7-PYRIMIDINE-2-YL-OXY-INDAZOLE DERIVATIVES AND THEIR USE AS HERBICIDES

Abstract

The present invention relates to compounds of Formula (I), or an agronomically acceptable salt of said compounds wherein X, Y.sup.1, Y.sup.2, Z.sup.1, Z.sup.2, R.sup.1, R.sup.2, R.sup.5, R.sup.6 and n are as defined herein. The invention further relates to herbicidal compositions which comprise a compound of Formula (I) and to the use of compounds of Formula (I) for controlling weeds, in particular in crops of useful plants.

##STR00001##

Claims

1. A compound of Formula (I): ##STR00136## or an agronomically acceptable salt thereof, wherein X is selected from the group consisting of CH.sub.2, O or S(O).sub.p; Y.sup.1 is N or CR.sup.3; Y.sup.2 is N or CR.sup.4; with the proviso that Y.sup.1 and Y.sup.2 are not both N; Z.sup.1 is N or CR.sup.7; Z.sup.2 is N or CR.sup.8; each R.sup.1 is independently selected from the group consisting of halogen, —CN, nitro, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy-, C.sub.1-C.sub.4haloalkoxy-, —S(O).sub.pC.sub.1-C.sub.4alkyl and —S(O).sub.pC.sub.1-C.sub.4haloalkyl; R.sup.2 is selected from the group consisting of C.sub.3-C.sub.8 alkyl, C.sub.3-C.sub.8 alkenyl, C.sub.3-C.sub.8 alkynyl, C.sub.3-C.sub.8 haloalkyl, C.sub.3-C.sub.8 haloalkenyl, C.sub.3-C.sub.8 haloalkynyl, C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.4haloalkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.4alkoxy-C.sub.1-C.sub.3haloalkyl- and —(CH.sub.2).sub.mR.sup.9 R.sup.3 is selected from the group consisting of hydrogen, halogen, —CN, nitro, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl-, C.sub.2-C.sub.4alkynyl-, C.sub.1-C.sub.4haloalkyl-, C.sub.1-C.sub.4alkoxy-, C.sub.1-C.sub.4haloalkoxy- and —S(O).sub.nC.sub.1-C.sub.4alkyl; R.sup.4 is selected from the group consisting of hydrogen, halogen, —CN, nitro, C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4alkenyl-, C.sub.2-C.sub.4alkynyl-, C.sub.1-C.sub.4haloalkyl-, C.sub.1-C.sub.4alkoxy-, C.sub.1-C.sub.4haloalkoxy- and —S(O).sub.nC.sub.1-C.sub.4alkyl; R.sup.5 is selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.3alkyl and C.sub.1-C.sub.3haloalkyl; R.sup.6 is selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkyl and C.sub.1-C.sub.3haloalkoxy; R.sup.7 is selected from the group consisting of hydrogen, halogen, —CN, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl- and C.sub.1-C.sub.4alkoxy-; R.sup.8 is selected from the group consisting of hydrogen, halogen, —CN, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl- and C.sub.1-C.sub.4alkoxy-; R.sup.9 is selected from C.sub.3-C.sub.6 cycloalkyl, phenyl and a 5 or 6 membered heteroaryl which comprises from 1 to 4 heteroatoms each independently selected from the group consisting of oxygen, nitrogen and sulphur, and wherein said phenyl or heteroaryl groups are optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, cyano, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, C.sub.1-C.sub.4alkoxy and C.sub.1-C.sub.4haloalkoxy; m is 1, 2, 3 or 4 n=0, 1 or 2; and p=0, 1 or 2.

2. A compound according to claim 1, wherein Y.sup.1 is CR.sup.3 and Y.sup.2 is N or Y.sup.1 is CR.sup.3 and Y.sup.2 is CR.sup.4 or Y.sup.1 is N and Y.sup.2 is CR.sup.4.

3. A compound according to claim 1, wherein Z.sup.1 is CR.sup.7 and Z.sup.2 is N or Z.sup.1 is N and Z.sup.2 is N or Z.sup.1 is N and Z.sup.2 is CR.sup.8.

4. A compound according to claim 1, wherein n=0.

5. A compound according to claim 1, wherein n=1 and R.sup.1 is Cl or CN.

6. A compound according to claim 1, wherein R.sup.2 is C.sub.3-C.sub.8 haloalkyl.

7. A compound according to claim 1, wherein R.sup.3 is halogen.

8. A compound according to claim 1, wherein R.sup.4 is selected from the group consisting of hydrogen, halogen and —CN.

9. A compound according to claim 1, wherein R.sup.5 is hydrogen.

10. A compound according to claim 1, wherein R.sup.6 is selected from the group consisting of hydrogen, C.sub.1-C.sub.4alkyl and C.sub.1-C.sub.3alkoxy.

11. A compound according to claim 1, wherein R.sup.7 is halogen.

12. A compound according to claim 1, wherein R.sup.8 is hydrogen.

13. A herbicidal composition comprising a compound according to claim 1 and an agriculturally acceptable formulation adjuvant.

14. A herbicidal composition according to claim 13, further comprising at least one additional pesticide.

15. A herbicidal composition according to claim 14, wherein the additional pesticide is a herbicide or herbicide safener.

16. A method of controlling weeds at a locus comprising application to the locus of a weed controlling amount of a composition according to claim 13.

17. Use of a compound of Formula (I) as defined in claim 1 as a herbicide.

Description

EXAMPLE 1: SYNTHESIS OF 7-(5-CHLOROPYRIMIDIN-2-YL)OXY-1-(4,4,4-TRIFLUOROBUTYL)INDAZOLE (1.001)

Step 1: Synthesis of 7-methoxy-1-(4,4,4-trifluorobutyl)indazole

[0087] ##STR00018##

[0088] A solution of 7-methoxy-1H-indazole (100 mg, 0.67 mmol), Cs.sub.2CO.sub.3 (440 mg, 2.3 mmol) and 4-bromo-1,1,1-trifluoro-butane (200 mg, 1.0 mmol) in DMF (5 mL) was stirred at RT 30 mins and then heated at 80° C. for 30 minutes under microwave irradiation. The reaction mixture was diluted with water and extracted with Et.sub.2O. The combined organic extracts were washed with water and brine, dried over MgSO.sub.4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane to give the desired product (150 mg, 86%) as a colourless oil.

[0089] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 7.92 (s, 1H) 7.27 (t, 1H) 7.04 (t, 1H) 6.72 (d, 1H) 4.72 (t, 2H) 3.98 (s, 3H) 2.21-2.03 (m, 4H).

Step 2: Synthesis of 1-(4,4,4-trifluorobutyl)indazol-7-ol

[0090] ##STR00019##

[0091] To a solution of 7-methoxy-1-(4,4,4-trifluorobutyl)indazole (1.9 g, 7.4 mmol) in DMF (50 mL) at RT under an atmosphere of N2 was added dodecane-1-thiol (3.3 mL, 14 mmol) followed by a solution of lithium t-butoxide (1M in THF) (14 mL, 14 mmol). The reaction was heated at 100° C. for 4 hours and then allowed to cool to RT. The reaction mixture was diluted with 2M HCl and extracted into Et.sub.2O. The combined organic extracts were washed with water and brine, dried over MgSO.sub.4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane to give the desired product (1.70 g, 95%) as a white waxy solid.

[0092] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.99 (s, 1H) 7.29 (t, 1H) 6.96 (t, 1H) 6.70 (d, 1H) 6.68 (s, 1H) 4.78 (t, 2H) 2.26-2.04 (m, 4H).

Step 3: Synthesis of 7-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)indazole (1.001)

[0093] ##STR00020##

[0094] To a solution of 1-(4,4,4-trifluorobutyl)indazol-7-ol (200 mg, 0.82 mmol) in DMF (10 mL) at RT was added 2,5-dichloropyrimidine (140 mg, 0.91 mmol) and K.sub.2CO.sub.3 (300 mg, 2.1 mmol). The reaction was heated to 80° C. for 1 hour and then allowed to cool to RT. The reaction mixture was diluted with 2M HCl and extracted with Et.sub.2O. The combined organic extracts were washed with water and brine, dried over MgSO.sub.4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of EtOAc in cyclohexane as eluent to give the desired product (265 mg, 91%) as a pale yellow gum.

[0095] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.53 (s, 2H), 8.05 (s, 1H), 7.68-7.62 (m, 1H), 7.20-7.15 (m, 2H), 4.48 (br t, 2H), 2.10-198 (m, 2H).

