Agricultural chemicals

Abstract

The present invention relates to compounds which are of use in the field of agriculture as herbicides. The invention also relates to methods of using said compounds and compositions comprising said compounds.

Claims

1. A compound of formula I: ##STR00074## wherein R.sup.1 has the structure ##STR00075## R.sup.13 is independently at each occurrence selected from C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, halogen, nitro, OR.sup.10, SR.sup.10, cyano, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl and NR.sup.10R.sup.11; R.sup.14 is independently selected from H and C.sub.1-C.sub.6-alkyl; and n is an integer independently selected from 0, 1 and 2; R.sup.2 is independently at each occurrence selected from C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, halogen, nitro, OR.sup.10, SR.sup.10, OS(O).sub.2R.sup.10, S(O).sub.2R.sup.10, S(O).sub.2NR.sup.10R.sup.10, S(O)(NR.sup.10)R.sup.10, S(O)R.sup.10, cyano, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl and NR.sup.10R.sup.11; R.sup.3 is independently selected from: H, C.sub.1-C.sub.6-alkyl and C.sub.3-C.sub.6-cycloalkyl; R.sup.4 is independently selected from H, fluoro, chloro, C.sub.1-C.sub.6-haloalkyl and C.sub.1-C.sub.6-alkyl; R.sup.5 and R.sup.6 together with the carbon atom to which they are attached form a cyclic group selected from C.sub.3-C.sub.8-cycloalkyl and 4- to 8-membered heterocycloalkyl; wherein the cyclic group is optionally substituted with from 1 to 4 R.sup.12 groups; R.sup.7 and R.sup.12 are independently at each occurrence selected from: ═O, ═S, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, halogen, nitro, OR.sup.10, SR.sup.10, S(O).sub.2R.sup.10, S(O).sub.2NR.sup.10R.sup.10, S(O)(NR.sup.10)R.sup.10, S(O)R.sup.10, C(O)R.sup.10, C(O)NR.sup.10R.sup.10, C(O)OR.sup.10, cyano, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl, 3-to 6-membered heterocycloalkyl and NR.sup.10R.sup.11; R.sup.10 is independently at each occurrence selected from: H and C.sub.1-C.sub.6-alkyl; R.sup.11 is independently at each occurrence selected from; H, C.sub.1-C.sub.6-alkyl, C(O)—C.sub.1-C.sub.6-alkyl and S(O).sub.2-C.sub.1-C.sub.6-alkyl; p is an integer independently selected from 0, 1, 2 and 3; wherein any R.sup.2, R.sup.3, R.sup.4, R.sup.7, R.sup.10, R.sup.11, R.sup.12 group that is alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted, where chemically possible, by 1 to 4 substituents which are each independently selected at each occurrence from the group consisting of: ═O; ═NR.sup.a, ═NOR.sup.a, C.sub.1-C.sub.6-alkyl, halo, nitro, cyano, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, NR.sup.aR.sup.b, S(O).sub.2R.sup.a, S(O)R.sup.a, S(O)(NR.sup.a)R.sup.a, S(O).sub.2NR.sup.aR.sup.a, CO.sub.2R.sup.a, C(O)R.sup.a, CONR.sup.aR.sup.a and OR.sup.a; wherein R.sup.a is independently selected from H and C.sub.1-C.sub.6-alkyl; and R.sup.b is independently H, C.sub.1-C.sub.6-alkyl, C(O)—C.sub.1-C.sub.6-alkyl, or S(O).sub.2-C.sub.1-C.sub.6-alkyl; or an agronomically acceptable salt or N-oxide thereof.

2. A compound of claim 1, wherein R.sup.1 has the structure: ##STR00076##

3. A compound of claim 1 wherein R.sup.3 is H.

4. A compound of claim 1 wherein R.sup.4 is H.

5. A compound of claim 1, wherein R.sup.4 is independently selected from fluoro, C.sub.1-C.sub.6-haloalkyl and C.sub.1-C.sub.6-alkyl.

6. A compound of claim 1, wherein R.sup.5 and R.sup.6 together with the carbon atom to which they are attached form a C.sub.3-C.sub.6-cycloalkyl group; wherein the cycloalkyl group is optionally substituted with from 1 to 4 R.sup.12 groups.

7. A compound of claim 6, wherein R.sup.5 and R.sup.6 together with the carbon atom to which they are attached form a cyclopropyl group; wherein the cyclopropyl group is optionally substituted with from 1 to 4 R.sup.12 groups.

8. A compound of claim 6, wherein R.sup.5 and R.sup.6 together with the carbon atom to which they are attached form a cyclobutyl group; wherein the cyclobutyl group is optionally substituted with from 1 to 4 R.sup.12 groups.

9. A compound of claim 6, wherein R.sup.5 and R.sup.6 together with the carbon atom to which they are attached form a cyclopentyl group; wherein the cyclopentyl group is optionally substituted with from 1 to 4 R.sup.12 groups.

10. A compound of claim 6, wherein R.sup.5 and R.sup.6 may together with the carbon atom to which they are attached form a cyclohexyl group; wherein the cyclohexyl group is optionally substituted with from 1 to 4 R.sup.12 groups.

11. A compound of claim 1, wherein the compound of formula (I) is selected from: ##STR00077## ##STR00078##

12. A compound of claim 11, wherein the compound of formula (I) is: ##STR00079##

13. A compound of claim 11, wherein the compound of formula (I) is: ##STR00080##

14. A compound of claim 11, wherein the compound of formula (I) is: ##STR00081##

15. A compound of claim 11, wherein the compound of formula (I) is: ##STR00082##

16. A herbicidal composition comprising an effective amount of an active compound of formula I: ##STR00083## wherein R.sup.1 is selected from 5- to 9-membered bicyclic or monocyclic heterocycloalkyl group and 5-, 6-, 9- or 10-membered heteroaryl group; wherein said heterocycloalkyl or heteroaryl group comprises at least one nitrogen atom in the ring and is optionally substituted with from 1 to 6 R.sup.7 groups; or wherein R.sup.1 is —N═CR.sup.8R.sup.9 wherein R.sup.8 and R.sup.9 together with the carbon atom to which they are attached form a 5- to 9-membered bicyclic or monocyclic heterocycloalkyl group; wherein said heterocycloalkyl group comprises at least one nitrogen atom in the ring and is optionally substituted with from 1 to 6 R.sup.7 groups; R.sup.2 is independently at each occurrence selected from C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, halogen, nitro, OR.sup.10, SR.sup.10, OS(O).sub.2R.sup.10, S(O).sub.2R.sup.10, S(O).sub.2NR.sup.10R.sup.10, S(O)(NR.sup.10)R.sup.10, S(O)R.sup.10, cyano, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl and NR.sup.10R.sup.11; R.sup.3 is independently selected from: H, C.sub.1-C.sub.6-alkyl and C.sub.3-C.sub.6-cycloalkyl; R.sup.4 is independently selected from H, fluoro, chloro, C.sub.1-C.sub.6-haloalkyl and C.sub.1-C.sub.6-alkyl; R.sup.5 and R.sup.6 together with the carbon atom to which they are attached form a cyclic group selected from C.sub.3-C.sub.8-cycloalkyl and 4- to 8-membered heterocycloalkyl; wherein the cyclic group is optionally substituted with from 1 to 4 R.sup.12 groups; R.sup.7 and R.sup.12 are independently at each occurrence selected from: ═O, ═S, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, halogen, nitro, OR.sup.10, SR.sup.10, S(O).sub.2R.sup.10, S(O).sub.2NR.sup.10R.sup.10, S(O)(NR.sup.10)R.sup.10, S(O)R.sup.10, C(O)R.sup.10, C(O)NR.sup.10R.sup.10, C(O)OR.sup.10, cyano, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl, 3-to 6-membered heterocycloalkyl and NR.sup.10R.sup.11; R.sup.10 is independently at each occurrence selected from: H and C.sub.1-C.sub.6-alkyl; R.sup.11 is independently at each occurrence selected from; H, C.sub.1-C.sub.6-alkyl, C(O)—C.sub.1-C.sub.6-alkyl and S(O).sub.2-C.sub.1-C.sub.6-alkyl; p is an integer independently selected from 0, 1, 2 and 3; wherein any R.sup.2, R.sup.3, R.sup.4, R.sup.7, R.sup.10, R.sup.11, R.sup.12 group that is alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted, where chemically possible, by 1 to 4 substituents which are each independently selected at each occurrence from the group consisting of: ═O; ═NR.sup.a, ═NOR.sup.a, C.sub.1-C.sub.6-alkyl, halo, nitro, cyano, C.sub.1-C.sub.6-haloalkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, NR.sup.aR.sup.b, S(O).sub.2R.sup.a, S(O)R.sup.a, S(O)(NR.sup.a)R.sup.a, S(O).sub.2NR.sup.aR.sup.a, CO.sub.2R.sup.a, C(O)R.sup.a, CONR.sup.aR.sup.a and OR.sup.a; wherein R.sup.a is independently selected from H and C.sub.1-C.sub.6-alkyl; and R.sup.b is independently H, C.sub.1-C.sub.6-alkyl, C(O)—C.sub.1-C.sub.6-alkyl, or S(O).sub.2-C.sub.1-C.sub.6-alkyl; or an agronomically acceptable salt or N-oxide thereof.

