Plant growth regulator compounds

Abstract

The present invention relates to novel sulfonamide derivatives, to processes and intermediates for preparing them, to plant growth regulator compositions comprising them and to methods of using them for controlling the growth of plants, improving plant tolerance to abiotic stress (including environmental and chemical stresses), inhibiting seed germination and/or safening a plant against phytotoxic effects of chemicals.

Claims

1. A compound of formula (I) ##STR00047## wherein: R1 is selected from the group consisting of C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 haloalkyl, C.sub.3-C.sub.5 cycloalkyl-C.sub.1-C.sub.7 alkyl, C.sub.3-C.sub.7 alkenyl, C.sub.3-C.sub.7 alkynyl, aryl-C.sub.1-C.sub.7 alkyl, (3-6 membered heterocyclyl)-C.sub.1-C.sub.7 alkyl, phenyl, C.sub.3-C.sub.5 cycloalkyl and a 4-6 membered heterocyclyl, each optionally substituted with one to three Rx; R2a and R2b are independently selected from the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 haloalkyl; or R2a and R2b, together with the atom to which they are attached, are joined to form a C.sub.3-C.sub.6 cycloalkyl; R3, R7 and R8 are independently selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy and C.sub.3-C.sub.4 cycloalkyl; R4 and R5 are independently selected from the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl and C.sub.3-C.sub.4 cycloalkyl; or R4 and R5 together with the atom to which they are attached, are joined to form a C.sub.3-C.sub.4 cycloalkyl or C.sub.4 heterocyclyl; R6 is selected from the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.4 alkenyl, C.sub.3-C.sub.4 alkynyl, and C.sub.1-C.sub.3 alkoxy-C.sub.1-C.sub.4-alkyl; L is selected from the group consisting of a bond, a linear C.sub.1-C.sub.4 alkyl chain, a linear C.sub.2-C.sub.4 alkenyl chain, a linear C.sub.2-C.sub.4 alkynyl chain, a linear C.sub.1-C.sub.4 alkoxy chain whereby the oxygen atom is attached to A, a linear -aminoC.sub.1-C.sub.4alkyl- chain whereby the nitrogen atom is attached to A, and a linear C.sub.1-C.sub.2alkyl-oxy-C.sub.1-C.sub.2alkyl, chain each optionally substituted with one to three halogen, cyano, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl or C.sub.1-C.sub.4 alkoxy; A is selected from the group consisting of hydrogen, C.sub.1-C.sub.7 alkyl, C.sub.3-C.sub.5 cycloalkyl, 3-10 membered heterocyclyl and aryl, each optionally substituted with one to three Ry; Y is selected from the group consisting of O and NRw; Rw is selected from the group consisting of hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxycarbonyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.4 alkenyl, and C.sub.3-C.sub.4 alkynyl; each Rx is, independently of the other, selected from the group consisting of halogen, cyano, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4 alkylcarbonyl, C.sub.1-C.sub.4 alkoxycarbonyl, carboxylic acid, aminocarbonyl, C.sub.1-C.sub.4 aminocarbonyl and C.sub.3-C.sub.4 cycloalkyl; each Ry is, independently of the other, selected from the group consisting of halogen, cyano, nitro, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkyloxy, C.sub.1-C.sub.4 alkylsulfanyl, C.sub.1-C.sub.4 haloalkylsulfanyl, C.sub.1-C.sub.4 alkylsulfinyl, C.sub.1-C.sub.4 haloalkylsulfinyl, C.sub.1-C.sub.4 alkylsulfonyl, C.sub.1-C.sub.4 haloalkylsulfonyl, C.sub.1-C.sub.4 alkylcarbonyl, C.sub.1-C.sub.4 alkoxycarbonyl, carboxylic acid, aminocarbonyl, C.sub.1-C.sub.4 aminocarbonyl and C.sub.3-C.sub.4 cycloalkyl which cycloalkyl is unsubstituted or substituted by one or more Rz; each Rz is, independently of the other, selected from the group consisting of halogen, C.sub.1-C.sub.4-alkyl and C.sub.1-C.sub.4-haloalkyl; wherein A is not butyl when either R4 or R5 is methyl; and wherein R1 is not methyl when R2, R3, R4, R5, R6, R7 and R8 are each hydrogen; or salts or N-oxides thereof.

2. A compound according to claim 1, wherein R1 is selected from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6 alkenyl and C.sub.3-C.sub.5 cyclopropyl-C.sub.1-C.sub.6-alkyl, each optionally substituted with one to three Rx.

3. A compound according to claim 2, wherein R1 is ethyl or propyl.

4. A compound according to claim 1, wherein L is a bond.

5. A compound according to claim 1, wherein A is selected from the group consisting of C.sub.1-C.sub.7 alkyl, phenyl and 3-6 membered heteroaryl, each optionally substituted with one to three Ry.

6. A compound according to claim 5, wherein A is phenyl optionally substituted with one to three substituents independently selected from the group consisting of halogen, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 haloalkoxy.

7. A compound according to claim 1, wherein Y is O.

8. A compound according to claim 1, wherein R2a and R2b are independently selected from the group consisting of hydrogen and C.sub.1-C.sub.4 alkyl.

9. A compound according to claim 1, wherein R3 is selected from the group consisting of hydrogen, halogen and C.sub.1-C.sub.4 alkyl.

10. A compound according to claim 1, wherein R2a is methyl, and R2b, R3, R4, R5, R6, R7 and R8 are hydrogen.

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

12. A mixture comprising a compound as defined in claim 1, and an active ingredient.

13. A crop yield enhancing composition, comprising a compound according to claim 1.

14. A crop yield enhancing composition, comprising a composition according to claim 11.

15. A crop yield enhancing composition, comprising a mixture according to claim 12.

16. A method for improving the tolerance of a plant to abiotic stress, regulating or improving the growth of a plant, or improving the yield of a plant, wherein the method comprises applying to the plant, plant part, plant propagation material, or plant growing locus a compound according to claim 1.

