CN106187910A - Pyridazine class derivant and its production and use - Google Patents

Abstract

The invention provides a pyridazine derivative and a pharmaceutically acceptable salt or hydrate thereof. The compounds provided by the present invention are active ligands of the novel cannabinoid type II receptor CB2, and the compounds and their pharmaceutically acceptable salts or hydrates generally exhibit higher calcium flux activity and Very good choice. The compound of the present invention is a specific agonist of the cannabinoid receptor CB2, and can be used for treating, preventing and inhibiting diseases mediated by the CB2 receptor. The compound I has the following general formula:

Description

Pyridazine derivatives and their preparation and use

technical field

The invention belongs to the technical field of medicine, and in particular relates to a compound with pyridazine as its core and its pharmaceutically acceptable salt or hydrate, its preparation method and the role of this type of compound in treating, preventing and inhibiting mediated by CB2 receptors. The application of drugs in the leading diseases.

Background technique

As early as several centuries ago, people have realized that plant cannabis has medicinal effects such as pain relief, anti-vomiting, anti-convulsion, and anti-inflammation. one. In 1964, Gaoni and Mechoulam reported that the main active substance of cannabis was Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC) and its structure confirmation, marking the beginning of modern human research on cannabinoids. Cannabinoids mainly act on cannabinoid receptors in the human body. There are two main types of cannabinoid receptors that are widely known, namely, cannabinoid type I receptor (CB1) and cannabinoid type II receptor (CB2), both of which belong to the rhodopsin of G protein-coupled receptors (GPCRs). Like family, the transmembrane structure with seven α-helices is involved in the regulation of various physiological functions of the human body. The homology of the entire amino acid sequence of CB1 and CB2 is 44%, and the amino acid sequence of the relatively conserved transmembrane region has a homology of 68% (Pertwee, RG Pharmacology of Cannabinoid CB1 and CB2 Receptors. Pharmacol. Ther. 1997, 74, 129-180). In terms of distribution, CB1 receptors are mainly distributed in the central nervous system, such as the hippocampus, olfactory area, substantia nigra, etc., and are mainly involved in the regulation of cognition, memory, and sensory transmission (Galiègue, S.; Mary, S.; Marchand, J.; Dussossoy, D.; Carrière, D.; Carayon, P.; in Human Immune Tissues and LeukocyteSubpopulations.Eur.J.Biochem.1995,232,54-61); while CB2 receptors are mainly distributed in peripheral tissues, especially immune tissues, such as spleen marginal area, thymus, tonsil, B and T cells , macrophages, etc., are mainly involved in the regulation of immune function (Di Marzo, V.; et al. The endocannabinoid system and its therapeutic exploitation. Nat. Rev. Drug Discov. 2004, 3, 771-784). Both CB1 receptor and CB2 receptor belong to Gi/o type G protein-coupled receptors, through which multiple intracellular signal transduction pathways can be activated. CB2 receptors can inhibit the production of cAMP, regulate phosphatidylinositol-3 kinase (PI3K) and ceramide metabolism by inhibiting adenylate cyclase and activating mitogen-activated protein kinase (MAP kinase) channels.

The basic structure of traditional cannabinoid ligands can be divided into the following five categories: 1) Classic cannabinoid compounds represented by Δ ⁹ -THC, which are cannabinoid substances extracted from natural plants or in natural products 2) non-classic cannabinoid compounds represented by CP55940, most of which are derivatives of classic cannabinoids; 3) endogenous neuronal cannabinoids The fatty acid amine compound represented by the transmitter Ananamide is a derivative of arachidonic acid; 4) the aminoalkyl indole compound represented by WIN55212-2; 5) the diarylpyridine compound represented by SR141716A and SR144528 Azole compounds. With the increasing application of new technologies such as high-throughput screening and virtual screening in the field of medicinal chemistry, more and more novel cannabinoid ligands have been reported, showing rich diversity in chemical structure.

Modern research has shown that cannabinoid receptors are related to various diseases in the human body. CB1 antagonists can be used in the development of new drugs such as weight loss and smoking cessation, while CB2 ligands can be used in the treatment of immune system diseases and inflammation, pain, acute and chronic liver diseases, osteoporosis, atherosclerosis and other diseases. Since CB1 is mainly located in the central nervous system, its ligands are prone to cause severe central nervous side effects, such as memory loss, depression, and decreased motor coordination. For example, rimonabant, which is a CB1 antagonist, was launched in Europe in 2006 for the treatment of obesity, but it was quickly taken off the shelves due to its possible side effects such as depression and anxiety. However, CB2 is mainly distributed in the peripheral system, avoiding this serious side effect of the central nervous system, and has become a more promising drug target because of its high safety. At present, the CB2 agonist GW842166X reported by GSK has completed three clinical phase II studies as an analgesic drug, but the drug effect is not satisfactory (Giblin, G.M.P.; et al.Discovery of2-[(2,4-Dichlorophenyl)amino ]-N-[(tetrahydro-2H-pyran-4-yl)methyl]-4-(trifluoromethyl)-5-pyrimi dinecarboxamide, a Selective CB2 Receptor Agonist for the Treatment of Inflammatory Pain.J.Med.Chem.2007,50, 2597-2600); CB2 agonist S-777469 as a candidate drug for the treatment of atopic dermatitis has also completed clinical phase II research (Odan, M., et al., Discovery of S-777469: an orally available CB2agonist as an orally available CB2agonist as an antipruriticagent. Bioorg. Med. Chem. Lett., 2012, 22, 2803-2806). At present, the research on CB2 selective ligands is mostly concentrated in the preclinical stage and clinical research stage, and there is no marketed drug yet. Therefore, the discovery of highly active and highly selective CB2 ligands is of great significance for drug development.

Contents of the invention

The first object of the present invention is to provide a kind of pyridazine derivative and pharmaceutically acceptable salt or hydrate thereof, its general structural formula is as shown in I:

in,

R ₁ is selected from a hydrogen atom, isopropyl;

R is selected from cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, isobutyl, 1-adamantyl, ₂ -adamantyl, benzyl, 4-methylbenzyl, 4- Fluorobenzyl, pyridin-3-methyl or 4-tetrahydropyranylmethyl;

R is selected from the following groups II or III:

in:

X is selected from O, S, N, CH2, NCH3;

R ₃ is selected from C ₂ -C ₄ straight chain or branched chain alkyl, C ₂ -C ₄ straight chain alkyl substituted by hydroxyl, C ₃ -C ₆ cyclic hydrocarbon group, alkane group with C ₃ -C ₆ ring , a substituted or unsubstituted phenyl group, a six-membered heterocyclic group containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen.

The compounds of general formula I of the present invention and pharmaceutically acceptable salts or hydrates thereof, preferred specific compounds include:

(1) N-cyclohexyl-6-morpholine pyridazine-3-carboxamide

(2) N-(adamantan-1-yl)-6-morpholine pyridazine-3-carboxamide

(3) N-(adamantan-2-yl)-6-morpholine pyridazine-3-carboxamide

(4) N-Benzyl-6-morpholine pyridazine-3-carboxamide

(5) N-Benzyl-6-thiomorpholine pyridazine-3-carboxamide

(6) N-benzyl-6-diethylaminopyridazine-3-carboxamide

(7) N-Benzyl-6-(piperidin-1-yl)pyridazine-3-carboxamide

(8) N-(4-methylbenzylamine)-6-(piperidin-1-yl)pyridazine-3-carboxamide

(9) N-(4-fluorobenzyl)-6-(piperidin-1-yl)pyridazine-3-carboxamide

(10) N-(pyridine-3-methyl)-6-(piperidin-1-yl)pyridazine-3-carboxamide

(11) N-cyclohexyl-6-(piperidin-1-yl)pyridazine-3-carboxamide

(12) N-cyclohexylmethyl-6-(piperidin-1-yl)pyridazine-3-carboxamide

(13) N-((tetrahydropyran-2H-4-yl)methyl)-6-(piperidin-1-yl)pyridazine-3-carboxamide

(14) N-cyclopropylmethyl-6-(piperidin-1-yl)pyridazine-3-carboxamide

(15) N-cyclobutylmethyl-6-(piperidin-1-yl)pyridazine-3-carboxamide

(16) N-isobutyl-6-(piperidin-1-yl)pyridazine-3-carboxamide

(17) N-Benzyl-6-anilinopyridazine-3-carboxamide

(18) N-benzyl-6-(4-methoxyanilino)pyridazine-3-carboxamide

(19) N-benzyl-6-(2,4-dichloroanilino)pyridazine-3-carboxamide

(20) N-benzyl-6-(3-chloroanilino)pyridazine-3-carboxamide

(21) N-benzyl-6-(4-chloroanilino) pyridazine-3-carboxamide

(22) N-(4-methylbenzyl)-6-(3-chloroanilino)pyridazine-3-carboxamide

(23) N-(4-fluorobenzyl)-6-(3-chloroanilino)pyridazine-3-carboxamide

(24) N-(pyridine-3-methyl)-6-anilinopyridazine-3-carboxamide

(25) N-cyclohexyl-6-anilinopyridazine-3-carboxamide

(26) N-cyclohexylmethyl-6-(3-chloroanilino) pyridazine-3-carboxamide

(27) N-((tetrahydropyran-2H-4-yl)methyl)-6-(2,4-dichloroanilino)pyridazine-3-carboxamide

(28) N-cyclopropylmethyl-6-(3-chloroanilino) pyridazine-3-carboxamide

(29) N-Benzyl-6-cyclohexylaminopyridazine-3-carboxamide

(30) N-benzyl-6-(piperidine-1-amino)pyridazine-3-carboxamide

(31) N-benzyl-6-morpholine aminopyridazine-3-carboxamide

(32) N-Benzyl-6-cyclopentylaminopyridazine-3-carboxamide

(33) N-benzyl-5-isopropyl-6-anilinopyridazine-3-carboxamide

(34) N-(pyridine-3-methyl)-5-isopropyl-6-anilinopyridazine-3-carboxamide

(35) N-cyclohexyl-5-isopropyl-6-morpholine pyridazine-3-carboxamide

(36) N-(adamantan-1-yl)-5-isopropyl-6-morpholine pyridazine-3-carboxamide

(37) N-(adamantan-2-yl)-5-isopropyl-6-morpholine pyridazine-3-carboxamide

(38) N-(adamantane-2-yl)-5-isopropyl-6-(piperidin-1-yl)pyridazine-3-carboxamide

(39) N-(adamantan-2-yl)-5-isopropyl-6-cyclohexylaminopyridazine-3-carboxamide

(40) N-(adamantan-2-yl)-5-isopropyl-6-cyclopentylaminopyridazine-3-carboxamide

(41) N-(adamantane-2-yl)-5-isopropyl-6-morpholine aminopyridazine-3-carboxamide

(42) N-(adamantane-2-yl)-5-isopropyl-6-(piperidine-1-amino)pyridazine-3-carboxamide

(43) N-(adamantane-2-yl)-5-isopropyl-6-cyclopropylmethylaminopyridazine-3-carboxamide

(44) N-(adamantane-2-yl)-5-isopropyl-6-n-butylaminopyridazine-3-carboxamide

(45) N-(adamantane-2-yl)-5-isopropyl-6-((pentyl-3-yl)amino)pyridazine-3-carboxamide

(46) N-(adamantane-2-yl)-5-isopropyl-6-((3-methylbutyl-2-yl)pyridazine-3-carboxamide

(47) N-(adamantane-2-yl)-5-isopropyl-6-((2-hydroxyethyl)amino)pyridazine-3-carboxamide

(48) N-(adamantane-2-yl)-5-isopropyl-6-(3-chloroanilino)pyridazine-3-carboxamide

(49) N-cyclohexyl-4-isopropyl-6-morpholine pyridazine-3-carboxamide

(50) N-cyclohexyl-4-isopropyl-6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide

(51) N-cyclohexyl-4-isopropyl-6-cyclopentylaminopyridazine-3-carboxamide

(52) N-cyclohexyl-4-isopropyl-6-n-butylaminopyridazine-3-carboxamide

(53) N-cyclohexyl-4-isopropyl-6-isobutylaminopyridazine-3-carboxamide

(54) N-cyclohexyl-4-isopropyl-6-((2-hydroxyethyl)amino)pyridazine-3-carboxamide

(55) N-(adamantan-1-yl)-4-isopropyl-6-morpholine pyridazine-3-carboxamide

(56) N-(adamantane-1-yl)-4-isopropyl-6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide

(57) N-(adamantan-1-yl)-4-isopropyl-6-cyclopentylaminopyridazine-3-carboxamide

(58) N-(adamantane-1-yl)-4-isopropyl-6-((2-hydroxyethyl)amino)pyridazine-3-carboxamide

(59) N-(adamantan-1-yl)-4-isopropyl-6-n-butylaminopyridazine-3-carboxamide

(60) N-(adamantan-1-yl)-4-isopropyl-6-isobutylaminopyridazine-3-carboxamide

(61) N-(adamantane-2-yl)-4-isopropyl-6-morpholine pyridazine-3-carboxamide

(62) N-(adamantane-2-yl)-4-isopropyl-6-(piperidin-1-yl)pyridazine-3-carboxamide

(63) N-(adamantane-2-yl)-4-isopropyl-6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide

(64) N-(adamantane-2-yl)-4-isopropyl-6-cyclohexylaminopyridazine-3-carboxamide

(65) N-(adamantane 2-yl)-4-isopropyl-6-cyclopentylaminopyridazine-3-carboxamide

(66) N-(adamantane-2-yl)-4-isopropyl-6-cyclopropylaminopyridazine-3-carboxamide

(67) N-(adamantane-2-yl)-4-isopropyl-6-cyclopropylmethylaminopyridazine-3-carboxamide

(68) N-(adamantane-2-yl)-4-isopropyl-6-(piperidine-1-amino)pyridazine-3-carboxamide

(69) N-(adamantane-2-yl)-4-isopropyl-6-morpholine aminopyridazine-3-carboxamide

(70) N-(adamantan-2-yl)-4-isopropyl-6-n-butylaminopyridazine-3-carboxamide

(71) N-(adamantane-2-yl)-4-isopropyl-6-((pentyl-3-yl)amino)pyridazine-3-carboxamide

(72) N-(adamantane-2-yl)-4-isopropyl-6-((3-methylbutyl)-2-yl)pyridazine-3-carboxamide

(73) N-(adamantane-2-yl)-4-isopropyl-6-((2-hydroxyethyl)amino)pyridazine-3-carboxamide

(74) N-(adamantane-2-yl)-4-isopropyl-6-(3-chloroanilino)pyridazine-3-carboxamide

(75) N-benzyl-4-isopropyl-6-anilinopyridazine-3-carboxamide;

and pharmaceutically acceptable salts or hydrates of the specific compounds mentioned above.

The "pharmaceutically acceptable salt" mentioned in this specification can specifically include the compound provided by the present invention and propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid , citric acid and other organic acids; or salts with hydrochloric acid, phosphoric acid, sulfuric acid, hydrofluoric acid, hydrobromic acid and other inorganic acids; , bromine or iodoalkanes.

