Compound used as TYK2 inhibitor, and preparation method and medical application thereof

Abstract

The invention discloses a compound used as a TYK2 inhibitor, a preparation method of the compound and application of the compound in medicine. Specifically, the compound has a structure as shown in a formula (I), and the definitions of all groups and substituent groups are described in the specification. In addition, the invention also discloses a preparation method of the compound and application of the compound in prevention and / or treatment of TYK2 mediated related diseases. # imgabs0 #

Description

Compounds used as TYK2 inhibitors, preparation methods thereof, and their use in medicine Technical Field

[0001] The present invention relates to the field of small molecule medicine, and in particular to a compound used as a TYK2 inhibitor, a preparation method thereof, and its application in medicine. Background Art

[0002] Autoimmune disease is an inflammatory disease in which the body's own immune system attacks normal cells, causing a decrease in normal immune capacity and an increase in abnormal immune capacity, ultimately leading to tissue damage or organ dysfunction. Currently, more than 80 autoimmune diseases have been reported, affecting approximately 5%-8% of the world's population. Among them, the most common 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 disease in these diseases cover almost all human organs. 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]. Autoimmune diseases have complex pathogenesis, high disability rates, and no cure. Most patients endure immense pain throughout their lives. Consequently, they are often called "immortal cancers."

[0003] Since 2000, the majority of small molecule drugs approved for the treatment of autoimmune diseases have been Janus kinase (JAK) inhibitors. This family includes JAK 1, JAK 2, JAK 3, and TYK2. JAK family members modulate immunomodulatory cytokine-initiated signaling by phosphorylating their receptors, leading to the recruitment, phosphorylation, and activation of signal transducer (STAT) proteins, thereby influencing STAT-dependent transcriptional and functional responses. These cytokine signaling pathways play a key role in the pathogenesis of autoimmune and inflammatory diseases. To date, the clinically approved JAK inhibitors, such as tofacitinib, baricitinib, and upadacitinib, all target the kinase domain (JH1 domain) of the JAK family, competing with ATP for binding in vivo. Due to their poor kinase isoform selectivity, these JAK inhibitors exhibit a range of serious clinical side effects, including anemia, infections, increased levels of creatinine, liver transaminases, creatine phosphokinase, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, and decreased counts of natural killer cells, lymphocytes, neutrophils, and platelets. Therefore, the above three marketed drugs all carry black box warnings about the risk of causing serious infections, malignant tumors and thrombosis, and their clinical applications are greatly limited.

[0004] Recent studies have shown that TYK2, also part of the JAK family, is the optimal target for balancing efficacy and safety in autoimmune diseases [J.Med.Chem.2019,62,20,8953–8972]. TYK2, in conjunction with JAK2, mediates signaling through IL-12 and IL-23 (containing the p40 subunit of cytokines), inducing / stabilizing the expression of IL-17 and other pro-inflammatory factors; and in conjunction with JAK1, mediates signaling of type 1 interferons (IFN-α, etc.). The aforementioned cytokines mediated by TYK2 have been identified as the most important inflammatory factors in the autoimmune system [Nature Reviews Drug Discovery 2021,20,39–63]. Blockade of the above-mentioned inflammatory cytokine signaling pathways has demonstrated excellent pharmacodynamic 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 Translational Medicine 2019,502(11),:eaaw1736; J Clin Invest.2020,130(4),1863–1878]. Monoclonal antibodies developed against the above-mentioned inflammatory factors IL-12, IL-23, IL-17, and IFN-α have shown excellent effects in the clinical treatment of multiple autoimmune diseases.

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

[0006] The present invention provides a class of TYK2 inhibitors with enhanced kinase inhibitory activity, high subtype selectivity, excellent metabolic properties, enhanced in vivo efficacy, and novel structures. The TYK2 inhibitors disclosed herein can be used to prevent and / or treat diseases mediated by TYK2, particularly autoimmune diseases associated with IL-12, IL-23, IL-17, and type 1 interferon (IFN-α, etc.).

[0007] Summary of the Invention

[0008] The object of the present invention is to provide a compound represented by formula (I), a preparation method thereof, and use thereof in preventing and / or treating diseases mediated by TYK2.

[0009] In the first aspect of the present invention, there is provided a compound represented by formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0010] Among them, R 1 Selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substitution refers to substitution by one or more substituents selected from the following group: deuterium, halogen;

[0011] A is NH or CH2;

[0012] B is CH or N;

[0013] L is selected from the following group:

[0014] R 2 Selected from the group consisting of H, -CD3, C1-C6 alkyl, C3-C6 cycloalkyl;

[0015] X is CH or N;

[0016] Y is NH, O or S;

[0017] R 3 、R 4 、R 5 Each is independently selected from the following group: H, -NH2, -OH, C1-C6 alkoxy, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, -CONH2, -CN, halogen, -O(CH2) n R 9 , C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl substituted C2-C6 alkynyl, and -NR 8 (CH2) n R 9 ;

[0018] n is 1, 2, 3, 4, or 5;

[0019] R 9 Selected from the group consisting of -OH, C1-C6 alkoxy, C4-C6 cycloalkoxy, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, and -CN;

[0020] R 8 is H or C1-C6 alkyl;

[0021] R 6 、R 7 Each is independently selected from the following group: H, C1-C6 alkyl, halogen.

[0022] In another preferred embodiment, R 1 Selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substitution refers to substitution by one or more substituents selected from the following group: deuterium, halogen;

[0023] A is NH or CH2;

[0024] B is CH or N;

[0025] L is selected from the following group:

[0026] R 2 Selected from the group consisting of H, -CD3, C1-C6 alkyl, C3-C6 cycloalkyl;

[0027] X is CH or N;

[0028] Y is NH, O or S;

[0029] R 3 、R 4 、R 5 Each is independently selected from the following group: H, -NH2, -OH, C1-C6 alkoxy, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, -CONH2, -CN, halogen, -O(CH2) n R 9 and -NR 8 (CH2) n R 9 ;

[0030] n is 1, 2, 3, 4, or 5;

[0031] R 9 Selected from the group consisting of -OH, C1-C6 alkoxy, C4-C6 cycloalkoxy, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, and -CN;

[0032] R 8 is H or C1-C6 alkyl;

[0033] R 6 、R 7 Each is independently selected from the following group: H, C1-C6 alkyl, halogen.

[0034] In another preferred embodiment, the additional condition is: when R 2 When H, R 3 -NH2 or R 4 and R 5 Not H at the same time.

[0035] In another preferred embodiment, R 1 is a deuterated or unsubstituted C1-C6 alkyl group.

[0036] In another preferred embodiment, R 1 It is a fully deuterated C1-C6 alkyl group.

[0037] In another preferred embodiment, the perdeuterated group means that all H groups of the group are replaced by D.

[0038] In another preferred embodiment, R 1 It is a C1-C6 alkyl group.

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

[0040] A is NH;

[0041] B is CH or N.

[0042] In another preferred embodiment, R 1 Selected from the group consisting of -CH3 and -CD3;

[0043] A is NH;

[0044] B is CH or N.

[0045] In another preferred embodiment, L is

[0046] R 2 Selected from the group consisting of: H, -CD3, C1-C6 alkyl;

[0047] X is N;

[0048] R 3 、R 4 、R 5 Each is independently selected from the following group: H, -NH2, -OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, -CONH2, -CN, halogen, -O(CH2) n R 9 , C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl substituted C2-C6 alkynyl, and -NR 8 (CH2) n R 9 ;

[0049] n is 1, 2, 3, 4, or 5;

[0050] R 9 Selected from the group consisting of C1-C6 alkoxy, C4-C6 cycloalkoxy, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, and -CN;

[0051] R 8 is H or C1-C6 alkyl.

[0052] In another preferred embodiment, L is

[0053] R 2 Selected from the group consisting of: H, -CD3, C1-C6 alkyl;

[0054] X is N;

[0055] R 3 、R 4 、R 5 Each is independently selected from the following group: H, -NH2, -OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, -CONH2, -CN, halogen, -O(CH2) n R 9 and -NR8 (CH2) n R 9 ;

[0056] n is 1, 2, 3, 4, or 5;

[0057] R 9 Selected from the group consisting of C1-C6 alkoxy, C4-C6 cycloalkoxy, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, and -CN;

[0058] R 8 is H or C1-C6 alkyl.

[0059] In another preferred embodiment, R 2 It is H, -CD3 and -CH3.

[0060] In another preferred embodiment, R 9 Selected from the group consisting of: -OCH3, -CN,

[0061] In another preferred embodiment, R 3 、R 4 Each is independently selected from the following group: -NH2, -OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, -CONH2, -CN, halogen, -O(CH2) n R 9 , C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl substituted C2-C6 alkynyl, and -NR 8 (CH2) n R 9 .

[0062] In another preferred embodiment, R 3 、R 4 Each is independently selected from the group consisting of -NH2, C1-C6 alkyl, halogen, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl-substituted C2-C6 alkynyl.

[0063] In another preferred embodiment, R 3 is -NH2.

[0064] In another preferred embodiment, R 4 It is C1-C6 alkyl, halogen, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C2-C6 alkynyl substituted by a C3-C6 cycloalkyl.

[0065] In another preferred embodiment, R 3 is -NH2; R 4 It is a halogen.

[0066] In another preferred embodiment, R 3 is -NH2; R 4 is Cl or Br.

[0067] In another preferred embodiment, R 1 is a fully deuterated C1-C6 alkyl group;

[0068] A is NH;

[0069] B is N;

[0070] L is

[0071] R 2 Selected from the group consisting of: H, -CD3, C1-C6 alkyl;

[0072] X is N;

[0073] R 3 is -NH2;

[0074] R 4 Selected from the group consisting of halogen, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl-substituted C2-C6 alkynyl;

[0075] R 5 For H.

[0076] In another preferred embodiment, R 1 is a fully deuterated C1-C6 alkyl group;

[0077] A is NH;

[0078] B is N;

[0079] L is

[0080] R 2 Selected from the group consisting of: H, C1-C6 alkyl;

[0081] X is N;

[0082] R 3 is -NH2;

[0083] R 4 is a halogen;

[0084] R 5 For H.

[0085] In another preferred embodiment, R 1 is a fully deuterated C1-C6 alkyl group;

[0086] A is NH;

[0087] B is N;

[0088] L is

[0089] R 2 is -CD3;

[0090] X is N;

[0091] R 3 is -NH2;

[0092] R 4 Selected from the group consisting of halogen, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl-substituted C2-C6 alkynyl;

[0093] R 5 For H.

[0094] In another preferred embodiment, the compound is selected from the following group:

[0095] The second aspect of the present invention provides a method for preparing the compound according to the first aspect of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

[0096] Formula Ic reacts with cyclopropylamide to obtain a compound of formula (I);

[0097] Among them, R 1 , A, B, L are as defined in the first aspect of the present invention;

[0098] G is a halogen.

[0099] The third aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more compounds described in the first aspect of the present invention or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0100] In another preferred embodiment, the pharmaceutical composition is an oral preparation.

[0101] In a fourth aspect, the present invention provides a use of the compound according to the first aspect of the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, for preparing a medicament for preventing and / or treating diseases mediated by TYK2.

[0102] In another preferred embodiment, the TYK2-mediated disease is an inflammatory or autoimmune disease in a mammal.

[0103] In another preferred embodiment, the inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, inflammatory bowel disease, psoriasis, Crohn's disease, psoriatic arthritis, Sjogren's syndrome, Syndrome, ss), systemic sclerosis, ulcerative colitis, Graves' disease, discoid lupus erythematosus, adult-onset Still's disease, systemic juvenile idiopathic arthritis, gout, gouty arthritis, type 1 diabetes mellitus, insulin-dependent diabetes mellitus, sepsis, septic shock, shigellosis, pancreatitis, glomerulonephritis, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis, pancreatitis, ankylosing spondylitis, pityriasis vulgaris, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-associated vasculitis, Kawasaki disease, chronic inflammatory demyelinating polyneuropathy, dermatomyositis, polymyositis, uveitis, Guillain-Barre syndrome, autoimmune pneumonia, autoimmune thyroiditis, autoimmune inflammatory eye disease, and chronic demyelinating polyneuropathy.

[0104] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0105] FIG1 shows the single crystal diffraction data of compound 28e of the present invention. DETAILED DESCRIPTION

[0106] After extensive and in-depth research, the inventors have developed a compound of formula (I) through structural optimization, which exhibits high TYK2 inhibitory activity and selectivity, excellent metabolic properties, and drugability, as well as a method for its preparation and its use in treating and / or preventing TYK2-mediated diseases. Based on this, the inventors have completed the present invention.

[0107] the term

[0108] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0109] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0110] In the present invention, "C1-C6 alkyl" refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like.

[0111] In the present invention, the term "C2-C6 alkenyl" refers to a straight chain or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.

[0112] In the present invention, the term "C2-C6 alkynyl" refers to a straight chain or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.

[0113] In the present invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The term "C3-C6 cycloalkyl" has a similar meaning.

[0114] In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is a C1-C4 alkoxy group.

[0115] In the present invention, the term "heterocyclic group" refers to a 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, including (but not limited to) the following groups:

[0116] In the present invention, the term "aromatic ring" or "aryl group" has the same meaning, preferably "C6-C10 aryl group". The term "C6-C10 aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms and no heteroatoms in the ring, such as phenyl, naphthyl, etc.

[0117] In the present invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning and refer to heteroaromatic groups containing one to multiple heteroatoms. For example, "C3-C10 heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen and 3 to 10 carbon atoms. Non-limiting examples include: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0118] In the present invention, the term "halo" means substituted with halogen.

[0119] In the present invention, the term "deuterated" means substituted with deuterium.

[0120] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described above or the substituent appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from the specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. 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- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, and the like.

[0121] In the present invention, the term 1-6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms independently have similar meanings. The term "plurality" refers to 2-6, such as 2, 3, 4, 5 or 6.

[0122] It should be understood that when a group is present at multiple different positions in a compound, its definition at each position is independent of each other and may be the same or different. That is, the term "selected from the group:" has the same meaning as the term "each independently selected from the group:".

[0123] Compound

[0124] For the first aspect of the present invention, the general formula (I) represents that the compound may contain one or more chiral centers, which may exist as enantiomers and diastereomers. The general formula (I) of the present invention represents that the compound may also contain many geometric isomers such as olefins, C=N double bonds, etc. Unless otherwise indicated, all chiralities (enantiomers and diastereomers), racemates, cis-geometric isomers, trans-geometric isomers, and mixtures of cis- and trans-geometric isomers described above are included in the present invention. For enantiomers, two enantiomers can be obtained by general chiral resolution methods or asymmetric synthesis methods. For diastereomers, they can be separated by methods such as fractional recrystallization or chromatographic separation.

[0125] In another preferred embodiment, in the compound, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R7 、R 8 、 R 9 Any one of A, B, L, X, Y, and n is independently a corresponding group in the specific compound described in the present invention.

[0126] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention formed with an acid or base that is suitable for pharmaceutical use. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are salts formed with a compound of the present invention and an acid. Suitable acids for forming salts 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.

[0127] Another preferred salt is a salt of the compound of the present invention formed with a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0128] Preparation method

[0129] The preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art.

[0130] Typically, the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0131] Typically, the compound is prepared as follows:

[0132] The amino compound of formula Ia reacts with formula Ib to obtain formula Ic, and formula Ic reacts with cyclopropylamide to obtain formula (I); wherein G is halogen; L, A, B, R 1 As described in the first aspect of the present invention.

[0133] In another preferred embodiment, L of Formula Ia is Provided is a method for preparing a compound of formula Ia-1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0134] Formula Ia-1A is introduced with a methylthio group to obtain Formula Ia-1B, Formula Ia-1B is oxidized to obtain a sulfoxide compound Formula Ia-1E, and the sulfoxide compound Formula Ia-1E is further oxidized to obtain a sulfoximine compound Formula Ia-1C. Formula Ia-1B can also be oxidized in one step to obtain a sulfoximine compound Formula Ia-1C, and a substituent is introduced into the sulfoximine compound Formula Ia-1C to obtain Formula Ia-1D, and Formula Ia-1D is deprotected to obtain Formula Ia-1; wherein Z 1 and Z 2 are the same or different and are each independently selected from the following group: H, -COtBu, -Boc, -Ts, -Ns, -Bn, -PMB, -DMB; Z 3 is H or halogen; X, R 2 、R 3 、R 4 、R 5 As described in the first aspect of the present invention.

[0135] In another preferred embodiment, a method for preparing a compound of a single chiral configuration represented by Formula Ia-2 or a pharmaceutically acceptable salt thereof is provided, the method further comprising the following steps:

[0136] Formula Ia-2A is subjected to strong base removal of H, followed by the introduction of a methylthio group to obtain Formula Ia-2B. Formula Ia-2B is oxidized by a suitable chiral oxidation method to obtain a sulfoxide compound of Formula Ia-2C with a single chiral configuration. Formula Ia-2C is subjected to removal of the tert-butyryl group to obtain Formula Ia-2D. Formula Ia-2D is further oxidized to obtain a sulfoximine compound of Formula Ia-2E with a single chiral configuration. Formula Ia-2E is subjected to a substitution reaction to obtain a compound of Formula Ia-2 with a single chiral configuration; X, R 2 、R 3 、R 4 、R 5 As described in the first aspect of the present invention.

