HERBICIDAL COMPOSITIONS

Abstract

The present invention relates to novel herbicidal combinations and their use in controlling plants or inhibiting plant growth. In particular, herbicidal combinations of the invention comprise at least one pyridazine derivative of Formula (I), in combination with at least one further herbicide that is a non-selective herbicide, a herbicide that acts through the inhibition of protoporphoryinogen oxidase, or a herbicide that inhibits photosystem II in photosynthesis.

Claims

1. A composition comprising as component (A) a compound of Formula (I), or an agrochemically acceptable salt or a zwitterionic species thereof, ##STR00123## wherein: A is 6-membered heteroaryl selected from the group consisting of ##STR00124## wherein the jagged line defines the point of attachment to the remaining part of a compound of Formula (I), p is 0, 1 or 2, and each R.sup.8 is independently selected from the group consisting of NH.sub.2, methyl, and methoxy; R.sup.1 and R.sup.2 are each independently hydrogen or methyl; Q is (CR.sup.1aR.sup.2b).sub.m; m is 0, 1, or 2; each R.sup.1a and R.sup.2b are independently selected from the group consisting of hydrogen, hydroxy, -methyl, and NH.sub.2; Z is —S(O).sub.2OR.sup.10, —C(O)OR.sup.10, —C(O)NHS(O).sub.2R.sup.12 and —C(O)NHCN; R.sup.10 is hydrogen, methyl, benzyl or phenyl; and R.sup.12 is methyl, —NH.sub.2, —N(CH.sub.3).sub.2, or —NHCH.sub.3; and, as component (B), at least one herbicide or salt thereof selected from the group consisting of: B1 a non-selective herbicide selected from the group consisting of glyphosate, glufosinate, hydantocidin, pelargonic acid, paraquat and diquat; B2 a herbicide that acts through the inhibition of protoporphoryinogen oxidase; and B3 a herbicide that inhibits photosystem II in photosynthesis.

2. The composition of claim 1, wherein Z is selected from the group consisting of: —C(O)OH, —C(O)OCH.sub.3, —S(O).sub.2OH, —C(O)OCH.sub.2C.sub.6H.sub.5, —C(O)OC.sub.6H.sub.5, and —C(O)NHS(O).sub.2N(CH.sub.3).sub.2.

3. The composition of claim 1, wherein A is selected from A-I, A-II, and A-III as defined in claim 1.

4. The composition of claim 1, wherein component (A) is selected from the group of 35 compounds shown in the table below: TABLE-US-00050 Compound No. Structure 1.001 1.002 1.003 1.004 1.005 1.006 1.007 1.008 1.009 1.010 1.011 1.012 1.013 1.014 1.015 1.016 1.017 1.018 1.019 1.020 1.021 1.022 1.023 1.024 1.025 1.026 1.027 1.028 1.029 1.030 1.031 1.032 1.033 1.034 1.035

5. The composition of claim 1, wherein component (B) is selected from the group of herbicides consisting of: B1 glyphosate, glufosinate, hydantocidin, pelargonic acid, paraquat and diquat; B2 a herbicide that acts through the inhibition of protoporphoryinogen oxidase, wherein said herbicide is a diphenyl ether, a thiadiazole, a phenypyrazole, an oxadiazole, an N-phenylphthalimides, a pyrimidinedione, a triazolinone, an oxazolidinedione, flufenpyr ethyl, pyraclonil, profluazol, the compound of formula B2.9 ##STR00160## or the compound of formula B2.10 ##STR00161## and B3 a herbicide that inhibits photosystem II in photosynthesis, wherein said herbicide is a pyridazinone, a phenyl carbamate, a uracil, a triazinone, an urea, a triazolinone, a triazine, an amide, a nitrile, a phenyl-pyridazine, or a benzothiadiazinone.

6. The composition of claim 5, wherein component B is selected from the group of herbicides consisting of: B1 glyphosate, glufosinate, hydantocidin, pelargonic acid, paraquat, diquat; B2 bifenox, ethoxyfen-ethyl, halosafen, lactofen, acifluorfen-sodium, chlomethoxyfen, fluoroglycofen-ethyl, oxyfluorfen, fomesafen, fluthiacet-methyl, thidazimin, fluazolate, pyraflufen-ethyl, oxadiargyl, oxadiazon, cinidon-ethyl, flumiclorac-pentyl, flumioxazin, benzfendizone, butafenacil, saflufenacil, azafenidin, bencarbazone, carfentrazone-ethyl, sulfentrazone, pentoxazone, flufenpyr ethyl, pyraclonil, profluazol, the compound of formula B2.9 ##STR00162## or the compound of formula B2.10 ##STR00163## B3 chloridazon/pyrazon, desmedipham, desmedipham, bromacil, lenacil, terbacil, tiafenacil, hexazinone, metamitron, metribuzin, fenuron, metobromuron, neburon, chlorobromuron, fluometuron, methabenzthiazuron, siduron, chlorotoluron, isoproturon, metoxuron, tebuthiuron, chloroxuron, isouron, monlinuron, dimefuron, linuron, diuron, ethidimuron, amicarbozone, atrazine, desmetryne, propazine, terbuthylazine, dimethametryn, simetryne, terbutryne, ametryne, prometon, simazine, trietazine, prometryne, terbumeton, pentanochlor, propanil, bromofenoxim, bromoxynil, ioxynil, pyridate, pyridafol, and bentazone.

7. The composition of claim 5, wherein component B is selected from the group of herbicides consisting of: B1: glyphosate, glufosinate, hydantocidin, pelargonic acid, paraquat, diquat; B2: B2(i) saflufenacil, B2(ii) fomesafen, B2(iii) oxyfluorfen, B2(iv) butafenacil, B2(v) carfentrazone-ethyl, B2(vi) pyraflufen-ethyl, B2(vii) sulfentrazone, B2(viii) flumioxazin, B2(ix) the compound of formula B2.9 ##STR00164## B2(x) the compound of formula B2.10 ##STR00165## B3: B3(i) atrazine, B3(ii) ametryn, B3(iii) metribuzin, B3(iv) hexazinone, B3(v) diuron, B3(vi) propanil, B3(vii) prometryn, B3(viii) tiafenacil, and B3(ix) trifludimoxazin.

8. The composition of claim 1, wherein the weight ratio of component (A) to component (B) is from 0.01:1 to 100:1.

9. The composition of claim 1 wherein the weight ratio of component (A) to component (B) is from 0.025:1 to 20:1.

10. The composition of claim 1, wherein the weight ratio of component (A) to component (B) is from 1:30 to 16:1.

11. The herbicidal composition of claim 1 additionally comprising an agriculturally acceptable formulation adjuvant.

12. The herbicidal composition of claim 11, further comprising at least one additional pesticide.

13. The herbicidal composition according to claim 12, wherein the additional pesticide is a herbicide or herbicide safener.

14. A method of controlling unwanted plant growth, comprising applying a compound of Formula (I) as defined in claim 1, and a herbicide selected from groups B1, B2 or B3 as defined in claim 1, to the unwanted plants or to the locus thereof.

15. The method of claim 14, wherein the compounds of Formula (I) and the herbicide selected from groups B1, B2, or B3, are applied in the form of a composition as defined in claim 1.

Description

EXAMPLES

Formulation Examples

[0116]

TABLE-US-00010 Wettable powders a) b) c) active ingredients 25% 50% 75% sodium lignosulfonate  5%  5% — sodium lauryl sulphate  3% —  5% sodium diisobutylnaphthalenesulfonate —  6% 10% phenol polyethylene glycol ether —  2% — (7-8 mol of ethylene oxide) highly dispersed silicic acid  5% 10% 10% Kaolin 62% 27% —

[0117] The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.

TABLE-US-00011 Powders for dry seed treatment a) b) c) active ingredients 25% 50% 75% light mineral oil  5%  5%  5% highly dispersed silicic acid  5%  5% — Kaolin 65% 40% — Talcum — 20

[0118] The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording powders that can be used directly for seed treatment.

TABLE-US-00012 Emulsifiable concentrate active ingredients 10% octylphenol polyethylene glycol ether  3% (4-5 mol of ethylene oxide) calcium dodecylbenzenesulfonate  3% castor oil polyglycol ether (35 mol of ethylene oxide)  4% Cyclohexanone 30% xylene mixture 50%

[0119] Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.

TABLE-US-00013 Dusts a) b) c) Active ingredients  5%  6%  4% Talcum 95% — — Kaolin — 94% — mineral filler — — 96%

[0120] Ready-for-use dusts are obtained by mixing the combination with the carrier and grinding the mixture in a suitable mill. Such powders can also be used for dry dressings for seed.

TABLE-US-00014 Extruded granules Active ingredients 15% sodium lignosulfonate  2% Carboxymethylcellulose  1% Kaolin 82%

[0121] The combination is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.

TABLE-US-00015 Coated granules Active ingredients 8% polyethylene glycol (mol. wt. 200) 3% Kaolin 89% 

[0122] The finely ground combination is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.

TABLE-US-00016 Suspension concentrate active ingredients 40% propylene glycol 10% nonylphenol polyethylene glycol ether (15 mol  6% of ethylene oxide) Sodium lignosulfonate 10% Carboxymethylcellulose  1% silicone oil (in the form of a 75% emulsion in  1% water) Water 32%

[0123] The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.

TABLE-US-00017 Flowable concentrate for seed treatment active ingredients 40% propylene glycol  5% copolymer butanol PO/EO  2% Tristyrenephenole with 10-20 moles EO  2% 1,2-benzisothiazolin-3-one (in the form of a 20% 0.5%  solution in water) monoazo-pigment calcium salt  5% Silicone oil (in the form of a 75% emulsion in 0.2%  water) Water 45.3%  

[0124] The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.

Slow Release Capsule Suspension

[0125] 28 Parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51.6 parts of water until the desired particle size is achieved. To this emulsion a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed. The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingredients. The medium capsule diameter is 8-15 microns. The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.

List of Abbreviations

[0126] Boc=tert-butyloxycarbonyl
br=broad
CDCl.sub.3=chloroform-d
CD.sub.3OD=methanol-d
° C.=degrees Celsius
D.sub.2O=water-d
DCM=dichloromethane
d=doublet
dd=double doublet
dt=double triplet
DMSO=dimethylsulfoxide
EtOAc=ethyl acetate
h=hour(s)
HCl=hydrochloric acid
HPLC=high-performance liquid chromatography (description of the apparatus and the
methods used for HPLC are given below)
m=multiplet
M=molar
min=minutes
MHz=mega hertz
mL=millilitre
mp=melting point
ppm=parts per million
q=quartet
quin=quintet
rt=room temperature
s=singlet
t=triplet
THF=tetrahydrofuran

LC/MS=Liquid Chromatography Mass Spectrometry

Preparative Reverse Phase HPLC Method:

[0127] Compounds purified by mass directed preparative HPLC using ES+/ES− on a Waters FractionLynx Autopurification system comprising a 2767 injector/collector with a 2545 gradient pump, two 515 isocratic pumps, SFO, 2998 photodiode array (Wavelength range (nm): 210 to 400), 2424 ELSD and QDa mass spectrometer. A Waters Atlantis T3 5 micron 19×10 mm guard column was used with a Waters Atlantis T3 OBD, 5 micron 30×100 mm prep column.

[0128] Ionisation method: Electrospray positive and negative: Cone (V) 20.00, Source Temperature (° C.) 120, Cone Gas Flow (L/Hr.) 50

[0129] Mass range (Da): positive 100 to 800, negative 115 to 800.

[0130] The preparative HPLC was conducted using an 11.4 minute run time (not using at column dilution, bypassed with the column selector), according to the following gradient table:

TABLE-US-00018 Time (mins) Solvent A (%) Solvent B (%) Flow (ml/min) 0.00 100 0 35 2.00 100 0 35 2.01 100 0 35 7.0 90 10 35 7.3 0 100 35 9.2 0 100 35 9.8 99 1 35 11.35 99 1 35 11.40 99 1 35

[0131] 515 pump 0 ml/min Acetonitrile (ACD)

[0132] 515 pump 1 ml/min 90% Methanol/10% Water (make up pump)

[0133] Solvent A: Water with 0.05% Trifluoroacetic Acid

[0134] Solvent B: Acetonitrile with 0.05% Trifluoroacetic Acid

Preparation Examples for Compounds of Formula (I)

Example 1: Preparation of 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethanesulfonate (compound 1.001)

[0135] ##STR00024##

Step 1: Preparation of tributyl(pyridazin-4-yl)stannane

[0136] ##STR00025##

[0137] To a solution of lithium diisopropylamide (1M solution in tetrahydrofuran, 125 mL) at −78° C. under nitrogen was added a solution of pyridazine (10 g) and tri-n-butyltin chloride (44.6 g) in THE (100 mL) drop wise. The reaction mixture was stirred at −78° C. for 1 hour. The reaction mixture was warmed to room temperature and quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3×150 mL). The organic layer was dried over sodium sulfate, concentrated and purified by chromatography on silica eluting with 30% ethyl acetate in hexanes to afford tributyl(pyridazin-4-yl)stannane as a pale brown liquid.

