HERBICIDAL COMPOUNDS

Abstract

Compounds of the formula (I) wherein the substituents are as defined in claim 1, useful as pesticides, especially as herbicides.

##STR00001##

Claims

1. A compound of formula (I) or an agronomically acceptable salt or zwitterionic species thereof: ##STR00329## wherein R.sup.1 is selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.3alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.6haloalkyl, OR.sup.7, OR.sup.15a, N(R.sup.6)S(O).sub.2R.sup.15, N(R.sup.6)C(O)R.sup.15, N(R.sup.6)C(O)OR.sup.15, N(R.sup.6)C(O)NR.sup.16R.sup.17, N(R.sup.6)CHO, N(R.sup.7a).sub.2 and S(O).sub.rR.sup.15; R.sup.2 is selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6haloalkyl; and wherein when R.sup.1 is selected from the group consisting of OR.sup.7, OR.sup.15a, N(R.sup.6)S(O).sub.2R.sup.15, N(R.sup.6)C(O)R.sup.15, N(R.sup.6)C(O)OR.sup.15, N(R.sup.6)C(O)NR.sup.16R.sup.17, N(R.sup.6)CHO, N(R.sup.7a).sub.2 and S(O).sub.rR.sup.15, R.sup.2 is selected from the group consisting of hydrogen and C.sub.1-C.sub.6alkyl; or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached form a C.sub.3-C.sub.6cycloalkyl ring or a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; and Q is (CR.sup.1aR.sup.2b).sub.m; m is 0, 1, 2 or 3; each R.sup.1a and R.sup.2b are independently selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, OH, OR.sup.7, OR.sup.5a NH.sub.2, NHR.sup.7, NHR.sup.15a, N(R.sup.6)CHO, NR.sup.7bR.sup.7c and S(O).sub.rR.sup.15; or each R.sup.1a and R.sup.2b together with the carbon atom to which they are attached form a C.sub.3-C.sub.6cycloalkyl ring or a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; and R.sup.3, R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, S(O).sub.rR.sup.15, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6fluoroalkoxy, C.sub.1-C.sub.6alkoxy, C.sub.3-C.sub.6cycloalkyl and N(R.sup.6).sub.2; each R.sup.6 is independently selected from hydrogen and C.sub.1-C.sub.3alkyl; each R.sup.7 is independently selected from the group consisting of C.sub.1-C.sub.3alkyl, S(O).sub.2R.sup.15, C(O)R.sup.15, C(O)OR.sup.15 and C(O)NR.sup.16R.sup.17; each R.sup.7a is independently selected from the group consisting of S(O).sub.2R.sup.15, C(O)R.sup.15, C(O)OR.sup.15, C(O)NR.sup.16R.sup.17 and C(O)NR.sup.6R.sup.15a; R.sup.7b and R.sup.7c are independently selected from the group consisting of C.sub.1-C.sub.3alkyl, S(O).sub.2R.sup.15, C(O)R.sup.15, C(O)OR.sup.15, C(O)NR.sup.16R.sup.17 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; or R.sup.7b and R.sup.7c together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S; and A is a 5-membered heteroaryl attached to the rest of the molecule via a ring carbon atom, which comprises 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, and wherein the heteroaryl is optionally substituted by 1, 2 or 3 R.sup.8 substituents, which may be the same or different, and wherein when A is substituted on one or more ring carbon atoms, each R.sup.8 is independently selected from the group consisting of halogen, nitro, cyano, NH.sub.2, NHR.sup.7, N(R.sup.7).sub.2, OH, OR.sup.7, S(O).sub.rR.sup.15, NR.sup.6S(O).sub.2R.sup.15, C(O)OR.sup.10, C(O)R.sup.15, C(O)NR.sup.16R.sup.17, S(O).sub.2NR.sup.16R.sup.17, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6halocycloalkyl, C.sub.3-C.sub.6cycloalkoxy, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.3alkoxyC.sub.1-C.sub.3alkyl-, hydroxyC.sub.1-C.sub.6alkyl-, C.sub.1-C.sub.3alkoxyC.sub.1-C.sub.3alkoxy-, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.3haloalkoxyC.sub.1-C.sub.3alkyl-, C.sub.3-C.sub.6alkenyloxy, C.sub.3-C.sub.6alkynyloxy, NC.sub.3-C.sub.6cycloalkylamino, C(R.sup.6)NOR.sup.6, phenyl, a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O, and a 5- or 6-membered heteroaryl, which comprises 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and wherein said phenyl, heterocyclyl or heteroaryl are optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; and/or when A is substituted on a ring nitrogen atom, R.sup.8 is selected from the group consisting of OR.sup.7, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6halocycloalkyl, C.sub.3-C.sub.6cycloalkoxy, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.3alkoxyC.sub.1-C.sub.3alkyl-, hydroxyC.sub.1-C.sub.6alkyl-, C.sub.1-C.sub.3alkoxyC.sub.1-C.sub.3alkoxy-, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.3haloalkoxyC.sub.1-C.sub.3alkyl-, C.sub.3-C.sub.6alkenyloxy and C.sub.3-C.sub.6alkynyloxy; and each R.sup.9 is independently selected from the group consisting of halogen, cyano, OH, N(R.sup.6).sub.2, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkyl and C.sub.1-C.sub.4haloalkoxy; X is independently selected from the group consisting of C.sub.3-C.sub.6cycloalkyl, phenyl, a 5- or 6-membered heteroaryl, which comprises 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and a 4- to 6-membered heterocyclyl, which comprises 1, 2 or 3 heteroatoms independently selected from N, O and S, and wherein said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties are optionally substituted by 1 or 2 R.sup.9 substituents, and wherein the aforementioned CR.sup.1R.sup.2 and Z, or Q and Z, moieties may be attached at any position of said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties; n is 0 or 1; Z is selected from the group consisting of C(O)OR.sup.10, CH.sub.2OH, CHO, C(O)NHOR.sup.11, C(O)NHCN, OC(O)NHOR.sup.11, OC(O)NHCN, NR.sup.6C(O)NHOR.sup.11, NR.sup.6C(O)NHCN, C(O)NHS(O).sub.2R.sup.12, OC(O)NHS(O).sub.2R.sup.12, NR.sup.6C(O)NHS(O).sub.2R.sup.12, S(O).sub.2OR.sup.0, OS(O).sub.2OR.sup.10, NR.sup.6S(O).sub.2OR.sup.10, NR.sup.6S(O)OR.sup.10, NHS(O).sub.2R.sup.14, S(O)OR.sup.10, OS(O)OR.sup.10, S(O).sub.2NHCN, S(O).sub.2NHC(O)R.sup.18, S(O).sub.2NHS(O).sub.2R.sup.12, OS(O).sub.2NHCN, OS(O).sub.2NHS(O).sub.2R.sup.12, OS(O).sub.2NHC(O)R.sup.18, NR.sup.6S(O).sub.2NHCN, NR.sup.6S(O).sub.2NHC(O)R.sup.18, N(OH)C(O)R.sup.15, ONHC(O)R.sup.15, NR.sup.6S(O).sub.2NHS(O).sub.2R.sup.12, P(O)(R.sup.13)(OR.sup.10), P(O)H(OR.sup.10), OP(O)(R.sup.13)(OR.sup.10), NR.sup.6P(O)(R.sup.13)(OR.sup.10) and tetrazole; R.sup.10 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, phenyl and benzyl, and wherein said phenyl or benzyl are optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; R.sup.11 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; R.sup.12 is selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, OH, N(R.sup.6).sub.2 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; R.sup.13 is selected from the group consisting of OH, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy and phenyl; R.sup.14 is C.sub.1-C.sub.6haloalkyl; R.sup.15 is selected from the group consisting of C.sub.1-C.sub.6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; R.sup.15a is phenyl, wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; R.sup.16 and R.sup.17 are independently selected from the group consisting of hydrogen and C.sub.1-C.sub.6alkyl; or R.sup.16 and R.sup.17 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom independently selected from N, O and S; and R.sup.18 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, N(R.sup.6).sub.2 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; and r is 0, 1 or 2.

2. The compound according to claim 1, wherein R.sup.1 and R.sup.2 are each independently hydrogen or C.sub.1-C.sub.6alkyl.

3. The compound according to claim 1, wherein each R.sup.1a and R.sup.2b are independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, OH and NH.sub.2.

4. The compound according to claim 1, wherein m is 1 or 2.

5. The compound according to claim 1, wherein R.sup.3, R.sup.4 and R.sup.5 are hydrogen.

6. The compound according to claim 1, wherein A is a heteroaryl selected from the group consisting of tetrazolyl, 1,2,4-triazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, imidazolyl, isothiazolyl, thienyl, furyl, 1,2,4-oxadiazolyl, 1,2,3-thiadiazolyl and 1,2,5-thiadiazolyl, wherein the heteroaryl is optionally substituted by 1, 2 or 3 R.sup.8 substituents, which may be the same or different and R.sup.8 is as defined in claim 1.

7. The compound according to claim 1, wherein A is selected from the group consisting of formula A-I to A-XXXIV below ##STR00330## wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I); R.sup.8a is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6haloalkyl; each R.sup.8b, R.sup.8c and R.sup.8d are independently selected from the group consisting of hydrogen, halogen, nitro, cyano, NH.sub.2, NHR.sup.7, N(R.sup.7).sub.2, OH, OR.sup.7, S(O).sub.rR.sup.15, NR.sup.6S(O).sub.2R.sup.15, C(O)OR.sup.10, C(O)R.sup.15, C(O)NR.sup.16R.sup.17, S(O).sub.2NR.sup.16R.sup.17, C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6haloalkyl; and R.sup.6, R.sup.7, R.sup.10, R.sup.15, R.sup.16, R.sup.17 and r are as defined in claim 1.

8. The compound according to claim 1, wherein A is selected from the group consisting of formula A-I to A-VIII, A-X, A-XIV, A-XVIII, A-XXVII, A-XXIX and A-XXX below ##STR00331## ##STR00332## wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I); R.sup.8a is hydrogen or C.sub.1-C.sub.6alkyl; each R.sup.8b, R.sup.8c and R.sup.8d are independently selected from the group consisting of hydrogen, halogen, cyano, NH.sub.2, NHR.sup.7, N(R.sup.7).sub.2, OH, OR.sup.7, S(O).sub.rR.sup.15, C(O)OR.sup.10, C(O)R.sup.15, C(O)NR.sup.16R.sup.17, C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6haloalkyl; and R.sup.7, R.sup.10, R.sup.15, R.sup.16, R.sup.17 and r as defined in claim 1.

9. The compound according to claim 8, wherein R.sup.8a is hydrogen or methyl and each R.sup.8b, R.sup.8c and R.sup.8d are independently selected from the group consisting of hydrogen, chloro, cyano, NH.sub.2, NHMe, OMe, C(O)OEt, C(O)NHMe, methyl, iso-propyl and trifluoromethyl.

10. The compound according to claim 1, wherein A is selected from the group consisting of formula A-Ia, A-IIa, A-IIIa, A-IVa, A-Va, A-VIa, A-VIb, A-VIc, A-VIIa, A-VIIb, A-VIIIa, A-VIIIb, A-Xa, A-XIVa, A-XVIIIa, A-XVIIIb, A-XXVIIa, A-XXIXa and A-XXXa below ##STR00333## ##STR00334##

11. The compound according to claim 1, wherein Z is selected from the group consisting of C(O)OR.sup.10, CH.sub.2OH, C(O)NHS(O).sub.2R.sup.12, S(O).sub.2OR.sup.10, OS(O).sub.2OR.sup.10, NR.sup.6S(O).sub.2OR.sup.10 and P(O)(R.sup.13)(OR.sup.10).

12. The compound according to claim 1, wherein Z is C(O)OH or S(O).sub.2OH.

13. A herbicidal composition comprising a herbicidally effective amount of a compound of formula (I) as defined in claim 1 and an agrochemically-acceptable diluent or carrier.

14. The composition according to claim 13, further comprising at least one additional active ingredient.

15. A method of controlling unwanted plant growth, comprising applying a compound of formula (I) as defined in claim 1 to the unwanted plants or to the locus thereof.

16. A method of controlling unwanted plant growth, comprising applying a herbicidal composition according to claim 13, to the unwanted plants or to the locus thereof.

Description

EXAMPLES

[0277] The Examples which follow serve to illustrate, but do not limit, the invention.

Formulation Examples

[0278]

TABLE-US-00058 Wettable powders a) b) c) active ingredients 25% 50% 75% sodium lignosulfonate 5% 5% sodium lauryl sulfate 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%

[0279] 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-00059 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%

[0280] Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.

TABLE-US-00060 Dusts a) b) c) Active ingredients 5% 6% 4% Talcum 95% Kaolin 94% mineral filler 96%

[0281] Ready-for-use dusts are obtained by mixing the combination with the carrier and grinding the mixture in a suitable mill.

TABLE-US-00061 Extruded granules Active ingredients 15% sodium lignosulfonate 2% carboxymethylcellu lose 1% Kaolin 82%

[0282] 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-00062 Coated granules Active ingredients 8% polyethylene glycol (mol. wt. 200) 3% Kaolin 89%

[0283] 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-00063 Suspension concentrate active ingredients 40% propylene glycol 10% nonylphenol polyethylene glycol ether 6% (15 mol of ethylene oxide) Sodium lignosulfonate 10% carboxymethylcellulose 1% silicone oil (in the form of a 75% 1% emulsion in water) Water 32%

[0284] 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.

[0285] Slow Release Capsule Suspension

[0286] 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.

[0287] 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.

[0288] The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.

LIST OF ABBREVIATIONS

[0289] Boc=tert-butyloxycarbonyl

[0290] br=broad

[0291] CDCl.sub.3=chloroform-d

[0292] CD.sub.3OD=methanol-d

[0293] C.=degrees Celsius

[0294] D.sub.2O=water-d

[0295] DCM=dichloromethane

[0296] d=doublet

[0297] dd=double doublet

[0298] dt=double triplet

[0299] DMSO=dimethylsulfoxide

[0300] EtOAc=ethyl acetate

[0301] h=hour(s)

[0302] HCl=hydrochloric acid

[0303] HPLC=high-performance liquid chromatography (description of the apparatus and the methods used for HPLC are given below)

[0304] m=multiplet

[0305] M=molar

[0306] min=minutes

[0307] MHz=megahertz

[0308] mL=millilitre

[0309] mp=melting point

[0310] ppm=parts per million

[0311] q=quartet

[0312] quin=quintet

[0313] rt=room temperature

[0314] s=singlet

[0315] t=triplet

[0316] THE=tetrahydrofuran

[0317] LC/MS=Liquid Chromatography Mass Spectrometry (description of the apparatus and the methods used for LC/MS analysis are given below)

[0318] Preparative Reverse Phase HPLC Method:

[0319] 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 1910 mm guard column was used with a Waters Atlantis T3 OBD, 5 micron 30100 mm prep column.

[0320] Ionisation method: Electrospray positive and negative: Cone (V) 20.00, Source Temperature ( C.) 120, Cone Gas Flow (L/Hr.) 50

[0321] Mass range (Da): positive 100 to 800, negative 115 to 800.

[0322] 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-00064 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

[0323] 515 pump 0 ml/min Acetonitrile (ACD)

[0324] 515 pump 1 ml/min 90% Methanol/10% Water (makeup pump)

[0325] Solvent A: Water with 0.05% Trifluoroacetic Acid

[0326] Solvent B: Acetonitrile with 0.05% Trifluoroacetic Acid

Preparation Examples

Example 1: Preparation of 2-(4-thiazol-2-ylpyridazin-1-ium-1-yl)ethanesulfonate A-1

[0327] ##STR00107##

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

[0328] ##STR00108##

[0329] To a mixture of 2-bromothiazole (68 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (86 mg) in N,N-dimethylformamide (1 mL) was added aqueous 2M sodium carbonate (0.4 mL), followed by degassing and purging with nitrogen for ten minutes.

