Pyridazine compound as well as preparation method and application thereof

Abstract

The invention provides a pyridazine compound as shown in a formula (II) as well as a preparation method and application of the pyridazine compound. The invention also discloses application of the compound or the pharmaceutical composition thereof in preparation of drugs for preventing and / or treating TYK2-mediated diseases. # imgabs0 #

Description

A pyridazine compound, its preparation method and use Technical Field

[0001] The present invention belongs to the field of medicine and relates to a pyridazine compound, a preparation method and use thereof. Background Art

[0002] Psoriasis is an autoimmune disease, a chronic, recurrent, inflammatory skin disease mediated by the immune system. Its pathogenesis is complex and currently incurable. Traditional treatments for psoriasis mainly include topical treatments such as hydrotherapy, phototherapy, traditional Chinese medicine, salicylates, as well as glucocorticoids, immunosuppressants, and retinoids. Due to the significant efficacy of biologics (primarily TNF inhibitors and IL inhibitors) and PDE4 small molecule inhibitors in recent years, they have become the main treatments for psoriasis.

[0003] Tyrosine kinase 2 (TYK2) is a non-receptor tyrosine kinase belonging to the Janus kinase (JAK) family that plays a key role in the pathogenesis of psoriasis. Existing studies suggest that overactivation of parts of the adaptive immune system is central to the pathogenesis of psoriasis. During the pathogenesis of psoriasis, multiple immune cells and cytokines work together to promote downstream keratinocyte proliferation, increase angiogenesis, and promote the expression of endothelial adhesion molecules. Simultaneously, activated immune cells infiltrate the affected skin, ultimately leading to the development of psoriasis. Activation of the TH17 pathway mediated by the cytokine IL-23 is considered the primary pathway, and IL-23 signaling primarily mediates its effects intracellularly through the TYK2-JAK2 and STAT3 pathways. New TYK2 inhibitors can block receptor-stimulated TYK2 activation, thereby inhibiting TYK2-induced phosphorylation of STAT1 and STAT3, thereby suppressing the pathogenesis of psoriasis.

[0004] The present invention provides a class of pyridazine compounds, pharmaceutically acceptable salts thereof and isotopic derivatives thereof, preparation methods thereof, pharmaceutical compositions thereof and uses thereof in preventing and treating diseases associated with the TYK2 signaling pathway.

[0005] Summary of the Invention

[0006] The present invention provides a compound represented by general formula (II) or a pharmaceutically acceptable salt or isotopic derivative thereof,

[0007] Where R1 is -C 1-3 deuterated alkyl;

[0008] R2 is -C 3-6 Cycloalkyl, wherein the -C 3-6The cycloalkyl group is optionally further selected from a hydrogen atom, a -C 1-3 substituted by one or more substituents selected from alkyl and halogen;

[0009] R3 is -C 1-3 Alkyloxy or -C 3-6 Cycloalkyloxy, wherein the -C 1-3 Alkyloxy or -C 3-6 Cycloalkyloxy is optionally further selected from hydrogen atoms, deuterium atoms, -C 1-3 substituted by one or more substituents selected from alkyl and halogen;

[0010] R4 is a 5-6 membered heteroaryl group, wherein said 5-6 membered heteroaryl group is optionally replaced by R a replace;

[0011] R a -H, -CN, -CF3, -C 1-3 Alkyl, -C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, wherein the -C 1-3 Alkyl or -C 3-6 The cycloalkyl group is optionally further selected from a hydrogen atom, a -C 1-3 The alkyl group and the halogen group are substituted with one or more substituents.

[0012] In some embodiments of the present invention,

[0013] R1 is -CD3;

[0014] R2 is a substituted or unsubstituted cyclopropane group;

[0015] R3 is -OCF3, -O-CH2CF3, -OCHF2, -O-CH2CHF2, -OCH(CH3)2 or

[0016] In some embodiments of the present invention,

[0017] R4 is

[0018] R a It is -H, -CN, -CHF2, methyl, ethyl, trifluoromethyl, -CH(CH3)2 or cyclopropane.

[0019] In some embodiments of the present invention, R1 is -C 1-3 deuterated alkyl;

[0020] R2 is -C 3-6 Cycloalkyl, wherein the -C 3-6 The cycloalkyl group is optionally further selected from a hydrogen atom, a -C 1-3substituted by one or more substituents selected from alkyl and halogen;

[0021] R3 is -C 1-3 Alkyloxy or -C 3-6 Cycloalkyloxy, wherein the -C 1-3 Alkyloxy or -C 3-6 Cycloalkyloxy is optionally further selected from hydrogen atoms, deuterium atoms, -C 1-3 substituted by one or more substituents selected from alkyl and halogen;

[0022] R4 is a 5-6 membered heteroaryl group, wherein said 5-6 membered heteroaryl group is optionally replaced by R a replace;

[0023] R a -H, -CN, -CF3, -C 1-3 Alkyl, -C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, wherein the -C 1-3 Alkyl or -C 3-6 The cycloalkyl group is optionally further selected from a hydrogen atom, a -C 1-3 The alkyl group and the halogen group are substituted with one or more substituents.

[0024] In some embodiments of the present invention,

[0025] R1 is -CD3;

[0026] R2 is a substituted or unsubstituted cyclopropane group;

[0027] R3 is -OCF3, -O-CH2CF3, -OCHF2, -O-CH2CHF2, -OCH(CH3)2 or

[0028] In some embodiments of the present invention,

[0029] R4 is

[0030] R a It is -H, -CN, -CHF2, methyl, ethyl, trifluoromethyl, -CH(CH3)2 or cyclopropane.

[0031] In some embodiments of the present invention,

[0032] R1 is -C 1-3 deuterated alkyl;

[0033] R2 is -C 3-6 Cycloalkyl;

[0034] R3 is halogen-substituted C 1-3 alkoxy;

[0035] R4 is a 5-6 membered heteroaryl group, wherein said 5-6 membered heteroaryl group is optionally replaced by R a replace;

[0036] R a -H, -C 1-3 Alkyl, -C 1-3 Haloalkyl, -C 3-6 Cycloalkyl or 4-6 membered heterocyclic group.

[0037] In some embodiments of the present invention, R1 is -CD3;

[0038] R2 is cyclopropane;

[0039] R3 is -OCF3 or -OCHF2.

[0040] In some embodiments of the present invention,

[0041] R4 is optionally replaced by R a Substituted 5-membered heteroaryl groups containing 1, 2, 3 or 4 nitrogen heteroatoms.

[0042] In some embodiments of the present invention, R4 is

[0043] R a is -H, methyl, ethyl, trifluoromethyl or cyclopropane.

[0044] In some embodiments of the present invention, R1 is -C 1-3 deuterated alkyl;

[0045] R2 is -C 3-6 Cycloalkyl;

[0046] R3 is -C 1-3 Alkyloxy or -C 3-6 Cycloalkyloxy, wherein the -C 1-3 Alkyloxy or -C 3-6 Cycloalkyloxy is optionally further selected from hydrogen atoms, deuterium atoms, -C 1-3 substituted by one or more substituents selected from alkyl and halogen;

[0047] R4 is a 5-6 membered heteroaryl group, wherein said 5-6 membered heteroaryl group is optionally replaced by R a replace;

[0048] R a -H, -CN, -CF3, -C 1-3 Alkyl, -C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, wherein the -C 1-3 Alkyl or -C3-6 The cycloalkyl group is optionally further selected from a hydrogen atom, a -C 1-3 The alkyl group and the halogen group are substituted with one or more substituents.

[0049] In some embodiments of the present invention,

[0050] R1 is -CD3;

[0051] R2 is cyclopropane;

[0052] R3 is -OCF3, -O-CH2CF3, -OCHF2, -O-CH2CHF2, -OCH(CH3)2 or

[0053] In some embodiments of the present invention,

[0054] R4 is

[0055] R a It is -H, -CN, -CHF2, methyl, ethyl, trifluoromethyl, -CH(CH3)2 or cyclopropane.

[0056] In some embodiments of the present invention, the compound of the present invention or its pharmaceutically acceptable salt or isotopic derivative is selected from the following compounds or its pharmaceutically acceptable salt or isotopic derivative:

[0057] The present invention also provides a method for preparing the compound represented by general formula II, which can be Scheme 1 or Scheme 2.

[0058] Option 1:

[0059] Option 2:

[0060] Compound IIa is borated and reacted with R4X to obtain compound IId, or compound IIa is directly reacted with R4H to obtain compound IId;

[0061] Compound IId reacts with compound IIe to obtain compound IIf;

[0062] Compound IIf reacts with R2C(O)NH2 to obtain compound II;

[0063] wherein X is Br or I, and R1, R2, R3 and R4 are as described above.

[0064] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by Formula II and one or more pharmaceutically acceptable carriers and / or diluents.

[0065] The present invention also provides use of the compound represented by formula II or the pharmaceutical composition in preparing a drug for preventing and / or treating TYK2-mediated diseases.

[0066] In some embodiments of the present invention, the TYK2-mediated disease comprises an inflammatory disease or an autoimmune disease.

[0067] In some embodiments of the present invention, the inflammatory disease and autoimmune disease are psoriasis, inflammatory bowel disease or lupus erythematosus.

[0068] The present invention also provides a method for treating a TYK2-mediated disease, comprising administering a therapeutically effective amount of a compound represented by Formula II to a patient in need of such treatment.

[0069] Definition and Description

[0070] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0071] Unless otherwise indicated, conventional methods within the technical scope of the art, such as mass spectrometry, NMR and pharmacological methods, are adopted. Unless specifically defined, the terms used herein in the relevant descriptions of analytical chemistry, organic synthesis chemistry and medicine and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, preparation and delivery, and in the treatment of patients. For example, the instructions for use of the manufacturer's test kit can be utilized, or reaction and purification can be implemented according to a manner well known in the art or the description of the present invention. Conventionally, the above-mentioned techniques and methods can be implemented according to conventional methods well known in the art, based on the description of a plurality of summaries and more specific documents cited and discussed in this specification.

[0072] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a designated atom or group with the selection of a designated group, provided that the normal valence of the designated atom is not exceeded. When the substituent is an oxo or keto group (i.e., =O), then two hydrogen atoms on the atom are replaced.

[0073] Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.A stable compound or structure is one that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and subsequent formulation into an efficacious therapeutic agent.

[0074] In the present invention, "optional" or "optionally" means that the subsequently described event or situation may or may not occur, and the description includes both cases where the event or situation occurs and cases where it does not occur. "Optionally substituted" refers to a group having 0, 1, 2 or more substituents. It will be understood by those skilled in the art that for any group containing one or more substituents, these groups do not introduce any substitution or substitution pattern that is sterically impractical, synthetically unfeasible and / or inherently unstable. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.

[0075] The terms "comprising" or "including" may be open, semi-closed or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0076] Unless otherwise specified, the compounds herein encompass within their scope the compound, its pharmaceutically acceptable salts, and its isotopic derivatives. The compounds of the present invention also encompass within their scope stereoisomers, polymorphs, solvates, and prodrugs.

[0077] Unless specifically indicated, stereoisomers herein are intended to encompass within their scope tautomers, mesomers, racemates, enantiomers, diastereomers, and mixtures thereof.

[0078] The term "isotopic derivative" refers to a derivative of a compound in which one or more atoms are replaced by an isotope thereof (an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature). Examples of isotopes include, but are not limited to, isotopes of hydrogen (e.g. 2 H. 3 H), carbon isotopes (e.g. 11 C. 13 C and 14 C), isotopes of fluorine (e.g. 18 F), nitrogen isotopes (e.g. 13 N and 15 N), oxygen isotopes (e.g. 15 O. 17 O and 18 O). The compounds of the present invention include isotopic derivatives of the compounds of the present invention, for example, isotopic derivatives of compound 2

[0079] The term "alkyl" or "alkylene" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C 10 Alkyl (or alkylene) refers to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10Alkyl. In addition, for example, "C1-C6 alkyl" means an alkyl group having 1 to 6 carbon atoms. The alkyl group may be unsubstituted or substituted such that one or more of its hydrogen atoms are replaced by another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl (e.g., n-hexyl, isohexyl), and the like. The term "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. 1-3 The term "alkyl" refers to an alkyl group containing 1 to 3 carbon atoms, specifically methyl, ethyl, n-propyl and isopropyl.

[0080] The term "deuterated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by deuterium. 1-3 Deuterated alkyl refers to methyl, ethyl, n-propyl and isopropyl groups in which one or more hydrogen atoms are replaced by deuterium. For example, deuterated methyl groups include CD3, CHD2 and CH2D.

[0081] The term "halo" or "halogen" refers to chlorine, bromine, fluorine and iodine.

[0082] The term "haloalkyl" refers to a substituted alkyl group having one or more halogen substituents. For example, "fluoromethyl" includes CF3, CHF2, and CH2F.

[0083] The term "alkyloxy" refers to a substituent formed by linking an alkyl group as defined herein to an oxygen atom. 1-3 The alkoxy group refers to an alkoxy group containing 1 to 3 carbon atoms, for example, methoxy, ethoxy, propoxy and isopropoxy.

[0084] The terms "haloalkoxy" and "halogen-substituted alkoxy" have the same meaning and refer to an alkoxy group having one or more halogen substituents. For example, "fluoromethoxy" includes OCF 3、 OCHF 2、 OCH2F.

[0085] The term "cycloalkyl" refers to a cyclized alkyl group, including a monocyclic, bicyclic or polycyclic ring system, wherein the ring of the monocyclic, bicyclic or polycyclic ring system does not contain an aromatic ring. The cycloalkyl group can be independently unsubstituted or substituted with one or more substituents described herein.

[0086] C 3-6 Cycloalkyl refers to a cycloalkyl group containing 3 to 6 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The term "heterocycle" or "heterocyclyl" has the same meaning and refers to any ring structure (saturated, unsaturated or aromatic) containing at least one ring heteroatom (for example, a nitrogen atom, an oxygen atom or a sulfur atom). Heterocycle includes "aliphatic heterocycle" and "aromatic heterocycle".

[0087] In some embodiments of the present invention, the heterocyclic group is a 4-6 membered heterocyclic group, examples of which include, but are not limited to, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, isoquinolinyl, thiazolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, oxazolidinyl, oxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 5-oxadiazolyl, 1,5-oxadiazolyl, 1,6-oxadiazolyl, 1,7-oxadiazolyl, 1,8-oxadiazolyl, 2,3-oxadiazolyl, 2,4-oxadiazolyl, 2,5-oxadiazolyl, 2,6-oxadiazolyl, 2,7-oxadiazolyl, 2,8-oxadiazolyl, 2,9-oxadiazolyl, 3,4-oxadiazolyl, 3,5 ... 4H)-keto, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrazolyl, thienyl, tetrahydrothiophene, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetane, azetidine. The term "alicyclic" or "alicyclic group" has the same meaning and refers to a heterocyclic compound without aromatic character, for example, oxetane, azetidine, pyrrolidinyl, 2H-pyrrolyl, tetrahydrofuranyl.

[0088] The terms "aromatic heterocycle", "aromatic heterocyclic group", "heteroaromatic ring" or "heteroaromatic ring group" have the same meaning and refer to heterocyclic compounds with aromatic characteristics, including single heterocyclic aromatic groups and fused heterocyclic aromatic groups. The heteroatoms are independently selected from nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted. The nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., N→O and S(O) p , wherein p=1 or 2), the total number of sulfur and oxygen atoms in the aromatic heterocyclic ring does not exceed 1.

[0089] In some embodiments of the present invention, the monocyclic heteroaryl group can be a 5-6 membered heteroaryl group that can contain 1-4 heteroatoms, such as pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine and pyrimidine.

[0090] Typical 5- to 6-membered heteroaryl groups include, but are not limited to, 2- or 3-thienyl; 2- or 3-furyl; 2- or 3-pyrrolyl; 2-, 4-, or 5-imidazolyl; 3-, 4-, or 5-pyrazolyl; 2-, 4-, or 5-thiazolyl; 3-, 4-, or 5-isothiazolyl; 2-, 4-, or 5-oxazolyl; 3-, 4-, or 5-isoxazolyl; 3- or 5-1,2,4-triazolyl; 4- or 5-1,2,3-triazolyl; tetrazolyl; 2-, 3-, or 4-pyridyl; 3- or 4-pyridazinyl; 3-, 4-, or 5-pyrazinyl; 2-pyrazinyl; 2-, 4-, or 5-pyrimidinyl.

[0091] In some embodiments of the present invention, the fused heterocyclic aromatic group can be tricyclic or bicyclic, such as benzoxazole, benzodiazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine or indolizine.

[0092] The aromatic ring of the "heteroaryl" group may be substituted at one or more ring positions with substituents as described above, for example, halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, hydroxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, cyano, amino (including alkylamino, dialkylamino, The invention also includes but is not limited to alkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, mercapto, alkylthio, arylthio, hydroxythiocarbonyl, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclic, alkylaryl, or aromatic or heteroaromatic groups, wherein the aryl group can also be fused or bridged with non-aromatic alicyclic or heterocyclic rings to form polycyclic rings (for example, tetralin).

[0093] The terms "pharmaceutically acceptable salts" and "pharmaceutically acceptable salts" are used interchangeably and include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0094] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Examples of inorganic acid salts include hydrochlorides and hydrobromides; and examples of organic acid salts include formates and acetates.

[0095] When the compound of the present invention contains at least one nitrogen atom capable of forming a salt, it can be converted into a corresponding salt by reacting with a corresponding organic acid or inorganic acid in an organic solvent such as acetonitrile or tetrahydrofuran. Typical organic acids include formic acid and acetic acid, and typical inorganic acids include hydrochloric acid and hydrobromic acid.

[0096] The present invention also provides a pharmaceutical composition comprising at least one compound as described above and optionally one or more pharmaceutically acceptable carriers and / or diluents.

