SUBSTITUTED PYRIDAZINONES AS HERBICIDES

Abstract

The present invention relates to herbicidal substituted phenyl-pyridazine-diones and substituted phenyl-pyridazinone derivatives of formula (I), as well as to processes and intermediates used for the preparation of such derivatives. The invention further extends to herbicidal compositions comprising such derivatives, as well as to the use of such compounds and compositions in controlling undesirable plant growth: in particular the use in controlling weeds, such as broad-leaved dicotyledonous weeds, in crops of useful plants.

##STR00001##

Claims

1. A compound of formula (I) ##STR00058## or a salt or N-oxide thereof, wherein R.sup.1 is selected from the group consisting of C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6alkoxy, C.sub.1-C.sub.2alkoxy-C.sub.1-C.sub.2alkyl-, C.sub.2-C.sub.4alkenyl, C.sub.1-C.sub.4haloalkyl, cyano-C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4haloalkenyl, C.sub.2-C.sub.4alkynyl and C.sub.2-C.sub.4haloalkynyl; R.sup.2 is selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.3haloalkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl-, C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6hydroxyalkyl-, C.sub.1-C.sub.6alkylcarbonyl-, —S(O).sub.mC.sub.1-C.sub.6alkyl, amino, C.sub.1-C.sub.6alkylamino, C.sub.1-C.sub.6dialkylamino, —C(C.sub.1-C.sub.3alkyl)=N—O—C.sub.1-C.sub.3alkyl and C.sub.2-C.sub.6 haloalkynyl; G is hydrogen, or C(O)R.sup.3; R.sup.3 is selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6alkyl-S—, C.sub.1-C.sub.6alkoxy, —NR.sup.4R.sup.5 and phenyl optionally substituted by one or more R.sup.6; each R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and C.sub.3-C.sub.6cycloalkyl, or R.sup.4 and R.sup.5 together can form a morpholinyl ring; and, R.sup.6 is selected from the group consisting of halogen, cyano, nitro, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkoxy and C.sub.1-C.sub.3haloalkoxy; X and Y are each independently hydrogen, C.sub.1-C.sub.3alkyl, cyclopropyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy, or halogen; D is either a substituted or unsubstituted naphthalene ring system, or a substituted or unsubstituted 8-10 membered bicyclic saturated, partially saturated or unsaturated, heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen and sulphur, and wherein when D is substituted it is substituted on at least one ring carbon atom with R.sup.8 and/or on at least one ring nitrogen atom by R.sup.9; each R.sup.8 is independently oxygen, hydroxyl, halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl-, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6alkynyl, C.sub.2-C.sub.6haloalkynyl, C.sub.1-C.sub.6hydroxyalkyl-, C.sub.1-C.sub.6alkylcarbonyl-, C.sub.1-C.sub.6haloalkylcarbonyl-, C.sub.3-C.sub.6cycloalkylcarbonyl-, C.sub.1-C.sub.6alkyl-S(O).sub.m—, —S(O).sub.m—C.sub.1-C.sub.6haloalkyl, —S(O).sub.m—C.sub.3-C.sub.6cycloalkyl, —O—S(O).sub.2C.sub.1-C.sub.3alkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.1-C.sub.6alkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.1-C.sub.6haloalkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.3-C.sub.6cycloalkyl, cyano-C.sub.1-C.sub.6-alkyl-, —NR.sup.4R.sup.5, —C(C.sub.1-C.sub.3alkyl)=N—O—C.sub.1-C.sub.3alkyl, —C(S)NH.sub.2, C.sub.1-C.sub.6alkylaminothiocarbonyl-, di(C.sub.1-C.sub.6alkyl)aminothiocarbonyl-, C.sub.3-C.sub.6-cycloalkylamino-thiocarbonyl-S(O).sub.2NH.sub.2, —S(O).sub.2NHC(O)C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.6alkylaminosulfonyl-, di(C.sub.1-C.sub.6alkyl)aminosulfonyl-, C.sub.3-C.sub.6-cycloalkylamino-sulfonyl-, —C(O)OH, —C(O)OC.sub.1-C.sub.6alkyl, —C(O)NHS—(O).sub.2C.sub.1-C.sub.6alkyl, —C(O)NR.sup.4R.sup.5, —NR.sup.4C(O)NR.sup.4R.sup.5, C.sub.1-C.sub.6alkylcarbonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.1-C.sub.6haloalkylcarbonylamino-, C.sub.1-C.sub.6haloalkylcarbonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.1-C.sub.6alkoxycarbonylamino-, C.sub.1-C.sub.6alkoxycarbonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.1-C.sub.6alkylsulfonylamino-, C.sub.1-C.sub.6alkylsulfonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.1-C.sub.6haloalkylsulfonylamino-, C.sub.1-C.sub.6haloalkylsulfonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.3-C.sub.6cycloalkylsulfonylamino-, C.sub.3-C.sub.6cycloalkylsulfonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.1-C.sub.6alkylaminocarbonylamino-, C.sub.1-C.sub.6alkylaminocarbonyl(C.sub.1-C.sub.6alkyl)amino, di(C.sub.1-C.sub.6alkyl)aminocarbonylamino-, C.sub.1-C.sub.6haloalkylaminocarbonylamino-, C.sub.1-C.sub.6haloalkylamino-carbonyl(C.sub.1-C.sub.6alkyl)amino, di(C.sub.1-C.sub.6haloalkyl)aminocarbonylamino-, di(C.sub.1-C.sub.6haloalkyl)amino-carbonyl(C.sub.1-C.sub.6alkyl)amino-, hydroxyamino-, hydroxy(C.sub.1-C.sub.6alkyl)amino, C.sub.1-C.sub.6alkoxyamino, C.sub.1-C.sub.6alkoxy(C.sub.1-C.sub.6alkyl)amino, C.sub.1-C.sub.6haloalkoxyamino, C.sub.1-C.sub.6haloalkoxy(C.sub.1-C.sub.6alkyl)amino; or a ring system selected from the group consisting: of a phenyl ring, a 5-6-membered heteroaryl ring and a 3-6-membered heterocyclyl ring, wherein said ring system is substituted by 0 to 5 R.sup.16; m is an integer of 0, 1, or 2; each R.sup.9 is independently C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, hydroxyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkylthio, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.6hydroxyalkyl-, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.1-C.sub.6alkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.1-C.sub.6haloalkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.3-C.sub.6cycloalkyl, cyano-C.sub.1-C.sub.6-alkyl-, or a ring system selected from the group consisting of: a phenyl ring, a 5-6-membered heteroaryl ring and a 3-6-membered heterocyclyl ring, wherein said ring system is substituted by 0 to 5 R.sup.16; each R.sup.16 is independently halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy or C.sub.1-C.sub.6haloalkoxy; and, W is ##STR00059## wherein “a” denotes the point of attachment to the phenyl-pyridazinone/phenyl-pyridazine dione moiety, “b” denotes the point of attachment to ring D, R.sup.10, R.sup.12, R.sup.14 and R.sup.15 are each independently hydrogen, C.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3haloalkyl; or R.sup.10 and R.sup.12 together with the carbon atoms to which they are joined form a C.sub.3-C.sub.6 carbocyclic ring; and R.sup.11 and R.sup.13 are each independently hydrogen, halogen, C.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3haloalkyl, provided that when one of R.sup.11 or R.sup.13 is halogen, C.sub.1-C.sub.3alkyl or C.sub.1-C.sub.3 haloalkyl, the other is hydrogen.

2. The compound according to claim 1, wherein G is hydrogen or C(O)R.sup.3 wherein R.sup.3 is isopropyl, t-butyl, methyl, ethyl, propargyl, methoxy, ethoxy, or tert-butoxy.

3. The compound of claim 1 wherein X is hydrogen, halogen, or C.sub.1haloalkyl.

4. The compound of claim 1 wherein Y is hydrogen, C.sub.1-C.sub.3 alkyl, cyclopropyl, C.sub.1-C.sub.3haloalkyl, or halogen.

5. The compound according to claim 1 wherein X is ortho with respect to the pyrdazinone/pyridazine-dione moiety.

6. The compound according to claim 1 wherein Y is ortho with respect to the —W-D moiety.

7. The compound according to claim 1 wherein R.sup.1 is methyl, ethyl, n-propyl, cyclopropyl, propargyl, or C.sub.1haloalkyl.

8. The compound according to claim 1 wherein R.sup.2 is selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6alkynyl and C.sub.2-C.sub.6haloalkynyl.

9. The compound according to claim 1 wherein D is a substituted or unsubstituted naphthalene, indolizine, indole, iso-indole, indoline, isoindoline, 3-H-indole, benzofuran, benzothiophene, 1H-indazole, benzimidazole, benzthiazole, benzoxazole, benzodioxole, purine, 4H-quinolizine, quinoline, isoquinoline, tetrahydroquinoline, cinnoline, phthalazine, quinoxaline, 1-8-naphthyridine, pteridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyrazine or 1H-benzotriazole ring system and wherein when D is substituted, it is substituted on at least one ring carbon atom by R.sup.8 and/or on at least one ring nitrogen atom by R.sup.9.