[0330] Chloro(crotyl)(tricyclohexylphosphine)palladium(II) (40 mg) was added and the reaction mixture was degassed once again. This mixture was heated at 100 C. under microwave irradiation for 30 minutes. After cooling to room temperature the reaction mixture was concentrated and purified by preparative reverse phase HPLC to afford 2-pyridazin-4-ylthiazole as a cream solid.

[0331] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.75 (dd, 1H) 9.31 (dd, 1H) 8.06 (d, 1H) 7.96 (dd, 1H) 7.60 (d, 1H)

Step 2: Preparation of 2-(4-thiazol-2-ylpyridazin-1-ium-1-yl)ethanesulfonate A-1

[0332] A mixture of 2-pyridazin-4-ylthiazole (40 mg) and sodium 2-bromoethanesulfonate (58 mg) was heated in water (1 mL) at 100 C. for 44 hours. The reaction mixture was cooled and washed with dichloromethane. The aqueous phase was concentrated and purified by preparative reverse phase HPLC to afford 2-(4-thiazol-2-ylpyridazin-1-ium-1-yl)ethanesulfonate as a white solid.

[0333] .sup.1H NMR (400 MHz, D.sub.2O) 9.84-9.94 (m, 1H) 9.63-9.72 (m, 1H) 8.82 (dd, 1H) 8.14-8.25 (m, 1H) 8.08 (d, 1H) 5.09-5.19 (m, 2H) 3.54-3.68 (m, 2H)

Example 2: Preparation of 4-(1-methylpyrazol-3-yl)pyridazine

[0334] ##STR00109##

[0335] To a mixture of 3-bromo-1-methyl-pyrazole (156 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (200 mg) in 1,4-dioxane (2 mL) was added potassium phosphate (0.5 g) and water (0.4 mL), followed by degassing and purging with nitrogen for 10 minutes.

[0336] Chloro(crotyl)(tricyclohexylphosphine)palladium(II) (28 mg) was added and the reaction mixture was degassed once again. This mixture was heated at 110 C. under microwave irradiation for 30 minutes. After cooling to room temperature the reaction mixture was concentrated and purified by preparative reverse phase HPLC to afford 4-(1-methylpyrazol-3-yl)pyridazine as a white solid.

[0337] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.77 (dd, 1H) 9.33 (dd, 1H) 8.41 (dd, 1H) 7.80 (d, 1H) 7.10 (d, 1H) 4.04 (s, 3H)

Example 3: Preparation of 3-(4-oxazol-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate A-3

[0338] ##STR00110##

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

[0339] ##STR00111##

[0340] To a mixture of tributyl(oxazol-2-yl)stannane (1 g), 4-bromopyridazine (0.4 g), palladium (0) tetrakis(triphenylphosphine) (0.291 g), cesium fluoride (0.382 g) and cuprous iodide (0.019 g) was added 1,4-dioxane (10 mL). This mixture was heated at 140 C. under microwave irradiation for 60 minutes. The reaction mixture was concentrated and purified by preparative reverse phase HPLC to afford 2-pyridazin-4-yloxazole as a beige solid.

[0341] .sup.1H NMR (400 MHz, D.sub.2O) 9.59 (dd, 1H) 9.24 (dd, 1H) 8.15 (dd, 1H) 8.03 (d, 1H) 7.37 (d, 1H)

Step 2: Preparation of 3-(4-oxazol-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate A-3

[0342] To a mixture of 2-pyridazin-4-yloxazole (30 mg) in 1,4-dioxane (1 mL) was added 1,3-propanesultone (30 mg). The mixture was heated at 90 C. for 44 hours. The resulting precipitate was filtered off, washed with acetone and purified by preparative reverse phase HPLC to afford 3-(4-oxazol-2-ylpyridazin-1-ium-1-yl)propane-1-sulfonate as a white solid.

[0343] .sup.1H NMR (400 MHz, D.sub.2O) 9.83-9.95 (m, 1H) 9.73 (d, 1H) 8.86 (dd, 1H) 8.08-8.31 (m, 1H) 7.49-7.71 (m, 1H) 4.85-5.08 (m, 2H) 2.85-3.16 (m, 2H) 2.50 (quin, 2H)

Example 4: Preparation of 2-pyridazin-4-yl-1,3,4-oxadiazole

[0344] ##STR00112##

Step 1: Preparation of pyridazine-4-carbohydrazide

[0345] ##STR00113##

[0346] To a solution of methyl pyridazine-4-carboxylate (0.4 g) in methanol (4.92 mL) was added hydrazine hydrate (1.16 g) and the mixture was heated at reflux overnight. The reaction mixture was cooled and concentrated to afford pyridazine-4-carbohydrazide as a brown solid.

[0347] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.52-9.48 (m, 1H) 9.36 (dd, 1H) 8.00 (dd, 1H) (three NH protons missing)

Step 2: Preparation of 2-pyridazin-4-yl-1,3,4-oxadiazole

[0348] A mixture of pyridazine-4-carbohydrazide (0.370 g) and trimethoxymethane (7.8 g) was heated at reflux overnight. The reaction mixture was cooled, concentrated and purified by silica gel chromatography eluting with 0 to 50% acetonitrile in dichloromethane to afford 2-pyridazin-4-yl-1,3,4-oxadiazole as a yellow solid.

[0349] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.87-9.84 (dd, 1H) 9.50-9.46 (dd, 1H) 8.66 (s, 1H) 8.10 (dd, 1H)

Example 5: Preparation of 5-pyridazin-4-y-1,2,4-thiadiazole

[0350] ##STR00114##

Step 1: Preparation of pyridazine-4-carbothioamide

[0351] ##STR00115##

[0352] To a solution of pyridazine-4-carbonitrile (0.5 g) in methanolic ammonia (2M solution, 5 mL) was added phosphorus pentasulfide (1.06 g), keeping the reaction temperature below 35 C. After stirring at room temperature overnight water was added. The reaction mixture was cooled and the resulting precipitate removed by filtration. The aqueous phase was washed with dichloromethane and the organic phase discarded. The aqueous phase was left to stand at room temperature for several days and the resulting solid was again removed by filtration. The combined solids were shown to be the desired compound pyridazine-4-carbothioamide.

[0353] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.53 (dd, 1H) 9.26 (dd, 1H) 7.94 (dd, 1H) (two NH protons missing)

Step 2: Preparation of N,N-(dimethylaminomethylene)pyridazine-4-carbothioamide

[0354] ##STR00116##

[0355] Pyridazine-4-carbothioamide (1.46 g) and 1,1-dimethoxy-N,N-dimethyl-methanamine (1.4 mL) were stirred together at room temperature for 6 hours. The reaction was concentrated and purified by silica gel chromatography eluting with 0 to 50% methanol in acetonitrile to afford N,N-(dimethylaminomethylene)pyridazine-4-carbothioamide as a dark red solid.

[0356] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.94 (dd, 1H) 9.27 (dd, 1H) 8.81 (s, 1H) 8.27 (dd, 1H) 3.38-3.32 (m, 6H)

Step 3: Preparation of 5-pyridazin-4-yl-1,2,4-thiadiazole

[0357] To a mixture of N,N-(dimethylaminomethylene)pyridazine-4-carbothioamide (1 g), pyridine (0.83 mL) and ethanol (25 mL) at room temperature was added a solution of hydroxylamine-O-sulfonic acid (640 mg) in methanol (10 mL). After 2 hours the reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic phase was concentrated and the resulting solid was triturated with methanol to afford 5-pyridazin-4-yl-1,2,4-thiadiazole as a beige solid.

[0358] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.75 (dd, 1H) 9.45 (dd, 1H) 8.90 (s, 1H) 8.00 (dd, 1H)

Example 6: Preparation of 2-[4-(1,2,4-oxadiazol-5-yl)pyridazin-1-ium-1-yl]ethyl sulfate A-8

[0359] ##STR00117##

Step 1: Preparation of 5-pyridazin-4-yl-1,2,4-oxadiazole

[0360] ##STR00118##

[0361] To a mixture of N,N-(dimethylaminomethylene)pyridazine-4-carbothioamide (0.2 g), pyridine (0.17 mL) and ethanol (4 mL) at room temperature was added a solution of wet hydroxylamine-O-sulfonic acid (128 mg) in methanol (1.6 mL). After stirring overnight at room temperature the mixture was concentrated and partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was concentrated to afford 5-pyridazin-4-yl-1,2,4-oxadiazole.

[0362] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.90 (dd, 1H) 9.52 (dd, 1H) 8.67 (s, 1H) 8.15 (dd, 1H)

Step 2: Preparation of 2-[4-(1,2,4-oxadiazol-5-yl)pyridazin-1-ium-1-yl]ethyl sulfate A-8

[0363] A mixture of 5-pyridazin-4-yl-1,2,4-oxadiazole (0.056 g) and 1,3,2-dioxathiolane 2,2-dioxide (0.054 g) was heated in 1,2-dichloroethane (3 mL) at 85 C. overnight. The resulting precipitate was filtered off, washed with acetone and purified by preparative reverse phase HPLC to afford 2-[4-(1,2,4-oxadiazol-5-yl)pyridazin-1-ium-1-yl]ethyl sulfate as a 1:1 mixture with 2-[5-(1,2,4-oxadiazol-5-yl)pyridazin-1-ium-1-yl]ethyl sulfate.

[0364] 1H NMR (400 MHz, DMSO-d.sub.6) 10.32-10.28 (m, 1H) 10.18-10.12 (m, 1H) 9.55-9.54 (m, 1H) 9.43-9.38 (m, 1H) 5.26-5.14 (m, 2H) 4.43-4.33 (m, 2H)

[0365] The other isomer 2-[5-(1,2,4-oxadiazol-5-yl)pyridazin-1-ium-1-yl]ethyl sulfate has the structure below

##STR00119##

[0366] 1H NMR (400 MHz, DMSO-d.sub.6) 10.72 (s, 1H) 9.95-9.90 (m, 1H) 9.53-9.52 (m, 1H) 9.27-9.22 (m, 1H) 5.26-5.14 (m, 2H) 4.43-4.33 (m, 2H)

Example 7: Preparation of 3-methyl-5-pyridazin-4-y-1,2,4-thiadiazole

[0367] ##STR00120##

[0368] To a mixture of N,N-[1-(dimethylamino)ethylidene]pyridazine-4-carbothioamide (700 mg), pyridine (0.56 mL) and ethanol (18 mL) was added a solution of hydroxylamine-O-sulfonic acid (0.42 g) in methanol (7 mL) at room temperature. After one hour the reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was concentrated and triturated with hexane to afford 3-methyl-5-pyridazin-4-yl-1,2,4-thiadiazole as a beige solid.

[0369] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.76 (dd, 1H) 9.41 (dd, 1H) 8.25 (dd, 1H) 2.75 (s, 3H)

Example 8: Preparation of 3-[4-(1-methylimidazol-2-yl)pyridazin-1-ium-1-yl]propanoic acid; 2,2,2-trifluoroacetate A-31

[0370] ##STR00121##

Step 1: Preparation of ethyl 3-pyridazin-1-ium-1-ylpropanoate bromide

[0371] ##STR00122##

[0372] To a solution of pyridazine (1 g) in acetonitrile (40 mL) was added ethyl 3-bromopropanoate (1.76 mL) and the reaction was stirred at 80 C. for 25 hours. The mixture was concentrated and partitioned between dichloromethane and water. The aqueous layer was freeze dried to afford ethyl 3-pyridazin-1-ium-1-ylpropanoate bromide as a beige solid.

[0373] .sup.1H NMR (400 MHz, D.sub.2O) 9.68-9.92 (m, 1H) 9.43-9.56 (m, 1H) 8.43-8.69 (m, 2H) 5.15 (t, 2H) 4.11 (q, 2H) 3.27 (t, 2H) 1.16 (t, 3H)

Step 2: Preparation of ethyl 3-[4-(1-methylimidazol-2-yl)-4H-pyridazin-1-yl]propanoate

[0374] ##STR00123##

[0375] To a solution of 1-methylimidazole (1 g) in tetrahydrofuran (10 mL) at 78 C. under a nitrogen atmosphere was added n-butyllithium (2.5M in hexanes, 5.4 mL) dropwise. After stirring at this temperature for 30 minutes zinc chloride (0.5M in THF, 7.7 mL) was added and the reaction mixture was allowed to warm to room temperature. To this mixture was added a solution of ethyl 3-pyridazin-1-ium-1-ylpropanoate (1.99 g) and iodocopper (2.1 g) in N,N-dimethylformamide (10 mL) and the reaction mixture was stirred at room temperature overnight. This reaction mixture was partitioned between ethyl acetate and water. The organic phase was concentrated to afford crude ethyl 3-[4-(1-methylimidazol-2-yl)-4H-pyridazin-1-yl]propanoate which was used directly in the next step. LC-MS 0.25 min MH+ 263.

Step 3: Preparation of ethyl 3-[4-(1-methylimidazol-2-yl)pyridazin-1-ium-1-yl]propanoate

[0376] ##STR00124##

[0377] To a solution of crude ethyl 3-[4-(1-methylimidazol-2-yl)-4H-pyridazin-1-yl]propanoate (2.52 g) in tetrahydrofuran (40 mL) was added 2,3,5,6-tetrachloro-1,4-benzoquinone (2.36 g) and the mixture stirred at room temperature for 2 hours. The reaction mixture was concentrated to afford crude ethyl 3-[4-(1-methylimidazol-2-yl)pyridazin-1-ium-1-yl]propanoate which was used directly in the next step.

[0378] LC-MS 0.26 min MH+ 261.

Step 4: Preparation of 3-[4-(1-methylimidazol-2-yl)pyridazin-1-ium-1-yl]propanoic acid; 2,2,2-trifluoroacetate A-31

[0379] A mixture of crude ethyl 3-[4-(1-methylimidazol-2-yl)pyridazin-1-ium-1-yl]propanoate (320 mg) and 2M hydrochloric acid (6 mL) was heated at 80 C. for 2 hours. After cooling to room temperature the reaction mixture was concentrated and purified by preparative reverse phase HPLC to afford 3-[4-(1-methylimidazol-2-yl)pyridazin-1-ium-1-yl]propanoate as a purple gum.

[0380] .sup.1H NMR (400 MHz, D.sub.2O) 9.71-9.90 (m, 2H) 8.67-8.81 (m, 1H) 7.59-7.69 (m, 1H) 7.54 (d, 1H) 5.07 (t, 2H) 3.95-4.07 (m, 3H) 3.13-3.31 (m, 2H) (one CO.sub.2H proton missing)

Example 9: Preparation of 4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]pyridazine (A) and 4-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]pyridazine (B)

[0381] ##STR00125##

Step 1: Preparation of 4,4,4-trifluoro-1-pyridazin-4-yl-butane-1,3-dione

[0382] ##STR00126##

[0383] To a mixture of ethyl 2,2,2-trifluoroacetate (0.256 g) and sodium methoxide (25% by wt in methanol, 0.449 mL) in tert-butyl methyl ether (0.409 mL) was added a suspension of 1-pyridazin-4-ylethanone (0.200 g) in tert-butyl methyl ether (2.87 mL) at room temperature and the mixture stirred at room temperature overnight. The reaction mixture was adjusted to pH 4 with 10% aqueous citric acid solution, diluted with water and extracted with dichloromethane (3). Both liquid phases were concentrated, combined, then purified by preparative reverse phase HPLC to afford 4,4,4-trifluoro-1-pyridazin-4-yl-butane-1,3-dione as a brown gum. The product was a 2:1 mixture of the enol:keto tautomers.

