PESTICIDALLY ACTIVE PYRIDAZINONE COMPOUNDS

Abstract

Compounds of formula (I) wherein the substituents are as defined in claim 1, and the agrochemically acceptable salts, stereoisomers, enantiomers, tautomers and N-oxides of those compounds, can be used as insecticides.

##STR00001##

Claims

1. A compound of the formula (I) ##STR00177## wherein: Q is ##STR00178## where the staggered line represents the connection of Q to the rest of compound of the formula (I); A is N or CR.sup.Y; R.sup.1 is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6cyanoalkyl, aminocarbonylC.sub.1-C.sub.6alkyl, hydroxycarbonylC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6nitroalkyl, trimethylsilaneC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6alkynyl, C.sub.2-C.sub.6haloalkynyl, C.sub.3-C.sub.4cycloalkyl-C.sub.1-C.sub.2alkyl, C.sub.3-C.sub.4cycloalkyl-C.sub.1-C.sub.2alkyl wherein the C.sub.3-C.sub.4cycloalkyl group is substituted with 1 or 2 halogen atoms, oxetan-3-yl-CH.sub.2, C.sub.1-C.sub.6alkylcarbonyl, C.sub.1-C.sub.6alkoxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl, benzyl, or benzyl substituted with 1 to 3 substituents independently selected from halogen, C.sub.1-C.sub.6alkoxy and C.sub.1-C.sub.6haloalkyl; R.sup.2a and R.sup.2b are independently selected from hydrogen, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1C.sub.3haloalkylsuflanyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, halogen, NO.sub.2, SF.sub.5, CN, C(O)NH.sub.2, C(O)OH, C(S)NH.sub.2, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6cycloalkyl substituted with one to three substituents independently selected from R.sup.X; C.sub.1-C.sub.6cycloalkylcarbonyl, phenyl, phenyl substituted with one to three substituents independently selected from R.sup.X; heteroaryl, heteroaryl substituted with one to three substituents independently selected from R.sup.X; OR.sup.6, piperidin-2-one-1-yl, piperidin-2-one-1-yl substituted with one to two substituents independently selected from R.sup.X; pyridin-2-one-1-yl, pyridin-2-one-1-yl substituted with one to two substituents independently selected from R.sup.X; azetidin-1-yl, azetidin-1-yl substituted with one to two substituents independently selected from R.sup.X; pyrrolidin-1-yl, pyrrolidin-1-yl substituted with one to two substituents independently selected from R.sup.X; C.sub.3-C.sub.6cycloalkyl-C.sub.1C.sub.4alkyl, C.sub.3-C.sub.6cycloalkyl-C.sub.1-C.sub.4alkyl substituted with one to two substituents independently selected from R.sup.Z; C.sub.3-C.sub.6cycloalkyl-C.sub.1-C.sub.3alkoxy, C.sub.3-C.sub.6cycloalkyl-C.sub.1-C.sub.3alkoxy substituted with one to two substituents independently selected from R.sup.X; C.sub.1-C.sub.5cyanoalkyl, C.sub.1-C.sub.5cyanoalkoxy, C.sub.1-C.sub.4alkylsulfanyl, C.sub.1-C.sub.4alkylsulfanyl substituted with one to three substituents independently selected from R.sup.X; C.sub.1C.sub.4alkylsulfonyl, C.sub.1-C.sub.4alkylsulfonyl substituted with one to three substituents independently selected from R.sup.X; C.sub.1-C.sub.4alkylsulfinyl, and C.sub.1-C.sub.4alkylsulfinyl substituted with one to three substituents independently selected from R.sup.X; R.sup.3 is C.sub.1-C.sub.3alkyl or C.sub.1-C.sub.3haloalkyl; R.sup.4 is ##STR00179## where the staggered line represents the connection of R.sup.4 to Q.sup.a or Q.sup.b; A.sup.1, A.sup.2, and A.sup.3 are, independently of each other, N or CH; R.sup.4c is C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, allyl, propargyl, or C.sub.3-C.sub.6cycloalkylC.sub.1-C.sub.4alkyl; R.sup.5 is hydrogen, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.3-C.sub.4cycloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.3-C.sub.4alkoxyC(O), (C.sub.1-C.sub.3alkoxy).sub.2CH, halogen, CN, NH.sub.2C(O), amino (i.e NH.sub.2), (C.sub.1-C.sub.3alkyl)amino, di(C.sub.1-C.sub.3alkyl)amino, hydroxy, C.sub.3-C.sub.4halocycloalkyl, C.sub.3-C.sub.4cyanocycloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6alkynyl, C.sub.2-C.sub.6haloalkynyl, C.sub.1-C.sub.4haloalkylsulfanyl, C.sub.1-C.sub.4haloalkylsulfinyl, C.sub.1-C.sub.4haloalkylsulfonyl, C.sub.1-C.sub.4alkylsulfanyl, C.sub.1-C.sub.4alkylsulfinyl, C.sub.1-C.sub.4alkylsulfonyl, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl, (C.sub.1-C.sub.3alkyl)sulfonylamino, (C.sub.1-C.sub.3alkyl)sulfonyl(C.sub.1-C.sub.3alkyl)amino, (C.sub.1-C.sub.3alkyl)NHC(O), (C.sub.1-C.sub.3alkyl).sub.2NC(O), (C.sub.3-C.sub.4cycloalkyl)NHC(O), (C.sub.3-C.sub.4cycloalkyl)(C.sub.1-C.sub.3alkyl)NC(O), (C.sub.1-C.sub.3alkyl)C(O)(C.sub.1-C.sub.3alkyl)N, (C.sub.1-C.sub.3alkyl)C(O)NH, (C.sub.1-C.sub.3alkyl)C(O), (C.sub.1-C.sub.3alkoxy)C(O), HC(O), diphenylmethanimine, C.sub.1-C.sub.3haloalkoxy, phenyl, or a 5-membered heteroaromatic ring; or R.sup.5 is phenyl substituted with one to three substituents selected from C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.3-C.sub.4cycloalkyl, halogen, CN and hydroxyl; or R.sup.5 is a 5-membered heteroaromatic ring substituted with one to three substituents selected from C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.3-C.sub.4cycloalkyl, halogen, CN and hydroxyl; R.sup.5a and R.sup.5b are, independently of each other, selected from hydrogen, halogen, CN, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.3-C.sub.4cycloalkyl, C.sub.1-C.sub.3alkoxy, and C.sub.1-C.sub.3haloalkoxy; R.sup.6 is phenyl, benzyl, heteroaryl, or C.sub.3-C.sub.6cycloalkyl; or R.sup.6 is phenyl, benzyl, heteroaryl, or C.sub.3-C.sub.6cycloalkyl, each of which, independently of each other, is substituted with one to three substituents independently selected from R.sup.X; R.sup.X is independently selected from halogen, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, NO.sub.2, SF.sub.5, CN, C(O)NH.sub.2, C(S)NH.sub.2, C.sub.1-C.sub.4haloalkylsulfanyl, C.sub.1-C.sub.4haloalkylsulfinyl, C.sub.1-C.sub.4haloalkylsulfonyl, C.sub.1-C.sub.4alkylsulfanyl, C.sub.1-C.sub.4alkylsulfinyl and C.sub.1-C.sub.4alkylsulfonyl; R.sup.Y is selected from hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3haloalkyl, hydroxy, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, halogen, CN and cyclopropyl; R.sup.Z is selected from oxo, halogen, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy and CN; X.sup.0 is O or S; and an agrochemically acceptable salt, stereoisomer, enantiomer, tautomer and N-oxide of the compound of formula I.

2. The compound according to claim 1, wherein A is N or CH.

3. The compound according to claim 1, wherein R.sup.4 is R.sup.4a, and A.sup.1 is N, A.sup.2 is N or CH, and A.sup.3 is N or CH; or A.sup.1 is N, A.sup.2 is N or CH, and A.sup.3 is CH; or A.sup.1 is N, A.sup.2 is CH, and A.sup.3 is N or CH; or A.sup.1 is N, A.sup.2 is CH, and A.sup.3 is CH: or A.sup.1 or A.sup.2 is N, the other is N or CH, and A.sup.3 is CH; or A.sup.1 or A.sup.2 is N, the other is CH, and A3 is CH.

4. The compound according to claim 1, wherein R.sup.4 is R.sup.4b, and A.sup.1 is N or CH.

5. The compound according to claim 1, wherein R.sup.4c is methyl, ethyl, propyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, allyl, propargyl, cyclopropylmethyl, cyclobutylmethyl, 2-cyclpropylethyl, or 3-cyclopropylpropyl; preferably R.sup.4 is methyl, ethyl, or 2,2-difluoroethyl.

6. The compound according to claim 1, wherein X.sup.0 is O.

7. The compound according to claim 1, wherein R.sup.1 is hydrogen, methyl, ethyl, cyanomethyl, methoxymethyl, cyclopropyl-methyl, allyl, propargyl, benzyloxycarbonyl, or benzyl; preferably R.sup.1 is hydrogen, or methyl.

8. The compound according to claim 1, wherein R.sup.2a is halogen, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkylsulfanyl, C.sub.1-C.sub.3haloalkoxy, C.sub.3-C.sub.6cycloalkyl optionally substituted with one or two substituents independently selected from C.sub.1-C.sub.3haloalkyl, cyano and halogen, C.sub.3-C.sub.6cycloalkylC.sub.1-C.sub.4alkyl optionally substituted with one to three substituents independently selected from C.sub.1-C.sub.3haloalkyl, cyano and halogen, C.sub.1-C.sub.5cyanoalkyl, C.sub.1-C.sub.4alkylsulfonyl, C.sub.1-C.sub.4haloalkylsulfonyl, C.sub.1-C.sub.4alkylsulfinyl, C.sub.1-C.sub.4haloalkylsulfinyl, C.sub.3-C.sub.6cycloalkylsulfanyl, C.sub.3-C.sub.6cycloalkylsulfinyl, or C.sub.3-C.sub.6cycloalkylsulfonyl; preferably chlorine, bromine, iodine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl, trifluoromethylsulfonyl, cyanoisopropyl, or cyanocyclopropyl.

9. The compound according to claim 1, wherein R.sup.2b is halogen, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkylsulfanyl, C.sub.1-C.sub.3haloalkylsulfonyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy, or CN: preferably R.sup.2b is chlorine, bromine, iodine, difluoromethyl, trifluoromethyl, or difluoromethoxy.

