Compounds used as TYK2 inhibitors, preparation method therefor, and pharmaceutical use thereof

Abstract

Disclosed are a compound used as a TYK2 inhibitor, a preparation method therefor, and pharmaceutical use thereof. Specifically, the compound has a structure represented by formula (I), wherein the definitions of the groups and substituents are as described in the specification. In addition, also disclosed are a preparation method for the compound and use thereof in preventing and / or treating a related disease mediated by TYK2.

Description

methylpyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide HN OHN PIPA, H2NCO2NH4 'g' 1 MeOH, 0 °C to RT^ T JJ Me3OBF4 PCM, RT 3N HCI (aq.) H2O, 100°C, 1 h o                        o nBuLi, THF, 0 °C s then MeSSMe -78 °C to RT 5b                              5c Pd2(dba)3j XantPhos Cs2CO3, PMF MW(130°C, 80W) 1 h Step 1:     Synthesis of A-(6-methyl-3-methylthiopyridin-2- methyl)trim ethylacetamide (5b) The synthesis of A-(6-methylpyridin-2-methyl)trimethylacetamide (5 a) referenced Org. Process Res. Dev. 2010, 14(1), 263-271. A-(6-methylpyridin-2-methyl)trimethylacetamide (5a) (5.5 g, 28.6 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), cooled down to 0°C under nitrogen atmosphere, n-butyllithium inn-hexane solution (35 mL, 2.5 M, 85.9 mmol) was slowly added dropwise, heated up to room temperature, and stirred for 2 hours. The reaction solution was cooled down to -78°C, dimethyl disulfide (5.5 mL, 57.2 mL) was added slowly dropwise, after the addition, then the solution was slowly heated up to room temperature, and the solution was continued to be stirred for 1 hour. The reaction was quenched by the addition of saturated ammonium chloride in an ice water bath, extracted with ethyl acetate, the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After being concentrated, the solution 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), yield 43%. MS m / z [M+H]+: 239. Step 2: Synthesis of A-(6-methyl-3-(5'-methylsulfoximino)pyridin-2-methyl)trim ethylacetamide (5c) The synthesis referenced the synthesis of 3-(5'-methylsulfoximino)-2-nitropyridine, yield 12%. 1HNMR (400 MHz, DMSO-t / 6) 5 10.78 (s, 1H), 8.11 (d,J= 8.0 Hz, 1H),7.21 (d, J= 8.0 Hz, 1H), 5.04 (s, 1H), 3.10 (s, 3H), 2.48 (s, 3H), 1.23 (s, 9H). MS m / z [M+H]+: 270. Step 3: Synthesis of 7V-(6-methyl-3-(7V,5'-dimethylsulfoximino)pyridin-2-methyl)trim ethylacetamide (5d) A-(6-methyl-3-(.S’-mcthy I sul fox i m i no )py ri di n-2-mcthy I )tri mcthy I acctam i de (5 c) (370 mg, 1.38 mmol) was dissolved in dichloromethane (6 mL), trimethoxynium tetrafluoroborate (265 mg, 1.79 mmol) was added, and the reaction was stirred for 1 h at room temperature. The reaction was quenched by water and stirred for 10 minutes. The aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate. After being concentrated, A-(6-methyl-3-(A,S-dimethylsulfoximino)pyridin-2-methyl)trimethylacetamide (5d) (190 mg, brown viscous liquid) was obtained by plate chromatography separation (methanol: dichloromethane = 1:10), yield 49%. MS m / z [M+H]+: 284. Step 4: Synthesis of 3-(A,5'-dimethylsulfoximino)-6-methylpyridin-2-amine (5e) A-(6-methyl-3-(A>S'-dimethylsulfoximino)pyridin-2-methyl)trimethylacetamide (5d) (190 mg, 0.67 mmol) was dissolved in 2 N hydrochloric acid solution (4 mL) and stirred at 100°C for 30 min. The solution was cooled to room temperature, pH = 8~9 was adjusted using saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After being concentrated, 3-(^5-dimethylsulfoximino)-6-methylpyridin-2-amine (5e) (79 mg, yellow liquid) was obtained by plate chromatography separation (methanol: dichloromethane = 1:10), yield 59%. 1H NMR (400 MHz, DMSO-^6) 8 7.69 (d, J= 7.9 Hz, 1H), 6.73 (s, 2H), 6.58 (d, J= 7.8 Hz, 1H), 3.01 (s, 3H), 2.46 (s, 3H), 2.29 (s, 3H). MS m / z [M+H]+: 200. Step 5: Synthesis of 6-chloro-4-((3-(A,5'-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide (5f) 3-(A,S-dimethylsulfoximino)-6-methylpyridin-2-amine (5e) (63 mg, 0.316 mmol) was dissolved in anhydrous DMF (1 mL), cooled down to 0°C under nitrogen atmosphere, sodium hydride (25 mg, 60% w / w, 0.632 mmol) was added, then stirred for 20 min, 4,6-dichloro-A-methylpyridazin-3-carboxamide (3b) (65 mg, 0.316 mmol) was added, heated up to room temperature, stirred for 2 hours. The reaction was quenched by saturated ammonium chloride, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After being concentrated, 6<hloro-4-((3-(AA-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide (5f) (40 mg, white solid) was obtained by Flash separation (methanol: dichloromethane = 1:10), yield 34%. 1H NMR (400 MHz, DMSO-^) 8 12.03 (s, 1H), 9.28 (d, J= 3.8 Hz, 1H), 8.97 (s, 1H), 8.12 (d, J= 7.9 Hz, 1H), 7.21 (d, J= 7.9 Hz, 1H), 3.19 (s, 3H), 2.85 (d, J= 4.6 Hz, 3H), 2.68 (s, 3H), 2.54 (s, 3H). MS m / z [M+H]+: 369. Step 6: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A / ,5'-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-V-methylpyridazine-3-carboxamide (5) The synthesis referenced the synthesis of 6-(cyclopropylcarboxamido)-4-((3-(7V,>S'-dimethylsulfoximino)pyridin-2-yl)amino)-7V-(methyl-£ / 3)pyridazine-3-carboxamide (Example 2), yield 33%. 1HNMR(4OO MHz, DMSO-t / 6) 5 11.88 (s, 1H), 11.36 (s, 1H), 9.82 (s, 1H), 9.08 (d, J= 4.6 Hz, 1H), 8.08 (d, J= 7.9 Hz, 1H), 7.12 (d, J= 7.9 Hz, 1H), 3.19 (s, 3H), 2.84 (d, J= 4.7 Hz, 3H), 2.66 (s, 3H), 2.51 (s, 3H), 2.11 (dt, J= 12.5, 6.2 Hz, 1H), 0.88 -0.81 (m, 4H). MS m / z [M+H ]+: 418. Example 6 Preparation of 4-((6-carbamoyl-3-(A(S-dimethylsulfoximino)pyridin-2- yl)amino)-6-(cyclopropylcarboxamido)-7V-methylpyridazine-3-carboxamide HN O N(Boc)2 AA L X M63OBF4 DCM, RT (Boc)2O DMAP, RT PIDA, H2NCO2NH4 MeOH, 0°Cto RT Zn(CN)2, Pd2(dba)3 Xantphos, DMF MW (80°C, 80W) 45 min NH2 Pd2(dba)3, XantPhos Cs2CO3, DMF MW (120°C, 80W) 1 h Step 1: Synthesis of 6-chloro-3-(methylthio)pyridin-2-amine (6b) The synthesis of / V-(6-ch I oro-3-(methyl th io)pyri di n-2-yl)tri methyl acetamide (6a) referenced J. Org. Chem. 1983, 48(20), 3401-3408. The synthesis referenced to the synthesis of 3-(A(S-dimethylsulfoximino)-6-methylpyridin-2-amine, yield 89%. 1H NMR (400 MHz, CDC13) 8 7.50 (d, J= 7.8 Hz, 1H), 6.63 (d, J= 7.8 Hz, 1H), 5.25 (s, 2H), 2.34 (s, 3H). MS m / z [M+H]+: 175. Step 2: Synthesis of    V,V-(di-tert-butoxycar bonyl)-6-chloro-3- (methylthio)pyridin-2-amine (6c) 6-Chloro-3-(methylthio)pyridin-2-amine (6b) (6.0 g, 34.4 mmol) was placed in a round bottomed vial, Boc anhydride (21.7 g, 99.7 mmol) was added slowly, stirred at room temperature for 10 min, then DMAP (840 mg, 6.88 mmol) was added, the solution was continued to be stirred for 1 hour at room temperature. The solution was diluted with petroleum ether, after being concentrated, and then the solution was passed over a short column of silica gel to remove the Boc anhydride, yielding 14.7 g of a crude product. Petroleum ether was added to the crude product, beated, suction filtered and washed with petroleum ether, dried to obtain A(A-(di-tert-butoxycarbonyl)-6-chloro-3-(methylthio)pyridin-2-amine (6c) (12.3 g, white solid), yield 96%. 1H NMR (400 MHz, CDC13) 5 7.55 (d, J= 8.2 Hz, 1H), 7.28 (d, J= 9.2 Hz, 1H), 2.45 (s, 3H), 1.42 (s, 18H). MS m / z [M+Na]+: 397. Step 3: Synthesis of   A,A-(d i-tert-bu toxycar bonyl)-6-ch loro-3-(5- methylsulfoximino)pyridin-2-amine (6d) The synthesis referenced the synthesis of 3-(5'-methylsulfoximino)-2-nitropyridine, yield 84%. 