 4.07 mmol) in tetrahydrofuran (20 mL). After the addition was complete the mixture was stirred for 20 min. The mixture was poured into water (150 mL), and the resulting mixture was extracted with ethyl acetate (2 x 100 mL). The combined extracts were dried and evaporated. Crystallization from hexanes gave the title product as an off- white solid (1.44 g, 77%) melting at 132-132.5 0C (after recrystallization from hexanes). IR (nujol) 1570, 1500, 1422, 1407, 1341, 1302, 1274, 1179, 1166, 1118, 1012, 913, 862,
822, 801 cm-1.
1H NMR (CDCl3) δ 7.86 (dd, J=6.3,2.4 Hz, IH), 7.66-7.61 (m, IH), 7.50 (d, J=I.3 Hz, IH), 7.44-7.43 (m, IH), 7.19 (t, J=8.4 Hz, IH), 4.05 (1/2 ABq, J=17.4 Hz, IH), 3.67 (1/2 ABq, J=IlA Uz, IH). SYNTHESIS EXAMPLE 6 Preparation of 3-(4-bromo-2-methylphenyl)-5-(3,5-dichlorophenyl)-4,5-dihydro-
5 -(trifluoromethyl)isoxazole
To a stirred solution of l-(4-bromo-2-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4- trifluoro-2-buten-l-one (200 mg, 0.45 mmol) in pyridine (3 rnL) at room temperature was added hydroxylamine hydrochloride (47 mg, 0.68 mmol). The reaction mixture was heated to reflux for 4 h. The resulting mixture was cooled to room temperature and then concentrated, and the residual oil was purified by chromatography on silica gel using 20:80 ethyl acetate/hexanes as eluent to afford the title product as a pale yellow oil (50 mg, 24% yield).
1H NMR (CDCl3): 7.17-7.50 (m, 6H), 4.1 l(d, IH), 3.74 (d, IH), 2.54 (s, 3H).
SYNTHESIS EXAMPLE 7
Preparation of 4-[5 - [3 -chloro-5 -(trifluoromethyl)phenyl] -4,5 -dihydro-5 -(trifluoromethyl)-3 - isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-l- naphthalenecarboxamide Step A: Preparation of 4-acetyl- 1 -naphthalenecarbonyl chloride
Thionyl chloride (35.00 g, 0.29 mol) was added to 4-acetyl- 1-naphthalenecarboxylic acid (51.70 g, 0.24 mol) in toluene (350 mL). The mixture was warmed to 90 0C for 8.5 h. After cooling to 25 0C, the solvent was removed under reduced pressure to give the title product as an off-white solid (55.1 g, 98.7% yield).
IR (nujol) 1758, 1681, 1515, 1352, 1282, 1245,1218, 1190, 1117, 1053, 923, 762 cm-1. 1H NMR (CDCl3): 8.72-8.69 (m, IH), 8.50 (d, J=7.6 Hz, IH), 8.44-8.41 (m, IH), 7.82 (d, J=7.9 Hz, IH), 7.76-7.65 (m, 2H), 2.77 (s, 3H). Step B: Preparation of 4-acetyl-Λ/-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-l- naphthalenecarboxamide
A solution of 2-amino-Λ/-(2,2,2-trifluoroethyl)acetamide (21.90 g, 0.14 mol) in 1,2- dichloroethane (80 mL) was added dropwise over 15 min to the product of Synthesis Example 7, Step A (32.50 g, 0.14 mol) in 1 ,2-dichloroethane (160 mL) at a temperature of 25 to 30 0C. The resulting mixture was further stirred for 10 min at 25 0C. Triethylamine (14.20 g, 0.14 mol) in 1 ,2-dichloroethane (80 mL) was then added dropwise over 44 min at 25 0C, and the mixture was stirred further for 20 min at 25 0C. The solvent was removed under reduced pressure, and the residue was dissolved in hot acetonitrile (50 mL). The mixture was then cooled to 25 0C, and water (40 mL) was added dropwise. The mixture was further cooled to 0 0C and filtered. The isolated solid was washed with water (100 mL) and dried overnight in a vacuum oven (approximately 16-33 kPa at 50 0C) to provide the title product as an off-white solid (37 g, 75% yield) melting at 169-169 0C. IR (nujol) 3303, 3233, 3072, 1698, 1683, 1636, 1572, 1548, 1447, 1279, 1241, 1186, 1159 cm"1.
1H NMR (CD3S(O)CD3): 8.95 (t, J=5.8 Hz, IH), 8.72 (t, J=6.5 Hz, IH), 8.55 (dd, J=6.5, 2 Hz, IH), 8.37-8.33 (m, IH), 8.13 (d, J=7.3 Hz, IH), 7.70-7.60 (m, 3H), 4.07-3.95 (m, 4H), 2.75 (s, 3H).
Step C: Preparation of 4-[3-[3-chloro-5-(trifluoromethyl)phenyl]-4,4,4-trifluoro-l- oxo-2-buten-l-yl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-l- naphthalenecarboxamide A mixture of the product of Synthesis Example 7, Step B (10.00 g, 28.38 mmol), l-[3- chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethanone (9.00 g, 32.5 mmol), calcium hydroxide (1.05 g, 14.2 mmol), Λ/,Λ/-dimethylformamide (20 mL) and tert-butyl methyl ether (32 mL) was placed in a thermometer-equipped reaction vessel. The reaction vessel was connected to a ten-plate Oldershaw column, the output of which was condensed and fed into a decanter initially filled with tert-butyl methyl ether. A nitrogen atmosphere was maintained in the apparatus. The upper part of the decanter was connected to return condensate to the fifth plate of the Oldershaw column. This arrangement ensured that wet (containing dissolved water) tert-butyl methyl ether was not returned from the decanter to the reaction vessel. A drain valve at the bottom of the decanter allowed removing tert-butyl methyl ether in addition to water from the decanter. The reaction mixture was heated to distill the tert-butyl methyl ether/water azeotrope. As the decanter trap contained an amount of tert-butyl methyl ether sufficient to dissolve all of the water formed by the reaction, the condensate in the trap did not separate into layers containing predominately water and predominately tert-butyl methyl ether. Because the reaction mixture initially contained mostly tert-butyl methyl ether, the mixture boiled at a temperature not much exceeding the normal boiling point of tert-butyl methyl ether (e.g., about 65-70 0C). The reaction proceeded relatively slowly at this temperature, so condensate was gradually drained from the decanter trap to remove tert-butyl methyl ether. As the concentration of tert-butyl methyl ether decreased in the reaction mixture, the temperature of the boiling mixture increased. Tert-butyl methyl ether was removed by draining the decanter until the temperature of the boiling reaction mixture reached about 85 0C. To maintain this temperature, tert-butyl methyl ether was added as needed to compensate for loss of solvent from the apparatus. The total time from the start of heating the reaction mixture to stopping distillation, not including a shutdown period overnight, was about 6 h.
To isolate the product, the mixture was cooled to room temperature and was added to a mixture of tert-butyl methyl ether (50 mL) and IN hydrochloric acid (100 mL). The organic phase was separated, and heptane (60 mL) was added dropwise. The mixture was filtered to provide the title product as an off white solid mixture of isomers (14 g, 81% yield) melting at 174.5-177 0C. IR (nujol) 3294, 1697, 1674, 1641, 1541, 1441, 1364, 1313, 1275, 1246, 1163, 1104 cm-1. 1H NMR (CD3S(O)CD3): (major isomer) 8.91 (t , J=6.2 Hz, IH), 8.73 (t, J=6.4 Hz, IH), 8.44-8.30 (m, 2H), 8.18 (d, J=7.7 Hz, IH), 7.97-7.61 (m, 7H), 4.06-3.95 (m, 4H). Step D: Preparation of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5- (trifluoromethyl)-3-isoxazolyl]-Λf-[2-oxo-2-[(2,2,2- trifluoroethyl)amino]ethyl]- 1 -naphthalenecarboxamide
Aqueous sodium hydroxide (50%, 3.04 g, 38.0 mmol) was added dropwise to a stirred solution of hydroxylamine sulphate (1.48 g, 9.02 mmol) in water (28 mL) at 25 0C. After this addition was complete the product of Synthesis Example 7, Step C (10.00 g, 16.33 mmol) in tetrahydrofuran (60 mL) was added dropwise over 40 min. After the addition was complete the mixture was stirred further for 30 min. The solvent was removed under reduced pressure and IN hydrochloric acid (100 mL) was added. The mixture was extracted with ether (2 x 100 mL) and the combined extracts were dried and evaporated. The residue was dissolved in acetonitrile (30 mL), cooled to 0 0C, and filtered to afford the title product as a white solid (7.84 g, 77% yield) melting at 107-108.5 0C (after recrystallisation from acetonitrile).
