Compounds for use as TYK2 inhibitors, their preparation method and their medical application

Abstract

The present invention discloses a compound used as a TYK2 inhibitor, its preparation method and its pharmaceutical application. Specifically, the compound has a structure as shown in formula (I), wherein the definitions of each group and substituent are as described in the specification. The present invention further discloses a method for preparing the compound and its use in preventing and / or treating TYK2-mediated related diseases. [Formula 1] JPEG2025508011000090.jpg42170

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to the field of small molecule pharmaceuticals, in particular to compounds used as TYK2 inhibitors, their preparation methods and their pharmaceutical applications.

[0002] [Background technology] Autoimmune diseases are inflammatory diseases in which the body's autoimmune system attacks normal cells, weakening normal immunity and causing abnormal immunity, ultimately leading to tissue damage or organ dysfunction. Currently, more than 80 types of autoimmune diseases have been reported, affecting approximately 5% to 8% of the world's population. Among the diseases with higher incidence rates are psoriasis (PSO), rheumatoid arthritis (RA), psoriatic arthritis (PsA), ulcerative colitis (UC), Crohn's disease (CD), multiple sclerosis (MS), type 1 diabetes, spondyloarthritis (SpA), chronic graft-versus-host disease (cGVHD), atopic dermatitis, alopecia areata, asthma, and systemic lupus erythematosus (SLE). The sites of onset of these diseases extend to almost all organs in humans. They can be systemic, such as SLE, which can affect the skin, joints, kidneys, and central nervous system, or organ-specific, such as type 1 diabetes (pancreas) and UC (colon) [Cell 2020 181(1):63-80]. The pathogenic mechanisms of autoimmune diseases are complex, the disease-related disability rate is high, there is no fundamental treatment, and most patients suffer from great suffering throughout their lives. Therefore, autoimmune diseases are called "immortal cancers."

[0003] Since 2000, small molecule drugs that have been clinically approved for the treatment of autoimmune diseases are mainly Janus kinase (JAK) inhibitors. The family includes JAK1, JAK2, JAK3 and TYK2. Members of the JAK family regulate signals initiated by regulatory immunoregulatory cytokines by phosphorylating their receptors, which leads to recruitment, phosphorylation and activation of signal transducer and activator of transcription (STAT) proteins, affecting STAT-dependent transcriptional and functional responses. These cytokine signaling pathways play an important role in the pathogenesis of autoimmune and inflammatory diseases. To date, JAK inhibitors approved for clinical use, such as tofacitinib, baricitinib and upadacitinib, all act on the kinase domain (JH1 domain) of the JAK family and play a role by competing with ATP in the body. Due to the low selectivity of kinase subtypes, the above JAK inhibitors show a series of serious clinical side effects, such as anemia, infection, increased creatinine, hepatic transaminase, creatine phosphokinase, low density lipoprotein cholesterol, high density lipoprotein cholesterol levels, decreased NK cell, lymphocyte, neutrophil, platelet levels, etc. Therefore, the above three marketed drugs all have black box warnings about the risk of serious infection, malignant tumor, and thrombosis, and their clinical applications are greatly limited.

[0004] Recent research shows that TYK2, which also belongs to the JAK family, is the optimal target point for balancing efficacy and safety in autoimmune diseases [J.Med.Chem.2019,62,20,8953-8972]. TYK2 binds to JAK2 and mediates signaling through IL-12 and IL-23 (p40 subunit containing cytokines), induces / stabilizes the expression of IL-17 and other pro-inflammatory factors, and mediates the signaling of type 1 interferons (IFN-α, etc.) in collaboration with JAK1. The above cytokines mediated by TYK2 are the most important pro-inflammatory factors in the autoimmune system [Nature Reviews Drug Discovery 2021,20,39-63]. Blockade of the above inflammatory cytokine signaling pathways shows excellent pharmacological activity in animal models of rheumatoid arthritis, multiple sclerosis, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, and spondyloarthritis [J.Med.Chem.2019, 62, 20, 8973-8995, Science TranslationalMedicine 2019, 502(11), eaaw1736, J Clin Invest.2020, 130(4), 1863-1878]. Monoclonal antibody drugs developed against the above inflammatory factors IL-12, IL-23, IL-17, and IFN-α show excellent efficacy in the clinical treatment of multiple autoimmune diseases.

[0005] The above evidence indicates that TYK2, as a key kinase mediating IL-12, IL-23, IL-17 and IFN-α inflammatory signaling cascades, is a good drug target point for inflammatory and autoimmune diseases. Obviously, a highly subtype-selective (JAK1, JAK2, JAK3) TYK2 inhibitor may be able to avoid the severe side effects of existing JAK inhibition. BMS-986165 (Deucravacitinib), a highly subtype-selective TYK2 inhibitor developed by Bristol-Myers Squibb, has shown excellent efficacy and safety in two Phase III clinical studies targeting moderate to severe psoriasis. At the same time, BMS-986165 is in Phase II clinical evaluation for indications such as psoriatic arthritis, systemic lupus erythematosus, ulcerative colitis and Crohn's disease, indicating its strong potential in the treatment of autoimmune diseases. Representative patents for developing TYK2 inhibitors with high kinase (subtype) selectivity include WO2014074660, WO2014074661, and WO2019103952.

[0006] The present invention provides a TYK2 inhibitor with stronger kinase inhibitory activity, higher subtype selectivity, and at the same time better metabolic properties, stronger in vivo efficacy, and novel structure. The TYK2 inhibitor disclosed by the present invention can be used for the prevention and / or treatment of TYK2-mediated related diseases, particularly autoimmune diseases associated with IL-12, IL-23, IL-17, and type 1 interferon (IFN-α, etc.).

[0007] [Summary of the Invention] [Problem to be solved by the invention] The object of the present invention is to provide compounds of formula (I) and their preparation processes and uses in the prevention and / or treatment of TYK2 mediated related diseases.

[0008] [Means for solving the problem] A first aspect of the present invention provides a compound of formula (I) or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof,

[0009] [ka]

[0010] Here, R 1 is selected from the group consisting of H, a substituted or unsubstituted C1-C6 alkyl group, and a substituted or unsubstituted C3-C6 cycloalkyl group, where the substitution refers to substitution with one or more substituents selected from the group consisting of deuterium and halogen; A is NH or CH2; B is CH or N; L is

[0011] [ka] is selected from the group consisting of

[0012] R 2 is selected from the group consisting of H, -CD3, a C1-C6 alkyl group, and a C3-C6 cycloalkyl group; X is CH or N; Y is NH, O or S; R 3 , R 4 , R 5 are each independently H, -NH2, -OH, a C1-C6 alkoxy group, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C3-C6 cycloalkyl group, -CONH2, -CN, a halogen, or -O(CH2) n R 9 , a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C6 cycloalkyl-substituted C2-C6 alkynyl group, and -NR 8 (CH2) n R 9 is selected from the group consisting of n is 1, 2, 3, 4 or 5; R 9 is selected from the group consisting of -OH, a C1-C6 alkoxy group, a C4-C6 cycloalkoxy group, a 4-8 membered heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, and -CN; R 8 is H or a C1-C6 alkyl group, R 6 , R 7 are each independently selected from the group consisting of H, a C1-C6 alkyl group, and halogen.

[0013] In another preferred embodiment, R 1 is selected from the group consisting of H, a substituted or unsubstituted C1-C6 alkyl group, and a substituted or unsubstituted C3-C6 cycloalkyl group, where the substitution refers to substitution with one or more substituents selected from the group consisting of deuterium and halogen; A is NH or CH2; B is CH or N; L is

[0014] [ka] is selected from the group consisting of

[0015] R 2 is selected from the group consisting of H, -CD3, a C1-C6 alkyl group, and a C3-C6 cycloalkyl group; X is CH or N; Y is NH, O or S; R 3 , R 4 , R 5 are each independently H, -NH2, -OH, a C1-C6 alkoxy group, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C3-C6 cycloalkyl group, -CONH2, -CN, a halogen, or -O(CH2) n R 9 and -NR 8 (CH2) n R9 is selected from the group consisting of n is 1, 2, 3, 4 or 5; R 9 is selected from the group consisting of -OH, a C1-C6 alkoxy group, a C4-C6 cycloalkoxy group, a 4-8 membered heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, and -CN; R 8 is H or a C1-C6 alkyl group, R 6 , R 7 are each independently selected from the group consisting of H, a C1-C6 alkyl group, and halogen.

[0016] In another preferred embodiment, the additional condition is 2 If H, then R 3 is -NH2 or R 4 and R 5 is not H at the same time.

[0017] In another preferred embodiment, R 1 is a deuterated or unsubstituted C1-C6 alkyl group. In another preferred embodiment, R 1 is a fully deuterated C1-C6 alkyl group.

[0018] In another preferred embodiment, the term "per-deuterated" refers to all H in the group being replaced by D. In another preferred embodiment, R 1 is a C1-C6 alkyl group.

[0019] In another preferred embodiment, R 1 is a fully deuterated C1-C6 alkyl group, A is NH, B is CH or N.

[0020] In another preferred embodiment, R 1 is selected from the group consisting of -CH3 and -CD3; A is NH, B is CH or N.

[0021] In another preferred embodiment, L is

[0022] [ka] and

[0023] R 2 is selected from the group consisting of H, -CD3, and a C1-C6 alkyl group; X is N; R 3 , R 4 , R 5 are each independently H, -NH2, -OH, a C1-C6 alkoxy group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, -CONH2, -CN, a halogen, or -O(CH2) n R 9 , a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C6 cycloalkyl-substituted C2-C6 alkynyl group, and -NR 8 (CH2) n R 9 is selected from the group consisting of n is 1, 2, 3, 4 or 5; R 9 is selected from the group consisting of a C1-C6 alkoxy group, a C4-C6 cycloalkoxy group, a 4-8 membered heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, and -CN; R 8 is H or a C1-C6 alkyl group.

[0024] In another preferred embodiment, L is

[0025] [ka] and

[0026] R 2is selected from the group consisting of H, -CD3, and a C1-C6 alkyl group; X is N; R 3 , R 4 , R 5 are each independently H, -NH2, -OH, a C1-C6 alkoxy group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, -CONH2, -CN, a halogen, or -O(CH2) n R 9 and -NR 8 (CH2) n R 9 is selected from the group consisting of n is 1, 2, 3, 4 or 5; R 9 is selected from the group consisting of a C1-C6 alkoxy group, a C4-C6 cycloalkoxy group, a 4-8 membered heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, and -CN; R 8 is H or a C1-C6 alkyl group.

[0027] In another preferred embodiment, R 2 are H, -CD3 and -CH3. In another preferred embodiment, R 9 -OCH3, -CN,

[0028] [ka] is selected from the group consisting of:

[0029] In another preferred embodiment, R 3 , R 4 are each independently -NH2, -OH, a C1-C6 alkoxy group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, -CONH2, -CN, a halogen, or -O(CH2) n R 9 , a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C6 cycloalkyl-substituted C2-C6 alkynyl group, and -NR 8 (CH2) n R9 is selected from the group consisting of:

[0030] In another preferred embodiment, R 3 , R 4 are each independently selected from the group consisting of -NH2, a C1-C6 alkyl group, a halogen, a C3-C6 cycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, and a C3-C6 cycloalkyl-substituted C2-C6 alkynyl group.

[0031] In another preferred embodiment, R 3 is -NH2. In another preferred embodiment, R 4 is a C1-C6 alkyl group, a halogen, a C3-C6 cycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, or a C3-C6 cycloalkyl-substituted C2-C6 alkynyl group.

[0032] In another preferred embodiment, R 3 is -NH2, R 4 is a halogen. In another preferred embodiment, R 3 is -NH2, R 4 is Cl or Br.

[0033] In another preferred embodiment, R 1 is a fully deuterated C1-C6 alkyl group, A is NH, B is N; L is

[0034] [ka] and

[0035] R 2 is selected from the group consisting of H, -CD3, and a C1-C6 alkyl group; X is N; R 3 is -NH2, R 4is selected from the group consisting of halogen, a C3-C6 cycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, and a C3-C6 cycloalkyl-substituted C2-C6 alkynyl group; R 5 is H.

[0036] In another preferred embodiment, R 1 is a fully deuterated C1-C6 alkyl group, A is NH, B is N; L is

[0037] [ka] and

[0038] R 2 is selected from the group consisting of H, C1-C6 alkyl groups; X is N; R 3 is -NH2, R 4 is a halogen, R 5 is H.

[0039] In another preferred embodiment, R 1 is a fully deuterated C1-C6 alkyl group, A is NH, B is N; L is

[0040] [ka] and

[0041] R 2 is -CD3, X is N; R 3 is -NH2, R 4is selected from the group consisting of halogen, a C3-C6 cycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, and a C3-C6 cycloalkyl-substituted C2-C6 alkynyl group; R 5 is H.

[0042] In another preferred embodiment, the compound is selected from the group consisting of:

[0043] [ka] JPEG2025508011000012.jpg222170JPEG2025508011000013.jpg129170

[0044] A second aspect of the present invention provides a process for the preparation of a compound according to the first aspect of the present invention or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof, comprising the steps of:

[0045] [ka]

[0046] reacting a compound of formula Ic with a cyclopropylamide to obtain a compound of formula (I), Here, R 1 , A, B, L are as defined in the first aspect of the invention, G is a halogen.

[0047] A third aspect of the present invention provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and a safe and effective amount of one or more compounds according to the first aspect of the present invention or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof.

[0048] In another preferred embodiment, the pharmaceutical composition is an oral formulation. A fourth aspect of the present invention provides the use of a compound according to the first aspect of the present invention or a tautomer, meso-isomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharma- ceutically acceptable salt thereof, for use in the preparation of a medicament for use in the prevention and / or treatment of a TYK2 mediated related disease.

[0049] In another preferred embodiment, the TYK2 mediated associated disease is an inflammatory or autoimmune disease in a mammalian body. In another preferred embodiment, the inflammatory or autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, inflammatory bowel disease, psoriasis, Crohn's disease, psoriatic arthritis, Sjogren's syndrome, or the like. Syndrome, ss), systemic scleroderma, ulcerative colitis, Gray's disease, discoid lupus erythematosus, adult Still's disease, systemic juvenile idiopathic arthritis, gout, gouty arthritis, type 1 diabetes, insulin-dependent diabetes mellitus, sepsis, septic shock, shigellosis, pancreatitis, glomerulonephritis, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, microplateletopenia, atopic dermatitis, myasthenia gravis, pancreatitis, ankylosing spondylitis, pemphigus vulgaris, antiphospholipid syndrome, idiopathic microplateletopenia, ANCA-associated vasculitis, Kawasaki disease, chronic inflammatory demyelinating polyradiculoneuropathy, dermatomyositis, polymyositis, uveitis, Guillain-Barbados syndrome, autoimmune pneumonia, autoimmune thyroiditis, autoimmune inflammatory eye disease and chronic demyelinating polyneuropathy.

[0050] [Effects of the invention] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. [Brief description of the drawings]

[0051] [Figure 1] 1 is single crystal diffraction data of compound 28e of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0052] As a result of long-term and thorough research, the present inventors have optimized the structure to obtain an excellent compound represented by formula (I) having high TYK2 inhibitory activity, high selectivity, metabolic properties and drug discovery potential, as well as a preparation method thereof and its use in the treatment and / or prevention of TYK2-mediated related diseases. Based on this, the present inventors have completed the present invention.

[0053] term In the present invention, unless otherwise specified, the terms used have their ordinary meanings known to those skilled in the art.

[0054] In the present invention, the term "halogen" refers to F, Cl, Br or I. In the present invention, the term "C1-C6 alkyl group" refers to a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, neopentyl, t-pentyl, or the like.

[0055] In the present invention, the term "C2-C6 alkenyl group" refers to a straight or branched alkenyl group containing one double bond and having 2 to 6 carbon atoms, and non-limiting examples include vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups.

[0056] In the present invention, the term "C2-C6 alkynyl group" refers to a straight or branched alkynyl group containing one triple bond and having 2 to 6 carbon atoms, and non-limiting examples include ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl groups.

[0057] In the present invention, the term "C3-C8 cycloalkyl group" refers to a cyclic alkyl group having 3 to 8 carbon atoms on the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The term "C3-C6 cycloalkyl group" has an analogous meaning.

[0058] In the present invention, the term "C1-C6 alkoxy group" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, and non-limiting examples include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group, etc. A C1-C4 alkoxy group is preferred.

[0059] In the present invention, the term "heterocyclyl group" means

[0060] [ka] It refers to a 4-8 membered heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O, S, including but not limited to:

[0061] In the present invention, the terms "aromatic ring" and "aryl group" have the same meaning, and are preferably "C6-C10 aryl group". The term "C6-C10 aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms without heteroatoms on the ring, such as a phenyl group, a naphthyl group, etc.

[0062] In the present invention, the terms "aromatic heterocycle" or "heteroaryl group" have the same meaning and refer to a heteroaromatic group containing one or more heteroatoms. For example, a "C3-C10 heteroaryl group" refers to an aromatic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, and 3-10 carbon atoms. Non-limiting examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring. The heteroaryl group may be optionally claimed or unsubstituted.

[0063] In the present invention, the term "halogenated" refers to substitution with halogen. In the present invention, the term "deuterated" refers to substitution with deuterium.

[0064] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a particular group by a particular substituent. The particular substituent is a substituent as described in the above specification as appropriate, or as described in each example. Unless otherwise specified, a particular substituent may have a substituent selected from a particular group at any substitutable position on the group, and the substituent at each position may be the same or different. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is stable or scientifically achievable. The substituents include, but are not limited to, halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, and the like.

[0065] In the present invention, the term 1 to 6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms each independently have the same meaning. The term "multiple" refers to 2 to 6, such as 2, 3, 4, 5 or 6.

[0066] It is to be understood that when a group is simultaneously present in several different positions on a compound, its definition at each position is independent of each other and may be the same or different, i.e., the term "selected from the group consisting of:" has the same meaning as the term "each independently selected from the group consisting of:".

[0067] compound Regarding the first aspect of the present invention, general formula (I) indicates that the compound may contain one or more chiral centers, and that enantiomers and diastereomers exist. The compound represented by general formula (I) of the present invention may also contain many geometric isomers such as olefins, C=N double bonds, etc. Unless otherwise stated, all the above chiral (enantiomers and diastereomers), racemates, cis geometric isomers, trans geometric isomers, and mixtures of cis and trans geometric isomers are included in the present invention. In the case of enantiomers, the two enantiomers can be obtained using common chiral resolution methods or asymmetric synthesis methods. In the case of diastereomers, they can be separated by methods such as fractional recrystallization or chromatographic separation.

[0068] In another preferred embodiment, in the compound, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , A, B, L, X, Y, and n are each independently the corresponding group in a specific compound described in the present invention.

[0069] As used herein, "pharmaceutically acceptable salt" refers to a medicamentously compatible salt formed by the compound of the present invention and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are salts formed by the compound of the present invention and an acid. Acids suitable for salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0070] Further preferred salts are salts formed between the compounds of the present invention and bases, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanol ammonium salts and other pharma- ceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, t-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0071] Preparation method The preparation method of the compound of formula I of the present invention will be described in more detail below, but these specific methods do not limit the present invention. The compound of the present invention can also be conveniently prepared by any combination of various synthetic methods described herein or known in the art, and such combination can be easily performed by those skilled in the art.

[0072] Typically, the preparation process of the compound of the present invention is as follows, in which the raw materials and reagents used therein can all be purchased through commercial routes unless otherwise specified.

[0073] Typically, the compounds are prepared as follows.

[0074] [ka]

[0075] Reacting the amino group compound of formula Ia with formula Ib to obtain formula Ic, and reacting formula Ic with cyclopropylamide to obtain formula (I), where G is halogen and L, A, B, R 1 is as described in the first aspect of the invention.

[0076] In another preferred embodiment, L in formula Ia is

[0077] [ka] and wherein the compound is a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof, said method comprising the steps of:

[0078] [ka]

[0079] The steps include introducing a methylthio group into formula Ia-1A to obtain formula Ia-1B, oxidizing formula Ia-1B to obtain a sulfoxide compound of formula Ia-1E, re-oxidizing the sulfoxide compound of formula Ia-1E to obtain a sulfoxide imine compound of formula Ia-1C, and oxidizing formula Ia-1B to a sulfoxide imine compound of formula Ia-1C in one step, introducing a substituent into the sulfoxide imine compound of formula Ia-1C to obtain formula Ia-1D, and deprotecting formula Ia-1D to obtain formula Ia-1, wherein Z 1 and Z 2 are the same or different and each independently selected from the group consisting of H, -COtBu, -Boc, -Ts, -Ns, -Bn, -PMB, and -DMB; Z 3 is H or halogen, and X, R 2 , R 3 , R 4 , R 5 is as described in the first aspect of the invention.

[0080] In another preferred embodiment, there is provided a method for preparing a compound having a single chiral configuration represented by formula Ia-2 or a pharma- ceutically acceptable salt thereof, the method comprising:

[0081] [ka]

[0082] The method further comprises the steps of removing H from formula Ia-2A with a strong base, followed by introducing a methylthio group to obtain formula Ia-2B, oxidizing formula Ia-2B by a suitable chiral oxidation method to obtain a sulfoxide compound of formula Ia-2C with a single chiral configuration, removing the t-butyryl group from formula Ia-2C to obtain formula Ia-2D, re-oxidizing formula Ia-2D to obtain a sulfoxide imine compound of formula Ia-2E with a single chiral configuration, and subjecting formula Ia-2E to a substitution reaction to obtain a compound of formula Ia-2 with a single chiral configuration, wherein X, R 2 , R 3 , R 4 , R 5 is as described in the first aspect of the invention.

[0083] In another preferred embodiment, there is provided a method for preparing a compound of a single chiral configuration represented by formula Ia-3 or a pharma- ceutically acceptable salt thereof, said method comprising:

[0084] [ka]

[0085] The method further comprises the steps of: condensing the carboxylic acid compound of formula Ia-3A with a chiral benzylamine to obtain an amide compound of formula Ia-3B; substituting formula Ia-3B with a methylthio group to obtain formula Ia-3C; oxidizing formula Ia-2B by a suitable chiral oxidation method to obtain a sulfoxide compound of formula Ia-3D; removing the benzyl group fragment in formula Ia-3D to obtain an amide compound of formula Ia-3E; rearranging to obtain an amino group compound of formula Ia-3F; re-oxidizing formula Ia-3F to obtain a sulfoxide imine compound of formula Ia-3G with a single chiral configuration; and displacing formula Ia-3G to obtain a compound of formula Ia-3 with a single chiral configuration, wherein G is selected from halogen; 2 , R 3 , R 4 , R 5 , R 10 , m is as described in the first aspect of the invention.

