Herbicides

Abstract

The present invention relates to herbicidally active pyridino-/pyrimidino-pyridine derivatives, 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, in crops of useful plants.

Claims

1. A compound of Formula (I-i) ##STR00142## or a salt thereof, wherein: R.sup.1 is selected from the group consisting of hydrogen, cyano, fluoro, chloro, methoxy-, difluoromethoxy, and trifluoromethyl; R.sup.2 is selected from the group consisting of halogen, cyano, nitro, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.6cycloalkyl, —C(O)OC.sub.1-C.sub.6alkyl, —S(O).sub.p(C.sub.1-C.sub.6alkyl), C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy and phenyl; R.sup.3 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.2-C.sub.6haloalkenyl, C.sub.1-C.sub.6alkoxyC.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.6haloalkyl- and —(CR.sup.aR.sup.b).sub.qR.sup.5; R.sup.a is hydrogen or C.sub.1-C.sub.2 alkyl; R.sup.b is hydrogen or C.sub.1-C.sub.2 alkyl; R.sup.4 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.2-C.sub.6haloalkenyl, C.sub.1-C.sub.6alkoxyC.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.6haloalkyl- and —(CR.sup.aR.sup.b).sub.qR.sup.5; R.sup.5 is —C(O)OC.sub.1-C.sub.6alkyl, —C.sub.3-C.sub.10cycloalkyl, -aryl and -heteroaryl wherein said aryl and heteroaryl are optionally substituted by 1 to 3 independent R.sup.8; or R.sup.3 and R.sup.4 together with the nitrogen to which they are attached, form a saturated or partially unsaturated 4-6 membered ring system optionally containing 1 or 2 further heteroatoms independently selected from S, O and N, wherein said ring is optionally substituted by 1 to 3 R.sup.8; R.sup.6 and R.sup.7 are independently selected from the group consisting of hydrogen and C.sub.1-C.sub.6alkyl; each R.sup.8 is independently selected from the group consisting of halogen, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6alkoxy-, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy-, cyano and S(O).sub.p(C.sub.1-C.sub.6alkyl); n is 0 or 1; p is 0, 1, or 2; and q is 0, 1, or 2; with the proviso that: (a) R.sup.3 and R.sup.4 are not both H, when R.sup.2 is methyl, n is 0, and R.sup.1 is methoxy, H, fluoro, or cyano; and (b) the compound of formula (Ia) is not (i) 2-chloro-6-(3-pyridyl)pyridine-3-amine, (ii) 2-fluoro-6-(3-pyridyl)pyridine-3-amine, (iii) 2-(difluoromethyl)-6-(3- pyridyl)pyridin-3-amine, or (iv) tert-butyl-N-[2-methyl- 6-(3-pyridyl)-3- pyridyl]-carbamate.

2. The compound of formula (I-i) according to claim 1, wherein R.sup.2 is C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, cyano, —C(O)OC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, or phenyl.

3. The compound of formula (I-i) according to claim 1, wherein R.sup.3 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, and (CR.sup.aR.sup.b).sub.qR.sup.5.

4. The compound of formula (I-i) according to claim 1, wherein R.sup.3 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl, benzyl, —(CH.sub.2)C.sub.3-C.sub.10cycloalkyl, —CH(CH.sub.3)phenyl, —CH.sub.2C(O)OC.sub.1-C.sub.6alkyl, and —CH—(CH.sub.3)C(O)OC.sub.1-C.sub.6alkyl, wherein said benzyl and phenyl are optionally substituted by one to three independent R.sup.8.

5. The compound of formula (I-i) according to claim 1, wherein R.sup.4 is hydrogen.

6. The compound of formula (I-i) according to claim 1, wherein R.sup.3 and R.sup.4 together with the nitrogen atom to which they are joined, form a saturated or partially unsaturated 5- or 6-membered ring system optionally containing from 1 or 2 further heteroatoms independently selected from S, O and N, wherein said ring is optionally substituted by 1 to 3 independent R.sup.8.

7. The compound of formula (I-i) according to claim 6, wherein R.sup.3 and R.sup.4 together with the nitrogen atom to which they are joined form a pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, triazolyl, piperidyl, morpholinyl, thiomorpholinyl, and piperazinyl ring, each optionally substituted by 1 to 3 independent R.sup.8.

8. The compound of formula (I-i) according to claim 2, wherein R.sup.3 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, and (CR.sup.aR.sup.b).sub.qR.sup.5.

9. The compound of formula (I-i) according to claim 8, wherein R.sup.1 is flourine.

10. The compound of formula (I-i) according to claim 9, wherein R.sup.4 is hydrogen.

11. The compound of formula (I-i) according to claim 10, wherein R.sup.2 is trifluoromethyl, methyl, or cyano.

12. The compound of formula (I-i) according to claim 2, wherein R.sup.3 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, phenyl, benzyl, —(CH.sub.2)C.sub.3-C.sub.10cycloalkyl, —CH(CH.sub.3)phenyl, —CH.sub.2C(O)OC.sub.1-C.sub.6alkyl, and —CH—(CH.sub.3)C(O)OC.sub.1-C.sub.6alkyl, wherein said benzyl and phenyl are optionally substituted by one to three independent R.sup.8.

13. The compound of formula (I-i) according to claim 2, wherein the compound is selected from the group consisting of: ##STR00143## ##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151##

14. The compound of formula (I-i) according to claim 13, wherein the compound is selected from the group consisting of: ##STR00152## ##STR00153##

15. The compound of formula (I-i) according to claim 13, wherein the compound is selected from the group consisting of: ##STR00154## ##STR00155## ##STR00156##

16. The compound of formula (I-i) according to claim 13, wherein the compound is selected from the group consisting of: ##STR00157## ##STR00158## ##STR00159## ##STR00160##

Description

PREPARATION EXAMPLES

(1) [Pd(IPr*)(cin)Cl] refers to the catalyst below—see Chem. Eur. J. 2012, 18, 4517

(2) ##STR00049##
Xantphos palladacycle 4th generation refers to the catalyst below—see Org. Lett. 2014, 16, 4296 and WO13184198.

(3) ##STR00050##
Xantphos palladacycle 3rd generation refers to the catalyst below—see Chem. Sci. 2014, 5, 2383 and WO13184198.

(4) ##STR00051##
RuPhos palladacycle first generation refers to the catalyst below—J. Am. Chem. Soc. 2008, 130, 6686.

(5) ##STR00052##

Example P1 Synthesis of 6-(5-fluoro-3-pyridyl)-2-(trifluoromethyl)pyridin-3-amine (Compound A33)

(6) ##STR00053##

Step 1: Synthesis of ethyl 1-oxido-2-(trifluoromethyl)pyridin-1-ium-3-carboxylate

(7) ##STR00054##

(8) To a stirred suspension of freshly ground urea hydrogen peroxide addition compound (0.099 g, 1.05 mmol) in DCM (10 mL) at 0° C. was added ethyl 2-(trifluoromethyl)pyridine-3-carboxylate (0.1 g, 0.46 mmol) followed by slow addition (ca. 5 minutes) of a solution of trifluoroacetic anhydride (0.13 mL, 0.91 mmol) in DCM (5 mL). The reaction was allowed to warm to ambient and left stirring overnight. The reaction was washed with 2M aq. sodium carbonate solution (5 mL) and 2M aq sodium metabisulphite solution (2×10 mL) and the solvent was removed in vacuo. The crude product was purified via flash column chromatography on silica gel using an EtOAc/isohexane gradient as eluent to give the desired product (76 mg, 73%) as a thick colourless oil.