IR (nujol) 3312, 1681, 1642, 1536, 1328, 1304, 1271, 1237, 1173, 1116 cm-1. 1H NMR (CD3S(O)CD3): 8.98 (t, J=5.8 Hz, IH), 8.82 (d, J=7.4 Hz, IH), 8.74 (t, J=6.5 Hz, IH), 8.40 (d, J=9.7 Hz, IH), 8.09 (d, J=15.3 Hz, 2H), 7.93 (d, J=7.6 Hz, 2H), 7.75-7.04 (m, 3H), 4.63 (s, 2H), 4.07-3.96 (4H, m).
SYNTHESIS EXAMPLE 8 Preparation of methyl 4- [5 - [3 -chloro-5 -(trifluoromethyl)phenyl] -4,5 -dihydro-5 -
(trifluoromethyl)-3 -isoxazoly 1] - 1 -naphthalenecarboxylate Step A: Preparation of methyl 4-[3-[3-chloro-5-(trifluoromethyl)phenyl]-4,4,4- trifluoro- 1 -oxo-2-buten- 1 -yl] - 1 -naphthalenecarboxylate
A mixture of methyl 4-acetyl-l -naphthalenecarboxylate (7.83 g, 34.3 mmol), l-[3- chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethanone (10.43 g, 37.71 mmol), calcium hydroxide (1.25 g, 16.9 mmol), Λ/,Λ/-dimethylformamide (27 mL) and tert-butyl methyl ether (44 mL) was heated to reflux. The tert-butyl methyl ether/water azeotrope was removed as described in Synthesis Example 7, Step C. As the decanter trap contained an amount of tert- butyl methyl ether sufficient to dissolve all of the water formed by the reaction, the condensate in the trap did not separate into layers containing predominately water and predominately tert-butyl methyl ether. Tert-butyl methyl ether was removed by gradually draining the decanter trap until the reaction temperature was 85 0C. To maintain this temperature, tert-butyl methyl ether was added as needed to compensate for loss of solvent from the apparatus. The total time from the start of heating the reaction mixture to stopping distillation was about 4.5 h. The mixture was cooled to 25 0C and poured into a mixture of 0.5 N hydrochloric acid (100 mL) and tert-butyi methyl ether (50 mL). The mixture was acidified with concentrated hydrochloric acid and evaporated, and the residue was crystallized from hexanes (40 mL) to give the title product as a yellow solid (13.24 g, 79% yield) melting at 90-90.5 0C (after recrystallization from hexanes).
IR(nujol) 3071, 1721, 1710, 1671, 1516, 1439, 1316, 1280, 1252, 1178, 1129, 1103, 1026, 888, 861 cm-1.
1H NMR (CDCl3): 8.77-8.73 (m, IH), 8.28-8.25 (m, IH), 8.0 (d, J= 7.6 Hz, IH), 7.67-7.60 (m, 3H), 7.40 (d, J= 1.4 Hz, IH), 7.32 (s, IH), 7.23 (s, IH), 7.20 (s, IH), 4.02 (s, 3H). Step B: Preparation of methyl 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-
5 -(trifluoromethyl)-3 -isoxazolyl] - 1 -naphthalenecarboxylate
Aqueous sodium hydroxide (50%, 2.08 g, 25.5 mmol) was added dropwise to a stirred solution of hydroxylamine sulfate (1.07 g, 6.52 mmol) in water (20 mL) at 25 0C. After this addition was complete the product of Synthesis Example 8, Step A (5 g, 10.27 mmol) in tetrahydrofuran (20 mL) was added dropwise over 40 min. After the addition was complete the mixture was stirred further for 30 min. The organic phase was separated and added to hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate (2 x 20 mL). The organic solvent was evaporated under reduced pressure. The residue was redissolved in acetic acid (16 mL) and then warmed to 100 0C. Water (2 mL) was added dropwise and the mixture was cooled to 50 0C. The mixture was seeded with a small amount of previously prepared methyl 4-[5 - [3 -chloro-5 -(trifluoromethyl)phenyl]-4,5 -dihydro-5 -(trifluoromethyl)- 3 -isoxazolyl] -1 -naphthalenecarboxylate and then cooled to 25 0C. Water (2 mL) was added and the mixture was cooled to 0 0C. The mixture was filtered and the solid was washed with acetic acid:water (8 mL:2 mL). The solid was dried in a vacuum oven to give the title product as a white solid (3.91 g, 76% yield) melting at 111.5-112 0C (after recrystallisation from acetonitrile).
IR(nujol) 1716, 1328, 1306, 1287, 1253, 1242, 1197, 1173, 1137, 1114, 1028,771 cm-1. 1H NMR (CDCl3): 8.90-8.87 (m, IH), 8.82-8.79 (m, IH), 8.10 (d, J=7.7 Hz), 7.87 (s, IH), 7.81 (s, IH), 7.72-7.67 (m, 3H) 7.55 (d, J=7.6 Hz, IH), 4.34 (1/2 ABq, J=17.3 Hz, IH), 4.03 (s, 3H), 3.93 (1/2 ABq, j=17.3 Hz, IH).
The following compounds of Formula 2 defined in Tables 1 to 14 are prepared from corresponding hydroxy ketone compounds of Formula 3 as shown in Scheme 2 by the procedures described herein together with methods known in the art. The compounds listed in Tables 1 to 14 further illustrate the method of Scheme 1, as each of these specifically identified compounds contacted with hydroxylamine and in the presence of base is converted according to the method to specific corresponding 4,5-dihydroisoxazole compounds of Formula 1. In Tables 1-14: Et means ethyl, Me means methyl, CN means cyano, Ph means phenyl, Py means pyridinyl, c-Pr means cyclopropyl, z-Pr means isopropyl, t-Bu means tertiary butyl, SMe means methylthio, SO2 means sulfonyl and Thz means thiazole. Concatenations of groups are abbreviated similarly; for example, "SO2Me" means methylsulfonyl.
TABLE 1
Figure imgf000046_0001
R2a is CL R2b is H, R2c is Cl
Ei Ei si
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3
CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3
CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is CL R2b is CL R2c is Cl
Ei Ei si
CH2CH3 CH2-C-Pr CH2CH2SO2Et Ei Ei si
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is CL R2b is F. R2c is Cl R! si
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(S-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2 Ei Ei si
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3
CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3
CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is Br, R2b is H, R2c is Br
Ei Ei si
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3
CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3
CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is CF,, R2b is H, R2c is H
Ei Ei Ei
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et s!
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(«-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is CF3. R2b is H. R2c is F
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(S-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3 s! s!
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3
CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3
CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is CF,, R2b is H, R2c is Cl s! s! s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3
CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3
CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is CF,, R2b is H, R2c is Br s! s! s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr) s!
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(«-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is CF3. R2b is H. R2c is CF3
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(S-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2 s! s!
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3
CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3
CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is 0CF,, R2b is H, R2c is Cl s! s! s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3
CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3
CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is OCHoCF,, R2b is H . R2c is F s! s! s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(S-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2 s!