[0138] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.17 (t, 1H) 9.02 (dd, 1H) 7.54 (dd, 1H) 1.57-1.49 (m, 6H) 1.37-1.29 (m, 6H) 1.19-1.13 (m, 6H) 0.92-0.86 (m, 9H).

Step 2: Preparation of 2-pyridazin-4-ylpyrimidine

[0139] ##STR00026##

[0140] A solution of 2-bromopyrimidine (2.50 g) and tributyl(pyridazin-4-yl)stannane (5.80 g) in tetrahydrofuran (25 mL) was degassed with argon for 20 min. Tetrakis (triphenylphosphine) palladium (0) (1.80 g) was added to the reaction mixture at room temperature and then irradiated in a microwave at 120° C. for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate (100 mL). The organic layer was concentrated and purified by chromatography on silica eluting with 80% ethyl acetate in hexanes to give 2-pyridazin-4-ylpyrimidine as a beige solid.

[0141] .sup.1H NMR (400 MHz, CDCl.sub.3) 10.17 (dd, 1H) 9.39 (dd, 1H) 8.92 (d, 2H) 8.43 (dd, 1H) 7.39 (t, 1H).

Step 3: Preparation of 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethanesulfonate (1.001)

[0142] A mixture of 2-pyridazin-4-ylpyrimidine (0.120 g) and sodium 2-bromoethanesulfonate (0.196 g) was stirred in water (2.3 mL) at 100° C. for 42 hours. The reaction mixture was concentrated and purified by preparative reverse phase HPLC to give 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethanesulfonate as a beige solid.

[0143] .sup.1H NMR (400 MHz, D.sub.2O) 10.19 (d, 1H) 9.84 (d, 1H) 9.20 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.27-5.18 (m, 2H) 3.71-3.63 (m, 2H).

Example 2: Preparation of 4-pyridazin-4-ylpyrimidine

[0144] ##STR00027##

[0145] A microwave vial was charged with tributyl(pyridazin-4-yl)stannane (0.387 g), 4-chloropyrimidine (0.100 g), palladium (0) tetrakis(triphenylphosphine) (0.101 g), cesium fluoride (0.265 g), cuprous iodide (0.00665 g) and 1,4-dioxane (4.37 mL) and heated to 140° C. under microwave conditions for 1 hour. The reaction mixture was concentrated and purified by chromatography on silica eluting with a gradient from 0 to 70% acetonitrile in dichloromethane to give 4-pyridazin-4-ylpyrimidine as an orange solid.

[0146] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.90-9.83 (m, 1H) 9.41 (dd, 2H) 8.97 (d, 1H) 8.21-8.13 (m, 1H) 7.89 (dd, 1H).

Example 3: Preparation of methyl 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)acetate bromide (compound 2.001)

[0147] ##STR00028##

[0148] Methyl bromoacetate (0.755 g) was added drop wise to a solution of 2-pyridazin-4-ylpyrimidine (0.505 g) in acetone (6.4 mL) and heated at 60° C. for 24 hours. The reaction mixture was concentrated and the residue triturated with dichloromethane. The resulting solid was filtered, washed with acetone and dried to give methyl 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)acetate bromide as a brown solid.

[0149] .sup.1H NMR (400 MHz, D.sub.2O) 10.22 (d, 1H) 9.84 (d, 1H) 9.30 (dd, 1H) 9.01 (d, 2H) 7.66 (t, 1H) 5.84 (s, 2H) 3.79 (s, 3H).

Example 4: Preparation of (4-pyrimidin-2-ylpyridazin-1-ium-1-yl)methanesulfonate (compound 2.002)

[0150] ##STR00029##

[0151] Methyl 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)acetate bromide (0.420 g) was stirred in trimethylsilyl chlorosulfonate (4.96 g) at 80° C. for 66 hours. The reaction mixture was carefully quenched with water, concentrated and purified by preparative reverse phase HPLC to give (4-pyrimidin-2-ylpyridazin-1-ium-1-yl)methanesulfonate as a pale brown solid.

[0152] .sup.1H NMR (400 MHz, D.sub.2O) 10.26 (brs, 1H) 9.94 (brd, 1H) 9.27-9.39 (m, 1H) 8.96-9.14 (m, 2H) 7.56-7.73 (m, 1H) 5.97 (s, 2H).

Example 5: Preparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate (compound 1.003)

[0153] ##STR00030##

[0154] To a solution of 2-pyridazin-4-ylpyrimidine (0.200 g) in 1,4-dioxane (3.79 mL) was added 1,3-propanesultone (0.189 g). The mixture was stirred at 90° C. for 44 hours. The resulting solid was filtered off and washed with acetone. The solid was purified by preparative reverse phase HPLC to give 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate.

[0155] .sup.1H NMR (400 MHz, D.sub.2O) 10.18 (d, 1H) 9.80 (d, 1H) 9.19 (dd, 1H) 9.00 (d, 2H) 7.64 (t, 1H) 5.01 (t, 2H) 2.98 (t, 2H) 2.53 (quin, 2H).

Example 6: Preparation of 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate (compound 1.005)

[0156] ##STR00031##

Step 1: Preparation of 2-pyridazin-4-ylpyrazine

[0157] ##STR00032##

[0158] A mixture of tributyl(pyridazin-4-yl)stannane (3.87 g), 2-chloropyrazine (1.00 g), palladium (0) tetrakis(triphenylphosphine) (1.03 g) and 1,4-dioxane (43.7 mL) was heated to 140° C. under microwave conditions for 1 hour. The reaction mixture was concentrated and purified on silica using a gradient of 0% to 50% acetonitrile in dichloromethane to give 2-pyridazin-4-ylpyrazine as an off white solid.

[0159] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.87 (dd, 1H) 9.39 (dd, 1H) 9.19 (d, 1H) 8.81-8.75 (m, 1H) 8.72 (d, 1H) 8.11 (dd, 1H).

Step 2: Preparation of methyl 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoate bromide

[0160] ##STR00033##

[0161] Methyl 3-bromopropanoate (0.518 mL) was added to a solution of 2-pyridazin-4-ylpyrazine (0.250 g) in acetonitrile (15.8 mL). The reaction mixture was heated to 80° C. for 24 hours. The reaction mixture was concentrated and the residue taken up in water and washed with dichloromethane. The aqueous phase was concentrated to give crude methyl 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoate bromide (as a 1:1 mixture with 3-(5-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid bromide) as a brown gum, which was used crude in subsequent reactions.

Step 3: Preparation of 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate (1.005)

[0162] The crude mixture of methyl 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoate bromide (0.515 g) and conc. hydrochloric acid (11.1 mL) was heated to 80° C. for 4 hours. The reaction mixture was cooled and allowed to stand overnight. The reaction mixture was concentrated and purified by preparative reverse phase HPLC to give 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate as a brown gum.

[0163] .sup.1H NMR (400 MHz, CD.sub.3OD) 10.28 (d, 1H) 10.00 (d, 1H) 9.62 (d, 1H) 9.28 (dd, 1H) 8.96-8.93 (m, 1H) 8.90 (d, 1H) 5.19-5.12 (t, 2H) 3.28 (t, 2H).

Example 7: Preparation of 2-(4-pyridazin-4-ylpyridazin-1-ium-1-yl)ethanesulfonate (compound 1.006)

[0164] ##STR00034##

Step 1: Preparation of 2,2-dimethylpropyl 2-(2-tert-butoxycarbonylhydrazino)ethanesulfonate

[0165] ##STR00035##

[0166] Boc-hydrazide (1.00 g) was added to a solution of 2,2-dimethylpropyl ethenesulfonate (1.35 g) in methanol (10.1 mL) and heated to 70° C. for 24 hours. The reaction was concentrated to give 2,2-dimethylpropyl 2-(2-tert-butoxycarbonylhydrazino)ethanesulfonate as a thick yellow liquid.

[0167] .sup.1H NMR (400 MHz, CDCl.sub.3) 3.90 (s, 2H) 3.38-3.30 (m, 4H) 1.50-1.43 (s, 9H) 1.00-0.97 (s, 9H).

Step 2: Preparation of [2-(2,2-dimethylpropoxysulfonyl)ethylamino]ammonium chloride

[0168] ##STR00036##

[0169] A mixture of 2,2-dimethylpropyl 2-(2-tert-butoxycarbonylhydrazino)ethanesulfonate (1.00 g) and 3M methanolic hydrogen chloride (24.2 mL) was heated to 70° C. for 7 hours. The reaction mixture was concentrated to give [2-(2,2-dimethylpropoxysulfonyl)ethylamino]ammonium chloride as a pink gum that solidified on standing.

[0170] .sup.1H NMR (400 MHz, CD.sub.3OD) 3.95 (s, 2H) 3.59-3.53 (m, 2H) 3.44-3.39 (m, 2H) 1.00 (s, 9H) sample contained ˜20% methanol and was used as such.

Step 3: Preparation of 4-(3-furyl)pyridazine

[0171] ##STR00037##

[0172] To a mixture of 4-bromopyridazin-1-ium bromide (2.50 g), sodium carbonate (2.2 g), degassed toluene (17.3 mL) and 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride (0.634 g) was added a solution of 3-furylboronic acid (1.00 g) in ethanol (17.3 mL). The mixture was heated to 80° C. under nitrogen atmosphere for 24 hours. The reaction mixture was filtered through celite and concentrated. The residue was partitioned between water and dichloromethane then extracted with further dichloromethane. The combined organic layers were washed with brine and dried with magnesium sulfate. The concentrated filtrate was purified on silica eluting with a gradient of 0-100% ethyl acetate in iso-hexane to give 4-(3-furyl)pyridazine as a dark red semi-solid.

[0173] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.45 (s, 1H) 9.03-9.16 (m, 1H) 8.36 (s, 1H) 7.86 (dd, 1H) 7.71 (t, 1H) 7.04 (d, 1H).

Step 4: Preparation of 4-(2,5-dimethoxy-2,5-dihydrofuran-3-yl)pyridazine

[0174] ##STR00038##

[0175] A mixture of 4-(3-furyl)pyridazine (0.025 g) and sodium bicarbonate (0.14 g) in methanol (0.5 mL) was cooled to −10° C. and bromine (0.069 g) was added drop wise. After 30 minutes the reaction was quenched with 1:1 sat. aqueous sodium bicarbonate and 1M aqueous sodium thiosulfate (3 mL). The aqueous layer was extracted with ethyl acetate. The organic layer was concentrated to give crude 4-(2,5-dimethoxy-2,5-dihydrofuran-3-yl)pyridazine.

[0176] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.42-9.41 (m, 1H) 9.20-9.19 (m, 1H) 7.85 (dt, 1H) 7.02-6.94 (m, 1H) 6.08-5.77 (m, 2H) 3.46 (d, 3H) 3.42 (d, 3H).

Step 5: Preparation of 2-(4-pyridazin-4-ylpyridazin-1-ium-1-yl)ethanesulfonate 1.006

[0177] A mixture of 4-(2,5-dimethoxy-2,5-dihydrofuran-3-yl)pyridazine (0.500 g) and [2-(2,2-dimethylpropoxysulfonyl)ethylamino]ammonium chloride (0.658 g) was heated in aqueous 3M hydrochloric acid (12 mL) at 60° C. for 2 hours. The reaction mixture was concentrated and purified by preparative reverse phase HPLC to give 2-(4-pyridazin-4-ylpyridazin-1-ium-1-yl)ethanesulfonate as a brown solid.

[0178] .sup.1H NMR (400 MHz, D.sub.2O) 9.80-9.97 (m, 2H) 9.62-9.75 (m, 1H) 9.35-9.50 (m, 1H) 8.97 (dd, 1H) 8.19-8.42 (m, 1H) 5.20-5.29 (m, 2H) 3.59-3.73 (m, 2H).