17. A herbicidal composition of claim 16, wherein R.sup.1 has the structure: ##STR00084## wherein R.sup.13 is independently at each occurrence selected from C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, halogen, nitro, OR.sup.10, SR.sup.10, cyano, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-cycloalkyl and NR.sup.10R.sup.11; R.sup.14 is independently selected from H and C.sub.1-C.sub.6-alkyl; and n is an integer independently selected from 0, 1 and 2.

18. A herbicidal composition of claim 16, wherein R.sup.1 has the structure: ##STR00085##

19. A herbicidal composition of claim 16 wherein R.sup.3 is H.

20. A herbicidal composition of claim 16 wherein R.sup.4 is H.

21. A herbicidal composition of claim 16, wherein R.sup.5 and R.sup.6 together with the carbon atom to which they are attached form a C.sub.3-C.sub.6-cycloalkyl group; wherein the cycloalkyl group is optionally substituted with from 1 to 4 R.sup.12 groups.

22. A herbicidal composition of claim 21, wherein R.sup.5 and R.sup.6 together with the carbon atom to which they are attached form a cyclopropyl group; wherein the cyclopropyl group is optionally substituted with from 1 to 4 R.sup.12 groups.

23. A herbicidal composition of claim 16, wherein the compound of formula (I) is selected from: ##STR00086## ##STR00087##

24. A herbicidal composition of claim 23, wherein the compound of formula (I) is: ##STR00088##

25. A herbicidal composition of claim 23, wherein the compound of formula (I) is: ##STR00089##

26. A herbicidal composition of claim 23, wherein the compound of formula (I) is: ##STR00090##

27. A herbicidal composition of claim 23, wherein the compound of formula (I) is: ##STR00091##

Description

DETAILED DESCRIPTION—SYNTHESIS

(1) The skilled person will appreciate that adaptation of methods known in the art could be applied in the manufacture of the compounds of the present invention.

(2) For example, the skilled person will be immediately familiar with standard textbooks such as “Comprehensive Organic Transformations—A Guide to Functional Group Transformations”, RC Larock, Wiley-VCH (1999 or later editions); “March's Advanced Organic Chemistry—Reactions, Mechanisms and Structure”, MB Smith, J. March, Wiley, (5th edition or later); “Advanced Organic Chemistry, Part B, Reactions and Synthesis”, F A Carey, R J Sundberg, Kluwer Academic/Plenum Publications, (2001 or later editions); “Organic Synthesis—The Disconnection Approach”, S Warren (Wiley), (1982 or later editions); “Designing Organic Syntheses” S Warren (Wiley) (1983 or later editions); “Heterocyclic Chemistry”, J. Joule (Wiley 2010 edition or later); (“Guidebook To Organic Synthesis” RK Mackie and DM Smith (Longman) (1982 or later editions), etc., and the references therein as a guide.

(3) The skilled person is familiar with a range of strategies for synthesising organic and particularly heterocyclic molecules and these represent common general knowledge as set out in text books such as Warren “Organic Synthesis: The Disconnection Approach”; Mackie and Smith “Guidebook to Organic Chemistry”; and Clayden, Greeves, Warren and Wothers “Organic Chemistry”.

(4) The skilled chemist will exercise his or her judgement and skill as to the most efficient sequence of reactions for synthesis of a given target compound and will employ protecting groups as necessary.

(5) This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the protection/deprotection steps. These and other reaction parameters will be evident to the skilled person by reference to standard textbooks and to the examples provided herein.

(6) Sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in “Protective Groups in Organic Synthesis” by TW Greene and PGM Wuts, John Wiley & Sons Inc (1999), and references therein.

(7) Throughout this specification these abbreviations have the following meanings:

(8) Boc—tert-butyloxycarbonyl DCM—dichloromethane

(9) DMF—N,N-dimethylformamide DIPEA—diisopropylethylamine

(10) DMAP—N,N-dimethylaminopyridine DMSO—dimethylsulfoxide

(11) HATU—(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide

(12) hexafluorophosphate) Et.sub.2O—Diethyl ether

(13) IPA—isopropyl alcohol EtOAc—Ethyl acetate

(14) PE—petroleum ether THF—tetrahydrofuran

(15) TFA—trifluoroacetic acid MeOH—methanol

(16) HPLC—high performance liquid chromatography r.t.—room temperature

(17) Certain compounds of the invention can be made according to the following general synthetic schemes. Certain compounds of the invention can be made according to or analogously to the methods described in Examples 1 to 14.

(18) General Synthetic Schemes

(19) Scheme A describes a general approach to certain compounds of the invention. Compounds of formula A can be reacted with N,N-dimethylchloroformamide (e.g. by deprotonating with NaH and reacting in DMF) to provide compounds of formula B. Treatment under ring closing conditions (e.g. with POCl3 and PCl.sub.5) can provide compounds of formula C. Reaction with amino acid D (e.g. in acetic acid at 90° C.) can provide compounds of formula E. Alkylation (where R.sup.14 is Me, this can be achieved with methyl iodide and potassium carbonate in DMF at 60° C.) can provide ester F which, on ester cleavage (where R.sup.14 is Me this can be achieved using BBr.sub.3 in DCM), can be converted to acid G. Acid G can be coupled with sulfonamide H to provide compounds of formula J, a subset of compounds of the invention. This can be achieved either by converting the acid to the acid chloride (e.g. using (COCl).sub.2 and DMF) and reacted with the sulfonamide H in the presence of a base (e.g. triethylamine in DCM in the presence of DMAP) or by using a suitable coupling system (e.g. HATU and DIPEA in DCM).