10. The compound according to claim 1 wherein D is a substituted or unsubstituted naphthalene, indolizine, indole, iso-indole, 3-H-indole, benzofuran, benzothiophene, 1H-indazole, benzimidazole, benzthiazole, benzoxazole, purine, 4H-quinolizine, quinoline, isoquinoline, tetrahydroquinoline, cinnoline, phthalazine, quinoxaline, 1-8-naphthyridine, or pteridine ring system, and wherein when D is substituted, it is substituted on at least one ring carbon atom by R.sup.8 and/or on at least one ring nitrogen atom by R.sup.9.

11. The compound according to claim 1 wherein each R.sup.8 is independently oxygen, hydroxyl, halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.3haloalkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl-, C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6hydroxyalkyl-, C.sub.1-C.sub.6alkylcarbonyl-, C.sub.1-C.sub.6alkyl-S(O).sub.m—, amino, C.sub.1-C.sub.6alkylamino, C.sub.1-C.sub.6dialkylamino, —C(C.sub.1-C.sub.3alkyl)=N—O—C.sub.1-C.sub.3alkyl or C.sub.2-C.sub.6 haloalkynyl.

12. The compound according to claim 1 wherein each R.sup.9 is independently C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl, hydroxyl, C.sub.1-C.sub.4alkoxy, or C.sub.1-C.sub.4alkylthio.

13. The compound according to claim 1 wherein W is Wi and each of R.sup.10, R.sup.11, R.sup.12, and R.sup.13 is hydrogen.

14. The compound according to claim 1 wherein W is W2 and each of R.sup.14 and R.sup.15 is hydrogen.

15. The compound according to claim 1 wherein W is cis ##STR00060## or trans ##STR00061##

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

17. A herbicidal composition according to claim 16, further comprising at least one additional pesticide.

18. A herbicidal composition according to claim 17, wherein the additional pesticide is a herbicide or herbicide safener.

19. A method of controlling unwanted plant growth, comprising applying a compound of formula (I) as defined in claim 1, to the unwanted plants or to the locus thereof.

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

21. A method of controlling unwanted plant growth, comprising applying an herbicidal composition according to claim 16, to the unwanted plants or to the locus thereof.

Description

PREPARATION EXAMPLES

Example 1 Preparation of [5-[3-chloro-6-fluoro-2-[2-(2-methyl-6-quinolyl)ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methyipropanoate (A-3.034)

[0127] ##STR00029##

1.1 3-Allyl-2-bromo-1-chloro-4-fluoro-benzene

[0128] A solution of lithium diisopropylamide (2M in tetrahydrofuran, 3.6 ml, 7.2 mmol) was cooled to −78° C. under N.sub.2. A solution of 2-bromo-1-chloro-4-fluoro-benzene (1.0 g, 4.8 mmol) in tetrahydrofuran was added dropwise at −78° C. The mixture was stirred for 45 minutes at the same temperature before being treated with allyl bromide (0.3 ml, 5.7 mmol). The reaction was continued at −78° C. for 2 h then allowed to warm to rt. The reaction was quenched with sat. NH.sub.4Cl (aq) and extracted with ethyl acetate. The organics were separated and kept, then washed with brine. The organics were dried over sodium sulfate and concentrated under reduced pressure to give 3-allyl-2-bromo-1-chloro-4-fluoro-benzene (1.2 g, 100%) as an oil.

##STR00030##

[0129] .sup.1H NMR (400 MHz, CDCl.sub.3) δ.sub.H: 7.34-7.30 (m, 1H), 7.01-6.96 (m, 1H), 5.94-5.83 (m, 1H), 5.10-5.00 (m, 2H), 3.64-3.58 (m, 2H).

1.2 2-(2-Bromo-3-chloro-6-fluoro-phenyl)acetic Acid

[0130] A solution of 3-allyl-2-bromo-1-chloro-4-fluoro-benzene (15.0 g, 60.1 mmol) in dichloromethane (200 mL) in a 2-necked flask was cooled to −78° C. One side neck was connected to a trap containing an aqueous solution of KI. Ozone was bubbled through the solution until the starting material was fully consumed (5 hours). Air was bubbled through the solution for 10 minutes to remove excess ozone. Dimethyl sulfide (44 ml, 601 mmol) was added and the mixture allowed to warm to rt. The reaction was continued for 16 h at rt.

[0131] The mixture was washed with brine (2×100 mL) and the organic layer kept. The organics were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude 2-(2-bromo-3-chloro-6-fluoro-phenyl)acetaldehyde (15.3 g) which was used for the next step without further purification.

[0132] Crude 2-(2-bromo-3-chloro-6-fluoro-phenyl)acetaldehyde (15.3 g, 60.8 mmol) was dissolved in a mixture of tert-butanol (92 mL) and water (46 mL) then cooled to 0° C. 2-methylbut-2-ene (64.5 mL, 608 mmol), sodium dihydrogen phosphate (34.6 g, 243 mmol) and sodium chlorite (16.5 g, 163 mmol) were added. The mixture was stirred for 2 h then diluted with brine (150 mL) and 2M hydrochloric acid (150 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium metabisulfite (100 mL) then dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to provide a pale yellow solid. The crude solid was dissolved in a mixture of water (100 mL) and 2.0 M NaOH (30 mL). The aqueous solution was washed with ethyl acetate (100 mL) and the organics discarded. The aqueous layer was acidified by addition of concentrated hydrochloric acid (20 mL) resulting in the formation of a white suspension. The mixture was extracted with ethyl acetate (3×200 mL). The combined organics were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to provide 2-(2-bromo-3-chloro-6-fluoro-phenyl)acetic acid (8.0 g, 49%) as a white solid.

##STR00031##

[0133] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ.sub.H: 12.79 (br.s, 1H), 7.67-7.59 (m, 1H), 7.39-7.31 (m, 1H), 3.82 (s, 2H).

1.3 2-(2-Bromo-3-chloro-6-fluoro-phenyl)-N-methyl-acetohydrazide

[0134] To a stirred solution of 2-(2-bromo-3-chloro-6-fluoro-phenyl)acetic acid (2.0 g, 7.5 mmol) in dichloromethane (20 ml) at 0° C. was added N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride [EDC.HCl] (1.4 g, 9.0 mmol), followed by dropwise addition of methyl hydrazine (0.4 ml, 7.5 mmol). The temperature of the reaction mixture was maintained at 0° C. for 3 h. The reaction was then quenched with water and extracted into dichloromethane. The organics were separated, washed with brine and dried over Na.sub.2SO.sub.4. Concentration under reduced pressure gave crude 2-(2-bromo-3-chloro-6-fluoro-phenyl)-N-methyl-acetohydrazide (1.8 g, 81%) which was used in the next step without further purification.

##STR00032##

[0135] .sup.1H NMR (400 MHz, DMSO-d6) δ.sub.H: 7.59 (dd, J=8.9 and 5.4, 1H), 7.30 (t, J=8.9, 1H), 4.91 (s, 2H), 4.10 (br. s, 2H), 3.02 (s, 3H).

1.4 2-{[2-(2-Bromo-3-chloro-6-fluoro-phenyl)-acetyl]-methyl-hydrazono}-propionic Acid Ethyl Ester

[0136] To a stirred solution of 2-(2-bromo-3-chloro-6-fluoro-phenyl)-N-methyl-acetohydrazide (1.8 g, 6.09 mmol) in ethanol (5 ml) was added ethyl pyruvate (0.7 ml, 6.7 mmol) dropwise. The reaction was heated at 80° C. for 4 h. The reaction mixture was then allowed to cool to rt, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent an ethyl acetate/hexane gradient) to give the desired compound 2-{[2-(2-Bromo-3-chloro-6-fluoro-phenyl)-acetyl]-methyl-hydrazono}-propionic acid ethyl ester (1.8 g, 75%) as an off-white solid.

##STR00033##

[0137] .sup.1H NMR (400 MHz, CDCl.sub.3) δ.sub.H: 7.40-7.35 (m, 1H), 7.04-6.98 (m, 1H), 4.32 (q, J=7.1, 2H), 4.24 (s, 2H), 3.41 (s, 3H), 2.32 (s, 3H), 1.36 (t, J=7.1, 3H).

1.5 4-(2-Bromo-3-chloro-6-fluoro-phenyl)-5-hydroxy-2,6-dimethyl-pyridazin-3-one

[0138] 2-{[2-(2-Bromo-3-chloro-6-fluoro-phenyl)-acetyl]-methyl-hydrazono}-propionic acid ethyl ester (500 mg, 1.27 mmol) was dissolved in acetonitrile (2.5 ml) and treated with 1,8-diazabicyclo[5.4.0]undec-7-ene [DBU] (0.47 ml, 3.2 mmol). The mixture was heated to 125° C. using microwave irradiation for 1 h. The reaction mixture was then evaporated under reduced pressure. The residue was dissolved in water and acidified to pH 1 with 2N hydrochloric acid. The mixture was extracted with DCM, the organics separated and washed with brine solution. The organic solution was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give crude product. The crude was purified by column chromatography on silica gel (eluent an ethyl acetate/hexane gradient) to give 4-(2-bromo-3-chloro-6-fluoro-phenyl)-5-hydroxy-2,6-dimethyl-pyridazin-3-one (340 mg, 77.1%) as an off-white solid.

##STR00034##

[0139] .sup.1H NMR (400 MHz, DMSO-d6) δ.sub.H: 11.01 (s, 1H), 7.77-7.73 (m, 1H), 7.39 (t, J=8.7, 1H), 3.58 (s, 3H), 2.24 (s, 3H).