The second object of the present invention is to provide a preparation method of pyridazine derivatives and pharmaceutically acceptable salts or hydrates thereof, specifically achieved through the following steps:

(1) the compound of formula A reacts with the compound of formula B to generate the compound of formula C;

(2) The compound of formula C reacts with the compound of formula D or E to generate the compound of formula I;

Wherein, R ₁ , R ₂ , R ₃ , and X are all the same as defined in the general formula I;

(3) Dissolve compound I in anhydrous methanol, add an appropriate amount of acid such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, etc. Organic acids, or inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, hydrofluoric acid, hydrobromic acid, etc., spin the solvent to obtain its pharmaceutically acceptable acid addition salt; or dissolve compound I in absolute ethanol, and add an equivalent amount of Sodium hydroxide, potassium iodide and halogenated hydrocarbon such as methyl iodide were heated to reflux overnight, and the crude product was purified by recrystallization from acetone to obtain the pharmaceutically acceptable quaternary ammonium salt of Compound I.

(4) Dissolving compound I in an aqueous acid solution, adding a non-acidic organic solvent to the system, and obtaining a hydrate of compound I by crystallization. Wherein suitable acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, hydrobromic acid, nitric acid, formic acid, tartaric acid, benzoic acid, phenylacetic acid, maleic acid, oxalic acid, trifluoroacetic acid; non-acidic organic solvent is selected from ethanol , methanol, acetonitrile, ethyl acetate, tetrahydrofuran, diethyl ether, petroleum ether, isopropanol, n-butanol, N,N-dimethylformamide.

The preparation method of the compound of formula A provided by the invention is realized through the following steps:

(1) Formula A compound is prepared as follows:

Compound A-1 and A-2 are subjected to condensation reaction to obtain compound A-3, and in the presence of acetic acid, compound A-3 and A-4 are respectively obtained through bromine addition and elimination reactions, and then chlorinated by thionyl chloride After obtaining compound A;

Wherein, R ₁ is a hydrogen atom, and R ₂ , R ₃ , and X are all the same as defined in the general formula I.

or

(2) Formula A compound is prepared as follows:

Compound A-1 and A-2 are subjected to condensation reaction to obtain compound A-3, and in the presence of acetic acid, compound A-3 and A-4 are respectively obtained through the addition and elimination of bromine, and then esterified by saturated ethanol solution of hydrogen chloride Compound A-5 was obtained by compound A-5, compound A-6 was obtained after chlorination by phosphorus oxychloride, and then in the presence of concentrated sulfuric acid, silver nitrate and ammonium persulfate, isobutyric acid was substituted on the pyridazine ring by dark reaction, Obtain compound A-7, then obtain compound A-8 through lithium hydroxide hydrolysis, and finally obtain compound A after chlorination with thionyl chloride;

Wherein, R ₁ is isopropyl, and R ₂ , R ₃ , and X are all the same as defined in the general formula I.

The third object of the present invention is to provide a pyridazine derivative and its pharmaceutically acceptable salt or hydrate for use in the preparation of medicines for treating, preventing and alleviating diseases mediated by CB2 receptors.

The diseases are diseases caused by the regulation of CB2 receptor active ligands, involving cancer, inflammation, acquired immune deficiency syndrome, autoimmune diseases, rheumatic diseases, allergies, pain, acute and chronic liver diseases, osteoporosis, arterial Atherosclerosis, multiple sclerosis, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, Huntington's disease.

The fourth object of the present invention is to provide a pharmaceutical composition of pyridazine derivatives and pharmaceutically acceptable salts or hydrates thereof, which may further include excipients, diluents and carriers. The compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, polyethylene glycol, propylene glycol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention. The pharmaceutical composition of the present invention may include one or more compounds of the present invention, and a typical formulation is carried out by mixing a compound of the present invention and a pharmaceutically acceptable salt or hydrate thereof with a carrier, excipient or diluent. preparation. Suitable carriers, excipients or diluents are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and/or expandable polymers, hydrophilic or hydrophobic substances, gelatin, solvents, water and other substances. The dosage form of the medicine is solid preparation or liquid preparation, specifically tablet, capsule, powder, solution, syrup, suspension or aerosol.

The compounds provided by the present invention are active ligands of the novel cannabinoid type II receptor CB2, and the compounds and their pharmaceutically acceptable salts or hydrates generally exhibit higher calcium flux activity and Very good choice. The compound of the invention is a specific agonist of the cannabinoid receptor CB2, can be used for treating, preventing and inhibiting the diseases mediated by CB2, and has good prospects for drug development.

detailed description

The present invention is further described in conjunction with examples, and the purpose of specific examples is to further illustrate the content of the present invention but not to limit the present invention.

The initial raw materials and reaction reagents used in the specific examples of the present invention are all commercially available products. Example 76 lists the preparation methods of the hydrochloride, quaternary ammonium salt, and monohydrate of compound 61. Other compounds can refer to this method, and other salts can also be formed by methods commonly used in the art.

Embodiment 1: N-cyclohexyl-6-morpholine pyridazine-3-carboxamide (compound 1)

a) 1,4,5,6-tetrahydro-6-oxypyridazine-3-carboxylic acid (compound 1a)

Sodium hydroxide (0.69g, 17.25mmol) and hydrazine sulfate (1.02g, 7.85mmol) were placed in a 10mL double-necked flask, 4.5mL of hot water was added to dissolve it, and 1.8mL of hot α - Aqueous solution of ketoglutaric acid (1.14g, 7.81mmol), after the dropwise addition, the reaction solution was heated to slight boiling and reacted overnight. Stop the reaction, cool and stand in an ice bath to precipitate a white solid, which is suction filtered. The white solid obtained by suction filtration was recrystallized with 2N hydrochloric acid to obtain 691.1 mg of colorless needle crystals. Yield: 62%; Melting point: 197.6-200.3°C.

b) 1,6-dihydro-6-oxopyridazine-3-carboxylic acid (compound 1b)

Put compound 1a (568mg, 4.0mmol) in a 10mL double-necked flask, add 2mL of acetic acid, stir magnetically, heat to boiling, add bromine (0.23mL, 4.5mmol) dropwise, add 2mL of water after the dropwise addition, and continue heating to reflux overnight. The reaction was stopped, cooled and left to stand, and a white solid was precipitated, which was filtered and dried to obtain 334.1mg. Yield: 60%; Melting point: 256.5-258.5°C.

c) 6-chloropyridazine-3-formyl chloride (compound 1c)

Compound 1b (0.1g, 0.72mmol) was placed in a 10mL single-necked round bottom flask, and after nitrogen replacement, 18μL N,N-dimethylformamide (DMF), 0.25mL thionyl chloride, 2.5mL 1, 2-Dichloroethane, heated to 68°C overnight. The reaction was stopped, and the solvent was removed after cooling and left to stand for the next step of reaction.

d) 6-chloro-N-cyclohexylpyridazine-3-carboxamide (compound 1d)

Cyclohexylamine (0.12mL, 1.08mmol) was placed in a 25mL double-necked flask, and after nitrogen replacement, 0.18mL triethylamine and 5.4mL dichloromethane were added successively, and 2.5mL dichloromethane was added to compound 1c, and The solution was slowly added dropwise to the mixture of cyclohexylamine in an ice bath, and after the dropwise addition was completed, the reaction was stirred overnight at room temperature. The reaction was stopped, and the reaction solution was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution, and the obtained organic layer was dried with anhydrous magnesium sulfate, and the organic solvent was removed by rotary evaporation under reduced pressure, and separated and purified by silica gel column chromatography to obtain Yellow solid 93.6 mg. Yield: 55%; Melting point: 157.1-158.2°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.29(d, J=9.0Hz, 1H), 7.94-7.96(m, 1H), 7.68(d, J=8.5Hz, 1H), 4.03-3.98(m, 1H),2.05-2.02(m,2H),1.82-1.77(m,2H),1.68-1.65(m,1H),1.49-1.40(m,2H),1.39-1.31(m,2H),1.30- 1.24(m,1H).

e) N-cyclohexyl-6-morpholine pyridazine-3-carboxamide (compound 1)

Compound 1d (18.5mg, 0.08mmol) was placed in a 5mL single-necked round bottom flask, 1.2mL 1,4-dioxane was added, stirred by magnetic force to dissolve, and 39μL N,N-diisopropylethylamine (DIPEA ), morpholine (14 μL, 0.16 mmol), heated to reflux overnight. Stop the reaction, extract with ethyl acetate/water, wash the organic layer with saturated sodium chloride, dry over anhydrous magnesium sulfate, remove the organic solvent by rotary evaporation under reduced pressure, and separate and purify by silica gel column chromatography to obtain 20.1 mg of white solid. Yield: 90%; Melting point: 146.4-147°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.04(d, J=9.5Hz, 1H), 7.85(d, J=7.5Hz, 1H), 6.96(d, J=9.5Hz, 1H), 4.00-3.94 (m,1H),3.86(t,J=4.5Hz,4H),3.72(t,J=5.0Hz,4H),2.02-1.99(m,2H),1.79-1.75(m,2H),1.65- 1.62 (m, 1H), 1.47-1.39 (m, 2H), 1.34-1.22 (m, 3H).

Example 2: N-(adamantan-1-yl)-6-morpholine pyridazine-3-carboxamide (compound 2)

a) N-(adamantan-1-yl)-6-chloropyridazine-3-carboxamide (compound 2a)

The experimental method was the same as the preparation of compound 1d in Example 1, except that 1-adamantanamine was used instead of cyclohexylamine to obtain 103.6 mg of a yellow solid. Yield: 50%; Melting point: 200.8-202.1°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.25(d, J=8.5Hz, 1H), 7.86(s, 1H), 7.66(d, J=8.5Hz, 1H), 2.16(s, 9H), 1.78 -1.72(m,6H).

b) N-(adamantan-1-yl)-6-morpholine pyridazine-3-carboxamide (compound 2)

The experimental method was the same as the preparation of compound 1 in Example 1 to obtain 19 mg of white solid. Yield: 93%; Melting point: 191.6-192°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.02(d, J=9.5Hz, 1H), 7.77(s, 1H), 6.96(d, J=9.5Hz, 1H), 3.86(t, J=4.5Hz , 4H), 3.72 (t, J=5.0Hz, 4H), 2.14 (s, 9H), 1.76-1.70 (m, 6H).

Example 3: N-(adamantan-2-yl)-6-morpholine pyridazine-3-carboxamide (compound 3)

a) N-(adamantan-2-yl)-6-chloropyridazine-3-carboxamide (compound 3a)

The experimental method was the same as the preparation of compound 1d in Example 1, except that 2-adamantanamine was used instead of cyclohexylamine to obtain 105.7 mg of a yellow solid. Yield: 51%; Melting point: 171.2-172.5°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.46(d, J=5.0Hz, 1H), 8.29(d, J=8.5Hz, 1H), 7.69(d, J=8.5Hz, 1H), 4.30-4.28 (m,1H),2.08(s,2H),1.97(d,J=13.5Hz,2H),1.92(s,6H),1.80(s,2H),1.72(d,J=13.0Hz,2H) .

b) N-(adamantan-2-yl)-6-morpholine pyridazine-3-carboxamide (compound 3)

The experimental method was the same as the preparation of compound 1 in Example 1 to obtain 19.4 mg of white solid. Yield: 85%; Melting point: 219.4-219.8°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.34(d, J=8.0Hz, 1H), 8.05(d, J=9.5Hz, 1H), 6.97(d, J=9.5Hz, 1H), 4.27-4.25 (m, J=8.5Hz, 1H), 3.86(t, J=4.5Hz, 4H), 3.73(t, J=5.0Hz, 4H), 2.05(s, 2H), 1.99(d, J=13.0Hz , 2H), 1.90-1.88 (m, 6H), 1.77 (s, 2H), 1.67 (d, J=13.0Hz, 2H).

Embodiment 4: N-benzyl-6-morpholine pyridazine-3-carboxamide (compound 4)

a) N-benzyl-6-chloropyridazine-3-carboxamide (compound 4a)

Benzylamine (0.12mL, 1.08mmol) was placed in a 25mL double-necked flask, and after nitrogen replacement, 0.18mL triethylamine and 5.4mL dichloromethane were added successively, and 2.5mL dichloromethane was added to the obtained product in Example 1. In compound 1c, its solution was slowly added dropwise to the above mixture of benzylamine in an ice bath, and after the dropwise addition was completed, the reaction was stirred overnight at room temperature. The reaction was stopped, and the reaction solution was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution, and the obtained organic layer was dried with anhydrous magnesium sulfate, and the organic solvent was removed by rotary evaporation under reduced pressure, and separated and purified by silica gel column chromatography to obtain White solid 97.8 mg. Yield: 55%; Melting point: 132.3-133.8°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.37(s, 1H), 8.32(d, J=9Hz, 1H), 7.70(d, J=9Hz, 1H), 7.37-7.30(m, 5H), 4.72 (d, J=6.5Hz, 2H).

b) N-benzyl-6-morpholine pyridazine-3-carboxamide (compound 4)

Put compound 4a (30mg, 0.12mmol) in a 5mL single-necked round bottom flask, add 1.2mL 1,4-dioxane, stir to dissolve, then add 61μL N,N-diisopropylethylamine (DIPEA) , morpholine (12 μL, 0.14 mmol), heated to reflux overnight. Stop the reaction, extract with ethyl acetate/water, wash the organic layer with saturated sodium chloride, dry over anhydrous magnesium sulfate, remove the organic solvent by rotary evaporation under reduced pressure, and separate and purify by silica gel column chromatography to obtain 24.5 mg of white solid. Yield: 68%; Melting point: 117.8-118.5°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.23(s, 1H), 8.06(d, J=9.5Hz, 1H), 7.36-7.26(m, 5H), 6.96(d, J=9.5Hz, 1H) , 4.67 (d, J=6Hz, 2H), 3.85 (t, J=5Hz, 4H), 3.72 (t, J=5Hz, 4H).

Embodiment 5: N-benzyl-6-thiomorpholine pyridazine-3-carboxamide (compound 5)

The experimental method was the same as the preparation of compound 4 in Example 4, except that morpholine was replaced by thiomorpholine to obtain 20.6 mg of yellow solid. Yield: 55%; Melting point: 98.5-99.6°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.21(s, 1H), 8.04(d, J=9.5Hz, 1H), 7.36-7.26(m, 5H), 6.96(d, J=9.5Hz, 1H) , 4.67 (d, J=5.5Hz, 2H), 4.12 (t, J=5Hz, 4H), 2.71 (t, J=5Hz, 4H).

Embodiment 6: N-benzyl-6-diethylaminopyridazine-3-carboxamide (compound 6)

The experimental method was the same as the preparation of compound 4 in Example 4, except that diethylamine was used instead of morpholine to obtain 21.5 mg of white solid. Yield: 63%; Melting point: 107.6-108.6°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.24(s, 1H), 7.98(d, J=9.5Hz, 1H), 7.36-7.31(m, 4H), 7.27(t, J=7Hz, 1H), 6.80 (d, J = 9.5Hz, 1H), 4.66 (d, J = 6Hz, 2H), 3.65-3.61 (q, 4H), 1.24 (t, J = 7Hz, 6H).

Example 7: N-benzyl-6-(piperidin-1-yl)pyridazine-3-carboxamide (compound 7)

The experimental method was the same as the preparation of compound 4 in Example 4, except that piperidine was used instead of morpholine to obtain 23.8 mg of a yellow solid. Yield: 67%; Melting point: 103.5-105.0°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.22(s, 1H), 7.98(d, J=10Hz, 1H), 7.36-7.25(m, 5H), 6.95(d, J=9.5Hz, 1H), 4.66 (d, J=6Hz, 2H), 3.73 (t, J=5Hz, 4H), 1.73-1.63 (m, 6H).