1H NMR (400 MHz, CDCI3) 5 8.43 (d, J= 8.1 Hz, 1H), 7.52 (d, J= 8.2 Hz, 1H), 3.17 (s, 3H), 1.80 (s, 1H), 1.50 (s, 9H), 1.47 (s, 9H). MS m / z [M+H]+: 406. Step 4: Synthesis of A,A-(di-tert-biitoxycarbonyl)-6-chloro-3-(A,.S-dimethylsulfoximino)pyridin-2-amine (6e) The synthesis referenced the synthesis of TV-^-methyl-S-^S-dimethylsulfoximino)pyridin-2-methyl)trimethylacetamide, the crude product was not isolated and directly proceeded to the next step. Step 5: Synthesis of 6-chloro-3-(A,.S’-dimethylsulfoximino)pyridin-2-amine (6f) The synthesis referenced the synthesis of 3-(A,S-dimethylsulfoximino)-6-methylpyridin-2-amine, yield in two steps 34%. 1H NMR (400 MHz, DMSO-t / 6) 8 7.83 (d, J= 8.0 Hz, 1H), 7.22 (s, 2H), 6.77 (d, J= 8.0 Hz, 1H), 3.08 (s, 3H), 2.49 (s, 3H). MS m / z [M+H]+: 220. Step 6:       Synthesis of 6-chloro-4-((6-chloro-3-(A,.S- dimethylsulfoximino)pyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide (6g) The synthesis referenced the synthesis of 6-chloro-4-((3-(A(>S'-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide, yield 39%. 1H NMR (400 MHz, DMSO-^6) 8 12.20 (s, 1H), 9.34 (d, J= 4.5 Hz, 1H), 8.77 (s, 1H), 8.22 (d, J= 8.1 Hz, 1H), 7.42 (d, J= 8.1 Hz, 1H), 3.23 (s, 3H), 2.84 (d, J= 4.7 Hz, 3H), 2.68 (s, 3H). MS m / z [M+H]+: 389. Step 7:        Synthesis of 6-chloro-4-((6-cyano-3-(A,.S- dimethylsulfoximino)pyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide (6h) 6-Chloro-4-((6-chloro-3-(AA-dimethylsulfoximino)pyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide (6 g) (133 mg, 0. 343 mmol), Zn(CN)2 (22 mg, 0.189 mmol), Pd2(dba)s (31 mg, 0.0343 mmol) and xantphos (40 mg, 0.0686 mmol) were dissolved in anhydrous DMF (2 mL), and reacted for 45 min under nitrogen atmosphere at 80°C, 80W microwave. After cooled to room temperature, the reaction was quenched with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After being concentrated, 6-chloro-4-((6-cyano-3-(ALS’-dimcthylsulfoximino)pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (6h) (118 mg, yellow solid) was obtained by plate chromatography separation (ethyl acetate: petroleum ether = 2:1), yield 91 %. 1H NMR (400 MHz, DMSO-< / 6) 8 12.25 (s, 1H), 9.37 (d, J= 4.4 Hz, 1H), 8.77 (s, 1H), 8.41 (d, J= 7 A Hz, 1H), 7.93 (d, J= 7 A Hz, 1H), 3.28 (s, 3H), 2.88 (s, 3H), 2.69 (s, 3H). MS m / z [M+H]+: 380. Step 8: Synthesis of 4-((6-cyano-3-(A,5'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (6i) The synthesis referenced the synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A5'-dimethylsulfoximino)pyridin-2-yl)amino)-A-(methyl-t / 3)pyridazine-3-carboxamide, yield 21%. 1H NMR (400 MHz, DMSO-< / 6) 8 12.09 (s, 1H), 11.47 (s, 1H), 9.47 (s, 1H),9.18 (d, J= 4.8 Hz, 1H), 8.38 (d, J= 7.9 Hz, 1H), 7.86 (d, J= 7.8 Hz, 1H), 3.30 (s, 3H), 2.85 (d, J= 4.7 Hz, 3H), 2.68 (s, 3H), 2.18 - 2.08 (m, 1H), 0.87 - 0.83 (m, 4H). MS m / z [M+H]+: 429. Step 9: Synthesis of 4-((6-carbamoyl-3-(A,5'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (6) 4-((6-cyano-3-(A,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (6i) (15 mg, 0.035 mmol) was dissolved in DMSO (1 mL), anhydrous potassium carbonate (12 mg, 0.088 mmol) was added, and stirred at room temperature for 5 min, and then 30% hydrogen peroxide aqueous solution (39 mg, 0.35 mmol) was added, and the solution was continued to be stirred for 30 min at room temperature. The reaction solution was poured into distilled water and extracted with ethyl acetate, organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After being concentrated, 4-((6-carbamoyl-3-(A,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (6) (4.5 mg, white solid) was obtained by prep-HPLC separation, yield 29%. 1H NMR (400 MHz, DMSO-^6) 8 11.99 (s, 1H), 11.60 (s, 1H), 9.48 (s, 1H), 9.13 (s, 1H), 8.38 (d, J= 8.0 Hz, 1H), 7.97 (s, 1H), 7.87 (d, J= 7.9 Hz, 1H), 7.75 (s, 1H), 3.27 (s, 3H), 2.85 (d, J= 4.8 Hz, 3H), 2.69 (s, 3H), 2.14 - 2.08 (m, 1H), 0.89 - 0.81 (m, 4H). MS m / z [M+H]+: 447. Example 7 Preparation of 4-((6-amino-3-(A,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide Pd2(dba)3, XantPhos Cs2CO3, xylene 145°C Pd2(dba)3, Xantphos Cs2CO3, DMF 125°C, 4h Step 1: Synthesis of 6-chloro-4-((3-(7V,5'-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide (7a) 6-Chloro-4-((6-chloro-3-(A5'-dimethylsulfoximino)pyridin-2-yl)amino)-A-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), benzophenone imine (3.8 g, 21.1 mmol) was added, and the reaction solution was stirred at 125 °C for 4 h under nitrogen atmosphere. The reaction was quenched by addition of water, extracted with dichloromethane, and the organic phases were combined, washed with distilled water and saline respectively, dried over anhydrous sodium sulfate, and separated by column chromatography (ethyl acetate: petroleum ether = 1:1 ~ methanol: dichloromethane = 1:20) to obtain 6-chloro-4-((3-(A,S-dimethylsulfoximino)-6-((diphenyhnethylene)amino)pyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide (7a) (4.17 g, earthy yellow solid), yield 74%. MS m / z [M+H]+: 534. Steps 2 and 3: Synthesis of 4-((6-amino-3-(7V,5'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (7) 6-Chloro-4-((3 -(N, S-dimethylsulfoximino)-6- ((diphenylmethylene)amino)pyridin-2-yl)amino)-7V-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, and stirred at 145°C for 3 h under nitrogen atmosphere. After being cooled to room temperature, the solution was diluted by a solvent mixture of methanol / dichloromethane (1:10), filtered through diatomaceous earth, and the filter cake was washed with a solvent mixture of methanol / dichloromethane (1:10). The crude product 6-(cyclopropylcarboxamido)-4-((3-(A,5'-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide (7b) was obtained after being concentrated, which was directly used in the next step of the reaction without separation. The crude 6-(cyclopropylcarboxarnido)-4-((3-(A,5-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide (7b) was dissolved in tetrahydro furan (40 mL), and 6 N hydrochloric acid (30 mL) was added in an ice bath, and the solution was heated up to room temperature and stirred for 1 hour. Anhydrous potassium carbonate was added slowly in batches to adjust pH = 9—10, suction fdtered and concentrated. 4-((6-amino-3-(A,5-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (7) (1.87 g, earthy yellow solid) was obtained by column chromatography separation (methanol: dichloromethane = 1:20 - 1:7), yield 51%. 1HNMR(4OO MHz, DMSO-^6) 5 11.55 (s, 1H), 11.31 (s, 1H), 9.51 (s, 1H), 9.01 (d, J= 4.7 Hz, 1H), 7.74 (d, J= 8.4 Hz, 1H), 6.54 (s, 2H), 6.24 (d, J= 8.7 Hz, 1H), 3.06 (s, 3H), 2.84 (d, J= 4.4 Hz, 3H), 2.63 (s, 3H), 2.16 - 2.06 (m, 1H), 0.92 - 0.80 (m, 4H). MS m / z [M+H]+: 419. Example 8 Preparation of 4-((5 -cyano-3 -(A, 5-di mcthy I sul fox i m i no )py ri di n-2-y I )am i no )-6- (cyclopropylcarboxamide)-A-methylpyridazine-3-carboxamide NBS, MeCN Zn(CN)2 Pd2(dba)3, XantPhos DMF * 80 °C, 80 w _ nh2 Pd2(dba)3, XantPhos DMF, Cs2CO3 ” MW (110 °C, 50 W) one pot Step 1: Synthesis of 5-bromo-3-(A,5'-dimethylsulfoximino)pyridin-2-amine (8a) 3-(A,5-dimethylsulfoximino)pyridin-2-amine (Id) (500 mg, 2.7 mmol) was dissolved in acetonitrile (15 mL), NBS (504 mg, 2.83 mmol) was added slowly, and stirred at room temperature for 1 h. TLC detection showed that the reaction was completed. Acetonitrile was spin-dried, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and Flash separated (ethyl acetate / petroleum ether = 40 - 90%) to obtain 5-bromo-3-(A5-dimethylsulfoximino)pyridin-2-amine (8a) (640 mg, white solid), yield 89%. 1H NMR (400 MHz, CDCI3) 5 8.29 (d, J= 2.1 Hz, 1H), 8.10 (d, J= 2.0 Hz, 1H), 6.07 (brs, 2H), 3.08 (s, 3H), 2.68 (s, 3H). MS m / z [M+H]+: 264. Step 2: Synthesis of 4-((5-bromo-3-(A / ,5'-dimethylsulfoximino)pyridin-2-yl)amino)-6-chloro-7V-methylpyridazine-3-carboxamide (8b) The synthesis referenced the synthesis of 6-chloro-4-((3-(A(>S'-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide, yield 61%. 