PESTICIDALLY ACTIVE PYRIDAZINONE COMPOUNDS
20250049033 · 2025-02-13
Assignee
Inventors
- Jagadeesh Prathap KILARU (Corlim, Ilhas, IN)
- Mangala PHADTE (Corlim, Ilhas, IN)
- Simone BERARDOZZI (Stein, CH)
- Roger Graham HALL (Stein, CH)
- André JEANGUENAT (Stein, CH)
- Thomas Pitterna (Stein, CH)
- Matthias Weiss (Stein, CH)
- Michel Muehlebach (Stein, CH)
Cpc classification
A01N43/713
HUMAN NECESSITIES
International classification
Abstract
Compounds of formula (I) where Q is Q.sup.a or Q.sup.b; and R.sup.4 is R.sup.4a or R.sup.4b, and 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) ##STR00197## wherein: A.sup.1, A.sup.2 and A.sup.3 are, independently from each other, N or CR.sup.Y; or A.sup.1=A.sup.2-A.sup.3, taken together, are NRC(X)N; wherein X is O or S; A.sup.4 and A.sup.5 are, independently from each other, N or CR.sup.Y; Q is ##STR00198## where the staggered line represents the connection of Q to the rest of compound of the formula (I); R is hydrogen, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkoxy, or C.sub.1-C.sub.3haloalkoxy; 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.4cycloalkylC.sub.1-C.sub.2alkyl-, C.sub.3-C.sub.4cycloalkylC.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 each independently selected from hydrogen, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkylsulfanyl, 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.3-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.6cycloalkylC.sub.1-C.sub.4alkyl, C.sub.3-C.sub.6cycloalkylC.sub.1-C.sub.4alkyl substituted with one to two substituents independently selected from R.sup.z, C.sub.3-C.sub.6cycloalkylC.sub.1-C.sub.3alkoxy, C.sub.3-C.sub.6cycloalkylC.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.1-C.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 ##STR00199## where the staggered line represents the connection of R.sup.4 to Q.sup.a or Q.sup.b; A.sup.14, A.sup.24, and A.sup.34 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.1-C.sub.3cycloalkyl)NHC(O), (C.sub.1-C.sub.3cycloalkyl)(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.6 cycloalkyl; or R.sup.6 is phenyl, benzyl, heteroaryl, or C.sub.3-C.sub.6 cycloalkyl, each of which, independent 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.3 haloalkyl, hydroxy, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkoxy, halogen, CN and cyclopropyl; and R.sup.Z is selected from oxo, halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkoxy and CN; or 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.sup.1 and A.sup.3 are N, and A.sup.2 is CR.sup.Y; and R.sup.Y is hydrogen, chlorine, methyl, trifluoromethyl, or methoxy.
3. The compound according to claim 1, wherein A.sup.1=A.sup.2-A.sup.3, taken together, are NRC(O)N; and R is hydrogen, methyl, ethyl, 2,2-difluoroethyl, or 2,2,2,-trifluoroethyl.
4. The compound according to claim 1, wherein A.sup.4 and A.sup.5 are, independently from each other, N or CH.
5. The compound according to claim 1, wherein A.sup.4 and A.sup.5 are both CH.
6. The compound according to claim 1, wherein when R.sup.4 is R.sup.4a: A.sup.14 is N, A.sup.24 is N or CH, and A.sup.34 is N or CH; or A.sup.14 is N, A.sup.24 is N or CH, and A.sup.34 is CH; or A.sup.14 is N, A.sup.24 is CH, and A.sup.34 is N or CH; or A.sup.14 is N, A.sup.24 is CH, and A.sup.34 is CH; and when R.sup.4 is R.sup.4b: A.sup.14 is N; or A.sup.14 is CH.
7. The compound according to 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.
8. The compound according to claim 1, wherein: A.sup.14 is N, and, when R.sup.4 is R.sup.4a, A.sup.24 and A.sup.34 are CH; and R.sup.4c is methyl, or ethyl.
9. The compound according to claim 1, wherein X.sup.0 is O.
10. The compound according to claim 1, wherein R.sup.1 is hydrogen, methyl, ethyl, cyanomethyl, methoxymethyl, cyclopropyl-methyl, allyl, propargyl, benzyloxycarbonyl, or benzyl.
11. 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.
12. 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.
13. The compound according to claim 1, wherein R.sup.2a and R.sup.2b are independently selected from chloro, bromo, iodo, and trifluoromethyl.
14. The compound according to claim 1, wherein R.sup.3 is C.sub.1-C.sub.3alkyl.
15. The compound according to claim 1, R.sup.3 is methyl.
16. 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.
17. A composition comprising a compound as defined in claim 1, one or more auxiliaries and diluent, and optionally one or more other active ingredient.
18. 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.
19. A plant propagation material, such as a seed, comprising, or treated with or adhered thereto, a compound as defined in claim 1.