Example 8: N-(4-methylbenzylamine)-6-(piperidin-1-yl)pyridazine-3-carboxamide (Compound 8)

The experimental method was the same as the preparation of compound 4 in Example 4, except that benzylamine and morpholine were replaced by 4-methylbenzylamine and piperidine, respectively, to obtain 36.3 mg of white solid. Yield: 97.4%; Melting point: 113.6-114.9°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.19(s, 1H), 7.98(d, J=9.5Hz, 1H), 7.24(d, J=8Hz, 2H), 7.13(d, J=8Hz, 2H ), 6.94(d, J=9.5Hz, 1H), 4.62(d, J=6Hz, 2H), 3.72(t, J=5Hz, 4H), 2.33(s, 3H), 1.74-1.64(m, 6H ).

Example 9: N-(4-fluorobenzyl)-6-(piperidin-1-yl)pyridazine-3-carboxamide (Compound 9)

The experimental method was the same as the preparation of compound 4 in Example 4, except that benzylamine and morpholine were replaced by 4-fluorobenzylamine and piperidine, respectively, to obtain 31.0 mg of light yellow solid. Yield: 82.2%; Melting point: 136.3-137.5°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.24(s, 1H), 7.97(d, J=9.5Hz, 1H), 7.33-7.30(m, 2H), 7.01(t, J=9Hz, 2H), 6.95 (d, J = 9.5Hz, 1H), 4.63 (d, J = 6Hz, 2H), 3.73 (t, J = 5.5Hz, 4H), 1.74-1.65 (m, 6H).

Example 10: N-(pyridine-3-methyl)-6-(piperidin-1-yl)pyridazine-3-carboxamide (compound 10)

The experimental method was the same as the preparation of compound 4 in Example 4, except that benzylamine and morpholine were replaced by pyridine-3-methylamine and piperidine, respectively, to obtain 33.1 mg of white solid. Yield: 92.8%; Melting point: 108.4-109.1°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.61(s, 1H), 8.52(s, 1H), 8.34(s, 1H), 7.96(d, J=9.5Hz, 1H), 7.69(d, J= 7.5Hz, 1H), 7.26(t, J=4Hz, 1H), 6.96(d, J=9.5Hz, 1H), 4.68(d, J=5.5Hz, 2H), 3.73(s, 4H), 1.72- 1.67(m,6H).

Example 11: N-cyclohexyl-6-(piperidin-1-yl)pyridazine-3-carboxamide (compound 11)

The experimental method was the same as the preparation of compound 1 in Example 1, except that piperidine was used instead of morpholine to obtain 54 mg of white solid. Yield: 89%; Melting point: 98.6-99.6°C.

¹ H NMR (500MHz, CDCl ₃ ) δ7.96(d, J=9.5Hz, 1H), 7.86(d, J=8Hz, 1H), 6.94(d, J=9.5Hz, 1H), 4.00-3.92( m,1H),3.74(t,J＝5Hz,4H),2.01-1.98(m,2H),1.78-1.61(m,8H),1.47-1.38(m,2H),1.32-1.19(m,4H ).

Example 12: N-cyclohexylmethyl-6-(piperidin-1-yl)pyridazine-3-carboxamide (compound 12)

The experimental method was the same as the preparation of compound 1 in Example 1, except that cyclohexylamine and morpholine were replaced by cyclohexylamine and piperidine, respectively, to obtain 30 mg of light yellow solid. Yield: 82.7%; Melting point: 89.6-90.1°C.

¹ H NMR (500MHz, CDCl ₃ ) δ7.96(d, J=10Hz, 2H), 6.95(d, J=9.5Hz, 1H), 3.74(s, 4H), 3.30(t, J=6.5Hz, 2H), 1.82-1.68(m, 11H), 1.62-1.54(m, 1H), 1.28-1.13(m, 3H), 1.05-0.97(m, 2H).

Example 13: N-((tetrahydropyran-2H-4-yl)methyl)-6-(piperidin-1-yl)pyridazine-3-carboxamide (Compound 13)

The experimental method was the same as the preparation of compound 1 in Example 1, except that cyclohexylamine and morpholine were replaced by (tetrahydropyran-2H-4-yl)methylamine and piperidine, respectively, to obtain 33 mg of light yellow solid. Yield: 90%; Melting point: 88.6-89.6°C.

¹ H NMR (500MHz, CDCl ₃ ) δ7.95-7.86(m, 2H), 6.88(d, J=9.5Hz, 1H), 3.93-3.88(m, 2H), 3.67(t, J=5Hz, 4H ), 3.34-3.27(m,4H), 1.80-1.72(m,1H), 1.65-1.60(m,8H), 1.35-1.27(m,2H).

Example 14: N-cyclopropylmethyl-6-(piperidin-1-yl)pyridazine-3-carboxamide (Compound 14)

The experimental method was the same as the preparation of compound 1 in Example 1, except that cyclohexylamine and morpholine were replaced by cyclopropylmethylamine and piperidine, respectively, to obtain 30.4 mg of a yellow solid. Yield: 97%; Melting point: 94.8-95.4°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.03(s, 1H), 7.97(d, J=9.5Hz, 1H), 6.95(d, J=9.5Hz, 1H), 3.75(d, J=4.5Hz ,4H),3.34(t,J=6.5Hz,2H),1.74-1.68(m,6H),1.09-1.01(m,1H),0.54(d,J=7.5Hz,2H),0.27(d, J=4.5Hz, 2H).

Example 15: N-cyclobutylmethyl-6-(piperidin-1-yl)pyridazine-3-carboxamide (Compound 15)

The experimental method was the same as the preparation of compound 1 in Example 1, except that cyclohexylamine and morpholine were replaced by cyclobutylmethylamine and piperidine, respectively, to obtain 32 mg of yellow solid. Yield: 97%; Melting point: 104.4-106.2°C.

¹ H NMR (500MHz, CDCl ₃ ) δ7.96(d, J=9.5Hz, 1H), 7.89(s, 1H), 6.95(d, J=10Hz, 1H), 3.74(t, J=5.5Hz, 4H), 3.51-3.48(m, 2H), 2.62-2.53(m, 1H), 2.12-2.05(m, 2H), 1.96-1.84(m, 2H), 1.80-1.66(m, 8H).

Example 16: N-isobutyl-6-(piperidin-1-yl)pyridazine-3-carboxamide (Compound 16)

The experimental method was the same as the preparation of compound 1 in Example 1, except that cyclohexylamine and morpholine were replaced by isobutylamine and piperidine, respectively, to obtain 31 mg of yellow solid. Yield: 98%; Melting point: 92.6-93.2°C.

¹ H NMR (500MHz, CDCl ₃ ) δ7.99(s, 1H), 7.97(d, J=10Hz, 1H), 6.96(d, J=9.5Hz, 1H), 3.74(t, J=5Hz, 4H ), 3.31 (t, J = 6.5Hz, 2H), 1.93-1.85 (m, 1H), 1.74-1.66 (m, 6H), 0.98 (d, J = 7Hz, 6H).

Example 17: N-Benzyl-6-anilinopyridazine-3-carboxamide (Compound 17)

a) N-benzyl-6-chloropyridazine-3-carboxamide (compound 17a)

Benzylamine (0.12mL, 1.08mmol) was placed in a 25mL double-necked flask, and after nitrogen replacement, 0.18mL triethylamine and 5.4mL dichloromethane were added successively, and 2.5mL dichloromethane was added to the obtained product in Example 1. In compound 1c, its solution was slowly added dropwise to the above mixture of benzylamine in an ice bath, and after the dropwise addition was completed, the reaction was stirred overnight at room temperature. The reaction was stopped, and the reaction solution was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution, and the obtained organic layer was dried with anhydrous magnesium sulfate, and the organic solvent was removed by rotary evaporation under reduced pressure, and separated and purified by silica gel column chromatography to obtain White solid 97.8 mg. Yield: 55%; Melting point: 132.3-133.8°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.37(s, 1H), 8.32(d, J=9Hz, 1H), 7.70(d, J=9Hz, 1H), 7.37-7.30(m, 5H), 4.72 (d, J=6.5Hz, 2H).

b) N-benzyl-6-anilinopyridazine-3-carboxamide (compound 17)

Compound 17a (30mg, 0.12mmol) was placed in a 5mL single-necked round-bottom flask, 1.2mL of acetonitrile was added, magnetically stirred to dissolve, and 61μL of N,N-diisopropylethylamine (DIPEA), aniline (13μL, 0.14mmol ), heated to reflux overnight, then gradually distilled off the solvent, and reacted without solvent at 160 ° C, monitored by TLC until the reaction was complete. Stop the reaction, add an appropriate amount of water to the residue after cooling and standing still, extract 3 times with ethyl acetate, combine the organic layers, wash with saturated sodium chloride, dry the organic layer with anhydrous magnesium sulfate, and remove the organic solvent by rotary evaporation under reduced pressure , separated and purified by silica gel column chromatography to obtain 16.5 mg of white solid. Yield: 45.0%; Melting point: 166.9-167.4°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.27(t, J=5Hz, 1H), 8.07(d, J=9.5Hz, 1H), 7.60(s, 1H), 7.40-7.33(m, 8H), 7.30-7.27 (m, 1H), 7.20-7.18 (m, 1H), 7.16 (d, J=9Hz, 1H), 4.68 (d, J=6Hz, 2H).

Example 18: N-Benzyl-6-(4-methoxyanilino)pyridazine-3-carboxamide (Compound 18)

The experimental method was the same as the preparation of compound 17 in Example 17, except that p-methoxyaniline was used instead of aniline to obtain 22 mg of a yellow solid. Yield: 41.2%; Melting point: 164.9-165.4°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.27(t, J=5.5Hz, 1H), 8.01(d, J=9.5Hz, 1H), 7.50(s, 1H), 7.36-7.32(m, 4H) , 7.29-7.25 (m, 3H), 6.96 (d, J=9Hz, 1H), 6.92 (d, J=9Hz, 2H), 4.67 (d, J=6Hz, 2H).

Example 19: N-Benzyl-6-(2,4-dichloroanilino)pyridazine-3-carboxamide (Compound 19)

The experimental method was the same as the preparation of compound 17 in Example 17, except that aniline was replaced by 2,4-dichloroaniline, and 10.7 mg of a yellow solid was obtained. Yield: 18%; Melting point: 146.4-147.8°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.27(t, J=5Hz, 1H), 8.17(dd, J=3.5Hz, 4Hz, 2H), 7.47(d, J=2.5Hz, 1H), 7.37- 7.33 (m, 4H), 7.30-7.28 (m, 2H), 7.20 (s, 1H), 7.10 (d, J=9Hz, 1H), 4.69 (d, J=6Hz, 2H).

Example 20: N-Benzyl-6-(3-chloroanilino)pyridazine-3-carboxamide (Compound 20)

The experimental method was the same as the preparation of compound 17 in Example 17, except that m-chloroaniline was used instead of aniline to obtain 36.4 mg of a yellow solid. Yield: 67%; Melting point: 159.9-161.0°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.52(s, 1H), 8.29(t, J=6Hz, 1H), 8.12(d, J=9Hz, 1H), 7.54(s, 1H), 7.37-7.22 (m, 8H), 7.11 (d, J=8Hz, 1H), 4.69 (d, J=6.5Hz, 2H).

Example 21: N-Benzyl-6-(4-chloroanilino)pyridazine-3-carboxamide (Compound 21)

The experimental method was the same as the preparation of compound 17 in Example 17, except that p-chloroaniline was used instead of aniline to obtain 36.2 mg of a yellow solid. Yield: 67%; Melting point: 188.9-189.3°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.251(t, J=5.5Hz, 1H), 8.09(d, J=9.5Hz, 1H), 7.82(s, 1H), 7.39-7.30(m, 9H) , 7.11 (d, J=9Hz, 1H), 4.68 (d, J=6Hz, 2H).

Example 22: N-(4-methylbenzyl)-6-(3-chloroanilino)pyridazine-3-carboxamide (Compound 22)

The experimental method was the same as the preparation of compound 17 in Example 17, except that benzylamine and aniline were replaced by 4-methylbenzylamine and m-chloroaniline, respectively, to obtain 29.3 mg of white solid. Yield: 54%; Melting point: 188.4-189.3°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.24(t, J=6Hz, 1H), 8.12(d, J=9.5Hz, 1H), 7.93(s, 1H), 7.51(d, J=2Hz, 1H ), 7.32-7.25 (m, 4H), 7.20 (d, J = 9Hz, 1H), 7.16-7.12 (m, 3H), 4.65 (d, J = 6Hz, 2H), 2.34 (s, 3H).

Example 23: N-(4-fluorobenzyl)-6-(3-chloroanilino)pyridazine-3-carboxamide (Compound 23)

The experimental method was the same as the preparation of compound 17 in Example 17, except that benzylamine and aniline were replaced by 4-fluorobenzylamine and m-chloroaniline, respectively, to obtain 34.8 mg of a brown solid. Yield: 81%; Melting point: 168.1-168.8°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.28(s, 1H), 8.19(s, 1H), 8.13(d, J=9.5Hz, 1H), 7.54(s, 1H), 7.35-7.22(m, 5H), 7.13 (d, J=6.5Hz, 1H), 7.03 (t, J=8.5Hz, 2H), 4.66 (d, J=6Hz, 2H).

Example 24: N-(Pyridine-3-methyl)-6-anilinopyridazine-3-carboxamide (Compound 24)

The experimental method was the same as the preparation of compound 17 in Example 17, except that benzylamine in compound 17a was replaced by pyridine-3-methylamine, and 16.3 mg of a yellow solid was obtained. Yield: 35%; Melting point: 247.1-247.7°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.64(d, J=1.5Hz, 1H), 8.55(d, J=3.5Hz, 1H), 8.33(t, J=5.5Hz, 1H), 8.07(d ,J=9.5Hz,1H),7.72(d,J=7.5Hz,1H),7.43-7.36(m,4H),7.29(t,J=4Hz,1H),7.25-7.20(m,2H), 7.15 (d, J=9Hz, 1H), 4.71 (d, J=7.5Hz, 2H).

Example 25: N-cyclohexyl-6-anilinopyridazine-3-carboxamide (Compound 25)

The experimental method was the same as the preparation of compound 17 in Example 17, except that benzylamine in compound 17a was replaced by cyclohexylamine to obtain 34.3 mg of white solid. Yield: 97%; Melting point: 187.5-187.9°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.09(s, 1H), 8.04(d, J=9Hz, 1H), 7.88(d, J=8.5Hz, 1H), 7.45-7.378(m, 4H), 7.18(t, J=8Hz, 2H), 4.02-3.94(m, 1H), 2.01(t, J=6Hz, 2H), 1.78-1.75(m, 2H), 1.66-1.63(m, 1H), 1.46 -1.38(m,2H),1.35-1.29(m,2H).

Example 26: N-cyclohexylmethyl-6-(3-chloroanilino)pyridazine-3-carboxamide (Compound 26)

The experimental method was the same as the preparation of compound 17 in Example 17, except that benzylamine and aniline were replaced by cyclohexylmethylamine and m-chloroaniline, respectively, to obtain 43.5 mg of gray solid. Yield 79%; melting point: 170.5-171.8°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.64(s, 1H), 8.10(d, J=9Hz, 1H), 8.03(t, J=6Hz, 1H), 7.59(s, 1H), 7.37(d ,J=8.5Hz,1H),7.32-7.24(m,2H),7.13(d,J=7.5Hz,1H),3.35(t,J=6.5Hz,2H),1.81-1.57(m,6H) ,1.28-1.12(m,3H),1.05-0.97(m,2H).

