Process for preparation of aminopyridazine derivatives

Abstract

The present invention provides a process for the preparation of aminopyridazine derivatives, as well as novel pyridazine-based and pyrazole-based compounds, which can be used as starting materials or intermediates in the process.

Description

Technical Field

[0001] The present invention provides a process for preparing aminopyridazine derivatives, and novel pyridazine-based and pyrazole-based compounds which can be used as starting materials or intermediates in the process. Background Art

[0002] Invertebrate pests, especially arthropods and nematodes, destroy growing and harvested crops and attack wooden homes and commercial buildings, causing enormous economic losses to food supplies and property.

[0003] The aminopyridazine derivatives have good pesticidal activity against a broad spectrum of different invertebrate pests, especially difficult-to-control pests such as insects, and are therefore useful for combating invertebrate pests.

[0004] WO 2018 / 082964 discloses a method for preparing aminopyridazine derivatives by reacting a pyridazine derivative having an amino group at the 4-position of the pyridazine moiety with a pyrazole derivative having a carbonyl group at the 4-position of the pyrazole moiety (e.g., acyl halide- and carboxylic acid-pyrazole derivatives).

[0005] There is a continuing need to develop new synthetic methods for the preparation of such compounds, providing alternative routes that enable diversification of the starting materials and intermediates used. Summary of the invention

[0006] The experimental part of this article shows the preparation of N-ethyl-5-methyl-1-(3-methylbutane-2-yl)-N-(pyridazine-4-yl)-1H-pyrazole-4-carboxamide. Specifically, in one flask, 4-bromo-5-methyl-1-(3-methylbutane-2-yl)-1H-pyrazole has been reacted with n-butyl lithium in the presence of a solvent at -78°C (identified herein as "reaction substance A"); and in another flask, N-ethylpyridazine-4-amine has been reacted with a base (such as trimethylamine and triethylamine) in the presence of a solvent, followed by a reaction with triphosgene (identified herein as "reaction substance B"). Then, at -78°C, reaction substance A is added to reaction substance B to obtain N-ethyl-5-methyl-1-(3-methylbutane-2-yl)-N-(pyridazine-4-yl)-1H-pyrazole-4-carboxamide.

[0007] In one aspect, the present invention therefore relates to a method for preparing a compound having formula I or a salt, N-oxide, tautomer, or enantiomer thereof, in: R 1is H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, or (C3-C7)cycloalkyl; R 2 and R 3 are each independently H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, or (C2-C6)alkenyl; and R 4 , R 5 , and R 6 are each independently H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, (C3-C7)heterocyclyl, or R 4 , R 5 , and R 6 Any two of the cycloalkyl and heterocyclyl groups are taken together with the carbon atoms to which they are attached to form a 5-7 membered ring, which is optionally substituted by one or more groups each independently selected from halogen, -CN, -COOH, and -NO2, wherein the cycloalkyl and heterocyclyl groups are each independently optionally substituted by one or more groups each independently selected from -CN, -C(O)NH2, halogen, -NO2, -COOH, The method comprises reacting a compound having formula III with either: (i) a compound of formula II, thereby obtaining a compound of formula I; or (ii) 4-isocyanatopyridazine, thereby obtaining a compound of formula I, wherein R 1 is H, and the hydrogen is optionally substituted with a group selected from the following: optionally interspersed with one or more groups each independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, and (C3-C7)cycloalkyl, in: T is each independently a group having the formula: M is of the formula -YZ(n) wherein Y is a boron ion, or a metal ion having an oxidation state of at least one, such as an alkali metal (e.g., lithium, sodium, potassium) ion, an alkaline earth metal (e.g., magnesium) ion, an aluminum ion, and a transition metal (e.g., copper, zinc, iron) ion, and Z represents a halogen anion; or M is selected from -B(halogen)3 - Cat + 、-B(OR')3 - Cat + , -B(-OC(O)-CH2-N(CH3)-CH2-COO-), -B(OH)2, -B(OH)3 - Cat + , -BR'(OH), -B(R')2, -BR'(OR'), B(OH)(OR'), and -B(OR')2, wherein each R' is independently (C1-C6)alkyl, (C2-C6)alkenyl, or (C3-C7)cycloalkyl, or two R' together with the boron atom to which they are attached form a 5-9 membered ring, which is optionally substituted with one or more groups each independently selected from (C1-C6)alkyl, (C2-C6)alkenyl, =O, -O-(C1-C6)alkyl, or -O-(C2-C6)alkenyl; or M forms an anionic complex together with one or more T groups, wherein M represents the metal ion optionally connected to an additional metal ion (e.g., an alkali metal ion or an alkaline earth metal ion) via one or more halogen anions, or one or more of the one or more T groups; X 1 is a leaving group such as halogen, imidazole, -O3SCH3 (-O-methylsulfonyl), -O3SC6H4CH3 (-O-toluenesulfonyl), -O-phenyl, and -O3SCF3 (-O-trifluoromethanesulfonyl); n is an integer from 0 to 3; m is an integer from 1 to 3; and Cat + It is a cation, such as an alkali metal cation.

[0008] In certain embodiments, disclosed herein is a method for preparing a compound of formula I, wherein M is a compound of formula -YZ (n) and Y is a metal ion as defined above having an oxidation state of 1, 2 or 3, ie, the sum of n and m is 1, 2, or 3.

[0009] In another aspect, the present invention provides a compound having formula III or a salt, N-oxide, tautomer, or enantiomer thereof, in: T is each independently a group having the formula: R 2 and R 3 are each independently H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, or (C2-C6)alkenyl; R 4 , R 5 , and R 6 are each independently H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, (C3-C7)heterocyclyl, or R 4 , R 5 , and R 6 Any two of the cycloalkyl and heterocyclyl groups are taken together with the carbon atoms to which they are attached to form a 5-7 membered ring, which is optionally substituted with one or more groups each independently selected from halogen, -CN, -COOH, and -NO2, wherein the cycloalkyl and heterocyclyl groups are each independently optionally substituted with one or more groups each independently selected from -CN, -C(O)NH2, halogen, -NO2, -COOH; M is of the formula -YZ (n) wherein Y is a boron ion, or a metal ion having an oxidation state of at least one, such as an alkali metal (e.g., lithium, sodium, potassium) ion, an alkaline earth metal (e.g., magnesium) ion, an aluminum ion, and a transition metal (e.g., copper, zinc, iron) ion, and Z represents a halogen anion; or M is selected from -B(halogen)3 - Cat + 、-B(OR')3 - Cat + , -B(-OC(O)-CH2-N(CH3)-CH2-COO-), -B(OH)2, -B(OH)3 - Cat +, -BR'(OH), -B(R')2, -BR'(OR'), B(OH)(OR'), and -B(OR')2, wherein each R' is independently (C1-C6)alkyl, (C2-C6)alkenyl, or (C3-C7)cycloalkyl, or two R' together with the boron atom to which they are attached form a 5-9 membered ring, which is optionally substituted with one or more groups each independently selected from (C1-C6)alkyl, (C2-C6)alkenyl, =O, -O-(C1-C6)alkyl, or -O-(C2-C6)alkenyl; or M forms an anionic complex together with one or more T groups, wherein M represents the metal ion optionally connected to an additional metal ion (e.g., an alkali metal ion or an alkaline earth metal ion) via one or more halogen anions, or one or more of the one or more T groups; n is an integer from 0 to 3; m is an integer from 1 to 3; and Cat + is a cation, such as an alkali metal cation, The premise is that when R 2 is methyl, R 3 Yes H, R 4 is -CH(CH3)2, R 5 is a methyl group, and R 6 When H, M is not -B(OH)2; 5,5-dimethyl-1,3,2-dioxaborolan-2-yl; or 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.

[0010] In certain embodiments, disclosed herein are compounds of formula III, wherein M is a compound of formula -YZ (n) and Y is a metal ion as defined above having an oxidation state of 1, 2 or 3, ie, the sum of n and m is 1, 2, or 3.

[0011] In yet another aspect, the present invention provides a compound having formula II or a salt, an N-oxide, or a tautomer thereof, in: R 1 is H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, or (C3-C7)cycloalkyl; and X 1is a leaving group such as halogen, imidazole, -O3SCH3 (-O-methylsulfonyl), -O3SC6H4CH3 (-O-toluenesulfonyl), -O-phenyl, and -O3SCF3 (-O-trifluoromethanesulfonyl), The premise is that when R 1 When H is 1 Not -O-phenyl.

[0012] In yet another aspect, the present invention provides a compound having formula IV or a salt, N-oxide, or enantiomer thereof, wherein X 2 is a halogen, such as Cl and Br; and (i)R 2 is methyl, R 3 Yes H, R 4 is -CH(CH3)2, R 5 is methyl, R 6 It is H; (ii) R 2 is methyl, R 3 Yes H, R 4 is -C(H)(F)CH3, R 5 is methyl, R 6 It is H; (iii) R 2 is methyl, R 3 Yes H, R 4 is 1-cyanocyclopropyl, R 5 is methyl, R 6 It is H; (iv) R 2 is methyl, R 3 Yes H, R 4 is methyl, R 5 is methyl, R 6 It is H; (v)R 2 is methyl, R 3 Yes H, R 4 Yes - CF3, R 5 is methyl, R 6 It is H; (vi)R 2 is methyl, R 3 Yes H, R 4 is 1-carbamoylcyclopropyl, R 5 is methyl, R 6 is H; or (vii) R 2 is methyl, R 3 Yes H, R 4 and R5 Together they represent 3,3-difluoro-1,5-pentadienyl, R 6 It's H.

[0013] In a further aspect, the present invention provides a composition comprising a compound of formula I as defined above, or a salt, N-oxide, tautomer, or enantiomer thereof, obtained by the method disclosed above, and at least one additional compound selected from the group consisting of: in: T is each independently a group having the formula: R 1 is H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, or (C3-C7)cycloalkyl; R 2 and R 3 are each independently H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, or (C2-C6)alkenyl; R 4 , R 5 , and R 6 are each independently H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, (C3-C7)heterocyclyl, or R 4 , R 5 , and R 6 Any two of the cycloalkyl and heterocyclyl groups are taken together with the carbon atoms to which they are attached to form a 5-7 membered ring, which is optionally substituted with one or more groups each independently selected from halogen, -CN, -COOH, and -NO2, wherein the cycloalkyl and heterocyclyl groups are each independently optionally substituted with one or more groups each independently selected from -CN, -C(O)NH2, halogen, -NO2, -COOH; M is of the formula -YZ (n)wherein Y is a boron ion, or a metal ion having an oxidation state of at least one, such as an alkali metal (e.g., lithium, sodium, potassium) ion, an alkaline earth metal (e.g., magnesium) ion, an aluminum ion, and a transition metal (e.g., copper, zinc, iron) ion, and Z represents a halogen anion; or M is selected from -B(halogen)3 - Cat + 、-B(OR')3 - Cat + , -B(-OC(O)-CH2-N(CH3)-CH2-COO-), -B(OH)2, -B(OH)3 - Cat + , -BR'(OH), -B(R')2, -BR'(OR'), B(OH)(OR'), and -B(OR')2, wherein each R' is independently (C1-C6)alkyl, (C2-C6)alkenyl, or (C3-C7)cycloalkyl, or two R' together with the boron atom to which they are attached form a 5-9 membered ring, which is optionally substituted with one or more groups each independently selected from (C1-C6)alkyl, (C2-C6)alkenyl, =O, -O-(C1-C6)alkyl, or -O-(C2-C6)alkenyl; or M forms an anionic complex together with one or more T groups, wherein M represents the metal ion optionally connected to an additional metal ion (e.g., an alkali metal ion or an alkaline earth metal ion) via one or more halogen anions, or one or more of the one or more T groups; X 1 is a leaving group such as halogen, imidazole, -O3SCH3 (-O-methylsulfonyl), -O3SC6H4CH3 (-O-toluenesulfonyl), -O-phenyl, and -O3SCF3 (-O-trifluoromethanesulfonyl); X 2 are halogens, such as Cl and Br; n is an integer from 0 to 3; m is an integer from 1 to 3; and Cat + It is a cation, such as an alkali metal cation.