10. The compound according to claim 1, wherein R.sup.3 is C.sub.1-C.sub.3alkyl or C.sub.1-C.sub.3haloalkyl, preferably R.sup.3 is methyl.

11. The compound according to claim 1, wherein when Q is Q.sup.a: R.sup.5 is hydrogen, methyl, trifluoromethoxy, methoxy, cyclopropyl, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2,2,2-trifluoroethyl, chloro, bromo, methoxyethoxy, methylcarbonyl or methoxycarbonyl; and when Q is Q.sup.b: R.sup.5a is hydrogen, halogen, CN, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.3-C.sub.4cycloalkyl, C.sub.1-C.sub.3alkoxy or C.sub.1-C.sub.3haloalkoxy; and R.sup.5b is hydrogen, halogen, CN, C.sub.1-C.sub.3haloalkyl, C.sub.3-C.sub.4cycloalkyl, C.sub.1-C.sub.3alkoxy or C.sub.1-C.sub.3haloalkoxy.

12. A composition comprising a compound as defined in claim 1, one or more auxiliaries and diluent, and optionally one or more other active ingredient.

13. A method (i) of combating and controlling insects, acarines, nematodes or molluscs which comprises applying to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound as defined in claim 1; or (ii) for the protection of plant propagation material from the attack by insects, acarines, nematodes or molluscs, which comprises treating the propagation material or the site, where the propagation material is planted, with an effective amount of a compound as defined in claim 1; or (iii) of controlling parasites in or on an animal in need thereof comprising administering an effective amount of a compound as defined in claim 1.

14. A plant propagation material, such as a seed, comprising, or treated with or adhered thereto, a compound as defined in claim 1.

15. A compound of the formula XII(i), or a tautomer thereof, ##STR00180## wherein A.sup.1, A.sup.2, A.sup.3 and R.sup.4c are as defined in claim 1, provided said compound is not ##STR00181## 6-hydrazinyl-2-methyl-3(2H)-pyridazinone, nor ##STR00182## 6-hydrazinyl-2-ethyl-3(2H)-pyridazinone, nor a tautomer thereof.

16. A compound of the formula XX(i), XXI(i) or XXII(i) ##STR00183## wherein R.sup.4a is as defined in claim 1; and wherein X.sup. is an anion selected from the conjugate base of an inorganic acid selected from hydrochloric acid, hydrobromic acid, hydrogen fluoride, hydrogen iodide, sulfuric acid, or the conjugate base of an organic acid selected from a carboxylic acid or a sulfonic acid.

Description

EXAMPLES

Formulation Examples

[0513] The following Examples further illustrate, but do not limit, the invention.

TABLE-US-00005 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 (7-8 mol of 2% ethylene oxide) highly dispersed silicic acid 5% 10% 10% Kaolin 62% 27%

[0514] 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-00006 Powders for dry seed treatment a) b) c) active ingredients 25% 50% 75% light mineral oil 5% 5% 5% highly dispersed silicic acid 5% 5% Kaolin 65% 40% Talcum 20%

[0515] The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording powders that can be used directly for seed treatment.

TABLE-US-00007 Emulsifiable concentrate active ingredients 10% octylphenol polyethylene glycol ether (4-5 mol of ethylene oxide) 3% calcium dodecylbenzenesulfonate 3% castor oil polyglycol ether (35 mol of ethylene oxide) 4% Cyclohexanone 30% xylene mixture 50%

[0516] Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.

TABLE-US-00008 Dusts a) b) c) Active ingredients 5% 6% 4% Talcum 95% Kaolin 94% mineral filler 96%

[0517] Ready-for-use dusts are obtained by mixing the combination with the carrier and grinding the mixture in a suitable mill. Such powders can also be used for dry dressings for seed.

TABLE-US-00009 Extruder granules Active ingredients 15% sodium lignosulfonate 2% carboxymethylcellulose 1% Kaolin 82%

[0518] 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-00010 Coated granules Active ingredients 8% polyethylene glycol (mol. wt. 200) 3% Kaolin 89%

[0519] 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-00011 Suspension concentrate active ingredients 40% propylene glycol 10% nonylphenol polyethylene glycol ether (15 mol of ethylene oxide) 6% Sodium lignosulfonate 10% carboxymethylcellulose 1% silicone oil (in the form of a 75% emulsion in water) 1% Water 32%

[0520] The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.

TABLE-US-00012 Flowable concentrate for seed treatment active ingredients 40% propylene glycol 5% copolymer butanol PO/EO 2% Tristyrenephenole with 10-20 moles EO 2% 1,2-benzisothiazolin-3-one (in the form of a 20% solution in 0.5%.sup. water) monoazo-pigment calcium salt 5% Silicone oil (in the form of a 75% emulsion in water) 0.2%.sup. Water 45.3%

[0521] The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.

Slow Release Capsule Suspension

[0522] 28 parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51.6 parts of water until the desired particle size is achieved. To this emulsion a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed. The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingredients. The medium capsule diameter is 8-15 microns. The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.

[0523] Formulation types include an emulsion concentrate (EC), a suspension concentrate (SC), a suspo-emulsion (SE), a capsule suspension (CS), a water dispersible granule (WG), an emulsifiable granule (EG), an emulsion, water in oil (EO), an emulsion, oil in water (EW), a micro-emulsion (ME), an oil dispersion (OD), an oil miscible flowable (OF), an oil miscible liquid (OL), a soluble concentrate (SL), an ultra-low volume suspension (SU), an ultra-low volume liquid (UL), a technical concentrate (TK), a dispersible concentrate (DC), a wettable powder (WP), a soluble granule (SG) or any technically feasible formulation in combination with agriculturally acceptable adjuvants.

Preparation Examples

[0524] The following examples further illustrate, but do not limit, the invention. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques. Throughout this description, temperatures are given in degrees Celsius ( C.). Mp means melting point in C. Unless indicated otherwise, .sup.1H NMR spectra are recorded at 400 MHz and .sup.19F NMR spectra are recorded at 377 MHz. Chemical shifts are recorded in ppm relevant to a TMS standard. The following abbreviations are used: s=singlet; br s=broad singlet; d=doublet; br d=broad doublet; dd=double doublet; dt=double triplet; t=triplet, tt=triple triplet, q=quartet, quin=quintuplet, sept=septet; m=multiplet. Either one of the LCMS methods below was used to characterize the compounds. The characteristic LCMS values obtained for each compound were the retention time (Rt, recorded in minutes) and the measured molecular ion (M+H).sup.+ or (MH).sup..

LCMS Methods:

Method 1:

[0525] Spectra were recorded on a Mass Spectrometer from Agilent Technologies (6410 Triple Quadrupole mass spectrometer) equipped with an equipped with an electrospray source (Polarity: positive or negative ions, MS2 Scan, Capillary: 7.00 kV, Fragmentor: 120 V, Desolvatation Temperature: 350 C., Gas Flow: 11 L/min, Nebulizer Gas: 40 psi, Mass range: 110 to 650 Da) and a 1200 Series HPLC from Agilent: quaternary pump, heated column compartment and diode-array detector. Column: KINETEX EVO C18, 2.6 m, 504.6 mm, Temp: 40 C., DAD Wavelength (nm): 254, Solvent Gradient: A=water+5% Acetonitrile+0.1% HCOOH, B=Acetonitrile+0.1% HCOOH, gradient: 0 min 10% B, 90% A; 0.9-1.8 min 100% B; 1.8-2.2 min 100-10% B; 2.2-2.5 min 10% B; Flow (mL/min) 1.8.

Method 2:

[0526] Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions, Capillary: 3.00 kV, Cone range: 41 V, Extractor: 2.00 V, Source Temperature: 150 C., Desolvatation Temperature: 5000 C., Cone Gas Flow: 50 L/h, Desolvatation Gas Flow: 1000 L/h, Mass range: 110 to 800 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment, diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 m, 302.1 mm, Temp: 40 C., PDA Wavelength range (nm): 200 to 400, Solvent Gradient: A=water+5% Acetonitrile+0.1% HCOOH, B=Acetonitrile+0.05% HCOOH, gradient: 10-100% B in 1.3 min; Flow (mL/min) 0.6.

Method 3:

[0527] Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII or QDA Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions), Capillary: 0.8-3.00 kV, Cone: 5-30 V, Source Temperature: 120-150 C., Desolvation Temperature: 350-600 C., Cone Gas Flow: 50-150 l/h, Desolvation Gas Flow: 650-1000 l/h, Mass range: 50 to 900 Da and an Acquity UPLC from Waters Corporation: Binary pump, heated column compartment, diode-array detector and ELSD. Column: Waters UPLC HSS T3, 1.8 m, 302.1 mm, Temp: 60 C., DAD Wavelength range (nm): 210 to 400, Runtime: 1.5 min; Solvents: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH; Flow (ml/min) 0.85, Gradient: 10% B isocratic for 0.2 min, then 10-100% B in 1.0 min, 100% B isocratic for 0.2 min, 100-10% B in 0.05 min, 10% B isocratic for 0.05 min.

Method 4:

[0528] Spectra were recorded on a ACQUITY Mass Spectrometer from Waters Corporations (SQD or SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.0 kV, Cone: 30V, Extractor: 3.00 V, Source Temperature: 150 C., Desolvation Temperature: 400 C., Cone Gas Flow: 60 L/hr, Desolvation Gas Flow: 700 L/hr, Mass range: 140 to 800 Da) and an ACQUITY UPLC from Waters Corporations with solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 m, 302.1 mm, Temp: 60 C., DAD Wavelength range (nm): 210 to 400, Solvent Gradient: A=Water/Methanol 9:1+0.1% formic acid, B=Acetonitrile+0.1% formic acid, gradient: 0-100% B in 2.5 min; Flow (ml/min) 0.75.

Example 1: Preparation of N-[(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (compound P1)

##STR00089##

Step A: Preparation of 6-chlor-2-methyl-pyridazin-3-one (I-1)

##STR00090##

[0529] To a solution of 6-chloropyridazin-3-ol (CAS 19064-67-6) (1.00 g, 7.661 mmol, 1.00 equiv.) in acetonitrile (10 mL) were added potassium carbonate (3.21 g, 22.98 mmol, 3.00 equiv.) followed by iodomethane (0.584 mL, 9.193 mmol, 1.20 equiv.). The reaction was stirred at room temperature for 48 hours. Then, water was added, and the aqueous layer was extracted with ethyl acetate. Then, the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the desired compound, 6-chloro-2-methyl-pyridazin-3-one, as a brown solid. LCMS (method 1): retention time 0.39 min m/z 145/147 [M+H].sup.+.