(9) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.28 (1H, d), 7.44 (1H, dd), 7.21 (1H, d), 4.43 (2H, q), 1.44 (3H, t)

Step 2: Synthesis of ethyl 6-chloro-2-(trifluoromethyl)pyridine-3-carboxylate

(10) ##STR00055##

(11) A mixture of ethyl 1-oxido-2-(trifluoromethyl)pyridin-1-ium-3-carboxylate (0.2 g, 0.85 mmol) and POCl.sub.3(2 mL, 21.24 mmol) was heated to 80° C. for 6 hours and then cooled to ambient. The reaction was quenched with 2M aq Na.sub.2CO.sub.3 solution and then extracted with Et.sub.2O (3×15 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4 and pre-absorbed onto silica for purification via flash column chromatography on silica using an EtOAc/isohexane gradient as eluent to give the desired product (0.14 g, 61%) as a colourless oil.

(12) .sup.1H NMR (400 MHz, CDCl.sub.3) (8.09 (d, 1H), 7.60 (d, 1H), 4.43 (q, 2H), 1.43 (t, 3H).

Step 3: Synthesis of 6-chloro-2-(trifluoromethyl)pyridine-3-carboxylic acid

(13) ##STR00056##

(14) To a solution of ethyl 6-chloro-2-(trifluoromethyl)pyridine-3-carboxylate (190 mg, 0.75 mmol) in THF (4 mL) and H.sub.2O (2 mL) was added LiOH.H.sub.2O (72 mg, 1.72 mmol) and the reaction stirred at room temperature for 3 h. The reaction was concentrated under reduced pressure and 2N HCl was added slowly to reach pH 3-4, then extracted with EtOAc (2×10 mL). The combined organic extracts were dried over MgSO.sub.4 and concentrated to dryness under reduced pressure to give the desired product (170 mg, quant) as a white solid.

(15) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.12 (1H, d), 7.62 (1H, d)

Step 4: Synthesis of tert-butyl N-[6-chloro-2-(trifluoromethyl)-3-pyridyl]carbamate

(16) ##STR00057##

(17) To a stirred solution of 6-chloro-2-(trifluoromethyl)pyridine-3-carboxylic acid (3.0 g, 13.3 mmol) in t-butanol (25 mL) was added triethylamine (17.29 mmol) and diphenylphosphoryl azide (DPPA) (17.29 mmol). This reaction was heated at 90° C. for 2 hrs and then was allowed to cool to room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water (×2), then brine (×1), dried over MgSO.sub.4 and evaporated to dryness under reduced pressure. The crude product was adsorbed onto silica and purified by flash chromatography on silica using a gradient from 5-50% EtOAc/isohexane as eluent to give the desired product (3.24 g, 82%) as a colourless oil.

(18) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.64 (d, 1H), 7.48 (d, 1H), 6.89 (br,s 1H), 1.52 (s, 9H)

Step 5: Synthesis of tert-butyl N-[6-(5-fluoro-3-pyridyl)-2-(trifluoromethyl)-3-pyridyl]carbamate

(19) ##STR00058##

(20) To a stirred suspension of (5-fluoro-3-pyridyl)boronic acid (1.7 g, 1 mmol), Xantphos palladacycle 4th generation (0.2 g, 0.21 mmol) and tert-butyl N-[6-chloro-2-(trifluoromethyl)-3-pyridyl]carbamate (2.50 g, 8.4 mmol) in a mixture of ethanol (6.8 mL) and toluene (25 mL) was added K.sub.2CO.sub.3 (8.4 mL of 2M in water, 17 mmol). The reaction mixture was heated at reflux for 3 hrs. The reaction mixture was cooled to room temperature and concentrated to dryness.

(21) The residue was adsorbed onto silica and purified by flash chromatography on silica using a gradient from 5-100% EtOAc/isohexane as eluent to give the desired compound (2.57 g, 85%).

(22) 1H NMR (400 MHz, CDCl.sub.3) δ 9.02 (dd, 1H), 8.79 (d, 1H), 8.52 (d, 1H), 8.12 (m, 1H), 7.94 (d, 1H), 7.01 (br.s, 1H), 1.56 (s, 9H)

Step 6: Synthesis of 6-(5-fluoro-3-pyridyl)-2-(trifluoromethyl)pyridin-3-amine (Compound A33)

(23) ##STR00059##

(24) Trifluoroacetic acid (1.4 mL, 18 mmol) was added to tert-butyl N-[6-(5-fluoro-3-pyridyl)-2-(trifluoromethyl)-3-pyridyl]carbamate (685 mg, 1.92 mmol) in DCM (7 mL) and the reaction mixture was heated at reflux for 3 h before being allowed to cool to room temperature. The reaction mixture was partitioned between 2M NaOH (so pH of aqueous was greater than 12) and DCM. The aqueous layer was extracted twice with DCM and the combined organic extracts were dried over MgSO.sub.4 and dry loaded onto celite. Purification by flash chromatography on silica using a gradient of 0-30% EtOAc in isohexane as eluent gave the desired compound (472 mg, 96%) as a white solid.

(25) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.93 (m, 1H), 8.45 (d, 1H), 8.12-8.00 (m, 1H), 7.75 (d 1H), 7.21 (d, 1H), 4.38 (br.s, 2H)

Example P2: Synthesis of 6-pyrimidin-5-yl-2-(trifluoromethyl)pyridin-3-amine (Compound A35)

(26) ##STR00060##

Step 1: Synthesis of tert-butyl N-[6-pyrimidin-5-yl-2-(trifluoromethyl)-3-pyridyl]carbamate

(27) ##STR00061##

(28) To a stirred suspension of tert-butyl N-[6-chloro-2-(trifluoromethyl)-3-pyridyl]carbamate (2.0 g, 6.74 mmol), pyrimidin-5-ylboronic acid (1.25 g, 10.1 mmol) and [Pd(IPr*)(cin)Cl) (0.395 g, 0.34 mmol) in ethanol (50 mL) was added K.sub.2CO.sub.3 (2.07 g, 14.8 mmol). This mixture was then heated at reflux for 2 hrs. The reaction mixture was adsorbed directly onto silica and purified by flash chromatography on silica using a gradient from 5-100% EtOAc/isohexane as eluent to give the desired product (1.98 g, 86%) as a pale yellow solid.

(29) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.33 (s, 2H), 9.27 (s, 1H), 8.81 (d, 1H), 7.92 (d, 1H), 7.02 (br.s, 1H), 1.54 (s, 9H)

Step 2: Synthesis of 6-pyrimidin-5-yl-2-(trifluoromethyl)pyridin-3-amine (Compound A35)

(30) ##STR00062##

(31) To a solution of tert-butyl N-[6-pyrimidin-5-yl-2-(trifluoromethyl)-3-pyridyl]carbamate (750 mg, 2.20 mmol) in DCM (20 mL) was added, portionwise, TFA (1.70 mL, 22.04 mmol). The reaction mixture was stirred overnight. Saturated sodium bicarbonate solution was added, portionwise, until effervescence ceased. The two layers were separated and the aqueous extracted again with DCM (×2). The organics were combined, washed with brine, dried over MgSO.sub.4 and concentrated to give a yellow solid. The crude product was adsorbed onto silica and purified by flash chromatography on silica using a gradient from 0-10% MeOH in DCM as eluent to give the desired product (404 mg, 76%) as a pale yellow solid.