[0014] In certain embodiments, disclosed herein is a composition as defined above, wherein the at least one additional compound comprises Where M is a binary system having the formula -YZ (n) and Y is a metal ion as defined above having an oxidation state of 1, 2 or 3, ie, the sum of n and m is 1, 2, or 3. DETAILED DESCRIPTION

[0015] In one aspect, disclosed herein is a process for preparing a compound of formula I as defined above, the process comprising reacting a compound of formula III as defined above with either: (i) a compound of formula II as defined above, thereby obtaining a compound of formula I; or (ii) 4-isocyanatopyridazine, thereby obtaining a compound of formula I, wherein R 1 is H, and the hydrogen is optionally substituted with a group selected from the following: optionally interspersed with one or more groups each independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, and (C3-C7)cycloalkyl.

[0016] As used herein, the term "N-oxide" refers to any of the compounds of formula I, II, III and IV, and relates to a form of the compound in which at least one (i.e., one or more) of the ring nitrogen atoms is oxidized (as NO). Such N-oxides can be prepared by standard methods, for example, as described in Botteghi et al., Journal of Organometallic Chemistry, 1989, 370, 17-31.

[0017] As used herein, the term "tautomer" refers to any of the compounds of Formula I, II and III, and refers to readily interconvertible structural (compositional) isomers of the compounds. Tautomers of the disclosed compounds include, for example, amide-imidic acid tautomers of the compounds.

[0018] As used herein, the term "enantiomer" with reference to any of the compounds of Formula I, III and IV refers to one of two stereoisomers that are mirror images of each other, which are non-superimposable (different).

[0019] The term "alkyl" typically means a straight or branched hydrocarbon radical having, for example, 1 to 12 carbon atoms, i.e., a monovalent radical derived from a saturated straight or branched aliphatic chain by removing a hydrogen atom from any of the carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, etc. The term "alkenyl" typically means a straight or branched hydrocarbon radical having, for example, 2 to 6 carbon atoms and one or more double bonds, and includes ethenyl, propenyl, 3-buten-1-yl, 2-vinylbutyl, 3-octen-1-yl, etc. The term "haloalkyl" typically means an alkyl as defined herein substituted by one or more groups each independently selected from halogen.

[0020] As used herein, the term "halogen" refers to halogen and includes fluorine, chlorine, bromine, and iodine, but is preferably bromine or chlorine.

[0021] As used herein, the term "carbocycle" refers to a monocyclic, bicyclic, or polycyclic non-aromatic hydrocarbon having, for example, 3-12, but preferably 3-7 carbon atoms. The carbocycle may be saturated, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc.; or unsaturated, that is, having at least one double bond, such as cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, etc. The carbocycle may, for example, be substituted by one or more alkyl groups. The term "cycloalkyl" means a monovalent group derived from a carbocycle by removing a hydrogen atom from any one of the carbon atoms. Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0022] The term "heterocycle" means a monocyclic or polycyclic non-aromatic ring of, for example, 3-7 atoms, containing at least one carbon atom and one to three heteroatoms selected from oxygen, nitrogen and sulfur (optionally oxidized), which may be saturated or unsaturated, i.e., contain at least one unsaturated bond. Preferred are 5- or 6-membered heterocycles. As used herein, the term "heterocyclyl" refers to any monovalent group derived from a heterocycle as defined herein by removing hydrogen from any ring atom. Examples of such groups include, but are not limited to, pyridyl, pyrimidinyl, aziridine, piperidinyl, pyrrolidinyl, aza 4-morpholinyl, oxazolyl, dihydrooxazolyl, oxadiazolyl; imidazolyl, imidazolinyl, dihydroimidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiadiazolyl, piperazinyl, tetrahydropyridinyl, and oxazolyl. Base (oxapinyl).

[0023] According to the process of the invention, a compound of formula III consisting of a group M connected to 1, 2 or 3 T groups (M-[T] m) is reacted with: (i) a compound of formula II to obtain a compound of formula I; or (ii) 4-isocyanatopyridazine to obtain a compound of formula I, wherein R 1 is H. In certain embodiments, the group M is attached to a single T group, i.e., m is 1. In other embodiments, the group M is attached to more than one (i.e., 2 or 3) T groups, wherein the groups T may be the same (where R 2 , R 3 , R 4 , R 5 , and R 6 are the same) or different.

[0024] In certain embodiments, M is a compound having the formula -YZ (n) wherein Y is a boron ion, or a metal ion having an oxidation state of at least one, such as an alkali metal (e.g., lithium, sodium, potassium) ion, an alkaline earth metal (e.g., magnesium) ion, an aluminum ion, and a transition metal (e.g., copper, zinc, iron) ion, and Z represents a halogen anion, such as Cl - or Br - .

[0025] In other embodiments, M is selected from -B(halogen)3 - Cat + 、-B(OR')3 - Cat + , -B(-OC(O)-CH2-N(CH3)-CH2-COO-), -B(OH)2, -B(OH)3 - Cat + , -BR'(OH), -B(R')2, -BR'(OR'), B(OH)(OR'), and -B(OR')2, wherein Cat + is a cation, such as an alkali metal cation; and R' is each independently (C1-C6)alkyl, (C2-C6)alkenyl, or (C3-C7)cycloalkyl, or two R' together with the boron atom to which they are attached form a 5-9 membered ring, which is optionally substituted by one or more groups each independently selected from (C1-C6)alkyl, (C2-C6)alkenyl, =O, -O-(C1-C6)alkyl, or -O-(C2-C6)alkenyl. Examples of such rings include, but are not limited to, 5,5-dimethyl-1,3,2-dioxaborolan-2-yl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, benzo[d][1,3,2]dioxaborolan-2-yl, 9-borabicyclo[3.3.1]nonan-9-yl, or 6-methyl-1,3,6,2-dioxazaborolan-4,8-dione-2-yl.

[0026] In further embodiments, M forms a cationic complex together with one or more T groups attached thereto, wherein M represents a metal ion having an oxidation state of at least one, such as an alkali metal ion, an alkaline earth metal ion, an aluminum ion, and a transition metal ion, which is optionally connected to an additional metal ion (e.g., an alkali metal ion or an alkaline earth metal ion) via one or more halogen anions or one or more of the one or more T groups.

[0027] As used herein, the term "anionic complex" refers to a salt comprising a bimetallic system in which one of the metals has a higher Lewis acidity than the second metal, for example, in which the first metal is Mg 2+ and the latter is, for example, Na + or Li + , and the former metal thus interacts with the Lewis basic anionic ligand (ie, the one or more T groups). Examples of anionic complexes disclosed in the literature include magnesium anionic complexes (Lida et al., Tetrahedron Letters, 2001, 42, 4841-4844) and complexes formed between dialkylmagnesium and alkyllithium (Carlotti et al., Polymer, 2009, 50, 3057-3067).

[0028] In certain embodiments, the methods of the invention are performed at a temperature of about -100°C to about 70°C, such as about -90°C to about 50°C, about -80°C to about 30°C or 40°C, or about -78°C to about 25°C.

[0029] In certain embodiments, a compound having formula III is reacted with a compound having formula II to obtain a compound having formula I.

[0030] In other embodiments, the compound of formula III is reacted with 4-isocyanatopyridazine to obtain a compound of formula I, wherein R 1 In some specific such embodiments, the obtained compound is reacted with a base and then with an alkylating agent, thereby optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 In other specific embodiments, the compound obtained after the reaction of the compound of formula III with 4-isocyanatopyridazine is reacted with the base and the alkylating agent simultaneously.

[0031] As used herein, the term "alkylating agent" refers to an alkyl-bearing reagent that can achieve (e.g., reduce) the molecular polarity of a molecule having an active hydrogen by replacing the active hydrogen with an alkyl group. For example, an alkylating agent can be used to form a carbon-nitrogen bond, such as by alkylation of an amide to form an N-alkylamide. Non-limiting examples of alkylating agents include iodoethane, iodomethane, ethyl methanesulfonate, trimethyloxonium tetrafluoroborate, triethyloxonium tetrafluoroborate, triethyloxonium hexachloroantimonate, ethyl bromide, and diethyl sulfate.

[0032] In certain embodiments, the compound of formula III is prepared from a compound of formula IV or a mixture thereof according to the following method: in: X 2 is a halogen, such as Cl and Br; and R 2 , R 3 , R 4 , R 5 , R 6 , M, and m are each independently defined as in any one of the above embodiments, by using the group -M-[T] m-1 Substituting (i.e., replacing) X in a compound of Formula IV 2 In certain specific embodiments of this invention, the compound of formula III is prepared by the same compound of formula IV, i.e., having the same R 2 , R 3 , R 4 , R 5 , R 6 , and X 2 The compound of formula IV is prepared by the above method, and the compound of formula III thus obtained has the structure M-[T] m , wherein m is an integer from 1 to 3; and the T groups are identical. In other specific such embodiments, the compound of formula III is prepared from a mixture of different compounds of formula IV, and the compound of formula III thus obtained has the structure M-[T] m , wherein m is an integer from 1 to 3; and the T groups are different.

[0033] According to the present invention, the number m of T groups combined with M can depend on the solvent in which the compound of formula IV is reacted with the reagent comprising group M. Suitable such solvents include, for example, ethers, such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, methyl tert-butyl ether, and ethylene glycol dimethyl ether. Due to the significant coordination of the oxygen atom in the ether with the metal, ethers are widely used in reactions involving organometallic reagents or intermediates, such as the reaction of obtaining a compound of formula III from a compound of formula IV.