[0384] .sup.1H NMR (400 MHz, CD.sub.3CN)

[0385] peaks for keto tautomer 9.57 (s, 1H) 9.51-9.43 (m, 1H) 8.04-7.98 (m, 1H) 3.52 (s, 2H)

[0386] peaks for enol tautomer (shown below) 9.64 (s, 1H) 9.5-9.44 (m, 1H) 8.10-8.04 (m, 1H) 6.96 (s, 1H)

##STR00127##

Step 2: Preparation of 4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]pyridazine (A) and 4-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]pyridazine (B)

[0387] Methylhydrazine (0.54 mL) was added slowly to a solution of 4,4,4-trifluoro-1-pyridazin-4-yl-butane-1,3-dione (1.5 g) in ethanol (11 mL), followed by heating at reflux for 4 hours.

[0388] After cooling to room temperature the mixture was concentrated and the residue dissolved in tetrahydrofuran (34 mL). To this solution was added 3M aqueous hydrochloric acid (6.9 mL), followed by heating at reflux for 2 hours. The reaction mixture was cooled to room temperature and allowed to stand overnight. The mixture was concentrated and purified by preparative reverse phase HPLC to afford 4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]pyridazine (A) as an orange solid and 4-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]pyridazine (B) as an orange liquid.

[0389] 4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]pyridazine (A) 1H NMR (400 MHz, CD.sub.3CN) 9.70-9.65 (m, 1H) 9.31-9.27 (m, 1H) 8.11 (dd, 1H) 7.45 (s, 1H) 4.11 (s, 3H)

[0390] 4-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]pyridazine (B) 1H NMR (400 MHz, CD.sub.3CN) 9.43-9.39 (m, 1H) 9.38-9.35 (m, 1H) 7.87 (dd, 1H) 7.05 (s, 1H) 4.04 (s, 3H)

Example 10: Preparation of 4-(2-methyltetrazol-5-yl)pyridazine

[0391] ##STR00128##

Step 1: Preparation of 4-(1H-tetrazol-5-yl)pyridazine

[0392] ##STR00129##

[0393] To a mixture of pyridazine-4-carbonitrile (0.200 g), sodium azide (0.187 g) and copper sulfate pentahydrate (0.048 g) was added dimethyl sulfoxide (0.4 mL). This mixture was heated at 145 C. under microwave irradiation for 10 minutes. After cooling to room temperature the reaction mixture was quenched with ice cold water (20 mL), acidified with 1M aqueous hydrochloric acid and extracted with a 9:1 ratio of ethyl acetate and methanol (330 mL). The combined organic phases were concentrated to afford crude 4-(1H-tetrazol-5-yl)pyridazine.

[0394] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.67 (br s, 1H) 9.15 (br d, 1H) 8.00 (br d, 1H) (one NH proton missing)

Step 2: Preparation of 4-(2-methyltetrazol-5-yl)pyridazine

[0395] A mixture of 4-(1H-tetrazol-5-yl)pyridazine (0.16 g), N,N-dimethylformamide (1 mL), dimethyl carbonate (0.5 mL) and 1,4-diazabicyclo[2.2.2]octane (0.026 g) was heated at 150 C. under microwave irradiation for 80 minutes. After cooling to room temperature the reaction mixture was concentrated and purified by silica gel chromatography eluting with 0 to 10% methanol in dichloromethane to afford 4-(2-methyltetrazol-5-yl)pyridazine as a brown solid.

[0396] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.85 (s, 1H) 9.39 (d, 1H) 8.34 (d, 1H) 4.50 (s, 3H)

[0397] The other isomer, 4-(1-methyltetrazol-5-yl)pyridazine was also obtained from this reaction.

##STR00130##

[0398] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.71 (s, 1H) 9.48 (d, 1H) 8.23 (d, 1H) 4.34 (s, 3H)

Example 11: Preparation of 4-methyl-2-pyridazin-4-yl-thiazole

[0399] ##STR00131##

[0400] To a solution of pyridazine-4-carbothioamide (0.5 g) in ethanol (10 mL) was added 1-chloropropan-2-one (0.432 g), followed by heating at 80 C. for 5 hours. The reaction mixture was concentrated and the residue dissolved in distilled water. The aqueous phase was basified with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic phase was concentrated and purified by silica gel chromatography eluting with 60 to 80% ethyl acetate in cyclohexane to afford 4-methyl-2-pyridazin-4-yl-thiazole.

[0401] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.70-9.80 (m, 1H) 9.24-9.33 (m, 1H) 8.08-8.24 (m, 1H) 7.47 (s, 1H) 2.55 (s, 3H)

Example 12: Preparation of 4,5-dimethyl-2-pyridazin-4-yl-oxazole

[0402] ##STR00132##

Step 1: Preparation of N-(1-methylprop-2-ynyl)pyridazine-4-carboxamide

[0403] ##STR00133##

[0404] To a mixture of methyl pyridazine-4-carboxylate (1.00 g) in methanol (4 mL) was added 1-methylprop-2-ynylammonium chloride (2.29 g) and N,N-diisopropylethylamine (3.92 mL), followed by heating at 100 C. under microwave irradiation for 2 hours. After cooling to room temperature the reaction mixture was concentrated and purified by silica gel chromatography eluting with ethyl acetate to afford N-(1-methylprop-2-ynyl)pyridazine-4-carboxamide.

[0405] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.49-9.67 (m, 1H) 9.38 (dd, 1H) 7.87 (dd, 1H) 6.83-7.07 (m, 1H) 4.94-5.13 (m, 1H) 2.37 (d, 1H) 1.48-1.63 (m, 3H)

Step 2: Preparation of N-(2-bromo-1-methyl-allyl)pyridazine-4-carboxamide

[0406] ##STR00134##

[0407] A mixture of N-(1-methylprop-2-ynyl)pyridazine-4-carboxamide (0.27 g) and hydrobromic acid (5.4 mL, 33% wt in acetic acid) was heated at 60 C. for 18 hours. After cooling to room temperature, saturated aqueous sodium bicarbonate was added and the product was extracted with ethyl acetate. The organic phase was concentrated to afford crude N-(2-bromo-1-methyl-allyl)pyridazine-4-carboxamide which was used directly in the next step.

Step 3: Preparation of 4,5-dimethyl-2-pyridazin-4-yl-oxazole

[0408] ##STR00135##

[0409] To a solution of crude N-(2-bromo-1-methyl-allyl)pyridazine-4-carboxamide (0.25 g) in dimethyl sulfoxide (2.5 mL) under nitrogen atmosphere was added cesium carbonate (1.05 g), followed by heating at 110 C. for 1 hour. After cooling to room temperature, aqueous saturated lithium chloride was added and the crude product was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and purified by silica gel chromatography eluting with ethyl acetate to afford 4,5-dimethyl-2-pyridazin-4-yl-oxazole.

[0410] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.63-9.90 (m, 1H) 9.23-9.47 (m, 1H) 7.92-8.15 (m, 1H) 2.34-2.51 (m, 3H) 2.22 (m, 3H)

Example 13: Preparation of 3-[4-(5-methyloxazol-2-yl)pyridazin-1-ium-1-yl]propanoic acid; 2,2,2-trifluoroacetate A-15

[0411] ##STR00136##

Step 1: Preparation of N-prop-2-ynylpyridazine-4-carboxamide

[0412] ##STR00137##

[0413] To a solution of methyl pyridazine-4-carboxylate (1 g) in methanol (2.5 mL) was added prop-2-yn-1-amine (4 g) and the mixture was heated at 100 C. under microwave irradiation for 4 hours. After cooling to room temperature, the reaction mixture was concentrated and purified by silica gel chromatography eluting with 90-100% ethyl acetate in cyclohexane to afford N-prop-2-ynylpyridazine-4-carboxamide as white solid.

[0414] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.53-9.56 (m, 1H) 9.47-9.52 (m, 1H) 9.42-9.46 (m, 1H) 7.96-8.03 (m, 1H) 4.06-4.16 (m, 2H) 3.19-3.26 (m, 1H)

Step 2: Preparation of N-(2-bromoallyl)pyridazine-4-carboxamide

[0415] ##STR00138##

[0416] A mixture of N-prop-2-ynylpyridazine-4-carboxamide (0.5 g) and hydrobromic acid (10 mL, 33% wt in acetic acid) was heated at 60 C. for 18 hours. After cooling to room temperature, water was added and the mixture was basified with aqueous saturated sodium bicarbonate. This aqueous mixture was extracted with ethyl acetate and the organic phase was further washed with brine, dried over sodium sulfate and concentrated to afford crude N-(2-bromoallyl)pyridazine-4-carboxamide which was used directly in the next step.

Step 3: Preparation of 5-methyl-2-pyridazin-4-yl-oxazole

[0417] ##STR00139##

[0418] To a mixture of crude N-(2-bromoallyl)pyridazine-4-carboxamide (0.1 g) in dimethyl sulfoxide (1 mL) under nitrogen atmosphere was added cesium carbonate (0.222 g) and the mixture heated at 110 C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (40 mL) and extracted with ethyl acetate (320 mL). The combined organic phases were washed with saturated aqueous lithium chloride (30 mL), brine (30 mL) and dried over anhydrous sodium sulfate. Concentration of the organic filtrate afforded 5-methyl-2-pyridazin-4-yl-oxazole.

[0419] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.78 (s, 1H) 9.36 (d, 1H) 8.06 (dd, 1H) 7.05 (s, 1H) 2.49 (s, 3H)

Step 4: Preparation of ethyl 3-[4-(5-methyloxazol-2-yl)pyridazin-1-ium-1-yl]propanoate bromide

[0420] ##STR00140##

[0421] To a solution of 5-methyl-2-pyridazin-4-yl-oxazole (0.1 g) in acetonitrile (2 mL) was added ethyl 3-bromopropanoate (0.159 mL), and the mixture was heated at 80 C. for 18 hours. After cooling to room temperature the solution was concentrated and the residue triturated with tert-butylmethyl ether to afford a crude 1:1 mixture of ethyl 3-[4-(5-methyloxazol-2-yl)pyridazin-1-ium-1-yl]propanoate bromide and ethyl 3-[5-(5-methyloxazol-2-yl)pyridazin-1-ium-1-yl]propanoate bromide which was used directly in the next step.

Step 5: Preparation of 3-[4-(5-methyloxazol-2-yl)pyridazin-1-ium-1-yl]propanoic acid 2,2,2-trifluoroacetate A-15

[0422] A crude 1:1 mixture of ethyl 3-[4-(5-methyloxazol-2-yl)pyridazin-1-ium-1-yl]propanoate bromide and ethyl 3-[5-(5-methyloxazol-2-yl)pyridazin-1-ium-1-yl]propanoate bromide (0.2 g) in 2M hydrochloric acid (4 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated and purified by preparative reverse phase HPLC to afford 3-[4-(5-methyloxazol-2-yl)pyridazin-1-ium-1-yl]propanoic acid 2,2,2-trifluoroacetate.

[0423] .sup.1H NMR (400 MHz, D.sub.2O) 9.82 (d, 1H) 9.74 (d, 1H) 8.77 (dd, 1H) 7.29 (d, 1H) 5.06 (t, 2H) 3.23 (t, 2H) 2.47 (d, 3H) (one CO.sub.2H proton missing)

Example 14: Preparation of 4-(2-methyl-1,2,4-triazol-3-yl)pyridazine

[0424] ##STR00141##

Step 1: Preparation of N-(dimethylaminomethylene)pyridazine-4-carboxamide

[0425] ##STR00142##

[0426] A mixture of pyridazine-4-carboxamide (2 g) and 1,1-dimethoxy-N,N-dimethyl-methanamine (20 mL), under nitrogen atmosphere, was heated at reflux for 1 hour. The reaction mixture was concentrated and the residue washed with cyclohexane (320 mL) to afford N-(dimethylaminomethylene) pyridazine-4-carboxamide which was used directly in the next step.

Step 2: Preparation of 4-(2-methyl-1,2,4-triazol-3-yl)pyridazine

[0427] ##STR00143##

[0428] To a mixture of N-(dimethylaminomethylene)pyridazine-4-carboxamide (0.5 g), acetic acid (5 mL) and 1,4-dioxane (5 mL) was added methylhydrazine sulfate (0.404 g). This mixture was heated at 70 C. under microwave irradiation for 30 minutes. After cooling to room temperature, the reaction mixture was concentrated and extracted with ethyl acetate (3100 mL). The organic layers were concentrated and purified by silica gel chromatography eluting with 0 to 90% methanol in dichloromethane to afford 4-(2-methyl-1,2,4-triazol-3-yl)pyridazine.

[0429] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.62 (dd, 1H) 9.41 (dd, 1H) 8.04 (s, 1H) 7.86 (dd, 1H) 4.15 (s, 3H)

Example 15: Preparation of 2-pyridazin-4-y-4-(trifluoromethyl)thiazole

[0430] ##STR00144##

[0431] To a mixture of pyridazine-4-carbothioamide (0.05 g) and ethanol (0.25 mL) was added 3-bromo-1,1,1-trifluoro-propan-2-one (0.089 g). The resulting mixture was heated at reflux for 6 hours then left to stand overnight. The reaction mixture was concentrated and dissolved in water (50 mL). The aqueous phase was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (380 mL). The organic layers were concentrated and purified by silica gel chromatography eluting with 50-60% ethyl acetate in cyclohexane to afford 2-pyridazin-4-yl-4-(trifluoromethyl)thiazole.

[0432] .sup.1H NMR (400 MHz, CD.sub.3CN) 9.73 (dd, 1H) 9.37 (dd, 1H) 8.32 (d, 1H) 8.06 (dd, 1H)

Example 16 Preparation of 4-chloro-2-pyridazin-4-yl-thiazole

[0433] ##STR00145##

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

[0434] ##STR00146##

[0435] 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 THF (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 (3150 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.

[0436] .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 4-chloro-2-pyridazin-4-yl-thiazole

[0437] ##STR00147##

[0438] To a solution of 2,4-dichlorothiazole (1 g) in 1,4-dioxane (15 mL) was added tributyl(pyridazin-4-yl)stannane (2.876 g), tetrakis(triphenylphosphine) palladium(0) (0.376 g), cuprous iodide (0.371 g) and lithium chloride (0.826 g). The reaction mixture was purged with nitrogen then heated at 130 C. under microwave irradiation for 40 minutes. After cooling to room temperature the mixture was filtered through Celite and washed with methanol. The filtrate was concentrated and purified by silica gel chromatography eluting with 50-60% ethyl acetate in cyclohexane to afford 4-chloro-2-pyridazin-4-yl-thiazole.

[0439] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.60-9.88 (m, 1H) 9.40 (d, 1H) 8.15 (dd, 1H) 8.11 (s, 1H)

Example 17: Preparation of 4-methoxy-2-pyridazin-4-yl-thiazole

[0440] ##STR00148##

[0441] A mixture of 4-chloro-2-pyridazin-4-yl-thiazole (0.2 g) in sodium methoxide (30% in methanol, 5 mL) was heated at 100 C. under microwave irradiation for 60 minutes. The reaction mixture was concentrated and purified by silica gel chromatography eluting with 50-60% ethyl acetate in cyclohexane to afford 4-methoxy-2-pyridazin-4-yl-thiazole.

[0442] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.64-9.75 (m, 1H) 9.28 (d, 1H) 7.90 (dd, 1H) 6.39 (s, 1H) 4.03 (s, 3H)

Example 18: Preparation of N-methyl-5-pyridazin-4-y-1,3,4-thiadiazol-2-amine

[0443] ##STR00149##

Step 1: Preparation of 1-methyl-3-(pyridazine-4-carbonylamino)thiourea

[0444] ##STR00150##

[0445] To a mixture of pyridazine-4-carbohydrazide (2 g) and propan-2-ol (40 mL) was added methyl isothiocyanate (1.059 g) and the mixture heated at reflux for 3 hours. After cooling to 0 C. the resulting precipitate was filtered, washed with tert-butylmethyl ether (250 mL) and dichloromethane (10 mL) and dried to afford 1-methyl-3-(pyridazine-4-carbonylamino)thiourea as a yellow solid.