(32) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.28 (s, 2H), 9.21 (s, 1H), 7.74 (d, 1H), 7.23 (d, 1H), 4.43 (br.s, 2H)

Example P3 Synthesis of 6-(5-fluoro-3-pyridyl)-N-phenyl-2-(trifluoromethyl)pyridin-3-amine (Compound A32)

(33) ##STR00063##

Step 1: Synthesis of 6-(5-fluoro-3-pyridyl)-N-phenyl-2-(trifluoromethyl)pyridin-3-amine (Compound A32)

(34) ##STR00064##

(35) To a microwave vial was added bromobenzene (0.39 mmol, 0.061 g), 6-(5-fluoro-3-pyridyl)-2-(trifluoromethyl)pyridin-3-amine (0.1 g, 0.39 mmol), Xantphos palladacycle 3rd generation (0.031 mmol, 0.033 g), caesium carbonate (0.19 g, 0.58 mmol) and toluene (2 mL). The vial was capped and heated under microwave irradiation for 40 minutes at 130° C. The mixture was filtered, concentrated and purified by flash chromatography on silica using an EtOAc/isohexane gradient as eluent to afford the desired product (18 mg, 14%) as a yellow gum.

(36) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.95 (s, 1H), 8.47 (d, 1H), 8.09 (m, 1H), 7.76 (d, 1H), 7.67 (d, 1H), 7.44-7.36 (m, 2H), 7.22-7.16 (m, 3H), 6.32 (br.s, 1H)

Example P4: Synthesis of 6-(5-fluoro-3-pyridyl)-N-methyl-2-(trifluoromethyl)pyridin-3-amine (Compound A34)

(37) ##STR00065##

Step 1: Synthesis of tert-butyl N-[6-(5-fluoro-3-pyridyl)-2-(trifluoromethyl)-3-pyridyl]-N-methyl-carbamate

(38) ##STR00066##

(39) A solution of tert-butyl N-[6-pyrimidin-5-yl-2-(trifluoromethyl)-3-pyridyl]carbamate (422 mg, 1.240 mmol) in N,N-dimethylformamide (4.2 mL) was cooled to 5° C. (ice bath), under nitrogen. Sodium hydride (60% dispersion in mineral oil) (1.49 mmol, 0.060 g) was added in one portion. This mixture was allowed to warm to room temperature and stir for 1 hr, then iodomethane (1.86 mmol) was added and the reaction mixture stirred for a further 2 hrs. The reaction mixture was diluted carefully with water and extracted with EtOAc (×3). The organics were combined, washed with brine, dried over MgSO.sub.4 and concentrated to give a yellow gum. The crude product was adsorbed directly onto silica and purified by flash chromatography on silica using a gradient from 5-100% EtOAc in isohexane as eluent to give the desired product (354 mg, 81%) as an orange gum.

(40) .sup.1H NMR (400 MHz, CDCl.sub.3, major rotamer) δ 9.07 (s, 1H), 8.57 (d, 1H), 8.20 (br.d, 1H), 8.01 (d, 1H), 7.76 (d, 1H), 3.22 (s, 3H), 1.33 (s, 9H)

Step 2: Synthesis of 6-(5-fluoro-3-pyridyl)-N-methyl-2-(trifluoromethyl)pyridin-3-amine (Compound A34)

(41) ##STR00067##

(42) To a solution of tert-butyl N-methyl-N-[6-pyrimidin-5-yl-2-(trifluoromethyl)-3-pyridyl]carbamate (453 mg, 1.28 mmol) in DCM (10 mL) was added, portionwise, TFA (0.27 mL, 6.39 mmol). The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with DCM and saturated sodium bicarbonate solution was added portionwise (no effervescence observed). The two layers were separated and the aqueous extracted again with DCM (×2). The organics were combined, washed with brine, dried over MgSO.sub.4 and concentrated. The crude product was adsorbed onto silica and purified by flash chromatography on silica using a gradient from 0-10% MeOH in DCM as eluent to give the desired product (317 mg, 98%) as a yellow powder.

(43) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.93 (s, 1H), 8.42 (d, 1H), 8.05 (m, 1H), 7.82 (d, 1H), 7.17 (d, 1H), 4.72 (br.s, 1H), 2.98 (app. d, 3H)

Example P5 Synthesis of 3-amino-6-(5-fluoro-3-pyridyl)pyridine-2-carbonitrile (Compound A9)

(44) ##STR00068##

Step 1: Synthesis of 3-amino-6-(5-fluoro-3-pyridyl)pyridine-2-carbonitrile (Compound A9)

(45) ##STR00069##

(46) A mixture of 3-amino-6-chloro-pyridine-2-carbonitrile (330 mg, 2.15 mmol), 5-fluoropyridine-3-boronic acid (394 mg, 2.69 mmol), potassium carbonate (633 mg, 4.73 mmol) and [Pd(IPr*)(cin)Cl) (126 mg, 0.11 mmol) in EtOH (9.9 mL) was heated at 80° C. for 1 hour under an N.sub.2 atmosphere and then allowed to cool to room temperature. The mixture was filtered through celite and concentrated in vacuo. The resultant orange-brown gum was adsorbed onto silica and purified by flash chromatography on silica using an EtOAc/isohexane gradient as eluent to give the desired product (80 mg, 17%) as a brown gum.

(47) .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.95 (d, 1H), 8.43 (d, 1H), 8.18-8.09 (m, 1H), 7.93 (d, 1H), 7.35 (d, 1H)

Example P6 Synthesis of 4-[6-(5-fluoro-3-pyridyl)-2-(trifluoromethyl)-3-pyridyl]morpholine (Compound A39)

(48) ##STR00070##

Step 1: Synthesis of 3-chloro-6-(5-fluoro-3-pyridyl)-2-(trifluoromethyl)pyridine

(49) ##STR00071##

(50) A mixture of 3,6-dichloro-2-(trifluoromethyl)pyridine (200 mg, 0.94 mmol) and (5-fluoro-3-pyridyl)boronic acid (144 mg, 1.02 mmol) in ethanol (0.54 mL), toluene (2 mL) and H.sub.2O (0.93 mL) was sparged with N.sub.2 for 30 minutes. K.sub.2CO.sub.3 (256 mg, 1.85 mmol) and Xantphos palladacycle G4 (22 mg, 0.023 mmol) were added and the reaction heated at 80° C. under an N.sub.2 atmosphere for 2 hours. The reaction was allowed to cool to RT, diluted with H.sub.2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO.sub.4 and evaporated to dryness under reduced pressure to give a yellow oil. The crude product was purified by flash chromatography on silica gel using an EtOAc/isohexane gradient as eluent to give the desired product (0.192 g, 75%) as a colourless oil that solidified on standing.

(51) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.03 (s, 1H), 8.58 (s, 1H), 8.15 (d, 1H), 7.98 (d, 1H), 7.92 (d, 1H).