[0034] In certain embodiments, the process for preparing the compound of formula III is carried out in THF, and the compound thus obtained contains mainly only one T group bound to M, i.e., m is 1. In certain other embodiments, the process is carried out in 1,4-dioxane, and the compound of formula (III) thus obtained contains mainly two T groups bound to M, i.e., m is 2.

[0035] In certain embodiments, the method of obtaining a compound having formula III according to any one of the above embodiments is carried out at a temperature of about -100 °C to about 100 °C.

[0036] In certain embodiments, the compound of formula III is a Grignard reagent, i.e., a compound of formula T-Mg-Hal, wherein Hal is a halogen, preferably Cl or Br; and T is as defined above, which is obtained by reacting a compound of formula IV (wherein X 2 The invention relates to a method for preparing a halogen-containing organic compound by reacting a solid magnesium or magnesium-halogen exchange reagent (such as i-PrMgCl and i-PrMgBr) in an anhydrous ether-based solvent (such as diethyl ether) or a mixture of an anhydrous ether-based solvent and an anhydrous aprotic solvent (such as toluene). Grignard reagents are widely accepted reagents for producing carbon-carbon bonds in organic synthesis.

[0037] In other embodiments, the compound of formula III is in the form of an anionic complex, more specifically an organic cuprate reagent, such as a Gilman reagent consisting of lithium, copper and two T groups, each independently as defined above, having the molecular formula T2CuLi, which is prepared by reacting a compound of formula IV with lithium metal and subsequently reacting the obtained compound with a copper halide (e.g., CuBr and CuI).

[0038] In further embodiments, the compound of formula III is an organolithium reagent of formula T-Li prepared by reacting a compound of formula IV with lithium metal or a lithium-based reagent of formula Li-R, wherein R is an organic group, such as an alkyl group. In specific such embodiments, M is a compound of formula -YZ (n)wherein Y is a lithium ion and n is 0, and the method for obtaining a compound of formula III according to any one of the above embodiments involves reacting a compound of formula IV with n-butyllithium or n-hexyllithium in a solvent such as THF at a temperature of about -78°C to about 0°C.

[0039] In certain embodiments, the compound of formula II is prepared from the compound of formula XI according to the following method: By using a compound having the formula -C(O)X 1 The carbonyl-containing group replaces the nitrogen atom of the secondary amine group, wherein R 1 and X 1 Each independently is as defined above (also referred to herein as "a method for preparing a compound of formula II"). In a specific embodiment, a compound of formula II is prepared by dissolving a compound of formula XI in a solvent, and then reacting the compound with a base at a temperature of about -100°C to about 50°C, such as about -90°C to about 40°C, about -80°C to about 30°C, or about -78°C to about 25°C, followed by reacting with a carbonyl-containing reagent. Non-limiting examples of suitable bases include trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, n-butyllithium, tert-butyllithium, n-hexyllithium, lithium diisopropylamide (LDA), potassium bis(trimethylsilyl)amide (KHMDS), sodium hydroxide (e.g., in the form of a solid or at least 20% sodium hydroxide in water), potassium carbonate, sodium carbonate, and sodium hydride; and examples of carbonyl-containing reagents include, but are not limited to, phenyl chloroformate, phosgene, 1,1,1-trichloromethylformate (diphosgene), bis(trichloromethyl)carbonate (BTC; triphosgene), and phenyl 4,5-dichloro-6-oxopyridazine-1(6H)-carboxylate.

[0040] In certain embodiments, the methods disclosed herein according to any one of the above embodiments are used to prepare a compound having formula I, wherein: (i) R 1 is ethyl, R 2 is methyl, R 3 Yes H, R 4 is -CH(CH3)2, R 5 is a methyl group, and R 6 is H; (ii) R 1 is ethyl, R 2 is methyl, R 3 Yes H, R 4 is -C(H)(F)CH3, R 5 is a methyl group, and R 6 is H; (iii) R 1 is ethyl, R 2 is methyl, R 3Yes H, R 4 is 1-cyanocyclopropyl, R 5 is a methyl group, and R 6 is H; (iv) R 1 is ethyl, R 2 is methyl, R 3 Yes H, R 4 is methyl, R 5 is a methyl group, and R 6 is H; (v) R 1 is ethyl, R 2 is methyl, R 3 Yes H, R 4 Yes - CF3, R 5 is a methyl group, and R 6 is H; (vi) R 1 is ethyl, R 2 is methyl, R 3 Yes H, R 4 is 1-carbamoylcyclopropyl, R 5 is a methyl group, and R 6 is H; or (vii) R 1 is ethyl, R 2 is methyl, R 3 Yes H, R 4 and R 5 together represent 3,3-difluoro-1,5-pentadienyl, and R 6 It's H.

[0041] In specific such embodiments, m is 1, i.e., only one T group is attached to the group M. In certain more specific embodiments, M is Li ion, Cu ion, -Mg(Hal)1, -Cu(Hal)1, -Zn(Hal)1, -BF3 - K + 、-B(OH)2、-B(-OiPr)3Cat + , 5,5-dimethyl-1,3,2-dioxaborolan-2-yl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, benzo[d][1,3,2]dioxaborolan-2-yl, 9-borabicyclo[3.3.1]nonane-9-yl, or 6-methyl-1,3,6,2-dioxazaborolan-4,8-dione-2-yl; and Hal is a halogen, preferably Cl or Br. In other more specific embodiments, M has the formula -Mg(Hal)2Li, -Zn(Hal)2Li, -Cu(Hal)2Mg, or -Cu(Hal)2Li, and forms a cationic complex with the T group; Hal is a halogen, preferably Cl or Br; and the Mg, Zn or Cu ion is bound to the T group and connected to the Li or Mg ion via the halogen anion.

[0042] In other specific such embodiments, m is 2, i.e., two identical T groups are attached to group M. In more specific embodiments, M is a Mg ion or a Zn ion; or M has the formula CuLi and forms a cationic complex with the T groups, wherein a Cu ion is bound to each of the T groups.

[0043] In yet other specific such embodiments, m is 3, i.e., three identical T groups are attached to the group M. In more specific such embodiments, M is a boron ion, an Al ion, or a Fe ion; or M has the formula MgLi and forms a cationic complex with the T groups, wherein a Mg ion is bound to each of the T groups.

[0044] The method disclosed herein according to any of the above embodiments can be carried out with different efficiencies depending on the reagents and conditions used. In other words, the product of the method can contain different percentages of the desired compound I, and a certain amount of other compounds, which are unreacted starting materials or by-products obtained by reactions other than the main reaction that produces the desired compound. In certain embodiments, the product obtained as a result of the method disclosed herein includes at least one of by-products A, B and C (pyridazine-4-amine) in addition to the compound having formula I: Where R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 Each independently is as defined above.

[0045] Byproduct A is a dimer, which can be obtained during the process disclosed above for the preparation of the compound of formula II. In particular, this dimer is obtained by a side reaction in which the starting material in the process for preparing the compound of formula II (i.e., the compound of formula XI) reacts with the product of the process (i.e., the compound of formula II) instead of with the compound of formula -C(O)X as defined above. 1 Reaction of carbonyl-containing groups.

[0046] Similarly, by-product B is a dimer, which can be obtained by side reactions during the process for preparing compounds of formula III. In particular, this dimer can be obtained by the Wurtz reaction, for example, as described in Anteunis et al., Bull. Soc. Chim. Belg. [Bulletin of the Belgian Chemical Society], 1963, 72, 787-796.

[0047] Pyridazine-4-amine (also referred to herein as byproduct C) can be obtained by a side reaction in which 4-isocyanatopyridazine reacts with water instead of with a compound having formula III to obtain an unstable pyridazine carbamate derivative, i.e., pyridazin-4-ylcarbamic acid, which then rapidly loses carbon dioxide to obtain pyridazine-based amine C. The obtained byproduct C can be further reacted with 4-isocyanatopyridazine to obtain byproduct A, wherein R 1 It's H.

[0048] In certain embodiments, the yield of the compound of formula I obtained by the process of the present invention is from about 5% to about 20%, from about 20% to about 40%, from about 40% to about 60%, from about 60% to about 70%, from about 70% to about 80%, from about 80% to about 90%, above 90%, or above 95%. Thus, in certain embodiments, when obtained in the process, the total amount of by-products A, B and / or C constitutes up to about 30%, 25%, 20%, 15%, 10%, or 5% of the final product by weight, or less than 5% of the product by weight.

[0049] According to the present invention, the compound with formula I obtained by the method disclosed herein according to any one of the above embodiments can be in the form of a salt. This salt can be obtained by reacting the compound in its free base form with an inorganic acid or an organic acid. Non-limiting examples of inorganic acids include HF, HCl, HBr, and H2SO4; and non-limiting examples of organic acids include carboxylic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, mandelic acid, citric acid, trifluoroacetic acid, trichloroacetic acid, tartaric acid (including chiral pure tartaric acid, such as D-tartaric acid and L-tartaric acid) or its derivatives such as dibenzoyltartaric acid, N-acetyl leucine and benzoic acid, and sulfonic acid, such as toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid and camphorsulfonic acid such as 3-bromo-10-camphorsulfonic acid and 3-bromo-8-camphorsulfonic acid optionally substituted by one or more Br atoms.

[0050] The compound of formula I obtained by the method disclosed herein according to any of the above embodiments may also be in the form of an N-oxide derivative. Such an N-oxide form may be obtained by oxidizing at least one of the nitrogen atoms of the compound. In specific such embodiments, one or two of the nitrogen atoms of the pyridazine portion of the compound of formula I are in the form of an N-oxide; and / or one or two of the nitrogen atoms of the pyrazole portion of the compound are in the form of an N-oxide, preferably one of the nitrogen atoms, more preferably the same as the one being R 3In more specific embodiments of this type, the nitrogen atom adjacent to the carbon substituted by the amide group is in the form of an N-oxide. In more specific embodiments of this type, the nitrogen at the para position of the amide group in the compound of Formula I is in the form of an N-oxide; the nitrogen at the meta position of the amide group is in the form of an N-oxide; and / or the nitrogen atom adjacent to the carbon substituted by the R 3 The nitrogen adjacent to the carbon substituted by the group is in the form of an N-oxide.

