Herbicidal Pyridino-/Pyrimidino-Thiazoles

Abstract

The present invention relates to herbicidally active pyridino-/pyrimidino-thiazole 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 method of controlling unwanted plant growth, comprising applying a compound of formula (I) ##STR00194## or a salt or N-oxide thereof, wherein, X.sub.1 is N or CR.sup.1; R.sup.1 is hydrogen, halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6alkoxy, —C(O)OR.sup.6 or S(O).sub.n(C.sub.1-C.sub.6alkyl), formyl, hydroxyl, —C(O)NR.sup.6R.sup.7, NR.sup.6R.sup.7, benzyloxy, C.sub.1-C.sub.6 haloalkoxy, or C.sub.1-C.sub.6 haloalkyl; R.sup.2 is hydrogen, halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6cycloalkyl, —C(O)OR.sup.6, S(O).sub.n(C.sub.1-C.sub.6alkyl), C.sub.1-C.sub.6 alkoxy, or C.sub.1-C.sub.6 haloalkoxy; n is 0, 1, or 2; R.sup.3 is hydrogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6haloalkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6haloalkoxy, C.sub.2-C.sub.6alkenyloxy, C.sub.3-C.sub.10cycloalkyl, NR.sup.6R.sup.7, R.sup.4 is O, S, or N(C.sub.1-C.sub.6alkyl); X.sub.2 is O, S, or NR.sup.8; R.sup.5 is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10cycloalkenyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.2-C.sub.6alkenyloxy, C.sub.2-C.sub.6alkynyloxy, C.sub.3-C.sub.10cycloalkyloxy, C.sub.3-C.sub.10cycloalkenyloxy, C.sub.2-C.sub.6haloalkenyloxy, C.sub.6-C.sub.10aryl or C.sub.6-C.sub.10aryl substituted by from 1 to 3 groups independently selected from halogen, nitro, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkyl, and C.sub.1-C.sub.3 haloalkoxy; C.sub.3-C.sub.10heterocylcyl or C.sub.3-C.sub.10heterocyclycl substituted by from 1 to 3 groups independently selected from halogen, nitro, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkyl, and C.sub.1-C.sub.3 haloalkoxy; or NR.sup.6R.sup.7; or R.sup.3 and R.sup.5 together with X.sub.2 and the atoms to which they are attached, form a saturated or partially unsaturated 5-9 membered ring system optionally comprising 1 to 3 heteroatoms independently selected from S, O and N and optionally substituted with 1 to 3 groups independently selected from halogen or C.sub.1-C.sub.6 alkyl; or R.sup.3 and R.sup.8 together with the atoms to which they are attached form a saturated or partially unsaturated 5-9 membered ring system optionally comprising 1 to 3 heteroatoms independently selected from S, O and N and optionally substituted with 1 to 3 groups independently selected from halogen or C.sub.1-C.sub.6 alkyl; R.sup.6 and R.sup.7 are each independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl, or R.sup.4 and R.sup.5 together with X.sub.2 and the atoms to which they are attached, form a saturated or partially unsaturated 5-9 membered ring system optionally comprising 1 to 3 heteroatoms independently selected from S, O and N and optionally substituted with 1 to 3 groups independently selected from halogen or C.sub.1-C.sub.6 alkyl; or R.sup.6 and R.sup.7 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 3-6 membered ring optionally comprising 1 to 3 heteroatoms independently selected from S, O and N and optionally substituted with 1 to 3 groups independently selected from halogen or C.sub.1-C.sub.6 alkyl; R.sup.8 is hydrogen, cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.2-C.sub.6alkenyloxy, C.sub.2-C.sub.6alkynyloxy, C.sub.3-C.sub.10cycloalkyloxy, C.sub.3-C.sub.10cycloalkenyloxy, C.sub.2-C.sub.6haloalkenyloxy; or R.sup.7 and R.sup.8 together with the carbon atoms to which they are attached form a saturated or partially unsaturated 3-9 membered ring optionally comprising 1 to 3 heteroatoms independently selected from S, O and N and optionally substituted with 1 to 3 groups independently selected from halogen or C.sub.1-C.sub.6 alkyl, to the unwanted plants or to the locus thereof.

2. The method according to claim 1, wherein R.sup.1 is hydrogen, halogen, formyl, cyano, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 haloalkoxy, —C(O)NR.sup.6R.sup.7, NR.sup.6R.sup.7, or C.sub.1-C.sub.6 haloalkyl

3. (canceled)

4. The method according to claim 1, wherein R.sup.2 is halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 alkylthio, —C(O)OR.sup.6, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy, C.sub.3-C.sub.6 cycloalkyl, or C.sub.2-C.sub.6 alkynyl

5. (canceled)

6. The method according to claim 1 wherein R.sup.3 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.3-C.sub.10 cycloalkyl, or NR.sup.6R.sup.7.

7. (canceled)

8. The method according to claim 1 wherein R.sup.5 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy, C.sub.3-C.sub.10 cycloalkyloxy, C.sub.3-C.sub.10 cycloalkenyloxy, C.sub.2-C.sub.6 haloalkenyloxy, C.sub.6-C.sub.20 aryl, C.sub.3-C.sub.20 heterocylcyl, or NR.sup.6R.sup.7.

9. The method according to claim 1, wherein R.sup.3 and R.sup.5 together with X.sub.2 and the atoms to which they are attached, form a ring system Q, selected from the group consisting of Q.sub.1 and Q.sub.2, ##STR00195## wherein X.sup.2 and R.sup.4 are as defined in claim 1, and A denotes the point of attachment to the pyridino/pyrimidino-thiazole moiety.

10. (canceled)

11. The method according to claim 1 wherein R.sup.4 is O.

12. The method according to claim 1 wherein X.sub.2 is O, or NR.sup.8.

13. (canceled)

14. (canceled)

15. (canceled)

16. A herbicidal composition comprising from 0.1 to 99% by weight, of a compound of Formula (I) as defined in claim 1, and from 1 to 99.9% by weight of a formulation adjuvant, wherein the formulation adjuvant comprises from 0 to 25% by weight of a surface-active substance.

17. (canceled)

18. The herbicidal composition of claim 16, further comprising at least one additional pesticide selected from a herbicide or herbicide safener.

19. (canceled)

20. (canceled)

21. A method of selectively controlling weeds at a locus comprising crop plants and weeds, wherein the method comprises application to the locus, of a weed-controlling amount of (i) a compound of formula (I): ##STR00196## or a salt or N-oxide thereof, wherein, X.sub.1 is N or CR.sup.1; R.sup.1 is hydrogen, halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6alkoxy, —C(O)OR.sup.6 or S(O).sub.n(C.sub.1-C.sub.6alkyl), formyl, hydroxyl, —C(O)NR.sup.6R.sup.7, NR.sup.6R.sup.7, benzyloxy, C.sub.1-C.sub.6 haloalkoxy, or C.sub.1-C.sub.6 haloalkyl; R.sup.2 is hydrogen, halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6cycloalkyl, —C(O)OR.sup.6, S(O).sub.n(C.sub.1-C.sub.6alkyl), C.sub.1-C.sub.6 alkoxy, or C.sub.1-C.sub.6 haloalkoxy; n is 0, 1, or 2; R.sup.3 is hydrogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6haloalkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6haloalkoxy, C.sub.2-C.sub.6alkenyloxy, C.sub.3-C.sub.10cycloalkyl, NR.sup.6R.sup.7, R.sup.4 is O, S, or N(C.sub.1-C.sub.6alkyl); X.sub.2 is O, S, or NR.sup.8; R.sup.5 is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, C.sub.3-C.sub.10cycloalkenyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6haloalkenyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.2-C.sub.6alkenyloxy, C.sub.2-C.sub.6alkynyloxy, C.sub.3-C.sub.10cycloalkyloxy, C.sub.3-C.sub.10cycloalkenyloxy, C.sub.2-C.sub.6haloalkenyloxy, C.sub.6-C.sub.10aryl or C.sub.6-C.sub.10aryl substituted by from 1 to 3 groups independently selected from halogen, nitro, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkyl, and C.sub.1-C.sub.3 haloalkoxy; C.sub.3-C.sub.10heterocylcyl or C.sub.3-C.sub.10heterocyclycl substituted by from 1 to 3 groups independently selected from halogen, nitro, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkyl, and C.sub.1-C.sub.3 haloalkoxy; or NR.sup.6R.sup.7; or R.sup.3 and R.sup.5 together with X.sub.2 and the atoms to which they are attached, form a saturated or partially unsaturated 5-9 membered ring system optionally comprising 1 to 3 heteroatoms independently selected from S, O and N and optionally substituted with 1 to 3 groups independently selected from halogen or C.sub.1-C.sub.6 alkyl; or R.sup.3 and R.sup.8 together with the atoms to which they are attached form a saturated or partially unsaturated 5-9 membered ring system optionally comprising 1 to 3 heteroatoms independently selected from S, O and N and optionally substituted with 1 to 3 groups independently selected from halogen or C.sub.1-C.sub.6 alkyl; R.sup.6 and R.sup.7 are each independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl, or R.sup.4 and R.sup.5 together with X.sub.2 and the atoms to which they are attached, form a saturated or partially unsaturated 5-9 membered ring system optionally comprising 1 to 3 heteroatoms independently selected from S, O and N and optionally substituted with 1 to 3 groups independently selected from halogen or C.sub.1-C.sub.6 alkyl; or R.sup.6 and R.sup.7 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 3-6 membered ring optionally comprising 1 to 3 heteroatoms independently selected from S, O and N and optionally substituted with 1 to 3 groups independently selected from halogen or C.sub.1-C.sub.6 alkyl; R.sup.8 is hydrogen, cyano, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.2-C.sub.6alkenyloxy, C.sub.2-C.sub.6alkynyloxy, C.sub.3-C.sub.10cycloalkyloxy, C.sub.3-C.sub.10cycloalkenyloxy, C.sub.2-C.sub.6haloalkenyloxy; or R.sup.7 and R.sup.8 together with the carbon atoms to which they are attached form a saturated or partially unsaturated 3-9 membered ring optionally comprising 1 to 3 heteroatoms independently selected from S, O and N and optionally substituted with 1 to 3 groups independently selected from halogen or C.sub.1-C.sub.6 alkyl.

