Pesticial compounds
11160280 · 2021-11-02
Assignee
Inventors
- Arun Narine (Ludwigshafen, DE)
- Ashokkumar Adisechan (Navi Mumbai, IN)
- Devendra Vyas (Navi Mumbai, IN)
- Gopal Krishna Datta (Goettingen, DE)
- Ramakrishnan Vallinayagam (Mumbai, IN)
- Rupsha Chaudhuri (Navi Mumbai, IN)
- Sunderraman Sambasivan (Navi Mumbai, IN)
Cpc classification
C07D417/12
CHEMISTRY; METALLURGY
A01N47/18
HUMAN NECESSITIES
A01N43/80
HUMAN NECESSITIES
A01N47/24
HUMAN NECESSITIES
C07D405/12
CHEMISTRY; METALLURGY
C07D231/56
CHEMISTRY; METALLURGY
A01N47/34
HUMAN NECESSITIES
International classification
C07D231/56
CHEMISTRY; METALLURGY
A01N47/18
HUMAN NECESSITIES
A01N43/90
HUMAN NECESSITIES
A01N43/80
HUMAN NECESSITIES
C07D231/24
CHEMISTRY; METALLURGY
A01N47/24
HUMAN NECESSITIES
Abstract
The present invention relates to the compounds of formula (I), and the N-oxides, stereoisomers, tautomers and agriculturally or veterinarily acceptable salts thereof wherein the variables are defined according to the description, ##STR00001## The compounds of formula (I), as well as the N-oxides, stereoisomers, tautomers and agriculturally or veterinarily acceptable salts thereof, are useful for combating or controlling invertebrate pests, in particular arthropod pests and nematodes. The invention also relates to a method for controlling invertebrate pests by using these compounds and to plant propagation material and to an agricultural and a veterinary composition comprising said compounds.
Claims
1. A compound of formula (I) ##STR00297## wherein A.sup.1 is N or CR.sup.A; A.sup.2 is N or CR.sup.B; A.sup.3 is N or CR.sup.B1; W is O, S(═O).sub.m, or NR.sup.6; R.sup.A, R.sup.B and R.sup.B1 independently of each other are H, halogen, N.sub.3, OH, CN, NO.sub.2, —SCN, —SF.sub.5, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, tri-C.sub.1-C.sub.6-alkylsilyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkoxy, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkoxy, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, O—C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, NH—C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, or S(═O).sub.mR.sup.e, phenyl, phenoxy, phenylcarbonyl, phenylthio, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; Q is —C(R.sup.4R.sup.5)—O—, —C(═O)—O—, —S(═O).sub.m—C(R.sup.7R.sup.8)—, —N(R.sup.2)—S(═O).sub.m—, —N(R.sup.2)—C(R.sup.9R.sup.10)—, —C(═O)—C(R.sup.19R.sup.20)—, —N(R.sup.2)—C(═O)—, —C(R.sup.13R.sup.14)—C(R.sup.15R.sup.16)—, or —C(R.sup.17)═C(R.sup.18)—; wherein Ar is bound to either side of Q; m is 0, 1, or 2; R.sup.2 is H, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, S(═O).sub.mR.sup.e, phenyl, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.4, R.sup.5, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.20 are, identical or different, H, halogen, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, S(═O).sub.mR.sup.e, phenyl, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.6 is H, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, S(═O).sub.mR.sup.e, phenyl, —CH.sub.2—C(═O)—OR.sup.a, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; Ar is phenyl or 5- or 6-membered hetaryl, which are unsubstituted or substituted with R.sup.Ar, wherein R.sup.Ar is halogen, N.sub.3, OH, CN, NO.sub.2, —SCN, —SF.sub.5, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, tri-C.sub.1-C.sub.6-alkylsilyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkoxy, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, O—C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, NH—C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, or S(═O).sub.mR.sup.e, phenyl, phenoxy, phenylcarbonyl, phenylthio or —CH.sub.2-phenyl, wherein phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.1 is a moiety of formula YZT-1 to YZT-9, wherein ##STR00298## denotes attachment to the 9 membered hetaryl; ##STR00299## ##STR00300## R.sup.11 is C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkoxy, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, aryl, aryl-carbonyl, aryl-C.sub.1-C.sub.4-alkyl, aryloxy-C.sub.1-C.sub.4-alkyl, hetaryl, carbonyl-hetaryl, hetaryl-C.sub.1-C.sub.4-alkyl or hetaryloxy-C.sub.1-C.sub.4-alkyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.9 and wherein the hetaryl is a 5- or 6-membered monocyclic hetaryl or a 8-, 9- or 10-membered bicyclic hetaryl; R.sup.12 is a radical of the formula A.sup.1; ##STR00301## wherein # indicates the point of attachment to T; R.sup.121, R.sup.122, R.sup.123 are, identical or different, H, halogen, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyloxy, C.sub.2-C.sub.6-alkynyloxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.6-alkylcarbonlyoxy, C.sub.1-C.sub.6-alkenylcarbonlyoxy, C.sub.3-C.sub.6-cycloalkylcarbonlyoxy, wherein the alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy and cycloalkyl moieties are unsubstituted or substituted with halogen, or NR.sup.bR.sup.c, or one of R.sup.121, R.sup.122, R.sup.123 may also be oxo; R.sup.124 is H, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy, or C.sub.2-C.sub.6-alkenyloxy, wherein the alkyl, alkoxy, alkenyl and alkenyloxy moieties are unsubstituted or substituted with halogen; and where R.sup.ya is H, halogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkoxy, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, S(═O).sub.mR.sup.e, phenyl, or —CH.sub.2— phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.yc, R.sup.2c are, identical or different, H, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.4-alkyl-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkyl, or C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkoxy, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen; R.sup.T is H, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.4-alkyl-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, S(═O).sub.mR.sup.e, phenyl, or —CH.sub.2— phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.zc together with R.sup.T if present, may form C.sub.1-C.sub.6-alkylene or a linear C.sub.2-C.sub.6-alkenylene group, where in the linear C.sub.1-C.sub.6-alkylene and the linear C.sub.2-C.sub.6-alkenylene a CH.sub.2 moiety may be replaced by a carbonyl or a C═N—R′ and/or wherein 1 or 2 CH.sub.2 moieties may be replaced by O or S and/or wherein the linear C.sub.1-C.sub.6-alkylene and the linear C.sub.2-C.sub.6-alkenylene may be unsubstituted or substituted with Rh; R.sup.za is H, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, tri-C.sub.1-C.sub.6-alkylsilyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.4-alkyl-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkoxy, C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.6-cycloalkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, phenyl, phenylcarbonyl, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.za together with R.sup.T if present, may form C.sub.1-C.sub.6-alkylene or a linear C.sub.2-C.sub.6-alkenylene group, where in the linear C.sub.1-C.sub.6-alkylene and the linear C.sub.2-C.sub.6-alkenylene a CH.sub.2 moiety may be replaced by a carbonyl or a C═N—R′ and/or wherein 1 or 2 CH.sub.2 moieties may be replaced by O or S and/or wherein the linear C.sub.1-C.sub.6-alkylene and the linear C.sub.2-C.sub.6-alkenylene may be unsubstituted or substituted with R.sup.h; R.sup.a, R.sup.b and R.sup.c are, identical or different, H, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C.sub.1-C.sub.6-alkylene-CN, phenyl, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.d is H, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, phenyl, or —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.e is C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, wherein the alkyl, cycloalkyl moieties are unsubstituted or substituted with halogen, phenyl and —CH.sub.2-phenyl, wherein the phenyl rings are unsubstituted or substituted with R.sup.f; R.sup.f is halogen, N.sub.3, OH, CN, NO.sub.2, —SCN, —SF.sub.5, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, tri-C.sub.1-C.sub.6-alkylsilyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkoxy, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, O—C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, NH—C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, or S(═O).sub.mR.sup.e; R.sup.9 is halogen, N.sub.3, OH, CN, NO.sub.2, —SCN, —SF.sub.5, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.2-C.sub.6-alkenyl, tri-C.sub.1-C.sub.6-alkylsilyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-cycloalkoxy, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkoxy-C.sub.1-C.sub.4-alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl and cycloalkoxy moieties are unsubstituted or substituted with halogen, C(═O)—OR.sup.a, NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, O—C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C.sub.1-C.sub.6-alkylene-CN, NH—C.sub.1-C.sub.6-alkylene-NR.sup.bR.sup.c, C(═O)—NR.sup.bR.sup.c, C(═O)—R.sup.d, SO.sub.2NR.sup.bR.sup.c, or S(═O).sub.mR.sup.e; R.sup.h is halogen, OH, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, or CN; with a proviso that when Z is a single bond, R.sup.T is other than H; and the N-oxides, stereoisomers, tautomers and agriculturally or veterinarily acceptable salts thereof.
2. The compound of claim 1, wherein W is O, A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, and A.sup.3 is N.
3. The compound of claim 1, wherein W is NR.sup.6, A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, and A.sup.3 is N.
4. The compound of claim 1, wherein W is O, A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, and A.sup.3 is CR.sup.B1.
5. The compound of claim 1, wherein W is NR.sup.6, A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, and A.sup.3 is CR.sup.B1.
6. The compound of claim 1, wherein W is N, A.sup.1 is N, A.sup.2 is N, and A.sup.3 is CR.sup.B1.
7. The compound of claim 1, wherein W is S(═O).sub.m, A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, and A.sup.3 is CR.sup.B1.
8. The compound of claim 1, wherein Ar is selected from formulas Ar-1 to Ar-16: ##STR00302## ##STR00303##
9. A composition, comprising a compound of claim 1, an N-oxide or an agriculturally acceptable salt thereof, and a further active substance.
10. A method for combating or controlling invertebrate pests, which method comprises contacting said pest or its food supply, habitat or breeding grounds with a pesticidally effective amount of at least a compound of claim 1.
11. A method for protecting growing plants from attack or infestation by invertebrate pests, which method comprises contacting a plant, or soil or water wherein the plant is growing, with a pesticidally effective amount of at least a compound of claim 1.
12. Seed treated with a compound of claim 1, or the enantiomers, diastereomers or salts thereof, in an amount of from 0.1 g to 10 kg per 100 kg of seed.
13. A method for treating or protecting an animal from infestation or infection by invertebrate pests which comprises bringing the animal in contact with a pesticidally effective amount of at least one compound of claim 1, a stereoisomer thereof and/or at least one veterinarily acceptable salt thereof.
14. The method of claim 10, wherein W is O, A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, and A.sup.3 is N.
15. The method of claim 10, wherein W is NR.sup.6, A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, and A.sup.3 is N.
16. The method of claim 10, wherein W is O, A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, and A.sup.3 is CR.sup.B1.
17. The method of claim 10, wherein W is NR.sup.6, A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, and A.sup.3 is CR.sup.B1.
18. The method of claim 10, wherein W is NR.sup.6, A.sup.1 is N, A.sup.2 is N, and A.sup.3 is CR.sup.B1.
19. The method of claim 10, wherein W is S(═O).sub.m, A.sup.1 is CR.sup.A, A.sup.2 is CR.sup.B, and A.sup.3 is CR.sup.B1.
20. The method of claim 10, wherein Ar is selected from formulas Ar-1 to Ar-16: ##STR00304## ##STR00305##
Description
EXAMPLES
Preparation Examples
(1) With appropriate modification of the starting materials, the procedures as described in the preparation examples below were used to obtain further compounds of formula I. The compounds obtained in this manner are listed in the table X that follows, together with physical data.
(2) Compounds can be characterized e.g. by coupled High Performance Liquid Chromatography/mass spectrometry (HPLC/MS), by .sup.1H-NMR and/or by their melting points.
(3) Analytical HPLC/MS—Method 1: Agilent Eclipse Plus C18, 50×4.6 mm, ID 5 μm; Elution: A=10 mM Amm. Formate (0.1% Formic Acid), B=Acetonitrile (0.1% Formic Acid), Flow=1.25 ml/min. at 40° C.; Gradient: 10% B to 100% B—1.5 min, hold for 1 min, 1 min—100% B. Run Time=3.5 min.
(4) Analytical HPLC/MS—Method 2: Kinetex XB C18 1.7μ 50×2.1 mm; A=Water+0.1% TFA, B=Acetonitrile, Flow=0.8 ml/min—1.0 ml/min in 1.5 min. at 60° C.; Gradient: 5% B to 100% B—1.5 min.
(5) .sup.1H-NMR: The signals are characterized by chemical shift (ppm, . . . [delta]) vs. tetramethylsilane respectively, CDCl.sub.3 for .sup.13C-NMR, by their multiplicity and by their integral (relative number of hydrogen atoms given). The following abbreviations are used to characterize the multiplicity of the signals: m=multiplet, h=heptet, q=quartet, t=triplet, d=doublet and s=singlet.
(6) Abbreviations used are: d for day(s), h for hour(s), min for minute(s), r.t./room temperature for 20-25° C., R.sub.t for retention time; DMSO for dimethyl sulfoxide, OAc for acetate, EtOAc for ethyl acetate, THF for tetrahydrofuran, t-BuOH for tert-butanol, dppfPdCl for [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), DIPEA for diisopropylethylamine, DCM for dichloromethane and DMAP for 4-Dimethylaminopyridine
Example 1
1-(2,6-dimethyl phenyl)-3-[(E)-[1-methyl-3-[[4-(trifluoromethoxy)phenoxy] methyl]indazol-6-yl]methyleneamino]thiourea (C-1 of Table X)
Step 1: Methyl 6-bromo-1-methyl-indazole-3-carboxylate
(7) To a solution of methyl 6-bromo-1H-indazole-3-carboxylate (1.3 gm) in Acetonitrile (20 ml) and DMF (3 ml) was added Potassium carbonate (3.52 gm) at ambient temperature. Then Methyl iodide (1.27 ml) was added to the reaction mixture at 0° C. Reaction mixture was stirred at room temperature for 16 h. Progress of reaction was monitored by TLC. After completion of reaction, reaction mixture was diluted with water (80 ml) and followed by extraction with ethyl acetate (50 ml×3). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 5-30% ethyl acetate in heptane as a mobile phase) to afford of title compound (0.750 g). HPLC/MS (method 1): R.sub.t: 1.876 min; MS: m/z=269.10 (M+1). .sup.1H NMR (300 MHz, Chloroform-d) δ 8.11 (d, J=8.6 Hz, 1H), 7.68 (s, 1H), 7.44 (dd, J=8.6, 1.3 Hz, 1H), 7.28 (s, 1H), 4.16 (s, 3H), 4.06 (s, 3H).