[0051] In another aspect, the present invention provides a compound having formula III or a salt, N-oxide, tautomer, or enantiomer thereof, in: T is each independently a group having the formula: R 2 and R 3 are each independently H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, or (C2-C6)alkenyl; R 4 , R 5 , and R 6 are each independently H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, (C3-C7)heterocyclyl, or R 4 , R 5 , and R 6 Any two of the cycloalkyl and heterocyclyl groups are taken together with the carbon atoms to which they are attached to form a 5-7 membered ring, which is optionally substituted with one or more groups each independently selected from halogen, -CN, -COOH, and -NO2, wherein the cycloalkyl and heterocyclyl groups are each independently optionally substituted with one or more groups each independently selected from -CN, -C(O)NH2, halogen, -NO2, -COOH; M is of the formula -YZ (n) wherein Y is a boron ion, or a metal ion having an oxidation state of at least one, such as an alkali metal (e.g., lithium, sodium, potassium) ion, an alkaline earth metal (e.g., magnesium) ion, an aluminum ion, and a transition metal (e.g., copper, zinc, iron) ion, and Z represents a halogen anion; or M is selected from -B(halogen)3 - Cat+ 、-B(OR')3 - Cat + , -B(-OC(O)-CH2-N(CH3)-CH2-COO-), -B(OH)2, -B(OH)3 - Cat + , -BR'(OH), -B(R')2, -BR'(OR'), B(OH)(OR'), and -B(OR')2, wherein each R' is independently (C1-C6)alkyl, (C2-C6)alkenyl, or (C3-C7)cycloalkyl, or two R' together with the boron atom to which they are attached form a 5-9 membered ring, which is optionally substituted with one or more groups each independently selected from (C1-C6)alkyl, (C2-C6)alkenyl, =O, -O-(C1-C6)alkyl, or -O-(C2-C6)alkenyl; or M forms an anionic complex together with one or more T groups, wherein M represents the metal ion optionally connected to an additional metal ion (e.g., an alkali metal ion or an alkaline earth metal ion) via one or more halogen anions, or one or more of the one or more T groups; n is an integer from 0 to 3; m is an integer from 1 to 3; and Cat + is a cation, such as an alkali metal cation, The premise is that when R 2 is methyl, R 3 Yes H, R 4 is -CH(CH3)2, R 5 is a methyl group, and R 6 When H, M is not -B(OH)2; 5,5-dimethyl-1,3,2-dioxaborolan-2-yl; or 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.

[0052] In certain embodiments, disclosed herein are compounds of formula III as defined above, wherein: (i) R 2 is methyl, R 3 Yes H, R 4 is -CH(CH3)2, R 5 is a methyl group, and R 6 is H; (ii) R 2 is methyl, R 3 Yes H, R 4 is -C(H)(F)CH3, R 5 is a methyl group, and R 6 is H; (iii) R 2 is methyl, R3 Yes H, R 4 is 1-cyanocyclopropyl, R 5 is a methyl group, and R 6 is H; (iv) R 2 is methyl, R 3 Yes H, R 4 is methyl, R 5 is a methyl group, and R 6 is H; (v) R 2 is methyl, R 3 Yes H, R 4 Yes - CF3, R 5 is a methyl group, and R 6 is H; (vi) R 2 is methyl, R 3 Yes H, R 4 is 1-carbamoylcyclopropyl, R 5 is a methyl group, and R 6 is H; or (vii) R 2 is methyl, R 3 Yes H, R 4 and R 5 Together they represent 3,3-difluoro-1,5-pentadienyl, and R 6 It's H.

[0053] In specific such embodiments, m is 1, i.e., only one T group is attached to the group M. In certain more specific such embodiments, M is Li ion, Cu ion, -Mg(Hal)1, -Cu(Hal)1, -Zn(Hal)1, -BF3 - K + 、-B(OH)2、-B(-OiPr)3Cat + , 5,5-dimethyl-1,3,2-dioxaborolan-2-yl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, benzo[d][1,3,2]dioxaborolan-2-yl, 9-borabicyclo[3.3.1]nonane-9-yl, or 6-methyl-1,3,6,2-dioxazaborolan-4,8-dione-2-yl, and Hal is a halogen, preferably Cl or Br. In other more specific embodiments, M has the formula -Mg(Hal)2Li, -Zn(Hal)2Li, -Cu(Hal)2Mg, or -Cu(Hal)2Li, and forms a cationic complex with the T group; Hal is a halogen, preferably Cl or Br; and the Mg, Zn or Cu ion is bound to the T group and connected to the Li or Mg ion via the halogen anion.

[0054] In other specific such embodiments, m is 2, i.e., two identical T groups are attached to group M. In more specific such embodiments, M is a Mg ion or a Zn ion; or M has the formula CuLi and together with the T groups forms a cationic complex in which a Cu ion is bound to each of the T groups.

[0055] In yet other specific such embodiments, m is 3, i.e., three identical T groups are attached to the group M. In more specific such embodiments, M is a boron ion, an Al ion, or a Fe ion; or M has the formula MgLi and forms a cationic complex with the T groups, wherein a Mg ion is bound to each of the T groups.

[0056] In certain embodiments, the compound of formula III according to any one of the above embodiments is in the form of a salt. In specific such embodiments, M is a boron-containing group, and such a salt can be obtained by reacting the compound in its free base form with an inorganic acid or an organic acid as defined herein.

[0057] In other embodiments, the compound of formula III according to any of the above embodiments is in the form of an N-oxide derivative. Such N-oxide derivatives can be obtained by oxidizing at least one of the nitrogen atoms of the compound. In specific such embodiments, one or two of the nitrogen atoms of the pyrazole portion of the compound of formula III are in the form of an N-oxide, preferably one of the nitrogen atoms, more preferably the same as R 3 The nitrogen atom adjacent to the carbon substituted by the group is in the form of an N-oxide.

[0058] In yet another aspect, the present invention provides a compound having formula II or a salt, an N-oxide, or a tautomer thereof, in: R 1 is H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, or (C3-C7)cycloalkyl; and X 1 is a leaving group such as halogen, imidazole, -O3SCH3 (-O-methylsulfonyl), -O3SC6H4CH3 (-O-toluenesulfonyl), -O-phenyl, and -O3SCF3 (-O-trifluoromethanesulfonyl), provided that when R 1 When H is 1 Not -O-phenyl.

[0059] Specific compounds of formula II disclosed herein are compounds wherein R 1 is ethyl; and X 1 It is halogen, -O3SCH3 (-O-methylsulfonyl), -O3SC6H4CH3 (-O-toluenesulfonyl), -O-phenyl, and -O3SCF3 (-O-trifluoromethanesulfonyl), or imidazole, preferably halogen, more preferably Cl.

[0060] In certain embodiments, the compound of formula II according to any one of the above embodiments is in the form of a salt. Such a salt can be obtained by reacting the compound in its free base form with an inorganic acid or an organic acid as defined herein.

[0061] In other embodiments, the compound with formula II according to any one of the above embodiments is in the form of an N-oxide derivative. This N-oxide form can be obtained by oxidizing at least one of the nitrogen atoms of the compound. In specific embodiments of this type, one or two of the nitrogen atoms of the pyridazine part are in the form of an N-oxide. In more specific embodiments of this type, the nitrogen atom in the para position of the amide group in the compound with formula II is in the form of an N-oxide and / or the nitrogen in the meta position of the amide group is in the form of an N-oxide.

[0062] In yet another aspect, the present invention provides a compound having formula IV or a salt, N-oxide, or enantiomer thereof, wherein X 2 is a halogen, such as Cl and Br; and (i) R 2 is methyl, R 3 Yes H, R 4 is -CH(CH3)2, R 5 is methyl, R 6 is H; (ii) R 2 is methyl, R 3 Yes H, R 4 is -C(H)(F)CH3, R 5 is methyl, R 6 is H; (iii) R 2 is methyl, R 3 Yes H, R 4 is 1-cyanocyclopropyl, R 5 is methyl, R 6 is H; (iv) R 2 is methyl, R 3 Yes H, R 4 is methyl, R 5 is methyl, R 6 is H; (v) R2 is methyl, R 3 Yes H, R 4 Yes - CF3, R 5 is methyl, R 6 is H; (vi) R 2 is methyl, R 3 Yes H, R 4 is 1-carbamoylcyclopropyl, R 5 is methyl, R 6 is H; or (vii) R 2 is methyl, R 3 Yes H, R 4 and R 5 Together they represent 3,3-difluoro-1,5-pentadienyl, R 6 It's H.

[0063] In a further aspect, the present invention provides a composition comprising a compound having formula I obtained by the method of the present invention according to any one of the above embodiments: or a salt, N-oxide, tautomer, or enantiomer thereof, and at least one of the additional compounds: in: T is each independently a group having the formula: R 1 is H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, or (C3-C7)cycloalkyl; R 2 and R 3 are each independently H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, or (C2-C6)alkenyl; R 4 , R 5 , and R 6 are each independently H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12)alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, (C3-C7)heterocyclyl, or R 4 , R 5 , and R 6 Any two of the cycloalkyl and heterocyclyl groups are taken together with the carbon atoms to which they are attached to form a 5-7 membered ring, which is optionally substituted with one or more groups each independently selected from halogen, -CN, -COOH, and -NO2, wherein the cycloalkyl and heterocyclyl groups are each independently optionally substituted with one or more groups each independently selected from -CN, -C(O)NH2, halogen, -NO2, -COOH; M is of the formula -YZ (n) wherein Y is a boron ion, or a metal ion having an oxidation state of at least one, such as an alkali metal (e.g., lithium, sodium, potassium) ion, an alkaline earth metal (e.g., magnesium) ion, an aluminum ion, and a transition metal (e.g., copper, zinc, iron) ion, and Z represents a halogen anion; or M is selected from -B(halogen)3 - Cat + 、-B(OR')3 - Cat + , -B(-OC(O)-CH2-N(CH3)-CH2-COO-), -B(OH)2, -B(OH)3 - Cat + , -BR'(OH), -B(R')2, -BR'(OR'), B(OH)(OR'), and -B(OR')2, wherein each R' is independently (C1-C6)alkyl, (C2-C6)alkenyl, or (C3-C7)cycloalkyl, or two R' together with the boron atom to which they are attached form a 5-9 membered ring, which is optionally substituted with one or more groups each independently selected from (C1-C6)alkyl, (C2-C6)alkenyl, =O, -O-(C1-C6)alkyl, or -O-(C2-C6)alkenyl; or M forms an anionic complex together with one or more T groups, wherein M represents the metal ion optionally connected to an additional metal ion (e.g., an alkali metal ion or an alkaline earth metal ion) via one or more halogen anions, or one or more of the one or more T groups; X 1 is a leaving group such as halogen, imidazole, -O3SCH3 (-O-methylsulfonyl), -O3SC6H4CH3 (-O-toluenesulfonyl), -O-phenyl, and -O3SCF3 (-O-trifluoromethanesulfonyl); X 2 are halogens, such as Cl and Br; n is an integer from 0 to 3; m is an integer from 1 to 3; and Cat + It is a cation, such as an alkali metal cation.

[0064] As explained above, the compositions of the present invention may contain different percentages, such as about 5% to about 20%, about 20% to about 40%, about 40% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 95% or more by weight of the compound having Formula I. Thus, in certain embodiments, the total amount of the at least one additional compound contained within the compositions of the present invention constitutes up to about 30%, 25%, 20%, 15%, 10%, or 5% by weight of the total amount of the compound having Formula I and the at least one additional compound.