[0446] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.89 (br s, 1H) 9.56-9.62 (m, 1H) 9.46-9.56 (m, 2H) 8.20 (br d, 1H) 8.04 (dd, 1H) 2.88 (d, 3H)

Step 2: Preparation of N-methyl-5-pyridazin-4-yl-1,3,4-thiadiazol-2-amine

[0447] ##STR00151##

[0448] A mixture of 1-methyl-3-(pyridazine-4-carbonylamino)thiourea (0.4 g) and concentrated sulfuric acid (4 mL) was stirred at room temperature for 12 hours. The reaction mixture was cooled over ice and carefully basified with aqueous ammonium hydroxide (28-30% NH.sub.3). The resulting precipitate was filtered off, washed with water then dried to afford N-methyl-5-pyridazin-4-yl-1,3,4-thiadiazol-2-amine.

[0449] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.60 (dd, 1H) 9.29 (dd, 1H) 8.33 (br s, 1H) 7.93 (dd, 1H) 2.98 ppm (s, 3H)

Example 19: Preparation of 5-pyridazin-4-y-1,3,4-thiadiazol-2-amine

[0450] ##STR00152##

Step 1: Preparation of (2,3,4,5,6-pentafluorophenyl) pyridazine-4-carboxylate

[0451] ##STR00153##

[0452] To a solution of pyridazine-4-carboxylic acid (5 g) in dichloromethane (50 mL) under a nitrogen atmosphere was added 2,3,4,5,6-pentafluorophenol (7.194 g). The mixture was cooled to 0 C. and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (8.99 g) and N,N-dimethylaminopyridine (0.964 g) were added. After 4 hours the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, brine and dried over sodium sulfate. The organic layer was concentrated and purified by silica gel chromatography eluting with 35% ethyl acetate in hexane to afford (2,3,4,5,6-pentafluorophenyl) pyridazine-4-carboxylate as a white solid.

[0453] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.90-9.76 (m, 1H) 9.67-9.47 (m, 1H) 8.36-7.88 (m, 1H)

Step 2: Preparation of (pyridazine-4-carbonylamino)thiourea

[0454] ##STR00154##

[0455] To a solution of (2,3,4,5,6-pentafluorophenyl) pyridazine-4-carboxylate (1 g) in acetonitrile (20 mL) was added thiosemicarbazide (0.377 g), followed by heating at 70 C. for 12 hours. After cooling to room temperature the reaction mixture was concentrated and purified by silica gel chromatography eluting with 0 to 10% methanol in dichloromethane to afford (pyridazine-4-carbonylamino)thiourea.

[0456] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.93 (br s, 1H) 9.50-9.59 (m, 2H) 9.46 (d, 1H) 8.02 (dd, 2H) 7.83 (br s, 1H)

Step 3: Preparation of 5-pyridazin-4-yl-1,3,4-thiadiazol-2-amine

[0457] ##STR00155##

[0458] A mixture of (pyridazine-4-carbonylamino)thiourea (1 g) and concentrated sulfuric acid (10 mL) was stirred at room temperature for 12 hours. The reaction mixture was the cooled over ice and carefully basified with aqueous ammonium hydroxide (28-30% NH.sub.3). The resulting precipitate was filtered off, washed with water and dried to afford 5-pyridazin-4-yl-1,3,4-thiadiazol-2-amine as a light green solid.

[0459] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.57-9.67 (m, 1H) 9.19-9.34 (m, 1H) 7.91-7.98 (m, 1H) 7.78-7.90 (m, 2H)

Example 20: Preparation of 4-(4-methyl-1,2,4-triazol-3-yl)pyridazine

[0460] ##STR00156##

Step 1: Preparation of 4-methyl-3-pyridazin-4-yl-1H-1,2,4-triazole-5-thione

[0461] ##STR00157##

[0462] A mixture of 1-methyl-3-(pyridazine-4-carbonylamino)thiourea (0.750 g) and acetic acid (10 mL) was heated at 120 C. for 16 hours. The reaction mixture was concentrated and the crude solid was triturated with tert-butylmethyl ether (30 mL) to afford 4-methyl-3-pyridazin-4-yl-1H-1,2,4-triazole-5-thione.

[0463] .sup.1H NMR (400 MHz, DMF-d.sub.7) 14.73 (br s, 1H) 10.00 (dd, 1H) 9.89 (dd, 1H) 8.53 (dd, 1H) 4.07 (s, 3H)

Step 2: Preparation of 4-(4-methyl-1,2,4-triazol-3-yl)pyridazine

[0464] ##STR00158##

[0465] To a mixture of Raney nickel (1.25 g, washed with ethanol, weighed approximately) in ethanol (8 mL), under nitrogen atmosphere, was added 4-methyl-3-pyridazin-4-yl-1H-1,2,4-triazole-5-thione (0.4 g) and the mixture heated at 90 C. for 20 hours. The reaction mixture was filtered through Celite, washed with ethanol and the filtrate was concentrated to afford 4-(4-methyl-1,2,4-triazol-3-yl)pyridazine.

[0466] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.60 (br s, 1H) 9.34 (br s, 1H) 8.23-8.40 (m, 1H) 7.86 (br s, 1H) 3.90 (br s, 3H)

Example 21: Preparation of 2-[4-(3,4-dimethylisothiazol-5-yl)pyridazin-1-ium-1-yl]ethanesulfonate A-54

[0467] ##STR00159##

[0468] To a mixture of 4,5-dibromo-3-methyl-isothiazole (1.95 g) in degassed 1,4-dioxane (29.3 mL), under nitrogen atmosphere, was added tetrakis(triphenylphosphine)palladium(0) (1.12 g) and tributyl(pyridazin-4-yl)stannane (2.02 g) and the reaction mixture was heated at 100 C. for 18 hours. After cooling to room temperature, potassium carbonate (1.82 g) and methylboronic acid (0.985 g) were added and the reaction mixture was heated at 100 C. for a further 20 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and washed through with methanol. The filtrate was concentrated and purified by silica gel chromatography eluting with 0 to 10% methanol in dichloromethane to afford 3,4-dimethyl-5-pyridazin-4-yl-isothiazole which was used directly in the next step.

Step 2: Preparation of 2-[4-(3,4-dimethylisothiazol-5-yl)pyridazin-1-ium-1-yl]ethanesulfonate A-54

[0469] A mixture of crude 3,4-dimethyl-5-pyridazin-4-yl-isothiazole (0.3 g) and sodium 2-bromoethanesulfonate (0.397 g) in water (6 mL) and 1,4-dioxane (6 mL) was heated at reflux for 48 hours. The reaction mixture was concentrated, washed with ethyl acetate and purified by preparative reverse phase HPLC to afford 2-[4-(3,4-dimethylisothiazol-5-yl)pyridazin-1-ium-1-yl]ethanesulfonate.

[0470] .sup.1H NMR (400 MHz, D.sub.2O) 9.73 (dd, 1H) 9.59 (dd, 1H) 8.61 (dd, 1H) 5.20 (t, 2H) 3.67 (t, 2H) 2.44 (s, 3H) 2.35 (s, 3H)

Example 22: Preparation of 3-pyridazin-4-ylisoxazole

[0471] ##STR00160##

Step 1: Preparation of pyridazine-4-carbaldehyde Oxime

[0472] ##STR00161##

[0473] To a solution of pyridazine-4-carbaldehyde (2 g) in ethanol (29.6 mL) was added a solution of sodium acetate (1.53 g) and hydroxylamine hydrochloride (1.29 g) in distilled water (69.4 mL). This resulting mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, concentrated and the resulting orange residue was triturated with water and azeotroped with methanol to afford pyridazine-4-carbaldehyde oxime as a beige solid.

[0474] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.41-9.37 (m, 1H) 9.17 (dd, 1H) 8.14 (s, 1H) 7.82 (dd, 1H) (one OH proton missing)

Step 2: Preparation of trimethyl-(3-pyridazin-4-ylisoxazol-5-yl)silane

[0475] ##STR00162##

[0476] To a solution of pyridazine-4-carbaldehyde oxime (1.45 g) in acetonitrile (141 mL) at 50 C. was added a solution of N-chlorosuccinimide (3.81 g) in acetonitrile (23.6 mL) and this mixture was heated at this temperature for 1 hour. Ethynyl(trimethyl)silane (17 mL) was added to the reaction mixture, followed by triethylamine (1.81 mL) and heating was continued for a further 3.5 hours. The reaction mixture was cooled to room temperature, concentrated and purified by silica gel chromatography eluting with 0 to 100% ethyl acetate in iso-hexane to afford trimethyl-(3-pyridazin-4-ylisoxazol-5-yl)silane as a yellow solid.

[0477] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.64-9.59 (m, 1H) 9.32 (dd, 1H) 7.88 (dd, 1H) 6.86 (s, 1H) 0.42 (s, 9H)

Step 3: Preparation of 3-pyridazin-4-ylisoxazole

[0478] ##STR00163##

[0479] To a solution of trimethyl-(3-pyridazin-4-ylisoxazol-5-yl)silane (0.100 g) in ethanol (2.51 mL) was added aqueous ammonium hydroxide (28-30% NH.sub.3, 0.150 mL) and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated to afford 3-pyridazin-4-ylisoxazole as a brown gum.

[0480] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.74-9.67 (m, 1H), 9.35 (dd, 1H), 8.91 (d, 1H), 8.17 (dd, 1H), 7.19 (d, 1H)

Example 23: Preparation of 2-(4-oxazol-4-ylpyridazin-1-ium-1-yl)ethanesulfonate A-22

[0481] ##STR00164##

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

[0482] ##STR00165##

[0483] To a solution of 2,2-dimethylpropyl ethenesulfonate (1.35 g) in methanol (10.1 mL) was added tert-butyl carbazate (1 g) and the mixture heated at 70 C. for 24 hours. The reaction mixture was then concentrated to afford 2,2-dimethylpropyl 2-(2-tert-butoxycarbonylhydrazino)ethanesulfonate as a yellow liquid.

[0484] .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) (two NH proton missing)

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

[0485] ##STR00166##

[0486] A solution of 2,2-dimethylpropyl 2-(2-tert-butoxycarbonylhydrazino)ethanesulfonate (1 g) in 3M methanolic hydrogen chloride (24.2 mL) was heated at 70 C. for 7 hours. After cooling to room temperature, the reaction mixture was concentrated to afford [2-(2,2-dimethylpropoxysulfonyl)ethylamino]ammonium chloride as a pink gum that solidified on standing.

[0487] .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) (three NH proton missing)

Step 3: Preparation of 2,2-dimethylpropyl 2-pyridazin-1-ium-1-ylethanesulfonate chloride

[0488] ##STR00167##

[0489] A solution of 2,5-dimethoxy-2,5-dihydrofuran (0.5 g) in acetic acid (2 mL) and water (1 mL) was stirred at room temperature for 4 hours. To this was added a solution of [2-(2,2-dimethylpropoxysulfonyl)ethylamino]ammonium chloride (1.04 g) in water (1 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by silica gel chromatography eluting with 0 to 50% methanol in dichloromethane to afford 2,2-dimethylpropyl 2-pyridazin-1-ium-1-ylethanesulfonate chloride.

[0490] .sup.1H NMR (400 MHz, CDCl.sub.3) 11.11 (d, 1H) 9.45 (d, 1H) 8.96 (ddd, 1H) 8.58 (dd, 1H) 5.68 (t, 2H) 4.30 (t, 2H) 3.99 (s, 2H) 0.98 (s, 9H)

Step 4: Preparation of 2,2-dimethylpropyl 2-(4-oxazol-4-yl-4H-pyridazin-1-yl)ethanesulfonate

[0491] ##STR00168##

[0492] A solution of oxazole (1 g) was stirred in tetrahydrofuran (10 mL) and cooled to 78 C. under nitrogen atmosphere. A solution of n-butyllithium (2.5M in hexanes, 5.8 mL) was added dropwise and the reaction mixture was stirred for 30 minutes. Zinc chloride (0.5M in THF, 9 mL) was added and the reaction mixture was allowed to warm to room temperature. To this was added a solution of 2,2-dimethylpropyl 2-pyridazin-1-ium-1-ylethanesulfonate (3.4 g) and iodocopper (2.5 g) in N,N-dimethylformamide (10 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water and the organic layer was concentrated to give 2,2-dimethylpropyl 2-(4-oxazol-4-yl-4H-pyridazin-1-yl)ethanesulfonate as a dark green gum. This material was used without further purification in the subsequent step.

Step 5: Preparation of 2,2-dimethylpropyl 2-(4-oxazol-4-ylpyridazin-1-ium-1-yl)ethanesulfonate; 2,2,2-trifluoroacetate A-21

[0493] ##STR00169##

[0494] To a solution of crude 2,2-dimethylpropyl 2-(4-oxazol-4-yl-4H-pyridazin-1-yl)ethanesulfonate (5.32 g) in tetrahydrofuran (160 mL) was added 2,3,5,6-tetrachloro-1,4-benzoquinone (4 g) and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated, washed with ethyl acetate and purified by preparative reverse phase HPLC to give 2,2-dimethylpropyl 2-(4-oxazol-4-ylpyridazin-1-ium-1-yl)ethanesulfonate; 2,2,2-trifluoroacetate as a brown gum.

[0495] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.04 (d, 1H) 9.97 (d, 1H) 9.45 (s, 1H) 8.99-8.94 (m, 1H) 8.89 (d, 1H) 5.24 (s, 2H) 4.26 (t, 2H) 3.95 (s, 2H) 0.91 (s, 9H)

Step 6: Preparation of 2-(4-oxazol-4-ylpyridazin-1-ium-1-yl)ethanesulfonate A-22

[0496] A mixture of 2,2-dimethylpropyl 2-(4-oxazol-2-ylpyridazin-1-ium-1-yl)ethanesulfonate 2,2,2-trifluoroacetate (0.2 g), trifluoroacetic acid (3 mL) and anisole (0.6 mL) was heated at 80 C. for 1.5 hours. The reaction mixture was freeze dried and purified by preparative reverse phase HPLC to give 2-(4-oxazol-4-ylpyridazin-1-ium-1-yl)ethanesulfonate as a pale yellow solid.

[0497] .sup.1H NMR (400 MHz, D.sub.2O) 9.70-9.77 (m, 1H) 9.58 (d, 1H) 8.88-8.97 (m, 1H) 8.63-8.70 (m, 1H) 8.35-8.42 (m, 1H) 5.04-5.18 (m, 2H) 3.53-3.71 (m, 2H)

Example 24: Preparation of 3-[4-(thiadiazol-4-yl)pyridazin-1-ium-1-yl]propanoic acid 2,2,2-trifluoroacetate A139

[0498] ##STR00170##

Step 1: Preparation of tert-butyl N-[(E)-1-pyridazin-4-ylethylideneamino]carbamate

[0499] ##STR00171##

[0500] To a solution of 1-pyridazin-4-ylethanone (0.3 g) in 1,4-dioxane (1.5 mL) was added tert-butyl N-aminocarbamate (0.327 g) and the reaction heated at 70 C. for 90 minutes. The reaction mixture was concentrated to give tert-butyl N-[(E)-1-pyridazin-4-ylethylideneamino]carbamate which was used without further purification.

[0501] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.59 (dd, 1H), 9.19 (dd, 1H), 8.00 (s, 1H), 7.77 (dd, 1H), 2.21 (s, 3H), 1.57 (s, 9H)

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

[0502] ##STR00172##

[0503] A solution of tert-butyl N-[(E)-1-pyridazin-4-ylethylideneamino]carbamate (0.25 g) in dichloromethane (4 mL), under nitrogen atmosphere, was cooled to 78 C. and thionyl chloride (0.386 mL) was added dropwise. The reaction was allowed to slowly warm to room temperature. The reaction was diluted with water and extracted with dichloromethane (2). The combined organic layers were concentrated and purified by silica gel chromatography eluting with 0 to 100% ethyl acetate in iso-hexane to afford 4-pyridazin-4-ylthiadiazole.