EXAMPLE 2: SYNTHESIS OF 3-CHLORO-7-(5-CHLOROPYRIMIDIN-2-yl)oxy-1-(4,4,4-Trifluorobutyl)indazole (1.005)

Step 1: Synthesis of 3-chloro-7-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)indazole (1.005)

[0096] ##STR00021##

[0097] A solution of 7-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)indazole (0.67 g, 1.88 mmol) and N-chlorosuccinimide (0.276 g, 2.07 mmol) in CH.sub.3CN (17 mL) was heated under microwave irradiation at 80° C. for 2 hours. Further N-chlorosuccinimide (200 mg) was added and the reaction was heated at 80° C. under microwave irradiation for a further 2 hours. The reaction mixture was cooled to RT and then evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0-80% EtOAc in cyclohexane as eluent to give the desired product (181 mg, 25%) as a colourless gum.

[0098] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.53 (s, 2H), 7.62-7.57 (m, 1H), 7.25-7.20 (m, 2H), 4.42 (br t, 2H), 2.10-1.98 (m, 4H).

EXAMPLE 3: SYNTHESIS OF 7-(5-CHLOROPYRIMIDIN-2-YL)OXY-1-(4,4,4-TRIFLUOROBUTYL)INDAZOLE-3-CARBONITRILE (1.007)

Step 1: Synthesis of 7-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4,4,4-trifluorobutyl)indazole

[0099] ##STR00022##

[0100] To a solution of bis(pinacolato)diboron (0.596 g, 2.32 mmol), 4,4′-di-tert-butyl-2,2′-bipyridine (0.032 g, 0.116 mmol) and (1,5-cyclooctadiene)(methoxy)iridium(1) dimer (0.039 g, 0.0581 mmol) in tert-butyl methyl ether (5.8 mL) was added 7-methoxy-1-(4,4,4-trifluorobutyl)indazole (0.50 g, 1.94 mmol). The reaction was heated at 80° C. under microwave irradiation for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure and the crude product purified by flash chromatography on silica gel using a gradient 0-10% EtOAc in cyclohexane as eluent to give the desired product (0.45 g, 61%) as a colourless gum.

[0101] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.65 (d, 1H), 7.09 (t, 1H), 6.72 (d, 1H), 4.79 (t, 2H), 3.97 (s, 3H), 2.23-2.05 (m, 4H), 1.41 (s, 12H).

Step 2: Synthesis of 7-methoxy-1-(4,4,4-trifluorobutyl)indazole-3-carbonitrile

[0102] ##STR00023##

[0103] A solution of 7-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4,4,4-trifluorobutyl)indazole (0.285 g, 0.742 mmol), Cu(NO.sub.3).sub.2.3H.sub.2O (0.272 g, 1.11 mmol), Zn(CN).sub.2 (0.269 g, 2.23 mmol) and CsF (0.114 g, 0.742 mmol) in MeOH (3.7 mL) and water (1.5 mL) were heated at 100° C. under microwave irradiation for 1 hour. The reaction mixture was diluted with sat. ammonium chloride and extracted with EtOAc. The combined organics were washed with water, brine, dried over MgSO.sub.4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0-20% EtOAc/cyclohexane as eluent to give the desired product (100 mg, 48%) as a colourless solid.

[0104] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.38 (d, 1H), 7.25 (t, 1H), 6.82 (d, 1H), 4.78 (t, 2H), 4.01 (s, 3H), 2.27-2.07 (m, 4H).

Step 3: Synthesis of 7-hydroxy-1-(4,4,4-trifluorobutyl)indazole-3-carbonitrile

[0105] ##STR00024##

[0106] To a solution of 7-methoxy-1-(4,4,4-trifluorobutyl)indazole-3-carbonitrile (0.100 g, 0.353 mmol) and 1-dodecanethiol (0.146 g, 0.706 mmol) in DMF (1 mL) was added lithium t-butoxide (1M in THF) (0.71 mL, 0.71 mmol) The reaction was heated at 100° C. for 2 hours, cooled to RT and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0-30% EtOAc/cyclohexane as eluent to give the impure desired product (105 mg) as a pale yellow oil which was used without further purification.

[0107] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.57 (s, 1H), 7.34 (d, 1H), 7.14 (t, 1H), 6.81 (d, 1H), 4.81 (t, 2H), 2.31-2.08 (m, 4H).

Step 4: Synthesis of 7-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)indazole-3-carbonitrile (1.007)

[0108] ##STR00025##

[0109] To a mixture of 7-hydroxy-1-(4,4,4-trifluorobutyl)indazole-3-carbonitrile (105 mg, 0.390 mmol) and K.sub.2CO.sub.3 (108 mg 0.78 mmol) in DMF (1 mL) was added 2,5-dichloropyrimidine (71 mg, 0.468 mmol). The reaction was heated at 70° C. for 20 hours, allowed to cool to RT and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0-15% EtOAc/cyclohexane as eluent (125 mg, 84%) as a colourless solid.

[0110] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.54 (s, 2H), 7.76 (dd, 1H), 7.37 (t, 1H), 7.31 (dd, 1H), 4.58 (t, 2H), 2.17-2.05 (m, 4H).

EXAMPLE 4: SYNTHESIS OF 7-(5-CHLOROPYRIMIDIN-2-YL)OXY-3-METHYL-1-(4,4,4-TRIFLUOROBUTYL)INDAZOLE (1.021)

Step 1: Synthesis of 7-methoxy-3-methyl-1-(4,4,4-trifluorobutyl)indazole

[0111] ##STR00026##

[0112] A mixture of Pd(OAc).sub.2 (0.011 g, 0.0651 mmol), di-tertbutyl(methyl)phosphonium tetrafluoroborate (0.033 g, 0.130 mmol), K.sub.2CO.sub.3 (0.216 g, 1.56 mmol) and 7-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4,4,4-trifluorobutyl)indazole (0.500 g, 1.30 mmol) in 2-methyl-2-butanol (13 mL) was degassed and purged with nitrogen three times. Iodomethane (0.371 g, 2.60 mmol) was added and the reaction heated at 65° C. for 24 hours. The reaction was cooled to RT and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0-20% EtOAc/cyclohexane as eluent to give the desired product as an inseparable mixture with 7-methoxy-1-(4,4,4-trifluorobutyl)indazole which was used in the next step without further purification.

Step 2: Synthesis of 3-methyl-1-(4,4,4-trifluorobutyl)indazol-7-ol

[0113] ##STR00027##

[0114] To a solution of the crude 7-methoxy-3-methyl-1-(4,4,4-trifluorobutyl)indazole (0.200 g, 0.734 mmol) and 1-dodecanethiol (0.303 g, 1.47 mmol) in DMF (2 mL) was added to which LiO.sup.tBu (1M solution in THF) (1.47 mL, 1.47 mmol). The reaction was heated at 100° C. for 3 hours then allowed to cool to RT. The reaction was quenched with sat. aq. ammonium chloride and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO.sub.4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0-25% EtOAc/cyclohexane to give the desired product as an inseparable mixture with 1-(4,4,4-trifluorobutyl)indazol-7-ol which was used in the next step without further purification.

Step 3: Synthesis of 7-(5-chloropyrimidin-2-yl)oxy-3-methyl-1-(4,4,4-trifluorobutyl)indazole (1.021)

[0115] ##STR00028##

[0116] To a solution of crude 3-methyl-1-(4,4,4-trifluorobutyl)indazol-7-ol (0.130 g, 0.503 mmol) and K.sub.2CO.sub.3 (0.139 g, 1.01 mmol) in DMF (1.3 mL) was added 2,5-dichloropyrimidine (0.091 g, 0.604 mmol). The reaction was heated at 80° C. for 3 hours the allowed to cool to RT. The reaction was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO.sub.4 and evaporated to dryness under reduced pressure. The crude product was purified by mass-directed reverse phase HPLC to give the desired product (0.116 g, 62%) as a pale brown solid.

[0117] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.53 (s, 2H), 7.58 (dd, 1H), 7.21-7.14 (m, 2H), 4.42 (t, 2H), 2.59 (s, 3H) 2.09-1.92 (m, 4H).