[0530] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.20 (d, J=9.66 Hz, 1H), 6.92 (d, J=9.66 Hz, 1H), 3.75 (s, 3H).

Step B: Preparation of 6-hydrazino-2-methyl-pyridazin-3-one (I-2)

##STR00091##

[0531] Under nitrogen atmosphere, to a solution of 6-chloro-2-methyl-pyridazin-3-one (0-6) (0.500 g, 3.459 mmol, 1.00 equiv.) in ethanol (10.38 ml) was added hydrazine hydrate (0.845 mL, 17.294 mmol, 5.00 equiv.). The reaction mixture was heated at 10000 for 5 hours. Then, the solution was evaporated under reduced pressure and the residue was purified by flash chromatography to afford the desired compound, 6-hydrazino-2-methyl-pyridazin-3-one. LCMS (method 1): retention time 0.29 min.

[0532] .sup.1H NMR (400 MHz, DMSO-d6) ppm 7.35-7.59 (m, 2H), 7.02 (d, J=9.66 Hz, 1H), 6.74 (d, J=9.78 Hz, 1H), 5.92 (s, 1H), 3.46 (s, 3H).

Step C: Preparation of N-[(1S)-2-amino-1-methyl-2-oxo-ethyl]-3,5-bis(trifluoromethyl)benzamide (I-3)

##STR00092##

[0533] To a solution of 3,5-bis(trifluoromethyl)benzoic acid (5.00 g, 19.37 mmol, 1.00 equiv.) in acetonitrile (50 mL) was added L-alaninamide hydrochloride (CAS 33208-99-0) (3.81 g, 29.06 mmol, 1.50 equiv.) followed by N,N-diisopropylethylamine (10.1 mL, 58.11 mmol, 3.00 equiv.) and 1-propanphosphonic acid cyclic anhydride (T3P, 50 mass % in ethyl acetate, 23.06 mL, 38.74 mmol, 2.00 equiv.). The reaction mixture was stirred at room temperature for 16 hours. Then, water was added, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated bicarbonate solution, then with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the desired compound N-[(1S)-2-amino-1-methyl-2-oxo-ethyl]-3,5-bis(trifluoromethyl)benzamide, as a light yellow solid.

[0534] LCMS (method 1): retention time 1.29 min, m/z 329 [M+H].sup.+.

[0535] .sup.1H NMR (400 MHz, DMSO-d6) ppm 9.11 (d, J=7.34 Hz, 1H), 8.57 (s, 2H), 8.32 (s, 1H), 7.53 (s, 1H), 7.07 (s, 1H), 4.44 (t, J=7.27 Hz, 1H), 1.37 (d, J=7.21 Hz, 3H).

[0536] .sup.19F NMR (377 MHz, DMSO-d6) ppm 61.27 (s, 6F).

Step D: Preparation of N-[(1S)-2-[(E)-dimethylaminomethyleneamino]-1-methyl-2-oxo-ethyl]-3,5-bis(trifluoromethyl)benzamide (I-4)

##STR00093##

[0537] To a solution of N-[(1S)-2-amino-1-methyl-2-oxo-ethyl]-3,5-bis(trifluoromethyl)benzamide (I-3) (0.500 g, 1.523 mmol, 1.00 equiv.) in 2-methyltetrahydrofuran (2.5 mL) was added N,N-dimethyl-formamide dimethyl acetal (0.258 mL, 1.828 mmol, 1.20 equiv.). The reaction mixture was stirred at 40 C. for 2 hours. The solution was concentrated under reduced pressure and the residue was washed with pentane, then dried again to afford the desired compound N-[(1S)-2-[(E)-dimethylaminomethylene-amino]-1-methyl-2-oxo-ethyl]-3,5-bis(trifluoromethyl)benzamide, which was used without further purification. LCMS (method 1): retention time 1.16 min, m/z 384 [M+H].sup.+.

[0538] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.52 (s, 1H), 8.29 (s, 2H), 7.99 (s, 1H), 7.61 (brd, J=5.88 Hz, 1H), 4.69-4.77 (m, 1H), 3.20 (s, 3H), 3.15 (s, 3H), 1.57 (d, J=7.13 Hz, 3H).

Step E: Preparation of N-[(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (compound P1)

##STR00094##

[0539] Under nitrogen atmosphere, to a solution of 6-hydrazino-2-methyl-pyridazin-3-one (I-2) (0.050 mg, 0.357 mmol, 1.00 equiv.) in 1,4-dioxane (0.357 mL) was added N-[(1S)-2-[(E)-dimethylamino-methylene-amino]-1-methyl-2-oxo-ethyl]-3,5-bis(trifluoromethyl)benzamide (I-4) (0.150 g, 0.392 mmol, 1.10 equiv.) and acetic acid (0.313 mL, 5.352 mmol, 15.00 equiv.). The reaction mixture was stirred at 80 C. for 1 hour. Then, water was added, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated bicarbonate solution, then with water, then with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography, then by preparative HPLC to afford the desired compound N-[(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide, as a white solid.

[0540] LCMS (method 1): retention time 1.38 min, m/z 461 [M+H].sup.+.

[0541] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.27 (s, 2H), 8.03 (s, 1H), 8.00 (s, 1H), 7.91 (d, J=9.88 Hz, 1H), 7.46 (br d, J=7.75 Hz, 1H), 7.17 (d, J=9.88 Hz, 1H), 5.99-6.07 (m, 1H), 3.88 (s, 3H), 1.72-1.80 (m, 3H).

[0542] .sup.19F NMR (377 MHz, CDCl.sub.3) ppm 62.90 (s, 6F).

Example 2: Preparation of N-[(1S)-1-[2-(1-methyl-6-oxo-4,5-dihydropyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (compound P2)

##STR00095##

[0543] Under nitrogen atmosphere, to a solution of N-[(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (compound P1, preparation described in Example 1, step E) (0.10 g, 0.217 mmol, 1.0 equiv.) in ethanol (1 mL) was added palladium on carbon (10 mass %, 0.231 g, 0.217, 1.0 equiv.). The reaction mixture was flushed with hydrogen gas and stirred at room temperature for 16 hours. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The crude was purified by preparative HPLC to afford the desired compound N-[(1S)-1-[2-(1-methyl-6-oxo-4,5-dihydropyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide, as an off white solid.

[0544] LCMS (method 1): retention time 1.10 min, m/z 463 [M+H].sup.+.

[0545] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 1.25 (s, 1H), 1.41 (s, 1H), 1.72 (d, J=6.8 Hz, 3H), 2.04 (s, 2H), 2.70-2.88 (m, 2H), 3.20-3.34 (m, 1H), 3.40 (br d, J=8.9 Hz, 1H), 3.44 (s, 3H), 6.04 (br t, J=7.2 Hz, 1H), 7.91 (br s, 1H), 7.92 (s, 1H), 7.97 (s, 1H), 8.27 (s, 2H).

[0546] .sup.19F NMR (377 MHz, chloroform-d) ppm 62.91 (s, 6F).

Example 3: Preparation of N-methyl-N-[(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (compound P5)

##STR00096##

[0547] To a solution of N-[(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (compound P1, preparation described in Example 1, step E) (0.055 g, 0.1195 mmol) in acetonitrile (0.55 mL, 10 mmol) were added cesium carbonate (0.116 g, 0.3585 mmol) and iodomethane (0.0852 g, 0.0374 mL) at room temperature. The reaction mixture was stirred at room temperature for 20 h. Progress of the reaction was monitored by LCMS. It showed formation of the desired compound. Water was added to the reaction mixture which was then extracted with EtOAc. The organic layer was washed well with brine, dried on sodium sulfate, filtered and concentrated to get the desired compound N-methyl-N-[(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (40 mg, 70% yield) as a solid. LCMS (method 2): retention time 1.02 min, m/z 475.5 [M+H].sup.+.

[0548] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.03 (s, 1H), 7.95 (s, 1H), 7.86 (d, J=9.78 Hz, 1H), 7.78 (s, 2H), 7.15 (d, J=9.78 Hz, 1H), 6.41 (br d, J=7.21 Hz, 1H), 3.73 (s, 3H), 2.94 (s, 3H), 1.76-1.80 (m, 3H).

Example 4: Preparation of N-[1-[3-(1-methyl-6-oxo-pyridazin-3-yl)pyrazin-2-yl]ethyl]-3,5-bis(trifluoromethyl) benzamide (compound P3)

##STR00097##

Step A: Preparation of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3-one (I-5)

##STR00098##

[0549] To a stirred solution of 6-chloro-2-methyl-pyridazin-3-one (I-1) (500 mg, 3.4588 mmol) in 1,4-dioxane (15 mL/g) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.2 equiv., 4.15 mmol), potassium acetate (10.37 mmol), XPhos (0.55 mmol), and palladium(II)acetate (0.38 mmol). The reaction mixture was degassed with nitrogen and then it was heated at 100 C. for 3 h. The reaction mixture was cooled to room temperature. Progress of the reaction was monitored by LCMS. The reaction mixture was then filtered through a celite bed. Water was added to the filtrate, followed by extraction with EtOAc. The organic layer was washed with brine, dried on sodium sulfate, filtered and concentrated to get the desired compound 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3-one (400 mg) as a brown thick oil which was taken for next step.

[0550] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 0.04 (s, 1H), 1.15-1.28 (m, 22H), 1.33 (s, 12H), 2.01 (s, 1H), 3.67 (s, 10H), 3.85 (s, 3H), 6.87 (d, J=9.51 Hz, 1H), 7.27 (s, 1H), 7.50 (d, J=9.38 Hz, 1H).

Step B: Preparation of N-[1-[3-(1-methyl-6-oxo-pyridazin-3-yl)pyrazin-2-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (compound P3)

##STR00099##

[0551] To a stirred solution of N-[1-(3-chloropyrazin-2-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide (CAS 2415178-03-7, prepared as described for example in WO20/070049) (800 mg, 2.012 mmol) in 1,4-dioxane (25 mL) were added 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3-one (1-5) (1.2 equiv., 2.414 mmol), potassium acetate (6.03 mmol) and finally 1,1-bis(diphenyl-phosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.201 mmol, 100 mass %). The reaction mixture was degassed with nitrogen and then it was heated at 85 C. for 16 h. Progress of the reaction was monitored by LCMS. The reaction mixture was cooled to room temperature and filtered through a celite bed. Water was added to the filtrate followed by extraction with EtOAc. The organic layer was washed well with brine, dried on sodium sulfate, filtered and concentrated to afford the crude compound. It was then purified by combiflash to get the desired compound as white solid N-[1-[3-(1-methyl-6-oxo-pyridazin-3-yl) pyrazin-2-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (250 mg, 26% yield).