Description

PREPARATION EXAMPLES

[0110] Throughout the following examples, 1H NMR spectra were recorded at 400 MHz or 500 MHz, unless otherwise stated, either on a Varian Unity Inova instrument or Bruker AVANCE-II instrument.

[0111] The following abbreviations are used: s=singlet; d=doublet; dd=double doublet; t=triplet, q=quartet; m=multiplet. The term app. is used for apparent and br. denotes a broader signal.

[0112] Molecules are given their known names or named according to the naming programs within Accelrys Draw 4.0 or Symyx Notebook 6.6. If such programs are unable to name a molecule, the molecule is named using agreed naming conventions.

Example 1 Preparation of compound A1 (tert-butyl N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate)

1.1 Preparation of 4-methyl-2-(3-pyridyl)thiazole-5-carboxylate ethyl ester (compound 1.1001)

[0113] ##STR00102##

[0114] To a flask charged with thionicotinamide (10 g, 72.3 mmol) was added ethyl-2-chloroacetoacetate (11.9 g, 72.4 mmol) and heated at reflux in ethanol (100 mL) overnight. The next morning solvent was removed in vacuo and the residue partitioned between EtOAc and sat. aq. NaHCO.sub.3 solution. The aqueous phase was extracted with two further portions of EtOAc. The combined organic extracts were washed with brine then dried over MgSO.sub.4 and concentrated in vacuo. The resulting mixture was purified via flash chromatography on silica gel using an EtOAc/isohexane gradient to give the desired compound (4-methyl-2-(3-pyridyl)thiazole-5-carboxylate ethyl ester, 11.9 g) as a pale brown oil which slowly solidified.

[0115] 1H NMR (400 MHz, CDCl.sub.3) δ=9.17 (1H, m), 8.69 (1H, dd), 8.24 (1H, m), 7.40 (1H, m), 4.37 (2H, q), 2.80 (3H, s), 1.40 (3H, t)

1.2 Preparation of 4-methyl-2-(3-pyridyl)thiazole-5-carboxylic acid (1.2001)

[0116] ##STR00103##

[0117] A solution of 4-methyl-2-(3-pyridyl)thiazole-5-carboxylate ethyl ester (compound 1.1001; 35.2 g, 142 mmol) in methanol (462 mL) was cooled in ice/water then a solution of NaOH (17.0 g, 425 mmol) in water (214 mL) was added slowly with stirring and stirred without cooling for one hour.

[0118] 2M HCl (216 mL) was added slowly with stirring and ice/water cooling. The mixture was stirred for a further 30 mins. The resulting precipitate was filtered, washed with water and air-dried to give the desired compound (4-methyl-2-(3-pyridyl)thiazole-5-carboxylic acid, 28.1 g) as an off white solid.

[0119] 1H NMR (400 MHz, d6-DMSO) δ=13.54 (1H, br. s.), 9.16 (1H, d), 8.72 (1H, dd), 8.35 (1H, m), 7.56 (1H, dd) 2.70 (3H, s)

1.3 Preparation of tert-butyl N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (1.3001)

[0120] ##STR00104##

[0121] To a suspension of 4-methyl-2-(3-pyridyl)thiazole-5-carboxylic acid (compound 1.2001; 22.4 g, 101.7 mmol) in 2-methylpropan-2-ol (448 mL) and toluene (448 mL) was added Et.sub.3N (14.2 mL, 101 mmol) and the reaction stirred for five minutes at room temperature before DPPA (27.8 g, 101 mmol) was added slowly with stirring and cooling to maintain the temperature below ambient. The reaction was heated gradually to reflux for 3 hours, then allowed to cool overnight to room temperature.

[0122] The solvent was removed in vacuo and the residue purified via flash column chromatography on silica gel using an EtOAc/isohexane gradient to give the desired compound (tert-butyl N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 25.8 g) as a beige solid.

[0123] 1H NMR (400 MHz, CDCl.sub.3) δ=9.09 (1H, s), 8.59 (1H, d), 8.16 (1H, dd), 7.36 (1H, m), 6.72 (1H, br. s), 2.37 (3H, s), 1.49 (9H, br. s.)

1.4 Preparation of tert-butyl N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (A1)

[0124] ##STR00105##

[0125] A solution of tert-butyl N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (compound 1.3001; 21.2 g, 72.7 mmol) in anhydrous DMF (245 mL) was cooled in ice/water and NaH 60% w/w (3.49 g, 87.3 mmol) was added portion-wise with stirring, then warmed to ambient over 5 minutes. The mixture was re-cooled in ice/water and then a solution of MeI (11.35 g, 80.0 mmol) in dry DMF (5 mL) was added dropwise with stirring and cooling over 30 minutes. The reaction was stirred at room temperature overnight and then cautiously quenched with water (1000 mL) and 2M HCl (7.29 mL). The reaction mixture was extracted three times with EtOAc, the combined organic extracts were washed twice with brine then dried over MgSO.sub.4. The solvent was removed in vacuo and the residue purified via flash chromatography on silica gel using an EtOAc/isohexane gradient to give the desired compound (tert-butyl N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 25.1 g) as a beige solid.

[0126] 1H NMR (400 MHz, CDCl.sub.3) δ=9.08 (1H, d), 8.63 (1H, dd), 8.17 (1H, d), 7.36 (1H, dd), 3.22 (3H, s), 2.33 (3H, s), 1.44 (9H, br.s.)

Example 2 Preparation of tert-butyl N-methyl-N-(4-methyl-2-pyrimidin-5-yl-thiazol-5-yl)carbamate (A2)

[0127] ##STR00106##

[0128] To a flask charged with pyrimidin-5-ylboronic acid (150.0 mg, 1.21 mmol) was added EtOH (2.7 mL) and toluene (5.3 mL) then 2M aq. K.sub.2CO.sub.3 (1.2 mL, 2.4 mmol) was added. The reaction was set stirring and tert-butyl N-(2-bromo-4-methyl-thiazol-5-yl)-N-methyl-carbamate (409 mg, 1.33 mmol) was added, followed by Pd(PPh.sub.3).sub.4 (70 mg, 0.06 mmol). The mixture was heated at 90° C. for two hours and then allowed to cool overnight to ambient.

[0129] The mixture was diluted with EtOAc and washed twice with brine. The combined aqueous washings were back-extracted with EtOAc and the combined organic extracts were washed with brine and then dried over MgSO.sub.4. The solvent was removed in vacuo and the residue purified via flash column chromatography on silica gel using an EtOAc/isohexane gradient to afford the desired compound (tert-butyl N-methyl-N-(4-methyl-2-pyrimidin-5-yl-thiazol-5-yl)carbamate, 170 mg) as a straw coloured gum.

[0130] 1H NMR (400 MHz, CDCl.sub.3) δ=9.23 (1H, s), 9.18 (2H, s), 3.23 (3H, s), 2.35 (3H, s), 1.45 (9H, br.s.)

Example 3 Preparation of tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate (A3)

[0131] ##STR00107##

[0132] To a flask charged with tert-butyl N-(2-bromo-4-methyl-thiazol-5-yl)-N-methyl-carbamate (8.78 g, 27.8 mmol) and (5-fluoro-3-pyridyl)boronic acid (4.71 g, 33.4 mmol) was added ethanol (55.7 mL) and toluene (111.6 mL). Pd(PPh.sub.3).sub.4 (1.50 g, 1.30 mmol) was added and the mixture stirred vigorously. 2M aq. K.sub.2CO.sub.3 (25.5 mL, 51.0 mmol) was added and the reaction was heated to reflux for 7 hours, then left to cool to ambient overnight.

[0133] Solvent was removed in vacuo and the crude material was re-dissolved in CHC1.sub.3 and washed with water. The organic phase was concentrated in vacuo and the residue purified via flash column chromatography on silica gel using an EtOAc/isohexane gradient to give the desired compound (tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate, 6.92 g) as a beige solid.

[0134] 1H NMR (400 MHz, CDCl.sub.3) δ=8.85-8.89 (1H, m), 8.49 (1H, d), 7.93 (1H, dd), 3.23 (3H, s), 2.33 (3H, s), 1.45 (9H, br.s).

Example 4 Preparation of tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate (A35)

4.1 Preparation of Compound A35

[0135] ##STR00108##

[0136] To a flask charged with tert-butyl N-(2-bromo-4-methyl-thiazol-5-yl)carbamate (11.31 g, 38.6 mmol) and (5-fluoro-3-pyridyl)boronic acid (6.52 g, 46.3 mmol) was added toluene (151 mL) and ethanol (75 mL). Pd(PPh.sub.3).sub.4 (2.20 g, 1.90 mmol) was added, followed by 2M aq K.sub.2CO.sub.3 (38.6 mL, 77.2 mmol). The reaction was heated to reflux for five and a half hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to remove the organics. The mixture was diluted with CHCl.sub.3 and washed with water. The organic phase was concentrated in vacuo and the residue purified via flash column chromatography on silica using an EtOAc/isohexane gradient to afford the desired compound (tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate, 10.2 g) as a beige solid.