[0086] In another preferred embodiment, the method further comprises: The method further comprises the step of reacting the obtained product with a first substance to obtain a compound represented by formula (I), wherein the first substance is selected from the group consisting of HCl, H2SO4, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0087] In order to ensure the smooth progress of each synthetic step, those skilled in the art can protect and deprotect the hydroxyl group in the compounds involved in the reaction in advance using common protecting groups such as TBS, TMS, TBDPS, Bn, THP, Tf, etc., and can protect and deprotect NH or NH2 in the compounds involved in the reaction using common protecting groups such as Boc, Cbz, Bn, Ts, THP, etc.

[0088] Here, the compounds represented by each formula may contain one or more chiral centers in which enantiomers and diastereomers exist, and may also contain many geometric isomers such as alkenes, C=N double bonds, etc. Unless otherwise stated, all of the above chiral (enantiomers and diastereomers), racemates, cis geometric isomers, trans geometric isomers, and mixtures of cis and trans geometric isomers are all included within the present invention. In the case of enantiomers, two enantiomers can be obtained using general chiral resolution methods or asymmetric synthesis methods. In the case of diastereomers, they can be separated by methods such as fractional recrystallization or chromatographic separation.

[0089] Pharmaceutical Compositions and Methods of Administration The pharmaceutical composition of the present invention contains the compound of the present invention or its pharmacologically acceptable salt and a pharmacologically acceptable excipient or carrier within a safe and effective amount. Here, the "safe and effective amount" refers to an amount of the compound sufficient to clearly improve the disease condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound / agent of the present invention, more preferably 10-1000 mg of the compound / agent of the present invention. Preferably, the "one agent" is one capsule or tablet.

[0090] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be suitable for human use, have sufficient purity and sufficiently low toxicity. "Compatibility" refers to the ability of the components of the composition to be blended with each other without significantly reducing the efficacy of the compounds of the present invention and between them. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0091] The pharmaceutical composition is in the form of an injection, a capsule, a tablet, a pill, a powder or a granule. The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

[0092] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as, for example, sodium citrate or dicalcium phosphate, or with a mixture of at least one conventional inert excipient (or carrier), such as, for example, sodium citrate or dicalcium phosphate, or with a mixture of at least one conventional inert excipient (or carrier), such as, for example, (a) a filler or compatibilizer, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, (b) a binder, such as hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, (c) a humectant, such as glycerin, (d) a disintegrant, such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) a retarder, such as paraffin, (f) an absorption promoter, such as a quaternary amine compound, (g) a glyceryl alcohol, such as glyceryl alcohol, or a mixture of at least one conventional inert excipient (or carrier), such as, for example, sodium citrate, sodium phosphate ... (h) an adsorbent such as kaolin, and (i) a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also include buffering agents.

[0093] Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coating and shell materials, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active compound or compounds of such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0094] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms can contain inert diluents conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers, such as, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0095] Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. In addition to the active compound, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0096] Compositions for parenteral injection can include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0097] Dosage forms of the compounds of the present invention used for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required.

[0098] The compounds of the present invention can be administered alone or in combination with other pharma- ceutically acceptable compounds (eg, anti-inflammatory drugs). The therapeutic methods of the present invention can be used alone or in combination with other therapeutic procedures or therapeutic agents.

[0099] When the pharmaceutical composition is used, a safe and popular amount of the compound of the present invention is applied to a mammal (e.g., human) in need of treatment, where the dosage at the time of administration is the effective dosage considered, and for a person weighing 60 kg, the daily dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, the specific dosage must also take into account factors such as the route of administration and the health condition of the patient, all of which are within the skill of a skilled physician.

[0100] Compared with the prior art, the present invention has the following main advantages: (1) The compounds of the present invention have excellent TYK2 inhibitory activity. (2) The compounds of the present invention have no inhibitory activity against JAK1, JAK2, or JAK3 kinases, and are highly selective for JAK family kinases.

[0101] (3) The compounds of the present invention have excellent IFN-α inflammatory pathway inhibitory activity. (4) The compounds of the present invention do not have hERG potassium channel inhibitory activity and have a low risk of cardiotoxicity.

[0102] (5) The compounds of the present invention have excellent drug metabolism properties and drug discoverability. (6) The compound of the present invention has excellent water solubility.

[0103] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, the experimental methods that do not show specific conditions usually follow conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or those suggested by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0104] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can all be applied to the method of the present invention. The preferred implementation methods and materials described herein are used for demonstration purposes only.

[0105] In the present invention, the structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR is measured using a Bruker AVANCE-400 nuclear magnetic device. LCMS is measured using a Waters 2695 liquid phase mass spectrometer (MS model: Micromass ZQ).

[0106] The HPLC measurements were performed using an Agilent 1100 high pressure liquid chromatograph (ZORBAX SP-C18 250x4.6mm chromatography column, Eclipse Plus-C18 250x4.6mm chromatography column).

[0107] Known starting materials of the present invention can be synthesized using or according to methods known in the art, or can be purchased commercially from companies such as AcrosOrganics, Aldrich Chemical Company, J&Chem, Accela ChemBio, Chembee, Energy Chemical, etc.

[0108] There are no special instructions in the examples, and all of the reactions can be carried out under an argon or nitrogen atmosphere. For microwave reactions a CEM Discover-SP 909155 microwave reactor is used.

[0109] There are no special instructions in the examples, and the reaction temperature is room temperature (20° C. to 35° C.). The specifications of the silica gel plate used in the thin layer chromatography (TLC) in the examples are 0.2 mm ± 0.03 mm. The specifications of the thin layer chromatography separation and purification (prep-TLC) used for the purification of the compound are 0.4 mm to 0.5 mm, and in column chromatography, Yantai Huanghai silica gel 200 to 300 mesh silica gel is usually used as the drug carrier, and a fully automatic medium pressure rapid purification device (Combi Flash Rf + UV-VIS) is used, and the models of the separation column are silica flash columns 4 g, 12 g, and 25 g. The eluents of the column chromatography and the development systems of the thin layer chromatography used include A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvents is adjusted according to the polarity of the compound, and can also be adjusted by dropping a small amount of basic or acidic reagents such as ammonia and acetic acid.

[0110] In the examples, a high pressure preparative liquid chromatograph (manufacturer: Shimadzu, model: LC-20AP) and an Ultimate XB-C18 chromatography column (150 x 30 mm, 5 μm) are used to purify the final sample compounds. The mobile phase system includes A: acetonitrile and water (containing 0.1% trifluoroacetic acid); B: acetonitrile and water (containing 0.1% acetic acid).

[0111] Example 1 Preparation of N-(4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide

[0112] [ka]

[0113] Step 1: Synthesis of 3-(S-methylsulfoximino)-2-nitropyridine (1b) For the synthesis of 3-(methylthio)-2-nitropyridine (1a), see WO2020 / 086616.

[0114] Ammonium carbamate (867 mg, 11.1 mmol) was added to a solution of 3-(methylthio)-2-nitropyridine (1a) (1.26 g, 7.41 mmol) in methanol (20 mL), cooled to 0° C., iodobenzene diacetate (4.77 g, 14.8 mmol) was added in batches, warmed to room temperature and stirred for 2 h. The solvent was spin-dried and flashed (ethyl acetate / petroleum ether=4:1) to give 3-(S-methylsulfoximino)-2-nitropyridine (1b) (1.3 g, pale yellow oil) in 79% yield.

[0115] 1 H NMR(400MHz, CDCl3)δ 8.71(d,J=4.7Hz,1H),8.61(d,J=7.9Hz,1H),7.78(dd,J=7.4,5.1Hz,1H),3.00(brs,1H),3.39(s,3H).

[0116] MS m / z[M+H] + :202. Step 2: Synthesis of 3-(N,S-dimethylsulfoximino)-2-nitropyridine (1c) Dissolve 3-(S-methylsulfoximino)-2-nitropyridine (1b) (23.3 g, 115.9 mmol) in DMF (230 mL), cool in an ice bath, add sodium hydride (6.96 g, 174 mmol) in a batch under nitrogen gas protection, and continue to stir in an ice bath for 20 minutes. Slowly add iodomethane (19.8 g, 139.1 mmol) dropwise, and continue to stir in an ice bath for 30 minutes. Add ice water (200 mL) and saturated ammonium chloride (200 mL) to the reaction solution, extract with ethyl acetate, wash the organic phase with saturated saline, dry over anhydrous sodium sulfate, and concentrate to obtain crude product 3-(N,S-dimethylsulfoximino)-2-nitropyridine (1c) (30 g).

[0117] MS m / z[M+H] + :216. Step 3: Synthesis of 3-(N,S-dimethylsulfoximino)pyridin-2-amine (1d) The crude product (30 g) of 3-(N,S-dimethylsulfoximino)-2-nitropyridine (1c) was dissolved in a mixed solvent of ethanol / water (1 / 1, 300 mL), ammonium chloride (62.6 g, 1.16 mml) was added, the temperature was raised to 70° C., iron powder (22.7 g, 405.8 mmol) was added in batches while stirring, and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature and then filtered under suction. The filter cake was rinsed with a mixed solution of methanol / dichloromethane (1:10). The filtrate was concentrated and then separated by column chromatography (methanol / ethyl acetate / petroleum ether=1:9:10) to obtain 3-(N,S-dimethylsulfoximino)pyridin-2-amine (1d) (7.3 g, pale yellow solid), with a two-step yield of 34%.

[0118] 1 H NMR(400MHz, CDCl3)δ 8.25(d,J=3.5Hz,1H),7.99(d,J=7.7Hz,1H),6.79(dd,J=7.4,5.0Hz,1H),6.02(s,2H),3.07(s,3H),2.68(s,3H).

[0119] MS m / z[M+H]+ :186. Step 4: Synthesis of N-(4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide (1) For the synthesis of N-(4-chloro-5-propionylpyridin-2-yl)cyclopropanecarboxamide (1e), see WO2020 / 086616.

[0120] N-(4-chloro-5-propionylpyridin-2-yl)cyclopropanecarboxamide (1e) (90 mg, 0.36 mmol) is dissolved in 1,4-dioxane (4 mL), and 3-(N,S-dimethylsulfoximino)pyridin-2-amine (1d) (61 mg, 0.21 mmol), Pb2(dba)3 (33 mg, 0.035 mmol), BINAP (44 mg, 0.071 mmol) and CsCO3 (232 mg, 0.71 mmol) are added. The reaction is carried out at 110 °C for 3 hours under nitrogen gas protection. After the reaction solution is cooled to room temperature, it is suction filtered through diatomaceous earth and the filter cake is rinsed with ethyl acetate. The filtrate was concentrated and then separated by flash (methanol / dichloromethane=1:20) to give the crude product (30 mg, yellow solid), which was purified by preparative HPLC to give N-(4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide (1) (12 mg, white solid), yield: 8%.

[0121] 1 H NMR(400MHz,DMSO-d6)δ 11.79(s,1H),10.92(s,1H),9.04(s,1H),8.90(s,1H),8.52(d,J=4.4Hz,1H),8.21(d,J=7.7Hz,1H),7.30-7.24(m,1H), 3.17(s,3H),3.09(dd,J=14.0,6.8Hz,2H),2.70(s,3H),2.06-1.98(m,1H),1.09(t,J=7.1Hz,3H),0.80(d,J=6.6Hz,4H).

[0122] MS(M+H) + :402. Example 2: Preparation of 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0123] [ka]

[0124] Step 1: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (2b) For the synthesis of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (2a), see US2019 / 152948.

[0125] 3-(N,S-dimethylsulfoximino)pyridin-2-amine (1d) (130 mg, 0.70 mmol) was dissolved in DMF and cooled to 0°C. Sodium hydride (57 mg, 1.41 mmol) was added, and the mixture was stirred at 0°C for 5 minutes. 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (2a) (145 mg, 0.7 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Saturated ammonium chloride solution (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration, separation by flash (methanol:dichloromethane=1:30) gave 6-chloro-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (2b) (89 mg, white solid), yield 35%.

[0126] 1H NMR(400MHz,CDCl3)δ 12.42(s,1H),9.09(s,1H),8.56(d,J=4.4Hz,1H),8.32(d,J=7.7Hz,1H),8.25(s,1H),7.22-7.17(m,1H),3.24(s,3H),2.85(s,3H).

[0127] MS m / z[M+H] + :358. Step 2: Synthesis of 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (2) 6-Chloro-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (2b) (89 mg, 230 mmol) was dissolved in 1,4-dioxane (2 mL), cyclopropanecarboxamide (40 mg, 46 mmol), Pd2(dba)3 (43 mg, 0.046 mmol), xantphos (41 mg, 0.70 mmol) and CsCO3 (152 mg, 0.460 mmol) were added, and the mixture was reacted in a microwave (110° C., 100 W) for 45 minutes under a nitrogen gas atmosphere. After the reaction mixture was cooled to room temperature, it was filtered through diatomaceous earth, the filter cake was rinsed with ethyl acetate, and the filtrate was concentrated and then separated by flash (methanol / dichloromethane=1:10) to give the crude product, which was purified by preparative HPLC to give 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (2) (45 mg, white solid), yield 44%.

[0128] 1H NMR(400MHz,dmso)δ 11.87(s,1H),11.38(s,1H),9.46(s,1H),9.07(s,1H),8.53(d,J=4.3Hz,1H),8.22(d,J=7.7Hz,1H ),7.28(dd,J=7.3,5.0Hz,1H),3.22(s,3H),2.67(s,3H),2.14-2.05(m,1H),0.84(d,J=6.4Hz,4H).

[0129] MS m / z[M+H] + :407. Example 3: Preparation of 6-(cyclopropanecarboxamide)-4-((2-(N,S-dimethylsulfoximino)phenyl)amino)-N-methylpyridazine-3-carboxamide

[0130] [ka]

[0131] Step 1: Synthesis of 6-chloro-4-((2-(N,S-dimethylsulfoximino)phenyl)amino)-N-methylpyridazine-3-carboxamide (3c) For the synthesis of 2-(N,S-dimethylsulfoximino)aniline (3a), see WO2018 / 075937.

[0132] For the synthesis of 4,6-dichloro-N-methylpyridazine-3-carboxamide (3b), see WO2020 / 086616. 2-(N,S-dimethylsulfoximino)aniline (3a) (155 mg, 0.84 mmol) and 4,6-dichloro-N-methylpyridazine-3-carboxamide (3b) (175 mg, 0.84 mmol) were dissolved in tetrahydrofuran (2 mL), and LiHMDS (2.53 mL, 2.53 mmol) was slowly added in an ice-water bath under a nitrogen gas atmosphere, and the mixture was allowed to react for 10 minutes after slowly warming to room temperature. The reaction solution was quenched by adding 1N HCl (1 mL), diluted with water (20 mL), and then extracted with ethyl acetate (60 mL). The organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration, separation by Flash (ethyl acetate:petroleum ether=1:1) gave 6-chloro-4-((2-(N,S-dimethylsulfoximino)phenyl)amino)-N-methylpyridazine-3-carboxamide (3c) (98 mg, yellow solid), yield 33%.

[0133] 1 H NMR(400MHz,CDCl3)δ 11.50(s,1H),8.17(s,1H),8.10(d,J=7.8Hz,1H),7.65(t,J=7.4Hz,1H),7.55(d, J=7.9Hz,1H),7.41(t,J=7.5Hz,1H),7.27(s,1H),3.11-3.03(m,6H),2.80(s,3H).

[0134] MS m / z[M+H] + :354. Step 2: Synthesis of 6-(cyclopropylcarboxamido)-4-((2-(N,S-dimethylsulfoximino)phenyl)amino)-N-methylpyridazine-3-carboxamide (3) The synthesis method is the same as that of 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (Example 2), and the yield is 40%.

[0135] 1H NMR(400MHz,dmso)δ 11.33(s,1H),11.03(s,1H),9.02(d,J=4.7Hz,1H),8.15(s,1H),7.91(d,J=8.1Hz,1H),7.67(d,J=14.1Hz,2H),7. 41-7.35(m,1H),3.04(s,3H),2.82(d,J=4.7Hz,3H),2.59(s,3H),2.03(dd,J=10.9,5.3Hz,1H),0.81-0.75(m,4H).

[0136] MS m / z[M+H] + :403. Example 4: Preparation of 6-(cyclopropanecarboxamido)-4-((2-(N-ethyl-S-methylsulfoximino)phenyl)amino)-N-methylpyridazine-3-carboxamide

[0137] [ka]

[0138] Step 1: Synthesis of 1-(N-ethyl-S-methylsulfoximino)-2-nitrobenzene (4b) For the synthesis of 1-(S-methylsulfoximino)-2-nitrobenzene (4a), see WO2018 / 075937.

[0139] 1-(S-methylsulfoximino)-2-nitrobenzene (4a) (260 mg, 1 mmol) is dissolved in DMSO (5 mL), KOH (112 mg, 2 mmol) is added, and the mixture is stirred at room temperature for 5 minutes. Iodoethane (360 mg, 2.3 mmol) is added, and the mixture is stirred at room temperature for 3 hours. Water (10 mL) is added to quench the reaction, and the mixture is extracted with ethyl acetate. The organic phases are combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration, the mixture is separated by a flash column (ethyl acetate / petroleum ether=40%-60%) to obtain 1-(N-ethyl-S-methylsulfoximino)-2-nitrobenzene (4b) (200 mg, yellow oil), with a yield of 68%.

[0140] MS m / z[M+H] + :229. Step 2: Synthesis of 2-(N-ethyl-S-methylsulfoximino)aniline (4c) 1-(N-ethyl-S-methylsulfoximino)-2-nitrobenzene (4b) (200 mg, 0.877 mmol) is dissolved in ethanol / water (2 / 1, 9 mL), ammonium chloride (511 mg, 9.65 mmol) is added, and iron powder (172 mg, 3.07 mmol) is added in batches at 75° C. After the addition is complete, the mixture is stirred at 75° C. for 1 hour. After cooling to room temperature, the mixture is filtered through diatomaceous earth and the filter cake is rinsed with ethanol. The filtrate is concentrated and then separated by flash (methanol / dichloromethane=5%-10%) to give 2-(N-ethyl-S-methylsulfoximino)aniline (4c) (150 mg, colorless oil), with a yield of 86%.

[0141] 1 H NMR(400MHz,CDCl3)δ 7.73(d,J=8.0Hz,1H),7.33(t,J=7.8Hz,1H),6.81(t,J=7.6Hz,1H),6.72(d,J= 8.1Hz, 1H), 5.29 (s, 2H), 3.05 (s, 3H), 2.95-2.80 (m, 2H), 1.21 (t, J=7.2Hz, 3H).

[0142] MS m / z[M+H] + :199. Step 3: Synthesis of 6-chloro-4-((2-(N-ethyl-S-methylsulfoximino)phenyl)amino)-N-methylpyridazine-3-carboxamide (4d) The synthesis method was as described for 6-chloro-4-((2-(N,S-dimethylsulfoximino)phenyl)amino)-N-methylpyridazine-3-carboxamide (3c), and the yield was 26%.

[0143] MS m / z[M+H] + :368. Step 4: Synthesis of 6-(cyclopropylcarboxamido)-4-((2-(N-ethyl-S-methylsulfoximino)phenyl)amino)-N-methylpyridazine-3-carboxamide (4) The synthesis method was the same as that of 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (Example 2), and the yield was 41.0%.

[0144] 1 H NMR(400MHz,DMSO-d6)δ 11.32(s,1H),10.96(s,1H),9.01(d,J=5.3Hz,1H),8.11(s,1H),7.92(d,J=7.8Hz,1H),7.73-7.59(m,2H),7.38(t,J=7.4H z,1H),3.04(s,3H),2.98-2.85(m,2H),2.81(d,J=4.8Hz,3H),2.09-1.97(m,1H),1.06(t,J=7.2Hz,3H),0.85-0.70(m,4H).

[0145] MS m / z[M+H] + :417. Example 5: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0146] [ka]

[0147] Step 1: Synthesis of N-(6-methyl-3-methylthiopyridine-2-methyl)trimethylacetamide (5b) For the synthesis of N-(6-methylpyridine-2-methyl)trimethylacetamide (5a), see Org. Process Res. Dev. 2010, 14(1), 263-271.

[0148] N-(6-methylpyridine-2-methyl)trimethylacetamide (5a) (5.5 g, 28.6 mmol) is dissolved in anhydrous tetrahydrofuran (30 mL), cooled to 0°C under nitrogen gas atmosphere, n-butyllithium in n-hexane (35 mL, 2.5 M, 85.9 mmol) is slowly added dropwise, warmed to room temperature and stirred for 2 hours. The reaction solution is cooled to -78°C, dimethyl sulfide (5.5 mL, 57.2 mL) is slowly added dropwise, and after the addition is complete, the solution is slowly warmed to room temperature and stirred for 1 hour. The reaction is quenched by adding saturated ammonium chloride in an ice-water bath, extracted with ethyl acetate, and the organic phase is washed with saturated saline and dried over anhydrous sodium sulfate. After concentration, separation by flash (ethyl acetate:petroleum ether=1:1) gave N-(6-methyl-3-methylthiopyridine-2-methyl)trimethylacetamide (5b) (2.95 g, white solid), the yield was 43%.

[0149] MS m / z[M+H] + :239. Step 2: Synthesis of N-(6-methyl-3-(S-methylsulfoximino)pyridine-2-methyl)trimethylacetamide (5c) For the synthesis method, refer to the synthesis method of 3-(S-methylsulfoximino)-2-nitropyridine, and the yield is 12%.

[0150] 1 H NMR(400MHz,DMSO-d6)δ 10.78(s,1H),8.11(d,J=8.0Hz,1H),7.21(d,J=8.0Hz,1H),5.04(s,1H),3.10(s,3H),2.48(s,3H),1.23(s,9H).