1.6 [5-(2-Bromo-3-chloro-6-fluoro-phenyl)-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate

[0140] To a stirred solution of 4-(2-bromo-3-chloro-6-fluoro-phenyl)-5-hydroxy-2,6-dimethyl-pyridazin-3-one (1.4 g, 4.02 mmol) in dichloromethane (32 ml) at rt were added triethylamine (1.1 ml, 8.06 mmol), 4-(dimethylamino)pyridine [DMAP] (49 mg, 0.40 mmol) and isobutyryl chloride (0.6 ml, 4.83 mmol).

[0141] Once judged complete, the reaction was diluted with dichloromethane and water. The organic layer was separated, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure to give crude product. The crude was purified by column chromatography on silica gel (eluent an ethyl acetate/hexane gradient) to give [5-(2-bromo-3-chloro-6-fluoro-phenyl)-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (1.47 g, 87%).

##STR00035##

[0142] .sup.1H NMR (400 MHz, CDCl.sub.3) δ.sub.H: 7.51-7.47 (m, 1H), 7.10-7.05 (m, 1H), 3.82 (s, 3H), 2.60-2.55 (m, 1H), 2.25 (s, 3H), 1.02-0.98 (m, 6H).

1.7 2-Methyl-6-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]quinoline

[0143] 4,4,5,5-Tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.73 mL, 4.32 mmol) and N,N-diisopropylethylamine (1.25 mL, 7.20 mmol) were added to a stirred solution of 6-bromo-2-methyl-quinoline (800 mg, 3.6 mmol) and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(II) (92 mg, 0.18 mmol) in toluene (14 mL). The reaction mixture was heated to 95° C. under nitrogen for 4 h.

[0144] Upon completion the reaction mixture was allowed to cool to room temperature then filtered through Celite® (eluting with DCM). The filtrate was concentrated in vacuo then purified by flash column chromatography (silica, eluent an ethyl acetate/iso-hexane gradient) to give 2-methyl-6-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]quinoline (886 mg, 83% yield).

##STR00036##

[0145] .sup.1H NMR (400 MHz, Solvent) δ ppm 1.34 (s, 12H) 2.74 (s, 3H) 6.29 (d, J=18.46 Hz, 1H) 7.26-7.29 (m, 1H) 7.55 (d, J=18.4 Hz, 1H) 7.77 (d, J=1.47 Hz, 1H) 7.85-7.92 (m, 1H) 7.94-7.99 (m, 1H) 8.02 (d, J=8.4 Hz, 1H).

1.8 [5-[3-Chloro-6-fluoro-2-[(E)-2-(2-methyl-6-quinolyl)vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (A-4.034)

[0146] A stirred solution of [5-(2-bromo-3-chloro-6-fluoro-phenyl)-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (1.03 g, 2.47 mmol), Cs.sub.2CO.sub.3 (2.43 g, 7.40 mmol), 2-methyl-6-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]quinoline (0.874 g, 2.96 mmol) and Pd(dppf)Cl.sub.2.DCM (0.101 g, 0.123 mmol) in 1,4-dioxane (21 mL) and water (6 mL) was heated at reflux.

[0147] After 16 h, the reaction mixture was concentrated in vacuo to remove the bulk of the dioxane, then diluted with water and EtOAc. The organic layer was separated and the aqueous phase extracted with portions of EtOAc (2×). The pH of the aqueous phase was then adjusted to pH 2 with 2M HCl (aq) then extracted with a further portion of EtOAc.

[0148] The crude product was purified by flash column chromatography (silica, eluent an ethyl acetate/iso-hexane gradient) to give [5-[3-chloro-6-fluoro-2-[(E)-2-(2-methyl-6-quinolyl)vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (86 mg, 7% yield, A-4.034) and 4-[3-chloro-6-fluoro-2-[(E)-2-(2-methyl-6-quinolyl)vinyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (51 mg, 5% yield, A-2.034).

##STR00037##

[0149] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.11 (app t, J=7.1 Hz, 6H) 2.23 (s, 3H) 2.63-2.71 (m, 1H) 2.74 (s, 3H) 3.69 (s, 3H) 6.81 (d, J=16.4 Hz, 1H) 7.04 (t, J=8.7 Hz, 1H) 7.15 (d, J=16.5 Hz, 1H) 7.27 (s, 1H) 7.45 (dd, J=8.9, 5.07 Hz, 1H) 7.63 (d, J=1.7 Hz, 1H) 7.75-7.81 (m, 1H) 7.94 (d, J=8.8 Hz, 1H) 8.01 (d, J=8.3 Hz, 1H).

##STR00038##

[0150] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 2.24 (s, 3H) 2.66 (s, 3H) 3.66 (s, 3H) 6.72 (d, J=16.4 Hz, 1H) 6.93-7.07 (m, 2H) 7.26 (s, 1H) 7.38 (dd, J=8.9, 5.14 Hz, 1H) 7.55 (d, J=1.7 Hz, 1H) 7.66 (dd, J=8.8, 2.0 Hz, 1H) 7.84 (d, J=8.8 Hz, 1H) 7.99 (d, J=8.4 Hz, 1H)

1.9 [5-[3-Chloro-6-fluoro-2-[2-(2-methyl-6-quinolyl)ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (A-3.034)

[0151] [5-[3-Chloro-6-fluoro-2-[(E)-2-(2-methyl-6-quinolyl)vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (56 mg, 0.12 mmol, 4.034) was subjected to catalytic hydrogenation in tetrahydrofuran (0.3 mL) over 5% Pd/C catalyst (24 mg) at 3 bar H.sub.2.

[0152] Upon completion, the reaction mixture was filtered through a pad of Celite®, eluting with DCM. The filtrate was concentrated in-vacuo to afford a crude residue.

[0153] The residue was adsorbed onto silica and purified by flash column chromatography (silica, eluent ethyl acetate/iso-hexane) to give [5-[3-chloro-6-fluoro-2-[2-(2-methyl-6-quinolyl)ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (15 mg, 27% yield, A-3.034) and a mixture of further-reduced products which was further purified by mass-directed reverse-phase preparative HPLC to give [5-[3-chloro-6-fluoro-2-[2-(2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (6 mg, 11% yield, A-3.030).

##STR00039##

[0154] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 0.97 (dd, J=7.0, 4.4 Hz, 6H) 2.24 (s, 3H) 2.47-2.57 (m, 1H) 2.73 (s, 3H) 2.79-3.09 (m, 4H) 3.84 (s, 3H) 7.00 (t, J=8.6 Hz, 1H) 7.25 (d, J=8.3 Hz, 1H) 7.49 (app d, J=1.1 Hz, 3H) 7.90 (d, J=8.4 Hz, 1H) 7.96 (d, J=8.3 Hz, 1H).

##STR00040##

[0155] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 0.96 (dd, J=7.03, 2.02 Hz, 6H) 1.25 (d, J=6.24 Hz, 3H) 1.58-1.69 (m, 1H) 1.90-1.98 (m, 1H) 2.24 (s, 3H) 2.54 (dt, J=13.94, 6.97 Hz, 1H) 2.63-2.84 (m, 6H) 3.39 (td, J=6.51, 3.12 Hz, 1H) 3.83 (s, 3H) 6.52 (br d, J=6.48 Hz, 1H) 6.72-6.79 (m, 2H) 6.96 (t, J=8.62 Hz, 1H) 7.40 (dd, J=8.80, 5.14 Hz, 1H).

Example 2 Preparation of 4-[3-chloro-6-fluoro-2-[2-(1H-indol-5-yl)ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (A-1.021)

[0156] ##STR00041##

2.1 5-Benzyloxy-4-(2-bromo-3-chloro-6-fluoro-phenyl)-2,6-dimethyl-pyridazin-3-one

[0157] Benzyl bromide (0.19 mL, 1.58 mmol) was added to a stirred suspension of 4-(2-bromo-3-chloro-6-fluoro-phenyl)-5-hydroxy-2,6-dimethyl-pyridazin-3-one (500 mg, 1.44 mmol) and K.sub.2CO.sub.3 (0.22 g, 1.58 mmol) in acetone (2.9 mL) and the mixture heated at reflux for 2 hrs.

[0158] Upon completion the reaction mixture as allowed to cool to RT then filtered (eluting with acetone). The filtrate was concentrated in vacuo then purified by flash column chromatography (silica, eluent an ethyl acetate/iso-hexane gradient) to give 5-benzyloxy-4-(2-bromo-3-chloro-6-fluoro-phenyl)-2,6-dimethyl-pyridazin-3-one (560 mg, 89% yield).

##STR00042##

[0159] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 2.29 (s, 3H) 3.77 (s, 3H) 4.59-4.76 (m, 2H) 7.09 (dd, J=8.93, 7.95 Hz, 1H) 7.13-7.20 (m, 2H) 7.29-7.36 (m, 3H) 7.52 (dd, J=8.93, 5.38 Hz, 1H).

2.2 2-[(E)-2-[2-(5-benzyloxy-2,6-dimethyl-3-oxo-pyridazin-4-yl)-6-chloro-3-fluoro-phenyl]vinyl]-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

[0160] A stirred solution of 5-benzyloxy-4-(2-bromo-3-chloro-6-fluoro-phenyl)-2,6-dimethyl-pyridazin-3-one (1.00 g, 2.28 mmol), chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (59 mg, 0.11 mmol), N,N-diisopropylethylamine (0.80 mL, 4.57 mmol) and 6-methyl-2-vinyl-1,3,6,2-dioxazaborocane-4,8-dione (0.50 g, 2.74 mmol) in THE (23 mL) was heated at 90° C. for 5 hrs then at 70° C. for a further 16 hrs.