(20) ##STR00030##

(21) Certain aminoacids of formula D can be made according to scheme B. A benzoic ester K can be nitrated at the meta position (e.g. using nitric acid and sulfuric acid) to form benzoic ester L. Reduction of the nitro group (e.g. using iron in the presence of ammonium chloride in methanol and water at 90° C.) followed by ester cleavage (e.g. using NaOH in ethanol) can provide aminoacid D.

(22) ##STR00031##

(23) Sulfonamides of formula H can be made from the corresponding sulfonyl chloride N, e.g. by reacting with ammonium hydroxide in THF (Scheme C).

(24) ##STR00032##
General Methods

(25) Flash chromatography was carried out using a Biotage Isolera 4, with Biotage® SNAP KP-Sil cartridges, packed with 50 μm silica particles with a surface area of 500 m.sup.2/g, or alternative cartridges (e.g. Puriflash, produced by Interchim) where stated, or using silica gel (40-63 μm particles). Visualisation was carried out with UV light (254 nm) and by staining with either potassium permanganate, phosphomolybdic acid (PMA) or ninhydrin solutions.

(26) All .sup.1H NMR spectra were obtained on a Bruker AVIII 400 with 5 mm QNP or Bruker AVI 500 with 5 mm QNP. Chemical shifts are expressed in parts per million (δ) and are referenced to the solvent. Coupling constants J are expressed in Hertz (Hz).

(27) ESI-MS data were obtained using a Waters Acquity H-Class UPLC. (Column: CSH C18 2.1×50 mm 1.7 μm @ 50 C, Solvents: A-Water B-Acetonitrile+0.1% Formic Acid or Solvents: A-Water B-Acetonitrile+0.1% by volume of 28% (by weight) aqueous ammonia solution, Gradient: 0.2-2.5 mins 2-98% B 2.5-3.0 mins 98% B, Flow rate: 1.0 mL/min.) Data for product ions alone are reported.

(28) MS was carried out on a Waters Alliance ZQ MS, using a LC column as described below under Method C, D and F. Wavelengths were 254 and 210 nM.

(29) Method C (5 Minute Acidic pH)

(30) Column: YMC-Triart C18 50×2 mm, 5 μm. Flow rate: 0.8 mL/min. Injection volume: 5 μL.

(31) TABLE-US-00001 Mobile Phase A H.sub.2O B CH.sub.3CN C 50% H.sub.2O/50% CH.sub.3CN + 1.0% formic acid Time (min) A (%) B (%) C (%) 0 95 0 5 4 0 95 5 4.4 0 95 5 4.5 95 5 0 4.5 STOP
Method D (15 Minute Acidic pH)

(32) Column YMC Triart-C18 50×2 mm, 5 μm Flow rate: 0.8 mL/min. Injection volume: 10 μL

(33) TABLE-US-00002 Mobile Phase A H.sub.2O B CH.sub.3CN C 50% H.sub.2O/50% CH.sub.3CN + 1.0% formic acid Time (min) A (%) B (%) C (%) 0 95 0 5 2.0 95 0 5 12.0 0 95 5 14.0 0 95 5 14.2 95 0 5
Method F (3.5 Minute Acidic pH)

(34) Mobile phases: Water (A)/Acetonitrile (B) both with 0.1% (v/v) Formic Acid

(35) TABLE-US-00003 Time % A % B Flow rate (mL/min) Initial 98 2 1.0 0.2 98 2 1.0 2.5 2 98 1.0 3.0 2 98 1.0 3.1 98 2 1.0 3.5 98 2 1.0

(36) Column: CSH C18 2.1×50 mm, 1.7 μm @ 50° C.

(37) All reagents were obtained from commercial suppliers and used as supplied unless otherwise stated.

(38) All examples are named using ChemBioDraw Ultra 14.0.

Example 1: 2-Chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)-N-((tetrahydro-2H-pyran-4-yl)sulfonyl)benzamide

(39) ##STR00033##

(40) 2-Chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)pyrimidin-1-yl]benzoic acid (Intermediate A) was prepared according to the procedure provided in US 2004/0018942. To a solution of Intermediate A (100.0 mg, 0.27 mmol) in dichloromethane (3.5 mL) was added DMF (5 drops). Oxalyl chloride (0.07 mL, 0.81 mmol) was then added dropwise to the reaction and it was stirred at r.t. for 1.5 h. The reaction mixture was then concentrated in vacuo. Toluene (2 mL) was then added to the crude acyl chloride concentrate and the flask was purged with nitrogen. A solution of tetrahydro-2H-pyran-4-sulfonamide (45.1 mg, 0.27 mmol), DMAP (1.7 mg, 0.01 mmol) and triethylamine (0.13 mL, 0.96 mmol) was prepared in toluene (1 mL) and was added to the pre-prepared acyl chloride solution and heated to 55° C. for 18 h. The reaction mixture was added to a stirred flask containing ice water. EtOAc (10 mL) and sat. brine (10 mL) were then added to the resultant biphasic mixture. The aqueous layer was re-extracted with EtOAc (3×5 mL) and the combined organics were then dried with Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography (SiO.sub.2, 25-100% EtOAc (0.1% AcOH) in PE (0.1% AcOH)) to afford the title compound as a brown solid (18.5 mg, 13%). .sup.1H NMR δ.sub.H(CDCl.sub.3, 500 MHz) 8.02 (s, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.31 (d, J=9.4 Hz, 1H), 6.35 (s, 2H), 4.08 (dd, J=11.0, 4.2 Hz, 2H), 3.55 (d, J=1.0 Hz, 3H), 3.38 (td, J=12.1, 2.2 Hz, 2H), 3.08 (t, J=3.7 Hz, 1H), 2.06-2.00 (m, 2H), 1.85 (ddd, J=25.5, 12.2, 4.7 Hz, 2H). LCMS (Method D): 6.62 min (513.0, [M+H].sup.+)

Intermediate B: tert-Butyl 4-sulfamoylpiperidine-1-carboxylate

(41) ##STR00034##

(42) To a solution of 1-boc-4-chlorosulfonylpiperidine (1.0 g, 3.52 mmol) in THF (22 mL) at 00° C. was added ammonium hydroxide (4.90 ml, 35.20 mmol) in a dropwise manner. The reaction was allowed to proceed for 3 h at r.t. The reaction mixture was concentrated under reduced pressure to afford a white solid. To the crude residue was added 20 mL water and 20 mL EtOAc and the layers separated. The aqueous layer was then re-extracted with 3×10 mL EtOAc and the combined organics were dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the title compound as a white solid (879.3 mg, 94%). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) δ 4.40 (s, 2H), 4.29 (s, 2H), 3.06 (tt, J=12.0, 3.6 Hz, 1H), 2.74 (t, J=13.0 Hz, 2H), 2.17 (t, J=6.6 Hz, 2H), 1.72 (qd, J=12.5, 4.6 Hz, 2H), 1.46 (s, 9H).

Intermediate C: tert-Butyl 4-(N-(2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzoyl)sulfamoyl)piperidine-1-carboxylate

(43) ##STR00035##

(44) Prepared according to the procedure described in Example 1 using Intermediate A (200.0 mg, 0.55 mmol, oxalyl chloride (0.14 mL, 1.64 mmol), Intermediate B (144.0 mg, 0.55 mmol), 4-(dimethylamino)pyridine (3.3 mg, 0.03 mmol) and triethylamine (0.27 mL, 1.91 mmol) to afford the title compound as a tan solid (250.0 mg, 75%). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 8.95 (s, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.41 (d, J=8.9 Hz, 1H), 6.38 (s, 1H), 4.28 (s, 2H), 3.90-3.76 (m, 1H), 3.57 (s, 3H), 2.78 (s, 1H), 1.86 (ddd, J=25.1, 12.5, 4.6 Hz, 2H), 1.25 (t, J=3.5 Hz, 2H). LCMS (Method C): 3.03 min (611.3, [M−H].sup.−).