Step 2: Synthesis of 4-[6-(5-fluoro-3-pyridyl)-2-(trifluoromethyl)-3-pyridyl]morpholine (Compound A39)

(52) ##STR00072##

(53) A microwave vial was charged with 3-chloro-6-(5-fluoro-3-pyridyl)-2-(trifluoromethyl)pyridine (150 mg, 0.542 mmol), RuPhos palladacycle first generation (11 mg, 0.014 mmol), RuPhos (7 mg, 0.014 mmol), NaO.sup.tBu (65 mg, 0.65 mmol), morpholine (0.06 mL, 0.65 mmol) and THF (1 mL). The reaction was heated at 120° C. under microwave irradiation for 1 hour and allowed to cool to RT. The reaction was diluted with DCM (20 mL) and washed with water (20 mL). The aqueous phase was extracted with DCM (2×20 mL), the combined organic extracts dried over MgSO.sub.4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel using an EtOAc/isohexane gradient as eluent to give the desired product (117 mg, 66%) as a pale yellow solid.

(54) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.00 (s, 1H), 8.51 (d, 1H), 8.16-8.11 (m, 1H), 7.93 (d, 1H), 7.74 (d, 1H), 3.92-3.86 (m, 4H), 3.07-3.00 (m, 4H).

Example P7: Synthesis of N-(cyclobutylmethyl)-6-(5-fluoro-3-pyridyl)-2-(trifluoromethyl)pyridin-3-amine (Compound A51)

(55) ##STR00073##

Step 1: Synthesis of N-(cyclobutylmethyl)-6-(5-fluoro-3-pyridyl)-2-(trifluoromethyl)pyridin-3-amine (Compound A51)

(56) ##STR00074##

(57) To a stirred solution of 6-(5-fluoro-3-pyridyl)-2-(trifluoromethyl)pyridin-3-amine (130 mg, 0.50 mmol) and cyclobutanaldehyde (73 mg, 0.85 mmol) in EtOAc (1.6 mL) was added trifluoroacetic acid (0.12 mL, 1.5 mmol) followed by portionwise addition of sodium triacetoxyborohydride (210 mg, 0.95 mmol). The reaction was stirred at RT for 2 hours, then quenched with 2N NaOH (3 mL), stirred vigorously for 5 minutes and extracted with EtOAc (3×5 mL). The combined organic extracts were evaporated to dryness under reduced pressure and purified by flash chromatography on silica gel using an EtOAc/isohexane gradient as eluent to give the desired product (102 mg, 63%) as a colourless oil.

(58) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.92 (s, 1H), 8.42 (d, 1H), 8.08-8.01 (m, 1H), 7.78 (d, 1H), 7.16 (d, 1H), 4.54 (br s, 1H), 3.23 (dd, 2H), 2.66 (m, 1H), 2.22-2.10 (m, 2H), 2.04-1.87 (m, 2H), 1.85-1.73 (m, 2H).

Example P8: Synthesis of 6-(5-fluoro-3-pyridyl)-N,N-dimethyl-2-(trifluoromethyl)pyridin-3-amine (compound A38)

(59) ##STR00075##

Step 1: Synthesis of 6-(5-fluoro-3-pyridyl)-N,N-dimethyl-2-(trifluoromethyl)pyridin-3-amine (compound A38)

(60) ##STR00076##

(61) To a stirred solution of 6-(5-fluoro-3-pyridyl)-2-(trifluoromethyl)pyridin-3-amine (300 mg, 1.17 mmol) in formic acid (4.5 mL) at 0° C. was added formaldehyde (37% solution in water) (3.75 mL 50.4 mmol) and the mixture allowed to warm to RT. The reaction was heated at reflux for 20 hours and then allowed to cool to RT. The reaction mixture was diluted in water (40 mL) then made basic by the careful addition of dil. aq. NaOH. The emulsion was then extracted with Et2O (3×50 mL) and the combined organic extracts were dried over MgSO.sub.4 and evaporated to dryness under reduced pressure. The crude yellow product was purified by flash chromatography on silica gel using an EtOAc/isohexane gradient as eluent to give the desired product (249 mg, 75%) as a very pale yellow oil which crystallised over time.

(62) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.97 (s, 1H), 8.48 (s, 1H), 8.12 (dt, 1H), 7.85 (d, 1H), 7.61 (d, 1H,), 2.90 (s, 6H).

(63) Further examples of the invention were made in an analogous manner using the methods described above in Examples P1 to P8, with respect to compounds A33, A35, A32, A34, A9, A39, A51 and A38. Table 2 below, shows the structure of these compounds and the physical characterising data obtained using one or more of methods A to C as outlined below.