Example 8: Preparation of 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride (compound 1.012)

[0179] ##STR00039##

[0180] A column packed with ion exchange resin (5.84 g, Discovery DSC-SCX) was washed with water (3 column volumes). The 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate (0.292 g) dissolved in a minimum amount of water was loaded onto the column. The column was first eluted with water (3 column volumes) and then eluted with 2M hydrochloric acid (3 column volumes). The collected washings were concentrated to give 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride as a yellow solid.

[0181] .sup.1H NMR (400 MHz, D.sub.2O) 10.03 (d, 1H) 9.80 (d, 1H) 9.35 (d, 1H) 9.05 (dd, 1H) 8.87-8.82 (m, 1H) 8.76 (d, 1H) 5.08 (t, 2H) 3.22 (t, 2H).

Example 9: Preparation of methyl 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoate chloride (compound 1.013)

[0182] ##STR00040##

[0183] A column packed with ion exchange resin (1.6 g, Discovery DSC-SCX) was washed with methanol (3 column volumes). The 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate (0.081 g) dissolved in a minimum amount of methanol was loaded onto the column. The column was first eluted with methanol (3 column volumes) and then eluted with 3M methanolic hydrochloric acid (3 column volumes). The collected washings were concentrated to give methyl 3-(4-pyrazin-2-ylpyridazin-1-ium-1-yl)propanoate chloride as a blue gum.

[0184] .sup.1H NMR (400 MHz, CD.sub.3OD) 10.30-10.26 (m, 1H) 10.04-10.00 (m, 1H) 9.66-9.64 (m, 1H) 9.33-9.30 (m, 1H) 8.97-8.93 (m, 1H) 8.91-8.88 (m, 1H) 5.25-5.14 (m, 2H) 3.71-3.68 (m, 3H) 3.35-3.27 (m, 2H).

Example 10: Preparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid bromide (compound 1.021)

[0185] ##STR00041##

[0186] A mixture of methyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate 2,2,2-trifluoroacetate (0.2 g), concentrated hydrogen bromide (1 mL, 48 mass %) and water (5 mL) was heated to 80° C. for 4 hours and left to cool overnight. After a further 4 hours heating at 80° C. the reaction mixture was concentrated and the resulting yellow gum was triturated with acetone to give 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid bromide as a cream solid.

[0187] .sup.1H NMR (400 MHz, D.sub.2O) 10.16 (d, 1H) 9.86 (d, 1H) 9.21-9.15 (m, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.11 (t, 2H) 3.24 (t, 2H).

Example 11: Preparation of 1-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-2-sulfonate (compound 1.026)

[0188] ##STR00042##

Step 1: Preparation of methyl 2-(2,2-dimethylpropoxysulfonyl)acetate

[0189] ##STR00043##

[0190] Methyl 2-chlorosulfonylacetate (0.5 g) was added drop wise to a cooled (ice bath) solution of 2,2-dimethylpropan-1-ol (0.306 g) and pyridine (0.284 mL) in dichloromethane (14.5 mL). The reaction mixture was stirred cold for a further 2 hours then partitioned with aqueous sat. ammonium chloride. The aqueous phase was extracted with further dichloromethane (×2). The combined organic extracts were concentrated and passed through a plug of silica eluting with diethyl ether. The filtrate was concentrated to give methyl 2-(2,2-dimethylpropoxysulfonyl)acetate as a yellow liquid.

[0191] .sup.1H NMR (400 MHz, CDCl.sub.3) 4.11 (s, 2H) 4.00 (s, 2H) 3.84 (s, 3H) 1.01 (s, 9H).

Step 2: Preparation of methyl 2-(2,2-dimethylpropoxysulfonyl)propanoate

[0192] ##STR00044##

[0193] A mixture of sodium hydride (60% in mineral oil, 0.039 g) in tetrahydrofuran (4.46 mL) was cooled (ice bath) to 0° C. under nitrogen atmosphere. To this was added a solution of methyl 2-(2,2-dimethylpropoxysulfonyl)acetate (0.2 g) in tetrahydrofuran (1.78 mL) and stirred at this temperature for 5 minutes. Iodomethane (0.067 mL) was added and the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was partitioned between 2M hydrochloric acid and ethyl acetate. The aqueous layer was extracted with further ethyl acetate (×2). The combined organic extracts were dried with magnesium sulfate and concentrated to give methyl 2-(2,2-dimethylpropoxysulfonyl)propanoate as a yellow liquid.

[0194] .sup.1H NMR (400 MHz, CDCl.sub.3) 4.12-4.09 (m, 1H) 3.97 (d, 2H) 3.83 (s, 3H) 1.69 (d, 3H) 0.99 (s, 9H).

Step 3: Preparation of 2,2-dimethylpropyl 1-hydroxypropane-2-sulfonate

[0195] ##STR00045##

[0196] To a cooled (ice bath) solution of methyl 2-(2,2-dimethylpropoxysulfonyl)propanoate (1 g) in dichloromethane (126 mL) was added dropwise, under nitrogen atmosphere, diisobutylaluminum hydride (1M in dichloromethane, 10.5 mL) maintaining the temperature below 5° C. during the addition. The reaction mixture was stirred at 0° C. for 1 hour. Propan-2-ol (12.6 mL) was added and the reaction mixture was stirred at 0° C. for 1 hour and then allowed to warm to room temperature. The reaction mixture was partitioned between 2M aqueous hydrochloric acid and dichloromethane. The organic phase was dried with magnesium sulfate, concentrated and chromatographed on silica using a gradient from 0 to 100% EtOAc in isohexane to give 2,2-dimethylpropyl 1-hydroxypropane-2-sulfonate as a colourless liquid.

[0197] .sup.1H NMR (400 MHz, CDCl.sub.3) 4.03-3.84 (m, 4H) 3.43-3.33 (m, 1H) 2.60-2.52 (m, 1H) 1.45 (d, 3H) 1.00 (s, 9H).

Step 4: Preparation of 1-hydroxypropane-2-sulfonic acid

[0198] ##STR00046##

[0199] A mixture of 2,2-dimethylpropyl 1-hydroxypropane-2-sulfonate (0.25 g) and 6M aqueous hydrochloric acid (9.51 mL) was heated to 95° C. for 4 hours. The reaction mixture was cooled and concentrated by freeze drying.

[0200] .sup.1H NMR (400 MHz, D.sub.2O) 3.88-3.78 (m, 1H) 3.56-3.47 (m, 1H) 2.98-2.89 (m, 1H) 1.18 (d, 3H).

Step 5: Preparation of 1-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-2-sulfonate 1.026

[0201] To a cooled (ice bath) solution of 2-pyridazin-4-ylpyrimidine (0.1 g) in dry acetonitrile (6.32 mL) was added 1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (0.131 mL) and the reaction mixture was stirred at room temperature for 15 minutes. To this mixture was added triphenylphosphine (0.332 g) and a solution of 1-hydroxypropane-2-sulfonic acid (0.133 g) in acetonitrile (0.5 mL), followed by drop wise addition of diisopropyl azodicarboxylate (0.25 mL). The reaction mixture was heated at 80° C. for 170 hours. The reaction mixture was concentrated and partitioned between water and diethyl ether. The aqueous layer was concentrated and purified by preparative reverse phase HPLC to give 1-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-2-sulfonate as a white solid.

[0202] .sup.1H NMR (400 MHz, D.sub.2O) 10.20-10.18 (m, 1H) 9.81 (dd, 1H) 9.19 (dd, 1H) 9.00 (d, 2H) 7.65 (t, 1H) 5.10-5.07 (m, 2H) 3.84-3.74 (m, 1H) 1.39 (d, 3H).

Example 12: Preparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoic acid 2,2,2-trifluoroacetate (compound 2.003)

[0203] ##STR00047##

[0204] To a mixture of 2-pyridazin-4-ylpyrimidine (0.5 g) in water (10 mL) was added but-2-enoic acid (0.816 g). The mixture was heated at reflux for 40 hours. The reaction mixture was concentrated and the resulting solid was triturated with tert-butylmethylether and acetone. The solid was purified by preparative reverse phase HPLC to give 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoic acid 2,2,2-trifluoroacetate.

[0205] .sup.1H NMR (400 MHz, D.sub.2O) 10.22 (d, 1H) 9.92 (d, 1H) 9.18-9.26 (m, 1H) 8.99-9.05 (m, 2H) 7.68 (t, 1H) 5.49-5.60 (m, 1H) 3.39 (dd, 1H) 3.10-3.21 (m, 1H) 1.71 (d, 3H).

Example 13: Preparation of 3-bromo-N-methylsulfonyl-propanamide

[0206] ##STR00048##

[0207] To a solution of methanesulfonamide (0.5 g) in toluene (25.8 mL) was added 3-bromopropionyl chloride (1.77 g) drop wise at room temperature. The reaction mixture was heated at 110° C. for 4 hours. The reaction was cooled in ice and the resulting solid was filtered and washed with cold toluene to give 3-bromo-N-methylsulfonyl-propanamide as a colourless solid.

[0208] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.28 (br s, 1H) 3.62 (t, 2H) 3.34 (s, 3H) 2.94 (t, 2H).

Example 14: Preparation of 2-hydroxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate (compound 2.004)

[0209] ##STR00049##

[0210] A mixture of 2-pyridazin-4-ylpyrimidine (0.3 g), water (6 mL) and sodium 3-chloro-2-hydroxy-propane-1-sulfonate (0.45 g) was heated at reflux for 3 days. The reaction mixture was concentrated and the resulting solid was washed with t-butylmethyl ether and acetone. The solid was purified by preparative reverse phase HPLC to give 2-hydroxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate, 2.004.

[0211] .sup.1H NMR (400 MHz, D.sub.2O) 10.24 (d, 1H) 9.80 (d, 1H) 9.25 (dd, 1H) 9.04 (d, 2H) 7.68 (t, 1H) 5.21 (dd, 1H) 4.93 (dd, 1H) 4.64-4.71 (m, 1H) 3.19-3.36 (m, 2H).

Example 15: Preparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate (compound 1.023) A125

[0212] ##STR00050##

[0213] 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride (0.119 g) was stirred in 2,2,2-trifluoroacetic acid (4 mL) at room temperature for two hours. The reaction mixture was concentrated and freeze dried to give 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate, A125, as a pale yellow gum, which solidified on standing.

[0214] .sup.1H NMR (400 MHz, D.sub.2O) 10.18-10.13 (m, 1H) 9.87-9.82 (m, 1H) 9.20-9.14 (m, 1H) 8.98 (d, 2H) 7.63 (s, 1H) 5.10 (s, 2H) 3.24 (t, 2H).

Example 16: Preparation of 3-methyl-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoic acid 2,2,2-trifluoroacetate (compound 1.025)

[0215] ##STR00051##

[0216] A mixture of 2-pyridazin-4-ylpyrimidine (1 g), 3,3-dimethylacrylic acid (1.96 g), 2,2,2-trifluoroacetic acid (5 mL) and water (5 mL) was heated at 100° C. under microwave conditions for 18 hours. The reaction mixture was concentrated and the resulting solid was washed with diethyl ether (5×10 mL). The solid was purified by preparative reverse phase HPLC to give 3-methyl-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoic acid 2,2,2-trifluoroacetate, 1.025.

[0217] .sup.1H NMR (400 MHz, D.sub.2O) 10.18 (m, 1H) 9.97 (m, 1H) 9.21 (m, 1H) 8.98 (m, 2H) 7.61 (m, 1H) 3.36 (s, 2H) 1.94 (s, 6H).

Example 17: Preparation of 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid chloride (compound 1.027)

[0218] ##STR00052##

Step 1: Preparation of 3-pyridazin-4-ylpyridazine

[0219] ##STR00053##

[0220] A microwave vial, under nitrogen atmosphere, was charged with tributyl(pyridazin-4-yl)stannane (0.697 g), 3-bromopyridazine (0.25 g), palladium (0) tetrakis(triphenylphosphine) (0.185 g) and 1,4-dioxane (7.86 mL) and heated at 140° C. in the microwave for 1 hour. The reaction mixture was concentrated and purified on silica using a gradient of 0% to 50% acetonitrile in dichloromethane to give 3-pyridazin-4-ylpyridazine as an orange solid.

[0221] 1H NMR (400 MHz, CDCl.sub.3) 9.94-9.89 (m, 1H) 9.42 (dd, 1H) 9.35 (dd, 1H) 8.24 (dd, 1H) 8.09 (dd, 1H) 7.79-7.72 (m, 1H).