EXAMPLE 5: SYNTHESIS OF 7-(5-CHLOROPYRIMIDIN-2-YL)OXY-1-(4,4,4-TRIFLUOROBUTYL)-3-(TRIFLUOROMETHYL)INDAZOLE (1.022)

Step 1: Synthesis of 7-methoxy-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)indazole

[0118] ##STR00029##

[0119] A stirred solution of 7-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(4,4,4-trifluorobutyl)indazole (0.500 g, 1.30 mmol), KF (0.076 g, 1.30 mmol) and (1,10-phenanthroline)(trifluoromethyl)copper(I) (0.543 g, 1.56 mmol) in DMF (13 mL) was heated at 50° C. for 3 hours and then allowed to cool to RT. The reaction mixture was filtered through a pad of Celite and washed through with EtOAc. The filtrate was evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0-5% EtOAc/cyclohexane as eluent to give the desired product as an inseparable mixture with 7-methoxy-1-(4,4,4-trifluorobutyl)indazole which was used in the next step without purification.

Step 2: Synthesis of 1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)indazol-7-ol

[0120] ##STR00030##

[0121] To a stirred solution of the crude 7-methoxy-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)indazole (0.420 g, 1.29 mmol) and 1-dodecanethiol (0.532 g, 2.58 mmol) in DMF (4.2 mL) was added LiO.sup.tBu (1M in THF (2.58 mL, 2.58 mmol). The reaction was stirred at 100° C. for 3 hours and then allowed to cool to RT. The reaction was quenched with sat. aq. ammonium chloride and extracted with EtOAc. The combined organics were washed with brine, dried over MgSO.sub.4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0-25% EtOAc/cyclohexane as eluent to give the desired product (0.370 g, 92%) as a pale yellow solid.

[0122] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.39 (d, 1H), 7.09 (t, 1H), 6.74 (d, 1H), 5.59 (s, 1H), 4.78 (t, 2H), 2.29-2.09 (m, 4H).

Step 3: Synthesis of 7-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)indazole (1.022)

[0123] ##STR00031##

[0124] To a stirred solution of 1-(4,4,4-trifluorobutyl)-3-(trifluoromethyl)indazol-7-ol (0.145 g, 0.464 mmol) and K.sub.2CO.sub.3 (0.128 g, 0.929 mmol) in DMF (1.45 mL) was added 2,5-dichloropyrimidine (0.084 g, 0.557 mmol). The reaction was heated at 80° C. for 4 hours, allowed to cool to RT and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using a gradient of 0-5% EtOAc/cyclohexane as eluent to give the desired product (0.178 g, 90%) as a pale-yellow gum.

[0125] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.54 (s, 2H), 7.75 (d, 1H), 7.35-7.27 (m, 2H), 4.55 (t, 2H), 2.13-2.04 (m, 4H).

EXAMPLE 6: SYNTHESIS OF 7-(5-CHLOROPYRIMIDIN-2-YL)OXY-1-(4,4,4-TRIFLUOROBUTYL)BENZOTRIAZOLE (1.020)

Step 1: Synthesis of 2-methoxy-6-nitro-N-(4,4,4-trifluorobutyl)aniline

[0126] ##STR00032##

[0127] To a solution of 2-chloro-1-methoxy-3-nitro-benzene (0.5 g, 3.0 mmol) in NMP (10 mL) was added N,N-diisopropylethylamine (0.9 mL, 5.0 mmol) and 4,4,4-trifluorobutylamine (0.4 mL, 3.0 mmol). The reaction was heated at 185° C. for 1 hour under microwave irradiation. The reaction was diluted with water (15 mL) and extracted with EtOAc (3×15 mL). The crude product was purified by flash chromatography on silica gel using a gradient of 0-10% EtOAc/cyclohexane as eluent to give the desired product (0.318 g, 40%) as an orange oil.

[0128] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.74 (d, 1H), 7.62 (br, 1H), 6.94 (d, 1H), 6.68 (t, 1H), 3.86 (s, 3H), 3.61 (q, 2H), 2.25-2.12 (m, 2H), 1.90-1.82 (m, 2H).

Step 2: Synthesis of 3-methoxy-N2-(4,4,4-trifluorobutyl)benzene-1,2-diamine

[0129] ##STR00033##

[0130] To a solution of 2-methoxy-6-nitro-N-(4,4,4-trifluorobutyl)aniline (0.318 g, 1.14 mmol) in MeOH (10 mL) was added 5% Pd/C (0.03 g) and the reaction stirred under an atmosphere of H.sub.2 (2 bar pressure) for 45 minutes. The reaction was filtered through Celite, washed through with further MeOH and then evaporated to dryness under reduced pressure to give the desired product (0.283 g, quant) as a red-brown oil which was used without further purification.

[0131] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.85 (t, 1H), 6.37 (br d, 1H), 6.34 (dd, 1H), 3.80 (s, 3H), 2.98 (t, 2H), 2.32-2.10 (m, 2H), 1.82-1.71 (m, 2H).

Step 3: Synthesis of 7-methoxy-1-(4,4,4-trifluorobutyl)benzotriazole

[0132] ##STR00034##

[0133] To a stirred solution of 3-methoxy-N2-(4,4,4-trifluorobutyl)benzene-1,2-diamine (0.283 g, 1.14 mmol) in 2M hydrochloric acid (24 mL) at 0° C. was added a solution of sodium nitrite (0.118 g, 1.71 mmol) in water (1 mL) drop-wise over a few minutes, keeping the reaction temp below 3° C. throughout. The mixture was stirred for 30 minutes, then allowed to warm to room temp. After 1.5 hrs, the stirred reaction mixture was slowly quenched by the addition of saturated NaHCO.sub.3 solution to around pH 7, then extracted with EtOAc (3×15 mL). The combined organic extracts were washed with water (2×10 mL) and evaporated to dryness under reduced pressure to give a red-brown oil. The crude product was purified by column chromatography on silica gel using a gradient of 0-100% EtOAc/cyclohexane to give the product (164 mg, 55%) as an amber oil that crystallised on standing. 1H NMR (400 MHz, CDCl.sub.3) δ 7.62 (d, 1H), 7.27 (dd, 1H), 6.81 (d, 1H), 4.91 (t, 2H), 4.01 (s, 3H), 2.31-2.10 (m, 4H).

Step 4: Synthesis of 3-(4,4,4-trifluorobutyl)benzotriazol-4-ol

[0134] ##STR00035##

[0135] To a solution of 7-methoxy-1-(4,4,4-trifluorobutyl)benzotriazole (0.114 g, 0.440 mmol) in DMF (1.2 mL) under a nitrogen atmosphere was added dodecane-1-thiol (0.211 mL, 0.880 mmol) followed by lithium tert-butoxide (1M in THF) (0.880 mL, 0.880 mmol) drop-wise over a few minutes. The mixture was then warmed to 100° C. for 2 hours. The reaction mixture was allowed to cool to room temp, then was quenched by the addition of water (2 mL) followed by 2N HCl to pH6. The mixture was extracted with Et.sub.2O (4×3 mL) and the combined organic extracts evaporated to dryness under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient of 0-100% EtOAc/cyclohexane to give the product (96 mg, 89%) as a light beige powdery solid.

[0136] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.62 (d, 1H), 7.19 (dd, 1H), 6.81 (d, 1H), 6.26 (br s, 1H), 4.96 (t, 2H), 2.37-2.25 (m, 2H), 2.25-2.13 (m, 2H).

Step 5: Synthesis of 7-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl) benzotriazole

[0137] ##STR00036##

[0138] To a solution of 3-(4,4,4-trifluorobutyl)benzotriazol-4-ol (0.047 g, 0.19 mmol) in DMF (1 mL) at room temp was added K.sub.2CO.sub.3 (0.04 g, 0.29 mmol) followed by 2,5-dichloropyrimidine (0.043 g, 0.29 mmol). The reaction mixture was stirred for 10 minutes then was left to stand at room temp overnight. The reaction mixture was diluted with water (10 mL) and extracted with CH.sub.2Cl.sub.2 (3×8 mL). The combined organic extracts were evaporated to dryness under reduced pressure and the crude material was purified by column chromatography on silica gel using a gradient of 0-100% EtOAc/cyclohexane giving the desired product (62 mg, 91%) as a colourless oil.

[0139] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.54 (s, 2H), 7.99 (dd, 1H), 7.41 (t, 1H), 7.32 (dd, 1H), 4.71 (t, 2H), 2.21-2.05 (m, 4H).