Example 2: 2-Chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)-N-(piperidin-4-ylsulfonyl)benzamide hydrochloride

(45) ##STR00036##

(46) To a solution of Intermediate C (70.0 mg, 0.11 mmol) in dioxane (1.4 mL), HCl (1.4 mL, 5.6 mmol, 4 M in dioxane) was added. The reaction was allowed to proceed for 3 hours at r.t. The reaction mixture was concentrated under reduced pressure and the resultant yellow solid was suspended in diethyl ether and filtered off, washing with diethyl ether (10 mL) to afford the title compound as a yellow powder (42.1 mg, 67%). .sup.1H NMR δ.sub.H (MeOD-d.sub.4, 500 MHz) 7.76 (d, J=7.4 Hz, 1H), 7.65 (d, J=9.4 Hz, 1H), 6.49 (s, 1H), 4.02 (t, J=11.4 Hz, 1H), 3.65-3.45 (m, 6H), 3.25-3.11 (m, 3H), 2.46 (d, J=13.6 Hz, 2H), 2.16 (td, J=15.5, 4.1 Hz, 2H). LCMS (Method D): 5.30 min (513.0, [M+H].sup.+).

Example 3: 2-Chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)-N-((1-methylpiperidin-4-yl)sulfonyl)benzamide hydrochloride

(47) ##STR00037##

(48) To a solution of Intermediate C (55.0 mg, 0.09 mmol), formic acid (179 μl) and formaldehyde (37% in water, 67 μl, 0.9 mmol) were added. The reaction was then sealed and heated to 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure and to the resultant brown solid was added HCl (1 mL, 4 M in dioxane) and the reaction was stirred for 1 h at r.t. The reaction mixture was then concentrated under reduced pressure and the resultant off-white solid was suspended in diethyl ether and filtered, washing with diethyl ether (10 mL) to afford the title compound as an off white powder (12.8 mg, 25%). .sup.1H NMR δ.sub.H (MeOD-d.sub.4, 500 MHz) 7.76 (d, J=7.2 Hz, 1H), 7.66 (d, J=9.3 Hz, 1H), 6.49 (s, 1H), 4.07-3.93 (m, 1H), 3.72 (d, J=12.7 Hz, 2H), 3.56 (s, 3H), 3.20 (d, J=13.3 Hz, 2H), 2.93 (s, 3H), 2.51 (d, J=12.9 Hz, 2H), 2.26-2.08 (m, 2H). LCMS (Method D): 5.31 min (527.0, [M+H].sup.+).

Intermediate D: tert-Butyl 3-sulfamoylpyrrolidine-1-carboxylate

(49) ##STR00038##

(50) Prepared according to the procedure described in Intermediate B using tert-butyl 3-(chlorosulfonyl)pyrrolidine-1-carboxylate (1.0 g, 3.71 mmol), THF (23.2 ml) and ammonium hydroxide (5.2 ml, 37.1 mmol) to afford the title compound as a colourless solid (744.6 mg, 80%). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 4.87 (s, 2H), 3.76 (br. s, 3H), 3.62 (m, 1H), 3.49-3.37 (m, 1H), 2.42-2.25 (m, 2H), 1.46 (s, 9H).

Intermediate E: tert-Butyl 3-(N-(2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzoyl)sulfamoyl)pyrrolidine-1-carboxylate

(51) ##STR00039##

(52) Prepared according to the procedure described in Example 1 using Intermediate A (200.0 mg, 0.55 mmol), oxalyl chloride (0.14 mL, 1.636 mmol), Intermediate D (137.0 mg, 0.55 mmol), 4-(dimethylamino)pyridine (3.3 mg, 0.03 mmol) and triethylamine (0.27 mL, 1.91 mmol) to afford the title compound as an orange solid (136.7 mg, 42%). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 8.04 (d, J=11.2 Hz, 2H), 7.34 (d, J=9.1 Hz, 1H), 6.34 (dd, J=9.1, 5.2 Hz, 1H), 3.95 (dd, J=23.4, 16.3 Hz, 2H), 3.58-3.53 (m, 3H), 3.43-3.32 (m, 2H), 2.55 (s, 1H), 2.42-2.27 (m, 2H), 1.45 (s, 9H). LCMS (Method C): 2.19 min (599.0, [M+H].sup.+).

Example 4: 2-Chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)-N-(pyrrolidin-3-ylsulfonyl)benzamide hydrochloride

(53) ##STR00040##

(54) Prepared according to the procedure described for Example 2 using Intermediate E (137.6 mg, 0.23 mmol), dioxane (2.8 mL) and HCl (2.8 mL, 11.2 mmol, 4 M in dioxane) to afford the title compound as an orange powder (56.6 mg, 49%). .sup.1H NMR δ.sub.H (MeOD-d.sub.4, 500 MHz) 8.12 (d, J=3.6 Hz, 1H), 7.62 (t, J=9.2 Hz, 1H), 7.57-7.47 (m, 1H), 6.47 (s, 1H), 3.99-3.81 (m, 2H), 3.44 (s, 3H), 3.45-3.35 (m, 2H), 2.60-2.30 (m, 4H).

Example 5: 2-Chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)-N-((1-methylpyrrolidin-3-yl)sulfonyl)benzamide hydrochloride

(55) ##STR00041##

(56) Prepared according to the procedure described for Example 3 using Intermediate E (100.0 mg, 0.167 mmol), formic acid (835 μl) and formaldehyde (37% in water, 188 μl, 2.5 mmol) to afford the title compound as an off white powder (54.2 mg, 59%). .sup.1H NMR δ.sub.H (MeOD-d.sub.4, 500 MHz) b 7.72 (d, J=7.4 Hz, 1H), 7.64 (d, J=9.4 Hz, 1H), 6.46 (s, 1H), 4.33-4.13 (m, 1H), 3.90-3.55 (m, 4H), 3.53 (s, 3H), 3.03 (t, J=7.6 Hz, 3H), 2.79-2.66 (m, 1H), 2.62-2.52 (m, 1H). LCMS (Method D): 5.32 min (513.1, [M+H].sup.+).

Intermediate F: tert-Butyl 3-sulfamoylazetidine-1-carboxylate

(57) ##STR00042##

(58) Prepared according to the procedure described in Intermediate B using tert-butyl 3-(chlorosulfonyl)azetidine-1-carboxylate (250.0 mg, 0.98 mmol), THF (3.3 ml) and ammonium hydroxide (1.36 ml, 9.78 mmol) to afford the title compound as a white solid (216.5 mg, 94%). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 4.76 (s, 2H), 4.28-4.21 (m, 2H), 4.17 (dd, J=10.1, 5.2 Hz, 2H), 4.00 (ddd, J=8.3, 6.6, 4.2 Hz, 1H), 1.44 (s, 9H).