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et) CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me) CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is OCH2CF2. R2b is H. R2c is Cl
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(S-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is OCH2CF2. R2b is H. R2c is Br
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
TABLE 2
Figure imgf000054_0001
R2a is CL R2b is H. R2^ is Cl s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is CL R2b is CL R2c is Cl s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(S-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr) CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr) Ei Ei si
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is CL R2b is F. R2c is Cl
R5 R5 R5
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(S-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3
CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3
CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is Br, R2b is H, R2c is Br si Ei Ei
CH2CH3 CH9-C-Pr CH2CH2SO2Et Ei Ei si
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is CF2. R2b is H. R2c is H
~ Ei Ei si
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(S-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2 s! s!
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3
CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3
CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is CF,, R2b is H, R2c is F s! s! s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3
CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3
CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is CF,, R2b is H, R2c is Cl s! s! s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et s!
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(«-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is CF3. R2b is H. R2c is Br
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(S-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3 s! s!
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3
CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3
CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is CF,, R2b is H, R2c is CF, s! s! s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3
CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3
CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is 0CF,, R2b is H, R2c is Cl s! s! s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr) s!
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(«-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is OCH2CF2. R2b is H. R2c is F
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(S-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2 s! s!
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3
CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3
CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is OCHoCF,, R2b is H . R2c is Cl s! s! s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3
CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3
CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R2a is OCHoCF,, R2b is H . R2c is Br s! s! s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(S-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2 s!
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et) CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me) CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(«-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
TABLE 3
3
Figure imgf000063_0001
3 3 3
Figure imgf000064_0001
R2a R2b R2C R2a R2b R2C
CF3 H Br (CH2)5CH3 OCF3 H Cl (CH2)5CH3
CF3 H Br CH2Ph OCF3 H Cl CH2Ph
OCH2CF3 H F CH3 OCH2CF3 H Cl CH3
OCH2CF3 H F CH2CH3 OCH2CF3 H Cl CH2CH3
OCH2CF3 H F CH2-Z-Pr OCH2CF3 H Cl CH2-Z-Pr
OCH2CF3 H F «-Pr OCH2CF3 H Cl «-Pr
OCH2CF3 H F z-Pr OCH2CF3 H Cl z-Pr
OCH2CF3 H F s-Bu OCH2CF3 H Cl s-Bu
OCH2CF3 H F t-Bu OCH2CF3 H Cl ^-Bu
OCH2CF3 H F (CH2)5CH3 OCH2CF3 H Cl (CH2)5CH3
OCH2CF3 H F CH2Ph OCH2CF3 H Cl CH2Ph
OCH2CF3 H Br CH3 OCH2CF3 H Br s-Bu
OCH2CF3 H Br CH2CH3 OCH2CF3 H Br ^-Bu
OCH2CF3 H Br CH2-Z-Pr OCH2CF3 H Br (CH2)5CH3
OCH2CF3 H Br «-Pr OCH2CF3 H Br CH2Ph
OCH2CF3 H Br z-Pr
TABLE 4
Figure imgf000065_0001
R2a R2b R2C El R2a R2b R2C El
Cl H Cl CH3 CF3 H Cl CH3
Cl H Cl CH2CH3 CF3 H Cl CH2CH3
Cl H Cl CH2-Z-Pr CF3 H Cl CH2-Z-Pr
Cl H Cl «-Pr CF3 H Cl w-Pr
Cl H Cl z-Pr CF3 H Cl z-Pr
Cl H Cl s-Bu CF3 H Cl s-Bu 3
3
3
3
Figure imgf000066_0001
R2a R2b R2C R2a R2b R2C
CF3 H Br CH2-Z-Pr OCF3 H Cl CH2-Z-Pr
CF3 H Br «-Pr OCF3 H Cl «-Pr
CF3 H Br z-Pr OCF3 H Cl z-Pr
CF3 H Br s-Bu OCF3 H Cl s-Bu
CF3 H Br t-Bu OCF3 H Cl ^-Bu
CF3 H Br (CH2)5CH3 OCF3 H Cl (CH2)5CH3
CF3 H Br CH2Ph OCF3 H Cl CH2Ph
OCH2CF3 H F CH3 OCH2CF3 H Cl CH3
OCH2CF3 H F CH2CH3 OCH2CF3 H Cl CH2CH3
OCH2CF3 H F CH2-Z-Pr OCH2CF3 H Cl CH2-Z-Pr
OCH2CF3 H F «-Pr OCH2CF3 H Cl w-Pr
OCH2CF3 H F z-Pr OCH2CF3 H Cl z-Pr
OCH2CF3 H F s-Bu OCH2CF3 H Cl s-Bu
OCH2CF3 H F t-Bu OCH2CF3 H Cl ^-Bu
OCH2CF3 H F (CH2)5CH3 OCH2CF3 H Cl (CH2)5CH3
OCH2CF3 H F CH2Ph OCH2CF3 H Cl CH2Ph
OCH2CF3 H Br CH3 OCH2CF3 H Br s-Bu
OCH2CF3 H Br CH2CH3 OCH2CF3 H Br ^-Bu
OCH2CF3 H Br CH2-Z-Pr OCH2CF3 H Br (CH2)5CH3
OCH2CF3 H Br «-Pr OCH2CF3 H Br CH2Ph
OCH2CF3 H Br z-Pr
TABLE 5
Figure imgf000067_0001
R1 is CFoCL R2 is Cl s! s! s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr) s!
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(«-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R1 is CF2CF2H. R2 is Cl s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(S-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3 s!
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R1 is CCl2F. R2 is Cl s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R1 is CF2CF2. R2 is Cl s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH9CH9OH CH2CH2CH2SMe CH9C(O)NH(Me) s!
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(«-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3
CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3
CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
TABLE 6
Figure imgf000070_0001
R1 is CF2CL R2 is Cl s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(S-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2 s!
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et) CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me) CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R1 is CF2CF2H. R2 is Cl s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(S-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 s! s!
CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R1 is CCIoF, R2 is Cl s! s! s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(.s-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me)
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(W-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3
CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3
CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3
CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
R1 is CFoCF,, R2 is Cl s! s! s!
CH2CH3 CH2-C-Pr CH2CH2SO2Et
CH2-Z-Pr CH2CH2SMe CH2CH2SO2(W-Pr)
CH2CH2Cl CH(Me)CH2SMe CH2CH2CH2SO2Et
CH2CH2OH CH2CH2CH2SMe CH2C(O)NH(Me)
CH(Me)CH2OH CH2CH2S(O)Me CH2C(O)NH(W-Pr)
CH2CH(Me)OH CH(Me)CH2S(O)Me CH2C(O)NH(S-Bu)
CH2C(Me)2OH CH2CH2CH2S(O)Me CH2C(O)NMe2
CH2CH2CH2OH CH2CH2SO2Me CH2C(O)NMe(Et)
CH2C(Me)2CH2OH CH(Me)CH2SO2Me CH(Me)C(O)NH(Me) s!
CH2CH2CH(Me)OH CH2CH2CH2SO2Me CH(Me)C(O)NH(Et)
CH2C(O)N(H)Et CH2C(O)N(H)CH2CF3 CH(Me)C(O)NH(«-Pr)
CH2C(O)N(H)-Z-Pr CH(Me)C(O)N(H)CH2CF3 CH(Me)C(O)NH(Z-Pr)