[0097] The pharmaceutical compositions provided by the present invention can be prepared in any form, such as granules, powders, tablets, coated tablets, capsules, pills, syrups, drops, solutions, suspensions and emulsions, or sustained-release preparations of the active ingredients, wherein examples of capsules include hard or soft gelatin capsules, and granules and powders can be non-effervescent or effervescent forms.

[0098] The pharmaceutical composition of the present invention may further include one or more pharmaceutically or physiologically acceptable carriers, which are suitably formulated for ease of administration. For example, the pharmaceutically or physiologically acceptable carrier may be one or more of saline, autoclaved water, Ringer's solution, buffered saline, glucose, alcohol, honey, mannitol, sorbitol, dextrin, lactose, caramel, gelatin, calcium sulfate, magnesium stearate, talc, kaolin, glycerol, Tween, agar, calcium carbonate, calcium bicarbonate, surfactants, cyclodextrin and its derivatives, phospholipids, phosphates, starch and its derivatives, silicon derivatives, cellulose and its derivatives, pyrrolidones, polyethylene glycols, acrylic resins, phthalates, acrylic acid copolymers, and trimellitic acid esters.

[0099] The pharmaceutical composition of the present invention may further include pharmaceutically or physiologically acceptable additives, such as diluents, lubricants, binders, glidants, disintegrants, sweeteners, flavoring agents, wetting agents, dispersants, surfactants, solvents, coating agents, foaming agents, or fragrances.

[0100] Examples of diluents that may be used include, but are not limited to, lactose, sucrose, starch, salt, mannitol, and dicalcium phosphate; examples of lubricants include, but are not limited to, talc, starch, magnesium or calcium stearate, lycopodium, and stearic acid; examples of binders include, but are not limited to, microcrystalline cellulose, tragacanth gum, glucose solution, acacia mucilage, gelatin solution, sucrose, and starch paste; examples of glidants include, but are not limited to, colloidal silicon dioxide; examples of disintegrants include, but are not limited to, cross-linked sodium carboxymethylcellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, and glutamic acid. Starch, bentonite, methylcellulose, agar and carboxymethylcellulose; examples of sweeteners include, but are not limited to, sucrose, lactose, mannitol and artificial sweeteners such as sodium cyclamate and saccharin, and any number of spray-dried flavors; examples of flavors include, but are not limited to, natural flavors extracted from plants, such as fruits, and flavorful compounds such as, but not limited to, mint and methyl salicylate; examples of wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.

[0101] The pharmaceutical composition of the present invention can be administered by various routes according to conventional methods, including oral, intravenous, intraarterial, intraperitoneal, intrathoracic, transdermal, nasal, inhalation, rectal, ocular and subcutaneous administration.

[0102] Pharmacological experiments have shown that the compounds or pharmaceutical compositions provided by the present invention can treat inflammatory diseases or autoimmune diseases through TYK2, such as psoriasis, inflammatory bowel disease or lupus erythematosus.

[0103] The general dosage range of the compounds provided by the present invention is about 0.05 mg / kg to 1000 mg / kg per day, preferably about 1 mg / kg to 100 mg / kg, and more preferably about 1 to 50 mg / kg. The dosage range of the pharmaceutical composition is calculated based on the amount of the above-mentioned compound contained therein. DETAILED DESCRIPTION

[0104] The present invention is further described by way of the following examples, which are illustrative and do not limit the present invention in any way. Any modifications or variations that are readily accomplished by one of ordinary skill in the art will fall within the scope of the present invention.

[0105] Preparation method of compound

[0106] Example 1

[0107] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (1)

[0108] Step 1: Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)aniline (1b)

[0109] 4-Bromo-2-(trifluoromethoxy)aniline (5.00 g, 19.5 mmol), bisborane (7.44 g, 29.3 mmol), potassium acetate (4.78 g, 48.7 mmol), and Pd(dppf)Cl2 (1.42 g, 1.95 mmol) were mixed in dioxane (100 mL) and refluxed at 110°C for 6 hours. The mixture was cooled and filtered, and the filtrate was concentrated and purified by silica gel column chromatography (0-20% EA / PE) to obtain the desired product, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)aniline (4.2 g, 71.0% yield).

[0110] LCMS [M+H] + =304.2.

[0111] Step 2 Synthesis of 4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(trifluoromethoxy)aniline (1d)

[0112] 1b (4.2 g, 13.9 mmol), 1c (2.24 g, 13.9 mmol), potassium carbonate (4.80 g, 34.8 mmol), and Pd(dppf)Cl2 (1.01 g, 1.39 mmol) were mixed in dioxane (100 mL) and water (12 mL). The mixture was heated to 110°C and refluxed for 8 hours. The mixture was cooled and filtered, and ethyl acetate was added to the filtrate. The layers were shaken and separated. The organic phase was dried, concentrated, and purified by silica gel column chromatography (0-100% EA / PE, 0-12% MeOH / DCM) to afford the desired product, 4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(trifluoromethoxy)aniline (2.3 g, 64.3% yield).

[0113] LCMS [M+H] + =259.2

[0114] Step 3 Synthesis of 6-chloro-N-(methyl-d3)-4-((4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (1f)

[0115] 1d (500 mg, 1.94 mmol) and 1e (524 mg, 2.52 mmol) were dissolved in anhydrous tetrahydrofuran (30 mL), cooled to 0°C, and LiHMDS (4.85 mL, 1 M in THF, 4.85 mmol) was slowly added dropwise. The mixture was stirred at 0°C for 1 hour. The mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (0-100% EA / PE, 0-12% MeOH / DCM) to afford the desired product, 6-chloro-N-(methyl-d3)-4-((4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (350 mg, 41.8% yield).

[0116] LCMS [M+H] + =431.2.

[0117] Step 4 Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (1)

[0118] 1f (350 mg, 0.81 mmol), cyclopropanamide (208 mg, 2.44 mmol), cesium carbonate (790 mg, 2.43 mmol), Pd2(dba)3 (222 mg, 0.24 mmol), and xantphos (280 mg, 0.48 mmol) were mixed in anhydrous dioxane (4 mL) under nitrogen atmosphere and heated to 120°C with stirring for 16 hours. The mixture was cooled, filtered, and the filtrate was concentrated and purified twice by silica gel column chromatography (0-100% EA / PE, 0-12% MeOH / DCM) to give the desired product, 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (80 mg, 20.6% yield).

[0119] LCMS [M+H] + =480.2.

[0120] 1 HNMR (400MHz, DMSO-d6) δ11.41(s,1H),11.11(s,1H),9.20(s,1H),8.57(s,1H),8.13(s,1H),8.01(dd,J=8. 4,1.9Hz,1H),7.98-7.95(m,1H),7.73(d,J=8.4Hz,1H),3.93(s,3H),2.11-2.00(m,1H),0.86-0.74(m,4H).

[0121] Example 2

[0122] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(2-methyl-tetrazol-5-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (2)

[0123] Referring to the synthesis method of Example 1, compound 2 can be obtained by replacing 1c with 5-bromo-2-methyl-tetrazolyl.

[0124] LCMS [M+H] + =481.2.

[0125] 1H NMR (400MHz, DMSO-d6) δ11.42(s,1H),11.27(s,1H),9.20(s,1H),8.21(s,1H),8.10(dd,J=8.5,1.9Hz,1H) ,8.04(q,J=1.6Hz,1H),7.83(d,J=8.4Hz,1H),4.43(s,3H),2.15–1.98(m,1H),0.81(dd,J=6.1,3.5Hz,4H).

[0126] Example 3

[0127] Synthesis of 6-(cyclopropanecarboxamido)-4-((4-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(trifluoromethoxy)phenyl)amino)-N-(methyl-d3)-pyridazine-3-carboxamide (3)

[0128] Referring to the synthesis method of Example 1, compound 3 can be obtained by replacing 1c with 3-bromo-1-cyclopropyl-1,2,4-triazole.

[0129] LCMS [M+H] + =506.2.

[0130] Example 4

[0131] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(5-methyl-2H-tetrazol-2-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (4)

[0132] Step 1: Synthesis of 4-(5-methyl-2H-tetrazol-2-yl)-2-(trifluoromethoxy)aniline (4b)

[0133] 1a (1.0 g, 3.90 mmol), 4a (656 mg, 7.80 mmol), cesium carbonate (3.17 g, 9.75 mmol), Pd2(dba)3 (892 mg, 0.98 mmol), and xantphos (1.13 g, 1.96 mmol) were mixed in anhydrous dioxane (20 mL) under nitrogen atmosphere. The mixture was heated to 120°C and stirred for 16 hours. The mixture was cooled and filtered, and the filtrate was concentrated and purified by silica gel column chromatography (0-100% EA / PE, 0-10% MeOH / DCM) to afford the desired product 4b (315 mg, 31.1% yield).

[0134] LCMS [M+H] + =260.2.

[0135] Step 2 Synthesis of 6-chloro-N-(methyl-d3)-4-((4-(5-methyl-2H-tetrazol-2-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (4c)

[0136] 1e (330 mg, 1.58 mmol) and 4b (315 mg, 1.22 mmol) were dissolved in anhydrous tetrahydrofuran (30 mL), cooled to 0°C, and LiHMDS (3.95 mL, 1 M in THF, 3.95 mmol) was slowly added dropwise. The mixture was stirred at 0°C for 1 hour. The mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (0-100% EA / PE, 0-12% MeOH / DCM) to afford the desired product 4c (234 mg, 44.5% yield).

[0137] [M+H] + =432.2.

[0138] Step 3 Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(5-methyl-2H-tetrazol-2-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (4)

[0139] 4c (234 mg, 0.54 mmol), cyclopropanamide (138 mg, 1.63 mmol), cesium carbonate (529 mg, 1.63 mmol), Pd2(dba)3 (146 mg, 0.16 mmol), and xantphos (185 mg, 0.32 mmol) were mixed in anhydrous dioxane (3 mL) under nitrogen atmosphere and heated to 120°C with stirring for 16 hours. The mixture was cooled and filtered, and the filtrate was concentrated and purified by silica gel column chromatography (0-100% EA / PE, 0-15% MeOH / DCM), followed by preparative HPLC to afford the desired product 4 (32 mg, 12.3% yield).

[0140] LCMS [M+H] + =481.2.

[0141] Example 5

[0142] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(1-methyl-1H-tetrazol-5-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (5)

[0143] Referring to the synthesis method of Example 1, compound 5 can be obtained by replacing 1c with 1-methyl-5-bromotetrazole.

[0144] LCMS [M+H] + =481.2.

[0145] 1 H NMR (400MHz, DMSO-d6) δ11.46(d,J=7.7Hz,2H),9.24(s,1H),8.30(s,1H),8.01(q,J=1.6Hz,1H),7.95 (dd,J=8.5,2.0Hz,1H),7.89(d,J=8.5Hz,1H),4.19(s,3H),2.12–2.03(m,1H),0.83(t,J=6.0Hz,4H).

[0146] Example 6

[0147] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(trifluoromethoxy)-4-(1-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (6)

[0148] Referring to the synthesis method of Example 1, compound 6 can be obtained by replacing 1c with 3-bromo-2-trifluoromethyl-1,2,4-triazole.

[0149] LCMS [M+H] + =534.2.

[0150] Example 7

[0151] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(difluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (7)

[0152] Referring to the synthesis method of Example 1, compound 7 can be obtained by replacing 1a with 2-(difluoromethoxy)-4-bromophenylamine.

[0153] LCMS [M+H] + =462.2.

[0154] 1 HNMR(400MHz,DMSO-d6)δ11.35(s,1H),10.9(s,1H),9.14(s,1H),8.56(s,1H),8.10(s,1H),7. 86-7.89(m,2H),7.61(d,1H),7.33(t,1H),3.92(s,3H),1.97-2.06(m,1H),0.79-1.02(m,4H).

[0155] Example 8

[0156] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(5-methyl-2H-tetrazol-2-yl)-2-(difluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (8)

[0157] Referring to the synthetic method of Example 4, compound 8 can be obtained by replacing 1a with 2-(difluoromethoxy)-4-bromophenylamine.

[0158] LCMS [M+H] + =463.2.

[0159] 1H NMR (400MHz, DMSO-d6) δ11.40(s,1H),11.05(s,1H),9.17(s,1H),8.15(s,1H),7.99(dq,J=5.0,2.4Hz, 2H),7.81(d,J=9.4Hz,1H),7.43(t,J=72.9Hz,1H),2.58(s,3H),2.12–2.01(m,1H),0.91–0.71(m,4H).

[0160] Example 9

[0161] Synthesis of 6-(cyclopropanecarboxamido)-4-((4-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(difluoromethoxy)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (9)

[0162] Referring to the synthetic method of Example 3, compound 9 can be obtained by replacing 1a with 2-(difluoromethoxy)-4-bromophenylamine.

[0163] LCMS [M+H] + =488.2.

[0164] Example 10

[0165] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(2-methyl-2H-tetrazol-5-yl)-2-(difluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (10)

[0166] Referring to the synthesis method of Example 2, compound 10 can be obtained by replacing 1a with 2-(difluoromethoxy)-4-bromophenylamine.

[0167] LCMS [M+H] + =463.2.

[0168] 1 HNMR(400MHz,DMSO-d6)δ11.38(s,1H),11.05(s,1H),9.15(s,1H),8.18(s,1H), 8.00-7.93(m,2H),7.74(d,1H),7.39(t,1H),4.43(s,3H),2.10-2.00(m,1H),0.82-0.79(m,4H).

[0169] Example 11

[0170] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(1-methyl-1H-tetrazol-5-yl)-2-(difluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (11)

[0171] Referring to the synthesis method of Example 5, compound 11 was obtained by replacing 1a with 2-(difluoromethoxy)-4-bromophenylamine.

[0172] LCMS [M+H] + =463.2.

[0173] Example 12

[0174] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(difluoromethoxy)-4-(1-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (12)

[0175] Referring to the synthesis method of Example 6, compound 12 can be obtained by replacing 1a with 2-(difluoromethoxy)-4-bromophenylamine.

[0176] LCMS [M+H] + =516.2.

[0177] Example 13

[0178] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(2-ethyl-tetrazol-5-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (13)

[0179] Referring to the synthesis method of Example 2, compound 13 can be obtained by replacing 1c with 5-bromo-2-ethyl-tetrazolyl.

[0180] LCMS [M+H] + =495.2.

[0181] 1 H NMR (400MHz, DMSO-d6) δ11.44(s,1H),11.26(s,1H),9.21(s,1H),8.20(s,1H),8.10(dd,J=8.4,1.7Hz,1H),8.05( s,1H),7.83(d,J=8.5Hz,1H),4.76(q,J=7.3Hz,2H),2.10–2.02(m,1H),1.56(t,J=7.3Hz,3H),0.85–0.77(m,4H).

[0182] Example 14

[0183] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(5-ethyl-2H-tetrazol-2-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (14)

[0184] Referring to the synthesis method of Example 4, compound 14 can be obtained by replacing 2-methyl-tetrazolyl with 2-ethyl-tetrazolyl.

[0185] LCMS [M+H] + =495.2.

[0186] Example 15

[0187] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(1-ethyl-1H-tetrazol-5-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (15)

[0188] Referring to the synthesis method of Example 5, compound 15 can be obtained by replacing 1-methyl-5-bromotetrazole with 1-ethyl-5-bromotetrazole.

[0189] LCMS [M+H] + =495.2.

[0190] 1 H NMR (400MHz, DMSO-d6) δ11.48(s,1H),11.45(s,1H),9.25(s,1H),8.29(s,1H),7.96(s,1H),7. 88(s,2H),4.51(q,J=7.2Hz,2H),2.11–2.05(m,1H),1.45(t,J=7.3Hz,3H),0.89–0.77(m,4H).

[0191] Example 16

[0192] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(5-ethyl-2H-tetrazol-2-yl)-2-(difluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (16)

[0193] Referring to the synthesis method of Example 8, compound 16 can be obtained by replacing 5-methyltetrazolyl with 5-ethyltetrazolyl.

[0194] LCMS [M+H] + =477.2.

[0195] 1 H NMR (400MHz, DMSO-d6) δ11.40(s,1H),11.05(s,1H),9.17(s,1H),8.15(s,1H),8.00(dq,J=5.4,2.3Hz,2H),7.81(d,J= 9.4Hz,1H),7.43(t,J=72.8Hz,1H),2.97(q,J=7.6Hz,2H),2.15–1.89(m,1H),1.34(t,J=7.6Hz,3H),0.91–0.67(m,4H).

[0196] Example 17

[0197] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(2-ethyl-2H-tetrazol-5-yl)-2-(difluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (17)

[0198] Referring to the synthesis method of Example 10, Compound 17 can be obtained by replacing 2-methyl-5-bromo-tetrazole with 2-ethyl-5-bromo-tetrazole.

[0199] LCMS [M+H] + =477.3.

[0200] 1 HNMR(400MHz,DMSO-d6)δ11.41(s,1H),11.07(s,1H),9.18(s,1H),8.21(s,1H),8.00-7.94(m,2H) ,7.77-7.54(m,1H),7.41(t,1H),4.82(q,2H),2.15-2.08(m,1H),1.59(t,3H),0.82-0.62(m,4H).

[0201] Example 18

[0202] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(1-ethyl-1H-tetrazol-5-yl)-2-(difluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (18)

[0203] Referring to the synthetic method of Example 15, compound 18 can be obtained by replacing 1a with 2-(difluoromethoxy)-4-bromophenylamine.

[0204] LCMS [M+H] + =477.3.

[0205] 1 HNMR(400MHz,DMSO-d6)δ11.42(s,1H),11.22(s,1H),9.19(s,1H),8.26(s,1H),7.81-7.74 (m,2H),7.54-7.18(t,2H),4.52(q,2H),2.10-2.06(m,1H),1.45(t,3H),0.84-0.80(m,4H).