Example 27: N-((tetrahydropyran-2H-4-yl)methyl)-6-(2,4-dichloroanilino)pyridazine-3-carboxamide (Compound 27)

The experimental method was the same as the preparation of compound 17 in Example 17, except that benzylamine and aniline were replaced by (tetrahydropyran-2H-4-yl)methylamine and 2,4-dichloroaniline, respectively, to obtain 8.1 mg of yellow solid. Yield: 13%; Melting point: 187.7-188.0°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.19(d, J=9Hz, 1H), 8.14(d, J=9Hz, 1H), 8.07(t, J=6Hz, 1H), 7.48(d, J= 2.5Hz, 1H), 7.31(dd, J=2.5Hz, 1H), 7.21(s, 1H), 7.11(d, J=9Hz, 1H), 3.99(dd, J=3.5Hz, J=3Hz, 2H ), 3.42-3.36 (m, 4H), 1.93-1.84 (m, 2H), 1.71-1.69 (m, 3H), 1.45-1.36 (m, 2H).

Example 28: N-cyclopropylmethyl-6-(3-chloroanilino)pyridazine-3-carboxamide (Compound 28)

The experimental method was the same as the preparation of compound 17 in Example 17, except that benzylamine and aniline were replaced by cyclopropylmethylamine and m-chloroaniline, respectively, to obtain 27.3 mg of a yellow solid. Yield: 75%; Melting point: 168.0-168.5°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.66(s, 1H), 8.11(d, J=9.5Hz, 1H), 8.08(t, J=5.5Hz, 1H), 7.60(s, 1H), 7.38 (d,J=8Hz,1H),7.32(tJ=8Hz,1H),7.26(d,J=9.5Hz,1H),7.13(d,J=8Hz,1H),3.37(t,J=6.5Hz ,2H), 1.13-1.05(m,1H),0.58-0.55(m,2H),0.31-0.28(m,2H).

Example 29: N-Benzyl-6-cyclohexylaminopyridazine-3-carboxamide (Compound 29)

Put compound 17a (30mg, 0.12mmol) in a 5ml single-necked round bottom flask, add 1.2mL 1,4-dioxane, stir to dissolve, then add 61μL N,N-diisopropylethylamine (DIPEA) , cyclohexylamine (15 μL, 0.14 mmol), heated to reflux overnight. Stop the reaction, extract with ethyl acetate/water, wash the organic layer with saturated sodium chloride, dry over anhydrous magnesium sulfate, remove the organic solvent by rotary evaporation under reduced pressure, separate and purify by silica gel column chromatography to obtain compound 29, yellow liquid 21.4 mg ; Yield: 57%.

¹ H NMR (500MHz, CDCl ₃ ) δ8.23(d, J=5Hz, 1H), 8.11(d, J=1Hz, 1H), 7.95(d, J=9Hz, 1H), 7.35-7.25(m, 5H), 6.69(d, J=9.5Hz, 1H), 4.65(d, J=6Hz, 2H), 3.90-3.83(m, 1H), 2.10-2.07(m, 2H), 1.95-1.87(m, 4H), 1.43-1.35 (m, 4H).

Example 30: N-Benzyl-6-(piperidine-1-amino)pyridazine-3-carboxamide (Compound 30)

The experimental method was the same as the preparation of compound 29 in Example 29, except that cyclohexylamine was replaced by 1-aminopiperidine, and 20 mg of light yellow solid was obtained. Yield: 40%; Melting point: 99.0-99.6°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.23(s, 1H), 7.98(d, J=9.5Hz, 1H), 7.36-7.25(m, 5H), 6.94(d, J=9.5Hz, 1H) , 4.66 (d, J=6Hz, 2H), 3.73 (t, J=5Hz, 4H), 1.81 (s, 1H), 1.72-1.67 (m, 6H).

Example 31: N-Benzyl-6-morpholinopyridazine-3-carboxamide (Compound 31)

The experimental method was the same as the preparation of compound 29 in Example 29, except that cyclohexylamine was replaced by N-aminomorpholine, and 6.9 mg of yellow solid was obtained. Yield: 18%; Melting point: 177.7-178.8°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.24(s, 1H), 8.13(d, J=9.5Hz, 1H), 7.37-7.26(m, 6H), 6.47(s, 1H), 4.68(d, J=6Hz, 2H), 3.86-3.82(m, 4H), 2.85(s, 4H).

Example 32: N-Benzyl-6-cyclopentylaminopyridazine-3-carboxamide (Compound 32)

The experimental method was the same as the preparation of compound 29 in Example 29, except that cyclohexylamine was replaced by cyclopentylamine to obtain 36.2 mg of a yellow solid. Yield: 76%; Melting point: 110.4-111.4°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.25(t, J=5.5Hz, 1H), 7.97(d, J=9Hz, 1H), 7.36-7.25(m, 5H), 6.71(d, J=9.5 Hz, 1H), 5.49(s, 1H), 4.66(d, J=5.5Hz, 2H), 4.18(d, J=6Hz, 1H), 2.13-2.07(m, 2H), 1.75-1.64(m, 4H), 1.57-1.50 (m, 2H).

Example 33: N-Benzyl-5-isopropyl-6-anilinopyridazine-3-carboxamide (Compound 33)

a) 1,6-dihydro-6-oxypyridazine-3-carboxylic acid ethyl ester (compound 33a)

Add 8 mL of hydrogen chloride ethanol solution (hydrogen chloride gas is obtained by reacting sodium chloride and concentrated hydrochloric acid, and pass it into ethanol under ice bath) to compound 1b (1.11 g, 7.9 mmol), and heat to reflux for 14 h. The reaction was stopped, cooled in an ice bath, and a white solid was precipitated, which was dried by suction filtration and directly put into the next reaction.

b) ethyl 6-chloropyridazine-3-carboxylate (compound 33b)

Put the compound 33a obtained in the previous step into a 25mL single-necked round-bottomed flask, replace with nitrogen, add 12mL of phosphorus oxychloride, heat to 100°C for 2 hours, stop the reaction, cool and stand, and pour the reaction solution slowly under magnetic stirring Pour it into ice water, then use 10% sodium hydroxide solution to adjust the pH value to about 7, and a solid precipitates, which is filtered by suction and separated and purified by silica gel column chromatography to obtain 812.4 mg of a white solid. Yield: 55%; Melting point: 147-149°C.

c) ethyl 6-chloro-4-isopropylpyridazine-3-carboxylate (compound 33c)

Compound 33b (534mg, 2.87mmol) was placed in a 25mL single-necked round bottom flask, 9mL of water, 60μL of isobutyric acid (0.65mmol), 230μL of concentrated sulfuric acid, 48.8mg of silver nitrate (0.29mmol) were added successively, and the temperature was maintained at At 65-75°C, ammonium persulfate (982.7mg, 4.3mmol) dissolved in 5mL of water was dropped into the above mixture, after the addition, the temperature was raised and kept at 70-75°C, and the reaction was performed with magnetic stirring for 30min. Stop the reaction, pour the reaction solution into ice water, adjust the pH value to about 8 with 30% ammonia water, extract 3 times with dichloromethane, combine the organic layers, dry with anhydrous magnesium sulfate, filter, and spin evaporate the solvent under reduced pressure. Separation and purification by silica gel column chromatography. 29.4 mg of yellow liquid was obtained; yield: 4.5%.

¹ H NMR (500MHz, CDCl ₃ ) δ7.51(s, 1H), .4.54-4.49(q, 2H), 3.47-3.41(m, 1H), 1.46(t, J=7.0Hz, 3H), 1.31 (s,3H),1.29(s,3H).

d) ethyl 6-chloro-5-isopropylpyridazine-3-carboxylate (compound 33d)

The experimental method was the same as the preparation of compound 33c to obtain 294.0 mg of yellow liquid; yield: 45%.

¹ H NMR (500MHz, CDCl ₃ ) δ8.06(s, 1H), 4.57-4.53(q, 2H), 3.38-3.32(m, 1H), 1.48(t, J=7.0Hz, 3H), 1.35( s,3H), 1.33(s,3H).

e) 6-chloro-5-isopropylpyridazine-3-formyl chloride (compound 33e)

The experimental method was the same as the preparation of compound 1c in Example 1, except that compound 33d was used instead of compound 1b, and the obtained product was directly put into the next reaction.

f) N-benzyl-6-chloro-5-isopropylpyridazine-3-carboxamide (compound 33f)

The experimental method was the same as the preparation of compound 1d in Example 1, except that compound 33e was used instead of compound 1c to obtain 56.9 mg of a yellow solid. Yield: 52%; Melting point: 108.5-110.0°C.

¹ H NMR (500MHz, CDCl ₃ )δ8.41(s,1H),8.23(s,1H),7.37-7.33(m,4H),7.31-7.28(m,1H),4.71(d,J=6Hz , 2H), 3.37-3.31 (m, 1H), 1.34 (d, J=6.5Hz, 6H).

g) N-benzyl-5-isopropyl-6-anilinopyridazine-3-carboxamide (compound 33)

Compound 33f (30mg, 0.12mmol) was placed in a 5mL single-necked round-bottom flask, 1.2mL of acetonitrile was added, magnetically stirred to dissolve, and 61μL of N,N-diisopropylethylamine (DIPEA), aniline (13μL, 0.14mmol ), heated to reflux overnight, then gradually distilled off the solvent, and reacted without solvent at 160 ° C, monitored by TLC until the reaction was complete. Stop the reaction, add an appropriate amount of water to the residue after cooling and standing still, extract 3 times with ethyl acetate, combine the organic layers, wash with saturated sodium chloride, dry the organic layer with anhydrous magnesium sulfate, and remove the organic solvent by rotary evaporation under reduced pressure , separated and purified by silica gel column chromatography to obtain 36.8 mg of a yellow solid. Yield: 71%; Melting point: 178.9-179.9°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.34(s, 1H), 8.04(s, 1H), 7.64-7.63(d, J=8Hz, 2H), 7.39-7.28(m, 7H), 7.13(t , J=7Hz, 1H), 6.52(s, 1H), 4.67(d, J=6Hz, 2H), 2.95-2.90(m, 1H), 1.40(d, J=6.5Hz, 6H).

Example 34: N-(Pyridine-3-methyl)-5-isopropyl-6-anilinopyridazine-3-carboxamide (Compound 34)

The experimental method was the same as the preparation of compound 33f and compound 33 in Example 33, except that benzylamine in compound 33f was replaced by pyridine-3-methylamine, and 19.2 mg of brown solid was obtained. Yield: 29%; Melting point: 157.2-158.2°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.61(d, J=2Hz, 1H), 8.53(dd, J=1Hz, J=1.5Hz, 1H), 8.43(t, J=6Hz, 1H), 8.01 (s,1H),7.69(d,J=8Hz,1H),7.63(d,J=8Hz,2H),7.38(t,J=8Hz,2H),7.27-7.24(m,1H),7.13( t, J=7.5Hz, 1H), 6.65(s, 1H), 4.68(d, J=6.5Hz, 2H), 2.96-2.91(m, 1H), 1.38(d, J=7Hz, 6H).

Example 35: N-cyclohexyl-5-isopropyl-6-morpholinopyridazine-3-carboxamide (compound 35)

a) N-cyclohexyl-6-chloro-5-isopropylpyridazine-3-carboxamide (compound 35a)

The experimental method was the same as the preparation of compound 33f in Example 33, except that benzylamine (118 μL, 1.08 mmol) was replaced by cyclohexylamine (86 μL, 0.75 mmol), and 137 mg of white solid was obtained. Yield: 97%; Melting point: 129.4-130.5°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.20(s, 1H), 7.97(d, J=7.5Hz, 1H), 4.04-3.97(m, 1H), 3.37-3.31(m, 1H), 2.04- 2.01(m,2H),1.81-1.77(m,2H),1.69-1.65(m,1H),1.49-1.41(m,2H),1.39-1.36(m,2H),1.34(s,3H), 1.33(s,3H),1.29-1.24(m,1H).

b) N-cyclohexyl-5-isopropyl-6-morpholine pyridazine-3-carboxamide (compound 35)

Put compound 35a (0.42mmol) in a 5mL single-necked round bottom flask, add 2mL 1,4-dioxane, stir to dissolve, then add 215μL N,N-diisopropylethylamine (DIPEA), morpholine (74 μL, 0.84 mmol), heated to reflux overnight. Stop the reaction, extract with ethyl acetate/water, wash the organic layer with saturated sodium chloride, dry over anhydrous magnesium sulfate, remove the organic solvent by rotary evaporation under reduced pressure, and separate and purify by silica gel column chromatography to obtain 62.1 mg of white solid. Yield: 44.1%; Melting point: 186.3-186.7°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.09(s, 1H), 8.00(d, J=8.0Hz, 1H), 4.02-3.96(m, 1H), 3.91(t, J=4.5Hz, 4H) ,3.35(t,J＝4.5Hz,4H),3.18-3.13(m,1H),2.02-1.99(m,2H),1.79-1.75(m,2H),1.67-1.63(m,1H),1.49 -1.40(m,3H),1.35-1.32(m,1H),1.30(s,3H),1.29(s,3H),1.27-1.23(m,1H).

Example 36: N-(Adamantan-1-yl)-5-isopropyl-6-morpholine pyridazine-3-carboxamide (Compound 36)

a) N-(adamantane-1-yl)-6-chloro-5-isopropylpyridazine-3-carboxamide (compound 36a)

The experimental method was the same as the preparation of compound 33f in Example 33, except that benzylamine (118 μL, 1.08 mmol) was replaced by 1-adamantanamine (113.4 mg, 0.75 mmol) to obtain 114.5 mg of a white solid. Yield: 69%; Melting point: 97.5-98.1°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.48(d, J=7.5Hz, 1H), 8.21(s, 1H), 4.29-4.27(m, 1H), 3.37-3.32(m, 1H), 2.07( s,2H),1.97(d,J=13.5Hz,2H),1.92(s,6H),1.79(s,2H),1.70(d,J=12.5Hz,2H),1.34(s,3H), 1.33(s,3H).

b) N-(adamantan-1-yl)-5-isopropyl-6-morpholine pyridazine-3-carboxamide (compound 36)

The experimental method was the same as the preparation of compound 35 in Example 35, except that compound 36a was used instead of compound 35a to obtain 75.5 mg of white solid. Yield: 47%; Melting point: 149.7-150.0°C.

¹ H NMR (500MHz, CDCl ₃ )δ8.08(s,1H),7.91(s,1H),3.91(t,J=4.5Hz,4H),3.34(t,J=4.5Hz,4H),3.17 -3.12(m,1H),2.15(s,9H),1.77-1.71(m,6H),1.29(s,3H),1.28(s,3H).