[0151] MS m / z[M+H] + :270. Step 3: Synthesis of N-(6-methyl-3-(N,S-dimethylsulfoximino)pyridine-2-methyl)trimethylacetamide (5d) Dissolve N-(6-methyl-3-(S-methylsulfoximino)pyridine-2-methyl)trimethylacetamide (5c) (370 mg, 1.38 mmol) in dichloromethane (6 mL), add trimethoxynium tetrafluoroborate (265 mg, 1.79 mmol), and stir at room temperature for 1 hour. Add water to quench the reaction and stir for 10 minutes. Extract the aqueous phase with dichloromethane, combine the organic phases, and dry over anhydrous sodium sulfate. After concentration, separate by plate chromatography (methanol:dichloromethane=1:10) to obtain N-(6-methyl-3-(N,S-dimethylsulfoximino)pyridine-2-methyl)trimethylacetamide (5d) (190 mg, brown viscous liquid), yield 49%.

[0152] MS m / z[M+H] + :284. Step 4: Synthesis of 3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-amine (5e) N-(6-methyl-3-(N,S-dimethylsulfoximino)pyridine-2-methyl)trimethylacetamide (5d) (190 mg, 0.67 mmol) is dissolved in 2N hydrochloric acid solution (4 mL) and stirred at 100 °C for 30 minutes. The mixture is cooled to room temperature and adjusted to pH = 8-9 with saturated aqueous sodium bicarbonate. The aqueous phase is extracted with ethyl acetate, and the organic phases are combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration, the mixture is separated by plate chromatography (methanol: dichloromethane = 1:10) to obtain 3-(N,S-dimethylsulfoximino)-6-methylpyridine-2-amine (5e) (79 mg, yellow liquid), with a yield of 59%.

[0153] 1 H NMR(400MHz,DMSO-d6)δ 7.69(d,J=7.9Hz,1H),6.73(s,2H),6.58(d,J=7.8Hz,1H),3.01(s,3H),2.46(s,3H),2.29(s,3H).

[0154] MS m / z[M+H] + :200. Step 5: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (5f) 3-(N,S-Dimethylsulfoximino)-6-methylpyridin-2-amine (5e) (63 mg, 0.316 mmol) is dissolved in anhydrous DMF (1 mL), cooled to 0°C under nitrogen gas atmosphere, sodium hydride (25 mg, 60% w / w, 0.632 mmol) is added, stirred for 20 minutes, 4,6-dichloro-N-methylpyridazine-3-carboxamide (3b) (65 mg, 0.316 mmol) is added, warmed to room temperature and stirred for 2 hours. The reaction is quenched with saturated ammonium chloride, extracted with ethyl acetate, the organic phases are combined, washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, separation by flash (methanol:dichloromethane=1:10) gave 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (5f) (40 mg, white solid), yield: 34%.

[0155] 1 H NMR(400MHz,DMSO-d6)δ 12.03(s,1H),9.28(d,J=3.8Hz,1H),8.97(s,1H),8.12(d,J=7.9Hz,1H),7.21( d,J=7.9Hz,1H),3.19(s,3H),2.85(d,J=4.6Hz,3H),2.68(s,3H),2.54(s,3H).

[0156] MS m / z[M+H] + :369. Step 6: Synthesis of 6-(cyclopropylcarboxamide)-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (5) The synthesis method was the same as that of 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (Example 2), and the yield was 33%.

[0157] 1 H NMR(400MHz,DMSO-d6)δ 11.88(s,1H),11.36(s,1H),9.82(s,1H),9.08(d,J=4.6Hz,1H),8.08(d,J=7.9Hz,1H),7.12(d,J=7.9Hz,1H), 3.19(s,3H),2.84(d,J=4.7Hz,3H),2.66(s,3H),2.51(s,3H),2.11(dt,J=12.5,6.2Hz,1H),0.88-0.81(m,4H).

[0158] MS m / z[M+H] + :418. Example 6: Preparation of 4-((6-carbamoyl-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide

[0159] [ka]

[0160] Step 1: Synthesis of 6-chloro-3-(methylthio)pyridin-2-amine (6b) For the synthesis of N-(6-chloro-3-(methylthio)pyridin-2-yl)trimethylacetamide (6a), see J. Org. Chem. 1983, 48(20), 3401-3408.

[0161] The synthesis method was the same as that of 3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-amine, and the yield was 89%. 1H NMR (400MHz, CDCl3) δ 7.50 (d, J = 7.8 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 5.25 (s, 2H), 2.34 (s, 3H).

[0162] MS m / z[M+H] + :175. Step 2: Synthesis of N,N-(di-t-butoxycarbonyl)-6-chloro-3-(methylthio)pyridin-2-amine (6c) 6-Chloro-3-(methylthio)pyridin-2-amine (6b) (6.0 g, 34.4 mmol) is placed in a round-bottom flask, Boc anhydride (21.7 g, 99.7 mmol) is slowly added, and the mixture is stirred at room temperature for 10 minutes. DMAP (840 mg, 6.88 mmol) is added, and the mixture is stirred at room temperature for 1 hour. Petroleum ether is added to dilute the solution, and the solution is concentrated. The solution is passed through a short silica gel column to remove Boc anhydride, and 14.7 g of crude product is obtained. The crude product is slurried with petroleum ether, suction filtered, and rinsed with petroleum ether, and dried to obtain N,N-(di-t-butoxycarbonyl)-6-chloro-3-(methylthio)pyridin-2-amine (6c) (12.3 g, white solid), with a yield of 96%.

[0163] 1 H NMR (400MHz, CDCl3) δ 7.55 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 2.45 (s, 3H), 1.42 (s, 18H).

[0164] MS m / z[M+Na] + :397. Step 3: Synthesis of N,N-(di-t-butoxycarbonyl)-6-chloro-3-(S-methylsulfoximino)pyridin-2-amine (6d) The synthesis method was the same as that of 3-(S-methylsulfoximino)-2-nitropyridine, and the yield was 84%.

[0165] 1H NMR (400MHz, CDCl3) δ 8.43(d,J=8.1Hz,1H),7.52(d,J=8.2Hz,1H),3.17(s,3H),1.80(s,1H),1.50(s,9H),1.47(s,9H).

[0166] MS m / z[M+H] + :406. Step 4: Synthesis of N,N-(di-t-butoxycarbonyl)-6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-amine (6e) For the synthesis method, refer to the synthesis method of N-(6-methyl-3-(N,S-dimethylsulfoximino)pyridine-2-methyl)trimethylacetamide, and use the crude product directly in the next step without separating it.

[0167] Step 5: Synthesis of 6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-amine (6f) For the synthesis method, refer to the synthesis method of 3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-amine, with a two-step yield of 34%.

[0168] 1 H NMR (400MHz, DMSO-d6) δ 7.83 (d, J = 8.0 Hz, 1H), 7.22 (s, 2H), 6.77 (d, J = 8.0 Hz, 1H), 3.08 (s, 3H), 2.49 (s, 3H).

[0169] MS m / z[M+H] + :220. Step 6: Synthesis of 6-chloro-4-((6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (6g) The synthesis method was as described in the synthesis method for 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, and the yield was 39%.

[0170] 1H NMR(400MHz,DMSO-d6)δ 12.20(s,1H),9.34(d,J=4.5Hz,1H),8.77(s,1H),8.22(d,J=8.1Hz,1H),7.42(d,J=8.1Hz,1H),3.23(s,3H),2.84(d,J=4.7Hz,3H),2.68(s,3H).

[0171] MS m / z[M+H] + :389. Step 7: Synthesis of 6-chloro-4-((6-cyano-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (6h) 6-Chloro-4-((6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (6g) (133 mg, 0.343 mmol), Zn(CN)2 (22 mg, 0.189 mmol), Pd2(dba)3 (31 mg, 0.0343 mmol) and xantphos (40 mg, 0.0686 mmol) are dissolved in anhydrous DMF (2 mL) and reacted in a microwave at 80 °C and 80 W for 45 min under nitrogen gas atmosphere. After cooling to room temperature, the reaction is quenched by adding water, extracted with ethyl acetate, the organic phases are combined, washed with saturated saline solution and dried over anhydrous sodium sulfate. After concentration, separation by plate chromatography (ethyl acetate:petroleum ether=2:1) ​​gave 6-chloro-4-((6-cyano-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (6h) (118 mg, yellow solid), yield 91%.

[0172] 1 H NMR(400MHz,DMSO-d6)δ 12.25(s,1H),9.37(d,J=4.4Hz,1H),8.77(s,1H),8.41(d,J=7.4Hz,1H),7.93(d,J=7.4Hz,1H),3.28(s,3H),2.88(s,3H),2.69(s,3H).

[0173] MS m / z[M+H]+ :380. Step 8: Synthesis of 4-((6-cyano-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (6i) The synthesis method is as described in the synthesis method for 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and the yield is 21%.

[0174] 1 H NMR(400MHz,DMSO-d6)δ 12.09(s,1H),11.47(s,1H),9.47(s,1H),9.18(d,J=4.8Hz,1H),8.38(d,J=7.9Hz,1H),7.86(d,J= 7.8Hz,1H),3.30(s,3H),2.85(d,J=4.7Hz,3H),2.68(s,3H),2.18-2.08(m,1H),0.87-0.83(m,4H).

[0175] MS m / z[M+H] + :429. Step 9: Synthesis of 4-((6-carbamoyl-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (6) 4-((6-cyano-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (6i) (15 mg, 0.035 mmol) was dissolved in DMSO (1 mL), anhydrous potassium carbonate (12 mg, 0.088 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. Then, 30% aqueous hydrogen peroxide solution (39 mg, 0.35 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into distilled water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. Concentration followed by separation by preparative HPLC gave 4-((6-carbamoyl-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (6) (4.5 mg, white solid), yield 29%.

[0176] 1 H NMR(400MHz,DMSO-d6)δ 11.99(s,1H),11.60(s,1H),9.48(s,1H),9.13(s,1H),8.38(d,J=8.0Hz,1H),7.97(s,1H),7.87(d,J=7.9H) z,1H),7.75(s,1H),3.27(s,3H),2.85(d,J=4.8Hz,3H),2.69(s,3H),2.14-2.08(m,1H),0.89-0.81(m,4H).

[0177] MS m / z[M+H] + :447. Example 7: Preparation of 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide

[0178] [ka]

[0179] Step 1: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (7a) 6-Chloro-4-((6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (6g) (4.1 g, 10.6 mmol), Pd2(dba)3 (484 mg, 0.53 mmol), xantphos (611 mg, 1.06 mmol) and Cs2CO3 (10.3 g, 31.7 mmol) are dissolved in anhydrous DMF (30 mL), benzophenone imine (3.8 g, 21.1 mmol) is added and the mixture is stirred at 125 °C for 4 hours under a nitrogen gas atmosphere. The reaction was quenched by adding water, extracted with dichloromethane, and the organic phases were combined, washed with distilled water and brine, respectively, dried over anhydrous sodium sulfate, and separated by column chromatography (ethyl acetate:petroleum ether=1:1 to methanol:dichloromethane=1:20) to obtain 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (7a) (4.17 g, earthy yellow solid), yield 74%.

[0180] MS m / z[M+H] + :534. Steps 2 and 3: Synthesis of 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (7) 6-Chloro-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (7a) (4.67 g, 8.75 mmol) was dissolved in xylene (50 mL), cyclopropanecarboxamide (1.48 g, 17.4 mmol), Pd2(dba)3 (500 mg, 0.875 mmol), xantphos (760 mg, 1.31 mmol), and Cs2CO3 (5.66 g, 17.4 mmol) were added, and the mixture was stirred at 145 °C for 3 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with a mixture of methanol / dichloromethane (1:10), filtered through diatomaceous earth, and the filter cake was rinsed with a mixture of methanol / dichloromethane (1:10). Concentration gives the crude product 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (7b), which is directly used in the next step without separation.

[0181] The crude product of 6-(cyclopropylcarboxamide)-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (7b) is dissolved in tetrahydrofuran (40 mL), 6N hydrochloric acid (30 mL) is added in an ice bath, and the mixture is warmed to room temperature and stirred for 1 hour. Anhydrous potassium carbonate is added in batches slowly to adjust the pH to 9-10, and the mixture is suction filtered and concentrated. Separation by column chromatography (methanol:dichloromethane=1:20-1:7) gave 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (7) (1.87 g, earthy yellow solid), yield 51%.

[0182] 1H NMR(400MHz,DMSO-d6)δ 11.55(s,1H),11.31(s,1H),9.51(s,1H),9.01(d,J=4.7Hz,1H),7.74(d,J=8.4Hz,1H),6.54(s,2H),6.24 (d,J=8.7Hz,1H),3.06(s,3H),2.84(d,J=4.4Hz,3H),2.63(s,3H),2.16-2.06(m,1H),0.92-0.80(m,4H).

[0183] MS m / z[M+H] + :419. Example 8: Preparation of 4-((5-cyano-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide

[0184] [ka]

[0185] Step 1: Synthesis of 5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-amine (8a) 3-(N,S-dimethylsulfoximino)pyridin-2-amine (1d) (500 mg, 2.7 mmol) was dissolved in acetonitrile (15 mL), NBS (504 mg, 2.83 mmol) was slowly added, and the mixture was stirred at room temperature for 1 h, and the reaction was detected by TLC. The acetonitrile was spin-dried, and the reaction was quenched by adding water, and the mixture was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated, followed by separation by flash (ethyl acetate / petroleum ether=40-90%) to obtain 5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-amine (8a) (640 mg, white solid), yield 89%.

[0186] 1H NMR (400MHz, CDCl3) δ 8.29(d,J=2.1Hz,1H),8.10(d,J=2.0Hz,1H),6.07(brs,2H),3.08(s,3H),2.68(s,3H).

[0187] MS m / z[M+H] + :264. Step 2: Synthesis of 4-((5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide (8b) The synthesis method was as described in the synthesis method for 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, and the yield was 61%.

[0188] 1 H NMR(400MHz, CDCl3)δ 12.43(s,1H),8.97(s,1H),8.59(s,1H),8.42(s,1H),8.28(brs,1H),3.26(s,3H),3.07(d,J=5.1Hz,3H),2.83(s,3H).

[0189] MS m / z[M+H] + :433. Steps 3 and 4: Synthesis of 4-((5-cyano-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (8) 4-((5-Bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide (8b) (205 mg, 0.472 mmol), Zn(CN)2 (28 mg, 0.236 mmol), Pd2(dba)3 (43 mg, 0.0472 mmol) and xantphos (55 mg, 0.0944 mmol) were dissolved in anhydrous DMF (3 mL) and reacted under nitrogen gas conditions at 60° C. in a microwave at 50 W for 1 h, then at 80° C. in a microwave at 80 W for 15 min. The reaction mixture was cooled to room temperature, and cyclopropanecarboxamide (44 mg, 0.519 mmol), Pd2(dba)3 (43 mg, 0.0472 mmol), xantphos (55 mg, 0.0944 mmol) and Cs2CO3 (308 mg, 0.944 mmol) were added to the reaction mixture, and the mixture was reacted in a microwave at 110 °C and 50 W for 1 hour under nitrogen gas atmosphere. The reaction was quenched by adding water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and separated by flash (methanol / dichloromethane = 5-7%) to obtain 4-((5-cyano-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (8) (114 mg, white solid), yield 56%.

[0190] 1 H NMR(400MHz,DMSO-d6)δ 12.20(s,1H),11.50(s,1H),9.46(s,1H),9.16(s,1H),8.93(s,1H),8.49(s,1H),3. 29(s,3H),2.84(d,J=4.4Hz,3H),2.66(s,3H),2.15-2.07(s,1H),0.92-0.80(m,4H).

[0191] MS m / z[M+H] + :429. Example 9: Preparation of 4-((5-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide

[0192] [ka]

[0193] Step 1: Synthesis of 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinic acid-2,4,6-trichlorophenyl ester (9a) 4-((5-Bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide (8b) (560 mg, 1.3 mmol), 2,4,6-trichlorophenyl formate (349 mg, 1.55 mmol), Pd(OAc)2 (63 mg, 0.26 mmol), xantphos (243 mg, 0.42 mmol) and triethylamine (263 mg, 2.6 mmol) were added to a solution of toluene (28 mL) and stirred at 100 °C for 2 h under a nitrogen atmosphere. The reaction was cooled to room temperature, filtered through diatomaceous earth and rinsed with ethyl acetate. The filtrate was concentrated and separated by flash (ethyl acetate / petroleum ether=40-80%) to give 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinic acid-2,4,6-trichlorophenyl ester (9a) (380 mg, pale yellow solid), the yield was 51%.

[0194] 1 H NMR(400MHz,DMSO-d6)δ 12.47(s,1H),9.42(d,J=4.7Hz,1H),9.37(d,J=1.8Hz,1H),9.02(s,1H),8.75(d,J=1 .9Hz,1H),7.95(s,2H),5.74(s,1H),3.36(s,3H),2.87(d,J=4.7Hz,3H),2.72(s,3H).

[0195] MS m / z[M+H] + :577. Step 2: Synthesis of 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinic acid (9b) Dissolve 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinic acid-2,4,6-trichlorophenyl ester (9a) (175 mg, 0.3 mmol) in DMSO (6.5 mL) and add 40% aqueous sodium hydroxide solution (500 mg, 40% w / w) under ice bath. Stir for 20 min at room temperature after completion of addition. Adjust pH=3-4 with 1N hydrochloric acid, extract with dichloromethane, combine organic phases and dry over anhydrous sodium sulfate. Concentrate to obtain crude product of 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinic acid (9b) (179 mg, pale yellow solid), which is used directly in the next step without separation.

[0196] MS m / z[M+H] + :399. Step 3: Synthesis of t-butyl (6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)pyridin-3-yl)carbamate (9c) A solution of 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinic acid (9b) (179 mg) in t-butanol (12 mL) is added with triethylamine (50 mg, 0.495 mmol) and DPPA (136 mg, 0.495 mmol) and stirred at 85° C. for 2 hours under N2 atmosphere. The reaction mixture is cooled to room temperature, concentrated, and separated by flash (ethyl acetate / petroleum ether=40-90%) to give t-butyl (6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)pyridin-3-yl)carbamate (9c) (69 mg, pale yellow solid), yield 33%.

[0197] MS m / z[M+H]+ :470. Step 4: Synthesis of t-butyl (6-((6-(cyclopropylcarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)pyridin-3-yl)carbamate (9d) The synthesis method is as described in the synthesis method for 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and the yield is 29%.

[0198] MS m / z[M+H] + :519. Step 5: Synthesis of 4-((5-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (9) Dissolve t-butyl (6-((6-(cyclopropylcarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)pyridin-3-yl)carbamate (9d) (22 mg, 0.042 mmol) in dichloromethane (1.5 mL), add 4 M hydrochloric acid in dioxane (1.5 mL, 6 mmol) and stir at room temperature for 1 h. Spin-dry the solvent, dilute with water (1.5 mL), adjust pH>11 with 33% aqueous potassium carbonate, extract with ethyl acetate, combine the organic phases and dry over anhydrous sodium sulfate. After filtration and concentration, the crude product was obtained and purified by preparative HPLC to give 4-((5-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (9) (6.7 mg, white solid), yield: 38%.

[0199] 1H NMR(400MHz,DMSO-d6)δ 11.34(s,1H),11.23(s,1H),9.00(d,J=4.9Hz,1H),8.92(s,1H),7.91(d,J=2.8Hz,1H),7.53(d,J=2.8Hz,1 H),5.66(s,2H),3.10(s,3H),2.82(d,J=4.8Hz,3H),2.63(s,3H),2.11-2.03(m,1H),0.82(d,J=6.7Hz,4H).

[0200] MS m / z[M+H] + :419. Example 10: Preparation of 4-((5-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide

[0201] [ka]

[0202] Step 1: Synthesis of 4-((5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (10a) The synthesis method was as described for 5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-amine, and the yield was 16%.

[0203] MS m / z[M+H] + :485. Step 2: Synthesis of 6-((6-(cyclopropylcarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinic acid-2,4,6-trichlorophenyl ester (10b) The synthesis method was as described in the synthesis method for 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinic acid-2,4,6-trichlorophenyl ester, and the yield was 82%.

[0204] MS m / z[M+H] + :629. Step 3: Synthesis of 6-((6-(cyclopropylcarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinic acid (10c) For the synthesis method, refer to the synthesis method of 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinic acid, and use the crude product directly in the next step without separation.

[0205] MS m / z[M+H] + :402. Step 4: Synthesis of t-butyl (6-((6-(cyclopropylcarboxamido)-3-((methyl-d3)carbamoyl))pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)pyridin-3-yl)carbamate (10d) For the synthesis method, refer to the synthesis method of t-butyl (6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)pyridin-3-yl)carbamate, and the yield of the two steps is 25%.

[0206] MS m / z[M+H] + :522. Step 5: Synthesis of 4-((5-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (10) The synthesis method is as described in the synthesis method for 4-((5-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide, and the yield is 16%.

[0207] 1 H NMR(400MHz,DMSO-d6)δ 11.34(s,1H),11.23(s,1H),8.97(s,1H),8.92(s,1H),7.91(d,J=2.7Hz,1H),7.53(d,J=2. 7Hz, 1H), 5.66 (s, 2H), 3.10 (s, 3H), 2.63 (s, 3H), 2.10-2.04 (m, 1H), 0.82 (d, J=6.6Hz, 4H).

[0208] MS m / z[M+H] + :422. Example 11: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0209] [ka]

[0210] Step 1: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (11a) 4-((5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide (8b) (200 mg, 0.463 mmol), pinacol diborate (151 mg, 0.594 mmol), Pd(dppf)Cl2 (34 mg, 0.046 mmol), anhydrous potassium acetate (133 mg, 1.400 mmol) are dissolved in dioxane and stirred at 100 °C for 1 hour under nitrogen gas atmosphere. After cooling to room temperature, 30% aqueous hydrogen peroxide solution (103 mg, 0.909 mmol) is added to the reaction solution and stirred at room temperature for 30 minutes. Ethyl acetate and water are added to dilute the reaction solution, the aqueous phase is extracted with ethyl acetate, the organic phase is combined, washed with saturated saline solution, and dried over anhydrous sodium sulfate. After concentration, separation by column chromatography (methanol:dichloromethane=1:20) gave 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (11a) (124 mg, yellow solid), the yield was 73%.