[0552] LCMS (method 2): retention time 1.10 min, m/z 472.1 [M+H].sup.+.

[0553] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.60-8.64 (m, 2H), 8.25 (s, 2H), 8.16 (d, 1H), 8.02 (s, 1H), 7.69 (br d, 1H), 7.11 (d, 1H), 6.18-6.26 (m, 1H), 3.97 (s, 3H), 1.67-1.74 (m, 3H).

Example 5: Preparation of N-methyl-N-[1-[3-(1-methyl-6-oxo-pyridazin-3-yl)pyrazin-2-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (compound P6)

##STR00100##

[0554] To a solution of N-[1-[3-(1-methyl-6-oxo-pyridazin-3-yl)pyrazin-2-yl]ethyl]-3,5-bis(trifluoro-methyl)benzamide (compound P3, prepared as described above) (0.07 g, 0.148 mmol) in acetonitrile (0.7 mL) were added cesium carbonate (0.1452 g, 0.4455 mmol) and iodomethane (0.106 g, 0.74 mmol) at room temperature. The reaction mixture was stirred at room temperature for 20 h. Progress of the reaction was monitored by LCMS. Water was added to the reaction mixture, followed by extraction with EtOAc. Then the organic layer was washed well with brine, dried over sodium sulfate, filtered and concentrated to afford the desired compound N-methyl-N-[1-[3-(1-methyl-6-oxo-pyridazin-3-yl)pyrazin-2-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (50 mg, 69%) as a brown gummy mass.

[0555] LCMS (method 2): retention time 1.08 min, m/z 486.4 [M+H].sup.+.

Example 6: Preparation of 3,5-dibromo-N-[1-[3-(1-methyl-6-oxo-pyridazin-3-yl)pyrazin-2-yl]ethyl]benzamide (compound P13)

##STR00101##

[0556] To a solution of 6-[3-(1-aminoethyl)pyrazin-2-yl]-2-methyl-pyridazin-3-one (XX.sup.C1) (309.8 mg, 1.340 mmol) in acetonitrile (2.5 mL) were added 3,5-dibromobenzoic acid (250 mg, 0.893 mmol) and N,N-diisopropylethylamine (346.3 mg, 2.679 mmol), followed by 1-propanphosphonic acid cyclic anhydride (T3P, 50 wt. % sol. in ethyl acetate, 1.063 mL, 1.786 mmol) slowly dropwise. The reaction mixture was stirred at room temperature for 16 hours. Water was added to the mixture and the product extracted with EtOAc. The organic layer was washed with brine, dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by combiflash (EtOAc in cyclohexane) to afford 3,5-dibromo-N-[1-[3-(1-methyl-6-oxo-pyridazin-3-yl)pyrazin-2-yl]ethyl]benzamide (compound P13) as a solid.

[0557] LCMS (method 2): retention time 1.11 min, m/z 492/494/496 [M+H].sup.+.

[0558] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.61 (s, 2H), 8.14 (d, 1H), 7.86 (d, 2H), 7.80 (d, 1H), 7.50 (br d, 1H), 7.10 (d, 1H), 6.14 (m, 1H), 3.96 (s, 3H), 1.66 (d, 3H).

Example 7: Preparation of 3-chloro-N-[(1S)-1-[2-(1-ethyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]-5-(trifluoromethylsulfonyl)benzamide (compound P17)

##STR00102##

[0559] To a solution of 3-chloro-5-(trifluoromethylsulfonyl)benzoic acid (CAS 2378554-12-0) (300 mg, 1.039 mmol) and [(1S)-1-[2-(1-ethyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;chloride (XX.sup.a2) (90%, 343.9 mg, 1.143 mmol) in acetonitrile (3 mL) were added N,N-diisopropylethylamine (407.1 mg, 3.118 mmol), followed by 1-propanphosphonic acid cyclic anhydride (T3P, 50 wt. % sol. in ethyl acetate, 1.84 mL, 3.118 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the mixture, the formed precipitate was filtered and dried in vacuo to afford 3-chloro-N-[(1S)-1-[2-(1-ethyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]-5-(trifluoromethyl-sulfonyl)benzamide (compound P17) as a solid.

[0560] LCMS (method 2): retention time 1.09 min, m/z 505/507 [M+H].sup.+.

[0561] .sup.1H NMR (400 MHz, DMSO-d6) ppm 1.22 (t, 3H), 1.66 (d, 3H), 4.04 (q, 2H), 5.71 (m, 1H), 7.15 (d, 1H), 7.83 (d, 1H), 8.24 (s, 1H), 8.43 (m, 1H), 8.47 (m, 1H), 8.51 (m, 1H), 9.64 (d, 1H).

Example 8: Preparation of 3-chloro-N-[(1S)-1-[2-(1-methyl-6-oxo-4,5-dihydropyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]-5-(trifluoromethyl)benzamide (compound P19)

##STR00103##

[0562] To a solution of 3-chloro-5-(trifluoromethyl)benzoic acid (260.4 mg, 1.160 mmol) and [(1S)-1-[2-(1-methyl-6-oxo-4,5-dihydropyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;chloride (XX.sup.b1) (300 mg, 1.160 mmol) in acetonitrile (9.3 mL) were added N,N-diisopropylethylamine (449.6 mg, 3.479 mmol), followed by 1-propanphosphonic acid cyclic anhydride (T3P, 50 wt. % sol. in ethyl acetate, 2.073 mL, 3.479 mmol) dropwise. The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the product extracted with EtOAc (3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by combiflash (0-60% EtOAc in cyclohexane) to afford 3-chloro-N-[(1S)-1-[2-(1-methyl-6-oxo-4,5-dihydropyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]-5-(trifluoromethyl)benzamide (compound P19) as a solid.

[0563] LCMS (method 2): retention time 1.09 min, m/z 429/431 [M+H]+.

Preparation of Intermediates

Example PI-1: Preparation of [(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;chloride (compound XX.SUP.a1.)

##STR00104##

Step A: Preparation of 6-hydrazino-2-methyl-pyridazin-3-one (I-2)

##STR00105##

[0564] To a 25 ml RBF charged with 6-chloro-2-methyl-pyridazin-3-one (compound 1-1 prepared as described above) (4.5 g, 31.129 mmol) were added methoxy cyclopentane (CPME) (45 mL) and then hydrazine hydrate (7.79 g, 155.64 mmol) at room temperature. The reaction mixture was heated at 100 C. for 1 hour (biphasic reaction mixture). The reaction mixture was cooled to room temperature. The CPME layer was separated, and the residue layer was washed with TBME using a separating funnel. The residue layer was concentrated at 50 C., and the obtained crude was adsorbed on celite and then purified by combiflash (silica gel column, elution with EtOAc/MeOH). The product was eluted in 95:5 EtOAc/MeOH to get 6-hydrazino-2-methyl-pyridazin-3-one (2.5 g, 14 mmol, 46%) as a white solid.

[0565] LCMS (method 2): retention time 0.14 min, m/z 141.1 [M+H]+.

Step B: Preparation of tert-butyl N-[(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-6)

##STR00106##

[0566] To a 250 mL RBF charged with 6-hydrazino-2-methyl-pyridazin-3-one (I-2) (2.5 g, 14.271 mmol) were added tert-butyl N-[(1S)-2-[(E)-dimethylaminomethyleneamino]-1-methyl-2-oxo-ethyl]carbamate (CAS 2641011-39-2, prepared as described for example in WO21/083936) (4.16 g, 17.126 mmol), 1,4-dioxane (25 mL), molecular sieves 4 A (5 g) and acetic acid (25 mL). After addition, the reaction mass was heated at 80 C. for 5 h. Progress of the reaction mass was monitored by LCMS. The reaction mixture was filtered through a celite bed, the celite bed was washed with EtOAc and the filtrate was concentrated. The residue was diluted with saturated aqueous NaHCO.sub.3 and the product extracted three times with EtOAc (100 mL3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was adsorbed on silica and purified by combiflash. The product was eluted in 80:20 EtOAc/cyclohexane to afford 2.8 g product, which was purified further by reverse phase column chromatography on 40 g C18 (40-60 m) and eluted using H.sub.2O/ACN. Product fractions were freeze dried to get tert-butyl N-[(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (1.2 g, 3.0 mmol, 21%) as a white solid.

[0567] .sup.1H NMR (400 MHz, CDCl.sub.3) : 7.95 (s, 1H), 7.86 (d, 1H), 7.13 (d, J=9.9 Hz, 1H), 5.46-5.55 (m, 1H), 5.42 (br, 1H), 3.84 (s, 3H), 1.54-1.64 (d, 3H), 1.42 (s, 9H).

Step C: Preparation of [(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;chloride (compound XX.SUP.a1.)

##STR00107##

[0568] In a 50 mL reaction flask, tert-butyl N-[(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (1.5 g, 3.745 mmol) was dissolved in CPME (15 mL) and then hydrochloric acid (4M in dioxane) (14.04 mL, 56.18 mmol) was added into the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 18 h, during which a white solid precipitated. Progress of the reaction was monitored by LCMS. The reaction mass was concentrated in vacuo and the resulting white solid was stirred in ACN (20 mL). The solid was separated by filtration and dried under reduced pressure to get [(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;chloride (1.2 g, 3.90 mmol) as a white solid.

[0569] .sup.1H NMR (400 MHz, DMSO-d6) ppm 8.39 (s, 1H), 7.93 (d, 1H), 7.24 (d, 1H), 5.07 (br, 1H), 3.72 (s, 3H), 1.63 (d, 3H).

Example PI-2: Preparation of [(1S)-1-[2-(1-ethyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;chloride (compound XX.SUP.a2.)