[0504] .sup.1H NMR (400 MHz, CDCl.sub.3) 10.18 (s, 1H), 9.66 (dd, 1H), 9.08 (dd, 1H), 7.57 (s, 1H)

Step 3: Preparation of 3-[4-(thiadiazol-4-yl)pyridazin-1-ium-1-yl]propanoic acid 2,2,2-trifluoroacetate A139

[0505] A mixture of 4-pyridazin-4-ylthiadiazole (0.08 g), water (5 mL) and 3-bromopropanoic acid (0.298 g) was heated at 100 C. for 2.5 hour. The reaction mixture was cooled, concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid was present in the eluent) to afford 3-[4-(thiadiazol-4-yl)pyridazin-1-ium-1-yl]propanoic acid 2,2,2-trifluoroacetate.

[0506] .sup.1H NMR (400 MHz, CD.sub.3OD) 10.26 (d, 1H), 10.23 (s, 1H), 9.97 (d, 1H), 9.24 (dd, 1H), 5.13 (t, 2H), 3.27 (t, 2H) (CO.sub.2H proton missing)

Example 25: Preparation of 5-pyridazin-4-ylisoxazole

[0507] ##STR00173##

Step 1: Preparation of (E)-3-(dimethylamino)-1-pyridazin-4-yl-prop-2-en-1-one

[0508] ##STR00174##

[0509] To 1-pyridazin-4-ylethanone (0.230 g) was added 1,1-dimethoxy-N,N-dimethyl-methanamine (0.275 mL) and the mixture was heated at reflux for 1 hour, cooled to room temperature and allowed to stand overnight. The combined organic layers were concentrated and purified by silica gel chromatography eluting with 0 to 50% acetonitrile in dichloromethane to afford (E)-3-(dimethylamino)-1-pyridazin-4-yl-prop-2-en-1-one as an orange solid.

[0510] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.57-9.53 (m, 1H), 9.32 (dd, 1H), 7.92 (d, 1H), 7.84 (dd, 1H), 5.66 (d, 1H), 3.24 (s, 3H), 3.00 (s, 3H)

Step 2: Preparation of 5-pyridazin-4-ylisoxazole

[0511] A mixture of (E)-3-(dimethylamino)-1-pyridazin-4-yl-prop-2-en-1-one (0.05 g) and 4M hydrochloric acid in dioxane (1 mL) was heated at reflux for 45 minutes. The mixture was cooled to room temperature and hydroxylamine hydrochloride (0.024 g) was added and then heated at reflux for 12 hours. The reaction mixture was concentrated, dissolved in water (10 mL) and extracted with ethyl acetate (330 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified by silica gel chromatography eluting with 0 to 50% methanol in dichloromethane to afford 5-pyridazin-4-ylisoxazole.

[0512] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.64-9.70 (m, 1H), 9.35 (d, 1H), 8.61 (d, 1H), 8.15 (d, 1H), 7.29 (d, 1H)

Example 26: Preparation of 2-methyl-5-pyridazin-4-y-1,3,4-thiadiazole

[0513] ##STR00175##

Step 1: Preparation of pyridazine-4-carbohydrazide

[0514] ##STR00176##

[0515] To a solution of methyl pyridazine-4-carboxylate (0.4 g) in methanol (4.92 mL) was added hydrazine hydrate (1.12 mL) and the mixture was heated at reflux for 26 hours. The reaction mixture was cooled to room temperature and concentrated to give pyridazine-4-carbohydrazide as a brown solid.

[0516] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.52-9.48 (m, 1H), 9.36 (dd, 1H), 8.00 (dd, 1H) (NH protons missing)

Step 2: Preparation of N-acetylpyridazine-4-carbohydrazide

[0517] ##STR00177##

[0518] A mixture of pyridazine-4-carbohydrazide (2.3 g), acetic acid (23 mL) and acetic anhydride (1.9 mL) was heated at 100 C. for 16 hours. The reaction mass was concentrated and the resulting solid was washed with tert-butyl methyl ether (220 mL) and ethyl acetate (220 mL) and dried under vacuum to give N-acetylpyridazine-4-carbohydrazide.

[0519] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.87 (s, 1H), 10.12 (s, 1H), 9.54 (dd, 1H), 9.47 (dd, 1H), 8.02 (dd, 1H), 1.94 (s, 3H)

Step 3: Preparation of 2-methyl-5-pyridazin-4-yl-1,3,4-thiadiazole

[0520] A microwave vial was charged with N-acetylpyridazine-4-carbohydrazide (0.1 g), 1,4-Dioxane (1 mL), phosphorus pentasulfide (0.123 g) and aluminium oxide (0.084 g) and heated at 140 C. for 1 hour. The reaction mass was quenched in ice cold water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified by silica gel chromatography eluting with 0 to 15% methanol in dichloromethane to afford 2-methyl-5-pyridazin-4-yl-1,3,4-thiadiazole.

[0521] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.76 (dd, 1H), 9.43 (dd, 1H), 8.18 (dd, 1H), 2.85 (s, 3H)

Example 27: Preparation of 3-[4-(1,2,4-thiadiazol-3-yl)pyridazin-1-ium-1-yl]propanoic acid 2,2,2-trifluoroacetate A142

[0522] ##STR00178##

Step 1: Preparation of pyridazine-4-carboxamidine hydrochloride

[0523] ##STR00179##

[0524] To a mixture of pyridazine-4-carbonitrile (3.5 g) in methanol (18 mL) was added sodium methoxide (25% in methanol, 0.78 mL) at room temperature and the reaction mixture was stirred for 3 hours. To this mixture was added ammonium chloride (2 g) and stirring was continued at room temperature for a further 18 hours. The reaction mixture was concentrated and the resulting residue was washed with tert-butyl methyl ether to give pyridazine-4-carboxamidine hydrochloride as a brown solid.

[0525] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.58-9.60 (m, 2H), 8.12-8.14 (m, 1H)

Step 2: Preparation of 3-pyridazin-4-yl-4H-1,2,4-thiadiazole-5-thione

[0526] ##STR00180##

[0527] To a mixture of pyridazine-4-carboxamidine hydrochloride (50 mg), carbon disulfide (0.5M in THF, 2 mL), sulfur (0.013 g) and methanol (0.5 mL) was added sodium methoxide (25% in methanol, 0.144 mL) and the reaction was heated at 60 C. for 5 hours. The reaction mixture was concentrated and purified by silica gel chromatography eluting with ethyl acetate in methanol to give 3-pyridazin-4-yl-4H-1,2,4-thiadiazole-5-thione as dark brown solid.

[0528] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H) 9.33 (dd, 1H) 8.12 (dd, 1H)

Step 3: Preparation of 3-pyridazin-4-yl-1,2,4-thiadiazole

[0529] ##STR00181##

[0530] A mixture of 3-pyridazin-4-yl-4H-1,2,4-thiadiazole-5-thione (0.5 g) and acetic acid (12.74 mL) was cooled to 15 C. and hydrogen peroxide (1.56 mL) was added drop wise. The mixture was stirred at room temperature for 3 hours, when further hydrogen peroxide (1.56 mL) was added. After a further 2 hours stirring the reaction mixture was quenched with sodium metabisulfite solution, neutralised and extracted with ethyl acetate (350 mL). The combined organic phases were dried over anhydrous sodium sulfate and purified by silica gel chromatography eluting with ethyl acetate to give 3-pyridazin-4-yl-1,2,4-thiadiazole.

[0531] .sup.1H NMR (400 MHz, CDCl.sub.3) 10.09 (dd, 1H), 10.01 (s, 1H), 9.41 (dd, 1H), 8.33 (dd, 1H)

Step 4: Preparation of 3-[4-(1,2,4-thiadiazol-3-yl)pyridazin-1-ium-1-yl]propanoic acid 2,2,2-trifluoroacetate A142

[0532] To a solution of 3-pyridazin-4-yl-1,2,4-thiadiazole (0.2 g) in acetonitrile (8 mL) was added 3-bromopropanoic acid (0.224 g) and the mixture heated at reflux for 30 hours. The reaction mixture was cooled, concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid was present in the eluent) to afford 3-[4-(1,2,4-thiadiazol-3-yl)pyridazin-1-ium-1-yl]propanoic acid 2,2,2-trifluoroacetate.

[0533] .sup.1H NMR (400 MHz, D.sub.2O) 10.35 (s, 1H), 10.19 (d, 1H), 9.90 (d, 1H), 9.18 (dd, 1H), 5.14 (t, 2H), 3.26 (t, 2H) (CO.sub.2H proton missing)

[0534] 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.

[0535] NMR spectra contained herein were recorded on a (400 MHz Bruker AVANCE III HD equipped with 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 abroad signal and app. is used to describe an apparent multiplicity.