(64) TABLE-US-00002 TABLE 2 Characterising data for Compounds of formula (I) made by the methods described above. .sup.1H NMR Data (400 MHz, Cmpd CDCl.sub.3 unless ID Structure stated) m/z method A1 9.31 (s, 1H), 8.81 (s, 1H), 8.58 (s, 1H), 7.83 (d, 1H), 7.19 (d, 1H), 4.80 (br. s, 1H), 2.99 (app. d, 3H) [MH+] 279; tr 0.64 mins C A2 9.31 (s, 1H), 8.83 (s, 1H), 8.58 (s, 1H), 7.77 (d, 1H), 7.23 (d, 1H), 4.47 (s, 2H) — — A3 8.99 (s, 1H), 8.54 (s, 1H), 8.31 (s, 1H), 7.72 (d, 1H), 7.21 (d, 1H), 4.39 (br. s, 2H) — — A4 0 8.95 (s, 1H), 8.40 (s, 1H), 8.08 (s, 1H), 7.45 (d, 1H), 7.00 (d, 1H), 6.61 (t, 1H), 3.81 (br. s, 2H), 2.49 (s, 3H) — — A5 8.93 (s, 1H), 8.42 (d, 1H), 8.05 (m, 1H), 7.82 (d, 1H), 7.17 (d, 1H), 4.72 (br. s, 1H), 2.98 (app. d, 3H) [MH+] 272; tr 0.67 mins C A6 8.90 (s, 1H), 8.39 (s, 1H), 8.10 (s, 1H), 7.79 (d, 1H), 7.14 (d, 1H), 4.71 (br. s, 1H), 2.94 (app. d, 3H), 2.39 (s, 3H) [MH+] 268; tr 0.39 mins C A7 9.31 (s, 1H), 8.71 (s, 1H), 8.50 (s, 1H), 7.85 (d, 1H), 7.19 (d, 1H), 4.76 (br. s, 1H), 2.98 (app. d, 3H) [MH+] 322; tr 0.78 mins C A8 8.91 (s, 1H), 8.39 (d, 1H), 8.02 (m, 1H), 7.47 (d, 1H), 7.01 (d, 1H), 3.78 (br. s ,2H), 2.50 (s, 3H) — — A9 (CD.sub.3OD) 8.95 (d, 1H), 8.43 (d, 1H), 8.18-8.09 (m, 1H), 7.93 (d, 1H), 7.35 (d, 1H) — — A10 8.70 (d, 1H), 8.27 (d, 1H), 7.88-7.84 (m, 1H), 7.81 (d, 1H), 7.17 (d, 1H), 4.67 (br. s, 1H), 3.93 (s, 3H), 2.97 (3H, app. d) [MH+] 284; tr 0.46 mins C A11 9.12 (d, 1H), 8.58 (m, 1H), 8.29 (m, 1H), 7.81 (d, 1H), 7.49-7.33 (m, 1H), 7.18 (d, 1H), 4.67 (br. s, 1H), 2.97 (app. d, 3H) [MH+] 254; tr 0.36 mins C A12 9.28 (d, 1H), 8.79 (s, 1H), 8.51 (s, 1H), 7.51 (d, 1H), 7.02 (d, 1H), 3.80 (br. s, 2H), 2.51 (s, 3H) — — A13 8.68 (d, 1H), 8.24 (d, 1H), 7.82 (m, 1H), 7.45 (d, 1H), 7.00 (d, 1H), 3.93 (s, 3H), 3.73 (br. s, 2H), 2.50 (s, 3H) — — A14 0 9.24 (s, 2H), 9.14 (s, 1H), 7.45 (d, 1H), 7.02 (d, 1H), 3.81 (br. s, 2H), 2.50 (s, 3H) — — A15 9.23 (s, 2H), 9.11 (s, 1H), 7.53 (d, 1H), 6.90 (d, 1H), 3.87 (br. s, 1H), 2.95 (app. d, 3H), 2.47 (s, 3H) [MH+] 201; tr 0.29 mins C A16 8.88 (s, 1H), 8.43 (d, 1H), 8.04 (m, 1H), 7.64-7.58 (m, 2H), 7.56-7.47 (m, 3H), 6.82 (d, 1H), 5.01 (br. s, 1H), 4.62 (m, 1H), 1.62 (d, 3H) [MH+] 430; tr 1.64 mins A A17 8.88 (s, 1H), 8.42 (d, 1H), 8.06 (m, 1H), 7.58 (d, 1H), 7.38-7.22 (m, 5H), 6.93 (d, 1H), 5.03 (br. s, 1H), 4.56 (m, 1H), 1.62 (d, 3H) [MH+] 262; tr 1.57 mins A A18 8.89 (s, 1H), 8.48 (d, 1H), 8.04 (m, 1H), 7.72 (d, 1H), 7.38-7.22 (m, 4H), 7.03 (d, 1H), 5.18 (br. s, 1H), 4.48 (app. d, 2H) [MH+] 382; tr 1.54 mins A A19 8.92 (s, 1H), 8.44 (d, 1H), 8.14-7.98 (m, 1H), 7.79 (d, 1H), 7.09 (d, 1H), 5.16 (br. d, 1H), 4.23 (m, 1H), 3.80 (s, 3H), 1.58 (d, 3H) — — A20 8.91 (s, 1H), 8.42 (d, 1H), 8.03 (m, 1H), 7.71 (d, 1H), 7.24 (d, 2H), 7.16 (d, 2H), 7.11 (d, 1H), 5.08 (br. s, 1H), 4.41 (app. d, 2H), 2.32 (s, 3H) [MH+] 362; tr 1.55 mins A A21 8.82 (s, 1H), 8.43 (d, 1H), 8.06 (m, 1H), 7.72 (d, 1H), 7.42-7.28 (m, 5H), 7.08 (d, 1H), 5.18 (br. s. 1H), 4.50 (s, 2H) [MH+] 348; tr 1.47 mins A A22 8.93 (s, 1H), 8.44 (d, 1H), 8.13-8.00 (m, 1H), 7.81 (d, 1H), 7.06 (d 1H), 5.34 (br. s, 1H), 4.03 (app. d, 2H), 3.85 (s, 3H) [MH+] 330; tr 0.92 mins B A23 8.96 (s, 1H), 8.43 (d, 1H), 8.06 (m, 1H), 7.70 (d, 1H), 7.33-7.28 (m, 1H), 7.11 (d, 1H), 6.94-6.82 (m, 3H), 5.21 (br. s, 1H), 4.43, (s, 2H), 3.81 (s, 3H) [MH+] 378; tr 1.46 mins A A24 00 8.88 (s, 1H), 8.44-8.31 (m, 1H), 8.02 (m, 1H), 7.70 (d, 1H), 7.41-7.18 (m, 4H), 7.05 (d, 1H), 5.19 (br. s, 1H), 4.47 (app. d, 2H) [MH+] 382; tr 1.23 mins B A25 01 8.92 (d, 1H), 8.42 (d, 1H), 8.05 (m, 1H), 7.78 (d, 1H), 7.16 (d, 1H), 5.99-5.88 (m, 1H), 5.37-5.23 (m, 2H), 4.85 (br. s, 1H), 3.97- 3.88 (m, 2H) [MH+] 298; tr 0.76 mins C A26 02 8.95 (br. s, 1H), 8.48 (br. s, 1H), 8.06 (d, 1H), 7.72 (d, 1H), 7.65 (d, 2H), 7.46 (d, 2H), 7.02 (d, 1H), 5.26 (br. s, 1H), 4.58 (app. d, 2H) [MH+] 416; tr 1.57 mins A A27 03 8.93 (d, 1H), 8.42 (d, 1H), 8.08 (m, 1H), 7.79 (d, 1H), 7.17 (d, 1H), 4.63-4.46 (br. s, 1H), 3.28 (app. m, 2H), 1.35 (t, 3H) [MH+] 286; tr 1.08 mins B A28 04 8.90 (s, 1H), 8.42 (d, 1H), 8.03 (m, 1H), 7.75 (d, 1H), 7.37-7.24 (m, 1H), 7.13 (d, 1H), 6.88 (m, 2H), 5.13 (br. s, 1H), 4.51 app. d, 2H) [MH+] 384; tr 1.22 mins B A29 05 8.92 (s, 1H), 8.41 (d, 1H), 8.05 (m, 1H), 7.79 (d, 1H), 7.13 (d, 1H), 4.75 (br. s, 1H), 3.11-3.02 (m, 2H), 1.21-1.09 (m, 1H), 0.69- 0.61 (m, 2H), 0.36-0.29 (m, 2H) [MH+] 312; tr 0.83 mins A A30 06 8.94 (s, 1H), 8.47 (s, 1H), 8.08 (m, 1H), 7.90 (d, 1H), 7.35 (d, 1H), 4.97-4.81 (br. s, 1H), 4.01 (br. m, 2H), 1.83 (dd, 3H) [MH+] 310; tr 1.10 mins B A31 07 8.92 (s, 1H), 8.47 (d, 1H), 8.08 (m, 1H), 7.72 (m, 1H), 7.38-7.24 (m, 2H), 7.11-6.98 (m, 3H), 5.17 (br. s, 1H), 4.46 (s, 2H) [MH+] 366; tr 1.49 mins A A32 08 8.95 (s, 1H), 8.47 (d, 1H), 8.09 (m, 1H), 7.76 (d, 