Step 2: Preparation of 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate (compound 2.005)

[0222] ##STR00054##

[0223] A mixture of 3-pyridazin-4-ylpyridazine (0.25 g), water (15 mL) and 3-bromopropanoic acid (0.363 g) was heated at 100° C. for 25 hours. The mixture was concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate, 2.005.

[0224] 1H NMR (400 MHz, D.sub.2O) 10.11 (d, 1H) 9.88 (d, 1H) 9.32 (dd, 1H) 9.10 (dd, 1H) 8.50 (dd, 1H) 7.99 (dd, 1H) 5.13 (t, 2H) 3.26 (t, 2H) (one CO2H proton missing).

Step 3: Preparation of 3-(4-pyridazin-1-ium-3-ylpyridazin-1-ium-1-yl)propanoic acid dichloride (compound 1.034)

[0225] ##STR00055##

[0226] A mixture of 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid 2,2,2-trifluoroacetate (6.56 g) and 2M aqueous hydrochloric acid (114 mL) was stirred at room temperature for 3 hours. The mixture was concentrated and the residue was taken up in a small amount of water and freeze dried. The resulting glassy yellow solid was stirred in acetone (105 mL) overnight. The solid material was collected by filtration, washed with further acetone and dried under vacuum to give 3-(4-pyridazin-1-ium-3-ylpyridazin-1-ium-1-yl)propanoic acid dichloride, 1.034, as a beige solid.

[0227] 1H NMR (400 MHz, D.sub.2O) 10.11 (d, 1H) 9.88 (d, 1H) 9.36 (br d, 1H) 9.10 (dd, 1H) 8.48-8.56 (m, 1H) 7.92-8.07 (m, 1H) 4.98-5.20 (m, 2H) 3.18-3.32 (m, 2H) (one CO.sub.2H proton missing)

Step 4: Preparation of 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid chloride (compound 1.027)

[0228] ##STR00056##

[0229] A mixture of 3-(4-pyridazin-1-ium-3-ylpyridazin-1-ium-1-yl)propanoic acid dichloride (0.541 g) and 2-propanol (10 mL) was heated at 90° C. Water was added drop wise until a clear solution was obtained, this took ˜0.8 mL. To this was added further hot 2-propanol (10 mL) and the solution left to cool. Filtered off the precipitate and washed with cold 2-propanol and acetone and dried under vacuum to give 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoic acid chloride, 1.027, as a beige solid.

[0230] 1H NMR (400 MHz, D.sub.2O) 10.11 (d, 1H) 9.87 (d, 1H) 9.32 (dd, 1H) 9.12-9.08 (m, 1H) 8.50 (dd, 1H) 7.99 (dd, 1H) 5.12 (t, 2H) 3.24 (t, 2H) (one CO.sub.2H proton missing)

Example 18: Preparation of 2-(4-pyridazin-1-ium-3-ylpyridazin-1-ium-1-yl)ethanesulfonate chloride (compound 1.031)

[0231] ##STR00057##

Step 1: Preparation of 2-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)ethanesulfonate (compound 1.002)

[0232] ##STR00058##

[0233] A mixture of 3-pyridazin-4-ylpyridazine (0.41 g), sodium 2-bromoethanesulfonic acid (0.656 g) and water (7.78 mL) was heated at 100° C. for 17 hours. The reaction mixture was cooled, filtered through a syringe filter and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give 2-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)ethanesulfonate as a yellow solid.

[0234] 1H NMR (400 MHz, D.sub.2O) 10.15 (d, 1H) 9.87 (d, 1H) 9.33 (dd, 1H) 9.12 (dd, 1H) 8.52 (dd, 1H) 7.99 (dd, 1H) 5.32-5.19 (m, 2H) 3.73-3.65 (m, 2H)

Step 2: Preparation of 2-(4-pyridazin-1-ium-3-ylpyridazin-1-ium-1-yl)ethanesulfonate chloride (compound 1.031)

[0235] A solution of 2-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)ethanesulfonate (0.2 g) and 2M aqueous hydrochloric acid (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was taken up in a small amount of water and freeze dried to give 2-(4-pyridazin-1-ium-3-ylpyridazin-1-ium-1-yl)ethanesulfonate chloride as a cream glass like solid.

[0236] 1H NMR (400 MHz, D.sub.2O) 10.13 (d, 1H) 9.86 (d, 1H) 9.35 (dd, 1H) 9.11 (dd, 1H) 8.57 (dd, 1H) 8.05 (dd, 1H) 5.27-5.21 (m, 2H) 3.71-3.64 (m, 2H) (one NH proton missing)

Example 19: Preparation of 4-pyridazin-4-ylpyrimidin-2-amine

[0237] ##STR00059##

[0238] A microwave vial, under nitrogen atmosphere, was charged with tributyl(pyridazin-4-yl)stannane (3.42 g), 4-pyridazin-4-ylpyrimidin-2-amine (0.727 g), palladium (0) tetrakis(triphenylphosphine) (0.892 g), N,N-diisopropylethylamine (1.35 mL) and 1,4-dioxane (38.6 mL) and heated to 140° C. in the microwave for 1 hour. The reaction mixture was concentrated and purified on silica using a gradient of 0% to 70% acetonitrile in dichloromethane to give 4-pyridazin-4-ylpyrimidin-2-amine as a beige solid.

[0239] 1H NMR (400 MHz, d.sub.6-DMSO) 9.82 (dd, 1H) 9.41 (dd, 1H) 8.47 (d, 1H) 8.22 (dd, 1H) 7.38 (d, 1H) 6.98 (br s, 2H)

Example 20: Preparation of 2-methyl-2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate (compound 2.006)

[0240] ##STR00060##

Step 1: Preparation of 2,2-dimethylpropyl methanesulfonate

[0241] ##STR00061##

[0242] A solution of triethylamine (8.1 mL) and 2,2-dimethylpropan-1-ol (2.3 g) in dichloromethane (40 mL) was cooled to 0° C. in an ice/acetone bath. To this was added methanesulfonyl chloride (2.2 mL) drop wise. The reaction mixture was stirred cold for 2 hours and washed with aqueous ammonium chloride. The organic layer was concentrated and the residue dissolved in ether. The ether solution was passed through a plug of silica eluting with further ether. Concentration of the ether filtrate gave 2,2-dimethylpropyl methanesulfonate as a light yellow liquid.

[0243] 1H NMR (400 MHz, CDCl.sub.3) 3.90-3.85 (m, 2H) 3.01 (s, 3H) 1.00 (s, 9H)

Step 2: Preparation of 2,2-dimethylpropyl 2-hydroxy-2-methyl-propane-1-sulfonate

[0244] ##STR00062##

[0245] A solution of 2,2-dimethylpropyl methanesulfonate (1.75 g) in tetrahydrofuran (22.1 mL) was cooled to −78° C. under nitrogen atmosphere. To this was added drop wise n-butyllithium (2.5 mol/L in hexane, 5.1 mL). The reaction mixture was gradually warmed to −30° C. over 2 hours and acetone (7.73 mL) was added. The reaction mixture was warmed to room temperature and stirred for a further 1.5 hours. The reaction was quenched with 2M aqueous hydrochloric acid and extracted with ethyl acetate (×3). The combined organic extracts were dried with magnesium sulfate, concentrated and purified on silica using a gradient from 0 to 100% ethyl acetate in iso-hexane to give 2,2-dimethylpropyl 2-hydroxy-2-methyl-propane-1-sulfonate as a colourless liquid.

[0246] 1H NMR (400 MHz, CDCl.sub.3) 3.90 (s, 2H) 3.32 (s, 2H) 2.79 (br s, 1H) 1.44 (s, 6H) 0.99 (s, 9H)

Step 3: Preparation of 2-hydroxy-2-methyl-propane-1-sulfonic acid

[0247] ##STR00063##

[0248] A mixture of 2,2-dimethylpropyl 2-hydroxy-2-methyl-propane-1-sulfonate (1.84 g) and 6M aqueous hydrochloric acid (32.8 mL) was heated at 95° C. for 4 hours. The reaction mixture was cooled to room temperature and freeze dried overnight to give 2-hydroxy-2-methyl-propane-1-sulfonic acid as an off white solid.

[0249] 1H NMR (400 MHz, D.sub.2O) 2.99 (s, 2H) 1.24 (s, 6H) (one OH proton and one SO.sub.3H proton missing)

Step 4: Preparation of 2-methyl-2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate (2.006)

[0250] A mixture of 2-pyridazin-4-ylpyrimidine (0.507 g) in dry acetonitrile (32.1 mL) was cooled in an ice bath. To this was added 1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (0.663 mL) and the reaction mixture stirred at room temperature for 15 minutes. To this was added triphenylphosphine (1.68 g) and a solution of 2-hydroxy-2-methyl-propane-1-sulfonic acid (0.741 g) in dry acetonitrile (0.5 mL) followed by drop wise addition of diisopropyl azodicarboxylate (1.26 mL, 1.30 g). The reaction mixture was then heated at 80° C. for 144 hours. The reaction mixture was partitioned between water and dichloromethane and the aqueous layer purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give 2-methyl-2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate as a yellow solid.

[0251] 1H NMR (400 MHz, CD.sub.3OD) 10.41-10.35 (m, 1H) 10.05-9.99 (m, 1H) 9.31 (dd, 1H) 9.12 (d, 2H) 7.67 (t, 1H) 3.67 (s, 2H) 2.10 (s, 6H)

Example 21: Preparation of 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate (compound 2.007)

[0252] ##STR00064##

Step 1: Preparation of 2,2-dimethylpropyl 2-hydroxypropane-1-sulfonate

[0253] ##STR00065##

[0254] A solution of 2,2-dimethylpropyl methanesulfonate (2 g) in tetrahydrofuran (25 mL) was cooled to −78° C. under nitrogen atmosphere and n-butyllithium (2.5 mol/L in hexane, 5.8 mL) was added drop wise. The reaction mixture was gradually warmed to −30° C. over 1 hour and acetaldehyde (6.8 mL) was added.

[0255] The reaction mixture was warmed to room temperature and stirred for a further 2.5 hours. The reaction was quenched with 2M aqueous hydrochloric acid and extracted with ethyl acetate (×3). The combined organic extracts were dried with magnesium sulfate, concentrated and purified on silica using a gradient from 0 to 100% ethyl acetate in iso-hexane to give 2,2-dimethylpropyl 2-hydroxypropane-1-sulfonate as a yellow liquid.

[0256] 1H NMR (400 MHz, CDCl.sub.3) 4.47-4.34 (m, 1H) 3.96-3.87 (m, 2H) 3.25-3.17 (m, 2H) 3.01 (br s, 1H) 1.34 (d, 3H) 1.00 (s, 9H)

Step 2: Preparation of 2-hydroxypropane-1-sulfonic acid

[0257] ##STR00066##

[0258] A mixture of 2,2-dimethylpropyl 2-hydroxypropane-1-sulfonate (1.35 g) and 6M aqueous hydrochloric acid (32.8 mL) was heated at 95° C. for 4 hours. The reaction mixture was cooled to room temperature and freeze dried overnight to give 2-hydroxypropane-1-sulfonic acid as a brown solid.

[0259] 1H NMR (400 MHz, D.sub.2O) 4.17-4.06 (m, 1H) 2.99-2.85 (m, 2H) 1.16 (d, 3H) (one OH proton and one SO.sub.3H proton missing)

Step 3: Preparation of 2-(trifluoromethylsulfonyloxy)propane-1-sulfonic acid

[0260] ##STR00067##

[0261] To a mixture of 2-hydroxypropane-1-sulfonic acid (0.2 g) in dichloromethane (2.57 mL) was added 2,6-dimethylpyridine (0.33 mL) and the resulting mixture was cooled to 0° C. To this was added drop wise trifluoromethylsulfonyl trifluoromethanesulfonate (0.264 mL) and stirring continued at this temperature for 15 minutes. Cooling was removed and the reaction mixture was stirred at room temperature for a further hour. The reaction mixture was quenched with water and extracted with dichloromethane (×3). The combined organic extracts were dried with magnesium sulfate and concentrated to give 2-(trifluoromethylsulfonyloxy)propane-1-sulfonic acid as a brown gum, ˜50% purity. The product was used immediately in subsequent reactions without further purification.