Intermediate G: tert-Butyl 3-(N-(2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzoyl)sulfamoyl)azetidine-1-carboxylate

(59) ##STR00043##

(60) A solution of Intermediate A (200.0 mg, 0.54 mmol), Intermediate F (155.0 mg, 0.65 mmol), HATU (249.0 mg, 0.65 mmol) and N,N-diisopropylethylamine (0.28 mL, 1.64 mmol) was prepared in anhydrous dichloromethane (1.65 mL). The flask was sealed and the reaction was allowed to proceed for 2 hours at r.t. Water (30 mL), HCl (1 M, 1.7 mL) and sat. brine (5 mL) were added to the reaction mixture and the layers separated. The aqueous layer was re-extracted with dichloromethane (3×5 mL) and the combined organics were then dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the title compound as an off-white solid (297.2 mg, 93%). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 7.78 (d, J=7.4 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 6.38 (s, 1H), 4.60 (ddd, J=8.5, 5.7, 3.0 Hz, 1H), 4.42-4.35 (m, 2H), 4.29-4.23 (m, 2H), 3.57 (s, 3H), 1.45 (s, 9H). LCMS (Method C): 2.81 min (583.2, [M−H].sup.−).

Example 6: N-(Azetidin-3-ylsulfonyl)-2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzamide hydrochloride

(61) ##STR00044##

(62) Prepared according to the procedure described for Example 2 using Intermediate G (100.0 mg, 0.17 mmol), dioxane (1 mL) and HCl (0.85 mL, 3.4 mmol, 4 M in dioxane) to afford the title compound as a white powder (77.1 mg, 87%). .sup.1H NMR δ.sub.H (MeOD-d.sub.4, 500 MHz) 7.71 (d, J=7.4 Hz, 1H), 7.62 (d, J=9.4 Hz, 1H), 6.46 (s, 1H), 4.53-4.49 (m, 4H), 4.29-4.22 (m, 1H), 3.52 (d, J=0.9 Hz, 3H). LCMS (Method D): 5.26 min (484.9, [M+H].sup.+).

Example 7: 2-Chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)-N-((1-methylcyclopropyl)sulfon yl)benzamide

(63) ##STR00045##

(64) Prepared according to the procedure described for Intermediate G using Intermediate A (100.0 mg, 0.27 mmol), 1-methylcyclopropanesulfonamide (44.2 mg, 0.33 mmol), HATU (124.0 mg, 0.33 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.82 mmol). The crude residue was purified by flash chromatography (SiO.sub.2, 0-25% EtOAc (0.5% AcOH) in PE (0.5% AcOH)) to afford the title compound as a white solid (81.6 mg, 62%). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 7.65 (d, J=7.4 Hz, 1H), 7.60 (d, J=9.4 Hz, 1H), 6.46 (s, 1H), 3.53 (d, J=1.1 Hz, 3H), 1.63 (td, J=5.7, 0.9 Hz, 2H), 1.60 (s, 3H), 1.00-0.95 (m, 2H). LCMS (Method D): 7.43 min (483.9, [M+H].sup.+).

Intermediate H: Ethyl (Z)-3-(3,3-dimethylureido)-4,4,4-trifluorobut-2-enoate

(65) ##STR00046##

(66) To a nitrogen purged suspension of sodium hydride (1.53 g, 38.2 mmol) in DMF (54.6 ml) at 0° C. was added ethyl 3-amino-4,4,4-trifluorocrotonate (5.0 g, 27.31 mmol, in 10 mL DMF) in a dropwise manner over a 30 min period and the reaction was allowed to proceed for 1 h. Dimethylcarbamyl chloride (7.54 ml, 82.0 mmol) was added in a dropwise manner over 30 min and the reaction was allowed to warm to r.t. before being heated to 60° C. for approx. 21 h under nitrogen. The reaction mixture was allowed to cool to room temperature before HCl (1 M, 50 mL) was slowly added to the reaction mixture and the solution was allowed to stir for 30 mins. Water (200 mL), EtOAc (50 mL) and sat. brine (25 mL) were then added and the two layers separated. The aqueous layer was re-extracted with 3×50 mL EtOAc and the combined organics were dried using Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford an orange oil. The residue was purified by flash chromatography (SiO.sub.2, 7-60% EtOAc (0.5% AcOH) in PE (0.5% AcOH)) to afford the title compound as a pale yellow liquid (1.248 g, 18% yield). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 5.76-5.63 (m, 1H), 4.23 (q, J=7.1 Hz, 2H), 3.05 (s, 6H), 1.31 (t, J=7.1 Hz, 3H). LCMS (Method C): 2.38 min (255.1, [M+H].sup.+).

Intermediate I: 2-(Dimethylamino)-4-(trifluoromethyl)-6H-1,3-oxazin-6-one

(67) ##STR00047##

(68) To a solution of ethyl (Z)-3-(3,3-dimethylureido)-4,4,4-trifluorobut-2-enoate (1.24 g, 4.91 mmol) in phosphorus(V) oxychloride (0.45 ml, 4.91 mmol) was added phosphorus pentachloride (1.02 g, 4.91 mmol) in five portions, giving time for the reaction mixture to fully homogenise between additions. The reaction was allowed to proceed at room temperature, monitoring by TLC every 15 minutes. After 45 min, the reaction was poured slowly in to a stirred flask of ice water (200 mL). Once the ice had melted, EtOAc (50 mL), sat. aq. NaHCO.sub.3 (50 mL) and sat. brine (30 mL) were then added and the two layers separated. The aqueous layer was re-extracted with 3×20 mL EtOAc and the combined organics were dried using Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound as a yellow solid (874.4 mg, 86%). .sup.1H NMR δ.sub.H(CDCl.sub.3, 500 MHz) 5.86 (s, 1H), 3.22 (s, 3H), 3.17 (s, 3H). LCMS (Method C): 2.50 min (209.1, [M+H].sup.+).

Intermediate J: 5-(2,6-Dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)-2,4-difluorobenzoic acid

(69) ##STR00048##

(70) To a solution of Intermediate I (300.0 mg, 1.44 mmol) in acetic acid (14.4 mL) was added 5-amino-2,4-difluorobenzoic acid (262.0 mg, 1.51 mmol). The vial was capped and the reaction was heated to 90° C. for approx. 18 hours. To the reaction mixture was added water (50 mL), sat. brine (10 mL) and EtOAc (10 mL) and the layers separated. The aqueous layer was re-extracted with 3×10 mL EtOAc and the combined organics were dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the title compound as a brown oil (206.1 mg, 43%). LCMS (Method C): 1.82 min (336.0, [M+H].sup.+).

Intermediate K: Methyl 2,4-difluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzoate

(71) ##STR00049##

(72) To a solution of Intermediate J (206.1 mg, 0.61 mmol) and potassium carbonate (424.0 mg, 3.07 mmol) in DMF (1.3 mL) was added iodomethane (0.38 mL, 6.13 mmol). The reaction was capped and heated to 60° C. for approx. 18 h. Ammonia (water solution, 5 mL) was added to quench excess iodomethane. Water (300 mL) and dichloromethane (50 mL) were added to the reaction mixture and the layers separated. The aqueous layer was re-extracted with 3×50 mL DCM and the combined organics were washed with water (3×50 mL), dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the title compound as a brown solid (171.0 mg, 77%). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 7.98-7.92 (m, 1H), 7.07 (t, J=9.7 Hz, 1H), 6.38 (s, 1H), 3.92 (s, 3H), 3.57 (d, J=1.2 Hz, 3H). LCMS (Method C): 2.68 min (365.1, [M+H].sup.+).