17. A method for improving the tolerance of a plant to abiotic stress, regulating or improving the growth of a plant, or improving the yield of a plant, wherein the method comprises applying to the plant, plant part, plant propagation material, or plant growing locus a composition according to claim 11.

18. A method for improving the tolerance of a plant to abiotic stress, regulating or improving the growth of a plant, or improving the yield of a plant, wherein the method comprises applying to the plant, plant part, plant propagation material, or plant growing locus a mixture according to claim 12.

19. A method for inhibiting seed germination of a plant, wherein the method comprises applying to the plant, plant part, plant propagation material or plant growing locus a compound according to claim 1.

20. A method for inhibiting seed germination of a plant, wherein the method comprises applying to the plant, plant part, plant propagation material or plant growing locus a composition according to claim 11.

21. A method for inhibiting seed germination of a plant, wherein the method comprises applying to the plant, plant part, plant propagation material or plant growing locus a mixture according to claim 12.

Description

PREPARATION EXAMPLES

(1) Schemes 1-7 provide methods of preparing the compounds of formula (I), compounds of formula (II) and compounds of formula (III) of the present invention, wherein R4, R5 and R6 are H when present.

(2) ##STR00035##

(3) Compounds of formula (I) may be prepared from a compound of formula (V) by reaction with sulfonyl chloride of formula A-L-SO.sub.2Cl. Such reactions are usually carried out in the presence of an organic base, such as N-ethyldiisopropylamine. For example, A-L-SO.sub.2Cl can be benzenesulfonyl chloride, benzylsulfonyl chloride or butylsulfonyl chloride. Compounds of formula A-L-SO.sub.2Cl are commercially available or can be made by methods known to a person skilled in the art.

(4) ##STR00036##

(5) Compounds of formula (V), wherein R4, R5 and R6 are H, may be prepared from a compound of formula (VI) by reaction with 2-chloro-N-(hydroxymethyl)acetamide in a solvent such as acetic acid, and optionally in the presence of stronger acid such as sulfuric acid, followed by hydrolysis of the resulting 2-chloroacetamide with an acid such as HCl in an alcoholic solvent. Compound (V) can be obtained as its hydrochloride salt or a free amine after neutralization with a base.

(6) ##STR00037##

(7) Compounds of formula (V), wherein R4, R5 and R6 are H, may be prepared from a compound of formula (VIII) by reduction of the cyano moiety under hydrogen atmosphere in the presence of a catalyst such as palladium on charcoal, or by reducing agent such as sodium borohydride in the presence of a catalyst such as nickel chloride or cobalt chloride for example.

(8) The compound of formula (VIII) may be obtained from a compound of formula (IX) wherein X is a leaving group such as Cl or Br, I or OTf by a coupling reaction with a cyanide salt such as CuCN, NaCN, K.sub.3[Fe(CN).sub.6], optionally in the presence of a catalyst such as palladium (0) or copper, optionally with an additional ligand as described in the literature (see Zanon et al, J. Am. Chem Soc. 2003, 125, 2890-2891; Buchwald, S & all, Angew. Chem. Int. Ed. 2013, 52: 10035-10039).

(9) The compound of formula (IX) may be obtained from a compound of formula (IXa) by reaction with an alkylating agent of formula R1-X, wherein X is a leaving group such as halogen, mesylate, triflate or tosylate. For example, R1-X can be propyl iodide, ethyl iodide, allyl bromide, or methyl iodide. Such reactions are usually carried out in the presence of a base, and optionally in the presence of a nucleophilic catalyst.

(10) Alternatively, compound of formula (VIII) may be obtained from a compound of formula (VIIIa) by reaction with an alkylating agent of formula R1-X, wherein X is a leaving group such as halogen, mesylate, triflate or tosylate. For example, R1-X can be propyl iodide, ethyl iodide, allyl bromide, or methyl iodide. Such reactions are usually carried out in the presence of a base, and optionally in the presence of a nucleophilic catalyst.

(11) Compound of formula (VIIIa) may be prepared from compound (IXa) wherein X is a leaving group such as Cl or Br, I or OTf by a coupling reaction with a cyanide salt as described for compound (VIIIa).

(12) ##STR00038##

(13) Compounds of formula (V), wherein R4 and R5 are H, may be prepared from a compound of formula (VIb) wherein X is a leaving group such as halogen, by reaction with an amine of formula R6-NH.sub.2 or its hydrochloride salt of formula R6-NH.sub.3Cl, optionally in the presence of a base such as triethyl amine or diisopropylamine. For example, R6NH.sub.2 can be ammonia, methyl amine or ethyl amine.

(14) The compound of formula (VIb) may be obtained from a compound of formula (Via) wherein X is a leaving group such as Cl or Br, by radical reaction with N-bromosuccinimide or N-chlorosuccinimide in the presence of an initiator such as AIBN or dibenzoyl peroxide.

(15) ##STR00039##

(16) Compounds of formula (VII) are commercially available or can be made by methods known to a person skilled in the art. Compounds of formula (VI) may be prepared from a compound of formula (VII) by reaction with an alkylating agent of formula R1-LG, wherein LG is a leaving group such as halogen, mesylate, triflate or tosylate. For example, R1-LG can be propyl iodide, ethyl iodide, allyl bromide or methyl iodide. Such reactions are usually carried out in the presence of a base, and optionally in the presence of a nucleophilic catalyst. Compound of formula (IX), wherein X is a halogen such as Cl, Br or I can be obtained from a compound of formula (VI) by reaction with the corresponding NX succinimide as for example N-bromosuccinimide when X is Br.

(17) ##STR00040##

(18) Compound of formula (IXa), wherein X is a halogen such as Cl, Br or I can be obtained from a compound of formula (VII) by reaction with the corresponding NX succinimide as for example N-bromosuccinimide when X is Br.