[0211] 1 H NMR(400MHz,DMSO-d6)δ 11.79(s,1H),10.45(s,1H),9.26(d,J=4.6Hz,1H),8.56(s,1H),8.21(d,J=2.8 Hz,1H),7.69(d,J=2.8Hz,1H),3.19(s,3H),2.84(d,J=4.7Hz,3H),2.67(s,3H).

[0212] MS m / z[M+H] + :371. Step 2: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (11) The synthesis method was as described in the synthesis method for 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and the yield was 69%.

[0213] 1 H NMR(400MHz,DMSO-d6)δ 11.52(s,1H),11.28(s,1H),9.07(s,1H),9.04(d,J=4.9Hz,1H),8.10(d,J=2.9Hz,1H),7.66(d,J=2. 9Hz,1H),3.16(s,3H),2.83(d,J=4.8Hz,3H),2.64(s,3H),2.12-2.03(m,1H),0.83(d,J=6.6Hz,4H).

[0214] MS m / z[M+H] + :420. Example 12: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-fluoropyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0215] [ka]

[0216] For the preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-fluoropyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (12), refer to the preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide in Example 5, using N-(5-fluoropyridin-2-yl)trimethylacetamide (12a) as the starting material instead of N-(6-methylpyridine-2-methyl)trimethylacetamide.

[0217] Step 1: Synthesis of N-(5-fluoro-3-methylthiopyridin-2-yl)trimethylacetamide (12b), yield: 26%. For the synthesis of N-(5-fluoropyridin-2-yl)trimethylacetamide (12a), see Org. Lett. 2013, 15(13), 3460-3463.

[0218] 1 H NMR(400MHz,DMSO-d6)δ 9.50(s,1H),8.16(d,J=2.2Hz,1H),7.70-7.63(d,J=8.0,2.2Hz,1H),2.42(s,3H),1.21(s,9H).

[0219] MS m / z[M+H] + :243. Step 2: Synthesis of N-(3-(S-methylsulfoximino)-5-fluoropyridin-2-yl)trimethylacetamide (12c), yield: 28%.

[0220] 1 H NMR(400MHz,DMSO-d6)δ 10.57(s,1H),8.66(s,1H),8.12(d,J=7.4Hz,1H),7.68(d,J=13.8Hz,1H),3.17(s,3H),1.22(s,9H).

[0221] MS m / z[M+H] + :274. Step 3: Synthesis of N-(3-(N,S-dimethylsulfoximino)-5-fluoropyridin-2-yl)trimethylacetamide (12d), yield: 14%.

[0222] 1 H NMR(400MHz,DMSO-d6)δ 10.30(s,0.65H),9.81(s,0.35H),8.78(s,0.35H),8.68(d,J=2.4Hz,0.65H),8.31(d,J=7.5H z,0.35H),8.09(dd,J=7.6,2.4Hz,0.65H),3.25(s,3H),2.56(s,3H),1.23(d,J=11.5Hz,9H).

[0223] MS m / z[M+H] +:288. Step 4: Synthesis of 3-(N,S-dimethylsulfoximino)-5-fluoropyridin-2-amine (12e), yield: 47%.

[0224] 1 H NMR (400MHz, DMSO-d6) δ 8.34 (s, 1H), 7.79 (d, J = 7.6 Hz, 1H), 6.82 (s, 2H), 3.19 (s, 3H), 2.57 (s, 3H).

[0225] MS m / z[M+H] + :204. Step 5: Preparation of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-fluoropyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (12f), yield: 32%.

[0226] 1 H NMR(400MHz,DMSO-d6)δ 12.03(s,1H),9.31(s,1H),8.71(s,2H),8.12(d,J=5.7Hz,1H),3.27(s,3H),2.85(d,J=4.4Hz,3H),2.68(s,3H).

[0227] MS m / z[M+H] + :373. Step 6: Preparation of 6-(cyclopropylcarboxamide)-4-((3-(N,S-dimethylsulfoximino)-5-fluoropyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (12), yield: 29%.

[0228] 1H NMR(400MHz,DMSO-d6)δ 11.82(s,1H),11.39(s,1H),9.29(s,1H),9.11(d,J=4.8Hz,1H),8.60(d,J=3.0Hz,1H),8.08(dd,J=7. 7,3.0Hz,1H),3.26(s,3H),2.84(d,J=4.8Hz,3H),2.66(s,3H),2.15-2.05(m,1H),0.90-0.78(m,4H).

[0229] MS m / z[M+H] + :422. Example 13: Preparation of 4-((5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide

[0230] [ka]

[0231] Step 1: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (13a) The synthesis method is the same as that of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, and the yield is 40%.

[0232] 1 H NMR(400MHz,DMSO-d6)δ 12.07(s,1H),9.28(s,1H),8.88(s,1H),8.63(d,J=3.5Hz,1H),8.24(d,J=7.6Hz, 1H),7.35(dd,J=7.3,5.1Hz,1H),3.21(s,3H),2.84(d,J=4.5Hz,3H),2.68(s,3H).

[0233] MS m / z[M+H] + :355. Step 2: Synthesis of 6-(cyclopropylcarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (13b) The synthesis method was as described in the synthesis method for 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and the yield was 44%.

[0234] 1 H NMR(400MHz,DMSO-d6)δ 11.85(s,1H),11.37(s,1H),9.45(s,1H),9.08(d,J=5.3Hz,1H),8.52(d,J=4.7Hz,1H),8.21(d,J=7.7Hz,1H),7.27 (dd,J=7.8,4.9Hz,1H),3.20(s,3H),2.83(d,J=4.6Hz,3H),2.66(s,3H),2.13-2.04(m,1H),0.83(d,J=7.0Hz,4H).

[0235] MS m / z[M+H] + :404. Step 3: Synthesis of 4-((5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (13) 6-(cyclopropylcarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (13b) (490 mg, 1.21 mmol) is dissolved in a mixture of acetonitrile (10 mL) and dichloromethane (10 mL), NBS (183 mg, 1.03 mmol) is added under ice-water bath, and the mixture is stirred at room temperature for 2 hours. The reaction is quenched by adding saturated ammonium chloride (35 mL), diluted with water, extracted with ethyl acetate, and the organic phases are combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration, separation by flash (methanol / dichloromethane=10%) gave 4-((5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (13) (100 mg, pale yellow solid), yield 17%.

[0236] 1 H NMR(400MHz,DMSO-d6)δ 11.88(s,1H),11.42(s,1H),9.34(s,1H),9.12(d,J=4.8Hz,1H),8.65(d,J=2.4Hz,1H),8.26(d,J= 2.4Hz,1H),3.27(s,3H),2.84(d,J=4.8Hz,3H),2.65(s,3H),2.15-2.05(m,1H),0.89-0.80(m,4H).

[0237] MS m / z[M+H] + :482. Example 14: Preparation of 6-(cyclopropylamido)-4-((3-(N,S-dimethylsulfoximino)-5-methoxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0238] [ka]

[0239] Step 1: Synthesis of N-(5-methoxy-3-methylthiopyridin-2-yl)trimethylacetamide (14b) For the synthesis of N-(5-methoxy-pyridin-2-yl)trimethylacetamide (14a), see US2011 / 178053.

[0240] The synthesis of 14b was carried out in accordance with the synthesis of N-(6-methyl-3-methylthiopyridine-2-methyl)trimethylacetamide, and the yield was 58%.

[0241] 1 H NMR (400MHz, CDCl3) δ 7.95(d,J=2.3Hz,1H),7.77(s,1H),7.14(d,J=2.1Hz,1H),3.86(s,3H),2.42(s,3H),1.34(s,9H).

[0242] MS m / z[M+H] + :255. Step 2: Synthesis of 5-methoxy-3-methylthiopyridin-2-amine (14c) The synthesis method was the same as that of 3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-amine, and the yield was 84%.

[0243] 1 H NMR (400MHz, CDCl3) δ 7.70-7.67(m,1H),7.20-7.17(m,1H),4.65(s,2H),3.78(s,3H),2.39(s,3H).

[0244] MS m / z[M+H] + :171. Step 3: Synthesis of N,N-(di-t-butoxycarbonyl)-5-methoxy-3-methylthiopyridin-2-amine 14d The synthesis method is the same as that of N,N-(di-t-butoxycarbonyl)-6-chloro-3-methylthiopyridin-2-amine, and the yield is 70%.

[0245] 1H NMR (400MHz, CDCl3) δ 7.93 (s, 1H), 7.07 (s, 1H), 3.89 (s, 3H), 2.43 (s, 3H), 1.41 (s, 18H).

[0246] MS m / z[M+H] + :371. Step 4: Synthesis of N,N-(di-t-butoxycarbonyl)-3-(S-methylsulfoximino)-5-methoxypyridin-2-amine (14e) For the synthesis method, refer to the synthesis method of 3-(S-methylsulfoximino)-2-nitropyridine, and the yield is 85%.

[0247] 1 H NMR (400MHz, CDCl3) δ 8.36(s,1H),7.94(s,1H),3.94(s,3H),3.16(s,3H),2.04(s,1H),1.47(d,J=9.8Hz,18H).

[0248] MS m / z[M+H] + :402. Step 5: Synthesis of N,N-(di-t-butoxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-methoxypyridin-2-amine (14f) The synthesis method is the same as that of N-(6-methyl-3-(N,S-dimethylsulfoximino)pyridine-2-methyl)trimethylacetamide, and the yield is 80%.

[0249] MS m / z[M+H] + :416. Step 6: Synthesis of 3-(N,S-dimethylsulfoximino)-5-methoxypyridin-2-amine (14g) The synthesis method was as described for 6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-amine, and the yield was 23%.

[0250] 1H NMR (400MHz, CDCl3) δ 8.04 (s, 1H), 7.61 (s, 1H), 5.64 (s, 2H), 3.82 (s, 3H), 3.10 (s, 3H), 2.68 (s, 3H).

[0251] MS m / z[M+H] + :202. Step 7: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-methoxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (14h) The synthesis method was as described in the synthesis method for 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, and the yield was 14%.

[0252] MS m / z[M+H] + :385. Step 8: Synthesis of 6-(cyclopropylamido)-4-((3-(N,S-dimethylsulfoximino)-5-methoxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (14) The synthesis method was as described in the synthesis method for 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and the yield was 79%.

[0253] 1 H NMR(400MHz,CDCl3)δ 11.65(s,1H),11.32(s,1H),9.17(s,1H),9.06(d,J=4.7Hz,1H),8.31(d,J=2.8Hz,1H),7.75(d,J=2.8Hz,1 H),3.90(s,3H),3.21(s,3H),2.84(d,J=4.7Hz,3H),2.66(s,3H),2.14-2.05(m,1H),0.84(d,J=7.1Hz,4H).

[0254] MS m / z[M+H] + :434. Example 15: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0255] [ka]

[0256] Step 1: Synthesis of 3-(N,S-dimethylsulfoximino)-5-methylpyridin-2-amine (15a) 5-Bromo-3-(N,S-dimethylsulfoximino)pyridin-2-amine (8a) (100 mg, 0.38 mmol), tetrakistriphenylphosphine palladium (88 mg, 0.076 mmol), and cesium carbonate (124 mg, 0.38 mmol) are dissolved in a mixture of dioxane (1.8 mL) and water (0.2 mL), and a 3M solution of trimethylborane in tetrahydrofuran (0.2 mL, 0.6 mmol) is added to the reaction solution, and the mixture is reacted at 100° C. for 3 hours under a nitrogen gas atmosphere. The mixture is cooled to room temperature, and the reaction is quenched by adding water, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration, separation by plate chromatography (methanol:dichloromethane=1:10) gave 3-(N,S-dimethylsulfoximino)-5-methylpyridin-2-amine (15a) (50 mg, white solid), yield 66%.

[0257] 1 H NMR (400MHz, CDCl3) δ 8.09 (s, 1H), 7.82 (s, 1H), 5.82 (s, 2H), 3.07 (s, 3H), 2.68 (s, 3H), 2.26 (s, 3H).

[0258] MS m / z[M+H] + :200. Step 2: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (15b) The synthesis method was as described in the synthesis method for 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, and the yield was 22%.

[0259] MS m / z[M+H] + :369. Step 3: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (15) The synthesis method was as described in the synthesis method for 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and the yield was 62%.

[0260] 1 H NMR(400MHz,DMSO-d6)δ 11.77(s,1H),11.34(s,1H),9.38(s,1H),9.06(d,J=4.3Hz,1H),8.39(s,1H),8.05(s,1H),3.19( s,3H),2.84(d,J=4.1Hz,3H),2.66(s,3H),2.34(s,3H),2.14-2.04(m,1H),0.84(d,J=6.4Hz,4H).

[0261] MS m / z[M+H] + :418. Example 16: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-(3-methoxypropoxy)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0262] [ka]

[0263] Step 1: Synthesis of N,N-(di-t-butoxycarbonyl)-5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-amine (16a) The synthesis method was as described for N,N-(di-t-butoxycarbonyl)-6-chloro-3-methylthiopyridin-2-amine, and the yield was 91%.

[0264] 1 H NMR (400MHz, CDCl3) δ 8.76 (s, 1H), 8.44 (s, 1H), 3.14s, 3H), 2.63 (s, 3H), 1.52 (s, 9H), 1.44 (s, 9H).

[0265] MS m / z[M+H] + :464. Step 2: Synthesis of N,N-(di-t-butoxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-amine (16b) The synthesis method was as described in the synthesis method for 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, and the yield was 96%.

[0266] 1 H NMR (400MHz, CDCl3) δ 8.38 (s, 1H), 7.83 (s, 1H), 3.16 (s, 3H), 2.70 (s, 3H), 1.53 (s, 9H), 1.44 (s, 9H).

[0267] MS m / z[M+H] + :402. Step 3: Synthesis of 3-(N,S-dimethylsulfoximino)-5-(3-methoxypropoxy)pyridin-2-amine (16c) To anhydrous DMF (10 mL) of N,N-(di-t-butoxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-amine (16b) (500 mg, 1.25 mmol), add anhydrous potassium carbonate (1.04 g, 7.5 mmol) and stir at room temperature for 10 minutes. Then, add 1-bromo-3-methoxypropane (230 mg, 1.5 mmol) to the reaction solution and stir at 120 ° C for 1 hour. The reaction solution is cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate, and the organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oily crude product. The yellow oily crude product is dissolved in dichloromethane (4 mL), and 4 M hydrogen chloride in dioxane (4 mL) is added at 0 ° C. The mixture is warmed to room temperature and stirred for 1 hour. The solvent is concentrated and spun dry, diluted with water, and adjusted to pH=8-9 with saturated sodium bicarbonate, and the aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration, the mixture is separated by flash (methanol / dichloromethane=3-5%) to give 3-(N,S-dimethylsulfoximino)-5-(3-methoxypropoxy)pyridin-2-amine (16c) (202 mg, yellow solid), yield 59%.

[0268] 1 H NMR(400MHz,DMSO-d6)δ 8.03(d,J=2.9Hz,1H),7.45(d,J=2.9Hz,1H),6.40(s,2H),3.99(t,J=6.4Hz,2H), 3.45(t,J=6.3Hz,2H),3.24(s,3H),3.08(s,3H),2.50(s,3H),1.95-1.87(m,2H).

[0269] MS m / z[M+H] + :274. Step 4: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-(3-methoxypropoxy)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (16d) The synthesis method was as described in the synthesis method for 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, and the yield was 39%.

[0270] MS m / z[M+H] + :443. Step 5: Synthesis of 6-(cyclopropylcarboxamide)-4-((3-(N,S-dimethylsulfoximino)-5-(3-methoxypropoxy)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (16) The synthesis method was as described in the synthesis method for 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and the yield was 58%.

[0271] 1 H NMR(400MHz,DMSO-d6)δ 11.65(s,1H),11.32(s,1H),9.16(s,1H),9.06(d,J=4.9Hz,1H),8.29(d,J=2.7Hz,1H),7.75(d,J=2.7Hz,1H),4.16(t,J=6.2Hz,2H),3.48( t,J=6.2Hz,2H),3.25(s,3H),3.21(s,3H),2.84(d,J=4.7Hz,3H),2.66(s,3H),2.13-2.06(m,1H),2.02-1.92(m,2H),0.84(d,J=7.1Hz,4H).

[0272] MS m / z[M+H] + :492. Example 17: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-(2-(epoxybutan-3-yl)ethoxy)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0273] [ka]

[0274] Steps 1, 2 and 3: Synthesis of 3-(N,S-dimethylsulfoximino)-5-(2-(epoxybutan-3-yl)ethoxy)pyridin-2-amine (17c) Dissolve N,N-(di-t-butoxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-amine (16b) (300 mg, 0.748 mmol), 3-hydroxyethyloxetane (76 mg, 0.748 mmol), and triphenylphosphine (393 mg, 1.5 mmol) in anhydrous tetrahydrofuran (5 mL), add DIAD (303 mg, 1.5 mmol) under a nitrogen gas atmosphere, and react at room temperature for 2 hours. Quench the reaction by adding water, extract with ethyl acetate, wash with saturated saline, and dry over anhydrous sodium sulfate. Concentration followed by separation by flash (methanol / dichloromethane=4-5%) gives the crude product (954 mg) of N,N-(di-t-butoxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-(2-(epoxybutan-3-yl)ethoxy)pyridin-2-amine (17a).

[0275] The crude product of N,N-(di-t-butoxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-(2-(epoxybutan-3-yl)ethoxy)pyridin-2-amine (17a) is dissolved in dichloromethane (10 mL), and a solution of 4N HCl in dioxane (10 mL) is added. The reaction is allowed to proceed at room temperature for 30 minutes, and the mixture is concentrated to give the crude product of 4-((6-amino-5-(N,S-dimethylsulfoximino)pyridin-3-yl)-oxy)-2-(chloromethyl)-1-ol (17b).

[0276] The crude product of 4-((6-amino-5-(N,S-dimethylsulfoximino)pyridin-3-yl)-oxy)-2-(chloromethyl)-1-ol (17b) is dissolved in ethanol (10 mL), potassium hydroxide (210 mg, 3.74 mmol) is added, and the mixture is refluxed for 4 hours. The reaction is detected as complete by LCMS. The reaction is cooled to room temperature, the ethanol is spin-dried, water is added to quench the reaction, the mixture is extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and separated by flash (methanol / dichloromethane=3-10%) to obtain 3-(N,S-dimethylsulfoximino)-5-(2-(epoxybutan-3-yl)ethoxy)pyridin-2-amine (17c) (62 mg, yellow solid), the yield of the three steps is 29%.

[0277] 1 H NMR(400MHz,CDCl3)δ 7.99(d,J=2.9Hz,1H),7.57(d,J=3.0Hz,1H),5.65(s,2H),4.84(dd,J=7.8,6.0Hz,2H),4.49(t,J=6.2Hz ,2H),3.93(t,J=6.1Hz,2H),3.22(dt,J=14.5,7.2Hz,1H),3.09(s,3H),2.67(s,3H),2.21-2.13(m,2H).

[0278] MS m / z[M+H] + :286. Step 4: Synthesis of 6-(chloro-4-((3-(N,S-dimethylsulfoximino)-5-(2-(epoxybutan-3-yl)ethoxy)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (17d) The synthesis method was as described in the synthesis method for 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, and the yield was 18%.

[0279] MS m / z[M+H] + :455. Step 5: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-(2-(epoxybutan-3-yl)ethoxy)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (17) The synthesis method is as described in the synthesis method for 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and the yield is 60%.

[0280] 1 H NMR(400MHz,DMSO-d6)δ 11.64(s,1H),11.32(s,1H),9.16(s,1H),9.06(d,J=4.9Hz,1H),8.27(d,J =3.0Hz,1H),7.71(d,J=3.0Hz,1H),4.67(dd,J=7.9,5.9Hz,2H),4.36(t,J =6.1Hz,2H),4.09(td,J=6.4,2.4Hz,2H),3.20(s,3H),3.17-3.11(m,1H), 2.83(d,J=4.8Hz,3H),2.65(s,3H),2.14-2.04(m,3H),0.87-0.78(m,4H).

[0281] MS m / z[M+H] + :504. Example 18: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-(2-morpholinoethoxy)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0282] [ka]

[0283] Step 1: Synthesis of 5-(2-bromoethoxy)-3-(N,S-dimethylsulfoximino)pyridin-2-amine (18a) N,N-(di-t-butoxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-amine (16b) (400 mg, 1.0 mmol) is dissolved in acetonitrile (20 mL), anhydrous potassium carbonate (688 mg, 5.0 mmol) and 1,3-dibromoethane (1.87 g, 10.0 mmol) are added, and the mixture is stirred at 80° C. for 45 minutes. The reaction mixture is cooled to room temperature, filtered, and the filter cake is rinsed with acetonitrile. The filtrate is concentrated and then separated by column chromatography (ethyl acetate / petroleum ether=10-65%) to obtain 5-(2-bromoethoxy)-3-(N,S-dimethylsulfoximino)pyridin-2-amine (18a) (462 mg, colorless oil), with a yield of 91%.

[0284] 1 H NMR(400MHz,CDCl3)δ 8.40(d,J=2.9Hz,1H),7.83(d,J=2.5Hz,1H),4.42(t,J=5.9Hz,2H),3.69(t,J=5.9Hz,2H),3.15(s,3H),2.62(s,3H),1.51(s,9H),1.43(s,9H).

[0285] MS m / z[M+H] + :508. Step 2: Synthesis of N,N-(di-t-butoxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-(2-morpholinoethoxy)pyridin-2-amine (18b) 5-(2-bromoethoxy)-3-(N,S-dimethylsulfoximino)pyridin-2-amine (18a) (300 mg, 0.59 mmol) is dissolved in DMF (4 mL), anhydrous potassium carbonate (245 mg, 1.77 mmol) and morpholine (154 mg, 1.77 mmol) are added, and the mixture is stirred at 80° C. for 1 hour. The reaction mixture is cooled to room temperature, filtered, and the filter cake is rinsed with ethyl acetate. The filtrate is concentrated and then separated by column chromatography (methanol / dichloromethane=0-6%) to obtain N,N-(di-t-butoxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-(2-morpholinoethoxy)pyridin-2-amine (18b) (273 mg, colorless oil), with a yield of 90%.