Step 2: (6-bromo-1-methyl-indazol-3-yl)methanol
(8) To a solution of Methyl 6-bromo-1-methyl-indazole-3-carboxylate (0.750 gm) in 10 ml of THF was added Di-isobutyl aluminium hydride (8.36 ml) at −78° C. Then reaction mixture was stirred at room temperature for 16 h. Progress of reaction was monitored by TLC. After completion of reaction, reaction mixture was quenched with sat. NH.sub.4Cl solution and with 1N HCl solution. Aqueous layer was extracted with ethyl acetate (30 ml×3). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 5-50% ethyl acetate in heptane as a mobile phase) to afford the title compound (0.500 g). HPLC/MS (method 1): R.sub.t: 1.567 min; MS: m/z=243.0 (M+1). .sup.1H NMR (300 MHz, Chloroform-d) δ 7.67 (d, J=8.5 Hz, 1H), 7.56 (s, 1H), 7.31-7.21 (m, 2H), 5.01 (s, 2H), 4.00 (s, 3H).
Step 3: 6-bromo-3-(chloromethyl)-1-methyl-indazole
(9) To a solution of (6-bromo-1-methyl-indazol-3-yl)methanol (0.500 g) in THF (10 ml) was added Phosphorus oxychloride (0.25 ml g) under inert atmosphere. Reaction mixture was heated at 70° C. for 3 h. Progress of reaction was monitored by TLC. After completion of reaction, reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 5-30% ethyl acetate in heptane as a mobile phase) to afford the title compound (0.450 g). HPLC/MS (method 1): R.sub.t: 2.053 min; MS: m/z=261.0 (M+1). .sup.1H NMR (300 MHz, Chloroform-d) δ 7.77 (d, J=8.6 Hz, 1H), 7.67 (s, 1H), 7.40 (dd, J=8.6, 1.3 Hz, 1H), 5.01 (s, 2H), 4.11 (s, 3H), 3.66 (t, J=6.6 Hz, 4H), 3.53 (t, J=6.0 Hz, 8H), 1.95 (dt, J=14.4, 6.6 Hz, 4H), 1.80 (dt, J=12.7, 6.2 Hz, 4H), 1.71 (t, J=2.8 Hz, 4H).
Step 4: 6-bromo-1-methyl-3-[[4-(trifluoromethoxy)phenoxy]methyl]indazole
(10) To a solution of 4-(trifluoromethoxy)phenol (0.27 ml) in DMF (5 ml) was added Potassium tertbutoxide (0.398 gm). Reaction mixture was stirred for 10 min at room temperature. Then 6-bromo-3-(chloromethyl)-1-methyl-indazole (0.460 gm) dissolved in 3 ml of DMF was added to the reaction mixture. Reaction mixture was stirred for 5 h at room temperature. Progress of reaction was monitored by TLC. After completion of reaction, reaction mixture was diluted with water (30 ml) and followed by extraction with ethyl acetate (30 ml×3). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 5-30% ethyl acetate in heptane as a mobile phase) to afford the title compound (0.610 g). HPLC/MS (method 1): R.sub.t: 2.347 min; MS: m/z=403.0 (M+1). .sup.1H NMR (300 MHz, Chloroform-d) δ 7.72-7.63 (m, 1H), 7.61-7.54 (m, 1H), 7.26 (s, 2H), 7.14 (d, J=8.6 Hz, 2H), 7.03 (d, J=9.2 Hz, 2H), 5.38 (s, 2H), 4.03 (s, 3H).
Step 5: 1-methyl-3-[[4-(trifluoromethoxy)phenoxy]methyl]-6-vinyl-indazole
(11) To a degassed solution of 6-bromo-1-methyl-3-[[4-(trifluoromethoxy)phenoxy] methyl]indazole (0.600 g) in Toluene (5 ml). was added Tributyl(vinyl)tin (0.52 ml) and 1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.066 gm). Reaction mixture was heated at 110° C. for 2 h. Progress of reaction was monitored by TLC. After completion of reaction, reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (30 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 0-30% ethyl acetate in heptane as a mobile phase) to afford the title compound (0.260 g). HPLC/MS (method 1): R.sub.t: 2.382 min; MS: m/z=349.2 (M+1). H NMR (300 MHz, Chloroform-d) δ 7.75 (d, J=8.7 Hz, 1H), 7.36-7.27 (m, 2H), 7.14 (d, J=8.7 Hz, 2H), 7.09-7.00 (m, 2H), 6.89-6.77 (m, 1H), 5.86 (d, J=17.5 Hz, 1H), 5.43-5.30 (m, 3H), 4.07 (s, 3H).
Step 6: 1-methyl-3-[[4-(trifluoromethoxy)phenoxy]methyl]indazole-6-carbaldehyde
(12) To a solution of 1-methyl-3-[[4-(trifluoromethoxy)phenoxy]methyl]-6-vinyl-indazole (0.341 g) in 1,4 Dioxane (5 ml) and Water (2 ml) was added Osmium tetraoxide (0.015 g) at 0° C. and reaction was stirred at the same temperature for 5 min. Then Sodium periodate (0.461 gm) was added. The reaction mixture was stirred for 3 h at room temperature. Progress of reaction was monitored by TLC. After completion of reaction, reaction mixture was quenched in aqueous Sodium sulfite solution (20 ml) and followed by extraction with ethyl acetate (30 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 5-50% ethyl acetate in heptane as a mobile phase) to afford the title compound (0.084 g). HPLC/MS (method 1): R.sub.t: 2.075 min; MS: m/z=351.25 (M+1). .sup.1H NMR (300 MHz, Chloroform-d) δ 10.18 (s, 1H), 7.98 (d, J=5.7 Hz, 2H), 7.73 (d, J=8.7 Hz, 1H), 7.22-7.02 (m, 5H), 6.86 (dd, J=13.5, 9.0 Hz, 1H), 5.46 (s, 2H), 4.19 (s, 3H), 3.73 (s, 5H), 3.59 (t, J=6.6 Hz, 1H), 3.51-3.41 (m, 3H), 1.76 (dd, J=64.8, 6.8 Hz, 13H), 1.42-1.24 (m, 5H), 0.94 (t, J=7.3 Hz, 2H).
Step 7: 1-(2,6-dimethylphenyl)-3-[(E)-[1-methyl-3-[[4-(trifluoromethoxy)phenoxy] methyl]indazol-6-yl]methyleneamino]thiourea (C-1 of Table X)
(13) A mixture of 1-methyl-3-[[4-(trifluoromethoxy)phenoxy]methyl]indazole-6-carbaldehyde (0.250 g) and 1-amino-3-(2,6-dimethylphenyl) thiourea (0.139 g) in EtOH (5 ml) was heated at 80° C. for 3 h. The progress of reaction was monitored by TLC. Reaction mixture was cooled and concentrated under reduced pressure. Then reaction mass was diluted with water (15 ml) and extracted with ethyl acetate (25 ml×2). The combined organic solvent was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 0-5% Methanol in Dichloromethane as a mobile phase) to afford the title compound (0.160 g). HPLC/MS (method 1): R.sub.t: 2.20 min; MS: m/z=528.90 (M+1). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.88 (s, 1H), 9.91 (s, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 7.86 (d, J=17.2 Hz, 2H), 7.31 (d, J=8.8 Hz, 2H), 7.23-7.10 (m, 5H), 5.45 (s, 2H), 4.10 (s, 3H), 2.21 (s, 6H).
Example 2
(2Z)-3-(2,6-dimethylphenyl)-2-[(E)-[1-methyl-3-[[4-(trifluoromethoxy)phenoxy] methyl]indazol-6-yl]methylenehydrazono]thiazolidin-4-one (C-2 of Table X)
(14) To a solution of 1-(2,6-dimethylphenyl)-3-[(E)-[1-methyl-3-[[4-(trifluoromethoxy) phenoxy] methyl]indazol-6-yl]methyleneamino]thiourea (0.160 g) in Ethanol (5.0 ml) were added NaOAc (0.100 g) and Methyl bromo acetate (0.139 g) at room temperature. Then the reaction mixture was stirred at 28° C. for 16 h. Progress of the reaction was monitored by TLC. The reaction mixture was diluted with Water (15 ml) and extracted with Ethyl acetate (25 ml×2). The combined organic solvent was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 0-5% Methanol in Dichloromethane as a mobile phase) to afford the title compound (0.074 g). HPLC/MS (method 1): R.sub.t: 2.33 min; MS: m/z=568.3 (M+1). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.45 (s, 1H), 7.89 (d, J=8.3 Hz, 2H), 7.66 (d, J=8.8 Hz, 1H), 7.42-7.13 (m, 8H), 5.45 (s, 2H), 4.29 (s, 2H), 4.06 (s, 3H), 2.12 (s, 6H).
Example 3
1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[[4-(trifluoromethoxy)phenoxy]methyl] indazol-6-yl]methyleneamino]thiourea (C-3 of Table X)
(15) A mixture of 1-methyl-3-[[4-(trifluoromethoxy)phenoxy]methyl]indazole-6-carbaldehyde (0.085 g) and 1-amino-3-(2-isopropylphenyl)thiourea (0.051 g) in EtOH (5 ml) was heated at 80° C. for 3 h. The progress of reaction was monitored by TLC. Reaction mixture was cooled and concentrated under reduced pressure. Then reaction mixture was diluted with Water (15 ml) and extracted with Ethyl acetate (25 ml×2). The combined organic solvent was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 10-50% EtOAc in Heptane as a mobile phase) to afford the title compound (0.131 g). HPLC/MS (method 1): R.sub.t: 2.31 min; MS: m/z=542.3 (M+1). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.91 (s, 1H), 10.02 (s, 1H), 8.28 (s, 1H), 8.03 (s, 1H), 8.01-7.87 (m, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.42-7.13 (m, 8H), 5.45 (s, 2H), 4.09 (s, 3H), 3.20-3.07 (m, 1H), 1.20 (d, J=6.9 Hz, 6H).
Example 4
(2Z)-3-(2-isopropylphenyl)-2-[(E)-[1-methyl-3-[[4-(trifluoromethoxy)phenoxy] methyl]indazol-6-yl]methylenehydrazono]thiazolidin-4-one (C-4 of Table X)
(16) To a solution of 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[[4-(trifluoromethoxy) phenoxy]methyl]indazol-6-yl]methyleneamino]thiourea (0.170 g, 0.314 mmol) in ethanol (5.0 ml) were added NaOAc (0.103 g, 1.256 mmol) and methyl bromo acetate (0.144 g, 0.942 mmol) at room temperature. Then the reaction mixture was stirred at 28° C. for 16 h. Progress of the reaction was monitored by TLC. The reaction mixture was diluted with Water (15 ml) and extracted with Ethyl acetate (25 ml×2). The combined organic solvent was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 10-50% EtOAc in Heptane as a mobile phase) to afford the title compound (0.183 g). HPLC/MS (method 1): R.sub.t: 2.36 min; MS: m/z=582.4 (M+1). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.43 (s, 1H), 7.89 (d, J=9.2 Hz, 2H), 7.67 (d, J=8.8 Hz, 1H), 7.50 (q, J=7.8, 7.2 Hz, 2H), 7.41-7.14 (m, 6H), 5.45 (s, 2H), 4.44-4.10 (m, 2H), 4.06 (s, 3H), 2.86-2.74 (m, 1H), 1.16 (dd, J=9.0, 7.0 Hz, 7H).
Example 5
[(2S,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl] N-[1-methyl-3-[[4-(trifluoromethoxy)benzoyl]amino]indazol-6-yl]carbamate (C-5 of Table X)
Step 1. N-(6-bromo-1-methyl-indazol-3-yl)-4-(trifluoromethoxy)benzamide
(17) To a solution of 3-amino-6-bromo-1-methyl-1H-indazole (1.00 g), DMAP (0.058 g) and DIPEA (3.8 ml) in THF (10 ml) at 0° C. was added 4-trifluoromethoxybenzoylchloride (0.80 g) and the reaction was allowed to slowly warm to room temperature and stirred for 16 h. The reaction mixture was poured into water, extracted with EtOAc and the organic layer was washed with brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. Purification by column chromatography using a gradient of EtOAc and Cyclohexane afforded the title compound (1.38 g). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.52 (s, 1H), 8.05-7.94 (m, 3H), 7.51 (d, J=1.7 Hz, 1H), 7.38-7.31 (m, 2H), 7.28-7.21 (m, 2H), 3.93 (s, 3H).
Step 2. Methyl 1-methyl-3-[[4-(trifluoromethoxy)benzoyl]amino]indazole-6-carboxylate
(18) A solution of N-(6-bromo-1-methyl-indazol-3-yl)-4-(trifluoromethoxy)benzamide (1.08 g), DIPEA (1.1 ml) and dppfPdCl.sub.2 (191 mg) in Methanol at 60° C. under an atmosphere of CO (g) (1 atm) was stirred for 16 h. The reaction mixture was poured into water and extracted with CH.sub.2Cl.sub.2 and the organic layer was dried over MgSO.sub.4, filtered and concentrated under reduced pressure and used without further purification (1.32 g). HPLC/MS (method 2): R.sub.t=1.15 min, MS: m/z=394(M+).