1H NMR (400 MHz, CDCI3) 5 12.43 (s, 1H), 8.97 (s, 1H), 8.59 (s, 1H), 8.42 (s, 1H), 8.28 (brs, 1H), 3.26 (s, 3H), 3.07 (d, J= 5.1 Hz, 3H), 2.83 (s, 3H). MS m / z [M+H]+: 433. Steps 3 and 4: Synthesis of 4-((5-cyano-3-(7V,5'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-ALmethylpyridazine-3-carboxamide (8) 4-((5-bromo-3-(AAS%limcthylsulfoximino)pyridin-2-yl)amino)-6-chloro-'V-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 the solution was reacted under nitrogen conditions at 60°C, 50W microwave for 1 h and then 80°C, 80W for 15 min. The reaction solution was cooled to room temperature, and cyclopropanamide (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 under nitrogen atmosphere, and the solution was reacted at 110°C, 50W microwave for 1 hour. The reaction was quenched with 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-(A',.S’- dimcthylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamidc)-A-methylpyridazine-3-carboxamide(8) ( 114 mg, white solid), yield 56%. 1H NMR (400 MHz, DMSO-< / 6) 8 12.20 (s, 1H), 11.50 (s, 1H), 9.46 (s, 1H),9.16 (s, 1H), 8.93 (s, 1H), 8.49 (s, 1H), 3.29 (s, 3H), 2.84 (d, J= 4.4 Hz, 3H), 2.66 (s, 3H), 2.15 - 2.07 (s, 1H), 0.92 - 0.80 (m, 4H). MS m / z [M+H]+: 429. Example 9 Preparation of 4-((5-amino-3-(A(S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-'V-mcthylpyridazinc-3-carboxamidc o nh2 Pd2(dba)3, xantphos Cs2CO3, dioxane MW (110 °C, 120 W) 9d HCI / dioxane DCM, RT, 1 h Step 1: Synthesis of 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(A,5'-dimethylsulfoximino)nicotinic acid-2,4,6-trichlorophenyl ester (9a) 4-((5-bromo-3-(A,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-chloro-7V-methylpyridazine-3-carboxamide (8b) (560 mg, 1.3 mmol), 2,4,6-trichlorophenyl formate (349 mg, 1.55 mmol), Pd(OAc)2 (63 mg, 0.26 mmol), xantphos (243 mg, 0.42 mmol) and triethylamine (263 mg, 2.6 mmol) were added to a solution of toluene (28 mL), and stirred at 100°C for 2 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered with diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated and Flash separated (ethyl acetate / petroleum ether = 40 - 80%) to obtain 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(AA-dimethylsulfoximinojnicotinic acid-2,4,6-trichlorophenyl ester (9a) (380 mg, pale yellow solid), yield 51%. 1H NMR (400 MHz, DMSO-t / 6) 8 12.47 (s, 1H), 9.42 (d, J= 4.7 Hz, 1H), 9.37 (d, J= 1.8 Hz, 1H), 9.02 (s, 1H), 8.75 (d, J= 1.9 Hz, 1H), 7.95 (s, 2H), 5.74 (s, 1H), 3.36 (s, 3H), 2.87 (d, J= 4.7 Hz, 3H), 2.72 (s, 3H). MS m / z [M+H]+: 577. Step 2: Synthesis of 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(A,5'-dimethylsulfoximino)nicotinic acid (9b) 6-((6-Chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(A>S'-dimethylsulfoximino)nicotinic acid-2,4,6-trichlorophenyl ester (9a) (175 mg, 0.3 mmol) was dissolved in DMSO (6.5 mL), and an aqueous 40% sodium hydroxide (500 mg, 40 % w / w) was added to the mixture in an ice bath, after the addition, and the solution was stirred at room temperature for 20 min. The pH was adjusted to 3~4 with IN hydrochloric acid, extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate. The crude 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5 -(N, S-di methylsul fox i m i no )n icoti n ic acid (9b) (179 mg, yellowish solid) was obtained by concentration, which was used directly in the next step without separation. MS m / z [M+H]+: 399. Step 3: Synthesis of tert-butyl (6-((6-chloro-3-(methylcarbamoyl)pyridazin- 4-yl)amino)-5-(7V,5'-dimethylsulfoximino)pyridin-3-yl)carbamate (9c) Triethylamine (50 mg, 0.495 mmol) and DPPA (136 mg, 0.495 mmol) were added to a crude 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(A>S'-dimethylsulfoximino)nicotinic acid (9b) (179 mg) in tert-butanol (12 mL), and stirred at 85°C for 2 hours under N2 atmosphere. The reaction solution was cooled to room temperature and concentrated and Flash separated (ethyl acetate / petroleum ether = 40 -90%) to obtain tert-butyl (6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(AA-dimethylsulfoximino)pyridin-3-yl)carbamate (9c) (69 mg, pale yellow solid), yield 33%. MS m / z [M+H]+: 470. Step 4: Synthesis of tert-butyl (6-((6-(cyclopropylcarboxamido)-3-(methykarbamoyl)pyridazin-4-yl)amino)-5-(V,.S’-dimethylsiilfoximino)pyridin-3-yl)carbamate (9d) The synthesis referenced the synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A5'-dimethylsulfoximino)pyridin-2-yl)amino)-A-(methyl-t / 3)pyridazine-3-carboxamide, yield 29%. MS m / z [M+H]+: 519. Step 5: Synthesis of 4-((5-amino-3-(A,.S’-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (9) Tert-butyl (6-((6-(cyclopropylcarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(A,S-dimethylsulfoximino)pyridin-3-yl)carbamate (9d) (22 mg, 0.042 mmol) was dissolved in dichloromethane (1.5 mL), 4 M dioxane hydrochloride solution (1.5 mL, 6 mmol) was added, and stirred for 1 h at room temperature. The solvent was spin-dried, diluted with water (1.5 mL), pH >11 was adjusted using 33% aqueous potassium carbonate, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. The crude product was obtained after filtration and concentration, 4-((5-amino-3-(ALS’-dimcthylsullbximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (9) (6.7 mg, white solid) was obtained by prep-HPLC preparation, yield 38%. 1H NMR (400 MHz, DMSO-^6) 8 11.34 (s, 1H), 11.23 (s, 1H), 9.00 (d, J= 4.9 Hz, 1H), 8.92 (s, 1H), 7.91 (d, J= 2.8 Hz, 1H), 7.53 (d, J= 2.8 Hz, 1H), 5.66 (s, 2H), 3.10 (s, 3H), 2.82 (d, J= 4.8 Hz, 3H), 2.63 (s, 3H), 2.11 - 2.03 (m, 1H), 0.82 (d, J= 6.7 Hz, 4H). MS m / z [M+H]+: 419. Example 10 Preparation of 4-((5-amino-3-(ALS’-dimcthylsullbximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A'-(mcthyl-J3)pyridazinc-3-carboxamidc NBS MeCN D3%h _______Cl__________. Pd(OAc)2, xantphos TEA, toluene 100 °C, 2 h NaOH, DMSO THF Step 1: Synthesis of 4-((5-bromo-3-(A / ,5'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-ALmethylpyridazine-3-carboxamide (10a) The synthesis referenced the synthesis of    5 -bromo-3 -(N, S- dimethylsulfoximino)pyridin-2-amine, yield 16%. MS m / z [M+H]+: 485. Step 2:      Synthesis of 6-((6-(cyclopropylcarboxamido)-3- (methylcarbamoyl)pyridazin-4-yl)amino)-5-(A / ,5'-dimethylsulfoximino)nicotinic acid-2,4,6-trichlorophenyl ester (10b) The synthesis referenced the synthesis of 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5 -(N, S-dimethylsul foximino)nicotinic acid-2,4,6-trichlorophenyl ester, yield 82%. MS m / z [M+H]+: 629. Step 3:      Synthesis of 6-((6-(cyclopropylcarboxamido)-3- (methylcarbamoyl)pyridazin-4-yl)amino)-5-(A / ,5'-dimethylsulfoximino)nicotinic acid (10c) The synthesis referenced the synthesis of 6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5 -(N, S-dimethylsul foximino)nicotinic acid, the crude product was directly used in the next step without separation. MS m / z [M+H]+: 402. Step 4: Synthesis of tert-butyl (6-((6-(cyclopropylcarboxamido)-3-((methyl-< / 3)carbamoyl))pyridazin-4-yl)amino)-5-( / V,5'-dimethylsulfoximino)pyridin-3-yl)carbamate (lOd) The synthesis referenced the synthesis of tert-butyl (6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5 -(N, .S’-di methyl sul fox i m i no )pyridi n-3 -yl)carbamate, two-step yield 25%. MS m / z [M+H]+: 522. Step 5: Synthesis of 4-((5-amino-3-(7V,5'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-AL(methyl-< / 3)pyridazine-3-carboxamide (10) The synthesis referenced the synthesis of 4-((5-amino-3-(M5'- dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide, yield 16%. 