EXAMPLE 7: SYNTHESIS OF 5-BROMO-3-CHLORO-7-(5-CHLOROPYRIMIDIN-2-YL)OXY-1-(4.4.4-TRIFLUOROBUTILINDAZOLE (1.010)

Step 1: Synthesis of 5-bromo-7-methoxy-2-(4,4,4-trifluorobutyl)indazole

[0140] ##STR00037##

[0141] To a solution of 5-bromo-7-methoxy-1H-indazole (1.00 g, 4.40 mmol) in N,N-dimethylformamide (16 mL) was added 4-bromo-1,1,1-trifluoro-butane (0.865 mL, 7.05 mmol) followed by Cs.sub.2CO.sub.3 (2.55 g, 13.2 mmol). The reaction was heated under microwave irradiation at 80° C. for 1 hour. The reaction mixture was poured into water and diluted with EtOAc. The phases were separated and the aqueous was extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo. The crude material was purified by column chromatography on silica gel using a gradient of 0-70% EtOAc/cyclohexane to give the desired product (1.10 g, 74%) as a yellow solid.

[0142] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.85 (s, 1H), 7.43 (d, 1H), 6.80 (d, 1H), 4.68 (t, 2H), 3.97 (s, 3H), 2.19-2.02 (m, 4H).

Step 2: Synthesis of 5-bromo-1-(4,4,4-trifluorobutyl)indazol-7-ol

[0143] ##STR00038##

[0144] To a solution of 5-bromo-7-methoxy-1-(4,4,4-trifluorobutyl)indazole (0.500 g, 1.48 mmol) in N,N-dimethylformamide (5 mL) at room temperature and under nitrogen was added 1-dodecanethiol (0.725 mL, 2.97 mmol) followed by lithium tert-butoxide (1M in THF) (2.97 mL, 2.97 mmol). On completion of addition, the reaction mixture was heated to 100° C. for 1 h. The reaction mixture was allowed to cool to RT, quenched with water and diluted with EtOAc. The mixture was acidified to pH 1 with 2M HCl and the phases were separated. The aqueous phase was extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO.sub.4 and concentrated in vacuo to afford a yellow liquid. The crude product was purified by column chromatography on silica gel using a gradient of 0-60% EtOAc/cyclohexane to give the desired product (460 mg, 96%) as a white solid.

[0145] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.88 (s, 1H), 7.44 (d, 1H), 6.80 (d, 1H), 6.50 (br s, 1H), 4.72 (t, 2H), 2.23-2.02 (m, 4H).

Step 3: Synthesis of 5-bromo-7-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)indazole

[0146] ##STR00039##

[0147] To a solution of 5-bromo-1-(4,4,4-trifluorobutyl)indazol-7-ol (0.460 g, 1.42 mmol) in DMF (23.0 mL) was added 2,5-dichloropyrimidine (0.233 g, 1.57 mmol) followed by K.sub.2CO.sub.3 (0.517 g, 3.70 mmol). The reaction mixture was heated to 80° C. for 1 hour. The reaction mixture was allowed to cool to RT, diluted with water and then acidified with 2M HCl. EtOAc was added and the phases were separated, before extracting into EtOAc. The combined organics were washed with brine, dried over MgSO.sub.4, filtered and concentrated to afford a brown liquid. The crude product was purified by column chromatography on silica gel using a gradient of 0-50% EtOAc in cyclohexane to give the desired product (0.6 g, 97%) as a yellow gum which solidified on standing to an off-white solid.

[0148] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.54 (s, 2H), 7.98 (s, 1H), 7.78 (d, 1H), 7.32 (d, 1H), 4.48 (t, 2H), 2.09-1.97 (m, 4H).

Step 4: Synthesis of 5-bromo-3-chloro-7-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)indazole

[0149] ##STR00040##

[0150] A solution of 5-bromo-7-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)indazole (0.300 g, 0.689 mmol) and N-chlorosuccinimide (0.193 g, 1.45 mmol) in CH.sub.3CN (4.50 mL) was heated under microwave irradiation at 80° C. for 2 hours. The reaction mixture was concentrated in vacuo to afford a yellow gum. The crude product was purified by column chromatography on silica gel using a gradient of 0-30% EtOAc in cyclohexane to give a yellow gum which solidified on standing to an off-white solid which was further purified by mass directed reverse phase HPLC. The desired product (49 mg, 15%) was obtained as a white solid.

[0151] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.55 (s, 2H), 7.74 (d, 1H), 7.37 (d, 1H), 4.42 (t, 2H), 2.09-1.99 (m, 4H).

EXAMPLE 8: SYNTHESIS OF 3-CHLORO-7-(5-CHLOROPYRIMIDIN-2-YL)OXY-6-METHYL-1-(4,4,4-TRIFLUOROBUTYL)INDAZOLE (1.043)

Step 1: Synthesis of 3-chloro-7-(5-chloropyrimidin-2-yl)oxy-6-methyl-1-(4,4,4-trifluorobutyl)indazole (1.043)

[0152] ##STR00041##

[0153] To a solution of 6-bromo-3-chloro-7-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)indazole (0.100 g, 0.213 mmol), tetrakis(triphenylphosphaniumyl) palladium (0.025 g, 0.021 mmol) and K.sub.2CO.sub.3 (0.148 g, 1.06 mmol) in a mixture of 1,4-dioxane (1.06 mL) and water (0.355 mL) was added trimethylboroxine (0.045 mL, 0.319 mmol). The mixture was heated under microwave irradiation at 140° C. for 1 hour. The reaction mixture was poured into water and diluted with dichloromethane. The aqueous phase was acidified to pH1 with 2M HCl. The phases were separated, and the organic phase was concentrated in vacuo to afford a yellow gum. The crude product was purified by column chromatography on silica gel using a gradient of 0-40% EtOAc in cyclohexane) to give the desired product (45 mg, 51%) as a white solid.

[0154] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.51 (s, 2H), 7.49 (d, 1H), 7.11 (d, 1H), 4.32 (t, 2H), 2.23 (s, 3H), 2.05-1.93 (m, 4H).

EXAMPLE 9: SYNTHESIS OF 4-CHLORO-7-(5-CHLOROPYRIMIDIN-2-YL)OXY-1-(4,4,4-TRIFLUOROBUTYL)INDAZOLE (1.013)

Step 1: Synthesis of 4-chloro-7-methoxy-1-(4,4,4-trifluorobutyl)indazole

[0155] ##STR00042##

[0156] To a solution of 7-methoxy-1-(4,4,4-trifluorobutyl)indazole (100 mg, 0.39 mmol) in DCM (3 mL) at 0° C. under an atmosphere of nitrogen was added dropwise a solution of sulfuryl chloride (0.032 mL, 0.39 mmol) in 1 mL of DCM. On complete addition the reaction mixture was stirred for 60 mins. The reaction mixture was poured into water and extracted into DCM. The organics were washed with brine, separated, dried over MgSO.sub.4 and concentrated. The crude reaction mixture was purified by column chromatography on silica gel using a gradient of EtOAc in cyclohexane to give the desired product (84 mg, 74% yield) as a colourless oil.

[0157] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.99 (s, 1H), 6.99 (d, 1H), 6.62 (d, 1H), 4.71 (t, 2H), 3.96 (s, 3H), 2.04-2.30 (m, 4H).

Step 2: Synthesis of 4-chloro-1-(4,4,4-trifluorobutyl)indazol-7-ol

[0158] ##STR00043##

[0159] To a solution of 4-chloro-7-methoxy-1-(4,4,4-trifluorobutyl)indazole (0.375 g, 1.28 mmol) in DMF (9.38 mL) under an atmosphere of nitrogen was added dodecane-1-thiol (0.583 mL, 2.43 mmol) and lithium tert-butoxide (1M in THF) (2.43 mL, 2.43 mmol). The reaction mixture was heated to 100° C. for 1 hr, allowed to cool to RT then poured into 2M HCl and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO.sub.4 and concentrated. The crude product was purified by column chromatography on silica gel using a gradient 0-95% EtOAc in cyclohexane to give the desired product (0.291 g, 82% Yield) as a white solid.

[0160] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.03 (s, 1H), 6.92 (d, 1H), 6.59 (d, 1H), 5.87 (s, 1H), 4.75 (t, 2H), 2.24-2.05 (m, 4H).

Step 3: Synthesis of 4-chloro-7-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)indazole

[0161] ##STR00044##

[0162] To a solution of 4-chloro-1-(4,4,4-trifluorobutyl)indazol-7-ol (0.287 g, 1.03 mmol) and 2,5-dichloropyrimidine (0.169 g, 1.13 mmol) in DMF (14.4 mL) was added K.sub.2CO.sub.3 (0.374 g, 2.68 mmol). The reaction was heated to 80° C. for 1 hour, then allowed to cool to RT, diluted with water and then acidified with 2M HCl. EtOAc was added, and the phases were separated, before extracting into EtOAc (×2). The combined organics were washed with brine, dried over MgSO.sub.4, filtered and concentrated. The crude product was purified by column chromatography on silica gel using a gradient of 0-100% EtOAc in cyclohexane to give the desired product (0.344 g, 85%) as a white solid.