[0161] The reaction mixture was allowed to cool to room temperature then diluted with DCM and filtered through Celite®, eluting with further portions of DCM. The filtrate was concentrated in vacuo then purified by flash column chromatography (silica, eluent an ethyl acetate/methanol gradient) to give 5-benzyloxy-4-(2-bromo-3-chloro-6-fluoro-phenyl)-2,6-dimethyl-pyridazin-3-one; 2-[(E)-2-[2-(5-benzyloxy-2,6-dimethyl-3-oxo-pyridazin-4-yl)-6-chloro-3-fluoro-phenyl]vinyl]-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (904 mg, 74% yield).

##STR00043##

[0162] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 2.26 (s, 3H) 2.79 (s, 3H) 3.73 (s, 7H) 4.60 (s, 2H) 5.97 (d, J=18.6 Hz, 1H) 6.76 (d, J=18.5 Hz, 1H) 7.02 (t, J=8.6 Hz, 1H) 7.09 (dd, J=6.7, 3.00 Hz, 2H) 7.29-7.34 (m, 3H) 7.44 (dd, J=8.9, 5.1 Hz, 1H).

2.3 5-benzyloxy-4-[3-chloro-6-fluoro-2-[(E)-2-(1H-indol-5-yl)vinyl]phenyl]-2,6-dimethyl-pyridazin-3-one

[0163] To a microwave-vial was added 2-[(E)-2-[2-(5-benzyloxy-2,6-dimethyl-3-oxo-pyridazin-4-yl) δ-chloro-3-fluoro-phenyl]vinyl]-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (300 mg, 0.56 mmol), 5-bromo-1H-indole (163 mg, 0.84 mmol), Pd(dppf)Cl.sub.2.DCM (23 mg, 0.028 mmol,) and K.sub.3PO.sub.4.H.sub.2O (512 mg, 2.22 mmol). The vial was then capped and purged with N.sub.2 before addition of THE (5.6 mL) and water (0.2 mL). The reaction mixture was then heated to 90° C. for 30 mins in under microwave irradiation.

[0164] The reaction mixture was cooled to room temperature then partitioned between water (20 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer extracted with extracted with EtOAc (2×20 mL). The combined organics were collected, dried (MgSO4), filtered, and concentrated in vacuo to give the crude product.

[0165] The crude product was purified by mass-directed reverse-phase preparative HPLC to give 5-benzyloxy-4-[3-chloro-6-fluoro-2-[(E)-2-(1H-indol-5-yl)vinyl]phenyl]-2,6-dimethyl-pyridazin-3-one (45 mg, 16% yield).

##STR00044##

[0166] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 2.20 (s, 3H) 3.76 (s, 3H) 4.70 (d, J=5.3 Hz, 2H) 6.53 (t, J=2.1 Hz, 1H) 6.78-6.86 (m, 1H) 6.88-6.94 (m, 1H) 7.01 (t, J=8.6 Hz, 1H) 7.12-7.17 (m, 2H) 7.19 (t, J=2.8 Hz, 1H) 7.21-7.25 (m, 1H) 7.29-7.35 (m, 4H) 7.47 (dd, J=8.9, 5.3 Hz, 1H) 7.55 (s, 1H) 8.25-8.44 (m, 1H).

2.4 4-[3-chloro-6-fluoro-2-[2-(1H-indol-5-yl)ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (A-1.021)

[0167] 5-benzyloxy-4-[3-chloro-6-fluoro-2-[(E)-2-(1H-indol-5-yl)vinyl]phenyl]-2,6-dimethyl-pyridazin-3-one (45 mg, 0.09 mmol) was subjected to catalytic hydrogenation in tetrahydrofuran (0.23 mL) over 5% Pd/C catalyst (38 mg×2) at 3 bar H.sub.2.

[0168] Upon completion, the reaction mixture was filtered through a pad of Celite@, eluting with DCM. The filtrate was concentrated in-vacuo to afford a crude residue.

[0169] The residue was adsorbed onto silica and purified by flash column chromatography (silica, eluent ethyl acetate/iso-hexane) to give 4-[3-chloro-6-fluoro-2-[2-(1H-indol-5-yl)ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (24 mg, 65% yield, A-1.021).

##STR00045##

[0170] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 2.18 (s, 3H) 2.70-2.96 (m, 4H) 3.69 (s, 3H) 6.44 (ddd, J=3.0, 2.0, 0.7 Hz, 1H) 6.78 (dd, J=8.3, 1.6 Hz, 1H) 6.89 (t, J=8.6 Hz, 1H) 7.14-7.18 (m, 1H) 7.18-7.26 (m, 2H) 7.37 (dd, J=8.8, 5.14 Hz, 1H) 8.21 (br s, 1H).

Example 3 Preparation of 4-[3-chloro-6-fluoro-2-[2-(3-methylbenzotriazol-5-yl)ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (1.343)

[0171] ##STR00046##

3.1 [5-[3-Chloro-6-fluoro-2-[(E)-2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate

[0172] [5-(2-Bromo-3-chloro-6-fluoro-phenyl)-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methyl-propanoate (5.00 g, 11.97 mmol, 1.0 eq), 6-methyl-2-vinyl-1,3,6,2-dioxazaborocane-4,8-dione (2.63 g, 14.36 mmol, 1.2 eq) and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(II) (307 mg, 0.60 mmol, 0.05 eq) were charged into a 250 ml round bottom flask fitted with a condenser, stirrer bar and nitrogen bubbler. THE (100 mL) was added followed by N,N-diisopropylethylamine (4.2 mL, 23.94 mmol, 2.0 eq) against a flow of nitrogen and the mixture heated to reflux for 3 h.

[0173] The reaction mixture was allowed to cool to room temperature then diluted in DCM and filtered through Celite®, washing with further portions of DCM. The eluent was then concentrated to dryness.

[0174] The crude product purified by flash column chromatography to afford [5-[3-chloro-6-fluoro-2-[(E)-2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (5.91 g, 11.4 mmol, 95% yield) as an off white solid.

##STR00047##

[0175] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.63 (dd, J=5.1, 8.9 Hz, 1H), 7.31 (t, J=8.9 Hz, 1H), 6.65 (d, J=18.3 Hz, 1H), 5.68 (d, J=18.3 Hz, 1H), 4.24 (dd, J=11.9, 17.2 Hz, 2H), 3.95-3.83 (m, 2H), 3.70 (s, 3H), 2.66 (spt, J=7.0 Hz, 1H), 2.16 (s, 3H), 0.90 (d, J=7.0 Hz, 3H), 0.89 (d, J=7.0 Hz, 3H)

3.2 [5-[3-chloro-6-fluoro-2-[(E)-2-(3-methylbenzotriazol-5-yl)vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (4.343)

[0176] [5-[3-Chloro-6-fluoro-2-[(E)-2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (700 mg, 1.35 mmol), 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex [PdCl.sub.2(dppf).DCM] (55 mg, 0.067 mmol), 6-bromo-1-methyl-benzotriazole (371 mg, 1.75 mmol) and potassium phosphate (1.17 g, 5.39 mmol) were added to a 10-20 ml microwave vial. 2-methyltetrahydrofuran (10 ml) and water (0.5 ml) were added then the reaction mixture degassed by evacuation and back-filling with nitrogen (×3). The reaction mixture was heated 120° C. for 60 mins under microwave irradiation.

[0177] The reaction mixture was filtered through a plug of Celite®, washing through with EtOAc & EtOH. The filtrate was concentrated under reduced pressure to give a brown gum (853 mg). The crude material was purified by automated flash chromatography on silica gel eluting with a cyclohexane/ethyl acetate gradient to give [5-[3-chloro-6-fluoro-2-[(E)-2-(3-methylbenzotriazol-5-yl)vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (4.343) as an orange gum (622 mg, 87% yield)

[0178] The purified material was dissolved in acetonitrile (10 ml) and treated with SiliCycle SiliaMetS® Thiol (SH) metal scavenger resin (622 mg) at room temperature. The suspension was stirred at room temperature for 1.5 h, then filtered to remove the resin, washing with further acetonitrile. The filtrate was concentrated in vacuo to provide [5-[3-chloro-6-fluoro-2-[(E)-2-(3-methylbenzotriazol-5-yl)vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (4.343) as a white solid (583 mg, 87% yield)

##STR00048##

[0179] .sup.1H NMR (400 MHz, chloroform) 7.96 (d, J=9.0 Hz, 1H), 7.39-7.49 (m, 3H), 7.15 (d, J=16.3 Hz, 1H), 7.05 (t, J=8.7 Hz, 1H), 6.81 (d, J=16.3 Hz, 1H), 4.29 (s, 3H), 3.68 (s, 3H), 2.67(spt, J=7.0 Hz, 1H), 2.23 (s, 3H), 1.13 (d, J=7.0 Hz, 3H), 1.09 (d, J=7.0 Hz, 3H)

3.3 [5-[3-chloro-6-fluoro-2-[2-(3-methylbenzotriazol-5-yl)ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate

[0180] [5-[3-chloro-6-fluoro-2-[(E)-2-(3-methylbenzotriazol-5-yl)vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (496 mg, 1.00 mmol) was subjected to catalytic hydrogenation in EtOAc (10 mL) over 5% Pd/C (50% wet) catalyst (0.21 g) at 3 bar H.sub.2 for 18 h.