(19) ##STR00041##

(20) Compounds of formula (VI) can be made from compound of formula (X) by reaction with a base such as a carbonate or sodium hydride. Compounds of formula (X), wherein R2b is H and R is a C1-C6 alkyl group can be made from a compound of formula (XI) by reaction of a metal hydride of formula R2b H such as sodium borohydride. Compounds of (XI) wherein R is a C1-C6 alkyl group can be made from a compound of formula (XII) by reaction with a carbonate of formula CO(OR).sub.2 or a alkylchloroformate of formula CO(OR)Cl in the presence of an organic base such as pyridine or triethylamine. Compounds of formula (XII) are commercially available or can be made by methods known to a person skilled in the art.

Example P1: Preparation of N-[(2-oxo-1-propyl-4H-3,1-benzoxazin-6-yl)methyl]benzenesulfonamide (Compound 3.001)

(21) ##STR00042##

a. 6-bromo-4H-3,1-benzoxazin-2-one

(22) 1,4-Dihydro-3,1-benzoxazin-2-one (1.00 g, 6.70 mmol) (prepared as in Synlett, 1999, (2), 207-209) was dissolved in dimethylformamide (13 mL) and cooled to 0 C. N-Bromosuccinimide (1.33 g, 7.38 mmol) was added in portions at 0 C. The reaction mixture was stirred at 40 C. for 3 h. The reaction mixture was poured on water and the white solid was filtered, washed with water and dried to give 6-bromo-4H-3,1-benzoxazin-2-one as a white powder (1.44 g, 94%). .sup.1H NMR (chloroform-d3) : 8.55-8.85 (s, 1H), 7.39 (dd, 1H), 7.27 (d, 1H), 6.85 (, 1H), 5.30 (s, 2H).

b. 6-bromo-1-propyl-4H-3,1-benzoxazin-2-one

(23) 6-Bromo-4H-3,1-benzoxazin-2-one (500 mg, 2.19 mmol) was dissolved in dimethylformamide (11 mL) and potassium carbonate (0.459 g, 3.289 mmol) was added followed by 1-bromopropane (0.400 mL, 4.38 mmol) dropwise. The reaction mixture was heated to 60 C. and stirred for 4 hours. The reaction mixture was poured into ice/water and extracted with ethyl acetate (220 mL). The combined organic layers were washed with brine (320 mL), dried over Na.sub.2SO.sub.4 and concentrated. The crude oil was purified by flash chromatography to give 6-bromo-1-propyl-4H-3,1-benzoxazin-2-one as a colourless solid (390 mg, 66%). .sup.1H NMR (chloroform-d3) Shift: 7.45 (d, 1H), 7.27 (s, 1H), 6.82 (d, 1H), 5.15 (s, 2H), 3.80-3.88 (m, 2H), 1.69-1.84 (m, 2H), 1.00 (t, 3H).

c. 2-oxo-1-propyl-4H-3,1-benzoxazine-6-carbonitrile

(24) 6-Bromo-1-propyl-4H-3,1-benzoxazin-2-one (0.175 g, 0.647 mmol) was dissolved in 1,4-dioxane (1.6 mL) and water (1.6 mL). Potassium acetate (9.6 mg, 0.097 mmol) and potassium hexacyanoferrate(II) trihydrate (0.119 g, 0.323 mmol) were added and the solution was purged with argon. tBuBrettphos Pd G3 (Sigma-Aldrich, 29 mg, 0.0324 mmol) and tBuBrettphos (15 mg, 0.032 mmol) were added under argon. The reaction mixture was heated to reflux and stirred for 1 h. The reaction mixture was cooled to room temperature and brine was added. It was extracted 3 times with ethyl acetate, the organic layers were combined, dried over Na.sub.2SO.sub.4 and the solvent was evaporated. The crude compound was purified by flash chromatography to give 2-oxo-1-propyl-4H-3,1-benzoxazine-6-carbonitrile as a pale yellow solid (62 mg, 44%). .sup.1H NMR (chloroform-d3) Shift: 7.61-7.69 (d, 1H), 7.43 (s, 1H), 7.02 (d, 1H), 5.22 (s, 2H), 5.11-5.19 (m, 1H), 3.81-3.94 (m, 2H), 1.71-1.87 (m, 2H), 1.02 (t, 3H).

d. 6-(aminomethyl)-1-propyl-4H-3,1-benzoxazin-2-one hydrochloride

(25) 2-Oxo-1-propyl-4H-3,1-benzoxazine-6-carbonitrile (0.078 g, 0.360 mmol) was dissolved in a mixture of ethanol (3.6 mL) and ethyl acetate (3.6 mL) and was purged with argon. Hydrochloric acid (32 mass % in H.sub.2O, 0.265 mL, 2.70 mmol) was added followed by Pd/C 10% (0.008 g, 0.007 mmol). The reaction mixture was placed under an atmosphere of hydrogen (balloon) and was stirred for 12 h. The atmosphere was changed to argon and more Pd/C (30 mg) was added. The atmosphere was changed again to hydrogen (balloon, 1 atm.) and the reaction mixture was stirred for 4 h. The reaction mixture was purged with argon and was filtered over Celite. Solvents were evaporated and tert-butyl methyl ether was added. The white solid was filtered to give 6-(aminomethyl)-1-propyl-4H-3,1-benzoxazin-2-one hydrochloride (0.092 g, 99%) as a pale yellow solid. .sup.1H NMR (methanol-d4) : 7.47 (br d, 1H), 7.32 (s, 1H), 7.18 (br d, 1H), 5.25 (s, 2H), 4.10 (s, 2H), 3.88 (br m, 2H), 1.63-1.80 (m, 2H), 0.98 (t, 3H).

e. N-[(2-oxo-1-propyl-4H-3,1-benzoxazin-6-yl)methyl]benzenesulfonamide (Compound 3.001)