[0286] MS m / z[M+H] + :515. Step 3: Synthesis of 3-(N,S-dimethylsulfoximino)-5-(2-morpholinoethoxy)pyridin-2-amine (18c) At 0°C, 4M hydrogen chloride in dioxane (2.5mL) is slowly added dropwise to a solution of N,N-(di-t-butoxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-(2-morpholinoethoxy)pyridin-2-amine (18b) (287mg, 0.558mmol) in dichloromethane (5mL), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is adjusted to pH=8-9 by adding saturated sodium bicarbonate, the solvent is spin-dried, and the mixture is separated by column chromatography (methanol / dichloromethane=0-9%) to obtain 3-(N,S-dimethylsulfoximino)-5-(2-morpholinoethoxy)pyridin-2-amine (18c) (156mg, pale yellow solid), with a yield of 89%.

[0287] MS m / z[M+H] + :315. Step 4: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-(2-morpholinoethoxy)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (18d) The synthesis method was as described in the synthesis method for 6-chloro-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and the yield was 41%.

[0288] 1 H NMR(400MHz,CDCl3)δ 12.21(s,1H),8.83(s,1H),8.27(d,J=3.0Hz,1H),8.21(s,1H),7.91(d,J=3.0Hz,1H),4.21(t ,J=5.5Hz,2H),3.75(t,J=4.7Hz,4H),3.22(s,3H),2.87-2.81(s,5H),2.59(d,J=4.9Hz,4H).

[0289] MS m / z[M+H] + :487. Step 5: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-(2-morpholinoethoxy)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (18) The synthesis method is as described in the synthesis method for 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and the yield is 28%.

[0290] 1 H NMR(400MHz,DMSO-d6)δ 11.65(s,1H),11.32(s,1H),9.16(s,1H),9.04(s,1H),8.31(d,J=2.9Hz,1H),7.77(d,J=2.9Hz,1H),4.27-4.18(m,2H),3. 61-3.54(m,4H),3.20(s,3H),2.70(t,J=5.5Hz,2H),2.65(s,3H),2.47-2.42(m,4H),2.12-2.04(m,1H),0.89-0.77(m,4H).

[0291] MS m / z[M+H] + :536. Example 19: Preparation of 4-((5-(3-cyanopropoxy)-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide

[0292] [ka]

[0293] Step 1: Synthesis of 6-amino-5-(N,S-dimethylsulfoximino)-3-hydroxypyridine (19a) The synthesis method was as described in the synthesis method for 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, and the yield was 63%.

[0294] 1 H NMR(400MHz,DMSO-d6)δ 9.29(s,1H),7.86(d,J=2.9Hz,1H),7.36(d,J=2.9Hz,1H),6.16(s,2H),3.05(s,3H),2.48(s,3H).

[0295] MS m / z[M+H] + :202. Step 2: Synthesis of 4-((6-amino-5-(N,S-dimethylsulfoximino)pyridin-3-yl)oxybutyronitrile (19b) 4-Bromobutyronitrile (172 mg, 1.16 mmol) was added to a solution of 6-amino-5-(N,S-dimethylsulfoximino)-3-hydroxypyridine (19a) (195 mg, 0.968 mmol) in DMF (4 mL), and anhydrous potassium carbonate (535 mg, 3.87 mmol) was added. The mixture was heated to 40° C. and stirred for 30 minutes. The reaction mixture was cooled to room temperature, filtered, rinsed with ethyl acetate, and the filtrate was concentrated and separated by column chromatography (methanol / dichloromethane=1-2.5%) to obtain 4-((6-amino-5-(N,S-dimethylsulfoximino)pyridin-3-yl)oxybutyronitrile (19b) (148 mg, yellow solid), with a yield of 57%.

[0296] 1 H NMR(400MHz,DMSO-d6)δ 8.06(d,J=3.0Hz,1H),7.49(d,J=3.1Hz,1H),6.44(s,2H),4.03(t,J=6.0Hz,2H ),3.09(s,3H),2.65(t,J=7.2Hz,2H),2.51(s,3H),1.99(tt,J=7.2,6.0Hz,2H).

[0297] MS m / z[M+H] + :269. Step 3: Synthesis of 6-chloro-4-((5-(3-cyanopropoxy)-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (19c) For the synthesis method, refer to the synthesis method of 6-chloro-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and the yield is 49%.

[0298] 1H NMR(400MHz,CDCl3)δ 12.23(s,1H),8.84(s,1H),8.27(s,1H),8.22(s,1H),7.89(s,1H),4.21(t,J=5 .7Hz,2H),3.23(s,3H),2.84(s,3H),2.64(t,J=6.9Hz,2H),2.26-2.17(m,2H).

[0299] MS m / z[M+H] + :441. Step 4: Synthesis of 4-((5-(3-cyanopropoxy)-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (19) The synthesis method is as described in the synthesis method for 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and the yield is 28%.

[0300] 1 H NMR(400MHz,DMSO-d6)δ 11.67(s,1H),11.33(s,1H),9.19(s,1H),9.04(s,1H),8.31(d,J=2.9Hz,1H),7.77(d,J=2.9Hz,1H),4. 24-4.14(m,2H),3.21(s,3H),2.69(t,J=7.1Hz,2H),2.66(s,3H),2.13-2.00(m,3H),0.88-0.79(m,4H).

[0301] MS m / z[M+H] + :490. Example 20: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-((2-methoxyethyl)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0302] [ka]

[0303] Step 1: Synthesis of (6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)pyridin-3-yl)boronic acid (20a) 4-((5-Bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide (8b) (140 mg, 0.324 mmol), pinacol diborate (107 mg, 0.421 mmol), Pd(dppf)Cl2 (24 mg, 0.032 mmol), anhydrous potassium acetate (92 mg, 0.972 mmol) are dissolved in dioxane (4 mL) and stirred at 105 °C for 1 hour under nitrogen gas atmosphere. After cooling to room temperature, 30% aqueous hydrogen peroxide solution (103 mg, 0.909 mmol) is added to the reaction solution and stirred at room temperature for 30 minutes. Water is added to dilute the reaction solution, extracted with dichloromethane, the organic phases are combined, washed with saturated saline solution, and dried over anhydrous sodium sulfate. Concentration followed by slurrying with ethyl acetate gave (6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)pyridin-3-yl)boronic acid (20a) (108 mg, grey solid), 83% yield.

[0304] MS m / z[M+H] + :399. Step 2: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-((2-methoxyethyl)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (20b) To a dichloromethane solution (2 mL) of (6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)pyridin-3-yl)boronic acid (20a) (50 mg, 0.126 mmol), copper acetate monohydrate (10 mg, 0.063 mmol), 4A molecular sieves (20 mg), and 2-methoxyethylamine (19 mg, 0.252 mmol) were added in that order, and the mixture was stirred overnight at 40° C. under an oxygen gas atmosphere. The reaction solution was concentrated and then separated by plate chromatography (methanol:dichloromethane=1:10) to obtain 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-((2-methoxyethyl)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (20b) (5 mg, yellow solid), the yield was 9%.

[0305] MS m / z[M+H] + :428. Step 3: Synthesis of 6-(cyclopropylcarboxamide)-4-((3-(N,S-dimethylsulfoximino)-5-((2-methoxyethyl)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (20) The synthesis method is as described in the synthesis method for 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and the yield is 45%.

[0306] 1 H NMR(400MHz,DMSO-d6)δ 11.37(s,1H),11.23(s,1H),9.00(s,1H),8.92(s,1H),7.98(d,J=2.9Hz,1H),7.49(d,J=2.9Hz,1H),6.29(s,1H),3.50(t ,J=5.3Hz,2H),3.30-3.27(m,5H),3.11(s,3H),2.83(d,J=4.8Hz,3H),2.64(s,3H),2.10-2.05(m,1H),0.84-0.77(m,4H).

[0307] MS m / z[M+H] + :477. Example 21: Preparation of 4-((5-bromo-3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide

[0308] [ka]

[0309] 6-(cyclopropylcarboxamide)-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (5) (10 mg, 0.024 mmol) was dissolved in acetonitrile (0.5 mL) and added with a solution of NBS (4.3 mg, 0.024 mmol) in acetonitrile (0.5 mL) at 0° C. and stirred at 0° C. for 1 h. The reaction was quenched by adding water, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, 21 (6 mg, yellow solid) was obtained in a yield of 50%.

[0310] 1 H NMR(400MHz,DMSO-d6)δ 11.95(s,1H),11.41(s,1H),9.84(s,1H),9.12(d,J=4.9Hz,1H),8.17(s,1H),3.26(s,3H), 2.84(d,J=4.7Hz,3H),2.64(s,3H),2.63(s,3H),2.15-2.07(m,1H),0.86(d,J=6.3Hz,4H).

[0311] MS m / z[M+H] + :496. Example 22: Preparation of 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-fluoropyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide

[0312] [ka]

[0313] 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (7) (168 mg, 0.402 mmol) was dissolved in DMF (4 mL), Selectfluor (284 mg, 0.802 mmol) was added at 0° C., and the mixture was stirred at 35° C. for 1 hour and at 50° C. for 1 hour. DMF was evaporated to dryness under reduced pressure, and separated by plate chromatography (methanol:dichloromethane=1:15) and then prepared by preparative HPLC to give 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-fluoropyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (22) (12 mg, white solid), yield 7%.

[0314] 1 H NMR(400MHz,DMSO-d6)δ 11.48(s,1H),11.32(s,1H),9.22(s,1H),9.03(d,J=4.8Hz,1H),7.60(d,J=10.3Hz,1H),6.95(s ,2H),3.09(s,3H),2.82(d,J=4.7Hz,3H),2.60(s,3H),2.13-2.05(m,1H),0.84(d,J=6.5Hz,4H).

[0315] MS m / z[M+H] + :437. Example 23: Preparation of 4-(6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-methylpyridazine-3-carboxamide

[0316] [ka]

[0317] 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (7) (9 mg, 0.022 mmol) is dissolved in anhydrous DMF (1 mL), NCS (3.5 mg, 0.024 mmol) is added under ice bath, and the mixture is reacted at 60° C. for 3 hours after the completion of the dropwise addition. The reaction solution is cooled to room temperature, and the reaction is quenched by adding saturated sodium bicarbonate (20 mL) and water (20 mL), extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration and preparation by preparative HPLC, 4-(6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-methylpyridazine-3-carboxamide (23) (4 mg, white solid) was obtained in a yield of 41%.

[0318] 1 H NMR(400MHz,DMSO-d6)δ 11.59(s,1H),11.36(s,1H),9.41(s,1H),9.06(d,J=4.9Hz,1H),7.78(s,1H),6.88(s,2H), 3.12(s,3H),2.82(d,J=4.7Hz,3H),2.60(s,3H),2.17-2.02(m,1H),0.85(d,J=6.9Hz,4H).

[0319] MS m / z[M+H] + :453. Example 24: Preparation of 4-((6-amino-5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide

[0320] [ka]

[0321] 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (7) (15 mg, 0.0359 mmol) is dissolved in dichloromethane (1 mL), NBS (6.3 mg, 0.0359 mmol) is added at 0° C., and the mixture is stirred at 0° C. for 3 hours. After concentration, the mixture is separated by flash (methanol / dichloromethane=0-5.5%) to obtain 4-((6-amino-5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (24) (15 mg, yellow solid), the yield is 44%.

[0322] 1 H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),11.35(s,1H),9.47(s,1H),9.05(d,J=5.0Hz,1H),7.90(s,1H),6.77(s,2H),3 .13(s,3H),2.82(d,J=4.8Hz,3H),2.61(s,3H),2.10(q,J=6.2Hz,1H),0.86(d,J=6.6Hz,4H).

[0323] MS m / z[M+H] + :497. Example 25: Preparation of 4-(6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide

[0324] [ka]

[0325] Step 1: Synthesis of 6-chloro-4-((6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (25a) To a solution of 6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-amine (6f) (4.9 g, 22.37 mmol) in tetrahydrofuran (120 mL), add sodium hydride (2.7 g, 67.1 mmol) in a batch, stir for 15 minutes, add 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (2a) (5.6 g, 26.8 mmol) and stir for 1 hour at 65° C. after addition is complete. Quench the reaction by adding ammonium chloride (80 mL) and water (40 mL), extract with dichloromethane (300 mL), wash with saturated brine (50 mL) and dry over anhydrous sodium sulfate. Concentration, slurrying the crude product with methyl t-butyl ether, suction filtering, rinsing the filter cake with methyl t-butyl ether and drying to give 6-chloro-4-((6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (25a) (6.8 g, earthy brown solid), 77% yield.

[0326] 1 H NMR(400MHz,DMSO-d6)δ 12.22(s,1H),9.34(s,1H),8.78(s,1H),8.22(d,J=8.2Hz,1H),7.42(d,J=8.1Hz,1H),3.24(s,3H),2.68(s,3H).

[0327] MS m / z[M+H] + :393. Step 2: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (25b) The synthesis method was as described in the synthesis method for 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, and the yield was 82%.

[0328] 1H NMR(400MHz,DMSO-d6)δ 11.95(s,1H),9.24(s,1H),8.47(s,1H),8.05(d,J=8.3Hz,1H),7.41(s,10H),6.79(d,J=8.3Hz,1H),3.16(s,3H),2.62(s,3H).

[0329] MS m / z[M+H] + :538. Step 3: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (25c) For the synthesis method, refer to the synthesis method of 6-(cyclopropylcarboxamide)-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, and use the crude product in the next step without separating it.

[0330] MS m / z[M+H] + :586. Step 4: Synthesis of 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (25d) For the synthesis method, refer to the synthesis method of 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide, and the yield of the two steps is 63%.

[0331] 1H NMR(400MHz,DMSO-d6)δ 11.55(s,1H),11.32(s,1H),9.49(s,1H),8.99(s,1H),7.73(d,J=8.5Hz,1H),6.56(s,2 H),6.23(d,J=8.7Hz,1H),3.05(s,3H),2.61(s,3H),2.09(s,1H),0.85(d,J=6.7Hz,4H).

[0332] MS m / z[M+H] + :422. Step 5: Synthesis of 4-(6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (25) The synthesis method is as described in the synthesis method of 4-(6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-methylpyridazine-3-carboxamide, and the yield is 50%.

[0333] 1 H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),11.37(s,1H),9.43(s,1H),9.04(s,1H),7.79(s,1H),6.89( s,2H),3.13(s,3H),2.61(s,3H),2.15-2.08(m,1H),0.86(d,J=7.1Hz,4H).

[0334] MS m / z[M+H] + :456. Example 26: Preparation of 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-methylpyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-methylpyridazine-3-carboxamide

[0335] [ka]

[0336] 4-((6-amino-5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (24) (160 mg, 0.322 mmol) is dissolved in dioxane (4 mL), and tetrakistriphenylphosphine palladium (110 mg, 0.096 mmol), anhydrous potassium carbonate (230 mg, 1.66 mmol) and methylboronic acid (496 mg, 1.66 mmol) are added, and the mixture is reacted in a microwave (120° C., 120 W) under a nitrogen gas atmosphere for 1 hour. The reaction solution was cooled to room temperature, dichloromethane was added, and the mixture was stirred and then suction filtered. The filter cake was rinsed with dichloromethane. The filtrate was concentrated and then separated by flash (methanol / dichloromethane=1:20) to obtain 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-methylpyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-methylpyridazine-3-carboxamide (26) (89 mg, yellow solid), the yield was 64%.

[0337] 1 H NMR(400MHz,DMSO-d6)δ 11.51(s,1H),11.30(s,1H),9.51(s,1H),9.00(d,J=4.9Hz,1H),7.58(s,1H),6.36(s,2H),3.04(s,3H) ,2.82(d,J=4.6Hz,3H),2.60(s,3H),2.09(dd,J=11.3,5.5Hz,1H),2.06(s,3H),0.85(d,J=7.0Hz,4H).

[0338] MS m / z[M+H] + :433. Example 27: Preparation of 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-methoxypyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-methylpyridazine-3-carboxamide

[0339] [ka]

[0340] Step 1: Synthesis of 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (27a) A suspension of 4-((6-amino-5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (24) (100 mg, 0.20 mmol) in toluene (3 mL) was added with pinacol diborate (77 mg, 0.30 mmol, 1.5 eq), potassium acetate (49 mg, 0.50 mmol) and Pd(PPh)2Cl2 (28 mg, 0.04 mmol) and reacted at 100 °C for 1 hour under nitrogen gas atmosphere, and Pd(PPh)2Cl2 (28 mg, 0.04 mmol, 0.2 eq) was added and the reaction was continued for 1 hour. The reaction solution was cooled to room temperature, tetrahydrofuran (3 mL) and hydrogen peroxide (0.10 mL, 0.88 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction is quenched with water (20 mL), diluted with dichloromethane, suction filtered, and the filter cake is rinsed with dichloromethane. The filter cake is separated by flushing (methanol / dichloromethane=1:10) to give 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (27a) (30 mg, tan solid), 28% yield.

[0341] 1 H NMR(400MHz,DMSO-d6)δ 11.27(s,1H),11.23(s,1H),9.88(s,1H),9.12(s,1H),8.99(d,J=4.7Hz,1H),7.24(s,1H),6.29( s,2H),3.01(s,3H),2.81(d,J=4.6Hz,3H),2.59(s,3H),2.12-2.04(m,1H),0.83(d,J=7.2Hz,4H).

[0342] MS m / z[M+H] + :435. Step 2: Synthesis of 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-methoxypyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-methylpyridazine-3-carboxamide (27) 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (27a) (10 mg, 0.023 mmol) is dissolved in DMF (0.6 mL), potassium carbonate (5 mg, 0.034 mmol) and iodomethane (3.3 mg, 0.023 mmol) are added and stirred at room temperature for 20 min. The reaction is quenched with water (5 mL), extracted with ethyl acetate, and the organic phases are combined, washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, preparative HPLC gave 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-methoxypyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-methylpyridazine-3-carboxamide (27) (2.2 mg, white solid), yield 22%.

[0343] 1 H NMR(400MHz,DMSO-d6)δ 11.35(s,1H),11.26(s,1H),9.13(s,1H),9.00(d,J=4.8Hz,1H),7.27(s,1H),6.54(s,2H),3.81( s,3H),3.05(s,3H),2.82(d,J=4.5Hz,3H),2.60(s,3H),2.12-2.04(m,1H),0.83(d,J=6.6Hz,4H).

[0344] MS m / z[M+H] + :449. Example 28: Preparation of (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-N-(methyl-d3)pyridazine-3-carboxamide

[0345] [ka]

[0346] Step 1: Synthesis of (R)-N-(6-chloro-3-(methylsulfinyl)pyridin-2-yl)trimethylacetamide (28b) For the synthesis of (1R,2S)-1-(3,5-dichloro-2-hydroxybenzylidene)amino-2-indanol (28a), see Comptes Rendus Chimie, 2014, 17(5), 403-412.

[0347] (1R,2S)-1-amino-2-indanol (61.5 g, 0.413 mmol) and 3,5-dichlorosalicylaldehyde (78.8 g, 0.413 mmol) were dissolved in anhydrous methanol (1.5 L) and stirred at 70° C. for 1 h. The methanol was removed under reduced pressure, the mixture was slurried with petroleum ether, suction filtered, and dried to give (1R,2S)-1-(3,5-dichloro-2-hydroxybenzylidene)amino-2-indanol (28a) (131 g, yellow solid), 99% yield.

[0348] 1 H NMR(400MHz,DMSO-d6)δ 14.79(s,1H),8.70(s,1H),7.56(t,J=2.0Hz,1H),7.48(t,J=1.9Hz,1H),7.31(q,J=7.7,7.3Hz,2H),7.24(d,J=5.8Hz,2H),5. 55(d,J=4.8Hz,1H),5.06(d,J=5.3Hz,1H),4.60(t,J=4.6Hz,1H),3.15(dd,J=16.1,5.7Hz,1H),2.91(dd,J=16.1,4.0Hz,1H).

[0349] MS m / z[M+H] + :322 (1R,2S)-1-(3,5-dichloro-2-hydroxybenzylidene)amino-2-indanol (28a) (4.62g, 14.4mmol) and acetylacetonate alum (2.38g, 9.0mmol) are added to a mixed solvent of toluene and dichloromethane (10:1,930mL), stirred for 20 minutes until completely dissolved, N-(6-chloro-3-(methylthio)pyridin-2-yl)trimethylacetamide (6a) (46.4g, 179.8mmol) is added, and stirred for 20 minutes. Hydrogen peroxide (26.5g, 234.0mmol) is added dropwise in an ice bath, and after the addition is complete, the mixture is stirred at room temperature for 2 hours, and hydrogen peroxide (3.6mL, 36.0mmol) is added, and the mixture is allowed to react for 1 hour. The reaction mixture is quenched by adding saturated sodium sulfite solution (150 mL), extracted with ethyl acetate, the organic phases are combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration, the mixture is slurried with a mixture of isopropanol (40 ml) and petroleum ether (280 mL), suction filtered, and the filtrate is separated by flushing (ethyl acetate / petroleum ether=1:1) to obtain (R)-N-(6-chloro-3-(methylsulfinyl)pyridin-2-yl)trimethylacetamide (28b) (51 g, pale yellow solid), with an ee value of 96.5% and a yield of 72%.

[0350] 1 H NMR(400MHz, CDCl3)δ 8.59(s,1H),8.11(d,J=8.2Hz,1H),7.27(d,J=8.2Hz,1H),2.94(s,3H),1.26(s,9H).

[0351] MS m / z[M+H] + :275. Step 2: Synthesis of (R)-6-chloro-3-(methylsulfinyl)-pyridin-2-amine (28c) (R)-N-(6-chloro-3-(methylsulfinyl)pyridin-2-yl)trimethylacetamide (28b) (50.2 g, 0.183 mml) was added to 3N aqueous hydrochloric acid (610 mL, 1.832 mml) and stirred at 50 °C for 5 hours. In an ice bath, the pH was adjusted to 9-10 with aqueous potassium carbonate (40%), the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration, the mixture was slurried with a mixture of dichloromethane / petroleum ether (2:3, 100 mL), suction filtered, and the filter cake was rinsed with petroleum ether to obtain (R)-6-chloro-3-(methylsulfinyl)-pyridin-2-amine (28c) (28.7 g, white solid), with an ee value of 98.2% and a yield of 80%.