[0137] In another preferred embodiment, a method for preparing a compound of a single chiral configuration represented by Formula Ia-3 or a pharmaceutically acceptable salt thereof is provided, the method further comprising the following steps:

[0138] The carboxylic acid compound of formula Ia-3A is condensed with chiral benzylamine to obtain an amide compound of formula Ia-3B. Formula Ia-3B is substituted with a methylthio group to obtain formula Ia-3C. Formula Ia-2B is oxidized by a suitable chiral oxidation method to obtain a sulfoxide compound of formula Ia-3D. The benzyl fragment of formula Ia-3D is removed to obtain an amide compound of formula Ia-3E. Formula Ia-3E is subjected to a rearrangement reaction to obtain an amino compound of formula Ia-3F. Formula Ia-3F is further oxidized to obtain a sulfoximine compound of formula Ia-3G with a single chiral configuration. Formula Ia-3G is subjected to a substitution reaction to obtain a compound of formula Ia-3 with a single chiral configuration; wherein G is selected from halogen; R 2 、R 3 、R 4 、R 5 、R 10 , m as described in the first aspect of the present invention.

[0139] In another preferred embodiment, the method further comprises the following steps:

[0140] The obtained product is further reacted with a first substance to obtain a compound represented by formula (I); the first substance is selected from the following group: HCl, H2SO4, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0141] To ensure that each synthesis step proceeds smoothly, those skilled in the art may use common protecting groups such as TBS, TMS, TBDPS, Bn, THP, Tf, etc. to perform protection and deprotection operations on the hydroxyl groups in the compounds involved in the reaction, and use common protecting groups such as Boc, Cbz, Bn, Ts, THP, etc. to perform protection and deprotection operations on the NH or NH2 in the compounds involved in the reaction.

[0142] The compounds represented by each formula may contain one or more chiral centers, which may exist as enantiomers and diastereomers, and may also contain many geometric isomers such as olefins and C=N double bonds. Unless otherwise specified, all chiralities (enantiomers and diastereomers), racemates, cis-geometric isomers, trans-geometric isomers, and mixtures of cis- and trans-geometric isomers described above are included in the present invention. For enantiomers, two enantiomers can be obtained using general chiral resolution methods or asymmetric synthesis methods. For diastereomers, they can be separated by methods such as fractional recrystallization or chromatographic separation.

[0143] Pharmaceutical compositions and methods of administration

[0144] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0145] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0146] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0147] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0148] 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 sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0149] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0150] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0151] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0152] Suspensions, in addition to the active compounds, 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.

[0153] Compositions for parenteral injection may comprise 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.

[0154] Dosage forms for topical administration of the compounds of this invention 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 that may be required.

[0155] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-inflammatory drugs).

[0156] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0157] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0158] Compared with the prior art, the present invention has the following main advantages:

[0159] (1) The compounds of the present invention have excellent TYK2 inhibitory activity;

[0160] (2) The compounds of the present invention have no inhibitory activity against JAK1, JAK2, and JAK3 kinases, and have very high selectivity for JAK family kinases;

[0161] (3) The compounds of the present invention have excellent IFN-α inflammatory pathway inhibitory activity;

[0162] (4) The compounds of the present invention have no hERG potassium channel inhibitory activity and have a low risk of cardiotoxicity;

[0163] (5) The compounds of the present invention have excellent drug metabolism properties and drugability;

[0164] (6) The compound of the present invention has excellent water solubility.

[0165] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, were generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0166] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0167] In the present invention, the structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR measurements are performed using a Bruker AVANCE-400 nuclear magnetic spectrometer. LCMS measurements are performed using a Waters 2695 liquid chromatography-mass spectrometer (MS model: Micromass ZQ).

[0168] HPLC determination was performed using an Agilent 1100 high pressure liquid chromatograph (ZORBAX SP-C18 250×4.6 mm column, Eclipse Plus-C18 250×4.6 mm column).

[0169] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from Acros Organics, Aldrich Chemical Company, J&Chem, Shaoyuan Chemical Technology, Darui Chemicals, Anaiji Chemical and other companies.

[0170] Unless otherwise specified in the examples, all operations were carried out under an argon or nitrogen atmosphere.

[0171] The microwave reaction was carried out using a CEM Discover-SP 909155 microwave reactor.

[0172] Unless otherwise specified in the examples, the reaction temperature is room temperature (20°C to 35°C).

[0173] The silica gel plate used in the thin-layer chromatography (TLC) method in the examples has a size of 0.2 mm ± 0.03 mm. The thin-layer chromatography separation and purification (prep-TLC) used for compound purification has a size of 0.4 mm to 0.5 mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as a carrier. The fully automatic medium-pressure rapid purification instrument (Combi Flash Rf+UV-VIS) is used, and the separation column models are: Silica Flash Column 4g, 12g, and 25g. The eluent system used for column chromatography and the development system for thin-layer chromatography include: A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of alkaline or acidic reagents such as ammonia or acetic acid.

[0174] The final sample compound was purified using a high-pressure preparative liquid chromatograph (Shimadzu, model: LC-20AP) using an Ultimate XB-C18 column (150 x 30 mm, 5 μm). The mobile phases were: A: acetonitrile and water (containing 0.1% trifluoroacetic acid); B: acetonitrile and water (containing 0.1% acetic acid).

[0175] Example 1

[0176] Preparation of N-(4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide

[0177] Step 1: Synthesis of 3-(S-methylsulfoximino)-2-nitropyridine (1b)

[0178] The synthesis of 3-(methylthio)-2-nitropyridine (1a) refers to WO2020 / 086616.

[0179] To a solution of 3-(methylthio)-2-nitropyridine (1a) (1.26 g, 7.41 mmol) in methanol (20 mL) was added ammonium carbamate (867 mg, 11.1 mmol). The temperature was cooled to 0°C, and iodophenyldiacetic acid (4.77 g, 14.8 mmol) was added portionwise. The mixture was warmed to room temperature and stirred for 2 hours. The solvent was evaporated, and flash chromatography (ethyl acetate / petroleum ether = 4:1) was used to obtain 3-(S-methylsulfoximido)-2-nitropyridine (1b) (1.3 g, light yellow oil) in a 79% yield.

[0180] 1H NMR (400MHz, CDCl3) δ8.71 (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).

[0181] MS m / z[M+H] + :202.

[0182] Step 2: Synthesis of 3-(N,S-dimethylsulfoximino)-2-nitropyridine (1c)

[0183] 3-(S-methylsulfoximino)-2-nitropyridine (1b) (23.3 g, 115.9 mmol) was dissolved in DMF (230 mL) and cooled in an ice bath. Sodium hydride (6.96 g, 174 mmol) was added portionwise under nitrogen protection and stirred in an ice bath for 20 minutes. Methyl iodide (19.8 g, 139.1 mmol) was slowly added dropwise and stirred in an ice bath for 30 minutes. Ice water (200 mL) and saturated ammonium chloride (200 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain crude 3-(N,S-dimethylsulfoximino)-2-nitropyridine (1c) (30 g).

[0184] MS m / z[M+H] + :216.

[0185] Step 3: Synthesis of 3-(N,S-dimethylsulfoximino)pyridine-2-amine (1d)

[0186] Crude 3-(N,S-dimethylsulfoximido)-2-nitropyridine (1c) (30 g) was dissolved in a 1 / 1 ethanol / water mixture (300 mL). Ammonium chloride (62.6 g, 1.16 mol) was added, and the mixture was heated to 70°C. Iron powder (22.7 g, 405.8 mmol) was added portionwise with stirring. Stirring was continued at 70°C for 1 hour. The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with a mixture of methanol and dichloromethane (1:10). The filtrate was concentrated and separated by column chromatography (methanol / ethyl acetate / petroleum ether = 1:9:10) to obtain 3-(N,S-dimethylsulfoximido)pyridine-2-amine (1d) (7.3 g, light yellow solid) in a two-step yield of 34%.

[0187] 1H NMR (400MHz, CDCl3) δ8.25(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).

[0188] MS m / z[M+H] + :186.

[0189] Step 4: Synthesis of N-(4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide (1)

[0190] The synthesis of N-(4-chloro-5-propionylpyridin-2-yl)cyclopropanecarboxamide (1e) refers to WO2020 / 086616.

[0191] Dissolve N-(4-chloro-5-propionylpyridin-2-yl)cyclopropanecarboxamide (1e) (90 mg, 0.36 mmol) in 1,4-dioxane (4 mL). Add 3-(N,S-dimethylsulfoximino)pyridine-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). Incubate at 110°C for 3 hours under nitrogen. After cooling to room temperature, filter through celite and rinse the filter cake with ethyl acetate. The filtrate was concentrated and flash separated (methanol / dichloromethane = 1:20) to give a crude product (30 mg, yellow solid). Prep-HPLC was used to obtain N-(4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide (1) (12 mg, white solid) in an 8% yield.

[0192] 1H NMR (400MHz, DMSO-d6) δ11.79(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).

[0193] MS(M+H) + :402.

[0194] Example 2: Preparation of 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0195] Step 1: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (2b)

[0196] The synthesis of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (2a) can be found in US2019 / 152948.

[0197] 3-(N,S-dimethylsulfoximino)pyridin-2-ylamine (1d) (130 mg, 0.70 mmol) was dissolved in DMF, cooled to 0°C, and sodium hydride (57 mg, 1.41 mmol) was added. The mixture was stirred at 0°C for 5 minutes, and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (2a) (145 mg, 0.7 mmol) was added. Stirring was continued at room temperature for 1 hour. Saturated ammonium chloride solution (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by flash chromatography (methanol:dichloromethane = 1:30) to obtain 6-chloro-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (2b) (89 mg, white solid) in a 35% yield.

[0198] 1H NMR (400MHz, CDCl3) δ12.42 (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).

[0199] MS m / z[M+H] + :358.

[0200] Step 2: Synthesis of 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (2)

[0201] 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), and cyclopropaneamide (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. Under a nitrogen atmosphere, microwave (110 ° C, 100 W) was used to react for 45 minutes. After the reaction solution was cooled to room temperature, it was filtered through celite and the filter cake was rinsed with ethyl acetate. The filtrate was concentrated and then flash separated (methanol / dichloromethane = 1:10) to obtain a crude product. Prep-HPLC was used to prepare 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (2) (45 mg, white solid) in a yield of 44%.

[0202] 1H NMR(400MHz,dmso)δ11.87(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).

[0203] MS m / z[M+H] + :407.

[0204] Example 3: Preparation of 6-(cyclopropanecarboxamido)-4-((2-(N,S-dimethylsulfoximino)phenyl)amino)-N-methylpyridazine-3-carboxamide

[0205] Step 1: Synthesis of 6-chloro-4-((2-(N,S-dimethylsulfoximino)phenyl)amino)-N-methylpyridazine-3-carboxamide (3c)

[0206] The synthesis of 2-(N,S-dimethylsulfoximino)aniline (3a) is described in WO2018 / 075937.

[0207] The synthesis of 4,6-dichloro-N-methylpyridazine-3-carboxamide (3b) refers to WO2020 / 086616.

[0208] 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). LiHMDS (2.53 mL, 2.53 mmol) was slowly added under a nitrogen atmosphere in an ice-water bath. The mixture was slowly warmed to room temperature and reacted for 10 minutes. The reaction solution was quenched with 1N HCl (1 mL), diluted with water (20 mL), and extracted with ethyl acetate (60 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by flash chromatography (ethyl acetate:petroleum ether = 1:1) to obtain 6-chloro-4-((2-(N,S-dimethylsulfoximino)phenyl)amino)-N-methylpyridazine-3-carboxamide (3c) (98 mg, yellow solid) in a 33% yield.

[0209] 1H NMR (400MHz, CDCl3) δ11.50(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).

[0210] MS m / z[M+H] + :354.

[0211] Step 2: Synthesis of 6-(cyclopropylcarboxamido)-4-((2-(N,S-dimethylsulfoximino)phenyl)amino)-N-methylpyridazine-3-carboxamide (3)

[0212] The synthesis method refers to the synthesis of 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (Example 2), with a yield of 40%.

[0213] 1H NMR(400MHz,dmso)δ11.33(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=14.1H z,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).

[0214] MS m / z[M+H] + :403.

[0215] Example 4: Preparation of 6-(cyclopropanecarboxamido)-4-((2-(N-ethyl-S-methylsulfoximino)phenyl)amino)-N-methylpyridazine-3-carboxamide

[0216] Step 1: Synthesis of 1-(N-ethyl-S-methylsulfoximino)-2-nitrobenzene (4b)

[0217] The synthesis of 1-(S-methylsulfoximino)-2-nitrobenzene (4a) is described in WO2018 / 075937.

[0218] 1-(S-Methylsulfoximino)-2-nitrobenzene (4a) (260 mg, 1 mmol) was dissolved in DMSO (5 mL), and KOH (112 mg, 2 mmol) was added. The mixture was stirred at room temperature for 5 minutes. Ethyl iodide (360 mg, 2.3 mmol) was added and stirred at room temperature for 3 hours. The reaction was quenched by adding water (10 mL) and extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the product was separated by flash column chromatography (ethyl acetate / petroleum ether = 40%–60%) to obtain 1-(N-ethyl-S-methylsulfoximino)-2-nitrobenzene (4b) (200 mg, yellow oil) in a 68% yield.

[0219] MS m / z[M+H] + :229.

[0220] Step 2: Synthesis of 2-(N-ethyl-S-methylsulfoximino)aniline (4c)

[0221] 1-(N-ethyl-S-methylsulfoximido)-2-nitrobenzene (4b) (200 mg, 0.877 mmol) was dissolved in ethanol / water (2 / 1, 9 mL). Ammonium chloride (511 mg, 9.65 mmol) was added, and iron powder (172 mg, 3.07 mmol) was added portionwise at 75°C. Stirring was continued at 75°C for 1 hour. After cooling to room temperature, the mixture was filtered through celite, and the filter cake was rinsed with ethanol. The filtrate was concentrated and flash chromatography (methanol / dichloromethane = 5%–10%) was performed to obtain 2-(N-ethyl-S-methylsulfoximido)aniline (4c) (150 mg, colorless oil) in 86% yield.

[0222] 1H NMR (400MHz, CDCl3) δ7.73(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).

[0223] MS m / z[M+H] + :199.

[0224] Step 3: Synthesis of 6-chloro-4-((2-(N-ethyl-S-methylsulfoximino)phenyl)amino)-N-methylpyridazine-3-carboxamide (4d)

[0225] The synthesis method was based on the synthesis of 6-chloro-4-((2-(N,S-dimethylsulfoximino)phenyl)amino)-N-methylpyridazine-3-carboxamide (3c), with a yield of 26%.

[0226] MS m / z[M+H] + :368.

[0227] Step 4: Synthesis of 6-(cyclopropylcarboxamido)-4-((2-(N-ethyl-S-methylsulfoximino)phenyl)amino)-N-methylpyridazine-3-carboxamide (4)

[0228] The synthesis method refers to the synthesis of 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (Example 2), with a yield of 41.0%.

[0229] 1H NMR (400MHz, DMSO-d6) δ11.32(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),7.3 8(t,J=7.4Hz,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).

[0230] MS m / z[M+H] + :417.

[0231] Example 5: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0232] Step 1: Synthesis of N-(6-methyl-3-methylthiopyridin-2-methyl)trimethylacetamide (5b)

[0233] The synthesis of N-(6-methylpyridin-2-methyl)trimethylacetamide (5a) was referred to Org. Process Res. Dev. 2010, 14(1), 263–271.

[0234] N-(6-Methylpyridin-2-methyl)trimethylacetamide (5a) (5.5 g, 28.6 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). The mixture was cooled to 0°C under a nitrogen atmosphere. A solution of n-butyllithium in n-hexane (35 mL, 2.5 M, 85.9 mmol) was slowly added dropwise. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to -78°C and dimethyl disulfide (5.5 mL, 57.2 mL) was slowly added dropwise. After addition, the mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction was quenched by the addition of saturated ammonium chloride under an ice-water bath. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was flash separated (ethyl acetate:petroleum ether = 1:1) to obtain N-(6-methyl-3-methylthiopyridin-2-methyl)trimethylacetamide (5b) (2.95 g, white solid) in a 43% yield.

[0235] MS m / z[M+H] + :239.

[0236] Step 2: Synthesis of N-(6-methyl-3-(S-methylsulfoximino)pyridin-2-methyl)trimethylacetamide (5c)

[0237] The synthesis method was based on the synthesis of 3-(S-methylsulfoximino)-2-nitropyridine, with a yield of 12%.

[0238] 1H NMR (400MHz, DMSO-d6) δ10.78(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).

[0239] MS m / z[M+H] + :270.

[0240] Step 3: Synthesis of N-(6-methyl-3-(N,S-dimethylsulfoximino)pyridin-2-methyl)trimethylacetamide (5d)

[0241] N-(6-methyl-3-(S-methylsulfoximino)pyridin-2-methyl)trimethylacetamide (5c) (370 mg, 1.38 mmol) was dissolved in dichloromethane (6 mL), and trimethoxonium tetrafluoroborate (265 mg, 1.79 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding water and stirred for 10 minutes. The aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate. After concentration, the mixture was separated by plate chromatography (methanol:dichloromethane = 1:10) to obtain N-(6-methyl-3-(N,S-dimethylsulfoximino)pyridin-2-methyl)trimethylacetamide (5d) (190 mg, brown viscous liquid) in a 49% yield.