[0181] The reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate. The filtrate was concentrated in-vacuo to afford a crude residue (503 mg) which was purified by mass-directed reverse-phase HPLC to afford [5-[3-chloro-6-fluoro-2-[2-(3-methylbenzotriazol-5-yl)ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate as a colourless gum (332 mg, 67% yield)

##STR00049##

[0182] .sup.1H NMR (400 MHz, chloroform) δ=7.92 (d, J=8.6 Hz, 1H), 7.43 (dd, J=5.1, 8.7 Hz, 1H), 7.24 (br s, 1H), 7.17 (dd, J=1.3, 8.6 Hz, 1H), 7.01 (t, J=8.7 Hz, 1H), 4.26 (s, 3H), 3.81 (s, 3H), 3.11-2.91 (m, 3H), 2.86-2.72 (m, 1H), 2.54 (spt, J=7.0 Hz, 1H), 2.25 (s, 3H), 0.98 (d, J=7.1 Hz, 3H), 0.96 (d, J=7.0 Hz, 3H)

3.4 Preparation of 4-[3-chloro-6-fluoro-2-[2-(3-methylbenzotriazol-5-yl)ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (1.343)

[0183] [5-[3-chloro-6-fluoro-2-[2-(3-methylbenzotriazol-5-yl)ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (332 mg, 0.67 mmol) was) stirred in ethanol (5 ml) at room temperature. A solution of lithium hydroxide monohydrate (85 mg, 2.00 mmol) in water (2 ml) was added dropwise and the reaction stirred at room temperature for 21 h.

[0184] The ethanol solvent was removed under reduced pressure, then residue diluted with water (20 ml). The aqueous phase was acidified to ˜pH 3-4 by the addition of 2M HCl (aq.), then extracted with EtOAc (3×10 ml). The combined organic extracts were concentrated under reduced pressure to give a white solid (240 mg). The crude residue was purified by automated flash chromatography on silica, eluting with a cyclohexane/ethyl acetate gradient to afford 4-[3-chloro-6-fluoro-2-[2-(3-methylbenzotriazol-5-yl)ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (1.343) as a white solid (196 mg, 69%)

##STR00050##

[0185] .sup.1H NMR (400 MHz, acetonitrile) δ ppm 7.83 (d, J=8.6 Hz, 1H), 7.57 (dd, J=5.2, 8.8 Hz, 1H), 7.33 (s, 1H), 7.10-7.18 (m, 2H), 4.22 (s, 3H), 3.64 (s, 3H), 2.84-3.07 (m, 4H) 2.21 (s, 3H)

Example 4 Preparation of 4-[2-[2-(1,3-benzothiazol-5-yl)ethyl]-3-chloro-6-fluoro-phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (1.350)

[0186] ##STR00051##

4.1 4-[2-[(E)-2-(1,3-benzothiazol-5-yl)vinyl]-3-chloro-6-fluoro-phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one

[0187] [5-[3-chloro-6-fluoro-2-[(E)-2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (500 mg, 0.96 mmol), 5-bromo-1,3-benzothiazole (309 mg, 1.44 mmol) 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex [PdCl2(dppf).DCM] (4 mg, 0.05 mmol) and POTASSIUM CARBONATE (403 mg, 2.89 mmol) were added to a 10-20 ml microwave vial under an atmosphere of nitrogen. De-gassed acetonitrile (8 ml) and water (2 ml) were added and the mixture heated to 150° C. for 30 min under microwave irradiation.

[0188] The reaction mixture was concentrated to dryness. The residue was treated with water (10 ml) and the aqueous phase acidified to pH 4 by addition of 1 M HCl (aq.). DCM (20 ml) was added and the layers separated. The aqueous phase was further extracted with DCM/MeOH (8:1) (2×10 ml), then the combined organic extracts were dried and concentrated to give a brown oil. The crude material was purified by automated flash chromatography on silica gel, eluting with a cyclohexane/ethyl acetate gradient to give 4-[2-[(E)-2-(1,3-benzothiazol-5-yl)vinyl]-3-chloro-6-fluoro-phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one as a white solid (302 mg, 73% yield).

[0189] The obtained product was dissolved in a 3:2 mixture of methanol/ethyl acetate (25 ml). The solution was treated with activated charcoal (100 mg) then stirred at rt for 1 h. The mixture was filtered through Celite®, then washed through with additional 3:2 MeOH/EtOAc (10 ml). The filtrate was treated with SiliCycle SiliaMetS® Thiol (SH) metal scavenger resin (300 mg) then stirred at rt for 16 h. The mixture was filtered to remove the resin, then the filtrate concentrated in vacuo to give an off white solid (286 mg).

##STR00052##

[0190] .sup.1H NMR (400 MHz, DMSO-d6) δ=10.84 (br s, 1H), 9.41 (s, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.00 (d, J=1.5 Hz, 1H), 7.62 (dd, J=5.1, 8.7 Hz, 1H), 7.54 (dd, J=1.5, 8.4 Hz, 1H), 7.29 (t, J=8.7 Hz, 1H), 7.09 (d, J=16.5 Hz, 1H), 6.74 (d, J=16.5 Hz, 1H), 3.54 (s, 3H), 2.18 (s, 3H)

4.2 4-[2-[2-(1,3-benzothiazol-5-yl)ethyl]-3-chloro-6-fluoro-phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (1.350)

[0191] To a solution of 4-[2-[(E)-2-(1,3-benzothiazol-5-yl)vinyl]-3-chloro-6-fluoro-phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (835 mg, 1.95 mmol) in tetrahydrofuran (30 ml) under a nitrogen atmosphere, was added N,N-Diisopropylethylamine (2.70 ml, 16.0 mmol). The stirred reaction mixture was heated to 70° C. and 2,4,6-Triisopropylbenzenesulfonyl hydrazide (5.17 g, 15.6 mmol) was added portionwise over 4 h then the mixture heated to reflux for 16 h. Additional N,N-Diisopropylethylamine (1.70 ml, 9.80 mmol) was added to the reaction mixture, followed by 2,4,6-Triisopropylbenzenesulfonyl hydrazide (3.24 g, 9.77 mmol) and the mixture heated to reflux for a further 6 h.

[0192] The reaction mixture was allowed to cool to room temperature, then concentrated directly onto silica. The crude material was partially purified by automated flash chromatography on silica gel eluting with a cyclohexane/ethyl acetate gradient. The material obtained was further purified by mass-directed reverse-phase HPLC to afford 4-[3-chloro-6-fluoro-2-[2-[4-(methylsulfanylmethyl)phenyl]ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (1.350) as a pale yellow solid (227 mg, 27% yield)

##STR00053##

[0193] 1HNMR (500 MHz, DMSO-d6) δ ppm 10.84 (br. s, 1H), 9.35 (s, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.71 (d, J=1.0 Hz, 1H), 7.55 (dd, J=5.2, 8.8 Hz, 1H), 7.23 (t, J=8.8 Hz, 1H), 7.16 (dd, J=1.0, 8.3 Hz, 1H), 3.62 (s, 3H), 2.93-2.70 (m, 4H), 2.26 (s, 3H)

Example 5 Preparation of [3-chloro-2-[2-(2,2-dimethyl-1,3-benzodioxol-5-yl)ethyl]-6-fluoro-phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (1.361)

[0194] ##STR00054##

5.1 [5-[3-Chloro-6-fluoro-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate

[0195] An oven-dried round-bottom flask was then charged with Ir(COD)Cl.sub.2 (299 mg, 0.45 mmol) and 4-diphenylphosphanylbutyl(diphenyl)phosphane (0380 mg, 0.89 mmol). The flask was evacuated and backfilled with nitrogen (×3), then THE (75 mL) was added and the reaction was stirred at room temperature for 30 mins. A solution of [5-(3-chloro-6-fluoro-2-vinyl-phenyl)-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate [prepared as described in Example 4] (6.7 g, 17.8 mmol) in THE was added dropwise and the mixture was stirred for 10 mins, followed by the dropwise addition of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.02 mL, 20.8 mmol). The reaction was stirred at 60° C. overnight.

[0196] After 24 h, the reaction was allowed to cool to room temperature then concentrated in vacuo. The crude product was purified by column chromatography on silica gel, eluting with a cyclohexane/ethylacetate gradient, to give [5-[3-chloro-6-fluoro-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (4.50 g, 51% yield) as a yellow solid.

##STR00055##

[0197] .sup.1H NMR (500 MHz, chloroform) δ=7.35 (dd, J=5.2, 8.9 Hz, 1H), 6.90 (t, J=8.6 Hz, 1H), 3.81 (s, 3H), 2.59 (t, J=8.5 Hz, 2H), 2.53 (spt, J=7.0 Hz, 1H), 2.24 (s, 3H), 1.32-1.16 (m, 12H), 1.08-1.00 (m, 2H), 0.98 (d, J=7.0 Hz, 3H), 0.94 (d, J=7.0 Hz, 3H).