Example 37: N-(Adamantan-2-yl)-5-isopropyl-6-morpholine pyridazine-3-carboxamide (Compound 37)

a) N-(adamantane-2-yl)-6-chloro-5-isopropylpyridazine-3-carboxamide (compound 37a)

The experimental method was the same as the preparation of compound 33f in Example 33, except that benzylamine (118 μL, 1.08 mmol) was replaced by 2-adamantanamine (113.4 mg, 0.75 mmol), and 125.2 mg of a white solid was obtained. Yield: 75%; Melting point: 132.6-134.0°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.48(d, J=7.5Hz, 1H), 8.21(s, 1H), 4.29-4.27(m, 1H), 3.37-3.32(m, 1H), 2.07( s,2H),1.97(d,J=13.5Hz,2H),1.92(s,6H),1.79(s,2H),1.70(d,J=12.5Hz,2H),1.34(s,3H), 1.33(s,3H).

b) N-(adamantane-2-yl)-5-isopropyl-6-morpholine pyridazine-3-carboxamide (compound 37)

The experimental method was the same as the preparation of compound 35 in Example 35, except that compound 37a was used instead of compound 35a to obtain 94.5 mg of white solid. Yield: 58%; Melting point: 232.2-232.6°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.49(d, J=8.5Hz, 1H), 8.11(s, 1H), 4.29-4.27(m, 1H), 3.92(t, J=4.5Hz, 4H) ,3.35(t,J=5.0Hz,4H),3.19-3.14(m,1H),2.05(s,2H),2.00(d,J=13.5Hz,2H),1.91-1.88(m,6H), 1.78 (s, 2H), 1.68 (d, J=12.0Hz, 2H), 1.31 (s, 3H), 1.29 (s, 3H).

Example 38: N-(Adamantan-2-yl)-5-isopropyl-6-(piperidin-1-yl)pyridazine-3-carboxamide (Compound 38)

The experimental method was the same as the preparation of compound 37 in Example 37, except that morpholine (74 μL, 0.84 mmol) was replaced by piperidine (12 μL, 0.12 mmol), to obtain 21.2 mg of white solid. Yield: 93%; Melting point: 227.7-228.5°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.50(d, J=8.0Hz, 1H), 8.04(s, 1H), 4.27-4.25(m, 1H), 3.26(t, J=5.0Hz, 4H) ,3.16-3.11(m,1H),2.03(s,2H),1.99(d,J＝13.5Hz,2H),1.93-1.87(m,6H),1.76-1.74(m,6H),1.68-1.65 (m,4H), 1.28(s,3H), 1.27(s,3H).

Example 39: N-(Adamantan-2-yl)-5-isopropyl-6-cyclohexylaminopyridazine-3-carboxamide (Compound 39)

The experimental method was the same as the preparation of compound 37 in Example 37, except that cyclohexylamine (27 μL, 0.24 mmol) was used instead of morpholine (74 μL, 0.84 mmol) to obtain 16.2 mg of white solid. Yield: 34%; Melting point: 184.7-185.9°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.35(d, J=8.0Hz, 1H), 7.85(s, 1H), 4.49(d, J=7.5Hz, 1H), 4.34-4.28(m, 1H) ,4.25-4.23(m,1H),2.70-2.64(m,1H),2.18-2.15(m,2H),2.03(s,2H),2.00(d,J＝13.0Hz,2H),1.92-1.86 (m,6H),1.79-1.78(m,2H),1.76(s,2H),1.70-1.67(m,1H),1.64(d,J＝12.5Hz,2H),1.53-1.45(m,2H ), 1.29(s,3H), 1.28(s,3H), 1.30-1.24(m,3H).

¹³ C NMR (CDCl ₃ , 125 MHz) δ163.00, 157.29, 145.62, 133.03, 121.34, 53.46, 53.34, 37.63, 37.21, 33.56, 32.15, 31.86, 27.29, 27.24, 26.99, 23.81, 20.73.

Example 40: N-(Adamantan-2-yl)-5-isopropyl-6-cyclopentylaminopyridazine-3-carboxamide (Compound 40)

The experimental method was the same as the preparation of compound 37 in Example 37, except that cyclopentylamine (20 μL, 0.19 mmol) was used instead of morpholine (74 μL, 0.84 mmol) to obtain 20 mg of a yellow solid. Yield: 54%; Melting point: 186.1-186.9°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.38(d, J=8.0Hz, 1H), 7.85(s, 1H), 4.66-4.62(m, 1H), 4.61-4.58(m, 1H), 4.25- 4.24(d,J=8.0Hz,1H),2.70-2.64(m,1H),2.25-2.19(m,2H),2.03(s,2H),1.99(d,J=13.0Hz,2H),1.92 -1.86(m,6H),1.78-1.69(m,6H),1.64(d,J＝12.5Hz,2H),1.55-1.48(m,2H),1.29(s,3H),1.27(s,3H ).

¹³ C NMR (CDCl ₃ , 125 MHz) δ163.00, 157.29, 145.62, 133.03, 121.34, 53.46, 53.34, 37.63, 37.21, 33.56, 32.15, 31.86, 27.29, 27.24, 26.99, 23.81, 20.73.

Example 41: N-(Adamantan-2-yl)-5-isopropyl-6-morpholinopyridazine-3-carboxamide (Compound 41)

The experimental method was the same as the preparation of compound 37 in Example 37, except that N-aminomorpholine (20 μL, 0.20 mmol) was used instead of morpholine (74 μL, 0.84 mmol) to obtain 18.9 mg of white solid. Yield: 48%; Melting point: 231.4-232.9°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.48(d, J=8.0Hz, 1H), 8.10(s, 1H), 4.26(d, J=8.5Hz, 1H), 3.91(t, J=4.0Hz ,4H),3.34(t,J=4.5Hz,4H),3.18-3.13(m,1H),2.04(s,2H),1.98(d,J=13.5Hz,2H),1.90-1.87(m, 6H), 1.77(s, 2H), 1.71-1.70(m, 1H), 1.66(d, J=13.5Hz, 2H), 1.30(s, 3H), 1.28(s, 3H).

¹³ C NMR (CDCl ₃ , 125 MHz) δ163.81, 162.05, 142.99, 124.63, 66.83, 53.47, 51.48, 37.55, 37.16, 32.12, 31.87, 27.53, 27.24, 27.17, 23.12.

Example 42: N-(Adamantan-2-yl)-5-isopropyl-6-(piperidin-1-amino)pyridazine-3-carboxamide (Compound 42)

The experimental method was the same as the preparation of compound 37 in Example 37, except that morpholine (74 μL, 0.84 mmol) was replaced by 1-aminopiperidine (19 μL, 0.17 mmol) to obtain 15.7 mg of white solid. Yield: 46%; Melting point: 227.2-228.3°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.50(d, J=8.0Hz, 1H), 8.04(s, 1H), 4.26(d, J=8.5Hz, 1H), 3.26(t, J=5.0Hz ,4H),3.16-3.11(m,1H),2.03(s,2H),1.99(d,J＝13.0Hz,2H),1.92-1.87(m,6H),1.78-1.74(m,6H), 1.71-1.65 (m, 4H), 1.28 (s, 3H), 1.27 (s, 3H).

¹³ C NMR (CDCl ₃ , 125 MHz) δ164.92, 162.34, 149.04, 143.00, 124.18, 53.38, 52.41, 37.58, 37.17, 32.14, 31.86, 27.66, 27.26, 27.19, 26.02, 24.28, 23.12.

Example 43: N-(Adamantan-2-yl)-5-isopropyl-6-cyclopropylmethylaminopyridazine-3-carboxamide (Compound 43)

The experimental method was the same as the preparation of compound 37 in Example 37, except that morpholine (74 μL, 0.84 mmol) was replaced by cyclopropylmethylamine (23 μL, 0.27 mmol), and 13.6 mg of white solid was obtained. Yield: 27%; Melting point: 202.5-203°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.41(d, J=8.0Hz, 1H), 7.88(s, 1H), 4.78-4.76(m, 1H), 4.25(d, J=8.5Hz, 1H) ,3.53-3.51(m,2H),2.78-2.73(m,1H),2.04(s,2H),2.00(d,J＝13.0Hz,2H),1.93-1.87(m,6H),1.77(s ,2H),1.65(d,J=14.0Hz,2H),1.33(s,3H),1.31(s,3H),1.24-1.18(m,1H),0.63-0.59(m,2H),0.34- 0.31(m,2H).

Example 44: N-(Adamantan-2-yl)-5-isopropyl-6-n-butylaminopyridazine-3-carboxamide (Compound 44)

The experimental method was the same as the preparation of compound 37 in Example 37, except that morpholine (74 μL, 0.84 mmol) was replaced by n-butylamine (22 μL, 0.27 mmol) to obtain 18.7 mg of white solid. Yield: 46%; Melting point: 78.6-79.9°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.39(d, J=8.5Hz, 1H), 7.86(s, 1H), 4.66-4.64(m, 1H), 4.24(d, J=8.5Hz, 1H) ,3.70-3.66(m,2H),2.72-2.66(m,1H),2.03(s,2H),1.99(d,J＝13.5Hz,2H),1.92-1.86(m,6H),1.76(s , 2H), 1.74-1.68 (m, 2H), 1.64 (d, J=12.5Hz, 2H), 1.50-1.42 (m, 2H), 1.30 (s, 3H), 1.28 (s, 3H).

¹³ C NMR (CDCl ₃ , 125MHz) δ162.95, 157.55, 145.71, 133.10, 121.34, 53.30, 42.02, 37.61, 37.19, 32.15, 31.86, 31.53, 27.28, 27.22, 27.01, 20.77, 230.893,

Example 45: N-(Adamantan-2-yl)-5-isopropyl-6-((pentyl-3-yl)amino)pyridazine-3-carboxamide (Compound 45)

The experimental method was the same as the preparation of compound 37 in Example 37, except that morpholine (74 μL, 0.84 mmol) was replaced by 3-aminopentane (22 μL, 0.19 mmol), and 6.9 mg of yellow oil was obtained. Yield: 19%.

¹ H NMR (500MHz, CDCl ₃ ) δ8.37(d, J=8.0Hz, 1H), 7.86(s, 1H), 4.46-4.42(m, 1H), 4.35(d, J=8.5Hz, 1H) ,4.25(d,J=8.0Hz,1H),2.72-2.66(m,1H),2.03(s,2H),2.00(d,J=13.0Hz,2H),1.93-1.86(m,6H), 1.78-1.73(m,4H),1.65(d,J=13.0Hz,2H),1.62-1.56(m,2H),1.32(s,3H),1.30(s,3H),0.97(t,J= 7.5Hz, 6H).

Example 46: N-(Adamantan-2-yl)-5-isopropyl-6-((3-methylbutyl)-2-yl)pyridazine-3-carboxamide (Compound 46)

The experimental method was the same as the preparation of compound 37 in Example 37, except that morpholine (74 μL, 0.84 mmol) was replaced by 1,2-methylpropylamine (22 μL, 0.19 mmol) to obtain 2.5 mg of white solid. Yield: 7%; Melting point: 75.1-76°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.37(d, J=7.0Hz, 1H), 7.86(s, 1H), 4.56-4.48(m, 2H), 4.25(d, J=8.5Hz, 1H) ,2.71-2.65(m,1H),2.04(s,2H),2.01(d,J＝13.0Hz,2H),1.97-1.87(m,7H),1.77(s,2H),1.65(d,J =13.0Hz, 2H), 1.32-1.30(m, 6H), 1.26-1.24(m, 3H), 1.02(d, J=7.0Hz, 3H), 0.98(d, J=7.0Hz, 3H).

Example 47: N-(Adamantan-2-yl)-5-isopropyl-6-((2-hydroxyethyl)amino)pyridazine-3-carboxamide (Compound 47)

The experimental method was the same as the preparation of compound 37 in Example 37, except that ethanolamine (11 μL, 0.17 mmol) was used instead of morpholine (74 μL, 0.84 mmol) to obtain 29.3 mg of a white solid. Yield: 94%; Melting point: 73.1-75.1°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.35 (d, J = 8.0Hz, 1H), 7.88 (s, 1H), 5.27-5.25 (m, 1H), 4.23 (d, J = 8.0Hz, 1H) ,3.95(t,J=4.5Hz,2H),3.87-3.84(q,2H),2.78-2.72(m,1H),2.03(s,2H),1.98(d,J=13.0Hz,2H), 1.90-1.87 (m, 6H), 1.76 (s, 2H), 1.66 (d, J=12.5Hz, 2H), 1.30 (s, 3H), 1.28 (s, 3H).

¹³ C NMR (CDCl ₃ , 125 MHz) δ162.78, 157.97, 146.12, 133.99, 121.71, 62.23, 53.38, 44.74, 37.58, 37.18, 32.13, 31.88, 27.26, 27.19, 27.08, 20.78.

Example 48: N-(Adamantan-2-yl)-5-isopropyl-6-(3-chloroanilino)pyridazine-3-carboxamide (Compound 48)

Compound 37a (39 mg, 0.12 mmol) was placed in a 5 mL single-necked round bottom flask, 1.2 mL of acetonitrile was added, and magnetically stirred to dissolve, and 61 μL of N,N-diisopropylethylamine (DIPEA), m-chloroaniline (15 μL, 0.14mmol), heated to reflux overnight, then gradually evaporated the solvent, and reacted without solvent at 160°C, monitored by TLC until the reaction was complete. Stop the reaction, add an appropriate amount of water to the residue after cooling and standing still, extract 3 times with ethyl acetate, combine the organic layers, wash with saturated sodium chloride, dry the organic layer with anhydrous magnesium sulfate, and remove the organic solvent by rotary evaporation under reduced pressure , separated and purified by silica gel column chromatography to obtain 5.5 mg of white solid. Yield: 11.1%; Melting point: 219.1-220°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.41(d, J=8.0Hz, 1H), 8.05(s, 1H), 7.75-7.74(m, 1H), 7.55-7.53(m, 1H), 7.32( t,J=8.0Hz,1H),7.11(d,J=8.0Hz,1H),6.53(s,1H),4.28-4.26(m,1H),2.95-2.89(m,1H),2.06(s ,2H),2.00(d,J=13.0Hz,2H),1.91-1.89(m,6H),1.78(s,2H),1.67(d,J=13.0Hz,2H),1.40(s,3H) ,1.38(s,3H).

Example 49: N-cyclohexyl-4-isopropyl-6-morpholinopyridazine-3-carboxamide (Compound 49)

a) 6-chloro-4-isopropylpyridazine-3-formyl chloride (compound 49a)

The experimental method was the same as the preparation of compound 1c in Example 1, except that compound 33c was used instead of compound 1b, and the obtained product was directly put into the next reaction.

b) N-cyclohexyl-6-chloro-4-isopropylpyridazine-3-carboxamide (compound 49b)

The experimental method was the same as the preparation of compound 1d in Example 1, except that compound 49a was used instead of compound 1c to obtain 150.2 mg of a yellow solid. Yield: 50%; Melting point: 116.4-118.4°C.

¹ H NMR (500MHz, CDCl ₃ ) δ7.80(d, J=6.5Hz, 1H), 7.54(s, 1H), 4.33-4.27(m, 1H), 3.98-3.91(m, 1H), 2.05- 2.01(m,2H),1.80-1.76(m,2H),1.68-1.64(m,1H),1.47-1.38(m,3H),1.36-1.31(m,2H),1.29(s,3H), 1.28(s,3H).

c) N-cyclohexyl-4-isopropyl-6-morpholine pyridazine-3-carboxamide (compound 49)

Put compound 49b (35mg, 0.12mmol) in a 5ml single-necked round bottom flask, add 1.2mL 1,4-dioxane, stir to dissolve, then add 63μL N,N-diisopropylethylamine (DIPEA) , morpholine (16 μL, 0.19 mmol), heated to reflux overnight. Stop the reaction, extract with ethyl acetate/water, wash the organic layer with saturated sodium chloride, dry over anhydrous magnesium sulfate, remove the organic solvent by rotary evaporation under reduced pressure, and separate and purify by silica gel column chromatography to obtain 14.6 mg of white solid. Yield: 35%; Melting point: 109.4-110.3°C.