Intermediate L: 2,4-Difluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzoic acid

(73) ##STR00050##

(74) To a 0° C. solution of Intermediate K (171.0 mg, 0.47 mmol) in DCM (2.3 mL) was added boron tribromide (1 M in DCM, 1.41 mL, 1.41 mmol) in a drop-wise manner. The reaction was allowed to proceed for 30 min before being removed from the ice bath and being allowed to proceed for approx. 18 h at r.t. The reaction mixture was added dropwise to a stirred flask containing ice water (10 mL). Once the ice had melted, DCM (10 mL) and sat. brine (5 mL) were then added to the resultant biphasic mixture. The aqueous layer was re-extracted with 3×20 mL DCM and the combined organics were then dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the title compound a yellow solid (159.1 mg, 97%). LCMS (Method C): 2.20 min (351.1, [M+H].sup.+).

Example 8: N-(Cyclopropylsulfonyl)-2,4-difluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzamide

(75) ##STR00051##

(76) Prepared according to the procedure described for Intermediate G using Intermediate L (159.1 mg, 0.45 mmol), cyclopropanesulfonamide (60.5 mg, 0.50 mmol), HATU (207.0 mg, 0.55 mmol) and N,N-diisopropylethylamine (0.24 mL, 0.14 mmol). The crude residue was purified by passing it through a pad of silica, eluting with 0-30% EtOAc (0.5% AcOH) in PE (0.5% AcOH) to afford the title compound as a yellow solid (62.8 mg, 30%). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 8.71 (d, J=14.0 Hz, 1H), 8.11 (t, J=7.9 Hz, 1H), 7.15 (dd, J=11.3, 8.8 Hz, 1H), 6.38 (s, 1H), 3.57 (d, J=1.0 Hz, 3H), 3.09 (ddd, J=8.1, 4.8, 3.3 Hz, 1H), 1.49-1.46 (m, 2H), 1.19-1.16 (m, 2H). LCMS (Method D): 6.95 min (454.1, [M+H].sup.+).

Intermediate M: 2-Chloro-5-(2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzoic acid

(77) ##STR00052##

(78) Prepared according to the procedure described for Intermediate J using Intermediate I (500.0 mg, 2.40 mmol), acetic acid (2.4 mL) and 5-amino-2-chlorobenzoic acid (412.0 mg, 2.40 mmol) to afford the title compound as a yellow solid (206.1 mg, 43%). LCMS (Method C): 1.70 min (335.1, [M+H].sup.+).

Intermediate N: Methyl 2-chloro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzoate

(79) ##STR00053##

(80) Prepared according to the procedure described for Intermediate K using Intermediate M (792.3 mg, 2.37 mmol), potassium carbonate (1.64 g, 11.84 mmol), DMF (2.4 mL) and iodomethane (1.47 mL, 23.68 mmol) to afford the title compound as a brown solid (822.2 mg, 96%). LCMS (Method C): 2.78 min (363.0, [M+H].sup.+).

Intermediate O: 2-Chloro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzoic acid

(81) ##STR00054##

(82) Prepared according to the procedure described for Intermediate L using Intermediate N (822.2 mg, 2.27 mmol), dichloromethane (11.3 mL) and boron tribromide (1 M in dichloromethane, 6.8 mL, 6.8 mmol) to afford the title compound a yellow solid (690.0 mg, 87%). LCMS (Method C): 1.95 min (349.1, [M+H].sup.+).

Example 9: 2-Chloro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)-N-((1-methylcyclopropyl)sulfon yl)benzamide

(83) ##STR00055##

(84) Prepared according to the procedure described for Intermediate G using Intermediate O (200.0 mg, 0.57 mmol), 1-methylcyclopropanesulfonamide (78.0 mg, 0.57 mmol), HATU (262.0 mg, 0.69 mmol) and N,N-diisopropylethylamine (0.24 mL, 0.14 mmol). The crude residue was purified by passing it through a pad of silica, eluting with 0-30% EtOAc (0.5% AcOH) in PE (0.5% AcOH) to afford the title compound as a white solid (90.0 mg, 34%). .sup.1H NMR δ.sub.H (DMSO-d.sub.6, 500 MHz) 12.43 (s, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.53 (d, J=2.3 Hz, 1H), 7.49-7.42 (m, 1H), 6.56 (s, 1H), 3.39 (s, 3H), 1.52 (s, 3H), 1.45 (s, 2H), 1.23 (s, 1H), 0.99 (s, 2H). LCMS (Method D): 7.09 min (466.0, [M+H].sup.+).

Intermediate P: Tetrahydrothiophene-3-sulfonamide 1,1-dioxide

(85) ##STR00056##

(86) Prepared according to the procedure described in Example 1 using tetrahydro-3-thiophenesulfonyl chloride (1.0 g, 4.57 mmol), THF (28.6 ml) and ammonium hydroxide (6.4 ml, 45.7 mmol) to afford the title compound as a white solid (622.9 mg, 68%). .sup.1H NMR δ.sub.H (DMSO-d.sub.6, 500 MHz) 7.24 (s, 2H), 4.02-3.93 (m, 1H), 3.49 (dd, J=14.0, 9.2 Hz, 1H), 3.34-3.18 (m, 3H), 2.48-2.41 (m, 1H), 2.37-2.27 (m, 1H).

Example 10: 2-Chloro-N-((1,1-dioxidotetrahydrothiophen-3-yl)sulfonyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzamide

(87) ##STR00057##

(88) Prepared according to the procedure described in Example 1 using Intermediate A (200.0 mg, 0.545 mmol), Intermediate P (109.0 mg, 0.55 mmol), oxalyl chloride (0.14 mL, 1.64 mmol), isothiazolidine 1,1-dioxide (66.1 mg, 0.55 mmol), 4-(dimethylamino)pyridine (3.3 mg, 0.03 mmol) and triethylamine (0.27 mL, 1.91 mmol). The crude residue was purified by flash chromatography (SiO.sub.2, 0-7.5% MeOH (0.5% AcOH) in dichloromethane (0.5% AcOH)) to afford the title compound as an orange solid (61.0 mg, 20%). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 7.75 (d, J=6.5 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 6.37 (s, 1H), 4.86 (s, 1H), 4.72-4.57 (m, 1H), 3.57 (s, 3H), 3.44-3.33 (m, 2H), 3.25-3.13 (m, 2H), 2.74 (dd, J=14.2, 6.7 Hz, 2H). LCMS (Method D): 5.86 min (547.8, [M+H].sup.+).

Intermediate Q: Methyl 2,4-dichloro-5-nitrobenzoate

(89) ##STR00058##

(90) To a flask of methyl 2,4-dichlorobenzoate (500.0 mg, 2.44 mmol) at 0° C. was added conc. sulfuric acid (2.73 mL, 51.2 mmol) and then conc. nitric acid (0.46 mL, 9.27 mmol) in a drop-wise manner. The reaction was allowed to warm to r.t. and to proceed for 18 h. The reaction mixture was carefully poured into a flask of stirred ice water (100 mL). Once the ice had melted, EtOAc (40 mL) and sat. brine (20 mL) were then added and the layers separated. The aqueous layer was re-extracted with 3×10 mL EtOAc washings and the combined organics were then dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the title compound as a yellow solid (579.2 mg, 95%). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 7.75 (d, J=6.5 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 6.37 (s, 1H), 4.86 (s, 1H), 4.72-4.57 (m, 1H), 3.57 (s, 3H), 3.44-3.33 (m, 2H), 3.25-3.13 (m, 2H), 2.74 (dd, J=14.2, 6.7 Hz, 2H).