##STR00108##

Step A: Preparation of tert-butyl N-[(1S)-1-[2-(6-chloropyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-7)

##STR00109##

[0570] To a stirred solution of tert-butyl N-[(1S)-2-[(E)-dimethylaminomethyleneamino]-1-methyl-2-oxo-ethyl]carbamate (CAS 2641011-39-2, prepared as described for example in WO21/083936) (5 g, 20.55 mmol) in 1,4-dioxane (50 mL) was added 3-chloro-6-hydrazinopyridazine (CAS 17284-97-8) (3.27 g, 22.61 mmol), followed by acetic acid (50 mL). The reaction mixture was heated to 80 C. for 2 hours, then cooled to RT and concentrated in vacuo. The residue was diluted with water and the product extracted with EtOAc. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by combiflash (gradient ethyl acetate in cyclohexane) to afford tert-butyl N-[(1S)-1-[2-(6-chloropyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-7).

[0571] LCMS (method 2): retention time 0.98 min, m/z 269/271 [M+H-tBu].sup.+, 225/227 [M+H-Boc].sup.+.

[0572] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.13 (d, 1H), 8.01 (s, 1H), 7.72 (d, 1H), 5.78 (quin, 1H), 5.51 (br s, 1H), 1.65 (d, 3H), 1.39 (s, 9H).

Step B: Preparation of tert-butyl N-[(1S)-1-[2-(6-oxo-1H-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-8)

##STR00110##

[0573] To a solution of tert-butyl N-[(1S)-1-[2-(6-chloropyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-7) (4.0 g, 12.32 mmol) and (E)-benzaldehyde oxime (1.99 g, 16.01 mmol) in N,N-dimethylformamide (40 mL) was added cesium carbonate (10.03 g, 30.79 mmol). The reaction mixture was stirred at 100 C. for 2 h, cooled to room temperature and diluted with water. The product was extracted thoroughly with 60% ACN in EtOAc, the combined organic layers washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by combiflash (EtOAc) to afford tert-butyl N-[(1S)-1-[2-(6-oxo-1H-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-8) as a gum.

[0574] LCMS (method 2): retention time 0.84 min, m/z 305 [MH].sup..

[0575] .sup.1H NMR (400 MHz, DMSO-d6) ppm 13.29 (s, 1H), 8.14 (s, 1H), 7.73 (d, 1H), 7.49 (d, 1H), 7.13 (d, 1H), 5.19 (quin, 1H), 1.42 (d, 3H), 1.30 (s, 9H).

Step C: Preparation of tert-butyl N-[(1S)-1-[2-(1-ethyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-9)

##STR00111##

[0576] A solution of tert-butyl N-[(1S)-1-[2-(6-oxo-1H-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-8) (7.15 g, 19.8 mmol), cesium carbonate (6.47 g, 19.8 mmol) and iodoethane (1.74 mL, 21.8 mmol) in acetonitrile (71.5 mL) was stirred at room temperature for 30 hours. The reaction mixture was filtered through a pad of celite and the residue washed with ACN. The filtrate was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by combiflash (40-50% gradient EtOAc in cyclohexane) to afford tert-butyl N-[(1S)-1-[2-(1-ethyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate as a solid.

[0577] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.96 (s, 1H), 7.85 (d, 1H), 7.12 (d, 1H), 5.52 (m, 1H), 5.44 (m, 1H), 4.22-4.33 (m, 2H), 1.61 (d, 3H), 1.47 (t, 3H), 1.43 (s, 9H).

Step D: Preparation of [(1S)-1-[2-(1-ethyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;chloride (compound XX.SUP.a2.)

##STR00112##

[0578] To a solution of tert-butyl N-[(1S)-1-[2-(1-ethyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (1-9) (1.90 g, 5.40 mmol) in CPME (19 mL) was added hydrochloric acid (4M in 1,4-dioxane)(40.0 mL, 160 mmol) and the reaction mixture was stirred at room temperature for 12 hours. Additional hydrochloric acid (4M in 1,4-dioxane, 20 equiv.) was added and stirring continued for 12 hours at room temperature. The mixture was concentrated under reduced pressure to afford [(1S)-1-[2-(1-ethyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;chloride as a white solid.

[0579] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.76 (brs, 3H), 8.40 (s, 1H), 7.93 (d, 1H), 7.24 (d, 1H), 5.09 (m, 1H), 4.15 (q, 2H) 1.64 (d, 3H), 1.33 (t, 3H).

Example PI-3: Preparation of [(1S)-1-[2-(6-oxo-1H-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;chloride (compound 1-10)

##STR00113##

[0580] To a solution of tert-butyl N-[(1S)-1-[2-(6-oxo-1H-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-8) (2 g, 5.88 mmol, 90 mass %) in CPME (20 mL) was added hydrochloric acid (4M in dioxane) (2.7 mL) at room temperature and the reaction mixture was stirred for 12 h. After further addition of hydrochloric acid (4M in dioxane) (3.6 mL) stirring was continued for another 12 h. The mixture was concentrated in vacuo and dried to afford [(1S)-1-[2-(6-oxo-1H-pyridazin-3-yl)-1,2,4-triazol-3-l]ethyl]ammonium;chloride (1-10) as a white solid.

[0581] .sup.1H NMR (400 MHz, DMSO-d6) ppm 13.33 (br s, 1H), 8.78 (br s, 3H), 8.37 (s, 1H), 7.88 (d, 1H), 7.17 (d, 1H), 4.99 (quin, 1H), 1.59 (d, 3H).

Example PI-4: Preparation of [(1S)-1-[2-(1-methyl-6-oxo-4,5-dihydropyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;chloride (compound XX.SUP.b.1)

##STR00114##

Step A: Preparation of tert-butyl N-[(1S)-1-[2-(1-methyl-6-oxo-4,5-dihydropyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-11)

##STR00115##

[0582] A solution of tert-butyl N-[(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (compound 1-6, prepared as described above)(300 mg, 0.936 mmol) in methanol (15 mL) was flushed with nitrogen. Palladium on carbon (10%, 199.3 mg) was added and the reaction mixture was stirred under hydrogen atmosphere at room temperature for 36 hours. The mixture was filtered through a pad of celite, the residue washed with methanol and the filtrate concentrated in vacuo. The crude product was purified by combiflash (gradient EtOAc in cyclohexane) to afford tert-butyl N-[(1S)-1-[2-(1-methyl-6-oxo-4,5-dihydropyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate as a gum. LCMS (method 2): retention time 1.01 min, m/z 323 [M+H].sup.+.

[0583] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 7.88 (s, 1H), 5.51 (m, 1H), 5.43 (m, 1H), 3.41 (s, 3H), 3.22 (m, 2H), 2.74 (m, 2H), 1.54 (d, 3H), 1.42 (s, 9H).

Step B: Preparation of [(1S)-1-[2-(1-methyl-6-oxo-4,5-dihydropyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;chloride (compound XX.SUP.b1.)

##STR00116##

[0584] To a solution of tert-butyl N-[(1S)-1-[2-(1-methyl-6-oxo-4,5-dihydropyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-11) (2.3 g, 7.1 mmol) in 1,4-dioxane (19 mL) was added hydrochloric acid (4M in 1,4-dioxane)(19 mL, 76 mmol) and the mixture was stirred for 5 hours at room temperature. The mixture was concentrated under reduced pressure and the residue triturated with TBME. The precipitate was filtered and dried to afford [(1S)-1-[2-(1-methyl-6-oxo-4,5-dihydropyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;chloride as a white solid.

[0585] LCMS (method 2): retention time 0.23 min, m/z 223 [M+H].sup.+ for the free base.

[0586] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 8.79 (br s, 3H), 8.30 (s, 1H), 5.06 (m, 1H), 3.29 (s, 3H), 3.18-3.28 (m, 2H), 2.69 (m, 2H), 1.61 (d, 3H).

Example PI-5: Preparation of 6-[3-(1-aminoethyl)pyrazin-2-yl]-2-methyl-pyridazin-3-one (compound XX.SUP.c1.)

##STR00117##

Step A: Preparation of 6-(3-acetylpyrazin-2-yl)-2-methyl-pyridazin-3-one (I-12)

##STR00118##

[0587] To a stirred solution of 1-(3-chloropyrazin-2-yl)ethanone (CAS 121246-90-0) (3.75 g, 24.0 mmol) in 1,4-dioxane (56.3 mL) was added 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3-one (compound 1-5, prepared as described above) (6.79 g, 28.7 mmol), followed by cesium carbonate (23.4 g, 71.9 mmol) and 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.96 g, 2.40 mmol). The reaction mixture was flushed with nitrogen and heated at 120 C. for 1 hour. After cooling to room temperature, the mixture was filtered through a pad of celite and the filtrate diluted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by combiflash (gradient EtOAc in cyclohexane) to afford 6-(3-acetylpyrazin-2-yl)-2-methyl-pyridazin-3-one as a brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.67 (d, 1H), 8.58 (d, 1H), 8.03 (d, 1H), 7.06 (d, 1H), 3.80 (s, 3H), 2.72 (s, 3H).

Alternative Preparation of 6-(3-acetylpyrazin-2-yl)-2-methyl-pyridazin-3-one (I-12)

[0588] To a solution of 6-[3-(1-hydroxyethyl)pyrazin-2-yl]-2-methyl-pyridazin-3-one (compound 1-14, prepared as described below) (100 mg, 0.431 mmol) in acetonitrile (8.6 mL) under argon at 0 C. was added Dess-Martin periodinane (CAS 87413-09-0) (188.3 mg, 0.431 mmol). The reaction mixture was stirred at 0 C. for 80 minutes, then at room temperature overnight. Additional Dess-Martin periodinane (56.5 mg, 0.129 mmol) was added and stirring continued for another 2 hours at room temperature. The mixture was quenched by addition of sodium thiosulfate, then diluted with ethyl acetate and stirred for 15 minutes at room temperature. The formed white precipitate was filtered off and the organic layer washed with water, aqueous NaHCO.sub.3 and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by combiflash (gradient ethyl acetate in cyclohexane) to afford 6-(3-acetylpyrazin-2-yl)-2-methyl-pyridazin-3-one as a solid. LCMS (method 3): retention time 0.53 min, m/z 231 [M+H].sup.+.

Step B: Preparation of 6-[3-(1-aminoethyl)pyrazin-2-yl]-2-methyl-pyridazin-3-one (compound XX.SUP.c1.)