TABLE-US-00065 TABLE A Physical Data for Compounds of the Invention Compound Number Structure .sup.1H NMR A1 [00182] (400 MHz, D.sub.2O) 9.84-9.94 (m, 1H) 9.63-9.72 (m, 1H) 8.82 (dd, 1H) 8.14- 8.25 (m, 1H) 8.08 (d, 1H) 5.09-5.19 (m, 2H) 3.54-3.68 (m, 2H) A2 [00183] (400 MHz, D.sub.2O) 9.67 (d, 1H) 9.45 (d, 1H) 8.55 (dd, 1H) 7.71 (d, 1H) 7.09(d, 1H) 5.10-5.01 (m, 2H) 3.94 (s, 3H) 3.64-3.54 (m, 2H) A3 [00184] (400 MHz, D.sub.2O) 9.83-9.95 (m, 1H) 9.73 (d, 1H) 8.86 (dd, 1H) 8.08-8.31 (m, 1H) 7.49-7.71 (m, 1H) 4.85-5.08 (m, 2H), 2.85-3.16 (m, 2H) 2.50 (quin, 2H) A4 [00185] (400 MHz, D.sub.2O) 9.52-9.69 (m, 2H) 8.52-8.67 (m, 1H) 7.59-7.70 (m, 1H) 7.03 (d, 1H) 4.92 (t, 2H) 3.93-4.15 (m, 3H) 2.89-3.02 (m, 2H) 2.39-2.62 (m, 2H) A5 [00186] (400 MHz, D.sub.2O) 9.73-9.79 (m, 1H) 9.62-9.74 (m, 1H) 8.72-8.81 (m, 1H) 8.58-8.69 (m, 1H) 8.04-8.23 (m, 1H) 5.17 (t, 2H) 3.53-3.77 (m, 2H) A6 [00187] (400 MHz, D.sub.2O) 9.74-9.92 (m, 1H) 9.54-9.69 (m, 1H) 8.64-8.85 (m, 1H) 8.41-8.60 (m, 1H) 5.09-5.24 (m, 2H) 4.18-4.40 (m, 3H) 3.56-3.76 (m, 2H) A7 [00188] (400 MHz, D.sub.2O) 10.06-10.03 (m, 1H) 9.95-9.92 (m, 1H) 9.24-9.21 (m, 1H) 9.11-9.07 (m, 1H) 5.06-5.01 (m, 2H) 3.03-2.94 (m, 2H) 2.60-2.47 (m, 2H) [isolated as a 1:1 mixture of isomers with 10.50-10.47 (m, 1H) 9.70-9.66 (m, 1H) 9.20-9.17 (m, 1H) 9.03-8.99 (m, 1H) 5.12-5.06 (m, 1H) 3.03-2.94 (m, 2H) 2.60-2.47 (m, 2H)] A8 [00189] (400 MHz, DMSO-d.sub.6) 10.32-10.28 (m, 1H) 10.18-10.12 (m, 1H) 9.55-9.54 (m, 1H) 9.43-9.38 (m, 1H) 5.26-5.14 (m, 2H) 4.43-4.33 (m, 2H) [isolated as a 1:1 mixture of isomers with 10.72 (s, 1H) 9.95-9.90 (m, 1H) 9.53-9.52 (m, 1H) 9.27-9.22 (m, 1H) 5.26-5.14 (m, 2H) 4.43-4.33 (m, 2H)] A9 [00190] (400 MHz, D.sub.2O) 10.00-10.06 (m, 1H) 9.91 (d, 1H) 9.07 (dd, 1H) 8.94-9.13 (m, 1H) 5.17-5.28 (m, 2H) 3.62-3.71 (m, 2H) A10 [00191] (400 MHz, D.sub.2O) 9.92-9.97 (m, 1H) 9.83-9.90 (m, 1H) 8.96-9.01 (m, 1H) 5.15-5.27 (m, 2H) 3.56-3.70 (m, 2H) 2.71 (s, 3H) A11 [00192] (400 MHz, D.sub.2O) 10.09 (d, 1H) 9.89 (d, 1H) 8.98-9.15 (m, 1H) 5.10-5.39 (m, 2H) 4.51 (s, 3H) 3.49-3.75 (m, 2H) (one SO.sub.3H proton missing) A12 [00193] (400 MHz, D.sub.2O) 10.01-10.08 (m, 2H) 9.10 (d, 1H) 5.30-5.38 (m, 2H) 4.40 (s, 3H) 3.69-3.77 (m, 2H) (one SO.sub.3H proton missing) A13 [00194] (400 MHz, D.sub.2O) 9.86 (d, 1H) 9.66 (d, 1H) 8.78 (dd, 1H) 7.72 (s, 1H) 5.16 (t, 2H) 3.66 (t, 2H) 2.52 (s, 3H) A14 [00195] (400 MHz, D.sub.2O) 9.74-9.78 (m, 1H) 9.66 (d, 1H) 8.68 (dd, 1H) 5.11-5.18 (m, 2H) 3.61-3.68 (m, 2H) 2.40 (s, 3H) 2.18 (s, 3H) A15 [00196] (400 MHz, D.sub.2O) 9.82 (d, 1H) 9.74 (d, 1H) 8.77 (dd, 1H) 7.29 (d, 1H) 5.06 (t, 2H) 3.23 (t, 2H) 2.47 (d, 3H) (one CO.sub.2H proton missing) A16 [00197] (400 MHz, D.sub.2O) 9.88-9.92 (m, 2H) 8.92 (dd, 1H) 8.21 (s, 1H) 5.20-5.23 (m, 2H) 4.17 (s, 3H) 3.63-3.75 (m, 2H) A17 [00198] (400 MHz, D.sub.2O) 9.76 (s, 1H) 9.57 (d, 1H) 8.65 (d, 1H) 5.13 (t, 2H) 3.66 (t, 2H) 2.51 (s, 3H) 2.42 ppm (s, 3H) A18 [00199] (400 MHz, D.sub.2O) 9.96 (m, 1H) 9.77 (d, 1H) 8.93 (dd, 1H) 8.60 (s, 1H) 5.16 (t, 2H) 3.64 (t, 2H) A19 [00200] 400 MHz, D.sub.2O) 10.01-9.93 (m, 1H) 9.88-9.78 (m, 1H) 8.97-8.90 (m, 1H) 8.33-8.26 (m, 1H) 7.69-7.62 (m, 1H) 5.29-5.19 (m, 2H) 3.75-3.65 (m, 2H) A20 [00201] (400 MHz, CD.sub.3OD) 9.89 (s, 1H) 9.78 (d, 1H) 9.16 (s, 1H) 8.83 (dd, 1H) 8.52 (s, 1H) 5.07 (t, 2H) 4.14 (q, 2H) 3.24 (t, 2H) 1.23 (t, 3H) A21 [00202] (400 MHz, DMSO-d.sub.6) 10.04 (d, 1H) 9.97 (d, 1H) 9.45 (s, 1H) 8.99-8.94 (m, 1H) 8.89 (d, 1H) 5.24 (s, 2H) 4.26 (t, 2H) 3.95 (s, 2H) 0.91 (s, 9H) A22 [00203] (400 MHz, D.sub.2O) 9.70-9.77 (m, 1H) 9.58 (d, 1H) 8.88-8.97 (m, 1H) 8.63- 8.70 (m, 1H) 8.35-8.42 (m, 1H) 5.04- 5.18 (m, 2H) 3.53-3.71 (m, 2H) A23 [00204] (400 MHz, D.sub.2O) 9.84 (m, 1H) 9.60 (m, 1H) 8.75 (br d, 1H) 7.71 (br s, 1H) 5.11 (br s, 2H) 3.61 (br s, 2H) 3.16 (br s, 1H) 1.25 (d, 6H) A24 [00205] (400 MHz, CDCl.sub.3) 9 86 (s, 1H) 9.67 (m, 1H) 8.79 (m, 1H) 7.75 (m, 1H) 5.01 (m, 2H) 3.17 (br t, 3H) 1.31 (d, 6H) (one CO.sub.2H proton missing) A25 [00206] (400 MHz, D.sub.2O) 9.88 (d, 1H) 9.73 (d, 1H) 8.83 (dd, 1H) 7.96 (s, 1H) 5.18 (t, 2H) 3.66 (t, 2H) A26 [00207] (400 MHz, D.sub.2O) 9.83 (s, 1H) 9.64 (d, 1H) 8.75 (dd, 1H) 7.11 (s, 1H) 5.12- 5.18 (m, 2H) 3.98 (s, 3H) 3.65-3.69 (m, 2H) A27 [00208] (400 MHz, D.sub.2O) 9.94 (d, 1H) 9.86-9.90 (m, 1H) 8.93 (dd, 1H) 8.23 (s, 1H) 5.16 (t, 2H) 4.18 (s, 3H) 3.26 (t, 2H) (one CO.sub.2H proton missing) A28 [00209] (400 MHz, D.sub.2O) 10.06 (d, 1H) 9.90 (d, 1H) 9.09 (d, 1H) 5.13 (dd, 2H) 4.51 (br s, 3H) 3.26 (dd, 2H) (one CO.sub.2H proton missing) A29 [00210] (400 MHz, D.sub.2O) 9.76-9.70 (m, 1H) 9.54 (d, 1H) 8.64 (dd, 1H) 7.57 (s, 1H) 5.09 (t, 2H) 4.05 (s, 3H) 3.59 (t, 2H) A30 [00211] (400 MHz, CD.sub.3OD) 9.91-9.86 (m, 1H) 9.85-9.80 (m, 1H) 8.83 (dd, 1H) 7.54 (s, 1H) 5.27-5.20 (m, 2H) 4.27 (s, 3H) 3.60-3.53 (m, 2H) A31 [00212] (400 MHz, D.sub.2O) 9.71-9.90 (m, 2H) 8.67-8.81 (m, 1H) 7.59-7.69 (m, 1H) 7.54 (d, 1H) 5.07 (t, 2H) 3.95-4.07 (m, 3H) 3.13-3.31 (m, 2H) (one CO.sub.2H proton missing) A32 [00213] (400 MHz, D.sub.2O) 9.84-9.92 (m, 1H) 9.74-9.82 (m, 1H) 8.77-8.90 (m, 1H) 8.14-8.28 (m, 1H) 7.51-7.62 (m, 1H) 4.94-5.15 (m, 2H) 3.10-3.26 (m, 2H) (one CO.sub.2H proton missing) A33 [00214] (400 MHz, D.sub.2O) 9.71 (d, 1H) 9.64 (s, 1H) 8.65 (s, 1H) 7.47 (s, 1H) 5.04 (t, 2H) 3.99 (s, 3H) 3.20 (t, 2H) (one CO.sub.2H proton missing) A34 [00215] (400 MHz, D.sub.2O) 9.69 (d, 1H) 9.67 (d, 1H) 8.65 (dd, 1H) 7.48 (s, 1H) 5.16 (t, 2H) 3.99 (s, 3H) 3.63 (t, 2H) A35 [00216] (400 MHz, D.sub.2O) 9.62 (m, 2H) 9.52 (s, 1H) 8.58 (dd, 1H) 5.14 (t, 2H) 3.63 (t, 2H) 2.61 (s, 3H) A36 [00217] (400 MHz, D.sub.2O) 9.63 (d, 1H) 9.38 (d, 1H) 8.47 (dd, 1H) 8.17 (dd, 1H) 8.04 (dd, 1H) 7.36 (dd, 1H) 5.05 (t, 2H) 3.63 ppm (t, 2H) A37 [00218] (400 MHz, D.sub.2O) 9.87 (d, 1H) 9.71 (d, 1H) 8.84 (d, 1H) 8.64 (s, 1H) 5.02 (t, 2H) 3.18 (t, 2H) (one NH proton and one CO.sub.2H proton missing) A38 [00219] (400 MHz, D.sub.2O) 10.00 (d, 1H) 9.77 (d, 1H) 8.94 (dd, 1H) 8.73 (s, 1H) 5.22 (t, 2H) 3.69 (t, 2H) (one NH proton missing) A39 [00220] (400 MHz, D.sub.2O) 9.96 (d, 1H) 9.76 (d, 1H) 8.90 (dd, 1H) 8.62 (s, 1H) 5.22 (t, 2H) 4.06 (s, 3H) 3.69 (t, 2H) A40 [00221] (400 MHz, D.sub.2O) 9.86 (d, 1H) 9.77 (d, 1H) 8.82 (dd, 1H) 8.00 (s, 1H) 5.20 (t, 2H) 3.67 (t, 2H) 2.27 (s, 3H) A41 [00222] (400 MHz, D.sub.2O) 9.61 (d, 1H) 9.41 (m, 1H) 8.47 (m, 1H) 8.16 (m, 1H) 8.05 (d, 1H) 7.37 (m, 1H) 5.01-4.89 (m, 2H) 3.23-3.12 (m, 2H) (one CO.sub.2H proton missing) A42 [00223] (400 MHz, D.sub.2O) 9.55 (d, 1H) 9.40 (d, 1H) 8.53 (d, 1H) 8.42 (dd, 1H) 7.70 (s, 1H) 7.05 (dd, 1H) 5.04 (m, 2H) 3.60 (m, 2H) A43 [00224] (400 MHz, D.sub.2O) 9.57 (d, 1H) 9.46 (d, 1H) 8.56 (s, 1H) 8.47 (dd, 1H) 7.74 (m, 1H) 7.09 (dd, 1H) 4.97 (t, 2H) 3.22 (t, 2H) (one CO.sub.2H proton missing) A44 [00225] (400 MHz, D.sub.2O) 9.90 (d, 1H) 9.73 (d, 1H) 8.81 (dd, 1H) 8.13 (s, 1H) 5.17- 5.22 (m, 2H) 3.66-3.71 (m, 2H) A45 [00226] (400 MHz, D.sub.2O) 9.82 (d, 1H) 9.63 (d, 1H) 8.58 (dd, 1H) 5.10-5.19 (m, 2H) 3.62-3.69 (m, 2H) 3.08 (s, 3H) (one NH proton missing) A46 [00227] (400 MHz, D.sub.2O) 9.89 (s, 1H) 9.77 (d, 1H) 8.86 (dd, 1H) 7.99 (s, 1H) 5.09 (t, 2H) 3.25 (t, 2H) (one CO.sub.2H proton missing) A47 [00228] (400 MHz, D.sub.2O) 9.80 (d, 1H) 9.67 (d, 1H) 8.60 (dd, 1H) 5.04 (t, 2H) 3.24 (t, 2H) (two NH protons and one CO.sub.2H proton missing) A48 [00229] (400 MHz, D.sub.2O) 9.76-9.82 (m, 1H) 9.65-9.72 (m, 1H) 8.68-8.79 (m, 1H) 8.37-8.43 (m, 1H) 5.02-5.13 (m, 2H) 4.22-4.34 (m, 3H) 3.18-3.25 (m, 2H) (one CO.sub.2H proton missing) A49 [00230] (400 MHz, D.sub.2O) 9.71-9.96 (m, 2H) 8.76-8.98 (m, 1H) 8.43-8.61 (m, 1H) 5.19-5.42 (m, 2H) 4.29-4.51 (m, 3H) 3.63-3.85 (m, 2H) A50 [00231] (400 MHz, D.sub.2O) 9.95 (d, 1H) 9.90-9.92 (d, 1H) 8.92-8.96 (m, 1H) 8.89 (s, 1H) 5.23-5.35 (m, 2H) 4.04 (s, 3H) 3.67- 3.73 (m, 2H) A51 [00232] (400 MHz, D.sub.2O) 9.92 (d, 1H) 9.77 (d, 1H) 8.88 (dd, 1H) 8.61 (s, 1H) 5.10 (t, 2H) 4.05 (s, 3H) 3.26 (t, 2H) (one CO.sub.2H proton missing) A52 [00233] (400 MHz, D.sub.2O) 9.56 (d, 1H) 9.40 (d, 1H) 8.41 (dd, 1H) 7.98 (d, 1H) 7.73 (d, 1H) 6.82 (dd, 1H) 4.93 (t, 2H) 3.18 (t, 2H) (one CO.sub.2H proton missing) A53 [00234] (400 MHz, D.sub.2O) 9.58 (d, 1H) 9.38 (d, 1H) 8.41 (dd, 1H) 7.98 (d, 1H) 7.75 (d, 1H) 6.82 (dd, 1H) 5.02-5.07 (m, 2H) 3.60-3.64 (m, 2H) A54 [00235] (400 MHz, D.sub.2O) 9.73 (dd, 1H) 9.59 (dd, 1H) 8.61 (dd, 1H) 5.20 (t, 2H) 3.67 (t, 2H) 2.44 (s, 3H) 2.35 (s, 3H) A55 [00236] (400 MHz, D.sub.2O) 9.85 (d, 1H) 9.80 (d, 1H) 8.83 (dd, 1H) 8.01 (s, 1H) 5.10 (t, 2H) 3.26 (t, 2H) 2.28 (s, 3H) (one CO.sub.2H proton missing) A56 [00237] (400 MHz, D.sub.2O) 9.99 (d, 1H) 9.95 (d, 1H) 9.02 (dd, 1H) 8.80 (s, 1H) 5.15 (t, 2H) 3.26 (t, 2H) (one CO.sub.2H proton missing) A57 [00238] (400 MHz, D.sub.2O) 10.03 (d, 1H) 9.95 (d, 1H) 9.04 (dd, 1H) 8.81 (s, 1H) 5.29 (t, 2H) 3.72 (t, 2H) A58 [00239] (400 MHz, D.sub.2O) 9.76 (d, 1H) 9.58 (d, 1H) 8.61 (dd, 1H) 5.09 (t, 2H) 3.24 (t, 2H) 2.45 (s, 3H) 2.35 (s, 3H) (one CO.sub.2H proton missing) A59 [00240] (400 MHz, D.sub.2O) 9.92-9.86 (m, 1H) 9.80-9.71 (m, 1H) 8.89 (dd, 1H) 8.86 (d, 1H) 7.22 (d, 1H) 4.98 (t, 2H) 2.96 (t, 2H) 2.51 (quin, 2H) A60 [00241] (400 MHz, D.sub.2O) 9.87 (s, 1H) 9.80 (d, 1H) 9.61 (d, 1H) 9.19 (s, 1H) 8.74 (dd, 1H) 5.12-5.17 (m, 2H) 3.63-3.68 (m, 2H) A61 [00242] (400 MHz, D.sub.2O) 9.91 (d, 1H) 9.62 (d, 1H) 9.21 (d, 1H) 8.79-8.85 (m, 2H) 5.16 (t, 2H) 3.67 (t, 2H) A62 [00243] (400 MHz, D.sub.2O) 9.87 (s, 1H) 9.79 (d, 1H) 9.64 (d, 1H) 9.19 (s, 1H) 8.74 (dd, 1H) 5.04 (t, 2H) 3.24 (t, 2H) (one CO.sub.2H proton missing) A63 [00244] (400 MHz, D.sub.2O) 9.67 (d, 1H) 9.48 (d, 1H) 8.52-8.58 (m, 2H) 7.75 (d, 1H) 7.68 (dd, 1H) 4.97 (t, 2H) 3.20 (t, 2H) (one CO.sub.2H proton missing) A64 [00245] (400 MHz, D.sub.2O) 9.91-9.87 (m, 1H) 9.82-9.77 (m, 1H) 8.89 (dd, 1H) 8.85 (d, 1H) 7.22 (d, 1H) 5.19 (t, 2H) 3.65 (t, 2H) A65 [00246] (400 MHz, D.sub.2O) 9.89 (d, 1H), 9.70 (d, 1H), 8.65-8.68 (m, 1H), 5.22 (t, 2H), 3.67-3.75 ppm (m, 2H) (NH protons missing) A66 [00247] (400 MHz, D.sub.2O) 9.92 (s, 1H) 9.76 (d, 1H) 8.94-8.98 (m, 1H) 8.26 (s, 1H) 7.62 (s, 1H) 5.78 (s, 3H) 3.78 (s, 2H) A67 [00248] (400 MHz, D.sub.2O) 9.90 (s, 1H) 9.72 (d, 1H) 8.86-8.90 (m, 1H) 8.22 (s, 1H) 7.58 (s, 1H) 5.06-5.12 (m, 2H) 4.52- 4.58 (m, 2H) A68 [00249] (400 MHz, D.sub.2O) 9.88 (s, 1H) 9.71 (d, 1H) 8.84-8.88 (m, 1H) 8.20 (s, 1H) 7.56 (s, 1H) 4.80-4.88 (m, 2H) 2.86- 2.92 (m, 2H) 2.14-2.24 (m, 2H) 1.70- 1.78 (m, 2H) A69 [00250] (400 MHz, D.sub.2O) 9.88 (s, 1H) 9.74 (d, 1H) 8.84-8.90 (m, 1H) 8.23 (s, 1H) 7.58 (s, 1H) 4.82-4.88 (m, 2H) 3.59 (s, 3H) 2.46-2.54 (m, 2H) 2.30-2.40 (m, 2H) A70 [00251] (400 MHz, D.sub.2O) 9.88 (s, 1H) 9.74 (d, 1H) 8.84-8.88 (m, 1H) 8.21 (s, 1H) 7.58 (s, 1H) 4.88-4.94 (m, 2H) 3.60- 3.68 (m, 2H) 2.22-2.31 (m, 2H) (one OH proton missing) A71 [00252] (400 MHz, D.sub.2O) 9.86 (d, 1H) 9.66 (d, 1H) 8.90 (dd, 1H) 8.21 (s, 1H) 7.57 (s, 1H) 5.50 (s, 2H) (one CO2H proton missing) A72 [00253] (400 MHz, D.sub.2O) 9.86 (d, 1H) 9.66 (dd, 1H) 8.90 (dd, 1H) 8.22 (s, 1H) 7.63- 7.50 (m, 1H) 5.51-5.44 (m, 2H) 2.98- 2.94 (m, 3H) A73 [00254] (400 MHz, D.sub.2O) 9.94 (d, 1H) 9.82 (d, 1H) 8.93 (dd, 1H) 8.23 (s, 1H) 7.59 (s, 1H) 5.22-5.14 (m, 2H) 3.79-3.73 (m, 2H) (one NH proton missing) A74 [00255] (400 MHz, D.sub.2O) 9.87 (d, 1H) 9.77-9.71 (m, 1H) 8.86 (dd, 1H) 8.21 (s, 1H) 7.57 (s, 1H) 4.90-4.82 (m, 2H) 3.17 (s, 3H) 2.59-2.51 (m, 2H) 2.42-2.32 (m, 2H) A75 [00256] (400 MHz, D.sub.2O) 9.97-9.88 (m, 1H) 9.78 (d, 1H) 8.90 (dd, 1H) 8.23 (d, 1H) 7.59 (d, 1H) 5.14-5.00 (m, 2H) 4.05 (qd, 4H) 2.77 (td, 2H) 1.23-1.12 (m, 6H) A76 [00257] (400 MHz, D.sub.2O) 9.89 (d, 1H) 9.71 (d, 1H) 8.87 (dd, 1H) 8.21 (d, 1H) 7.58 (d, 1H) 4.90-4.83 (m, 2H) 3.69 (s, 3H) 3.66 (s, 3H) 2.40-2.26 (m, 2H) 2.05- 1.93 (m, 2H) A77 [00258] (400 MHz, D.sub.2O) 9.87-9.83 (m, 1H) 9.74-9.69 (m, 1H) 8.85-8.80 (m, 1H) 8.20-8.17 (m, 1H) 7.57-7.53 (m, 1H) 5.00-4.90 (m, 2H) 2.42-2.31 (m, 2H) (two OH protons missing) A78 [00259] (400 MHz, D.sub.2O) 9.87 (d, 1H) 9.72 (d, 1H) 8.85 (dd, 1H) 8.20 (s, 1H) 7.56 (s, 1H) 4.86 (br t, 2H) 2.35-2.21 (m, 2H) 1.74-1.59 (m, 2H) (two OH protons missing) A79 [00260] (400 MHz, D.sub.2O) 9.92 (d, 1H) 9.85 (d, 1H) 8.91 (dd, 1H) 8.74 (d, 1H) 7.59 (d, 1H) 5.24-5.28 (m, 2H) 3.70-3.74 (m, 2H) A80 [00261] (400 MHz, D.sub.2O) 9.83 (d, 1H), 9.66 (d, 1H), 8.87 (s, 1H), 8.78 (dd, 1H), 5.06 (t, 2H), 4.22 (s, 3H), 3.25 (t, 2H) (CO.sub.2H proton missing) A81 [00262] (400 MHz, D.sub.2O) 9.87 (d, 1H), 9.66 (d, 1H), 8.90 (s, 1H), 8.80 (dd, 1H), 5.19 (m, 2H), 4.24 (s, 3H), 3.70 (m, 2H) A82 [00263] (400 MHz, D.sub.2O) 9.87 (d, 1H), 9.74 (d, 1H), 9.09 (s, 1H), 8.81 (dd, 1H), 8.36 (s, 1H), 5.14 (t, 2H), 4.13 (s, 3H), 3.29 (t, 2H) (CO.sub.2H proton missing) A83 [00264] (400 MHz, D.sub.2O) 9.89 (d, 1H) 9.63 (d, 1H) 8.84 (dd, 1H) 8.23-8.18 (m, 1H) 7.57 (s, 1H) 5.18-5.08 (m, 1H) 3.53- 3.33 (m, 2H) 1.64 (d, 3H) (one NH proton missing) A84 [00265] (400 MHz, D.sub.2O) 9.93-9.88 (m, 1H) 9.70-9.66 (m, 1H) 8.92-8.86 (m, 1H) 8.24- 8.21 (m, 1H) 7.60-7.57 (m, 1H) 5.16-5.07 (m, 1H) 4.88-4.78 (m, 2H) 3.25-3.15 (m, 2H) (one OH proton missing) A85 [00266] (400 MHz, D.sub.2O) 9.92-9.87 (m, 1H) 9.78-9.71 (m, 1H) 8.91-8.84 (m, 1H) 8.22 (s, 1H) 7.58 (d, 1H) 5.00-4.90 (m, 2H) 3.86-3.73 (m, 2H) 2.45-2.33 (m, 2H) 1.13-1.07 (m, 3H) (one OH proton missing) A86 [00267] (400 MHz, D.sub.2O) 9.88-9.83 (m, 1H), 9.73-9.67 (m, 1H), 8.88-8.80 (m, 1H), 8.19 (s, 1H), 7.55 (s, 1H), 4.88- 4.78 (m, 2H), 3.46 (d, J = 10.5 Hz, 3H), 2.35-2.17 (m, 2H), 1.74-1.57 (m, 2H) (one OH proton missing) A87 [00268] (400 MHz, D.sub.2O) 9.90 (d, 1H) 9.68 (dd, 1H) 8.92 (dd, 1H) 8.56 (s, 1H) 5.75 (s, 2H) 4.00 (s, 3H) 3.76 (s, 3H) A88 [00269] (400 MHz, D.sub.2O) 9.84 (d, 1H) 9.66 (d, 1H) 8.86-8.80 (m, 1H) 8.19 (s, 1H) 7.55 (s, 1H) 4.95-4.76 (m, 2H) 3.18- 3.06 (m, 1H) 1.18 (d, 3H) (one CO.sub.2H proton missing) A89 [00270] (400 MHz, D.sub.2O) 9.87-9.82 (m, 1H) 9.65-9.58 (m, 1H) 8.88-8.81 (m, 1H) 8.20 (s, 1H) 7.57 (s, 1H) 4.96-4.88 (m, 1H) 4.58-4.49 (m, 1H) 3.87-3.74 (m, 1H) 1.31 (d, 3H) (one NH proton missing) A90 [00271] (400 MHz, D.sub.2O) 9.92-9.89 (m, 1H) 9.78-9.73 (m, 1H) 8.94-8.89 (m, 1H) 8.26-8.24 (m, 1H) 7.62-7.60 (m, 1H) 5.77 (q, 1H) 1.91 (d, 3H) (one CO.sub.2H proton missing) A91 [00272] (400 MHz, D.sub.2O) 9.74 (d, 1H) 9.63 (d, 1H) 8.79 (dd, 1H) 8.18 (s, 1H) 8.03 (dd, 1H) 7.68-7.53 (m, 4H) 6.22 (s, 2H) (one CO.sub.2H proton missing) A92 [00273] (400 MHz, DMSO-d.sub.6) 10.21 (d, 1H) 10.06 (d, 1H) 9.11 (dd, 1H) 8.72 (s, 1H) 8.24 (s, 1H) 8.02 (d, 1H) 7.88-7.83 (m, 2H) 7.63 (t, 1H) 6.17 (s, 2H) 3.87 (s, 3H) A93 [00274] (400 MHz, D.sub.2O) 9.95-9.88 (m, 1H) 9.84-9.75 (m, 1H) 9.00-8.89 (m, 1H) 8.24 (s, 1H) 7.60 (s, 1H) 6.04-5.92 (m, 1H) 3.73 (s, 3H) 1.93 (br d, 3H) A94 [00275] (400 MHz, D.sub.2O) 9.93 (d, 1H) 9.76 (d, 1H) 8.97-8.91 (m, 1H) 8.25 (s, 1H) 7.61 (s, 1H) 5.62-5.53 (m, 2H) 3.86- 3.80 (m, 6H) A95 [00276] (400 MHz, DMSO-d.sub.6) 10.10-10.04 (m, 1H) 10.03-9.99 (m, 1H) 9.09 (dd, 1H) 8.73 (s, 1H) 8.15-7.97 (m, 1H) 7.85 (s, 1H) 7.79-7.70 (m, 1H) 7.70-7.56 (m, 2H) 6.39 (s, 2H) 3.82 (s, 3H) A96 [00277] (400 MHz, D.sub.2O) 9.87 (m, 2H), 8.89 (m, 1H), 8.74 (m, 1H), 7.58 (m, 1H), 5.13 (m, 2H), 3.32 (m,2H) (CO.sub.2H proton missing) A97 [00278] (400 MHz, D.sub.2O) 10.01 (s, 1H), 9.77 (br d, 1H), 9.16 (d, 1H), 8.93 (dd, 1H), 8.18 (d, 1H), 5.09 (br t, 2H), 3.26 (br t, 2H) (CO.sub.2H proton missing) A98 [00279] (400 MHz, D.sub.2O) 10.05 (dd, 1H), 9.95 (d, 1H), 9.02 (dd, 1H), 5.20 (t, 2H), 3.34 (t, 2H), 2.96 (s, 3H) (CO.sub.2H proton missing) A99 [00280] (400 MHz, D.sub.2O) 9.98 (dd, 1H), 9.83 (d, 1H), 8.93 (dd, 1H), 5.19-5.25 (m, 2H), 3.63-3.70 (m, 2H), 2.87 (s, 3H) A100 [00281] (400 MHz, D.sub.2O) 9.90 (d, 1H), 9.65 (d, 1H), 9.23 (d, 1H), 8.79-8.85 (m, 2H), 5.05 (t, 2H), 3.25 (t, 2H) (CO.sub.2H proton missing) A101 [00282] (400 MHz, D.sub.2O) 9.83 (d, 1H) 9.59 (d, 1H) 8.84 (dd, 1H) 8.21 (s, 1H) 7.57 (s, 1H) 4.90 (dd, 1H) 4.62-4.52 (m, 1H) 4.13-4.02 (m, 1H) 3.30-3.17 (m, 2H) 2.19-2.04 (m, 1H) 2.01-1.70 (m, 3H) A102 [00283] (400 MHz, D.sub.2O) 9.91-9.86 (m, 1H) 9.69-9.63 (m, 1H) 8.95-8.88 (m, 1H) 8.28-8.22 (m, 1H) 7.64-7.57 (m, 1H) 5.09 (d, 2H) (one POH proton missing) A103 [00284] (400 MHz, D.sub.2O) 9.91-9.83 (m, 1H) 9.68-9.58 (m, 1H) 8.97-8.83 (m, 1H) 8.27-8.18 (m, 1H) 7.65-7.54 (m, 1H) 5.18-5.07 (m, 2H) 3.64-3.54 (m, 3H) A104 [00285] (400 MHz, D.sub.2O) 9.81 (br d, 2H) 8.86 (dd, 1H) 8.21 (s, 1H) 8.08 (s, 1H) 8.02- 7.95 (m, 1H) 7.78-7.71 (m, 1H) 7.60- 7.56 (m, 1H) 7.52 (s, 1H) 6.04 (s, 2H) (one CO.sub.2H proton missing) A105 [00286] (400 MHz, D.sub.2O) 10.04 (d, 1H), 9.76 (d, 1H), 9.16 (d, 1H), 8.94 (dd, 1H), 8.19 (d, 1H), 5.21 (t, 2H), 3.70 (t, 2H) A106 [00287] (400 MHz, D.sub.2O) 9.94-9.91 (m, 1H) 9.79-9.75 (m, 1H) 8.91-8.87 (m, 1H) 8.26-8.23 (m, 1H) 7.62-7.60 (m, 1H) 5.04-4.93 (m, 2H) 3.47 (d, 3H) 2.49- 2.37 (m, 2H) (one POH proton missing) A107 [00288] (400 MHz, DMSO-d.sub.6) 10.16-10.10 (m, 2H) 8.98 (dd, 1H) 8.74 (s, 1H) 7.87 (s, 1H) 3.28 (s, 2H) 1.91-1.83 (m, 6H) (one CO.sub.2H proton missing) A108 [00289] (400 MHz, D.sub.2O) 9.95-9.92 (m, 1H) 9.81-9.77 (m, 1H) 8.94-8.88 (m, 1H) 8.26-8.23 (m, 1H) 7.61 (d, 1H) 5.14- 5.04 (m, 2H) 3.73-3.67 (m, 6H) 2.87- 2.76 (m, 2H) A109 [00290] (400 MHz, D.sub.2O) 9.95-9.91 (m, 1H) 9.80-9.74 (m, 1H) 8.93-8.88 (m, 1H) 8.24 (s, 1H) 7.62-7.58 (m, 1H) 5.11- 5.04 (m, 2H) 4.32-4.25 (m, 1H) 3.79 (s, 3H) 2.84-2.61 (m, 2H) (two NH protons missing) A110 [00291] (400 MHz, D.sub.2O) 9.99-9.86 (m, 1H) 9.78 (d, 1H) 8.90 (dd, 1H) 8.24 (s, 1H) 7.61 (s, 1H) 5.05 (br t, 2H) 4.00-3.92 (m, 1H) 2.74-2.61 (m, 2H) (two NH protons and one CO.sub.2H proton missing) A111 [00292] (400 MHz, D.sub.2O) 9.91-9.86 (m, 1H) 9.69 (d, 1H) 8.85-8.80 (m, 1H) 8.21- 8.18 (m, 1H) 8.11-8.07 (m, 1H) 5.03 (t, 2H) 3.21 (t, 2H) (one CO.sub.2H proton missing) A112 [00293] (400 MHz, D.sub.2O) 9.89-9.86 (m, 1H) 9.72-9.68 (m, 1H) 8.85-8.80 (m, 1H) 8.20-8.17 (m, 1H) 8.11-8.07 (m, 1H) 5.07-5.01 (m, 2H) 3.60 (s, 3H) 3.26- 3.20 (m, 2H) A113 [00294] (400 MHz, D.sub.2O) 9.94-9.91 (m, 1H) 9.66-9.63 (m, 1H) 8.89-8.84 (m, 1H) 8.21 (d, 1H) 8.12-8.09 (m, 1H) 5.10- 5.06 (m, 2H) 4.60-4.55 (m, 2H) A114 [00295] (400 MHz, D.sub.2O) 9.94-9.90 (m, 1H) 9.70-9.65 (m, 1H) 8.90-8.85 (m, 1H) 8.25-8.21 (m, 1H) 8.14-8.11 (m, 1H) 4.89-4.83 (m, 2H) 3.63 (s, 3H) 2.58- 2.51 (m, 2H) 2.43-2.34 (m, 2H) A115 [00296] (400 MHz, D.sub.2O) 9.87 (d, 1H) 9.63 (d, 1H) 8.82 (dd, 1H) 8.19-8.16 (m, 1H) 8.09-8.06 (m, 1H) 4.85-4.79 (m, 2H) 2.56-2.40 (m, 2H) 2.40-2.25 (m, 2H) (one CO.sub.2H proton missing) A116 [00297] (400 MHz, D.sub.2O) 9.92-9.89 (m, 1H) 9.67-9.63 (m, 1H) 8.87-8.82 (m, 1H) 8.20 (d, 1H) 8.11-8.08 (m, 1H) 4.97- 4.91 (m, 2H) 3.01-2.95 (m, 2H) 2.57- 2.46 (m, 2H) A117 [00298] (400 MHz, D.sub.2O) 9.90 (d, 1H) 9.68 (d, 1H) 8.85 (dd, 1H) 8.57 (s, 1H) 4.95 (t, 2H) 4.01 (s, 3H) 2.97 (t, 2H) 2.55-2.47 (m, 2H) A118 [00299] (400 MHz, D.sub.2O) 9.95-9.91 (m, 1H) 9.68 (dd, 1H) 8.91-8.87 (m, 1H) 8.58 (s, 1H) 5.13-5.09 (m, 2H) 4.62-4.57 (m, 2H) 4.03 (s, 3H) A119 [00300] (400 MHz, D.sub.2O) 9.92-9.89 (m, 1H) 9.72-9.68 (m, 1H) 8.89-8.85 (m, 1H) 8.59 (s, 1H) 4.91-4.85 (m, 2H) 4.03 (s, 3H) 2.55-2.50 (m, 2H) 2.41-2.32 (m, 2H) (one CO.sub.2H proton missing) A120 [00301] (400 MHz, D.sub.2O) 9.92 (d, 1H) 9.66 (dd, 1H) 8.92 (dd, 1H) 8.22 (d, 1H) 8.13 (d, 1H) 5.75 (s, 2H) 3.79 (s, 3H) A121 [00302] (400 MHz, D.sub.2O) 9.91 (d, 1H) 9.71 (d, 1H) 8.89 (dd, 1H) 8.61 (s, 1H) 4.88 (t, 2H) 4.05 (s, 3H) 3.63 (s, 3H) 2.55 (t, 2H) 2.44-2.34 (m, 2H) A122 [00303] (400 MHz, D.sub.2O) 9.74 (d, 1H), 9.61 (d, 1H), 9.39 (s, 1H) 8.84 (s, 1H), 8.65 (dd, 1H), 5.04 (t, 2H), 3.25 (t, 2H) (CO.sub.2H proton missing) A123 [00304] (400 MHz, CD.sub.3OD) 10.11 (d, 1H), 9.80 (dd, 1H), 9.09 (dd, 1H), 8.34 (d, 1H), 8.28 (d, 1H), 5.71 (s, 2H) (CO.sub.2H proton missing) A124 [00305] (400 MHz, D.sub.2O) 10.01-9.98 (m, 1H), 9.91-9.87 (m, 1H), 9.03-8.98 (m, 1H), 8.85 (s, 1H), 5.28-5.22 (m, 2H), 4.40 (q, 2H), 3.72-3.66 (m, 2H), 1.34 (t, 3H) A125 [00306] (400 MHz, D.sub.2O) 9.99 (s, 1H), 9.86 (d, 1H), 9.01-8.96 (m, 1H), 8.68 (s, 1H), 5.27-5.21 (m, 2H), 4.76 (s, 3H), 3.72- 3.66 (m, 2H) (NH proton missing) A126 [00307] (400 MHz, D.sub.2O) 9.94 (s, 1H), 9.89- 9.85 (m, 1H), 8.98-8.93 (m, 1H), 8.81 (s, 1H), 5.13-5.07 (m, 2H), 4.37 (q, 2H), 3.27-3.21 (m, 2H), 1.34-1.27 (m, 3H) (CO.sub.2H proton missing) A127 [00308] (400 MHz, D.sub.2O) 9.94-9.91 (m, 1H), 9.86-9.82 (m, 1H), 8.95-8.91 (m, 1H), 8.64 (s, 1H), 5.10-5.05 (m, 2H), 3.23- 3.18 (m, 2H), 2.87 (s, 3H) (NH and CO.sub.2H protons missing) A128 [00309] (400 MHz, D.sub.2O) 9.84 (s, 1H), 9.74- 9.69 (m, 1H), 8.85-8.79 (m, 1H), 7.99 (s, 1H), 4.90-4.84 (m, 2H), 3.62 (s, 3H), 2.57-2.51 (m, 2H), 2.43-2.34 (m, 2H), 2.26 (s, 3H) A129 [00310] (400 MHz, D.sub.2O) 9.87-9.85 (m, 1H), 9.85-9.82 (m, 1H), 8.89-8.85 (m, 1H), 5.11-5.06 (m, 2H), 3.25-3.20 (m, 2H), 2.86 (s, 3H), 2.46 (s, 3H) (NH and CO.sub.2H protons missing) A130 [00311] (400 MHz, D.sub.2O) 9.94-9.89 (m, 1H), 9.89-9.84 (m, 1H), 8.97-8.92 (m, 1H), 5.09 (br t, 2H), 4.45-4.34 (m, 2H), 3.23 (br t, 2H), 2.49 (s, 3H), 1.32 (t, 3H) (CO.sub.2H proton missing) A131 [00312] (400 MHz, D.sub.2O) 9.91-9.88 (m, 1H), 9.88-9.83 (m, 1H), 8.96-8.91 (m, 1H), 5.12-5.06 (m, 2H), 4.40-4.32 (m, 2H), 3.58 (s, 3H), 3.25-3.20 (m, 2H), 2.47 (s, 3H), 1.30 (t, 3H) A132 [00313] (400 MHz, D.sub.2O) 9.79 (s, 1H), 9.64 (d, 1H), 8.82 (dd, 1H), 7.95 (s, 1H), 5.54 (s, 2H), 2.21 (s, 3H) (CO.sub.2H proton missing) A133 [00314] (400 MHz, D.sub.2O) 9.86-9.83 (m, 1H), 9.75-9.71 (m, 1H), 8.91-8.85 (m, 1H), 8.00 (s, 1H), 5.78 (s, 2H), 3.79 (s, 3H), 2.24 (s, 3H) A134 [00315] (400 MHz, D.sub.2O) 9.86-9.82 (m, 1H), 9.69 (d, 1H), 8.81 (dd, 1H), 7.97 (s, 1H), 5.13-5.06 (m, 2H), 4.60-4.55 (m, 2H), 2.24 (s, 3H) A135 [00316] (400 MHz, D.sub.2O) 9.85-9.82 (m, 1H), 9.74-9.69 (m, 1H), 8.84-8.79 (m, 1H), 7.98 (s, 1H), 4.91-4.84 (m, 2H), 2.55- 2.50 (m, 2H), 2.41-2.33 (m, 2H), 2.25 (s, 3H) (CO.sub.2H proton missing) A136 [00317] (400 MHz, D.sub.2O) 9.84-9.80 (m, 1H), 9.70 (d, 1H), 8.79 (dd, 1H), 7.96 (s, 1H), 4.95 (t, 2H), 2.97 (t, 2H), 2.55- 2.45 (m, 2H), 2.23 (s, 3H) A137 [00318] (400 MHz, D.sub.2O) 9.91-9.86 (m, 2H), 8.94-8.90 (m, 1H), 5.16-5.11 (m, 2H), 3.64 (s, 3H), 3.31-3.25 (m, 2H), 2.90 (s, 3H), 2.51 (s, 3H) (NH proton missing) A138 [00319] (400 MHz, CD.sub.3OD) 10.00 (d, 1H). 9.98 (d, 1H), 9.67 (s, 1H), 9.01 (dd, 1H), 5.13 (t, 2H), 3.25 (t, 2H) (CO.sub.2H proton missing) A139 [00320] (400 MHz, CD.sub.3OD) 10.26 (d, 1H), 10.23 (s, 1H), 9.97 (d, 1H), 9.24 (dd, 1H), 5.13 (t, 2H), 3.27 (t, 2H) (CO.sub.2H proton missing) A140 [00321] (400 MHz, D.sub.2O) 10.05 (d, 1H), 10.03 (d, 1H), 9.08 (dd, 1H), 5.21 (t, 2H), 3.30 (t, 2H), 2.76 (s, 3H) (CO.sub.2H proton missing) A141 [00322] (400 MHz, D.sub.2O) 9.95 (d, 1H), 9.90 (d, 1H), 8.98 (dd, 1H), 5.28 (t, 2H), 3.73 (t, 2H) (NH protons missing) A142 [00323] (400 MHz, D.sub.2O) 10.35 (s, 1H), 10.19 (d, 1H), 9.90 (d, 1H), 9.18 (dd, 1H), 5.14 (t, 2H), 3.26 (t, 2H) (CO.sub.2H proton missing) A143 [00324] (400 MHz, D.sub.2O) 10.35 (s, 1H), 10.23 (d, 1H), 9.90 (d, 1H), 9.21 (dd, 1H), 5.28 (t, 2H), 3.73 (t, 2H) A144 [00325] (400 MHz, D.sub.2O) 10.03 (d, 1H), 9.89 (d, 1H), 9.01-9.04 (m, 1H), 8.95 (s, 1H), 5.15 (t, 2H) 3.26 (t, 2H) (CO.sub.2H proton missing) A145 [00326] (400 MHz, D.sub.2O) 9.92-9.93 (m, 2H), 8.89-8.94 (m, 1H), 8.77 (s, 1H), 5.16 (t, 2H), 4.02 (s, 3H), 3.29 (t, 2H) (CO.sub.2H proton missing) A146 [00327] (400 MHz, CD.sub.3OD) 10.06 (d, 1H), 10.03 (d, 1H), 9.12-9.02 (m, 2H), 7.42 (d, 1H), 5.15 (t, 2H), 3.27 (t, 2H) (CO.sub.2H proton missing) A147 [00328] (400 MHz, D.sub.2O) 9.65-9.73 (m, 2H), 8.69-8.74 (m, 1H), 8.62-8.67 (m, 1H), 8.04-8.11 (m, 1H), 4.96-5.05 (m, 2H), 3.16-3.22 (m, 2H) (CO.sub.2H proton missing)