Intermediate R: Methyl 5-amino-2,4-dichlorobenzoate

(91) ##STR00059##

(92) A mixture of Intermediate Q (580.0 mg, 2.32 mmol), iron powder (259.0 mg, 4.64 mmol), ammonium chloride (869.0 mg, 16.24 mmol), methanol (1.55 mL) and water (3.09 mL) was purged with nitrogen and heated to 90° C. for 18 h. The crude solution was filtered through a pad of Celite®, eluting with 50% EtOAc in petroleum ether to afford a filtrate which was then dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound as an orange solid (339.0 mg, 66%). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 7.35 (s, 1H), 7.26 (s, 1H), 3.90 (s, 3H). LCMS (Method C): 2.70 min (220.0, [M+H].sup.+).

Intermediate S: 5-Amino-2,4-dichlorobenzoic acid

(93) ##STR00060##

(94) A solution of Intermediate R (339.0 mg, 1.54 mmol) in methanol (4.67 mL) was added 1 M aq. sodium hydroxide (4.6 mL, 4.6 mmol). The reaction was then allowed to proceed at r.t. for approx. 18 h. Water (20 mL) and 1 M HCl (4 mL) were added to the reaction and the solution was brought to approx. pH 6. EtOAc (50 mL) was then added and the layers separated. The aqueous layer was re-extracted with EtOAc (3×10 mL) and the combined organics were dried using Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the title compound as a yellow solid (308.4 mg, 97%). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 13.25 (s, 1H), 7.38 (s, 1H), 7.23 (s, 1H), 5.75 (s, 2H).

Intermediate T: 2,4-Dichloro-5-(2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzoic acid

(95) ##STR00061##

(96) Prepared according to the procedure described for Intermediate J using Intermediate R (331.0 mg, 1.60 mmol), Intermediate I(318.0 mg, 1.53 mmol) and acetic acid (1.5 mL) to afford the title compound as an orange solid (455.7 mg, 81%). .sup.1H NMR δ.sub.H (DMSO-d.sub.6, 500 MHz) 13.82 (s, 1H), 12.84 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 6.47 (s, 1H).

Intermediate U: Methyl 2,4-dichloro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzoate

(97) ##STR00062##

(98) Prepared according to the procedure described for Intermediate N using Intermediate T (495.0 mg, 1.34 mmol), potassium carbonate (927.0 mg, 6.71 mmol) in DMF (1.34 mL) and iodomethane (0.84 mL, 13.41 mmol) to afford the title compound as a brown solid (429.7 mg, 81%). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 7.86 (s, 1H), 7.69 (s, 1H), 6.38 (s, 1H), 3.88 (m, 3H), 3.57 (d, J=1.0 Hz, 3H).

Intermediate V: 2,4-Dichloro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzoic acid

(99) ##STR00063##

(100) Prepared according to the procedure described for Intermediate L using Intermediate U (429.7 mg, 1.08 mmol), dichloromethane (5.4 mL) and boron tribromide (1 M in dichloromethane, 3.25 mL, 3.25 mmol) to afford the title compound a white solid (400.5 mg, 97%). LCMS (Method C): 2.63 min (383.0, [M+H].sup.+).

Example 11: 2,4-Dichloro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)-N-((1-methylcyclopropyl)sulfon yl)benzamide

(101) ##STR00064##

(102) Prepared according to the procedure described for Intermediate G using Intermediate V (415.0 mg, 1.08 mmol), 1-methylcyclopropanesulfonamide (146.0 mg, 1.08 mmol), HATU (494.0 mg, 1.30 mmol) and N,N-diisopropylethylamine (0.57 mL, 0.33 mmol). The crude residue was purified by flash chromatography (SiO.sub.2, 0-30% EtOAc (0.5% AcOH) in PE (0.5% AcOH)) to afford the title compound as an off-white solid (154.4 mg, 29%). .sup.1H NMR δ.sub.H (DMSO-d.sub.6, 500 MHz) 12.54 (s, 1H), 8.05 (s, 1H), 7.78 (s, 1H), 6.66 (s, 1H), 3.43 (s, 3H), 1.52 (s, 3H), 1.46 (s, 2H), 1.23 (s, 1H), 1.01 (s, 2H). LCMS (Method D): 7.77 min (499.9, [M+H].sup.+).

Example 12: 2-Chloro-N-(cyclopropylsulfonyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzamide

(103) ##STR00065##

(104) Prepared according to the procedure described for Example 1 using Intermediate A (200.0 mg, 0.55 mmol), cyclopropylsulfonamide (86.0 mg, 0.71 mmol), oxalyl chloride (0.14 mL, 1.64 mmol), 4-(dimethylamino)pyridine (5.0 mg, 0.04 mmol) and triethylamine (0.29 mL, 2.05 mmol). The residue was purified by flash chromatography (SiO.sub.2, 10-50% EtOAc (0.1% AcOH) in PE (0.1% AcOH)) to afford the title compound as a white solid (115.0 mg, 45%). .sup.1H NMR δ.sub.H (CDCl.sub.3, 400 MHz) 8.77 (s, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.42 (d, J=9.0 Hz, 1H), 6.39 (s, 1H), 3.58 (s, 1H), 3.11 (tt, J=8.0, 5.0 Hz, 1H), 1.52-1.48 (m, 2H), 1.23-1.18 (m, 2H). LCMS (Method C): 1.69 min (469.9, [M+H].sup.+).

Example 13: 2-Chloro-N-(cyclopentylsulfonyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzamide

(105) ##STR00066##

(106) Prepared according to the procedure described for Example 1 using Intermediate A (200.0 mg, 0.55 mmol), cyclopentylsulfonamide (82.0 mg, 0.55 mmol), oxalyl chloride (0.14 mL, 1.64 mmol), 4-(dimethylamino)pyridine (5.0 mg, 0.04 mmol) and triethylamine (0.29 mL, 2.05 mmol). The residue was purified by flash chromatography (SiO.sub.2, 20-50% EtOAc in PE) to afford the title compound as an off-white solid (90.0 mg, 33%). .sup.1H NMR δ.sub.H (CDCl.sub.3, 400 MHz) 8.63 (s, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.42 (d, J=9.0 Hz, 1H), 6.39 (s, 1H), 4.31-4.23 (m, 1H), 3.59 (s, 1H), 2.24-2.09 (m, 5H), 1.93-1.84 (m, 2H), 1.78-1.70 (m, 2H). LCMS (Method C): 1.82 min (496.0, [M−H].sup.−).

Example 14: 2-Chloro-N-(cyclohexylsulfonyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzamide

(107) ##STR00067##

(108) Prepared according to the procedure described for Example 1 using Intermediate A (150.0 mg, 0.41 mmol), cyclohexylsulfonamide (87.0 mg, 0.53 mmol), oxalyl chloride (0.10 mL, 1.23 mmol), 4-(dimethylamino)pyridine (4.0 mg, 0.03 mmol) and triethylamine (0.21 mL, 1.53 mmol). The residue was purified by flash chromatography (SiO.sub.2, 10-40% EtOAc (0.1% AcOH) in PE (0.1% AcOH)) to afford the title compound as a white solid (60.0 mg, 29%). .sup.1H NMR δ.sub.H (CDCl.sub.3, 300 MHz) 8.72 (s, 1H), 7.68 (d, J=6.0 Hz, 1H), 7.33 (d, J=6.0 Hz, 1H), 6.30 (s, 1H), 3.72-3.56 (m, 1H), 3.49 (s, 3H), 2.26-2.02 (m, 2H), 1.89-1.85 (m, 2H), 1.65-1.57 (m, 4H), 1.48-1.17 (m, 2H). LCMS (Method C): 2.00 min (512.0, [M+H].sup.+).