CH2C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SMe CH(Me)C(O)NH(S-Bu)
CH(Me)C(O)N(H)CH2-Z-Pr CH2C(O)N(H)CH2CH2SO2Me CH2C(O)NHCH2CHF2
CH2C(O)N(H)CH2CH2Cl CH2C(O)NHCH2CH2CF3
CH(Me)C(O)N(H)CH2CH2Cl CH2CH2SEt CH2C(O)NHCH(Me)CF3
CH2C(O)N(H)CH2CH2F CH2CH2S(W-Pr) CH2C(O)NHCH2CH(Me)CF3 CH(Me)C(O)N(H)CH2CH2F CH2CH2CH2SEt CH(Me)C(O)NHCH2CHF2
CH2CF3 CH2CH2S(O)Et CH(Me)C(O)NHCH2CH2CF3 CH2-(2-Py) CH2CH2S(O)(W-Pr) CH(Me)C(O)NHCH(Me)CF3 CH2-(4-Thz) CH2CH2CH2S(O)Et CH(Me)C(O)NHCH2CH(Me)CF3
TABLE 7
Figure imgf000073_0001
R≥ R2b R2C Ei si R2a R2b R2C El si
Cl H Cl CF3 H Cl Cl Cl CF3 H
Cl H Cl CF3 Me Cl Cl Cl CF3 Me
Cl H Cl CF3 CN Cl Cl Cl CF3 CN
Cl F Cl CF3 H Br H Br CF3 H
Cl Cl CF3 Me Br H Br CF3 Me
Cl F Cl CF3 CN Br H Br CF3 CN
CF3 H H CF3 H CF3 H CF3 H
CF3 H H CF3 Me CF3 H F CF3 Me
CF3 H H CF3 CN CF3 H CF3 CN
CF3 H Cl CF3 H CF3 H Br CF3 H
CF3 H Cl CF3 Me CF3 H Br CF3 Me
CF3 H Cl CF3 CN CF3 H Br CF3 CN
CF3 H CF3 CF3 H Cl H Cl CCl2F CN
CF3 H CF3 CF3 Me Cl H Cl CF2CF2H H
CF3 H CF3 CF3 CN Cl H Cl CF2CF2H Me R≥ R2b R2C Ei El R2a ^2b R2C RI R3
Cl H Cl CF2Cl H Cl H Cl CF2CF2H CN
Cl H Cl CF2Cl Me Cl H Cl CF2CF3 H
Cl H Cl CF2Cl CN Cl H Cl CF2CF3 Me
Cl H Cl CCl2F H Cl H Cl CF2CF3 CN
Cl H Cl CCl2F Me
TABLE 8
Figure imgf000074_0001
R≥ R2b R2C Ei El R2a R2b R2C Ri Sl
Cl H Cl CF3 H Cl Cl Cl CF3 H
Cl H Cl CF3 Me Cl Cl Cl CF3 Me
Cl H Cl CF3 CN Cl Cl Cl CF3 CN
Cl F Cl CF3 H Br H Br CF3 H
Cl Cl CF3 Me Br H Br CF3 Me
Cl F Cl CF3 CN Br H Br CF3 CN
CF3 H H CF3 H CF3 H CF3 H
CF3 H H CF3 Me CF3 H F CF3 Me
CF3 H H CF3 CN CF3 H CF3 CN
CF3 H Cl CF3 H CF3 H Br CF3 H
CF3 H Cl CF3 Me CF3 H Br CF3 Me
CF3 H Cl CF3 CN CF3 H Br CF3 CN
CF3 H CF3 CF3 H Cl H Cl CCl2F CN
CF3 H CF3 CF3 Me Cl H Cl CF2CF2H H
CF3 H CF3 CF3 CN Cl H Cl CF2CF2H Me
Cl H Cl CF2Cl H Cl H Cl CF2CF2H CN
Cl H Cl CF2Cl Me Cl H Cl CF2CF3 H
Cl H Cl CF2Cl CN Cl H Cl CF2CF3 Me R2a R2b R2c Rl R3 g2a R^b R2C RI ^3
Cl H Cl CCl2F H Cl H Cl CF2CF3 CN Cl H Cl CCl2F Me
TABLE 9
Figure imgf000075_0001
R2a R2b R2C Ei El R2a R2b R2C Ei si
Cl H Cl CF3 H Cl Cl Cl CF3 H
Cl H Cl CF3 Me Cl Cl Cl CF3 Me
Cl H Cl CF3 CN Cl Cl Cl CF3 CN
Cl F Cl CF3 H Br H Br CF3 H
Cl Cl CF3 Me Br H Br CF3 Me
Cl F Cl CF3 CN Br H Br CF3 CN
CF3 H H CF3 H CF3 H CF3 H
CF3 H H CF3 Me CF3 H F CF3 Me
CF3 H H CF3 CN CF3 H CF3 CN
CF3 H Cl CF3 H CF3 H Br CF3 H
CF3 H Cl CF3 Me CF3 H Br CF3 Me
CF3 H Cl CF3 CN CF3 H Br CF3 CN
CF3 H CF3 CF3 H Cl H Cl CCl2F CN
CF3 H CF3 CF3 Me Cl H Cl CF2CF2H H
CF3 H CF3 CF3 CN Cl H Cl CF2CF2H Me
Cl H Cl CF2Cl H Cl H Cl CF2CF2H CN
Cl H Cl CF2Cl Me Cl H Cl CF2CF3 H
Cl H Cl CF2Cl CN Cl H Cl CF2CF3 Me
Cl H Cl CCl2F H Cl H Cl CF2CF3 CN
Cl H Cl CCl2F Me TABLE 10
Figure imgf000076_0001
R2a R2b R2C Ei El R2a R2b R2C Ei si
Cl H Cl CF3 H Cl Cl Cl CF3 H
Cl H Cl CF3 Me Cl Cl Cl CF3 Me
Cl H Cl CF3 CN Cl Cl Cl CF3 CN
Cl F Cl CF3 H Br H Br CF3 H
Cl Cl CF3 Me Br H Br CF3 Me
Cl F Cl CF3 CN Br H Br CF3 CN
CF3 H H CF3 H CF3 H CF3 H
CF3 H H CF3 Me CF3 H F CF3 Me
CF3 H H CF3 CN CF3 H CF3 CN
CF3 H Cl CF3 H CF3 H Br CF3 H
CF3 H Cl CF3 Me CF3 H Br CF3 Me
CF3 H Cl CF3 CN CF3 H Br CF3 CN
CF3 H CF3 CF3 H Cl H Cl CCl2F CN
CF3 H CF3 CF3 Me Cl H Cl CF2CF2H H
CF3 H CF3 CF3 CN Cl H Cl CF2CF2H Me
Cl H Cl CF2Cl H Cl H Cl CF2CF2H CN
Cl H Cl CF2Cl Me Cl H Cl CF2CF3 H
Cl H Cl CF2Cl CN Cl H Cl CF2CF3 Me
Cl H Cl CCl2F H Cl H Cl CF2CF3 CN
Cl H Cl CCl2F Me TABLE 11
Figure imgf000077_0001
Figure imgf000078_0001
R2a R2b R2C SX El R2a R2b R2C SX si
Cl H Cl Br H Cl Cl Br H
Cl H Cl Br Me Cl Cl Br CN
Cl H Cl Br CN Cl F Cl Br Me
Cl Cl Cl Br H Br H Br Br H
Cl Cl Cl Br CN Br H Br Br Me
Cl Cl Cl Br Me Br H Br Br CN
CF3 H H Br H CF3 H F Br H
CF3 H H Br Me CF3 H Br Me
CF3 H H Br CN CF3 H F Br CN
CF3 H Cl Br H CF3 H Br Br H
CF3 H Cl Br Me CF3 H Br Br Me
CF3 H Cl Br CN CF3 H Br Br CN
CF3 H CF3 Br H Cl H Cl CN H
CF3 H CF3 Br Me Cl H Cl CN Me
CF3 H CF3 Br CN Cl H Cl CN CN
Cl Cl Cl CN H Cl Cl CN H
Cl Cl Cl CN CN Cl F Cl CN CN
Cl Cl Cl CN Me Cl Cl CN Me
CF3 H H CN H Br H Br CN H
CF3 H H CN Me Br H Br CN Me
CF3 H H CN CN Br H Br CN CN
CF3 H Cl CN H CF3 H CN H
CF3 H Cl CN Me CF3 H F CN Me
CF3 H Cl CN CN CF3 H CN CN
CF3 H CF3 CN H CF3 H Br CN H R2a R2b R2C SX El R2a R2b R2C SZ El
CF3 H CF3 CN Me CF3 H Br CN Me
CF3 H CF3 CN CN CF3 H Br CN CN
TABLE 13
Figure imgf000079_0001
R2a R2b R2C EI R2a R2b R2C EI
Cl H Cl Cl CF3 H Cl Cl
Cl H Cl Br CF3 H Cl Br
Cl H Cl I CF3 H Cl I
Cl H Cl OH CF3 H Cl OH
Cl H Cl OMe CF3 H Cl OMe
Cl H Cl OS(O)2CF3 CF3 H Cl OS(O)2CF3
Cl H Cl nitro CF3 H Cl nitro
Cl H Cl NH2 CF3 H Cl NH2
Cl H Cl cyano CF3 H Cl cyano
Cl H Cl Me CF3 H Cl Me
Cl H Cl CH2Cl CF3 H Cl CH2Cl
Cl H Cl CH2Br CF3 H Cl CH2Br
Cl H Cl CH2OH CF3 H Cl CH2OH
Cl H Cl CH2OC(O)Me CF3 H Cl CH2OC(O)Me
Cl H Cl CO2H CF3 H Cl CO2H
Cl H Cl «-Pr CF3 H Cl «-Pr
Br H Br Cl CF3 H CF3 Cl
Br H Br Br CF3 H CF3 Br
Br H Br I CF3 H CF3 I
Br H Br OH CF3 H CF3 OH
Br H Br OMe CF3 H CF3 OMe
Br H Br OS(O)2CF3 CF3 H CF3 OS(O)2CF3
Br H Br nitro CF3 H CF3 nitro
e
Cl OMe e
Figure imgf000080_0001
Figure imgf000081_0001
R2a R2b R2C R2a R2b R2C
OCH2CF3 H Br Cl OCH2CF3 H Br cyano
OCH2CF3 H Br Br OCH2CF3 H Br Me
OCH2CF3 H Br I OCH2CF3 H Br CH2Cl
OCH2CF3 H Br OH OCH2CF3 H Br CH2Br
OCH2CF3 H Br OMe OCH2CF3 H Br CH2OH
OCH2CF3 H Br OS(O)2CF OCH2CF3 H Br CH2OC(O)Me
OCH2CF3 H Br nitro OCH2CF3 H Br CO2H
OCH2CF3 H Br NH2 OCH2CF3 H Br «-Pr
TABLE 14
Figure imgf000082_0001
R2a R2b R2C Ei R2a R2b R2C
Cl H Cl Cl CF3 H Cl Cl
Cl H Cl Br CF3 H Cl Br
Cl H Cl I CF3 H Cl I
Cl H Cl OH CF3 H Cl OH
Cl H Cl OMe CF3 H Cl OMe
Cl H Cl OS(O)2CF3 CF3 H Cl OS(O)2CF3
Cl H Cl nitro CF3 H Cl nitro
Cl H Cl NH2 CF3 H Cl NH2
Cl H Cl cyano CF3 H Cl cyano
Cl H Cl Me CF3 H Cl Me
Cl H Cl CH2Cl CF3 H Cl CH2Cl
Cl H Cl CH2Br CF3 H Cl CH2Br
Cl H Cl CH2OH CF3 H Cl CH2OH
Cl H Cl CH2OC(O)Me CF3 H Cl CH2OC(O)Me
Cl H Cl CO2H CF3 H Cl CO2H
Cl H Cl «-Pr CF3 H Cl «-Pr
e
e
Figure imgf000083_0001
R2a R2b R2C R2a R2b R2C
CF3 H F OH Cl F Cl OH
CF3 H OMe Cl Cl OMe
CF3 H F OS(O)2CF3 Cl F Cl OS(O)2CF3
CF3 H nitro Cl Cl nitro
CF3 H F NH2 Cl F Cl NH2
PH PH PH PH PH PH PH PH PH
CF3 H cyano Cl Cl cyano
CF3 H F Me Cl F Cl Me
CF3 H CH2Cl Cl Cl CH2Cl
CF3 H F CH2Br Cl F Cl CH2Br
CF3 H CH2OH Cl Cl CH2OH
CF3 H F CH2OC(O)Me Cl F Cl CH2OC(O)Me
CF3 H CO2H Cl Cl CO2H
CF3 H F «-Pr Cl F Cl «-Pr
CF3 H Br Cl OCF3 H PH PH PH PH PH PH Cl Cl
CF3 H Br Br OCF3 H Cl Br
CF3 H Br I OCF3 H Cl I
CF3 H Br OH OCF3 H Cl OH
CF3 H Br OMe OCF3 H Cl OMe
CF3 H Br OS(O)2CF3 OCF3 H Cl OS(O)2CF3
CF3 H Br nitro OCF3 H Cl nitro
CF3 H Br NH2 OCF3 H Cl NH2
CF3 H Br cyano OCF3 H Cl cyano
CF3 H Br Me OCF3 H Cl Me
CF3 H Br CH2Cl OCF3 H Cl CH2Cl
CF3 H Br CH2Br OCF3 H Cl CH2Br
CF3 H Br CH2OH OCF3 H Cl CH2OH
CF3 H Br CH2OC(O)Me OCF3 H Cl CH2OC(O)Me
CF3 H Br CO2H OCF3 H Cl CO2H
CF3 H Br «-Pr OCF3 H Cl «-Pr
OCH2CF3 H Cl OCH2CF3 H Cl Cl
OCH2CF3 H F Br OCH2CF3 H Cl Br
OCH2CF3 H I OCH2CF3 H Cl I
OCH2CF3 H F OH OCH2CF3 H Cl OH
OCH2CF3 H OMe OCH2CF3 H Cl OMe
OCH2CF3 H F OS(O)2CF3 OCH2CF3 H Cl OS(O)2CF3
OCH2CF3 H nitro OCH2CF3 H Cl nitro
OCH2CF3 H F NH2 OCH2CF3 H Cl NH2 R2a R2b R2C g2a R2b R2C si
OCH2CF3 H F cyano OCH2CF3 H Cl cyano
OCH2CF3 H F Me OCH2CF3 H Cl Me
OCH2CF3 H F CH2Cl OCH2CF3 H Cl CH2Cl
OCH2CF3 H F CH2Br OCH2CF3 H Cl CH2Br
OCH2CF3 H F CH2OH OCH2CF3 H Cl CH2OH
OCH2CF3 H F CH2OC(O)Me OCH2CF3 H Cl CH2OC(O)Me
OCH2CF3 H F CO2H OCH2CF3 H Cl CO2H
OCH2CF3 H F «-Pr OCH2CF3 H Cl «-Pr
OCH2CF3 H Br Cl OCH2CF3 H Br cyano
OCH2CF3 H Br Br OCH2CF3 H Br Me
OCH2CF3 H Br I OCH2CF3 H Br CH2Cl
OCH2CF3 H Br OH OCH2CF3 H Br CH2Br
OCH2CF3 H Br OMe OCH2CF3 H Br CH2OH
OCH2CF3 H Br OS(O)2CF3 OCH2CF3 H Br CH2OC(O)Me
OCH2CF3 H Br nitro OCH2CF3 H Br CO2H
OCH2CF3 H Br NH2 OCH2CF3 H Br «-Pr