##STR00119##

[0589] To a stirred solution of 6-(3-acetylpyrazin-2-yl)-2-methyl-pyridazin-3-one (I-12) (1.0 g, 4.34 mmol) in ammonia (7M in methanol, 3.1 mL, 21.7 mmol) at room temperature was added titanium(IV) isopropoxide (2.48 mL, 8.69 mmol) dropwise and the reaction mixture stirred for 16 hours at room temperature. Sodium borohydride (259 mg, 6.52 mmol) was added slowly in portions and stirring continued at room temperature overnight. The mixture was quenched with water and concentrated under reduced pressure. The residue was treated with methanol (10 mL) and stirred for 5 minutes, then filtered through a pad of celite and the filtrate was concentrated in vacuo. 2N HCl was added to the residue, the mixture concentrated, the residue was dissolved in methanol and solid sodium carbonate was added. The mixture was stirred for 30 minutes, the methanol layer carefully decanted and concentrated under reduced pressure. The crude product was purified by combiflash (gradient methanol in ethyl acetate) to afford 6-[3-(1-aminoethyl)pyrazin-2-yl]-2-methyl-pyridazin-3-one as a solid. LCMS (method 2): retention time 0.15 min, m/z 232 [M+H].sup.+.

[0590] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.61 (d, 1H), 8.59 (d, 1H), 8.15 (d, 1H), 7.08 (d, 1H), 5.26 (m, 1H), 3.90 (s, 3H), 1.74 (d, 3H).

Example PI-6: Alternative preparation of 6-[3-(1-aminoethyl)pyrazin-2-yl]-2-methyl-pyridazin-3-one (compound XX.SUP.c1.)

##STR00120##

Step A: Preparation of 1-(3-iodopyrazin-2-yl)ethanol (Int-A)

##STR00121##

[0591] Under an argon atmosphere THE (35 mL) was cooled to 0 C. Then 2,2,6,6-tetramethylpiperidine (5.4 mL, 30.9 mmol, 1.34 equiv.) was added at 0 C. followed by a dropwise addition of 2.5M n-BuLi (12 mL, 29.98 mmol, 1.3 equiv.). The reaction mixture was cooled to 78 C., then a solution of 2-iodopyrazine (5.0 g, 23.06 mmol, 1.0 equiv.) in THE (5 mL) was added dropwise. After stirring for 1 hour, acetaldehyde (12 mL, 210 mmol, 9.2 equiv.) was added dropwise at 78 C. After addition, the reaction mixture was allowed to warm up to room temperature before it was quenched with saturated aqueous ammonium chloride solution. The reaction mixture was diluted with water and a mixture of TBME and ethyl acetate. The aqueous layer was acidified with 1M HCl to pH 1-2. The phases were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude extract was purified by flash chromatography (0-10% ethyl acetate in cyclohexane) to afford 1-(3-iodopyrazin-2-yl)ethanol.

[0592] LCMS (method 3): retention time 0.54 min, m/z 251 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.47 (d, 1H), 8.31 (d, 1H), 5.10 (dd, 1H), 3.66-3.73 (m, 1H), 1.52 (d, 3H).

Step B: Preparation of tert-butyl-[1-(3-iodopyrazin-2-yl)ethoxy]-dimethyl-silane (Int-B)

##STR00122##

[0593] To a solution of 1-(3-iodopyrazin-2-yl)ethanol (Int-A) (1.20 g, 4.80 mmol, 1.0 equiv.) in THE (10 mL) was added imidazole (660 mg, 9.60 mmol, 2.0 equiv.) followed by tert-butyldimethylchlorosilane (1.1 mL, 5.76 mmol, 1.2 equiv.). The resulting reaction mixture was heated to 50 C. and was stirred at this temperature for 2 hours before it was allowed to cool down to room temperature. The reaction mixture was filtered. The filtration cake was washed with TBME and the filtrate way concentrated in vacuo. The crude extract was purified by flash chromatography (0-3% ethyl acetate in cyclohexane) to afford tert-butyl-[1-(3-iodopyrazin-2-yl)ethoxy]-dimethyl-silane.

[0594] LCMS (method 3): retention time 1.30 min, m/z 365 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.52 (d, 1H), 8.24 (d, 1H), 5.31 (q, 1H), 1.51 (d, 3H), 0.88 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H).

Step C: Preparation of 6-[3-[1-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazin-2-yl]-2-methyl-pyridazin-3-one (I-13)

##STR00123##

[0595] Tert-butyl-[1-(3-iodopyrazin-2-yl)ethoxy]-dimethyl-silane (Int-B, prepared as described above) (1.20 g, 3.29 mmol) was dissolved in dry THF (16.5 mL) in a heat-gun dried RBF under argon. The solution was cooled to 78 C., then turbo Grignard (1.3 M in THF) (3.3 mL, 4.28 mmol) was added dropwise. The reaction mixture was stirred for 1.5 hours at 78 C., then zinc chloride was added (1.9 M in 2-methyltetrahydrofuran) (2.3 mL, 4.28 mmol) and stirring continued for 3 hours (resulting solution A). A solution of 6-bromo-2-methyl-pyridazin-3-one (CAS 1123169-25-4) (762 mg, 3.95 mmol), tri(2-furyl)phosphine (96.6 mg, 0.395 mmol) and tris(dibenzylideneacetone) dipalladium(0) (187 mg, 0.198 mmol) in dry THF (16.5 mL) under argon was prepared in a separate vessel and added to solution A at 0 C. The reaction mixture was heated at 60 C. for 1 hour. After cooling to room temperature, the mixture was diluted with an aqueous saturated solution of ammonium chloride and ethyl acetate. The phases were separated, the aqueous layer extracted with ethyl acetate (3) and the combined organic layers washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by combiflash (ethyl acetate in cyclohexane) to afford 6-[3-[1-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazin-2-yl]-2-methyl-pyridazin-3-one as a gum.

[0596] LCMS (method 3): retention time 1.05 min, m/z 347 [M+H].sup.+.

[0597] .sup.1H NMR (400 MHz, MeOD) ppm 8.69 (d, 1H), 8.66 (d, 1H), 8.11 (d, 1H), 7.16 (d, 1H), 5.70 (q, 1H), 3.88 (s, 3H), 1.67 (d, 3H), 0.78 (s, 9H), 0.04 (s, 3H), 0.10 (s, 3H).

Step D: Preparation of 6-[3-(1-hydroxyethyl)pyrazin-2-yl]-2-methyl-pyridazin-3-one (I-14)

##STR00124##

[0598] To a solution of 6-[3-[1-[tert-butyl(dimethyl)silyl]oxyethyl]pyrazin-2-yl]-2-methyl-pyridazin-3-one (I-13) (330 mg, 0.629 mmol) in THF (6.29 mL) was added tetrabutylammonium fluoride (1M in THF) (0.94 mL, 0.94 mmol) at 0 C. under argon. The reaction mixture was stirred at room temperature for 1.5 hours, then diluted with brine and ethyl acetate. The phases were separated and the aqueous layer extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by combiflash (ethyl acetate in cyclohexane) to afford 6-[3-(1-hydroxyethyl)pyrazin-2-yl]-2-methyl-pyridazin-3-one as an oil.

[0599] LCMS (method 3): retention time 0.47 min, m/z 233 [M+H].sup.+.

[0600] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.54-8.68 (m, 2H), 8.18 (d, 1H), 7.10 (d, 1H), 5.54 (q, 1H), 3.93 (s, 3H), 1.59 (d, 3H).

Step E: Preparation of 2-[1-[3-(1-methyl-6-oxo-pyridazin-3-yl)pyrazin-2-yl]ethyl]isoindoline-1,3-dione (I-15)

##STR00125##

[0601] To a solution of 6-[3-(1-hydroxyethyl)pyrazin-2-yl]-2-methyl-pyridazin-3-one (I-14) (150 mg, 0.646 mmol), phthalimide (105.6 mg, 0.71 mmol) and triphenylphosphine (205.3 mg, 0.78 mmol) in THE (1.94 mL) under argon at 0 C. was added diisopropyl azodicarboxylate (0.162 mL, 0.7751 mmol). The reaction mixture was allowed to warm to room temperature over 1 hour under stirring, then diluted with water and ethyl acetate. The phases were separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by combiflash (ethyl acetate in cyclohexane) to afford 2-[1-[3-(1-methyl-6-oxo-pyridazin-3-yl)pyrazin-2-yl]ethyl]isoindoline-1,3-dione as a white foam. LCMS (method 3): retention time 0.81 min, m/z 362 [M+H].sup.+.

[0602] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 8.61 (d, 1H), 8.55 (d, 1H), 7.84 (d, 1H), 7.79-7.73 (m, 2H), 7.72-7.67 (m, 2H), 6.89 (d, 1H), 6.35 (q, 1H), 3.85 (s, 3H), 1.94 (d, 3H).

Step F: Preparation of 6-[3-(1-aminoethyl)pyrazin-2-yl]-2-methyl-pyridazin-3-one (compound XX.SUP.c1.)

##STR00126##

[0603] To a suspension of 2-[1-[3-(1-methyl-6-oxo-pyridazin-3-yl)pyrazin-2-yl]ethyl]isoindoline-1,3-dione (I-15) (220 mg, 0.61 mmol) in ethanol (6.09 mL) was added hydrazine hydrate (0.0354 mL, 0.73 mmol) at room temperature. The reaction mixture was stirred overnight at 80 C., then cooled to room temperature. Few mL of TBME were added and stirring continued for 20 minutes. The white suspension was filtered, and the filtrate evaporated under reduced pressure and dried to afford crude 6-[3-(1-aminoethyl)pyrazin-2-yl]-2-methyl-pyridazin-3-one.

[0604] LCMS (method 3): retention time 0.15 min, m/z 232 [M+H].sup.+.