1H), 7.67 (d, 1H), 7.44-7.36 (m, 2H), 7.22-7.16 (m, 3H), 6.32 (br. s, 1H) [MH+] 334; tr 1.21 mins B A33 09 8.93 (m, 1H), 8.45 (d, 1H), 8.12-8.00 (m, 1H), 7.75 (d 1H), 7.21 (d, 1H), 4.38 (br. s, 2H) A34 0 9.28 (s, 2H), 9.19 (s, 1H), 7.80 (d, 1H), 7.19 (d, 1H), 4.77 (br. s, 1H), 2.98 (app. d, 3H) [MH+] 255; tr 0.69 mins B A35 9.28 (s, 2H), 9.21 (s, 1H), 7.74 (d, 1H), 7.23 (d, 1H), 4.43 (br. s, 2H) [MH+] 279; tr 0.64 mins A A36 9.10 (s, 1H), 8.53 (d, 1H), 8.43 (m, 1H), 7.45 (d, 1H), 7.37-7.31 (m, 1H), 7.00 (d, 1H), 3.72 (br. s, 2H), 2.50 (s, 3H) A38 8.97 (s, 1H), 8.48 (s, 1H), 8.12 (dt, 1H), 7.85 (d, 1H), 7.61 (d, 1H), 2.90 (s, 6H) A39 9.00 (s, 1H), 8.51 (d, 1H), 8.16-8.11 (m, 1H), 7.93 (d, 1H), 7.74 (d, 1H), 3.92- 3.86 (m, 4H), 3.07-3.00 (m, 4H). A40 8.95 (s, 1H), 8.43 (d, 1H), 8.13-8.08 (m, 1H), 7.75 (d, 1H), 7.29 (d, 1H), 3.50-3.45 (m, 4H), 2.06- 2.01 (m, 4H). A41 (2:1 d4- MeOH:d6- DMSO) 9.08 (s, 1H), 8.51 (d, 1H), 8.26-8.23 (m, 1H), 8.00 (d, 1H), 7.41 (d, 1H), 3.95 (s, 3H) A42 8.94 (s, 1H), 8.43 (d, 1H), 8.09-8.03 (m, 1H), 7.80 (d, 1H), 7.18 (d, 1H), 4.61 (br. s, 1H), 3.26-3.19 (m, 2H), 1.75- 1.66 (m, 2H), 1.49-1.32 (m, 6H), 0.96-0.89 (m, 3H) A43 9.0 (s, 1H), 8.35 (s, 1H), 8.00 (dd, 1H), 7.25 (s, 1H), 6.90 (d, 1H), 4.10 (s, 3H), 4.00 (br. s, 2H) A44 (CD.sub.3OD) 9.24 (s, 2H), 9.19 (s, 1H), 7.73 (d, 1H), 7.26 (d, 1H) A45 0 9.00 (s, 1H), 8.48 (d, 1H), 8.30-8.27 (m, 1H), 7.79 (d, 1H), 7.19 (d, 1H), 4.61 (br. s, 1H), 3.55-3.29 (m, 1H), 2.08- 2.01 (m, 2H), 1.85-1.76 (m, 2H), 1.73-1.64 (m, 1H), 1.50- 1.25 (m, 5H). A46 8.99 (s, 1H), 8.47 (d, 1H), 8.21-8.16 (m, 1H), 7.85 (d, 1H), 7.65 (d, 1H), 5.08, (br. s, 1H), 2.59-2.51 (m, 1H), 0.96- 0.89 (m, 2H), 0.68-0.61 (m, 2H) A47 8.92 (s, 1H), 8.42 (d, 1H), 8.08-8.02 (m, 1H), 7.78 (d, 1H), 7.17 (d, 1H), 4.63 (br. s, 1H), 3.20 (dt, 2H), 1.76-1.67 (m, 2H), 1.05 (t, 3H) A48 8.99 (t, 1H), 8.49 (d, 1H), 8.17-8.11 (m, 1H), 7.87 (d, 1H), 7.71 (d, 1H), 3.09-3.02 (m, 4H), 1.57- 1.45 (m, 4H), 0.87 (t, 6H) A49 8.91 (s, 1H), 8.41 (d, 1H), 8.08-8.00 (m, 1H), 7.77 (d, 1H), 7.38-7.32 (m, 2H), 7.30- 7.22 (m, 3H), 7.17 (d, 1H), 4.69 (br. s, 1H), 3.52-3.45 (m, 2H), 2.99 (t, 2H) A50 8.97 (s, 1H), 8.41 (d, 1H), 8.12-8.07 (m, 1H), 7.79-7.75 (m, 2H), 7.59 (d, 1H), 7.56-7.50 (m, 2H), 7.48- 7.42 (m, 1H), 7.16 (d, 1H), 4.05 (br. s, 2H). A51 8.92 (s, 1H), 8.42 (d, 1H), 8.08-8.01 (m, 1H), 7.78 (d, 1H), 7.16 (d, 1H), 4.54 (br. s, 1H), 3.23 (dd, 2H), 2.66 (m, 1H), 2.22-2.10 (m, 2H), 2.04- 1.87 (m, 2H), 1.85-1.73 (m, 2H) A52 8.92 (t, 1H), 8.42 (d, 1H), 8.09-8.01 (m, 1H), 7.78 (d, 1H), 7.16 (d, 1H), 4.69 (br. s, 1H), 3.10-3.03 (m, 2H), 1.8- 1.60 (m, 6H), 1.35-1.17 (m, 3H), 1.10-0.96 (m, 2H) A53 8.93 (t, 1H), 8.42 (d, 1H), 8.09-8.03 (m, 1H), 7.79 (d, 1H), 7.17 (d, 1H), 4.56 (br. s, 1H), 3.23 (dt, 2H), 1.82-1.67 (m, 1H), 1.60 (q, 2H), 0.99 (d, 6H) A54 8.93 (t, 1H), 8.42 (d, 1H), 8.08-8.02 (m, 1H), 7.79 (d, 1H), 7.17 (d, 1H), 4.60 (br. s, 1H), 3.22 (dt, 2H), 1.76-1.64 (m, 2H), 1.45- 1.34 (m, 4H), 0.98-0.91 (m, 3H) A55 0 8.91 (t, 1H), 8.46-8.39 (m, 2H), 8.10-8.00 (m, 1H), 7.76 (d, 1H), 7.47 (td, 1H), 7.29 (d, 1H), 7.12 (ddd, 1H), 6.77 (dt, 1H), 6.44 (s, 1H), 5.42 (br. s, 1H), 4.68 (d, 2H) A56 8.92 (t, 1H), 8.44 (d, 1H), 8.09-8.01 (m, 1H), 7.81-7.74 (m, 2H), 7.33 (d, 1H), 7.28-7.25 (m, 1H), 5.58 (br. s, 1H), 4.83 (d, 2H) A57 8.92 (t, 1H), 8.86 (d, 1H), 8.43 (d, 1H), 8.09-8.02 (m, 1H), 7.77 (d, 1H), 7.25-7.19 (m, 2H), 5.41 (br. s, 1H), 4.68 (d, 2H) A59 8.92 (t, 1H), 8.42 (d, 1H), 8.08-8.03 (m, 1H), 7.77 (d, 1H), 7.33 (d, 1H), 7.29 (d, 1H), 6.19 (d, 1H), 5.25 (br. s, 1H), 4.45 (d, 2H), 3.90 (s, 3H) A60 8.93 (t, 1H), 8.45 (d, 1H), 8.09-8.03 (m, 1H), 7.88 (s, 1H), 7.82 (d, 1H), 7.29-7.25 (m, 1H), 7.05 (s, 1H), 5.06 (br. s, 1H), 4.56 (d, 2H) A61 9.02-8.99 (m, 1H), 8.52 (d, 1H), 8.17-8.12 (m, 1H), 7.93 (d, 1H), 7.76 (d, 1H), 3.09 (t, 4H), 2.69-2.59 (br. m, 4H), 2.40 (s, 3H) A62 9.01 (s, 1H), 8.55-8.51 (m, 1H), 8.17-8.11 (m, 1H), 7.94 (d, 1H), 7.49 (d, 1H), 3.97-3.86 (m, 4H) A63 8.94 (s, 1H), 8.43 (d, 1H), 8.11-8.05 (m, 1H), 7.76 (d, 1H), 6.92 (d, 1H), 4.18 (t, 4H), 2.43 (m, 2H) A64 9.01 (s, 1H), 8.52 (d, 1H), 8.18-8.12 (m, 1H), 7.91 (d, 1H), 7.75 (d, 1H), 4.40-4.30 (m, 1H), 3.78- 3.70 (m, 1H), 3.21-3.13 (m, 1H), 2.42-2.31 (m, 1H), 2.25- 2.08 (m, 2H), 2.05-1.94 (m, 1H) A65 9.00 (s, 1H), 8.49 (d, 1H), 8.19-8.12 (m, 1H), 7.89 (d, 1H), 7.69 (d, 1H), 5.89-5.76 (m, 2H), 5.22- 5.11 (m, 4H), 3.69 (d, 4H) A66 0 8.91 (s, 1H), 8.41 (s, 1H), 8.04 (d, 1H), 7.77 (d, 1H), 7.15 (d, 1H), 4.70 (br. s, 1H), 3.06 (t, 2H), 1.97 (m, 1H), 1.03 (d, 6H) A67 8.96 (s, 1H), 8.45 (s, 1H), 8.07 (d, 1H), 7.84 (d, 1H), 7.20 (d, 1H), 4.82 (br. s, 1H), 3.58 (m, 2H), 2.53 (m, 2H),
Physical Characterisation
Compounds of the invention were characterised using one or more of the following methods.
NMR