20. A compound of the formula XII(i), or a tautomer thereof, ##STR00200## wherein A.sup.14, A.sup.24, A.sup.34 and R.sup.4c are as defined in claim 1, provided said compound is not ##STR00201## 6-hydrazinyl-2-methyl-3(2H)-pyridazinone, nor a tautomer thereof, nor ##STR00202## 6-hydrazinyl-2-ethyl-3(2H)-pyridazinone, nor a tautomer thereof.
21. A compound of the formula XX(i), XXI(i) or XXII(i) ##STR00203## 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, and sulfuric acid; and the conjugate base of an organic acid selected from a carboxylic acid and a sulfonic acid.
Description
EXAMPLES
Formulation Examples
[0766] The following Examples further illustrate, but do not limit, the invention.
TABLE-US-00010 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%
[0767] The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.
TABLE-US-00011 Powders for dry seed treatment a) b) c) active ingredients 25% 50% 75% light mineral oil 5% 5% 5% highly dispersed silicic acid 5% 5% Kaolin 65% 40% Talcum 20%
[0768] The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording powders that can be used directly for seed treatment.
TABLE-US-00012 Emulsifiable concentrate active ingredients 10% octylphenol polyethylene glycol ether 3% (4-5 mol of ethylene oxide) calcium dodecylbenzenesulfonate 3% castor oil polyglycol ether 4% (35 mol of ethylene oxide) Cyclohexanone 30% xylene mixture 50%
[0769] Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.
TABLE-US-00013 Dusts a) b) c) Active ingredients 5% 6% 4% Talcum 95% Kaolin 94% mineral filler 96%
[0770] Ready-for-use dusts are obtained by mixing the combination with the carrier and grinding the mixture in a suitable mill. Such powders can also be used for dry dressings for seed.
TABLE-US-00014 Extruder granules Active ingredients 15% sodium lignosulfonate 2% carboxymethylcellulose 1% Kaolin 82%
[0771] The combination is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.
TABLE-US-00015 Coated granules Active ingredients 8% polyethylene glycol (mol. wt. 200) 3% Kaolin 89%
[0772] The finely ground combination is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.
TABLE-US-00016 Suspension concentrate active ingredients 40% propylene glycol 10% nonylphenol polyethylene glycol ether 6% (15 mol of ethylene oxide) Sodium lignosulfonate 10% carboxymethylcellulose 1% silicone oil (in the form of a 1% 75% emulsion in water) Water 32%
[0773] The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
TABLE-US-00017 Flowable concentrate for seed treatment active ingredients 40% propylene glycol 5% copolymer butanol PO/EO 2% Tristyrenephenole with 10-20 moles EO 2% 1,2-benzisothiazolin-3-one (in the 0.5%.sup. form of a 20% solution in water) monoazo-pigment calcium salt 5% Silicone oil (in the form of a 75% 0.2%.sup. emulsion in water) Water 45.3%
[0774] 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
[0775] 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.
Preparation Examples
[0776] The following preparation 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. 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:
[0777] 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, Desolvation 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:
[0778] 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., Desolvation Temperature: 5000 C., Cone Gas Flow: 50 l/h, Desolvation Gas Flow: 1000 I/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 C18, 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:
[0779] 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 I/h, Desolvation Gas Flow: 650-1000 I/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:
[0780] Spectra were recorded on a Mass Spectrometer from Agilent Technologies (6410 Triple Quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, MS2 Scan, Capillary: 4.00 kV, Fragmentor: 100 V, Desolvation Temperature: 350 C., Gas Flow: 11 L/min, Nebulizer Gas: 45 psi, Mass range: 110 to 1000 Da) and a 1200 Series HPLC from Agilent: quaternary pump, heated column compartment and VWD detector. Column: KINETEX EVO C18, 2.6 m, 504.6 mm, Temp: 40 C., Detector VWD Wavelength: 254 nm, 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 5:
[0781] SFC: Waters Acquity UPC.sup.2/QDa; PDA Detector Waters Acquity UPC.sup.2; Column: Daicel SFC CHIRALPAK OZ, 3 m, 0.46 cm10 cm, 40 C.; Mobile phase: A: CO.sub.2 B: MeOH isocratic: 20% B in 4.8 min; ABPR: 1800 psi; Flow rate: 2.0 ml/min; Detection: 290 nm; Sample concentration: 1 mg/mL in ACN; Injection: 2 L.
[0782] QDa: [MS+]: Mass Spectrometer from Waters (QDa) (Polarity: positive and negative ions), Detector Gain 1, Temperature Sample: 500 C., Cone Voltage: 10V, ESI Capillary Positive Voltage 0.8-Negative Voltage 0.8, Sampling Frequency 5 Hz, Mass range: 100 to 850 Da.