[0206] Example 19

[0207] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(difluoromethoxy)-4-(2-(trifluoromethyl)-tetrazol-5-yl)phenyl)amino)pyridazine-3-carboxamide (19)

[0208] Referring to the synthesis method of Example 12, Compound 19 was obtained by replacing 3-bromo-2-trifluoromethyl-1,2,4-triazole with 2-(trifluoromethyl)-5-bromotetrazole.

[0209] LCMS [M+H] + =517.2

[0210] Example 20

[0211] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-isopropoxy-4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (20)

[0212] Step 1 Synthesis of 2-isopropoxy-4-bromonitrobenzene (20b)

[0213] To a three-necked flask, add isopropanol (4.2 g, 70 mmol) and THF (180 ml) sequentially. Under an ice-water bath, replace the atmosphere with nitrogen, then add NaH (3.0 g, 75 mmol). Stir under an ice-water bath for 10 min, and then dropwise add compound 20a (10.95 g, 50 mmol) in THF (20 ml). The reaction mixture is allowed to react overnight at room temperature. The reaction mixture is saturated with NH4Cl and extracted with EA. The combined organic phases are dried over anhydrous Na2SO4, filtered, and concentrated. The residue is purified by SiO2 column chromatography (PE / EA = 2%) to afford compound 20b (7.2 g).

[0214] LCMS [M+H] + =261.2.

[0215] Step 2 Synthesis of 2-isopropoxy-4-(1-isopropyl-1H-pyrazol-4-yl)nitrobenzene (20f)

[0216] To a single-necked flask, compound 20b (2.6 g, 10 mmol), 20c (3.04 g, 12 mmol), Pd(dppf)Cl2 (731 mg, 1 mmol), KOAc (1.56 g, 20 mmol), and 1,4-dioxane (100 ml) were added sequentially. The atmosphere was replaced with N2 three times at room temperature, and the reaction mixture was allowed to react at 100°C for 2 hours. After cooling, 20e (2.07 g, 11 mmol), K2CO3 (3.0 g, 20 mmol), and H2O (40 mL) were added to the mother liquor. The atmosphere was replaced with N2 three times at room temperature, and the reaction mixture was allowed to react at 110°C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with EA. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by SiO2 column chromatography (PE / (EA:EtOH=3:1) = 2-30%) to afford compound 20f (2.6 g) as an oil.

[0217] LCMS [M+H] + =290.2

[0218] Step 3 Synthesis of 2-isopropoxy-4-(1-isopropyl-1H-pyrazol-4-yl)aniline (20 g)

[0219] To a single-necked flask, compound 20f (2.6 g, 8.99 mmol), Fe (2.5 g, 45 mmol), saturated aqueous ammonium chloride (5 ml), and EtOH (30 mL) were added in sequence. The reaction mixture was reacted at 80°C for 1 hour. Filtered and concentrated. The residue was purified with SiO2 (DCM / MeOH = 2 to 5%) to afford compound 20g (2.2 g) as a brown oil.

[0220] LCMS [M+H] + =260.2.

[0221] Step 4 Synthesis of N-(methyl-d3)-4-((2-isopropoxy-4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)amino)-6-chloro-pyridazine-3-carboxamide (20h)

[0222] To a three-necked flask, compound 20g (388 mg, 1.5 mmol), 1e (407 mg, 1.95 mmol), and THF (30 mL) were added sequentially. The atmosphere was replaced with nitrogen three times at room temperature, and LiHDMS (4.5 ml, 4.5 mmol) was added. The reaction mixture was allowed to react at room temperature for 3 h. Water was added, and the mixture was extracted with EA, dried, filtered, and concentrated. The residue was purified by SiO2 column chromatography (PE / (EA:EtOH=3:1)=5-10%) to afford compound 20h (370 mg).

[0223] LCMS [M+H] + =432.3.

[0224] Step 5 Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-isopropoxy-4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (20)

[0225] To a single-necked flask, compound 20h (200 mg, 0.46 mmol), cyclopropaneamide (79 mg, 0.92 mmol), 1,4-dioxane (5 mL), Pd(OAc)2 (10 mg, 0.046 mmol), Xantphos (53 mg, 0.092 mmol), and Cs2CO3 (373 g, 1.15 mmol) were added sequentially. The mixture was replaced with nitrogen three times at room temperature and the reaction mixture was allowed to react at 110°C for 3 h. DCM / MeOH = 10:1 was added, the mixture was filtered through NaSO4, and the mixture was concentrated. The residue was purified with SiO2 (PE / (EA:EtOH=3:1) = 5-40% to DCM / MeOH = 2%) to give compound 20 (68 mg).

[0226] LCMS [M+H] + =481.3.

[0227] 1H NMR (400MHz, DMSO-d6) δ11.22(s,1H),10.66(s,1H),9.02(s,1H),8.26(d,J=0.8Hz,1H),8.03(s,1H),7.89(d,J=0.8Hz,1H),7.37–7.28(m,2H),7.2 0(dd,J=8.1,1.8Hz,1H),4.75–4.66(m,1H),4.52–4.41(m,1H),2.11–2.0 1(m,1H),1.43(d,J=6.7Hz,6H),1.24(d,J=6.0Hz,6H),0.87–0.73(m,4H).

[0228] Example 21

[0229] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-isopropoxy-4-(1-ethyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (21)

[0230] Referring to the synthetic method of Example 20, Compound 21 can be obtained by replacing 1-isopropyl-4-bromo-1H-pyrazole with 1-ethyl-4-bromo-1H-pyrazole.

[0231] LCMS [M+H] + =467.3.

[0232] 1 H NMR (400MHz, DMSO-d6) δ11.25(s,1H),10.68(s,1H),9.05(s,1H),8.25(s,1H),8.05(s,1H),7.92(s,1H),7.35–7.33(m,2H),7.22–7. 19(m,1H),4.75–7.69(m,1H),4.17–4.12(m,2H),2.09–2.04(m,1H),1.41(t,J=8.0Hz,3H),1.26(d,J=4.0Hz,6H),0.84–0.78(m,4H).

[0233] Example 22

[0234] 6-(Cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(2,2,2-trifluoroethoxy)-4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide

[0235] Referring to the synthesis method of Example 20, Compound 22 can be obtained by replacing isopropanol with 2,2,2-trifluoroethanol.

[0236] MS m / z(ESI):521.3[M+H] + .

[0237] 1 H NMR(400MHz,DMSO-d6)δ11.23(s,1H),10.56(s,1H),9.03(s,1H),8.28(s,1 H),7.93(s,1H),7.86(s,1H),7.48(d,J=1.6Hz,1H),7.35(d,J=8.2Hz,1H), 7.31(dd,J=8.2,1.6Hz,1H),4.83(q,J=8.7Hz,2H),4.49(p,J=6.6Hz,1H),2 .04(ddd,J=12.4,7.7,4.9Hz,1H),1.44(d,J=6.7Hz,6H),0.82–0.72(m,4H).

[0238] Example 23

[0239] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-isopropoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (23)

[0240] Referring to the synthetic method of Example 20, Compound 23 can be obtained by replacing 1-isopropyl-4-bromo-1H-pyrazole with 1-methyl-4-bromo-1H-pyrazole.

[0241] LCMS: 453.3 (M+1)

[0242] 1 H NMR (400MHz, DMSO-d6) δ11.23(s,1H),10.66(s,1H),9.03(s,1H),8.17(s,1H),8.03(s,1H),7.89(d,J=0.8Hz,1H),7.36–7.25(m,2H),7. 18(dd,J=8.2,1.9Hz,1H),4.69(hept,J=6.2Hz,1H),3.84(s,3H),2.05(qd,J=7.4,5.0Hz,1H),1.24(d,J=6.0Hz,6H),0.87–0.71(m,4H).

[0243] Example 24

[0244] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-isopropoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (24)

[0245] Referring to the synthetic method of Example 20, Compound 24 can be obtained by replacing 1-isopropyl-4-bromo-1H-pyrazole with 1-methyl-4-bromo-1H-1,2,4-triazole.

[0246] LCMS: 454.3 (M+1)

[0247] 1 H NMR (400MHz, DMSO-d6) δ11.27(s,1H),10.80(s,1H),9.06(s,1H),8.50(s,1H),8.13(s,1H),7.64(d,J=1.7Hz,1H),7.58(dd,J=8.3,1 .7Hz,1H),7.45(d,J=8.2Hz,1H),4.65(hept,J=6.1Hz,1H),3.91(s,3H),2.11–1.99(m,1H),1.28(d,J=6.0Hz,6H),0.87–0.73(m,4H).

[0248] Example 25

[0249] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-isopropoxy-4-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (25)

[0250] Referring to the synthetic method of Example 20, Compound 25 can be obtained by replacing 1-isopropyl-4-bromo-1H-pyrazole with 1-cyclopropyl-4-bromo-1H-1,2,4-triazole.

[0251] LCMS (ESI-MS) m / z: 480.3 (M+H+).

[0252] 1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),10.80(s,1H),9.06(s,1H),8.62(s,1H), 8.13(s,1H),7.64(d,J=1.7Hz,1H),7.58(dd,J=8.2,1.7Hz,1H),7.45(d,J=8.2Hz,1H),4.66(p,J=6.0Hz,1H),3.8 5–3.75(m,1H),2.10–2.00(m,1H),1.28(d,J=6.0Hz,6H),1.17–1.11(m,2H),1.07–1.00(m,2H),0.82–0.77(m,4H).

[0253] Example 26

[0254] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-isopropoxy-4-(5-cyanopyridin-2-yl)phenyl)amino)pyridazine-3-carboxamide (26)

[0255] Referring to the synthetic method of Example 20, Compound 26 can be obtained by replacing 1-isopropyl-4-bromo-1H-pyrazole with 2-bromo-5-cyanopyridine.

[0256] LCMS (ESI-MS) m / z: 475.3 (M+H + ).

[0257] 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),11.05(s,1H),9.16–8.99(m,2H),8.38–8.21(m,3H),7.93(d,J=1.9Hz,1H),7.83(dd,J=8.4, 1.9Hz,1H),7.56(d,J=8.4Hz,1H),4.92–4.56(m,1H),2.07(ddd,J=7.4,4.2,1.9Hz,1H),1.31(d,J=6.0Hz,6H),0.91–0.72(m,4H).

[0258] Example 27

[0259] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-cyclopropyloxy-4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (27)

[0260] Referring to the synthetic method of Example 20, Compound 27 can be obtained by replacing isopropanol with cyclopropanol.

[0261] MS m / z(ESI):479.3[M+H] + .

[0262] 1 H NMR (400MHz, DMSO-d6) δ11.22(s,1H),10.50(s,1H),9.03(s,1H),8.25(d,J=0.8Hz, 1H),7.90–7.86(m,2H),7.55(d,J=1.8Hz,1H),7.34–7.20(m,2H),4.49(m,1H),3.98 (tt,J=6.0,2.9Hz,1H),2.05(ddd,J=12.4,7.6,4.8Hz,1H),1.44(d,J=6.6Hz,6H),0.84–0.74(m,6H),0.65–0.58(m,2H).

[0263] Example 28

[0264] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(2,2-difluoroethoxy)-4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (28)

[0265] The first step is the synthesis of compound 4-bromo-2-(2,2-difluoroethoxy)-1-nitrobenzene (28b)

[0266] Compound 28a (9.0 g, 41.3 mmol) was dissolved in DMF (165 mL), and CsCO (26.8 g, 82.6 mmol) and 1,1-difluoro-2-iodoethane (9.5 g, 49.5 mmol) were added sequentially. The reaction mixture was reacted at 110°C under N2 protection for 7 hours. LCMS showed some residual starting material. The reaction mixture was quenched by pouring into ice water (300 mL). The precipitated solid was filtered, the filter cake was washed with water, and the solid was collected and dried to obtain compound 28b (7.2 g, 61.8% yield).

[0267] LCMS (ESI-MS) m / z: 282.0 (M+H + ).

[0268] Step 2: Synthesis of compound 4-[3-(2,2-difluoroethoxy)-4-nitrophenyl]-1-(isopropyl)-1H-pyrazole (28d)

[0269] Compound 28b (1.5 g, 5.3 mmol) was dissolved in 1,4-dioxane / H₂O (20 mL / 4 mL), and compound 28c (1.51 g, 6.4 mmol), Pd(dppf)Cl₂ (387 mg, 0.53 mmol), and Cs₂CO₃ (5.2 g, 15.9 mmol) were added. The reaction mixture was incubated at 90°C under nitrogen for 4 hours. LCMS confirmed the complete reaction. The reaction mixture was cooled to room temperature, water (100 mL) was added, and extracted with EA (80 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (EA / PE = 0-35%) to afford compound 28d (1.4 g, 84.8% yield).

[0270] LCMS (ESI-MS) m / z: 312.2 (M+H + ).

[0271] Step 3: Synthesis of compound 2-(2,2-difluoroethoxy)-4-[1-(isopropyl)-1H-pyrazol-4-yl]aniline (28e)

[0272] Compound 28d (1.3 g, 4.2 mmol) was dissolved in THF (20 mL) and 10% Pd / C (500 mg) was added. The reaction was allowed to react at room temperature overnight under H₂ protection. LCMS indicated the reaction was complete. The reaction solution was filtered through Celite and rinsed with THF (20 mL). The filtrate was concentrated under reduced pressure to afford compound 28e (1.1 g, 98% yield), which was used directly in the next step.

[0273] LCMS (ESI-MS) m / z: 282.2 (M+H + ).

[0274] Step 4: Synthesis of compound 6-chloro-4-((4-[1-(isopropyl)-1H-pyrazole)-2-(2,2-difluoroethoxy)phenyl]amino)-N-(methyl-d3)pyridazine-3-carboxamide (28f)

[0275] Compound 28e (0.9 g, 3.2 mmol) and compound 1e (0.67 g, 3.2 mmol) were dissolved in THF (15 mL) and LiHMDS (9.6 mL, 9.6 mmol) was added at room temperature. The reaction was allowed to react at room temperature for 30 min. LCMS indicated the reaction was complete. The reaction solution was poured into ice water (80 mL), and a solid precipitated. The solid was washed twice with water, collected, and dried to afford compound 28f (1.0 g, 69% yield).

[0276] LCMS (ESI-MS) m / z: 454.2 (M+H + ).

[0277] Step 5 Synthesis of 6-(cyclopropanecarboxamide)-4-((4-[1-(isopropyl)-1H-pyrazole)-2-(2,2-difluoroethoxy)phenyl]amino)-N-(methyl-d3)pyridazine-3-carboxamide (28)

[0278] Compound 28f (400 mg, 0.88 mmol), cyclopropanamide (150 mg, 1.76 mmol), dppf (98 mg, 0.176 mmol), K₃PO₄ (560 mg, 2.64 mmol), and 1,4-dioxane (10 mL) were added to a reaction flask. After evacuating the flask and replacing it with nitrogen, Pd₂(dba)₃ (81 mg, 0.088 mmol) was added. After evacuating the flask again and replacing it with nitrogen, the flask was placed in a 90°C oil bath and allowed to react for 5 hours. LCMS indicated the reaction was complete. The reaction mixture was cooled to room temperature, water (80 mL) was added, and extraction with EA (50 mL x 2) was performed. The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by Prep-HPLC to yield compound 28 (79 mg, 17.8% yield).

[0279] LCMS (ESI-MS) m / z: 503.3 (M+H + ).

[0280] 1 H NMR (400MHz, DMSO-d6) δ11.23(s,1H),10.58(s,1H),9.04(s,1H),8.30(s,1H),7.91(d,J=15.0Hz,2H),7.42(s,1H), 7.37–7.22(m,2H),6.28(t,J=54.8Hz,1H),4.56–4.34(m,3H),2.05(s,1H),1.44(d,J=6.7Hz,6H),0.86–0.68(m,4H).

[0281] Example 29

[0282] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(2,2-difluoroethoxy)-4-(5-cyanopyridin-2-yl)phenyl)amino)pyridazine-3-carboxamide (29)

[0283] Referring to the synthesis method of Example 26, compound 29 can be obtained by replacing 20b with 28b.

[0284] LCMS (ESI-MS) m / z: 497.3 (M+H + ).

[0285] 1 H NMR (400MHz, DMSO-d6) δ11.33(s,1H),10.96(s,1H),9.10(s,1H),9.06(d,J= 2.1Hz,1H),8.38(dd,J=8.4,2.2Hz,1H),8.29(d,J=8.4Hz,1H),8.16(s,1H), 7.97(d,J=1.9Hz,1H),7.91(dd,J=8.4,1.9Hz,1H),7.57(d,J=8.4Hz,1H),6. 35(t,J=3.6Hz,1H),4.47-4.59(m,2H),2.03-2.09(m,1H),0.78-0.84(m,4H).

[0286] Example 30

[0287] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(2,2-difluoroethoxy)-4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (30)

[0288] Referring to the synthesis method of Example 24, compound 30 can be obtained by replacing isopropanol with 2,2-difluoroethanol.

[0289] LCMS (ESI-MS) m / z: 476.3 (M+H + ).

[0290] 1 H NMR(400MHz,DMSO-d6)δ11.29(s,1H),10.75(s,1H),9.08(s,1H),8.54(s,1H),8.03(s,1H),7.78–7.61(m,2H),7.49( d,J=8.2Hz,1H),6.78–5.90(m,1H),4.46(td,J=14.5,3.5Hz,2H),3.93(s,3H),2.14–1.90(m,1H),0.92–0.72(m,4H).

[0291] Example 31

[0292] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(2,2,2-trifluoroethoxy)-4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxamide (31)

[0293] Referring to the synthesis method of Example 24, compound 31 can be obtained by replacing isopropanol with 2,2,2-trifluoroethanol.