[0352] 1 H NMR (400MHz, CDCl3) δ 7.42 (d, J = 7.8 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 6.07 (s, 2H), 2.89 (s, 3H).

[0353] MS m / z[M+H] + :191. Step 3: Synthesis of (R)-6-chloro-3-(S-methylsulfoximino)pyridin-2-amine (28d) The synthesis method is the same as that of 3-(S-methylsulfoximino)-2-nitropyridine, and the yield is 70%.

[0354] 1 H NMR (400MHz, CDCl3) δ 7.98(d,J=8.1Hz,1H),6.76(d,J=8.1Hz,1H),6.35(s,2H),3.11(s,3H),2.46(s,1H).

[0355] MS m / z[M+H] + :206. Step 4: Synthesis of (R)-6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-amine (28e) (R)-6-chloro-3-(S-methylsulfoximino)pyridin-2-amine (28d) (11.63 g, 56.7 mmol), methylboronic acid (8.16 g, 136.1 mmol) and copper acetate (15.5 g, 85 mmol) are dissolved in a mixture of anhydrous DMF (69 mL) and pyridine (46 mL) and reacted at 80° C. for 4 hours under an oxygen gas atmosphere. The reaction solution is cooled to room temperature, suction filtered, the filter cake is rinsed with ethyl acetate, water (200 mL) and ammonia (60 mL) are added to the filtrate, extracted with ethyl acetate, the organic phases are combined, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration, separation by column chromatography (ethyl acetate / petroleum ether=40-50%) gave (R)-6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-amine (28e) (8.69 g, pale yellow solid), with an ee value of 98.2% and a yield of 70%.

[0356] 1 H NMR (400MHz, CDCl3) δ 7.91 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.26 (s, 2H), 3.07 (s, 3H), 2.68 (s, 3H).

[0357] MS m / z[M+H] + :220. Step 5: Synthesis of (R)-6-chloro-4-((6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (28f) The synthesis method was as described in the synthesis method for 6-chloro-4-((6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and the yield was 79%.

[0358] 1H NMR(400MHz,DMSO-d6)δ 12.21(s,1H),9.32(s,1H),8.78(s,1H),8.22(d,J=8.1Hz,1H),7.42(d,J=8.1Hz,1H),3.24(s,3H),2.68(s,3H).

[0359] MS m / z[M+H] + :393. Step 6: Synthesis of (R)-6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (28g) The synthesis method was as described in the synthesis method for 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, and the yield was 68%.

[0360] MS m / z[M+H] + :538. Step 7: Synthesis of (R)-6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (28h) The synthesis method was as described in the synthesis method for 6-(cyclopropylcarboxamide)-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, and the yield was 91%.

[0361] MS m / z[M+H] + :586. Step 8: Synthesis of (R)-4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (28i) The synthesis method was as described in the synthesis method for 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide, and the yield was 69%.

[0362] 1 H NMR(400MHz,DMSO-d6)δ 11.55(s,1H),11.30(s,1H),9.50(s,1H),8.98(s,1H),7.73(d,J=8.6Hz,1H),6.54(s,2H) ),6.23(d,J=8.6Hz,1H),3.05(s,3H),2.61(s,3H),2.14-2.05(m,1H),0.90-0.82(m,4H).

[0363] MS m / z[M+H] + :422. Step 9: Synthesis of (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-N-(methyl-d3)pyridazine-3-carboxamide (28) For the synthesis method, refer to the synthesis method of 4-(6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-methylpyridazine-3-carboxamide, the ee value is 98.2%, and the yield is 50%.

[0364] 1 H NMR(400MHz,DMSO-d6)δ 11.59(s,1H),11.34(s,1H),9.43(s,1H),9.01(s,1H),7.78(s,1H),6.86( s, 2H), 3.12 (s, 3H), 2.61 (s, 3H), 2.15-2.06 (m, 1H), 0.85 (d, J=6.1Hz, 4H).

[0365] MS m / z[M+H] + :456. The asymmetric synthesis of the chiral fragment (R)-6-chloro-3-(methylsulfinyl)-pyridin-2-amine (28c) can also be achieved via the following route.

[0366] [ka]

[0367] Step 1: Synthesis of (R)-3,6-dichloro-N-(1-(4-methoxyphenyl)ethyl)-2-pyridinecarboxamide (28j) Dissolve 3,6-dichloro-2-pyridineformic acid (5 g, 26.04 mmol) in anhydrous DMF (20 mL), add N,N-carbonyldiimidazole (4.64 g, 28.65 mmol) in batches, and stir at room temperature for 20 minutes after the addition is complete. Cool the reaction solution to 0°C, add (R)-(+)-1-(4-methoxybenzene)ethylamine (4.33 g, 28.65 mmol) dropwise, control the internal temperature to be less than 10°C, and continue to stir at room temperature for 1.5 hours after the addition is complete. Add water (60 mL) to quench the reaction, and continue to stir for 1 hour, suction filter, and rinse the filter cake with distilled water. Dissolve the filter cake in dichloromethane, wash with 1% HCl, and dry with anhydrous sodium sulfate. Concentration gave (R)-3,6-dichloro-N-(1-(4-methoxyphenyl)ethyl)-2-pyridinecarboxamide (28j) (7.77 g, white solid), the yield was 92%.

[0368] 1 H NMR(400MHz,CDCl3)δ 7.80(d,J=7.3Hz,1H),7.76(d,J=8.4Hz,1H),7.39-7.31(m,3H),6.90(d,J=8.5Hz,2H),5.28-5.20(m,1H),3.81(s,3H),1.61(d,J=6.9Hz,3H).

[0369] MS m / z[M+H] + :325. Step 2: Synthesis of (R)-6-chloro-N-(1-(4-methoxyphenyl)ethyl)-3-(methylthio)-2-pyridinecarboxamide (28k) (R)-3,6-dichloro-N-(1-(4-methoxyphenyl)ethyl)-2-pyridinecarboxamide (28j) (7.2 g, 22.15 mmol) is dissolved in DMF (35 mL), and 20% aqueous sodium methylmercaptide (11.6 g, 33.23 mmol) is slowly added dropwise at room temperature. After the addition is complete, the mixture is stirred at room temperature for 1 h. Water (100 mL) is added to quench the reaction, and the mixture is stirred at room temperature for 2 h. The mixture is suction filtered and the filter cake is rinsed with distilled water. The filter cake is dissolved in dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, separation by column chromatography (ethyl acetate:petroleum ether=1:1) gave (R)-6-chloro-N-(1-(4-methoxyphenyl)ethyl)-3-(methylthio)-2-pyridinecarboxamide (28k) (4.84 g, white solid), the yield was 65%.

[0370] 1 H NMR(400MHz,CDCl3)δ 8.03(d,J=7.5Hz,1H),7.58(d,J=8.4Hz,1H),7.41-7.29(m,3H),6.89(d,J=8. 0Hz, 2H), 5.31-5.19 (m, 1H), 3.80 (s, 3H), 2.40 (s, 3H), 1.60 (d, J = 7.6Hz, 3H).

[0371] MS m / z[M+H] + :337. Step 3: Synthesis of 6-chloro-N-((R)-1-(4-methoxyphenyl)ethyl)-3-((R)-methylsulfinyl)-2-pyridinecarboxamide (28l) For the synthesis method, refer to the synthesis method of (R)-N-(6-chloro-3-(methylsulfinyl)pyridin-2-yl)trimethylacetamide. For post-treatment, recrystallization is performed using ethanol. The yield is 64% and the de value is 99.9%.

[0372] 1 H NMR(400MHz,CDCl3)δ 8.55(d,J=8.3Hz,1H),7.97(d,J=8.0Hz,1H),7.63(d,J=8.2Hz,1H),7.24(d,J=8.5Hz,2H), 6.83(d,J=8.4Hz,2H),5.17-5.07(m,1H),3.73(s,3H),2.87(s,3H),1.55(d,J=6.9Hz,3H).

[0373] MS m / z[M+H] + :353. Step 4: Synthesis of (R)-6-chloro-3-(methylsulfinyl)-2-pyridinecarboxamide (28m) 6-Chloro-N-((R)-1-(4-methoxyphenyl)ethyl)-3-((R)-methylsulfinyl)-2-pyridinecarboxamide (28l) (6.0 g, 17.05 mmol) is dissolved in trifluoroacetic acid (20 mL) and stirred at 40° C. for 1.5 hours. The solvent is evaporated under reduced pressure and dilution is added with dichloromethane (50 mL). The mixture is slowly dripped into saturated sodium bicarbonate solution (100 mL), the aqueous phase is extracted with dichloromethane, the organic phases are combined, washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, it is slurried with a mixture of dichloromethane / petroleum ether (1:10, 100 mL) and suction filtered to give (R)-6-chloro-3-(methylsulfinyl)-2-pyridinecarboxamide (28l) (3.4 g, white solid), the yield is 92%.

[0374] 1 H NMR (400MHz, CDCl3) δ 8.65 (d, J = 8.3 Hz, 1H), 7.81-6.76 (m, 2H), 6.03 (s, 1H), 2.92 (s, 3H).

[0375] MS m / z[M+H] + :219. Step 5: Synthesis of (R)-6-chloro-3-(methylsulfinyl)-pyridin-2-amine (28c) (R)-6-chloro-3-(methylsulfinyl)-2-pyridinecarboxamide (28l) (55 g, 0.252 mml) is dissolved in dioxane (250 mL), 10% aqueous sodium hydroxide solution (250 mL) precooled to 0 °C is added, 7.5% aqueous sodium hypochlorite solution (180 g, 0.378 mml) is added dropwise at room temperature, and after the addition is complete, the mixture is stirred at 70 °C for 1 hour. The reaction solution is cooled to room temperature, and the reaction is quenched by adding saturated sodium sulfite solution (10 mL) dropwise until the color of the potassium starch iodide test paper does not change, and then the mixture is diluted with saturated saline. Extract with ethyl acetate, combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. After concentration, the mixture was slurried with dichloromethane (100 mL) and petroleum ether (100 mL), suction filtered, rinsed with petroleum ether, and dried to give (R)-6-chloro-3-(methylsulfinyl)-pyridin-2-amine (28c) (39.4 g, white solid), yield 82%.

[0376] 1 H NMR (400MHz, CDCl3) δ 7.42 (d, J = 7.8 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 6.07 (s, 2H), 2.89 (s, 3H).

[0377] MS m / z[M+H] + :191. Example 29: Preparation of (R)-4-((6-amino-5-chloro-3-(S-methylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide

[0378] [ka]

[0379] Step 1: Synthesis of 6-chloro-3-(S-methyl-N-(4-nitrobenzenesulfonyl)-sulfoximino)pyridin-2-amine (29a) N,N-(di-t-butoxycarbonyl)-6-chloro-3-(S-methylsulfoximino)pyridin-2-amine (6d) (2.05 g, 5.06 mmol) was dissolved in anhydrous pyridine (30 mL), p-nitrobenzenesulfonyl chloride (1.34 g, 6.07 mmol) was slowly added at room temperature, and the mixture was stirred for 2 h. Water (60 mL) was added to quench the reaction, followed by extraction with ethyl acetate. The organic phases were combined, washed with 1N hydrochloric acid and saturated brine, respectively, dried over anhydrous sodium sulfate, and concentrated to give the crude product (yellow solid, 3.3 g).

[0380] The crude product is dissolved in dichloromethane (10 mL), 4M hydrogen chloride in dioxane (10 mL) is added under ice-water bath, and the mixture is stirred at room temperature for 1 hour. After concentration, the mixture is diluted with water, adjusted to pH=8-9 with saturated potassium carbonate solution, and extracted with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, concentrated, and separated by flash (ethyl acetate:petroleum ether=1:1) to obtain 6-chloro-3-(S-methyl-N-(4-nitrobenzenesulfonyl)-sulfoximino)pyridin-2-amine (29a) (1.68 g, yellow solid), yield 85%.

[0381] 1 H NMR(400MHz,DMSO-d6)δ 8.34(d,J=8.8Hz,2H),8.00(d,J=8.8Hz,2H),7.89(d,J=8.3Hz,1H),7.28(s,2H),6.82(d,J=8.3Hz,1H),3.65(s,3H).

[0382] MS m / z[M+H] + :391. Step 2: Synthesis of 6-chloro-4-((6-chloro-3-(S-methyl-N-(4-nitrobenzenesulfonyl)sulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (29b) The synthesis method is the same as that of 6-chloro-4-((6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and the yield is 50%.

[0383] 1 H NMR(400MHz,DMSO-d6)δ 12.29(s,1H),9.50(s,1H),8.71(s,1H),8.38(d,J=8.4Hz,1H),8.20(d,J=8.6Hz,2H),7.93(d,J=8.7Hz,2H),7.54(d,J=8.3Hz,1H),3.82(s,3H).

[0384] MS m / z[M+H] + :563. Step 3: Synthesis of 6-chloro-4-((6-((diphenylmethylene)amino)-3-(S-methyl-N-((4-nitrobenzenesulfonyl)sulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (29c) The synthesis method is based on the synthesis method of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, and dioxane is used as the solvent instead of DMF. The reaction temperature is 110°C, and the yield is 25%.

[0385] 1 H NMR(400MHz,DMSO-d6)δ 11.89(s,1H),9.40(s,1H),8.27(s,1H),8.21(d,J=8.5Hz,1H),8.03(d,J=8.4Hz,2 H),7.68(d,J=8.4Hz,2H),7.59-7.45(m,10H),6.98(d,J=8.5Hz,1H),3.76(s,3H).

[0386] MS m / z[M+H] + :708. Step 4: Synthesis of 6-(cyclopropylcarboxamido)-4-((6-((diphenylmethylene)amino)-3-(S-methyl-N-((4-nitrobenzenesulfonyl)sulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (29d) For the synthesis method, refer to the synthesis method of 6-(cyclopropanecarboxamide)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide. After the reaction is completed, do not separate, and use the crude product as it is for the next step.

[0387] MS m / z[M+H] + :757. Step 5: Synthesis of 4-((6-amino-3-(S-methyl-N-(4-nitrobenzenesulfonyl)-sulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (29e) For the synthesis method, refer to the synthesis method of 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide, and use the crude product of 29d instead of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, and the yield of the two steps is 43%.

[0388] MS m / z[M+H] + :593. Step 6: Synthesis of (R)-4-((6-amino-5-chloro-3-(S-methylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (29) NCS (248 mg, 1.86 mmol) is added to a solution of 4-((6-amino-3-(S-methyl-N-(4-nitrobenzenesulfonyl)-sulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (29e) (1.1 g, 1.86 mmol) in anhydrous DMF (20 mL) and stirred at 60 °C for 1 h. After cooling to room temperature, the reaction is quenched by adding saturated aqueous sodium sulfite (10 mL) and water (80 mL), stirred for 10 min, and then filtered under suction. The filter cake is rinsed with water, dried, slurried in dichloromethane, and filtered to give the crude chlorinated product (380 mg, earthy yellow solid).

[0389] Add aqueous solution (1 mL) of potassium hydroxide (851 mg, 15.2 mmol) to a solution of p-methoxythiophenol (2.18 g, 15.6 mmol) in acetonitrile (5 mL), stir for 5 minutes, then add chlorinated crude product (380 mg) and continue stirring at room temperature for 1 hour. Quench the reaction with saturated potassium carbonate solution, extract with ethyl acetate, combine the organic phases and dry over anhydrous sodium sulfate. After concentration, separate by flash (methanol:dichloromethane=1:10) to obtain 4-((6-amino-5-chloro-3-(S-methylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide racemic compound (250 mg, yellow solid), yield 30%. The racemic compound is subjected to SFC chiral resolution to give (S)-4-((6-amino-5-chloro-3-(S-methylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (29f) (85 mg, white solid, 10% yield) and (R)-4-((6-amino-5-chloro-3-(S-methylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (29) (85 mg, light yellow solid, 10% yield).

[0390] 29f: 1 H NMR(400MHz,DMSO-d6)δ 11.70(s,1H),11.36(s,1H),9.41(s,1H),9.04(s,1H),7.87(s,1H),6.83( s, 2H), 4.50 (s, 1H), 3.09 (s, 3H), 2.17-2.06 (m, 1H), 0.85 (d, J=6.0Hz, 4H).

[0391] MS m / z[M+H] + :442. 29: 1 H NMR(400MHz,DMSO-d6)δ 11.71(s,1H),11.36(s,1H),9.41(s,1H),9.04(s,1H),7.87(s,1H),6.83( s, 2H), 4.50 (s, 1H), 3.09 (s, 3H), 2.17-2.06 (m, 1H), 0.85 (d, J=5.2Hz, 4H).

[0392] MS m / z[M+H] + :442. Example 30: Preparation of (R)-4-((6-amino-5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-N-(methyl-d3)pyridazine-3-carboxamide (30)

[0393] [ka]

[0394] (R)-4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (28i) (7.95 g, 18.9 mmol) is dissolved in NMP (48 mL), NBS (3.38 g, 19 mmol) is added in batches under ice bath cooling, and the mixture is stirred under ice bath for 30 min. After the reaction is complete, Na2SO3 saturated aqueous solution (6.5 mL) is added under ice bath, the mixture is stirred for 10 min, ice water (500 mL) is added in batches to precipitate a solid, and the mixture is stirred for 1 h. Suction filter, and the filter cake is rinsed with water (50 mL). The filter cake is dissolved in DCM / MeOH (10 / 1, 300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Slurry with EtOH / DCM (1 / 10, 30 mL) to give 5.2 g of off-white solid. Mix the mother liquor with silica gel and separate by column chromatography (methanol / dichloromethane=2-5%) to give 4.3 g of white solid. Combine the two batches of solid, add EA (97 mL), heat in 75° C. oil bath for 30 min, slowly cool to room temperature, and suction filter to give 8.15 g of off-white solid. Yield is 86%.

[0395] 1 H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),11.35(s,1H),9.46(s,1H),9.02(s,1H),7.89(s,1H),6.77( s, 2H), 3.12 (s, 3H), 2.60 (s, 3H), 2.14-2.06 (m, 1H), 0.85 (d, J=6.5Hz, 4H).

[0396] MS m / z[M+H] + :500. Example 31: Preparation of 6-(cyclopropylcarboxamido)-4-((5-(N,S-dimethylsulfoximino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-N-methylpyridazine-3-carboxamide

[0397] [ka]

[0398] Step 1: Synthesis of 6-(cyclopropylcarboxamide)-4-((5-(N,S-dimethylsulfoximino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-N-methylpyridazine-3-carboxamide (31) For the synthesis of 2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane, see WO2012 / 010538, 2012, A2.

[0399] 4-((6-amino-5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (24) (12 mg, 0.0241 mmol), 2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (5.7 mg, 0.0290 mmol), Pd(dppf)Cl2 (1.8 mg, 0.00241 mmol), lithium hydroxide monohydrate (3.0 mg, 0.0723 mmol) are dissolved in anhydrous DMF (0.5 mL) and stirred at 70 ° C for 1 hour under nitrogen gas atmosphere. The reaction solution is cooled to room temperature, 25% hydrochloric acid aqueous solution (53 mg) is added, and the reaction is allowed to proceed at 50 ° C for 1 hour. The reaction is quenched by adding water, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration and separation by flash (methanol / dichloromethane=4-7%), 6-(cyclopropylcarboxamide)-4-((5-(N,S-dimethylsulfoximino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-N-methylpyridazine-3-carboxamide (31) (1.2 mg, yellow solid) is obtained in 11% yield.

[0400] 1H NMR(400MHz,DMSO-d6)δ 11.93(s,1H),11.66(s,1H),11.33(s,1H),9.11(s,1H),9.04(d,J=5.0Hz,1H),8.48(s,1H),7.48(d,J=3.4Hz,1H) ),6.62(d,J=3.4Hz,1H),3.14(s,3H),2.84(d,J=4.6Hz,3H),2.67(s,3H),2.12-2.04(m,1H),0.90-0.73(m,4H).

[0401] MS m / z[M+H] + :443. Example 32: Preparation of 4-((3-chloro-5-(N,S-dimethylsulfoximino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-6-(cyclopropylamido)-N-methylpyridazine-3-carboxamide

[0402] [ka]

[0403] 6-(cyclopropylcarboxamide)-4-((5-(N,S-dimethylsulfoximino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-N-methylpyridazine-3-carboxamide (31) (16 mg, 0.0362 mmol) was dissolved in DMF (0.5 mL), and NCS (6 mg, 0.0434 mmol) was added at room temperature. The mixture was stirred at 80° C. for 1.5 hours, cooled to room temperature, and the reaction solution was directly subjected to preparative HPLC to obtain 4-((3-chloro-5-(N,S-dimethylsulfoximino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-6-(cyclopropylamido)-N-methylpyridazine-3-carboxamide (32) (5.3 mg, pale yellow solid), the yield was 31%.

[0404] 1H NMR(400MHz,DMSO-d6)δ 12.24(s,1H),11.74(s,1H),11.38(s,1H),9.14(s,1H),9.09(d,J=4.6Hz,1H),8.35(s,1H),7.7 1(s,1H),3.19(s,3H),2.84(d,J=4.5Hz,3H),2.67(s,3H),2.13-2.05(s,1H),0.92-0.74(m,4H).

[0405] MS m / z[M+H] + :477. Example 33: Preparation of 6-(cyclopropylamido)-4-((2,3-dichloro-5-(N,S-dimethylsulfoximino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-N-methylpyridazine-3-carboxamide

[0406] [ka]

[0407] 6-(cyclopropylcarboxamide)-4-((5-(N,S-dimethylsulfoximino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-N-methylpyridazine-3-carboxamide (31) (21 mg, 0.0475 mmol) was dissolved in DMF (1 mL), NCS (14 mg, 0.104 mmol) was added at room temperature, and the mixture was stirred at 80 °C for 1 h. The mixture was cooled to room temperature, and the reaction was quenched by adding water. The mixture was extracted with ethyl acetate and saturated aqueous solution. Washing with brine, drying over anhydrous sodium sulfate, concentration, separation by flash (methanol / dichloromethane=3-5%) and preparative HPLC afforded 6-(cyclopropylamido)-4-((2,3-dichloro-5-(N,S-dimethylsulfoximino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-N-methylpyridazine-3-carboxamide (33) (1.0 mg, tan solid), yield 4%.