Example P1: Preparation of 8-chloro-1-methyl-4-[[(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]amino]-6-(trifluoromethyl)quinazolin-2-one (compound P1)
##STR00128##
Step A: Preparation of 8-chloro-1-methyl-6-(trifluoromethyl)quinazoline-2,4-dione (I-1)
##STR00129##
[0783] To a mixture of 3-chloro-2-(methylamino)-5-(trifluoromethyl)benzonitrile (CAS 2673195-89-4) (4.26 mmol, 1 g) in dichloromethane (10 mL) was added N-(oxomethylene)sulfamoyl chloride (0.904, 6.39 mmol) at room temperature. The reaction mass was stirred at room temperature for 24 h. The reaction was monitored by thin layer chromatography (TLC) and the conversion was confirmed. The solvent was evaporated on rotavapor and the residue was heated in 150 ml of 2N HCl in water at 100 C. for 6 h. The resulting solid was filtered and dried to afford 8-chloro-4-hydroxy-1-methyl-6-(trifluoromethyl)quinazolin-2-one (1.1 g, 83%) as a white solid.
[0784] .sup.1H NMR (400 MHz, DMSO-d6) : 12.03 (s, 1H), 8.22 (d, 1H), 8.16 (d, 1H), 3.65 (m, 3H).
[0785] LCMS (method 2): retention time 1.06 min, m/z 276.9 [MH].sup..
Step B: Preparation of 8-chloro-1-methyl-4-thioxo-6-(trifluoromethyl)quinazolin-2-one (I-2)
##STR00130##
[0786] In a 25 ml round bottom flask (RBF), 8-chloro-1-methyl-6-(trifluoromethyl)quinazoline-2,4-dione (I-1) (0.2 g, 0.717 mmol) was taken in toluene (4 mL). Then Lawesson reagent (2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2.sup.5,4.sup.5-dithiadiphosphetane) (0.299 g, 0.717 mmol) was added at room temperature. The reaction mixture was heated at 90 C. for 20 h. The reaction was monitored by LCMS and the conversion was confirmed. The reaction mass was quenched with 2N NaOH and was extracted with EtOAc (50 ml2). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude was adsorbed on silica gel and purified by combi flash using silica gel column and eluted with gradient system of EtOAc in cyclohexane and the desired fractions were concentrated to get 8-chloro-1-methyl-4-thioxo-6-(trifluoromethyl)quinazolin-2-one (0.25 g, 60 mass %, 70.913%) as a yellow solid. The product was taken for the next reaction as such, without further purification.
[0787] LCMS (method 2): retention time 1.13 min, m/z 293.0 [MH].sup..
Step C: Preparation of 8-chloro-1-methyl-4-thioxo-6-(trifluoromethyl)quinazolin-2-one (I-3)
##STR00131##
[0788] In a 50 mL RBF, 8-chloro-1-methyl-4-thioxo-6-(trifluoromethyl)quinazolin-2-one (I-2) (0.62 g, 1.262 mmol, 60 mass %) was taken in acetonitrile (12.4 mL), then were added iodomethane (0.900 g, 6.3119 mmol) and dicesium carbonate (1.23 g, 3.787 mmol). The reaction mass was stirred at room temperature for 20 h. The reaction was monitored by TLC and the conversion was confirmed. The reaction mass was filtered through a celite bed, washed with EtOAc and the filtrate was concentrated to get the crude. The crude was adsorbed on silica gel and purified by combiflash using silica gel column and eluted with gradient system of EtOAc in cyclohexane. The desired fractions were concentrated to afford 8-chloro-1-methyl-4-methylsulfanyl-6-(trifluoromethyl)quinazolin-2-one (0.2 g, 0.648 mmol, yield 51.3%) as a white solid.
[0789] .sup.1H NMR (400 MHz, CDCl.sub.3) : 8.16 (s, 1H), 7.94 (d, 1H), 4.01 (s, 3H), 2.72 (s, 3H).
[0790] LCMS (method 2): retention time 0.96 min, m/z 309.1 [M+H].sup.+.
Step D: Preparation of 8-chloro-1-methyl-4-[[(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]amino]-6-(trifluoromethyl)quinazolin-2-one (compound P1)
##STR00132##
[0791] In a 10 mL microwave vial were added 8-chloro-1-methyl-4-methylsulfanyl-6-(trifluoromethyl)-quinazolin-2-one (I-3) (0.085 g, 0.275 mmol), [(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]ammoniu;chloride (compound XX.sup.a1 prepared as described below) (0.0848 g, 0.330 mmol) and acetic acid (0.8908 g, 0.85 mL, 14.8 mmol, 53.6 equiv., 99.5 mass %). The vial was sealed and heated in a microwave at 120 C. for 60 min. The reaction was monitored by LCMS and the conversion was confirmed. The reaction mass was concentrated on rotavapor. The crude was adsorbed on celite and purified by reverse phase column chromatography on 40 g C18 (40-60 m) using H.sub.2O:ACN. The product fractions were freeze dried to afford 8-chloro-1-methyl-4-[[(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]amino]-6-(trifluoromethyl)-quinazolin-2-one (0.065 g, 49.1% yield) as white solid.
[0792] .sup.1H NMR (400 MHz, acetonitrile-d3) : 8.16 (d, 1H), 7.97-8.04 (m, 2H), 7.78-7.84 (m, 1H), 7.02 (d, 1H), 5.94 (q, 1H), 3.76 (s, 3H), 3.65 (s, 3H), 1.76 (d, 3H).
[0793] LCMS (method 2): retention time 0.85 min, m/z 481.2 [M+H].sup.+.