[0262] 1H NMR (400 MHz, CDCl.sub.3) product peaks only 5.57-5.41 (m, 1H) 4.18-3.98 (m, 1H) 3.58-3.35 (m, 1H) 1.76-1.65 (m, 3H) (one SO.sub.3H proton missing)

Step 4: Preparation of 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate 2.007

[0263] A mixture of 2-pyridazin-4-ylpyrimidine (0.15 g), 2-(trifluoromethylsulfonyloxy)propane-1-sulfonate (0.55 g) and 1,4-dioxane (7.8 mL) was heated at 90° C. for 24 hours. The reaction mixture was partitioned between water and dichloromethane and the aqueous layer purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate as a yellow solid.

[0264] 1H NMR (400 MHz, CD.sub.3OD) 10.43-10.37 (m, 1H) 9.93 (dd, 1H) 9.34 (dd, 1H) 9.11 (d, 2H) 7.68 (t, 1H) 5.66-5.53 (m, 1H) 3.66 (dd, 1H) 3.43 (dd, 1H) 1.83 (d, 3H)

Example 22: Preparation of [(1S)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]-ammonium 2,2,2-trifluoroacetate (compound 1.035)

[0265] ##STR00068##

Step 1: Preparation of [(1S)-3-bromo-1-methoxycarbonyl-propyl]ammonium chloride

[0266] ##STR00069##

[0267] To a mixture of (2S)-2-amino-4-bromo-butanoic acid (0.2 g) in dry methanol (4 mL) at 0° C., under nitrogen atmosphere, was added thionyl chloride (0.392 g) drop wise. The reaction mixture was stirred overnight at room temperature and concentrated to give crude [(1S)-3-bromo-1-methoxycarbonyl-propyl]ammonium chloride as an orange gum, which was used without further purification.

Step 2: Preparation of methyl-(2S)-2-(benzyloxycarbonylamino)-4-bromo-butanoate

[0268] ##STR00070##

[0269] Crude [(1S)-3-bromo-1-methoxycarbonyl-propyl]ammonium chloride was stirred in dichloromethane (4 mL) and a solution of sodium hydrogen carbonate (0.28 g) in water (4 ml) was added. The mixture was cooled to 0° C. and benzyl carbonochloridate (0.225 g) was added. The reaction mass was warmed to room temperature and stirred for 15 hours. The reaction mixture was diluted with water (10 ml) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate concentrated and purified on silica using a gradient from 0 to 100% ethyl acetate in cyclohexane to give methyl (2S)-2-(benzyloxycarbonylamino)-4-bromo-butanoate.

[0270] 1H NMR (400 MHz, CDCl.sub.3) 7.30-7.40 (m, 5H) 5.37-5.43 (m, 1H) 5.13 (s, 2H) 3.78 (s, 3H) 3.42-3.46 (m, 2H) 2.25-2.49 (m, 2H)

Step 3: Preparation of methyl (2S)-2-(benzyloxycarbonylamino)-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoate iodide

[0271] ##STR00071##

[0272] To a solution of methyl (2S)-2-(benzyloxycarbonylamino)-4-bromo-butanoate (0.1 g) in dry acetone (2 mL), under nitrogen atmosphere, was added sodium iodide (0.054 g). The reaction mixture was stirred at room temperature overnight. To this was added 2-pyridazin-4-ylpyrimidine (0.048 g) and the mixture heated at reflux for 16 hours. The reaction mixture was concentrated and the crude methyl (2S)-2-(benzyloxycarbonylamino)-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoate iodide was used in the next step without further purification.

Step 4: Preparation of [(1S)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium 2,2,2-trifluoroacetate 1.035

[0273] A mixture of methyl (2S)-2-(benzyloxycarbonylamino)-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butanoate iodide (0.5 g) and concentrated hydrochloric acid (4.9 mL) was heated at 80° C. for 30 minutes. The reaction mixture was concentrated, dissolved in water and extracted with ethyl acetate (3×20 mL). The aqueous layer was purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give [(1S)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium 2,2,2-trifluoroacetate.

[0274] 1H NMR (400 MHz, D.sub.2O) 10.26 (d, 1H) 9.90 (d, 1H) 9.27 (dd, 1H) 9.06 (d, 2H) 7.72 (t, 1H) 5.17 (t, 2H) 4.09 (dd, 1H) 2.76-2.79 (m, 2H) (Three NH protons and one CO2H proton missing)

Example 23: Preparation of [(1R)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]-ammonium 2,2,2-trifluoroacetate (compound 1.029)

[0275] ##STR00072##

Step 1: Preparation of [(1R)-3-bromo-1-methoxycarbonyl-propyl]ammonium chloride

[0276] ##STR00073##

[0277] To a mixture of [(1R)-3-bromo-1-carboxy-propyl]ammonium bromide (0.1 g) in dry methanol (2 mL) at 0° C., under nitrogen atmosphere, was added thionyl chloride (0.083 mL) drop wise. The reaction mixture was stirred overnight at room temperature and concentrated to give crude [(1S)-3-bromo-1-methoxycarbonyl-propyl]ammonium chloride as a yellow solid, which was used without further purification.

Step 2: Preparation of [(1R)-1-methoxycarbonyl-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium bromide chloride

[0278] ##STR00074##

[0279] To a mixture of 2-pyridazin-4-ylpyrimidine (0.1 g) in acetonitrile (3.16 mL) was added [(1R)-3-bromo-1-methoxycarbonyl-propyl]ammonium chloride (0.16 g) The mixture was heated at reflux for 12 hours. The reaction mixture was concentrated to give crude [(1R)-1-methoxycarbonyl-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium bromide as a dark brown gum, which was used without further purification.

Step 3: Preparation of [(1R)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium 2,2,2-trifluoroacetate, 1.029

[0280] A mixture of [(1R)-1-methoxycarbonyl-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium bromide (0.5 g) and 2M aqueous hydrochloric acid (7.29 mL) was heated at 80° C. for 2 hours. The reaction mixture was concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give [(1R)-1-carboxy-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propyl]ammonium 2,2,2-trifluoroacetate.

[0281] 1H NMR (400 MHz, D.sub.2O) 10.22 (s, 1H) 9.87 (d, 1H) 9.24 (d, 1H) 8.99-9.04 (m, 2H) 7.66 (t, 1H) 5.16 (t, 2H) 4.17 (dd, 1H) 2.69-2.85 (m, 2H) (Three NH protons and one CO2H proton missing)

Example 24: Preparation of [(1S)-1-carboxy-2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethyl]-ammonium 2,2,2-trifluoroacetate (compound 2.009)

[0282] ##STR00075##

Step 1: Preparation of (2S)-2-(tert-butoxycarbonylamino)-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate

[0283] ##STR00076##

[0284] To a mixture of 2-pyridazin-4-ylpyrimidine (0.05 g) in dry acetonitrile (1 mL) was added tert-butyl N-[(3S)-2-oxooxetan-3-yl]carbamate (0.071 g) and the reaction mixture was stirred at room temperature for 48 hours. Concentration of the reaction mixture gave crude (2S)-2-(tert-butoxycarbonylamino)-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate, which was used without further purification.

Step 2: Preparation of [(1S)-1-carboxy-2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethyl]ammonium 2,2,2-trifluoroacetate, 2.009

[0285] A mixture of (2S)-2-(tert-butoxycarbonylamino)-3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate (0.4 g) and 2M aqueous hydrochloric acid (10 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give [(1S)-1-carboxy-2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethyl]ammonium 2,2,2-trifluoroacetate.

[0286] 1H NMR (400 MHz, D.sub.2O) 10.26 (s, 1H) 9.94 (d, 1H) 9.31-9.34 (m, 1H) 9.04 (dd, 2H) 7.69 (t, 1H) 5.48 (d, 2H) 4.75 (t, 1H) (Three NH protons and one CO2H proton missing)

Example 25: Preparation of dimethylsulfamoyl-[2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)-acetyl]azanide (compound 1.032)

[0287] ##STR00077##

Step 1: Preparation of 2-bromo-N-(dimethylsulfamoyl)acetamide

[0288] ##STR00078##

[0289] To a solution of dimethylsulfamide (0.5 g) and 4-(dimethylamino)pyridine (0.541 g) in dichloromethane (19.9 mL) at 0° C. was added bromoacetyl bromide (0.903 g) drop wise. The reaction was slowly warmed to room temperature and stirred for 24 hours. The reaction was partitioned with 0.5M aqueous hydrochloric acid. The organic layer was dried over magnesium sulfate and concentrated to give crude 2-bromo-N-(dimethylsulfamoyl)acetamide as a pale yellow oil. The product was used without further purification.

Step 2: Preparation of dimethylsulfamoyl-[2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)acetyl]azanide 1.032

[0290] To a solution of 2-pyridazin-4-ylpyrimidine (0.15 g) in acetonitrile (10 mL) was added 2-bromo-N-(dimethylsulfamoyl)acetamide (0.21 g) and the mixture heated at 80° C. for 16 hours. The resulting precipitate was filtered, washed with acetonitrile (2×20 mL) to give dimethylsulfamoyl-[2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)acetyl]azanide as a light green solid.

[0291] 1H NMR (400 MHz, d.sub.6-DMSO) 10.36 (s, 1H) 10.06-10.10 (m, 1H) 9.56-9.62 (m, 1H) 9.18-9.22 (m, 2H) 7.82-7.86 (m, 1H) 5.88-5.94 (m, 2H) 2.80-2.86 (m, 6H)

Example 26: Preparation of 3-bromo-N-cyano-propanamide

[0292] ##STR00079##

[0293] To a stirred solution of cyanamide (0.5 g) in water (10 mL) and tetrahydrofuran (10 mL) at 0° C. was added sodium hydroxide (1.427 g). After 10 minutes at 0° C. a solution of 3-bromopropanoyl chloride (1.27 mL) in tetrahydrofuran (5 mL) was added drop wise. The resulting reaction mixture was stirred at room temperature for 3 hours. Water was added and the mixture was extracted with dichloromethane (2×75 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 3-bromo-N-cyano-propanamide as a light yellow liquid.

[0294] 1H NMR (400 MHz, d.sub.6-DMSO) 12.40 (br s, 1H) 3.54-3.70 (m, 2H) 2.80-2.94 (m, 2H)

Example 27: Preparation of [(1S)-1-carboxy-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butyl]-ammonium dichloride (compound 1.030)

[0295] ##STR00080##

Step 1: Preparation of dimethyl (2S)-2-[bis(tert-butoxycarbonyl)amino]pentanedioate

[0296] ##STR00081##

[0297] To a solution of dimethyl (2S)-2-(tert-butoxycarbonylamino)pentanedioate (0.3 g) in acetonitrile (6 mL), under nitrogen atmosphere, was added 4-dimethylaminopyridine (0.028 g). The mixture was cooled to 0° C. and di-tert-butyl dicarbonate (0.264 g) was added. The reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was partitioned between water and ethyl acetate (80 mL) and extracted with further ethyl acetate (80 mL). The combined organic layers were washed with 10% aqueous citric acid, followed by saturated sodium bicarbonate solution and brine. The combined organic layers were dried over sodium sulfate, concentrated and purified on silica using ethyl acetate in cyclohexane to give dimethyl (2S)-2-[bis(tert-butoxycarbonyl)amino]pentanedioate as a colourless gum.

[0298] 1H NMR (400 MHz, CDCl.sub.3) 4.95 (dd, 1H) 3.73 (s, 3H) 3.68 (s, 3H) 2.36-2.54 (m, 3H) 2.15-2.23 (m, 1H) 1.50 (s, 18H)

Step 2: Preparation of methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-oxo-pentanoate

[0299] ##STR00082##

[0300] Cooled a solution of dimethyl (2S)-2-[bis(tert-butoxycarbonyl)amino]pentanedioate (0.28 g) in diethyl ether (5.6 mL), under nitrogen atmosphere, to −78° C. and added slowly diisobutylaluminum hydride (1 M in Toluene, 0.82 mL). The reaction was stirred at −78° C. for 10 minutes, then quenched with water (0.094 mL) and stirred for a further 30 minutes. After warming to room temperature solid sodium sulfate was added. The mixture was filtered through Celite, washed with tert-butylmethylether and the filtrate concentrated to give methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-oxo-pentanoate.

[0301] 1H NMR (400 MHz, CDCl.sub.3) 9.78 (s, 1H) 4.90 (dd, 1H) 3.73 (m, 3H) 2.45-2.66 (m, 3H) 2.11-2.28 (m, 1H) 1.42-1.63 (m, 18H)

Step 3: Preparation of methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-hydroxy-pentanoate

[0302] ##STR00083##

[0303] Cooled a solution of methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-oxo-pentanoate (0.2 g) in dry methanol (4 mL), under nitrogen atmosphere, to 0° C. and added sodium borohydride (0.025 g) portion wise and stirred for 2 hours. The reaction mixture was concentrated and purified on silica using ethyl acetate in cyclohexane to give methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-hydroxy-pentanoate as a colourless gum.