Step 3. 1-Methyl-3-[[4-(trifluoromethoxy)benzoyl]amino]indazole-6-carboxylic Acid
(19) A suspension of methyl 1-methyl-3-[[4-(trifluoromethoxy)benzoyl]amino]indazole-6-carboxylate (1.63 g) and LiOH.H.sub.2O in THF/Water (3:1, 60 ml) was stirred at room temperature for 16 h. The reaction was then quenched with aq. HCl (1 M) and the resultant precipitate was isolated by filtration, washing with ice water then dried (0.95 g). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.12 (s, 1H), 11.07 (s, 1H), 8.28-8.16 (m, 3H), 7.84 (d, J=8.6 Hz, 1H), 7.66 (dd, J=8.6, 1.3 Hz, 1H), 7.59-7.52 (m, 2H), 4.10 (s, 3H).
Step 4. 1-Methyl-3-[[4-(trifluoromethoxy)benzoyl]amino]indazole-6-carbonyl Azide
(20) A suspension of 1-methyl-3-[[4-(trifluoromethoxy)benzoyl]amino]indazole-6-carboxylate (0.45 g) in Thionyl chloride (3 ml,) and DMF (2 drops) was stirred and heated at reflux for 4 h during which time a solution formed. The reaction mixture was concentrated under reduced pressure, re-dissolved in CH.sub.2Cl.sub.2 then concentrated. The crude solid (0.49 g) was suspended in Acetone (4 ml) at 0° C. and a solution of NaN.sub.3 (0.19 g) in Water (6.5 ml) was slowly added. After stirring for 16 h while slowly allowing the reaction mixture to warm to room temperature, the resultant precipitate (0.19 g over 2 steps) was isolated by filtration and washed with water.
Step 5. [(2S,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl] N-[1-methyl-3-[[4-(trifluoromethoxy)benzoyl]amino]indazol-6-yl]carbamate (C-5 of Table X)
(21) A stirred solution of 1-methyl-3-[[4-(trifluoromethoxy)benzoyl]amino]indazole-6-carbonyl azide (0.140 g) in Toluene (6 ml) was heated at 100° C. for 2 h then cooled to room temperature and concentrated under reduced pressure. The resultant oil was dissolved in Acetonitrile (6 ml), (3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-ol (0.11 g) and Cs.sub.2CO.sub.3 (0.056 g) were added and the suspension was stirred at room temperature for 16 h. The reaction mixture was poured into water and extracted with EtOAc and the organic layer was dried over MgSO.sub.4, filtered and concentrated under reduced pressure. Purification by column chromatography using a gradient of EtOAc and cyclohexane afforded the title compound (40 mg). .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.13 (s, 1H), 7.83 (d, J=8.5 Hz, 2H), 7.48-7.40 (m, 2H), 7.25 (d, J=8.4 Hz, 2H), 6.94 (dd, J=8.8, 1.7 Hz, 1H), 6.24 (d, J=2.0 Hz, 1H), 4.09 (s, 3H), 3.71 (dq, J=12.9, 5.1, 3.8 Hz, 1H), 3.70 (s, 1H), 3.61-3.46 (m, 11H), 3.22 (t, J=9.4 Hz, 1H), 2.05 (s, 1H), 1.42 (s, 1H), 1.32 (d, J=6.2 Hz, 3H), 1.28 (dt, J=19.0, 6.7 Hz, 1H).
Example 6
[(2S,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl] N-[1-methyl-3-[[4-(trifluoromethoxy)phenyl]carbamoyl]indazol-6-yl]carbamate (C-6 of Table X)
Step 1: Methyl 1-methyl-3-[[4-(trifluoromethoxy)phenyl]carbamoyl]indazole-6-carboxylate
(22) A solution of methyl 3-bromo-1-methyl-indazole-6-carboxylate (0.90 g), 4-(trifluoromethoxy)aniline (0.89 g), DIPEA (1.4 ml) and Pd(dppf)Cl.sub.2 (0.24 g) in dimethylacetamide (60 ml) was heated at 80° C. with stirring under an atmosphere of CO (g) (5 atm) for 19 h. The reaction mixture was allowed to cool to room temperature, then extracted with ethyl acetate washing with water, dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of ethyl acetate/cyclohexane afforded the title compound (0.65 g). HPLC/MS (method 2): R.sub.t: 1.32 min; MS: m/z=394 (M+1).
Step 2: 1-methyl-3-[[4-(trifluoromethoxy)phenyl]carbamoyl]indazole-6-carboxylic Acid
(23) A solution of methyl 1-methyl-3-[[4-(trifluoromethoxy)phenyl]carbamoyl]indazole-6-carboxylate (0.83 g) and LiOH.H.sub.2O (0.13 g) in THF (15 ml) and H.sub.2O (5 ml) was stirred at room temperature for 16 h. The reaction mixture was then poured onto an ice-cold solution of aq. HCl (1 M) and the resultant precipitate was isolated by filtration washing with cold water. The wet solid was dried by co-distillation with toluene (3×) then precipitation from diisopropylether (0.40 g) and used without further purification.
Step 3: 1-methyl-3-[[4-(trifluoromethoxy)phenyl]carbamoyl]indazole-6-carbonyl Azide
(24) To a solution of 1-methyl-3-[[4-(trifluoromethoxy)phenyl]carbamoyl]indazole-6-carboxylic acid (0.40 g) in CH.sub.2Cl.sub.2 at 0° C. was added oxalyl chloride (0.11 ml) followed by 1 drop of DMF. The reaction mixture was warmed to room temperature and stirred for 3 h then concentrated to dryness. The resultant crude oil was suspended in acetone (7 ml) then added to a stirred solution of NaN.sub.3 (0.18 g) at 0° C. The reaction mixture was stirred for 16 h at room temperature, then the resultant precipitate was isolated by filtration washing with cold water and dried to afford the title compound (285 mg). HPLC/MS (method 2): R.sub.t: 1.33 min; MS: m/z=405 (M+1).
Step 4: [(2S,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl] N-[1-methyl-3-[[4-(trifluoromethoxy)phenyl]carbamoyl]indazol-6-yl]carbamate (C-6 of Table X)
(25) A suspension of 1-methyl-3-[[4-(trifluoromethoxy)phenyl]carbamoyl]indazole-6-carbonyl azide (0.14 g) in Toluene was heated at 80° C. for 2 h, cooled to r.t. then concentrated. The resultant crude oil was dissolved in CH.sub.3CN (6 ml) at r.t. then Cs.sub.2CO.sub.3 (56 mg) and (3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-ol (0.11 g) were added. After 16 h, the reaction mixture was concentrated and partitioned between ethyl acetate and aq. NaHCO.sub.3. The organic layer was dried over MgSO.sub.4, filtered, and concentration. Purification by silica gel chromatography using a gradient of ethyl acetate/cyclohexane afforded the title compound (70 mg). HPLC/MS (method 2): R.sub.t: 1.25 min; MS: m/z=584 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.84 (s, 1H), 8.29 (d, J=8.7 Hz, 1H), 8.10-8.04 (m, 1H), 7.82-7.73 (m, 2H), 7.23 (d, J=8.6 Hz, 2H), 6.99 (s, 1H), 6.92 (dd, J=8.7, 1.8 Hz, 1H), 6.23 (d, J=2.0 Hz, 1H), 4.10 (s, 2H), 3.77-3.65 (m, 2H), 3.61-3.47 (m, 8H), 3.22 (t, J=9.4 Hz, 1H), 1.34 (d, J=6.2 Hz, 2H).
Example 7
6-[(E)-[(2-isopropylphenyl)carbamothioylhydrazono]methyl]-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (C-7 of Table X)
Step 1: 6-bromo-1H-indazole-3-carbaldehyde
(26) A solution of 6-bromoindole (6 g) in Acetone (200 ml) was cooled to 0° C. under inert atmosphere. To the solution was added NaNO.sub.2 (16.89 g) in Water (30 ml) and 2N Aq. HCl (70 ml) drop wise at 0° C. under inert atmosphere. Reaction mixture was stirred at room temperature for 1 h. Progress of reaction was monitored by TLC. After completion of the reaction, the solvents were evaporated under vacuum and precipitated product was filtered through a filter paper. Product was washed with cold DCM (50 ml) and dried under reduced pressure to afford the title compound (6.5 g). HPLC/MS (method 1): R.sub.t: 1.699 min; MS: m/z=225 (M−1).
Step 2: 6-bromo-1-methyl-indazole-3-carbaldehyde
(27) To a solution of 6-bromo-1H-indazole-3-carbaldehyde (3 g) in dry THF (30 ml) were added methyl iodide (2.27 g) and K.sub.2CO.sub.3 (2.76 g) under inert atmosphere. Reaction mixture was stirred at room temperature for 12 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (60 ml) and extracted with Ethyl acetate (80 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 15-20% ethyl acetate in heptane as a mobile phase) to afford (2.1 g) of the title compound. HPLC/MS (method 1): R.sub.t: 1.898 min; MS: m/z=238.2 (M+1).
Step 3: 6-bromo-1-methyl-indazole-3-carboxylic Acid
(28) To a solution of 6-bromo-1-methyl-indazole-3-carbaldehyde (1 g) in CH.sub.3CN (10 ml) and Water (4 ml) was added KMnO.sub.4 (1.32 g) at room temperature. The reaction mixture was stirred for 12 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was poured in ice cold water and filtered through a celite bed. Celite bed was washed with water and pH of filtrate was adjusted up to ˜3-4 using Aq. 1N HCl solution. The precipitated product was filtered through a filter paper and dried under reduced pressure to afford (0.8 g) of title the compound. HPLC/MS (method 1): R.sub.t: 1.569 min; MS: m/z=253 (M−1).
Step 4: 6-bromo-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide
(29) To a solution of 6-bromo-1-methyl-indazole-3-carboxylic acid (0.8 g) in dry DCM (10 ml) were added 4-trifluromethoxy aniline (0.61 g) and Triethyl amine (1.04 g) at 0° C. under inert atmosphere. Reaction mixture was stirred at room temperature for 5 min and then Propyl phosphonic anhydride solution (5.98 g, 50% in ethyl acetate) was added to the reaction mixture. Reaction mixture was continued to stir for 12 h at room temperature. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (50 ml) and extracted with Ethyl acetate (60 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-25% ethyl acetate in heptane as a mobile phase) to afford (1.2 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.186 min; MS: m/z=413.9 (M−1).
Step 5: 1-methyl-N-[4-(trifluoromethoxy)phenyl]-6-vinyl-indazole-3-carboxamide
(30) A solution of 6-bromo-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (1 g) in dry Toluene (10 ml) was purged with Nitrogen for 10 min. To the solution was added Pd(dppf)C2 (0.106 g) and Nitrogen purging was continued for another 10 min. Then Tributyl vinyl tin (1.148 g) was added to the solution. The reaction mixture was stirred for 3 h at 110° C. Progress of reaction was monitored by TLC. After completion, the reaction mixture was allow to cool to room temperature, then diluted with Water (50 ml) and extracted with Ethyl acetate (60 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-25% ethyl acetate in heptane as a mobile phase) to afford (0.450 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.196 min; MS: m/z=362.15 (M+1).
Step 6: 6-formyl-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide
(31) A solution of 1-methyl-N-[4-(trifluoromethoxy)phenyl]-6-vinyl-indazole-3-carboxamide (0.450 g) in 1,4-dioxane (5 ml) and Water (2 ml) was cooled to 0° C. under inert atmosphere. To the stirred solution OsO.sub.4 (0.005 g) and NaIO.sub.4 (0.584 g) were added under inert atmosphere. The reaction mixture was stirred at room temperature for 4 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (10 ml), quenched with Aq. sodium sulfite solution (10 ml) and extracted with Ethyl acetate (20 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-22% ethyl acetate in heptane as a mobile phase) to afford (0.300 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.098 min; MS: m/z=362.0 (M−1).
Step 7: 6-[(E)-[(2-isopropylphenyl)carbamothioylhydrazono]methyl]-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (C-7 of Table X)
(32) 1-amino-3-(2-isopropylphenyl)thiourea (0.173 g) was added to a solution of 6-formyl-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (0.3 g) in Ethanol (3 ml) at room temperature under inert atmosphere. The reaction mixture was stirred for 3 h at 85° C. Progress of reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and the precipitated product was filtered through a filter paper. The residue was washed with cold EtOH (2 ml), triturated with Pentane (5 ml) and dried under reduced pressure to afford (0.280 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.229 min; MS: m/z=553.3 (M−1). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.96 (s, 1H), 10.62 (s, 1H), 10.07 (s, 1H), 8.32 (s, 1H), 8.22-8.15 (m, 2H), 8.09 (d, J=8.6 Hz, 1H), 8.06-7.99 (m, 2H), 7.37 (t, J=8.8 Hz, 3H), 7.32 (ddd, J=8.0, 6.0, 2.7 Hz, 1H), 7.29-7.20 (m, 2H), 4.25 (s, 3H), 3.16 (hept, J=6.9 Hz, 1H), 1.21 (d, J=6.9 Hz, 6H).
Example 8
6-[(E)-[(Z)-[3-(2-isopropylphenyl)-4-oxo-thiazolidin-2-ylidene]hydrazono]methyl]-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (C-8 of Table X)
(33) To a stirred solution of 6-[(E)-[(2-isopropylphenyl)carbamothioylhydrazono]methyl]-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (0.24 g) in EtOH (5 ml) were added NaOAc (0.071 g) and Methyl bromo acetate (0.099 g) at room temperature. The reaction mixture was continued to stir at room temperature for 12 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (20 ml) and extracted with Ethyl acetate (25 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-25% ethyl acetate in heptane as a mobile phase) to afford (0.2 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.325 min; MS: m/z=595.1 (M+1). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.63 (s, 1H), 8.47 (s, 1H), 8.26 (d, J=8.5 Hz, 1H), 8.06-7.98 (m, 3H), 7.83 (d, J=8.5 Hz, 1H), 7.56-7.45 (m, 2H), 7.40-7.32 (m, 3H), 7.29 (dd, J=7.9, 1.2 Hz, 1H), 4.32-4.22 (m, 1H), 4.22 (s, 3H), 4.17 (d, J=17.3 Hz, 1H), 2.81 (hept, J=6.9 Hz, 1H), 1.16 (dd, J=16.7, 6.8 Hz, 6H).