(26) 6-(aminomethyl)-1-propyl-4H-3,1-benzoxazin-2-one hydrochloride (0.086 g, 0.335 mmol) was suspended in ethyl acetate (3 mL) and diisopropylethyl amine (0.143 mL, 0.837 mmol) was added, followed by benzenesulfonyl chloride (0.067 g, 0.368 mmol). The reaction mixture was stirred at room temperature for 90 min. Water and brine were added and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over Na.sub.2SO.sub.4 and the solvent was evaporated to give the crude compound, which was purified on silica gel to give N-[(2-oxo-1-propyl-4H-3,1-benzoxazin-6-yl)methyl]benzenesulfonamide as a colorless solid (0.052 g, 43%). .sup.1H NMR (chloroform-d3) : 7.87 (d, 2H), 7.44-7.66 (m, 3H), 7.09-7.25 (d, 1H), 6.97 (s, 1H), 6.84 (d, 1H), 5.09 (s, 2H), 4.77 (br m, 1H), 4.13 (d, 2H), 3.74-3.89 (m, 2H), 1.72 (sxm, 2H), 0.99 (t, 3H). LC-MS: RT 0.89, ES+ (392, MH.sup.+).

Example P2: Preparation of N-[(8-fluoro-4-methyl-2-oxo-1-propyl-4H-3,1-benzoxazin-6-yl)methyl]benzenesulfonamide (Compound 25.001)

(27) ##STR00043##

Step a: 1-[3-fluoro-2-(propylamino)phenyl]ethanone

(28) A solution of 1-(2,3-difluorophenyl)ethanone (7.81 g, 50 mmol), K.sub.2CO.sub.3 (10.4 g, 75 mmol) and propylamine (12.3 mL. 150 mmol) in DMF (55 mL) was heated at 50 C. for 42 h. The reaction mixture was then poured into ice water and extracted 3 times with a 1/1 mixture of ethyl acetate and cyclohexane. The combined organic layer was washed with brine and concentrated under vacuo to give 1-[3-fluoro-2-(propylamino)phenyl]ethanone (9.38 g, 96%) as a pale green oil.

(29) LCMS: 1.09 min; ES+ 196 (M+H+); 1H NMR (400 MHz, CHLOROFORM-d) 8.78 (s, 1H), 7.52 (d, 1H), 7.08 (dd, 1H), 6.51 (m, 1H), 3.42 (m, 2H), 2.52 (s, 3H), 1.61 (m, 2H), 0.94 (t, 3H).

Step b: 8-fluoro-4-methyl-1-propyl-4H-3,1-benzoxazin-2-one

(30) To a solution of 1-[3-fluoro-2-(propylamino)phenyl]ethanone (9.35 g, 47 mmol) in dioxane (95 mL) was added K.sub.2CO.sub.3 (7.74 g, 57.5 mmol) and ethyl chloroformate (5.67 mL, 57.5 mmol). The suspension was stirred at 85 C. for 5 h, cooled down to room temperature and filtered. The solvent was evaporated and the crude oil was purified by flash chromatography to give ethyl N-(2-acetyl-6-fluoro-phenyl)-N-propyl-carbamate (11.3 g, 88%) as an oil.

(31) To a solution of ethyl N-(2-acetyl-6-fluoro-phenyl)-N-propyl-carbamate (4.01 g, 15.0 mmol) in methanol (38 mL) was added portionwise sodium borohydride (567 mg, 15.0 mmol) at 0 C. The solution was stirred for 30 min and then quenched with a saturated solution of NH.sub.4Cl. The solution was extracted two times with ethyl acetate and the organic layers were washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to give ethyl N-[2-fluoro-6-(1-hydroxyethyl)phenyl]-N-propyl-carbamate (4.06 g, quant) as an oil which was used directly in the next step.

(32) To a solution of ethyl N-[2-fluoro-6-(1-hydroxyethyl)phenyl]-N-propyl-carbamate (4.04 g, 15.0 mmol) in THF (75 mL) under Ar cooled at 20 C. was added NaH (55% in mineral oil, 654 mg, 15.0 mmol) and the solution was stirred for 15 min at 0 C. The reaction mixture was then quenched with iPrOH (1 mL) followed by a saturated solution of NH.sub.4Cl. The solution was extracted two times with ethyl acetate and the organic layers were washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude compound was crystallized from pentane to give 8-fluoro-4-methyl-1-propyl-4H-3,1-benzoxazin-2-one (2.57 g, 77%).

(33) LCMS: 0.96 min; ES+ 224 (M+H+); 1H NMR (400 MHz, CHLOROFORM-d) 7.10-7.15 (m, 2H), 6.91 (m, 1H), 5.25 (q, 1H), 3.98 (m, 2H), 1.75 (m, 2H), 1.66 (d, 3H), 0.94 (t, 3H).

Step c: 6-Bromo-8-fluoro-4-methyl-1-propyl-4H-3,1-benzoxazin-2-one

(34) To a solution of 8-fluoro-4-methyl-1-propyl-4H-3,1-benzoxazin-2-one (1.10 g, 4.93 mmol) in trifluoroacetic acid (11 mL) was added at room temperature N-bromosuccinimide (1.33 g. 7.39 mmol) and the reaction mixture was heated to 60 C. for 16 h. The reaction mixture was then cooled down to room temperature and poured into a cold aqueous solution of NaOH (2 M) and sodium thiosulfate was added. The solution was extracted two times with ethyl acetate and the organic layers were washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The crude compound was crystallized from dichloromethane and petrolether to give 6-bromo-8-fluoro-4-methyl-1-propyl-4H-3,1-benzoxazin-2-one (780 mg, 52%).

(35) LCMS: 1.08 min; ES+ 302/304 (M+H+); 1H NMR (400 MHz, CHLOROFORM-d) 7.22 (s, 1H), 7.07 (s, 1H), 5.21 (q, 1H), 3.96 (m, 2H), 1.71 (m, 2H), 1.65 (d, 3H), 0.93 (t, 3H).