[0242] MS m / z[M+H] + :284.

[0243] Step 4: Synthesis of 3-(N,S-dimethylsulfoximino)-6-methylpyridine-2-amine (5e)

[0244] N-(6-methyl-3-(N,S-dimethylsulfoximino)pyridin-2-methyl)trimethylacetamide (5d) (190 mg, 0.67 mmol) was dissolved in 2N hydrochloric acid solution (4 mL) and stirred at 100°C for 30 minutes. The mixture was cooled to room temperature and the pH was adjusted to 8-9 using saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by plate chromatography (methanol:dichloromethane = 1:10) to obtain 3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-amine (5e) (79 mg, yellow liquid) in a 59% yield.

[0245] 1H NMR (400MHz, DMSO-d6) δ7.69(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).

[0246] MS m / z[M+H] + :200.

[0247] Step 5: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (5f)

[0248] 3-(N,S-Dimethylsulfoximino)-6-methylpyridin-2-amine (5e) (63 mg, 0.316 mmol) was dissolved in anhydrous DMF (1 mL). The mixture was cooled to 0°C under a nitrogen atmosphere. Sodium hydride (25 mg, 60% w / w, 0.632 mmol) was added and stirred for 20 minutes. 4,6-Dichloro-N-methylpyridazine-3-carboxamide (3b) (65 mg, 0.316 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched by adding saturated ammonium chloride and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, flash separation (methanol: dichloromethane = 1:10) was carried out to give 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (5f) (40 mg, white solid) in a 34% yield.

[0249] 1H NMR (400MHz, DMSO-d6) δ12.03(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).

[0250] MS m / z[M+H] + :369.

[0251] Step 6: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (5)

[0252] The synthesis method refers to the synthesis of 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (Example 2), with a yield of 33%.

[0253] 1H NMR (400MHz, DMSO-d6) δ11.88(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).

[0254] MS m / z[M+H] + :418.

[0255] Example 6: Preparation of 4-((6-carbamoyl-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide

[0256] Step 1: Synthesis of 6-chloro-3-(methylthio)pyridine-2-amine (6b)

[0257] The synthesis of N-(6-chloro-3-(methylthio)pyridin-2-yl)trimethylacetamide (6a) was carried out with reference to J. Org. Chem. 1983, 48(20), 3401–3408.

[0258] The synthesis method refers to the synthesis of 3-(N,S-dimethylsulfoximino)-6-methylpyridine-2-amine, with a yield of 89%.

[0259] 1H NMR (400MHz, CDCl3) δ7.50 (d, J = 7.8Hz, 1H), 6.63 (d, J = 7.8Hz, 1H), 5.25 (s, 2H), 2.34 (s, 3H).

[0260] MS m / z[M+H] + :175.

[0261] Step 2: Synthesis of N,N-(di-tert-butyloxycarbonyl)-6-chloro-3-(methylthio)pyridine-2-amine (6c)

[0262] 6-Chloro-3-(methylthio)pyridine-2-amine (6b) (6.0 g, 34.4 mmol) was placed in a round-bottom flask, and Boc anhydride (21.7 g, 99.7 mmol) was slowly added. After stirring at room temperature for 10 minutes, DMAP (840 mg, 6.88 mmol) was added and continued to stir at room temperature for 1 hour. Petroleum ether was added to dilute the solution, concentrated, and passed through a silica gel short column to remove Boc anhydride to obtain 14.7 g of crude product. Petroleum ether was added to the crude product to make a pulp, filtered and rinsed with petroleum ether, and dried to obtain N,N-(di-tert-butyloxycarbonyl)-6-chloro-3-(methylthio)pyridine-2-amine (6c) (12.3 g, white solid) with a yield of 96%.

[0263] 1H NMR (400MHz, CDCl3) δ7.55 (d, J = 8.2Hz, 1H), 7.28 (d, J = 9.2Hz, 1H), 2.45 (s, 3H), 1.42 (s, 18H).

[0264] MS m / z[M+Na]+ :397.

[0265] Step 3: Synthesis of N,N-(di-tert-butyloxycarbonyl)-6-chloro-3-(S-methylsulfoximino)pyridine-2-amine (6d)

[0266] The synthesis method was based on the synthesis of 3-(S-methylsulfoximino)-2-nitropyridine, with a yield of 84%.

[0267] 1H NMR (400MHz, CDCl3) δ8.43(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).

[0268] MS m / z[M+H] + :406.

[0269] Step 4: Synthesis of N,N-(di-tert-butyloxycarbonyl)-6-chloro-3-(N,S-dimethylsulfoximino)pyridine-2-amine (6e)

[0270] The synthesis method was based on the synthesis of N-(6-methyl-3-(N,S-dimethylsulfoximino)pyridine-2-methyl)trimethylacetamide, and the crude product was directly used for the next reaction without separation.

[0271] Step 5: Synthesis of 6-chloro-3-(N,S-dimethylsulfoximino)pyridine-2-amine (6f)

[0272] The synthesis method refers to the synthesis of 3-(N,S-dimethylsulfoximino)-6-methylpyridine-2-amine, and the two-step yield is 34%.

[0273] 1H NMR (400MHz, DMSO-d6) δ7.83(d,J=8.0Hz,1H),7.22(s,2H),6.77(d,J=8.0Hz,1H),3.08(s,3H),2.49(s,3H).

[0274] MS m / z[M+H] + :220.

[0275] Step 6: Synthesis of 6-chloro-4-((6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (6 g)

[0276] The synthesis method refers to the synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, with a yield of 39%.

[0277] 1H NMR (400MHz, DMSO-d6) δ12.20(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).

[0278] MS m / z[M+H] + :389.

[0279] Step 7: Synthesis of 6-chloro-4-((6-cyano-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (6h)

[0280] 6-Chloro-4-((6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (6 g) (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) were dissolved in anhydrous DMF (2 mL) and reacted in a microwave oven at 80°C and 80W for 45 minutes under a nitrogen atmosphere. After cooling to room temperature, the reaction was quenched by adding water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the residue was separated by plate chromatography (ethyl acetate:petroleum ether=2:1) ​​to give 6-chloro-4-((6-cyano-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (6h) (118 mg, yellow solid) in a yield of 91%.

[0281] 1H NMR (400MHz, DMSO-d6) δ12.25 (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).

[0282] MS m / z[M+H] + :380.

[0283] Step 8: Synthesis of 4-((6-cyano-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (6i)

[0284] The synthesis method refers to the synthesis of 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, with a yield of 21%.

[0285] 1H NMR (400MHz, DMSO-d6) δ12.09(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).

[0286] MS m / z[M+H] + :429.

[0287] Step 9: Synthesis of 4-((6-carbamoyl-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (6)

[0288] 4-((6-cyano-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (6i) (15 mg, 0.035 mmol) was dissolved in DMSO (1 mL), and anhydrous potassium carbonate (12 mg, 0.088 mmol) was added. After stirring at room temperature for 5 minutes, 30% aqueous hydrogen peroxide solution (39 mg, 0.35 mmol) was added and stirring continued at room temperature for 30 minutes. The reaction solution was poured into distilled water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, prep-HPLC separation was performed to obtain 4-((6-carbamoyl-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (6) (4.5 mg, white solid) in a yield of 29%.

[0289] 1H NMR (400MHz, DMSO-d6) δ11.99(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),7.8 7(d,J=7.9Hz,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).

[0290] MS m / z[M+H] + :447.

[0291] Example 7: Preparation of 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide

[0292] Step 1: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (7a)

[0293] 6-Chloro-4-((6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (6 g) (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) were dissolved in anhydrous DMF (30 mL), and benzophenone imine (3.8 g, 21.1 mmol) was added. The mixture was stirred at 125 ° C for 4 hours under a nitrogen atmosphere. The reaction was quenched with 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 ~ methanol:dichloromethane = 1:20) to give 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (7a) (4.17 g, khaki solid) in a yield of 74%.

[0294] MS m / z[M+H] + :534.

[0295] Steps 2 and 3: Synthesis of 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (7)

[0296] 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). Cyclopropanamide (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. The mixture was stirred at 145°C for 3 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with a methanol / dichloromethane (1:10) mixture and filtered through celite. The filter cake was rinsed with a methanol / dichloromethane (1:10) mixture. After concentration, the crude product of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (7b) was obtained and directly used for the next reaction without separation.

[0297] The crude product of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (7b) was dissolved in tetrahydrofuran (40 mL). 6N hydrochloric acid (30 mL) was added under ice-cooling and the mixture was warmed to room temperature and stirred for 1 hour. Anhydrous potassium carbonate was slowly added in portions to adjust the pH to 9-10. The mixture was filtered and concentrated. Column chromatography (methanol:dichloromethane = 1:20–1:7) was used to obtain 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (7) (1.87 g, khaki solid) in a yield of 51%.

[0298] 1H NMR (400MHz, DMSO-d6) δ11.55(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).

[0299] MS m / z[M+H]+ :419.

[0300] Example 8: Preparation of 4-((5-cyano-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide

[0301] Step 1: Synthesis of 5-bromo-3-(N,S-dimethylsulfoximino)pyridine-2-amine (8a)

[0302] 3-(N,S-dimethylsulfoximino)pyridine-2-amine (1d) (500 mg, 2.7 mmol) was dissolved in acetonitrile (15 mL), and NBS (504 mg, 2.83 mmol) was slowly added. The mixture was stirred at room temperature for 1 hour. The reaction was complete by TLC. The acetonitrile was dried and quenched with water. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Flash separation (ethyl acetate / petroleum ether = 40–90%) was performed to obtain 5-bromo-3-(N,S-dimethylsulfoximino)pyridine-2-amine (8a) (640 mg, white solid) in an 89% yield.

[0303] 1H NMR (400MHz, CDCl3) δ8.29 (d, J = 2.1Hz, 1H), 8.10 (d, J = 2.0Hz, 1H), 6.07 (brs, 2H), 3.08 (s, 3H), 2.68 (s, 3H).

[0304] MS m / z[M+H] + :264.

[0305] Step 2: Synthesis of 4-((5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide (8b)

[0306] The synthesis method refers to the synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, with a yield of 61%.

[0307] 1H NMR (400MHz, CDCl3) δ12.43(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).

[0308] MS m / z[M+H] + :433.

[0309] Steps 3 and 4: Synthesis of 4-((5-cyano-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-methylpyridazine-3-carboxamide (8)

[0310] 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 in a microwave oven at 60°C and 50W under nitrogen for 1 hour, then at 80°C and 80W for 15 minutes. The reaction solution 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 system. The reaction was carried out in a microwave oven at 110°C and 50W under a nitrogen atmosphere for 1 hour. The reaction was quenched by adding water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and flash separated (methanol / dichloromethane = 5–7%) to obtain 4-((5-cyano-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-methylpyridazine-3-carboxamide (8) (114 mg, white solid) in a yield of 56%.

[0311] 1H NMR(400MHz,DMSO-d6)δ12.20(s,1H),11.50(s,1H),9.46(s,1H),9.16(s,1H),8.93(s,1H),8.4 9(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).

[0312] MS m / z[M+H] + :429.

[0313] Example 9: Preparation of 4-((5-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide

[0314] Step 1: Synthesis of 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinate-2,4,6-trichlorophenyl ester (9a)

[0315] 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 toluene (28 mL) solution and stirred at 100°C for 2 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered through celite, and rinsed with ethyl acetate. The filtrate was concentrated and flash separated (ethyl acetate / petroleum ether = 40–80%) to give 2,4,6-trichlorophenyl 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinate (9a) (380 mg, light yellow solid) in a yield of 51%.

[0316] 1H NMR (400MHz, DMSO-d6) δ12.47(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).

[0317] MS m / z[M+H] + :577.

[0318] Step 2: Synthesis of 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinic acid (9b)

[0319] 2,4,6-trichlorophenyl 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinate (9a) (175 mg, 0.3 mmol) was dissolved in DMSO (6.5 mL). 40% aqueous sodium hydroxide solution (500 mg, 40% w / w) was added under ice-cooling and stirred at room temperature for 20 minutes. The pH was adjusted to 3-4 with 1N hydrochloric acid. The mixture was extracted with dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate. After concentration, crude 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinic acid (9b) (179 mg, light yellow solid) was obtained, which was used directly in the next step without isolation.

[0320] MS m / z[M+H] + :399.

[0321] Step 3: Synthesis of tert-butyl (6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)pyridin-3-yl)carbamate (9c)

[0322] To a solution of crude 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinic acid (9b) (179 mg) in tert-butanol (12 mL) were added triethylamine (50 mg, 0.495 mmol) and DPPA (136 mg, 0.495 mmol), and the mixture was stirred at 85°C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated by flash separation (ethyl acetate / petroleum ether = 40–90%) to afford tert-butyl (6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)pyridin-3-yl)carbamate (9c) (69 mg, light yellow solid) in a 33% yield.

[0323] MS m / z[M+H] + :470.

[0324] Step 4: Synthesis of tert-butyl (6-((6-(cyclopropylcarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)pyridin-3-yl)carbamate (9d)

[0325] The synthesis method refers to the synthesis of 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, with a yield of 29%.

[0326] MS m / z[M+H]+ :519.

[0327] Step 5: Synthesis of 4-((5-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (9)

[0328] Tert-butyl (6-((6-(cyclopropylcarboxamido)-3-(methylcarbamoyl)pyridin-4-yl)amino)-5-(N,S-dimethylsulfoximino)pyridin-3-yl)carbamate (9d) (22 mg, 0.042 mmol) was dissolved in dichloromethane (1.5 mL), and a 4 M hydrochloric acid solution in dioxane (1.5 mL, 6 mmol) was added. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated, diluted with water (1.5 mL), and the pH was adjusted to >11 with 33% aqueous potassium carbonate solution. The mixture was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product was filtered and concentrated to obtain a crude product. Prep-HPLC was used to obtain 4-((5-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (9) (6.7 mg, white solid) in a yield of 38%.

[0329] 1H NMR (400MHz, DMSO-d6) δ11.34(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,1H),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).

[0330] MS m / z[M+H] + :419.

[0331] Example 10: Preparation of 4-((5-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide

[0332] Step 1: Synthesis of 4-((5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (10a)

[0333] The synthesis method refers to the synthesis of 5-bromo-3-(N,S-dimethylsulfoximino)pyridine-2-amine, with a yield of 16%.

[0334] MS m / z[M+H] + :485.

[0335] Step 2: Synthesis of 6-((6-(cyclopropylcarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinate-2,4,6-trichlorophenyl ester (10b)

[0336] The synthesis method was based on the synthesis of 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinic acid-2,4,6-trichlorophenyl ester, with a yield of 82%.

[0337] MS m / z[M+H] + :629.

[0338] Step 3: Synthesis of 6-((6-(cyclopropylcarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinic acid (10c)

[0339] The synthesis method was based on the synthesis of 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)nicotinic acid, and the crude product was directly used in the next step without separation.

[0340] MS m / z[M+H] + :402.

[0341] Step 4: Synthesis of tert-butyl (6-((6-(cyclopropylcarboxamido)-3-((methyl-d3)carbamoyl))pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)pyridin-3-yl)carbamate (10d)

[0342] The synthesis method refers to the synthesis of tert-butyl (6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)pyridin-3-yl)carbamate, with a two-step yield of 25%.

[0343] MS m / z[M+H] + :522.

[0344] Step 5: Synthesis of 4-((5-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (10)

[0345] The synthesis method refers to the synthesis of 4-((5-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide, with a yield of 16%.

[0346] 1H NMR (400MHz, DMSO-d6) δ11.34(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).

[0347] MS m / z[M+H] + :422.

[0348] Example 11: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0349] Step 1: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (11a)

[0350] 4-((5-Bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide (8b) (200 mg, 0.463 mmol), diboronic acid pinacol ester (151 mg, 0.594 mmol), Pd(dppf)Cl2 (34 mg, 0.046 mmol), and anhydrous potassium acetate (133 mg, 1.400 mmol) were dissolved in dioxane and stirred at 100°C for 1 hour under a nitrogen atmosphere. After cooling to room temperature, 30% aqueous hydrogen peroxide (103 mg, 0.909 mmol) was added to the reaction solution and stirred at room temperature for 30 minutes. Ethyl acetate and water were added to dilute the reaction solution, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography (methanol:dichloromethane=1:20) was used to obtain 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (11a) (124 mg, yellow solid) in a yield of 73%.

[0351] 1H NMR (400MHz, DMSO-d6) δ11.79(s,1H),10.45(s,1H),9.26(d,J=4.6Hz,1H),8.56(s,1H),8.21(d,J=2.8Hz,1H),7.69(d,J=2.8Hz,1H),3.19(s, 3H), 2.84 (d, J = 4.7Hz, 3H), 2.67 (s, 3H).

[0352] MS m / z[M+H] + :371.

[0353] Step 2: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (11)

[0354] The synthesis method refers to the synthesis of 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, with a yield of 69%.

[0355] 1H NMR (400MHz, DMSO-d6) δ11.52(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).

[0356] MS m / z[M+H] + :420.

[0357] Example 12: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-fluoropyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0358] Preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-fluoropyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (12) The preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide was prepared with reference to Example 5, except that N-(5-fluoropyridin-2-yl)trimethylacetamide (12a) was used instead of N-(6-methylpyridin-2-methyl)trimethylacetamide as the starting material.