¹ H NMR (500MHz, CDCl ₃ ) δ7.89(d, J=8.0Hz, 1H), 6.80(s, 1H), 4.34-4.29(m, 1H), 3.94-3.90(m, 1H), 3.86( t,J=4.5Hz,4H),3.70(t,J=5.0Hz,4H),2.02-1.99(m,2H),1.78-1.71(m,2H),1.66-1.62(m,1H),1.45 -1.37(m,3H),1.31-1.28(m,2H),1.26(s,3H),1.24(s,3H).

Example 50: N-cyclohexyl-4-isopropyl-6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide (Compound 50)

The experimental method was the same as the preparation of compound 49 in Example 49, except that N-methylpiperazine (21 μL, 0.19 mmol) was used instead of morpholine (16 μL, 0.19 mmol) to obtain 15.4 mg of a white solid. Yield: 34%; Melting point: 87.2-88.5°C.

¹ H NMR (500MHz, CDCl ₃ ) δ7.90(d, J=8.0Hz, 1H), 6.80(s, 1H), 4.33-4.28(m, 1H), 3.95-3.88(m, 1H), 3.76( t,J=5.0Hz,4H),2.57(t,J=5.0Hz,4H),2.37(s,3H),2.03-1.98(m,2H),1.78-1.74(m,2H),1.65-1.60 (m,1H), 1.45-1.36(m,3H), 1.31-1.26(m,2H), 1.25(s,3H), 1.24(s,3H).

Example 51: N-cyclohexyl-4-isopropyl-6-cyclopentylaminopyridazine-3-carboxamide (Compound 51)

The experimental method was the same as the preparation of compound 49 in Example 49, except that cyclopentylamine (23 μL, 0.24 mmol) was used instead of morpholine (16 μL, 0.19 mmol) to obtain 5.3 mg of a white solid. Yield: 10%; Melting point: 172.1-173.1°C.

¹ H NMR (500MHz, CDCl ₃ ) δ7.89 (d, J=8.0Hz, 1H), 6.55 (s, 1H), 4.89 (s, 1H), 4.30-4.23 (m, 2H), 3.94-3.86 ( m,1H),2.17-2.10(m,2H),2.01-1.98(m,2H),1.79-1.74(m,4H),1.70-1.67(m,1H),1.65-1.62(m,2H), 1.56-1.49 (m, 2H), 1.45-1.34 (m, 3H), 1.30-1.26 (m, 2H), 1.23 (s, 3H), 1.22 (s, 3H).

Example 52: N-Cyclohexyl-4-isopropyl-6-n-butylaminopyridazine-3-carboxamide (Compound 52)

The experimental method was the same as the preparation of compound 49 in Example 49, except that n-butylamine (17 μL, 0.17 mmol) was used instead of morpholine (16 μL, 0.19 mmol) to obtain 5.6 mg of a yellow solid. Yield: 16%; Melting point: 109.5-110.7°C.

¹ H NMR (500MHz, CDCl ₃ ) δ7.89(d, J=8.0Hz, 1H), 6.54(s, 1H), 4.81(s, 1H), 4.30-4.25(m, 1H), 3.94-3.86( m,1H),3.48-3.44(q,2H),2.01-1.98(m,2H),1.78-1.74(m,2H),1.70-1.64(m,2H),1.63-1.61(m,1H), 1.49-1.45(m,2H),1.43-1.33(m,3H),1.31-1.26(m,2H),1.23(s,3H),1.22(s,3H),0.98(t,J＝7.5Hz, 3H).

Example 53: N-Cyclohexyl-4-isopropyl-6-isobutylaminopyridazine-3-carboxamide (Compound 53)

The experimental method was the same as the preparation of compound 49 in Example 49, except that morpholine (16 μL, 0.19 mmol) was replaced by isobutylamine (25 μL, 0.25 mmol) to obtain 6.9 mg of a yellow solid. Yield: 9%; Melting point: 138.8-139.6°C.

¹ H NMR (500MHz, CDCl ₃ ) δ7.89(d, J=7.5Hz, 1H), 6.55(s, 1H), 4.94(s, 1H), 4.30-4.24(m, 1H), 3.93-3.86( m,1H),3.29(t,J＝6.5Hz,2H),2.01-1.95(m,3H),1.78-1.74(m,2H),1.64-1.61(m,1H),1.45-1.34(m, 3H), 1.30-1.26(m,2H), 1.23(s,3H), 1.22(s,3H), 1.02(s,3H), 1.00(s,3H).

Example 54: N-Cyclohexyl-4-isopropyl-6-((2-hydroxyethyl)amino)pyridazine-3-carboxamide (Compound 54)

The experimental method was the same as the preparation of compound 49 in Example 49, except that ethanolamine (14 μL, 0.24 mmol) was used instead of morpholine (16 μL, 0.19 mmol) to obtain 5.7 mg of a white solid. Yield: 12%; Melting point: 169.2-171.2°C.

¹ H NMR (500MHz, CDCl ₃ ) δ7.78(d, J=7.5Hz, 1H), 6.63(s, 1H), 5.46(s, 1H), 4.26-4.20(m, 1H), 3.92(t, J＝5.0Hz, 2H), 3.94-3.87(m, 1H), 3.71-3.68(q, 2H), 2.02-1.98(m, 2H), 1.78-1.74(m, 2H), 1.65-1.61(m, 1H), 1.48-1.36(m,3H), 1.31-1.26(m,2H), 1.23(s,3H), 1.21(s,3H).

Example 55: N-(Adamantan-1-yl)-4-isopropyl-6-morpholine pyridazine-3-carboxamide (Compound 55)

a) N-(adamantan-1-yl)-6-chloro-4-isopropylpyridazine-3-carboxamide (compound 55a)

The experimental method was the same as the preparation of compound 1d in Example 1, except that cyclohexylamine (0.12ml, 1.08mmol) was replaced by 1-adamantanamine (120.2mg, 0.80mmol) to obtain 57mg of a yellow solid. Yield: 32%; Melting point: 148.5-149.5°C.

¹ H NMR (500MHz, CDCl ₃ )δ7.60(s,1H),7.52(s,1H),4.27-4.22(m,1H),2.15(s,9H),1.76-1.70(m,6H), 1.29(s,3H),1.27(s,3H).

b) N-(adamantan-1-yl)-4-isopropyl-6-morpholine pyridazine-3-carboxamide (compound 55)

Compound 55a (45.2mg, 0.14mmol) was placed in a 5mL single-necked round bottom flask, 1.4mL 1,4-dioxane was added, magnetically stirred to dissolve, and 69μL N,N-diisopropylethylamine (DIPEA ), morpholine (18 μL, 0.20 mmol), heated to reflux overnight. Stop the reaction, extract with ethyl acetate/water, wash the organic layer with saturated sodium chloride, dry over anhydrous magnesium sulfate, remove the organic solvent by rotary evaporation under reduced pressure, and separate and purify by silica gel column chromatography to obtain 13.5 mg of white solid. Yield: 26%; Melting point: 156.6-158°C.

¹ H NMR (500MHz, CDCl ₃ )δ7.74(s,1H),6.79(s,1H),4.31-4.25(m,1H),3.86(t,J＝5Hz,4H),3.69(t,J =5.0Hz, 4H), 2.14-2.11(m, 9H), 1.75-1.69(m, 6H), 1.25(s, 3H), 1.23(s, 3H).

Example 56: N-(Adamantan-1-yl)-4-isopropyl-6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide (Compound 56)

The experimental method was the same as that of Compound 55 in Example 55, except that N-methylpiperazine (27 μL, 0.24 mmol) was used instead of morpholine (18 μL, 0.20 mmol) to obtain 17 mg of a white solid. Yield: 36%; Melting point: 158.3-159.2°C.

¹ H NMR (500MHz, CDCl ₃ )δ7.75(s,1H),6.79(s,1H),4.30-4.24(m,1H),3.74(t,J=5.0Hz,4H),2.55(t, J=5.0Hz, 4H), 2.36(s, 3H), 2.13-2.11(m, 9H), 1.75-1.68(m, 6H), 1.24(s, 3H), 1.23(s, 3H).

Example 57: N-(Adamantan-1-yl)-4-isopropyl-6-cyclopentylaminopyridazine-3-carboxamide (Compound 57)

The experimental method was the same as the preparation of compound 55 in Example 55, except that cyclopentylamine (19 μL, 0.24 mmol) was used instead of morpholine (18 μL, 0.20 mmol) to obtain 6.1 mg of a white solid. Yield: 12%; Melting point: 229.6-230.6°C.

¹ H NMR (500MHz, CDCl ₃ )δ7.73(s,1H),6.54(s,1H),4.27-4.21(m,2H),2.15-2.11(m,11H),1.78-1.68(m,10H ), 1.55-1.50(m,2H), 1.22(s,3H), 1.21(s,3H).

Example 58: N-(Adamantan-1-yl)-4-isopropyl-6-((2-hydroxyethyl)amino)pyridazine-3-carboxamide (Compound 58)

The experimental method was the same as the preparation of compound 55 in Example 55, except that ethanolamine (12 μL, 0.20 mmol) was used instead of morpholine (18 μL, 0.20 mmol) to obtain 6.1 mg of a yellow solid. Yield: 13%; Melting point: 82.4-83.2°C.

¹ H NMR (500MHz, CDCl ₃ )δ7.58(s,1H),6.61(s,1H),5.48(s,1H),4.22-4.17(m,1H),3.92-3.90(t,J=5.0 Hz, 2H), 3.70-3.67(m, 2H), 2.13-2.11(m, 9H), 1.75-1.68(m, 6H), 1.22(s, 3H), 1.21(s, 3H).

Example 59: N-(Adamantan-1-yl)-4-isopropyl-6-n-butylaminopyridazine-3-carboxamide (Compound 59)

The experimental method was the same as the preparation of compound 55 in Example 55, except that morpholine (18 μL, 0.20 mmol) was replaced by n-butylamine (29 μL, 0.30 mmol) to obtain 6 mg of white solid. Yield: 8%; Melting point: 77.2-73°C.

¹ H NMR (500MHz, CDCl ₃ )δ7.74(s,1H),6.53(s,1H),4.79(s,1H),4.27-4.21(m,1H),3.47-3.43(q,2H), 2.13-2.11(m,9H),1.75-1.69(m,6H),1.68-1.63(m,2H),1.49-1.41(m,2H),1.22(s,3H),1.21(s,3H), 0.97 (t, J=7.5Hz, 3H).

Example 60: N-(Adamantan-1-yl)-4-isopropyl-6-isobutylaminopyridazine-3-carboxamide (Compound 60)

The experimental method was the same as the preparation of compound 55 in Example 55, except that morpholine (18 μL, 0.20 mmol) was replaced by isobutylamine (19 μL, 0.19 mmol) to obtain 8.6 mg of white solid. Yield: 18%; Melting point: 141.2-142.2°C.

¹ H NMR (500MHz, CDCl ₃ )δ7.74(s,1H),6.53(s,1H),4.85(s,1H),4.27-4.21(m,1H),3.28(t,J=6.5Hz, 2H),2.13-2.11(m,9H),1.99-1.94(m,1H),1.75-1.68(m,6H),1.23(s,3H),1.21(s,3H),1.01(s,3H) ,1.00(s,3H).

Example 61: N-(Adamantan-2-yl)-4-isopropyl-6-morpholine pyridazine-3-carboxamide (Compound 61)

a) N-(adamantane-2-yl)-6-chloro-4-isopropylpyridazine-3-carboxamide (compound 61a)

The experimental method was the same as the preparation of compound 1d in Example 1, except that cyclohexylamine (0.12ml, 1.08mmol) was replaced by 2-adamantanamine (152mg, 0.81mmol) to obtain 38.4mg of white solid. Yield: 28%; Melting point: 118.5-120.0°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.31(d, J=7.0Hz, 1H), 7.55(s, 1H), 4.34-4.28(m, 1H), 4.25-4.23(m, 1H), 2.07( s,2H),1.94(d,J=14.0Hz,2H),1.91(s,6H),1.78(s,2H),1.70(d,J=12.5Hz,2H),1.30(s,3H), 1.29(s,3H).

b) N-(adamantane-2-yl)-4-isopropyl-6-morpholine pyridazine-3-carboxamide (compound 61)

Compound 61a (47.4mg, 0.14mmol) was placed in a 5ml single-necked round-bottom flask, 1.4mL 1,4-dioxane was added, magnetically stirred to dissolve, and 72μL N,N-diisopropylethylamine (DIPEA ), morpholine (19 μL, 0.21 mmol), heated to reflux overnight. Stop the reaction, extract with ethyl acetate/water, wash the organic layer with saturated sodium chloride, dry over anhydrous magnesium sulfate, remove the organic solvent by rotary evaporation under reduced pressure, and separate and purify by silica gel column chromatography to obtain 16.2 mg of white solid. Yield: 30%; Melting point: 180.6-181.7°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.36(d, J=8.0Hz, 1H), 6.81(s, 1H), 4.34-4.29(m, 1H), 4.22-4.21(m, 1H), 3.87( t,J=4.5Hz,4H),3.71(t,J=5.0Hz,4H),2.05(s,2H),1.98(d,J=13.0Hz,2H),1.89-1.86(m,6H), 1.77(s, 2H), 1.66(d, J=13.0Hz, 2H), 1.26(s, 3H), 1.25(s, 3H).

Example 62: N-(Adamantan-2-yl)-4-isopropyl-6-(piperidin-1-yl)pyridazine-3-carboxamide (Compound 62)

The experimental method was the same as that of Compound 61 in Example 61, except that piperidine (11 μL, 0.11 mmol) was used instead of morpholine (19 μL, 0.21 mmol) to obtain 11.3 mg of a yellow solid. Yield: 56%; Melting point: 175.4-176.9°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.39(d, J=8.0Hz, 1H), 6.80(s, 1H), 4.32-4.27(m, 1H), 4.22-4.20(m, 1H), 3.72( t,J=5.5Hz,4H),2.04(s,2H),1.99(d,J=13.0Hz,2H),1.89-1.85(m,6H),1.76(s,2H),1.72-1.66(m ,8H), 1.25(s,3H), 1.24(s,3H).

¹³ C NMR (CDCl ₃ , 125 MHz) δ164.33, 160.50, 150.94, 143.02, 108.75, 53.34, 46.00, 37.65, 37.27, 32.11, 31.99, 27.76, 27.30, 25.45, 24.55, 22.91.

Example 63: N-(Adamantan-2-yl)-4-isopropyl-6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide (Compound 63)

The experimental method was the same as the preparation of compound 61 in Example 61, except that N-methylpiperazine (32 μL, 0.29 mmol) was used instead of morpholine (19 μL, 0.21 mmol) to obtain 22.4 mg of a yellow solid. Yield: 29%; Melting point: 154.8-155.8°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.38(d, J=8.0Hz, 1H), 6.82(s, 1H), 4.33-4.28(m, 1H), 4.22-4.20(m, 1H), 3.77( t,J=5.0Hz,4H),2.57(t,J=5.0Hz,4H),2.37(s,3H),2.04(s,2H),1.98(d,J=12.5Hz,2H),1.89- 1.86 (m, 6H), 1.76 (s, 2H), 1.65 (d, J=12.5Hz, 2H), 1.26 (s, 3H), 1.24 (s, 3H).