(65) NMR spectra contained herein were recorded on either a 400 MHz Bruker AVANCE III HD equipped with a Bruker SMART probe or a 500 MHz Bruker AVANCE III equipped with a Bruker Prodigy probe. Chemical shifts are expressed as ppm downfield from TMS, with an internal reference of either TMS or the residual solvent signals. The following multiplicities are used to describe the peaks: s=singlet, d=doublet, t=triplet, dd=double doublet, m=multiplet. Additionally br. is used to describe a broad signal and app. is used to describe and apparent multiplicity.

(66) LCMS

(67) LCMS data contained herein consists of the molecular ion [MH+] and the retention time (tr) of the peak recorded on the chromatogram. The following instruments, methods and conditions were used to obtain LCMS data:

(68) Method A

(69) Instrumentation:

(70) Waters Acquity UPLC-MS using a Sample Organizer with Sample Manager FTN, H-Class QSM, Column Manager, 2×Column Manager Aux, Photodiode Array (Wavelength range (nm): 210 to 400, ELSD and SQD 2 equipped with a Waters HSS T3 C18 column (column length 30 mm, internal diameter of column 2.1 mm, particle size 1.8 micron).
Ionisation Method:
Electrospray positive and negative: Capillary (kV) 3.00, Cone (V) 30.00, Source Temperature (° C.) 500, Cone Gas Flow (L/Hr.) 10, Desolvation Gas Flow (L/Hr.) 1000. Mass range (Da): positive 95 to 800, negative 115 to 800.
The analysis was conducted using a two minute run time, according to the following gradient table at 40° C.:

(71) TABLE-US-00003 Time (mins) Solvent A (%) Solvent B (%) Flow (ml/mm) 0.00 95.0 5.0 0.7 1.75 0.0 100 0.7 1.76 0.0 100 0.7 2.0 0.0 5.0 0.7 2.01 95.0 5.0 0.7 2.11 95.0 5.0 0.7
Solvent A: H.sub.2O with 0.05% TFA
Solvent B: CH.sub.3CN with 0.05% TFA
Method B (2 min Method)
Instrumentation:
Either (a) Waters Acquity UPLC system with Waters SQD2 single-quad MS detector, Photodiode Array Detector (Absorbance Wavelength: 254 nm, 10 pts/sec, Time Constant: 0.2000 sec), Charged Aerosol Detector (Corona) and Waters CTC 2770 auto-sampler unit (injection volume: 2 microliters, 1 min seal wash); or (b) Waters Acquity UPLC system with Waters QDa single-quad MS detector, Photodiode Array Detector (Absorbance Wavelength: 254 nm, 10 pts/sec, Time Constant: 0.2000 sec), Charged Aerosol Detector (Corona) and Waters CTC 2770 auto-sampler unit (injection volume: 2 microliters, 1 min seal wash).
L C-Method:
Phenomenex ‘Kinetex C18 100A’ column (50 mm×4.6 mm, particle size 2.6 micron),
Flow rate: 2 mL/min at 313K (40 Celsius),
Gradient (Solvent A: H.sub.2O with 0.1% Formic Acid; Solvent B: Acetonitrile with 0.1% Formic Acid):
The analysis was conducted using a two minute run time, according to the following gradient table at 40° C.

(72) TABLE-US-00004 Time (mins) Solvent A (%) Solvent B (%) Flow (ml/mm) Initial 70.0 30.0 2.000 1.20 10.0 90.0 2.000 1.70 10.0 90.0 2.000 1.80 70.0 30.0 2.000 2.00 70.0 30.0 2.000 2.20 70.0 30.0 2.000
Method C (1 min Method)
Instrumentation:
Either (a) Waters Acquity UPLC system with Waters SQD2 single-quad MS detector, Photodiode Array Detector (Absorbance Wavelength: 254 nm, 10 pts/sec, Time Constant: 0.2000 sec), Charged Aerosol Detector (Corona) and Waters CTC 2770 auto-sampler unit (injection volume: 2 microliters, 1 min seal wash); or (b) Waters Acquity UPLC system with Waters QDa single-quad MS detector, Photodiode Array Detector (Absorbance Wavelength: 254 nm, 10 pts/sec, Time Constant: 0.2000 sec), Charged Aerosol Detector (Corona) and Waters CTC 2770 auto-sampler unit (injection volume: 2 microliters, 1 min seal wash).
L C-Method:
Phenomenex ‘Kinetex C18 100A’ column (50 mm×4.6 mm, particle size 2.6 micron),
Flow rate: 2 mL/min at 313K (40 Celsius),
Gradient (Solvent A: H.sub.2O with 0.1% Formic Acid; Solvent B: Acetonitrile with 0.1% Formic Acid):
The analysis was conducted using a one minute run time, according to the following gradient table at 40° C.

(73) TABLE-US-00005 Time (mins) Solvent A (%) Solvent B (%) Flow (ml/mm) Initial 60.0 40.0 2.000 0.80 0.0 100.0 2.000 0.95 0.0 100.0 2.000 1.00 60.0 40.0 2.000 1.10 60.0 40.0 2.000 1.25 60.0 40.0 2.000

BIOLOGICIAL EXAMPLES

(74) B1 Pre-Emergence Herbicidal Activity

(75) Seeds of a variety of test species were sown in standard soil in pots: Triticum aestivium (TRZAW), Avena fatua (AVEFA), Alopecurus myosuroides (ALOMY), Echinochloa crus-galli (ECHCG), Lolium perenne (LOLPE), Zea Mays (ZEAMX), Abutilon theophrasti (ABUTH), Amaranthus retroflexus (AMARE) and Setaria faberi (SETFA). 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). 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 was evaluated (5=total damage to plant; 0=no damage to plant). Results are shown in Tables B1a and B1b.