1H NMR (400 MHz, DMSO-t / 6) 5 11.34 (s, 1H), 11.23 (s, 1H), 8.97 (s, 1H), 8.92 (s, 1H), 7.91 (d, J= 2.7 Hz, 1H), 7.53 (d, J= 2.7 Hz, 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). MS m / z [M+H]+: 422. Example 11 Preparation of 6-(cyclopropylcarboxamido)-4-((3-(A>S'-dimethylsulfoximino)-5- hydroxypyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide Step 1: Synthesis of 6-chloro-4-((3-(7V,5'-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide (Ha) 4-((5-bromo-3-(A,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-chloro-A-methylpyridazine-3-carboxamide (8b) (200 mg, 0.463 mmol), bis(pinacolato)diboron (151 mg, 0.594 mmol), Pd(dppf)C12 (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 h under nitrogen atmosphere. After being cooled 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 min. The reaction solution was diluted by adding ethyl acetate and water, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After being concentrated, 6-chloro-4-((3-(A,S-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide (Ila) (124 mg, yellow solid) was obtained by column chromatography separation (methanol: dichloromethane = 1:20), yield 73%. 1H NMR (400 MHz, DMSO-^6) 8 11.79 (s, 1H), 10.45 (s, 1H), 9.26 (d, J= 4.6 Hz, 1H), 8.56 (s, 1H), 8.21 (d, J= 2.8 Hz, 1H), 7.69 (d, J= 2.8 Hz, 1H), 3.19 (s, 3H), 2.84 (d, J= 4.7 Hz, 3H), 2.67 (s, 3H). MS m / z [M+H]+: 371. Step 2: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A,5'-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide (11) The synthesis referenced the synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A>S'-dimethylsulfoximino)pyridin-2-yl)amino)-A-(methyl-t / 3)pyridazine-3-carboxamide, yield 69%. 1H NMR (400 MHz, DMSO-t / 6) 8 11.52 (s, 1H), 11.28 (s, 1H), 9.07 (s, 1H), 9.04 (d, J= 4.9 Hz, 1H), 8.10 (d, J= 2.9 Hz, 1H), 7.66 (d, J= 2.9 Hz, 1H), 3.16 (s, 3H), 2.83 (d, J= 4.8 Hz, 3H), 2.64 (s, 3H), 2.12 - 2.03 (m, 1H), 0.83 (d, J= 6.6 Hz, 4H). MS m / z [M+H]+: 420. Example 12 Preparation of 6-(cyclopropylcarboxamido)-4-((3-(7V,S-dimethylsulfoximino)-5- fluoropyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide Preparation of 6-(cyclopropylcarboxamido)-4-((3-(7V,S'-dimethylsulfoximino)-5-fluoropyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide (12) referenced to Example 5 for the preparation of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-N-methylpyridazine-3          - carboxamide, 7V-(6-methylpyridin-2-methyl)trimethylacetamide was replaced with N-(5-fluoropyridin-2-yl)trimethylacetamide (12a) as starting material. Step 1:      Synthesis of 7V-(5-fhioro-3-methylthiopyridin-2- yl)trimethylacetamide (12b), yield 26%. The synthesis of 7 / -(5-fluoropyridin-2-yl)trimethylacetamide (12a) referenced Org. Lett. 2013, 15(13), 3460-3463. 1H NMR (400 MHz, DMSO-O 5 9.50 (s, 1H), 8.16 (d, J = 2.2 Hz, 1H), 7.70 -7.63 (d, J = 8.0, 2.2 Hz, 1H), 2.42 (s, 3H), 1.21 (s, 9H). MS m / z [M+H]+: 243. Step 2: Synthesis of 7V-(3-(5’-methylsulfoximino)-5-fluoropyridin-2-yl)trimethylacetamide (12c), yield 28%. 1H NMR (400 MHz, DMSO-t / 6) 8 10.57 (s, 1H), 8.66 (s, 1H), 8.12 (d, J= 7.4 Hz, 1H), 7.68 (d, 7=13.8 Hz, 1H), 3.17 (s, 3H), 1.22 (s, 9H). MS m / z [M+H]+: 274. Step 3: Synthesis of jV-(3-(7V,5'-dimethylsulfoximino)-5-fluoropyridin-2-yl)trimethylacetamide (12d), yield 14%. 1H NMR (400 MHz, DMSO-O 5 10.30 (s, 0.65H), 9.81 (s, 0.35H), 8.78 (s, 0.35H), 8.68 (d, J= 2.4 Hz, 0.65H), 8.31 (d, J= 7.5 Hz, 0.35H), 8.09 (dd, J = 7.6, 2.4 Hz, 0.65H), 3.25 (s, 3H), 2.56 (s, 3H), 1.23 (d, J= 11.5 Hz, 9H). MS m / z [M+H]+: 288. Step 4: Synthesis of 3-(Az,5'-dimethylsulfoximino)-5-fluoropyridin-2-amine (12e), yield 47%. 1H NMR (400 MHz, DMSO-O 8 8.34 (s, 1H), 7.79 (d, J= 7.6 Hz, 1H), 6.82 (s, 2H), 3.19 (s, 3H), 2.57 (s, 3H). MS m / z [M+H]+: 204. Step 5: Synthesis of 6-chloro-4-((3-( / V,5'-dimethylsulfoximino)-5-fluoropyridin-2-yl)amino)-ALmethylpyridazine-3-carboxamide (12f), yield 32%. 1HNMR(4OO MHz, DMSO-t / 6) 5 12.03 (s, 1H), 9.31 (s, 1H), 8.71 (s, 2H), 8.12 (d, J= 5.7 Hz, 1H), 3.27 (s, 3H), 2.85 (d, J= 4.4 Hz, 3H), 2.68 (s, 3H). MS m / z [M+H]+: 373. Step 6: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A / ,5'-dimethylsulfoximino)-5-fluoropyridin-2-yl)amino)-ALmethylpyridazine-3-carboxamide (12), yield 29%. 1HNMR(4OO MHz, DMSO-^6) 5 11.82 (s, 1H), 11.39 (s, 1H), 9.29 (s, 1H), 9.11 (d, J= 4.8 Hz, 1H), 8.60 (d, J= 3.0 Hz, 1H), 8.08 (dd, J= 7.7, 3.0 Hz, 1H), 3.26 (s, 3H), 2.84 (d, J= 4.8 Hz, 3H), 2.66 (s, 3H), 2.15 - 2.05 (m, 1H), 0.90 - 0.78 (m, 4H). MS m / z [M+H]+: 422. Example 13 Preparation of 4-((5-bromo-3-(A^5'-dimethylsulfoximino)pyridin-2-yl)amino)-6- (cyclopropylcarboxamido)-'V-mcthylpyridazinc-3-carboxamidc Step 1: Synthesis of 6-chloro-4-((3-(7V,5'-dimethylsulfoximino)pyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide (13a) The synthesis referenced the synthesis of 6-chloro-4-((3-(A^5'-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide, yield 40%. 1HNMR(4OO MHz, DMSO-t / 6) 8 12.07 (s, 1H), 9.28 (s, 1H), 8.88 (s, 1H), 8.63 (d, J= 3.5 Hz, 1H), 8.24 (d, J= 7.6 Hz, 1H), 7.35 (dd, J= 7.3, 5.1 Hz, 1H), 3.21 (s, 3H), 2.84 (d, J= 4.5 Hz, 3H), 2.68 (s, 3H). MS m / z [M+H]+: 355. Step 2: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A / ,5'-dimethylsulfoximino)pyridin-2-yl)amino)-ALmethylpyridazine-3-carboxamide (13b) The synthesis referenced the synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A>S'-dimethylsulfoximino)pyridin-2-yl)amino)-7V-(methyl-£ / 5)pyridazine-3-carboxamide, yield 44%. 1HNMR(4OO MHz, DMSO-t / 6) 5 11.85 (s, 1H), 11.37 (s, 1H), 9.45 (s, 1H), 9.08 (d, J= 5.3 Hz, 1H), 8.52 (d, J= 4.7 Hz, 1H), 8.21 (d, J= 7.7 Hz, 1H), 7.27 (dd, J= 7.8, 4.9 Hz, 1H), 3.20 (s, 3H), 2.83 (d, J= 4.6 Hz, 3H), 2.66 (s, 3H), 2.13 - 2.04 (m, 1H), 0.83 (d, J =7.0 Hz, 4H). MS m / z [M+H]+: 404. Step 3: Synthesis of 4-((5-bromo-3-(A,5'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (13) 6-(Cyclopropylcarboxamido)-4-((3-(A5'-dimethylsulfoximino)pyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide (13b) (490 mg, 1.21 mmol) was dissolved in a solvent mixture of acetonitrile (10 mL) and dichloromethane (10 mL), and NBS (183 mg, 1.03 mmol) was added to the mixture under an ice water bath, and stirred at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride (35 mL), diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After being concentrated, 4-((5-bromo-3-(A5'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (13) (100 mg, pale yellow solid) was obtained by Flash separation (methanol / dichloromethane = 10%), yield 17%. *HNMR(400 MHz, DMSO-t / 6) 5 11.88 (s, 1H), 11.42 (s, 1H), 9.34 (s, 1H), 9.12 (d, J= 4.8 Hz, 1H), 8.65 (d, J= 2.4 Hz, 1H), 8.26 (d, J= 2.4 Hz, 1H), 3.27 (s, 3H), 2.84 (d, J= 4.8 Hz, 3H), 2.65 (s, 3H), 2.15 - 2.05 (m, 1H), 0.89 - 0.80 (m, 4H). MS m / z [M+H]+: 482. Example 14 Preparation of    6-(cyclopropylamido)-4-((3 -(A, .S’-di methyl sul fox i m i no )-5 - methoxypyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide och3 14a (Boc)2O DMAP BoCx..xBoc N h2nco2nh4 Ljl PIDA.MeOH och3 14d Bocs ,Boc Me3OBF4 DCM OCH3 14e nBuLi, THF 0°C to RT then MeSSMe -78 °C to RT yl)trimethylacetamide (14b) The synthesis of A-(5-methoxy-pyridin-2-yl)trimethylacetamide (14a) referenced US2011 / 178053. The synthesis of 14b referenced the synthesis of Af-(6-methyl-3-methylthio-pyridin-2-methyl)trimethylacetamide, yield 58%. 1H NMR (400 MHz, CDCI3) 5 7.95 (d, J= 2.3 Hz, 1H), 7.77 (s, 1H), 7.14 (d, J= 2.1 Hz, 1H), 3.86 (s, 3H), 2.42 (s, 3H), 1.34 (s, 9H). MS m / z [M+H]+: 255. Step 2: Synthesis of 5-methoxy-3-methylthiopyridin-2-amine (14c) The synthesis referenced the synthesis of 3-(A(S-dimethylsulfoximino)-6-methylpyridin-2-amine, yield 84%. 1H NMR (400 MHz, CDCI3) 5 7.70 - 7.67 (m, 1H), 7.20 - 7.17 (m, 1H), 4.65 (s, 2H), 3.78 (s, 3H), 2.39 (s, 3H). MS m / z [M+H]+: 171. Step 3: Synthesis of   V,V-(d i-tert-bu toxy car bony l)-5-methoxy-3- methylthiopyridin-2-amine 14d The synthesis referenced the synthesis of A; A%di-tcrt-butoxycarbonyl)-6-chloro-3-methylthiopyridin-2-amine, yield 70%. 