[0408] 1H NMR(400MHz,DMSO-d6)δ 13.29(s,1H),11.74(s,1H),11.37(s,1H),9.05(s,2H),8.27(s,1H),3.18( s, 3H), 2.84 (d, J=4.7Hz, 3H), 2.66 (s, 3H), 2.09 (s, 1H), 0.90-0.79 (m, 4H).

[0409] MS m / z[M+H] + :511. Example 34: Preparation of 4-((3-bromo-5-(N,S-dimethylsulfoximino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-6-(cyclopropylamido)-N-methylpyridazine-3-carboxamide

[0410] [ka]

[0411] 6-(cyclopropylcarboxamide)-4-((5-(N,S-dimethylsulfoximino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-N-methylpyridazine-3-carboxamide (31) (67 mg, 0.151 mmol) was dissolved in dichloromethane (2 mL), NBS (26.6 mg, 0.151 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The solvent was spin-dried and separated by flash (methanol / dichloromethane=2-5%) to obtain 4-((3-bromo-5-(N,S-dimethylsulfoximino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-6-(cyclopropylamido)-N-methylpyridazine-3-carboxamide (34) (60 mg, yellow solid), the yield was 76%.

[0412] 1H NMR(400MHz,DMSO-d6)δ 12.29(s,1H),11.73(s,1H),11.37(s,1H),9.14(s,1H),9.08(d,J=4.7Hz,1H),8.27(s,1H),7.7 3(s,1H),3.19(s,3H),2.84(d,J=4.7Hz,3H),2.67(s,3H),2.18-2.02(m,1H),0.89-0.75(m,4H).

[0413] MS m / z[M+H] + :521. Example 35: Preparation of (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-N-(methyl-d3)pyridazine-3-oxalic acid carboxamide

[0414] [ka]

[0415] (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-N-(methyl-d3)pyridazine-3-carboxamide (28) (100 mg, 0.22 mmol) is dissolved in DCM / MeOH (9:1, 6 mL), and a methanol solution (0.2 mL) of oxalic acid dihydrate (27 mg, 0.22 mmol) is added and stirred at room temperature for 10 minutes. The solvent is evaporated under reduced pressure and DCM / THF (1:1, 3 mL) is added. The solid is precipitated, suction filtered, rinsed with DCM / THF (1:1, 1 mL) and rinsed with PE (3 mL) to give 72 mg of a pale yellow solid. The yield is 56.7%.

[0416] 1H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),11.36(s,1H),9.43(s,1H),9.04(s,1H),7.79(s,1H),6.90( s,2H),3.14(s,3H),2.62(s,3H),2.15-2.07(m,1H),0.86(d,J=6.4Hz,4H).

[0417] Example 36: Preparation of (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-N-(methyl-d3)pyridazine-3-carboxamide hydrochloride

[0418] [ka]

[0419] (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-N-(methyl-d3)pyridazine-3-carboxamide (28) (500 mg, 1.10 mmol) is added to MeCN (5 mL) to form a suspension. 37% HCl aq. (271 mg, 2.75 mmol) is added dropwise at room temperature, and the mixture is heated to reflux in an oil bath at 85° C., and water (2 mL) is added dropwise to dissolve the mixture under reflux. The mixture is then left at room temperature and stirred for 1 hour. The solid is precipitated, suction filtered, the filter cake is rinsed with MeCN (1 mL×2), and the filter cake is dried under reduced pressure at 50° C. to obtain 336 mg of a yellow solid. The yield is 57.9%.

[0420] 1 H NMR(400MHz,DMSO-d6)δ 12.03(s,1H),11.92(s,1H),9.49(s,1H),9.23(s,1H),7.92(s,1H),7.86( s, 2H), 3.92 (s, 3H), 2.83 (s, 3H), 2.21-2.14 (m, 1H), 0.90 (d, J=6.7Hz, 4H).

[0421] Example 37: Preparation of (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-N-(methyl-d3)pyridazine-3-carboxamide sulfate

[0422] [ka]

[0423] (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-N-(methyl-d3)pyridazine-3-carboxamide (28) (500 mg, 1.10 mmol) was added to THF (5 mL) to form a suspension. 20% H2SO4 aq. (646 mg, 1.32 mmol) was added dropwise at room temperature, and water (0.5 mL) was added dropwise under reflux in an oil bath at 70°C to dissolve under reflux, and then the mixture was stirred at room temperature for 1 hour to precipitate a solid, which was then filtered with suction, the filter cake was rinsed with THF (1 mL x 2), and the filter cake was dried under reduced pressure at 50°C to obtain 495 mg of a yellow solid. Y=81.5%, HPLC: 99.0%.

[0424] 1 H NMR(400MHz,DMSO-d6)δ 11.81(s,1H),11.45(s,1H),9.33(s,1H),9.29(s,1H),7.89(s,1H),7.62( s, 2H), 3.90 (s, 3H), 2.85 (s, 3H), 2.16-2.08 (m, 1H), 0.87 (d, J=6.7Hz, 4H).

[0425] Example 38: Preparation of (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-N-(methyl-d3)pyridazine-3-carboxamide methanesulfonate

[0426] [ka]

[0427] (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-N-(methyl-d3)pyridazine-3-carboxamide (28) (100 mg, 0.22 mmol) is dissolved in DCM / MeOH (9:1, 6 mL), methanesulfonic acid (42 mg, 0.44 mmol) is added, and the mixture is stirred at room temperature for 10 min. The solvent is evaporated under reduced pressure, and DCM / THF (1:1, 3 mL) is added. The solid is precipitated, suction filtered, rinsed with DCM / THF (1:1, 1 mL), and rinsed with PE (3 mL) to give 110 mg of a yellow solid. The yield is 77.4%.

[0428] 1 H NMR(400MHz,DMSO-d6)δ 11.82(s,1H),11.47(s,1H),9.34(s,1H),9.30(s,1H),7.90(s,1H),7.63(s,2H),3.91( s,3H),2.86(s,3H),2.35(d,J=1.0Hz,6H),2.12(d,J=5.7Hz,1H),0.88(d,J=6.7Hz,4H).

[0429] Example 39: Preparation of 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((3-(S-methyl-N-(methyl-d3)sulfoximino)pyridin-2-yl)amino)pyridazine-3-carboxamide

[0430] [ka]

[0431] The synthesis is prepared with reference to Example 1 and Example 2, using CD3I instead of MeI. 1H NMR(400MHz,dmso)δ 11.86(s,1H),11.37(s,1H),9.46(s,1H),9.06(s,1H),8.53(d,J=4.0Hz,1H),8.22(d,J=7.6 Hz,1H),7.32-7.24(m,1H),3.21(s,3H),2.09(dd,J=13.2,7.3Hz,1H),0.85(d,J=6.7Hz,4H).

[0432] MS m / z[M+H] + :410. Example 40: Preparation of (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide

[0433] [ka]

[0434] Step 1: Synthesis of (R)-6-chloro-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-amine (40a) (R)-6-chloro-3-(S-methylsulfoximino)pyridin-2-amine (28d) (29.7 g, 144.88 mmol) is dissolved in 600 mL of tetrahydrofuran, NaI (2.18 g, 14.5 mmol) is added, and sodium t-butoxide (13.91 g, 144.88 mmol) is added in batches under a water bath. After stirring for 20 minutes, a solution of CD3I (21 g, 144.88 mmol) dissolved in tetrahydrofuran (50 mL) is added dropwise, and after the addition is completed, the mixture is stirred at room temperature overnight. The reaction mixture was quenched by dripping saturated ammonium chloride solution, diluted with water, and separated. The aqueous layer was extracted with ethyl acetate. The organic phases were combined and concentrated, then ethyl acetate was added to dissolve, and the mixture was separated. The aqueous layer was extracted with ethyl acetate. The organic phases were combined and washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography (petroleum ether:ethyl acetate=2:1) ​​to obtain (R)-6-chloro-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-amine (22.5 g, off-white solid), yield: 70%.

[0435] 1 H NMR (400MHz, DMSO-d6) δ 7.84 (d, J = 8.0 Hz, 1H), 7.24 (s, 2H), 6.78 (d, J = 8.0Hz 1H), 3.09 (s, 3H).

[0436] MS m / z[M+H] + :223. Step 2: Synthesis of (R)-6-chloro-4-((6-chloro-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40b) (R)-6-chloro-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-amine (40a) (36.7 g, 0.165 mml) is dissolved in 1 L of tetrahydrofuran, cooled to 0-5 ° C under N2 protection, NaH (19.8 g, 60% w / w, 0.496 mml) is added in batches, stirred for 25 minutes, 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (41.3 g, 0.198 mml) is added in batches, stirred for 15 minutes, and then heated to 70 ° C and reacted for 2 hours. Quench with saturated ammonium chloride solution in an ice bath, dilute with water, extract with ethyl acetate, separate, combine the organic phase, wash with saturated saline, and dry with anhydrous sodium sulfate. After concentration, add ethanol and cold beat for 30 minutes, suction filter, rinse the filter cake with ethanol, and drain to give (R)-6-chloro-4-((6-chloro-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40.25 g, 61.8%).

[0437] 1 H NMR(400MHz,DMSO-d6)δ 12.23(s,1H),9.33(s,1H),8.79(d,J=1.4Hz,1H),8.23(dd,J=8.0,1.4Hz,1H),7.43(dd,J=8.1,1.4Hz,1H),3.24(s,3H).

[0438] MS m / z[M+H] + :395. Step 3: Synthesis of (R)-6-chloro-4-((6-((diphenylidene)amino)-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40c) Add Pd2(dba)3 (4.6 g, 0.005 mml), XantPhos (5.78 g, 0.01 mml), (R)-6-chloro-4-((6-chloro-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40b) (40 g, 0.1 mml), K2CO3 (34.5 g, 0.25 mml), and diphenylimine (27.6 g, 0.15 mml) to DMAC (400 mL) under N2 atmosphere and react at 130 °C for 5 h. After cooling, quench with saturated ammonium chloride solution, dilute with water, dissolve in ethyl acetate, filter through diatomaceous earth, and rinse the filter cake with ethyl acetate. The layers are separated, the aqueous phase is extracted with ethyl acetate, the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, then slurried with MTBE for 30 minutes, suction filtered, the filter cake is rinsed with MTBE, and drained to give (R)-6-chloro-4-((6-((diphenylidene)amino)-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (38 g, 69.5%).

[0439] 1 H NMR(400MHz,DMSO-d6)δ 11.96(s,1H),9.24(s,1H),8.48(s,1H),8.06(d,J=8.2Hz,1H),7.43(m,10H),6.79(d,J=8.0Hz,1H),3.16(s,3H).

[0440] MS m / z[M+H] + :540. Step 4: Synthesis of (R)-6-(cyclopropanecarboxamide)-4-((6-((diphenylidene)amino)-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40d) Pd2(dba)3 (238 mg, 0.26 mmol), XantPhos (300 mg, 0.52 mml), (R)-6-chloro-4-((6-((diphenylidene)amino)-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40c) (2.8 g, 5.19 mmol), K2CO3 (1.79 g, 12.98 mmol), and cyclopropanecarboxamide (882 mg, 10.38 mmol) were added to xylene:DMAC=10:1 (33 mL) under N2 atmosphere, and the mixture was reacted at 130°C for 2 hours. After cooling, the mixture is quenched with saturated ammonium chloride solution, diluted with water, dissolved in dichloromethane, filtered through diatomaceous earth, and the filter cake is rinsed with dichloromethane. The layers are separated, the aqueous phase is extracted with dichloromethane, the organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, slurried with petroleum ether for 10 minutes, suction filtered, the filter cake is rinsed with petroleum ether, and drained to obtain the crude product of (R)-6-(cyclopropanecarboxamide)-4-((6-((diphenylidene)amino)-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, which is used directly in the next step without separation.

[0441] MS m / z[M+H] + :589. Step 5: Synthesis of (R)-4-((6-amino-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (40e) The crude product of (R)-6-(cyclopropanecarboxamide)-4-((6-((diphenylidene)amino)-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40d) is dissolved in tetrahydrofuran (30 mL), and 12N HCl (0.6 mL) is added under ice bath. The mixture is warmed to room temperature and stirred for 1.5 hours. Add water to dilute, add ethyl acetate to extract, add water to wash the organic phase, combine the aqueous layers, slowly add 10% potassium carbonate solution to adjust the pH value to 9-10, add methanol:dichloromethane=10:1 to extract, separate, combine the organic phases, add saturated saline to wash, dry with anhydrous sodium sulfate, concentrate, add ethanol and heat to reflux, slurry for 20 minutes under ice bath, suction filter, rinse the filter cake with ethanol, drain to obtain (R)-4-((6-amino-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (1.4 g, 65%).

[0442] 1 H NMR(400MHz,DMSO-d6)δ 11.56(s,1H),11.32(s,1H),9.51(s,1H),9.00(s,1H),7.75(d,J=8.8Hz,1H),6 .55(s,2H),6.24(d,J=8.6Hz,1H),3.06(s,3H),2.15-2.03(m,1H),0.86(m,4H).

[0443] MS m / z[M+H] + :425. Step 6: Synthesis of (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (40) Dissolve (R)-4-((6-amino-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (40e) (1.4 g, 3.30 mmol) in DMAC (14 mL), cool in an ice bath (0-5 °C) under N2 protection, add 1,3-dichloro-5,5-dimethylhydantoin (683 mg, 3.47 mmol) in a batch and react for 15 min. Quench with ice water and saturated sodium sulfite solution, suction filter, rinse the filter cake with water, then dissolve in dichloromethane:methanol=10:1, separate, wash the organic phase with saturated saline, dry with anhydrous sodium sulfate, concentrate, and separate by flash (methanol / dichloromethane=3%) to obtain (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (669 mg, off-white solid), yield 44%.

[0444] 1 H NMR(400MHz,DMSO-d6)δ 11.62(s,1H),11.37(s,1H),9.43(s,1H),9.04(s,1H),7.79(s,1H),6.89(s,2H),3.13(s,3H),2.16-2.07(m,1H),0.87(m,4H).

[0445] MS m / z[M+H] + :459. Example 41: Preparation of (R)-4-((6-amino-5-bromo-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide

[0446] [ka]

[0447] Dissolve (R)-4-((6-amino-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (40e) (113 mg, 0.26 mmol) in DMF (1.4 mL), cool to 0-5 °C in an ice bath under N2 protection, add NBS (50 mg, 0.28 mmol) and react for 30 min. The mixture was quenched with saturated sodium sulfite solution, diluted with water, extracted with ethyl acetate, and separated. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and then separated by flash (methanol / dichloromethane=3%) to obtain (R)-4-((6-amino-5-bromo-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (62 mg, pale yellow solid), yield: 46%.

[0448] 1 H NMR(400MHz,DMSO-d6)δ 11.62(s,1H),11.37(s,1H),9.48(s,1H),9.04(s,1H),7.91(s,1H),6.79(s,2H),3.13(s,3H),2.12(s,1H),0.88(m,4H).

[0449] MS m / z[M+H] + :503. Example 42: Preparation of (R)-4-((6-amino-5-iodo-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide

[0450] [ka]

[0451] (R)-4-((6-amino-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (40e) (2.1 g, 2.59 mmol) is dissolved in DMAC (6 mL) and NIS (759 mg, 3.41 mmol) is added in a batch and reacted at 50 °C for 1 h. The mixture was quenched with saturated sodium sulfite solution under ice bath, diluted with water, extracted with dichloromethane:methanol=10:1, separated, the organic phases were combined, washed with saturated saline, dried with anhydrous sodium sulfate, concentrated, and separated by flash (methanol / dichloromethane=3%) to obtain (R)-4-((6-amino-5-iodo-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (912 mg, pale yellow solid), yield 64%.

[0452] 1 H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),11.37(s,1H),9.54(s,1H),9.04(s,1H),8.06(s,1H),6.60(s,2H),3.12(s,3H),2.17-2.07(m,1H),0.87(d,J=6.0Hz,4H).

[0453] MS m / z[M+H] + :551. Example 43: Preparation of (R)-4-((6-amino-5-cyclopropyl-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide

[0454] [ka]

[0455] Under a N2 gas atmosphere, (R)-4-((6-amino-5-iodo-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (42) (203 mg, 0.367 mmol) is dissolved in anhydrous 1,4-dioxane (4 mL), cyclopropylboronic acid (63 mg, 0.734 mmol), Pd(PPh3)4 (81 mg, 0.07 mmol) and K2CO3 (127 mg, 0.92 mmol) are added, and the mixture is reacted in a microwave (120 °C, 120 W) for 2.5 hours. After the reaction mixture was cooled to room temperature, it was filtered through diatomaceous earth, the filter cake was rinsed with dichloromethane:methanol=10:1, and the filtrate was concentrated and then separated by flash (methanol / dichloromethane=7%) to give (R)-4-((6-amino-5-cyclopropyl-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (32 mg, pale yellow solid), the yield was 18.7%.

[0456] 1 H NMR(400MHz,DMSO-d6)δ 11.55(s,1H),11.32(s,1H),9.57(s,1H),8.99(s,1H),7.42(s,1H),6.49(s,2) H),3.05(s,3H),2.12(s,1H),1.66(s,1H),0.88(m,6H),0.51(d,J=4.4Hz,2H).

[0457] MS m / z[M+H] + :465. Example 44: Preparation of (R)-4-((6-amino-3-(S-methyl-N-(methyl-d3)sulfonimide)-5-vinylpyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide

[0458] [ka]

[0459] Under a N2 gas atmosphere, (R)-4-((6-amino-5-iodo-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (42) (103 mg, 0.187 mmol) was dissolved in anhydrous 1,4-dioxane (2 mL), and potassium ethylenetrifluoroborate (50 mg, 0.37 mmol), Pd(PPh3)4 (46 mg, 0.04 mmol) and K2CO3 (52 mg, 0.37 mmol) were added, and the mixture was reacted in a microwave (120 °C, 120 W) for 1 hour. After the reaction mixture was cooled to room temperature, it was filtered through diatomaceous earth, the filter cake was rinsed with dichloromethane, and the filtrate was concentrated and then separated by flash (methanol / dichloromethane=3%) to give (R)-4-((6-amino-3-(S-methyl-N-(methyl-d3)sulfonimide)-5-vinylpyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (40 mg, pale yellow solid), the yield was 47%.

[0460] 1 H NMR(400MHz,DMSO-d6)δ 11.68(s,1H),11.36(s,1H),9.67(s,1H),9.02(s,1H),7.92(s,1H),6.81(dd,J=17.6,10.6Hz,1H), 6.59(s,2H),5.63(d,J=16.9Hz,1H),5.25(d,J=10.2Hz,1H),3.12(s,3H),2.12(s,1H),0.87(m,4H).

[0461] MS m / z[M+H] + :451. Example 45: Preparation of (R)-4-((6-amino-3-(S-methyl-N-(methyl-d3)sulfonimide)-5-(propyn-1-yl)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide

[0462] [ka]

[0463] (R)-4-((6-amino-5-iodo-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (42) (100 mg, 0.182 mmol) is dissolved in DMF (2 mL), CuI (4 mg, 0.0182 mmol), Pd(PPh3)2Cl2 (13 mg, 0.0182 mmol), KF (16 mg, 0.273 mmol) and triethylamine (0.7 mL) are added, and a DMF solution (0.5 mL) in which 1-(trimethylsilyl)propyne (31 mg, 0.273 mmol) is dissolved is added under a N2 atmosphere, and the mixture is reacted at 50 °C for 1 hour. The reaction mixture is cooled to room temperature, quenched with saturated ammonium chloride solution, diluted with water, extracted with dichloromethane, the organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and separated by flash (methanol / dichloromethane=3%) to give (R)--4-((6-amino-3-(S-methyl-N-(methyl-d3)sulfonimide)-5-(propyn-1-yl)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (64 mg, yellow solid), yield 76%.

[0464] 1 H NMR(400MHz,DMSO-d6)δ 11.67(s,1H),11.36(s,1H),9.55(s,1H),9.02(s,1H),7.71(s,1H),6.67(s,2H),3.10(s,3H),2.10(m,,4H),0.87(m,4H).

[0465] MS m / z[M+H] + :463. Example 46: Preparation of (R)-4-((6-amino-5-(cyclopropylethynyl)-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide

[0466] [ka]

[0467] (R)-4-((6-amino-5-iodo-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (42) (100 mg, 0.182 mmol) was dissolved in DMF (2 mL), CuI (4 mg, 0.0182 mmol), Pd(PPh3)2Cl2 (13 mg, 0.0182 mmol), KF (16 mg, 0.273 mmol) and triethylamine (0.7 mL) were added, and a solution of cyclopropyl(trimethylsilyl)acetylene (38 mg, 0.273 mmol) in DMF (0.5 mL) was added under N2 atmosphere and stirred at room temperature overnight. The reaction mixture is quenched with saturated ammonium chloride solution, diluted with water, extracted with dichloromethane, separated, the organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and separated by flash (methanol / dichloromethane=3%) to give (R)-4-((6-amino-5-(cyclopropylethynyl)-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (74 mg, pale yellow solid), yield 83%.

[0468] 1H NMR(400MHz,DMSO-d6)δ 11.68(s,1H),11.36(s,1H),9.56(s,1H),9.02(s,1H),7.70(s,1H),6.59(s,2H),3.10(s,3H),2.12(s,1H),1.56(s,1H),0.96-0.74(m,8H).

[0469] MS m / z[M+H] + :489 Example 47: Synthesis of (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide hydrochloride

[0470] [ka]

[0471] (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (200 mg, 0.44 mmol) was added to DMF (2 mL), stirred at room temperature, added concentrated HCl (108 mg, 1.09 mmol), stirred in a 90°C oil bath for 5 minutes to make it cloudy, added acetonitrile (10 mL), refluxed for 5 minutes, stirred the suspension at room temperature for 1.5 hours, filtered by suction, rinsed with acetonitrile (0.5 mL x 2), and dried the filter cake under reduced pressure at 50°C for 1 hour to obtain 230 mg of pale yellow solid dihydrochloride, the yield is 99.2%.