Example P2: Preparation of 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-pyridazin-3-one (compound P2)
##STR00133##
[0794] To a mixture of [(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;chloride (compound XX.sup.a1 prepared as described below) (0.2 g, 0.623 mmol, 80 mass %) and 4,6-dichloro-8-(trifluoromethyl)quinazoline (CAS 1565368-05-9) (0.208 g, 0.77915 mmol) in acetonitrile (4 mL) was added dicesium carbonate Cs2CO.sub.3 (0.305 g, 0.934 mmol) at room temperature. The reaction mixture was heated at 80 C. for 60 min. The reaction was monitored by LCMS and the conversion was confirmed. The dicesium carbonate was separated by filtration and the solid was washed with can. The filtrate was then concentrated. The crude was adsorbed on silica gel and purified by combiflash using a silica gel column, and then eluted with gradient system of EtOAc in cyclohexane. The desired fractions were concentrated to afford 6-[5-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-pyridazin-3-one (0.2 g, yield 64%) as a white solid.
[0795] .sup.1H NMR (400 MHz, DMSO-d6) : 9.04 (d, 1H), 8.82 (d, 1H), 8.45 (s, 1H), 8.21 (d, 1H), 8.19 (s, 1H), 7.80 (d, 1H), 7.12 (d, 1H), 5.91 (quin, 1H), 3.48 (s, 3H), 1.75 (d, 3H).
[0796] LCMS (method 2): retention time 1.02 min, m/z 451.2 [M+H].sup.+.
Example P3: Preparation of 6-[5-[(1S)-1-[[6,8-bis(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-pyridazin-3-one (compound P3)
##STR00134##
[0797] To a mixture of 4-chloro-6,8-bis(trifluoromethyl)quinazoline (CAS 2641011-24-5) (0.234 g, 0.779 mmol) and [(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;chloride (compound XX.sup.a1 prepared as described below) (0.2 g, 0.623 mmol) in acetonitrile (4 mL) was added dicesium carbonate (0.304 g, 0.934 mmol) at room temperature. The reaction mixture was heated at 80 C. for 60 min. The reaction was monitored by LCMS and the conversion was confirmed. Cs2CO.sub.3 was separated by filtration and solid was washed with can. The filtrate was concentrated. The crude was adsorbed on silica gel and purified by combiflash using silica gel column and then eluted with a gradient system of EtOAc in cyclohexane. The desired fractions were concentrated to afford 6-[5-[(1S)-1-[[6,8-bis(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-pyridazin-3-one (0.15 g, yield 49.6%) as white solid.
[0798] .sup.1H NMR (400 MHz, acetonitrile-d3) : 8.53 (s, 1H), 8.46 (s, 1H), 8.37 (br d, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.81 (d, 1H), 7.09 (d, 1H), 6.04 (quin, 1H), 3.67 (s, 3H), 1.86 (d, 3H).
[0799] LCMS (method 2): retention time 0.91 min, m/z 485.2 [M+H].sup.+.
Example P4: Preparation of 6-[5-[(1S)-1-[[2,8-dichloro-6-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-pyridazin-3-one (compound P4)
##STR00135##
[0800] To a mixture of 2,4,8-trichloro-6-(trifluoromethyl)quinazoline (CAS 2673195-86-1) (0.258 g, 0.857 mmol) and [(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;chloride (compound XX.sup.a1 prepared as described below) (0.2 g, 0.779 mmol) in acetonitrile (4 mL) was added dicesium carbonate (0.38 g, 1.1687 mmol). The reaction mixture was heated at 80 C. for 15 min. The reaction was monitored by LCMS and the conversion was confirmed. Cs2CO.sub.3 was separated by filtration and solid was washed with ACN, and filtrate was concentrated. The crude was adsorbed on silica gel and purified by combiflash using a silica gel column and then eluted with a gradient system of EtOAc in cyclohexane. The desired fractions were concentrated to afford 6-[5-[(1S)-1-[[2,8-dichloro-6-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-pyridazin-3-one (0.22 g, yield 54.7%) as a white solid.
[0801] .sup.1H NMR (400 MHz, DMSO-d6) : 9.75 (br d, 1H), 8.88 (s, 1H), 8.34 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.81 (d, 1H), 7.15 (d, 1H), 5.93-6.00 (m, 1H), 3.54 (s, 3H), 1.76 (d, 3H).
[0802] LCMS (method 2): retention time 1.10 min, m/z 485.2 [M+H].sup.+.
Example P5: Preparation of 8-chloro-4-[[(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]amino]-6-(trifluoromethyl)-1H-quinazolin-2-one (compound P5)
##STR00136##
[0803] In a 25 ml RBF were charged 6-[5-[(1S)-1-[[2,8-dichloro-6-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-pyridazin-3-one (compound P4) (0.2 g, 0.412 mmol) and acetic acid (2 mL, 99.5 mass %). Then the reaction mass was heated at 80 C. for 45 minutes. The reaction was monitored by LCMS and confirmed the conversion. The reaction mass was concentrated on rotavapor. Crude was adsorbed on celite and purified by reverse phase column chromatography on 40 g C18 (40-60 m) and eluted using H2O and ACN (0.01% TFA). Product fractions were freeze dried and further purified by preparative HPLC to get 8-chloro-4-[[(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]amino]-6-(trifluoromethyl)-1H-quinazolin-2-one (0.1 g, 51.9%) as white solid.