Example 9
[(E)-[1-methyl-3-[[4-(trifluoromethoxy)phenyl]carbamoyl]indazol-6-yl] methyleneamino]N-(2-isopropylphenyl)carbamate (C-9 of Table X)
Step 1: 6-[(E)-hydroxyiminomethyl]-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide
(34) Hydroxyl amine hydrochloride (0.191 g) and Sodium acetate (0.226 g) were added to a solution of 6-formyl-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (0.25 g) in EtOH (3 ml) at room temperature under inert atmosphere. The reaction mixture was stirred for 3 h at 85° C. Progress of reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, diluted with Water (25 ml) and extracted with Ethyl acetate (30 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 25-30% ethyl acetate in heptane as a mobile phase) to afford (0.275 g) of the title compound. HPLC/MS (method 1): R.sub.t: 1.941 min; MS: m/z=379 (M+1).
Step 2: [(E)-[1-methyl-3-[[4-(trifluoromethoxy)phenyl]carbamoyl]indazol-6-yl]methyleneamino]N-(2-isopropylphenyl)carbamate (C-9 of Table X)
(35) 1-isocyanato-2-isopropyl-benzene (0.143 g) and Triethyl amine (0.150 g) were added to a solution of 6-[(E)-hydroxyiminomethyl]-1-methyl-N-[4-(trifluoromethoxy) phenyl] indazole-3-carboxamide (0.28 g) in Toluene (3 ml) at room temperature under inert atmosphere. The reaction mixture was stirred at room temperature for 12 h. Progress of reaction was monitored by TLC. After completion, the reaction mass was diluted with Water (25 ml) and extracted with Ethyl acetate (30 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by Prep. HPLC to afford (0.170 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.250 min; MS: m/z=538.2 (M−1). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.66 (s, 1H), 9.36 (s, 1H), 8.81 (s, 1H), 8.30 (d, J=8.5 Hz, 1H), 8.25 (s, 1H), 8.06-7.99 (m, 2H), 7.90 (dd, J=8.6, 1.2 Hz, 1H), 7.41-7.34 (m, 3H), 7.38-7.20 (m, 2H), 4.27 (s, 3H), 3.23 (p, J=6.9 Hz, 1H), 1.20 (d, J=6.8 Hz, 6H).
Example 10:1-(2-isopropyl phenyl)-3-[(E)-[1-methyl-3-[[4-(trifluoromethoxy) anilino]methyl]indazol-6-yl]methyleneamino]thiourea (C-10 of Table X)
Step 1: 6-(1,3-dioxolan-2-yl)-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide
(36) To a stirred solution of 6-formyl-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (1.4 g) in Toluene (14 ml) were added Ethylene glycol (0.718 g) and p-Toluenesulfonic acid (0.073 g) at room temperature under inert atmosphere. The reaction mixture was stirred for 12 h at 110° C. Progress of reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, diluted with Water (20 ml), quenched with Aq. sodium bicarbonate solution (20 ml) and extracted with Ethyl acetate (60 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-22% ethyl acetate in heptane as a mobile phase) to afford (1.1 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.038 min; MS: m/z=408.15 (M+1).
Step 2: N-[[6-(1,3-dioxolan-2-yl)-1-methyl-indazol-3-yl]methyl]-4-(trifluoromethoxy) aniline
(37) To a stirred solution of 6-(1,3-dioxolan-2-yl)-1-methyl-N-[4-(trifluoromethoxy) phenyl]indazole-3-carboxamide (0.5 g) in dry DCM (10 ml) was added DIBAL-H (0.610 g) at 0° C. under inert atmosphere. Reaction mixture was stirred at room temperature for 2 h. Again (0.610 g) of DIBALH was added to the reaction mixture. The reaction mixture was then stirred for 12 h at 45° C. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (20 ml), quenched with Aq. 1N HCl solution and extracted with Ethyl acetate (30 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 22-25% ethyl acetate in heptane as a mobile phase) to afford (0.25 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.022 min; MS: m/z=394.1 (M+1).
Step 3: 1-methyl-3-[[4-(trifluoromethoxy)anilino]methyl]indazole-6-carbaldehyde
(38) To a solution of N-[[6-(1,3-dioxolan-2-yl)-1-methyl-indazol-3-yl]methyl]-4-(trifluoromethoxy)aniline (0.25 g) in Acetone (3 ml) was added p-Toluenesulfonic acid (0.012 g) and the reaction mixture was stirred at room temperature for 12 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (15 ml), quenched with Aq. sodium bicarbonate solution (10 ml) and extracted with Ethyl acetate (30 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 25-30% ethyl acetate in heptane as a mobile phase) to afford (0.1 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.018 min; MS: m/z=350.0 (M+1).
Step 4: 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[[4-(trifluoromethoxy)anilino] methyl] indazol-6-yl]methyleneamino]thiourea (C-10 of Table X)
(39) 1-amino-3-(2-isopropylphenyl)thiourea (0.06 g) was added to a solution of 1-methyl-3-[[4-(trifluoromethoxy)anilino]methyl]indazole-6-carbaldehyde (0.1 g) in EtOH (2 ml) at room temperature under inert atmosphere. Then the reaction mixture was stirred for 3 h at 85° C. Progress of reaction was monitored by TLC. After completion, the reaction mixture was cooled to r.t. and the precipitated product was filtered through a filter paper. The residue washed with cold EtOH (2 ml), triturated with Pentane (5 ml) and dried under reduced pressure to afford (0.07 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.217 min; MS: m/z=541.3 (M+1). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 11.88 (s, 1H), 9.99 (s, 1H), 8.25 (s, 1H), 7.94 (s, 1H), 7.84 (s, 2H), 7.46-7.20 (m, 2H), 7.02 (d, J=8.4 Hz, 2H), 6.71 (d, J=8.9 Hz, 2H), 6.65-6.47 (m, 1H), 4.56 (d, J=5.8 Hz, 2H), 4.039 (s, 3H), 3.13 (p, J=7.0 Hz, 1H), 1.19 (d, J=6.9 Hz, 6H).
Example 11
(2Z)-3-(2-isopropylphenyl)-2-[(E)-[1-methyl-3-[[4-(trifluoromethoxy) anilino] methyl]indazol-6-yl]methylenehydrazono]thiazolidin-4-one (C-11 of Table X)
(40) To a stirred solution of 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[[4-(trifluoromethoxy) anilino]methyl]indazol-6-yl]methyleneamino]thiourea (0.170 g) in EtOH (4 ml) were added NaOAc (0.052 g) and Methyl bromo acetate (0.072 g) at room temperature. The reaction mixture was continued to stir at room temperature for 12 h. Progress of reaction was monitored by TLC. After completion, reaction mixture was diluted with Water (20 ml) and extracted in Ethyl acetate (30 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-25% ethyl acetate in heptane as a mobile phase) to afford (0.065 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.240 min; MS: m/z=581.3 (M+1). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.40 (s, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.84 (s, 1H), 7.59 (dd, J=8.6, 1.2 Hz, 1H), 7.50 (dtd, J=14.9, 7.9, 1.6 Hz, 2H), 7.34 (td, J=7.6, 1.7 Hz, 1H), 7.27 (dd, J=7.9, 1.4 Hz, 1H), 7.03 (d, J=8.6 Hz, 2H), 6.77-6.68 (m, 2H), 6.57 (s, 1H), 4.56 (s, 2H), 4.26 (d, J=17.2 Hz, 1H), 4.20-4.09 (m, 1H), 4.01 (s, 3H), 2.80 (p, J=6.8 Hz, 1H), 1.15 (dd, J=13.5, 6.8 Hz, 6H).
Example 12
1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[1-[4-(trifluoromethoxy)phenoxy] ethyl]indazol-6-yl]methyleneamino]thiourea (C-12 of Table X)
Step 1: 1-(6-bromo-1-methyl-indazol-3-yl)ethanol
(41) To a stirred solution of 6-bromo-1-methyl-indazole-3-carbaldehyde (1.5 g) in dry THF (15 ml) was added methyl magnesium bromide (0.823 g, 1M in THF) at 0° C. under inert atmosphere. Reaction temperature was slowly raised to room temperature. Reaction mixture was continued to stir at room temperature for 2 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was quenched with Aq. ammonium chloride solution (25 ml) and extracted with Ethyl acetate (30 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-22% ethyl acetate in heptane as a mobile phase) to afford (0.750 g) of the title compound. HPLC/MS (method 1): R.sub.t: 1.602 min; MS: m/z=255.05 (M+1).
Step 2: 6-bromo-1-methyl-3-[1-[4-(trifluoromethoxy)phenoxy]ethyl]indazole
(42) In a microwave vial, 4-trifluromethoxy phenol (0.168 g) and triphenyl phosphine (0.217 g) were added to a solution of 1-(6-bromo-1-methyl-indazol-3-yl)ethanol (0.2 g) in dry THF (2 ml) under inert atmosphere and cooled to 0° C. The reaction mixture was stirred at 0° C. for 5 min and then DBAD (0.217 g) was added to the reaction mixture. Reaction mixture was continued to stir at 42° C. for 2 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (10 ml) and extracted with Ethyl acetate (10 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-25% ethyl acetate in heptane as a mobile phase) to afford (0.2 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.400 min; MS: m/z=416.9 (M+1).
Step 3: 1-methyl-3-[1-[4-(trifluoromethoxy)phenoxy]ethyl]-6-vinyl-indazole
(43) A solution of 6-bromo-1-methyl-3-[1-[4-(trifluoromethoxy) phenoxy]ethyl]indazole (0.2 g) in dry Toluene (2 ml) was purged with Nitrogen for 10 min. To the solution was added Pd(dppf)Cl.sub.2 (0.021 g) and Nitrogen purging was continued for another 10 min. Then Tributyl vinyl tin (0.229 g) was added to the solution and the reaction mixture was heated at 110° C. for 3 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, diluted with Water (10 ml) and extracted with Ethyl acetate (20 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-25% ethyl acetate in heptane as a mobile phase) to afford (0.150 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.287 min; MS: m/z=363.15 (M+1).
Step 4: 1-methyl-3-[1-[4-(trifluoromethoxy)phenoxy]ethyl]indazole-6-carbaldehyde
(44) To a stirred solution of 1-methyl-3-[1-[4-(trifluoromethoxy)phenoxy]ethyl]-6-vinyl-indazole (0.15 g) in 1,4-dioxane (2 ml) and Water (1 ml), OsO.sub.4 (0.002 g) and NaIO.sub.4 (0.194 g) were added at 0° C. under inert atmosphere. Reaction mixture was stirred at room temperature for 3 h. Progress of reaction was monitored by TLC. After completion, reaction mixture was diluted with Water (10 ml), quenched with Aq. Sodium sulfite solution (10 ml) and extracted with Ethyl acetate (20 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-22% ethyl acetate in heptane as a mobile phase) to afford (0.05 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.112 min; MS: m/z=365.1 (M+1).
Step 5: 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[1-[4-(trifluoromethoxy) phenoxy] ethyl]indazol-6-yl]methyleneamino]thiourea (C-12 of Table X)
(45) To a solution of 1-methyl-3-[1-[4-(trifluoromethoxy)phenoxy]ethyl]indazole-6-carbaldehyde (0.05 g) in EtOH (1 ml) was added 1-amino-3-(2-isopropylphenyl)thiourea (0.029 g) at room temperature under inert atmosphere. Then the reaction mixture was stirred for 3 h at 85° C. Progress of reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and the precipitated product was filtered through a filter paper. The residue was washed with cold EtOH (2 ml), triturated with Pentane (5 ml) and dried under reduced pressure to afford (0.05 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.272 min; MS: m/z=554.2 (M−1). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.89 (s, 1H), 9.99 (s, 1H), 8.25 (s, 1H), 7.97 (s, 1H), 7.89-7.78 (m, 2H), 7.37 (d, J=7.7 Hz, 1H), 7.31 (dt, J=8.1, 4.0 Hz, 1H), 7.27-7.15 (m, 4H), 7.13-7.06 (m, 2H), 5.92 (q, J=6.5 Hz, 1H), 4.05 (s, 3H), 3.13 (p, J=6.9 Hz, 1H), 1.76 (d, J=6.5 Hz, 3H), 1.22-1.12 (m, 6H).
Example 13
(2Z)-3-(2-isopropylphenyl)-2-[(E)-[1-methyl-3-[1-[4-(trifluoromethoxy) phenoxy]ethyl]indazol-6-yl]methylenehydrazono]thiazolidin-4-one (C-13 of Table X)
(46) A mixture of 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[1-[4-(trifluoromethoxy) phenoxy]ethyl]indazol-6-yl]methyleneamino]thiourea (0.320 g), NaOAc (0.095 g) and Methyl bromo acetate (0.132 g) in EtOH (6.0 ml) was stirred at room temperature for 12 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (25 ml) and extracted with Ethyl acetate (30 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-25% ethyl acetate in heptane as a mobile phase) to afford (0.15 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.342 min; MS: m/z=596.25 (M+1). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.39 (s, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.85 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.49 (dt, J=14.9, 7.8 Hz, 2H), 7.34 (t, J=7.5 Hz, 1H), 7.30-7.19 (m, 3H), 7.09 (d, J=8.7 Hz, 2H), 5.91 (q, J=6.4 Hz, 1H), 4.26 (d, J=17.3 Hz, 1H), 4.14 (d, J=17.6 Hz, 1H), 4.02 (s, 3H), 2.79 (p, J=6.9 Hz, 1H), 1.75 (d, J=6.5 Hz, 3H), 1.19-1.08 (m, 6H).