1H NMR (400 MHz, CDCI3) 5 7.93 (s, 1H), 7.07 (s, 1H), 3.89 (s, 3H), 2.43 (s, 3H), 1.41 (s, 18H). MS m / z [M+H]+: 371. Step 4: Synthesis of A,A-(di-tert-butoxy car bony I )-3-(.S’-methylsulfoximi 110)-5-methoxypyridin-2 amine (14e) The synthesis referenced the synthesis of 3-(5'-methylsulfoximino)-2-nitropyridine, yield 85%. 1H NMR (400 MHz, CDCI3) 5 8.36 (s, 1H), 7.94 (s, 1H), 3.94 (s, 3H), 3.16 (s, 3H), 2.04 (s, 1H), 1.47 (d,J=9.8Hz, 18H). MS m / z [M+H]+: 402. Step 5:     Synthesis of V,V-(di-tert-biitoxycarbonyl)-3-(V,.S- dimethylsulfoximino)-5-methoxypyridin-2-amine (14f) The synthesis referenced the synthesis of A%6-mcthyl-3-(AAS’-dimethylsulfoximino)pyridin-2-methyl)trimethylacetamide, yield 80%. MS m / z [M+H]+: 416. Step 6: Synthesis of 3-(7V,5'-dimethylsulfoximino)-5-methoxypyridin-2-amine (14g) The synthesis referenced the synthesis of 6-chloro-3-(A(>S'-dimethylsulfoximino)pyridin-2-amine, yield 23%. 1H NMR (400 MHz, CDCI3) 5 8.04 (s, 1H), 7.61 (s, 1H), 5.64 (s, 2H), 3.82 (s, 3H), 3.10 (s, 3H), 2.68 (s, 3H). MS m / z [M+H]+: 202. Step 7: Synthesis of 6-chloro-4-((3-(7V,5'-dimethylsulfoximino)-5-methoxypyridin-2-yl)amino)-. / V-methylpyridazine-3-carboxamide (14h) The synthesis referenced the synthesis of 6-chloro-4-((3-(A(>S'-dimcthylsulfoximino)-6-mcthylpyridin-2-yl)amino)-'V-mcthylpyridazinc-3-carboxamide, yield 14%. MS m / z [M+H]+: 385. Step 8: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A / ,5'- dimethylsiilfoximino)-5-methoxypyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide (14) The synthesis referenced the synthesis of 6-(cyclopropylcarboxamido)-4-((3-(N,S-dimethylsulfoximino)pyridin-2-yl)amino)-7V-(methyl-d3)pyridazine-3-carboxamide, yield 79%. 1HNMR(4OO MHz, CDCI3) 5 11.65 (s, 1H), 11.32 (s, 1H), 9.17 (s, 1H), 9.06 (d, J = 4.7 Hz, 1H), 8.31 (d, J = 2.8 Hz, 1H), 7.75 (d, J = 2.8 Hz, 1H), 3.90 (s, 3H), 3.21 (s, 3H), 2.84 (d, J= 4.7 Hz, 3H), 2.66 (s, 3H), 2.14 - 2.05 (m, 1H), 0.84 (d, J= 1A Hz, 4H). MS m / z [M+H]+: 434. Example 15 Preparation of 6Tcyclopropylcarboxamido)-4-((3-0VA’-dimcthylsulfoximino)-5- methylpyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide Br 8a dioxane / H2O Trimethylboroxine Pd2(dba)3, CS2CO3 ^NH NaH, DMF, 0°C to RT ^NH CH3 15b Pd2(dba)3, XantPhos Cs2CO3, dioxane MW (110°C, 100W) 2 h ^NH CH3 15 Step 1: Synthesis of 3-(VA’-dimethylsulfoximino)-5-methylpyridin-2-amine (15a) 5 -Bromo-3-(AA-dimethylsulfoximino^yridin^-amine (8a) (100 mg, 0.38 mmol), palladium tetrakis(triphenylphosphine) (88 mg, 0.076 mmol) and cesium carbonate (124 mg, 0.38 mmol) were dissolved in a mixed solvent of dioxane (1.8 mL) and water (0.2 mL), and 3 M trimethyl epoxide borane in tetrahydrofuran (0.2 mL, 0.6 mmol)was added to the reaction solution, and the solution was reacted for 3 hours at 100°C under nitrogen atmosphere. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. After being concentrated, 3-(N,S-dimethylsulfoximino)-5-methylpyridin-2- amine (15a) (50 mg, white solid) was obtained by plate chromatography separation (methanol: dichloromethane = 1:10), yield 66%. 1H NMR (400 MHz, CDCI3) 5 8.09 (s, 1H), 7.82 (s, 1H), 5.82 (s, 2H), 3.07 (s, 3H), 2.68 (s, 3H), 2.26 (s, 3H). MS m / z [M+H]+: 200. Step 2: Synthesis of 6-chloro-4-((3-(7V,5'-dimethylsulfoximino)-5-metliylpyridin-2-yl)amino)- V-methylpyridazine-3-carboxamide (15b) The synthesis referenced the synthesis of 6-chloro-4-((3-(A(>S'-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide, yield 22%. MS m / z [M+H]+: 369. Step 3: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A / ,5'-dimethylsulfoximino)-5-methylpyridin-2-yl)amino)-. / V-methylpyridazine-3-carboxamide (15) The synthesis referenced the synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A(>S'-dimethylsulfoximino)pyridin-2-yl)amino)-7V-(methyl-£ / 3)pyridazine-3-carboxamide, yield 62%. 1H NMR (400 MHz, DMSO-^6) 8 11.77 (s, 1H), 11.34 (s, 1H), 9.38 (s, 1H), 9.06 (d, J = 4.3 Hz, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 3.19 (s, 3H), 2.84 (d, J = 4.1 Hz, 3H), 2.66 (s, 3H), 2.34 (s, 3H), 2.14 - 2.04 (m, 1H), 0.84 (d, J= 6.4 Hz, 4H). MS m / z [M+H]+: 418. Example 16 Preparation of 6-(cyclopropylcarboxamido)-4-((3-(A(>S'-dimethylsulfoximino)-5- (3-methoxypropoxy)pyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide Boc2O DMAP, RT (Bpin)2, KOAc Pd(dppf)2, dioxane 100 °C r then H2O2, RT 1) K2CO3,DMF 120°C,1 h , 2) HCI / dioxane DCM,rt,1 h 16a Pd2(dba)3, XantPhos Cs2CO3, DMF MW (110 °C, 120W) 1 h Step 1: Synthesis of 7V,7V-(di-tert-butoxycarbonyl)-5-bromo-3-(N,S-dimethylsulfoximino)pyridin-2-amine (16a) The synthesis referenced the synthesis of A; A%di-tcrt-butoxycarbonyl)-6-chloro-3-methylthiopyridin-2-amine, yield 91%. 1H NMR (400 MHz, CDCI3) 5 8.76 (s, 1H), 8.44 (s, 1H), 3.14 s, 3H), 2.63 (s, 3H), 1.52 (s, 9H), 1.44 (s, 9H). MS m / z [M+H]+: 464. Step 2:      Synthesis of V,V-(di-tert-biitoxycarboiiyl)-3-(V,.S- dimethylsulfoximino)-5-hydroxypyridin-2-amine (16b) The synthesis referenced the synthesis of 6-chloro-4-((3-(A,lS'-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, yield 96%. 1H NMR (400 MHz, CDC13) 8 8.38 (s, 1H), 7.83 (s, 1H), 3.16 (s, 3H), 2.70 (s, 3H), 1.53 (s, 9H), 1.44 (s, 9H). MS m / z [M+H]+: 402. Step 3:      Synthesis of 3-(Az,5'-dimethylsulfoximino)-5-(3- methoxypropoxy)pyridin-2-amine (16c) Anhydrous potassium carbonate (1.04 g, 7.5 mmol) was added to A,A-(di-tert-butoxycarbonyl)-3-(A,5,-dimethylsulfoximino)-5-hydroxypyridin-2-amine (16b) (500 mg, 1.25 mmol) in anhydrous DMF (10 mL), and stirred at room temperature for 10 min, 1 -bromo-3-methoxypropane (230 mg, 1.5 mmol) was added to the reaction solution, and stirred at 120°C for 1 hour. The reaction solution was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product as a yellow oil. The yellow oily crude was dissolved in dichloromethane (4 mL), and 4 M hydrogen chloride in dioxane (4 mL) was added at 0°C, heated up to room temperature and stirred for 1 hour. The solvent was concentrated and spin-dried, diluted with water, pH = 8 ~ 9 was adjusted by adding saturated sodium bicarbonate, 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 being concentrated, 3-(A,5-dimethylsulfoximino)-5-(3-methoxypropoxy)pyridin-2-amine (16c) (202 mg, yellow solid) was obtained by Flash separation (methanol / dichloromethane = 3 - 5%), yield 59%. 1H NMR (400 MHz, DMSO-6?6) 8 8.03 (d, J= 2.9 Hz, 1H), 7.45 (d, J = 2.9 Hz, 1H), 6.40 (s, 2H), 3.99 (t, J= 6.4 Hz, 2H), 3.45 (t, J = 6.3 Hz, 2H), 3.24 (s, 3H), 3.08 (s, 3H), 2.50 (s, 3H), 1.95 - 1.87 (m, 2H). MS m / z [M+H]+: 274. Step 4: Synthesis of 6-chIoro-4-((3-(A,5’-dimethylsulfoximino)-5-(3-methoxypropoxy)pyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide (16d) The synthesis referenced the synthesis of 6-chloro-4-((3-(A,>S,-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide, yield 39%. MS m / z [M+H]+: 443. Step 5: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A,5'-dimethylsulfoximino)-5-(3-methoxypropoxy)pyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide (16) The synthesis referenced the synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A,>S,-dimethylsulfoximino)pyridin-2-yl)amino)-A-(methyl-e / 3)pyridazine-3-carboxamide, yield 58%. 