Step d: 8-fluoro-4-methyl-2-oxo-1-propyl-4H-3,1-benzoxazine-6-carbonitrile

(36) 6-bromo-8-fluoro-4-methyl-1-propyl-4H-3,1-benzoxazin-2-one (0.400 g, 1.32 mmol) was dissolved in 1,4-dioxane (3.3 mL) and water (3.3 mL). Potassium acetate (19.7 mg, 0.199 mmol) and potassium hexacyanoferrate(II) trihydrate (0.244 g, 0.323 mmol) were added and the solution was purged with argon. tBuBrettphos Pd G3 (Sigma-Aldrich, 59 mg, 0.066 mmol) and tBuBrettphos (32 mg, 0.066 mmol) were added under argon. The reaction mixture was heated to reflux and stirred for 2 h. The reaction mixture was cooled to room temperature and brine was added. It was extracted 3 times with ethyl acetate, the organic layers were combined, dried over Na.sub.2SO.sub.4 and the solvent was evaporated. The crude compound was purified by flash chromatography to give 8-fluoro-4-methyl-2-oxo-1-propyl-4H-3,1-benzoxazine-6-carbonitrile as a pale yellow solid (355 mg, quant).

(37) LCMS: 0.93 min; ES+ 259 (M+H+); 1H NMR (400 MHz, CHLOROFORM-d) =7.42 (d, 1H), 7.24 (s, 1H), 5.28 (q, 1H), 4.08-3.92 (m, 2H), 1.82-1.65 (m, 2H), 1.71 (d, 3H), 0.97 (t, 3H).

Step e: 6-(aminomethyl)-8-fluoro-4-methyl-1-propyl-4H-3,1-benzoxazin-2-one

(38) 8-Fluoro-4-methyl-2-oxo-1-propyl-4H-3,1-benzoxazine-6-carbonitrile (0.328 g, 1.32 mmol) was dissolved in a mixture of ethanol (7 mL) and ethyl acetate (7 mL) and was purged with argon. Hydrochloric acid (32 mass % in H.sub.2O, 0.303 mL, 9.90 mmol) was added followed by Pd/C 10% (0.033 g, 0.031 mmol). The reaction mixture was placed under an atmosphere of hydrogen (balloon) and was stirred for 12 h. The atmosphere was changed to argon and more Pd/C (30 mg) was added. The atmosphere was changed again to hydrogen (balloon, 1 atm.) and the reaction mixture was stirred for 4 h. The reaction mixture was purged with argon and was filtered over Celite. Sovents were evaporated and tert-butyl methyl ether was added. The white solid was filtered to give 6-(aminomethyl)-8-fluoro-4-methyl-1-propyl-4H-3,1-benzoxazin-2-one (0.320 g, 82%) as a pale yellow solid. 1H NMR (400 MHz, METHANOL-d4) ppm 0.97 (t, 3H), 1.70 (d, 3H), 1.76 (m, 2H), 3.95 (t, 2H), 4.15 (s, 2H), 5.44 (q, 1H), 7.21 (d, 1H), 7.36 (dd, 1H).

Step f: N-[(8-fluoro-4-methyl-2-oxo-1-propyl-4H-3,1-benzoxazin-6-yl)methyl]benzenesulfonamide (Compound 25.001)

(39) 6-(Aminomethyl)-8-fluoro-4-methyl-1-propyl-4H-3,1-benzoxazin-2-one (0.130 g, 0.450 mmol) was suspended in ethyl acetate (4 mL) and diisopropylethyl amine (0.193 mL, 1.13 mmol) was added, followed by benzenesulfonyl chloride (0.103 g, 0.585 mmol). The reaction mixture was stirred at room temperature for 90 min. Water and brine were added and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over Na.sub.2SO.sub.4 and the solvent was evaporated to give the crude compound, which was purified on silica gel to give N-[(8-fluoro-4-methyl-2-oxo-1-propyl-4H-3,1-benzoxazin-6-yl)methyl]benzenesulfonamide as a colorless solid (0.160 mg, 90%). 0.92 (t, 3H), 1.60 (d, 3H), 1.62-1.78 (m, 2H), 3.88-4.00 (m, 2H), 4.09-4.15 (m, 2H), 4.91 (br t, 1H), 5.17 (q, 1H), 6.77 (s, 1H), 6.93 (dd, 1H), 7.50-7.55 (m, 2H), 7.57-7.63 (m, 1H), 7.83-7.89 (m, 2H).

Example P3: Preparation of 5-chloro-N-[[1-(2-methoxyethyl)-4-methyl-2-oxo-4H-3,1-benzoxazin-6-yl]methyl]thiophene-2-sulfonamide (Compound 26.048)

Step a: ethyl N-(2-acetylphenyl)carbamate

(40) ##STR00044##

(41) 2-Acetylaniline (10.0 g, 72.5 mmol) was dissolved in ethyl acetate (72 mL) and cooled to 0 C. Ethyl chloroformate (7.86 mL, 79.8 mmol) was added followed by pyridine dropwise (6.22 mL, 76.1 mmol). Water was added and the reaction was extracted with ethyl acetate. The organic layers were washed with 1N HCl, dried and concentrated to give ethyl N-(2-acetylphenyl)carbamate (15.0 g, quant.) as an orange solid.

(42) LCMS: 0.97 min; ES+ 208 (M+H+); .sup.1H NMR (CHLOROFORM-d, 400 MHz): (ppm) 11.15 (br s, 1H), 8.49 (d, 1H), 7.88 (d, 1H), 7.55 (t, 1H), 7.06 (t, 1H), 4.23 (q, 2H), 2.66 (s, 3H), 1.33 (t, 3H).