5.2 [3-chloro-2-[2-(2,2-dimethyl-1,3-benzodioxol-5-yl)ethyl]-6-fluoro-phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (1.361)

[0198] 5-bromo-2,2-dimethyl-1,3-benzodioxole (70 mg, 0.30 mmol) was charged into a 2-5 ml microwave vial. [5-[3-chloro-6-fluoro-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (100 mg, 0.20 mmol) was added as a solution in 1,4-dioxane (2 ml), followed by chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (RuPhos Pd-G2) (26 mg, 0.03 mmol) as a solution in 1,4-dioxane (2 ml). A 2 M aqueous solution of potassium carbonate (0.30 ml, 0.61 mmol) was added and the mixture heated to 140° C. for 80 min under microwave irradiation.

[0199] The reaction mixture was cooled to room temperature then filtered through a pre-wetted 0.5 g Silica-TMT cartridge, washing through with acetonitrile (2×2 ml). The filtrate was concentrated to dryness, then purified by mass-directed reverse-phase HPLC to afford [3-chloro-2-[2-(2,2-dimethyl-1,3-benzodioxol-5-yl)ethyl]-6-fluoro-phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (1.361) as a white solid (15 mg, 17% yield).

##STR00056##

[0200] .sup.1H NMR (500 MHz, chloroform) δ ppm 7.43 (dd, J=5.2, 8.7 Hz, 1H), 6.99 (t, J=8.7 Hz, 1H), 6.56 (d, J=7.7 Hz, 1H), 6.40-6.36 (m, 2H), 3.74 (s, 3H), 2.85-2.78 (m, 1H), 2.77-2.61 (m, 3H), 2.30 (s, 3H), 1.65 (s, 3H), 1.64 (s, 3H)

[0201] Compounds 1.019, 1.021, 1.027, 1.028, 1.036, 2.034, 3.030, 3.034, 4.034, 1.339, 1.340, 1.341, 1.342, 1.344, 1.345, 1.346, 1.347, 1.348, 1.349, 1.351, 1.352, 1.353, 1.354, 1.355, 1.356, 1.044, 1.053, 1.357, 1.358, 1.359, 1.360, 2.362, 2.363, and 4.342 were prepared using the general methods as described supra. Table 5 below shows the structure of these compounds and NMR characterising data.