Example 14
(2Z)-2-(2-isopropylphenyl)imino-3-[(E)-[1-methyl-3-[1-[4-(trifluoromethoxy) phenoxy]ethyl]indazol-6-yl]methyleneamino]thiazolidin-4-one (C-14 of Table X)
(47) A mixture of 1-methyl-3-[1-[4-(trifluoromethoxy)phenoxy]ethyl]indazole-6-carbaldehyde (0.2 g) and (2Z)-3-amino-2-(2-isopropylphenyl)imino-thiazolidin-4-one (0.137 g) in Acetic acid (2 ml) was stirred at room temperature for 3 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (15 ml) and extracted with Ethyl acetate (25 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 25-30% ethyl acetate in heptane as a mobile phase) to afford (0.075 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.399 min; MS: m/z=596.25 (M+1). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.28 (s, 1H), 8.17 (d, J=1.2 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.81 (dd, J=8.6, 1.3 Hz, 1H), 7.36 (dd, J=7.7, 1.6 Hz, 1H), 7.32-7.20 (m, 3H), 7.21-7.13 (m, 3H), 6.93 (dd, J=7.7, 1.4 Hz, 1H), 6.01 (q, J=6.5 Hz, 1H), 4.21 (s, 2H), 4.15 (s, 3H), 3.05 (hept, J=6.9 Hz, 1H), 1.83 (d, J=6.4 Hz, 3H), 1.19 (d, J=6.9 Hz, 6H).
Example 15
1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[[4-(trifluoromethoxy) phenoxy] methyl]pyrazolo[4,3-c]pyridin-6 yl]methyleneamino]thiourea (C-15 of Table X)
Step 1: 4,6-dichloro-N-methoxy-N-methyl-pyridine-3-carboxamide
(48) To a solution of 4,6-dichloropyridine-3-carboxylic acid (5.0 g) in DMF (100 ml) EDC.HCl (4.85 g), N-Methylmorpholine (3.43 ml) and N, O-Dimethylhydroxylamine (3.04 g) were added and the reaction mixture was stirred for 16 h at room temperature. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (100 ml) and extracted with Ethyl acetate (50 ml×3). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 0-50% ethyl acetate in heptane as a mobile phase) to afford (5.7 g) of the title compound as a solid. LC/MS (method 1): R.sub.t: 1.59 min; MS: m/z=235.0 (M+1).
Step 2: 1-(4,6-dichloro-3-pyridyl)ethenone
(49) To a stirred solution of 4,6-dichloro-N-methoxy-N-methyl-pyridine-3-carboxamide (5.7 gm) in THF (40 ml) was added Methyl magnesium bromide (16.16 gm) at 0° C. The reaction mass was stirred for 16 h at room temperature. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with saturated solution of Ammonium chloride (100 ml) and extracted with Ethyl acetate (50 ml×3). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 0-50% ethyl acetate in heptane as a mobile phase) to afford (4.0 g) of the title compound. HPLC/MS (method 1): R.sub.t: 1.73 min; MS: m/z=231.0 (M+1).
Step 3: 6-chloro-1,3-dimethyl-pyrazolo[4,3-c]pyridine
(50) To a stirred solution of 1-(4,6-dichloro-3-pyridyl)ethanone (4.0 gm) in Methanol (25 ml) was added Methyl hydrazine (2.28 gm) at 0 CC. Then the reaction mixture was heated at 50° C. for 2 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure, diluted with Water (100 ml) and extracted with Ethyl acetate (30 ml×3). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 0-20% ethyl acetate in heptane as a mobile phase) to afford (1.6 gm) of the title compound. HPLC/MS (method 1): R.sub.t: 1.52 min; MS: m/z=182.1 (M+1).
Step 4: 3-(bromomethyl)-6-chloro-1-methyl-pyrazolo[4,3-c]pyridine
(51) To a stirred solution of 6-chloro-1,3-dimethyl-pyrazolo[4,3-c]pyridine (3.1 gm) in CCl.sub.4 (25 ml) was added N-Bromosuccinimide (3.66 gm) and Benzoyl peroxide (0.332 gm) at room temperature. Then reaction mixture was heated at 78° C. for 16 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure, diluted with Water (100 ml) and extracted with Ethyl acetate (30 ml×3). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 0-20% ethyl acetate in heptane as a mobile phase) to afford (1.6 g) of the title compound. HPLC/MS (method 1): R.sub.t: 1.69 min; MS: m/z=302.95 (M+1).
Step 5: 6-chloro-1-methyl-3-[[4-(trifluoromethoxy)phenoxy]methyl]pyrazolo[4,3-c]pyridine
(52) To a stirred solution of 4-(trifluoromethoxy)phenol (0.342 ml) in DMF (5 ml) was added Potassium tert-butoxide (0.323 gm) at room temperature under inert atmosphere. After 10 min, 3-(bromomethyl)-6-chloro-1-methyl-pyrazolo[4,3-c]pyridine (0.5 g) was added to the reaction mixture and the reaction mixture was stirred at r.t. for 5 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (25 ml) and extracted with Ethyl acetate (30 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-25% ethyl acetate in heptane as a mobile phase) to afford (0.470 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.099 min; MS: m/z=358 (M+1).
Step 6: 1-methyl-3-[[4-(trifluoromethoxy)phenoxy]methyl]-6-vinyl-pyrazolo[4,3-c]pyridine
(53) A stirred solution of 6-chloro-1-methyl-3-[[4-(trifluoromethoxy)phenoxy]methyl] pyrazolo[4,3-c]pyridine (0.47 g) in dry 1,4-dioxane (5 ml) was purged with Nitrogen for 10 min. To the solution Pd(dppf)C2 (0.058 g) was added and Nitrogen purging was continued for another 10 min. Tributyl vinyl tin (0.625 g) was added to the reaction mixture and heated at 110° C. for 12 h with stirring. Progress of reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, diluted with Water (30 ml) and extracted with Ethyl acetate (40 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-25% ethyl acetate in heptane as a mobile phase) to afford (0.2 g) of the title compound. HPLC/MS (method 1): R.sub.t: 1.921 min; MS: m/z=350.3 (M+1).
Step 7: 1-methyl-3-[[4-(trifluoromethoxy)phenoxy]methyl]pyrazolo[4,3-c]pyridine-6-carbaldehyde
(54) To a stirred solution of 1-methyl-3-[[4-(trifluoromethoxy)phenoxy]methyl]-6-vinyl-pyrazolo[4,3-c]pyridine (0.2 g) in 1,4-dioxane (2 ml), OsO.sub.4 (0.003 g) and NaIO.sub.4 (0.268 g) were added at 0° C. under inert atmosphere. The reaction mixture was continued to stir at room temperature for 3 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (10 ml), quenched with Aq. Sodium sulfite solution (10 ml) and extracted with Ethyl acetate (20 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-22% ethyl acetate in heptane as a mobile phase) to afford (0.055 g) of the title compound. HPLC/MS (method 1): R.sub.t: 1.905 min; MS: m/z=352.1 (M+1).
Step 8: 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[[4-(trifluoromethoxy) phenoxy] methyl]pyrazolo[4,3-c]pyridin-6-yl]methyleneamino]thiourea (C-15 of Table X)
(55) A mixture of 1-methyl-3-[[4-(trifluoromethoxy)phenoxy]methyl]pyrazolo[4,3-c]pyridine-6-carbaldehyde (0.053 g) and 1-amino-3-(2-isopropylphenyl)thiourea (0.033 g) in EtOH (2 ml) was heated at 85° C. for 3 h under inert atmosphere. Progress of reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and the precipitated product was filtered through a filter paper. The residue was washed with cold EtOH (2 ml), triturated with Pentane (5 ml) and dried under reduced pressure to afford (0.045 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.115 min; MS: m/z=541.25 (M−1). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 14.46 (s, 1H), 12.06 (s, 1H), 10.26 (s, 1H), 10.03 (s, 1H), 9.17 (s, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 8.21 (d, J=7.4 Hz, 1H), 7.55 (s, 1H), 7.40 (d, J=7.7 Hz, 1H), 7.34 (d, J=8.8 Hz, 6H), 7.32-7.18 (m, 7H), 5.60 (s, 1H), 5.54 (s, 2H), 4.15 (s, 2H), 4.09 (s, 3H), 3.38 (s, 1H), 3.32 (s, 7H), 3.19-3.08 (m, 1H), 2.58 (d, J=18.8 Hz, 1H), 2.43 (s, OH), 1.31 (d, J=9.7 Hz, 1H), 1.19 (dd, J=22.4, 6.8 Hz, 14H).
Example 16
(2Z)-3-(2-isopropylphenyl)-2-[(E)-[1-methyl-3-[[4-(trifluoromethoxy) phenoxy]methyl]pyrazolo[4,3-c]pyridin-6-yl]methylenehydrazono]thiazolidin-4-one (C-16 of Table X)
(56) A mixture of 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[[4-(trifluoromethoxy) phenoxy] methyl]pyrazolo[4,3-c]pyridin-6-yl]methyleneamino]thiourea (0.045 g), NaOAc (0.014 g) and Methyl bromo acetate (0.019 g) in EtOH (2 ml) was stirred at room temperature for 12 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (15 ml) and extracted with Ethyl acetate (20 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 25-30% ethyl acetate in heptane as a mobile phase) to afford (0.022 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.221 min; MS: m/z=583.6 (M+1). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.25 (s, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 7.61-7.44 (m, 2H), 7.41-7.26 (m, 4H), 7.26-7.18 (m, 2H), 5.55 (s, 2H), 4.30 (d, J=17.4 Hz, 1H), 4.19 (d, J=17.4 Hz, 1H), 4.14 (s, 3H), 2.94-2.72 (m, 1H), 1.16 (dd, J=13.6, 6.9 Hz, 6H).
Example 17
4-fluoro-6-[[(2-isopropylphenyl)carbamothioylhydrazono]methyl]—1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (C-17 of Table X)
Step 1: Ethyl 2-(4-bromo-2,6-difluoro-phenyl)-2-oxo-acetate
(57) To a mixture of 1-bromo-3,5-difluoro-benzene (1 g) in THF (5 ml) cooled to −78° C. was added a solution of Lithium bis(trimethylsilyl)amide (1.04 g) in THF. Diethyl oxalate (0.87 g) was added and the mixture stirred for 4 h. A saturated solution of ammonium chloride was added and the mixture extracted with Ethyl acetate, the extracts washed with a saturated solution of Sodium chloride, dried over anhydrous Sodium sulphate and evaporated under reduced pressure. The resultant solid was subjected to silica gel flash column chromatography eluting with a gradient of Ethyl acetate and Heptane to get the title compound (0.61 g). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.71 (d, J=8.3 Hz, 2H), 4.29 (d, J=7.1 Hz, 2H), 1.22 (t, J=7.1 Hz, 3H).
Step 2: Ethyl 6-bromo-4-fluoro-1-methyl-indazole-3-carboxylate
(58) A mixture of Ethyl 2-(4-bromo-2,6-difluoro-phenyl)-2-oxo-acetate (0.1 g), Methyl hydrazine sulfate (0.10 g) and Triethyl amine (0.089 g) in N-Methylpyrollidinone (3 ml) was heated at 80° C. for 1 h. The mixture was diluted with water and extracted with Ethyl acetate. The organic extracts were separated, washed with a saturated solution of Sodium chloride, dried over anhydrous Sodium sulphate and evaporated in vacuo. The residue obtained was subjected to silica gel flash column chromatography eluting with a gradient of Ethyl acetate and Heptane to afford the title compound (0.07 g). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.00 (d, J=1.1 Hz, 1H), 7.34 (dd, J=10.1, 1.2 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 4.14 (s, 3H), 1.34 (t, J=7.1 Hz, 3H).
Step 3: 6-bromo-4-fluoro-1-methyl-indazole-3-carboxylic Acid
(59) Ethyl 6-bromo-4-fluoro-1-methyl-indazole-3-carboxylate (2.4 g) and Lithium hydroxide (1.0 g) in a mixture of THF (15 ml) and Water was stirred at room temperature for 3 h. The reaction mixture was neutralized with 2M Hydrochloric acid solution. The precipitated solids were filtered, washed with water and pentane and dried to afford the title compound (2.16 g). .sup.1H NMR (500 MHz, DMSO-d.sub.6); .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 13.14 (s, 1H), 8.00 (s, 1H), 7.33 (d, J=10.0 Hz, 1H), 4.13 (s, 3H).
Step 4: 6-bromo-4-fluoro-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide
(60) A mixture of 6-bromo-4-fluoro-1-methyl-indazole-3-carboxylic acid (0.06 g, 0.22 mmol), 4-(trifluoromethoxy) aniline (0.04 g), 1-[Bis(dimethylamino) methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.167 g) and N,N diisopropyl ethyl amine (0.057 g) in DMF (3 ml) was stirred at room temperature for 16 h. The mixture was poured into a mixture of ice and water and the precipitated solids were filtered, washed with water and pentane and dried to obtain the title compound (0.07 g). HPLC/MS (method 1): R.sub.t: 2.22 min, m/z=431.6 (M+1); .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.70 (s, 1H), 8.05 (s, 1H), 7.95 (d, J=8.7 Hz, 2H), 7.36 (t, J=8.1 Hz, 3H), 4.19 (s, 3H).
Step 5: 4-fluoro-1-methyl-N-[4-(trifluoromethoxy)phenyl]-6-vinyl-indazole-3-carboxamide
(61) 6-bromo-4-fluoro-N,1-dimethyl-N-[4-(trifluoromethoxy)phenylindazole-3-carboxamide (0.2 g), [1,1′-Bis(diphenylphosphino) ferrocene] dichloropalladium(II) (0.017 g) and Tri-n-butyl-vinyl tin (0.220 g) in 1,4-Dioxane (4 ml) was heated at 100° C. for 3 h. The mixture was filtered through Celite then the filtrate, diluted with water and extracted with Ethyl acetate. The organic extracts were dried over anhydrous Sodium sulphate and evaporated under reduced pressure and the residue obtained was subjected to flash column chromatography using a gradient of Ethyl acetate and Heptane to afford the title compound (0.1 g). HPLC/MS (method 1): R.sub.t: 2.18 min; m/z=390.2 (M+1); .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 10.64 (s, 1H), 7.96 (d, J=8.6 Hz, 2H), 7.69 (s, 1H), 7.36 (dd, J=16.9, 10.2 Hz, 3H), 6.89 (dd, J=17.6, 10.9 Hz, 1H), 6.09 (d, J=17.6 Hz, 1H), 5.46 (d, J=10.9 Hz, 1H), 4.20 (s, 3H).