Step b: 4-methyl-1,4-dihydro-3,1-benzoxazin-2-one

(43) Ethyl N-(2-acetylphenyl)carbamate (1.00 g, 4.83 mmol) was solved in THF (25 mL) and added sodium borohydride (0.369 g, 9.65 mmol). The reaction mixture was stirred for 5 h at room temperature. The reaction mixture was quenched with water (10 mL) and then 10 mL of HCl (1 M) were added very slowly. The reaction mixture was then extracted with ethyl acetate (325 mL) and washed with brine, dried and concentrated to give a crude oil of ethyl N-[2-(1-hydroxyethyl)phenyl]carbamate and 4-methyl-1,4-dihydro-3,1-benzoxazin-2-one. The crude mixture was taken up in acetonitrile (20 mL) and potassium carbonate (0.667 g, 4.83 mmol) was added. The suspension was heated to reflux for 5 h, cooled down to room temperature, filtered and concentrated. The crude solid was purified by flash chromatography to give 4-methyl-1,4-dihydro-3,1-benzoxazin-2-one (0.727 g, 92%) as a white solid.

(44) LCMS: 0.64 min; ES+ 164 (M+H+); .sup.1H NMR (CHLOROFORM-d, 400 MHz): (ppm) 8.79 (br s, 1H), 7.44 (t, 1H), 7.19-7.31 (m, 2H), 7.09 (d, 1H), 5.65-5.76 (q, 1H), 1.90 (d, 3H).

Step c: 6-bromo-4-methyl-1,4-dihydro-3,1-benzoxazin-2-one

(45) 4-methyl-1,4-dihydro-3,1-benzoxazin-2-one (13.7 g, 84.0 mmol) was dissolved in dimethylformamide (340 mL) and cooled to 0 C. N-Bromosuccinimide (19.6 g, 109 mmol) was added in portions at 0 C. Reaction was warmed up to room temperature and stirred for 15 h. The reaction mixture was poured on water/ice and a suspension was formed. It was filtered and washed with water, and dried to give the crude 6-bromo-4-methyl-1,4-dihydro-3,1-benzoxazin-2-one (18.7 g, 92%) as a beige powder.

(46) LCMS: 0.79 min; ES+ 243/245 (M+H+); 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.68(d, 3H), 5.45 (q, 1H), 6.72 (d, 1H), 7.22 (s, 1H), 7.35 (d, 1H), 8.52 (brs, 1H).

Step d: 4-methyl-2-oxo-1,4-dihydro-3,1-benzoxazine-6-carbonitrile

(47) 6-Bromo-4-methyl-1,4-dihydro-3,1-benzoxazin-2-one (3.33 g, 13.8 mmol), potassium acetate (0.205 g, 2.06 mmol) and potassium hexacyanoferrate(II) trihydrate (2.53 g, 6.88 mmol) were suspended in dioxane (34 mL) and water (34 mL) and degassed with argon. tBuBrettphos Pd G3 (0.245 g, 0.275 mmol) and tBuBrettphos (0.133 g, 0.275 mmol) were added and the reaction mixture was heated to 110 C. for 2 h. tBuBrettphos Pd G3 (0.245 g, 0.275 mmol) and tBuBrettphos (0.133 g, 0.275 mmol) were added to the reaction mixture which was stirred for a further 1 h. It was cooled to room temperature, brine was added and it was extracted 3 times with ethyl acetate. The combined organic layers were combined, dried over Na.sub.2SO.sub.4 and the solvent was evaporated to give the crude which was crystallised from tert butyl methyl ether to give 4-methyl-2-oxo-1,4-dihydro-3,1-benzoxazine-6-carbonitrile (1.92 g, 74%) as a beige solid.

(48) LCMS: 0.60 min; ES+ 189 (M+H+); .sup.1H NMR (400 MHz, DMSO-d) d ppm 1.56 (d, 3H), 5.56 (q, 1H), 7.00 (d, 1H), 7.72 (m, 2H), 10.62 (brs, 1H).

Step e: 1-(2-methoxyethyl)-4-methyl-2-oxo-4H-3,1-benzoxazine-6-carbonitrile

(49) 6-cyano-4-methyl-1,4-dihydro-3,1-benzoxazin-2-one (600 mg, 3.18 mmol) was dissolved in dimethylformamide (13 mL) and potassium carbonate (1.11 g, 7.97 mmol) was added. 1-bromo-2-methoxy-ethane (0.473 mL, 4.78 mmol) was added dropwise and the reaction mixture was heated to 50 C. and stirred for 2 h. 1-Bromo-2-methoxy-ethane (0.473 mL) were added and it was stirred for another 1 h. Water and ethyl acetate were added and it was extracted with ethyl acetate. The organic layers were combined, washed twice with a 5% LiCl-solution and once with brine, dried over Na.sub.2SO.sub.4 and the solvent was evaporated to give the crude (1.29 g) as a yellow oily solid which was purified by flash chromatography to give 6-cyano-1-(2-methoxyethyl)-4-methyl-4H-3,1-benzoxazin-2-one (0.713 g, 90%) as an oil.

(50) .sup.1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.68 (d, 3H), 3.32 (s, 3H), 3.68 (dd, 2H), 4.05 (m, 2H), 5.38 (q, 1H), 7.29 (d, 1H), 7.40 (s, 1H), 7.63 (d, 1H).

Step f: 6-(aminomethyl)-1-(2-methoxyethyl)-4-methyl-4H-3,1-benzoxazin-2-one

(51) To a solution of 1-(2-methoxyethyl)-4-methyl-2-oxo-4H-3,1-benzoxazine-6-carbonitrile (500 mg, 2.030 mmol) in methanol (20 mL) was added Nickel(II) chloride hexahydrate (96 mg, 0.406 mmol). Then the reaction mixture was cooled to 0 C. and sodium borohydride (313 mg, 8.12 mmol) was added portionwise. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was filtered over Celite and the filter cake was washed with methanol. The solvent was removed and the residue was partitioned between 1N HCl and ethyl acetate. The aqueous layer was then neutralized with NaOH (2M) and extracted with ethyl acetate. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated to give 6-(aminomethyl)-1-(2-methoxyethyl)-4-methyl-4H-3,1-benzoxazin-2-one (356 mg, 70%). LCMS: 0.24 min; ES+ 250 (M-NH2).