[0359] Step 1: Synthesis of N-(5-fluoro-3-methylthiopyridin-2-yl)trimethylacetamide (12b), yield 26%.

[0360] The synthesis of N-(5-fluoropyridin-2-yl)trimethylacetamide (12a) is described in Org. Lett. 2013, 15(13), 3460–3463.

[0361] 1H NMR (400MHz, DMSO-d6) δ9.50(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).

[0362] MS m / z[M+H] + :243.

[0363] Step 2: Synthesis of N-(3-(S-methylsulfoximino)-5-fluoropyridin-2-yl)trimethylacetamide (12c), yield 28%.

[0364] 1H NMR (400MHz, DMSO-d6) δ10.57(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).

[0365] MS m / z[M+H] + :274.

[0366] Step 3: Synthesis of N-(3-(N,S-dimethylsulfoximino)-5-fluoropyridin-2-yl)trimethylacetamide (12d), yield 14%.

[0367] 1H NMR (400MHz, DMSO-d6) δ10.30(s,0.65H),9.81(s,0.35H),8.78(s,0.35H),8.68(d,J=2.4Hz,0.65H),8.3 1(d,J=7.5Hz,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).

[0368] MS m / z[M+H] + :288.

[0369] Step 4: Synthesis of 3-(N,S-dimethylsulfoximino)-5-fluoropyridine-2-amine (12e) with a yield of 47%.

[0370] 1H NMR (400MHz, DMSO-d6) δ8.34 (s, 1H), 7.79 (d, J = 7.6Hz, 1H), 6.82 (s, 2H), 3.19 (s, 3H), 2.57 (s, 3H).

[0371] MS m / z[M+H] + :204.

[0372] Step 5: Preparation of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-fluoropyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (12f) was synthesized with a yield of 32%.

[0373] 1H NMR (400MHz, DMSO-d6) δ12.03(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).

[0374] MS m / z[M+H] + :373.

[0375] Step 6: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-fluoropyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (12) with a yield of 29%.

[0376] 1H NMR (400MHz, DMSO-d6) δ11.82(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).

[0377] MS m / z[M+H] + :422.

[0378] Example 13: Preparation of 4-((5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide

[0379] Step 1: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (13a)

[0380] The synthesis method refers to the synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, with a yield of 40%.

[0381] 1H NMR (400MHz, DMSO-d6) δ12.07(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).

[0382] MS m / z[M+H] + :355.

[0383] Step 2: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (13b)

[0384] The synthesis method refers to the synthesis of 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, with a yield of 44%.

[0385] 1H NMR (400MHz, DMSO-d6) δ11.85(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).

[0386] MS m / z[M+H] + :404.

[0387] Step 3: Synthesis of 4-((5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (13)

[0388] 6-(Cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (13b) (490 mg, 1.21 mmol) was dissolved in a mixed solvent of acetonitrile (10 mL) and dichloromethane (10 mL). NBS (183 mg, 1.03 mmol) was added under ice-water bath and stirred at room temperature for 2 hours. The reaction was quenched by adding saturated ammonium chloride (35 mL), diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, flash separation (methanol / dichloromethane = 10%) was performed to obtain 4-((5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (13) (100 mg, light yellow solid) in a yield of 17%.

[0389] 1 H NMR (400MHz, DMSO-d6) δ11.88(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).

[0390] MS m / z[M+H] + :482.

[0391] Example 14: Preparation of 6-(cyclopropylamido)-4-((3-(N,S-dimethylsulfoximino)-5-methoxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0392] Step 1: Synthesis of N-(5-methoxy-3-methylthiopyridin-2-yl)trimethylacetamide (14b)

[0393] The synthesis of N-(5-methoxy-pyridin-2-yl)trimethylacetamide (14a) can be found in US 2011 / 178053.

[0394] The synthesis method of 14b was based on the synthesis of N-(6-methyl-3-methylthiopyridin-2-methyl)trimethylacetamide, with a yield of 58%.

[0395] 1H NMR (400MHz, CDCl3) δ7.95(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).

[0396] MS m / z[M+H] + :255.

[0397] Step 2: Synthesis of 5-methoxy-3-methylthiopyridine-2-amine (14c)

[0398] The synthesis method refers to the synthesis of 3-(N,S-dimethylsulfoximino)-6-methylpyridine-2-amine, with a yield of 84%.

[0399] 1H NMR (400MHz, CDCl3) δ7.70–7.67(m,1H),7.20–7.17(m,1H),4.65(s,2H),3.78(s,3H),2.39(s,3H).

[0400] MS m / z[M+H] + :171.

[0401] Step 3: Synthesis of N,N-(di-tert-butyloxycarbonyl)-5-methoxy-3-methylthiopyridine-2-amine 14d

[0402] The synthesis method refers to the synthesis of N,N-(di-tert-butyloxycarbonyl)-6-chloro-3-methylthiopyridine-2-amine, with a yield of 70%.

[0403] 1H NMR (400MHz, CDCl3) δ7.93(s,1H),7.07(s,1H),3.89(s,3H),2.43(s,3H),1.41(s,18H).

[0404] MS m / z[M+H] + :371.

[0405] Step 4: Synthesis of N,N-(di-tert-butyloxycarbonyl)-3-(S-methylsulfoximino)-5-methoxypyridine-2-amine (14e)

[0406] The synthesis method refers to the synthesis of 3-(S-methylsulfoximino)-2-nitropyridine, with a yield of 85%.

[0407] 1H NMR (400MHz, CDCl3) δ8.36 (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).

[0408] MS m / z[M+H] + :402.

[0409] Step 5: Synthesis of N,N-(di-tert-butyloxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-methoxypyridine-2-amine (14f)

[0410] The synthesis method refers to the synthesis of N-(6-methyl-3-(N,S-dimethylsulfoximino)pyridine-2-methyl)trimethylacetamide, with a yield of 80%.

[0411] MS m / z[M+H] + :416.

[0412] Step 6: Synthesis of 3-(N,S-dimethylsulfoximino)-5-methoxypyridine-2-amine (14 g)

[0413] The synthesis method refers to the synthesis of 6-chloro-3-(N,S-dimethylsulfoximino)pyridine-2-amine, with a yield of 23%.

[0414] 1H NMR (400MHz, CDCl3) δ8.04(s,1H),7.61(s,1H),5.64(s,2H),3.82(s,3H),3.10(s,3H),2.68(s,3H).

[0415] MS m / z[M+H] + :202.

[0416] Step 7: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-methoxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (14h)

[0417] The synthesis method refers to the synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, with a yield of 14%.

[0418] MS m / z[M+H] + :385.

[0419] Step 8: Synthesis of 6-(cyclopropylamido)-4-((3-(N,S-dimethylsulfoximino)-5-methoxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (14)

[0420] The synthesis method refers to the synthesis of 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, with a yield of 79%.

[0421] 1H NMR (400MHz, CDCl3) δ11.65(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,1H),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).

[0422] MS m / z[M+H] + :434.

[0423] Example 15: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0424] Step 1: Synthesis of 3-(N,S-dimethylsulfoximino)-5-methylpyridine-2-amine (15a)

[0425] 5-Bromo-3-(N,S-dimethylsulfoximino)pyridine-2-amine (8a) (100 mg, 0.38 mmol), tetrakistriphenylphosphine palladium (88 mg, 0.076 mmol), and cesium carbonate (124 mg, 0.38 mmol) were dissolved in a mixture of dioxane (1.8 mL) and water (0.2 mL). A 3M solution of trimethylborane in tetrahydrofuran (0.2 mL, 0.6 mmol) was added to the reaction mixture, and the mixture was reacted at 100°C under a nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature and quenched with water. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the product was separated by plate chromatography (methanol:dichloromethane = 1:10) to obtain 3-(N,S-dimethylsulfoximino)-5-methylpyridine-2-amine (15a) (50 mg, white solid) in a 66% yield.

[0426] 1H NMR (400MHz, CDCl3) δ8.09(s,1H),7.82(s,1H),5.82(s,2H),3.07(s,3H),2.68(s,3H),2.26(s,3H).

[0427] MS m / z[M+H] + :200.

[0428] Step 2: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (15b)

[0429] The synthesis method refers to the synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, with a yield of 22%.

[0430] MS m / z[M+H] + :369.

[0431] Step 3: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (15)

[0432] The synthesis method refers to the synthesis of 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, with a yield of 62%.

[0433] 1H NMR (400MHz, DMSO-d6) δ11.77(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).

[0434] MS m / z[M+H] + :418.

[0435] Example 16: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-(3-methoxypropoxy)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0436] Step 1: Synthesis of N,N-(di-tert-butyloxycarbonyl)-5-bromo-3-(N,S-dimethylsulfoximino)pyridine-2-amine (16a)

[0437] The synthesis method refers to the synthesis of N,N-(di-tert-butyloxycarbonyl)-6-chloro-3-methylthiopyridine-2-amine, with a yield of 91%.

[0438] 1H NMR (400MHz, CDCl3) δ8.76(s,1H),8.44(s,1H),3.14s,3H),2.63(s,3H),1.52(s,9H),1.44(s,9H).

[0439] MS m / z[M+H] + :464.

[0440] Step 2: Synthesis of N,N-(di-tert-butyloxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-hydroxypyridine-2-amine (16b)

[0441] The synthesis method refers to the synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, with a yield of 96%.

[0442] 1H NMR (400MHz, CDCl3) δ8.38(s,1H),7.83(s,1H),3.16(s,3H),2.70(s,3H),1.53(s,9H),1.44(s,9H).

[0443] MS m / z[M+H]+ :402.

[0444] Step 3: Synthesis of 3-(N,S-dimethylsulfoximino)-5-(3-methoxypropoxy)pyridine-2-amine (16c)

[0445] To a solution of N,N-(di-tert-butyloxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-hydroxypyridine-2-amine (16b) (500 mg, 1.25 mmol) in anhydrous DMF (10 mL) was added anhydrous potassium carbonate (1.04 g, 7.5 mmol). After stirring at room temperature for 10 minutes, 1-bromo-3-methoxypropane (230 mg, 1.5 mmol) was added to the reaction mixture and stirred at 120°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude yellow oil. The crude yellow oil was dissolved in dichloromethane (4 mL), and a 4M solution of hydrogen chloride in dioxane (4 mL) was added at 0°C. The mixture was warmed to room temperature and stirred for 1 hour. The solvent was concentrated to dryness, diluted with water, and saturated sodium bicarbonate was added to adjust the pH to 8-9. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the product was separated by flash chromatography (methanol / dichloromethane = 3–5%) to afford 3-(N,S-dimethylsulfoximino)-5-(3-methoxypropoxy)pyridine-2-amine (16c) (202 mg, yellow solid) in a 59% yield.

[0446] 1H NMR (400MHz, DMSO-d6) δ8.03(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).

[0447] MS m / z[M+H] + :274.

[0448] Step 4: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-(3-methoxypropoxy)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (16d)

[0449] The synthesis method refers to the synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, with a yield of 39%.

[0450] MS m / z[M+H]+ :443.

[0451] Step 5: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-(3-methoxypropoxy)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (16)

[0452] The synthesis method refers to the synthesis of 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, with a yield of 58%.

[0453] 1H NMR(400MHz,DMSO-d6)δ11.65(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).

[0454] MS m / z[M+H] + :492.

[0455] Example 17: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-(2-(epoxybutane-3-yl)ethoxy)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0456] Steps 1, 2, and 3: Synthesis of 3-(N,S-dimethylsulfoximino)-5-(2-(epoxybutane-3-yl)ethoxy)pyridine-2-amine (17c)

[0457] N,N-(di-tert-butyloxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-hydroxypyridine-2-amine (16b) (300 mg, 0.748 mmol), 3-hydroxyethyloxetane (76 mg, 0.748 mmol), and triphenylphosphine (393 mg, 1.5 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL). DIAD (303 mg, 1.5 mmol) was added under a nitrogen atmosphere and allowed to react at room temperature for 2 hours. The reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, flash chromatography (methanol / dichloromethane = 4–5%) was used to obtain crude N,N-(di-tert-butyloxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-(2-(oxiran-3-yl)ethoxy)pyridine-2-amine (17a) (954 mg).

[0458] The crude N,N-(di-tert-butyloxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-(2-(epoxybutane-3-yl)ethoxy)pyridine-2-amine (17a) was dissolved in dichloromethane (10 mL), and a 4N HCl solution in dioxane (10 mL) was added. The mixture was reacted at room temperature for 30 minutes and concentrated to give the crude 4-((6-amino-5-(N,S-dimethylsulfoximino)pyridin-3-yl)-oxy)-2-(chloromethyl)-1-ol (17b).

[0459] The crude product of 4-((6-amino-5-(N,S-dimethylsulfoximino)pyridin-3-yl)-oxy)-2-(chloromethyl)-1-ol (17b) was dissolved in ethanol (10 mL) and potassium hydroxide (210 mg, 3.74 mmol) was added. The mixture was refluxed for 4 hours and the reaction was complete after LCMS analysis. The reaction solution was cooled to room temperature, the ethanol was dried by spin drying, and the reaction was quenched by water. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. After flash separation (methanol / dichloromethane = 3-10%), 3-(N,S-dimethylsulfoximino)-5-(2-(butylene oxide-3-yl)ethoxy)pyridine-2-amine (17c) (62 mg, yellow solid) was obtained with a three-step yield of 29%.

[0460] 1H NMR (400MHz, CDCl3) δ7.99(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).

[0461] MS m / z[M+H] + :286.

[0462] Step 4: Synthesis of 6-(chloro-4-((3-(N,S-dimethylsulfoximino)-5-(2-(epoxybutane-3-yl)ethoxy)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (17d)

[0463] The synthesis method refers to the synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, with a yield of 18%.

[0464] MS m / z[M+H] + :455.

[0465] Step 5: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-(2-(epoxybutane-3-yl)ethoxy)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (17)

[0466] The synthesis method refers to the synthesis of 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, with a yield of 60%.

[0467] 1H NMR (400MHz, DMSO-d6) δ11.64(s,1H),11.32(s,1H),9.16(s,1H),9.06(d,J=4.9 Hz,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).

[0468] MS m / z[M+H] + :504.

[0469] Example 18: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-(2-morpholinoethoxy)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

[0470] Step 1: Synthesis of 5-(2-bromoethoxy)-3-(N,S-dimethylsulfoximino)pyridine-2-amine (18a)

[0471] N,N-(di-tert-butyloxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-hydroxypyridine-2-amine (16b) (400 mg, 1.0 mmol) was dissolved in acetonitrile (20 mL). Anhydrous potassium carbonate (688 mg, 5.0 mmol) and 1,3-dibromoethane (1.87 g, 10.0 mmol) were added and stirred at 80°C for 45 minutes. The reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with acetonitrile. The filtrate was concentrated and separated by column chromatography (ethyl acetate / petroleum ether = 10–65%) to afford 5-(2-bromoethoxy)-3-(N,S-dimethylsulfoximino)pyridine-2-amine (18a) (462 mg, colorless oil) in a 91% yield.

[0472] 1H NMR (400MHz, CDCl3) δ8.40(d,J=2.9Hz,1H),7.83(d,J=2.5Hz,1H),4.42(t,J=5.9H z,2H),3.69(t,J=5.9Hz,2H),3.15(s,3H),2.62(s,3H),1.51(s,9H),1.43(s,9H).

[0473] MS m / z[M+H] + :508.

[0474] Step 2: Synthesis of N,N-(di-tert-butyloxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-(2-morpholinoethoxy)pyridine-2-amine (18b)

[0475] 5-(2-Bromoethoxy)-3-(N,S-dimethylsulfoximino)pyridine-2-amine (18a) (300 mg, 0.59 mmol) was dissolved in DMF (4 mL), and anhydrous potassium carbonate (245 mg, 1.77 mmol) and morpholine (154 mg, 1.77 mmol) were added. The mixture was stirred at 80°C for 1 hour. The reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate. The filtrate was concentrated and separated by column chromatography (methanol / dichloromethane = 0–6%) to obtain N,N-(di-tert-butyloxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-(2-morpholinoethoxy)pyridine-2-amine (18b) (273 mg, colorless oil) in a 90% yield.

[0476] MS m / z[M+H] + :515.

[0477] Step 3: Synthesis of 3-(N,S-dimethylsulfoximino)-5-(2-morpholinoethoxy)pyridine-2-amine (18c)

[0478] To a solution of N,N-(di-tert-butyloxycarbonyl)-3-(N,S-dimethylsulfoximino)-5-(2-morpholinoethoxy)pyridine-2-amine (18b) (287 mg, 0.558 mmol) in dichloromethane (5 mL) was slowly added dropwise a 4M solution of hydrogen chloride in dioxane (2.5 mL) at 0°C. After the addition, the mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate was added to the reaction solution to adjust the pH to 8-9, the solvent was evaporated, and the mixture was separated by column chromatography (methanol / dichloromethane = 0-9%) to obtain 3-(N,S-dimethylsulfoximino)-5-(2-morpholinoethoxy)pyridine-2-amine (18c) (156 mg, light yellow solid) in an 89% yield.

[0479] MS m / z[M+H] + :315.

[0480] 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)

[0481] The synthesis method refers to the synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, with a yield of 41%.