[0137] 1H NMR (400 MHz, CDCl.sub.3) δ=8.87 (1H, m), 8.44 (1H, d), 7.94-7.87 (1H, m), 6.73 (1H, br. s), 2.39 (3H, s), 1.55 (9H, s)

4.2 Alternative preparation of tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate (A3)

[0138] Compound A35 may also be used as an intermediate in an alternative method of producing compound A3.

##STR00109##

[0139] To a round bottomed flask charged with tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate (800 mg, 2.59 mmol) and K.sub.2CO.sub.3 (429 mg, 3.10 mmol) was added iodomethane (807 mg, 5.69 mmol) as a solution in MeCN (20 mL) and the mixture set vigorously stirring. After 5 minutes the reaction was heated to reflux for 2 hours. Upon cooling the mixture was filtered through celite and concentrated in vacuo. The resulting semi-solid was purified via flash column chromatography on silica gel using an EtOAc/isohexane gradient to afford the desired compound (tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate, 449 mg) as a yellow gum.

[0140] 1H NMR (400 MHz, CDCl.sub.3) δ=8.85-8.89 (1H, m), 8.49 (1H, d), 7.93 (1H, dd), 3.23 (3H, s), 2.33 (3H, s), 1.45 (9H, br.s.)

Example 5 Preparation of tert-butyl N-[2-[5-(difluoromethoxy)-3-pyridyl]-4-methyl-thiazol-5-yl]-N-methyl-carbamate (A16)

5.1 Preparation of tert-butyl N-(2-bromo-4-methyl-thiazol-5-yl)carbamate (compound 5.1001)

[0141] ##STR00110##

[0142] To a flask charged with 2-bromo-4-methyl-thiazole-5-carboxylic acid (5.0 g, 22.5 mmol) and Et.sub.3N (3.14 mL, 22.5 mmol) was added t-BuOH (193 mL) and the mixture was heated to reflux. DPPA (4.89 mL, 22.5 mmol) was added dropwise over ca. 15 mins, then stirred at reflux for a further 6.5 hours, then allowed to cool overnight.

[0143] The reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc (95 mL) and washed with water (140 mL). The aqueous phase was back-extracted twice more with EtOAc and the combined organics were washed with brine and dried over MgSO.sub.4. The solvent was removed in vacuo and the residue purified via flash column chromatography on silica gel using an EtOAc/isohexane gradient to afford the desired compound (tert-butyl N-(2-bromo-4-methyl-thiazol-5-yl)carbamate, 5.4 g) as an opaque gum.

[0144] 1H NMR (400 MHz, CDCl.sub.3) 6.32 (1H, br. s), 2.29 (3H, s), 1.51 (9H, s)

5.2 Preparation of tert-butyl N-(2-bromo-4-methyl-thiazol-5-yl)-N-methyl-carbamate (5.2001)

[0145] ##STR00111##

[0146] To a flask charged with tert-butyl N-(2-bromo-4-methyl-thiazol-5-yl)carbamate (32.0 g, 109.12 mmol) was added DMF (130 mL), the reaction was cooled in an ice bath and NaH 60% w/w (4.8 g, 120 mmol) added portion-wise with stirring and cooling to maintain the temperature in the range 5-10° C. The mixture was stirred for 10 mins then allowed to warm to ambient over ca. 40 mins. The reaction was cooled in an ice bath then iodomethane (16.27 g, 114.6 mmol) in DMF (100 mL) was added slowly with stirring and cooling to maintain the temperature in the range 5-10° C. The reaction was allowed to warm to ambient and stirred for a further 5 hours. The reaction mixture was cooled in an ice bath and quenched by the cautious addition of water (920 mL).

[0147] The reaction mixture was extracted three times with EtOAc and the combined organics washed with brine and dried over MgSO.sub.4. The solvent was removed in vacuo and the residue purified via flash column chromatography on silica gel eluting with an EtOAc/isohexane gradient to afford the desired compound (tert-butyl N-(2-bromo-4-methyl-thiazol-5-yl)-N-methyl-carbamate, 33.2 g) as a colourless oil.

[0148] 1H NMR (400 MHz, CDCl.sub.3) δ=1.43 (9H, br. s.), 2.24 (3H, s), 3.16 (3H, s)

5.3 Preparation of 3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (5.3001)

[0149] ##STR00112##

[0150] To a flask charged with 3-bromo-5-(difluoromethoxy)pyridine (4.50 g, 20.1 mmol) was added bispinacolatodiboron (7.65 g, 30.1 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]palladium(ii) dichloride dichloromethane adduct (837 mg, 1.00 mmol) and KOAc (6.5 g, 64.0 mmol). 1,4-Dioxane (95 mL) was added and the mixture was purged with dry N.sub.2 and heated at 100° C. for 1 hour.

[0151] The reaction was cooled to ambient and concentrated in vacuo. The residue was dissolved in CH.sub.2Cl.sub.2 and filtered through celite. The filtrate was concentrated in vacuo to give a thick black oil which was purified via flash column chromatography on silica gel using an EtOAc/isohexane gradient to afford the desired compound (3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 3.95 g) as a straw coloured oil which crystallized on standing.

[0152] .sup.11H NMR (400 MHz, CDCl.sub.3) δ=8.80 (1H, d), 8.54 (1H, d), 7.82 (1H, m), 6.76-6.36 (1H, t), 1.36 (12H, s)

5.4 Preparation of tert-butyl N-[2-[5-(difluoromethoxy)-3-pyridyl]-4-methyl-thiazol-5-yl]-N-methyl-carbamate (A16)

[0153] ##STR00113##

[0154] To a microwave vial charged with tert-butyl N-(2-bromo-4-methyl-thiazol-5-yl)-N-methyl-carbamate (500 mg, 1.59 mmol) and 3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (430 mg, 1.59 mmol) was added EtOH (2 mL) and toluene (4 mL). Pd(PPh.sub.3).sub.4 (85.3 mg, 0.074 mmol) was added, followed by 2M K.sub.2CO.sub.3 (1.45 mL, 2.90 mmol) and the tube sealed. The mixture was heated to 130 C for 30 minutes under microwave irradiation.

[0155] Upon cooling the solvent was removed in vacuo and residue partitioned between CHCl.sub.3 and water. The organic phase was concentrated in vacuo to give a black gum which was purified via flash column chromatography on silica gel using a EtOAc/isohexane gradient to afford impure tert-butyl N-[2-[5-(difluoromethoxy)-3-pyridyl]-4-methyl-thiazol-5-yl]-N-methyl-carbamate. This material was further purified via flash column chromatography on a C.sub.18 reverse phase column using a water (0.1% formic acid modifier)/MeCN (0.1% formic acid modifier) gradient to afford the desired compound (tert-butyl N-[2-[5-(difluoromethoxy)-3-pyridyl]-4-methyl-thiazol-5-yl]-N-methyl-carbamate, 352 mg).

[0156] 1H NMR (400 MHz, CDCl.sub.3) δ=8.91 (1H, d), 8.50 (1H, d), 7.99 (1H, s), 6.82-6.41 (1H, t), 3.23 (3H, s), 2.33 (3H, s), 1.45 (9H, br. s)

Example 6 Preparation of ethyl N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (A19)

[0157] ##STR00114##

[0158] To a flask charged with N,4-dimethyl-2-(3-pyridyl)thiazol-5-amine (300.0 mg, 1.46 mmol) dissolved in CH.sub.2Cl.sub.2 (4 mL) was added pyridine (173.4 mg, 2.192 mmol) and DMAP (17.9 mg, 0.147 mmol). The reaction mixture was cooled in an ice bath and a solution of ethyl chloroformate (206 mg, 1.90 mmol) in CH.sub.2Cl.sub.2 (1 mL) was added drop-wise. After one hour at ambient the solvent was removed in vacuo. The residue was partitioned between water and EtOAc and the organic phase washed once with brine then dried (MgSO.sub.4). The solvent was removed in vacuo and the residue purified via flash column chromatography on silica gel using an EtOAc/isohexane gradient as eluent to afford the target compound (ethyl N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 280 mg) as a straw coloured gum.

[0159] 1H NMR (400 MHz, CDCl.sub.3) δ=9.08 (1H, d), 8.64 (1H, dd), 8.17 (1H, m), 7.37 (1H, dd), 4.20 (2H, q), 3.27 (3H, s), 2.33 (3H, s), 1.24 (3H, app. br. s)

Example 7 Preparation of 3-tert-butyl-1-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]urea (A21)

7.1 Preparation of 2-(5-fluoro-3-pyridyl)-N,4-dimethyl-thiazol-5-amine hydrochloride (7.1001)

[0160] ##STR00115##

[0161] To a solution of tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate (4.23 g, 13.1 mmol) in CH.sub.2Cl.sub.2 (66 mL), cooled with an ice bath, was added 2M hydrogen chloride in Et.sub.2O (65.4 mL, 130.7 mmol) slowly with stirring. The mixture was stirred in the ice bath for a further 5 minutes then allowed to stand overnight and stirred at ambient for a further 2 days.