[0163] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.53 (s, 2H), 8.11 (s, 1H), 7.13 (d, 1H), 7.11 (d, 1H), 4.52-4.43 (m, 2H), 2.09-1.97 (m, 4H).

EXAMPLE 10: SYNTHESIS OF 3-CHLORO-7-(5-CHLOROPYRIMIDIN-2-YL)OXY-1-(4,4,4-TRIFLUOROBUTYL)INDAZOLE-6-CARBONITRILE (1.041)

Step 1: Synthesis of 3-chloro-7-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)indazole-6-carbonitrile

[0164] ##STR00045##

To a solution of 6-bromo-3-chloro-7-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)indazole (0.060 g, 0.13 mmol) and Zn(CN).sub.2 (0.018 g, 0.15 mmol) in DMF (1.3 mL) was added tetrakis(triphenylphosphine) palladium(0) (0.015 g, 0.013 mmol). The mixture was then heated under microwave irradiation at 125° C. for 90 minutes. The reaction mixture was concentrated and purified by column chromatography on silica gel using a gradient of 0-40% EtOAc in cyclohexane to give the desired product (15 mg, 28%) as a white solid.

[0165] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.55 (s, 2H), 7.69 (d, 1H), 7.43 (d, 1H), 4.45 (t, 2H), 2.10-1.97 (m, 4H).

EXAMPLE 11: SYNTHESIS OF 3-BROMO-7-(5-CHLOROPYRIMIDIN-2-YL)OXY-1-(4,4,4-TRIFLUOROBUTYL)INDAZOLE (1.006) AND 7-(5-CHLOROPYRIMIDIN-2-YL)OXY-3-METHOXY-1-(4,4,4-TRIFLUOROBUTYL)INDAZOLE (1.033)

Step 1: Synthesis of 3-bromo-7-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)indazole

[0166] ##STR00046##

[0167] To a solution of 7-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)indazole (0.530 g, 1.49 mmol) acetonitrile (7.45 mL) was added N-bromosuccinimide (0.588 g, 3.27 mmol). The reaction was heated at 80° C. for 90 minutes under microwave irradiation. The reaction mixture was concentrated and purified by column chromatography on silica gel using a gradient of 0-20% EtOAc/cyclohexane to give the desired product (0.50 g, 77%) as a colourless oil.

[0168] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.53 (s, 2H), 7.56-7.52 (m, 1H), 7.25-7.21 (m, 2H), 4.45 (br t, 2H), 2.10-1.99 (m, 4H).

Step 2: Synthesis of 7-(5-chloropyrimidin-2-yl)oxy-3-methoxy-1-(4,4,4-trifluorobutyl)indazole (1.033)

[0169] ##STR00047##

[0170] To a solution of 3-bromo-7-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)indazole (0.100 g, 0.23 mmol), cesium carbonate (0.075 g, 0.23 mmol), Rockphos Pd G3 (0.01 g, 0.01 mmol) and MeOH (0.074 g, 2.30 mmol) in 1,4-dioxane (1 mL) were heated at 90° C. for 1 hour under microwave irradiation. The reaction mixture was diluted with water and extracted with DCM. The organics were dried over MgSO.sub.4, filtered and concentrated under vacuum and purified by mass directed reverse phase HPLC to afford the desired product (0.020 g, 23%) as a brown gum.

[0171] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.52 (s, 2H), 7.56 (dd, 1H), 7.17-7.12 (m, 1H), 7.09-7.03 (m, 1H), 4.25 (t, 2H). 4.08 (s, 3H), 2.06-1.90 (m, 4H).

EXAMPLE 12: SYNTHESIS OF 3-CHLORO-7-(5-CHLOROPYRIMIDIN-2-YL)OXY-1-(4,4,4-TRIFLUOROBUTYL)-4-(TRIFLUOROMETHYL)INDAZOLE (1.079)

Step 1: Synthesis of 1H-indazol-7-yl trifluoromethanesulfonate

[0172] ##STR00048##

[0173] To a solution of 1H-indazol-7-ol (25.0 g, 186 mmol) in THF (500 mL) at 4° C. was added Cs.sub.2CO.sub.3 (60.8 g, 186 mmol). To this was added portion-wise, over 30 minutes 1,1,1-trifluoro-N-(2-pyridyl)-N-(trifluoromethylsulfonyl)methanesulfon-amide (66.8 g, 186 mmol). The mixture was stirred at 5° C. for 2 hours, then, to the reaction mixture at 5° C. was added water (200 mL). The mixture was warmed to 20° C. and the THF was removed in vacuo. The resultant aqueous solution was extracted into EtOAc and the combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated under vacuum. The crude material was purified by column chromatography on silica gel using a gradient of 0-40% EtOAc in cyclohexane to give the desired product (42.87 g, 86%) as a beige solid.

[0174] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.70 (br s, 1H), 8.20 (s, 1H), 7.80 (d, 1H), 7.36 (d, H), 7.24-7.19 (m, 1H).

Step 2: Synthesis of (3-chloro-1H-indazol-7-yl) trifluoromethanesulfonate

[0175] ##STR00049##

[0176] To a stirred solution of 1H-indazol-7-yl trifluoromethanesulfonate (42.8 g, 161 mmol) in DMF (400 mL) at 20° C. was added N-chlorosuccinimide (21.5 g, 161 mmol) portion-wise over 10 minutes. The reaction was heated at 30° C. for 18 hours overnight. The reaction mixture was concentrated afford a yellow liquid and purified by column chromatography on silica gel using a gradient of 0-40% EtOAc in cyclohexane to give the desired product (46.63 g, 97%) as a beige solid.

[0177] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.50 (br s, 1H), 7.75 (d, 1H), 7.42 (d, 1H), 7.31-7.24 (m, 1H).

Step 3: Synthesis of [3-chloro-1-(4,4,4-trifluorobutyl)indazol-7-yl] trifluoro methanesulfonate

[0178] ##STR00050##

[0179] To a stirred solution of (3-chloro-1H-indazol-7-yl) trifluoromethanesulfonate (0.500 g, 1.66 mmol) in THF (5 mL) under an atmosphere of N2 was added (NE)-N-(piperidine-1-carbonylimino)piperidine-1-carboxamide (0.441 g, 1.75 mmol) followed by 4,4,4-trifluorobutan-1-ol (0.185 mL, 1.75 mmol). The reaction was cooled to 0° C. and tributylphosphane (0.50 mL, 2.00 mmol) was added dropwise. After 10 mins, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched by addition of H.sub.2O and diluted with EtOAc, the organic layer was separated and aqueous was re-extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium thiosulphate solution then brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel using a gradient of 0-20% EtOAc/cyclohexane to give the desired product (0.356 g, 52%) as a colourless oil.

[0180] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.70 (d, 1H), 7.40 (d, 1H), 7.24 (d, 1H), 4.60 (m, 2H), 2.20 (m, 4H).

Step 4: Synthesis of [3-chloro-1-(4,4,4-trifluorobutyl)-4-(trifluoromethyl)indazol-7-yl]trifluoromethanesulfonate

[0181] ##STR00051##

[0182] A vial equipped with a stir bar was charged with pyridine-N-oxide (0.29 g, 3.0 mmol), tris(2,2′-bipyridyl)dichlororuthenium(II) hexahydrate (0.0075 g, 0.010 mmol) and [3-chloro-1-(4,4,4-trifluorobutyl)indazol-7-yl] trifluoromethanesulfonate (0.41 g, 1.0 mmol) and acetonitrile (2.5 mL). (2,2,2-Trifluoroacetyl)-2,2,2-trifluoroacetate (0.83 mL, 6.0 mmol) was then added and the reaction irradiated with blue light for 18 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The combined organic extracts were concentrated under vacuum and purified by column chromatography on silica gel using a gradient of 0-20% EtOAc/cyclohexane to give the desired product (0.229 g, 48%) as a colourless oil.

[0183] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.63-7.58 (m, 1H), 7.46 (d, 1H), 4.67-4.56 (m, 2H), 2.31-2.16 (m, 4H).