[0472] 1 H NMR(400MHz,DMSO-d6)δ 11.88(s,1H),11.82(s,1H),9.44(d,J=2.2Hz,1H),9.24(s,1H),7.91(d,J= 2.6Hz, 1H), 7.77 (s, 2H), 3.91 (s, 3H), 2.21-2.11 (m, 1H), 0.94-0.86 (m, 4H).

[0473] MS m / z[M+H] + :459. Example 48: Synthesis of (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide sulfate

[0474] [ka]

[0475] (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (200 mg, 0.44 mmol) was added to DMF (1 mL), stirred at room temperature to form a suspension, concentrated H2SO4 (109 mg, 1.09 mmol) was added, acetonitrile (1 mL) was stirred at room temperature to dissolve, the mixture was placed in a 90°C oil bath and stirred for 5 minutes, acetonitrile (6 mL) was added, refluxed for 5 minutes, solids were precipitated, stirred at room temperature for 1.5 hours, suction filtered, rinsed with acetonitrile (0.5 mL x 2), and the filter cake was dried under reduced pressure at 50°C for 1 hour to give 268 mg of off-white solid disulfate salt, the yield being 93.8%.

[0476] 1 H NMR(400MHz,DMSO-d6)δ 11.82(s,1H),11.46(s,1H),9.34(s,1H),9.30(s,1H),8.92(s,4H),7.90 (s,1H),7.64(s,2H),3.92(s,3H),2.15-2.08(m,1H),0.90-0.82(m,4H).

[0477] MS m / z[M+H] + :459. Example 49: Synthesis of (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide methanesulfonate

[0478] [ka]

[0479] (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-d3)sulfonimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (200 mg, 0.44 mmol) was added to DMF (0.5 mL), stirred at room temperature to form a suspension, methanesulfonic acid (105 mg, 1.09 mmol) was added, acetonitrile (1 mL) was stirred at room temperature to dissolve, and the mixture was placed in a 90°C oil bath and stirred for 5 minutes, acetonitrile (8 mL) was added, refluxed for 5 minutes, solids were precipitated, stirred at room temperature for 1.5 hours, suction filtered, rinsed with acetonitrile (0.5 mL x 2), and the filter cake was dried under reduced pressure at 50°C for 1 hour to obtain 268 mg of off-white solid dimethanesulfonate, with a yield of 94.4%.

[0480] 1 H NMR(400MHz,DMSO-d6)δ 11.82(s,1H),11.46(s,1H),9.34(s,1H),9.30(s,1H),7.90(s,1H),7.63 (s,2H),3.92(s,3H),2.35(s,6H),2.17-2.09(m,,1H),0.90-0.82(m,4H).

[0481] MS m / z[M+H] + :459. Biological evaluation Test Example 1: TYK2 kinase activity inhibition experiment 1.1. Experimental principle and objectives The TYK2 kinase gene is introduced into wild-type mouse B lymphocytes (BaF3) to construct the Ba / F3-FL-TYK2-E957D stable cell line. The growth and proliferation of Ba / F3-FL-TYK2-E957D is independent of IL-3, but instead depends on the exogenously introduced TYK2 kinase. Compounds that selectively inhibit the activity of TYK2 kinase have an inhibitory effect on the proliferation of this cell line.

[0482] In this experiment, we tested the inhibitory effect of the compounds on Ba / F3-FL-TYK2-E957D cell proliferation, detected the apoptotic status of the cells, and determined the IC 50 Calculate the value of IC 50 The inhibitory activity of the compound against TYK2 kinase is evaluated based on the magnitude of the .

[0483] 1.2. Experimental Method 1.2.1. Preparation of stock solutions Test compounds are stored as powders at room temperature, reconstituted to 10 mM stock solutions in DMSO, and stored in the dark at -20°C for stockpiling.

[0484] Experimental procedure Preparation of compounds Compounds are diluted to a final concentration of 1000. Compounds are diluted in media to a final concentration of 20. Add 2ul of 1000x compound to 98ul of media per well.

[0485] Plating Resuspend the cells (provided by SUNDIA Pharmaceutical Technology (Shanghai) Co., Ltd.) and count using an automatic cell counter. Dilute the cell suspension to the desired density, 2000 cells per well, according to BaF3 seeding density. Plate 95ul of cells in each well and incubate at 37°C for stable equilibration. Add 5ul of 20x compound to each well and add the same amount of DMSO to the wells as control. Incubate at 37°C, 5% CO2 for 72 hours.

[0486] detection Equilibrate cell plates to room temperature. Add 40ul of CellTiter-Glo® Reagent to each well, shake for 2 minutes, and let sit for 10 minutes. Detect in SpectraMax paradigm.

[0487] Data analysis (1) Using GraphPad Prism5, IC 50 Calculate.

[0488] (2) %Inh=(maximum signal−complex signal) / (maximum signal−minimum signal)×100. (3) The maximum signal is the positive control well with only DMSO in the same amount as compound.

[0489] (4) The minimum signal is the negative control wells containing medium only. The results are shown in Table 1 below.

[0490] [Table 1] JPEG2025508011000072.jpg39170

[0491] Here, the structural formula of the compound BMS-986165 is:

[0492] [ka] It is.

[0493] The test results show that the compounds provided by the present invention have excellent TYK2 inhibitory activity, and the TYK2 inhibitory activity of most of the compounds is superior to that of the positive control BMS-986165, and the IC 50 It shows that the values ​​reach the pM level. In particular, the TYK2 inhibitory activity of Examples 28, 32, 40, 41, 42 and 44 is 4 to 7 times higher than that of BMS-986165, and Examples 45 and 46 increase the TYK2 inhibitory activity by 20 times or more compared to BMS-986165.

[0494] Test Example 2: JAK family kinase selectivity experiment 2.1. Experimental principle and objectives There are four kinases in the JAK family: TYK2, JAK1, JAK2, and JAK3. JAK family kinase genes were introduced into wild-type mouse B lymphocytes (BaF3) to construct four BaF3 engineered cell lines (Ba / F3-FL-TYK2-E957D, Ba / F3-TEL-JAK1, Ba / F3-TEL-JAK2, and Ba / F3-TEL-JAK3). The growth and proliferation of such engineered cell lines is independent of IL-3, but instead depends on the exogenously introduced JAK family kinase. When a compound selectively inhibits the activity of a particular JAK kinase, it has an inhibitory effect on the proliferation of the corresponding cell line.

[0495] In this experiment, we tested the inhibitory effects of the compounds on the proliferation of four cells, Ba / F3-FL-TYK2-E957D, Ba / F3-TEL-JAK1, Ba / F3-TEL-JAK2, and Ba / F3-TEL-JAK3, detected the apoptosis status of the cells, and calculated the IC 50 Calculate the value of IC 50 Based on the magnitude of the , the inhibitory activity of the compound against TYK2, JAK1, JAK2, and JAK3 kinases is evaluated, thereby evaluating the JAK family kinase selectivity of the compound.

[0496] 2.2.Experimental Method 2.2.1. Preparation of stock solutions Test compounds are stored as powders at room temperature, reconstituted to 10 mM stock solutions in DMSO, and stored in the dark at -20°C for stockpiling.

[0497] Experimental procedure Preparation of compounds Compounds are diluted to a final concentration of 1000. Compounds are diluted in media to a final concentration of 20. Add 2ul of 1000x compound to 98ul of media per well.

[0498] Plating Resuspend the cells (provided by SUNDIA Pharmaceutical Technology (Shanghai) Co., Ltd.) and count using an automatic cell counter. Dilute the cell suspension to the desired density, 2000 cells per well, according to BaF3 seeding density. Plate 95ul of cells in each well and incubate at 37°C for stable equilibration. Add 5ul of 20x compound to each well and add the same amount of DMSO to the wells as control. Incubate at 37°C, 5% CO2 for 72 hours.

[0499] detection Equilibrate cell plates to room temperature. Add 40ul of CellTiter-Glo® Reagent to each well, shake for 2 minutes, and let sit for 10 minutes. Detect in SpectraMax paradigm.

[0500] Data analysis (1) Using GraphPad Prism5, IC 50 Calculate.

[0501] (2) %Inh=(maximum signal−complex signal) / (maximum signal−minimum signal)×100. (3) The maximum signal is the positive control well with only DMSO in the same amount as compound.

[0502] (4) The minimum signal is the negative control wells containing medium only. The results are shown in Table 2 below.

[0503] [Table 2]

[0504] The test results show that the compounds provided by the present invention have excellent TYK2 inhibitory activity, and at the same time have no inhibitory activity against JAK1, JAK2 and JAK3 kinases, and have very high selectivity for JAK family kinases.

[0505] Basic research and clinical results of existing JAK kinase inhibitors show that non-selective kinase inhibitors cause serious side effects, including thrombosis, anemia, and severe infections, etc., and therefore low kinase subtype selectivity is a problem that needs to be overcome in the research and development of next-generation JAK inhibitors. The compounds of the present invention have excellent kinase selectivity and show very high drug safety.

[0506] Test Example 3: IFN-α-induced STAT phosphorylation in human whole blood 3.1. Experimental principle and objectives Cytokine receptors attached to TYK2 can mediate the signal transduction of type 1 interferon (IFN-α), which is identified as the most important pro-inflammatory factor in the autoimmune system. Human whole blood is induced with IFN-α, and TYK2 in lymphocytes in the whole blood causes STAT phosphorylation and mediates subsequent inflammatory signal transduction. Thus, TYK2 inhibitors have an inhibitory effect on IFN-α signal transduction, and the stronger the TYK2 inhibitory activity, the lower the STAT phosphorylation level and the stronger the corresponding anti-inflammatory effect.

[0507] In this study, we tested the inhibitory ability of compounds against IFN-α-induced STAT phosphorylation in human whole blood and determined IC 50 Calculate the value of IC 50 Based on the magnitude of the IFN-α signal, the inhibitory activity of the compound against the IFN-α inflammatory pathway is evaluated, and the anti-inflammatory activity of the compound at the tissue level is evaluated.

[0508] 3.2. Experimental process 3.2.1. Preparation of stock solutions Test compounds are stored as powders at room temperature, reconstituted to 10 mM stock solutions in DMSO and stored in a -80°C refrigerator.

[0509] The positive control compound BMS-986165 is stored as a powder at room temperature and prepared as a 10 mM stock solution in DMSO and stored in a -80°C refrigerator. 3.2.2. Preparation of solutions Prepare 1X Fix / Lysis solution: Dilute 5X Fix / Lysis and ddH2O 1:4 and pre-heat the incubator at 37 °C until ready to use.

[0510] Prepare flow cytometry staining buffer: add 1 g of bovine serum albumin (BSA) and 1 mL of EDTA (0.5 M) solution to 500 mL of phosphate buffered saline (PBS) and store in a 4 °C refrigerator.

[0511] Compound dilution solution: Add 0.5 g of bovine serum albumin (BSA) to 500 mL of phosphate buffered saline (PBS) and store in a refrigerator at 4°C. Experimental procedure Preparation of compounds and cytokines Dilute 10 mM of the test compound and positive compound BMS-986165 into 5 mM working solution with DMSO, and further dilute DMSO into 8 concentrations with 3-fold gradient.Each concentration point of the test compound and BMS-986165 in 8 concentration gradient is diluted 25-fold with compound diluent and then stockpiled.

[0512] Dilute IFN-alpha (50 μg / mL) to 400 ng / mL in compound diluent and stockpile. Human whole blood processing Add 67.5μL of human whole blood to a 96-well plate using a 300μL electric vortex gun. Add 3.5μL of the prepared test compound, mix evenly, and then place in a cell incubator. After 60 minutes of incubation, add 400ng / mL of IFN-α (Biolegend592702, final concentration is 20ng / ml). Similarly, mix evenly, then place in a cell incubator and continue to incubate for 15 minutes.

[0513] After cytokine stimulation, 5 μl of PE-CD3 (BD555333) antibody is added to each well, mixed uniformly, and then incubated in a 4°C refrigerator. After completion, whole blood is transferred to a 96-well deep-well plate using a volute gun, and pre-warmed 1X Fix / Lysis solution is added to lyse and fix the cells in a 37°C incubator for 12 minutes. After washing, 400 μL of PermIII solution is added, vortexed, and incubated on ice for 30 minutes. The cells are then stained with 100 μL of APC-pSTAT5 (1:100) antibody for 50 minutes at room temperature, followed by detection by flow cytometry. After gating on the CD3 positive signal population, the expression of pSTAT5 is quantified by median fluorescence intensity.

[0514] The results are shown in Table 3 below.

[0515] [Table 3]

[0516] The test results show that the compounds provided by the present invention have very high inhibitory activity against IFN-α-induced STAT phosphorylation in human whole blood, which indicates that the compounds of the present invention can strongly inhibit the IFN-α inflammatory pathway at the tissue level.Compared with the control BMS-986165, the present invention shows better IFN-α inflammatory pathway inhibitory activity, and in particular, the anti-inflammatory activity of Example 28 and Example 29 is increased by about 6 times.

[0517] Test Example 4: hERG potassium channel inhibition experiment with the compound of the present invention 4.1. Purpose of the experiment Automated patch clamp is applied to test the blocking effect of the compounds of the present invention on hERG potassium currents on a stable cell line transfected with the hERG potassium channel.

[0518] 4.2.Experimental Method 4.2.1. Cell preparation CHO-hERG cells were cultured at 175 cm2 Culture the cells in a culture flask, and when the cell density reaches 60-80%, remove the culture medium, wash the cells once with 7 ml of phosphate-buffered saline (PBS), and then add 3 ml of Detachin to digest the cells.

[0519] After digestion was complete, 7 ml of culture medium was added to neutralize the cells, and the cells were then centrifuged to remove the supernatant. 6 Add 5 ml of culture medium to resuspend the cells at a concentration of 1 / ml.

[0520] 4.2.2. Preparation of solutions

[0521] [Table 4]

[0522] 4.2.3. Electrophysiological recording process The single cell high impedance sealing and whole cell patterning process are all completed automatically by the Qpatch instrument, after obtaining the recording pattern, the cell is clamped at -80mV, and a single 50ms pre-voltage of -50mV is given before a single 5s depolarizing stimulus of +40mV, then repolarized to -50mV for 5s, and then back to -80mV. This voltage stimulus is applied every 15s, and after recording for 2min, extracellular solution is added and recorded for 5min, and then the administration process is started, and the compound concentrations are administered starting from the lowest test concentration, each test concentration is administered for 2.5min, and after all concentrations are administered consecutively, the positive control compound 3μM Cisapride is administered. At least three cells (n≧3) are tested for each concentration.

[0523] 4.2.4. Preparation of compounds The 20 mM compound stock solution is diluted with extracellular solution, and 5 μL of the 20 mM compound stock solution is added to 2495 μL of extracellular solution, diluted 500-fold to 40 μM, and then serially diluted 3-fold with extracellular solution containing 0.2% DMSO to obtain the final concentration required for testing.

[0524] The highest concentration tested was 40 μM, followed by six concentrations in succession: 40, 13.33, 4.44, 1.48, 0.49, and 0.16 μM, respectively.

[0525] The DMSO content in the final test concentrations did not exceed 0.2%, a concentration of DMSO that has no effect on the hERG potassium channel. Data Analysis The experimental data are analyzed by XLFit software.

[0526] Experimental Results The results are shown in Table 4 below.

[0527] [Table 5]

[0528] The test results show that the compounds provided by the present invention have no hERG potassium channel inhibitory activity and low risk of cardiotoxicity.

[0529] Test Example 5: In vivo pharmacokinetics of the compounds of the present invention 5.1. In vivo pharmacokinetic studies in rats Experimental method: Healthy male SD rats were randomly divided into groups of 3 rats each, and the test compounds were orally administered. Before the intragastric administration experiment, they were fasted for 12 hours, allowed to drink water freely, and fed uniformly 4 hours after administration. Before administration (0h) and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration, 0.2mL of blood was collected from the jugular vein at the above-mentioned set time points and placed in an EDTA-K2 test tube. After the whole blood was collected, it was temporarily stored in an ice-water bath, and within 30 minutes, it was centrifuged at 11000 rpm for 5 minutes, and the plasma was separated and frozen in a -70℃ refrigerator for testing.

[0530] The results of Test Example 5.1 are shown in Table 5.1 below.

[0531] [Table 6]

[0532] 5.2. In vivo pharmacokinetic study in beagle dogs Experimental method: Healthy male beagle dogs are randomly divided into groups of 3 dogs each, and the test compound is orally administered. Before the intragastric administration experiment, they are fasted for 12 hours, allowed to drink water freely, and fed uniformly 4 hours after administration. At 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10 and 24 hours after administration, about 600μL of blood is collected from the front or rear legs at the above set time points and placed in EDTA-K2 test tubes. After the whole blood is collected, it is temporarily stored in an ice-water bath, and within 30 minutes, it is centrifuged at at least 3500 rpm for 10 minutes, and the plasma is separated and frozen in a refrigerator at -70℃ for testing.

[0533] The results of Test Example 5.2 are shown in Table 5.2 below.

[0534] [Table 7]

[0535] The test results show that the compound provided by the present invention has good drug metabolism properties, good drug potential, and high plasma exposure (AUC).The compound provided by the present invention has significant advantages over BMS-986165 in oral bioavailability (F%) and plasma exposure in rats and dogs, and it shows good oral absorption properties and good metabolic characteristics.

[0536] Test Example 6: Solubility of the compounds of the present invention in water (under pH=7 condition) The results of Test Example 6 are shown in Table 6 below.

[0537] [Table 8]

[0538] The test results show that the water solubility properties of the compounds provided by the present invention are significantly superior to BMS-986165. Water solubility is an important index for evaluating the druggability of small molecule oral drugs. Only when a drug is dissolved can it be absorbed through the gastrointestinal tract and enter the systemic circulation. Drugs with low water solubility have slow absorption and low bioavailability, which affects the blood drug concentration and pharmacological effect, and directly leads to a high clinical failure rate. The compound provided by the present invention has higher solubility than BMS-986165, and therefore has better oral absorption and druggability properties.

[0539] All documents mentioned in the present invention are incorporated by reference in this application as if each document was incorporated by reference individually. Furthermore, 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 these equivalents are also included in the scope defined by the appended claims of this application.

Claims

1. A compound of formula (I) or a tautomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 Here, R １ is selected from the group consisting of H, a substituted or unsubstituted C1-C6 alkyl group, and a substituted or unsubstituted C3-C6 cycloalkyl group, where the substitution refers to substitution with one or more substituents selected from the group consisting of deuterium and halogen; A is NH or CH ２ and B is CH or N; L is, 【Chemistry 2】 is selected from the group consisting of R ２ is H, -CD ３ , a C1-C6 alkyl group, and a C3-C6 cycloalkyl group; X is CH or N; Y is NH, O or S; R ３ , R ４ , R ５ are each independently H, -NH ２ , —OH, a C1-C6 alkoxy group, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C3-C6 cycloalkyl group, —CONH ２ , -CN, halogen, -O(CH ２ ) ｎ R ９ , a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C6 cycloalkyl-substituted C2-C6 alkynyl group, and -NR ８ (CH ２ ) ｎ R ９ is selected from the group consisting of n is 1, 2, 3, 4 or 5; R ９ is selected from the group consisting of -OH, a C1-C6 alkoxy group, a C4-C6 cycloalkoxy group, a 4-8 membered heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, and -CN; R ８ is H or a C1-C6 alkyl group, R ６ , R ７ are each independently selected from the group consisting of H, a C1-C6 alkyl group, and halogen, or a tautomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, of the compound represented by formula (I) or a pharma- ceutically acceptable salt thereof.

2. R １ is a fully deuterated C1-C6 alkyl group, A is NH; B is CH or N 2. A compound according to claim 1 or a tautomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof.

3. L is, 【Chemistry 3】 and R ２ is H, -CD ３ , C1-C6 alkyl groups; X is N; R ３ , R ４ , R ５ are each independently H, -NH ２ , —OH, a C1-C6 alkoxy group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, —CONH ２ , -CN, halogen, -O(CH ２ ) ｎ R ９ , a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C6 cycloalkyl-substituted C2-C6 alkynyl group, and -NR ８ (CH ２ ) ｎ R ９ is selected from the group consisting of n is 1, 2, 3, 4 or 5; R ９ is selected from the group consisting of a C1-C6 alkoxy group, a C4-C6 cycloalkoxy group, a 4-8 membered heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, and -CN; R ８ is H or a C1-C6 alkyl group.

2. A compound according to claim 1 or a tautomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof.

4. R １ is a fully deuterated C1-C6 alkyl group, A is NH; B is N; L is, 【Chemistry 4】 and R ２ is H, -CD ３ , C1-C6 alkyl groups; X is N; R ３ is -NH ２ and R ４ is selected from the group consisting of halogen, a C3-C6 cycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, and a C3-C6 cycloalkyl-substituted C2-C6 alkynyl group; R ５ is H 2. A compound according to claim 1 or a tautomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof.

5. R １ is a fully deuterated C1-C6 alkyl group, A is NH; B is N; L is, 【Chemistry 5】 and R ２ -CD ３ and X is N; R ３ is -NH ２ and R ４ is selected from the group consisting of halogen, a C3-C6 cycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, and a C3-C6 cycloalkyl-substituted C2-C6 alkynyl group; R ５ is H 2. A compound according to claim 1 or a tautomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof.

6. The compound is characterized in that it is selected from the group consisting of 2. A compound according to claim 1 or a tautomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof. 【Chemistry 6】 【change】 【change】

7. 10. A process for preparing a compound of claim 1 or a tautomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof, comprising the steps of: 【Chemistry 7】 reacting a compound of formula I-c with cyclopropylamide to obtain a compound of formula (I), Here, R １ , A, B, L are as defined in claim 1; 2. A process for preparing the compound of claim 1, or a tautomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof, characterized in that G is halogen.

8. 1. A pharmaceutical composition comprising: The pharmaceutical composition comprises a pharma- ceutically acceptable carrier and a safe and effective amount of one or more compounds of claim 1 or a tautomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof.

9. 2. Use of the compound of claim 1 or a tautomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharma- ceutically acceptable salt thereof, comprising: The above use, characterized in that it is used for the preparation of a medicament for the prevention and / or treatment of a TYK2-mediated associated disease.

10. The TYK2-mediated disease is an inflammatory or autoimmune disease in a mammal.

10. The use according to claim 9.

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