[0804] .sup.1H NMR (400 MHz, acetonitrile-d3) : 8.82 (br s, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.96 (s, 1H), 7.82 (d, 1H), 7.73 (br d, 1H), 7.01 (d, 1H), 5.96 (quin, 1H), 3.66 (s, 3H), 1.76 (d, 3H).
[0805] LCMS (method 2): retention time 0.81 min, m/z 467.2 [M+H].sup.+.
Example P6: Preparation of 6-[5-[(1S)-1-[(6,8-dibromoquinazolin-4-yl)-methyl-amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-pyridazin-3-one (compound P14)
##STR00137##
[0806] To a mixture of 6-[5-[(1S)-1-[(6,8-dibromoquinazolin-4-yl)amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-pyridazin-3-one (compound P18) (0.1 g, 0.198 mmol) and cesium carbonate (0.193 g, 0.592 mmol) in acetonitrile (1.5 mL) was added iodomethane (0.141 g, 0.98 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours, then diluted with water and the product extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by combiflash (ethyl acetate/cyclohexane) to afford 6-[5-[(1S)-1-[(6,8-dibromoquinazolin-4-yl)-methyl-amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-pyridazin-3-one as pale yellow solid. LCMS (method 3): retention time 1.09 min, m/z 519/521/523 [M+H].sup.+.
[0807] .sup.1H NMR (400 MHz, CDCl.sub.3) : 8.62 (s, 1H), 8.16 (d, 1H), 8.01 (s, 1H), 7.93 (d, 1H), 7.81 (d, 1H), 7.09 (d, 1H), 6.47 (q, 1H), 3.37 (s, 3H), 3.26 (s, 3H), 1.88 (d, 3H).
Example P7: Preparation of 6-[3-[1-[[8-chloro-6-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]pyrazin-2-yl]-2-methyl-pyridazin-3-one (compound P13)
##STR00138##
[0808] To a solution of 4,8-dichloro-6-(trifluoromethyl)quinazoline (prepared in analogy to descriptions found in WO 2021/083936) (0.162 g, 0.605 mmol) and 6-[3-(1-aminoethyl)pyrazin-2-yl]-2-methyl-pyridazin-3-one (compound XX.sup.c1 prepared as described below) (0.140 g, 0.605 mmol) in tetrahydrofuran (2 mL) was added triethylamine (0.308 g, 3.027 mmol) at room temperature. The reaction mixture was heated in the microwave at 100 C. for 1 hour, then concentrated in vacuo. The residue was purified by combiflash (ethyl acetate/cyclohexane) to afford 6-[3-[1-[[8-chloro-6-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]pyrazin-2-yl]-2-methyl-pyridazin-3-one as a white solid.
[0809] LCMS (method 2): retention time 0.88 min, m/z 462/464 [M+H].sup.+.
[0810] .sup.1H NMR (400 MHz, CDCl.sub.3) : 8.73 (s, 1H), 8.60-8.67 (m, 2H), 8.17 (d, 1H), 8.04 (d, 2H), 7.53 (br d, 1H), 7.13 (d, 1H), 6.47 (quin, 1H), 4.00 (s, 3H), 1.75 (d, 3H).
Example P8: Preparation of 6-[3-[1-[[8-chloro-6-(trifluoromethyl)quinazolin-4-yl]-methyl-amino]ethyl]pyrazin-2-yl]-2-methyl-pyridazin-3-one (compound P12)
##STR00139##
[0811] To mixture of 6-[3-[1-[[8-chloro-6-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]pyrazin-2-yl]-2-methyl-pyridazin-3-one (compound P13) (0.075 g, 0.162 mmol) and cesium carbonate (0.159 g, 0.487 mmol) in acetonitrile (1.5 mL) was added iodomethane (0.116 g, 0.812 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours, then diluted with water and the product extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by combiflash (ethyl acetate/cyclohexane) to afford 6-[3-[1-[[8-chloro-6-(trifluoromethyl)quinazolin-4-yl]-methyl-amino]ethyl]pyrazin-2-yl]-2-methyl-pyridazin-3-one as a pale yellow solid.
[0812] LCMS (method 3): retention time 1.14 min, m/z 474/476 [MH].sup..
[0813] .sup.1H NMR (400 MHz, CDCl.sub.3) : 8.51-8.59 (m, 3H), 8.10 (s, 1H), 7.99 (s, 1H), 7.98 (d, 1H), 7.04 (d, 1H), 6.55 (q, 1H), 3.55 (s, 3H), 3.54 (s, 3H), 1.90 (d, 3H).