Step 6: 4-fluoro-6-formyl-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide
(62) A mixture of 4-fluoro-N,1-dimethyl-N-[4-(trifluoromethoxy)phenyl]-6-vinyl-indazole-3-carboxamide (0.1 g), Osmium tetroxide (0.004 g) and Sodium periodate (0.17 g) in 1,4-Dioxane (4 ml) and water (1 ml) was stirred at room temperature for 12 h. Sodium sulfite solution (0.5%) was added and the mixture extracted with Ethyl acetate. The organic extracts were dried over anhydrous Sodium sulfate, concentrated under reduced pressure and the residue obtained was subjected to silica gel flash column chromatography to get the title compound (0.07 g); HPLC/MS (method 1): R.sub.t: 1.961 min; m/z=392.1 (M+1); .sup.1H NMR (500 MHz, DMSO-d.sub.6): δ 10.77 (s, 1H), 10.14 (d, J=2.1 Hz, 1H), 8.39 (d, J=0.9 Hz, 1H), 8.01-7.92 (m, 2H), 7.47 (dd, J=10.4, 1.0 Hz, 1H), 7.42-7.34 (m, 2H), 4.32 (s, 3H).
Step 7: 4-fluoro-6-[[(2-isopropylphenyl)carbamothioylhydrazono]methyl]-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (C-17 of Table X)
(63) A mixture of 4-fluoro-6-formyl-N,1-dimethyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (0.065 g) and 1-amino-3-(2-isopropylphenyl)thiourea (0.037 g) in Ethanol (3 ml) was heated at 80° C. for 6 h. The mixture was concentrated under reduced pressure and residue was subjected to Silica gel flash column chromatography eluting with a gradient of Dichloromethane and Methanol to afford the title compound (0.026 g). HPLC/MS (method 1): R.sub.t: 2.237 min; m/z=573.2 (M+1); .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.01 (s, 1H), 10.69 (s, 1H), 10.20 (s, 1H), 8.28 (s, 1H), 8.10 (d, J=12.1 Hz, 1H), 8.01-7.91 (m, 3H), 7.42-7.29 (m, 4H), 7.25 (td, J=7.5, 1.5 Hz, 1H), 7.19 (dd, J=7.8, 1.4 Hz, 1H), 4.24 (s, 3H), 3.15 (hept, J=7.0 Hz, 1H), 1.21 (d, J=6.9 Hz, 6H).
Example 18
(64) 4-fluoro-6-[[(2-isopropylphenyl)carbamothioylhydrazono]methyl]-N,1-dimethyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (C-18 of Table X)
Step 1: 6-bromo-4-fluoro-N,1-dimethyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide
(65) To a stirred solution of 6-bromo-4-fluoro-1-methyl-N-[4-(trifluoromethoxy)phenyl] indazole-3-carboxamide (0.3 g) in DMF (3 ml) at 0° C. was added Sodium hydride (0.02 g) and stirred for 15 min. Methyl iodide (0.128 g) was subsequently added and the mixture was stirred at room temperature for 12 h. Saturated Ammonium chloride solution was added and the mixture extracted with Ethyl acetate. The organic extracts were dried over anhydrous Sodium sulfate, concentrated under reduced pressure and the residue subjected to silica gel flash column chromatography to get the title compound (0.26 g). HPLC/MS (method 1): R.sub.t: 2.14 min; m/z=447.3 (M+1); .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.28 (d, J=12.9 Hz, 2H), 7.19 (s, 1H), 7.05 (d, J=8.2 Hz, 2H), 6.96 (d, J=9.4 Hz, 1H), 3.88 (s, 3H), 3.54 (s, 3H).
Step 2: 4-fluoro-N,1-dimethyl-N-[4-(trifluoromethoxy)phenyl]-6-vinyl-indazole-3-carboxamide
(66) A mixture of 6-bromo-4-fluoro-N,1-dimethyl-N-[4-(trifluoromethoxy)phenylindazole-3-carboxamide (0.35 g), 1,1′-Bis(diphenylphosphino) ferrocene] dichloropalladium(II) (0.03 g) and Tri-n-butyl vinyl tin (0.37 g) in 1,4-Dioxane (6 ml) was heated at 100° C. for 3 h. The reaction mixture was filtered through celite and the filtrate, diluted with water and extracted with Ethyl acetate. The organic extracts were dried over anhydrous Sodium sulphate and evaporated under reduced pressure and the resultant residue was subjected to Silica gel flash column chromatography to get the title compound (0.27 g). LC/MS (method 1): R.sub.t: 2.09 min, m/z=390.4 (M+1); .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.52 (s, 1H), 7.42-7.16 (m, 5H), 6.82 (dd, J=17.5, 10.9 Hz, 1H), 6.02 (d, J=17.6 Hz, 1H), 5.41 (d, J=11.0 Hz, 1H), 3.91 (d, J=18.0 Hz, 3H), 3.45 (s, 3H).
Step 3: 4-fluoro-6-formyl-N,1-dimethyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide
(67) A mixture of 4-fluoro-N,1-dimethyl-N-[4-(trifluoromethoxy)phenyl]-6-vinyl-indazole-3-carboxamide (0.4 g), Osmium tetroxide (0.013 g), Sodium periodate (0.65 g) in 1,4-Dioxane (6 ml) and water (3 ml) was stirred at r.t. for 12 h. Sodium sulfite solution (0.5%) was added and the mixture extracted with Ethyl acetate. The organic extracts were dried over anhydrous Sodium sulfate and concentrated under reduced pressure and the residue obtained was subjected to silica gel flash column chromatography to afford the title compound (0.3 g). HPLC/MS (method 1): R.sub.t: 1.9 min; m/z=396 (M+1); .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.07 (d, J=2.1 Hz, 1H), 8.24 (s, 1H), 7.43-7.18 (m, 5H), 4.12-3.99 (s, 3H), 3.47 (s, 3H).
Step 4: 4-fluoro-6-[[(2-isopropylphenyl)carbamothioylhydrazono]methyl]-N,1-dimethyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (C-18 of Table X)
(68) A mixture of 4-fluoro-6-formyl-N,1-dimethyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (0.29 g) and 1-amino-3-(2-isopropylphenyl)thiourea (0.16 g) in THF (10 ml) was heated at 60° C. for 2 h. The mixture was evaporated in vacuo and the residue was subjected to silica gel flash column chromatography eluting with a gradient of Dichloromethane and Methanol to get the desired compound (0.3 g). HPLC/MS (method 1): R.sub.t: 2.15 min, m/z=587.2 (M+1); .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.96 (s, 1H), 10.15 (s, 1H), 8.21 (s, 1H), 7.98 (d, J=12.1 Hz, 1H), 7.76 (s, 1H), 7.45-6.90 (m, 8H), 3.97 (s, 3H), 3.45 (s, 3H), 3.13 (p, J=6.8 Hz, 1H), 1.20 (d, J=6.9 Hz, 6H).
Example 19: 4-fluoro-6-[[(Z)-[3-(2-isopropylphenyl)-4-oxo-thiazolidin-2-ylidene]hydrazono]methyl]-N,1-dimethyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (C-19 of Table X)
(69) A mixture of 4-fluoro-6-[(E)-[(2-isopropylphenyl)carbamothioylhydrazono]methyl]-N,1-dimethyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (0.18 g), Sodium acetate (0.05 g) and Methyl bromo acetate (0.187 g) in THF (4 ml) was heated at 40° C. for 6 h. The mixture was diluted with Water and extracted with Ethyl acetate, the organic extracts dried over Sodium sulphate, concentrated under reduced pressure and the residue subjected to silica gel flash column chromatography to obtain the title compound (0.12 g). HPLC/MS (method 1): R.sub.t: 2.299 min; m/z=627.4 (M+1)+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.39 (d, J=1.5 Hz, 1H), 7.75 (s, 1H), 7.49 (dtd, J=15.0, 7.9, 1.6 Hz, 2H), 7.38-7.24 (m, 7H), 4.28 (d, J=17.4 Hz, 1H), 4.16 (d, J=17.3 Hz, 1H), 3.94 (s, 3H), 3.45 (s, 3H), 2.79 (h, J=6.8 Hz, 1H), 1.15 (dd, J=10.6, 6.8 Hz, 6H).
Example 20
1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[(E)-2-[4-(trifluoromethoxy)phenyl]vinyl] indazol-6-yl]methyleneamino]thiourea (C-20 of Table X)
Step 1: 1H-indazol-6-ylmethanol
(70) To a stirred solution of methyl 1H-indazole-6-carboxylate (6 g) in THF (150 ml) was added 1 M LiAlH.sub.4 solution in THF (34.7 ml) at 0° C. Reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with NaOH solution and extracted with Ethyl acetate. The crude was filtered through celite and the organic layer was separated, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the title compound (4.5 g). HPLC/MS (method 1): R.sub.t:1.114 min; m/z=149 (M+1).
Step 2: 1H-indazole-6-carbaldehyde
(71) To the stirred solution of 1H-indazol-6-ylmethanol (1.5 g) in DCM (15 ml) and THF (15 ml) was added Dess Martin Periodinane (4.29 g) and stirred at room temperature for 16 h. DCM was added and filtered through celite. Filtrate was evaporated under vacuum to afford the title compound (1.3 g). HPLC/MS (method 1): R.sub.t:1.290 min; m/z=146 (M+1).
Step 3: 3-iodo-1H-indazole-6-carbaldehyde
(72) To a stirred solution of 1H-indazole-6-carbaldehyde (2.4 g) in DMF (20 ml), K.sub.2CO.sub.3 (5.6 g) and I.sub.2 (7.5 g) were added. Reaction mixture was stirred at room temperature for 2 h. After completion, reaction mixture was diluted with Sodium thiosulphate solution and stirred for 10 min, solid was precipitated. Solid was filtered and dried under vacuum to afford the title compound (3.8 g). HPLC/MS (method 1): R.sub.t:1.624 min; m/z=271 (M−1).
Step 4: 3-iodo-1-methyl-indazole-6-carbaldehyde
(73) To a stirred solution of 3-iodo-1H-indazole-6-carbaldehyde (3.2 g) in THF (50 ml), K.sub.2CO.sub.3 (3.2 g) and MeI (2.5 g) were added. Reaction mixture was stirred at room temperature for 16 h. After completion, reaction mixture was quenched with Water, extracted with Ethyl acetate, concentrated under reduced pressure and the residue subjected to silica gel flash column chromatography to obtain the title compound (1.2 g). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.16 (s, 1H), 8.37 (s, 1H), 7.80-7.47 (m, 2H), 4.18 (s, 3H).
Step 5: 1-methyl-3-[(E)-2-[4-(trifluoromethoxy)phenyl]vinyl]indazole-6-carbaldehyde
(74) To a stirred solution of 3-iodo-1-methyl-indazole-6-carbaldehyde (0.15 g) in DMF (1 ml), 1-(trifluoromethoxy)-4-vinyl-benzene (0.118 g) and DIPEA (0.141 g) were added. The reaction mixture was purged with Ar gas for 10 min and Pd(OAc).sub.2 (0.012 g), Tri(o-tolyl)phosphine (0.048 g) were added. Reaction mixture was heated at 110° C. for 24 h. After completion, the reaction mixture was diluted with Water and extracted with Ethyl acetate, the organic extracts dried over sodium sulphate, concentrated under reduced pressure and the residue subjected to silica gel flash column chromatography to obtain the title compound (0.04 g).
Step 6: 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[(E)-2-[4-(trifluoromethoxy) phenyl] vinyl]indazol-6-yl]methyleneamino]thiourea (C-20 of Table X)
(75) A mixture of 1-methyl-3-[(E)-2-[4-(trifluoromethoxy)phenyl] vinyl] indazole-6-carbaldehyde (0.1 g) and 1-amino-3-(2-isopropylphenyl)thiourea (0.03 g) in EtOH (1 ml) was heated at 90° C. for 2 h. Solid precipitated after 2 h. The solid was filtered, washed with cold EtOH and dried under vacuum to afford the title compound (0.093 g). HPLC/MS (method 1): R.sub.t: 2.323 min; m/z=538 (M+1). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.02 (s, 1H), 8.29 (s, 1H), 8.17 (d, J=8.6 Hz, 1H), 8.04 (s, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.90-7.81 (m, 2H), 7.58 (d, J=16.6 Hz, 1H), 7.53 (d, J=16.6 Hz, 1H), 7.37 (m, J=7.8, 3.9 Hz, 3H), 7.31 (s, 1H), 7.27-7.20 (m, 2H), 4.11 (s, 3H), 3.20-3.08 (m, 1H), 1.20 (d, J=6.9 Hz, 6H).
Example 21
(2Z)-3-(2-isopropylphenyl)-2-[(E)-[1-methyl-3-[(E)-2-[4-(trifluoromethoxy)phenyl] vinyl]indazol-6-yl]methylenehydrazono]thiazolidin-4-one (C-21 of Table X)
(76) A mixture of 1-(2-isopropylphenyl)-3-[(E)-[1-methyl-3-[(E)-2-[4-(trifluoromethoxy) phenyl] vinyl]indazol-6-yl]methyleneamino]thiourea (0.08 g), NaOAc (0.049 g) and Methyl bromo acetate (0.046 g) in EtOH (5 ml) was heated at 40° C. for 8 h. After completion, the reaction mixture was diluted with Water and extracted with Ethyl acetate, the organic extracts dried over Sodium sulphate, concentrated under reduced pressure and the residue subjected to silica gel flash column chromatography to obtain the title compound (0.060 g). H PLC/MS (method 1): R.sub.t: 2.377 min; m/z=578 (M+1). 6 .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.46 (s, 1H), 8.25 (d, J=8.6 Hz, 1H), 7.92 (s, 1H), 7.90-7.83 (m, 2H), 7.73 (dd, J=8.7, 1.2 Hz, 1H), 7.60-7.45 (m, 4H), 7.44-7.32 (m, 3H), 7.28 (dd, J=7.8, 1.4 Hz, 1H), 4.28 (d, J=17.2 Hz, 1H), 4.16 (d, J=17.3 Hz, 1H), 4.08 (s, 3H), 2.82 (h, J=6.7 Hz, 1H), 1.17 (dd, J=16.6, 6.8 Hz, 6H).