[0294] MS m / z(ESI):494.3[M+H] + .

[0295] 1 H NMR (400MHz, DMSO-d6) δ11.27(s,1H),10.72(s,1H),9.06(s,1H),8.54(s,1H),7.99(s,1H),7.76(d,J=1.7Hz,1H),7.70(d d,J=8.2,1.7Hz,1H),7.50(d,J=8.3Hz,1H),4.89(q,J=8.7Hz,2H),3.92(s,3H),2.05(t,J=5.5Hz,1H),0.83–0.73(m,4H).

[0296] Example 32

[0297] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(2,2,2-trifluoroethoxy)-4-(1-difluoromethyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (32)

[0298] Referring to the synthetic method of Example 31, Compound 32 can be obtained by replacing 1-methyl-3-bromo-1H-1,2,4-triazole with 1-difluoromethyl-4-bromo-1H-pyrazole.

[0299] LCMS [M+H] = 529.3

[0300] 1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),10.66(s,1H),9.05(s,1H),8.79(s,1H),8.35(s,1H),7.93(s,1H),7.85(t,J= 26.4Hz,1H),7.63(d,J=1.6Hz,1H),7.48–7.40(m,2H),4.86(q,J=8.7Hz,2H),2.09–2.01(m,1H),0.84–0.74(m,4H).

[0301] Example 33

[0302] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(2,2,2-trifluoroethoxy)-4-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (33)

[0303] Referring to the synthetic method of Example 31, Compound 33 can be obtained by replacing 1-methyl-3-bromo-1H-1,2,4-triazole with 1-cyclopropyl-4-bromo-1H-pyrazole.

[0304] LCMS (ESI-MS) m / z: 519.3 (M+H + ).

[0305] 1 H NMR (400MHz, DMSO-d6) δ11.23(s,1H),10.57(s,1H),9.04(s,1H),8.29(s,1H),7.93(s,1H),7.87(s,1H),7.48(d,J=1.7Hz,1H),7.41–7.28(m,2H) ,4.83(q,J=8.8Hz,2H),3.73(tt,J=7.4,3.9Hz,1H),2.09–2.02(m,1H),1 .05(q,J=3.8,3.0Hz,2H),0.99(dd,J=7.2,4.5Hz,2H),0.83–0.71(m,4H).

[0306] Example 34

[0307] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(2,2,2-trifluoroethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (34)

[0308] Referring to the synthetic method of Example 31, Compound 34 can be obtained by replacing 1-methyl-3-bromo-1H-1,2,4-triazole with 1-methyl-4-bromo-1H-pyrazole.

[0309] LCMS (ESI-MS) m / z: 493.20 (M+H + ).

[0310] 1 H NMR(400MHz,DMSO-d6)δ11.24(s,1H),10.57(s,1H),9.01(s,1H),8.19(s,1H),7.93(s,1H),7.87(s,1H) ,7.47(s,1H),7.35–7.28(m,2H),4.87–4.80(q,2H),3.86(s,3H),2.06–2.01(m,1H),0.80–0.76(m,4H).

[0311] Example 35

[0312] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(2,2,2-trifluoroethoxy)-4-(1-trifluoromethyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (35)

[0313] Referring to the synthetic method of Example 31, Compound 35 can be obtained by replacing 1-methyl-3-bromo-1H-1,2,4-triazole with 1-trifluoromethyl-4-bromo-1H-pyrazole.

[0314] LCMS (ESI-MS) m / z: 547.2 (M+H + ).

[0315] 1 H NMR (400MHz, DMSO-d6) δ11.27(s,1H),10.70(s,1H),9.09–9.00(m,2H),8.54(s,1H),7.96(s,1H),7. 66(d,J=1.7Hz,1H),7.53–7.44(m,2H),4.86(q,J=8.7Hz,2H),2.09–2.01(m,1H),0.84–0.71(m,4H).

[0316] Example 36

[0317] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(2,2-difluoroethoxy)-4-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (36)

[0318] Referring to the synthetic method of Example 28, compound 36 can be obtained by replacing 28c with 1-cyclopropyl-1H-pyrazole-4-boronic acid pinacol ester.

[0319] LCMS (ESI-MS) m / z: 501.3 (M+H + ).

[0320] 1H NMR (400MHz, DMSO-d6) δ11.25(s,1H),10.60(s,1H),9.06(s,1H),8.32(s,1H),7.95(s,1H),7.91(s,1H),7.44(d,J=1.7Hz,1H),7. 38–7.27(m,2H),6.46-6.13(m,1H),4.5-4.36(m,2H),3.79-3.69(m,1H),2.11–2.02(m,1H),1.12-0.95(m,4H),0.87-0.73(m,4H).

[0321] Example 37

[0322] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(2,2,2-trifluoroethoxy)-4-(1-ethyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (37)

[0323] Referring to the synthetic method of Example 31, Compound 37 can be obtained by replacing 1-methyl-3-bromo-1H-1,2,4-triazole with 1-ethyl-4-bromo-1H-pyrazole.

[0324] LCMS (ESI-MS) m / z: 507.3 (M+H + ).

[0325] 1 H NMR (400MHz, DMSO-d6) δ11.23(s,1H),10.56(s,1H),9.04(s,1H),8.25(s,1H),7.94(s,1H),7.87(s,1H),7.48(d,J=1.7Hz,1H) ,7.38–7.27(m,2H),4.84(q,J=8.7Hz,2H),4.14(q,J=7.3Hz,2H),2.08–2.00(m,1H),1.40(t,J=7.3Hz,3H),0.89–0.70(m,4H)..

[0326] Example 38

[0327] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(2,2-difluoroethoxy)-4-(1-ethyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (38)

[0328] Referring to the synthetic method of Example 28, compound 38 can be obtained by replacing 28c with 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester.

[0329] LCMS (ESI-MS) m / z: 489.3 (M+H + ).

[0330] 1 H NMR(400MHz,DMSO-d6)δ11.23(s,1H),10.58(s,1H),9.04(s,1H),8.25(s,1H),7.9 2(d,J=16.9Hz,2H),7.42(d,J=1.8Hz,1H),7.33(d,J=8.2Hz,1H),7.26(dd,J=8.2, 1.8Hz,1H),6.28(t,J=3.8Hz,1H),4.42(td,J=14.2,3.8Hz,2H),4.13(q,J=7.3Hz, 2H), 2.05 (ddd, J=10.0, 7.6, 4.9Hz, 1H), 1.40 (t, J=7.3Hz, 3H), 0.83–0.73 (m, 4H).

[0331] Example 39

[0332] Synthesis of 6-((1s,2s)-2-fluorocyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(2,2-difluoroethoxy)-4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (39)

[0333] Referring to the synthesis method of Example 28, compound 39 can be obtained by replacing propanecarboxamide with (1s,2s)-2-fluorocyclopropanecarboxamide.

[0334] LCMS (ESI-MS) m / z: 521.0 (M+H + ).

[0335] 1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),10.60(s,1H),9.06(s,1H),8.30(s,1H),7.94(s ,1H),7.89(s,1H),7.43(d,J=1.7Hz,1H),7.34(d,J=8.2Hz,1H),7.29(dd,J=8.2,1.7Hz ,1H),6.27(t,J=3.8Hz,1H),4.99–4.79(m,1H),4.45(dtd,J=18.1,14.3,13.8,5.3Hz, 3H),2.24(p,J=6.7Hz,1H),1.63–1.52(m,1H),1.44(d,J=6.7Hz,6H),1.18-1.10(m,1H)

[0336] Example 40

[0337] Synthesis of 6-((1s,2s)-2-fluorocyclopropanecarboxamido)-N-(methyl-d3)-4-((2-isopropoxy-4-(1-ethyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (40)

[0338] Referring to the synthetic method of Example 21, compound 40 can be obtained by replacing propanecarboxamide with (1s,2s)-2-fluorocyclopropanecarboxamide.

[0339] LCMS (ESI-MS) m / z: 485.0 (M+H + ).

[0340] 1 H NMR(400MHz,DMSO-d6)δ11.30(s,1H),10.69(s,1H),9.06(s,1H),8.25(s, 1H),8.03(s,1H),7.92(s,1H),7.36–7.34(m,2H),7.23–7.21(m,1H),5.02 –4.84(m,1H),4.75–4.69(m,1H),4.17–4.12(m,2H),2.29–2.25(m,1H),1. 64–1.57(m,1H),1.43–1.39(t,3H),1.27–1.25(d,6H),1.19–1.14(m,1H).

[0341] Example 41

[0342] Synthesis of 6-(2,2-difluorocyclopropane-1-carboxamido)-N-(methyl-d3)-4-((4-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (41)

[0343] Referring to the synthesis method of Example 1, compound 41 can be obtained by replacing propanecarboxamide with 2,2-difluorocyclopropanecarboxamide.

[0344] LCMS (ESI-MS) m / z: 516.2 (M+H + ).

[0345] 1 H NMR (400MHz, DMSO-d6) δ11.59(s,1H),11.13(s,1H),9.22(s,1H),8.57(s,1H),8.06(s,1H),8.03(dd,J=8.5,1.8H z,1H),8.00–7.97(m,1H),7.74(d,J=8.4Hz,1H),3.93(s,3H),3.03(q,J=11.4,10.6Hz,1H),2.02(t,J=9.4Hz,2H).

[0346] Example 42

[0347] Synthesis of 6-(2,2-difluoropropane-1-carboxamide)-4-((2-(2-(difluoromethoxy))-4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-N-(methyl-D3)pyridazine-3-carboxamide (42)

[0348] Referring to the synthesis method of Example 16, 3-bromo-1-methyl-1H-1,2,4-triazole was substituted for 1c, and 2,2-difluorocyclopropane-1-carboxamide was substituted for cyclopropaneamide to obtain compound 42.

[0349] LCMS [M+H] + =498.20

[0350] 1 H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.01(s,1H),7.91-7.83(m,2H),7.63(d,J=8 .3Hz,1H),7.45-7.08(m,1H),3.91(s,3H),3.06-2.95(m,1H),2.04-1.93(m,2H).

[0351] Example 43

[0352] Synthesis of 6-(2,2-difluorocyclopropane-1-carboxamide)-4-(2-difluoromethyl)oxy-4-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (43)

[0353] Referring to the synthesis method of Example 10, compound 43 can be obtained by replacing cyclopropylcarboxamide with 2,2-difluorocyclopropane-1-carboxamide.

[0354] MS m / z(ESI):499.3[M+H] + .

[0355] 1 H NMR(400MHz,DMSO-d6)δ11.58(s,1H),11.08(s,1H),9.20(s,1H),8.12(s,1H),8.00–7.92(m,2H),7 .76(d,J=8.4Hz,1H),7.39(t,J=73.1Hz,1H),4.43(s,3H),3.10–2.98(m,2H),2.01(q,J=9.6Hz,3H).

[0356] Example 44

[0357] Synthesis of 4-((4-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(difluoromethoxy)phenyl)amino)-6-(2,2-difluorocyclopropane-1-carboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (44)

[0358] Referring to the synthesis method of Example 42, Compound 44 can be obtained by replacing 3-bromo-1-methyl-1H-1,2,4-triazole with 3-bromo-1-cyclopropyl-1H-1,2,4-triazole.

[0359] LCMS (ESI-MS) m / z: 524.3 (M+H + ).

[0360] 1H NMR (400MHz, DMSO-d6) δ11.54(s,1H),10.93(s,1H),9.17(s,1H),8.67(s,1H),8.03(s,1H),7.90-7.86(m,2H),7.63(d, J=8.4Hz,1H),7.51-7.14(t,J=73.2Hz,1H),3.84-3.72(m,1H),3.07-2.99(m,1H),2.02-1.96(m,2H),1.21–1.02(m,4H).

[0361] Example 45

[0362] Synthesis of 6-(cyclopropanecarboxamide)-4-((2-(difluoromethoxy)-4-(1-(oxetan-3-ylmethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (45)

[0363] Referring to the synthesis method of Example 9, 3-bromo-1-(oxetane-3-methyl)-1H-1,2,4-triazole was substituted for 3-bromo-1-cyclopropyl-1H-1,2,4-triazole to obtain Compound 45.

[0364] LCMS (ESI-MS) m / z: 507.3 (M+H + ).

[0365] 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),10.75(s,1H),9.11(s,1H),8.32(s,1H),7. 95(d,J=13.8Hz,2H),7.56(dq,J=3.6,1.9Hz,2H),7.49(d,J=8.8Hz,1H),7.24(s,1 H),4.99(q,J=5.8Hz,0.5H),4.83(q,J=5.7,5.3Hz,0.5H),4.49(p,J=6.6Hz,1H),2 .25(t,J=7.1Hz,1H),1.63–1.54(m,1H),1.44(d,J=6.7Hz,6H),1.19–1.11(m,1H).

[0366] Example 46

[0367] Synthesis of 6-(cyclopropyl-assisted acyl)-4-((2-(difluoromethoxy)-4-(1-ethyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-D3)-3-carboxamide

[0368] Referring to the synthesis method of Example 7, compound 46 was obtained by replacing 3-bromo-1-methyl-1H-1,2,4-triazole with 3-bromo-1-ethyl-1H-1,2,4-triazole.

[0369] LCMS [M+H] + =476.20

[0370] 1 H NMR(400MHz,DMSO-d6)δ11.35(s,1H),10.90(s,1H),9.14(s,1H),8.60(s,1H),8.10(s,1H),7.93-7.82(m,2H),7.62(d ,J=8.3Hz,1H),7.50-7.14(m,1H),4.25(q,J=7.3Hz,2H),2.08-1.96(m,1H),1.43(t,J=7.3Hz,3H),0.83-0.79(m,4H).

[0371] Example 47

[0372] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(5-methyl-1H-tetrazol-1-yl)-2-(difluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (47)

[0373] Referring to the synthesis method of Example 4, compound 47 was obtained by replacing 1a with 2-(difluoromethoxy)-4-bromophenylamine.

[0374] LCMS [M+H] + =463.3.

[0375] 1 H NMR (400MHz, DMSO-d6) δ11.43(s,1H),11.17(s,1H),9.20(s,1H),8.24(s,1H),7.83(d,J=8.6Hz,1H),7.76(d,J=2.3Hz ,1H),7.67(dd,J=8.6,2.4Hz,1H),7.35(t,J=72.8Hz,1H),2.60(s,3H),2.09(td,J=7.6,3.8Hz,1H),0.92–0.76(m,4H).

[0376] Example 48

[0377] Synthesis of 6-[(cyclopropylcarbonyl)amino]-4-[2-(difluoromethoxy)-4-(1-propyl-1H-1,2,4-triazol-3-yl)anilino]-N-(trideuterated methyl)-pyridazine-3-carboxamide (48)

[0378] Referring to the synthesis method of Example 7, Compound 48 was obtained by replacing 3-bromo-1-propyl[1.2.4]triazole with 3-bromo-1-methyl[1.2.4]triazole.

[0379] LCMS (ESI-MS) m / z: 490.3 (M+H + ).

[0380] 1 H NMR(400MHz,DMSO-d6)δ11.35(s,1H),10.91(s,1H),9.14(s,1H),8.62(s,1H),8.11(s,1H),7.91–7.88(m,2H),7 .64–7.63(m,1H),7.46–7.22(m,1H),4.21–4.18(m,2H),2.09–2.06(m,1H),1.87–1.84(m,2H),0.88–0.81(m,7H).

[0381] Example 49

[0382] Synthesis of 6-(3,3-difluorocyclobutane-1-carboxamido)-N-(methyl-d3)-4-((4-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(trifluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (49)

[0383] Referring to the synthesis method of Example 3, compound 49 was obtained by replacing propanecarboxamide with 3,3-difluorocyclobutanecarboxamide.

[0384] LCMS (ESI-MS) m / z: 556.3 (M+H+).

[0385] 1H NMR(600MHz,Chloroform-d)δ13.29(s,1H),10.39(s,1H),9.67(s,1H),8.17 (s,1H),7.45(dd,J=8.0,1.7Hz,1H),7.40(td,J=7.6,1.3Hz,1H),7.35(td,J= 7.8,1.6Hz,1H),7.17(d,J=8.2Hz,1H),3.68(dd,J=7.5,3.9Hz,1H),3.26(t,J =8.4Hz,1H),3.02–2.81(m,4H),1.30(d,J=3.8Hz,2H),1.19(d,J=7.2Hz,2H).

[0386] Example 50

[0387] Synthesis of 6-(cyclopropyl-assisted acyl)-4-((2-(2-(difluoromethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)phenyl)amino)-n-(methyl-D3)pyridazine-3-carboxamide (50)

[0388] Referring to the synthesis method of Example 16, 1-methyl-4-bromopyrazole was substituted for 3-bromo-1-methyl[1.2.4]triazole to obtain compound 50.

[0389] LCMS [M+H] + =461.30

[0390] 1 H NMR(400MHz,DMSO-d6)δ11.32(s,1H),10.80(s,1H),9.11(s,1H),8.04(s,1H), 7.75(d,J=2.2Hz,1H),7.70(d,J=8.6Hz,2H),7.53(d,J=8.2Hz,1H),7.46-7.10(m,1H), 7.28(s,1H),6.76(d,J=2.3Hz,1H),3.88(s,3H),2.08-1.09(m,1H),0.81-0.77(m,4H).

[0391] Example 51

[0392] Synthesis of 6-(2,2-difluorocyclopropane-1-carboxamido)-4-((2-(difluoromethoxy)-4-(1-(methoxymethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (51)

[0393] Referring to the synthesis method of Example 42, Compound 51 can be obtained by replacing 3-bromo-1-methyl[1.2.4]triazole with 3-bromo-1-methoxymethyl[1.2.4]triazole.

[0394] LCMS (ESI-MS) m / z: 528.3 (M+H + ).