Example P9: Preparation of 6-[5-[(1S)-1-[[8-chloro-6-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-2-ethyl-pyridazin-3-one (compound P17)
##STR00140##
[0814] To a solution of 4,8-dichloro-6-(trifluoromethyl)quinazoline (prepared in analogy to descriptions found in WO 2021/083936) (0.271 g. 1.016 mmol) and [(1S)-1-[2-(1-ethyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]ammonium;chloride (compound XX.sup.az prepared as described below) (0.250 g, 0.924 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.470 g, 4.617 mmol) at room temperature. The reaction mixture was heated in the microwave at 100 C. for 1 hour, then concentrated in vacuo. The residue was purified by combiflash (ethyl acetate/cyclohexane) to afford 6-[5-[(1S)-1-[[8-chloro-6-(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-2-ethyl-pyridazin-3-one as a white solid.
[0815] LCMS (method 3): retention time 1.10 min, m/z 463/465 [MH].sup..
[0816] .sup.1H NMR (400 MHz, CDCl.sub.3) : 8.72 (br d, 1H), 8.48 (s, 1H), 8.11 (s, 1H), 7.96 (d, 1H), 7.83 (s, 1H), 7.81 (s, 1H), 7.24 (d, 1H), 6.14 (quin, 1H), 4.31 (q, 2H), 1.92 (d, 3H), 1.49 (t, 3H).
Example P10: Preparation of 6-[5-[(1S)-1-[[6,8-bis(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-4,5-dihydropyridazin-3-one (compound P7)
##STR00141##
[0817] To a degassed solution of 6-[5-[(1S)-1-[[6,8-bis(trifluoromethyl)quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-pyridazin-3-one (compound P3) (0.06 g, 0.124 mmol) in methanol (3 mL) was was added palladium on carbon (0.132 g). The reaction mixture was stirred under a hydrogen balloon atmosphere at room temperature for 20 hours, then filtered through a celite bed. The celite bed was washed with MeOH and the combined filtrate concentrated under reduced pressure. The residue was purified by combiflash (ethyl acetate/cyclohexane) to afford 6-[5-[(1S)-1-[[6,8-bis(trifluoromethyl)-quinazolin-4-yl]amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-4,5-dihydropyridazin-3-one as a white solid.
[0818] LCMS (method 3): retention time 1.11 min. m/z 487 [M+H].sup.+.
[0819] .sup.1H NMR (400 MHz, acetonitrile-d.sub.3) : 8.65 (s, 1H), 8.57 (s, 1H), 8.25 (s, 1H), 8.18 (br d, 1H), 8.01 (s, 1H), 6.19 (quin, 1H), 3.20-3.41 (m, 5H), 2.71 (t, 2H), 1.81 (d, 3H).
Example P11: Preparation of 6-[5-[(1S)-1-[(6-chloro-8-iodo-quinazolin-4-yl)amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-4,5-dihydropyridazin-3-one (compound P25)
##STR00142##
[0820] To a solution of 4,6-dichloro-8-iodo-quinazoline (CAS 100949-33-5) (0.165 g, 0.508 mmol) and [(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 prepared as described below) (0.144 g, 0.559 mmol) in tetrahydrofuran (4 mL) was added triethylamine (0.258 g, 2.53 mmol) at room temperature. The reaction mixture was heated in the microwave at 100 C. for 1 hour, then concentrated in vacuo. The residue was purified by combiflash (ethyl acetate in cyclohexane) to afford 6-[5-[(1S)-1-[(6-chloro-8-iodo-quinazolin-4-yl)amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-4,5-dihydropyridazin-3-one as a white solid.
[0821] LCMS (method 3): retention time 1.06 min, m/z 511/513 [M+H].sup.+.
[0822] .sup.1H NMR (400 MHz, CDCl.sub.3) : 8.52 (s, 1H), 8.24 (s, 1H), 8.03 (s, 2H), 7.61 (s, 1H), 6.05-6.11 (m, 1H), 3.27-3.56 (m, 4H), 3.29-3.46 (m, 1H), 2.78-2.94 (m, 2H), 1.82 (d, 3H).
Example P12: Preparation of 6-[5-[(1S)-1-[(6-chloro-8-iodo-quinazolin-4-yl)-methyl-amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-4,5-dihydropyridazin-3-one (compound P26)
##STR00143##
[0823] To mixture of 6-[5-[(1S)-1-[(6-chloro-8-iodo-quinazolin-4-yl)amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-4,5-dihydropyridazin-3-one (compound P25) (0.140 g, 0.274 mmol) and cesium carbonate (0.268 g, 0.822 mmol) in acetonitrile (2 mL) was added iodomethane (0.196 g, 1.371 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours, then diluted with water and the product extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by combiflash (ethyl acetate in cyclohexane) to afford 6-[5-[(1S)-1-[(6-chloro-8-iodo-quinazolin-4-yl)-methyl-amino]ethyl]-1,2,4-triazol-1-yl]-2-methyl-4,5-dihydropyridazin-3-one as a white solid.
[0824] LCMS (method 3): retention time 1.10 min, m/z 525/527 [M+H].sup.+.