Example 64: N-(Adamantan-2-yl)-4-isopropyl-6-cyclohexylaminopyridazine-3-carboxamide (Compound 64)

The experimental method was the same as the preparation of compound 61 in Example 61, except that cyclohexylamine (18 μL, 0.16 mmol) was used instead of morpholine (19 μL, 0.21 mmol) to obtain 19.9 mg of a yellow solid. Yield: 63%; Melting point: 189.4-190.7°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.33(d, J=8.0Hz, 1H), 6.52(s, 1H), 4.81-4.80(m, 1H), 4.27-4.22(m, 1H), 4.20- 4.18(m,1H),3.93-3.92(m,1H),2.11-2.08(m,2H),2.02(s,2H),1.97(d,J＝13.0Hz,2H),1.87-1.84(m, 6H), 1.79-1.76(m, 2H), 1.75(s, 2H), 1.68-1.67(m, 1H), 1.64(d, J=13.0Hz, 2H), 1.48-1.39(m, 2H), 1.29 -1.24(m,3H),1.21(s,3H),1.20(s,3H).

¹³ C NMR (CDCl ₃ , 125 MHz) δ164.33, 159.31, 151.14, 143.98, 110.39, 53.39, 49.95, 37.64, 37.27, 33.20, 32.09, 31.98, 27.56, 27.32, 25.65, 24.79, 22.79.

Example 65: N-(Adamantan 2-yl)-4-isopropyl-6-cyclopentylaminopyridazine-3-carboxamide (Compound 65)

The experimental method was the same as the preparation of compound 61 in Example 61, except that cyclopentylamine (11 μL, 0.11 mmol) was used instead of morpholine (19 μL, 0.21 mmol) to obtain 1.3 mg of a yellow solid. Yield: 6%; Melting point: 138.8-139.2°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.36(d, J=8.0Hz, 1H), 6.55(s, 1H), 4.81(d, J=6.0Hz, 1H), 4.30-4.26(m, 1H) ,4.21-4.19(m,1H),2.17-2.11(m,2H),2.04(s,2H),1.98(d,J＝13.0Hz,2H),1.89-1.86(m,6H),1.79-1.76 (m, 4H), 1.70-1.68 (m, 2H), 1.65 (d, J=13.0Hz, 2H), 1.54-1.50 (m, 2H), 1.23 (s, 3H), 1.22 (s, 3H).

Example 66: N-(Adamantan-2-yl)-4-isopropyl-6-cyclopropylaminopyridazine-3-carboxamide (Compound 66)

The experimental method was the same as the preparation of compound 61 in Example 61, except that cyclopropylamine (12 μL, 0.17 mmol) was used instead of morpholine (19 μL, 0.21 mmol) to obtain 24.8 mg of white solid. Yield: 82%; Melting point: 224.5-225.9°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.39(d, J=8.0Hz, 1H), 6.89(s, 1H), 6.00-5.96(m, 1H), 4.33-4.28(m, 1H), 4.20( d,J=8.0Hz,1H),2.66-2.62(m,1H),2.04(s,2H),1.97(d,J=13.0Hz,2H),1.90-1.86(m,6H),1.76(s , 2H), 1.65 (d, J=12.5Hz, 2H), 1.26 (s, 3H), 1.25 (s, 3H), 0.91-0.87 (m, 2H), 0.66-0.63 (m, 2H).

Example 67: N-(Adamantan-2-yl)-4-isopropyl-6-cyclopropylmethylaminopyridazine-3-carboxamide (Compound 67)

The experimental method was the same as the preparation of compound 61 in Example 61, except that morpholine (19 μL, 0.21 mmol) was replaced by cyclopropylmethylamine (18 μL, 0.21 mmol) to obtain 12.1 mg of white solid. Yield: 31%; Melting point: 138.3-139.5°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.38(d, J=8.0Hz, 1H), 8.59(s, 1H), 4.97(s, 1H), 4.30-4.25(m, 1H), 4.20(d, J＝8.5Hz, 1H), 3.36-3.34(m, 2H), 2.03(s, 2H), 1.98(d, J＝13.0Hz, 2H), 1.90-1.86(m, 6H), 1.76(s, 2H) ),1.65(d,J＝12.5Hz,2H),1.24(s,3H),1.22(s,3H),1.18-1.12(m,1H),0.62-0.58(m,2H),0.32-0.29( m,2H).

Example 68: N-(Adamantan-2-yl)-4-isopropyl-6-(piperidin-1-amino)pyridazine-3-carboxamide (Compound 68)

The experimental method was the same as the preparation of compound 61 in Example 61, except that morpholine (19 μL, 0.21 mmol) was replaced by 1-aminopiperidine (12 μL, 0.12 mmol) to obtain 18.1 mg of white solid. Yield: 79%; Melting point: 180.5-181.2°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.40(d, J=8.0Hz, 1H), 6.80(s, 1H), 4.32-4.26(m, 1H), 4.21(d, J=8.0Hz, 1H) ,3.72(t,J=5.5Hz,4H),2.05(s,2H),1.99(d,J=13.5Hz,2H),1.91-1.85(m,6H),1.76(s,2H),1.72- 1.69 (m, 7H), 1.64 (d, J=13.5Hz, 2H), 1.25 (s, 3H), 1.24 (s, 3H).

¹³ C NMR (CDCl ₃ , 125 MHz) δ164.33, 160.49, 150.94, 142.99, 108.75, 53.33, 45.99, 37.64, 37.27, 32.10, 31.98, 27.76, 27.31, 25.45, 24.55, 22.91.

Example 69: N-(Adamantan-2-yl)-4-isopropyl-6-morpholinopyridazine-3-carboxamide (Compound 69)

The experimental method was the same as the preparation of compound 61 in Example 61, except that N-aminomorpholine (11 μL, 0.12 mmol) was used instead of morpholine (19 μL, 0.21 mmol) to obtain 22.5 mg of white solid. Yield: 98%; Melting point: 181.7-182.9°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.36(d, J=8.0Hz, 1H), 6.81(s, 1H), 4.33-4.28(m, 1H), 4.21(d, J=8.0Hz, 1H) ,3.86(t,J=5.0Hz,4H),3.71(t,J=5.0Hz,4H),2.04(s,2H),1.97(d,J=13.0Hz,2H),1.90-1.86(m, 6H), 1.76(s, 2H), 1.72-1.70(m, 1H), 1.65(d, J=13.0Hz, 2H), 1.25(s, 3H), 1.24(s, 3H).

¹³ C NMR (CDCl ₃ , 125 MHz) δ164.05, 160.66, 151.36, 144.24, 108.98, 66.51, 53.41, 45.06, 37.60, 37.24, 32.06, 31.98, 27.82, 27.28, 27.25, 22.90.

Example 70: N-(Adamantan-2-yl)-4-isopropyl-6-n-butylaminopyridazine-3-carboxamide (Compound 70)

The experimental method was the same as the preparation of compound 61 in Example 61, except that morpholine (19 μL, 0.21 mmol) was replaced by n-butylamine (21 μL, 0.21 mmol) to obtain 15.7 mg of white solid. Yield: 41%; Melting point: 116.2-117.7°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.38(d, J=8.0Hz, 1H), 6.56(s, 1H), 4.89(s, 1H), 4.30-4.24(m, 1H), 4.20(d, J＝8.5Hz, 1H), 3.50-3.46(m, 2H), 2.03(s, 2H), 1.97(d, J＝13.0Hz, 2H), 1.88-1.86(m, 6H), 1.76(s, 2H ), 1.70-1.63 (m, 4H), 1.49-1.42 (m, 2H), 1.23 (s, 3H), 1.22 (s, 3H), 0.97 (t, J=7.5Hz, 3H).

Example 71: N-(Adamantan-2-yl)-4-isopropyl-6-((pentyl-3-yl)amino)pyridazine-3-carboxamide (Compound 71)

The experimental method was the same as the preparation of compound 61 in Example 61, except that morpholine (19 μL, 0.21 mmol) was replaced by 3-aminopentane (17 μL, 0.14 mmol) to obtain 10.3 mg of white solid. Yield: 37%; Melting point: 198.1-199.3°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.36(d, J=8.0Hz, 1H), 6.54(s, 1H), 4.70(s, 1H), 4.29-4.23(m, 1H), 4.20(d, J＝8.0Hz, 1H), 3.95-3.94(m, 1H), 2.03(s, 2H), 1.98(d, J＝13.0Hz, 2H), 1.88-1.86(m, 6H), 1.76(s, 2H ),1.72-1.68(m,2H),1.65(d,J＝12.5Hz,2H),1.58-1.52(m,2H),1.24(s,3H),1.22(s,3H),0.96(t, J=7.5Hz, 6H).

Example 72: N-(Adamantan-2-yl)-4-isopropyl-6-((3-methylbutyl)-2-yl)pyridazine-3-carboxamide (Compound 72)

The experimental method was the same as the preparation of compound 61 in Example 61, except that morpholine (19 μL, 0.21 mmol) was replaced by 1,2-methylpropylamine (12 μL, 0.11 mmol) to obtain 6.8 mg of white solid. Yield: 33%; Melting point: 167.2-168.7°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.36(d, J=8.0Hz, 1H), 6.54(s, 1H), 4.72(s, 1H), 4.29-4.24(m, 1H), 4.20(d, J＝8.5Hz, 1H), 4.04-4.01(m, 1H), 2.03(s, 2H), 1.98(d, J＝13.5Hz, 2H), 1.90-1.86(m, 7H), 1.76(s, 2H) ), 1.65 (d, J=12.5Hz, 2H), 1.24-1.21 (m, 9H), 1.01 (d, J=7.0Hz, 3H), 0.97 (d, J=7.0Hz, 3H).

Example 73: N-(Adamantan-2-yl)-4-isopropyl-6-((2-hydroxyethyl)amino)pyridazine-3-carboxamide (Compound 73)

The experimental method was the same as the preparation of compound 61 in Example 61, except that ethanolamine (15 μL, 0.25 mmol) was used instead of morpholine (19 μL, 0.21 mmol) to obtain 13.1 mg of a white solid. Yield: 29%; Melting point: 79.4-82°C.

¹ H NMR (500MHz, CDCl ₃ )δ8.19(s,1H),6.64(s,1H),5.90(s,1H),4.23-4.19(m,2H),3.93-3.91(m,2H), 3.67-3.65(m,2H),2.03(s,2H),1.97(d,J=13.0Hz,2H),1.88-1.86(m,6H),1.76(s,2H),1.66(d,J= 13.0Hz, 2H), 1.23(s, 3H), 1.21(s, 3H).

Example 74: N-(Adamantan-2-yl)-4-isopropyl-6-(3-chloroanilino)pyridazine-3-carboxamide (Compound 74)

Compound 61a (39mg, 0.12mmol) was placed in a 5mL single-necked round bottom flask, 1.2mL of acetonitrile was added, magnetically stirred to dissolve, and 61μL of N,N-diisopropylethylamine (DIPEA), m-chloroaniline (15μL, 0.14mmol), heated to reflux overnight, then gradually evaporated the solvent, and reacted without solvent at 160°C, monitored by TLC until the reaction was complete. Stop the reaction, add an appropriate amount of water to the residue after cooling and standing still, extract 3 times with ethyl acetate, combine the organic layers, wash with saturated sodium chloride, dry the organic layer with anhydrous magnesium sulfate, and remove the organic solvent by rotary evaporation under reduced pressure , separated and purified by silica gel column chromatography to obtain 9.5 mg of white solid. Yield: 19%; Melting point: 178.2-179°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.33(d, J=8.0Hz, 1H), 7.92(s, 1H), 7.52-7.51(m, 1H), 7.36-7.34(m, 1H), 7.30( t,J=7.5Hz,1H),7.11(d,J=8.0Hz,1H),7.08(s,1H),4.33-4.28(m,1H),4.24-4.23(m,1H),2.07(s ,2H),1.96(d,J=13.5Hz,2H),1.90(s,6H),1.78(s,2H),1.68(d,J=12.5Hz,2H),1.25(s,3H),1.23 (s,3H).

Example 75: N-Benzyl-4-isopropyl-6-anilinopyridazine-3-carboxamide (Compound 75)

The experimental method is the same as the preparation of compound 33 in Example 33, except that N-benzyl-6-chloro-4-isopropylpyridazine-3-carboxamide is used instead of N-benzyl-6-chloro-5-iso Propylpyridazine-3-carboxamide to obtain 11.0 mg of white solid. Yield: 37%; Melting point: 185.9-187.3°C.

¹ H NMR (500MHz, CDCl ₃ ) δ8.33(s, 1H), 7.38-7.32(m, 8H), 7.29(d, J=7Hz, 1H), 7.18-7.14(m, 1H), 7.05(s , 1H), 4.64 (d, J = 6Hz, 2H), 4.36-4.31 (m, 1H), 1.24 (d, J = 7Hz, 6H).

Example 76: Preparation of hydrochloride 61A, quaternary ammonium salt 61B and monohydrate 61C of compound 61

a) Preparation of the hydrochloride 61A of compound 61

Dissolve compound 61 (38.5mg, 0.1mmol) in anhydrous methanol (1mL) at room temperature, slowly add saturated methanolic hydrogen chloride solution (2mL) dropwise under ice bath, evaporate the solvent under reduced pressure, add diethyl ether with stirring, and precipitate The white solid was filtered and washed with ether to obtain 38.0 mg of the hydrochloride 61A of compound 61 as a white solid, yield: 90%.

ESI-MS: m/z 385.26[M ⁺ ]

b) Preparation of quaternary ammonium salt 61B of compound 61

Dissolve compound 61 (38.5mg, 0.1mmol) in absolute ethanol (1mL) at room temperature, add equivalents of sodium hydroxide, potassium iodide and methyl iodide, heat to reflux overnight, spin dry the solvent under reduced pressure, and use Purified by recrystallization from acetone, the quaternary ammonium salt 61B of compound 61 was obtained as a white solid 20 mg, yield: 38%.

ESI-MS: m/z 413.29[M ⁺ ]

c) Preparation of Monohydrate 61C of Compound 61

At room temperature, compound 61 (38.5 mg, 0.1 mmol) was dissolved in 1N HCl solution, and petroleum ether was slowly added dropwise under stirring until the solution became cloudy, and left at room temperature until no crystals were precipitated, and the monohydrate 61C of compound 61 was obtained by filtration .

Elem. Anal.: C, 65.64%; H, 8.51%; N, 13.92%; O, 11.92%.

According to the similar method described in this example, it can be used to prepare the pharmaceutically acceptable salt or hydrate of compound I of the present invention, including propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, Salts formed with organic acids such as malic acid, tartaric acid, and citric acid; or salts formed with inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, hydrofluoric acid, and hydrobromic acid; or quaternary ammonium salts formed with haloalkane, said haloalkane being Fluorine, chlorine, bromine or iodoalkanes.

Example 77: Pharmaceutical composition

Compound 61A 20g

Starch 140g

Microcrystalline Cellulose 60g

According to the conventional operation method, after the above-mentioned 3 kinds of substances are mixed physically, they are packed into gelatin capsules to obtain 1000 capsules.

Example 78: Pharmaceutical composition

Compound 61A 50g

Starch 400g

Microcrystalline Cellulose 200g

According to the conventional operation method, after the above-mentioned 3 kinds of substances are mixed physically, they are packed into gelatin capsules to obtain 1000 capsules.