[0395] 1 H NMR (400MHz, DMSO-d6) δ11.57(s,1H),10.96(s,1H),9.19(s,1H),8.83(s,1H),8.06(s,1H),7.93(dd,J=8.3,1.8Hz,1H),7.90( d,J=1.7Hz,1H),7.67(d,J=8.3Hz,1H),7.35(t,J=73.2Hz,1H),5.53(s,2H),3.30(s,3H),3.08–2.98(m,1H),2.06–1.95(m,2H).

[0396] Example 52

[0397] Synthesis of 6-(cyclopropanecarboxamide)-4-((2-(difluoromethoxy)-4-(1-(2-(methylamino)ethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (52)

[0398] Referring to the synthesis method of Example 7, Compound 52 was obtained by replacing 3-bromo-1-methyl[1.2.4]triazole with 3-bromo-1-(2-aminomethyleth-2-yl)-[1.2.4]triazole.

[0399] LCMS (ESI-MS) m / z: 505.3 (M+H + ).

[0400] 1 H NMR(400MHz, Methanol-d4)δ8.70(s,1H),8.17–8.12(m,2H),7.76(d,J=8.9Hz,1H),7.08(s,1H),7.05(t,J =7.2Hz,1H),4.74–4.67(m,2H),3.63(t,J=5.7Hz,2H),2.81(s,3H),1.92–1.85(m,1H),1.18–1.05(m,4H).

[0401] Example 53

[0402] Synthesis of 4-((4-(1-cyclopropyl-1H-1,2,4-triazol-3-yl)-2-(trifluoromethoxy)phenyl)amino)-6-(2,2-difluorocyclopropane-1-carboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (53)

[0403] Referring to the synthesis method of Example 3, compound 53 can be obtained by replacing propanecarboxamide with 2,2-difluorocyclopropanecarboxamide.

[0404] LCMS (ESI-MS) m / z: 542.2 (M+H + ).

[0405] 1 H NMR(400MHz,DMSO-d6)δ11.61(s,1H),11.65(s,1H),9.24(s,1H),8.71(s,1H),8.11-7.99(m,3H), 7.76(d,J=5.6Hz,1H),3.87-3.83(m,1H),3.08–3.02(m,1H),2.05–2.00(m,2H),1.19–1.06(m,4H).

[0406] Example 54

[0407] Synthesis of 6-(cyclopropanecarboxamide)-4-((2-(difluoromethoxy)-4-(1-(methoxymethyl)-1H-pyrazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (54)

[0408] Referring to the synthetic method of Example 51, Compound 54 can be obtained by replacing 2,2-difluorocyclopropanecarboxamide with cyclopropanecarboxamide.

[0409] LCMS (ESI-MS) m / z: 491.3 (M+H + ).

[0410] 1 H NMR (400MHz, DMSO-d6) δ11.30(s,1H),10.75(s,1H),9.10(s,1H),8.44(s,1H),8.07(d,J=0.80Hz,1H),7.99(s,1H),7.59 -7.56(m,2H),7.51-7.49(m,1H),7.25(t,J=73.6Hz,1H),5.38(s,2H),3.25(s,3H),2.07–2.03(m,1H),0.81–0.77(m,4H).

[0411] Example 55

[0412] Synthesis of 6-[(cyclopropylcarbonyl)amino]-4-{2-(difluoromethoxy)-4-[1-isopropyl-1H-1,2,4-triazol-3-yl]anilino}-N-(trideuterated methyl)-pyridazine-3-carboxamide (55)

[0413] Referring to the synthesis method of Example 7, Compound 55 was obtained by replacing 3-bromo-1-isopropyl[1.2.4]triazole with 3-bromo-1-methyl[1.2.4]triazole.

[0414] LCMS (ESI-MS) m / z: 490.3 (M+H + ).

[0415] 1 H NMR(400MHz,DMSO-d6)δ11.36(s,1H),10.91(s,1H),9.15(s,1H),8.65(s,1H),8.11(s,1H),7.92–7.87(m,2H),7 .65–7.63(m,1H),7.52–7.15(m,1H),4.70–4.63(m,1H),2.09–2.06(m,1H),1.51–1.50(m,6H),0.85–0.81(m,4H).

[0416] Example 56

[0417] Synthesis of 6-(cyclopropyl-assisted acyl)-4-((2-(2-(difluoromethoxy)-4-(1-ethyl-1H-pyrazol-4-yl)phenyl)amino)amino)-n-(methyl-D3)pyridazine-3-carboxamide

[0418] Referring to the synthesis method of Example 7, 1-ethyl-4-bromopyrazole was substituted for 3-bromo-1-methyl[1.2.4]triazole to obtain compound 56.

[0419] LCMS [M+H] + =475.30

[0420] 1H NMR (400MHz, DMSO-d6) δ11.29(s,1H),10.72(s,1H),9.09(s,1H),8.27(d,J=0.8Hz,1H),7.99–7.90(m,2H),7.57–7 .44(m,3H),7.42-7.05(m,1H),4.14(q,J=7.3Hz,2H),2.04-2.03(m,1H),1.39(t,J=7.3Hz,3H),0.85–0.74(m,4H).

[0421] Example 57

[0422] Synthesis of 6-(cyclopropanecarboxamide)-4-((2-(difluoromethoxy)-4-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (57)

[0423] Referring to the synthesis method of Example 7, compound 57 can be obtained by replacing 3-bromo-1-methyl[1.2.4]triazole with 1-methyl-3-bromopyrazole.

[0424] LCMS (ESI-MS) m / z: 461.3 (M+H + ).

[0425] 1 H NMR (400MHz, DMSO-d6) δ11.31(s,1H),10.80(s,1H),9.11(s,1H),8.03(s,1H),7.75(d,J=2.2Hz,1H),7.71(d,J=1.9Hz,1H),7. 68(d,J=1.8Hz,1H),7.53(d,J=8.1Hz,1H),6.76(d,J=2.3Hz,1H),3.88(s,3H),2.06(dt,J=6.1,3.7Hz,1H),0.85–0.66(m,4H).

[0426] Example 58

[0427] Synthesis of 6-(cyclopropanecarboxamide)-4-((2-(difluoromethoxy)-4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (58)

[0428] Referring to the synthesis method of Example 7, compound 58 can be obtained by replacing 3-bromo-1-methyl[1.2.4]triazole with 1-isopropyl-4-bromopyrazole.

[0429] LCMS (ESI-MS) m / z: 489.3 (M+H + ).

[0430] 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),10.72(s,1H),9.09(s,1H),8.31(d,J=0.8Hz,1H),7.97(s,1H),7.92(d,J=0.8Hz,1H),7.56–7.51( m,2H),7.47(d,J=8.9Hz,1H),7.24(s,1H),4.49(p,J=6.6Hz,1H),2.04(td,J=7.6,3.9Hz,1H),1.43(d,J=6.7Hz,6H),0.86–0.73(m,4H).

[0431] Example 59

[0432] Synthesis of 6-(cyclopropanecarboxamide)-4-((4-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(difluoromethoxy)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (59)

[0433] Referring to the synthesis method of Example 7, compound 59 was obtained by replacing 3-bromo-1-methyl[1.2.4]triazole with 1-cyclopropyl-4-bromopyrazole.

[0434] LCMS (ESI-MS) m / z: 487.3 (M+H + ).

[0435] 1 H NMR (400MHz, DMSO-d6) δ11.30(s,1H),10.73(s,1H),9.09(s,1H),8.32(d,J=0.8Hz,1H),7.97(s,1H),7.92(d,J=0.8Hz,1H),7.56–7.51 (m,2H),7.47(d,J=8.4Hz,1H),3.73(tt,J=7.4,3.9Hz,1H),2.10–2.01(m,1H),1.09–1.01(m,2H),1.01–0.93(m,2H),0.84–0.73(m,4H).

[0436] Example 60

[0437] Synthesis of 6-[(cyclopropylcarbonyl)amino]-4-{2-(difluoromethoxy)-4-[1-(2-amino-eth-1-yl)-1H-1,2,4-triazol-3-yl]anilino}-N-(trideuterated methyl)-pyridazine-3-carboxamide (60)

[0438] Referring to the synthetic method of Example 7, compound 60 can be obtained by replacing 3-bromo-1-methyl[1.2.4]triazole with 3-bromo-1-(2-amino-ethyl-1-yl)[1.2.4]triazole.

[0439] MS m / z(ESI):491.3[M+H] + .

[0440] 1 H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.89(s,1H),9.13(s,1H),8.57(s,1H),8.35(s,2H),8.08(s,1H),7.91–7.84(m,2H ),7.62(d,J=8.3Hz,1H),7.32(t,J=73.2Hz,1H),4.20(s,2H),2.99(s,2H),2.10–2.01(m,1H),0.80(dd,J=6.4,3.2Hz,4H).

[0441] Example 61

[0442] Synthesis of 6-(cyclopropanecarboxamide)-4-((2-(difluoromethoxy)-4-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (61)

[0443] Referring to the synthesis method of Example 7, 3-bromo-1-(2-amino-ethyl-1-yl)[1.2.4]triazole was substituted for 3-bromo-1-methyl[1.2.4]triazole to obtain Compound 61.

[0444] LCMS (ESI-MS) m / z: 530.3 (M+H + ).

[0445] 1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),11.16(s,1H),9.18(s,1H),8.24(s,1H),8.21(s,1H),7.78–7.71(m, 1H),7.69–7.63(m,2H),7.36(t,J=7.2Hz,1H),5.31(q,J=8.8Hz,2H),2.12–2.02(m,1H),0.89–0.76(m,4H).

[0446] Example 62

[0447] 6-((Cyclopropylcarboxamido)-4-((2-isobutoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3))pyridazine-3-carboxamide

[0448] Referring to the synthetic method of Example 24, compound 62 can be obtained by replacing isopropanol with isobutanol.

[0449] LCMS: 468 (M+1)

[0450] 1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),10.76(s,1H),9.06(s,1H),8.51(d,J=0.7Hz,1H),8.05(s,1H),7.64–7.55(m,2H),7. 44(d,J=8.2Hz,1H),3.93–3.88(m,3H),3.85(d,J=6.3Hz,2H),2.10–1.91(m,2H),0.94(d,J=6.7Hz,6H),0.85–0.72(m,4H).

[0451] Example 63

[0452] Synthesis of 4-((4-(1-(cyanomethyl)-1H-1,2,4-triazol-3-yl)-2-(difluoromethoxy)phenyl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (63)

[0453] Referring to the synthesis method of Example 7, compound 63 can be obtained by replacing isopropoxy with difluoromethoxy.

[0454] LCMS (ESI-MS) m / z: 487.3 (M+H + ).

[0455] 1H NMR (400MHz, DMSO-d6) δ11.45(s,1H),8.55(s,1H),7.65(d,J=1.9Hz,1H),7.36(d,J=7.7Hz,1H),7 .19(s,1H),7.10(s,2H),6.82(d,J=8.9Hz,1H),5.43(s,2H),2.05–1.96(m,1H),0.83–0.67(m,4H).

[0456] Example 64

[0457] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(5-ethyl-1H-tetrazol-1-yl)-2-(difluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (64)

[0458] Referring to the synthesis method of Example 8, compound 64 can be obtained by replacing 5-methyltetrazolyl with 5-ethyltetrazolyl.

[0459] LCMS [M+H] + =477.3.

[0460] 1 H NMR (400MHz, DMSO-d6) δ11.42(s,1H),11.15(s,1H),9.18(s,1H),8.22(s,1H),7.80(d,J=8.6Hz,1H),7.73(d,J=2.3Hz,1H),7.63(dd,J =8.6,2.3Hz,1H),7.32(t,J=72.8Hz,1H),2.90(q,J=7.5Hz,2H),2.14–1.99(m,1H),1.26(t,J=7.5Hz,3H),0.82(dd,J=6.6,4.4Hz,4H).

[0461] Example 65

[0462] Synthesis of 6-(cyclopropanecarboxamido)-N-(trideuterated methyl)-4-((4-(5-methyl-[1.3.4]oxadiazol-2-yl)-2-(difluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (65)

[0463] Referring to the synthesis method of Example 7, Compound 65 was obtained by replacing 3-bromo-1-methyl[1.2.4]triazole with 2-bromo-5-methyl-[1.3.4]oxadiazole.

[0464] MS m / z(ESI):463.2[M+H] + .

[0465] 1H NMR (400MHz, DMSO-d6) δ11.41(s,1H),11.17(s,1H),9.17(s,1H),8.24(s,1H),7.91–7.82(m,2H),7.76(d,J=8 .4Hz,1H),7.49(d,J=73.0Hz,1H),2.53(d,J=34.5Hz,3H),2.07(tt,J=7.3,5.1Hz,1H),0.81(t,J=2.3Hz,4H).

[0466] Example 66

[0467] Synthesis of 6-(2,2-difluorocyclopropane-1-carboxamide)-4-((2-(difluoromethoxy)-4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (66)

[0468] Referring to the synthetic method of Example 7, compound 66 can be obtained.

[0469] LCMS (ESI-MS) m / z: 525.3 (M+H + ).

[0470] 1 H NMR (400MHz, DMSO-d6) δ11.51(s,1H),10.78(s,1H),9.15(s,1H),8.34(d,J=0.8Hz,1H),7.98–7.90(m,2H),7.59–7.4 8(m,3H),7.26(t,J=73.6Hz,1H),4.51(p,J=6.7Hz,1H),3.11–2.99(m,1H),2.06–1.95(m,2H),1.45(d,J=6.7Hz,6H).

[0471] Example 67

[0472] Synthesis of 6-[(cyclopropylcarbonyl)amino]-4-{2-(difluoromethoxy)-4-[1-(2-methoxy-ethyl-1-yl)-1H-pyrazol-4-yl]anilino}-N-(trideuterated methyl)-pyridazine-3-carboxamide (67)

[0473] Referring to the synthesis method of Example 7, compound 67 can be obtained by replacing 3-bromo-1-methyl[1.2.4]triazole with 4-bromo-1-(2-methoxy-ethyl-1-yl)pyrazole.

[0474] MS m / z(ESI):505.3[M+H] + .

[0475] 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),10.73(s,1H),9.09(s,1H),8.23(s,1H),7.96(d,J=9.2Hz,2H),7.56–7.46(m,3H),7.25 (t,J=73.6Hz,1H),4.26(t,J=5.2Hz,2H),3.70(t,J=5.3Hz,2H),3.23(s,3H),2.05(dd,J=8.5,4.0Hz,1H),0.83–0.75(m,4H).

[0476] Example 68

[0477] 6-(cyclopropanecarboxamide)-4-((4-(1-isopropyl-1H-pyrazol-4-yl)-2-(trifluoromethoxy)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0478] Referring to the synthetic method of Example 20, compound 68 can be obtained by replacing isopropanol with trifluoromethanol.

[0479] LCMS: 507 (M+1)

[0480] 1 H NMR (400MHz, DMSO-d6) δ11.35(s,1H),10.92(s,1H),9.15(s,1H),8.39(d,J=0.8Hz,1H),8.12–7.94(m,2H),7.79–7.64(m,2 H),7.58(d,J=8.3Hz,1H),4.50(hept,J=6.6Hz,1H),2.07(tt,J=7.3,4.9Hz,1H),1.45(d,J=6.7Hz,6H),0.93–0.58(m,4H).

[0481] Example 69

[0482] Synthesis of 6-(cyclopropanecarboxamide)-4-((2-(difluoromethoxy)-4-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-5-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (69)

[0483] Referring to the synthetic method of Example 20, compound 69 can be obtained by replacing the isopropoxy group with a difluoromethoxy group.

[0484] LCMS (ESI-MS) m / z: 486.3 (M+H + ).

[0485] 1 H NMR (400MHz, DMSO-d6) δ11.40(s,1H),9.17(s,1H),8.40(s,1H),8.22(s,1H),8.09(s,1H),7.74(d,J= 9.3Hz,3H),7.34(s,1H),5.23(d,J=2.6Hz,2H),3.56(s,1H),2.07(d,J=8.4Hz,1H),0.86–0.77(m,4H).

[0486] Example 70

[0487] Synthesis of 6-(cyclopropanecarboxamide)-4-((2-(difluoromethoxy)-4-(1-(prop-2-yn-1-yl)-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (70)

[0488] Referring to the synthesis method of Example 7, 4-bromo-1-(3,3,3-trifluoropropyl)pyrazole was used instead of 3-bromo-1-methyltriazole to obtain Compound 70.

[0489] LCMS (ESI-MS) m / z: 486.3 (M+H + ).

[0490] 1 H NMR(400MHz,DMSO-d6)δ11.35(s,1H),10.92(s,1H),9.13(s,1H),8.67(s,1H),8.11(s,1H),7.93–7.85(m,2H),7 .64(d,J=8.3Hz,1H),5.21(d,J=2.6Hz,2H),3.58(t,J=2.5Hz,1H),2.05(q,J=6.1Hz,1H),0.80(d,J=6.1Hz,4H).

[0491] Example 71

[0492] Synthesis of -((2-(difluoromethoxy)-4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)amino)-6-(2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (71)

[0493] Referring to the synthetic method of Example 58, Compound 71 can be obtained by replacing the cyclopropyl group with a fluorocyclopropyl group.

[0494] LCMS (ESI-MS) m / z: 507.3 (M+H + ).

[0495] 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),10.74(s,1H),9.11(s,1H),8.32(d,J=0.8Hz,1H ),7.96(s,1H),7.93(d,J=0.8Hz,1H),7.55(dq,J=3.5,1.9Hz,2H),7.49(d,J=8.8Hz,1H ),5.00(dd,J=6.3,3.9Hz,1H),4.87–4.80(m,1H),4.49(p,J=6.7Hz,1H),2.25(p,J=6. 8Hz,1H),1.64–1.51(m,1H),1.44(d,J=6.7Hz,6H),1.15(ddd,J=12.6,6.2,2.8Hz,1H).