Step 5: Synthesis of 3-chloro-7-(5-chloropyrimidin-2-yl)oxy-1-(4,4,4-trifluorobutyl)-4-(trifluoromethyl)indazole

[0184] ##STR00052##

[0185] To a solution of [3-chloro-1-(4,4,4-trifluorobutyl)-4-(trifluoromethyl)indazol-7-yl] trifluoromethanesulfonate (50 mg, 0.104 mmol) in acetonitrile (0.4 mL) was added Cs.sub.2CO.sub.3 (101 mg, 0.522 mmol) followed by 2,5-dichloropyrimidine (23 mg, 0.157 mmol). The reaction mixture was then heated at 80° C. overnight. The crude reaction mixture was quenched with 2M HCl (10 mL) and extracted with EtOAc. The combined organic extracts were concentrated under vacuum and purified by column chromatography on silica gel, using a gradient of 10-20% cyclohexane/EtOAc to give the desired product (21 mg, 44%) as a colourless oil.

[0186] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.58-8.54 (m, 2H), 7.58 (d, 1H), 7.29 (d, 1H), 4.54 (t, 2H), 2.12-2.03 (m, 4H).

TABLE-US-00001 TABLE 1 Examples of herbicidal compounds of the present invention. .sup.1H NMR (400 MHz, Compound Structure CDCl.sub.3 unless stated) 1.001 [00053] 8.53 (s, 2H), 8.05 (s, 1H), 7.68-7.62 (m, 1H), 7.20-7.15 (m, 2H), 4.48 (br t, 2H), 2.10- 198 (m, 2H) 1.002 [00054] 8.04 (s, 1H), 7.92 (d, 1H), 7.64-7.58 (m, 2H), 7.15 (s, 1H), 7.13 (d, 1H), 4.54 (t, 2H), 2.14-2.01 (m, 4H) 1.003 [00055] 8.51 (s, 2H), 7.53 (s, 1H), 7.11 (t, 1H), 7.02 (d, 1H), 6.96 (dd, 1H), 6.55 (d, 1H), 4.21 (br t, 2H), 2.07-1.92 (m, 4H) 1.004 [00056] 7.92 (d, 1H), 7.58 (dd, 1H), 7.49 (dd, 1H), 7.08 (t, 1H), 7.02 (d, 1H), 6.91 (dd, 1H), 6.54 (d, 1H), 4.25 (br t, 2H), 2.11-1.96 (m, 4H) 1.005 [00057] 8.53 (s, 2H), 7.62-7.57 (m, 1H), 7.25-7.20 (m, 2H), 4.45 (br t, 2H), 2.10-1.99 (m, 4H) 1.006 [00058] 8.53 (s, 2H), 7.56-7.52 (m, 1H), 7.25-7.21 (m, 2H), 4.45 (br t, 2H), 2.10-1.99 (m, 4H) 1.007 [00059] 8.54 (s, 2H), 7.76 (dd, 1H), 7.37 (t, 1H), 7.31 (dd, 1H), 4.58 (br t, 2H), 2.17-2.05 (m, 4H) 1.008 [00060] 8.26 (d, 1H), 8.07 (d, 1H), 7.61 (dd, 1H), 7.26-7.21 (m, 2H), 4.47 (t, 2H), 2.15-2.03 (m, 4H) 1.009 [00061] 8.45 (s, 1H), 7.58 (dd, 1H), 7.21 (t, 1H), 7.15 (d, 1H), 6.27 (s, 1H), 4.38 (t, 2H), 4.01 (s, 3H), 2.11-1.99 (m, 4H) 1.010 [00062] 8.55 (s, 2H), 7.74 (d, 1H), 7.37 (d, 1H), 4.42 (t, 2H), 2.09-1.99 (m, 4H) 1.011 [00063] 8.54 (s, 2H), 7.98 (s, 1H), 7.78 (d, 1H), 7.32 (d, 1H), 4.48 (t, 2H), 2.09-1.97 (m, 4H) 1.012 [00064] 8.48 (s, 1H), 8.04 (s, 1H), 7.64 (dd, 1H), 7.16 (t, 1H), 7.10 (d, 1H), 6.23 (s, 1H), 4.44 (t, 2H), 4.00 (s, 3H), 2.11-1.97 (m, 4H) 1.013 [00065] 8.53 (s, 2H), 8.11 (s, 1H), 7.12 (q, 2H), 4.48 (br t, 2H), 2.10-1.97 (m, 4H) 1.014 [00066][00067] 8.26 (d, 1H), 8.07 (s, 1H), 8.06 (s, 1H) 7.69-7.63 (m, 1H), 7.18 (s, 1H), 7.17 (d, 1H), 4.53 (t, 2H), 2.15-2.05 (m, 4H) 1.015 [00068] 8.53 (s, 2H), 7.37 (d, 1H), 7.07 (d, 1H), 4.46 (t, 2H), 2.10-1.98 (m, 4H) 1.016 [00069] 8.55 (s, 2H), 7.68 (d, 1H), 7.38 (d, 1H), 4.44 (t, 2H), 2.11-1.98 (m, 4H) 1.017 [00070] 8.31 (d, 1H), 8.08 (d, 1H), 8.00 (s, 1H), 7.63 (d, 1H), 7.24 (d, 1H), 4.54 (b rt, 2H), 2.13-2.04 (m, 4H) 1.018 [00071] 8.53 (s, 2H), 8.08 (s, 1H), 7.23 (s, 1H), 4.44 (s, 2H), 2.08-1.94 (m, 4H) 1.019 [00072] 8.55 (s, 2H), 7.46 (s, 1H), 4.42 (t, 2H), 2.10-1.99 (m, 4H) 1.020 [00073] 8.54 (s, 2H), 7.99 (dd, 1H), 7.41 (t, 1H), 7.32 (dd, 1H), 4.71 (t, 2H), 2.21-2.05 (m, 4H) 1.021 [00074] 8.53 (s, 2H), 7.58 (dd, 1H), 7.21-7.14 (m, 2H), 4.42 (t, 2H), 2.59 (s,3H) 2.09-1.92 (m, 4H) 1.022 [00075] 8.54 (s, 2H), 7.75 (d, 1H), 7.35-7.27 (m, 2H), 4.55 (t, 2H), 2.13-2.04 (m, 4H) 1.023 [00076] 8.44 (d, 1H), 7.98 (dd, 1H), 7.39 (dd, 1H), 7.23 (dd, 1H), 4.03 (s, 3H), 2.22-2.04 (m, 4H) 1.024 [00077] 8.56 (s, 2H), 8.16 (s, 1H), 8.03 (d, 1H), 7.45 (d, 1H), 4.56 (t, 2H), 2.13-2.01 (m, 4H) 1.025 [00078] 8.53 (s, 2H), 8.05 (s, 1H), 7.31 (d, 1H), 7.05 (d, 1H), 4.47 (t, 2H), 2.10-1.97 (m, 4H) 1.026 [00079] 8.53 (s, 2H), 7.18-7.11 (m, 2H), 4.42 (t, 2H), 2.10-1.98 (m, 4H) 1.027 [00080] 8.55 (s, 2H), 7.34 (s, 1H), 4.43 (t, 2H), 2.11-1.98 (m, 4H) 1.028 [00081] 8.53 (s, 2H), 7.36 (d, 1H), 7.07 (d, 1H), 4.43 (t, 2H), 2.10-1.98 (m, 4H) 1.029 [00082] 8.57 (s, 2H), 7.62 (d, 1H), 7.34 (d, 1H), 4.54 (t, 2H), 2.14-2.03 (m, 4H) 1.030 [00083] 8.56 (s, 2H), 7.98 (d, 1H), 7.51 (d, 1H), 4.50 (t, 2H), 2.13-2.01 (m, 4H) 1.031 [00084] 8.10 (s, 1H), 7.92 (d, 1H), 7.62 (dd, 1H), 7.10 (d, 2H), 4.53 (t, 2H), 2.15-2.01 (m, 4H) 1.032 [00085] 7.92 (d, 1H), 7.64-7.60 (m, 1H), 7.55 (dd, 1H), 7.22-7.17 (m, 2H), 4.49 (t, 2H), 2.15- 2.02 (m, 4H) 1.033 [00086] 8.52 (s, 2H), 7.56 (dd, 1H), 7.17-7.12 (m, 1H), 7.09- 7.03 (m, 1H), 4.25 (t, 2H), 4.08 (s, 3H), 2.06-1.90 (m, 4H) 1.034 [00087] 8.51 (s, 2H), 7.61-7.54 (m, 1H), 7.25-7.18 (m, 2H), 4.55 (t, 2H), 3.67 (t, 2H), 3.06 (s, 3H) 1.035 [00088] 8.53 (s, 2H), 7.60-7.52 (m, 1H), 7.26-7.20 (m, 2H), 4.65- 4.58 (m, 2H), 2.72-2.60 (m, 2H) 1.036 [00089] 8.53 (s, 2H), 8.03 (s, 1H), 7.53 (d, 1H), 7.37 (d, 1H), 4.43 (t, 2H), 2.11-1.95 (m, 4H) 1.037 [00090] 8.53 (s, 2H), 7.47 (d, 1H), 7.42 (d, 1H), 4.36 (t, 2H), 2.08-1.95 (m, 4H) 