1HNMR(4OO MHz, DMSO-t / 6) 5 11.65 (s, 1H), 11.32 (s, 1H), 9.16 (s, 1H), 9.06 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 2.7 Hz, 1H), 7.75 (d, J = 2.7 Hz, 1H), 4.16 (t, J = 6.2 Hz, 2H), 3.48 (t, J = 6.2 Hz, 2H), 3.25 (s, 3H), 3.21 (s, 3H), 2.84 (d, J = 4.7 Hz, 3H), 2.66 (s, 3H), 2.13 - 2.06 (m, 1H), 2.02 - 1.92 (m, 2H), 0.84 (d, J= 1A Hz, 4H). MS m / z [M+H]+: 492. Example 17 Preparation of 6-(cyclopropylcarboxamido)-4-((3-(A5'-dimethylsulfoximino)-5-(2-(epoxybutan-3-yl)ethoxy)pyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide Steps 1,2 and 3: Synthesis of 3-(A,5-dimethylsulfoximino)-5-(2-(epoxybutan-3-yl)ethoxy)pyridin-2-amine (17c) A, A-(di-tcrt-butoxycarbonyl)-3-(AA’-dimcthylsulfoximino)-5-hydroxypyridin-2-amine (16b) (300 mg, 0.748 mmol), 3-hydroxyethyl oxetane (76 mg, 0.748 mmol) and triphenylphosphine (393 mg, 1.5 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and DIAD (303 mg, 1.5 mmol) was added under nitrogen atmosphere, and the reaction was carried out 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 being concentrated, crude A,A-(di-tert-butoxycarbonyl)-3-(A>S'-dimethylsulfoximino)-5-(2-(epoxybutan-3-yl)ethoxy)pyridin-2- amine (17a) (954 mg) was obtained by Flash separation (methanol / dichloromethane = 4 - 5%). Crude           A, A-(di-tert-butoxycarbonyl)-3 -(A, .S’-di methyl sul fox i m i no )-5 -(2- (epoxybutan-3-yl)ethoxy)pyridin-2-amine (17a) was dissolved in dichloromethane (10 mL), 4 N HC1 in dioxane (10 mL) was added, and the reaction was carried out for 30 min at room temperature, and concentrated to give crude 4-((6-amino-5-(A>S'-dimethylsulfoximino)pyridin-3-yl)-oxy)-2-(chloromethyl)-l -ol (17b). The crude 4-((6-amino-5 -(A 5’-di methy I sul fox i m i no )py ri di n-3 -yl)-oxy)-2-(chloromethyl)-l-ol (17b) was dissolved in ethanol (10 mL), potassium hydroxide (210 mg, 3.74 mmol) was added, and refluxed for 4 h. LCMS detection showed that the reaction was completed. The reaction solution was cooled to room temperature, ethanol was spin-dried, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and Flash separated (methanol / dichloromethane = 3-10%) to give 3-(N,S-dimethylsulfoximino)-5-(2-(epoxybutan-3-yl)ethoxy)pyridin-2-amine (17c) (62 mg, yellow solid), three-step yield 29%. 1H NMR (400 MHz, CDC13) 5 7.99 (d, J= 2.9 Hz, 1H), 7.57 (d, J= 3.0 Hz, 1H), 5.65 (s, 2H), 4.84 (dd, J= 7.8, 6.0 Hz, 2H), 4.49 (t, J= 6.2 Hz, 2H), 3.93 (t, J= 6.1 Hz, 2H), 3.22 (dt, J= 14.5, 7.2 Hz, 1H), 3.09 (s, 3H), 2.67 (s, 3H), 2.21 - 2.13 (m, 2H). MS m / z [M+H]+: 286. Step 4: Synthesis of 6-(chloro-4-((3-(7V,5'-dimethylsulfoximino)-5-(2-(epoxybiitan-3-yl)ethoxy)pyridin-2-yl)amino)-V-methylpyridazine-3-carboxamide (17d) The synthesis referenced the synthesis of 6-chloro-4-((3-(A(>S'-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide, yield 18%. MS m / z [M+H]+: 455. Step 5: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(7V,5'-dimethylsulfoximino)-5-(2-(epoxybutan-3-yl)ethoxy)pyridin-2-yl)amino)-AL methylpyridazine-3-carboxamide (17) The synthesis referenced the synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A(>S'-dimethylsulfoximino)pyridin-2-yl)amino)-7V-(methyl-£ / 3)pyridazine-3-carboxamide, yield 60%. 1H NMR (400 MHz, DMSO-^6) 8 11.64 (s, 1H), 11.32 (s, 1H), 9.16 (s, 1H), 9.06 (d, J= 4.9 Hz, 1H), 8.27 (d, J= 3.0 Hz, 1H), 7.71 (d, J= 3.0 Hz, 1H), 4.67 (dd, J= 7.9, 5.9 Hz, 2H), 4.36 (t, J= 6.1 Hz, 2H), 4.09 (td, J= 6.4, 2.4 Hz, 2H), 3.20 (s, 3H), 3.17 -3.11 (m, 1H), 2.83 (d, J= 4.8 Hz, 3H), 2.65 (s, 3H), 2.14 - 2.04 (m, 3H), 0.87 - 0.78 (m, 4H). MS m / z [M+H]+: 504. Example 18 Preparation of 6-(cyclopropylcarboxamido)-4-((3-(A(>S'-dimethylsulfoximino)-5-(2-morpholinocthoxy)pyridin-2-yl)amino)-'V-(mcthyl-<73)pyridazinc-3-carboxamidc —N ZO N(Boc)2 —N O N(Boc)2                          HN^% Br^Bf                , K2CO3, MeCN         O      K2CO3, DMF (1)H         80°C                ?         80°C 16b                         18a        Br d3c~NH o                   .4 n or I n         (A* N    .. P H     H    —NpHN     Cl       nh2 Cl         Cl                            Pd2(dba)3, XantPhos 2a__________||    ।            Cs2CO3, dioxane NaH,DMF,0°C to RT                      MW (110°C, 100W) °> 18d              1      1 N O N(Boc)2                 — N O NH2 I              HCI / dioxane            T CL       ---------*       °\ [           DCM, RT              | 18b                       18c      l^O D3C'NH FT -N 0 CL 18             1 Step 1: Synthesis of 5-(2-bromoethoxy)-3-(7V,5'-dimethylsulfoximino)pyridin-2-amine (18a) Af-(di-tert-butoxycarbonyl)-3-(7V,>S'-dimethylsulfoximino)-5-hydroxypyridin-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 solution was cooled to room temperature, filtered and the filter cake was washed with acetonitrile. The filtrate was concentrated and separated by column chromatography (ethyl acetate / petroleum ether = 10 - 65%) to obtain 5-(2-bromoethoxy)-3-(Af S-dimethylsulfoximino)pyridin-2-amine (18a) (462 mg, colorless oil), yield 91%. 1H NMR (400 MHz, CDC13) 5 8.40 (d, J= 2.9 Hz, 1H), 7.83 (d, J= 2.5 Hz, 1H), 4.42 (t, J= 5.9 Hz, 2H), 3.69 (t, J= 5.9 Hz, 2H), 3.15 (s, 3H), 2.62 (s, 3H), 1.51 (s, 9H), 1.43 (s, 9H). MS m / z [M+H]+: 508. Step 2:     Synthesis of V,V-(di-tert-biitoxycarbonyl)-3-(V,.S- dimethylsulfoximino)-5-(2-morpholinoethoxy)pyridin-2-amine (18b) 5-(2-Bromoethoxy)-3-(AfS-dimethylsulfoximino)pyridin-2-amine (18a) (300 mg, 0.59 mmol) was dissolved in DMF (4 mL), anhydrous potassium carbonate (245 mg, 1.77 mmol) and morpholine (154 mg, 1.77 mmol) were added, and stirred at 80 °C for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated and separated by column chromatography (methanol / dichloromethane = 0 - 6%) to obtain AyV-(di-tcrt-butoxycarbonyl)-3 -(N, .S’-di mcthy I sul fox i m i no )-5-(2-morphol i nocthoxy )py ri di n-2-amine (18b) (273 mg, colorless oil), yield 90%. MS m / z [M+H]+: 515. Step 3:      Synthesis of 3-(A^5'-dimethylsulfoximino)-5-(2- morpholinoethoxy)pyridin-2-amine (18c) 4 M hydrogen chloride in dioxane (2.5 mL) was slowly added dropwise to N,N-(di-tert-butoxycarbonyl)-3-(AfS-dimethylsulfoximino)-5-(2-morpholinoethoxy)pyridin-2- amine (18b) (287 mg, 0.558 mmol) in dichloromethane (5 mL) at 0°C, and stirred for 1 hour at room temperature. pH = 8~9 was adjusted by adding saturated sodium bicarbonate to the reaction solution, the solvent was spin-dried, 3-(A / S-dimethylsulfoximino)-5-(2-morpholinoethoxy)pyridin-2-amine (18c) (156 mg, light yellow solid) was obtained by column chromatography separation (methanol / dichloromethane = 0-9%), yield 89%. MS m / z [M+H]+: 315. Step 4: Synthesis of 6-chloro-4-((3-(7V,5,-dimethylsulfoximino)-5-(2-morpholinylethoxy)pyridin-2-yl)amino)-AL(methyl-< / 3)pyridazine-3-carboxamide (18d) The synthesis referenced the synthesis of 6-chloro-4-((3-(A / 5'-dimethylsulfoximino)pyridin-2-yl)amino)-7V-(methyl-£ / 3)pyridazine-3-carboxamide, yield 41%. 1H NMR (400 MHz, CDCI3) 5 12.21 (s, 1H), 8.83 (s, 1H), 8.27 (d, J= 3.0 Hz, 1H), 8.21 (s, 1H), 7.91 (d, J= 3.0 Hz, 1H), 4.21 (t, J= 5.5 Hz, 2H), 3.75 (t, J= 4.7 Hz, 4H), 3.22 (s, 3H), 2.87 - 2.81 (s, 5H), 2.59 (d, J= 4.9 Hz, 4H). MS m / z [M+H]+: 487. Step 5: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A / ,5'-dimethylsulfoximino)-5-(2-morpholinylethoxy)pyridin-2-yl)amino)-7V-(methyl-< / 3)pyridazine-3-carboxamide (18) The synthesis referenced the synthesis of 6-(cyclopropylcarboxamido)-4-((3-(7V,>S'-dimethylsulfoximino)pyridin-2-yl)amino)-7V-(methyl-£ / 3)pyridazine-3-carboxamide, yield 28%. 1HNMR(4OO MHz, DMSO-^6) 5 11.65 (s, 1H), 11.32 (s, 1H), 9.16 (s, 1H), 9.04 (s, 1H), 8.31 (d, J= 2.9 Hz, 1H), 7.77 (d, J= 2.9 Hz, 1H), 4.27 - 4.18 (m, 2H), 3.61 -3.54 (m, 4H), 3.20 (s, 3H), 2.70 (t, J= 5.5 Hz, 2H), 2.65 (s, 3H), 2.47 - 2.42 (m, 4H), 2.12 - 2.04 (m, 1H), 0.89 - 0.77 (m, 4H). MS m / z [M+H]+: 536. Example 19 Preparation of 4-((5-(3 -cyanopropoxy)-3-(N,5'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-7V-(methyl-d3)pyridazine-3-carboxamide (BPin)2, Pd(dppf)CI2 KOAc, dioxane, 100°C then H2O2, RT 8a                                19a K2CO3,DMF 40°C NaH, DMF, 0°C to RT Pd2(dba)3, XantPhos Cs2CO3, dioxane MW (110°C, 80W) Step 1: Synthesis of 6-amino-5-(7V,5'-dimethylsulfoximino)-3-hydroxypyridine (19a) The synthesis referenced the synthesis of 6-chloro-4-((3-(A^5'-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, yield 63%. 