Example 22
1-(2-isopropylphenyl)-3-[(E)-[3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzothiazol-6-yl]methyleneamino]thiourea (C-22 of Table X)
Step 1: (6-bromo-1,2-benzothiazol-3-yl)methanol
(77) To a stirred solution of ethyl 6-bromo-1,2-benzothiazole-3-carboxylate (0.6 g) in THF (6 ml) and EtOH (3 ml), LiBH.sub.4 (0.069 g) was added drop wise at 0° C. under inert atmosphere. Reaction mixture was stirred at 00° C. for 2 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (30 ml) and quenched with Aq. 5% NaOH solution, extracted with Ethyl acetate (40 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-22% ethyl acetate in heptane as a mobile phase) to afford (0.380 g) of the title compound. HPLC/MS (method 1): R.sub.t: 1.680 min; MS: m/z=246 (M+1).
Step 2: 6-bromo-3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzothiazole
(78) To a stirred solution of (6-bromo-1,2-benzothiazol-3-yl)methanol (1.1 g) in dry THF (11 ml), 4-trifluromethoxy phenol (0.963 g) and triphenyl phosphine (1.182 g) were added at 00° C. under inert atmosphere. Reaction mixture was continued to stir at 00° C. for 5 min and then DBAD (1.038 g) was added. Then the reaction mixture was stirred at 42° C. for 2 h in microwave. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (50 ml) and extracted with Ethyl acetate (60 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 8-10% ethyl acetate in heptane as a mobile phase) to afford (1 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.428 min; MS: m/z=404 (M−1).
Step 3: 3-[[4-(trifluoromethoxy)phenoxy]methyl]-6-vinyl-1,2-benzothiazole
(79) A solution of 6-bromo-3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzothiazole (0.9 g) in dry Toluene (10 ml) was purged with Nitrogen for 10 min. To the solution Pd(dppf)Cl.sub.2 (0.098 g) was added and purging was continued for another 10 min. Tributyl vinyl tin (0.847 g) was added to the reaction mixture and heated at 110° C. for 3 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, diluted with Water (50 ml) and extracted with Ethyl acetate (60 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 15-20% ethyl acetate in heptane as a mobile phase) to afford (0.660 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.391 min; MS: m/z=352 (M+1).
Step 4: 3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzothiazole-6-carbaldehyde
(80) To a stirred solution of 3-[[4-(trifluoromethoxy)phenoxy]methyl]-6-vinyl-1,2-benzothiazole (0.660 g) in 1,4-dioxane (6 ml) and Water (2 ml), OsO.sub.4 (0.007 g) and NaIO.sub.4 (0.880 g) were added at 0° C. under inert atmosphere. The reaction mixture was stirred at room temperature for 3 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (20 ml), quenched with Aq. Sodium sulfite solution (15 ml) and extracted with Ethyl acetate (40 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-22% ethyl acetate in heptane as a mobile phase) to afford (0.170 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.108 min; MS: m/z=354.4 (M+1).
Step 5: 1-(2-isopropylphenyl)-3-[(E)-[3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzothiazol-6-yl]methyleneamino]thiourea (C-22 of Table X)
(81) A mixture of 3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzothiazole-6-carbaldehyde (0.17 g) and 1-amino-3-(2-isopropylphenyl)thiourea (0.101 g) in EtOH (2 ml) was heated at 85° C. for 3 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and the precipitated product was filtered through a filter paper. The residue was washed with cold EtOH (2 ml), triturated with Pentane (5 ml) and dried under reduced pressure to afford (0.165 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.347 min; MS: m/z=545.1 (M+1). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.97 (s, 1H), 10.12 (s, 1H), 8.63 (s, 1H), 8.31-8.19 (m, 3H), 7.41-7.29 (m, 4H), 7.28-7.15 (m, 4H), 5.63 (s, 2H), 3.14 (h, J=6.9 Hz, 1H), 1.20 (d, J=6.9 Hz, 6H).
Example 23: (2Z)-3-(2-isopropylphenyl)-2-[(E)-[3-[[4-(trifluoromethoxy)phenoxy] methyl]-1,2-benzothiazol-6-yl]methylenehydrazono]thiazolidin-4-one (C-23 of Table X)
(82) A mixture of 1-(2-isopropylphenyl)-3-[(E)-[3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzothiazol-6-yl]methyleneamino]thiourea (0.115 g), NaOAc (0.035 g) and Methyl bromo acetate (0.048 g) in EtOH (2.0 ml) was stirred at room temperature for 12 h. Progress of reaction was monitored by TLC. After completion the reaction mixture was diluted with Water (15 ml) and extracted with Ethyl acetate (20 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-25% ethyl acetate in heptane as a mobile phase) to afford (0.060 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.419 min; MS: m/z=585.2 (M+1). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.50 (d, J=7.1 Hz, 2H), 8.31 (d, J=8.5 Hz, 1H), 7.95 (dd, J=8.5, 1.3 Hz, 1H), 7.55-7.44 (m, 2H), 7.38-7.25 (m, 4H), 7.23-7.16 (m, 2H), 5.62 (s, 2H), 4.29 (d, J=17.4 Hz, 1H), 4.17 (d, J=17.3 Hz, 1H), 2.80 (h, J=6.9 Hz, 1H), 1.16 (dd, J=12.6, 6.8 Hz, 6H).
Example 24
1-(2-isopropylphenyl)-3-[(E)-[3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzoxazol-6-yl]methyleneamino]thiourea (C-24 of Table X)
Step 1: (6-bromo-1,2-benzoxazol-3-yl) Methanol
(83) To a stirred solution of ethyl 6-bromo-1,2-benzoxazole-3-carboxylate (1.1 g) in THF (10 ml) and EtOH (3 ml), LiBH.sub.4 (0.133 g) was added drop wise at 0° C. under inert atmosphere. The reaction mixture was stirred at 0° C. for 2 h. Reaction was monitored by TLC. After the completion, the reaction mixture was diluted with Water (20 ml), quenched with 5% NaOH solution and extracted with Ethyl acetate (30 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 15-20% ethyl acetate in heptane as a mobile phase) to afford (0.8 g) of the title compound. HPLC/MS (method 1): R.sub.t: 1.587 min; MS: m/z=229 (M+1).
Step 2: 6-bromo-3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzoxazole
(84) To a stirred solution of (6-bromo-1,2-benzoxazol-3-yl) methanol (0.5 g) in dry THF (5 ml), 4-trifluromethoxy phenol (0.469 g) and Triphenyl phosphine (0.575 g) were added at 0° C. under inert atmosphere. The reaction mixture was stirred at 0° C. for 5 min and then DBAD (0.505 g) was added. Then the reaction mixture was stirred at 35° C. for 2 h in microwave. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (20 ml) and extracted with Ethyl acetate (30 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 10-12% ethyl acetate in heptane as a mobile phase) to afford (1.5 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.296 min; MS: m/z=389 (M+1).
Step 3: 3-[[4-(trifluoromethoxy)phenoxy]methyl]-6-vinyl-1,2-benzoxazole
(85) A solution of 6-bromo-3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzoxazole (1.5 g) in dry Toluene (15 ml) was purged with Nitrogen for 10 min. To the solution Pd(dppf)C2 (0.170 g) was added and purging was continued for another 10 min. Tributyl vinyl tin (1.838 g) was added to the reaction mixture and heated at 105° C. for 3 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, diluted with Water (40 ml) and extracted with Ethyl acetate (50 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 15-20% ethyl acetate in heptane as a mobile phase) to afford (1.4 g) of the title compound. HPLC/MS (method 1): R.sub.t: 1.929 min; MS: m/z=332.1 (M+1).
Step 4: 3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzoxazole-6-carbaldehyde
(86) To a stirred solution of 3-[[4-(trifluoromethoxy)phenoxy]methyl]-6-vinyl-1,2-benzoxazole (2 g) in 1,4-dioxane (16 ml) and Water (4 ml), OsO.sub.4 (0.030 g) and NaIO.sub.4 (2.795 g) were added at 0° C. under inert atmosphere. The reaction mixture was stirred at room temperature for 3 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (50 ml), quenched with Aq. sodium sulfite solution (20 ml) and extracted with Ethyl acetate (60 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 25-30% ethyl acetate in heptane as a mobile phase) to afford (0.6 g) of the title compound, which was further used without characterization.
Step 5: 1-(2-isopropylphenyl)-3-[(E)-[3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzoxazol-6-yl]methyleneamino]thiourea (C-24 of Table X)
(87) A mixture of 3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzoxazole-6-carbaldehyde (0.2 g) and 1-amino-3-(2-isopropylphenyl)thiourea (0.124 g) in EtOH (2 ml) was heated at 85° C. for 3 h. Progress of reaction was monitored by TLC. After completion the reaction mixture was cooled to room temperature and the precipitated product was filtered through a filter paper. The residue was washed with cold EtOH (2 ml), triturated with Pentane (5 ml) and dried under reduced pressure to afford (0.180 g) of the title compound. H PLC/MS (method 1): R.sub.t: 2.276 min; MS: m/z=529.3 (M+1). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.99 (s, 1H), 10.19 (s, 1H), 8.44 (s, 1H), 8.27 (s, 1H), 8.00-7.92 (m, 2H), 7.35 (dddd, J=16.6, 15.0, 7.8, 1.6 Hz, 4H), 7.28-7.16 (m, 4H), 5.65 (s, 2H), 3.13 (h, J=6.9 Hz, 1H), 1.19 (d, J=6.9 Hz, 6H).
Example 25
(2Z)-3-(2-isopropylphenyl)-2-[(E)-[3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzoxazol-6-yl]methylenehydrazono]thiazolidin-4-one (C-25 of Table X)
(88) A mixture of 1-(2-isopropylphenyl)-3-[(E)-[3-[[4-(trifluoromethoxy)phenoxy] methyl]-1,2-benzoxazol-6-yl]methyleneamino]thiourea (0.125 g), NaOAc (0.029 g) and methyl bromo acetate (0.054 g) in EtOH (3 ml) was stirred at room temperature for 12 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with Water (15 ml) and extracted with Ethyl acetate (20 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting in 20-25% ethyl acetate in heptane as a mobile phase) to afford (0.11 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.335 min; MS: m/z=569.3 (M+1). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.56 (s, 1H), 8.11-8.05 (m, 2H), 7.93 (dd, J=8.3, 1.1 Hz, 1H), 7.61-7.50 (m, 2H), 7.45-7.36 (m, 3H), 7.40-7.30 (m, 1H), 7.33-7.24 (m, 2H), 5.71 (s, 2H), 4.35 (d, J=17.3 Hz, 1H), 4.22 (d, J=17.3 Hz, 1H), 2.85 (h, J=6.8 Hz, 1H), 1.21 (dd, J=11.0, 6.8 Hz, 6H).
Example 26
(E)-1-[3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzoxazol-6-yl]-N-[(2S,3R,4S,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl]oxy-methanimine (C-26 of Table X)
(89) A mixture of 3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzoxazole-6-carbaldehyde (0.15 g) and O-[(2S,3R,4S,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl]hydroxylamine (0.108 g) in EtOH (2 ml) was heated at 85° C. for 4 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was evaporated under reduced pressure and the crude product was purified by flash chromatography (eluting in 35-40% ethyl acetate in heptane as a mobile phase). to afford (0.045 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.179 min; MS: m/z=539.25 (M−1). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.60 (s, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.78 (dd, J=8.2, 1.2 Hz, 1H), 7.38-7.31 (m, 2H), 7.27-7.19 (m, 2H), 5.66 (s, 2H), 5.56 (d, J=2.1 Hz, 1H), 3.82 (dd, J=3.2, 2.1 Hz, 1H), 3.60-3.50 (m, 1H), 3.47-3.36 (m, 9H), 3.06 (t, J=9.2 Hz, 1H), 1.17 (d, J=6.2 Hz, 3H).
Example 27
[(2S,3R,4S,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl] N-[3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzoxazol-6-yl]carbamate (C-27 of Table X)
Step 1: 3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzoxazole-6-carboxylic Acid
(90) To a solution of 3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzoxazole-6-carbaldehyde (0.35 g) in CH.sub.3CN (4 ml) and Water (1.5 ml), KMnO.sub.4 (0.328 g) was added and the reaction mixture was stirred at room temperature for 12 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was poured in ice cold water and filtered through a celite bed. Celite bed was washed with water and pH of filtrate was adjusted up to ˜3-4 using Aq. 1N HCl solution. The precipitated product was filtered through a filter paper and dried under reduced pressure to afford (0.360 g) of the title compound. HPLC/MS (method 1): R.sub.t: 1.947 min; MS: m/z=352 (M−1).
Step 2: [[3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzoxazole-6-carbonyl]iminio-lambda5-azanylidene]azanide
(91) To a stirred solution of -[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzoxazole-6-carboxylic acid (0.31 g) in Acetone (4 ml), Triethyl amine (0.124 g) and Ethyl chloroformate (0.143 g) were added at 0° C. The reaction mixture was stirred at room temperature for 2 h and then NaN.sub.3 (0.068 g) in Water (1 ml) was added and the reaction was continued to stir at room temperature for 12 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (10 ml) and extracted with DCM (20 ml×2). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford (0.3 g) of the title compound, which was further used without characterization.