[0065] Unless otherwise indicated, all numbers used in this specification indicating, for example, the amount of a component or the ratio between components should be understood as being modified in all cases by the term "about". Therefore, unless indicated to the contrary, the numerical parameters set forth in this specification are approximate values ​​that may vary by up to plus or minus 10% depending on the desired properties to be obtained by the present invention.

[0066] The invention will now be illustrated by the following non-limiting examples. Examples Materials and Methods

[0067] Materials. All reagents and starting materials were purchased from Thermo Fisher Scientific, Finar Limited, Avra, Merck, Symax, BLD pharma, RCP, Hindustan Platinum, CS reagents, Hychem, and Combi-Blocks. Example 1. Synthesis of 5-methyl-1-(3-methylbutan-2-yl)-1H-pyrazole

[0068] To a stirred solution of 3-methyl-2-butanone (50 g, 0.582 mole, HPLC purity about 93%) was added hydrazine hydrate (31.97 g, 0.640 mole) followed by 300 mL of 50% HCl at 25°C-30°C. The reaction mass was cooled and stirred at 0°C-5°C for 1 h. Sodium borohydride (22.8 g, 0.582 mole) was added to the reaction mixture at 0°C-5°C. The reaction mass was then warmed to 25°C-30°C and stirred for 12 h.

[0069] In another round-bottom flask, a solution of 4,4-dimethoxy-2-butanone (100 g, 0.756 mole) and 630 mL of 50% aqueous HCl was stirred at 25 ° C -30 ° C for 2 h. At 0 ° C -5 ° C, the solution was added to the above reaction mass (made from a mixture of 3-methyl-2-butanone, hydrazine hydrate and sodium borohydride) over a period of 30 min. Then, it was warmed to 25 ° C -30 ° C and stirred for 14 h. The reaction progress was monitored by LCMS. Then, a saturated solution of K2CO3 was used to neutralize the reaction mass to pH 7. The reaction mass was extracted with methyl tert-butyl ether (MTBE) (4 × 250 mL), and the combined organic layer was washed with brine (100 mL). The organic layer obtained was evaporated under vacuum to provide a crude product. The crude product was purified by silica gel column chromatography using ethyl acetate (EtOAc) / hexane as eluent to obtain 5-methyl-1-(3-methylbutan-2-yl)-1H-pyrazole (28.9 g) as a pale yellow solid with a yield close to about 32% and a purity of about 96% (according to LC-MS analysis).

[0070] 1 H NMR(DMSO-d6): δ7.30(d,J=8Hz,1H),5.94(d,J=8Hz,1H),3.86-3.92(m,1H),2.23(s,3H),1.99 -2.07(m,1H),1.33-1.36(m,3H),0.938-0.955(d,J=6.8Hz,3H),0.577-0.594(d,J=6.8Hz,3H). LCMS(EI): m / z 153.2(M+1). Example 2. Synthesis of 4-bromo-5-methyl-1-(3-methylbutan-2-yl)-1H-pyrazole

[0071] At 18 ℃-20 ℃ in the span of 2h, bromine (6.78mL, 0.131 mole) was added dropwise to a stirred solution of 5-methyl-1-(3-methylbutane-2-yl)-1H-pyrazole (20g, 0.131 mole) in acetic acid (300mL). The reaction mixture was stirred for 12h at 25 ℃-30 ℃. The reaction progress was monitored by TLC. The reaction mass was quenched with saturated sodium metabisulfite solution and kept stirring at room temperature for 1h. Then, saturated NaHCO3 solution was added to the reaction mass to neutralize pH. The reaction mass was extracted with MTBE (4×100mL), and the combined organic layer was washed with brine (100mL). Then, MTBE was distilled to dryness to provide 4-bromo-5-methyl-1-(3-methylbutan-2-yl)-1H-pyrazole (25 g) as a brown oil in approximately 82% yield with approximately 90% purity (according to LC-MS analysis).

[0072] 1 H NMR (DMSO-d6): δ7.48(s,1H),3.98-4.02(m,1H),2.23(s,3H),1.98-2.04(m,1H),1.33-1.35(m,3H),0.92-0.94(m,3H),0.60-0.61(m,3H). LCMS(EI): m / z 231.1(M+1). Example 3. Synthesis of ethyl(pyridazin-4-yl)carbamate

[0073] In a 250mL round-bottom flask, N-ethylpyridazine-4-amine (2g, 0.016 mole) is added in dichloromethane (DCM; 50mL), triethylamine (4.2mL, 0.032 mole) is loaded. At 0°C-5°C, ethyl chloroformate (2.27mL, 0.024 mole) is slowly added to the reaction mass, and the resulting mixture is stirred for 3h at 0°C-5°C. The reaction mass is filtered out and the filtrate is evaporated under vacuum to provide a crude product. The crude product is purified by silica gel column chromatography using methanol (MeOH) / DCM as eluent to provide pure ethyl (pyridazine-4-yl) ethyl carbamate (1.69g) in a brown viscous liquid with a purity of about 99% (according to LC-MS analysis).

[0074] 1H NMR(DMSO-d6): δ9.37-9.38(m,1H),9.09-9.11(m,1H),7.66-7.68(m,1H), 4.18-4.23(m,2H)3.80-3.84(m,2H),1.22-1.26(m,3H),1.14-1.17(m,3H). LCMS(EI): m / z 196.1. Example 4. Synthesis of phenyl ethyl(pyridazin-4-yl)carbamate

[0075] In a 250mL round-bottom flask equipped with triethylamine (1.1mL, 0.008g), N-ethylpyridazine-4-amine (0.5g, 0.004 mole) added in EtOAc (20mL). At 0°C-5°C, phenylchloroformate (0.6mL, 0.0048 mole) is slowly added to the reaction mass. The mixture is stirred for 2h at 0°C-5°C. The reaction mass is filtered out and the filtrate is evaporated under vacuum to provide a crude product. The crude product is purified by silica gel column chromatography using EtOAc / hexane as eluent to provide pure ethyl (pyridazine-4-yl) phenylcarbamate (0.85g) in a brown viscous liquid, and its yield is close to about 86%, with a purity of about 93% (according to LC-MS analysis).

[0076] 1 H NMR(DMSO-d6): δ9.50(m,1H),9.19-9.21(m,1H),7.81-7.83(m,1H),7.42-7.46(m,1H),7.26-7.30(m,3H),3.94-3.99(m,2H),1.23-1.28(m,3H). LCMS(EI): m / z 244.2. Example 5. Synthesis of N-ethyl-5-methyl-1-(3-methylbutan-2-yl)-N-(pyridazin-4-yl)-1H-pyrazole-4-carboxamide

[0077] Case 1. 4-Bromo-5-methyl-1-(3-methylbutan-2-yl)-1H-pyrazole (0.828 g, 0.0036 mole) in anhydrous tetrahydrofuran (THF; 5 mL) in an oven-dried two-necked round bottom flask. The solution was actively purged with nitrogen. The flask was cooled to -78°C. 2.5 M n-butyllithium (1.5 mL, 0.0036 mole) was added dropwise for a period of 20 min, and the reaction mass was stirred at -78°C for 30 min (reaction mass A).

[0078] In another oven-dried two-necked round-bottom flask, trimethylamine (0.5 mL, 0.0036 mole) was added to N-ethylpyridazine-4-amine (0.3 g, 0.0024 mole) in THF (5 mL) under a nitrogen atmosphere at 25° C.-30° C. Then, a solution of triphosgene (0.355 g, 0.0012 mole) in THF was added to the reaction mass. The resulting reaction mass was stirred at 25° C.-30° C. for 1 h and then cooled to -78° C. (reaction mass B).

[0079] Reaction material A is taken out in a 10ml syringe and added dropwise to a stirred solution of reaction material B at -78 °C. The reaction material is warmed to 25 °C-30 °C for 1h. The crude material is quenched with a saturated ammonium chloride solution (20mL). The reaction material is extracted with EtOAc (2 × 30mL), washed with water (2 × 20mL) and brine (20mL). The combined organic layer is evaporated to obtain a crude product and analyzed by LCMS. According to LCMS, the crude product shows about 47% N-ethyl-5-methyl-1-(3-methylbutane-2-yl)-N-(pyridazine-4-yl)-1H-pyrazole-4-carboxamide. The sample from the crude product is purified by preparative HPLC (0.1% formic acid in water: acetonitrile, column: XBridge Prep C18 (250 × 19) mm, 5.0 μ). The obtained fractions were lyophilized to give a solid compound (70 mg) with a purity of about 99% (according to LC-MS analysis).

[0080] 1 H NMR(CDCl3): δ9.04-9.05(m,1H),8.95-8.96(m,1H),7.19-7.22(m,1H),6.98(s,1H),3.99-4.04(m,2H),3.79-3.83(m ,1H),2.4(s,3H),2.07-2.12(m,1H),1.41(d,J=8Hz,3H),1.27(t,J=8Hz,3H),0.98(d,J=8Hz,3H),0.62(d,J=8Hz,3H). 13C NMR (CDCl3): δ 164.3, 150.1, 148.3, 142.1, 140.7, 137.9, 119.6, 112.1, 59.3, 43.1, 33.0, 18.6, 18.3, 17.3, 12.5, 9.62. LCMS(EI): m / z 302.38.

[0081] Case 2. In an oven-dried two-necked round bottom flask, 4-bromo-5-methyl-1-(3-methylbutan-2-yl)-1H-pyrazole (0.935 g, 0.004 mole) and anhydrous THF (5 mL) were added under a nitrogen atmosphere. The solution was actively purged with nitrogen. The flask was cooled to -78°C with a combination of dry ice / acetone. 2.5 M n-butyllithium (2 mL, 0.005 mole) was added dropwise for a period of 20 min, and the reaction mass was stirred at -78°C for 30 min (reaction mass A).

[0082] In another oven-dried two-necked round-bottom flask, N-ethylpyridazine-4-amine (0.25 g, 0.002 mole), TEA (0.4 mL, 0.003 mole) and DCM (3 mL) were stirred under a nitrogen atmosphere. Triphosgene (0.296 g, 0.001 mole) in DCM (2 mL) was added dropwise to the reaction mixture at 25-30° C., and the reaction mixture was stirred for 2 h at 25-30° C. DCM was evaporated to dryness under reduced pressure at less than 35° C., followed by addition of anhydrous THF (5 mL), and the reaction mass was then cooled to -78° C. (reaction mass B).

[0083] The reaction mixture was stirred at 25 ℃ for 12 hours.Then, reaction mass A is taken out into 10ml syringe and added dropwise to the stirring solution of reaction mass B at -78 ℃ in the time period of 30min.All reaction masses are stirred for 12h at 25 ℃-30 ℃.The thick material is quenched with saturated ammonium chloride solution (20mL).The reaction mass is extracted with EtOAc (2 × 30mL), washed with water (2 × 20mL) and brine (20mL).The organic layer merged is evaporated to obtain crude product and analyzed by LCMS.According to LCMS, crude product shows about 18% N-ethyl-5-methyl-1-(3-methylbutane-2-yl)-N-(pyridazine-4-yl)-1H-pyrazole-4-carboxamide.