BIOLOGICAL EXAMPLES

Post-Emergence Efficacy

[0536] Seeds of a variety of test species were sown in standard soil in pots. 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-methyl pyrrolidone+44.44% Dowanol DPM glycolether), to create a 50 g/l solution which was then diluted to required concentration using 0.25% or 1% Empicol ESC.sub.70 (Sodium lauryl ether sulphate)+1% ammonium sulphate as diluent. 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).

[0537] 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.

Test Plants:

[0538] 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), Setaia fabei (SETFA)

TABLE-US-00066 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 ELEIN LOLPE DIGSA SETFA ECHCG A1 500 100 70 70 50 50 90 100 50 60 A2 125 0 0 30 10 10 0 20 20 10 A3 125 20 60 70 40 50 20 80 80 70 A4 500 10 30 40 10 10 0 30 20 20 A5 500 100 100 100 70 80 100 60 60 70 A6 500 90 40 20 10 60 60 60 70 60 A7 (tested as 500 0 0 20 10 20 10 30 10 10 a 1:1 regioisomeric mixture) A8 (tested as 500 10 10 30 30 20 10 50 40 50 a 1:1 regioisomeric mixture) A9 500 90 70 90 80 80 30 70 60 60 A10 500 60 80 60 50 60 60 50 60 30 A11 500 100 90 100 60 100 80 90 100 100 A12 500 60 30 20 20 30 70 60 40 30 A13 500 90 70 90 40 80 60 30 60 40 A14 500 100 40 50 40 70 40 50 50 40 A15 500 100 80 100 30 100 60 80 70 80 A16 500 100 100 90 80 80 90 70 80 80 A17 500 30 30 40 30 60 50 50 50 40 A18 500 90 10 50 30 30 40 30 40 30 A19 500 40 100 100 70 100 90 70 60 80 A20 500 40 20 10 10 50 10 60 20 30 A21 500 10 40 40 10 10 0 10 10 10 A22 500 30 20 30 10 20 10 20 20 20 A23 500 50 10 70 30 60 40 50 40 30 A24 500 0 0 n/a 10 20 10 10 20 30 A25 500 80 70 80 40 40 20 40 40 30 A26 500 20 40 n/a 40 40 30 30 40 20 A27 500 100 90 90 70 50 30 90 90 90 A28 500 100 90 n/a 30 100 70 70 100 100 A29 500 20 50 20 20 30 20 30 20 20 A30 500 80 40 40 20 40 50 30 40 20 A31 500 30 20 30 10 50 20 50 60 40 A32 500 80 90 80 60 90 40 90 80 90 A33 500 100 70 80 10 50 30 70 30 20 A34 500 60 20 30 20 20 20 30 40 50 A35 500 100 100 90 50 70 70 50 60 50 A36 500 100 60 30 30 20 20 10 10 0 A37 500 30 50 30 20 10 0 10 10 10 A38 500 20 30 20 20 0 10 20 10 10 A39 500 90 90 90 80 80 70 90 90 80 A40 500 100 100 100 90 100 80 80 80 80 A41 500 0 60 n/a 10 0 0 0 0 0 A42 500 20 40 30 20 20 0 20 10 10 A43 500 100 90 80 20 10 0 20 10 10 A44 500 100 n/a n/a 60 50 30 50 60 30 A45 500 100 80 90 20 70 70 50 70 40 A46 500 n/a 70 n/a 50 60 40 60 60 80 A47 500 100 100 100 30 100 100 90 90 90 A48 500 100 90 90 90 70 40 100 90 70 A49 500 100 100 90 70 60 40 70 60 60 A50 500 100 100 100 70 70 80 100 100 100 A51 500 100 100 90 30 70 60 90 90 90 A52 500 50 n/a n/a 10 10 0 30 10 10 A53 500 60 n/a n/a 50 60 20 90 40 30 A54 500 80 50 n/a 10 80 60 90 70 70 A55 500 100 80 n/a 20 100 70 100 100 100 A56 500 100 80 90 30 80 50 70 80 90 A57 500 100 100 90 60 60 50 70 60 80 A58 500 80 50 n/a 20 40 30 90 90 70 A59 500 90 90 100 80 90 70 70 80 70 A60 500 90 90 50 10 70 30 50 50 40 A61 500 100 70 40 20 60 30 80 70 50 A62 500 0 20 40 20 0 0 10 0 0 A63 500 0 30 40 20 20 10 20 30 20 A64 500 100 90 100 90 30 40 90 80 80 A65 500 80 70 90 60 100 90 100 100 60 A66 500 50 60 n/a 10 90 20 60 70 70 A67 500 100 80 80 80 90 60 90 80 70 A68 500 100 90 90 50 70 70 70 80 60 A69 500 90 90 n/a 40 90 30 90 90 80 A70 500 40 40 n/a 30 40 20 80 40 40 A71 500 100 90 90 60 100 80 90 90 100 A72 500 90 70 70 70 80 40 60 60 40 A73 500 80 70 50 30 70 10 70 60 50 A74 500 100 90 70 80 100 60 90 80 40 A75 125 0 40 n/a 0 0 0 10 0 0 A76 500 30 20 40 30 70 30 60 40 30 A77 500 50 70 n/a 60 0 0 90 80 60 A78 500 70 80 n/a 50 0 10 60 50 20 A79 500 100 90 n/a 80 100 70 90 90 80 A80 500 40 10 n/a 10 10 0 60 40 0 A81 500 50 40 n/a 10 10 10 70 50 30 A83 500 100 70 70 40 70 50 60 60 60 A84 500 100 90 90 40 70 50 70 50 70 A85 500 10 0 20 30 30 10 40 20 20 A86 500 40 30 30 40 20 20 30 20 10 A87 500 80 20 80 10 80 0 90 40 50 A88 500 100 100 50 30 30 30 70 60 80 A89 500 100 90 100 30 70 60 90 60 60 A90 500 20 20 20 10 10 0 10 10 10 A91 500 40 60 n/a 20 40 10 40 20 20 A92 500 10 10 20 10 10 0 20 0 0 A93 500 0 0 10 20 30 10 50 40 30 A94 500 90 90 100 90 100 40 100 90 90 A95 500 10 0 30 10 10 0 30 20 10 A96 500 100 90 100 80 80 70 40 80 30 A97 500 100 80 50 20 70 30 50 40 60 A98 500 100 90 90 40 80 80 90 100 70 A99 500 30 90 90 40 40 60 60 70 20 A100 500 0 0 30 20 30 10 40 30 30 A101 500 70 60 70 40 30 20 70 60 40 A102 500 100 90 90 60 30 10 60 60 70 A103 500 70 40 70 40 60 30 90 80 70 A104 500 40 20 30 10 20 10 50 60 50 A105 500 90 90 100 70 90 70 100 90 80 A106 500 10 0 60 20 20 0 80 50 40 A107 500 100 50 30 20 30 20 70 50 40 A108 500 20 20 30 30 20 10 60 30 30 A109 500 90 90 60 0 n/a 10 n/a 90 n/a A110 500 90 80 40 20 100 20 90 80 100 A111 500 90 90 90 70 100 90 100 100 100 A112 500 50 60 50 20 90 30 90 60 50 A113 500 100 60 70 50 70 60 70 70 70 A114 500 100 60 n/a 10 90 30 70 50 40 A115 500 100 70 100 20 100 60 90 100 90 A116 500 100 40 70 20 80 80 60 60 60 A117 500 40 20 70 30 20 40 80 90 70 A118 500 50 30 70 30 70 40 90 90 90 A119 500 100 50 80 30 90 30 90 100 80 A120 500 100 50 70 10 90 0 80 60 70 A121 500 30 10 40 10 50 10 60 40 100 A122 500 90 0 70 30 70 20 90 50 30 A123 500 0 0 30 10 20 10 20 10 10 A124 500 90 30 90 40 80 40 90 70 40 A125 500 30 10 40 10 40 40 60 70 60 A126 500 90 70 70 30 90 60 90 70 60 A127 500 100 100 70 60 70 20 90 70 80 A128 500 90 20 70 20 100 60 90 90 80 A129 500 100 70 90 80 90 60 70 100 60 A130 500 100 50 100 50 80 50 60 30 60 A131 500 10 0 10 10 10 10 30 20 20 A132 500 90 70 70 10 90 50 90 80 90 A133 500 0 0 0 10 10 0 20 0 10 A134 500 90 30 70 50 80 40 60 70 70 A135 500 90 20 90 10 80 40 90 90 90 A136 500 70 30 70 20 60 60 70 80 40 A137 500 20 10 20 10 30 10 50 30 40 A138 500 90 40 100 70 70 0 60 30 40 A139 500 80 70 100 60 70 10 70 60 60 A140 500 10 0 0 0 90 10 70 70 20 A141 500 100 100 100 100 10 30 10 50 30 A142 500 100 90 100 30 100 90 100 90 100 A143 500 100 90 100 60 100 100 100 90 100