1H NMR (400 MHz, DMSO-^6) 8 9.29 (s, 1H), 7.86 (d, J= 2.9 Hz, 1H), 7.36 (d, J= 2.9 Hz, 1H), 6.16 (s, 2H), 3.05 (s, 3H), 2.48 (s, 3H). MS m / z [M+H]+: 202. Step 2: Synthesis of 4-((6-amino-5-(7V,5'-dimethylsulfoximino)pyridin-3-yl)oxybutyronitrile (19b) 4-bromobutyronitrile (172 mg, 1.16 mmol) was added to 6-amino-5-f'V,8’-dimethylsulfoximino)-3-hydroxypyridine (19a) (195 mg, 0.968 mmol) in DMF (4 mL), anhydrous potassium carbonate (535 mg, 3.87 mmol) was added, and the reaction solution was heated up to 40°C and stirred for 30 min. The reaction solution was cooled to room temperature and filtered, washed with ethyl acetate, the filtrate was concentrated and separated by column chromatography (methanol / dichloromethane = 1   -   2.5%) to obtain 4-((6-amino-5-(A(S-dimethylsulfoximino)pyridin-3- yl)oxybutyronitrile (19b) (148 mg, yellow solid), yield 57%. *H NMR (400 MHz, DMSO-< / 6) 5 8.06 (d, J = 3.0 Hz, 1H), 7.49 (d, J = 3.1 Hz, 1H), 6.44 (s, 2H), 4.03 (t, J = 6.0 Hz, 2H), 3.09 (s, 3H), 2.65 (t, J = 12 Hz, 2H), 2.51 (s, 3H), 1.99 (tt, J= 12, 6.0 Hz, 2H). MS m / z [M+H]+: 269. Step 3: Synthesis of 6-chloro-4-((5-(3-cyanopropoxy)-3-(7V,5'-dimethylsulfoximino)pyridin-2-yl)amino)-           V-(methyl-f / 3)pyridazine-3- carboxamide (19c) The synthesis referenced the synthesis of 6-chloro-4-((3-(A(>S'-dimethylsulfoximino)pyridin-2-yl)amino)-7V-(methyl-£ / 3)pyridazine-3-carboxamide, yield 49%. 1H NMR (400 MHz, CDCfi) 5 12.23 (s, 1H), 8.84 (s, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 7.89 (s, 1H), 4.21 (t, J = 5.7 Hz, 2H), 3.23 (s, 3H), 2.84 (s, 3H), 2.64 (t, J = 6.9 Hz, 2H), 2.26-2.17 (m, 2H). MS m / z [M+H]+: 441. Step 4:       Synthesis of 4-((5-(3-cyanopropoxy)-3-(7V,5- dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-AL (methyl-< / 3)pyridazine-3-carboxamide (19) The synthesis referenced the synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A(>S'-dimethylsulfoximino)pyridin-2-yl)amino)-7V-(methyl-£ / 3)pyridazine-3-carboxamide, yield 28%. 1H NMR (400 MHz, DMSO-t / 6) 8 11.67 (s, 1H), 11.33 (s, 1H), 9.19 (s, 1H), 9.04 (s, 1H), 8.31 (d,J=2.9Hz, 1H), 7.77 (d, J =2.9 Hz, 1H), 4.24 - 4.14 (m, 2H), 3.21 (s, 3H), 2.69 (t, J= 1A Hz, 2H), 2.66 (s, 3H), 2.13 - 2.00 (m, 3H), 0.88 - 0.79 (m, 4H). MS m / z [M+H]+: 490. Example 20 Preparation of 6-(cyclopropylcarboxamido)-4-((3-(A(>S'-dimethylsulfoximino)-5-((2-methoxyethyl)amino)pyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide (BPin)2, Pd(dppf)CI2 KOAc, dioxane 105°C Step 1: Synthesis of (6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(7V,5'-dimethylsulfoximino)pyridin-3-yl)boronic acid (20a) 4-((5-bromo-3-(AA-dimethylsulfoximino)pyridin-2-yl)amino)-6-chloro-A-methylpyridazine-3-carboxamide (8b) (140 mg, 0.324 mmol), bis(pinacolato)diboron (107 mg, 0.421 mmol), Pd(dppf)C12 (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 nitrogen atmosphere. After cooled 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 min. The reaction solution was diluted with water, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. (6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5 -(N, S-di methylsul fox i m i no )    pyridin-3 - yl)boronic acid (20a) (108 mg, gray solid) was obtained after being concentrated and beated with ethyl acetate, yield 83%. MS m / z [M+H]+: 399. Step 2: Synthesis of 6-chloro-4-((3-(A,5'-dimethylsulfoximino)-5-((2-methoxyethyl)amino)pyridin-2-yl)amino)-A-methylpyridazine-3-carboxamide (20b) Copper acetate monohydrate (10 mg, 0.063 mmol), 4A molecular sieve (20 mg) and 2-methoxyethylamine (19 mg, 0.252 mmol) were added in sequence to (6-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-5-(A>S'-dimethylsulfoximino)pyridin-3-yl)boronic acid (20a) (50 mg, 0.126 mmol) in dichloromethane (2 mL), and stirred overnight at 40°C under oxygen atmosphere. The reaction solution was concentrated and separated by plate chromatography (methanol: dichloromethane = 1:10) to obtain 6-chloro-4-((3-(A^5'-dimethylsulfoximino)-5-((2-methoxyethyl)amino)pyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide (20b) (5 mg, yellow solid), yield 9%. MS m / z [M+H]+: 428. Step 3: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A / ,5-dimethylsulfoximino)-5-((2-methoxyethyl)amino)pyridin-2-yl)amino)-AL methylpyridazine-3-carboxamide (20) The synthesis referenced the synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A(>S'-dimethylsulfoximino)pyridin-2-yl)amino)-7V-(methyl-£ / 3)pyridazine-3-carboxamide, yield 45%. 1HNMR(4OO MHz, DMSO-^6) 5 11.37 (s, 1H), 11.23 (s, 1H), 9.00 (s, 1H), 8.92 (s, 1H), 7.98 (d, J= 2.9 Hz, 1H), 7.49 (d, J= 2.9 Hz, 1H), 6.29 (s, 1H), 3.50 (t, J= 5.3 Hz, 2H), 3.30 - 3.27 (m, 5H), 3.11 (s, 3H), 2.83 (d, J= 4.8 Hz, 3H), 2.64 (s, 3H), 2.10 - 2.05 (m, 1H), 0.84 - 0.77 (m, 4H). MS m / z [M+H]+: 477. Example 21 Preparation of 4-((54)romo-3-(A(S-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-7V-methylpyridazine-3-carboxamide 5 NBS, MeCN 0°C 21 6-(cyclopropylcarboxamido)-4-((3-(A(>S'-dimethylsulfoximino)-6-methylpyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide (5) (10 mg, 0.024 mmol) was dissolved in acetonitrile (0.5 mL), and 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. The obtained was concentrated and prepared to obtain 21 (6 mg, yellow solid), yield 50%. 1HNMR(4OO MHz, DMSO-^6) 8 11.95 (s, 1H), 11.41 (s, 1H), 9.84 (s, 1H), 9.12 (d, J= 4.9 Hz, 1H), 8.17 (s, 1H), 3.26 (s, 3H), 2.84 (d, J= 4.7 Hz, 3H), 2.64 (s, 3H), 2.63 (s, 3H), 2.15 - 2.07 (m, 1H), 0.86 (d, J= 6.3 Hz, 4H). MS m / z [M+H]+: 496. Example 22 Preparation of 4-((6-amino-3-(A(S-dimethylsulfoximino)-5-fLuoropyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-7V-methylpyridazine-3-carboxamide 4-((6-Amino-3-(A,5-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-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, stirred at 35°C for 1 hour and 50°C for 1 hour. The DMF was evaporated to dryness under reduced pressure, separated by plate chromatography (methanol: dichloromethane = 1:15) and prepared by prep-HPLC to obtain 4-((6^111010-3-(^5-dimethylsulfoximino)-5-fluoropyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazin-3-carboxamide (22) (12 mg, white solid), yield 7%. 1HNMR(4OO MHz, DMSO-^6) 8 11.48 (s, 1H), 11.32 (s, 1H), 9.22 (s, 1H), 9.03 (d, J= 4.8 Hz, 1H), 7.60 (d, J= 10.3 Hz, 1H), 6.95 (s, 2H), 3.09 (s, 3H), 2.82 (d, J = 4.7 Hz, 3H), 2.60 (s, 3H), 2.13 - 2.05 (m, 1H), 0.84 (d, J= 6.5 Hz, 4H). MS m / z [M+H]+: 437. Example 23 Preparation of 4-(6-amino-5-chloro-3-(A,5-dimethylsulfoximino)pyridin-2- yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide NCS DMF, 60°C 4-((6-Amino-3-(A,5-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (7) (9 mg, 0.022 mmol) was dissolved in anhydrous DMF (1 mL), and NCS (3.5 mg, 0.024 mmol) was added in an ice bath, after the addition, the reaction was carried out at 60°C for 3 hours. The reaction solution was cooled to room temperature, quenched by saturated sodium bicarbonate (20 mL) and water (20 mL), extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The obtained was concentrated and prepared by prep-HPLC to obtain 4-(6-amino-5-chloro-3-(A,5-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (23) (4 mg, white solid), yield 41%. 1HNMR(4OO MHz, DMSO-^6) 5 11.59 (s, 1H), 11.36 (s, 1H), 9.41 (s, 1H), 9.06 (d, J= 4.9 Hz, 1H), 7.78 (s, 1H), 6.88 (s, 2H), 3.12 (s, 3H), 2.82 (d, J= 4.7 Hz, 3H), 2.60 (s, 3H), 2.17 - 2.02 (m, 1H), 0.85 (d, J= 6.9 Hz, 4H). MS m / z [M+H]+: 453. Example 24 Preparation of 4-((6-amino-5-bromo-3-(AyS’-dimcthylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide NBS, MeCN 0°C ^NH Br 24 4-((6-Amino-3-(A,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-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, and stirred for 3 hours at 0°C. After being concentrated and Flash separated to obtain (methanol / dichloromethane = 0 - 5.5%), 4-((6-amino-5-bromo-3-(A5'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (24) (15 mg, yellow solid) was obtained, yield 44%. 