[0084] Case 3. In an oven-dried two-necked round bottom flask, 4-bromo-5-methyl-1-(3-methylbutan-2-yl)-1H-pyrazole (0.736 g, 0.0032 mole) in anhydrous THF (5 mL) was stirred under a nitrogen atmosphere and the solution was actively purged with nitrogen. The flask was cooled to -78°C and 1.6 mL of 2.5 M n-butyllithium (1.6 mL, 0.004 mole) was added dropwise to the reaction mass at -78°C over 30 min (Reaction mass A).

[0085] In another oven-dried two-necked round-bottom flask, N-ethylpyridazine-4-amine (0.2 g, 0.0016 mole), TEA (0.33 mL, 0.0024 mole) and DCM (3 mL) were added under a nitrogen atmosphere. Triphosgene (0.236 g, 0.0008 mole) in DCM (2 mL) was added dropwise to the reaction mixture. The reaction mass was stirred at 25° C.-30° C. for 2 h, and then cooled to -10° C. (reaction mass B).

[0086] The reaction mixture was stirred at 25 ℃-30 ℃ for 12h. The reaction mixture was quenched with saturated ammonium chloride solution (10mL). The reaction mixture was extracted with EtOAc (2 × 30mL), washed with water (2 × 20mL) and brine (20mL). The organic layer merged was evaporated to obtain a crude product and analyzed by LCMS. According to LCMS, crude product shows about 5% N-ethyl-5-methyl-1-(3-methylbutane-2-yl)-N-(pyridazine-4-yl)-1H-pyrazole-4-carboxamide.

[0087] Case 4. To an oven dried two-necked round bottom flask under nitrogen atmosphere was added 4-bromo-5-methyl-1-(3-methylbutan-2-yl)-1H-pyrazole (0.736 g, 0.0032 mole) in anhydrous THF (5 mL). The solution was actively purged with nitrogen. The flask was cooled to -78°C. 2.5 M n-butyllithium (1.6 mL, 0.004 mole) was added dropwise to the reaction mass at -78°C for 30 min (Reaction mass A).

[0088] In another oven-dried two-necked round-bottom flask, N-ethylpyridazine-4-amine (0.2g, 0.0016 mole), TEA (0.33mL, 0.0024 mole) and DCM (3mL) were added under a nitrogen atmosphere. Triphosgene (0.236g, 0.0008 mole) dissolved in DCM (2mL) was added dropwise to the reaction mixture. The reaction mass was stirred for 2h at 25°C-30°C. DCM was distilled under reduced pressure at less than 35°C, anhydrous THF (5mL) and catalyst NiCl (PPh ) (10mg) were added subsequently and then cooled to -10°C (reaction mass B).

[0089] The reaction mixture was stirred at 25 ℃ for 12 hours.Then, reaction mass A is taken out into 10ml syringe, and is added dropwise to the stirring solution of reaction mass B in the time period of 30min at-10 ℃.All reaction masses are stirred for 12h at 25 ℃-30 ℃.The thick material is quenched with saturated ammonium chloride solution (10mL).The reaction mass is extracted with EtOAc (2 × 30mL), washed with water (2 × 20mL) and saline (20mL).The organic layer merged is evaporated to obtain crude product and analyzed by LCMS.According to LCMS, crude product shows about 2% N-ethyl-5-methyl-1-(3-methylbutane-2-yl)-N-(pyridazine-4-yl)-1H-pyrazole-4-carboxamide.

[0090] Case 5. To an oven dried two neck round bottom flask under nitrogen atmosphere was added 4-bromo-5-methyl-1-(3-methylbutan-2-yl)-1H-pyrazole (0.736 g, 0.0032 mole) in anhydrous THF (5 mL). The solution was actively purged with nitrogen. The flask was cooled to -78°C. 2.5 M n-butyllithium (1.6 mL, 0.004 mole) was added dropwise over a period of 20 min and the reaction mass was stirred at -78°C for 30 min (reaction mass A).

[0091] In another oven-dried two-necked round-bottom flask, N-ethylpyridazine-4-amine (0.2g, 0.0016 mole), TEA (0.33mL, 0.0024 mole) and DCM (3mL) were added under a nitrogen atmosphere. Triphosgene (0.236g, 0.0008 mole) dissolved in DCM (2mL) was added dropwise to the reaction mixture. The reaction mass was stirred for 2h at 25°C-30°C. DCM was distilled under reduced pressure at less than 35°C, followed by addition of anhydrous THF (5mL) and PPh (0.461g, 0.00176 mole), and then cooled to -10°C (reaction mass B).

[0092] The product of 4-nitropropene was added to 4-nitropropene in 1% ethyl acetate (10mL).Then, reaction material A is taken out in a 10ml syringe, and is added dropwise to the stirring solution of reaction material B at -10 ℃ in a time period of 30min.All reaction materials are stirred for 12h at 25 ℃-30 ℃.Crude material is quenched with saturated ammonium chloride solution (10mL).Reaction material is extracted with EtOAc (2 × 30mL), washed with water (2 × 20mL) and brine (20mL).The organic layer merged is evaporated to obtain a crude product, and analyzed by LCMS.According to LCMS, crude product shows about 3% N-ethyl-5-methyl-1-(3-methylbutane-2-yl)-N-(pyridazine-4-yl)-1H-pyrazole-4-carboxamide.

[0093] Case 6. In an oven dried two neck round bottom flask, 4-bromo-5-methyl-1-(3-methylbutan-2-yl)-1H-pyrazole (1.1 g, 0.0048 mole) in anhydrous THF (5 mL) was added under nitrogen atmosphere. The solution was actively purged with nitrogen. The flask was cooled to -78°C. 2.5 M n-butyl lithium (2.1 mL, 0.0053 mole) was added dropwise over a period of 20 min, and the reaction mass was stirred at -78°C for 30 min (reaction mass A).

[0094] In another oven-dried two-necked round bottom flask, N-ethylpyridazin-4-amine (0.3 g, 0.0024 mole), triphosgene (0.355 g, 0.0012 mole) and anhydrous THF (5 mL) were added under nitrogen atmosphere and cooled to -78° C. 2.5 M n-butyllithium (0.96 mL, 0.0024 mole) was added dropwise and the reaction mass was stirred at -78° C. for 1 h (reaction mass B).

[0095] Then, reaction material A is taken out in 10ml syringe, and is added dropwise to the stirring solution of reaction material B in the time period of 30min at-78 ℃ and stirs for 1h at-25 ℃.Crude material is quenched with saturated ammonium chloride solution (10mL).Reaction material is extracted with EtOAc (2×30mL), washed with water (2×20mL) and brine (20mL).The combined organic layer is evaporated to obtain crude product and analyzed by LCMS, and about 30% N-ethyl-5-methyl-1-(3-methylbutane-2-yl)-N-(pyridazine-4-yl)-1H-pyrazole-4-carboxamide is shown.The sample from crude product is purified by preparative HPLC (0.1% formic acid in water: acetonitrile, column: XBridge Prep C18 (250×19) mm, 5.0μ). The obtained fractions were lyophilized to give a solid compound (70 mg) with a purity of about 93% (according to LC-MS analysis).

[0096] Case 7. In an oven-dried two-necked round bottom flask, 4-bromo-5-methyl-1-(3-methylbutan-2-yl)-1H-pyrazole (0.828 g, 0.0036 mole) in anhydrous THF (5 mL) was added under nitrogen atmosphere and the solution was actively purged with nitrogen. The flask was cooled to -78°C. 2.5 M n-butyllithium (1.5 mL, 0.0036 mole) was added dropwise over a period of 20 min and the reaction mass was stirred at -78°C for 30 min (reaction mass A).

[0097] In another oven-dried two-necked round-bottom flask, N-ethylpyridazine-4-amine (0.3 g, 0.0024 mole) was added in THF. Then, NaH (0.086 g, 0.0036 mole) was added to the solution. Finally, a solution of triphosgene (0.355 g, 0.0012 mole) in THF (5 mL) was added dropwise (5-10 min) under a nitrogen atmosphere. The reaction mass was stirred for 1 h at 25 ° C -30 ° C, and then cooled to -78 ° C (reaction mass B).

[0098] The product of 4-nitropropene was added to 4-nitropropene in 1H- pyridine-4-carboxamide.Then, reaction material A is taken out in a 10ml syringe, and is added dropwise to the stirring solution of reaction material B at -78 °C in a time period of 30min.Reaction material is stirred for 1h at 25 °C-30 °C.Crude material is quenched with saturated ammonium chloride solution (10mL).Reaction material is extracted with EtOAc (2 × 30mL), washed with water (2 × 20mL) and brine (20mL).The combined organic layer is evaporated to obtain a crude product and analyzed by LCMS.According to LCMS, crude product shows about 24% N- ethyl -5- methyl -1- (3- methylbutane -2- bases) -N- (pyridazine -4- bases) -1H- pyrazole -4- carboxamide.

[0099] Case 8. In an oven-dried two-necked round bottom flask, 4-bromo-5-methyl-1-(3-methylbutan-2-yl)-1H-pyrazole (0.828 g, 0.0036 mole) in anhydrous THF (5 mL) was added under nitrogen atmosphere and the solution was actively purged with nitrogen. The flask was cooled to -78°C. 2.5 M n-butyllithium (1.5 mL, 0.0036 mole) was added dropwise over a period of 20 min and the reaction mass was stirred at -78°C for 30 min (reaction mass A).

[0100] In another oven-dried two-necked round-bottom flask, NaH (0.086 g, 0.0036 mole) was added to a solution of N-ethylpyridazine-4-amine (0.3 g, 0.0024 mole) in DCM (5 mL). Then, a solution of triphosgene (0.355 g, 0.0012 mole) in DCM (2 mL) was added under a nitrogen atmosphere. The reaction mass was stirred at 25° C.-30° C. for 1 h, and then cooled to -78° C. (reaction mass B).

[0101] Reaction material A is taken out in 10ml syringe, and is added dropwise in the stirring solution of reaction material B at-78 ℃ in the time period of 30min.Reaction material is stirred at room temperature for 1h.Crude material is quenched with saturated ammonium chloride solution (20mL).Reaction material is extracted with EtOAc (2 × 30mL), washed with water (2 × 20mL) and brine (20mL).The organic layer merged is evaporated to obtain crude product and analyzed by LCMS.According to LCMS, crude product shows about 23% N-ethyl-5-methyl-1-(3-methylbutane-2-yl)-N-(pyridazine-4-yl)-1H-pyrazole-4-carboxamide. Example 6. Synthesis of 5-methyl-1-(3-methylbutan-2-yl)-N-(pyridazin-4-yl)-1H-pyrazole-4-carboxamide

[0102] In an oven-dried two-necked round-bottom flask, 4-bromo-5-methyl-1-(3-methylbutane-2-yl)-1H-pyrazole (0.828 g, 0.0036 mole) was added to anhydrous THF (5 mL) and stirred. The solution was actively purged with nitrogen. The flask was cooled to -78 ° C. 2.5 M n-butyl lithium (1.5 mL, 0.0036 mole) was added dropwise for a period of 20 min, and the reaction mass was stirred at -78 ° C for 30 min (reaction mass A).