Example 79: Example of Pharmacological Test——Calcium current assay

Activation of cannabinoid receptors leads to inhibition of intracellular calcium flow. However, after the G protein Gɑ16 was transferred, it showed the activation of intracellular calcium flow, and other physiological functions were not affected. By establishing cell lines co-transfected with CB1 and Gɑ16, CB2 and Gɑ16, the receptors are activated to activate the Gɑ16 protein, and then activate phospholipase C (PLC) to produce IP3 and DAG, and IP3 can bind to the endoplasmic reticulum in the cell Binding to the IP3 receptor, thereby causing the release of intracellular calcium. Therefore, measuring the change of intracellular calcium can be used as a method to detect the activation state of CB1 and CB2. Fluo-4/AM is a calcium fluorescent probe indicator used to measure calcium ions. As a non-polar fat-soluble compound, after entering the cell, under the action of cell lipolytic enzymes, the AM group dissociates and releases Fluo -4; Since Fluo-4 is a polar molecule, it is not easy to pass through the lipid bilayer membrane, so it can keep Fluo-4 in the cell for a long time. Finally, the activated level of Gɑ protein can be reflected by measuring the amount of excited photons. Based on this principle, a calcium flux screening model was established.

Experimental method: Cells were simultaneously transfected with human cannabinoid receptors (hCB1, hCB2) and Gɑ16, and stable transfected cell lines CHO-hCB1-Gɑ16 and CHO-hCB2-Gɑ16 were established by antibiotic selection. Appropriate concentration of CHO/CB2-Gɑ16 or CHO/CB1-Gɑ16 (about 20,000 cells/well) in the 96-well cell plate 24 hours before the test, so that the cells in each well are about 40,000-60,000 cells/well during the test. After culturing overnight, the culture medium was removed after the cells adhered to the wall, and incubated with 2 μmol/L fluo-4AM dye in a 37°C incubator for 50 minutes at a constant temperature. After aspirating excess dye, cells were washed once with Hanks' Balanced Salt Solution (HBSS) buffer. In the antagonistic mode, cells were incubated with HBSS buffer containing positive control or test compound or negative control containing DMSO for 10 minutes at room temperature, and 25 μL agonist was automatically added to the reaction system by the FlexStation detector to detect intracellular calcium ion flux in real time Changes in fluorescence intensity of the dye caused by the change. In the activation mode, the cells are incubated with HBSS buffer at room temperature for 10 minutes, and the HBSS buffer containing positive control or test compound or negative control DMSO is automatically added to the reaction system by the FlexStation detector to detect the change of intracellular calcium ion flow in real time The resulting change in the fluorescence intensity of the dye. The inhibitory rate or relative agonistic ratio value of the test compound can be obtained.

Inhibition rate=(peak calcium current of negative control-peak calcium current of test compound)/(peak calcium current of negative control-peak calcium current of positive control)×100%.

Relative agonism ratio=(peak calcium current of test compound-peak calcium current of negative control)/(peak calcium current of positive control-peak calcium current of negative control)×100%.

The half inhibitory concentration IC ₅₀ or the half effective dose EC ₅₀ of the compound was determined by the above method, which was mainly obtained by making a response rate and dose curve, and a total of 100μM, 10μM, 1μM, 100nM, 10nM, 1nM, 100pM, and 0 were selected. For each dose concentration, the calcium flow detection was carried out according to the above-mentioned experimental procedure, and each concentration was measured in parallel three times, that is, an 8-gradient 3-multiple well plate was used. Data were analyzed with GraphPad Prism software. The dose-dependent curve of the test compound was fitted by nonlinear regression method and IC ₅₀ or EC ₅₀ was calculated.

Table 1 In vitro activity data of pyridazine derivatives

Experimental results illustrate: the compound of the present invention generally shows higher calcium flux activity and good selectivity to human cannabinoid receptor CB2, in a word, the compound of the present invention is the specific agonist of cannabinoid receptor CB2, has better Drug development prospects.

Claims (8)

1. The pyridazine derivative and the pharmaceutically acceptable salt or hydrate thereof are characterized in that the structural general formula I is as follows:

wherein,

R₁selected from hydrogen atom, isopropyl;

R₂selected from cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, isoButyl, 1-adamantyl, 2-adamantyl, benzyl, 4-methylbenzyl, 4-fluorobenzyl, pyridine-3-methyl or 4-tetrahydropyranylmethyl;

r is selected from the following groups II or III:

wherein:

x is selected from O, S, N, CH₂、NCH₃；

R₃Is selected from C₂-C₄Straight or branched alkyl, hydroxy substituted C₂-C₄Straight chain alkyl, C₃-C₆Cycloalkyl radical, with C₃-C₆A cyclic alkyl group, a substituted or unsubstituted phenyl group, a six-membered heterocyclic group containing 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen.

2. The pyridazine derivative according to claim 1, wherein the pyridazine derivative is selected from the group consisting of:

(1) n-cyclohexyl-6-morpholinopyridazine-3-carboxamides

(2) N- (adamantan-1-yl) -6-morpholinopyridazine-3-carboxamide

(3) N- (adamantan-2-yl) -6-morpholinopyridazine-3-carboxamide

(4) N-benzyl-6-morpholinopyridazine-3-carboxamide

(5) N-benzyl-6-thiomorpholinopyridazine-3-carboxamide

(6) N-benzyl-6-diethylaminopyridazine-3-carboxamide

(7) N-benzyl-6- (piperidin-1-yl) pyridazine-3-carboxamides

(8) N- (4-methylbenzylamine) -6- (piperidin-1-yl) pyridazine-3-carboxamide

(9) N- (4-fluorobenzyl) -6- (piperidin-1-yl) pyridazine-3-carboxamide

(10) N- (pyridin-3-ylmethyl) -6- (piperidin-1-yl) pyridazine-3-carboxamide

(11) N-cyclohexyl-6- (piperidin-1-yl) pyridazine-3-carboxamides

(12) N-cyclohexylmethyl-6- (piperidin-1-yl) pyridazine-3-carboxamide

(13) N- ((tetrahydropyran-2H-4-yl) methyl) -6- (piperidin-1-yl) pyridazine-3-carboxamide

(14) N-cyclopropylmethyl-6- (piperidin-1-yl) pyridazine-3-carboxamide

(15) N-cyclobutylmethyl-6- (piperidin-1-yl) pyridazine-3-carboxamide

(16) N-isobutyl-6- (piperidin-1-yl) pyridazine-3-carboxamides

(17) N-benzyl-6-anilinopyridazine-3-carboxamides

(18) N-benzyl-6- (4-methoxyanilino) pyridazine-3-carboxamide

(19) N-benzyl-6- (2, 4-dichloroanilino) pyridazine-3-carboxamide

(20) N-benzyl-6- (3-chloroanilino) pyridazine-3-carboxamide

(21) N-benzyl-6- (4-chloroanilino) pyridazine-3-carboxamide

(22) N- (4-methylbenzyl) -6- (3-chloroanilino) pyridazine-3-carboxamide

(23) N- (4-fluorobenzyl) -6- (3-chloroanilino) pyridazine-3-carboxamide

(24) N- (pyridine-3-methyl) -6-anilinopyridazine-3-carboxamides

(25) N-cyclohexyl-6-anilinopyridazine-3-carboxamides

(26) N-cyclohexylmethyl-6- (3-chloroanilino) pyridazine-3-carboxamide

(27) N- ((tetrahydropyran-2H-4-yl) methyl) -6- (2, 4-dichloroanilino) pyridazine-3-carboxamide

(28) N-cyclopropylmethyl-6- (3-chloroanilino) pyridazine-3-carboxamide

(29) N-benzyl-6-cyclohexylaminopyridazine-3-carboxamide

(30) N-benzyl-6- (piperidine-1-amino) pyridazine-3-carboxamide

(31) N-benzyl-6-morpholinopyridazine-3-carboxamide

(32) N-benzyl-6-cyclopentylaminopyridazine-3-carboxamides

(33) N-benzyl-5-isopropyl-6-anilinopyridazine-3-carboxamide

(34) N- (pyridine-3-methyl) -5-isopropyl-6-anilinopyridazine-3-carboxamide

(35) N-cyclohexyl-5-isopropyl-6-morpholinopyridazine-3-carboxamide

(36) N- (adamantan-1-yl) -5-isopropyl-6-morpholinopyridazine-3-carboxamide

(37) N- (adamantan-2-yl) -5-isopropyl-6-morpholinopyridazine-3-carboxamide

(38) N- (adamantan-2-yl) -5-isopropyl-6- (piperidin-1-yl) pyridazine-3-carboxamide

(39) N- (adamantan-2-yl) -5-isopropyl-6-cyclohexylaminopyridazine-3-carboxamide

(40) N- (adamantan-2-yl) -5-isopropyl-6-cyclopentylaminopyridazine-3-carboxamide

(41) N- (adamantan-2-yl) -5-isopropyl-6-morpholinylaminopyridazine-3-carboxamide

(42) N- (adamantan-2-yl) -5-isopropyl-6- (piperidin-1-amino) pyridazine-3-carboxamide

(43) N- (adamantan-2-yl) -5-isopropyl-6-cyclopropylmethylaminopyridazine-3-carboxamide

(44) N- (adamantan-2-yl) -5-isopropyl-6-N-butylaminopyridazine-3-carboxamide

(45) N- (adamantan-2-yl) -5-isopropyl-6- ((pentyl-3-yl) amino) pyridazine-3-carboxamide

(46) N- (adamantan-2-yl) -5-isopropyl-6- ((3-methylbutyl-2-yl) pyridazine-3-carboxamide

(47) N- (adamantan-2-yl) -5-isopropyl-6- ((2-hydroxyethyl) amino) pyridazine-3-carboxamide

(48) N- (adamantan-2-yl) -5-isopropyl-6- (3-chloroanilino) pyridazine-3-carboxamide

(49) N-cyclohexyl-4-isopropyl-6-morpholinopyridazine-3-carboxamide

(50) N-cyclohexyl-4-isopropyl-6- (4-methylpiperazin-1-yl) pyridazine-3-carboxamide

(51) N-cyclohexyl-4-isopropyl-6-cyclopentylaminopyridazine-3-carboxamide

(52) N-cyclohexyl-4-isopropyl-6-N-butylaminopyridazine-3-carboxamide

(53) N-cyclohexyl-4-isopropyl-6-isobutylaminopyridazine-3-carboxamide

(54) N-cyclohexyl-4-isopropyl-6- ((2-hydroxyethyl) amino) pyridazine-3-carboxamide

(55) N- (adamantan-1-yl) -4-isopropyl-6-morpholinopyridazine-3-carboxamide

(56) N- (adamantan-1-yl) -4-isopropyl-6- (4-methylpiperazin-1-yl) pyridazine-3-carboxamide

(57) N- (adamantan-1-yl) -4-isopropyl-6-cyclopentylaminopyridazine-3-carboxamide

(58) N- (adamantan-1-yl) -4-isopropyl-6- ((2-hydroxyethyl) amino) pyridazine-3-carboxamide

(59) N- (adamantan-1-yl) -4-isopropyl-6-N-butylaminopyridazine-3-carboxamide

(60) N- (adamantan-1-yl) -4-isopropyl-6-isobutylaminopyridazine-3-carboxamide

(61) N- (adamantan-2-yl) -4-isopropyl-6-morpholinopyridazine-3-carboxamide

(62) N- (adamantan-2-yl) -4-isopropyl-6- (piperidin-1-yl) pyridazine-3-carboxamide

(63) N- (adamantan-2-yl) -4-isopropyl-6- (4-methylpiperazin-1-yl) pyridazine-3-carboxamide

(64) N- (adamantan-2-yl) -4-isopropyl-6-cyclohexylaminopyridazine-3-carboxamide

(65) N- (adamantane 2-yl) -4-isopropyl-6-cyclopentylaminopyridazine-3-carboxamide

(66) N- (adamantan-2-yl) -4-isopropyl-6-cyclopropylaminopyridazine-3-carboxamide

(67) N- (adamantan-2-yl) -4-isopropyl-6-cyclopropylmethylaminopyridazine-3-carboxamide

(68) N- (adamantan-2-yl) -4-isopropyl-6- (piperidin-1-amino) pyridazine-3-carboxamide

(69) N- (adamantan-2-yl) -4-isopropyl-6-morpholinylaminopyridazine-3-carboxamide

(70) N- (adamantan-2-yl) -4-isopropyl-6-N-butylaminopyridazine-3-carboxamide

(71) N- (adamantan-2-yl) -4-isopropyl-6- ((pentyl-3-yl) amino) pyridazine-3-carboxamide

(72) N- (adamantan-2-yl) -4-isopropyl-6- ((3-methylbutyl) -2-yl) pyridazine-3-carboxamide

(73) N- (adamantan-2-yl) -4-isopropyl-6- ((2-hydroxyethyl) amino) pyridazine-3-carboxamide

(74) N- (adamantan-2-yl) -4-isopropyl-6- (3-chloroanilino) pyridazine-3-carboxamide

(75) N-benzyl-4-isopropyl-6-anilinopyridazine-3-carboxamide

And pharmaceutically acceptable salts or hydrates of the above specific compounds.

3. The pyridazine derivative and the pharmaceutically acceptable salt or hydrate thereof according to claim 1, wherein the pharmaceutically acceptable salt is a salt formed by the compound represented by the general formula I and organic acids such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid and the like; or salts with inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, hydrofluoric acid, and hydrobromic acid; or a quaternary ammonium salt formed with a haloalkane, said haloalkane being a fluoro, chloro, bromo or iodo alkane.

4. The preparation method of the pyridazine derivative and the pharmaceutically acceptable salt or hydrate thereof according to claim 1, which is realized by the following steps:

(1) reacting the compound of the formula A with the compound of the formula B to generate a compound of the formula C;

(2) reacting the compound of the formula C with a compound of a formula D or a formula E to generate a compound of a formula I;

wherein R is₁、R₂、R₃And X is as defined in claim 1.

5. The process of claim 4, wherein the compound of formula a is prepared by:

the compound A-1 and the compound A-2 are condensed to obtain a compound A-3, in the presence of acetic acid, the compound A-3 and the compound A-4 are respectively obtained through the addition reaction and the elimination reaction of bromine, and the compound A is obtained through thionyl chloride chlorination,

wherein R is₁Is a hydrogen atom, R₂、R₃And X is as defined in claim 1.

6. The process of claim 4, wherein the compound of formula a is prepared by:

carrying out condensation reaction on a compound A-1 and a compound A-2 to obtain a compound A-3, respectively obtaining a compound A-3 and a-4 through addition and elimination reaction of bromine in the presence of acetic acid, esterifying the compound A-5 by using supersaturated ethanol solution of hydrogen chloride, obtaining a compound A-6 through chlorination of phosphorus oxychloride, substituting isobutyric acid on a pyridazine ring through reaction in the presence of concentrated sulfuric acid, silver nitrate and ammonium persulfate to obtain a compound A-7 through dark reaction, hydrolyzing the compound A-8 through lithium hydroxide, and finally obtaining the compound A through chlorination of thionyl chloride,

wherein R is₁Is isopropyl, R₂、R₃And X is as defined in claim 1.

7. The use of the pyridazine derivative according to claim 1and the pharmaceutically acceptable salt or hydrate thereof in the preparation of medicaments for treating, preventing and relieving diseases mediated by a CB2 receptor.

8. The use according to claim 7, wherein the disease is cancer, inflammation, acquired immunodeficiency syndrome, autoimmune disease, rheumatic disease, allergy, pain, acute and chronic liver disease, osteoporosis, atherosclerosis, multiple sclerosis, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, Huntington's disease.