[0162] Concentration in vacuo yielded the desired compound (2-(5-fluoro-3-pyridyl)-N,4-dimethyl-thiazol-5-amine hydrochloride, 3.84 g) as an orange solid.

[0163] 1H NMR (400 MHz, d6-DMSO) δ=8.79 (1H, m), 8.51 (1H, d), 8.01 (1H, m), 2.85 (3H, s), 2.25 (3H, s)

7.2 Preparation of 3-tert-butyl-1-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]urea (A21)

[0164] ##STR00116##

[0165] A solution of N,4-dimethyl-2-(3-pyridyl)thiazol-5-amine hydrochloride (600.0 mg, 2.92 mmol) in CH.sub.2Cl.sub.2 (9 mL) was cooled in an ice bath and a solution of t-butylisocyanate (348 mg, 3.51 mmol) in CH.sub.2Cl.sub.2 (1 mL) was added drop-wise. The reaction was allowed to warm to ambient and allowed to stir for 3 days.

[0166] The solvent was removed in vacuo and the residue purified via flash column chromatography on silica gel eluted with a CH.sub.2Cl.sub.2/EtOAc gradient to afford the desired compound (3-tert-butyl-1-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]urea, 300 mg) as a white solid.

[0167] 1H NMR (400 MHz, CDCl.sub.3) δ=9.12 (1H, d), 8.67 (1H, dd), 8.19 (1H, m), 7.39 (1H, dd), 4.48 (1H, br. s), 3.20 (3H, s), 2.35 (3H, s), 1.30 (9H, br. s)

Example 8 Preparation of S-tert-butyl N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamothioate (A22)

[0168] ##STR00117##

[0169] To a flask charged with N,4-dimethyl-2-(3-pyridyl)thiazol-5-amine hydrochloride (300.0 mg, 1.46 mmol) was added CH.sub.2Cl.sub.2 (4 mL), pyridine (173.4 mg, 2.19 mmol) and DMAP (17.9 mg, 0.15 mmol). The reaction mixture was cooled in an ice bath and a solution of S-tert-butyl chlorothioformate (290 mg, 1.90 mmol) in CH.sub.2Cl.sub.2 (1 mL) was added drop-wise. The reaction was allowed to stir at ambient for one hour.

[0170] The solvent was removed in vacuo and the residue partitioned between water and EtOAc. The organic phase was washed with brine then dried (MgSO.sub.4). Concentration in vacuo afforded a thick residue which was purified via flash column chromatography on silica gel using an EtOAc/isohexane gradient to afford the desired compound (S-tert-butyl N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamothioate, 290 mg) as a pale yellow gum.

[0171] 1H NMR (400 MHz, CDCl.sub.3) δ=9.12 (1H, d), 8.66 (1H, dd), 8.20 (1H, m), 7.38 (1H, dd), 3.25 (3H, s), 2.35 (3H, s), 1.47 (9H, m)

Example 9 Preparation of tert-butyl N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamodithioate (A23)

[0172] ##STR00118##

[0173] To a flask charged with N,4-dimethyl-2-(3-pyridyl)thiazol-5-amine hydrochloride (300.0 mg, 1.47 mmol) was added EtOH (1.0 mL). The mixture was cooled in an ice bath and carbon disulphide (127 μL, 2.11 mmol) was added followed by K.sub.2CO.sub.3 (235 mg, 1.68 mmol). The mixture was allowed to warm gradually to ambient overnight.

[0174] 2-Iodo-2-methyl-propane (194 μL, 1.47 mmol) was added and the reaction stirred at ambient for three days. The solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The organic phase was washed once with brine and concentrated in vacuo and the residue purified via flash column chromatography on silica gel using an EtOAc/isohexane gradient to afford the desired compound (tert-butyl N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamodithioate, 37 mg) as a pale yellow gum.

[0175] 1H NMR (400 MHz, CDCl.sub.3) δ=9.14 (1H, d), 8.68 (1H, dd), 8.25 (1H, m), 7.44 (1H, m), 3.65 (3H, s), 2.32 (3H, s), 1.59 (9H, s)

Example 10 Preparation of tert-butyl N-[2-(5-methoxy-3-pyridyl)-4-(trifluoromethyl)thiazol-5-yl]-N-methyl-carbamate (A28)

[0176] ##STR00119##

[0177] To a microwave tube charged with tert-butyl N-[2-bromo-4-(trifluoromethyl)thiazol-5-yl]-N-methyl-carbamate (200 mg, 0.55 mmol) and 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (131 mg, 0.56 mmol) was added ethanol (1.2 mL) and toluene (2.4 mL) then 2M K.sub.2CO.sub.3 (549 μL, 1.1 mmol) followed by Pd(PPh.sub.3).sub.4 (33 mg, 0.03 mmol). The tube was sealed and the reaction was heated to 130° C. for 20 mins under microwave irradiation.

[0178] Upon cooling the solvent was removed in vacuo and the residue dissolved in CHCl.sub.3, and washed with water. The reaction mixture was concentrated in vacuo to leave a dark brown gum, which was purified via flash column chromatography on silica gel using an EtOAc/isohexane gradient to afford the desired compound (tert-butyl N-[2-(5-methoxy-3-pyridyl)-4-(trifluoromethyl)thiazol-5-yl]-N-methyl-carbamate, 92 mg) as a beige solid.

[0179] 1H NMR (500 MHz, CDCl.sub.3) δ=8.64 (1H, d), 8.40 (1H, d), 7.77 (1H, br. s), 3.95 (3H, s), 3.26 (3H, s), 1.43 (9H, br. s)

Example 11 Preparation of of tert-butyl N-[4-bromo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (A30)

[0180] ##STR00120##

[0181] To a flask charged with tert-butyl N-methyl-N-[2-(3-pyridyl)thiazol-5-yl]carbamate (150 mg, 0.52 mmol) was added MeCN (3.0 mL), the mixture was purged with dry N.sub.2 then NBS (183 mg, 1.03 mmol) was added in a single portion. The mixture was stirred for an hour at ambient and then left to stand for 4 days.

[0182] The reaction mixture was concentrated in vacuo and the residue purified via flash column chromatography on silica gel eluting with a EtOAc/isohexane gradient to afford the desired compound (tert-butyl N-[4-bromo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate, 110 mg) as colourless gum.

[0183] 1H NMR (400 MHz, CDCl.sub.3) δ=9.08 (1H, d), 8.70-8.64 (1H, m), 8.20 (1H, m), 7.42-7.37 (1H, m), 3.25 (3H, s), 1.46 (9H, br. s)

Example 12 Preparation of tert-butyl N-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (A31)

[0184] ##STR00121##

[0185] To a flask charged with tert-butyl N-methyl-N-[2-(3-pyridyl)thiazol-5-yl]carbamate (1.1 g, 3.8 mmol) was added MeCN (33 mL), the reaction was cooled in ice, purged with dry N.sub.2 then NIS (1.78 g, 7.91 mmol) was added in a single portion. The mixture was allowed to warm to ambient and stirred for a further 7 days.

[0186] The reaction mixture was concentrated in vacuo and the residue purified via flash column chromatography on silica gel eluting with a EtOAc/isohexane gradient to afford the desired compound (tert-butyl N-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate, 1.02 g) as a beige solid.

[0187] 1H NMR (400 MHz, CDCl.sub.3) δ=9.08 (1H, d), 8.67 (1H, dd), 8.22 (1H, m), 7.40 (1H, dd), 3.24 (3H, s), 1.46 (9H, br. s)

Example 13 Preparation of tert-butyl N-[4-fluoro-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (A32)

[0188] ##STR00122##

[0189] To a flask charged with tert-butyl N-methyl-N-[2-(3-pyridyl)thiazol-5-yl]carbamate (150 mg, 0.51 mmol), dissolved in MeCN (6.1 mL) and purged with dry N.sub.2 was added SelectFluor® (364.7 mg, 1.03 mmol) in a single portion. The reaction was again flushed with dry N.sub.2 then stirred ambientfor 5 hours. Water (15 mL) added then the mixture was extracted three times with EtOAc. The combined organics were dried (MgSO.sub.4) and the solvent was concentrated in vacuo. The residue was purified via flash column chromatography on silica gel eluting with an EtOAc/isohexane gradient to afford the desired compound (tert-butyl N-[4-fluoro-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate, 60 mg) as a straw coloured gum.

[0190] 1H NMR (500 MHz, CDCl.sub.3) δ=9.06 (1H, d), 8.65 (1H, d), 8.13 (1H, d), 7.38 (1H, dd), 3.30 (3H, br. s), 1.50 (9H, br. s)

Example 14 Preparation of 3-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]imidazolidine-2,4-dione (A33)

14.1 Preparation of 4-methyl-2-(3-pyridyl)thiazole (14.1001)

[0191] ##STR00123##

[0192] To a flask charged with thionicotinamide (50 g, 361.8 mmol) was added EtOH (300 mL) followed by chloroacetone (40 g, 432.3 mmol) and the mixture was heated to reflux overnight.

[0193] Upon cooling the solvent was removed in vacuo and the residue was dissolved in water (400 mL) and made basic with NaHCO.sub.3. This mixture was extracted three times with EtOAc and the combined organics washed once with brine then dried (MgSO.sub.4). The organics were concentrated in vacuo and the residue purified via flash column chromatography on silica gel using an EtOAc/isohexane gradient to give the desired compound (4-methyl-2-(3-pyridyl)thiazole, 38.8 g) as a straw coloured oil.