(76) Tables B1a and B1b Control of Weed Species by Compound of Formula (I) after Pre-Emergence Application

(77) TABLE-US-00006 TABLE B1a Test 1a Compound ID Rate (g/ha) LOLPE SETFA ALOMY ECHCG AVEFA TRAZW A1 1000 1 4 0 1 1 0 A2 1000 1 4 0 2 0 0 A3 1000 1 5 0 3 1 0 A4 1000 1 2 0 1 0 0 A38 1000 0 5 0 5 2 0 A39 1000 0 3 0 3 0 0 A40 1000 1 4 1 4 1 0 A41 1000 0 2 0 2 0 0 A42 1000 1 5 0 4 2 0 A43 1000 1 1 0 0 0 0 A44 1000 2 5 0 3 1 0 A45 1000 0 4 0 3 1 NT A46 1000 0 4 0 2 1 0 A47 1000 1 4 0 3 1 0 A48 1000 0 4 0 4 0 0 A49 1000 1 5 0 3 1 0 A50 1000 0 1 0 1 0 0 A51 1000 1 5 1 5 1 1 A52 1000 1 5 0 3 1 0 A53 1000 2 5 1 4 1 1 A54 1000 1 5 0 3 1 0 A55 1000 1 5 0 5 2 0 A56 1000 1 5 0 4 2 1 A57 1000 1 5 1 5 3 0 A59 1000 1 5 0 4 3 0 A60 1000 1 5 0 5 3 0 A61 1000 0 5 0 4 2 0 A62 1000 0 5 0 3 1 0 A63 1000 0 5 0 2 0 0 A64 1000 0 1 0 1 0 0

(78) TABLE-US-00007 TABLE B1b Test 1b Compound ID Rate (g/ha) LOLPE AMARE SETFA ECHCG ZEAMX ABUTH A5 1000 1 2 5 2 4 1 A6 1000 0 1 1 0 0 1 A7 1000 0 1 3 0 0 1 A8 1000 1 0 5 2 3 0 A9 1000 0 1 4 4 2 1 A10 1000 0 1 2 0 1 1 A11 1000 1 1 5 2 1 1 A12 1000 0 0 0 0 0 0 A13 1000 0 0 0 0 0 0 A14 1000 1 0 2 1 1 0 A15 1000 0 0 1 1 1 0 A16 1000 0 0 4 1 1 0 A17 1000 0 0 2 0 0 0 A18 1000 0 0 4 2 4 0 A19 1000 2 1 4 3 5 0 A20 1000 0 0 5 2 3 0 A21 1000 2 1 5 3 3 0 A22 1000 2 3 4 4 5 0 A23 1000 0 0 4 1 2 0 A24 1000 1 0 4 2 3 0 A25 1000 2 1 4 4 5 0 A26 1000 0 0 4 2 2 0 A27 1000 2 0 4 5 5 0 A28 1000 0 0 4 2 2 0 A29 1000 3 3 5 4 5 1 A30 1000 2 2 5 4 5 0 A31 1000 2 1 5 4 4 1 A32 1000 1 1 5 4 1 1 A33 1000 2 1 4 2 4 0 A34 1000 3 1 4 4 4 0 A35 1000 2 1 4 3 5 0 A36 1000 0 1 1 0 0 1
B2 Post-Emergence Herbicidal Activity

(79) Seeds of a variety of test species were sown in standard soil in pots: Triticum aestivium (TRZAW), Avena fatua (AVEFA), Alopecurus myosuroides (ALOMY), Echinochloa crus-galli (ECHCG), Lolium perenne (LOLPE), Zea Mays (ZEAMX), Abutilon theophrasti (ABUTH), Amaranthus retroflexus (AMARE) and Setaria faberi (SETFA). 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 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). 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 was evaluated (5=total damage to plant; 0=no damage to plant). Results are shown in Tables B2a and B2b.

(80) Tables B2a and B2b Control of Weed Species by Compound of Formula (I) after Post-Emergence Application

(81) TABLE-US-00008 TABLE B2a Test B2a Compound ID Rate (g/ha) LOLPE SETFA ALOMY ECHCG AVEFA TRAZW A1 1000 2 5 0 3 3 2 A2 1000 2 5 1 4 3 0 A3 1000 2 4 1 3 3 0 A4 1000 1 4 1 2 3 1 A38 1000 2 5 1 5 4 1 A39 1000 2 4 0 4 2 0 A40 1000 2 5 0 5 3 0 A41 1000 0 2 0 2 1 0 A42 1000 2 5 1 5 3 1 A43 1000 1 2 0 1 1 0 A44 1000 1 4 0 3 2 0 A45 1000 1 4 0 2 2 0 A46 1000 2 4 1 4 3 1 A47 1000 2 5 0 4 2 2 A48 1000 2 5 0 4 3 1 A49 1000 3 5 0 3 3 0 A50 1000 0 2 0 1 0 0 A51 1000 3 4 1 5 4 2 A52 1000 3 5 0 3 3 0 A53 1000 3 5 1 5 3 1 A54 1000 2 5 0 3 3 0 A55 1000 3 5 1 5 4 2 A56 1000 3 5 1 5 4 1 A57 1000 4 5 1 5 4 2 A59 1000 3 5 1 5 3 2 A60 1000 4 5 1 5 3 2 A61 1000 2 5 1 5 3 1 A62 1000 2 5 0 3 3 0 A63 1000 2 5 0 3 3 0 A64 1000 0 4 0 2 1 0

(82) TABLE-US-00009 TABLE B2b Test B2b Compound ID Rate (g/ha) LOLPE AMARE SETFA ECHCG ZEAMX ABUTH A5 1000 4 1 5 4 5 1 A6 1000 1 0 3 1 1 0 A7 1000 1 1 3 1 1 0 A8 1000 3 0 5 4 5 0 A9 1000 1 1 4 4 4 1 A10 1000 1 1 3 1 2 0 A11 1000 4 1 5 4 2 1 A12 1000 0 0 1 1 1 0 A13 1000 0 1 1 1 2 0 A14 1000 1 2 3 2 2 0 A15 1000 1 1 2 2 1 0 A16 1000 1 0 5 3 3 0 A17 1000 1 0 4 4 4 0 A18 1000 2 0 5 3 5 0 A19 1000 3 2 5 4 5 1 A20 1000 2 0 5 3 5 0 A21 1000 1 1 5 1 5 0 A22 1000 4 3 5 5 5 2 A23 1000 2 0 5 2 5 0 A24 1000 2 0 5 3 5 0 A25 1000 3 2 5 4 5 0 A26 1000 2 0 4 3 5 0 A27 1000 4 0 5 4 5 0 A28 1000 2 1 5 3 5 0 A29 1000 4 2 5 5 5 2 A30 1000 4 2 5 5 5 2 A31 1000 3 1 5 4 5 0 A32 1000 3 0 5 4 4 0 A33 1000 3 2 5 3 5 1 A34 1000 3 2 5 5 5 1 A35 1000 4 2 5 4 5 1 A36 1000 1 1 2 1 2 0