TABLE-US-00013 TABLE P Physical data of compounds of formula (I) RT [M + H].sup.+ mp Entry IUPAC name Structure (min) (measured) Method ( C.) P1 N-[(1S)-1-[2-(1-methyl-6- oxo-pyridazin-3-yl)-1,2,4- triazol-3-yl]ethyl]-3,5- bis(trifluoromethyl) benzamide [00127] 1.38 461 1 170-172 P2 N-[(1S)-1-[2-(1-methyl-6- oxo-4,5-dihydro pyridazin- 3-yl)-1,2,4-triazol-3- yl]ethyl]-3,5- bis(trifluoromethyl) benzamide [00128] 1.10 463 1 130-132 P3 N-[1-[3-(1-methyl-6-oxo- pyridazin-3-yl)pyrazin-2- yl]ethyl]-3,5-bis(trifluoro methyl)benzamide [00129] 1.10 472.1 2 205-207 P4 3-chloro-N-[(1S)-1-[2-(1- methyl-6-oxo-pyridazin-3- yl)-1,2,4-triazol-3-yl]ethyl]- 5-(trifluoromethyl) benzamide [00130] 1.05 427/429 2 140-142 P5 N-methyl-N-[(1S)-1-[2-(1- methyl-6-oxo-pyridazin-3- yl)-1,2,4-triazol-3-yl]ethyl]- 3,5- bis(trifluoromethyl) benzamide [00131] 1.02 475.5 2 128-130 P6 N-methyl-N-[1-[3-(1- methyl-6-oxo-pyridazin-3- yl)pyrazin-2-yl]ethyl]-3,5- bis(trifluoromethyl) benzamide [00132] 1.08 486.4 2 P7 3-chloro-N-[1-[3-(1- methyl-6-oxo-pyridazin-3- yl)pyrazin-2-yl]ethyl]-5- (trifluoromethyl)benzamide [00133] 2.38 438/440 1 186-188 P8 N-[(1S)-1-[2-(1-methyl-6- oxo-pyridazin-3-yl)-1,2,4- triazol-3-yl]ethyl]-3- (trifluoromethyl)-5- (trifluoromethylsulfonyl) benzamide [00134] 1.09 525.1 2 171-173 P9 3-chloro-N-[(1S)-1-[2-(1- methyl-6-oxo-pyridazin-3- yl)-1,2,4-triazol-3-yl]ethyl]- 5-methylsulfonyl- benzamide [00135] 0.93 437/439 2 122-124 P10 3-bromo-N-[1-[3-(1- methyl-6-oxo-pyridazin-3- yl)pyrazin-2-yl]ethyl]-5- (trifluoromethyl)benzamide [00136] 1.45 482.17 4 P11 3-chloro-N-[1-[3-(1- methyl-6-oxopyridazin-3- yl)pyrazin-2-yl]ethyl]-5- (trifluoromethoxy) benzamide [00137] 1.47 454.23 4 P12 3-chloro-5-iodo-N-[1-[3- (1-methyl-6-oxo- pyridazin-3-yl)pyrazin-2- yl]ethyl]benzamide [00138] 1.42 496.11 4 P13 3,5-dibromo-N-[1-[3-(1- methyl-6-oxo-pyridazin-3- yl)pyrazin-2- yl]ethyl]benzamide [00139] 1.11 492/494/ 496 2 208-210 P14 3-(difluoromethoxy)-N-[1- [3-(1-methyl-6-oxo- pyridazin-3-yl)pyrazin-2- yl]ethyl]-5- (trifluoromethyl)benzamide [00140] 1.39 470.24 4 P15 3-bromo-5-iodo-N-[1-[3- (1-methyl-6-oxo- pyridazin-3-yl)pyrazin-2- yl]ethyl]benzamide [00141] 1.45 540.09 4 P16 3-chloro-N-[(1S)-1-[2-(1- ethyl-6-oxo-pyridazin-3- yl)-1,2,4-triazol-3-yl]ethy]- 5- (trifluoromethyl)benzamide [00142] 1.00 441/443 2 88-90 P17 3-chloro-N-[(1S)-1-[2-(1- ethyl-6-oxo-pyridazin-3- yl)-1,2,4-triazol-3-yl]ethyl]- 5- (trifluoromethylsulfonyl) benzamide [00143] 1.09 505/507 2 174-176 P18 3-chloro-N-methyl-N- [(1S)-1-[2-(1-methyl-6- oxo-pyridazin-3-yl)-1,2,4- triazol-3-yl]ethyl]-5- (trifluoromethylsulfonyl) benzamide [00144] 1.09 505/507 2 68-70 P19 3-chloro-N-[(1S)-1-[2-(1- methyl-6-oxo-4,5- dihydropyridazin-3-yl)- 1,2,4-triazol-3-yl]ethyl]-5- (trifluoromethyl)benzamide [00145] 1.09 429/431 2 96-98 P20 3-chloro-N-[(1S)-1-[2-(1- methyl-6-oxo-pyridazin-3- yl)-1,2,4-triazol-3-yl]ethyl]- 5- (trifluoromethylsulfonyl) benzamide [00146] 1.09 491/493 2 192-194 P21 3-chloro-N-[(1S)-1-[2-(1- methyl-6-oxo-4,5- dihydropyridazin-3-yl)- 1,2,4-triazol-3-yl]ethyl]-5- (trifluoromethylsulfonyl) benzamide [00147] 1.06 493/495 2 188-190 P22 3-chloro-N-methyl-N- [(1S)-1-[2-(1-methyl-6- oxo-4,5-dihydropyridazin- 3-yl)-1,2,4-triazol-3- yl]ethyl]-5- (trifluoromethylsulfonyl) benzamide [00148] 1.11 507/509 2 114-116 P23 3-chloro-N-methyl-N- [(1S)-1-[2-(1-methyl-6- oxo-4,5-dihydropyridazin- 3-yl)-1,2,4-triazol-3- yl]ethyl]-5- (trifluoromethyl)benzamide [00149] 1.12 443/445 2 P24 3-(1-cyanocyclopropyl)-N- [1-[3-(1-methyl-6-oxo- pyridazin-3-yl)pyrazin-2- yl]ethyl]-5- (trifluoromethyl) benzamide [00150] 1.32 469.47 4 P25 3-(1-cyanocyclopropyl)-N- [(1S)-1-[2-(1-methyl-6- oxo-pyridazin-3-yl)-1,2,4- triazol-3-yl]ethyl]-5- (trifluoromethyl)benzamide [00151] 1.19 458.46 4 P26 3-chloro-N-[(1S)-1-[2-(1- methyl-6-oxo-pyridazin-3- yl)-1,2,4-triazol-3-yl]ethyl]- 5- (trifluoromethoxy)benzamide [00152] 1.33 443.41 4 P27 3-bromo-5-chloro-N-[(1S)- 1-[2-(1-methyl-6-oxo- pyridazin-3-yl)-1,2,4- triazol-3- yl]ethyl]benzamide [00153] 1.22 437.34 4 P28 3-chloro-5-iodo-N-[(1S)-1- [2-(1-methyl-6-oxo- pyridazin-3-yl)-1,2,4- triazol-3- yl]ethyl]benzamide [00154] 1.27 485.32 4 P29 3,5-dibromo-N-[(1S)-1-[2- (1-methyl-6-oxo- pyridazin-3-yl)-1,2,4- triazol-3- yl]ethyl]benzamide [00155] 1.25 481.28 4 P30 3-bromo-5-iodo-N-[(1S)- 1-[2-(1-methyl-6-oxo- pyridazin-3-yl)-1,2,4- triazol-3- yl]ethyl]benzamide [00156] 1.30 529.31 4 P31 3-chloro-N-[1-[3-(1- methyl-6-oxo-pyridazin-3- yl)pyrazin-2-yl]ethyl]-5- (trifluoromethylsulfonyl) benzamide [00157] 1.44 502.39 4 P32 2-(1-cyanocyclopropyl)-N- [1-[3-(1-methyl-6-oxo- pyridazin-3-yl)pyrazin-2- yl]ethyl]-6- (trifluoromethyl)pyridine- 4-carboxamide [00158] 1.36 470.47 4 P33 2-(1-cyanocyclopropyl)-N- [(1S)-1-[2-(1-methyl-6- oxo-pyridazin-3-yl)-1,2,4- triazol-3-yl]ethyl]-6- (trifluoromethyl)pyridine- 4-carboxamide [00159] 1.24 459.46 4 P34 2-chloro-6-(1- cyanocyclopropyl)-N-[1- [3-(1-methyl-6-oxo- pyridazin-3-yl)pyrazin-2- yl]ethyl]pyridine-4- carboxamide [00160] 1.24 436.44 4 P35 2-chloro-6-(1- cyanocyclopropyl)-N- [(1S)-1-[2-(1-methyl-6- oxo-pyridazin-3-yl)-1,2,4- triazol-3-yl]ethyl]pyridine- 4-carboxamide [00161] 1.10 425.44 4 P36 3-iodo-N-[(1S)-1-[2-(1- methyl-6-oxo-pyridazin-3- yl)-1,2,4-triazol-3-yl]ethyl]- 5- (trifluoromethyl)benzamide [00162] 1.35 519.38 4 P37 3-chloro-5- (difluoromethoxy)-N- [(1S)-1-[2-(1-methyl-6- oxo-pyridazin-3-yl)-1,2,4- triazol-3- yl]ethyl]benzamide [00163] 1.17 425.43 4 P38 2-bromo-6-(1- cyanocyclopropyl)-N-[1- [3-(1-methyl-6-oxo- pyridazin-3-yl)pyrazin-2- yl]ethyl]pyridine-4- carboxamide [00164] 1.27 480.38 4 P39 2-bromo-6-(1- cyanocyclopropyl)-N- [(1S)-1-[2-(1-methyl-6- oxo-pyridazin-3-yl)-1,2,4- triazol-3-yl]ethyl]pyridine- 4-carboxamide [00165] 1.13 469.38 4 P40 3-bromo-N-[(1S)-1-[2-(1- methyl-6-oxo-pyridazin-3- yl)-1,2,4-triazol-3-yl]ethyl]- 5- (trifluoromethoxy)benzamide [00166] 1.36 487.35 4 P41 3-chloro-5- (difluoromethyl)-N-[1-[3- (1-methyl-6-oxo- pyridazin-3-yl)pyrazin-2- yl]ethyl]benzamide [00167] 1.28 420.43 4 P42 3-chloro-5- (difluoromethyl)-N-[(1S)- 1-[2-(1-methyl-6-oxo- pyridazin-3-yl)-1,2,4- triazol-3- yl]ethyl]benzamide [00168] 1.12 409.44 4 P43 3-(1-cyano-1-methyl- ethyl)-N-[(1S)-1-[2-(1- methyl-6-oxo-pyridazin-3- yl)-1,2,4-triazol-3-yl]ethyl]- 5- (trifluoromethyl)benzamide [00169] 1.24 460.49 4 P44 3-(1-cyanocyclopropyl)-5- (difluoromethoxy)-N-[1-[3- (1-methyl-6-oxo- pyridazin-3-yl)pyrazin-2- yl]ethyl]benzamide [00170] 1.22 467.49 4 P45 3-(1-cyanocyclopropyl)-5- (difluoromethoxy)-N- [(1S)-1-[2-(1-methyl-6- oxo-pyridazin-3-yl)-1,2,4- triazol-3- yl]ethyl]benzamide [00171] 1.09 456.47 4 P46 3-chloro-N-methyl-N- [(1S)-1-[2-(1-methyl-6- oxo-pyridazin-3-yl)-1,2,4- triazol-3-yl]ethyl]-5- (trifluoromethyl)benzamide [00172] 1.03 441/443 2 P47 3-chloro-N-[(1S)-1-[2-(1- ethyl-6-oxo-pyridazin-3- yl)-1,2,4-triazol-3-yl]ethyl]- N-methyl-5- (trifluoromethyl)benzamide [00173] 1.04 455/457 2 P48 3-bromo-N-[1-[3-(4- methyl-5-oxo-pyrazin-2- yl)pyrazin-2-yl]ethyl]-5- (trifluoromethyl)benzamide [00174] 0.95 482/484 3 P49 3-bromo-N-[1-[3-[4-(2,2- difluoroethyl)-5-oxo- pyrazin-2-yl]pyrazin-2- yl]ethyl]-5- (trifluoromethyl)benzamide [00175] 1.02 532/534 3 P50 3-chloro-N-[(1S)-1-[2-(1- ethyl-6-oxo-pyridazin-3- yl)-1,2,4-triazol-3-yl]ethyl]- N-methyl-5- (trifluoromethylsulfonyl) benzamide [00176] 1.07 519/521 2