[0304] 1H NMR (400 MHz, CDCl.sub.3) 4.90 (dd, 1H) 3.74-3.67 (m, 5H) 2.30-2.20 (m, 1H) 1.99-1.89 (m, 1H) 1.68-1.41 (s, 20H) (one OH proton missing)

Step 4: Preparation of methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-bromo-pentanoate

[0305] ##STR00084##

[0306] Cooled a solution of methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-hydroxy-pentanoate (4 g) in dry tetrahydrofuran (40 mL) to 0° C. and added carbon tetrabromide (5.728 g). To this was added drop wise a solution of triphenylphosphine (4.576 g) in tetrahydrofuran (40 mL). The reaction was allowed to warm to room temperature and stirred for 24 hours. The reaction mixture was concentrated and purified on silica using ethyl acetate in cyclohexane to give methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-bromo-pentanoate.

[0307] 1H NMR (400 MHz, CDCl.sub.3) 4.88 (dd, 1H) 3.73 (s, 3H) 3.38-3.50 (m, 2H) 2.24-2.27 (m, 1H) 1.85-2.12 (m, 3H) 1.51 (s, 18H)

Step 5: Preparation of [(1S)-1-methoxycarbonyl-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butyl]ammonium 2,2,2-trifluoroacetate

[0308] ##STR00085##

[0309] To a mixture of 2-pyridazin-4-ylpyrimidine (0.4 g) in acetonitrile (12.6 mL) was added methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-bromo-pentanoate (1.141 g) and the reaction mixture was heated at reflux for 12 hours. The reaction mixture was concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent which led to the loss of the BOC-protecting groups) to give [(1S)-1-methoxycarbonyl-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butyl]ammonium 2,2,2-trifluoroacetate.

[0310] 1H NMR (400 MHz, D.sub.2O) 10.22 (d, 1H) 9.80-9.86 (m, 1H) 9.20-9.27 (m, 1H) 8.99-9.06 (m, 2H) 7.66-7.73 (m, 1H) 4.90-5.01 (m, 2H) 4.20 (t, 1H) 3.76-3.84 (m, 3H) 2.20-2.40 (m, 2H) 1.97-2.18 (m, 2H) (NH protons are missing)

Step 6: Preparation of [(1S)-1-carboxy-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butyl]ammonium dichloride, 1.030

[0311] A mixture of [(1S)-1-methoxycarbonyl-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butyl]ammonium;2,2,2-trifluoroacetate (0.1 g) and 4M aqueous hydrochloric acid (0.78 mL) was heated at 60° C. for 14 hours. The reaction mixture was concentrated to give [(1S)-1-carboxy-4-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)butyl]ammonium dichloride.

[0312] 1H NMR (400 MHz, D.sub.2O) 10.24 (dd, 1H) 9.87 (dd, 1H) 9.27 (dd, 1H) 9.06 (d, 2H) 7.72 (t, 1H) 4.99 (t, 2H) 4.08 (t, 1H) 2.23-2.44 (m, 2H) 2.00-2.16 (m, 2H) (three NH protons and one CO2H proton missing)

Example 28: Preparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride (compound 1.010)

[0313] ##STR00086##

Step 1: Preparation of methyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate 2,2,2-trifluoroacetate (compound 2.011)

[0314] ##STR00087##

[0315] A mixture of methyl 3-bromopropanoate (1.58 g), 2-pyridazin-4-ylpyrimidine (0.5 g) in acetonitrile (31.6 mL) was heated at 80° C. for 24 hours. The reaction mixture was cooled, concentrated and partitioned between water (10 mL) and dichloromethane (20 mL). The aqueous layer was purified by preparative reverse phase HPLC (trifluoroacetic acid is present in the eluent) to give methyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate 2,2,2-trifluoroacetate as an orange gum.

[0316] .sup.1H NMR (400 MHz, D.sub.2O) 10.15 (d, 1H) 9.85 (d, 1H) 9.18 (dd, 1H) 8.98 (d, 2H) 7.63 (t, 1H) 5.12 (t, 2H) 3.59 (s, 3H) 3.25 (t, 2H)

[0317] .sup.1H NMR (400 MHz, CD.sub.3OD) 10.43-10.32 (m, 1H) 10.04 (d, 1H) 9.43 (dd, 1H) 9.12 (d, 2H) 7.65 (t, 1H) 5.18 (t, 2H) 3.70 (s, 3H) 3.36-3.27 (m, 2H)

Step 2: 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride, 1.010

[0318] A mixture of methyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate;2,2,2-trifluoroacetate (0.392 g) and conc. hydrochloric acid (7.66 mL) was heated at 80° C. for 3 hours. The reaction mixture was cooled, concentrated and triturated with acetone to give 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride as a beige solid.

[0319] .sup.1H NMR (400 MHz, D.sub.2O) 10.16 (d, 1H) 9.85 (d, 1H) 9.18 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.11 (t, 2H) 3.24 (t, 2H) (one CO.sub.2H proton missing)

[0320] Additional compounds in Table A (below) were prepared by analogues procedures, from appropriate starting materials. The skilled person would understand that the compounds of Formula (I) may exist as an agronomically acceptable salt, a zwitterion or an agronomically acceptable salt of a zwitterion as described hereinbefore. Where mentioned the specific counterion is not considered to be limiting, and the compound of Formula (I) may be formed with any suitable counter ion.

[0321] NMR spectra contained herein were recorded on either a 400 MHz Bruker AVANCE III HD equipped with a Bruker SMART probe unless otherwise stated. Chemical shifts are expressed as ppm downfield from TMS, with an internal reference of either TMS or the residual solvent signals. The following multiplicities are used to describe the peaks: s=singlet, d=doublet, t=triplet, dd=double doublet, dt=double triplet, q=quartet, quin=quintet, m=multiplet. Additionally br. is used to describe a broad signal and app. is used to describe and apparent multiplicity.

[0322] Compounds 1.001, 1.002, 1.003, 1.004, 1.005, 1.006, 1.007, 1.008, 1.009, 1.010, 1.011, 1.012, 1.013, 1.014, 1.015, 1.016, 1.017, 1.018, 1.019, 1.020, 1.021, 1.022, 1.023, 1.024, 1.025, 1.026, 1.027, 1.028, 1.029, 1.030, 1.031, 1.032, 1.033, 1.034 and 1.035 were prepared using the general methods as described above, or in an analagous manner. Table A below shows the structure of these compounds and NMR characterising data.