[0103] In another oven-dried two-necked round bottom flask, 4-isocyanatopyridazine (0.29 g, 0.0024 mol) was stirred in THF (5 mL) under nitrogen atmosphere at 25-30° C. The resulting reaction mass was cooled to −78° C. (reaction mass B).

[0104] Reaction material A is taken out in a 10ml syringe and added dropwise to a stirred solution of reaction material B at -78 °C. The reaction material is warmed to 25 °C-30 °C for 4h. The crude material is quenched with a saturated ammonium chloride solution (20mL). The reaction mixture is extracted with EtOAc (2 × 30mL), washed with water (2 × 20mL) and brine (20mL). The combined organic layer is evaporated to obtain a crude product and analyzed by LCMS. According to LCMS, the crude product shows about 50% 5-methyl-1-(3-methylbutane-2-yl)-N-(pyridazine-4-yl)-1H-pyrazole-4-carboxamide. The sample from the crude product is purified by preparative HPLC (0.1% formic acid in water: acetonitrile, column: XBridge Prep C18 (250 × 19) mm, 5.0 μ). The fraction obtained is freeze-dried to obtain a solid compound with a purity of about 95% (according to LC-MS analysis). Example 7. Synthesis of N-ethyl-5-methyl-1-(3-methylbutan-2-yl)-N-(pyridazin-4-yl)-1H-pyrazole-4-carboxamide

[0105] In an oven-dried double-necked round-bottom flask, 5-methyl-1-(3-methylbutane-2-yl)-N-(pyridazine-4-yl)-1H-pyrazole-4-carboxamide (0.65g, 0.0024 mole) was dissolved in 6ml THF at room temperature. Then, NaH (0.086g, 0.0036 mole) was added at 0°C. Finally, a solution (5-10min) of iodoethane (0.44g, 0.0028mol) in THF (5mL) was added dropwise under a nitrogen atmosphere. The reaction mass was warmed to 25°C-30°C in 12h. The crude material was quenched with a saturated ammonium chloride solution (20mL). The reaction mixture was extracted with EtOAc (2×30mL), washed with water (2×20mL) and brine (20mL). The combined organic layer was evaporated to obtain a crude product and analyzed by LCMS. The crude product showed about 20% N-ethyl-5-methyl-1-(3-methylbutan-2-yl)-N-(pyridazin-4-yl)-1H-pyrazole-4-carboxamide by LCMS.

Claims

1. A method for preparing a compound having formula I or a salt, N-oxide, tautomer, or enantiomer thereof, in: R 1 is H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, or (C3-C7)cycloalkyl; R 2 and R 3 are each independently H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, or (C2-C6)alkenyl; and R 4 , R 5 , and R 6 are each independently H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, (C3-C7)heterocyclyl, or R 4 , R 5 , and R 6 Any two of the cycloalkyl and heterocyclyl groups are taken together with the carbon atoms to which they are attached to form a 5-7 membered ring, the 5-7 membered ring being optionally substituted by one or more groups each independently selected from halogen, -CN, -COOH, and -NO2, wherein the cycloalkyl and heterocyclyl groups are each independently optionally substituted by one or more groups each independently selected from -CN, -C(O)NH2, halogen, -NO2, -COOH, The method comprises reacting a compound having formula III with either: (i) a compound having formula II, thereby obtaining the compound having formula I; or (ii) 4-isocyanatopyridazine, thereby obtaining the compound of formula I, wherein R 1 is H, and the hydrogen is optionally substituted with a group selected from the following: optionally interspersed with one or more groups each independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, and (C3-C7)cycloalkyl, in: T is each independently a group having the formula: M is of the formula -YZ (n) wherein Y is a boron ion, or a metal ion having an oxidation state of at least one, such as an alkali metal (e.g., lithium, sodium, potassium) ion, an alkaline earth metal (e.g., magnesium) ion, an aluminum ion, and a transition metal (e.g., copper, zinc, iron) ion, and Z represents a halogen anion; or M is selected from -B(halogen)3 - Cat + 、-B(OR')3 - Cat + , -B(-OC(O)-CH2-N(CH3)-CH2-COO-), -B(OH)2, -B(OH)3 - Cat + , -BR'(OH), -B(R')2, -BR'(OR'), B(OH)(OR'), and -B(OR')2, wherein each R' is independently (C1-C6)alkyl, (C2-C6)alkenyl, or (C3-C7)cycloalkyl, or two R' together with the boron atom to which they are attached form a 5-9 membered ring, and the 5-9 membered ring is optionally substituted with one or more groups each independently selected from (C1-C6)alkyl, (C2-C6)alkenyl, =O, -O-(C1-C6)alkyl, or -O-(C2-C6)alkenyl; or M forms an anionic complex together with one or more T groups, wherein M represents the metal ion optionally connected to an additional metal ion (e.g., an alkali metal ion or an alkaline earth metal ion) via one or more halogen anions, or one or more of the one or more T groups; X 1 is a leaving group such as halogen, imidazole, -O3SCH3 (-O-methylsulfonyl), -O3SC6H4CH3 (-O-toluenesulfonyl), -O-phenyl, and -O3SCF3 (-O-trifluoromethanesulfonyl); n is an integer from 0 to 3; m is an integer from 1 to 3; and Cat + It is a cation, such as an alkali metal cation.

2. The process of claim 1, which is carried out at a temperature of about -100°C to about 70°C, preferably about -78°C to about 25°C.

3. The method of claim 1, wherein: The compound having formula III is reacted with a compound having formula II.

4. The method of claim 1, wherein: The compound of formula III is reacted with 4-isocyanatopyridazine, and the compound thus obtained is reacted with a base and subsequently with an alkylating agent.

5. The method of claim 4, wherein: The alkylating agent is iodoethane, iodomethane, ethyl methanesulfonate, trimethyloxonium tetrafluoroborate, triethyloxonium tetrafluoroborate, triethyloxonium hexachloroantimonate, ethyl bromide, or diethyl sulfate.

6. The method of claim 1, wherein: The compound of formula III is prepared from a compound of formula IV or a mixture thereof according to the following method: in: X 2 is a halogen, such as Cl and Br; and R 2 , R 3 , R 4 , R 5 , R 6 , M, and m are each independently as defined in claim 1, By using -M-[T] m-1 Replace the X 2 Group.

7. The method of claim 6, wherein: The reaction is carried out at a temperature of about -100°C to about 100°C.

8. The method according to claim 6 or 7, wherein: M is of the formula -YZ (n) wherein Y is a lithium ion and n is 0, the method comprising reacting the compound having formula IV with n-butyllithium or n-hexyllithium in a solvent such as tetrahydrofuran at a temperature of about -78°C to about 0°C.

9. The method of claim 1, wherein: The compound of formula II is prepared from the compound of formula XI according to the following method: By using a compound having the formula -C(O)X 1 The carbonyl-containing group replaces the nitrogen atom of the secondary amine group, wherein R 1 and X 1 Each is independently as defined in claim 1.

10. The method of claim 9, wherein: The substitution is performed by dissolving the compound having formula XI in a solvent and then reacting the compound with a base at a temperature of about -100°C to about 50°C, followed by reacting with a carbonyl-containing reagent.

11. The method of claim 10, wherein: The base is trimethylamine, triethylamine, tributylamine, N,N-diisopropylethylamine, n-butyllithium, tert-butyllithium, n-hexyllithium, lithium diisopropylamide (LDA), potassium bis(trimethylsilyl)amide (KHMDS), sodium hydroxide (e.g., in the form of a solid or an aqueous solution of at least 20% sodium hydroxide), potassium carbonate, sodium carbonate, or sodium hydride.

12. The method of claim 10, wherein: The carbonyl-containing reagent is phenyl chloroformate, phosgene, 1,1,1-trichloromethyl formate (diphosgene), bis(trichloromethyl) carbonate (BTC; triphosgene), or phenyl 4,5-dichloro-6-oxopyridazine-1(6H)-carboxylate.

13. The method of any one of claims 1 to 12, wherein: (i)R 1 is ethyl, R 2 is methyl, R 3 Yes H, R 4 is -CH(CH3)2, R 5 is a methyl group, and R 6 It is H; (ii) R 1 is ethyl, R 2 is methyl, R 3 Yes H, R 4 is -C(H)(F)CH3, R 5 is a methyl group, and R 6 It is H; (iii) R 1 is ethyl, R 2 is methyl, R 3 Yes H, R 4 is 1-cyanocyclopropyl, R 5 is a methyl group, and R 6 It is H; (iv) R 1 is ethyl, R 2 is methyl, R 3 Yes H, R 4 is methyl, R 5 is a methyl group, and R 6 It is H; (v)R 1 is ethyl, R 2 is methyl, R 3 Yes H, R 4 Yes - CF3, R 5 is a methyl group, and R 6 It is H; (vi)R 1 is ethyl, R 2 is methyl, R 3 Yes H, R 4 is 1-carbamoylcyclopropyl, R 5 is a methyl group, and R 6 is H; or (vii) R 1 is ethyl, R 2 is methyl, R 3 Yes H, R 4 and R 5 Together they represent 3,3-difluoro-1,5-pentadienyl, and R 6 It's H.

14. The method of claim 13, wherein: m is 1.

15. The method of claim 14, wherein: M is Li ion, Cu ion, -Mg(Hal)1, -Cu(Hal)1, -Zn(Hal)1, -BF3 - K + 、-B(OH)2、-B(-OiPr)3Cat + , 5,5-dimethyl-1,3,2-dioxaborolan-2-yl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, benzo[d][1,3,2]dioxaborolan-2-yl, 9-borabicyclo[3.3.1]nonane-9-yl, or 6-methyl-1,3,6,2-dioxazaborolan-4,8-dione-2-yl, and Hal is a halogen, preferably Cl or Br; or M has the formula -Mg(Hal)2Li, -Zn(Hal)2Li, -Cu(Hal)2Mg, or -Cu(Hal)2Li, and forms a negative ionic complex together with the T group, Hal is a halogen, preferably Cl or Br, and the Mg, Zn or Cu ion is bound to the T group and connected to the Li or Mg ion via a halogen anion.

16. The method of claim 13, wherein: m is 2.

17. The method of claim 16, wherein: M is a Mg ion or a Zn ion, or M forms a cationic complex together with the T groups, wherein M has the formula CuLi, wherein a Cu ion is bound to each of the two T groups.