TABLE-US-00003 TABLE 5 Preparation examples of compounds of formula (I). The numbering system used to describe the positions of X and Y is shown for the purposes of clarity only. (I) [00057] Cmpd No. R.sup.1 R.sup.2 G X Y W D NMR details 1.019 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 1,2,3,4- .sup.1H NMR (400 MHz, tetrahydroquinolin- chloroform) δ ppm 1.91 6-yl- (br d, J = 5.26 Hz, 3 H) 2.30 (s, 3 H) 2.50-2.84 (m, 5 H) 3.19-3.30 (m, 2 H) 3.46 (s, 1 H) 3.73 (s, 3 H) 6.35 (d, J = 8.56 Hz, 1 H) 6.57-6.65 (m, 2 H) 6.97 (t, J = 8.56 Hz, 1 H) 7.41 (dd, J = 8.80, 5.14 Hz, 1 H) 1.021 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 1H-indol-5-yl- .sup.1H NMR (400 MHz, chloroform) δ ppm 2.18 (s, 3 H) 2.70-2.96 (m, 4 H) 3.69 (s, 3 H) 6.44 (ddd, J = 3.00, 2.02, 0.73 Hz, 1 H) 6.78 (dd, J = 8.31, 1.59 Hz, 1 H) 6.89 (t, J = 8.56 Hz, 1 H) 7.14-7.18 (m, 1 H) 7.18- 7.26 (m, 2 H) 7.37 (dd, J = 8.80, 5.14 Hz, 1 H) 8.21 (br s, 1 H) 1.027 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 2-(trifluoromethyl)- .sup.1H NMR (400 MHz, 4-quinolyl- chloroform) δ ppm 2.28 (s, 3 H) 2.81-2.94 (m, 1 H) 3.01 (br d, J = 6.11 Hz, 1 H) 3.35 (s, 2 H) 3.75 (s, 3 H) 7.04 (t, J = 8.56 Hz, 1 H) 7.42-7.49 (m, 2 H) 7.58 (ddd, J = 8.31, 6.97, 1.10 Hz, 1 H) 7.79 (ddd, J = 8.41, 6.94, 1.28 Hz, 1 H) 7.86 (d, J = 8.07 Hz, 1 H) 8.20 (d, J = 8.56 Hz, 1 H) 1.028 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 2-ethyl-1,3- .sup.1H NMR (400 MHz, benzoxazol-6-yl- methanol) δ = 7.49 (dd, J = 5.3, 8.8 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 1.2 Hz, 1H), 7.08 (t, J = 8.8 Hz, 1H), 7.02 (dd, J = 1.2, 8.3 Hz, 1H), 3.73 (s, 3H), 2.96 (q, J = 7.6 Hz, 2H), 2.91- 2.74 (m, 4H), 2.33 (s, 3H), 1.42 (t, J = 7.6 Hz, 3H) 1.036 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 4-quinolyl- .sup.1H NMR (400 MHz, chloroform) δ ppm 2.28 (s, 3 H) 2.88-3.02 (m, 2 H) 3.24 (ddd, J = 19.47, 10.48, 6.24 Hz, 2 H) 3.74 (s, 3 H) 7.00 (t, J = 8.56 Hz, 1 H) 7.17 (d, J = 4.52 Hz, 1 H) 7.38- 7.51 (m, 2 H) 7.64-7.79 (m, 2 H) 8.03 (d, J = 8.19 Hz, 1 H) 8.65 (d, J = 4.40 Hz, 1 H) 2.034 —Me —Me —H 6-F 3-Cl (E)- 2-methyl-6- .sup.1H NMR (400 MHz, CH═CH— quinolyl- Solvent) δ ppm 1.11 (t, J = 7.15 Hz, 6 H) 2.23 (s, 3 H) 2.63-2.71 (m, 1 H) 2.74 (s, 3 H) 3.69 (s, 3 H) 6.81 (d, J = 16.38 Hz, 1 H) 7.04 (t, J = 8.68 Hz, 1 H) 7.15 (d, J = 16.51 Hz, 1 H) 7.27 (s, 1 H) 7.45 (dd, J = 8.86, 5.07 Hz, 1 H) 7.63 (d, J = 1.71 Hz, 1 H) 7.75-7.81 (m, 1 H) 7.94 (d, J = 8.80 Hz, 1 H) 8.01 (d, J = 8.31 Hz, 1 H) 3.030 —Me —Me —(C═O)iPr 6-F 3-Cl —CH.sub.2—CH.sub.2— 2-methyl-1,2,3,4- .sup.1H NMR (400 MHz, tetrahydroquinolin- Solvent) δ ppm 0.96 (dd, 6-yl- J = 7.03, 2.02 Hz, 6 H) 1.25 (d, J = 6.24 Hz, 3 H) 1.58-1.69 (m, 1 H) 1.90- 1.98 (m, 1 H) 2.24 (s, 3 H) 2.54 (dt, J = 13.94, 6.97 Hz, 1 H) 2.63-2.84 (m, 6 H) 3.39 (td, J = 6.51, 3.12 Hz, 1 H) 3.83 (s, 3 H) 6.52 (br d, J = 6.48 Hz, 1 H) 6.72- 6.79 (m, 2 H) 6.96 (t, J = 8.62 Hz, 1 H) 7.40 (dd, J = 8.80, 5.14 Hz, 1 H) 3.034 —Me —Me —(C═O)iPr 6-F 3-Cl —CH.sub.2—CH.sub.2— 2-methyl-6- .sup.1H NMR (400 MHz, quinolyl- Solvent) δ ppm 0.97 (dd, J = 6.97, 4.40 Hz, 6 H) 2.24 (s, 3 H) 2.47-2.57 (m, 1 H) 2.73 (s, 3 H) 2.79-3.09 (m, 4 H) 3.84 (s, 3 H) 7.00 (t, J = 8.62 Hz, 1 H) 7.25 (d, J = 8.31 Hz, 1 H) 7.49 (d, J = 1.10 Hz, 3 H) 7.90 (d, J = 8.44 Hz, 1 H) 7.96 (d, J = 8.31 Hz, 1 H) 4.034 —Me —Me —(C═O)iPr 6-F 3-Cl (E)- 2-methyl-6- .sup.1H NMR (400 MHz, CH═CH— quinolyl- Solvent) δ ppm 2.24 (s, 3 H) 2.66 (s, 3 H) 3.66 (s, 3 H) 6.72 (d, J = 16.38 Hz, 1 H) 6.93-7.07 (m, 2 H) 7.26 (s, 1 H) 7.38 (dd, J = 8.93, 5.14 Hz, 1 H) 7.55 (d, J = 1.71 Hz, 1 H) 7.66 (dd, J = 8.80, 1.96 Hz, 1 H) 7.84 (d, J = 8.80 Hz, 1 H) 7.99 (d, J = 8.44 Hz, 1 H) 1.339 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 2-methyl-5-1,3- .sup.1H NMR (500 MHz, benzothiazolyl- chloroform) δ ppm 7.64 (d, J = 8.1 Hz, 1H), 7.52 (br s, 1H), 7.19 (dd, J = 5.1, 8.6 Hz, 1H), 7.01 (br d, J = 8.1 Hz, 1H), 6.92 (t, J = 8.6 Hz, 1H), 3.80 (s, 3H), 2.90-2.74 (m, 4H), 2.69 (s, 3H), 2.32 (s, 3H) 1.340 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 2,2-dimethyl-6- .sup.1H NMR (400 MHz, 3H-benzofuranyl- methanol) δ ppm 7.50 (dd, J = 5.1, 8.8 Hz, 1H), 7.08 (t, J = 8.8 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.44 (dd, J = 1.2, 7.5 Hz, 1H), 6.29 (d, J = 1.2 Hz, 1H), 3.73 (s, 3H), 2.93 (s, 2H), 2.79-2.50 (m, 4H), 2.33 (s, 3H), 1.41 (s, 6H) 1.341 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 2-methyl-6-1,3- .sup.1H NMR (400 MHz, benzoxazolyl- DMSO-d6) δ ppm 10.83 (br.s, 1H), 7.54 (dd, J = 5.2, 8.9 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 1.4 Hz, 1H), 7.22 (t, J = 8.9 Hz, 1H), 6.96 (dd, J = 1.4, 8.1 Hz, 1H), 3.61 (s, 3H), 2.87- 2.66 (m, 4H) ,2.57 (s, 3H), 2.25 (s, 3H) 1.342 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 2,2-difluoro-5-1,3- .sup.1H NMR (400 MHz, benzodioxolyl- chloroform) δ ppm 7.38 (dd, J = 8.8, 5.1 Hz, 1H), 6.94 (t, J = 8.8 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.70-6.63 (m, 2H), 3.68 (s, 3H), 2.76-2.65 (m, 4H), 2.26 (s, 3H) 1.344 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 1-methyl-3- .sup.1H NMR (400 MHz, indazolyl- DMSO-d6) δ ppm 10.86 (s, 1H), 7.59- 7.53 (m, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.27- 7.21 (m, 2H), 7.02 (t, J = 7.2 Hz, 1H), 3.93 (s, 3H), 3.58 (s, 3H), 2.99- 2.92 (m, 2H), 2.87-2.83 (m, 2H), 2.23 (s. 3H) 1.345 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 1-methyl-5- .sup.1H NMR (400 MHz, pyrrolo[2,3- methanol) δ ppm 8.12 b]pyridinyl- (d, J = 1.7 Hz, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.52 (d, J = 3.5 Hz, 1H), 7.46 (dd, J = 5.1, 8.8 Hz, 1H), 7.10 (t, J = 8.8 Hz, 1H), 6.64 (d, J = 3.5 Hz, 1H), 3.93 (s, 3H), 3.63 (s, 3H), 3.11-2.99 (m, 2H), 2.98-2.82 (m, 2H), 2.30 (s, 3H) 1.346 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 5-benzofuranyl- .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (s, 1H), 7.93 (d, J = 1.8 Hz,1H), 7.57-7.53 (m, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.28 (br. s, 1H), 7.21 (t, J = 8.5 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.87 (br. s, 1H), 3.61 (s, 3H), 2.76-2.67 (m, 4H), 2.25 (s, 3H) 1.347 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 6- .sup.1H NMR (400 MHz, benzothiophenyl- DMSO-d6) δ ppm 10.83 (s, 1H), 7.87 (d, J = 8.24 Hz, 1H), 7.72 (d, J = 5.4 Hz,1H), 7.58- 7.54 (m, 1H), 7.52 (s, 1H), 7.37 (d, J = 5.4 Hz, 1H), 7.22 (t, J = 8.8 Hz, 1H), 7.00 (d, J = 8.24 Hz, 1H), 3.61 (s, 3H), 2.79- 2.69 (m, 4H), 2.25 (s. 3H) 1.348 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 5- .sup.1H NMR (400 MHz, benzothiophenyl- DMSO-d6) δ ppm 10.83 (s, 1H), 7.86 (m, 1H), 7.72 (m, 1H), 7.58- 7.52 (m, 2H), 7.37 (m, 1H), 7.22 (m, 1H), 7.01- 6.98 (m, 1H), 3.61 (s, 3H), 2.79-2.71 (m, 4H), 2.25 (s, 3H) 1.349 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 6-1,3- .sup.1H NMR (400 MHz, benzothiazolyl- DMSO-d6) δ ppm 10.81 (s, 1H), 9.30 (s, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.81 (s, 1H), 7.57-7.53 (m, 1H), 7.24-7.16 (m, 2H), 3.59 (s, 3H), 2.82- 2.73 (m, 4H), 2.24 (s. 3H) 1.351 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 3-methyl-6-1,2- .sup.1H NMR (400 MHz, benzoxazolyl- DMSO-d6) δ ppm 10.81 (s, 1H), 7.70 (d, J = 8.04 Hz, 1H), 7.54 (m, 1H), 7.29 (s, 1H), 7.21 (t, J = 8.7 Hz, 1H), 7.01 (d, J = 8.04 Hz, 1H), 3.60 (s, 3H), 2.86-2.73 (m, 4H), 2.50 (s, 3H), 2.24 (s. 3H) 1.352 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 5-2-oxo-3H-1,3- .sup.1H NMR (400 MHz, benzoxazolyl- methanol) δ ppm 7.49 (dd, J = 5.1, 8.8 Hz, 1H), 7.09 (t, J = 8.8 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.74 (dd, J = 1.5, 8.2 Hz, 1H), 6.71 (d, J = 1.5 Hz, 1H), 3.72 (s, 3H), 2.88- 2.65 (m, 4H), 2.32 (s, 3H) 1.353 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 6-1- .sup.1H NMR (400 MHz, methylindazolyl- methanol) δ ppm 7.90 (d, J = 1.0 Hz, 1H), 7.58 (dd, J = 0.6, 8.3 Hz, 1H), 7.51 (dd, J = 5.1, 8.8 Hz, 1H), 7.10 (br. s, 1H), 7.11 (t, J = 8.8 Hz, 1H), 6.81 (dd, J = 1.0, 8.3 Hz, 1H), 3.98 (s, 3H), 3.68 (s, 3H), 2.99-2.77 (m, 4H), 2.27 (s, 3H) 1.354 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 5-1- .sup.1H NMR (400 MHz, methylindazolyl- methanol) 7.86 (s, 1H), 7.49 (dd, J = 5.1, 8.8 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.35 (s, 1H), 7.09 (t, J = 8.8 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 4.00 (s, 3H), 3.70 (s, 3H), 2.92-2.74 (m, 4H), 2.30 (s, 3H) 1.355 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 6-1-methylindolyl- .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (s, 1H), 7.58- 7.55 (m, 1H), 7.40 (d,1H), 7.23-7.20 (m, 2H), 6.93 (s, 1H), 6.66 (d, 1H), 6.33 (d, 1H), 3.71 (s, 3H), 3.62 (s, 3H), 2.76-2.68 (m, 4H), 2.26 (s, 3H) 1.356 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 5-1-methylindolyl- .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1H), 7.57- 7.54 (m, 1H), 7.33-7.29 (m, 1H), 7.26 (d, 1H), 7.21 (t, 1H), 7.15 (s, 1H), 6.76 (d, 1H), 6.31 (d, 1H), 3.73 (s, 3H), 3.61 (s, 3H), 2.72-2.64 (m, 4H), 2.27 (s, 3H) 1.044 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 1-naphthyl- .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 10.96 (s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.63-7.59 (m, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.44-7.36 (m, 2H), 7.28-7.23 (m, 2H), 3.64 (s, 3H), 3.12-3.03 (m, 2H), 2.80-2.72 (m, 2H), 2.28 (s. 3H) 1.053 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 2-naphthyl- .sup.1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (s, 1H), 7.86- 7.78 (m, 3H), 7.58-7.55 (m, 1H), 7.51-7.42 (m, 3H), 7.23 (t, J = 8.7 Hz, 1H), 7.16-7.14 (1H), 3.61 (s, 3H), 2.88-2.72 (m, 4H), 2.25 (s, 3H) 1.357 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 5-2-oxoindolinyl- .sup.1HNMR (400 MHz, DMSO-d6) 10.82 (br. s, 1H), 10.28 (s, 1H), 7.55 (dd, J = 5.3, 8.7 Hz, 1H), 7.21 (t, J = 8.7 Hz, 1H), 6.85 (br. s, 1H), 6.79 (br.d, J = 7.8 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 3.61 (s, 3H), 3.40 (s, 2H), 2.73-2.52 (m, 4H), 2.26 (s, 3H) 1.358 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 2-methyl-1,3- .sup.1H NMR (500 MHz, dioxo-isoindolin-5- chloroform) δ ppm 7.68 yl- (d, J = 7.6 Hz, 1H), 7.52 (br s, 1H), 7.45 (dd, J = 5.2, 8.7 Hz, 1H), 7.39- 7.34 (m, 1H), 7.05 (t, J = 8.7 Hz, 1H), 3.78 (s, 3H), 3.15 (s, 3H), 3.04- 2.85 (m, 3H), 2.82-2.71 (m, 1H), 2.32 (s, 3H) 1.359 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 2-1,3- .sup.1H NMR (400 MHz, d6- benzoxazolyl- DMSO), δ ppm 10.81 (s, 1H), 7.65-7.57 (m, 3H), 7.36-7.30 (m, 2H), 7.28-7.23 (t, 1H), 3.53 (s, 3H), 3.09-2.99 (m, 4H), 2.19 (s, 3H) 1.360 —Me —Me —H 6-F 3-Cl —CH.sub.2—CH.sub.2— 2-1,3- .sup.1H NMR (400 MHz, benzothiazolyl DMSO-D6) δ ppm 10.85 (br. s, 1H), 8.04-8.02 (d, 1H), 7.91-7.89 (d, 1H), 7.61-7.58 (dd, 1H), 7.49-7.46 (t, 1H), 7.41- 7.37 (t, 1H), 7.28-7.23 (t, 1H), 3.57 (s, 3H), 3.26-3.13 (m, 2H), 3.07- 2.92 (m, 2H), 2.21 (s, 3H) 2.362 —Me —Me —H 6-F 3-Cl (E)- 6-2,2-dimethyl- .sup.1H NMR (400 MHz, CH═CH— 3H-benzofuranyl- methanol) 7.52 (dd, J = 5.1, 8.8 Hz, 1H), 7.12 (t, J = 8.8 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 16.4 Hz, 1H), 6.70 (dd, J = 1.3, 7.6 Hz, 1H), 6.62 (s, 1H), 6.47 (d, J = 16.4 Hz, 1H), 3.66 (s, 3H), 2.97 (s, 2H), 2.26 (s, 3H), 1.42 (s, 6H) 2.363 —Me —Me —H 6-F 3-Cl (E)- 6-imidazo[1,2- .sup.1H NMR (400 MHz, CH═CH— a]pyrazinyl- DMSO-d6) 10.83 (br. s, 1H), 9.06 (s, 1H), 8.55 (d, J = 1.1 Hz, 1H), 8.07 (s, 1H), 7.79 (d, J = 1.1 Hz, 1H), 7.63 (dd, J = 5.3, 8.8 Hz, 1H), 7.48 (d, J = 15.9 Hz, 1H), 7.28 (t, J = 8.8 Hz, 1H), 6.65 (d, J = 15.9 Hz, 1H), 3.56 (s, 3H), 2.20 (s, 3H) 4.342 —Me —Me —(C═O)iPr 6-F 3-Cl (E)- 2,2-difluoro-5-1,3- .sup.1H NMR (400 MHz, CH═CH— benzodioxolyl- chloroform) δ = 7.43 (dd, J = 5.1, 8.9 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H), 7.05-6.95 (m, 3H), 6.91 (d, J = 16.5 Hz, 1H), 6.60 (d, J = 16.5 Hz, 1H), 3.71 (s, 3H), 2.64 (spt, J = 7.0 Hz, 1H), 2.23 (s, 3H), 1.10 (d, J = 7.0 Hz, 3H), 1.07 (d, J = 7.0 Hz, 3H)