Step g: 5-chloro-N-[[1-(2-methoxyethyl)-4-methyl-2-oxo-4H-3,1-benzoxazin-6-yl]methyl]thiophene-2-sulfonamide (Compound 26.048)

(52) To a solution of 6-(aminomethyl)-1-(2-methoxyethyl)-4-methyl-4H-3,1-benzoxazin-2-one (119 mg, 0.474 mmol) in ethyl acetate (4 mL) were added 5-chlorothiophene-2-sulfonyl chloride (0.206 g) and n,n-diisopropylethylamine (0.248 mL, 1.42 mmol). The reaction mixture was stirred for 1 h at room temperature, water was added and it was extracted with ethyl acetate. The combined organic layers were dried over Na.sub.2SO.sub.4 and evaporated to give a yellow gum which was purified by flash chromatography to give 5-chloro-N-[[1-(2-methoxyethyl)-4-methyl-2-oxo-4H-3,1-benzoxazin-6-yl]methyl]thiophene-2-sulfonamide (58 mg, 28%) of a colourless gum.

(53) LCMS: 0.91 min; ES+ 431/433 (M+H+); 1H NMR (400 MHz, CHLOROFORM-d) 7.42 (d, 1H), 7.23 (dd, 1H), 7.14 (d, 1H), 7.03 (d, 1H), 6.96 (d, 1H), 5.35 (q, 1H), 4.84 (t, 1H), 4.24 (d, 2H), 4.15-4.04 (m, 2H), 3.73 (t, 2H), 3.38 (s, 3H), 1.68 (d, 3H).

(54) Further compounds of the present invention were made using the same methods, as shown in Table 2 below.

(55) TABLE-US-00003 TABLE 2 Additional compounds synthesised RT [M + H] Compound Name (min) (measured) 13.001 N-[(1-ethyl-4-methyl-2-oxo-4H-3,1- 0.87 361 benzoxazin-6-yl)methyl]- benzenesulfonamide 13.006 N-[(1-ethyl-4-methyl-2-oxo-4H-3,1- 0.89 397 benzoxazin-6-yl)methyl]-2,4-difluoro- benzenesulfonamide 14.012 4-methyl-N-[(4-methyl-2-oxo-1-propyl- 0.97 389 4H-3,1-benzoxazin-6-yl)methyl] benzenesulfonamide 14.006 N-[(4-methyl-2-oxo-1-propyl-4H-3,1- 0.94 411 benzoxazin-6-yl)methyl]-2,4-difluoro- benzenesulfonamide 14.001 N-[(4-methyl-2-oxo-1-propyl-4H-3,1- 0.92 375 benzoxazin-6-yl)methyl]- benzenesulfonamide 30.001 N-[[8-fluoro-1-(3-fluoropropyl)-4-methyl- 0.89 411 2-oxo-4H-3,1-benzoxazin-6- yl]methyl]benzenesulfonamide 29.001 N-[[8-fluoro-1-(2-methoxyethyl)-4- 0.88 409 methyl-2-oxo-4H-3,1-benzoxazin-6- yl]methyl]benzenesulfonamide 26.048 5-chloro-N-[[1-(2-methoxyethyl)- 0.91 431/433 4-methyl-2-oxo-4H-3,1-benzoxazin-6-yl] methyl]thiophene-2-sulfonamide 28.048 5-chloro-N-[[1-(2,2-difluoroethyl)-4- 0.98 437/439 methyl-2-oxo-4H-3,1-benzoxazin-6-yl] methyl]thiophene-2-sulfonamide 18.048 5-chloro-N-[[4-methyl-2-oxo-1-(2,2,2- 0.98 455/457 trifluoroethyl)-4H-3,1-benzoxazin-6- yl]methyl]thiophene-2-sulfonamide 24.048 5-chloro-N-[[1-(cyclopropylmethyl)-4- 0.99 427/429 methyl-2-oxo-4H-3,1-benzoxazin-6-yl] methyl]thiophene-2-sulfonamide 24.009 N-[[1-(cyclopropylmethyl)-4-methyl- 0.93 405 2-oxo-4H-3,1-benzoxazin-6-yl]methyl]- 4-fluoro-benzenesulfonamide 28.009 N-[[1-(2,2-difluoroethyl)-4-methyl- 0.88 415 2-oxo-4H-3,1-benzoxazin-6-yl]methyl]- 4-fluoro-benzenesulfonamide 18.009 4-fluoro-N-[[4-methyl-2-oxo-1-(2,2,2- 0.92 433 trifluoroethyl)-4H-3,1-benzoxazin-6- yl]methyl]benzenesulfonamide 26.009 4-fluoro-N-[[1-(2-methoxyethyl)-4- 0.84 408 methyl-2-oxo-4H-3,1-benzoxazin-6- yl]methyl]benzenesulfonamide 28.001 N-[[1-(2,2-difluoroethyl)-4-methyl-2- 0.86 397 oxo-4H-3,1-benzoxazin-6-yl]methyl] benzenesulfonamide 27.001 N-[[1-(3-fluoropropyl)-4-methyl-2- 0.87 393 oxo-4H-3,1-benzoxazin-6-yl]methyl] benzenesulfonamide 24.001 N-[[1-(cyclopropylmethyl)-4-methyl-2- 0.92 387 oxo-4H-3,1-benzoxazin-6-yl]methyl] benzenesulfonamide 18.001 N-[[4-methyl-2-oxo-1-(2,2,2- 0.91 415 trifluoroethyl)-4H-3,1-benzoxazin-6-yl] methyl]benzenesulfonamide 26.001 N-[[1-(2-methoxyethyl)-4-methyl- 0.83 391 2-oxo-4H-3,1-benzoxazin-6-yl]methyl] benzenesulfonamide 20.001 N-[(1-ethyl-8-fluoro-4-methy1-2- 0.90 379 oxo-4H-3,1-benzoxazin-6-yl)methyl] benzenesulfonamide 25.001 N-[(8-fluoro-4-methyl-2-oxo-1-propyl- 0.95 393 4H-3,1-benzoxazin-6-yl)methyl] benzenesulfonamide 14.048 5-chloro-N-[(4-methyl-2-oxo-1-propyl- 1.00 415/417 4H-3,1-benzoxazin-6-yl)methyl] thiophene-2-sulfonamide 13.048 5-chloro-N-[(1-ethyl-4-methyl-2-oxo- 0.94 401/403 4H-3,1-benzoxazin-6-yl)methyl] thiophene-2-sulfonamide
LCMSMethod