[0496] Example 72

[0497] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)-2-(difluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (72)

[0498] Referring to the synthesis method of Example 7, Compound 72 was obtained by replacing 3-bromo-1-methyltriazole with 4-bromo-1-(3,3,3-trifluoropropyl)pyrazole.

[0499] LCMS (ESI-MS) m / z: 543.3 (M+H + ).

[0500] 1 H NMR (400MHz, DMSO-d6) δ11.30(s,1H),10.74(s,1H),9.09(s,1H),8.34(s,1H),7.99(d,J=8.7Hz,2H),7.59–7.46(m,3H),7.25(t,J =73.5Hz,1H),4.39(t,J=6.8Hz,2H),2.90(tdd,J=11.2,6.9,4.4Hz,2H),2.05(tt,J=7.2,5.0Hz,1H),0.79(dq,J=7.5,3.3Hz,4H).

[0501] Example 73

[0502] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(1-cyanomethyl-1H-pyrazol-4-yl)-2-(difluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (72)

[0503] Referring to the synthesis method of Example 7, Compound 73 was obtained by replacing 3-bromo-1-methyltriazole with 4-bromo-1-cyanomethylpyrazole.

[0504] LCMS [M+H] + =486.3.

[0505] 1 H NMR(400MHz,DMSO-d6)δ11.31(s,1H),10.77(s,1H),9.10(s,1H),8.36(s,1H),8.12(s,1H),8.00(s ,1H),7.60–7.48(m,3H),7.26(t,J=73.5Hz,1H),5.52(s,2H),2.00–1.90(m,1H),0.84–0.78(m,4H).

[0506] Example 74

[0507] Synthesis of 4-((4-(5-cyanopyridin-2-yl)-2-(difluoromethoxy)phenyl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (74)

[0508] Referring to the synthesis method of Example 7, 2-bromo-5-cyanopyridine was used instead of 3-bromo-1-methyltriazole to obtain Compound 74.

[0509] LCMS (ESI-MS) m / z: 483.3 (M+H + ).

[0510] 1H NMR (400MHz, DMSO-d6) δ11.40(s,1H),11.14(s,1H),9.17(s,1H),9.09(dd,J=2.2,0.9Hz,1H),8.40(dd,J=8.4,2.2Hz,1H),8.28(dd,J= 8.4,1.0Hz,1H),8.25(s,1H),8.18–8.11(m,2H),7.71(d,J=8.4Hz,1H),7.37(t,J=72Hz,1H),2.10-2.05(m,1H),0.81(h,J=3.1Hz,4H).

[0511] Example 75

[0512] Synthesis of 4-((2-(difluoromethoxy)-4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)amino)-6-((1R,2S)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (75)

[0513] Referring to the synthesis method of Example 66, 2-fluoro-cyclopropanamide was substituted for 2,2-difluoro-cyclopropanamide to obtain Compound 75.

[0514] LCMS (ESI-MS) m / z: 507.3 (M+H + ).

[0515] 1 H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.72(s,1H),9.12(s,1H),8.31(s,1 H),7.92(s,1H),7.89(s,1H),7.54(s,1H),7.52–7.43(m,2H),7.23(t,J=72H z,1H),4.94–4.89(m,0.5H),4.78–4.74(m,0.5H),4.49(p,J=6.6Hz,1H),2.6 4–2.53(m,1H),1.57–1.47(m,1H),1.43(d,J=6.7Hz,6H),1.21–1.13(m,1H).

[0516] Example 76

[0517] Synthesis of 4-((2-(difluoromethoxy)-4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)amino)-6-((1S,2S)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (76)

[0518] Referring to the synthetic method of Example 75, compound 76 can be obtained.

[0519] LCMS (ESI-MS) m / z: 507.3 (M+H + ).

[0520] 1 H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.75(s,1H),9.11(s,1H),8.32(s,1H ),7.95(d,J=13.8Hz,2H),7.56(dq,J=3.6,1.9Hz,2H),7.49(d,J=8.8Hz,1H), 7.06-7.43(s,1H),4.83-4.99(q,J=5.8Hz,1H),4.49(p,J=6.6Hz,1H),2.25( t,J=7.1Hz,1H),1.63–1.54(m,1H),1.44(d,J=6.7Hz,6H),1.19–1.11(m,1H).

[0521] Example 77

[0522] Synthesis of 4-((2-(2-(difluoromethoxy)-4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)phenyl)amino)-6-((1R,2R)-2-fluorocyclopropane-1-carboxamide)-n-(methyl-D3)pyridazine-3-carboxamide

[0523] Referring to the synthetic method of Example 75, compound 77 can be obtained.

[0524] LCMS [M+H] + =507.30

[0525] 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),10.75(s,1H),9.11(s,1H),8.32(s,1H),7.96(s,1H),7.93(d,J=0.7Hz,1H),7.56-7.54(m,2H),7.49-7.47 (m,1H),7.42-7.05(m,1H),5.00–4.80(m,1H),4.51-4.45(m,1H),2.26–2 .22(m,1H),1.62–1.54(m,1H),1.43(d,J=6.7Hz,6H),1.17-1.12(m,1H).

[0526] Example 78

[0527] 6-(cyclopropanecarboxamide)-4-((2-(difluoromethoxy)-4-(5-(methylsulfonyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0528] Referring to the synthesis method of Example 8, Compound 78 was obtained by replacing 5-methyl-2H-tetrazole with 5-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole.

[0529] LCMS: 566 (M+1)

[0530] 1 H NMR (400MHz, DMSO-d6) δ11.33(s,1H),10.79(s,1H),9.12(s,1H),8.44(s,1H),7.99(d,J=0.9Hz,1H),7.84–7.72(m,2H),7.63(d,J =8.7Hz,1H),7.32(d,J=1.0Hz,1H),4.50(d,J=12.8Hz,4H),3.03(d,J=0.9Hz,3H),2.05(td,J=7.5,3.8Hz,1H),0.87–0.72(m,4H).

[0531] Example 79

[0532] Referring to the synthesis method of Example 58, Compound 79 can be obtained by replacing the cyclopropyl group with a fluorocyclopropyl group.

[0533] LCMS (ESI-MS) m / z: 507.3 (M+H + ).

[0534] 1 H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.72(s,1H),9.12(s,1H),8.31(s,1H) ,7.91(d,J=13.3Hz,2H),7.56–7.50(m,2H),7.46(d,J=8.2Hz,1H),7.23(s,1H ),4.92(s,1H),4.49(p,J=6.6Hz,1H),2.61(dt,J=20.2,8.9Hz,1H),1.52(ddd ,J=18.6,6.5,3.3Hz,1H),1.43(d,J=6.7Hz,6H),1.20(dt,J=13.3,6.6Hz,1H).

[0535] Example 80

[0536] Synthesis of 6-[(cyclopropylcarbonyl)amino]-4-({2-[(difluoromethyl)oxy]-4-(5-fluoropyrimidin-2-yl)phenyl}amino)-N-(trideuteriomethyl)-1,2-pyridazine-3-carboxamide (80)

[0537] Referring to the synthetic method of Example 7, compound 80 can be obtained by replacing 3-bromo-1-methyl[1.2.4]triazole with 5-fluoro-2-bromopyrimidine.

[0538] LCMS (ESI-MS) m / z: 477.2 (M+H + ).

[0539] 1 H NMR(400MHz,DMSO-d6)δ11.40(s,1H),11.07(s,1H),9.16(s,1H),9.00(s,2H),8.40(s,1H),8 .26–8.22(m,2H),7.73–7.71(m,1H),7.55–7.18(m,1H),2.10–2.04(m,1H),0.85–0.81(m,4H).

[0540] Example 81

[0541] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(4-trifluoromethyl-pyrazol-1-yl)-2-(difluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (81)

[0542] Referring to the synthesis method of Example 8, compound 83 can be obtained by replacing 5-methyltetrazolyl with 4-trifluoromethylpyrazole.

[0543] MS m / z(ESI):515.2[M+H] + .

[0544] 1 H NMR(400MHz,DMSO-d6)δ11.36(s,1H),10.88(s,1H),9.27(s,1H),9.14(s,1H),8.25(s,1H),8.04(s,1H),7.92–7 .82(m,2H),7.70(d,J=8.8Hz,1H),7.33(t,J=73.0Hz,1H),2.06(ddd,J=12.5,7.5,4.7Hz,1H),0.86–0.69(m,4H).

[0545] Example 82

[0546] 6-(cyclopropanecarboxamide)-4-((2-(difluoromethoxy)-4-(5-(S-methylsulfonylimino)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0547] Referring to the synthesis method of Example 8, Compound 82 was obtained by replacing 5-methyl-2H-tetrazole with 5-(S-methylsulfonylimino)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole.

[0548] LCMS: 565 (M+1)

[0549] 1 H NMR(400MHz,DMSO-d6)δ11.33(s,1H),10.78(s,1H),9.12(s,1H),8.41(s,1H),7.98(s,1H),7.82–7.72(m,2H ),7.62(d,J=8.7Hz,1H),7.32(s,1H),4.52–4.33(m,5H),2.95(s,3H),2.09–2.00(m,1H),0.88–0.72(m,4H).

[0550] Example 83

[0551] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((4-(4-cyano-pyrazol-1-yl)-2-(difluoromethoxy)phenyl)amino)pyridazine-3-carboxamide (83)

[0552] Referring to the synthesis method of Example 8, Compound 83 can be obtained by replacing 5-methyltetrazolyl with 4-cyanopyrazole.

[0553] MS m / z(ESI):472.2[M+H] + .

[0554] 1H NMR (400MHz, DMSO-d6) δ11.36(s,1H),10.91(s,1H),9.39(s,1H),9.14(s,1H),8.39(s,1H),8.05(s,1H),7.86(d,J=2. 4Hz,1H),7.84–7.78(m,1H),7.72(d,J=8.8Hz,1H),7.55–7.10(t,J=332Hz,1H),2.10–2.02(m,1H),0.87–0.72(m,4H).

[0555] Example 84

[0556] Synthesis of 6-[(cyclopropylcarbonyl)amino]-4-{2-(2,2-difluoroethoxy)-4-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]anilino}-N-(trideuteriomethyl)-pyridazine-3-carboxamide (84)

[0557] Referring to the synthesis method of Example 38, Compound 84 can be obtained by replacing 1-ethyl-4-bromopyrazole with 1-(2,2,2-trifluoroethyl)ethyl-4-bromopyrazole.

[0558] LCMS (ESI-MS) m / z: 543.3 (M+H + ).

[0559] 1 H NMR(400MHz,DMSO-d6)δ11.25(s,1H),10.64(s,1H),9.07(s,1H),8.37(s,1H),8.14(s,1H),7.94(s,1H),7.49–7.48(m, 1H),7.40–7.32(m,2H),6.45–6.16(m,1H),5.20–5.13(m,2H),4.50–4.42(m,2H),2.08–2.03(m,1H),0.82–0.78(m,4H).

[0560] Example 85

[0561] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-cyclopropyloxy-4-(1-ethyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (85)

[0562] Referring to the synthetic method of Example 27, Compound 85 can be obtained by replacing 4-bromo-1-ethyl-1H-pyrazole with 4-bromo-1-isopropyl-1H-pyrazole.

[0563] LCMS [M+H] + =465.3.

[0564] 1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),10.50(s,1H),9.04(s,1H),8.22(s,1H),7 .97–7.77(m,2H),7.54(d,J=1.8Hz,1H),7.29(d,J=8.1Hz,1H),7.21(dd,J=8.1,1 .8Hz,1H),4.14(q,J=7.3Hz,2H),3.97(tt,J=6.0,2.9Hz,1H),2.04(td,J=7.4,3 .8Hz,1H),1.40(t,J=7.2Hz,3H),0.88–0.70(m,6H),0.62(dt,J=4.7,3.1Hz,2H).

[0565] Example 86

[0566] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-difluoromethoxy)-4-(1-isopropyl-1H-imidazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (86)

[0567] Referring to the synthesis method of Example 8, 4-bromo-1-isopropyl-1H-imidazolyl replaced 5-methyltetrazolyl to obtain compound 86

[0568] LCMS (ESI-MS) m / z: 488.5 (M+H + ).

[0569] 1 H NMR (400MHz, DMSO-d6) δ11.28(s,1H),10.70(s,1H),9.09(s,1H),7.97(s,1H),7.87(d,J=1.4Hz,1H),7.76(d,J=1.3Hz,1H),7.71–7.63(m,2 H),7.47(d,J=8.3Hz,1H),7.23(s,1H),4.43(p,J=6.7Hz,1H),2.04(h,J=5.9,5.1Hz,1H),1.43(d,J=6.7Hz,6H),0.79(dt,J=4.9,2.4Hz,4H).

[0570] Example 87

[0571] 6-(cyclopropanecarboxamide)-4-((2-(2,2-difluoroethoxy)-4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0572] Referring to the synthesis method of Example 28, compound 87 was obtained by replacing 28c with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazole.

[0573] LCMS: 529 (M+1)

[0574] 1 H NMR (400MHz, DMSO-d6) δ11.27(s,1H),10.72(s,1H),9.06(d,J=9.9Hz,2H),8.55(s,1H),7.98(s,1H),7.61(d,J=1.6Hz, 1H),7.50–7.36(m,2H),6.46–6.19(m,1H),4.45(td,J=14.1,3.9Hz,2H),2.05(td,J=7.7,4.0Hz,1H),0.89–0.68(m,4H).

[0575] Example 88

[0576] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(2,2-difluoroethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (88)

[0577] Referring to the synthetic method of Example 28, compound 88 was obtained by substituting 1-methyl-1H-pyrazole-4-boronic acid pinacol ester for 28c.

[0578] LCMS (ESI-MS) m / z: 475 (M+H + ).

[0579] 1 H NMR (400MHz, DMSO-d6) δ11.23(s,1H),10.59(s,1H),9.04(s,1H),8.20(s,1H),7.92(d,J=14.9Hz,2H),7.41(d,J=1.8Hz,1H),7.33(d,J=8.2Hz,1 H),7.25(dd,J=8.2,1.7Hz,1H),6.28(t,J=3.8Hz,1H),4.42(td,J=14.2, 3.8Hz, 2H), 3.85 (s, 3H), 2.05 (tt, J=7.4, 5.0Hz, 1H), 0.85–0.72 (m, 4H).

[0580] Example 89

[0581] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-cyclopropyloxy-4-(1-difluoromethyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (89)

[0582] Referring to the synthetic method of Example 27, Compound 89 can be obtained by substituting 4-bromo-1-(difluoromethyl)-1H-pyrazole for 4-bromo-1-isopropyl-1H-pyrazole.

[0583] LCMS [M+H] + =487.3.

[0584] 1 H NMR(400MHz,DMSO-d6)δ11.26(s,1H),10.60(s,1H),9.05(s,1H),8.78(s,1H),8.32(s,1H),8.06–7.59(m ,3H),7.36(s,2H),4.01(dt,J=6.0,3.1Hz,1H),2.14–1.95(m,1H),0.89–0.71(m,6H),0.69–0.57(m,2H).

[0585] Example 90

[0586] Synthesis of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-cyclopropyloxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (90)

[0587] Referring to the synthetic method of Example 27, Compound 90 can be obtained by substituting 4-bromo-1-methyl-1H-pyrazole for 4-bromo-1-isopropyl-1H-pyrazole.

[0588] LCMS [M+H] = 451.3

[0589] 1H NMR (400MHz, DMSO-d6) δ11.24(s,1H),10.52(s,1H),9.05(s,1H),8.53–8.39(m,1H),8.19(s,1H),7.90(d,J=6.6Hz,2H), 7.55(s,1H),7.36–7.18(m,2H),4.04–3.93(m,1H),3.87(s,2H),2.17–1.90(m,2H),0.91–0.71(m,5H),0.70–0.54(m,2H).

[0590] Example 91

[0591] Synthesis of 6-[(cyclopropylcarbonyl)amino]-4-{[2-(cyclopropyloxy)-4-(1-methyl-1,2,4-triazol-3-yl)phenyl]amino}-N-(trideuteriomethyl)-1,2-pyridazine-3-carboxamide (91)

[0592] Referring to the synthesis method of Example 27, Compound 91 was obtained by replacing 4-bromo-1-isopropylpyrazole with 3-bromo-1-methyl[1.2.4]triazole.

[0593] LCMS (ESI-MS) m / z: 452.3 (M+H+).

[0594] 1H NMR (400MHz, DMSO-d6) δ11.26(s,1H),10.64(s,1H),9.06(s,1H),8.52(s,1H),8.01–7.92(m,2H),7.62(dd,J=8.2,1.8Hz,1H),7 .42(d,J=8.2Hz,1H),3.98(dt,J=6.0,3.0Hz,1H),3.92(s,3H),2.05(p,J=6.6Hz,1H),0.86–0.74(m,5H),0.66(d,J=3.4Hz,2H).

[0595] Example 92

[0596] Synthesis of 6-[(cyclopropylcarbonyl)amino]-N-(trideuteriomethyl)-4-({2-[(2,2,2-trifluoroethyl)oxy]-4-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]phenyl}amino)-pyridazine-3-carboxamide (92)

[0597] Referring to the synthetic method of Example 22, Compound 92 can be obtained by replacing 4-bromo-1-isopropylpyrazole with 4-bromo-1-trifluoroethylpyrazole.

[0598] LCMS [M+H] = 560.9

[0599] 1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),10.63(s,1H),9.07(s,1H),8.36(s,1H),8.14(s,1H),7.91(s,1H),7 .54(s,1H),7.44-7.33(m,2H),5.25-5.11(m,2H),4.94-4.82(m,2H),2.09–2.03(m,1H),0.90–0.68(m,4H).