[0482] 1H NMR (400MHz, CDCl3) δ12.21(s,1H),8.83(s,1H),8.27(d,J=3.0Hz,1H),8.21(s,1H),7.91(d,J=3.0Hz,1 H),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).

[0483] MS m / z[M+H] + :487.

[0484] 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)

[0485] The synthesis method refers to the synthesis of 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, with a yield of 28%.

[0486] 1H NMR (400MHz, DMSO-d6) δ11.65(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),4.27–4.1 8(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).

[0487] MS m / z[M+H] + :536.

[0488] Example 19: Preparation of 4-((5-(3-cyanopropoxy)-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide

[0489] Step 1: Synthesis of 6-amino-5-(N,S-dimethylsulfoximino)-3-hydroxypyridine (19a)

[0490] The synthesis method refers to the synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, with a yield of 63%.

[0491] 1H NMR (400MHz, DMSO-d6) δ9.29(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).

[0492] MS m / z[M+H] + :202.

[0493] Step 2: Synthesis of 4-((6-amino-5-(N,S-dimethylsulfoximino)pyridin-3-yl)oxybutanenitrile (19b)

[0494] To a solution of 6-amino-5-(N,S-dimethylsulfoximino)-3-hydroxypyridine (19a) (195 mg, 0.968 mmol) in DMF (4 mL) was added 4-bromobutyronitrile (172 mg, 1.16 mmol) and anhydrous potassium carbonate (535 mg, 3.87 mmol), and the mixture was heated to 40°C and stirred for 30 minutes. The reaction solution was cooled to room temperature and filtered, washed 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%.

[0495] 1 H NMR(400MHz, DMSO-d6)δ8.06(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).

[0496] MS m / z[M+H] + :269.

[0497] 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)

[0498] The synthesis method refers to the synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, with a yield of 49%.

[0499] 1H NMR (400MHz, CDCl3) δ12.23(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).

[0500] MS m / z[M+H] + :441.

[0501] Step 4: Synthesis of 4-((5-(3-cyanopropoxy)-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (19)

[0502] The synthesis method refers to the synthesis of 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, with a yield of 28%.

[0503] 1H NMR (400MHz, DMSO-d6) δ11.67(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).

[0504] MS m / z[M+H] + :490.

[0505] Example 20: Preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-((2-methoxyethyl)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0506] Step 1: Synthesis of (6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)pyridin-3-yl)boronic acid (20a)

[0507] 4-((5-Bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide (8b) (140 mg, 0.324 mmol), pinacol diboron (107 mg, 0.421 mmol), Pd(dppf)Cl2 (24 mg, 0.032 mmol), and anhydrous potassium acetate (92 mg, 0.972 mmol) were dissolved in dioxane (4 mL) and stirred at 105°C for 1 hour under a nitrogen atmosphere. After cooling to room temperature, 30% aqueous hydrogen peroxide (103 mg, 0.909 mmol) was added to the reaction mixture and stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was slurried with ethyl acetate to give (6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(N,S-dimethylsulfoximino)pyridin-3-yl)boronic acid (20a) (108 mg, gray solid) in a yield of 83%.

[0508] MS m / z[M+H] + :399.

[0509] Step 2: Synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-((2-methoxyethyl)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (20b)

[0510] To a solution 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) in dichloromethane (2 mL) were added copper acetate monohydrate (10 mg, 0.063 mmol), 4A molecular sieves (20 mg), and 2-methoxyethylamine (19 mg, 0.252 mmol) in sequence. The mixture was stirred at 40°C overnight under an oxygen atmosphere. The reaction mixture was concentrated and separated by plate chromatography (methanol:dichloromethane = 1:10) to afford 6-chloro-4-((3-(N,S-dimethylsulfoximino)-5-((2-methoxyethyl)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (20b) (5 mg, yellow solid) in a 9% yield.

[0511] MS m / z[M+H] + :428.

[0512] Step 3: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-5-((2-methoxyethyl)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (20)

[0513] The synthesis method refers to the synthesis of 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, with a yield of 45%.

[0514] 1H NMR (400MHz, DMSO-d6) δ11.37(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).

[0515] MS m / z[M+H] + :477.

[0516] Example 21: Preparation of 4-((5-bromo-3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide

[0517] 6-(Cyclopropylcarboxamido)-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). A solution of NBS (4.3 mg, 0.024 mmol) in acetonitrile (0.5 mL) was added at 0°C and stirred at 0°C for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, 21 (6 mg, yellow solid) was obtained with a yield of 50%.

[0518] 1H NMR(400MHz,DMSO-d6)δ11.95(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).

[0519] MS m / z[M+H] + :496.

[0520] Example 22: Preparation of 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-fluoropyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide

[0521] 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), and Selectfluor (284 mg, 0.802 mmol) was added at 0°C, and stirred at 35°C for 1 hour and at 50°C for 1 hour. DMF was evaporated to dryness under reduced pressure, separated by plate chromatography (methanol:dichloromethane = 1:15), and then prepared by prep-HPLC to obtain 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-fluoropyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (22) (12 mg, white solid) in a yield of 7%.

[0522] 1H NMR (400MHz, DMSO-d6) δ11.48(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).

[0523] MS m / z[M+H] + :437.

[0524] Example 23: Preparation of 4-(6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide

[0525] 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (7) (9 mg, 0.022 mmol) was dissolved in anhydrous DMF (1 mL). NCS (3.5 mg, 0.024 mmol) was added under ice-cooling and the mixture was reacted at 60°C for 3 hours. The reaction solution was cooled to room temperature and quenched with saturated sodium bicarbonate (20 mL) and water (20 mL). The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, prep-HPLC preparation was performed to obtain 4-(6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (23) (4 mg, white solid) in a yield of 41%.

[0526] 1H NMR (400MHz, DMSO-d6) δ11.59(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).

[0527] MS m / z[M+H] + :453.

[0528] Example 24: Preparation of 4-((6-amino-5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide

[0529] 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (7) (15 mg, 0.0359 mmol) was dissolved in dichloromethane (1 mL), and NBS (6.3 mg, 0.0359 mmol) was added at 0°C. The mixture was stirred at 0°C for 3 hours. After concentration, flash separation (methanol / dichloromethane = 0–5.5%) was performed to give 4-((6-amino-5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (24) (15 mg, yellow solid) in a 44% yield.

[0530] 1H NMR (400MHz, DMSO-d6) δ11.60(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).

[0531] MS m / z[M+H] + :497.

[0532] Example 25: Preparation of 4-(6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide

[0533] Step 1: Synthesis of 6-chloro-4-((6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (25a)

[0534] To a solution of 6-chloro-3-(N,S-dimethylsulfoximino)pyridine-2-amine (6f) (4.9 g, 22.37 mmol) in tetrahydrofuran (120 mL) was added sodium hydride (2.7 g, 67.1 mmol) in portions. The mixture was stirred for 15 minutes, followed by the addition of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (2a) (5.6 g, 26.8 mmol). After the addition, the mixture was stirred at 65°C for 1 hour. The reaction was quenched by the addition of ammonium chloride (80 mL) and water (40 mL). The mixture was extracted with dichloromethane (300 mL), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was concentrated, slurried with methyl tert-butyl ether, filtered, and the filter cake was rinsed with methyl tert-butyl ether. After drying, 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) was obtained with a yield of 77%.

[0535] 1H NMR (400MHz, DMSO-d6) δ12.22(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).

[0536] MS m / z[M+H] + :393.

[0537] 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)

[0538] The synthesis method refers to the synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, with a yield of 82%.

[0539] 1 H NMR (400MHz, DMSO-d6) δ11.95(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).

[0540] MS m / z[M+H] + :538.

[0541] 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)

[0542] The synthesis method was based on the synthesis of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, and the crude product was directly used in the next reaction without isolation.

[0543] MS m / z[M+H] + :586.

[0544] Step 4: Synthesis of 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (25d)

[0545] The synthesis method refers to the synthesis of 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide, and the two-step yield is 63%.

[0546] 1H NMR (400MHz, DMSO-d6) δ11.55(s,1H),11.32(s,1H),9.49(s,1H),8.99(s,1H),7.73(d,J=8.5Hz,1H ),6.56(s,2H),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).

[0547] MS m / z[M+H] + :422.

[0548] Step 5: Synthesis of 4-(6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (25)

[0549] The synthesis method refers to the synthesis of 4-(6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide, with a yield of 50%.

[0550] 1H NMR(400MHz,DMSO-d6)δ11.61(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).

[0551] MS m / z[M+H] + :456.

[0552] Example 26: Preparation of 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-methylpyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide

[0553] 4-((6-amino-5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (24) (160 mg, 0.322 mmol) was dissolved in dioxane (4 mL), and tetrakistriphenylphosphine palladium (110 mg, 0.096 mmol), anhydrous potassium carbonate (230 mg, 1.66 mmol) and methylboric acid (496 mg, 1.66 mmol) were added, and the reaction was carried out under a nitrogen atmosphere in a microwave (120 ° C, 120 W) for 1 hour. After the reaction solution was cooled to room temperature, dichloromethane was added, stirred, and then filtered. The filter cake was rinsed with dichloromethane. The filtrate was concentrated and flash separated (methanol / dichloromethane = 1:20) to give 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-methylpyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (26) (89 mg, yellow solid) in a yield of 64%.

[0554] 1H NMR (400MHz, DMSO-d6) δ11.51(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).

[0555] MS m / z[M+H] + :433.

[0556] Example 27: Preparation of 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-methoxypyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide

[0557] Step 1: Synthesis of 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (27a)

[0558] To a suspension of 4-((6-amino-5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (24) (100 mg, 0.20 mmol) in toluene (3 mL) were added pinacol diboron (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 the mixture was reacted at 100 ° C for 1 hour under nitrogen atmosphere. Pd(PPh)2Cl2 (28 mg, 0.04 mmol, 0 .2eq) and continued the reaction 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 stirred at room temperature for 30 minutes. Water (20 mL) was added to quench the reaction, and dichloromethane was added to dilute the reaction solution. The solution was filtered with suction, and the filter cake was rinsed with dichloromethane. The filter cake was separated by Flash chromatography (methanol / dichloromethane = 1:10) to obtain 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (27a) (30 mg, brown solid) in a yield of 28%.

[0559] 1 H NMR (400MHz, DMSO-d6) δ11.27(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).

[0560] MS m / z[M+H] + :435.

[0561] Step 2: Synthesis of 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-methoxypyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (27)

[0562] 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (27a) (10 mg, 0.023 mmol) was dissolved in DMF (0.6 mL), potassium carbonate (5 mg, 0.034 mmol) and iodomethane (3.3 mg, 0.023 mmol) were added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was quenched with water (5 mL) and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, prep-HPLC was performed to obtain 4-((6-amino-3-(N,S-dimethylsulfoximino)-5-methoxypyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (27) (2.2 mg, white solid) in a yield of 22%.

[0563] 1 H NMR (400MHz, DMSO-d6) δ11.35(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).

[0564] MS m / z[M+H] + :449.

[0565] 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

[0566] Step 1: Synthesis of (R)-N-(6-c-chloro-3-(methylsulfinyl)pyridin-2-yl)trimethylacetamide (28b)

[0567] The synthesis of (1R,2S)-1-(3,5-dichloro-2-hydroxybenzylidene)amino-2-indanol (28a) was carried out according to Comptes Rendus Chimie, 2014, 17(5), 403-412.

[0568] (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 hour. The methanol was removed under reduced pressure, and the product was slurried with petroleum ether, filtered, and dried to obtain (1R,2S)-1-(3,5-dichloro-2-hydroxybenzylidene)amino-2-indanol (28a) (131 g, yellow solid) in a 99% yield.

[0569] 1H NMR (400MHz, DMSO-d6) δ14.79(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).

[0570] MS m / z[M+H] + :322.

[0571] (1R,2S)-1-(3,5-Dichloro-2-hydroxybenzylidene)amino-2-indanol (28a) (4.62 g, 14.4 mmol) and acetylacetonate (2.38 g, 9.0 mmol) were added to a mixture of toluene and dichloromethane (10:1, 930 mL) and stirred for 20 minutes until completely dissolved. N-(6-chloro-3-(methylthio)pyridin-2-yl)trimethylacetamide (6a) (46.4 g, 179.8 mmol) was then added and stirred for 20 minutes. Hydrogen peroxide (26.5 g, 234.0 mmol) was added dropwise under ice-cooling. After addition, the mixture was stirred at room temperature for 2 hours. An additional amount of hydrogen peroxide (3.6 mL, 36.0 mmol) was added and the reaction continued for 1 hour. Saturated sodium sulfite solution (150 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the product was slurried with a mixed solution of isopropanol (40 ml) and petroleum ether (280 mL), filtered, and the filtrate was separated by flash chromatography (ethyl acetate / petroleum ether = 1:1) to give (R)-N-(6-chloro-3-(methylsulfinyl)pyridin-2-yl)trimethylacetamide (28b) (51 g, light yellow solid) with an ee value of 96.5% and a yield of 72%.

[0572] 1H NMR (400MHz, CDCl3) δ8.59 (s, 1H), 8.11 (d, J = 8.2Hz, 1H), 7.27 (d, J = 8.2Hz, 1H), 2.94 (s, 3H), 1.26 (s, 9H).

[0573] MS m / z[M+H] + :275.

[0574] Step 2: Synthesis of (R)-6-chloro-3-(methylsulfinyl)-pyridine-2-amine (28c)

[0575] (R)-N-(6-chloro-3-(methylsulfinyl)pyridin-2-yl)trimethylacetamide (28b) (50.2 g, 0.183 mol) was added to a 3N aqueous hydrochloric acid solution (610 mL, 1.832 mol) and stirred at 50°C for 5 hours. Under ice-cooling, the pH was adjusted to 9-10 with a 40% aqueous potassium carbonate solution. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the mixture was slurried with a mixture of dichloromethane and petroleum ether (2:3, 100 mL), 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%.

[0576] 1H NMR (400MHz, CDCl3) δ7.42 (d, J = 7.8Hz, 1H), 6.69 (d, J = 7.8Hz, 1H), 6.07 (s, 2H), 2.89 (s, 3H).

[0577] MS m / z[M+H] + :191.

[0578] Step 3: Synthesis of (R)-6-chloro-3-(S-methylsulfoximino)pyridine-2-amine (28d)

[0579] The synthesis method is based on the synthesis of 3-(S-methylsulfoximino)-2-nitropyridine, with a yield of 70%.

[0580] 1H NMR (400MHz, CDCl3) δ7.98 (d, J = 8.1Hz, 1H), 6.76 (d, J = 8.1Hz, 1H), 6.35 (s, 2H), 3.11 (s, 3H), 2.46 (s, 1H).

[0581] MS m / z[M+H] + :206.

[0582] Step 4: Synthesis of (R)-6-chloro-3-(N,S-dimethylsulfoximino)pyridine-2-amine (28e)

[0583] (R)-6-chloro-3-(S-methylsulfoximino)pyridine-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) were dissolved in a mixture of anhydrous DMF (69 mL) and pyridine (46 mL) and reacted at 80°C under an oxygen atmosphere for 4 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate. The filtrate was added with water (200 mL) and aqueous ammonia (60 mL) and extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the product was separated by column chromatography (ethyl acetate / petroleum ether = 40–50%) to afford (R)-6-chloro-3-(N,S-dimethylsulfoximino)pyridine-2-amine (28e) (8.69 g, light yellow solid) with an ee of 98.2% and a yield of 70%.

[0584] 1H NMR (400MHz, CDCl3) δ7.91 (d, J = 8.0Hz, 1H), 6.78 (d, J = 8.1Hz, 1H), 6.26 (s, 2H), 3.07 (s, 3H), 2.68 (s, 3H).

[0585] MS m / z[M+H] + :220.

[0586] 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)

[0587] The synthesis method refers to the synthesis of 6-chloro-4-((6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, with a yield of 79%.

[0588] 1H NMR (400MHz, DMSO-d6) δ12.21(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).

[0589] MS m / z[M+H] + :393.

[0590] 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 (28 g)

[0591] The synthesis method refers to the synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, with a yield of 68%.

[0592] MS m / z[M+H] + :538.

[0593] 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)

[0594] The synthesis method refers to the synthesis of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, with a yield of 91%.

[0595] MS m / z[M+H] + :586.

[0596] Step 8: Synthesis of (R)-4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (28i)

[0597] The synthesis method refers to the synthesis of 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide, with a yield of 69%.

[0598] 1H NMR (400MHz, DMSO-d6) δ11.55(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).

[0599] MS m / z[M+H] + :422.

[0600] Step 9: Synthesis of (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarbonyl)-N-(methyl-d3)pyridazine-3-carboxamide (28)

[0601] The synthesis method refers to the synthesis of 4-(6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide, with an ee value of 98.2% and a yield of 50%.

[0602] 1H NMR(400MHz,DMSO-d6)δ11.59(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).

[0603] MS m / z[M+H] + :456.