TABLE-US-00019 TABLE A Preparation Examples of compounds of Formula (I) Compound No. Structure .sup.1H NMR 1.001 [00088] (400 MHz, D.sub.2O) 10.19 (d, 1H) 9.84 (d, 1H) 9.20 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.27-5.18 (m, 2H) 3.71-3.63 (m, 2H) 1.002 [00089] (400 MHz, D.sub.2O) 10.15 (d, 1H) 9.87 (d, 1H) 9.33 (dd, 1H) 9.12 (dd, 1H) 8.52 (dd, 1H) 7.99 (dd,1H) 5.32-5.19 (m, 2H) 3.73-3.65 (m, 2H) 1.003 [00090] (400 MHz, D.sub.2O) 10.18 (d, 1H) 9.80 (d, 1H) 9.19 (dd, 1H) 9.00 (d, 2H) 7.64 (t, 1H) 5.01 (t, 2H) 2.98 (t, 2H) 2.53 (quin, 2H) 1.004 [00091] (400 MHz, D.sub.2O) 10.08 (d, 1H) 9.79 (d, 1H) 9.39 (d, 1H) 9.08 (dd, 1H) 8.89-8.83 (m, 1H) 8.78 (d, 1H) 5.24-5.16 (t, 2H) 3.65 (t, 2H) 1.005 [00092] (400 MHz, CD.sub.3OD) 10.28 (d, 1H) 10.00 (d, 1H) 9.62 (d, 1H) 9.28 (dd, 1H) 8.96-8.93 (m, 1H) 8.90 (d, 1H) 5.19-5.12 (t, 2H) 3.28 (t, 2H) (one CO.sub.2H proton missing) 1.006 [00093] (400 MHz, D.sub.2O) 9.80-9.97 (m, 2H) 9.62-9.75 (m, 1H) 9.35-9.50 (m, 1H) 8.97 (dd, 1H) 8.19-8.42 (m, 1H) 5.20-5.29 (m, 2H) 3.59-3.73 (m, 2H) 1.007 [00094] (400 MHz, D.sub.2O) 9.86-9.95 (m, 2H) 8.90-9.00 (m, 3H) 8.35 (brd, 2H) 5.27 (t, 2H) 3.69 (t, 2H) (one NH proton missing) 1.008 [00095] (400 MHz, D.sub.2O) 10.11 (d, 1H) 9.96 (d, 1H) 9.13 (dd, 1H) 8.29 (d, 1H) 6.83 (d, 1H) 5.31 (m, 2H) 3.73 (m, 2H) (Two NH.sub.2 protons and one SO.sub.3H proton missing) 1.009 [00096] (400 MHz, D.sub.2O) 10.22 (d, 1H) 9.86 (d, 1H) 9.21 (dd, 1H) 8.90 (s, 2H) 5.25-5.31 (m, 2H) 3.69-3.77 (m, 2H) 2.44 (s, 3H) 1.010 [00097] (400 MHz, D.sub.2O) 10.16 (d, 1H) 9.85 (d, 1H) 9.18 (dd, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.11 (t, 2H) 3.24 (t, 2H) (one CO.sub.2H proton missing) 1.011 [00098] (400 MHz, CD.sub.3OD) 10.32 (d, 1H) 10.13 (d, 1H) 9.56 (s, 1H) 9.42-9.35 (m, 1H) 9.23 (d, 1H) 8.61 (d, 1H) 5.21 (t, 2H) 3.32-3.27 (m, 2H) (one CO.sub.2H proton missing) 1.012 [00099] (400 MHz, D.sub.2O) 10.03 (d, 1H) 9.80 (d, 1H) 9.35 (d, 1H) 9.05 (dd, 1H) 8.87-8.82 (m, 1H) 8.76 (d, 1H) 5.08 (t, 2H) 3.22 (t, 2H) (one CO.sub.2H proton missing) 1.013 [00100] (400 MHz, CD.sub.3OD) 10.30-10.26 (m, 1H) 10.04- 10.00 (m, 1H) 9.66-9.64 (m, 1H) 9.33-9.30 (m, 1H) 8.97-8.93 (m, 1H) 8.91-8.88 (m, 1H) 5.25- 5.14 (m, 2H) 3.71-3.68 (m, 3H) 3.35-3.27 (m, 2H) 1.014 [00101] (400 MHz, D.sub.2O) 10.12 (d, 1H) 9.83 (d, 1H) 9.08 (dd, 1H) 8.42 (d, 1H) 7.89 (d, 1H) 5.28-5.19 (m, 2H) 3.71-3.64 (m, 2H) 2.74 (s, 3H) 1.015 [00102] (400 MHz, D.sub.2O) 10.20 (d, 1H) 9.91 (d, 1H) 9.22 (dd, 1H) 8.86 (d, 1H) 7.58 (d, 1H) 5.18 (t, 2H) 3.31 (t, 2H) 2.66 (s, 3H) 1.016 [00103] (400 MHz, D.sub.2O) 10.06 (s, 1H) 10.00 (d, 1H) 9.13 (dd, 1H) 8.28 (d, 1H) 6.85 (d, 1H) 5.20 (t, 2H) 3.31 (t, 2H) (Two NH.sub.2 protons and one CO.sub.2H proton missing) 1.017 [00104] (400 MHz, D.sub.2O) 10.09 (d, 1H) 9.81 (d, 1H) 9.10 (m, 1H) 7.37 (s, 1H) 5.08 (t, 2H) 3.21 (t, 2H) 2.51 (s, 6H) 1.018 [00105] (400 MHz, CD.sub.3OD) 10.21-10.34 (m, 1H) 9.97 (d, 1H) 9.25-9.35 (m, 1H) 9.10-9.15 (m, 2H) 7.60- 7.76 (m, 1H) 7.16-7.34 (m, 5H) 5.16-5.24 (m, 2H) 5.05-5.15 (m, 2H) 3.31-3.39 (m, 2H) 1.019 [00106] (400 MHz, CD.sub.3OD) 10.24-10.20 (m, 1H) 9.93 (d, 1H) 9.24 (dd, 1H) 9.02 (d, 1H) 7.89 (d, 1H) 5.11 (t, 2H) 4.11 (s, 3H) 2.93 (t, 2H) 2.61 (quin, 2H) 1.020 [00107] (400 MHz, CD.sub.3OD) 10.35-10.47 (m, 1H) 10.05 (d, 1H) 9.37-9.44 (m, 1H) 9.08-9.15 (m, 2H) 7.65- 7.78 (m, 1H) 7.32-7.43 (m, 2H) 7.18-7.27 (m, 1H) 7.03-7.15 (m, 2H) 5.30 (t, 2H) 3.58 (t, 2H) 1.021 [00108] (400 MHz, D.sub.2O) 10.16 (d, 1H) 9.86 (d, 1H) 9.21- 9.15 (m, 1H) 8.99 (d, 2H) 7.64 (t, 1H) 5.11 (t, 2H) 3.24 (t, 2H) (one CO.sub.2H proton missing) 1.022 [00109] (400 MHz, D.sub.2O) 10.16 (d, 1H) 9.79 (d, 1H) 9.20 (dd, 1H) 9.00 (d, 2H) 7.64 (t, 1H) 5.04 (s, 2H) 1.25 (s, 6H) (one CO.sub.2H proton missing) 1.023 [00110] (400 MHz, D.sub.2O) 10.18-10.13 (m, 1H) 9.87-9.82 (m, 1H) 9.20-9.14 (m, 1H) 8.98 (d, 2H) 7.63 (s, 1H) 5.10 (s, 2H) 3.24 (t, 2H) (one CO.sub.2H proton missing) 1.024 [00111] (400 MHz, D.sub.2O) 10.16-10.25 (m, 1H) 9.81-9.89 (m, 1H) 9.19-9.27 (m, 1H) 8.97-9.09 (m, 2H) 7.63-7.74 (m, 1H) 5.08-5.20 (m, 1H) 4.92-5.01 (m, 1H) 3.35-3.47 (m, 1H) 1.31 (d, 3H) (one CO.sub.2H proton missing) 1.025 [00112] (400 MHz, D.sub.2O) 10.18 (m, 1H) 9.97 (m, 1H) 9.21 (m, 1H) 8.98 (m, 2H) 7.61 (m, 1H) 3.36 (s, 2H) 1.94 (s, 6H) (one CO.sub.2H proton missing) 1.026 [00113] (400 MHz, D.sub.2O) 10.20-10.18 (m, 1H) 9.81 (dd, 1H) 9.19 (dd, 1H) 9.00 (d, 2H), 7.65 (t, 1H) 5.10- 5.07 (m, 2H) 3.84-3.74 (m, 1H) 1.39 (d, 3H) 1.027 [00114] (400 MHz, D.sub.2O) 10.11 (d, 1H) 9.87 (d, 1H) 9.32 (dd, 1H) 9.12-9.08 (m, 1H) 8.50 (dd, 1H) 7.99 (dd, 1H) 5.12 (t, 2H) 3.24 (t, 2H) (one CO2H proton missing) 1.028 [00115] (400 MHz, D.sub.2O) 10.24 (d, 1H) 9.80 (d, 1H) 9.25 (dd, 1H) 9.04 (d, 2H) 7.68 (t, 1H) 5.21 (dd, 1H) 4.93 (dd, 1H) 4.64-4.71 (m, 1H) 3.19-3.36 (m, 2H) (one OH proton missing) 1.029 [00116] (400 MHz, D.sub.2O) 10.22 (s, 1H) 9.87 (d, 1H) 9.24 (d, 1H) 8.99-9.04 (m, 2H) 7.66 (t, 1H) 5.16 (t, 2H) 4.17 (dd, 1H) 2.69-2.85 (m, 2H) (Three NH protons and one CO.sub.2H proton missing) 1.030 [00117] (400 MHz, D.sub.2O) 10.24 (dd, 1H) 9.87 (dd, 1H) 9.27 (dd, 1H) 9.06 (d, 2H) 7.72 (t, 1H) 4.99 (t, 2H) 4.08 (t, 1H) 2.23-2.44 (m, 2H) 2.00-2.16 (m, 2H) (three NH protons and one CO2H proton missing) 1.031 [00118] (400 MHz, D.sub.2O) 10.13 (d, 1H) 9.86 (d, 1H) 9.35 (dd, 1H) 9.11 (dd, 1H) 8.57 (dd, 1H) 8.05 (dd, 1H) 5.27-5.21 (m, 2H) 3.71-3.64 (m, 2H) (one proton missing) 1.032 [00119] (400 MHz, d.sub.6-DMSO) 10.36 (s, 1H) 10.06-10.10 (m, 1H) 9.56-9.62 (m, 1H) 9.18-9.22 (m, 2H) 7.82-7.86 (m, 1H) 5.88-5.94 (m, 2H) 2.80-2.86 (m, 6H) 1.033 [00120] (400 MHz, D.sub.2O) 10.16 (s, 1H) 9.86 (d, 1H) 9.16- 9.20 (m, 1H) 8.96-9.02 (m, 2H) 7.60-7.66 (m, 1H) 5.08-5.14 (m, 2H) 3.20-3.28 (m, 2H) 1.034 [00121] (400 MHz, D.sub.2O) 10.11 (d, 1H) 9.88 (d, 1H) 9.36 (br d, 1H) 9.10 (dd, 1H) 8.48-8.56 (m, 1H) 7.92- 8.07 (m, 1H) 4.98-5.20 (m, 2H) 3.18-3.32 (m, 2H) (one CO.sub.2H proton missing) 1.035 [00122] (400 MHz, D2O) 10.26 (d, 1H) 9.90 (d, 1H) 9.27 (dd, 1H) 9.06 (d, 2H) 7.72 (t, 1H) 5.17 (t, 2H) 4.09 (dd, 1H) 2.76-2.79 (m, 2H) (Three NH protons and one CO2H proton missing)

Biological Efficacy for Compounds of Formula (I)

B1 Post-Emergence Efficacy

[0323] Seeds of a variety of test species were sown in standard laom-based soil in pots:—Ipomoea hederacea (IPOHE), Euphorbia heterophylla (EPHHL), Chenopodium album (CHEAL), Amaranthus palmeri (AMAPA), Lolium perenne (LOLPE), Digitaria sanguinalis (DIGSA), Eleusine indica (ELEIN), Echinochloa crus-galli (ECHCG), Setaria faberi (SETFA). After cultivation for 14 days (post-emergence) under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity), the plants were sprayed with an aqueous spray solution derived from the dissolution of the technical active ingredient Formula (I) in a small amount of acetone and a special solvent and emulsifier mixture referred to as IF50 (11.12% Emulsogen EL360 TM+44.44% N-methylpyrrolidone+44.44% Dowanol DPM glycol ether), to create a 50 g/l solution which was then diluted to required concentration using 0.25% or 1% Empicol ESC70 (Sodium lauryl ether sulphate)+1% ammonium sulphate as diluent. The delivery of the aqueous spray solution was via a laboratory track sprayer which delivered the aqueous spray composition at a rate of 200 litres per hectare, using a flat fan nozzle (Teejet 11002VS) and an application volume of 200 litre/ha (at 2 bar).

[0324] The test plants were then grown in a glasshouse under controlled conditions (at 24/16° C., day/night; 14 hours light; 65% humidity) and watered twice daily. After 13 days the test was evaluated (100=total damage to plant; 0=no damage to plant).

[0325] The results are shown in Table B (below). A value of n/a indicates that this combination of weed and test compound was not tested/assessed.

TABLE-US-00020 TABLE B Control of weed species by compounds of Formula (I) after post-emergence application Compound Application Number Rate g/Ha AMAPA CHEAL EPHHL IPOHE SETFA ECHCG ELEIN DIGSA LOLPE 1.001 500 100 100 100 100 100 70 100 100 70 1.002 500 100 100 100 40 90 100 100 100 100 1.003 500 100 100 100 60 100 80 100 100 60 1.004 500 100 100 100 60 90 80 100 100 60 1.005 500 100 100 70 30 60 100 100 100 80 1.006 500 100 100 100 100 30 60 100 80 80 1.007 500 100 100 40 30 70 80 100 100 90 1.008 500 n/a 100 80 40 100 100 100 100 60 1.009 500 n/a 100 70 30 100 100 100 100 80 1.010 500 n/a 100 100 40 100 100 100 100 90 1.011 500 100 100 100 100 100 90 100 90 70 1.012 500 100 100 100 20 90 90 90 100 50 1.013 500 100 90 100 80 100 80 100 100 70 1.014 500 100 100 100 n/a 100 80 90 100 90 1.015 500 n/a 100 80 30 100 100 100 100 80 1.016 500 n/a 90 90 30 100 100 100 100 70 1.017 500 n/a 100 80 50 100 70 100 100 60 1.018 500 90 90 100 30 100 80 100 100 40 1.019 500 n/a 100 100 60 100 70 90 100 30 1.020 500 100 80 80 30 100 90 100 100 80 1.021 500 100 100 100 100 100 100 100 100 70 1.022 500 100 80 100 100 100 90 100 100 60 1.023 500 100 80 100 30 100 100 100 100 90 1.024 500 100 90 100 40 100 100 100 90 80 1.025 500 100 70 40 50 100 100 100 90 30 1.026 500 100 80 90 70 100 80 100 100 80 1.027 500 100 100 100 30 100 100 80 100 100 1.028 500 100 90 80 30 100 100 100 90 70 1.029 500 100 100 90 90 100 60 100 90 20 1.030 500 100 100 100 60 100 100 90 100 60 1.031 500 100 90 100 70 100 100 100 100 90 1.032 500 100 100 100 40 90 100 100 100 80 1.033 500 100 100 100 50 90 90 100 100 90 1.034 500 100 100 100 60 100 100 100 100 90 1.035 500 100 100 90 90 100 60 100 90 20

Biological Efficacy for Combinations of the Invention

[0326] Using the methodology described above under B1, the efficacy of various combinations of the invention were tested against plants selected from the following species: Ipomoea hederacea (IPOHE), Euphorbia heterophylla (EPHHL), Chenopodium album (CHEAL), Amaranthus palmeri (AMAPA), Lolium perenne (LOLPE), Digitaria sanguinalis (DIGSA), Eleusine indica (ELEIN), Echinochloa crus-galli (ECHCG), Setaria faberi (SETFA), Triticum aestivum (TRZAW), Portulaca oleracea (POROL), Digitaria horizontalis (DIGHO), Lolium multiflorum (LOLMU), Conyza canadensis (ERICA), Conyza bonariensis (ERIBO), Alopecurus myosuroides (ALOMY). After 21 days the tests were evaluated (100=total damage to plant; 0=no damage to plant), and the results are shown below in tables B2.1 to B2.21.