[0600] Example 93

[0601] Synthesis of 6-{[(2,2-difluorocyclopropyl)carbonyl]amino}-4-{[4-(1-ethylpyrazol-4-yl)-2-(propan-2-yloxy)phenyl]amino}-N-(trideuteriomethyl)-1,2-diazacyclohexane-3-carboxamide (93)

[0602] Referring to the synthesis method of Example 21, Compound 93 can be obtained by replacing cyclopropanecarboxamide with 2,2-difluorocyclopropane-1-carboxamide.

[0603] LCMS (ESI-MS) m / z: 503.0 (M+H + ).

[0604] 1 H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.69(s,1H),9.07(s,1H),8.24(s,1H),7.95-7.91(m,2H),7. 33-7.20(m,3H),4.71(s,1H),4.12(s,2H),3.03(s,1H),1.99(s,2H),1.39(s,3H),1.24–1.21(m,6H).

[0605] Example 94

[0606] Synthesis of 6-(2,2-difluorocyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(2,2-difluoroethoxy)-4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (94)

[0607] Referring to the synthesis method of Example 28, compound 94 can be obtained by replacing propanecarboxamide with 2,2-difluorocyclopropanecarboxamide.

[0608] LCMS (ESI-MS) m / z: 539 (M+H + ).

[0609] 1H NMR (400MHz, DMSO-d6) δ11.23(s,1H),10.58(s,1H),9.04(s,1H),8.30(s,1H),7.91(d,J=15.0Hz,2H),7.42(s,1H),7.3 7–7.22(m,3H),6.28(t,J=54.8Hz,2H),4.51–4.37(m,3H),3.06–2.98(m,1H),2.01–1.94(m,2H),1.44(d,J=6.7Hz,6H).

[0610] Example 95

[0611] Synthesis of 6-({[(2S)-2-fluorocyclopropyl]carbonyl}amino)-4-{[4-(1-methylpyrazol-4-yl)-2-[(2,2,2-trifluoroethyl)oxy]phenyl]amino}-N-(trideuteriomethyl)-1,2-diazacyclohexane-3-carboxamide (95)

[0612] Referring to the synthetic method of Example 34, Compound 95 can be obtained by replacing cyclopropanecarboxamide with (2S)-2-fluorocyclopropane-1-carboxamide.

[0613] LCMS (ESI-MS) m / z: 511.0 (M+H + ).

[0614] 1 H NMR(400MHz,DMSO-d6)δ11.28(s,1H),10.59(s,1H),9.06(s,1H),8.20(s,1H),7.95(s,1H),7.86(s,1H),7.49(s,1H),7.38–7.36(m ,1H),7.32–7.30(m,1H),5.01–4.97(m,1H)4.89–4.78(m,2H),3.86(s,3H),2.28–2.21(m,1H),1.60–1.52(m,1H),1.17–1.13(m,1H).

[0615] Example 96

[0616] Synthesis of 6-({[(1R,2S)-2-fluorocyclopropyl]carbonyl}amino)-4-[2-isopropoxy-4-(1-ethyl-1H-pyrazol-4-yl)anilino]-N-(trideuteriomethyl)-pyridazine-3-carboxamide (96)

[0617] Referring to the synthesis method of Example 21, compound 96 can be obtained by replacing propanecarboxamide with (1s,2s)-2-fluorocyclopropanecarboxamide.

[0618] LCMS (ESI-MS) m / z: 485.0 (M+H + ).

[0619] 1 H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.69(s,1H),9.07(s,1H),8.25(s, 1H),7.99(s,1H),7.92(s,1H),7.34–7.31(m,2H),7.21–7.18(m,1H),4.96 –4.77(m,1H),4.74–4.68(m,1H),4.17–4.12(m,2H),2.66–2.58(m,1H),1. 57–1.49(m,1H),1.43–1.39(m,3H),1.27–1.25(m,6H),1.23–1.18(m,1H).

[0620] Example 97

[0621] Synthesis of 6-((1s,2s)-2-fluoropropane-1-carboxamide)-4-(((2-isopropoxy-4-1-isopropyl-1H-pyrazol-4-phenyl)phenyl)-n-(methyl-d3)pyridazine-3-carboxamide

[0622] Referring to the synthesis method of Example 20, compound 97 was obtained by replacing cyclopropaneamide with 1s,2s-2-fluorocyclopropane-1-carboxamide.

[0623] LCMS [M+H] + =499.00

[0624] 1H NMR (400MHz, DMSO-d6) δ11.28(s,1H),10.68(s,1H),9.05(s,1H),8.27(d,J=0.8Hz,1 H),8.02(s,1H),7.90(d,J=0.8Hz,1H),7.33(d,J=8.2Hz,2H),7.22(dd,J=8.2,1.8Hz, 1H),5.01-4.81(m,1H),4.74-4.68(m,1H),4.50-4.44(m,1H),2.27-2.22(m,1H),1.6 3-1.54(m,1H),1.44(d,J=6.7Hz,6H),1.24(dd,J=6.0,3.6Hz,6H),1.18–1.09(m,1H).

[0625] \

[0626] Example 98

[0627] Synthesis of 6-((1R,2s)-2-fluoropropane-1-carboxamide)-4-(((2-isopropoxy-4-)(1-isopropyl-1H-pyrazol-4-phenyl)phenyl)-n-(methyl-d3)pyridazine-3-carboxamide

[0628] Referring to the synthesis method of Example 20, compound 97 was obtained by replacing cyclopropaneamide with 1R,2s-2-fluorocyclopropane-1-carboxamide.

[0629] LCMS [M+H] + =499.00

[0630] 1 H NMR (400MHz, DMSO-d6) δ11.39(s,1H),10.67(s,1H),9.06(s,1H),8.27(s,1H),7.97(s,1H),7.90(d,J=0.8Hz,1H),7.37–7.28(m,2H),7.1 9(dd,J=8.2,1.8Hz,1H),4.93-4.77(m,1H),4.75-4.58(m,1H),4.48(m,1H),2.66-2.55(m,1H),1.44(d,J=6.7Hz,6H),1.28–1.16(m,8H).

[0631] Example 99

[0632] Synthesis of 4-((4-(1-cyclopropyl-1H-pyrazol-4-yl)-2-(2,2,2-trifluoroethoxy)phenyl)amino)-6-((1S,2S)-2-fluorocyclopropane-1-carboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (99)

[0633] Referring to the synthetic method of Example 33, Compound 99 was obtained by replacing cyclopropaneamide with 1s,2s-2-fluorocyclopropane-1-carboxamide.

[0634] LCMS (ESI-MS) m / z: 537.0 (M+H + ).

[0635] 1 H NMR (400MHz, DMSO-d6) δ11.28(s,1H),10.59(s,1H),9.06(s,1H),8.30(s,1H),7.94(s,1H),7.86(s,1H),7.49(d,J=1.7Hz,1H),7.41–7.29( m,2H),5.03–4.95(m,1H),4.92–4.75(m,2H),3.78–3.69(m,1H),2.29– 2.19(m,1H),1.63–1.50(m,1H),1.18–1.11(m,1H),1.09–0.94(m,4H).

[0636] Example 100

[0637] Synthesis of 6-(cyclopropanecarboxamide)-4-((4-(1-ethyl-1H-pyrazol-4-yl)-2-(2-fluoroethoxy)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (100)

[0638] Referring to the synthetic method of Example 38, compound 100 was obtained by replacing 2,2-difluoroethanol with 2-fluoroethanol.

[0639] LCMS (ESI-MS) m / z: 471.0 (M+H + ).

[0640] 1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),10.63(s,1H),9.04(s,1H),8.24(d,J=0.9Hz,1H), 7.96(s,1H),7.92(d,J=0.8Hz,1H),7.36(d,J=1.8Hz,1H),7.35–7.31(m,1H),7.23(dd,J =8.2,1.8Hz,1H),4.78–4.70(m,1H),4.66–4.59(m,1H),4.43–4.37(m,1H),4.35–4.29(m ,1H),4.13(q,J=7.3Hz,2H),2.10–2.01(m,1H),1.40(t,J=7.3Hz,3H),0.84–0.72(m,4H).

[0641] Example 101

[0642] Synthesis of 6-[(cyclopropylcarbonyl)amino]-4-[2-ethoxy-4-(1-ethyl-1H-pyrazol-4-yl)anilino]-N-(trideuteriomethyl)-pyridazine-3-carboxamide (101)

[0643] Referring to the synthetic method of Example 21, compound 101 can be obtained by replacing isopropanol with ethanol.

[0644] LCMS (ESI-MS) m / z: 453.0 (M+H + ).

[0645] 1 H NMR (400MHz, DMSO-d6) δ11.24(s,1H),10.65(s,1H),9.05(s,1H),8.25(s,1H),8.00(s,1H),7.92(s,1H),7.33–7.31(m, 2H),7.21–7.19(m,1H),4.18–4.12(m,4H),2.09–2.05(m,1H),1.43–1.39(m,3H),1.31–1.28(m,3H),0.83–0.78(m,4H).

[0646] Example 102

[0647] 6-(cyclopropanecarboxamide)-4-((2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0648] Referring to the synthetic method of Example 101, Compound 102 can be obtained by replacing 4-bromo-1-methylpyrazole with 4-bromo-1-ethylpyrazole.

[0649] LCMS: 439 (M+1)

[0650] 1 H NMR (400MHz, DMSO-d6) δ11.24(s,1H),10.64(s,1H),9.05(s,1H),8.18(s,1H),7.98(s,1H),7.90(d,J=0.9Hz,1H),7.34–7.25(m,2H),7.17(d d,J=8.1,1.8Hz,1H),4.13(q,J=6.9Hz,2H),3.84(s,3H),2.05(td,J=7.4,3.8Hz,1H),1.28(t,J=6.9Hz,3H),0.79(dq,J=9.6,3.9,3.4Hz,4H).

[0651] Example 103

[0652] Synthesis of 6-[(cyclopropylcarbonyl)amino]-N-(trideuteriomethyl)-4-({2-methoxy-4-[1-ethyl-pyrazol-4-yl]phenyl}amino)-pyridazine-3-carboxamide (103)

[0653] Referring to the synthetic method of Example 21, compound 103 can be obtained by replacing isopropanol with methanol.

[0654] LCMS [M+H] = 439.0

[0655] 1H NMR (400MHz, DMSO-d6) δ11.26(s,1H),10.61(s,1H),9.08(s,1H),8.27(s,1H),7.97(d,J=19.1Hz,2H),7.40–7.27(m,2 H),7.21(d,J=8.3Hz,1H),4.20-4.05(m,2H),3.87(s,3H),2.13-2.01(m,1H),1.50-1.30(m,3H),0.81(d,J=7.4Hz,4H).

[0656] Example 104

[0657] Synthesis of 6-((1s,2s)-2-fluorocyclopropanecarboxamido)-N-(methyl-d3)-4-((2-(2,2-difluoroethoxy)-4-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)amino)pyridazine-3-carboxamide (104)

[0658] Referring to the synthesis method of Example 39, Compound 104 was obtained by replacing 4-bromo-1-isopropylpyrazole with 4-bromo-1-cyclopropylpyrazole.

[0659] LCMS [M+H] = 519.0

[0660] 1H NMR (400MHz, DMSO-d6) δ11.33(d,J=11.3Hz,1H),10.63(s,1H),9.09(s,1H),8. 33(s,1H),7.93(d,J=19.6Hz,2H),7.43(d,J=14.7Hz,1H),7.40–7.22(m,2H),6 .29(s,1H),5.00(s,1H),4.84(s,1H),4.54-4.32(m,2H),3.79–3.67(m,1H),2. 31–2.20(m,1H),1.58(d,J=24.1Hz,1H),1.22–1.11(m,1H),1.11–0.90(m,4H).

[0661] Example 105

[0662] Synthesis of 6-[(cyclopropylcarbonyl)amino]-4-{[2-(isopropyloxy)-4-(1-aminomethylcarbonylmethyl-1,2,4-triazol-3-yl)phenyl]amino}-N-(trideuteriomethyl)-1,2-pyridazine-3-carboxamide (105)

[0663] Referring to the synthetic method of Example 21, Compound 105 was obtained by replacing 1-ethyl-4-bromopyrazole with 3-bromo-1-aminomethylcarbonylmethyl-1,2,4-triazole.

[0664] MS m / z(ESI):511.2[M+H] + .

[0665] 1H NMR (400MHz, DMSO-d6) δ11.29(s,1H),10.82(s,1H),9.07(s,1H),8.53(d,J=1.0Hz,1 H),8.23–8.15(m,1H),8.14(d,J=1.1Hz,1H),7.64(d,J=1.7Hz,1H),7.58(dd,J=8.2, 1.7Hz,1H),7.46(d,J=8.3Hz,1H),4.91(s,2H),4.66(hept,J=6.0Hz,1H),2.63(d,J= 4.6Hz, 3H), 2.05 (p, J = 6.2Hz, 1H), 1.28 (dd, J = 6.1, 0.9Hz, 6H), 0.80 (d, J = 6.1Hz, 3H).

[0666] Example 106

[0667] Synthesis of 6-(cyclopropanecarboxamide)-4-((2-ethoxy-4-(1-methoxy-1H-pyrazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (106)

[0668] Referring to the synthetic method of Example 101, Compound 106 can be obtained by replacing 4-bromo-1-ethylpyrazole with 4-bromo-1-methoxypyrazole.

[0669] LCMS (ESI-MS) m / z: 455.0 (M+H + ).

[0670] 1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),10.67(s,1H),9.06(s,1H),8.37(d,J=1.2Hz,1H),8.00(s,1H),7.80(d,J=1.2Hz,1H),7.35–7.3 0(m,2H),7.22(dd,J=8.2,1.7Hz,1H),4.14(q,J=6.9Hz,2H),4.08(s,3H),2.09–2.01(m,1H),1.28(t,J=6.9Hz,3H),0.84–0.73(m,4H).

[0671] Biological activity test

[0672] Experiment 1: In vitro activity determination of the small molecule TYK2 inhibitor compounds of the present invention

[0673] 1. Purpose of the experiment

[0674] In this study, the inhibitory effects of the compounds of the present invention (Compounds 1 to 40) on TYK2JH2 pseudokinase were tested by fluorescence resonance energy transfer (TR-FRET). 50 ) To evaluate the in vitro activity of the compounds.

[0675] 2. Experimental Methods

[0676] 2.1 Prepare 1× experimental working solution

[0677] Preparation of experimental working solution

[0678] 2.2 Experimental Procedure

[0679] (1) Dissolve the compound in DMSO to a stock concentration of 10 mM.

[0680] (2) Prepare a compound dilution plate with a compound concentration 200 times the final concentration, dilute from the highest concentration point using a 27-fold dilution method, for a total of 4 concentration points, and transfer to an Echo plate.

[0681] (3) Use the Echo instrument to pulse the compounds from the Echo plate to the 384 assay plate, so that the compounds become a 3-fold serial dilution matrix with 11 concentration points.

[0682] (4) Add 5 μl of 3X TYK2JH2 kinase to the 384-well assay plate.

[0683] (5) Add 5 μl of 3X Tb to the 384 assay plate.

[0684] (6) Add 5 μl of 3X Tracer to a 384-well assay plate.

[0685] (7) Centrifuge for 30 seconds and incubate at room temperature for 60 minutes.

[0686] (8) Fluorescence signal value of Envision microplate reader (PerkinElmer) 495 / 520.

[0687] (9) Use XL-Fit software to analyze the data and obtain the compound IC 50 .

[0688] 2.3 Experimental Results

[0689] Table 1 In vitro activity test results of the compounds of the present invention

[0690] Conclusion: The compounds of the present invention have significant inhibitory activity against TYK2JH2 pseudokinase.

[0691] Experiment 2: Pharmacokinetics of the compounds of the present invention in rats

[0692] 1. Experimental purpose:

[0693] Taking SD rats as an example, the drug concentrations in the plasma of rats at different times after oral and intravenous administration of compound 1 and compound 7 were determined by liquid chromatography-tandem mass spectrometry (LS / MS / MS) and the relevant pharmacokinetic parameters were calculated to evaluate the pharmacokinetic properties of the example compounds of the present invention in rats.

[0694] 2. Experimental Plan

[0695] 2.1 Trial Drugs

[0696] Example Compound 1, Example Compound 7.

[0697] 2.2 Experimental animals

[0698] Healthy adult male SD rats, SPF grade, were purchased from Shanghai Xipu-Bikai Laboratory Animal Co., Ltd., license number SCXK (Shanghai) 2018-0006, animal certificate number: 20180006006321.

[0699] 2.3 Drug configuration

[0700] Weigh a predetermined amount of compound and dissolve it in 5% ethanol, vortex and sonicate. Add 5% water-soluble natural vitamin E (TPGS, heat before preparation) and mix thoroughly. Add 90% purified water and mix thoroughly to prepare a 1 mg / mL homogeneous oral solution. Weigh a predetermined amount of compound and dissolve it in 80% polyethylene glycol 400 (PEG400) and vortex and sonicate. Add 20% purified water to prepare a 0.4 mg / mL clear, transparent intravenous solution.

[0701] 2.4 Administration

[0702] The specific administration was carried out according to the experimental plan, and the details are shown in Table 2.

[0703] Table 2 Pharmacokinetic study protocol in rats

[0704] 2.5 Blood collection time and sample processing

[0705] Blood was collected from the eye socket before administration and 5 minutes, 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours after administration. 0.2 milliliters (mL) of blood was collected each time, placed in an anticoagulant tube, mixed, and stored in a -20°C refrigerator for use.

[0706] 3. Sample testing and data analysis

[0707] Liquid chromatography-tandem mass spectrometry (LS / MS / MS) was used to determine the content of the compound in rat whole blood.

[0708] The pharmacokinetic parameters of the compounds after administration were calculated using the non-compartmental model of WinNonLin5.3 software.