Claims

CLAIMSWhat is claimed is:
1. A method for preparing a compound of Formula 1
Figure imgf000086_0001
1 wherein
R1 is CHX2, CX3, CX2CHX2 or CX2CX3; each X is independently Cl or F; Z is optionally substituted phenyl;
Figure imgf000086_0002
Qa is phenyl substituted with one Q1 and optionally substituted with one to four substituents independently selected from R3;
Q1 is a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, -CN, -NO2, -N(R4)R5, -C(=W)N(R4)R5, -C(=O)OR5 and R7;
Qb is optionally substituted 1-naphthalenyl; each R3 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl,
C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C2-C7 alkylcarbonyl, C2-C7 haloalkylcarbonyl, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, -N(R4)R5, -C(=W)N(R4)R5, -C(=W)0R5, -CN, -OR11 or
-NO2; or a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 haloalkylsulfinyl,
C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, -CN, -NO2, -N(R4)R5, -C(=W)N(R4)R5, -C(=O)OR5 and R7; each R4 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; each R5 is independently H; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R6; each R6 is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfmyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, C2-Cg dialkylamino, C3-C6 cycloalkylamino, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl,
C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-Cg halodialkylaminocarbonyl, -OH, -NH2, -CN or -NO2; or QΛ each R7 is independently a phenyl ring or a pyridinyl ring, each ring optionally substituted with one or more substituents independently selected from R8; each R8 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy,
C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfmyl, C1-C6 haloalkylsulfmyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-C7 dialkylaminocarbonyl, -OH, -NH2,
-C(=O)OH, -CN or -NO2; each Q2 is independently a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfmyl, C1-C6 haloalkylsulfmyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, -CN, -NO2, -C(=W)N(R9)R10 and -C(=O)OR10; each R9 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl,
C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; each R10 is independently H; or C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl; each R11 is independently H; or C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C1-C6 alkylsulfonyl or C1-C6 haloalkylsulfonyl; and each W is independently O or S; comprising contacting a compound of Formula 2
R1 O
wherein R1, Q and Z are as previously defined for Formula 1, with hydroxylamine in the presence of a base.
2. The method of Claim 1 wherein
Z is phenyl optionally substituted with one to five substituents independently selected from R2; and each R2 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino,
C2-C6 dialkylamino, -CN or -NO2.
3. The method of Claim 2 wherein R1 is CF3;
Z is phenyl substituted with one to three substituents independently selected from R2, said substituents attached at the 3-, 4- or 5 -positions of the phenyl ring; and each R2 is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy or -CN.
4. The method of Claim 3 wherein Q is Qa.
5. The method of Claim 4 wherein
Qa is phenyl substituted with one Q1 attached at the 4-position of the phenyl ring, said phenyl ring further optionally substituted with one or two substituents independently selected from R3;
Q1 is a 5-membered heteroaromatic ring optionally substituted with one or two substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl,
C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -CN, -C(=W)N(R4)R5 and -C(=O)OR5; and each R3 is independently halogen, C1-C6 alkyl or -CN.
6. The method of Claim 5 wherein Q1 is a pyrazole or triazole ring optionally substituted with one or two substituents independently selected from halogen, -CN and -C(=W)N(R4)R5; one R3 is Cl, CH3 or -CN and is attached at the 3-position of the phenyl ring adjacent to Q1;
R4 is H; and
R5 is H; or C1-C3 alkyl, cyclopropyl or cyclopropylmethyl, each optionally substituted with halogen and further optionally substituted with 1 or 2 CH3.
7. The method of Claim 3 wherein Q is Qb.
8. The method of Claim 7 wherein
Qb is 1-naphthalenyl substituted with one or two substituents independently selected from R3.
9. The method of Claim 8 wherein one R3 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -N(R4)R5,
-C(=W)N(R4)R5, -C(=W)0R5, -CN, -OR11 or -NO2, and said R3 is attached at the 4-position of the naphthalene ring; each R4 is independently H, C1-C6 alkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl;
R5 is C1-C6 alkyl substituted with one substituent selected from hydroxy, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C7 alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl, C2-C7 haloalkylaminocarbonyl, C3-Cg halodialkylaminocarbonyl and Q2;
Q2 is a pyridinyl ring optionally substituted with one to four halogen; and
R11 is H, C2-C6 alkenyl, C2-C6 alkynyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C1-C6 alkylsulfonyl or C1-C6 haloalkylsulfonyl.
10. The method of Claim 9 wherein Qb is 1-naphthalenyl substituted with one R3 attached at the 4-position of the naphthalene ring; R3 is -C(=O)N(R4)R5; R4 is H; and
R5 is C1-C2 alkyl substituted with C2-C7 haloalkylaminocarbonyl.
11. The method of Claim 1 wherein the hydroxylamine is derived from a hydroxylamine salt.
12. The method of Claim 11 wherein the hydroxylamine salt is a hydroxylamine salt of hydrochloric acid, sulfuric acid, phosphoric acid, or a mixture thereof.
13. The method of Claim 1 wherein the base comprises one or more compounds selected from amine bases, alkali metal hydroxide bases, alkali metal alkoxide bases and alkali metal carbonate bases.
14. The method of Claim 13 wherein the base comprises sodium carbonate, potassium carbonate, or a mixture thereof.
15. The method of Claim 13 wherein the base comprises sodium hydroxide, potassium hydroxide, or a mixture thereof.
16. A compound selected from Formula 2, JV-oxides and salts thereof,
R1 O
wherein
R1 is CHX2, CX3, CX2CHX2 or CX2CX3; each X is independently Cl or F; Z is optionally substituted phenyl; Q is Qa or Qb; Qa is phenyl substituted with one Q1 and optionally substituted with one to four substituents independently selected from R3;
Q1 is a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfϊnyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, -CN, -NO2, -N(R4)R5, -C(=W)N(R4)R5, -C(=O)OR5 and R7;
Qb is optionally substituted 1-naphthalenyl; each R3 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl,
C2-C6 haloalkenyl, C2-C6 alkynyl, C3-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C2-C7 alkylcarbonyl, C2-C7 haloalkylcarbonyl, C1-C6 haloalkylthio, C1-C6 alkylsulfϊnyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, -N(R4)R5, -C(=W)N(R4)R5, -C(=W)0R5, -CN, -OR11 or
-NO2; or a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfϊnyl, C1-C6 haloalkylsulfϊnyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, -CN, -NO2, -N(R4)R5, -C(=W)N(R4)R5, -C(=O)OR5 and R7; each R4 is independently H, C ^C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; each R5 is independently H; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C 4-C7 alkylcycloalkyl or C^C7 cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R6; each R6 is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfmyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, C2-Cg dialkylamino, C3-C6 cycloalkylamino, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 haloalkylaminocarbonyl, C3-Cg halodialkylaminocarbonyl, -OH, -NH2, -CN or -NO2; or QΛ each R7 is independently a phenyl ring or a pyridinyl ring, each ring optionally substituted with one or more substituents independently selected from R8; each R8 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy,
C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfmyl, C1-C6 haloalkylsulfϊnyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl, C2-C7 alkylaminocarbonyl, C3-C7 dialkylaminocarbonyl, -OH, -NH2, -C(=O)OH, -CN or -NO2; each Q2 is independently a phenyl ring or a 5- or 6-membered saturated or unsaturated heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfmyl, C1-C6 haloalkylsulfϊnyl,
C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C1-C6 alkylamino, C2-C6 dialkylamino, -CN, -NO2, -C(=W)N(R9)R10 and -C(=O)OR10; each R9 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C 4-C7 alkylcycloalkyl, C 4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl; each R10 is independently H; or C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl or C4-C7 cycloalkylalkyl; each R11 is independently H; or C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C4-C7 cycloalkylalkyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C1-C6 alkylsulfonyl or C1-C6 haloalkylsulfonyl; and each W is independently O or S.
17. A compound of Claim 16 wherein
Z is phenyl optionally substituted with one to five substituents independently selected from R2; and each R2 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy,
C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino, C2-C6 dialkylamino, -CN or -NO2.
18. A compound of Claim 17 wherein R1 is CF3; Z is phenyl substituted with one to three substituents independently selected from R2, said substituents attached at the 3-, 4- or 5 -positions of the phenyl ring; and each R2 is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy or -CN.
19. A compound of Claim 18 wherein Q is Qa.
20. A compound of Claim 19 wherein
Qa is phenyl substituted with one Q1 attached at the 4-position of the phenyl ring, said phenyl ring further optionally substituted with one or two substituents independently selected from R3; Q1 is a 5-membered heteroaromatic ring optionally substituted with one or two substituents independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -CN, -C(=W)N(R4)R5 and -C(=O)OR5; and each R3 is independently halogen, C1-C6 alkyl or -CN.
21. A compound of Claim 20 wherein
Q1 is a pyrazole or triazole ring optionally substituted with one or two substituents independently selected from halogen, -CN and -C(=W)N(R4)R5; one R3 is Cl, CH3 or -CN and is attached at the 3-position of the phenyl ring adjacent to Ql; R4 is H; and R5 is H; or C1-C3 alkyl, cyclopropyl or cyclopropylmethyl, each optionally substituted with halogen and further optionally substituted with 1 or 2 CH3.
22. A compound of Claim 18 wherein Q is Qb.
23. A compound of Claim 22 wherein
Qb is 1-naphthalenyl substituted with one or two substituents independently selected from R3.
24. A compound of Claim 23 wherein one R3 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -N(R4)R5, -C(=W)N(R4)R5, -C(=W)0R5, -CN, -OR11 or -NO2, and said R3 is attached at the 4-position of the naphthalene ring; each R4 is independently H, C1-C6 alkyl, C2-C7 alkylcarbonyl or C2-C7 alkoxycarbonyl;
R5 is C1-C6 alkyl substituted with one substituent selected from hydroxy, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfϊnyl, C1-C6 alkylsulfonyl, C2-C7 alkylaminocarbonyl, C3-Cg dialkylaminocarbonyl, C2-C7 haloalkylaminocarbonyl, C3-Cg halodialkylaminocarbonyl and Q2; Q2 is a pyridinyl ring optionally substituted with one to four halogen; and R11 is H, C2-C6 alkenyl, C2-C6 alkynyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl, C1-C6 alkylsulfonyl or C1-C6 haloalkylsulfonyl.
25. A compound of Claim 24 wherein
Qb is 1-naphthalenyl substituted with one R3 attached at the 4-position of the naphthalene ring; R3 is -C(=O)N(R4)R5; R4 is H; and
R5 is C1-C2 alkyl substituted with C2-C7 haloalkylaminocarbonyl.
PCT/US2008/072074 2007-08-17 2008-08-04 Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives WO2009025983A2 (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
AU2008289321A AU2008289321B2 (en) 2007-08-17 2008-08-04 Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives
RU2010109881/04A RU2536039C2 (en) 2007-08-17 2008-08-04 Method of obtaining 5- halogenalkyl-4,5-dihydroisoxazole derivatives
EP08797091.9A EP2176244B1 (en) 2007-08-17 2008-08-04 Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives
JP2010521081A JP5965102B2 (en) 2007-08-17 2008-08-04 Process for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives
ES08797091.9T ES2587386T3 (en) 2007-08-17 2008-08-04 Method for the preparation of 5-haloalkyl-4,5-dihydroisoxazole derivatives
MX2010001773A MX2010001773A (en) 2007-08-17 2008-08-04 Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives.
BRPI0814153A BRPI0814153B8 (en) 2007-08-17 2008-08-04 METHOD FOR PREPARING 5-HALOALKYL-4,5-DIHYDROISOXAZOLE DERIVATIVES AND STARTING COMPOUNDS USEFUL IN THE METHOD
CA2693067A CA2693067C (en) 2007-08-17 2008-08-04 Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives
MX2013011829A MX337588B (en) 2007-08-17 2008-08-04 Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives.
KR1020157017534A KR20150082693A (en) 2007-08-17 2008-08-04 Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives
US12/679,382 US8217180B2 (en) 2007-08-17 2008-08-04 Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives
CN200880103362A CN101855215A (en) 2007-08-17 2008-08-04 Process for the preparation of 5-haloalkyl-4, 5-dihydroisoxazole derivatives
IL203174A IL203174A (en) 2007-08-17 2010-01-06 Naphthalenecarnoxylate and phenylcarnoxylate derivatives and a method for preparing the derivatives
ZA2010/00214A ZA201000214B (en) 2007-08-17 2010-01-12 Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives
HK10109984.7A HK1143373A1 (en) 2007-08-17 2010-10-21 Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives 5--45-
US13/544,113 US8513431B2 (en) 2007-08-17 2012-07-09 Method for preparing 5-haloalkyl-4, 5-dihydroisoxazole derivatives

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US96511507P 2007-08-17 2007-08-17
US60/965,115 2007-08-17
US4345908P 2008-04-09 2008-04-09
US61/043,459 2008-04-09
US8045408P 2008-07-14 2008-07-14
US61/080,454 2008-07-14

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US12/679,382 A-371-Of-International US8217180B2 (en) 2007-08-17 2008-08-04 Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives
US13/544,113 Division US8513431B2 (en) 2007-08-17 2012-07-09 Method for preparing 5-haloalkyl-4, 5-dihydroisoxazole derivatives