[0194] 1H NMR (400 MHz, CDCl.sub.3) δ=9.15 (1H, d), 8.63 (1H, dd), 8.22 (1H, m), 7.36 (1H, m), 6.95 (1H, s), 2.53 (3H, s)

14.2 Preparation of 5-bromo-4-methyl-2-(3-pyridyl)thiazole (14.2001)

[0195] ##STR00124##

[0196] 4-Methyl-2-(3-pyridyl)thiazole (10.0 g, 56.7 mmol) was dissolved in DMF (100 mL) and NBS (11.1 g, 62.4 mmol) was added with cooling to keep the temperature at below ambient. The reaction was heated at 50 C for ca. 3 hours and left to cool overnight.

[0197] The reaction was quenched with water (400 mL) and extracted three times with EtOAc. The combined organics were washed three times with brine and dried (MgSO.sub.4).

[0198] The reaction mixture was concentrated in vacuo and the residue was purified via flash column chromatography on silica gel using an EtOAc/isohexane gradient to give 5-bromo-4-methyl-2-(3-pyridyl)thiazole (13.24 g, 51.9 mmol) as a beige solid.

[0199] 1H NMR (400 MHz, CDCl.sub.3) δ=9.06 (1H, m) 8.66 (1H, dd) 8.15 (1H, s) 7.35-7.41 (1H, m) 2.48 (3H, s)

14.3 Preparation of 3-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]imidazolidine-2,4-dione (A33)

[0200] ##STR00125##

[0201] To a microwave tube charged with 5-bromo-4-methyl-2-(3-pyridyl)thiazole (136 mg, 0.53 mmol) was added 3-methylimidazolidine-2,4-dione (121.6 mg, 1.07 mmol) and N,N′-dimethylethylenediamine (4.7 mg, 0.05 mmol) dissolved in 1,4-dioxane (3.2 mL). CuI (10.2 mg, 0.05 mmol) and K.sub.2CO.sub.3 (295 mg, 2.13 mmol) were added, the tube was sealed the mixture was heated at 160° C. for 1 hour under microwave irradiation.

[0202] The solvent was removed in vacuo and the residue partitioned between water and EtOAc, filtered to remove residual solid and partitioned. The aqueous phase was extracted with two further portions of EtOAc. The combined organic extracts were washed with brine, dried (MgSO.sub.4), and concentrated in vacuo. The residue was purified via reverse phase flash chromatography a C.sub.18 column eluted with a water and MeCN gradient to give the desired compound (3-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]imidazolidine-2,4-dione, 21 mg) as a white solid.

[0203] 1H NMR (400 MHz, CDCl.sub.3) δ=9.08 (1H, d), 8.66 (1H, dd), 8.17 (1H, m), 7.39 (1H, m), 4.28 (2H, s), 3.15 (3H, s), 2.43 (3H, s)

Example 15 Preparation of 3-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]oxazolidin-2-one (A38)

15.1 Preparation of 2-chloroethyl N-tert-butoxycarbonyl-N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate (16.1001)

[0204] ##STR00126##

[0205] To a flask charged with tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate (800 mg, 2.59 mmol) was added dry THF (7 mL). The reaction was cooled in ice then sodium hydride 60% w/w (114 mg, 2.85 mmol) was added portionwise with stirring over 10 mins during which time the reaction had set solid. After standing at ambient for 20 mins, a solution of chloroethyl chloroformate (407 mg, 2.85 mmol) in THF (0.3 mL) was added. After a further 10 minutes stirring a hazy solution resulted, which was stirred for a further 3 hours at ambient.

[0206] The reaction was quenched with water (1 mL) and 2M HCl (528 μl) and then concentrated in vacuo, redissolved in CH.sub.3Cl and partitioned with water. The organic solvent was concentrated in vacuo to yield a pale orange gum which was purified via flash column chromatography on silica gel using an EtOAc/isohexane gradient to give the desired compound (2-chloroethyl N-tert-butoxycarbonyl-N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate, 520 mg) as a colourless gum.

[0207] 1H NMR (400 MHz, CDCl.sub.3) δ=8.90 (1H, m), 8.52 (1H, d), 7.96 (1H, m), 4.46 (2H, m), 3.68 (2H, m), 2.33 (3H, s), 1.48 (9H, s)

15.2 Preparation of 2-chloroethyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate (16.2001)

[0208] ##STR00127##

[0209] A flask charged with 2-chloroethyl N-tert-butoxycarbonyl-N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate (625 mg, 1.50 mmol) and CH.sub.2Cl.sub.2 (6 mL) was cooled in an ice bath and TFA (3 mL) was added slowly with stirring for 5 minutes then left at ambient for 1 hour 45 minutes.

[0210] The solvent was removed in vacuo to leave a gum which was dissolved in CHCl.sub.3, shaken with water and passed through a hydrophobic phase separating cartridge. The aqueous phase was neutralised with sat. aq. NaHCO.sub.3, extracted with CHCl.sub.3 and passed through a hydrophobic phase separating cartridge. The combined organics were concentrated in vacuo to give the desired compound (2-chloroethyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate, 393 mg).

[0211] 1H NMR (400 MHz, CDCl.sub.3) δ=8.88 (1H, m), 8.47 (1H, d), 7.94 (1H, m), 6.93 (1H, br. s), 4.50 (2H, m), 3.77 (2H, m), 2.41 (3H, s)

15.3 Preparation of 3-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]oxazolidin-2-one (A38)

[0212] ##STR00128##

[0213] A flask charged with 2-chloroethyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate (202 mg, 0.64 mmol) and DMF (1.45 mL) was cooled in a salt/ice bath then sodium hydride 60% w/w (30.7 mg, 0.768 mmol) was added in one portion. The reaction mixture was stirred with cooling for 20 minutes then at ambient for a further 3 hours.

[0214] The reaction was cooled in ice then quenched with water (5.8 mL) and 2M HCl (63 μL). The reaction mixture was extracted three times with EtOAc and the combined organics washed once with brine and dried (MgSO.sub.4), then concentrated in vacuo. The residue was purified via column chromatography on silica gel using an EtOAc/isohexane gradient to afford the desired compound (3-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]oxazolidin-2-one, 120 mg).

[0215] 1H NMR (400 MHz, CDCl.sub.3) δ=8.87 (1H, m), 8.51 (1H, d), 7.96-7.90 (1H, m), 4.64-4.53 (2H, m), 4.06-3.97 (2H, m), 2.52 (3H, s)

Example 16 Preparation of methyl 5-[tert-butoxycarbonyl(methyl)amino]-2-(3-pyridyl)thiazole-4-carboxylate (A39)

[0216] ##STR00129##

[0217] To a flask charged with a solution of tert-butyl N-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (0.19 g, 0.44 mmol) in THF (1 mL) cooled to −78° C. was added n-BuLi (1.6M) in hexanes (0.55 mL, 0.89 mmol) drop-wise over 5 min. After 30 min stirring at −78° C., methyl chloroformate (0.07 mL, 0.89 mmol) was added. The mixture was stirred at −78° C. for one hour before being allowed to warm to ambient.

[0218] The reaction was quenched at room temperature by the addition of sat. aq. NH.sub.4Cl solution and extracted with three portions of CH.sub.2Cl.sub.2. The combined organic extracts were dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified via flash column chromatography on silica gel eluted with an EtOAc/isohexane gradient, followed by further purification with reverse phase HPLC to give the desired compound (methyl 5-[tert-butoxycarbonyl(methyl)amino]-2-(3-pyridyl)thiazole-4-carboxylate, 4.7 mg).

[0219] 1H NMR (400 MHz, CDCl.sub.3) δ=9.23 (1H, br. s), 8.80 (1H, d), 8.64 (1H, d), 7.74 (1H, dd), 3.98 (3H, s), 3.31 (3H, s), 1.65-1.32 (9H, br. s)

Example 17 Preparation of tert-butyl N-methyl-N-[2-(3-pyridyl)-4-vinyl-thiazol-5-yl]carbamate (A40)

[0220] ##STR00130##

[0221] To a microwave tube charged with tert-butyl N-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (80 mg, 0.19 mmol), tributyl(vinyl)stannane (0.122 g, 0.38 mmol) and PdCl.sub.2(PPh.sub.3).sub.2 (0.14 mg, 0.02 mmol) was added 1,4-dioxane (1 mL). The tube was sealed and heated at 140° C. for 30 min under microwave irradiation.

[0222] The reaction mixture was concentrated in vacuo and the residue purified via flash column chromatography on silica gel eluting with an EtOAc/isohexane gradient to give the desired compound (tert-butyl N-methyl-N-[2-(3-pyridyl)-4-vinyl-thiazol-5-yl]carbamate, 41.4 mg) as a brown gum.

[0223] 1H NMR (400 MHz, CDCl.sub.3) δ=9.08-9.01 (1H, m), 8.58 (1H, dd), 8.16 (1H, dd), 7.31 (1H, m), 6.50 (1H, dd), 6.16 (1H, dd), 5.42 (1H, dd), 3.17 (3H, s), 1.36 (9H, br. s)

Example 18 Preparation of tert-butyl N-[4-ethynyl-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (A41)

[0224] ##STR00131##

[0225] To a microwave tube charged with tert-butyl N-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (100 mg, 0.24 mmol), tributyl(ethynyl)stannane (150 mg, 0.45 mmol) and PdCl.sub.2(PPh.sub.3).sub.2 (17 mg, 0.024 mmol) was added 1,4-dioxane (2 mL) and the tube was sealed. The reaction was sealed and heated to 140° C. for 30 min under microwave irradiation.