Step 3: [(2S,3R,4S,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl] N-[3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzoxazol-6-yl]carbamate (C-27 of Table X)
(92) A mixture of [[3-[[4-(trifluoromethoxy)phenoxy]methyl]-1,2-benzoxazole-6-carbonyl] iminio-lambda5-azanylidene]azanide (0.3 g) and (3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-ol (0.164 g) in CH.sub.3CN (3 ml) was heated at 85° C. for 2 h. Then the reaction mixture was cooled to 0° C. and Cesium carbonate (0.085 g) was added. Reaction mixture was further stirred for 12 h at room temperature. Progress of reaction was monitored by TLC. After completion, the solvent of the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting in 25-30% ethyl acetate in heptane as a mobile phase) to afford (0.026 g) of the title compound. HPLC/MS (method 1): R.sub.t: 2.127 min; MS: m/z=557.3 (M+1). .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 10.40 (s, 1H), 8.04 (s, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.47 (dd, J=8.7, 1.6 Hz, 1H), 7.40 (d, J=8.7 Hz, 2H), 7.27 (d, J=9.1 Hz, 2H), 6.06 (d, J=2.1 Hz, 1H), 5.64 (s, 2H), 3.83 (t, J=2.7 Hz, 1H), 3.69 (dt, J=12.4, 6.3 Hz, 1H), 3.57 (dd, J=9.3, 3.2 Hz, 1H), 3.53-3.44 (m, 9H), 3.10-3.14 (t, 1H), 1.27-1.19 (m, 3H).
Example 64
Synthesis of 6-[[[(2-isopropylanilino)-methylsulfanyl-methylene]hydrazono] methyl]-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (C-64 of Table X)
(93) To a mixture of 6-[[(2-isopropylphenyl)carbamothioylhydrazono]methyl]-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (0.15 g) in Ethanol (10 ml) were added Sodium acetate (0.075 g) and Methyl iodide (0.18 g). The mixture was heated at 68° C. for 4 h. The mixture was subsequently cooled to ambient temperature, diluted with water and extracted with Ethyl acetate. The Ethyl acetate extracts were washed with brine, dried over anhydrous Sodium sulphate and evaporated under reduced pressure. The resultant residue was purified by silica gel flash column chromatography using a gradient of Ethyl acetate and Heptane as eluent to afford the title compound (0.06 g). HPLC/MS (method 1): R.sub.t: 2.48 min; m/z=569 (M+1); .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.85 (s, 1H), 8.61 (s, 1H), 8.40 (d, J=8.5 Hz, 1H), 8.26 (s, 1H), 7.85 (dd, J=8.5, 1.2 Hz, 1H), 7.81-7.74 (m, 2H), 7.72 (d, J=4.4 Hz, 1H), 7.34 (m, 3H), 7.23 (m, 3H), 4.18 (s, 3H), 3.29 (m, 1H), 2.48 (s, 3H), 1.29 (d, J=6.9 Hz, 6H).
Example 65
Synthesis of 6-[[[3-(2-isopropylphenyl)thiazolidin-2-ylidene]hydrazono] methyl]-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (C-65 of Table X)
(94) To a stirred solution of 6-[[(2-isopropylphenyl)carbamothioylhydrazono]methyl]-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (0.2 g) in Acetone (10 ml) were added potassium carbonate (0.1 g) and 1-bromo-2-chloro ethane (0.12 g). The mixture was heated at 65° C. for 3 h. The mixture was cooled to ambient temperature, diluted with brine solution and extracted with Ethyl acetate. The Ethylacetate extracts were washed with brine, dried over Sodium sulphate and concentrated under reduced pressure and the resultant residue subjected to Silica gel flash column chromatography to get the title compound (0.1 g). HPLC/MS (method 1): R.sub.t: 2.34 min; m/z=581 (M+1); .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.85 (s, 1H), 8.40-8.24 (m, 2H), 7.84-7.69 (m, 3H), 7.62 (s, 1H), 7.45-7.38 (m, 1H), 7.38-7.30 (m, 1H), 7.30-7.20 (m, 4H), 4.14 (s, 3H), 4.11-4.00 (m, 1H), 4.00-3.85 (m, 1H), 3.45-3.26 (m, 2H), 3.12 (m, 1H), 1.25 (dd, J=15.0, 6.9 Hz, 6H).
Example 66
Synthesis of 6-[[[3-(2-isopropylphenyl)-1,3-thiazinan-2-ylidene] hydrazono] methyl]-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide (C-66 of Table X)
(95) To a stirred solution of 6-[[(2-isopropylphenyl)carbamothioylhydrazono]methyl]-1-methyl-N-[4-(trifluoromethoxy)phenyl]indazole-3-carboxamide in acetone were added Potassium carbonate (0.2 g) and 1-bromo-3-chloro propane (0.103 g). The mixture was heated at 66° C. for 12 h. The reaction mixture was subsequently cooled to ambient temperature, diluted with brine solution and extracted with Ethyl acetate. The organic extracts were washed with brine, dried over Sodium sulphate and concentrated under reduced pressure. The resultant residue was subjected to silica gel flash column chromatography using a gradient of Ethyl acetate and Heptane as eluent to afford the title compound (0.09 g). HPLC/MS (method 1): R.sub.t: 2.46 min; m/z=595 (M+1); .sup.1H NMR (500 MHz, CDCl.sub.3) δ 8.83 (s, 1H), 8.31 (d, J=8.5 Hz, 1H), 8.14 (s, 1H), 7.79-7.74 (m, 2H), 7.72 (dd, J=8.5, 1.1 Hz, 1H), 7.59 (s, 1H), 7.39 (dd, J=7.8, 1.6 Hz, 1H), 7.33 (m, 1H), 7.29-7.24 (m, 1H), 7.23 (d, J=8.6 Hz, 2H), 7.19 (dd, J=7.7, 1.4 Hz, 1H), 4.12 (s, 3H), 3.84-3.62 (m, 1H), 3.54 (m, 1H), 3.11 (m, 3H), 2.36 (m, 2H), 1.23 (d, J=6.9 Hz, 6H).
(96) Examples of compound of formula I given in table X were prepared using the method analogous to preparation of the above examples or by derivatization of the above examples or intermediates thereof, or using the method analogous to the methods mentioned in the general procedure.
(97) ##STR00097##
(98) TABLE-US-00003 TABLE X No Ar-Q
BIOLOGICAL EXAMPLES
Example B1: Action on Yellow Fever Mosquito (Aedes aegypti)
(99) For evaluating control of yellow fever mosquito (Aedes aegypti) the test unit consisted of 96-well-microtiter plates containing 200 μl of tap water per well and 5-15 freshly hatched A. aegypti larvae.
(100) The active compounds were formulated using a solution containing 75% (v/v) water and 25% (v/v) DMSO. Different concentrations of formulated compounds or mixtures were sprayed onto the insect diet at 2.5 μl, using a custom built micro atomizer, at two replications.
(101) After application, microtiter plates were incubated at 28+1° C., 80+5% RH for 2 days. Larval mortality was then visually assessed.
(102) In this test, compounds C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-12, C-13, C-14, C-15, C-19, C-25, C-30, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-46, C-51, C-57 and C-58 at 800 ppm showed at least 75% mortality in comparison with untreated controls.
Example B2: Action on Orchid thrips (Dichromothrips corbetti)
(103) Dichromothrips corbetti adults used for bioassay were obtained from a colony maintained continuously under laboratory conditions. For testing purposes, the test compound is diluted in a 1:1 mixture of acetone:water (vol:vol), plus Kinetic® HV at a rate of 0.01% v/v.
(104) Thrips potency of each compound was evaluated by using a floral-immersion technique. All petals of individual, intact orchid flowers were dipped into treatment solution and allowed to dry in Petri dishes. Treated petals were placed into individual re-sealable plastic along with about adult thrips. All test arenas were held under continuous light and a temperature of about 28° C. for duration of the assay. After 3 days, the numbers of live thrips were counted on each petal. The percent mortality was recorded 72 hours after treatment.
(105) In this test, compounds C-1, C-2, C-3, C-4, C-6, C-12, C-13, C-14, C-15, C-19, C-28, C-30, C37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-46, C-51, C-52 and C-56 at 500 ppm showed at least 75% mortality in comparison with untreated controls.
Example B3: Action on Boll Weevil (Anthonomus grandis)
(106) For evaluating control of boll weevil (Anthonomus grandis) the test unit consisted of 96-well-microtiter plates containing an insect diet and 5-10 A. grandis eggs.
(107) The compounds were formulated using a solution containing 75% v/v water and 25% v/v DMSO. Different concentrations of formulated compounds were sprayed onto the insect diet at 5 μl, using a custom built micro atomizer, at two replications.
(108) After application, microtiter plates were incubated at about 25±1° C. and about 75±5% relative humidity for 5 days. Egg and larval mortality was then visually assessed.
(109) In this test, compounds C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-12, C-15, C-17, C-18, C-19, C-22, C-23, C-24, C-25, C-28, C-29, C-30, C-33, C-34, C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-46, C-50, C-51, C-55, C-56, C-57, C-58 and C-60 at 800 ppm showed at least 75% mortality in comparison with untreated controls.
Example B4: Action on Silverleaf Whitefly (Bemisia argentifoli) (Adults)
(110) The active compounds were formulated by a Tecan liquid handler in 100% cyclohexanone as a 10,000 ppm solution supplied in tubes. The 10,000 ppm solution was serially diluted in 100% cyclohexanone to make interim solutions. These served as stock solutions for which final dilutions were made by the Tecan in 50% acetone:50% water (v/v) into 5 or 10 ml glass vials. A nonionic surfactant (Kinetic®) was included in the solution at a volume of 0.01% (v/v). The vials were then inserted into an automated electrostatic sprayer equipped with an atomizing nozzle for application to plants/insects.
(111) Cotton plants at the cotyledon stage (one plant per pot) were sprayed by an automated electrostatic plant sprayer equipped with an atomizing spray nozzle. The plants were dried in the sprayer fume hood and then removed from the sprayer. Each pot was pla-ced into a plastic cup and about 10 to 12 whitefly adults (approximately 3-5 days old) were introduced. The insects were collected using an aspirator and a nontoxic Tygon® tubing connected to a barrier pipette tip. The tip, containing the collected insects, was then gently inserted into the soil containing the treated plant, allowing insects to crawl out of the tip to reach the foliage for feeding. Cups were covered with a reusable screened lid. Test plants were maintained in a growth room at about 25° C. and about 20-40% relative humidity for 3 days, avoiding direct exposure to fluorescent light (24 hour photoperiod) to prevent trapping of heat inside the cup. Mortality was assessed 3 days after treatment, compared to untreated control plants.
(112) In this test, compounds C-3, C-6, C-12, C-13, C-14, C-28, C-39, C-40, C-42, C-55 and C-56 at 300 ppm showed at least 75% mortality in comparison with untreated controls.
Example B5: Action on Tobacco Budworm (Heliothis virescens)
(113) For evaluating control of tobacco budworm (Heliothis virescens) the test unit consisted of 96-well-microtiter plates containing an insect diet and 15-25 H. virescens eggs.
(114) The compounds were formulated using a solution containing 75% v/v water and 25% v/v DMSO. Different concentrations of formulated compounds were sprayed onto the insect diet at 10 μl, using a custom built micro atomizer, at two replications.
(115) After application, microtiter plates were incubated at about 28±1° C. and about 80±5% relative humidity for 5 days. Egg and larval mortality was then visually assessed.
(116) In this test, compounds C-1, C-2, C-3, C-6, C-7, C-8, C-12, C-13, C-14, C-15, C-17, C-18, C-19, C-22, C-23, C-24, C-25, C-29, C-30, C-33, C-34, C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-46, C-47, C-50, C-51, C-55, C-56, C-57, C-58 and C-61 at 800 ppm showed at least 75% mortality in comparison with untreated controls.
Example B6: Action on Diamond Back Moth (Plutella xylostella)
(117) The active compound is dissolved at the desired concentration in a mixture of 1:1 (vol:vol) distilled water:acetone. Surfactant (Kinetic® HV) is added at a rate of 0.01% (vol/vol). The test solution is prepared at the day of use.
(118) Leaves of cabbage were dipped in test solution and air-dried. Treated leaves were placed in petri dishes lined with moist filter paper and inoculated with ten 3.sup.rd instar larvae. Mortality was recorded 72 hours after treatment. Feeding damages were also recorded using a scale of 0-100%.
(119) In this test, compounds C-1, C-2, C-3, C-4, C-6, C-7, C-8, C-12, C-13, C-14, C-15, C-18, C-19, C-22, C-23, C-24, C-25, C-28, C-30, C-34, C-37, C-38, C-39, C-40, C-41, C-42, C-43, C-44, C-45, C-46, C-50, C-51, C-52, C-55, C-56, C-57, C-58, C-60 and C-61 at 500 ppm showed at least 75% mortality in comparison with untreated controls.
Example B7: Action on Southern Armyworm (Spodoptera eridania), 2nd Instar Larvae
(120) The active compounds were formulated by a Tecan liquid handler in 100% cyclohexanone as a 10,000 ppm solution supplied in tubes. The 10,000 ppm solution was serially diluted in 100% cyclohexanone to make interim solutions. These served as stock solutions for which final dilutions were made by the Tecan in 50% acetone:50% water (v/v) into 10 or 20 ml glass vials. A nonionic surfactant (Kinetic®) was included in the solution at a volume of 0.01% (v/v). The vials were then inserted into an automated electrostatic sprayer equipped with an atomizing nozzle for application to plants/insects.
(121) Lima bean plants (variety Sieva) were grown 2 plants to a pot and selected for treatment at the 1.sup.st true leaf stage. Test solutions were sprayed onto the foliage by an automated electrostatic plant sprayer equipped with an atomizing spray nozzle. The plants were dried in the sprayer fume hood and then removed from the sprayer. Each pot was placed into perforated plastic bags with a zip closure. About 10 to 11 armyworm larvae were placed into the bag and the bags zipped closed. Test plants were maintained in a growth room at about 25° C. and about 20-40% relative humidity for 4 days, avoiding direct exposure to fluorescent light (24 hour photoperiod) to prevent trapping of heat inside the bags. Mortality and reduced feeding were assessed 4 days after treatment, compared to untreated control plants.
(122) In this test, compounds C-1, C-3, C-6, C-7, C-8, C-12, C-13, C-14, C-15, C-17, C-18, C-19, C-22, C-23, C-38, C-39, C-40, C-42, C-43, C-44, C-45, C-46, C-51, C-55, C-57 and C-58 at 300 ppm showed at least 75% mortality in comparison with untreated controls.