[0604] The asymmetric synthesis of the chiral fragment (R)-6-chloro-3-(methylsulfinyl)-pyridine-2-amine (28c) can also be achieved by the following route:

[0605] Step 1: Synthesis of (R)-3,6-dichloro-N-(1-(4-methoxyphenyl)ethyl)-2-pyridinecarboxamide (28j)

[0606] Dissolve 3,6-dichloro-2-pyridinecarboxylic acid (5 g, 26.04 mmol) in anhydrous DMF (20 mL). Add N,N-carbonyldiimidazole (4.64 g, 28.65 mmol) portionwise and stir at room temperature for 20 minutes. Cool the reaction mixture to 0°C and add (R)-(+)-1-(4-methoxyphenyl)ethylamine (4.33 g, 28.65 mmol) dropwise, maintaining the internal temperature below 10°C. Stir at room temperature for 1.5 hours after the addition is complete. Quench the reaction with water (60 mL) and continue stirring for 1 hour. Filter the mixture and rinse the filter cake with distilled water. Dissolve the filter cake in dichloromethane, wash with 1% HCl, and dry over anhydrous sodium sulfate. After concentration, (R)-3,6-dichloro-N-(1-(4-methoxyphenyl)ethyl)-2-pyridinecarboxamide (28j) (7.77 g, white solid) was obtained in a yield of 92%.

[0607] 1H NMR(400MHz, CDCl3)δ7.80(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).

[0608] MS m / z[M+H] + :325.

[0609] Step 2: Synthesis of (R)-6-chloro-N-(1-(4-methoxyphenyl)ethyl)-3-(methylthio)-2-pyridinecarboxamide (28k)

[0610] (R)-3,6-Dichloro-N-(1-(4-methoxyphenyl)ethyl)-2-pyridinecarboxamide (28j) (7.2 g, 22.15 mmol) was dissolved in DMF (35 mL). 20% aqueous sodium thiomethoxide solution (11.6 g, 33.23 mmol) was slowly added dropwise at room temperature. Stirring was continued at room temperature for 1 hour after the addition was complete. The reaction was quenched by adding water (100 mL). The mixture was stirred at room temperature for 2 hours, filtered, and the filter cake was rinsed with distilled water. The filter cake was dissolved in dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was separated by column chromatography (ethyl acetate:petroleum ether = 1:1) to obtain (R)-6-chloro-N-(1-(4-methoxyphenyl)ethyl)-3-(methylthio)-2-pyridinecarboxamide (28k) (4.84 g, white solid) in a 65% yield.

[0611] 1H NMR(400MHz, CDCl3) δ8.03(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).

[0612] MS m / z[M+H] + :337.

[0613] Step 3: Synthesis of 6-chloro-N-((R)-1-(4-methoxyphenyl)ethyl)-3-((R)-methylsulfinyl)-2-pyridinecarboxamide (281)

[0614] The synthesis method refers to the synthesis of (R)-N-(6-chloro-3-(methylsulfinyl)pyridin-2-yl)trimethylacetamide, and the post-treatment is carried out by recrystallization using ethanol, with a yield of 64% and a de value of 99.9%.

[0615] 1H NMR (400MHz, CDCl3) δ8.55(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).

[0616] MS m / z[M+H] + :353.

[0617] Step 4: Synthesis of (R)-6-chloro-3-(methylsulfinyl)-2-pyridinecarboxamide (28m)

[0618] 6-Chloro-N-((R)-1-(4-methoxyphenyl)ethyl)-3-((R)-methylsulfinyl)-2-pyridinecarboxamide (28l) (6.0 g, 17.05 mmol) was dissolved in trifluoroacetic acid (20 mL) and stirred at 40 ° C for 1.5 hours. The solvent was evaporated under reduced pressure and diluted with dichloromethane (50 mL). The mixture was slowly added dropwise to a saturated sodium bicarbonate solution (100 mL), the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, the mixture was slurried with a mixed solution of dichloromethane / petroleum ether (1:10, 100 mL) and filtered to obtain (R)-6-chloro-3-(methylsulfinyl)-2-pyridinecarboxamide (28l) (3.4 g, white solid) with a yield of 92%.

[0619] 1H NMR (400MHz, CDCl3) δ8.65 (d, J = 8.3Hz, 1H), 7.81–6.76 (m, 2H), 6.03 (s, 1H), 2.92 (s, 3H).

[0620] MS m / z[M+H] + :219.

[0621] Step 5: Synthesis of (R)-6-chloro-3-(methylsulfinyl)-pyridine-2-amine (28c)

[0622] Dissolve (R)-6-chloro-3-(methylsulfinyl)-2-pyridinecarboxamide (28L) (55g, 0.252mol) in dioxane (250mL). Add 10% aqueous sodium hydroxide solution (250mL) precooled to 0°C. Add 7.5% aqueous sodium hypochlorite solution (180g, 0.378mol) dropwise at room temperature. Stir at 70°C for 1 hour. Cool the reaction mixture to room temperature and quench the reaction by adding saturated sodium sulfite solution (10mL) dropwise until the starch potassium iodide test paper does not change color. Dilute with saturated brine. Extract with ethyl acetate. Combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. After concentration, dichloromethane (100 mL) and petroleum ether (100 mL) were added to slurry, filtered and rinsed with petroleum ether, and dried to obtain (R)-6-chloro-3-(methylsulfinyl)-pyridine-2-amine (28c) (39.4 g, white solid) with a yield of 82%.

[0623] 1H NMR (400MHz, CDCl3) δ7.42 (d, J = 7.8Hz, 1H), 6.69 (d, J = 7.8Hz, 1H), 6.07 (s, 2H), 2.89 (s, 3H).

[0624] MS m / z[M+H] + :191.

[0625] 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

[0626] Step 1: Synthesis of 6-chloro-3-(S-methyl-N-(4-nitrobenzenesulfonyl)-sulfoximino)pyridine-2-amine (29a)

[0627] Dissolve N,N-(di-tert-butyloxycarbonyl)-6-chloro-3-(S-methylsulfoximino)pyridine-2-amine (6d) (2.05 g, 5.06 mmol) in anhydrous pyridine (30 mL). Slowly add p-nitrobenzenesulfonyl chloride (1.34 g, 6.07 mmol) at room temperature and continue stirring for 2 hours. Add water (60 mL) to quench the reaction, extract with ethyl acetate, and combine the organic phases, wash with 1N hydrochloric acid and saturated brine, respectively, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product (yellow solid, 3.3 g).

[0628] The crude product was dissolved in dichloromethane (10 mL), and a 4M solution of hydrogen chloride in dioxane (10 mL) was added under an ice-water bath. The mixture was stirred at room temperature for 1 hour. After concentration, the mixture was diluted with water, the pH was adjusted to 8-9 with saturated potassium carbonate solution, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and flash separated (ethyl acetate: petroleum ether = 1:1) to obtain 6-chloro-3-(S-methyl-N-(4-nitrobenzenesulfonyl)-sulfoximino)pyridine-2-amine (29a) (1.68 g, yellow solid) in an 85% yield.

[0629] 1H NMR (400MHz, DMSO-d6) δ8.34(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).

[0630] MS m / z[M+H] + :391.

[0631] 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)

[0632] The synthesis method refers to the synthesis of 6-chloro-4-((6-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, with a yield of 50%.

[0633] 1H NMR (400MHz, DMSO-d6) δ12.29(s,1H),9.50(s,1H),8.71(s,1H),8.38(d,J=8.4Hz,1 H),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).

[0634] MS m / z[M+H] + :563.

[0635] 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)

[0636] The synthesis method refers to the synthesis of 6-chloro-4-((3-(N,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, except that dioxane was used as the solvent instead of DMF, the reaction temperature was 110°C, and the yield was 25%.

[0637] 1H NMR (400MHz, DMSO-d6) δ11.89(s,1H),9.40(s,1H),8.27(s,1H),8.21(d,J=8.5Hz,1H),8.03(d ,J=8.4Hz,2H),7.68(d,J=8.4Hz,2H),7.59–7.45(m,10H),6.98(d,J=8.5Hz,1H),3.76(s,3H).

[0638] MS m / z[M+H] + :708.

[0639] 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)

[0640] The synthesis method refers to the synthesis of 6-(cyclopropanecarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide. After the reaction is completed, no separation is performed and the crude product is directly used for the next step.

[0641] MS m / z[M+H] + :757.

[0642] Step 5: Synthesis of 4-((6-amino-3-(S-methyl-N-(4-nitrobenzenesulfonyl)-sulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (29e)

[0643] The synthesis method was based on the synthesis of 4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide, using 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, with a two-step yield of 43%.

[0644] MS m / z[M+H] + :593.

[0645] Step 6: Synthesis of (R)-4-((6-amino-5-chloro-3-(S-methylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (29)

[0646] To a solution of 4-((6-amino-3-(S-methyl-N-(4-nitrobenzenesulfonyl)-sulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (29e) (1.1 g, 1.86 mmol) in anhydrous DMF (20 mL) was added NCS (248 mg, 1.86 mmol) and stirred at 60°C for 1 hour. After cooling to room temperature, the reaction mixture was quenched by adding saturated aqueous sodium sulfite solution (10 mL) and water (80 mL). The mixture was stirred for 10 minutes and then filtered. The filter cake was rinsed with water, dried, slurried with dichloromethane, and filtered to obtain the crude chloro product (380 mg, khaki solid).

[0647] To a solution of p-methoxythiophenol (2.18 g, 15.6 mmol) in acetonitrile (5 mL) was added a solution of potassium hydroxide (851 mg, 15.2 mmol) in water (1 mL). After stirring for 5 minutes, the crude chloroformate (380 mg) was added and stirring continued at room temperature for 1 hour. The reaction was quenched by adding saturated potassium carbonate solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. After concentration, flash separation (methanol:dichloromethane = 1:10) was performed to obtain the racemic compound 4-((6-amino-5-chloro-3-(S-methylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (250 mg, yellow solid) in a 30% yield. The racemic compound was subjected to SFC chiral separation 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).

[0648] 29f:1H NMR(400MHz,DMSO-d6)δ11.70(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).

[0649] MS m / z[M+H] + :442.

[0650] 29:1H NMR(400MHz,DMSO-d6)δ11.71(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).

[0651] MS m / z[M+H] + :442.

[0652] Example 30: Preparation of (R)-4-((6-amino-5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarbonyl)-N-(methyl-d3)pyridazine-3-carboxamide (30)

[0653] (R)-4-((6-amino-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide (28i) (7.95 g, 18.9 mmol) was dissolved in NMP (48 mL). NBS (3.38 g, 19 mmol) was added portionwise under ice-cooling and stirred for half an hour under ice-cooling. After the reaction, a saturated aqueous solution of Na2SO3 (6.5 mL) was added under ice-cooling and stirred for 10 minutes. Ice water (500 mL) was added portionwise to precipitate a solid and stirred for 1 hour. The mixture was filtered and the filter cake was rinsed with water (50 mL). The filter cake was dissolved in DCM / MeOH (10 / 1, 300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was slurried with EtOH / DCM (1 / 10, 30 mL) to obtain 5.2 g of an off-white solid. The mother liquor was mixed with silica gel and column chromatography (methanol / dichloromethane = 2-5%) yielded 4.3 g of a white solid. The two batches of solid were combined, EA (97 mL) was added, and the mixture was heated in an oil bath at 75°C for half an hour. The mixture was then slowly cooled to room temperature and filtered to yield 8.15 g of an off-white solid. The yield was 86%.

[0654] 1H NMR(400MHz,DMSO-d6)δ11.60(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).

[0655] MS m / z[M+H] + :500.

[0656] Example 31: Preparation of 6-(cyclopropylcarboxamido)-4-((5-(N,S-dimethylsulfoximino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-N-methylpyridazine-3-carboxamide

[0657] Step 1: Synthesis of 6-(cyclopropylcarboxamido)-4-((5-(N,S-dimethylsulfoximino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-N-methylpyridazine-3-carboxamide (31)

[0658] The synthesis of 2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane is described in WO 2012 / 010538, 2012, A2.

[0659] 4-((6-amino-5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (24) (12 mg, 0.0241 mmol), 2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.7 mg, 0.0290 mmol), Pd(dppf)Cl2 (1.8 mg, 0.00241 mmol), and lithium hydroxide monohydrate (3.0 mg, 0.0723 mmol) were dissolved in anhydrous DMF (0.5 mL) and stirred at 70°C for 1 hour under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and 25% aqueous hydrochloric acid (53 mg) was added and reacted at 50°C for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration and flash separation (methanol / dichloromethane = 4–7%), prep-HPLC was used to obtain 6-(cyclopropylcarboxamido)-4-((5-(N,S-dimethylsulfoximino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-N-methylpyridazine-3-carboxamide (31) (1.2 mg, yellow solid) in an 11% yield.

[0660] 1H NMR (400MHz, DMSO-d6) δ11.93(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).

[0661] MS m / z[M+H] + :443.

[0662] 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

[0663] 6-(Cyclopropylcarboxamido)-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 prep-HPLC to obtain 4-((3-chloro-5-(N,S-dimethylsulfoximino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (32) (5.3 mg, light yellow solid) in a yield of 31%.

[0664] 1H NMR (400MHz, DMSO-d6) δ12.24(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),7.71(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).

[0665] MS m / z[M+H] + :477.

[0666] 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

[0667] 6-(Cyclopropylcarboxamido)-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), and NCS (14 mg, 0.104 mmol) was added at room temperature. The mixture was stirred at 80 °C for 1 hour, cooled to room temperature, and quenched with water. The mixture was extracted with ethyl acetate. The resulting product was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and flash separated (methanol / dichloromethane = 3-5%). Prep-HPLC was used to obtain 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, brown solid) in a yield of 4%.

[0668] 1H NMR(400MHz,DMSO-d6)δ13.29(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).

[0669] MS m / z[M+H] + :511.

[0670] 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

[0671] 6-(Cyclopropylcarboxamido)-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), and NBS (26.6 mg, 0.151 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, the solvent was dried by spin drying, and flash separation (methanol / dichloromethane = 2-5%) was performed to obtain 4-((3-bromo-5-(N,S-dimethylsulfoximino)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (34) (60 mg, yellow solid) in a yield of 76%.

[0672] 1H NMR (400MHz, DMSO-d6) δ12.29(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),7.73(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).

[0673] MS m / z[M+H] + :521.

[0674] Example 35: Preparation of (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarbonyl)-N-(methyl-d3)pyridazine-3-carboxamide oxalate

[0675] (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarbonyl)-N-(methyl-d3)pyridazine-3-carboxamide (28) (100 mg, 0.22 mmol) was dissolved in DCM / MeOH (9:1, 6 mL), and a methanol solution of oxalic acid dihydrate (27 mg, 0.22 mmol) (0.2 mL) was added and stirred at room temperature for 10 min. The solvent was evaporated under reduced pressure, and DCM / THF (1:1, 3 mL) was added. The precipitated solid was filtered, rinsed with DCM / THF (1:1, 1 mL), and rinsed with PE (3 mL). 72 mg of a light yellow solid was obtained. Yield: 56.7%.

[0676] 1 H NMR (400 MHz, DMSO-d 6)δ11.61(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).

[0677] Example 36: Preparation of (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarbonyl)-N-(methyl-d3)pyridazine-3-carboxamide hydrochloride

[0678] (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarbonyl)-N-(methyl-d3)pyridazine-3-carboxamide (28) (500 mg, 1.10 mmol) was added to MeCN (5 mL) to form a suspension. 37% HCl (271 mg, 2.75 mmol) was added dropwise at room temperature. The mixture was heated to reflux in an 85°C oil bath, and water (2 mL) was added dropwise to dissolve under reflux. The mixture was then stirred at room temperature for 1 hour. A solid precipitated and was filtered. The filter cake was rinsed with MeCN (1 mL x 2) and dried under reduced pressure at 50°C to obtain 336 mg of a yellow solid. The yield was 57.9%.

[0679] 1 H NMR (400 MHz, DMSO-d 6 )δ12.03(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).

[0680] Example 37: Preparation of (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarbonyl)-N-(methyl-d3)pyridazine-3-carboxamide sulfate

[0681] (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarbonyl)-N-(methyl-d3)pyridazine-3-carboxamide (28) (500 mg, 1.10 mmol) was added to THF (5 mL) to form a suspension. 20% H2SO4aq. (646 mg, 1.32 mmol) was added dropwise at room temperature. The mixture was placed in a 70°C oil bath and refluxed with water (0.5 mL). The mixture dissolved under reflux and then stirred at room temperature for 1 hour. A solid precipitated and was filtered. The filter cake was rinsed with THF (1 mL x 2) and dried under reduced pressure at 50°C to obtain 495 mg of a yellow solid. Y = 81.5%, HPLC: 99.0%

[0682] 1 H NMR (400 MHz, DMSO-d 6 )δ11.81(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).

[0683] 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

[0684] (R)-4-((6-amino-5-chloro-3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarbonyl)-N-(methyl-d3)pyridazine-3-carboxamide (28) (100 mg, 0.22 mmol) was dissolved in DCM / MeOH (9:1, 6 mL), and methanesulfonic acid (42 mg, 0.44 mmol) was added and stirred at room temperature for 10 min. The solvent was evaporated under reduced pressure, and DCM / THF (1:1, 3 mL) was added. The precipitated solid was filtered, rinsed with DCM / THF (1:1, 1 mL), and rinsed with PE (3 mL). 110 mg of a yellow solid was obtained. Yield: 77.4%.

[0685] 1 H NMR (400 MHz, DMSO-d 6)δ11.82(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).

[0686] Example 39: Preparation of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((3-(S-methyl-N-(methyl-d3)sulfoximino)pyridin-2-yl)amino)pyridazine-3-carboxamide

[0687] Synthesis Method: CD3I was used instead of MeI for preparation according to Example 1 and Example 2.