[0825] .sup.1H NMR (400 MHz, CDCl.sub.3) : 8.66 (s, 1H), 8.29 (d, 1H), 7.94 (s, 1H), 7.91 (d, 1H), 6.48 (q, 1H), 3.39 (s, 3H), 3.23-3.37 (m, 2H), 2.82 (s, 3H) 2.60-2.75 (m, 2H), 1.84 (d, 3H).
Example P13: Preparation of 6-[3-[(1S)-1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]-methyl-amino]ethyl]pyrazin-2-yl]-2-methyl-pyridazin-3-one (compound P27)
##STR00144##
[0826] The racemic 6-[3-[1-[[6-chloro-8-(trifluoromethyl)quinazolin-4-yl]-methyl-amino]ethyl]pyrazin-2-yl]-2-methyl-pyridazin-3-one (compound P21) mixture (65 mg) was submitted to chiral resolution by preparative SFC using the conditions outlined hereafter.
[0827] Preparative method: Sepiatec Prep SFC 100; Column: Daicel CHIRALPAK OZ, 5 m, 2.0 cm25 cm; Mobile phase: A: CO.sub.2 B: MeOH isocratic: 20% B; Backpressure: 150 bar; GLS: -; Flow rate: 60 ml/min; Detection: UV 290 nm; Sample concentration: 65 mg in 2 ml MeOH/DCM (1/1); Injection: 350 l.
Results (Chiral Analytical Method 5):
TABLE-US-00018 Second eluting enantiomer First eluting enantiomer (compound P27) Retention time (min) ~2.54 Retention time (min) ~4.03 Chemical purity (area % at Chemical purity (area % at 290 nm) 98 290 nm) >99 Enantiomeric excess (%) >99 Enantiomeric excess (%) >99 [M+H].sup.+ measured: [M+H].sup.+ measured: 476/478 476/478 Amount: 26.5 mg Amount: 32.2 mg
TABLE-US-00019 TABLE P Physical data of compounds of formula (I) RT [M + H].sup.+ Meth. MP Entry IUPAC name STRUCTURE (min) * ** ( C) P1 8-chloro-1-methyl- 4-[(1S)-1-[2-(1- methyl-6-oxo-pyr- idazin-3-yl)-1,2,4- triazol-3-yl]ethyl] amino]-6-(trifluoro- methyl)quinazolin- 2-one
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.)
##STR00172##
Step A: Preparation of 6-chloro-2-methyl-pyridazin-3-one (I-4)
##STR00173##
[0828] 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.+.
[0829] .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-5)
##STR00174##
[0830] To a 25 ml RBF charged with 6-chloro-2-methyl-pyridazin-3-one (I-4) (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.
[0831] LCMS (method 2): retention time 0.14 min, m/z 141.1 [M+H].sup.+.
Alternative preparation of 6-hydrazino-2-methyl-pyridazin-3-one (I-5)
[0832] Under nitrogen atmosphere, to a solution of 6-chloro-2-methyl-pyridazin-3-one (I-4) (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 100 C. 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.
[0833] .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 tert-butyl N-[(1S)-1-[2-(1-methyl-6-oxo-pyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-6)
##STR00175##
[0834] To a 250 mL RBF charged with 6-hydrazino-2-methyl-pyridazin-3-one (I-5) (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.
[0835] .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 D: 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.)
##STR00176##
[0836] 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 (I-6) (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.
[0837] .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.)
##STR00177##
Step A: Preparation of tert-butyl N-[(1S)-1-[2-(6-chloropyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-7)
##STR00178##
[0838] 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).
[0839] LCMS (method 2): retention time 0.98 min, m/z 269/271 [M+H-tBu].sup.+, 225/227 [M+H-Boc].sup.+.
[0840] .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)
##STR00179##
[0841] 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.
[0842] LCMS (method 2): retention time 0.84 min, m/z 305 [MH].sup..
[0843] .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)
##STR00180##
[0844] 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.
[0845] .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.)
##STR00181##
[0846] 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 (I-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.
[0847] .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)
##STR00182##
[0848] 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-3yl]ethyl]ammonium;chloride (I-10) as a white solid.
[0849] .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.b1.)
##STR00183##
Step A: Preparation of tert-butyl N-[(1 S)-1-[2-(1-methyl-6-oxo-4,5-dihydropyridazin-3-yl)-1,2,4-triazol-3-yl]ethyl]carbamate (I-11)
##STR00184##
[0850] 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.+.
[0851] .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.)
##STR00185##
[0852] 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.
[0853] LCMS (method 2): retention time 0.23 min, m/z 223 [M+H].sup.+ for the free base.
[0854] .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.)
##STR00186##
Step A: Preparation of 6-(3-acetylpyrazin-2-yl)-2-methyl-pyridazin-3-one (I-12)
##STR00187##
[0855] 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 1-16, prepared as described below) (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)
[0856] 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.0 .1)
##STR00188##
[0857] 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.+.
[0858] .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.0 .1)
##STR00189##
Step A: Preparation of 1-(3-iodopyrazin-2-yl)ethanol (Int-A)
##STR00190##
[0859] 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.