Publications (3)

Publication Number Publication Date
WO2009025983A2 true WO2009025983A2 (en) 2009-02-26
WO2009025983A3 WO2009025983A3 (en) 2009-05-07
WO2009025983A4 WO2009025983A4 (en) 2009-06-25

Family

ID=40350174

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/072074 WO2009025983A2 (en) 2007-08-17 2008-08-04 Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives

Country Status (20)

Country Link
US (2) US8217180B2 (en)
EP (1) EP2176244B1 (en)
JP (2) JP5965102B2 (en)
KR (2) KR101597839B1 (en)
CN (2) CN101855215A (en)
AR (1) AR067948A1 (en)
AU (1) AU2008289321B2 (en)
BR (1) BRPI0814153B8 (en)
CA (1) CA2693067C (en)
CO (1) CO6260136A2 (en)
ES (1) ES2587386T3 (en)
HK (1) HK1143373A1 (en)
IL (1) IL203174A (en)
MX (2) MX337588B (en)
MY (2) MY150980A (en)
PT (1) PT2176244T (en)
RU (1) RU2536039C2 (en)
TW (3) TWI461411B (en)
WO (1) WO2009025983A2 (en)
ZA (1) ZA201000214B (en)

Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009126668A2 (en) * 2008-04-09 2009-10-15 E. I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
EP2172462A1 (en) * 2007-06-27 2010-04-07 Nissan Chemical Industries, Ltd. Method for production of 3-hydroxypropan-1-one compound, method for production of 2-propen-1-one compound, and method for production of isoxazoline compound
WO2010112545A1 (en) * 2009-04-01 2010-10-07 Basf Se Isoxazoline compounds for combating invertebrate pests
US7964204B2 (en) 2005-12-30 2011-06-21 E.I. Du Pont De Nemours And Company Isoxazolines for controlling invertebrate pests
WO2011075591A1 (en) 2009-12-17 2011-06-23 Merial Limited Anti parasitic dihydroazole compounds and compositions comprising same
WO2011149749A1 (en) 2010-05-27 2011-12-01 E.I. Du Pont De Nemours And Company Crystalline form of 4- [5 - [3 -chloro-5 - (trifluoromethyl) phenyl] -4, 5 - dihydro - 5 - (trifluoromethyl) -3 - isoxazolyl] -n- [2-0x0-2- [ ( 2, 2, 2 - trifluoroethyl) amino] ethyl] -1- naphthalenecarboxamide
WO2011157748A1 (en) 2010-06-17 2011-12-22 Novartis Ag 5-aryl isoxazolines for controlling pests
WO2012038851A1 (en) 2010-09-24 2012-03-29 Pfizer Inc. Isoxazoline oximes as antiparasitic agents
WO2012047543A1 (en) 2010-09-27 2012-04-12 E.I. Du Pont De Nemours And Company Method for preparing 2-amino-n-(2,2,2-trifluoroethyl) acetamide
US8217180B2 (en) 2007-08-17 2012-07-10 E.I. Du Pont De Nemours And Company Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives
WO2012107533A1 (en) 2011-02-10 2012-08-16 Novartis Ag Isoxazoline derivatives for controlling invertebrate pests
WO2012120135A1 (en) 2011-03-10 2012-09-13 Novartis Ag Isoxazole derivatives
US8367584B2 (en) 2007-10-03 2013-02-05 E.I. Du Pont De Nemours And Company Naphthalene isoxazoline compounds for control of invertebrate pests
US8410153B2 (en) 2007-06-26 2013-04-02 E.I. Du Pont De Nemours And Company Naphthalene isoxazoline invertebrate pest control agents
US8563474B2 (en) 2008-07-09 2013-10-22 Basf Se Pestcidal active mixtures comprising isoxazoline compounds I
US8597688B2 (en) 2008-07-09 2013-12-03 Basf Se Pesticidal mixtures comprising isoxazoline compounds II
US8623875B2 (en) 2007-06-13 2014-01-07 E.I. Du Pont De Nemours And Company Isoxazoline insecticides
US8633134B2 (en) 2008-12-23 2014-01-21 Basf Se Substituted amidine compounds for combating animal pests
US8686014B2 (en) 2008-09-04 2014-04-01 Syngenta Limited Insecticidal compounds
US8722673B2 (en) 2008-12-23 2014-05-13 Basf Se Imine compounds for combating invertebrate pests
WO2014081697A2 (en) 2012-11-20 2014-05-30 Merial Limited Anthelmintic compounds and compositions and method of using thereof
US8822502B2 (en) 2008-08-22 2014-09-02 Syngenta Crop Protection Llc Insecticidal compounds
US8999889B2 (en) 2010-02-01 2015-04-07 Basf Se Substituted ketonic isoxazoline compounds and derivatives for combating animal pests
WO2015066277A1 (en) 2013-11-01 2015-05-07 Merial Limited Antiparisitic and pesticidal isoxazoline compounds
US9073910B2 (en) 2005-12-16 2015-07-07 E.I. Du Pont De Nemours And Company 5-aryl isoxazolines for controlling invertebrate pests
US9126995B2 (en) 2011-11-08 2015-09-08 Nissan Chemical Industries, Ltd. Method for catalytic asymmetric synthesis of optically active isoxazoline compound and optically active isoxazoline compound
WO2015179414A1 (en) 2014-05-19 2015-11-26 Merial, Inc. Anthelmintic compounds
US9216973B2 (en) 2008-08-22 2015-12-22 Syngenta Participations Ag Insecticidal compounds
WO2016069983A1 (en) 2014-10-31 2016-05-06 Merial, Inc. Parasiticidal composition comprising fipronil
US9732051B2 (en) 2011-12-23 2017-08-15 Basf Se Isothiazoline compounds for combating invertebrate pests
US10045969B2 (en) 2004-03-05 2018-08-14 Nissan Chemical Industries, Inc. Isoxazoline-substituted benzamide compound and pesticide
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11278533B2 (en) 2007-06-27 2022-03-22 E.I. Du Pont De Nemours And Company Animal pest control method
WO2023012821A1 (en) * 2021-08-01 2023-02-09 Zenfold Sustainable Technologies Private Limited A process for the preparation of carbamoyl benzamide phenyl isoxazoline class drug/s and its intermediates
US11591544B2 (en) 2020-11-25 2023-02-28 Akagera Medicines, Inc. Ionizable cationic lipids
US11951094B2 (en) 2020-05-27 2024-04-09 Axial Therapeutics, Inc. TLR2 modulator compounds, pharmaceutical compositions and uses thereof
US12064479B2 (en) 2022-05-25 2024-08-20 Akagera Medicines, Inc. Lipid nanoparticles for delivery of nucleic acids and methods of use thereof

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UY37137A (en) 2016-02-24 2017-09-29 Merial Inc ANTIPARASITARY COMPOUNDS OF ISOXAZOLINE, INJECTABLE FORMULATIONS OF PROLONGED ACTION THAT INCLUDE THEM, METHODS AND USES OF THE SAME
LT3440062T (en) 2016-04-06 2021-12-10 Boehringer Ingelheim Animal Health USA Inc. Process for the preparation of enantiomerically enriched isoxazoline compounds - crystalline toluene solvate of (s)-afoxolaner
WO2018071535A1 (en) 2016-10-14 2018-04-19 Merial, Inc. Pesticidal and parasiticidal vinyl isoxazoline compounds
JP7222909B2 (en) * 2017-04-05 2023-02-15 ベーリンガー・インゲルハイム・アニマル・ヘルス・ユーエスエー・インコーポレイテッド Crystal Forms of (S)-Afoxolaner
US11589586B2 (en) 2017-08-14 2023-02-28 Boehringer Ingelheim Animal Health USA Inc. Pesticidal and parasiticidal pyrazole-isoxazoline compounds
EP3789382B1 (en) * 2018-04-27 2023-07-05 Kumiai Chemical Industry Co., Ltd. Production method for 5,5-di-substituted-4,5-dihydroisoxazole
CN115710185B (en) * 2021-08-23 2024-05-03 中国石油化工股份有限公司 Method for producing methylamine using metal carbide catalyst
CN116903488B (en) * 2022-11-25 2023-12-15 济南久隆医药科技有限公司 Synthesis method of aforana
CN115772091B (en) * 2023-01-05 2023-06-23 济南久隆医药科技有限公司 Synthesis method of 2-amino-N- (2, 2-trifluoroethyl) acetamide

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009001942A1 (en) * 2007-06-27 2008-12-31 Nissan Chemical Industries, Ltd. Method for production of 3-hydroxypropan-1-one compound, method for production of 2-propen-1-one compound, and method for production of isoxazoline compound