TABLE-US-00021 TABLE B2.1 Herbicidal activity of a compound of Formula (I) (compound 1.001) as component (A) and glufosinate as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B ZEAMX TRZAW POROL SETFA LOLMU C1 125 250 1:2 37 40 97 72 67 C2 250 250 1:1 33 53 93 73 72 C3 500 250 2:1 50 78 100 90 75

TABLE-US-00022 TABLE B2.2 Herbicidal activity of a compound of Formula (I) (compound 1.002) as component (A) and glufosinate as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B DIGSA CHEAL AMAPA IPOHE C4 50 200 1:4 95 92 98 77 C5 100 200 1:2 88 93 93 69 C6 200 200 1:1 95 97 100 83 C7 400 200 2:1 87 98 100 91

TABLE-US-00023 TABLE B2.3 Herbicidal activity of a compound of Formula (I) (compound 1.001) as component (A) and glyphosate as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B ZEAMX TRZAW POROL SETFA LOLMU C8 125 500 1:4 52 83 92 93 72 C9 250 500 1:2 70 92 99 91 75  C10 500 500 1:1 80 80 100 93 78

TABLE-US-00024 TABLE B2.4 Herbicidal activity of a compound of Formula (I) (compound 1.002) as component (A) and glyphosate as component (B) Compo- Compo- Compo- sition nent (A) nent (B) Ratio ID no. (g/Ha) (g/Ha) A:B DIGSA CHEAL AMAPA IPOHE C11 50 200 1:4 93 77 96 53 C12 100 200 1:2 90 80 98 57 C13 200 200 1:1 96 88 98 58 C14 400 200 2:1 96 91 98 60

TABLE-US-00025 TABLE B2.5 Herbicidal activity of a compound of Formula (I) (compound 1.001) as component (A) and hydantocidin as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B ZEAMX TRZAW POROL SETFA LOLMU C15 125 250 1:2 38 52 100 70 82 C16 250 250 1:1 40 68 100 75 77 C17 500 250 2:1 40 70 100 83 80

TABLE-US-00026 TABLE B2.6 Herbicidal activity of a compound of Formula (I) (compound 1.001) as component (A) and diquat as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B IPOHE LOLPE ECHCG ERICA AMAPA C18 50 100 1:2 80 83 25 100 83 C19 100 100 1:1 100 75 25 100 92 C20 200 100 2:1 100 97 25 100 77 C21 400 100 4:1 100 97 88 100 90

TABLE-US-00027 TABLE B2.7 Herbicidal activity of a compound of Formula (I) (compound 1.001) as component (A) and diquat as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B ZEAMX TRZAW POROL SETFA LOLMU C22 125 150 1:2 38 81 100 47 95 C23 250 150 1:1 38 86 100 58 95 C24 500 150 2:1 53 90 100 57 94

TABLE-US-00028 TABLE B2.8 Herbicidal activity of a compound of Formula (I) (compound 1.002) as component (A) and diquat as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B IPOHE LOLPE ECHCG ERICA AMAPA C25 50 100 1:2 95 85 35 100 78 C26 100 100 1:1 100 95 40 100 90 C27 200 100 2:1 100 91 40 100 87 C28 400 100 4:1 100 99 69 100 92

TABLE-US-00029 TABLE B2.9 Herbicidal activity of a compound of Formula (I) (compound 1.010) as component (A) and diquat as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B IPOHE ELEIN LOLPE ECHCG ERICA AMAPA C29 50 100 1:2 100 93 88 96 100 100 C30 100 100 1:1 100 83 97 94 100 100 C31 200 100 2:1 100 40 78 98 100 100 C32 400 100 4:1 100 50 85 94 100 100

TABLE-US-00030 TABLE B2.10 Herbicidal activity of a compound of Formula (I) (compound 1.027) as component (A) and diquat as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B IPOHE ELEIN LOLPE ECHCG ERICA AMAPA C33 50 100 1:2 100 83 96 95 100 100 C34 100 100 1:1 100 75 97 100 100 100 C35 200 100 2:1 100 70 97 95 100 100 C36 400 100 4:1 100 60 97 98 100 100

TABLE-US-00031 TABLE B2.11 Herbicidal activity of a compound of Formula (I) (compound 1.001) as component (A) and saflufenacil as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B ERICA ERIBO C37 50 25 2:1 100 98 C38 100 25 4:1 100 100 C39 200 25 8:1 100 100 C40 400 25 16:1  100 100

TABLE-US-00032 TABLE B2.12 Herbicidal activity of a compound of Formula (I) (compound 1.001) as component (A) and fomesafen as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B IPOHE ELEIN LOLPE ECHCG ERICA AMAPA C41 50 200 1:4 100 88 78 83 100 100 C42 100 200 1:2 100 88 73 90 100 100 C43 200 200 1:1 100 90 80 83 100 100 C44 400 200 2:1 99 83 80 78 100 100

TABLE-US-00033 TABLE B2.13 Herbicidal activity of a compound of Formula (I) (compound 1.001) as component (A) and fomesafen as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B ZEAMX TRZAW POROL DIGHO SETFA LOLMU ERIBO C45 75 200 3:8 17 40 99 75 48 25 40 C46 150 200 3:4 17 57 99 83 62 33 68 C47 300 200 3:2 18 70 98 97 84 53 89

TABLE-US-00034 TABLE B2.14 Herbicidal activity of a compound of Formula (I) (compound 1.002) as component (A) and fomesafen as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B ZEAMX TRZAW POROL DIGHO SETFA LOLMU ERIBO C48 75 200 3:8 22 33 98 55 97 53 50 C49 150 200 3:4 22 58 98 75 87 77 67 C50 300 200 3:2 25 75 98 66 88 88 75

TABLE-US-00035 TABLE B2.15 Herbicidal activity of a compound of Formula (I) (compound 1.001) as component (A) and oxyfluorfen as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B ZEAMX TRZAW DIGHO SETFA LOLMU ERICA ERIBO C51 100 100 1:1 62 87 97 99 87 100 77 C52 400 100 4:1 58 95 97 99 96 100 90 C53 800 100 8:1 68 98 99 99 96 100 94

TABLE-US-00036 TABLE B2.16 Herbicidal activity of a compound of Formula (I) (compound 1.002) as component (A) and oxyfluorfen as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B ZEAMX TRZAW DIGHO SETFA LOLMU ERICA ERIBO C54 100 100 1:1 48 92 97 98 97 100 80 C55 400 100 4:1 43 95 95 97 98 100 91 C56 800 100 8:1 72 97 98 99 99 100 100

TABLE-US-00037 TABLE B2.17 Herbicidal activity of a compound of Formula (I) (compound 1.001) as component (A) and atrazine as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B IPOHE ELEIN LOLPE ECHCG ERICA AMAPA C57 50 150 1:3 25 95 88 100 100 93 C58 100 150 2:3 50 96 88 100 100 100 C59 200 150 4:3 70 98 95 100 100 98 C60 400 150 8:3 73 96 96 100 100 100 C61 50 300 1:6 73 95 98 100 100 100 C62 100 300 1:3 78 95 98 100 100 100 C63 200 300 2:3 83 98 98 100 100 100 C64 400 300 4:3 85 97 98 100 100 100

TABLE-US-00038 TABLE B2.18 Herbicidal activity of a compound of Formula (I) (compound 1.001) as component (A) and atrazine as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B ZEAMX TRZAW POROL DIGHO SETFA LOLMU ERIBO C65 75 250 3:10 17 20 99 63 86 88 62 C66 150 250 3:5  17 22 99 65 77 98 72 C67 300 250 6:5  28 50 100 73 85 98 88

TABLE-US-00039 TABLE B2.19 Herbicidal activity of a compound of Formula (I) (compound 1.002) as component (A) and atrazine as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B ZEAMX TRZAW POROL DIGHO SETFA LOLMU ERIBO C68 75 250 3:10 20 67 100 88 98 98 82 C69 150 250 3:5  22 81 100 95 98 98 86 C70 300 250 6:5  27 94 100 100 98 98 93

TABLE-US-00040 TABLE B2.20 Herbicidal activity of a compound of Formula (I) (compound 1.002) as component (A) and atrazine as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B DIGSA CHEAL AMAPA IPOHE C71 50 250 1:5 96 98 100 27 C72 100 250 2:5 96 98 100 30 C73 200 250 4:5 98 98 100 40 C74 400 250 8:5 96 99 100 38

TABLE-US-00041 TABLE B2.21 Herbicidal activity of a compound of Formula (I) (compound 1.001) as component (A) and metribuzin as component (B) Composition Component Component Ratio ID no. (A) (g/Ha) (B) (g/Ha) A:B IPOHE ELEIN LOLPE ECHCG ERICA AMAPA C75 50 140  5:14 96 98 100 100 100 15 C76 100 140 5:7 96 96 100 100 100 15 C77 200 140 10:7  96 98 100 100 100 18 C78 400 140 20:7  94 97 100 100 100 20

TABLE-US-00042 TABLE B2.22a Herbicidal activity against IPOHE of a compound of Formula (I) (compound 1.010) as component (A) and compound B2.9 as component (B) (*Expected activity as calculated by the Colby Formula) Composition Component Component Ratio IPOHE ID no. (A) (g/Ha) (B) (g/Ha) A:B Observed (*Expected) C79  50 12.5  4:1 100 100 C80 100 12.5  8:1 100 100 C81 200 12.5 16:1 100 100 C82 400 12.5 32:1 100 100 C83 — 12.5 — 100 — C84  50 — —  23 — C85 100 — —  23 — C86 200 — —  28 — C87 400 — —  28 —

TABLE-US-00043 TABLE B2.22b Herbicidal activity against ELEIN of a compound of Formula (I) (compound 1.010) as component (A) and compound B2.9 as component (B) (*Expected activity as calculated by the Colby Formula) Composition Component Component Ratio ELEIN ID no. (A) (g/Ha) (B) (g/Ha) A:B Observed (*Expected) C88  50 12.5  4:1 98 98 C89 100 12.5  8:1 96 98 C90 200 12.5 16:1 96 98 C91 400 12.5 32:1 93 98 C92 — 12.5 — 90 — C93  50 — — 80 — C94 100 — — 83 — C95 200 — — 78 — C96 400 — — 75 —

TABLE-US-00044 TABLE B2.22c Herbicidal activity against LOLPE of a compound of Formula (I) (compound 1.010) as component (A) and compound B2.9 as component (B) (*Expected activity as calculated by the Colby Formula) Composition Component Component Ratio LOLPE ID no. (A) (g/Ha) (B) (g/Ha) A:B Observed (*Expected) C97   50 12.5  4:1 43 18 C98  100 12.5  8:1 63 45 C99  200 12.5 16:1 63 54 C100 400 12.5 32:1 75 50 C101 — 12.5 —  3 — C102  50 — — 15 — C103 100 — — 40 — C104 200 — — 53 — C105 400 — — 48 —

TABLE-US-00045 TABLE B2.22d Herbicidal activity against ECHCG of a compound of Formula (I) (compound 1.010) as component (A) and compound B2.9 as component (B) (*Expected activity as calculated by the Colby Formula) Composition Component Component Ratio ECHCG ID no. (A) (g/Ha) (B) (g/Ha) A:B Observed (*Expected) C106  50 12.5  4:1 93 98 C107 100 12.5  8:1 93 99 C108 200 12.5 16:1 97 99 C109 400 12.5 32:1 93 99 C110 — 12.5 — 73 — C111  50 — — 94 — C112 100 — — 98 — C113 200 — — 98 — C114 400 — — 98 —

TABLE-US-00046 TABLE B2.22e Herbicidal activity against AMAPA of a compound of Formula (I) (compound 1.010) as component (A) and compound B2.9 as component (B) (*Expected activity as calculated by the Colby Formula) Composition Component Component Ratio AMAPA ID no. (A) (g/Ha) (B) (g/Ha) A:B Observed (*Expected) C115  50 12.5  4:1  92 100 C116 100 12.5  8:1  80 100 C117 200 12.5 16:1 100 100 C118 400 12.5 32:1 100 100 C119 — 12.5 — 100 — C120  50 — —  60 — C121 100 — —  88 — C122 200 — — 100 — C123 400 — — 100 —

TABLE-US-00047 TABLE B2.23a Herbicidal activity against IPOHE of a compound of Formula (I) (compound 1.027) as component (A) and compound B2.9 as component (B) Composition Component Component Ratio AMAPA ID no. (A) (g/Ha) (B) (g/Ha) A:B Observed (*Expected) C124  50 10.0  5:1 100 100 C125 100 10.0 10:1 100 100 C126 200 10.0 20:1 100 100 C127 400 10.0 40:1 100 100 C128 — 10.0 — 100 — C129  50 — —  15 — C130 100 — —  15 — C131 200 — —  15 — C132 400 — —  15 —

TABLE-US-00048 TABLE B2.23b Herbicidal activity against ECHCG of a compound of Formula (I) (compound 1.027) as component (A) and compound B2.9 as component (B) (*Expected activity as calculated by the Colby Formula) Composition Component Component Ratio ECHCG ID no. (A) (g/Ha) (B) (g/Ha) A:B Observed (*Expected) C133  50 10.0  5:1 100 100 C134 100 10.0 10:1 100 100 C135 200 10.0 20:1 100 100 C136 400 10.0 40:1 100 100 C137 — 10.0 —  80 — C138  50 — — 100 — C139 100 — — 100 — C140 200 — — 100 — C141 400 — — 100 —

TABLE-US-00049 TABLE B2.23c Herbicidal activity against AMAPA of a compound of Formula (I) (compound 1.027) as component (A) and compound B2.9 as component (B) (*Expected activity as calculated by the Colby Formula) Composition Component Component Ratio AMAPA ID no. (A) (g/Ha) (B) (g/Ha) A:B Observed (*Expected) C142  50 10.0  5:1 100 100 C143 100 10.0 10:1  93 100 C144 200 10.0 20:1 100 100 C145 — 10.0 — 100 — C146  50 — —  83 — C147 100 — — 100 — C148 200 — — 100 —