[0226] The reaction mixture was concentrated in vacuo and the residue purified via flash column chromatography on silica gel eluting with an EtOAc/isohexane gradient to afford the desired compound (tert-butyl N-[4-ethynyl-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate, 37 mg) as a brown gum.

[0227] 1H NMR (400 MHz, CDCl.sub.3) δ=9.09 (1H, d), 8.66 (1H, dd), 8.22 (1H, m), 7.38 (1H, dd), 3.43 (3H, s), 1.81 (1H, s), 1.51 (9H, br. s)

Example 19 Preparation of tert-butyl N-[4-cyclopropyl-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (A43)

[0228] ##STR00132##

[0229] To a microwave tube charged with tert-butyl N-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (100 mg, 0.24 mmol), cyclopropylboronic acid (27 mg, 0.31 mmol), tricyclohexylphosphine (6.7 mg, 0.024 mmol) and K.sub.3PO.sub.4 (180 mg, 0.84 mmol) was added toluene (0.72 mL) and water (50 μL). The solution was degassed by vacuum and purged with Ar, Pd(OAc).sub.2 (2.6 mg, 0.012 mmol) was added and the reaction was sealed and heated to 120° C. for 35 min under microwave irradiation.

[0230] The reaction mixture was then diluted with water and extracted with three portions of CH.sub.2Cl.sub.2. The combined organics were dried (MgSO.sub.4) and concentrated in vacuo to give a brown gum which was purified via preparative reverse phase HPLC to afford the desired compound (tert-butyl N-[4-cyclopropyl-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate, 1.6 mg).

[0231] 1H NMR (400 MHz, CDCl.sub.3) δ=9.01 (1H, s), 8.60 (1H, d), 8.14 (1H, m), 7.32 (1H, dd), 3.20 (3H, s), 1.89-1.63 (5H, m), 1.39 (9H, br. s)

Example 20 Preparation of 5-[tert-butoxycarbonyl(methyl)amino]-2-(3-pyridyl)thiazole-4-carboxylic acid (A44)

[0232] ##STR00133##

[0233] To a flask charged with tert-butyl N-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (0.1 g, 0.24 mmol) was added THF (1 mL, 12.3 mmol) and the reaction cooled to −78° C. n-Butyllithium (1.6M) in hexanes (0.30 mL, 0.48 mmol) was then added dropwise over the course of 5 min. After 30 min stirring at −78° C., carbon dioxide was bubbled through the reaction mixture for 10 minutes from subliming dry ice. The reaction was allowed to warm to room temperature then quenched by the addition of sat. aqueous NH.sub.4Cl and the resulting mixture was extracted with three portions CH.sub.2Cl.sub.2. The combined organic phases were dried over MgSO.sub.4 and concentrated in vacuo to give a brown gum which was purified via reverse phase HPLC to give the desired compound (5-[tert-butoxycarbonyl(methyl)amino]-2-(3-pyridyl)thiazole-4-carboxylic acid, 5.9 mg).

[0234] 1H NMR (400 MHz, CDCl.sub.3) δ=9.37 (1H, app. br. s), 8.78 (1H, app. br.s), 8.43 (1H, d), 7.68 (1H, app. br. s), 3.37 (3H, s), 1.46 (9H, br.s)

Example 21 Preparation of 3-tert-butoxy-1-methyl-1-(4-methyl-2-(3-pyridyl)thiazol-5-yl)urea (A45)

[0235] ##STR00134##

[0236] To a flask charged with tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate (93 mg, 0.45 mmol) dissolved in DMF (2 mL) was added K.sub.2CO.sub.3 (82.0 mg, 0.59 mmol) and the reaction mixture was cooled to ca. 10° C. Then (tert-butoxycarbonylamino)-4-methylbenzenesulfonate (prepared according to the procedure of Thambidurai et al., Synlett 2011, 1993) (156.2 mg, 0.54 mmol) was added The resulting orange reaction was stirred for 3 days at ambient.

[0237] The solvent was removed in vacuo and the residue was dissolved in EtOAc, washed with water and the aqueous phase back-extracted three times with EtOAc. The combined organics were dried (Na.sub.2SO.sub.4), concentrated in vacuo and the residue purified via flash column chromatography on silica gel eluting with a CH.sub.2Cl.sub.2/methanol gradient to afford the desired compound (3-tert-butoxy-1-methyl-1-(4-methyl-2-(3-pyridyl)thiazol-5-yl)urea, 93 mg) as an orange solid.

[0238] 1H NMR (400 MHz, CDCl.sub.3) δ=9.12 (1H, s), 8.58 (1H, d), 8.18 (1H, d), 7.43 (1H, dd), 6.96 (1H, br. s), 3.28 (3H, s), 2.41 (3H, s), 1.23 (9H, s)

Example 22 Preparation of (4-nitrophenyl) N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (A61)

[0239] ##STR00135##

[0240] N,4-Dimethyl-2-(3-pyridyl)thiazol-5-amine (5.19 g, 23.0 mmol) and pyridine (2.73 g, 34.5 mmol) plus DMAP (287 mg, 2.30 mmol) were dissolved in CH.sub.2Cl.sub.2 (75 mL), cooled in an ice bath and a solution of (4-nitrophenyl) chloroformate (6.03 g, 29.9 mmol) in CH.sub.2Cl.sub.2 (25 mL) was added drop-wise with stirring. The flask was allowed to warm to ambient and stirred for a further 2 days. The reaction mixture was concentrated in vacuo and the residue partitioned between water and EtOAc. The aqueous phase was back extracted with EtOAc. The combined organic extracts were combined, washed once with brine, dried over MgSO.sub.4, filtered and the filtrate concentrated in vacuo. The residue was purified via flash column chromatography on silica gel and eluted with a CH.sub.2Cl.sub.2/EtOAc gradient to afford the desired compound ((4-nitrophenyl)-N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 7.51 g, ca. 92% purity) as a beige solid.

[0241] 1H NMR (400 MHz, CDCl.sub.3) δ=9.14 (1H, s), 8.67 (1H, dd), 8.33-8.26 (3H, m), 7.39 (1H, dd), 7.23-2.33 (2H, m), 3.40 (3H, s), 2.46 (3H, s)

Example 23 Preparation of 1,1-dimethylprop-2-ynyl N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (B3)

[0242] ##STR00136##

[0243] To a flask charged with 2-methylbut-3-yn-2-ol (84 mg, 1.00 mmol) dissolved in N,N-dimethylformamide (1.5 mL) and cooled in ice was added sodium hydride (60% suspension in oil w/w) (44 mg, 1.10 mmol). The flask was removed from the ice bath and stirred for 15 mins then re-cooled in ice/water. (4-Nitrophenyl) N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (200 mg, 0.497 mmol) was added with stirring and cooling. The reaction was warmed to room temperature and stirred for one further hour. The reaction was quenched with water (6 mL), extracted three times with EtOAc and the organic extracts washed with brine. The combined organics extracts were dried over MgSO.sub.4 and solvent removed in vacuo. The crude residue was purified via reverse phase flash chromatography using a C.sub.18 silica column and a water/acetonitrile gradient to afford the desired compound (1,1-dimethylprop-2-ynyl N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 81 mg).

[0244] 1H NMR (400 MHz, CDCl.sub.3) δ=9.09 (1H, d), 8.64 (1H, dd), 8.18 (1H, d), 7.37 (1H, dd), 3.27 (3H, s), 2.59 (1H, s), 2.5 (3H, s), 1.81-1.53 (6H, br. s)

Example 24 Preparation of 1-methylprop-2-ynyl N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (B2)

[0245] ##STR00137##

[0246] To a flask charged with but-3-yn-2-ol (70 mg, 1.00 mmol) dissolved in N,N-dimethylformamide (1.5 mL) and cooled in ice was added sodium hydride (60% suspension in oil w/w) (44 mg, 1.10 mmol). The flask was removed from the ice bath and stirred for 15 mins, then re-cooled with an ice bath. (4-Nitrophenyl) N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (200 mg, 0.50 mmol) was added with stirring and cooling. The reaction was warmed to room temperature and stirred for one further hour.

[0247] The reaction was quenched with water (6 mL) and extracted three times with EtOAc then the organic extracts washed with brine. The combined organic extracts were dried over MgSO.sub.4 and solvent removed in vacuo. The crude residue was purified via reverse phase flash chromatography using a C.sub.18 silica column and a water/acetonitrile gradient to afford the desired compound (1-methylprop-2-ynyl N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 96 mg) as a straw coloured gum.

[0248] 1H NMR (400 MHz, CDCl.sub.3) δ=9.09 (1H, d), 8.65 (1H, dd), 8.18 (1H, d), 7.38 (1H, dd), 5.43 (1H, br.s), 3.30 (3H, s), 2.51 (1H, br. s), 2.35 (3H, s), 1.45 (3H, br. s)

Example 25 Preparation of prop-2-ynyl N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (B1)

[0249] ##STR00138##

[0250] To a flask charged with propargyl alcohol (55.7 mg, 1.00 mmol) dissolved in N,N-dimethylformamide (1.5 mL), and cooled in ice was added sodium hydride (60% suspension in oil w/w) (44 mg, 1.10 mmol). The flask was removed from the ice bath and stirred for 15 mins, then re-cooled with an ice bath. (4-Nitrophenyl) N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (200 mg, 0.50 mmol) was added with stirring and cooling. The reaction was warmed to room temperature and stirred for one further hour.