Family Cites Families (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3879532A (en) * 1974-01-18 1975-04-22 Shell Oil Co Control by isoxazoles of endoparasitic nematodes
US4129568A (en) * 1977-05-12 1978-12-12 Monsanto Company 2-[3-Aryl-2-isoxazolin-5-yl]benzoates
US5849736A (en) 1993-11-24 1998-12-15 The Dupont Merck Pharmaceutical Company Isoxazoline and isoxazole fibrinogen receptor antagonists
GB9505651D0 (en) 1995-03-21 1995-05-10 Agrevo Uk Ltd AgrEvo UK Limited
BR9708828A (en) 1996-04-26 1999-08-03 Nippon Soda Co Herbicidal compound and composition
AU726670B2 (en) 1996-06-06 2000-11-16 Dow Agrosciences Llc Benzyloxy substituted aromatics and their use as fungicides and insecticides
GB2351081A (en) 1999-06-18 2000-12-20 Lilly Forschung Gmbh Pharmaceutically active imidazoline compounds and analogues thereof
DE10114597A1 (en) * 2001-03-23 2002-10-02 Bayer Cropscience Gmbh Arylisoxazoline derivatives, process for their preparation and their use as pesticides
WO2004018410A1 (en) * 2002-08-26 2004-03-04 Nissan Chemical Industries, Ltd. Substituted benzanilide compound and pest control agent
DE10320782A1 (en) 2003-05-09 2004-11-25 Bayer Cropscience Ag Substituted oxyarenes
JP2005272452A (en) 2004-02-23 2005-10-06 Nissan Chem Ind Ltd Substituted benzanilide compound and pesticide
ES2526614T3 (en) 2004-03-05 2015-01-13 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and harmful organisms control agent
AU2005228417A1 (en) 2004-03-26 2005-10-13 Cytokine Pharmasciences, Inc. Compouns, compositions, processes of making, and methods of use related to inhibiting macrophage migration inhibitory factor
JP5051340B2 (en) * 2005-06-06 2012-10-17 日産化学工業株式会社 Substituted isoxazoline compounds and pest control agents
MY146795A (en) 2005-06-09 2012-09-28 Novartis Ag Process for the synthesis of organic compounds
GB0514071D0 (en) 2005-07-07 2005-08-17 Zealand Pharma As N- or C- terminally modified small peptides
KR100546831B1 (en) 2005-08-31 2006-01-25 (주) 마이크로프랜드 Method for fabricating probe needle tip of probe card
AU2006285613B2 (en) * 2005-09-02 2011-11-17 Nissan Chemical Corporation Isoxazoline-substituted benzamide compound and harmful organism-controlling agent
JP2007106756A (en) 2005-09-14 2007-04-26 Nissan Chem Ind Ltd Substituted isoxazoline compound and pesticide
TWI266597B (en) * 2005-09-27 2006-11-11 Delta Electronics Inc Electronic apparatus capable of dissipating heat uniformly
BRPI0620668A2 (en) * 2005-12-14 2011-11-22 Du Pont compound of formula 1, composition comprising compound, invertebrate pest control composition, spray composition, bait composition, trap device, invertebrate pest control methods, cockroach, ants or termites control method and protection method. seeds against invertebrate pests
TW200803740A (en) * 2005-12-16 2008-01-16 Du Pont 5-aryl isoxazolines for controlling invertebrate pests
JP5304981B2 (en) 2005-12-26 2013-10-02 日産化学工業株式会社 1,3-bis (substituted phenyl) -3-hydroxypropan-1-one and 2-propen-1-one compounds and salts thereof
TWI412322B (en) 2005-12-30 2013-10-21 Du Pont Isoxazolines for controlling invertebrate pests
EP1997813B1 (en) * 2006-03-10 2010-05-05 Nissan Chemical Industries, Ltd. Substituted isoxazoline compound and pest control agent
BRPI0710403A2 (en) 2006-04-20 2011-08-09 Du Pont compound composition, control composition, spraying, bait, trap device, control methods, protection methods, treated seed, protective composition
JPWO2007125984A1 (en) 2006-04-28 2009-09-10 日本農薬株式会社 Isoxazoline derivatives, pest control agents and methods of use
JP2008044880A (en) 2006-08-15 2008-02-28 Bayer Cropscience Ag Insecticidal isooxazolines
JP5206993B2 (en) 2007-03-07 2013-06-12 日産化学工業株式会社 Isoxazoline-substituted benzamide compounds and pest control agents
KR20090130064A (en) 2007-04-10 2009-12-17 바이엘 크롭사이언스 아게 Insecticidal aryl isoxazoline derivatives
ES2445651T3 (en) 2007-06-13 2014-03-04 E. I. Du Pont De Nemours And Company Isoxazoline insecticides
TWI430995B (en) * 2007-06-26 2014-03-21 Du Pont Naphthalene isoxazoline invertebrate pest control agents
ES2666187T3 (en) 2007-06-27 2018-05-03 E. I. Du Pont De Nemours And Company Pest control procedure in animals
TWI556741B (en) 2007-08-17 2016-11-11 英特威特國際股份有限公司 Isoxazoline compositions and their use as antiparasitics
TWI461411B (en) 2007-08-17 2014-11-21 Du Pont Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives
CN101801940B (en) 2007-09-10 2013-04-10 日产化学工业株式会社 Substituted isoxazoline compound and pest control agent
JP5676262B2 (en) * 2007-10-03 2015-02-25 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニーＥ．Ｉ．Ｄｕ Ｐｏｎｔ Ｄｅ Ｎｅｍｏｕｒｓ Ａｎｄ Ｃｏｍｐａｎｙ Naphthalene isoxazoline compounds for the control of harmful invertebrates

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009001942A1 (en) * 2007-06-27 2008-12-31 Nissan Chemical Industries, Ltd. Method for production of 3-hydroxypropan-1-one compound, method for production of 2-propen-1-one compound, and method for production of isoxazoline compound

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE CASREACT CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 1988, XP002516318 retrieved from STN Database accession no. 111:115084 & A. A. H. RAGAILA ET AL.: "Newer heterocycles and carbamates from naphthyl chalcones" EGYPTIAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 29, no. 1-4, 1988, pages 71-87, NATIONAL INFORMATION AND DOCUMENTATION CENTRE, CAIRO; EG ISSN: 0301-5068 *
DATABASE CASREACT CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 1996, XP002516333 retrieved from STN Database accession no. 126:31303 & O. A. KUZNETSOVA: "Synthesis of fluorinated functionalized isoxazolinones" ROSSIISKAYA AKADEMIYA NAUK. IZVESTIYA. SERIYA KHIMICHESKAYA, no. 5, 1996, pages 1306-1307, IZDATEL'STVO NAUKA; RU ISSN: 1026-3500 *
R. R. KAMBLE ET AL.: "An Efficient Synthesis of Pharmacologically Active Derivatives of 1,3,4-Oxadiazoles" JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 43, no. 345, 2006, pages 345-352, XP002516317 PROVO, UT; US ISSN: 0022-152X *
See also references of EP2176244A2 *