BIOLOGICAL EXAMPLES

B1 Post-Emergence Efficacy—Test 1

[0202] Seeds of a variety of test species are sown in standard soil in pots:— Solanum nigrum (SOLNI), Amaranthus retoflexus (AMARE), Setaria faberi (SETFA), Echinochloa crus-galli (ECHCG), Ipomoea hederacea (IPOHE), Lolium perenne (LOLPE). 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 (polyoxyethylene sorbitan monolaurate, CAS RN 9005-64-5). Compounds are applied at 250 g/ha. 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, the test is evaluated for the percentage damage caused to the plant. The biological activities are assessed on a five point scale (5=80-100%; 4=60-79%; 3=40-59%; 2=20-39%; 1=0-19%). A blank value in the table is indicative that the compound was not tested on that species.

TABLE-US-00004 TABLE 6 Control of weed species by compounds of formula (I) after post-emergence application Com- pound AMARE SOLNI SETFA LOLPE ECHCG IPOHE 1.019 4 5 5 5 3 5 1.027 2 4 4 4 5 1.028 5 5 5 5 5 5 1.036 5 5 5 5 5 5 2.034 1 5 2 2 3 3.030 5 5 5 5 5 5 3.034 4 5 5 5 4 4 4.034 1 5 2 1 3 1.357 5 5 5 5 4 5 4.342 0 4 1 2 1 3

B2 Post-Emergence Efficacy—Test 2

[0203] Seeds of a variety of test species are sown in standard soil in pots:— Amaranthus retoflexus (AMARE), Setaria faberi (SETFA), Echinochloa crus-galli (ECHCG), Ipomoea hederacea (IPOHE), Zea Mays (ZEAMX), Abutilon theophrasti (ABUTH). 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 (polyoxyethylene sorbitan monolaurate, CAS RN 9005-64-5). Compounds are applied at 250 g/ha. 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, the test is evaluated for the percentage damage caused to the plant. The biological activities are assessed on a five point scale (5=80-100%; 4=60-79%; 3=40-59%; 2=20-39%; 1=0-19%). A blank value in the table is indicative that the compound was not tested on that species.

TABLE-US-00005 TABLE 7 Control of weed species by compounds of formula (I) after post-emergence application Com- pound AMARE ZEAMX SETFA ABUTH ECHCG IPOHE 1.339 4 0 4 3 5 4 1.340 5 5 5 5 5 4 1.341 5 4 4 5 5 5 1.342 5 4 4 5 5 5 1.318 4 2 5 4 4 4 1.344 3 1 4 2 3 1.345 4 2 4 4 3 4 1.346 2 2 0 4 4 3 1.347 4 4 4 4 4 4 1.348 4 4 4 3 4 4 1.349 4 2 4 4 4 4 1.350 4 3 4 5 4 3 1.351 5 5 4 5 4 5 1.352 4 3 4 4 4 3 1.353 4 3 4 4 4 3 1.354 4 4 4 4 5 4 1.355 4 1 2 3 1 4 1.356 5 2 5 4 4 4 1.044 3 1 0 3 0 4 1.053 4 4 4 3 3 4 1.357 2 5 4 4 4 1.359 3 1 3 4 3 2 1.361 3 4 5 5 4 5 2.363 1 0 0 0 0 2

B3 Pre-Emergence Efficacy—Test 1

[0204] Seeds of a variety of test species were sown in standard soil in pots: Solanum nigrum (SOLNI), Amaranthus retoflexus (AMARE), Setaria faberi (SETFA), Echinochloa crus-galli (ECHCG), Ipomoea hederacea (IPOHE), Lolium perenne (LOLPE). After cultivation for one day (pre-emergence) under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity), the plants were 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. The test plants were then grown in a glasshouse under controlled conditions (at 24/16° C., day/night; 14 hours light; 65% humidity) and watered twice daily. After 13 days, the test is evaluated for the percentage damage caused to the plant. The biological activities are assessed on a five point scale (5=80-100%; 4=60-79%; 3=40-59%; 2=20-39%; 1=0-19%). A blank value in the table is indicative that the compound was not tested on that species.

TABLE-US-00006 TABLE 8 Control of weed species by compounds of formula (I) after pre-emergence application Com- pound AMARE SOLNI SETFA LOLPE ECHCG IPOHE 1.019 5 5 4 3 1 1 1.027 1 4 1 3 3 3 1.028 5 5 5 5 1 5 1.036 5 5 5 5 5 5 2.034 1 2 1 1 1 0 3.030 5 5 5 5 5 5 3.034 5 5 5 5 5 2 4.034 0 1 0 0 0 0 4.342 1 3 0 0 0 1

B4 Pre-Emergence Efficacy—Test 2

[0205] Seeds of a variety of test species were sown in standard soil in pots: Amaranthus retoflexus (AMARE), Setaria faberi (SETFA), Echinochloa crus-galli (ECHCG), Ipomoea hederacea (IPOHE), Zea Mays (ZEAMX), Abutilon theophrasti (ABUTH). After cultivation for one day (pre-emergence) under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity), the plants were 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. The test plants were then grown in a glasshouse under controlled conditions (at 24/16° C., day/night; 14 hours light; 65% humidity) and watered twice daily. After 13 days, the test is evaluated for the percentage damage caused to the plant. The biological activities are assessed on a five point scale (5=80-100%; 4=60-79%; 3=40-59%; 2=20-39%; 1=0-19%). A blank value in the table is indicative that the compound was not tested on that species.

TABLE-US-00007 TABLE 9 Control of weed species by compounds of formula (I) after pre-emergence application Com- pound AMARE ZEAMX SETFA ABUTH ECHCG IPOHE 1.339 5 1 5 4 5 2 1.340 5 3 5 5 5 5 1.341 5 4 5 5 5 5 1.342 5 1 5 4 5 1.318 5 2 5 3 5 4 1.344 3 0 2 4 2 3 1.345 5 1 5 4 2 5 1.346 3 1 0 4 0 3 1.347 5 3 3 5 2 5 1.348 5 1 3 3 4 5 1.349 5 4 5 4 5 5 1.350 5 4 5 5 5 5 1.351 5 5 5 5 5 5 1.352 5 4 5 4 3 3 1.353 5 4 5 4 5 5 1.354 4 4 5 4 5 5 1.355 3 1 1 0 0 2 1.356 3 0 1 1 1 2 1.044 2 1 0 3 0 3 1.053 4 1 2 2 2 1 1.357 4 1 4 4 4 3 1.359 5 3 5 5 5 4 1.361 4 1 5 5 3 4 2.363 5 2 4 5 5 5 1.339 1 0 1 0 1 0