[0251] The reaction was quenched with water (6 mL) and extracted three times with EtOAc then the organic extracts washed once with brine. The combined organic extracts were dried over MgSO.sub.4, filtered and solvent removed in vacuo. The crude residue was purified via reverse phase flash chromatography using a C.sub.18 silica column and a water/acetonitrile gradient to afford the desired compound (prop-2-ynyl N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 78 mg) as a straw coloured gum.

[0252] 1H NMR (400 MHz, CDCl.sub.3) δ=9.08 (1H, d), 8.65 (1H, dd), 8.18 (1H, m), 7.38 (1H, dd), 4.72 (2H, br. s), 3.31 (3H, s), 2.51 (1H, br. s), 2.35 (3H, s)

Example 26 Preparation of tert-butyl N-[2-(5-fluoro-3-pyridyl N-oxide)-4-methyl-thiazol-5-yl]-N-methyl-carbamate (A62)

[0253] ##STR00139##

[0254] To a flask charged with tert-butyl N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate (A3) (250 mg, 0.77 mmol) was added CH.sub.2Cl.sub.2 (25 mL) and the mixture stirred vigorously at 0° C. (ice bath). mCPBA (382 mg, 1.55 mmol) was added as a single portion and mixture was allowed to warm to ambient and left stirring overnight.

[0255] The reaction mixture was quenched by the addition of sodium metabisulfite solution (10% w/w, 100 mL) and the phases separated. The organic phase was tested for peroxide (Quantofix® Peroxide 100 test strips, manufactured by Machery-Nagel) and found to be free of residual peroxide.

[0256] The reaction mixture was concentrated in vacuo and the residue purified via flash column chromatography on silica gel eluting with an EtOAc/isohexane gradient to give the desired compound (tert-butyl N-[2-(5-fluoro-3-pyridyl N-oxide)-4-methyl-thiazol-5-yl]-N-methyl-carbamate (A62), 14 mg) as a colourless glass

[0257] 1H NMR (400 MHz, CDCl.sub.3) δ=8.55 (1H, s), 8.12 (1H, d), 7.54 (1H, dd), 3.21 (3H, s), 2.32 (3H, s), 1.46 (9H, br. s)

[0258] Tables 3 and 4 below shows compound of formula (I) as made using the methods described above, or in analogous manner to the compounds described in Examples 1 to 25.

TABLE-US-00003 TABLE 3 Compounds of formula (I) Physical Data (.sup.1H NMR, 400 MHz, CDCl.sub.3 unless Compound Structure stated) A1 [00140] 9.08 (1H, d), 8.63 (1H, dd), 8.17 (1H, d), 7.36 (1H, dd), 3.22 (3H, s), 2.33 (3H, s), 1.44 (9H, br.s.) A2 [00141] 9.23 (1H, s), 9.18 (2H, s), 3.23 (3H, s), 2.35 (3H, s), 1.45 (9H, br.s.) A3 [00142] 8.85-8.89 (1H, m), 8.49 (1H, d), 7.93 (1H, dd), 3.23 (3H, s), 2.33 (3H, s), 1.45 (9H, br.s.) A4 [00143] 8.92 (1H, d), 8.58 (1H, d), 8.20 (1H, t), 3.23 (3H, s), 2.33 (3H, s), 1.45 (9H, br.s.) A5 [00144] 10.2 (1H, s), 9.32 (1H, s), 9.08 (1H, s), 8.58 (1H, s), 3.21 (3H, s), 2.35 (3H, s), 1.44 (9H, br. s) A6 [00145] 8.62 (1H, d), 8.33 (1H, d), 7.71 (1H, br. s), 3.92 (3H, s), 3.21 (3H, s), 2.32 (3H, s), 1.47 (9H, br. s) A7 [00146] 9.23 (1H, d), 8.87 (1H, d), 8.47 (1H, dd), 3.24 (3H, s), 2.34 (3H, s), 1.45 (9H, br. s) A8 [00147] (500 MHz, CDCl.sub.3) 9.19 (1H, s), 9.07 (1H, s), 8.59 (1H, s), 6.76 (1H, br. s), 6.42 (1H, br. s), 3.23 (3H, s), 2.33 (3H, s), 1.45 (9H, br. s) A9 [00148] (500 MHz, CDCl.sub.3) 9.31 (1H, d), 9.14 (1H, d), 8.69 (1H, m), 3.24 (3H, s), 3.18 (3H, s), 2.35 (3H, s), 1.46 (9H,br. s) A10 [00149] (500 MHz, CDCl.sub.3) 9.23 (1H, d), 8.89 (1H, d), 8.44 (1H, s), 3.25 (3H, m), 2.36 (3H, s), 1.46 (9H, br. s) A11 [00150] (500 MHz, CDCl.sub.3) 8.42 (1H, d), 8.09 (1H, d), 7.49 (1H, s), 4.04 (2H, br. s), 3.21 (3H, s), 2.31 (3H, s), 1.44 (9H, br. s) A12 [00151] (500 MHz, CDCl.sub.3) 8.79 (1H, d), 8.50 (1H, m), 8.05 (1H, m), 3.23 (3H, s), 2.57 (3H, s), 2.33 (3H, s), 1.59-1.32 (9H, br. s) A13 [00152] (500 MHz, CDCl.sub.3) 8.38 (1H, d), 8.15 (1H, d), 7.46 (1H, m), 3.22 (3H, s), 3.05 (6H, 2x s), 2.32 (3H, s), 1.44 (9H, br. s) A14 [00153] 8.66 (1H, d), 8.40 (1H, d), 7.80 (1H, dd), 7.48-7.33 (5H, m), 5.18 (2H, s), 3.22 (3H, s), 2.32 (3H, s), 1.44 (9H, br. s) A15 [00154] (400 MHz, DMSO-d6) 10.33 (1H, br. s), 8.50 (1H, d), 8.20 (1H, d), 7.60-7.53 (1H, m), 3.15 (3H, s), 2.24 (3H, s), 1.39 (9H, s) A16 [00155] 8.91 (1H, d), 8.50 (1H, d), 7.99 (1H, s), 6.82-6.41 (1H, t), 3.23 (3H, s), 2.33 (3H, s), 1.45 (9H, br. s) A17 [00156] 9.18 (1H, d), 8.62 (1H, dd), 8.17 (1H, m), 7.38 (1H, m), 3.63 (2H, q), 2.32 (3H, s), 1.43 (9H, br. s), 1.18 (3H, t) A18 [00157] 9.08 (1H, d), 8.64 (1H, dd), 8.17 (1H, dt), 7.37 (1H, m), 3.74 (3H, br. s), 3.28 (3H, s), 2.33 (3H, s) A19 [00158] 9.08 (1H, d), 8.64 (1H, dd), 8.17 (1H, m), 7.37 (1H, dd), 4.20 (2H, q), 3.27 (3H, s), 2.33 (3H, s), 1.24 (3H, app. br. s) A20 [00159] 9.09 (1H, d), 8.64 (1H, dd), 8.18 (1H, m), 7.37 (1H, dd), 4.98 (1H, m), 3.26 (3H, s), 2.33 (3H, s), 1.23 (6H, br. d) A21 [00160] 9.12 (1H, d), 8.67 (1H, dd), 8.19 (1H, m), 7.39 (1H, dd), 4.48 (1H, br. s), 3.20 (3H, s), 2.35 (3H, s), 1.30 (9H, br. s) A22 [00161] 9.12 (1H, d), 8.66 (1H, dd), 8.20 (1H, m), 7.38 (1H, dd), 3.25 (3H, s), 2.35 (3H, s), 1.47 (9H, m) A23 [00162] 9.14 (1H, d), 8.68 (1H, dd), 8.25 (1H, m), 7.44 (1H, m), 3.65 (3H, s), 2.32 (3H, s), 1.59 (9H, s) A24 [00163] 8.89 (1H, s), 8.57 (1H, d), 8.02 (1H, m), 3.27 (3H, s), 1.44 (9H, br. s) A25 [00164] 9.10 (1H, d), 8.71 (1H, dd), 8.25 (1H, d), 7.42 (1H, dd), 3.27 (3H, s), 1.44 (9H, br. s) A26 [00165] (500 MHz, CDCl.sub.3) 9.31 (1H, s), 9.23 (2H, s), 3.28 (3H, s), 1.44 (9H, br. s) A27 [00166] (500 MHz, CDCl.sub.3) 8.94 (1H, d), 8.66 (1H, d), 8.28 (1H, t), 3.27 (3H, s), 1.57-1.33 (9H, br. s) A28 [00167] (500 MHz, CDCl.sub.3) 8.64 (1H, d), 8.40 (1H, d), 7.77 (1H, br. s), 3.95 (3H, s), 3.26 (3H, s), 1.43 (9H, br. s) A29 [00168] (300 MHz, CDCl.sub.3) 9.08 (1H, s), 8.67 (1H, d), 8.22-8.16 (1H, m), 7.39 (1H, dd), 3.26 (3H, s), 1.46 (9H, s) A30 [00169] 9.08 (1H, d), 8.70-8.64 (1H, m), 8.20 (1H, m), 7.42- 7.37 (1H, m), 3.25 (3H, s), 1.46 (9H, br. s) A31 [00170] 9.08 (1H, d), 8.67 (1H, dd), 8.22 (1H, m), 7.40 (1H, dd), 3.24 (3H, s), 1.46 (9H, br. s) A32 [00171] (500 MHz, CDCl.sub.3) 9.06 (1H, d), 8.65 (1H, d), 8.13 (1H, d), 7.38 (1H, dd), 3.30 (3H, br. s), 1.50 (9H, br. s) A33 [00172] 9.08 (1H, d), 8.66 (1H, dd), 8.17 (1H, m), 7.39 (1H, m), 4.28 (2H, s), 3.15 (3H, s), 2.43 (3H, s) A34 [00173] 9.07 (1H, d), 8.62 (1H, dd), 8.15 (1H, m), 7.35 (1H, m), 3.77 (2H, m), 3.54 (2H, m), 2.91 (3H, s), 2.42 (3H, s) A35 [00174] 8.87 (1H, m), 8.44 (1H, d), 7.94-7.87 (1H, m), 6.73 (1H, br. s), 2.39 (3H, s), 1.55 (9H, s) A38 [00175] 8.87 (1H, m), 8.51 (1H, d), 7.96-7.90 (1H, m), 4.64- 4.53 (2H, m), 4.06-3.97 (2H, m), 2.52 (3H, s) A39 [00176] 9.23 (1H, br. s), 8.80 (1H, d), 8.64 (1H, d), 7.74 (1H, dd), 3.98 (3H, s), 3.31 (3H, s), 1.65-1.32 (9H, br. s) A40 [00177] 9.08-9.01 (1H, m), 8.58 (1H, dd), 8.16 (1H, dd), 7.31 (1H, m), 6.50 (1H, dd), 6.16 (1H, dd), 5.42 (1H, dd), 3.17 (3H, s), 1.36 (9H, br. s) A41 [00178] 9.09 (1H, d), 8.66 (1H, dd), 8.22 (1H, m), 7.38 (1H, dd), 3.43 (3H, s), 1.81 (1H, s), 1.51 (9H, br. s) A43 [00179] 9.01 (1H, s), 8.60 (1H, d), 8.14 (1H, m), 7.32 (1H, dd), 3.20 (3H, s), 1.89-1.63 (5H, m), 1.39 (9H, br. s) A44 [00180] 9.37 (1H, app. br. s), 8.78 (1H, app. br. s), 8.43 (1H, d), 7.68 (1H, app. br. s), 3.37 (3H, s), 1.46 (9H, br. s) A45 [00181] 9.12 (1H, s), 8.58 (1H, d), 8.18 (1H, d), 7.43 (1H, dd), 6.96 (1H, br. s), 3.28 (3H, s), 2.41 (3H, s), 1.23 (9H, s) A50 [00182] 8.87 (1H, s), 8.54 (1H, d), 7.95 (1H, m), 3.27 (3H, s), 1.57-1.34 (9H, m) A51 [00183] 8.88 (1H, br. s), 8.55 (1H, br. s), 8.06-7.82 (1H, m), 3.26 (3H, s), 1.46 (9H, br. s) A52 [00184] 8.87 (s, 1H), 8.53 (1H, d), 7.97 (1H, m), 3.24 (3H, s), 1.46 (9H, br. s) A61 [00185] 9.14 (1H, s), 8.67 (1H, dd), 8.33-8.26 (3H, m), 7.39 (1H, dd), 7.23-2.33 (2H, m), 3.40 (3H, s), 2.46 (3H, s) A62 [00186] 8.55 (1H, s), 8.12 (1H, d), 7.54 (1H, dd), 3.21 (3H, s), 2.32 (3H, s), 1.46 (9H, br. s) A63 [00187] 8.57 (1H, s), 8.21 (1H, d), 7.63 (1H, d), 3.27 (3H, s), 1.44 (9H, s)