List of Abbreviations

[0605] ACN=acetonitrile [0606] CPME=cyclopentyl methyl ether (or methoxy cyclopentane) [0607] DCM=dichloromethane [0608] DMF=dimethylformamide [0609] DMSO=dimethylsulfoxide [0610] DMSO-d.sub.6=deuterated dimethylsulfoxide [0611] EtOAc=ethyl acetate [0612] EtOH=ethanol [0613] HCl=hydrochloric acid [0614] MeOH=methanol [0615] n-BuLi=n-butyllithium [0616] NaHCO.sub.3=sodium hydrogen carbonate [0617] PdCl.sub.2dppf=1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride [0618] TBME=methyl tertiary-butyl ether [0619] THE=tetrahydrofuran [0620] XPhos=2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl [0621] aq.=aqueous [0622] C.=degrees Celsius [0623] equiv.=equivalent [0624] h=hour(s) [0625] LCMS=Liquid Chromatography Mass Spectrometry (description of the apparatus and the [0626] methods used for LCMS analysis are given above) [0627] M=molar [0628] MHz=megahertz [0629] min=minutes [0630] mp=melting point [0631] ppm=parts per million [0632] RT=room temperature [0633] Rt=retention time [0634] RBF=round-bottom flask

Biological Examples

[0635] The Examples which follow serve to illustrate the invention. Certain compounds of the invention can be distinguished from known compounds by virtue of greater efficacy at low application rates, which can be verified by the person skilled in the art using the experimental procedures outlined in the Examples, using lower application rates if necessary, for example 50 ppm, 24 ppm, 12.5 ppm, 6 ppm, 3 ppm, 1.5 ppm, 0.8 ppm or 0.2 ppm.

Example B1: Activity Against Chilo suppressalis (Striped Rice Stemborer)

[0636] 24-well microtiter plates with artificial diet were treated with aqueous test solutions prepared from 10000 ppm DMSO stock solutions by pipetting. After drying, the plates were infested with L2 larvae (6-8 per well). The samples were assessed for mortality, anti-feeding effect, and growth inhibition in comparison to untreated samples 6 days after infestation. Control of Chilo suppressalis by a test sample is given when at least one of the categories mortality, anti-feedant effect, and growth inhibition is higher than the untreated sample.

[0637] The following compounds resulted in at least 80% control in at least one of the three categories (mortality, anti-feedant effect, or growth inhibition) at an application rate of 200 ppm: P1, P2, P3, P4, P5, P6, P7, P8, P10, P11, P12, P13, P14, P15, P16, P17, P18, P19, P20, P21, P22, P23, P24, P25, P26, P27, P28, P29, P30, P31, P32, P33, P34, P35, P36, P38, P40, P41, P43, P44, P45, P48, P49.

Example B2: Activity Against Diabrotica Balteata (Corn Root Worm)

[0638] Maize sprouts placed onto an agar layer in 24-well microtiter plates were treated with aqueous test solutions prepared from 10000 ppm DMSO stock solutions by spraying. After drying, the plates were infested with L2 larvae (6 to 10 per well). The samples were assessed for mortality and growth inhibition in comparison to untreated samples 4 days after infestation.

[0639] The following compounds gave an effect of at least 80% control in at least one of the two categories (mortality or growth inhibition) at an application rate of 200 ppm: P1, P2, P3, P4, P5, P6, P7, P8, P10, P11, P12, P13, P14, P16, P17, P18, P19, P20, P21, P22, P23, P25, P26, P27, P28, P29, P30, P32, P33, P36, P37, P40, P41, P42, P43, P48, P49.

Example B3: Activity Against Euschistus heros (Neotropical Brown Stink Bug)

[0640] Soybean leaves on agar in 24-well microtiter plates were sprayed with aqueous test solutions prepared from 10000 ppm DMSO stock solutions. After drying the leaves were infested with N2 nymphs. The samples were assessed for mortality and growth inhibition in comparison to untreated samples 5 days after infestation.

[0641] The following compounds gave an effect of at least 80% in at least one of the two categories (mortality or growth inhibition) at an application rate of 200 ppm: P1, P2, P4, P5, P8, P9, P11, P14, P16, P18, P19, P20, P21, P23, P25, P26, P27, P28, P29, P30, P32, P33, P35, P36, P37, P39, P40, P42, P43, P44, P45.

Example B4: Activity Against Frankliniella occidentalis (Western Flower Thrips). Feeding/Contact Activity

[0642] Sunflower leaf discs were placed on agar in 24-well microtiter plates and sprayed with aqueous test solutions prepared from 10000 DMSO stock solutions. After drying the leaf discs were infested with a Frankliniella population of mixed ages. The samples were assessed for mortality 7 days after infestation.

[0643] The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P2, P9, P19.

Example B5: Activity Against Myzus persicae (Green Peach Aphid). Feeding/Contact Activity

[0644] Sunflower leaf discs were placed onto agar in a 24-well microtiter plate and sprayed with aqueous test solutions prepared from 10000 ppm DMSO stock solutions. After drying, the leaf discs were infested with an aphid population of mixed ages. The samples were assessed for mortality 6 days after infestation.

[0645] The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P1, P2, P5, P6, P7, P8, P9, P10, P11, P14, P16, P17, P18, P20, P22, P23, P24, P26, P27, P28, P29, P30, P32, P33, P34, P35, P40, P43, P44, P45, P49.

Example B6: Activity Against Myzus persicae (Green Peach Aphid). Intrinsic Activity

[0646] Test compounds prepared from 10000 ppm DMSO stock solutions were applied by pipette into 24-well microtiter plates and mixed with sucrose solution. The plates were closed with a stretched Parafilm. A plastic stencil with 24 holes was placed onto the plate and infested pea seedlings were placed directly on the Parafilm. The infested plate was closed with a gel blotting paper and another plastic stencil and then turned upside down. The samples were assessed for mortality 5 days after infestation.

[0647] The following compounds resulted in at least 80% mortality at a test rate of 12 ppm: P1, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12, P13, P14, P15, P16, P17, P18, P19, P20, P21, P22, P23, P24, P25, P26, P27, P28, P29, P30, P31, P32, P33, P34, P35, P36, P37, P40, P41, P42, P43, P44, P45, P48, P49.

Example B7: Activity Against Plutella xylostella (Diamond Back Moth)

[0648] 24-well microtiter plates with artificial diet were treated with aqueous test solutions prepared from 10000 ppm DMSO stock solutions by pipetting. After drying, Plutella eggs were pipetted through a plastic stencil onto a gel blotting paper and the plate was closed with it. The samples were assessed for mortality and growth inhibition in comparison to untreated samples 8 days after infestation.

[0649] The following compounds gave an effect of at least 80% control in at least one of the two categories (mortality or growth inhibition) at an application rate of 200 ppm: P1, P2, P3, P4, P5, P6, P7, P8, P10, P11, P12, P13, P14, P15, P16, P17, P18, P19, P20, P21, P22, P23, P24, P25, P26, P27, P28, P29, P30, P31, P32, P33, P34, P35, P36, P37, P38, P40, P41, P42, P43, P44, P48, P49.

Example B8: Activity Against Spodoptera littoralis (Egyptian Cotton Leaf Worm)

[0650] Cotton leaf discs were placed onto agar in 24-well microtiter plates and sprayed with aqueous test solutions prepared from 10000 ppm DMSO stock solutions. After drying the leaf discs were infested with five L1 larvae. The samples were assessed for mortality, anti-feeding effect, and growth inhibition in comparison to untreated samples 3 days after infestation. Control of Spodoptera littoralis by a test sample is given when at least one of the categories mortality, anti-feedant effect, and growth inhibition is higher than the untreated sample.

[0651] The following compounds resulted in at least 80% control in at least one of the three categories (mortality, anti-feedant effect, or growth inhibition) at an application rate of 200 ppm: P1, P2, P3, P4, P5, P6, P7, P8, P10, P11, P12, P13, P14, P15, P16, P17, P18, P19, P20, P21, P22, P23, P24, P25, P26, P27, P28, P29, P30, P31, P32, P33, P34, P36, P38, P40, P41, P42, P43, P44, P48, P49.

Example B9: Activity Against Myzus persicae (Green Peach Aphid). Systemic Activity

[0652] Roots of pea seedlings infested with an aphid population of mixed ages were placed directly into aqueous test solutions prepared from 10000 DMSO stock solutions. The samples were assessed for mortality 6 days after placing seedlings into test solutions.

[0653] The following compounds resulted in at least 80% mortality at a test rate of 24 ppm: P5, P6, P18.

Example B10: Activity Against Tetranychus urticae (Two-Spotted Spider Mite). Feeding/Contact Activity

[0654] Bean leaf discs on agar in 24-well microtiter plates were sprayed with aqueous test solutions prepared from 10000 ppm DMSO stock solutions. After drying the leaf discs were infested with a mite population of mixed ages. The samples were assessed for mortality on mixed population (mobile stages) 8 days after infestation.

[0655] The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P19.