[0688] 1H NMR(400MHz,dmso)δ11.86(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=7.6Hz,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).

[0689] MS m / z[M+H] + :410.

[0690] 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

[0691] Step 1: Synthesis of (R)-6-chloro-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridine-2-amine (40a)

[0692] (R)-6-Chloro-3-(S-methylsulfoximino)pyridine-2-amine (28d) (29.7 g, 144.88 mmol) was dissolved in 600 mL of tetrahydrofuran, and NaI (2.18 g, 14.5 mmol) was added. Sodium tert-butoxide (13.91 g, 144.88 mmol) was added portionwise under a water bath. After stirring for 20 min, a solution of CD3I (21 g, 144.88 mmol) in tetrahydrofuran (50 mL) was added dropwise. After completion of the addition, the mixture was stirred at room temperature overnight. The reaction solution was dropped into a saturated ammonium chloride solution to quench the reaction solution, diluted with water, separated, the aqueous layer was extracted with ethyl acetate, the organic phases were combined, concentrated, ethyl acetate was added to dissolve, separated, the aqueous layer was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether: ethyl acetate = 2:1) to give (R)-6-chloro-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridine-2-amine (22.5 g, off-white solid) with a yield of 70%.

[0693] 1 H NMR (400MHz, DMSO-d6) δ7.84 (d, J = 8.0 Hz, 1H), 7.24 (s, 2H), 6.78 (d, J = 8.0 Hz 1H), 3.09 (s, 3H).

[0694] MS m / z[M+H] + :223.

[0695] Step 2: Synthesis of (R)-6-chloro-4-((6-chloro-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40b)

[0696] (R)-6-Chloro-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridine-2-amine (40a) (36.7 g, 0.165 mol) was dissolved in 1 L of tetrahydrofuran and cooled to 0-5°C under N2 protection. NaH (19.8 g, 60% w / w, 0.496 mol) was added portionwise and stirred for 25 min. 4,6-Dichloro-N-(methyl-d3)pyridazine-3-carboxamide (41.3 g, 0.198 mol) was added portionwise and stirred for 15 min. The temperature was then raised to 70°C and allowed to react for 2 h. Saturated ammonium chloride solution was added to quench the reaction under ice-cooling, the mixture was diluted with water, and extracted with ethyl acetate. The layers were separated, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, ethanol was added and the mixture was cold-beaten for 30 minutes, filtered, the filter cake was rinsed with ethanol, and dried to obtain (R)-6-chloro-4-((6-chloro-3-(S-methyl-N-(methyl-d3)sulfonyl imide)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40.25 g, 61.8%).

[0697] 1H NMR (400MHz, DMSO-d6) δ12.23(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).

[0698] MS m / z[M+H] + :395

[0699] Step 3: Synthesis of (R)-6-chloro-4-((6-((diphenylmethylene)amino)-3-(S-methyl-N-(methyl-d3)sulfonyl imide)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40c)

[0700] Under N2 atmosphere, Pd2(dba)3 (4.6 g, 0.005 mol), XantPhos (5.78 g, 0.01 mol), (R)-6-chloro-4-((6-chloro-3-(S-methyl-N-(methyl-d3)sulfonylimino)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40b) (40 g, 0.1 mol), K2CO3 (34.5 g, 0.25 mol), and diphenylimine (27.6 g, 0.15 mol) were added to DMAC (400 mL) and reacted at 130°C for 5 h. After cooling, the mixture was quenched by the addition of saturated ammonium chloride solution, diluted with water, dissolved in ethyl acetate, filtered through celite, and the filter cake rinsed with ethyl acetate. The liquids were separated, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and slurried with MTBE for 30 minutes, filtered, the filter cake was rinsed with MTBE, and dried to obtain (R)-6-chloro-4-((6-((diphenylmethylene)amino)-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (38 g, 69.5%).

[0701] 1 H NMR (400MHz, DMSO-d6) δ11.96(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).

[0702] MS m / z[M+H] + :540

[0703] Step 4: Synthesis of (R)-6-(cyclopropanecarboxamide)-4-((6-((diphenylmethylene)amino)-3-(S-methyl-N-(methyl-d3)sulfonyl imide)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40d)

[0704] Under N2 atmosphere, Pd2(dba)3 (238 mg, 0.26 mmol), XantPhos (300 mg, 0.52 mol), (R)-6-chloro-4-((6-((diphenylmethylene)amino)-3-(S-methyl-N-(methyl-d3)sulfonylimide)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 cyclopropaneamide (882 mg, 10.38 mmol) were added to xylene:DMAC = 10:1 (33 mL) and reacted at 130°C for 2 h. After cooling, the mixture was quenched by the addition of saturated ammonium chloride solution, diluted with water, dissolved in dichloromethane, filtered through celite, and the filter cake rinsed with dichloromethane. The liquids were separated, the aqueous phase was extracted with dichloromethane, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and beaten with petroleum ether for 10 minutes, filtered, the filter cake was rinsed with petroleum ether, and dried to obtain the crude product of (R)-6-(cyclopropanecarboxamide)-4-((6-((diphenylmethylene)amino)-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, which was directly used for the next reaction without separation.

[0705] MS m / z[M+H] + :589

[0706] Step 5: Synthesis of (R)-4-((6-amino-3-(S-methyl-N-(methyl-d3)sulfonyl imide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (40e)

[0707] The crude (R)-6-(cyclopropanecarboxamide)-4-((6-((diphenylmethylene)amino)-3-(S-methyl-N-(methyl-d3)sulfonyl imide)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40d) was dissolved in tetrahydrofuran (30 mL), and 12N HCl (0.6 mL) was added under ice cooling. The mixture was warmed to room temperature and stirred for 1.5 h. The mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed with water. The aqueous layers were combined, and 10% potassium carbonate solution was slowly added to adjust the pH to 9-10. Methanol: dichloromethane = 10:1 was added for extraction. The liquids were separated, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and heated to reflux with ethanol. The mixture was beaten in an ice bath for 20 minutes, filtered, and the filter cake was rinsed with ethanol and dried to obtain (R)-4-((6-amino-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (1.4 g, 65%).

[0708] 1 H NMR (400MHz, DMSO-d6) δ11.56(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).

[0709] MS m / z[M+H] + :425

[0710] Step 6: Synthesis of (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-d3)sulfonyl imide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (40)

[0711] (R)-4-((6-amino-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (40e) (1.4 g, 3.30 mmol) was dissolved in DMAC (14 mL), cooled in an ice bath under N2 protection (0-5°C), and 1,3-dichloro-5,5-dimethylhydantoin (683 mg, 3.47 mmol) was added portionwise and reacted for 15 min. The mixture was quenched with ice water and saturated sodium sulfite solution, filtered, and the filter cake was rinsed with water and dissolved in dichloromethane:methanol = 10:1. The liquids were separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Flash separation (methanol / dichloromethane = 3%) was performed to give (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (669 mg, off-white solid) in a yield of 44%.

[0712] 1 H NMR(400MHz,DMSO-d6)δ11.62(s,1H),11.37(s,1H),9.43(s,1H),9.04(s,1 H),7.79(s,1H),6.89(s,2H),3.13(s,3H),2.16-2.07(m,1H),0.87(m,4H).

[0713] MS m / z[M+H]+:459

[0714] Example 41: Preparation of (R)-4-((6-amino-5-bromo-3-(S-methyl-N-(methyl-d3)sulfonyl imide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide

[0715] (R)-4-((6-amino-3-(S-methyl-N-(methyl-d3)sulfonyl imide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (40e) (113 mg, 0.26 mmol) was dissolved in DMF (1.4 mL), cooled to 0-5°C in an ice bath under N2 protection, and NBS (50 mg, 0.28 mmol) was added and reacted for 30 min. The reaction mixture was quenched with saturated sodium sulfite solution, diluted with water, extracted with ethyl acetate, separated, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to Flash separation (methanol / dichloromethane = 3%) to give (R)-4-((6-amino-5-bromo-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (62 mg, light yellow solid) in a yield of 46%.

[0716] 1 H NMR (400MHz, DMSO-d6) δ11.62(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).

[0717] MS m / z[M+H] + :503

[0718] Example 42: Preparation of (R)-4-((6-amino-5-iodo-3-(S-methyl-N-(methyl-d3)sulfonyl imide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide

[0719] (R)-4-((6-amino-3-(S-methyl-N-(methyl-d3)sulfonyl imide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (40e) (2.1 g, 2.59 mmol) was dissolved in DMAC (6 mL), and NIS (759 mg, 3.41 mmol) was added portionwise and reacted at 50°C for 1 h. The reaction mixture was quenched with saturated sodium sulfite solution under ice bath, diluted with water, extracted with dichloromethane:methanol = 10:1, separated, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and flash separated (methanol / dichloromethane = 3%) to give (R)-4-((6-amino-5-iodo-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (912 mg, light yellow solid) in a yield of 64%.

[0720] 1 H NMR(400MHz,DMSO-d6)δ11.61(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).

[0721] MS m / z[M+H] + :551

[0722] 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

[0723] Under N2 atmosphere, (R)-4-((6-amino-5-iodo-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (42) (203 mg, 0.367 mmol) was dissolved in anhydrous 1.4-dioxane (4 mL), and cyclopropylboronic acid (63 mg, 0.734 mmol), Pd(PPh3)4 (81 mg, 0.07 mmol) and K2CO3 (127 mg, 0.92 mmol) were added, and the reaction was carried out under microwave (120 ° C, 120 W) for 2.5 h. After the reaction solution was cooled to room temperature, it was filtered through celite and the filter cake was rinsed with dichloromethane:methanol = 10:1. The filtrate was concentrated and flash separation (methanol / dichloromethane = 7%) was performed to give (R)-4-((6-amino-5-cyclopropyl-3-(S-methyl-N-(methyl-d3)sulfonyl imide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (32 mg, light yellow solid) in a yield of 18.7%.

[0724] 1 H NMR(400MHz,DMSO-d6)δ11.55(s,1H),11.32(s,1H),9.57(s,1H),8.99(s,1H),7.42(s,1H ),6.49(s,2H),3.05(s,3H),2.12(s,1H),1.66(s,1H),0.88(m,6H),0.51(d,J=4.4Hz,2H).

[0725] MS m / z[M+H] + :465

[0726] Example 44: Preparation of (R)-4-((6-amino-3-(S-methyl-N-(methyl-d3)sulfonyl imide)-5-vinylpyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide

[0727] Under N2 atmosphere, (R)-4-((6-amino-5-iodo-3-(S-methyl-N-(methyl-d3)sulfonylimide)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 ethylene trifluoroborate (50 mg, 0.37 mmol), Pd(PPh3)4 (46 mg, 0.04 mmol) and K2CO3 (52 mg, 0.37 mmol) were added, and the reaction was carried out under microwave (120°C, 120 W) for 1 h. After the reaction solution was cooled to room temperature, it was filtered through celite and the filter cake was rinsed with dichloromethane. The filtrate was concentrated and flash separated (methanol / dichloromethane = 3%) to give (R)-4-((6-amino-3-(S-methyl-N-(methyl-d3)sulfonyl imide)-5-vinylpyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (40 mg, light yellow solid) in a yield of 47%.

[0728] 1 H NMR (400MHz, DMSO-d6) δ11.68(s,1H),11.36(s,1H),9.67(s,1H),9.02(s,1H),7.92(s,1H),6.81(dd,J=17.6,1 0.6Hz,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).

[0729] MS m / z[M+H] + :451

[0730] 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

[0731] (R)-4-((6-amino-5-iodo-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (42) (100 mg, 0.182 mmol) was dissolved in DMF (2 mL), and 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. A DMF solution (0.5 mL) containing 1-(trimethylsilyl)propyne (31 mg, 0.273 mmol) was added under N2 atmosphere and reacted at 50°C for 1 h. After the reaction solution cooled to room temperature, it was quenched with saturated ammonium chloride solution, diluted with water, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, flash separation (methanol / dichloromethane = 3%) gave (R)-4-((6-amino-3-(S-methyl-N-(methyl-d3)sulfonyl imide)-5-(propyn-1-yl)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (64 mg, yellow solid) with a yield of 76%.

[0732] 1 H NMR (400MHz, DMSO-d6) δ11.67(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).

[0733] MS m / z[M+H] + :463

[0734] 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

[0735] (R)-4-((6-amino-5-iodo-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (42) (100 mg, 0.182 mmol) was dissolved in DMF (2 mL), and 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. A solution of cyclopropyl(trimethylsilyl)acetylene (38 mg, 0.273 mmol) in DMF (0.5 mL) was added under a N2 atmosphere, and the mixture was stirred at room temperature overnight. The reaction solution was quenched with saturated ammonium chloride solution, diluted with water, extracted with dichloromethane, separated, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, flash separation (methanol / dichloromethane = 3%) gave (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, light yellow solid) with a yield of 83%.

[0736] 1 H NMR (400MHz, DMSO-d6) δ11.68(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).

[0737] MS m / z[M+H] + :489

[0738] 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

[0739] (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (200 mg, 0.44 mmol) was added to DMF (2 mL) and stirred at room temperature. Concentrated HCl (108 mg, 1.09 mmol) was added and stirred in a 90°C oil bath for 5 min. The solution became turbid, and acetonitrile (10 mL) was added and refluxed for 5 min. The suspension was stirred at room temperature for 1.5 h, filtered, rinsed with acetonitrile (0.5 mL*2), and the filter cake was dried under reduced pressure at 50°C for 1 h to give the dihydrochloride salt as a light yellow solid: 230 mg, yield: 99.2%.

[0740] 1 H NMR (400 MHz, DMSO-d 6 )δ11.88(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).

[0741] MS m / z[M+H] + :459

[0742] Example 48: Synthesis of (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-d3)sulfonyl imide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide sulfate

[0743] (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (200 mg, 0.44 mmol) was added to DMF (1 mL) and stirred at room temperature to form a suspension. Concentrated H2SO4 (109 mg, 1.09 mmol) and acetonitrile (1 mL) were added and dissolved with stirring at room temperature. The mixture was placed in a 90°C oil bath and stirred for 5 min. Acetonitrile (6 mL) was added and refluxed for 5 min. A solid precipitated and the mixture was stirred at room temperature for 1.5 h. The mixture was filtered and rinsed with acetonitrile (0.5 mL*2). The filter cake was dried under reduced pressure at 50°C for 1 h to obtain the disulfate salt as an off-white solid: 268 mg, yield: 93.8%.

[0744] 1 H NMR (400 MHz, DMSO-d 6)δ11.82(s,1H),11.46(s,1H),9.34(s,1H),9.30(s,1H),8.92(s,4H),7.9 0(s,1H),7.64(s,2H),3.92(s,3H),2.15-2.08(m,1H),0.90-0.82(m,4H).

[0745] MS m / z[M+H] + :459

[0746] Example 49: Synthesis of (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide methanesulfonate

[0747] (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-d3)sulfonylimide)pyridin-2-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (200 mg, 0.44 mmol) was added to DMF (0.5 mL) and stirred at room temperature to form a suspension. Methanesulfonic acid (105 mg, 1.09 mmol) and acetonitrile (1 mL) were added and dissolved with stirring at room temperature. The mixture was placed in a 90°C oil bath and stirred for 5 min. Acetonitrile (8 mL) was added and refluxed for 5 min. A solid precipitated and the mixture was stirred at room temperature for 1.5 h. The mixture was filtered and rinsed with acetonitrile (0.5 mL*2). The filter cake was dried under reduced pressure at 50°C for 1 h to obtain a dimethanesulfonate salt as an off-white solid: 268 mg, yield: 94.4%.

[0748] 1 H NMR (400 MHz, DMSO-d 6 )δ11.82(s,1H),11.46(s,1H),9.34(s,1H),9.30(s,1H),7.90(s,1H),7.6 3(s,2H),3.92(s,3H),2.35(s,6H),2.17-2.09(m,,1H),0.90-0.82(m,4H).

[0749] MS m / z[M+H] + :459

[0750] Biological evaluation

[0751] Test Example 1: TYK2 kinase activity inhibition experiment

[0752] 1.1 Experimental Principle and Purpose

[0753] The TYK2 kinase gene was introduced into wild-type murine B lymphocytes (BaF3) to construct the Ba / F3-FL-TYK2-E957D stable cell line. The growth and proliferation of Ba / F3-FL-TYK2-E957D cells no longer depend on IL-3, but instead rely on the exogenously introduced TYK2 kinase. Compounds that selectively inhibit TYK2 kinase activity will inhibit the proliferation of this cell line.

[0754] This study tested the inhibitory effect of the compounds on Ba / F3-FL-TYK2-E957D cell proliferation, detected cell apoptosis, and calculated the IC 50 Value. According to IC 50 The inhibitory activity of the compounds against TYK2 kinase was evaluated.

[0755] 1.2 Experimental methods

[0756] 1.2.1 Preparation of stock solution

[0757] The test compound powder was stored at room temperature, prepared into a 10 mM stock solution with DMSO, and stored at -20°C in the dark until use.

[0758] 1.2.2 Experimental steps

[0759] Formulated compounds

[0760] Prepare a dilution solution of the compound to a final concentration of 1000x. Dilute the compound in culture medium to a final concentration of 20x. Add 2 μl of the 1000x compound to 98 μl of culture medium per well.