Cited By (86)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10596157B2 (en) 2004-03-05 2020-03-24 Nissan Chemical Corporation Isoxazoline-substituted benzamide compound and pesticide
US10045969B2 (en) 2004-03-05 2018-08-14 Nissan Chemical Industries, Inc. Isoxazoline-substituted benzamide compound and pesticide
US10874645B2 (en) 2004-03-05 2020-12-29 Nissan Chemical Corporation Isoxazoline-substituted benzamide compound and pesticide
US9073910B2 (en) 2005-12-16 2015-07-07 E.I. Du Pont De Nemours And Company 5-aryl isoxazolines for controlling invertebrate pests
US8871941B2 (en) 2005-12-30 2014-10-28 E.I. Du Pont De Nemours And Company 8-bromo-5-quinolinecarboxaldehyde oxime
US8231888B2 (en) 2005-12-30 2012-07-31 E.I. Du Pont De Nemours And Company Isoxazolines for controlling invertebrate pests
US7964204B2 (en) 2005-12-30 2011-06-21 E.I. Du Pont De Nemours And Company Isoxazolines for controlling invertebrate pests
US8552218B2 (en) 2005-12-30 2013-10-08 E.I. Du Pont De Nemours And Company Isoxazolines for controlling invertebrate pests
US8623875B2 (en) 2007-06-13 2014-01-07 E.I. Du Pont De Nemours And Company Isoxazoline insecticides
US9095138B2 (en) 2007-06-13 2015-08-04 E.I. Du Pont De Nemours And Company Isoxazoline insecticides
US8410153B2 (en) 2007-06-26 2013-04-02 E.I. Du Pont De Nemours And Company Naphthalene isoxazoline invertebrate pest control agents
US9751821B1 (en) 2007-06-27 2017-09-05 Nissan Chemical Industries, Ltd. Method for production of 3-hydroxypropan-1-one compound, method for production of 2-propen-1-one compound and method for production of isoxazoline compound
US8952175B2 (en) 2007-06-27 2015-02-10 Nissan Chemical Industries, Ltd. Method for production of 3-hydroxypropan-1-one compound, method for production of 2-propen-1-one compound and method for production of isoxazoline compound
EP2172462A1 (en) * 2007-06-27 2010-04-07 Nissan Chemical Industries, Ltd. Method for production of 3-hydroxypropan-1-one compound, method for production of 2-propen-1-one compound, and method for production of isoxazoline compound
US9676692B2 (en) 2007-06-27 2017-06-13 Nissan Chemical Industries, Ltd. Method for production of 3-hydroxypropan-1-one compound, method for production of 2-propen-1-one compound and method for production of isoxazoline compound
EP2172462A4 (en) * 2007-06-27 2010-12-15 Nissan Chemical Ind Ltd Method for production of 3-hydroxypropan-1-one compound, method for production of 2-propen-1-one compound, and method for production of isoxazoline compound
US11278533B2 (en) 2007-06-27 2022-03-22 E.I. Du Pont De Nemours And Company Animal pest control method
US8217180B2 (en) 2007-08-17 2012-07-10 E.I. Du Pont De Nemours And Company Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives
US8513431B2 (en) 2007-08-17 2013-08-20 E.I. Du Pont De Nemours And Company Method for preparing 5-haloalkyl-4, 5-dihydroisoxazole derivatives
US8367584B2 (en) 2007-10-03 2013-02-05 E.I. Du Pont De Nemours And Company Naphthalene isoxazoline compounds for control of invertebrate pests
US9938248B2 (en) 2008-04-09 2018-04-10 E.I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
US10160731B2 (en) 2008-04-09 2018-12-25 E.I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
US8546618B2 (en) 2008-04-09 2013-10-01 E.I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
AU2015202911B2 (en) * 2008-04-09 2017-02-23 Corteva Agriscience Llc Method for preparing 3-trifluoromethyl chalcones
CN101990530B (en) * 2008-04-09 2016-02-10 杜邦公司 For the preparation of the method for 3-trifluoromethyl chalcones
WO2009126668A3 (en) * 2008-04-09 2010-04-08 E. I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
US9611231B2 (en) 2008-04-09 2017-04-04 E.I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
US9527822B2 (en) 2008-04-09 2016-12-27 E.I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
AU2015202910B2 (en) * 2008-04-09 2017-06-29 Corteva Agriscience Llc Method for preparing 3-trifluoromethyl chalcones
US9035101B2 (en) 2008-04-09 2015-05-19 E.I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
US9834523B2 (en) 2008-04-09 2017-12-05 E.I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
WO2009126668A2 (en) * 2008-04-09 2009-10-15 E. I. Du Pont De Nemours And Company Method for preparing 3-trifluoromethyl chalcones
CN101990530A (en) * 2008-04-09 2011-03-23 杜邦公司 Method for preparing 3-trifluoromethyl chalcones
AU2009233858B2 (en) * 2008-04-09 2015-03-12 Corteva Agriscience Llc Method for preparing 3-trifluoromethyl chalcones
US10888094B2 (en) 2008-07-09 2021-01-12 Basf Se Pesticidal active mixtures comprising isoxazoline compounds I
US8597688B2 (en) 2008-07-09 2013-12-03 Basf Se Pesticidal mixtures comprising isoxazoline compounds II
US8563474B2 (en) 2008-07-09 2013-10-22 Basf Se Pestcidal active mixtures comprising isoxazoline compounds I
US10231455B2 (en) 2008-07-09 2019-03-19 Basf Se Pesticidal active mixtures comprising isoxazoline compounds I
US9770029B2 (en) 2008-07-09 2017-09-26 Basf Se Pesticidal active mixtures comprising isoxazoline compounds I
US8822502B2 (en) 2008-08-22 2014-09-02 Syngenta Crop Protection Llc Insecticidal compounds
US9216973B2 (en) 2008-08-22 2015-12-22 Syngenta Participations Ag Insecticidal compounds
US8686014B2 (en) 2008-09-04 2014-04-01 Syngenta Limited Insecticidal compounds
US9282742B2 (en) 2008-09-04 2016-03-15 Syngenta Participations Ag Insecticidal compounds
US8633134B2 (en) 2008-12-23 2014-01-21 Basf Se Substituted amidine compounds for combating animal pests
US8722673B2 (en) 2008-12-23 2014-05-13 Basf Se Imine compounds for combating invertebrate pests
WO2010112545A1 (en) * 2009-04-01 2010-10-07 Basf Se Isoxazoline compounds for combating invertebrate pests
CN102369199A (en) * 2009-04-01 2012-03-07 巴斯夫欧洲公司 Isoxazoline compounds for combating invertebrate pests
JP2012522750A (en) * 2009-04-01 2012-09-27 ビーエーエスエフ ソシエタス・ヨーロピア Isoxazoline compounds for combating invertebrate pests
EP3560923A1 (en) 2009-12-17 2019-10-30 Boehringer Ingelheim Animal Health USA Inc. Anti parasitic dihydroazole compounds and compositions comprising same
US8618126B2 (en) 2009-12-17 2013-12-31 Merial Limited Antiparisitic dihydroazole compounds and compositions comprising same
EP3078664A1 (en) 2009-12-17 2016-10-12 Merial Inc. Antiparasitic dihydroazole compositions
US9376434B2 (en) 2009-12-17 2016-06-28 Merial Inc. Antiparisitic dihydroazole compounds and compositions comprising same
WO2011075591A1 (en) 2009-12-17 2011-06-23 Merial Limited Anti parasitic dihydroazole compounds and compositions comprising same
US9776999B2 (en) 2009-12-17 2017-10-03 Merial Inc. Antiparisitic dihydroazole compounds and compositions comprising same
US8999889B2 (en) 2010-02-01 2015-04-07 Basf Se Substituted ketonic isoxazoline compounds and derivatives for combating animal pests
CN102947278A (en) * 2010-05-27 2013-02-27 杜邦公司 Crystalline form of 4- [5 - [3 -chloro-5 - (trifluoromethyl) phenyl] -4, 5 - dihydro - 5 - (trifluoromethyl) -3 - isoxazolyl] -n- [2-0x0-2- [ ( 2, 2, 2 - trifluoroethyl) amino] ethyl] -1- naphthalenecarboxamide
WO2011149749A1 (en) 2010-05-27 2011-12-01 E.I. Du Pont De Nemours And Company Crystalline form of 4- [5 - [3 -chloro-5 - (trifluoromethyl) phenyl] -4, 5 - dihydro - 5 - (trifluoromethyl) -3 - isoxazolyl] -n- [2-0x0-2- [ ( 2, 2, 2 - trifluoroethyl) amino] ethyl] -1- naphthalenecarboxamide
US8598087B2 (en) 2010-05-27 2013-12-03 E. I. Du Pont De Nemours And Company Crystalline form of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4, 5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-0X0-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1- naph-thalenecarboxamide
WO2011157748A1 (en) 2010-06-17 2011-12-22 Novartis Ag 5-aryl isoxazolines for controlling pests
WO2012038851A1 (en) 2010-09-24 2012-03-29 Pfizer Inc. Isoxazoline oximes as antiparasitic agents
US10202332B2 (en) 2010-09-27 2019-02-12 E. I. Du Pont De Nemours And Company Method for preparing 2-amino-N-(2,2,2-trifluoroethyl) acetamide
EP3150575A1 (en) 2010-09-27 2017-04-05 E. I. du Pont de Nemours and Company Method for preparing 2-amino-n-(2,2,2-trifluoroethyl) acetamide
US20190144374A1 (en) * 2010-09-27 2019-05-16 E.I. Du Pont De Nemours And Company Method for preparing 2-amino-n-(2,2,2-trifluoroethyl) acetamide
US11613516B2 (en) * 2010-09-27 2023-03-28 E. I. Du Pont De Nemours And Company Method for preparing 2-amino-n-(2,2,2-trifluoroethyl) acetamide
WO2012047543A1 (en) 2010-09-27 2012-04-12 E.I. Du Pont De Nemours And Company Method for preparing 2-amino-n-(2,2,2-trifluoroethyl) acetamide
JP2016117720A (en) * 2010-09-27 2016-06-30 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニーＥ．Ｉ．Ｄｕ Ｐｏｎｔ Ｄｅ Ｎｅｍｏｕｒｓ Ａｎｄ Ｃｏｍｐａｎｙ Method for preparing 2-amino-n-(2,2,2-trifluoroethyl) acetamide
WO2012107533A1 (en) 2011-02-10 2012-08-16 Novartis Ag Isoxazoline derivatives for controlling invertebrate pests
WO2012120135A1 (en) 2011-03-10 2012-09-13 Novartis Ag Isoxazole derivatives
US9126995B2 (en) 2011-11-08 2015-09-08 Nissan Chemical Industries, Ltd. Method for catalytic asymmetric synthesis of optically active isoxazoline compound and optically active isoxazoline compound
US9732051B2 (en) 2011-12-23 2017-08-15 Basf Se Isothiazoline compounds for combating invertebrate pests
WO2014081697A2 (en) 2012-11-20 2014-05-30 Merial Limited Anthelmintic compounds and compositions and method of using thereof
EP3428162A1 (en) 2012-11-20 2019-01-16 Merial Inc. Anthelmintic compounds and compositions and method of using thereof
WO2015066277A1 (en) 2013-11-01 2015-05-07 Merial Limited Antiparisitic and pesticidal isoxazoline compounds
EP3733664A1 (en) 2013-11-01 2020-11-04 Boehringer Ingelheim Animal Health USA Inc. Antiparisitic and pesticidal isoxazoline compounds
WO2015179414A1 (en) 2014-05-19 2015-11-26 Merial, Inc. Anthelmintic compounds
WO2016069983A1 (en) 2014-10-31 2016-05-06 Merial, Inc. Parasiticidal composition comprising fipronil
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11951094B2 (en) 2020-05-27 2024-04-09 Axial Therapeutics, Inc. TLR2 modulator compounds, pharmaceutical compositions and uses thereof
US11591544B2 (en) 2020-11-25 2023-02-28 Akagera Medicines, Inc. Ionizable cationic lipids
US12077725B2 (en) 2020-11-25 2024-09-03 Akagera Medicines, Inc. Ionizable cationic lipids
WO2023012821A1 (en) * 2021-08-01 2023-02-09 Zenfold Sustainable Technologies Private Limited A process for the preparation of carbamoyl benzamide phenyl isoxazoline class drug/s and its intermediates
US12064479B2 (en) 2022-05-25 2024-08-20 Akagera Medicines, Inc. Lipid nanoparticles for delivery of nucleic acids and methods of use thereof

Also Published As

Publication number Publication date
ZA201000214B (en) 2011-03-30
WO2009025983A3 (en) 2009-05-07
CN101855215A (en) 2010-10-06
TWI649303B (en) 2019-02-01
RU2010109881A (en) 2011-09-27
PT2176244T (en) 2016-07-27
KR20100044892A (en) 2010-04-30
IL203174A (en) 2014-08-31
TWI461411B (en) 2014-11-21
CN105693646A (en) 2016-06-22
US8513431B2 (en) 2013-08-20
BRPI0814153B8 (en) 2022-12-06
EP2176244A2 (en) 2010-04-21
MY176115A (en) 2020-07-24
JP2014221775A (en) 2014-11-27
ES2587386T3 (en) 2016-10-24
US20130165663A9 (en) 2013-06-27
JP2010536767A (en) 2010-12-02
KR20150082693A (en) 2015-07-15
TW201718454A (en) 2017-06-01
MX337588B (en) 2016-03-11
TW200914429A (en) 2009-04-01
TW201434808A (en) 2014-09-16
BRPI0814153B1 (en) 2018-08-21
AR067948A1 (en) 2009-10-28
HK1143373A1 (en) 2010-12-31
JP5965102B2 (en) 2016-08-03
CA2693067C (en) 2016-10-11
MX2010001773A (en) 2010-03-10
TWI600639B (en) 2017-10-01
EP2176244B1 (en) 2016-06-01
MY150980A (en) 2014-03-31
WO2009025983A4 (en) 2009-06-25
BRPI0814153A2 (en) 2015-01-06
CA2693067A1 (en) 2009-02-26
US20120277442A1 (en) 2012-11-01
RU2536039C2 (en) 2014-12-20
KR101597839B1 (en) 2016-02-25
AU2008289321A1 (en) 2009-02-26
US20100249424A1 (en) 2010-09-30
AU2008289321B2 (en) 2014-02-20
CO6260136A2 (en) 2011-03-22
US8217180B2 (en) 2012-07-10

Similar Documents

Publication Publication Date Title
AU2008289321B2 (en) Method for preparing 5-haloalkyl-4,5-dihydroisoxazole derivatives
US9938248B2 (en) Method for preparing 3-trifluoromethyl chalcones

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200880103362.6

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08797091

Country of ref document: EP

Kind code of ref document: A2

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2008289321

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 203174

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 197/DELNP/2010

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2693067

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2008797091

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2008289321

Country of ref document: AU

Date of ref document: 20080804

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: MX/A/2010/001773

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2010521081

Country of ref document: JP

Ref document number: PI 2010000137

Country of ref document: MY

WWE Wipo information: entry into national phase

Ref document number: 10018337

Country of ref document: CO

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20107005776

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2010109881

Country of ref document: RU

WWE Wipo information: entry into national phase

Ref document number: 12679382

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: A201000552

Country of ref document: UA

ENP Entry into the national phase

Ref document number: PI0814153

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20100210