1.038 [00091] 8.52 (s, 2H), 7.44-7.40 (m, 1H), 7.25-7.23 (m, 2H), 4.48 (t, 2H), 2.11-1.99 (m, 4H) 1.039 [00092] 8.52 (s, 2H), 7.62-7.55 (m, 1H), 7.24-7.19 (m, 2H), 4.42 (t, 1H), 4.37 (t, 2H), 4.30 (t, 1H), 1.94-1.84 (m, 2H), 1.68- 1.53 (m, 2H) 1.040 [00093] 8.52 (s, 2H), 7.61-7.57 (m, 1H), 7.22 (dd, 2H), 5.75 tt, 1H), 4.39 (t, 2H), 2.00- 1.89 (m, 2H), 1.86-1.66 (m, 2H) 1.041 [00094] 8.55 (s, 2H), 7.69 (d, 1H), 7.43 (d, 1H), 4.45 (t, 2H), 2.10-1.97 (m, 4H) 1.042 [00095] 8.52 (s, 2H), 8.05 (s, 1H), 7.65-7.60 (m, 1H), 7.20- 7.16 (m, 2H), 4.70-4.62 (m, 2H), 2.72-2.60 (m, 2H) 1.043 [00096] 8.51 (s, 2H), 7.49 (d, 1H), 7.11 (d, 1H), 4.32 (t, 2H), 2.23 (s, 3H), 2.05-1.93 (m, 4H) 1.044 [00097] 8.51 (s, 2H), 7.98 (s, 1H), 7.55 (d, 1H), 7.06 (d, 1H), 4.38 (t, 2H), 2.23 (s, 3H), 2.04-1.92 (m, 4H) 1.045 [00098] 8.91 (br s, 1H), 8.56 (s, 2H), 7.83 (d, 1H), 7.53 (t, 1H), 7.35 (d, 1H), 4.46 (br t, 2H), 2.20-2.15 (m, 4H) 1.046 [00099] 8.55 (s, 2H), 8.13 (s, 1H), 7.73 (d, 1H), 7.38 (d, 1H), 4.51 (t, 2H), 2.09-1.97 (m, 4H) 1.047 [00100] 8.45 (s, 2H), 7.62-7.55 (m, 1H), 7.25-7.21 (m, 2H), 4.44 (t, 2H), 2.10-1.97 (m, 4H) 1.048 [00101] 8.25 (s, 2H), 7.59-7.52 (m, 1H), 7.23-7.18 (m, 2H), 4.45 (t, 2H), 3.89 (s, 3H) 2.08- 1.96 (m, 4H) 1.049 [00102] 8.40 (s, 2H), 7.60-7.53 (m, 1H), 7.25-7.20 (m, 2H), 4.43 (t, 2H), 2.29 (s, 3H), 2.07- 1.90 (m, 4H) 1.050 [00103] 8.56 (s, 2H), 7.97 (s, 1H), 7.38 (s, 1H), 4.70 (t, 2H), 2.21-2.04 (m, 4H) 1.051 [00104] 8.51 (s, 2H), 7.48 (dd, 1H), 7.25-7.20 (m, 2H), 5.91 (t, 1H), 4.65 (t, 2H), 4.15 (t, 2H) 1.052 [00105] 8.50 (s, 2H), 7.59 (d, 1H), 7.25-7.21 (m, 2H), 4.72 (t, 2H), 4.30 (t, 2H) 1.054 [00106] 8.52 (s, 2H), 7.59-7.55 (m, 1H), 7.22-7.18 (m, 2H), 5.70- 5.58 (m, 1H), 4.92-4.88 (m, 2H), 4.38 (t, 2H), 2.51 (q, 2H) 1.055 [00107] 8.52 (s, 2H), 7.58-7.55 (m, 1H), 7.20-7.15 (m, 2H), 4.30 (t, 2H), 1.78-1.70 (m, 2H), 1.23-1.10 (m, 4H), 0.78 (t, 3H) 1.056 [00108] 8.52 (s, 2H), 7.58 (dd, 1H), 7.20-7.15 (m, 2H), 4.30 (t, 2H), 1.67-1.60 (m, 2H), 1.52- 1.45 (m, 1H), 0.83 (d, 6H) 1.057 [00109] 8.52 (s, 2H), 7.59-7.55 (m, 1H), 7.20-7.17 (m, 2H), 4.11 (d, 2H), 2.22-2.12 (m, 1H), 0.80 (d, 6H) 1.058 [00110] 8.52 (s, 2H), 7.58-7.55 (m, 1H), 7.20-7.15 (m, 2H), 4.30 (t, 2H), 1.75-1.70 (m, 2H), 1.21-1.10 (m, 6H), 0.80 (t, 3H) 1.059 [00111] 8.52 (s, 2H), 7.60 (d, 1H), 7.28-7.25 (m, 2H), 5.19 (s, 2H), 2.08 (t, 1H) 1.060 [00112] 8.52 (s, 2H), 7.58-7.55 (m, 1H), 7.20-7.16 (m, 2H), 4.41 (t, 2H), 3.27 (t, 2H), 3.19 (s, 3H), 2.05-1.99 (m, 2H) 1.061 [00113] 8.52 (s, 2H), 7.60-7.55 (m, 1H), 7.20-7.15 (m, 2H), 4.26 (t, 2H), 1.81-1.75 (m, 2H), 0.78 (t, 3H) 1.062 [00114] (CD.sub.3CN) 8.60 (s, 2H), 7.63 (dd, 1H), 7.34 (dd, 1H), 7.31 (t, 1H), 4.77 (t, 1H), 4.70- 4.63 (m, 2H), 4.63-4.58 (m, 1H) 1.063 [00115] 8.53 (s, 2H), 7.60 (d, 1H), 7.31-7.25 (m, 2H), 6.08 (tt, 1H), 4.78 (td, 2H) 1.064 [00116] 8.48 (s, 2H), 7.61-7.55 (m, 1H), 7.24-7.20 (m, 2H), 4.93 (s, 2H), 4.63 (s, 1H), 4.35 (s, 1H), 1.55 (s, 3H) 1.065 [00117] 8.49 (s, 2H), 7.61-7.55 (m, 1H), 7.23-7.18 (m, 2H), 5.87- 5.80 (m, 1H), 5.00-4.88 (m, 4H) 1.066 [00118] 8.51 (s, 2H), 7.58-7.52 (m, 1H), 7.20-7.16 (m, 2H), 4.92 (t, 1H), 4.30 (t, 2H), 2.45 (q, 2H), 1.55 (s, 3H), 1.40 (s, 3H) 1.067 [00119] 8.50 (s, 2H), 7.48 (dd, 1H), 7.20-7.15 (m, 2H), 5.15 (t, 1H), 4.94 (d, 2H), 1.63 (s, 3H), 1.55 (s, 3H) 1.068 [00120] 8.51 (s, 2H), 7.59-7.55 (m, 1H), 7.22-7.19 (m, 2H), 4.35 (t, 2H), 2.08-1.97 (m, 2H), 1.88-1.82 (m, 2H), 1.45-1.40 (m, 2H) 1.069 [00121] 8.51 (s, 2H), 7.60-7.56 (m, 1H), 7.26-7.21 (m, 2H), 6.00- 5.90 (m, 2H), 4.99 (d, 2H) 1.070 [00122] 8.41 (s, 2H), 7.73 (d, 1H), 7.34-7.26 (m, 2H), 4.56 (t, 2H), 2.30 (s, 3H), 2.11- 1.95 (m, 4H) 1.071 [00123] 8.47 (s, 2H), 7.75 (dt, 1H), 7.35-7.27 (m, 2H), 4.57 (t, 2H), 2.25-2.02 (m, 4H) 1.072 [00124] 8.53 (s, 2H), 7.41 (d, 1H), 7.29 (d, 1H), 4.70 (t, 2H), 2.20-2.04 (m, 4H) 1.073 [00125] 8.59 (s, 2H), 8.32 (s, 1H), 7.65 (s, 1H), 4.80 (t, 2H), 2.26-2.08 (m, 4H) 1.074 [00126] 8.48 (s, 2H), 7.56- 7.52 (m, 1H), 7.28-7.24 (m, 2H), 6.57 (t, 1H), 4.48 (t, 2H), 2.10-1.95 (m, 4H) 1.075 [00127] 8.40 (s, 2H), 7.54- 7.48 (m, 1H), 7.23-7.20 (m, 2H), 4.45 (t, 2H), 2.30 (s, 3H), 2.05-1.92 (m, 4H) 1.076 [00128] 8.43 (s, 2H), 7.56-7.51 (m, 1H), 7.25-7.20 (m, 2H), 4.47 (t, 2H), 2.10-2.00 (m, 4H) 1.077 [00129] 8.85 (s, 2H), 7.60-7.55 (m, 1H), 7.28-7.23 (m, 2H), 4.42 (t, 2H), 2.11-2.00 (m, 4H) 1.078 [00130] 8.86 (s, 2H), 7.66-7.60 (m, 1H), 7.27-7.23 (m, 2H), 4.40 (t, 1H), 2.12-2.00 (m, 4H) 1.079 [00131] 8.58-8.54 (m, 2H), 7.58 (d, 1H), 7.29 (d, 1H), 4.54 (t, 2H), 2.12-2.03 (m, 4H) 1.080 [00132] 8.49 (s, 2H), 8.11 (d, 1H), 7.41 (d, 1H), 7.19 (d, 1H), 4.49 (t, 2H), 2.05-1.92 (m, 4H) 1.081 [00133] 8.47 (s, 2H), 7.61- 7.55 (m, 1H), 7.29-7.21 (m, 2H), 6.57 (t, 1H), 4.48- 4.40 (m, 2H), 2.12-1.95 (m, 4H) 1.082 [00134] 8.86 (s, 2H), 7.66-7.60 (m, 1H), 7.27-7.22 (m, 2H), 4.41- 4.37 (m, 2H), 2.14-1.98 (m, 4H) 1.083 [00135] 8.58 (s, 2H), 8.29 (s, 1H), 7.61 (s, 1H), 4.76 (t, 2H), 2.22-2.06 (m, 4H)