[0709] 4. Test results

[0710] The pharmacokinetic parameters of the compounds of the present invention after administration are shown in the following Table 3. As shown in Table 3, the compounds of the present invention have good metabolic characteristics and bioavailability.

[0711] Table 3 Pharmacokinetic parameters of the compounds of the present invention

[0712] Experiment 3: In vivo efficacy study of the compounds of the present invention in mice

[0713] 1. Psoriasis Model

[0714] 1. Modeling and Drug Administration

[0715] Eight-week-old female BALB / c mice with an average weight of 20 g were purchased. Experiments began after the mice were acclimated for three days. The mice were divided into five groups: a normal control group, a model group, a group receiving the example compound, and a positive drug group (BMS-986165), with 5-8 mice per group. Mice in the model, example compound, and positive drug groups were anesthetized with an intraperitoneal injection of sodium pentobarbital (80 mg / kg). After hair removal, 62.5 mg of 5% imiquimod cream was evenly applied to the back once daily. The normal control group was treated with an equal amount of petrolatum. The example compound group (10 mg / kg) was administered orally at 10 mL / kg once daily. The normal control group was given an equal amount of purified water, and the model group was given an equal amount of vehicle for 7 consecutive days. The detailed design is shown in Table 4.

[0716] Table 4 In vivo efficacy experimental plan of compounds NA represents a blank entry.

[0717] 2. Experimental Animals

[0718] Thirty-seven female BALB / c mice, 8 weeks old, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd., license number SCXK(Shanghai)2017-0011, animal qualification certificate number: 20170011003865.

[0719] 3. Experimental drugs

[0720] Example Compound 1, Example Compound 7.

[0721] 4. Drug configuration

[0722] Weigh an appropriate amount of compound, dissolve in 5% ethanol, vortex and sonicate, add 5% water-soluble natural vitamin E (TPGS, which needs to be heated before preparation) and mix well, then add 90% pure water and mix well to prepare a uniform solution of 1 mg / mL.

[0723] 5. Medication

[0724] The specific administration is carried out according to the administration plan.

[0725] 6. Detection indicators and methods

[0726] The skin lesions of the mice were observed every day and digital photography was used to score the erythema, scaling and infiltration degree of the skin lesions of the mice according to the psoriasis area and severity index (PASI) scoring standard (0: none; 1: mild; 2: moderate; 3: severe; 4: very severe). The changes of skin lesions in each group of mice were observed.

[0727] 7. Experimental results and conclusions

[0728] Five days after applying imiquimod to the back skin of mice, the model control group experienced significant thickening and infiltration of lesions on the back, with the appearance of numerous plaque-like scales and reddening of the skin. The erythema and scales in the lesions of mice treated with Example Compound 1 and Example Compound 7 were significantly reduced, and infiltration was alleviated. While the PASI scores of mice in the model control group continued to increase over the days, those in the Example Compound 1 and Example Compound 7 groups began to significantly decrease after the third day, demonstrating superior efficacy to the positive drug group.

[0729] 2. Psoriasis Model

[0730] 1. Modeling and drug administration.

[0731] Forty eight-week-old female C57BL / 6 mice with an average weight of 20 g were purchased. Animal experiments began after the mice had been acclimated for seven days. Each mouse received a subcutaneous injection of murine IL-23 into the right ear, once every other day for a total of seven injections over a 14-day period. The control and treatment groups received oral administration twice daily starting on the first day of modeling. The detailed protocol is shown in Table 5.

[0732] Table 5 In vivo efficacy experimental plan of compounds NA represents a blank item

[0733] 2. Experimental drugs

[0734] Example test substance 1, Example test substance 7

[0735] 1. Drug configuration

[0736] Weigh an appropriate amount of compound, dissolve in 5% ethanol, vortex and sonicate, add 5% water-soluble natural vitamin E (TPGS, which needs to be heated before preparation) and mix well, then add 90% pure water and mix well to prepare a uniform solution of 1.5 mg / mL.

[0737] 2. Medication

[0738] The specific drug administration was carried out according to the experimental design

[0739] 3. Detection indicators and methods

[0740] The efficacy results were analyzed by measuring the thickness of the right ear skin. After the administration, the right ear skin tissue was taken for HE staining, and the final efficacy results were confirmed by pathological scoring.

[0741] 4. Experimental Results and Discussion

[0742] After 14 days of administration, Example Compound 1, Example Compound 7 and BMS-986165 were able to reduce the thickness of the right ear skin of mice. The final pathological results showed that Example Compound 1, Example Compound 7 and BMS-986165 were able to improve inflammatory infiltration. Comprehensive efficacy analysis showed that Example Compound 1 and Example Compound 7 were able to achieve the efficacy of high-dose BMS-986165 at low doses. Statistics showed that the efficacy of Example Compound 1 and Example Compound 7 in mice was better than that of BMS-986165.

[0743] 3. Inflammatory Bowel Disease Model

[0744] After oral gavage with 2.5% dextran sulfate sodium (DSS) to induce IBD in mice, the model group exhibited symptoms such as weight loss, lethargy, lethargy, bloody stools, and diarrhea, with a significantly higher disease activity index (DAI) than the control group. On the third day of administration, Example Compounds 1 and 7 significantly reduced the DAI scores of mice, inhibited DSS-induced weight loss and colon shortening, and significantly reduced DSS-induced intestinal damage. Pathological examination revealed that the Example Compounds effectively inhibited inflammatory infiltration in the colon.

[0745] 4. Lupus erythematosus model

[0746] Female MRL / lpr mice were selected as experimental animals for the lupus erythematosus model. Lymph node enlargement and skin lesions in the mice were assessed weekly, as well as related urine albumin and creatinine indicators. In vivo efficacy studies found that Example Compound 1 and Example Compound 7 could significantly reduce pristane-induced lupus mouse autoantibodies (anti-ds DNA, anti-SLE) and urine protein concentrations, and reduce glomerular swelling. Pathological tissue examinations found that they could effectively reduce inflammatory cell infiltration.

[0747] Experiment 4: Acute toxicity test of the compound of the present invention in mice

[0748] 1. Purpose of the experiment

[0749] The purpose of this experiment is to test the acute toxicity of the example compounds in mice.

[0750] 2. Experimental Animals

[0751] ICR mice, SPF grade, 6-8 weeks old, half male and half female, were purchased from Shanghai Xipu-Bikai Laboratory Animal Co., Ltd., license number SCXK (Shanghai) 2018-0006, animal certificate number: 20180006010983.

[0752] 3. Trial Drugs

[0753] Example Compound 1, Example Compound 7.

[0754] 4. Experimental Methods

[0755] ICR mice were given a single dose of different compounds and observed for 14 consecutive days. Death, toxic reactions, weight changes, diet, appearance, behavior, etc. were recorded. At the endpoint, the animals were dissected and organs were removed for histopathological examination and related hematological examinations.

[0756] 5. Experimental results and conclusions

[0757] The no-toxic effect dose (NOAEL) of Example Compound 1 and Example Compound 7 was greater than 1000 mg per kilogram (mg / kg). Compared with the mice in the control group, the mice in the drug-treated group showed no abnormalities in weight and behavior within 14 days from the date of administration, and no obvious abnormalities were found in related hematology. No toxic effects of the relevant example compounds were found in pathological examinations, indicating that Example Compound 1 and Example Compound 7 of the present invention are safe and can be safely tolerated by animals.

[0758] Experiment 5: Long-term toxicity test of the compound of the present invention in mice

[0759] 1. Purpose of the experiment

[0760] The purpose of this experiment is to test the long-term toxic effects of the example compounds on mice.

[0761] 2. Experimental Animals

[0762] ICR mice, SPF grade, 6-8 weeks old, half male and half female, were purchased from Shanghai Xipu-Bikai Laboratory Animal Co., Ltd., license number SCXK (Shanghai) 2018-0006, animal certificate number: 20180006010983.

[0763] 3. Trial Drugs

[0764] Example Compound 1, Example Compound 7.

[0765] 4. Experimental Methods

[0766] ICR mice were administered different doses of the compound and observed for 14 consecutive days. Death, toxic reactions, weight changes, diet, appearance, behavior, etc. were recorded. At the endpoint, the animals were dissected and organs were removed for histopathological examination and related hematological examinations.

[0767] 5. Experimental results and conclusions

[0768] The no-toxic effect dose (NOAEL) of Example Compound 1 and Example Compound 7 was greater than 500 mg per kilogram (mg / kg). Compared with the mice in the control group, the mice in the drug-treated group showed no abnormalities in body weight and behavior within 14 days from the date of administration, and no obvious abnormalities were found in related hematology. No toxic effects of the relevant example compounds were found in pathological examinations, indicating that Example Compound 1 and Example Compound 7 of the present invention are safe and can be safely tolerated by animals.

[0769] All documents mentioned in this application are incorporated herein by reference, just as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and any equivalent changes or modifications made in accordance with the spirit of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A compound represented by general formula (II) or a pharmaceutically acceptable salt or isotopic derivative thereof, Where R1 is -C 1-3 deuterated alkyl; R2 is -C 3-6 Cycloalkyl, wherein the -C 3-6 The cycloalkyl group is optionally further selected from a hydrogen atom, a -C 1-3 substituted by one or more substituents selected from alkyl and halogen; R3 is -C 1-3 Alkyloxy or -C 3-6 Cycloalkyloxy, wherein the -C 1-3 Alkyloxy or -C 3-6 Cycloalkyloxy is optionally further selected from hydrogen atoms, deuterium atoms, -C 1-3 substituted by one or more substituents selected from alkyl and halogen; R4 is a 5-6 membered heteroaryl or a 6- to 10-membered bicyclic ring, wherein the 5- to 6-membered heteroaryl is optionally replaced by R a Substituted, the bicyclic rings are fused and connected, and at least one ring is an aromatic ring, and the bicyclic ring is optionally replaced by R b replace; R a -H, halogen, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, wherein the -C 1-3 Alkyl, -C 1-3 Alkoxy or -C 3-6 The cycloalkyl group is optionally further selected from hydrogen atoms, -NH2, -CF3, -CN, -C 1-3 Alkyl, -C 2-3 Alkenyl, -C 2-3 Alkynyl, -C 1-3 Alkoxy, -C 1-3 Alkylamino, -C(O)NH-C 1-3 Alkyl, -C 3-6 substituted by one or more substituents selected from cycloalkyl, 4-6 membered heterocyclic group or halogen; R b -S(O)2-C 1-3 Alkyl or -S(O)NH-C 1-3 alkyl; 2. The compound according to claim 1, or a pharmaceutically acceptable salt or isotopic derivative thereof, characterized in that: R1 is -CD3; R2 is a substituted or unsubstituted cyclopropane group; R3 is -OCH3, -OCF3, -O-CH2CH3, -O-CH2CF3, -OCHF2, -O-CH2CHF2, -O-CH2CH2F, -O-CH2CH(CH3) 2、 -OCH(CH3)2 or 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or isotopic derivative thereof, characterized in that: R4 is 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or isotopic derivative thereof, characterized in that: R a -H, -F, -CN, -CHF2, methyl, ethyl, propyl, trifluoromethyl, methoxy, -CH2-CF3, -CH2-CN, -CH2-CCH, -CH2-OCH3, -CH2CH2-CF3, -CH2CH2-OCH3, -CH2CH2-NH2, -CH2CH2-NH-CH3, -CH(CH3)2, -CH2-C(O)NH-CH3, or cyclopropane; R b It is -S(O)2-CH3 or -S(O)NH-CH3.

5. A compound represented by general formula (II) or a pharmaceutically acceptable salt or isotopic derivative thereof according to any one of claims 1 to 4, characterized in that: R1 is -C 1-3 deuterated alkyl; R2 is -C 3-6 Cycloalkyl, wherein the -C 3-6 The cycloalkyl group is optionally further selected from a hydrogen atom, a -C 1-3 substituted by one or more substituents selected from alkyl and halogen; R3 is -C 1-3 Alkyloxy or -C 3-6 Cycloalkyloxy, wherein the -C 1-3 Alkyloxy or -C 3-6 Cycloalkyloxy is optionally further selected from hydrogen atoms, deuterium atoms, -C 1-3 substituted by one or more substituents selected from alkyl and halogen; R4 is a 5-6 membered heteroaryl group, wherein said 5-6 membered heteroaryl group is optionally replaced by R a replace; R a -H, -CN, -CF3, -C 1-3 Alkyl, -C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, wherein the -C 1-3 Alkyl or -C 3-6 The cycloalkyl group is optionally further selected from a hydrogen atom, a -C 1-3 The alkyl group and the halogen group are substituted with one or more substituents.

6. The compound according to claim 5, or a pharmaceutically acceptable salt or isotopic derivative thereof, characterized in that: R1 is -CD3; R2 is a substituted or unsubstituted cyclopropane; R3 is -OCF3, -O-CH2CF3, -OCHF2, -O-CH2CHF2, -OCH(CH3)2 or 7. The compound according to claim 5 or 6, or a pharmaceutically acceptable salt or isotopic derivative thereof, characterized in that: R4 is 8. The compound according to any one of claims 5 to 7, or a pharmaceutically acceptable salt or isotopic derivative thereof, characterized in that: R a It is -H, -CN, -CHF2, methyl, ethyl, trifluoromethyl, -CH(CH3)2 or cyclopropane.

9. A compound represented by general formula (II) or a pharmaceutically acceptable salt or isotopic derivative thereof according to any one of claims 1 to 4, characterized in that: R1 is -C 1-3 deuterated alkyl; R2 is -C 3-6 Cycloalkyl; R3 is halogen-substituted C 1-3 alkoxy; R4 is a 5-6 membered heteroaryl group, wherein said 5-6 membered heteroaryl group is optionally replaced by R a replace; R a -H, -C 1-3 Alkyl, -C 1-3 Haloalkyl, -C 3-6 Cycloalkyl or 4-6 membered heterocyclic group.

10. The compound according to claim 9, or a pharmaceutically acceptable salt or isotopic derivative thereof, characterized in that: R1 is -CD3; R2 is cyclopropane; R3 is -OCF3 or -OCHF2.

11. The compound according to claim 9 or 10, or a pharmaceutically acceptable salt or isotopic derivative thereof, characterized in that: R4 is optionally replaced by R a Substituted 5-membered heteroaryl groups containing 1, 2, 3 or 4 nitrogen heteroatoms.

12. The compound according to any one of claims 9 to 11, or a pharmaceutically acceptable salt or isotopic derivative thereof, characterized in that: R4 is R a is -H, methyl, ethyl, trifluoromethyl or cyclopropane.

13. A compound represented by general formula (II) or a pharmaceutically acceptable salt or isotopic derivative thereof according to any one of claims 1 to 4, characterized in that: R1 is -C 1-3 deuterated alkyl; R2 is -C 3-6 Cycloalkyl; R3 is -C 1-3 Alkyloxy or -C 3-6 Cycloalkyloxy, wherein the -C 1-3 Alkyloxy or -C 3-6 Cycloalkyloxy is optionally further selected from hydrogen atoms, deuterium atoms, -C 1-3 substituted by one or more substituents selected from alkyl and halogen; R4 is a 5-6 membered heteroaryl group, wherein said 5-6 membered heteroaryl group is optionally replaced by R a replace; R a -H, -CN, -CF3, -C 1-3 Alkyl, -C 3-6 Cycloalkyl or 4-6 membered heterocyclic group, wherein the -C 1-3 Alkyl or -C 3-6 The cycloalkyl group is optionally further selected from a hydrogen atom, a -C 1-3 The alkyl group and the halogen group are substituted with one or more substituents.

14. The compound according to claim 13, or a pharmaceutically acceptable salt or isotopic derivative thereof, characterized in that: R1 is -CD3; R2 is cyclopropane; R3 is -OCF3, -O-CH2CF3, -OCHF2, -O-CH2CHF2, -OCH(CH3)2 or 15. The compound according to claim 13 or 14, or a pharmaceutically acceptable salt or isotopic derivative thereof, characterized in that: R4 is 16. The compound according to any one of claims 12 to 15, or a pharmaceutically acceptable salt or isotopic derivative thereof, characterized in that: R a It is -H, -CN, -CHF2, methyl, ethyl, trifluoromethyl, -CH(CH3)2 or cyclopropane.

17. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or isotopic derivative thereof, characterized in that: The compound is selected from the following compounds or pharmaceutically acceptable salts or isotopic derivatives thereof:

18. A method for preparing the compound of formula II according to any one of claims 1 to 17, characterized in that: Contains the steps of Option 1 or Option 2. Option 1: Option 2: Compound IIa is borated and reacted with R4X to obtain compound IId, or compound IIa is directly reacted with R4H to obtain compound IId; Compound IId reacts with compound IIe to obtain compound IIf; Compound IIf reacts with R2C(O)NH2 to obtain compound II; wherein X is Br or I, and R1, R2, R3 and R4 are as described in any one of claims 1 to 17.

19. A pharmaceutical composition, characterized in that The invention comprises a therapeutically effective amount of a compound represented by formula II according to any one of claims 1 to 17 or a pharmaceutically acceptable salt or isotopic derivative thereof, and optionally one or more pharmaceutically acceptable carriers and / or diluents.

20. Use of the compound of formula II according to any one of claims 1 to 17 or a pharmaceutically acceptable salt or isotopic derivative thereof, or the pharmaceutical composition according to claim 19 in the preparation of a medicament for preventing and / or treating TYK2-mediated diseases.

21. The use according to claim 20, characterized in that The TYK2-mediated diseases include inflammatory diseases or autoimmune diseases.

22. The use according to claim 20, characterized in that The inflammatory disease and autoimmune disease are psoriasis, inflammatory bowel disease or lupus erythematosus.

23. A method for treating a disease mediated by TYK2, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula II according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or isotopic derivative thereof.

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