[0860] 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)
##STR00191##
[0861] 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.
[0862] 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)
##STR00192##
[0863] 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.
[0864] LCMS (method 3): retention time 1.05 min, m/z 347 [M+H].sup.+.
[0865] .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)
##STR00193##
[0866] 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 (1 M 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.
[0867] LCMS (method 3): retention time 0.47 min. m/z 233 [M+H].sup.+.
[0868] .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)
##STR00194##
[0869] 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.+.
[0870] .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.)
##STR00195##
[0871] 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.
[0872] LCMS (method 3): retention time 0.15 min. m/z 232 [M+H].sup.+.
Example PI-7: Preparation of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3-one (I-16)
##STR00196##
[0873] To a stirred solution of 6-chloro-2-methyl-pyridazin-3-one (I-4) (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.
[0874] .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).
Abbreviations Used in Synthesis Schemes and Preparatory Examples
[0875] ACN acetonitrile [0876] CPME cyclopentyl methyl ether (or methoxy cyclopentane) [0877] Boc t-butoxycarbonyl [0878] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene [0879] DCM dichloromethane [0880] DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone [0881] DMF dimethylformamide [0882] DMSO dimethyl sulfoxide [0883] DMSO-d.sub.6 deuterated dimethylsulfoxide [0884] DPEN diphenylethylenediamine [0885] Et.sub.3N triethylamine [0886] EtOAc ethyl acetate [0887] EtOH ethanol [0888] HCl hydrochloric acid [0889] MeCN acetonitrile [0890] MeOH methanol [0891] Ms methanesulfonyl (mesyl) [0892] n-Bu n-butyl [0893] n-BuLi n-butyllithium [0894] NaHCO.sub.3 sodium hydrogen carbonate [0895] NHC N-heterocyclic carbene [0896] NPhth phthalimide-1-yl [0897] OMs mesylate group [0898] OTf triflate group [0899] OTs tosylate group [0900] PdCl2dppf 1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride [0901] TBME tert-butyl methyl ether [0902] TEA triethylamine [0903] TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl [0904] Tf trifluoromethanesulfonyl (triflyl) [0905] TFA trifluoroacetic acid [0906] THE tetrahydrofuran [0907] Ts p-toluenesulfonyl (tosyl) [0908] XPhos 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl [0909] aq. aqueous [0910] C. degrees Celsius [0911] equiv. equivalent [0912] h hour(s) [0913] LC/MS or LCMS liquid chromatography mass spectrometry [0914] M molar [0915] MHz megahertz [0916] min minutes [0917] mp or M.P. melting point [0918] NMR nuclear magnetic resonance [0919] ppm parts per million [0920] RT room temperature [0921] Rt retention time [0922] RBF round-bottom flask [0923] TLC thin layer chromatography
Biological Examples
[0924] 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)
[0925] 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.
[0926] 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, P6, P7, P8, P9, P10, P11, P12, P13, P15, P16, P17, P19, P21, P22, P23, P24, P25, P26, P27.
Example B2: Activity Against Diabrotica balteata (Corn Root Worm)
[0927] 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.
[0928] 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: P2, P3, P4, P6, P7, P8, P9, P10, P12, P13, P14, P15, P16, P17, P19, P21, P22, P23, P24, P25, P26, P27.
Example B3: Activity Against Euschistus heros (Neotropical Brown Stink Bug)
[0929] 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.
[0930] 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, P3, P5, P6, P7, P8, P9, P10, P11, P12, P13, P14, P15, P16, P17, P19, P21, P22, P23, P24, P25, P26, P27.
Example B4: Activity Against Frankliniella occidentalis (Western Flower Thrips). Feeding/Contact Activity
[0931] 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.
[0932] The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P5.
Example B5: Activity Against Myzus persicae (Green Peach Aphid). Feeding/Contact Activity
[0933] 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.
[0934] The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P2, P3, P4, P6, P7, P8, P9, P10, P12, P13, P14, P15, P17, P19, P20, P21, P22, P24, P27.
Example B6: Activity Against Myzus persicae (Green Peach Aphid). Intrinsic Activity
[0935] 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.
[0936] The following compounds resulted in at least 80% mortality at a test rate of 12 ppm: P3, P6, P7, P8, P9, P10, P11, P12, P13, P14, P15, P16, P17, P19, P21, P22, P23, P24, P25, P26, P27.
Example B7: Activity Against Plutella xylostella (Diamond Back Moth)
[0937] 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. 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, P6, P7, P8, P9, P10, P11, P12, P13, P14, P15, P16, P17, P18, P19, P20, P21, P22, P23, P24, P25, P26, P27.
Example B8: Activity Against Spodoptera littoralis (Egyptian Cotton Leaf Worm)
[0938] 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.
[0939] 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: P2, P3, P6, P7, P8, P9, P10, P11, P12, P13, P14, P15, P16, P17, P19, P21, P22, P23, P24, P25, P26, P27.
Example B9: Activity Against Tetranychus urticae (Two-Spotted Spider Mite). Feeding/Contact Activity
[0940] 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.
[0941] The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P6, P27.