TABLE-US-00004 TABLE 4 Compounds of formula (I) Compound Structure Physical Data B1 [00188] 9.08 (1H, d), 8.65 (1H, dd), 8.18 (1H, m), 7.38 (1H, dd), 4.72 (2H, br. s), 3.31 (3H, s), 2.51 (1H, br. s), 2.35 (3H, s) B2 [00189] 9.09 (1H, d), 8.65 (1H, dd), 8.18 (1H, d), 7.38 (1H, dd), 5.43 (1H, br. s), 3.30 (3H, s), 2.51 (1H, br. s), 2.35 (3H, s), 1.45 (3H, br. s) B3 [00190] 9.09 (1H, d), 8.64 (1H, dd), 8.18 (1H, d), 7.37 (1H, dd), 3.27 (3H, s), 2.59 (1H, s), 2.5 (3H, s), 1.81-1.53 (6H, br. s) B10 [00191] 8.87 (1H, s), 8.50 (1H, d), 7.95 (1H, d), 3.28 (3H, s), 2.59 (1H, s), 2.35 (3H, s), 1.64 (6H, br. s) B11 [00192] 8.87 (1H, s), 8.51 (1H, d), 7.95 (1H, m), 4.73 (2H, br. s), 3.30 (3H, s), 2.51 (1H, br. s), 2.36 (3H, s) B12 [00193] 8.87 (1H, s), 8.50 (1H, d), 7.95 (1H, m), 4.70 (2H, br. s), 3.30 (3H, s), 2.35 (3H, s), 1.85 (3H, s)

BIOLOGICAL EXAMPLES

B1 Pre-Emergence Herbicidal Activity

[0259] Seeds of a variety of test species were sown in standard soil in pots: Triticum aestivium (TRZAW), Oryza sativa (ORYSA), 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 5 and 6.

B2 Post-Emergence Herbicidal Activity

[0260] Seeds of a variety of test species were sown in standard soil in pots: Triticum aestivium (TRZAW), Oryza sativa (ORYSA), 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 7 and 8.

TABLE-US-00005 TABLE 5 Control of weed species by compound of formula (I) after pre-emergence application at a rate of 1000 g/Ha Com- pound ORYSA TRZAW ALOMY AVEFA LOLPE ECHCG A1 2 2 2 4 2 4 A2 1 0 0 3 2 5 A3 1 1 1 3 2 4 A4 0 0 1 4 2 4 A5 0 0 0 0 0 0 A6 1 0 1 0 1 2 A7 1 1 1 4 2 2 A8 0 0 0 0 0 0 A9 0 0 0 0 0 0 A10 1 1 0 1 1 1 A11 2 2 1 1 0 2 A12 0 0 0 3 1 3 A13 1 0 0 0 0 1 A14 0 1 0 0 1 0 A15 0 0 0 0 0 0 A16 1 3 0 3 4 4 A17 0 0 0 0 0 0 A18 0 1 1 2 2 5 A19 0 0 1 1 1 5 A20 0 0 0 2 2 5 A21 0 0 0 2 1 5 A22 0 0 0 0 0 0 A23 0 0 0 0 0 0 A24 0 1 2 4 3 4 A25 1 0 1 4 3 4 A26 1 0 2 4 3 4 A27 0 0 0 2 2 2 A28 0 0 0 1 2 3 A29 2 3 1 2 2 3 A30 1 0 1 3 2 4 A31 1 1 1 1 2 3 A32 2 0 0 1 1 2 A38 3 0 1 1 2 5 A45 2 1 2 3 2 3 A51 0 0 0 2 3 1 A52 1 0 0 3 3 2 A62 1 1 2 2 2 3 A63 0 0 0 1 1 1

TABLE-US-00006 TABLE 6 Control of weed species by compound of formula (I)-(i) after pre-emergence application at a rate of 1000 g/Ha Com- pound ZEAMX ABUTH SETFA AMARE LOLPE ECHCG B1 5 2 5 2 3 2 B2 5 3 5 3 3 1 B3 5 4 4 3 3 3

TABLE-US-00007 TABLE 7 Control of weed species by compound of formula (I) after post-emergence application at a rate of 1000 g/Ha Com- pound TRZAW ORYSA AVEFA ALOMY ECHCG LOLPE A1 0 1 4 0 4 4 A2 1 1 5 1 5 3 A3 1 1 4 1 5 3 A4 1 1 5 0 4 2 A5 0 0 0 0 0 0 A6 1 0 2 1 4 2 A7 2 1 4 1 5 3 A8 2 1 2 1 3 0 A9 2 1 2 1 2 1 A10 1 1 2 0 4 0 A11 2 1 1 1 2 1 A12 2 1 2 0 4 3 A13 2 1 0 1 2 0 A14 0 0 0 0 1 0 A15 1 0 2 0 1 1 A16 4 0 5 3 5 4 A17 1 2 4 1 1 2 A18 1 0 3 1 5 2 A19 1 0 3 1 5 2 A20 1 0 3 1 5 3 A21 1 0 4 2 5 3 A22 0 0 2 0 2 2 A23 0 0 1 0 1 0 A24 1 2 4 0 5 4 A25 2 1 4 1 5 4 A26 1 2 5 0 5 4 A27 2 1 4 1 5 3 A28 1 1 2 1 4 3 A29 1 1 4 1 5 4 A30 2 1 4 1 5 4 A31 1 1 5 1 4 3 A32 0 1 3 1 3 2 A35 1 0 1 0 2 0 A38 1 0 4 1 5 3 A45 2 2 5 1 4 4 A51 0 0 4 0 4 2 A52 1 0 4 1 4 3 A61 1 0 2 0 1 1 A62 1 0 4 1 4 4 A63 0 0 3 1 5 2

TABLE-US-00008 TABLE 8 Control of weed species by compound of formula (I)-(i) after post-emergence application at a rate of 1000 g/Ha Com- pound SETFA ZEAMX ECHCG LOLPE AMARE ABUTH B1 5 5 4 3 1 1 B2 5 4 2 4 2 2 B3 5 5 4 4 2 1