18. The method of claim 13, wherein: m is 3.

19. The method of claim 18, wherein: M is a boron ion, an Al ion or an Fe ion, or M forms a cationic complex together with the T groups, wherein M has the formula MgLi, wherein a Mg ion is bound to each of the three T groups.

20. The method of any one of claims 1 to 19, wherein: In addition to the compound of formula I, at least one of the following by-products is obtained: Where R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 Each is independently as defined in claim 1.

21. The method of claim 20, wherein: The total amount of the at least one by-product constitutes up to about 20% by weight of the final product.

22. The method of claim 1, wherein: The salts of the compounds of formula I are obtained by reacting the compounds in their free base form with inorganic acids such as HF, HCl, HBr, and H2SO4; or organic acids such as carboxylic acids (e.g., formic acid, acetic acid, propionic acid, oxalic acid, mandelic acid, citric acid, trifluoroacetic acid, trichloroacetic acid, tartaric acid or derivatives thereof such as dibenzoyltartaric acid, N-acetylleucine, and benzoic acid) and sulfonic acids (e.g., toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, and camphorsulfonic acid optionally substituted with one or more Br atoms such as 3-bromo-10-camphorsulfonic acid and 3-bromo-8-camphorsulfonic acid).

23. A compound having formula III or a salt, N-oxide, tautomer, or enantiomer thereof, in: T is each independently a group having the formula: R 2 and R 3 are each independently H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, or (C2-C6)alkenyl; R 4 , R 5 , and R 6 are each independently H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, (C3-C7)heterocyclyl, or R 4 , R 5 , and R 6 Any two of the cycloalkyl and heterocyclyl groups are taken together with the carbon atoms to which they are attached to form a 5-7 membered ring, the 5-7 membered ring being optionally substituted with one or more groups each independently selected from halogen, -CN, -COOH, and -NO2, wherein the cycloalkyl and heterocyclyl groups are each independently optionally substituted with one or more groups each independently selected from -CN, -C(O)NH2, halogen, -NO2, -COOH; M is of the formula -YZ (n) wherein Y is a boron ion, or a metal ion having an oxidation state of at least one, such as an alkali metal (e.g., lithium, sodium, potassium) ion, an alkaline earth metal (e.g., magnesium) ion, an aluminum ion, and a transition metal (e.g., copper, zinc, iron) ion, and Z represents a halogen anion; or M is selected from -B(halogen)3 - Cat + 、-B(OR')3 - Cat + , -B(-OC(O)-CH2-N(CH3)-CH2-COO-), -B(OH)2, -B(OH)3 - Cat + , -BR'(OH), -B(R')2, -BR'(OR'), B(OH)(OR'), and -B(OR')2, wherein each R' is independently (C1-C6)alkyl, (C2-C6)alkenyl, or (C3-C7)cycloalkyl, or two R' together with the boron atom to which they are attached form a 5-9 membered ring, and the 5-9 membered ring is optionally substituted with one or more groups each independently selected from (C1-C6)alkyl, (C2-C6)alkenyl, =O, -O-(C1-C6)alkyl, or -O-(C2-C6)alkenyl; or M forms an anionic complex together with one or more T groups, wherein M represents the metal ion optionally connected to an additional metal ion (e.g., an alkali metal ion or an alkaline earth metal ion) via one or more halogen anions, or one or more of the one or more T groups; n is an integer from 0 to 3; m is an integer from 1 to 3; and Cat + is a cation, such as an alkali metal cation, The premise is that when R 2 is methyl, R 3 Yes H, R 4 is -CH(CH3)2, R 5 is a methyl group, and R 6 When H, M is not -B(OH)2; 5,5-dimethyl-1,3,2-dioxaborolan-2-yl; or 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.

24. The compound of claim 23, wherein: (i)R 2 is methyl, R 3 Yes H, R 4 is -CH(CH3)2, R 5 is a methyl group, and R 6 It is H; (ii) R 2 is methyl, R 3 Yes H, R 4 is -C(H)(F)CH3, R 5 is a methyl group, and R 6 It is H; (iii) R 2 is methyl, R 3 Yes H, R 4 is 1-cyanocyclopropyl, R 5 is a methyl group, and R 6 It is H; (iv) R 2 is methyl, R 3 Yes H, R 4 is methyl, R 5 is a methyl group, and R 6 It is H; (v)R 2 is methyl, R 3 Yes H, R 4 Yes - CF3, R 5 is a methyl group, and R 6 It is H; (vi)R 2 is methyl, R 3 Yes H, R 4 is 1-carbamoylcyclopropyl, R 5 is a methyl group, and R 6 is H; or (vii) R 2 is methyl, R 3 Yes H, R 4 and R 5 together represent 3,3-difluoro-1,5-pentadienyl, and R 6 It's H.

25. The compound of claim 24, wherein m is 1.

26. The compound of claim 25, wherein M is Li ion, Cu ion, -Mg(Hal)1, -Cu(Hal)1, -Zn(Hal)1, -BF3 - K + 、-B(OH)2、-B(-OiPr)3Cat + , 5,5-dimethyl-1,3,2-dioxaborolan-2-yl, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, benzo[d][1,3,2]dioxaborolan-2-yl, 9-borabicyclo[3.3.1]nonane-9-yl, or 6-methyl-1,3,6,2-dioxazaborolan-4,8-dione-2-yl, and Hal is a halogen, preferably Cl or Br; or M has the formula -Mg(Hal)2Li, -Zn(Hal)2Li, -Cu(Hal)2Mg, or -Cu(Hal)2Li, and forms a negative ionic complex together with the T group, Hal is a halogen, preferably Cl or Br, and the Mg, Zn or Cu ion is bound to the T group and connected to the Li or Mg ion via a halogen anion.

27. The compound of claim 24, wherein m is 2.

28. The compound of claim 27, wherein M is a Mg ion or a Zn ion; or M has the formula CuLi, and forms a cationic complex together with the T groups, wherein a Cu ion is bound to each of the T groups.

29. The compound of claim 24, wherein m is 3.

30. The compound of claim 29, wherein M is a boron ion, an Al ion or an Fe ion; or M has the formula MgLi, and forms a cationic complex together with the T groups, wherein a Mg ion is bound to each of the T groups.

31. A compound having formula II or a salt, an N-oxide, or a tautomer thereof, in: R 1 is H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, or (C3-C7)cycloalkyl; and X 1 is a leaving group such as halogen, imidazole, -O3SCH3 (-O-methylsulfonyl), -O3SC6H4CH3 (-O-toluenesulfonyl), -O-phenyl, and -O3SCF3 (-O-trifluoromethanesulfonyl), The premise is that when R 1 When H is 1 Not -O-phenyl.

32. The compound of claim 31, wherein R 1 is ethyl; and X 1 It is halogen, -O3SCH3 (-O-methylsulfonyl), -O3SC6H4CH3 (-O-toluenesulfonyl), -O-phenyl, and -O3SCF3 (-O-trifluoromethanesulfonyl), or imidazole, preferably halogen, more preferably Cl.

33. A compound having formula IV or a salt, N-oxide, or enantiomer thereof, wherein X 2 is a halogen, such as Cl and Br; and (i)R 2 is methyl, R 3 Yes H, R 4 is -CH(CH3)2, R 5 is methyl, R 6 It is H; (ii) R 2 is methyl, R 3 Yes H, R 4 is -C(H)(F)CH3, R 5 is methyl, R 6 It is H; (iii) R 2 is methyl, R 3 Yes H, R 4 is 1-cyanocyclopropyl, R 5 is methyl, R 6 It is H; (iv) R 2 is methyl, R 3 Yes H, R 4 is methyl, R 5 is methyl, R 6 It is H; (v)R 2 is methyl, R 3 Yes H, R 4 Yes - CF3, R 5 is methyl, R 6 It is H; (vi)R 2 is methyl, R 3 Yes H, R 4 is 1-carbamoylcyclopropyl, R 5 is methyl, R 6 is H; or (vii) R 2 is methyl, R 3 Yes H, R 4 and R 5 Together they represent 3,3-difluoro-1,5-pentadienyl, R 6 It's H.

34. A composition comprising a compound of formula I obtained by the method of any one of claims 1 to 22: or a salt, N-oxide, tautomer, or enantiomer thereof, and at least one additional compound selected from: in: T is each independently a group having the formula: R 1 is H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, or (C3-C7)cycloalkyl; R 2 and R 3 are each independently H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, or (C2-C6)alkenyl; R 4 , R 5 , and R 6 are each independently H, optionally interspersed with one or more independently selected from -O-, -S-, and -N((C1-C 12 )alkyl)-group (C1-C 12 )alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, (C3-C7)heterocyclyl, or R 4 , R 5 , and R 6 Any two of the cycloalkyl and heterocyclyl groups are taken together with the carbon atoms to which they are attached to form a 5-7 membered ring, the 5-7 membered ring being optionally substituted with one or more groups each independently selected from halogen, -CN, -COOH, and -NO2, wherein the cycloalkyl and heterocyclyl groups are each independently optionally substituted with one or more groups each independently selected from -CN, -C(O)NH2, halogen, -NO2, -COOH; M is of the formula -YZ (n) wherein Y is a boron ion, or a metal ion having an oxidation state of at least one, such as an alkali metal (e.g., lithium, sodium, potassium) ion, an alkaline earth metal (e.g., magnesium) ion, an aluminum ion, and a transition metal (e.g., copper, zinc, iron) ion, and Z represents a halogen anion; or M is selected from -B(halogen)3 - Cat + 、-B(OR')3 - Cat + , -B(-OC(O)-CH2-N(CH3)-CH2-COO-), -B(OH)2, -B(OH)3 - Cat + , -BR'(OH), -B(R')2, -BR'(OR'), B(OH)(OR'), and -B(OR')2, wherein each R' is independently (C1-C6)alkyl, (C2-C6)alkenyl, or (C3-C7)cycloalkyl, or two R' together with the boron atom to which they are attached form a 5-9 membered ring, and the 5-9 membered ring is optionally substituted with one or more groups each independently selected from (C1-C6)alkyl, (C2-C6)alkenyl, =O, -O-(C1-C6)alkyl, or -O-(C2-C6)alkenyl; or M forms an anionic complex together with one or more T groups, wherein M represents the metal ion optionally connected to an additional metal ion (e.g., an alkali metal ion or an alkaline earth metal ion) via one or more halogen anions, or one or more of the one or more T groups; X 1 is a leaving group such as halogen, imidazole, -O3SCH3 (-O-methylsulfonyl), -O3SC6H4CH3 (-O-toluenesulfonyl), -O-phenyl, and -O3SCF3 (-O-trifluoromethanesulfonyl); X 2 are halogens, such as Cl and Br; n is an integer from 0 to 3; m is an integer from 1 to 3; and Cat + It is a cation, such as an alkali metal cation.

35. The composition of claim 34, wherein The amount of the at least one additional compound constitutes up to about 20% by weight of the total amount of the compound having formula I and the at least one additional compound.

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