Intermediate W: 3-(2,6-Dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)-4-fluorobenzoic acid

(109) ##STR00068##

(110) Prepared according to the procedure described for Intermediate J using Intermediate 1 (300.0 mg, 1.44 mmol) and acetic acid (14.4 mL) was added 3-amino-4-fluorobenzoic acid (235 mg, 1.51 mmol) to afford the title compound as a yellow oil (137.5 mg, 29% yield) which was used without further purification.

Intermediate X: Methyl 4-fluoro-3-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzoate

(111) ##STR00069##

(112) Prepared according to the procedure described for Intermediate K using Intermediate W (137 mg, 0.432 mmol) and potassium carbonate (299 mg, 2.16 mmol) and DMF (1.4 mL) to afford the title compound as a brown solid (125.4 mg, 84% yield). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 8.17 (ddd, J=8.7, 4.9, 2.2 Hz, 1H), 8.00 (dd, J=7.0, 2.1 Hz, 1H), 7.31 (t, J=8.9 Hz, 1H), 6.38 (s, 1H), 3.91 (s, 3H), 3.57 (d, J=1.2 Hz, 3H). LCMS (Method C): 2.63 min (347.1, [M+H].sup.+).

Intermediate Y: 4-Fluoro-3-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzoic acid

(113) ##STR00070##

(114) Prepared according to the procedure described for Intermediate L using Intermediate X (125 mg, 0.362 mmol), dichloromethane (1.8 mL) and boron tribromide (1 M in dichloromethane, 1.09 mL, 1.09 mmol) to afford the title compound a brown solid (101.2 mg, 85% yield). .sup.1H NMR δ.sub.H(CDCl.sub.3, 500 MHz) 8.22 (ddd, J=8.7, 4.8, 2.2 Hz, 1H), 8.06 (dd, J=6.9, 2.1 Hz, 1H), 7.34 (t, J=8.9 Hz, 1H), 6.40 (s, 1H), 3.58 (d, J=0.9 Hz, 3H). LCMS (Method C): 2.22 min (333.1, [M+H].sup.+).

Example 15: N-(Cyclopropylsulfonyl)-4-fluoro-3-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzamide

(115) ##STR00071##

(116) Prepared according to the procedure described for Intermediate G using Intermediate Y (385.3 mg, 1.160 mmol), cyclopropane sulfonamide (155 mg, 1.28 mmol), HATU (529 mg, 1.39 mmol) and N,N-diisopropylethylamine (0.606 mL, 3.48 mmol). The crude residue was purified by flash chromatography (SiO.sub.2, 0-30% EtOAc (0.5% AcOH) in PE (0.5% AcOH)) to afford the title compound as an off-white solid (244.1 mg, 48% yield). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 8.89 (s, 1H), 7.96 (ddd, J=8.7, 4.6, 2.3 Hz, 1H), 7.81 (dd, J=6.6, 2.3 Hz, 1H), 7.34 (t, J=8.8 Hz, 1H), 6.39 (s, 1H), 3.58 (s, 3H), 3.13-3.05 (m, 1H), 1.47-1.40 (m, 2H), 1.16 (qd, J=6.3, 1.6 Hz, 2H). LCMS (Method D): 6.67 min (435.9, [M+H].sup.+).

Example 16: 2-Chloro-4-fluoro-N-((1-fluorocyclopropyl)sulfonyl)-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzamide

(117) ##STR00072##

(118) Prepared according to the procedure described for Intermediate G using Intermediate A (200 mg, 0.6 mmol), 1-fluorocyclopropane-1-sulfonamide (95 mg, 0.68 mmol), HATU (259 mg, 0.682 mmol) and N,N-diisopropylethylamine (0.285 mL, 1.64 mmol). The crude residue was purified by flash chromatography (SiO.sub.2, 0-25% EtOAc (0.5% AcOH) in PE (0.5% AcOH)) to afford the title compound as an off-white solid (180.2 mg, 68% yield). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 9.59 (s, 1H), 7.71 (d, J=7.4 Hz, 1H), 7.41 (d, J=8.9 Hz, 1H), 6.40 (s, 1H), 3.56 (s, 3H), 1.93 (m, 2H), 1.58 (dt, J=16.7, 8.3 Hz, 2H). LCMS (Method F): 1.99 min (488.0, [M+H].sup.+).

Example 17: 2-Chloro-N-((1-ethylcyclopropyl)sulfonyl)-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzamide

(119) ##STR00073##

(120) Prepared according to the procedure described for Intermediate G using Intermediate A (200 mg, 0.6 mmol), 1-ethylcyclopropane-1-sulfonamide (102 mg, 0.682 mmol), HATU (259 mg, 0.682 mmol) and N,N-diisopropylethylamine (0.285 mL, 1.64 mmol). The crude residue was purified by flash chromatography (SiO.sub.2, 0-25% EtOAc (0.5% AcOH) in PE (0.5% AcOH)) to afford the title compound as a white solid (23.5 mg, 9% yield). .sup.1H NMR δ.sub.H (CDCl.sub.3, 500 MHz) 8.67 (s, 1H), 7.80 (d, J=7.4 Hz, 1H), 7.43 (d, J=8.9 Hz, 1H), 6.40 (s, 1H), 3.59 (s, 3H), 2.04 (q, J=7.5 Hz, 2H), 1.79 (m, 2H), 1.07 (m, 5H). LCMS (Method F): 1.88 min (498.0, [M+H].sup.+).

Example 18—Testing the Herbicidal Activity of Compounds of the Invention

(121) Compounds were screened at four concentrations (100, 50, 25 and 12.5 g/ha) against four weed species (Stellaria media—Chickweed; Abutilon theophrasti—velvetleaf; Amaranthus retroflexus—common amaranthus; Echinochloa crus-galli—Barnyard grass) and maize as a crop species.

(122) Seed were sown in 12.5 cm diameter pots (20 per pot for the weed species and 5 for maize).

(123) Seedlings were sprayed with 2 ml of compound two weeks after sowing, with 2 ml water used as the control.

(124) Each treatment was replicated three times. Plants were maintained at 20° C. and assessed 10 days after treatment.

(125) The assessment was based on the % plant in each pot showing growth. The data is presented in Table 1 in which d represents no detected effect at this concentration; c represents a percentage increase in necrosis relative to the control of 0.1-50; b represents a percentage increase in necrosis of 50-80; and a represents a percentage increase in necrosis of 80-100.

(126) All of the compounds showed some herbicidal activity against the weed species but comparatively little activity against the crop species (maize). Certain compounds (2, 5, 7, 13, 14, 16, 17) showed good activity across several of the weed species.

(127) TABLE-US-00004 TABLE 1 Dose Plant applied species (g/ha) 1 2 4 5 6 7 8 10 12 13 14 15 16 17 Chickweed 100 c a b b b a b c c c a c a a 50 c b c b c b c c c c b d c b 25 c b c c c b c c c c c d c b 12.5 c b c c c c c c c c c d c c Abutilon 100 b a b a b a b c b a a b a a 50 b b c a b a b c c b a b b b 25 b b c b c a c c c b b c c c 12.5 c b c c c c c c c c b d c c Amaranthus 100 a a a a a a a b a a a b a a 50 b a a a a a a b a a a b a a 25 b a b a b a c b b b a d c b 12.5 c a b a b a c b b b a d c c Echinochloa 100 c a c b c a b c c c c c b b 50 c b c c c b b c c c c c b b 25 c b c c c c c c c c c d c b 12.5 c c c c c c c c c c c d c c Maize 100 c b c c c b c c c c c c c c 50 c b c c c c c c c c c c c c 25 c c c c c c c c c c c d c c 12.5 c c c c c c c c c c c d c c