[0761] planking

[0762] Cells (provided by Sundia Medical Technology (Shanghai) Co., Ltd.) were resuspended and counted using an automated cell counter. Based on the BaF3 seeding density, 2000 cells per well were plated and the cell suspension was diluted to the desired density. 95 μl of cells were plated per well and incubated at 37°C for stabilization. 5 μl of a 20-fold concentration of compound was added to each well, with the same volume of DMSO added to serve as a control. The cells were incubated at 37°C, 5% CO2 for 72 hours.

[0763] Detection

[0764] Equilibrate the cell plate to room temperature. Reagent, shake for 2 minutes, let stand for 10 minutes. Detection was performed using SpectraMax Paradigm.

[0765] Data Analysis

[0766] (1) IC50 was calculated using GraphPad Prism 5.

[0767] (2)%Inh=(Max signal-Compound signal) / (Max signal-Min signal)x100.

[0768] (3) Max signal is the positive control well, which contains only DMSO with the same volume as the compound.

[0769] (4) Min signal is the negative control well, only culture medium

[0770] The results are shown in Table 1 below

[0771] Table 1 Inhibitory activity of representative compounds of the present invention against TYK2 kinase

[0772] Among them, the structural formula of compound BMS-986165 is

[0773] The test results show that the compounds provided by the present invention have excellent TYK2 inhibitory activity, and the TYK2 inhibitory activity of most compounds is better than that of the positive control BMS-986165. 50 In particular, Examples 28, 32, 40, 41, 42, and 44 showed 4 to 7 times higher TYK2 inhibitory activity than BMS-986165, and Examples 45 and 46 showed more than 20 times higher TYK2 inhibitory activity than BMS-986165.

[0774] Test Example 2: JAK family kinase selectivity assay

[0775] 2.1 Experimental Principle and Purpose

[0776] The JAK family comprises four kinases: TYK2, JAK1, JAK2, and JAK3. JAK family kinase genes were introduced into wild-type murine B lymphocytes (BaF3) to construct four engineered BaF3 cell lines (Ba / F3-FL-TYK2-E957D, Ba / F3-TEL-JAK1, Ba / F3-TEL-JAK2, and Ba / F3-TEL-JAK3). These engineered cell lines no longer rely on IL-3 for growth and proliferation, instead relying on the exogenously introduced JAK family kinase. Compounds that selectively inhibit the activity of a specific JAK kinase will inhibit the proliferation of the corresponding cell line.

[0777] This study tested the inhibitory effect of the compounds on the proliferation of four cell lines: Ba / F3-FL-TYK2-E957D, Ba / F3-TEL-JAK1, Ba / F3-TEL-JAK2, and Ba / F3-TEL-JAK3. The apoptosis of the cells was detected and the IC 50 Value. According to IC 50 The inhibitory activity of the compound against TYK2, JAK1, JAK2, and JAK3 kinases was evaluated, thereby assessing the JAK family kinase selectivity of the compound.

[0778] 2.2 Experimental methods

[0779] 2.2.1 Preparation of stock solution

[0780] The test compound powder was stored at room temperature, prepared into a 10 mM stock solution with DMSO, and stored at -20°C in the dark until use.

[0781] 2.2.2 Experimental steps

[0782] Formulated compounds

[0783] Prepare a dilution solution of the compound to a final concentration of 1000x. Dilute the compound in culture medium to a final concentration of 20x. Add 2 μl of the 1000x compound to 98 μl of culture medium per well.

[0784] planking

[0785] Cells (provided by Sundia Medical Technology (Shanghai) Co., Ltd.) were resuspended and counted using an automated cell counter. Based on the BaF3 seeding density, 2000 cells per well were plated and the cell suspension was diluted to the desired density. 95 μl of cells were plated per well and incubated at 37°C for stabilization. 5 μl of a 20-fold concentration of compound was added to each well, with the same volume of DMSO added to serve as a control. The cells were incubated at 37°C, 5% CO2 for 72 hours.

[0786] Detection

[0787] Equilibrate the cell plate to room temperature. Reagent, shake for 2 minutes, let stand for 10 minutes. Detection was performed using SpectraMax Paradigm.

[0788] Data Analysis

[0789] (1) IC50 was calculated using GraphPad Prism 5.

[0790] (2)%Inh=(Max signal-Compound signal) / (Max signal-Min signal)x100.

[0791] (3) Max signal is the positive control well, which contains only DMSO with the same volume as the compound.

[0792] (4) Min signal is the negative control well, only culture medium

[0793] The results are shown in Table 2 below

[0794] Table 2 Selectivity of representative compounds of the present invention for TYK2 kinase

[0795] The test results show that the compound provided by the present invention has excellent TYK2 inhibitory activity, while having no inhibitory activity against JAK1, JAK2, and JAK3 kinases, and has very high selectivity for JAK family kinases.

[0796] Basic research and clinical results of existing JAK kinase inhibitors have shown that non-selective kinase inhibitors can cause serious side effects, including thrombosis, anemia, and severe infections. Therefore, poor kinase isotype selectivity is a challenge that needs to be overcome in the development of next-generation JAK inhibitors. The compounds of this invention possess excellent kinase selectivity and demonstrate a high safety profile.

[0797] Test Example 3: IFN-α-induced STAT phosphorylation in human whole blood

[0798] 3.1 Experimental Principle and Purpose

[0799] The cytokine receptor to which TYK2 binds mediates type 1 interferon (IFN-α) signaling, which has been identified as the most important inflammatory factor in the autoimmune system. When human whole blood is induced with IFN-α, TYK2 in lymphocytes in the blood triggers STAT phosphorylation, mediating subsequent inflammatory signaling. Therefore, TYK2 inhibitors have an inhibitory effect on IFN-α signaling. The stronger the TYK2 inhibitory activity, the lower the STAT phosphorylation level, and the correspondingly stronger the anti-inflammatory effect.

[0800] This study tested the ability of compounds to inhibit IFN-α-induced STAT phosphorylation in human whole blood and calculated the IC 50 Value. According to IC 50 The inhibitory activity of the compounds on the IFN-α inflammatory pathway was evaluated by size, and the anti-inflammatory activity of the compounds was assessed at the tissue level.

[0801] Experimental procedures

[0802] 3.2.1 Preparation of stock solution

[0803] The test compound powder was stored at room temperature, prepared into 10 mM stock solution with DMSO, and stored in a -80°C refrigerator.

[0804] The positive control compound BMS-986165 was stored as a powder at room temperature and prepared into a 10 mM stock solution with DMSO and stored in a -80°C refrigerator.

[0805] 3.2.2 Solution preparation

[0806] Preparation of 1X Fix / Lysis solution: Dilute 5X Fix / Lysis with ddH2O at a ratio of 1:4 and preheat in a 37°C incubator until ready for use.

[0807] Preparation of flow cytometry staining buffer: Add 1 g bovine serum albumin (BSA) and 1 mL EDTA (0.5 M) solution to 500 mL phosphate buffered saline (PBS) and store in a refrigerator at 4°C.

[0808] Compound dilution solution: Add 0.5 g bovine serum albumin (BSA) to 500 mL phosphate buffered saline (PBS) and store in a refrigerator at 4°C.

[0809] 3.2.3 Experimental steps

[0810] Preparation of compounds and cytokines

[0811] 10 mM of the test compound and the positive compound BMS-986165 were diluted with DMSO to a 5 mM working solution, and then further diluted with DMSO in a 3-fold gradient to 8 concentrations. Each concentration point of the test compound and BMS-986165 in the 8-concentration gradient was diluted 25-fold with compound diluent and set aside.

[0812] Dilute 50 μg / mL IFN-alpha to 400 ng / mL with compound diluent and set aside.

[0813] Processing of human whole blood

[0814] Using a 300μL electric dispenser, add 67.5μL of human whole blood to a 96-well plate. Add 3.5μL of the prepared test compound, mix thoroughly, and place in a cell culture incubator. After a 60-minute incubation, add 400ng / mL IFN-α (Biolegend 592702, final concentration 20ng / mL). Mix thoroughly and place in a cell culture incubator for a further 15 minutes.

[0815] After cytokine stimulation, 5 μl of PE-CD3 (BD ​​555333) antibody was added to each well, mixed and continued to incubate in a 4-degree refrigerator. After completion, the whole blood was transferred to a 96-well deep-well plate with a dispenser, and preheated 1X Fix / Lysis solution was added. The cells were lysed and fixed in a 37°C incubator for 12 minutes. Washed, 400 μL of Perm III solution was added, vortexed and incubated on ice for 30 minutes. The cells were then stained with 100 μL of APC-pSTAT5 (1:100) antibody at room temperature for 50 minutes. Afterwards, the cells were detected by flow cytometry. After gating the CD3-positive signal group, the expression of pSTAT5 was quantified by the median fluorescence intensity.

[0816] The results are shown in Table 3 below

[0817] Table 3 Inhibitory activity of representative compounds of the present invention on IFN-α inflammatory pathway

[0818] Test results demonstrate that the compounds provided herein exhibit significant inhibitory activity against IFN-α-induced STAT phosphorylation in human whole blood, demonstrating that the compounds can potently inhibit the IFN-α inflammatory pathway at the tissue level. Compared to the control, BMS-986165, the compounds provided herein exhibit superior IFN-α inflammatory pathway inhibitory activity. In particular, Examples 28 and 29 exhibit approximately six-fold increased anti-inflammatory activity.

[0819] Test Example 4: hERG potassium channel inhibition experiment of the compound of the present invention

[0820] 4.1 Experimental Purpose

[0821] The blocking effect of the compounds of the present invention on hERG potassium current was tested using fully automated patch clamp on a stable cell line transfected with hERG potassium channel.

[0822] 4.2 Experimental Methods

[0823] 4.2.1 Cell Preparation

[0824] CHO-hERG cells were cultured at 175 cm 2 When the cell density in the culture flask grows to 60-80%, the culture medium is removed, the cells are washed once with 7 ml of PBS (Phosphate Buffered Saline), and then 3 ml of Detachin is added for digestion.

[0825] After digestion is complete, add 7 ml of culture medium to neutralize, then centrifuge, remove the supernatant, and add 5 ml of culture medium to resuspend to ensure that the cell density is 2-5×10 6 / ml.

[0826] 4.2.2 Solution preparation

[0827] 4.2.3 Electrophysiological Recording Process

[0828] The Qpatch instrument automatically performed the single-cell high-impedance sealing and whole-cell patterning process. After acquiring the recording mode, the cell was clamped at -80 mV. A 50-millisecond pre-voltage of -50 mV was applied before a 5-second depolarizing stimulus of +40 mV was applied. The cell then repolarized to -50 mV for 5 seconds before returning to -80 mV. This voltage stimulus was applied every 15 seconds. After recording for 2 minutes, the extracellular solution was added for 5 minutes. Drug administration then began, starting with the lowest tested concentration. Each test concentration was administered for 2.5 minutes. After all concentrations were administered, the positive control compound, 3 μM Cisapride, was administered. At least three cells were tested for each concentration (n ≥ 3).

[0829] 4.2.4 Compound Preparation

[0830] The 20 mM compound stock solution was diluted with extracellular fluid. 5 μL of the 20 mM compound stock solution was added to 2495 μL of extracellular fluid, diluted 500-fold to 40 μM, and then serially diluted 3-fold in extracellular fluid containing 0.2% DMSO to obtain the final concentration to be tested.

[0831] The highest tested concentration was 40 μM, and there were 6 concentrations in total, namely 40, 13.33, 4.44, 1.48, 0.49, and 0.16 μM.

[0832] The DMSO content in the final test concentration did not exceed 0.2%, and this concentration of DMSO had no effect on hERG potassium channels.

[0833] 4.3 Data Analysis

[0834] The experimental data were analyzed by XLFit software.

[0835] 4.4 Experimental results The results are shown in Table 4 below.

[0836] Table 4 Inhibitory activity of representative compounds of the present invention on hERG potassium channels

[0837] The test results show that the compound provided by the present invention has no hERG potassium channel inhibitory activity and has a low risk of cardiac toxicity.

[0838] Test Example 5: In vivo pharmacokinetic study of the compound of the present invention

[0839] 5.1 Pharmacokinetics in rats

[0840] Experimental Methods: Healthy male Sprague-Dawley rats were randomly divided into groups of three and orally administered with the test compound. Rats were fasted for 12 hours prior to gavage, with free access to water. Four hours after administration, rats were fed. Blood (0.2 mL) was collected via the jugular vein at the designated time points before (0 hour) and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after administration. The blood was collected in EDTA-K2 tubes and stored in an ice-water bath. Within 30 minutes, the blood was centrifuged at 11,000 rpm for 5 minutes to separate the plasma, which was then frozen at –70°C until analysis.

[0841] Test Example 5.1 Results: See Table 5.1 below.

[0842] Table 5.1 Metabolic parameters of representative compounds of the present invention in rats

[0843] 5.2 In vivo pharmacokinetic studies in beagle dogs

[0844] Experimental Methods: Healthy male beagle dogs were randomly divided into groups of three and orally administered with the test compound. They were fasted for 12 hours prior to the gavage experiment, with free access to water. Four hours after dosing, they were fed. Approximately 600 μL of blood was collected from the forelimb or hindlimb at these time points, 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, and 24 hours after dosing. The blood was collected in EDTA-K2 tubes and stored in an ice-water bath. Within 30 minutes, the blood was centrifuged at 3500 rpm for at least 10 minutes to separate the plasma, which was then frozen at –70°C until analysis.

[0845] Test Example 5.2 Results: See Table 5.2 below.

[0846] Table 5.2 Metabolic parameters of representative compounds of the present invention in dogs

[0847] Test results demonstrate that the compound provided by the present invention exhibits favorable drug metabolism, good drugability, and high plasma exposure (AUC). The oral bioavailability (F%) and plasma exposure of the compound provided by the present invention in rats and dogs are significantly superior to those of BMS-986165, demonstrating excellent oral absorption and metabolic characteristics.

[0848] Test Example 6: Solubility of the Compound of the Present Invention in Water (pH = 7)

[0849] Test Example 6 results: See Table 6 below.

[0850] Table 6 Solubility of representative compounds of the present invention

[0851] The test results show that the water solubility of the compound provided by the present invention is significantly better than that of BMS-986165.

[0852] Aqueous solubility is a key indicator for evaluating the drugability of small molecule oral drugs. Only when a drug dissolves can it be absorbed through the gastrointestinal tract and enter the systemic circulation. Drugs with poor water solubility are slowly absorbed and have low bioavailability, which affects blood drug concentrations and the onset of pharmacological effects, leading to high clinical failure rates. The compounds provided by this invention have higher solubility than BMS-986165, resulting in better oral absorption and drugability.

[0853] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound represented by formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, in, R 1 Selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the substitution refers to substitution by one or more substituents selected from the following group: deuterium, halogen; A is NH or CH2; B is CH or N; L is selected from the following group: R 2 Selected from the group consisting of H, -CD3, C1-C6 alkyl, C3-C6 cycloalkyl; X is CH or N; Y is NH, O or S; R 3 、R 4 、R 5 Each is independently selected from the following group: H, -NH2, -OH, C1-C6 alkoxy, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, -CONH2, -CN, halogen, -O(CH2) n R 9 , C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl substituted C2-C6 alkynyl and -NR 8 (CH2) n R 9 ; n is 1, 2, 3, 4, or 5; R 9 Selected from the group consisting of -OH, C1-C6 alkoxy, C4-C6 cycloalkoxy, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, and -CN; R 8 is H or C1-C6 alkyl; R 6 、R 7 Each is independently selected from the following group: H, C1-C6 alkyl, halogen.

2. The compound according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a fully deuterated C1-C6 alkyl group; A is NH; B is CH or N.

3. The compound according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: L is R 2 Selected from the group consisting of: H, -CD3, C1-C6 alkyl; X is N; R 3 、R 4 、R 5 Each is independently selected from the following group: H, -NH2, -OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, -CONH2, -CN, halogen, -O(CH2) n R 9 , C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl substituted C2-C6 alkynyl, and -NR 8 (CH2) n R 9 ; n is 1, 2, 3, 4, or 5; R 9 Selected from the group consisting of C1-C6 alkoxy, C4-C6 cycloalkoxy, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, and -CN; R 8 is H or C1-C6 alkyl.

4. The compound according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a fully deuterated C1-C6 alkyl group; A is NH; B is N; L is R 2 Selected from the group consisting of: H, -CD3, C1-C6 alkyl; X is N; R 3 is -NH2; R 4 Selected from the group consisting of halogen, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl-substituted C2-C6 alkynyl; R 5 For H.

5. The compound according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a fully deuterated C1-C6 alkyl group; A is NH; B is N; L is R 2 is -CD3; X is N; R 3 is -NH2; R 4 Selected from the group consisting of halogen, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl-substituted C2-C6 alkynyl; R 5 For H.

6. The compound according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the group consisting of:

7. A method for preparing the compound of claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The steps include: Formula Ic reacts with cyclopropylamide to obtain a compound of formula (I); Among them, R 1 , A, B, L as defined in claim 1; G is a halogen.

8. A pharmaceutical composition, characterized in that The invention comprises a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

9. Use of the compound according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, characterized in that: Used for preparing medicines for preventing and / or treating diseases mediated by TYK2.

10. The use according to claim 9, characterized in that The TYK2-mediated related diseases are inflammatory or autoimmune diseases in mammals.

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