BIOLOGICAL EXAMPLES

[0187] Seeds of a variety of test species are sown in standard soil in pots Amaranthus retoflexus (AMARE), Echinochloa crus-galli (ECHCG), Setaria faberi (SETFA)). After cultivation for one day (pre-emergence) or after 8 days cultivation (post-emergence) under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity), the plants are sprayed with an aqueous spray solution derived from the formulation of the technical active ingredient in acetone/water (50:50) solution containing 0.5% Tween™ 20 (polyoxyethelyene sorbitan monolaurate, CAS RN 9005-64-5). Compounds are applied at 250 g/ha unless otherwise stated. The test plants are then grown in a glasshouse under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity) and watered twice daily. After 13 days for pre- and post-emergence, the test is evaluated for the percentage damage caused to the plant. The biological activities are shown in the following table on a five-point scale (5=81-100%; 4=61-80%; 3=41-60%; 2=21-40%; 1=0-20%).

TABLE-US-00002 TABLE B1 Post-emergence Test Compound AMARE ABUTH SETFA ECHCG IPOHE 1.001 2 4 4 3 1 1.002 2 2 3 3 1 1.003 3 2 1 1 2 1.004 3 1 1 1 2 1.005 5 5 5 5 3 1.006 5 5 4 5 2 1.007 5 5 5 5 4 1.008 5 4 4 4 2 1.010 4 1 2 2 1 1.011 3 1 1 1 1 1.012 1 1 1 1 1 1.013 5 5 5 5 2 1.014 4 4 3 2 2 1.015 4 4 2 2 1 1.016 4 2 1 1 1 1.017 4 1 1 1 1 1.018 1 1 1 1 1 1.019 4 1 2 2 1 1.020 2 3 5 NT 2 1.021 1 4 4 NT 3 1.022 5 5 5 NT 4 1.023 1 1 1 NT 1 1.024 2 2 1 NT 1 1.025 2 2 2 NT 1 1.026 5 4 5 NT 2 1.027 4 2 3 4 1 1.028 5 2 3 NT 1 1.029 4 1 1 NT 1 1.030 4 1 2 2 1 1.031 4 1 1 1 1 1.032 5 3 NT 3 3 1.033 1 1 1 1 1 1.034 5 4 4 4 4 1.035 5 5 4 5 4 1.036 1 1 1 1 1 1.037 2 1 1 1 1 1.039 5 4 4 4 4 1.040 5 4 4 5 5 1.041 1 1 1 1 1 1.042 4 4 4 4 2 1.043 4 3 3 3 4 1.044 1 1 1 1 1 1.046 2 2 1 1 1 1.047 5 5 4 5 5 1.048 5 4 3 3 4 1.049 4 5 4 5 3 1.050 5 2 1 1 3 1.051 5 4 4 4 3 1.052 5 5 3 4 3 1.054 4 4 2 3 2 1.055 4 3 3 3 2 1.056 4 3 2 2 3 1.057 3 2 1 1 1 1.058 4 3 2 3 2 1.059 4 2 1 1 1 1.060 3 3 3 4 2 1.061 4 2 2 2 2 1.062 3 2 1 1 1 1.063 4 3 2 2 2 1.064 2 2 1 1 1 1.065 4 2 2 2 2 1.066 4 4 3 3 2 1.067 4 3 3 3 2 1.068 5 4 3 3 2 1.069 5 4 2 3 2 1.070 3 5 3 4 3 1.071 5 5 4 4 4 1.072 4 1 3 3 3 NT = Not Tested.

TABLE-US-00003 TABLE B2 Pre-emergence Test Compound AMARE ABUTH SETFA ECHCG IPOHE 1.001 4 4 5 5 1 1.002 1 1 2 2 1 1.003 1 1 1 1 1 1.004 1 1 2 1 1 1.005 5 3 5 5 1 1.006 5 2 5 5 1 1.007 5 3 5 5 2 1.008 4 2 4 4 1 1.010 4 1 2 2 1 1.011 1 1 1 1 1 1.012 2 1 1 1 1 1.013 5 2 5 5 1 1.014 4 1 4 4 1 1.015 2 1 1 1 1 1.016 1 1 1 1 1 1.017 1 1 1 1 1 1.018 NT 1 1 1 1 1.019 1 1 1 1 1 1.020 5 4 5 NT 2 1.021 5 3 5 NT 2 1.022 5 4 5 5 4 1.023 1 1 1 NT 1 1.024 4 1 4 NT 1 1.025 1 1 2 NT 1 1.026 5 2 3 5 1 1.027 4 1 1 NT 1 1.028 4 1 2 NT 1 1.029 2 1 1 NT 1 1.030 1 1 1 NT 1 1.031 1 1 1 1 1 1.032 3 1 4 3 1 1.033 2 1 1 1 1 1.034 5 2 5 5 3 1.035 4 3 5 5 3 1.036 1 1 1 1 1 1.037 1 1 1 1 1 1.039 5 3 5 5 1 1.040 5 4 5 5 2 1.041 1 1 1 1 1 1.042 5 4 5 5 1 1.043 5 1 4 3 1 1.044 2 1 3 3 1 1.046 1 2 1 1 1 1.047 5 5 5 5 3 1.048 4 2 5 4 1 1.049 5 3 5 5 1 1.050 1 1 1 1 1 1.051 5 3 5 4 2 1.052 5 3 5 4 1 1.054 4 1 5 4 1 1.055 4 1 4 4 1 1.056 4 1 4 3 1 1.057 2 2 4 2 1 1.058 2 2 3 3 1 1.059 2 2 2 2 1 1.060 4 4 4 4 2 1.061 3 1 5 4 1 1.062 4 1 4 2 1 1.063 3 2 2 2 1 1.064 1 1 1 1 1 1.065 2 2 4 3 1 1.066 3 2 5 4 1 1.067 3 2 4 3 1 1.068 5 2 5 4 2 1.069 3 2 5 3 1 1.070 5 3 4 4 1 1.071 5 3 5 5 2 1.072 4 1 4 2 1 N1.T = Not Tested.