(56) Spectra were recorded on a Mass Spectrometer from Waters (SQD or ZQ Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.00 kV, Cone range: 30-60 V, Extractor: 2.00 V, Source Temperature: 150 C., Desolvation Temperature: 350 C., Cone Gas Flow: 0 L/Hr, Desolvation Gas Flow: 650 L/Hr, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment and diode-array detector. Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 m, 302.1 mm, Temp: 60 C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH: gradient: gradient: 0 min 0% B, 100% A; 1.2-1.5 min 100% B; Flow (ml/min) 0.85.

Biological Examples

(57) A) Reduced Plant Water Use in Corn

(58) Compounds were tested for their effect on reducing plant water use as follows. The compounds were applied by foliar spray to 12 day old corn plants (variety NK OCTET) grown in controlled environment plant growth chambers. All compounds were applied using an emulsifiable concentrate (EC) formulation that was diluted to the desired concentrations with water containing 0.4% of the adjuvant rape seed methyl ester. Plant water use during the day was assessed by repeated weighing of the pots in which the plants were grown before and after application of the compounds at the indicated times (expressed in days after application (DAA)). The water use data before application was used to correct any differences in water use arising due to non-treatment effects (e.g. due to differences in plant size). The untransformed water use values were subjected to an analysis of covariance, fitting the effect of treatment and using the baseline water use 1 day before application as a covariate.

(59) Application of the chemicals (0 DAA) took place approximately between 08:00 and 09:30 a.m. Water use (WU) was measured within day time (chamber light is on 06:00 to 20:00) at these timepoints: 0 DAA a.m. (10:30-12:50), 0 DAA p.m. (14:00-19:50).

(60) TABLE-US-00004 TABLE A1 Percent increase or decrease of water use (WU) during day time of corn plants sprayed with the indicated compounds at 500 M compared to a negative control treatment (e.g. 0 = identical to negative control; 8.5 = 8.5% decrease in water use compared to negative control treatment). Average WU values of 6 pots (each with three plants) per treatment are shown. % WU 0 DAA ODAA Compound (AM) (PM) Untreated Control 0 0 3.001 12% 7%

(61) A further trial was conducted to test further compounds of the present invention using the same protocol.

(62) TABLE-US-00005 TABLE A2 Percent increase or decrease of water use (WU) during day time of corn plants sprayed with the indicated compounds at 500 M compared to a negative control treatment (e.g. 0 = identical to negative control; 8.5 = 8.5% decrease in water use compared to negative control treatment). Average WU values of 6 pots (each with three plants) per treatment are shown. % WU 0 DAA ODAA Compound (AM) (PM) Untreated Control 0 0 26.048 17 12 28.048 33 39 18.048 25 27 24.048 40 47 24.009 18 13 18.009 18 14 26.009 47 46 28.001 27 31 27.001 50 58 24.001 29 27 18.001 19 16 26.001 25 20 20.001 37 42 25.001 48 56 14.001 48 52 14.006 34 37 14.012 36 40 14.048 54 57 13.048 48 51 13.001 38 40 13.006 24 21

(63) The results show that corn plants treated with compounds of the present invention use less water than untreated plants.

(64) A further trial was conducted to compare the water use of a compound of the present invention with a corresponding compound where Y is not a heteroatom.

(65) TABLE-US-00006 TABLE A3 Percent increase or decrease of water use (WU) during day time of corn plants sprayed with the indicated compounds at 500 M compared to a negative control treatment (e.g. 0 = identical to negative control; 8.5 = 8.5% decrease in water use compared to negative control treatment). Average WU values of 6 pots (each with three plants) per treatment are shown. % WU 0 DAA 0 DAA Compounds (AM) (PM) Untreated Control 0 0 25 24 38 40

(66) This data shows that compound 13.001 is a more potent ABA agonist than dihydroquinolinone compound A, which is the corresponding compound without a heteroatom.

(67) B) Reduced Plant Water Use in Soybean

(68) Compounds were tested for their effect on reducing plant water use as follows. The compounds were applied by foliar spray to 12 day old soybean plants (variety S20-G7) grown in controlled environment plant growth chambers. All compounds were applied using an emulsifiable concentrate (EC) formulation that was diluted to the desired concentration with water containing additional surfactant (EXTRAVON 1 g/20 L). Plant water use during the day was assessed by repeated weighing of the pots in which the plants were grown before and after application of the compounds at the indicated times (expressed in days after application (DAA)). The water use data before application was used to correct any differences in water use arising due to non-treatment effects (e.g. due to differences in plant size). The untransformed water use values were subjected to an analysis of covariance, fitting the effect of treatment and using the baseline water use 1 day before application as a covariate.

(69) Application of the chemicals (0 DAA) took place approximately between 08:00 and 09:30 a.m. Water use (WU) was measured within day time (chamber light is on 06:00 to 20:00) at these timepoints: 0 DAA a.m. (10:30-12:50), 0 DAA p.m. (14:00-19:50).

(70) TABLE-US-00007 TABLE A4 Percent increase or decrease of water use (WU) during day time of soybean plants sprayed with the indicated compounds at 125 M compared to a negative control treatment (e.g. 0 = identical to negative control; 8.5 = 8.5% decrease in water use compared to negative control treatment). Average WU values of 6 pots (each with three plants) per treatment are shown. % WU 0 DAA 0 DAA Compounds (AM) (PM) Untreated 0 0 control 14.048 51 55 14.001 49 55 25.001 48 53

(71) The results show that soybean plants treated with compounds of the present invention use less water than untreated plants.