1HNMR(4OO MHz, DMSO-t / 6) 8 11.60 (s, 1H), 11.35 (s, 1H), 9.47 (s, 1H), 9.05 (d, J = 5.0 Hz, 1H), 7.90 (s, 1H), 6.77 (s, 2H), 3.13 (s, 3H), 2.82 (d, J = 4.8 Hz, 3H), 2.61 (s, 3H), 2.10 (q, J= 62 Hz, 1H), 0.86 (d, J= 6.6 Hz, 4H). MS m / z [M+H]+: 497. Example 25 Preparation of 4-(6-amino-5-chloro-3-(A,5'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-A-(methyl-t / 3)pyridazine-3-carboxamide Pd2(dba)3, Xantphos Cs2CO3, DMF 125°C, 3 h Pd2(dba)3, XantPhos Cs2CO3, xylene 145°C 6N HCI (aq.) r THF, RT,15 min Step 1:       Synthesis of 6-chloro-4-((6-chloro-3-(A,5'- dimethylsulfoximino)pyridin-2-yl)amino)-A-(methyl-< / 3)pyridazine-3- carboxamide (25a) Sodium hydride (2.7 g, 67.1 mmol) was added in batches to 6-chloro-3-(AA- dimethylsulfoximino)pyridin-2-amine (6f) (4.9 g, 22.37 mmol) in tetrahydrofuran (120 mL), and stirred for 15 min, 4,6-dichloro-7V-(methyl-£ / 3)pyridazine-3-carboxamide (2a) (5.6 g, 26.8 mmol) was added, after the addition, and stirred at 65°C for 1 hour. The reaction was quenched by ammonium chloride (80 mL) and water (40 mL), extracted with dichloromethane (300 mL), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The obtained was concentrated, the crude product was beated with methyl tert-butyl ether, suction filtered, the filter cake was washed with methyl tert-butyl ether, and dried to obtain 6-chloro-4-((6-chloro-3-(A(5-dimethylsulfoximino)pyridin-2-yl)amino)-7V-(methyl-£ / 3)pyridazine-3-carboxamide (25a) (6.8 g, earthy brown solid), yield 77%. 1H NMR (400 MHz, DMSO-< / 6) 8 12.22 (s, 1H), 9.34 (s, 1H), 8.78 (s, 1H), 8.22 (d, J= 8.2 Hz, 1H), 7.42 (d, J= 8.1 Hz, 1H), 3.24 (s, 3H), 2.68 (s, 3H). MS m / z [M+H]+: 393. Step 2: Synthesis of 6-chloro-4-((3-(7V,5-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-AL(methyl-< / 3)pyridazine-3-carboxamide (25b) The synthesis referenced the synthesis of 6-chloro-4-((3-(A(5-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide, yield 82%. *H NMR (400 MHz, DMSO-^6) 8 11.95 (s, 1H), 9.24 (s, 1H), 8.47 (s, 1H), 8.05 (d, J= 8.3 Hz, 1H), 7.41 (s, 10H), 6.79 (d, J= 8.3 Hz, 1H), 3.16 (s, 3H), 2.62 (s, 3H). MS m / z [M+H]+: 538. Step 3: Synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A / ,5-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-AL (methyl-< / 3)pyridazine-3-carboxamide (25c) The synthesis referenced the synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A(5-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide, the crude product was not separated and directly used in the next step of the reaction. MS m / z [M+H]+: 586. Step 4: Synthesis of 4-((6-amino-3-(7V,5-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-AL(methyl-< / 3)pyridazine-3-carboxamide (25d) The synthesis referenced the synthesis of 4-((6-amino-3-(M5-dimcthylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide, two-step yield 63%. *H NMR (400 MHz, DMSO-t / 6) 8 11.55 (s, 1H), 11.32 (s, 1H), 9.49 (s, 1H), 8.99 (s, 1H), 7.73 (d, J= 8.5 Hz, 1H), 6.56 (s, 2H), 6.23 (d, J= 8.7 Hz, 1H), 3.05 (s, 3H), 2.61 (s, 3H), 2.09 (s, 1H), 0.85 (d, J= 6.7 Hz, 4H). MS m / z [M+H]+: 422. Step 5:        Synthesis of 4-(6-amino-5-chloro-3-(7V,5- dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-AL (methyl-< / 3)pyridazine-3-carboxamide (25) The synthesis referenced the synthesis of 4-(6-amino-5-chloro-3-(A(5- dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide, yield 50%. 1HNMR(4OO MHz, DMSO-t / 6) 5 11.61 (s, 1H), 11.37 (s, 1H), 9.43 (s, 1H), 9.04 (s, 1H), 7.79 (s, 1H), 6.89 (s, 2H), 3.13 (s, 3H), 2.61 (s, 3H), 2.15 - 2.08 (m, 1H), 0.86 (d, J=1A Hz, 4H). MS m / z [M+H]+: 456. Example 26 Preparation of 4 -((6-amino-3-(A,S-dimethylsulfoximino)-5-methylpyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide ^NH Br MeB(OH)2, Pd(OAc)2 Sphos, CsCO3 dioxane, 100°C, 2 h 24                                        26 4-((6-Amino-5-bromo-3-(A,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (24) (160 mg, 0.322 mmol) was dissolved in dioxane (4 mL), tetrakis(triphenylphosphine)palladium (110 mg, 0.096 mmol), anhydrous potassium carbonate (230 mg, 1.66 mmol) and methylboronic acid (496 mg, 1.66 mmol) were added, and the reaction was carried out in microwave (120°C, 120W) under nitrogen atmosphere for 1 hour. After the reaction solution was cooled to room temperature, dichloromethane was added, stirred and then filtered, the filter cake was washed with dichloromethane, and the filtrate was concentrated and Flash separated (methanol / dichloromethane = 1:20) to obtain 4 -((6-amino-3-(A,5-dimethylsulfoximino)-5-methylpyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazin-3-carboxamide (26) ( 89 mg, yellow solid), yield 64%. 1HNMR(4OO MHz, DMSO-^6) 8 11.51 (s, 1H), 11.30 (s, 1H), 9.51 (s, 1H), 9.00 (d, J= 4.9 Hz, 1H), 7.58 (s, 1H), 6.36 (s, 2H), 3.04 (s, 3H), 2.82 (d, J = 4.6 Hz, 3H), 2.60 (s, 3H), 2.09 (dd, J= 11.3, 5.5 Hz, 1H), 2.06 (s, 3H), 0.85 (d, J= 7.0 Hz, 4H). MS m / z [M+H]+: 433. Example 27 Preparation of 4-((6-amino-3-(A,S-dimethylsulfoximino)-5-methoxypyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (BPin)2, Pd(dppf)2 KOAc, dioxane 100°C,1 h then H2O2, RT OH 27a Mel,K2CO3 DMF.rt Step 1: Synthesis of 4-((6-amino-3-(7V,5'-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-6-(cyclopropykarboxamido)-A-methylpyridazine-3-carboxamide (27a) Bis(pinacolato)diboron (77 mg, 0.30 mmol, 1.5 eq), potassium acetate (49 mg, 0.50 mmol) and Pd(PPh)2C12 (28 mg, 0.04 mmol) were added to a suspension of 4-((6-amino-5 -bromo-3 -(N, S-dimethylsulfoximino)pyridin-2-y l)amino)-6-(cyclopropylcarboxamido)-N-methylpyridazine-3-carboxamide (24) (100 mg, 0.20 mmol) in toluene (3 mL), and the reaction was carried out at 100°C under nitrogen for 1 hour, followed by addition of Pd(PPh)2C12 (28 mg, 0.04 mmol, 0.2 eq) and continued to react for 1 hour. The reaction solution was cooled to room temperature, tetrahydro furan (3 mL) and hydrogen peroxide (0.10 mL, 0.88 mmol) were added, and the reaction solution was stirred at room temperature for 30 min. The reaction was quenched with water (20 mL), diluted with dichloromethane, suction fdtered and the filter cake was washed with dichloromethane. The filtrate was separated by Flash (methanol / dichloromethane =     1:10) to obtain 4-((6-amino-3-(A'',5’- dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-7V-methylpyridazine-3-carboxamide (27a) (30 mg, brownish yellow solid), yield 28%. *HNMR(400 MHz, DMSO-< / 6) 5 11.27 (s, 1H), 11.23 (s, 1H), 9.88 (s, 1H), 9.12 (s, 1H), 8.99 (d, J= 4.7 Hz, 1H), 7.24 (s, 1H), 6.29 (s, 2H), 3.01 (s, 3H), 2.81 (d, J = 4.6 Hz, 3H), 2.59 (s, 3H), 2.12 - 2.04 (m, 1H), 0.83 (d, J= 7.2 Hz, 4H). MS m / z [M+H]+: 435. Step 2: Synthesis of 4-((6-amino-3-(7V,5'-dimethylsulfoximino)-5-methoxypyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (27) 4-((6-Amino-3-(AA-dimethylsulfoximino)-5-hydroxypyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (27a) (10 mg, 0.023 mmol) was dissolved in DMF (0.6 mL), potassium carbonate (5 mg, 0.034 mmol) and methyl iodide (3.3 mg 0.023 mmol) were added, stirred at room temperature for 20 minutes. The reaction solution was quenched with water (5 mL), extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The obtained was concentrated and prepared by prep-HPLC to obtain 4-((6-amino-3-(N,5'-dimethylsulfoximino)-5-methoxypyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (27) (2.2 mg, white solid), yield 22%. *HNMR(400 MHz, DMSO-t / 6) 8 11.35 (s, 1H), 11.26 (s, 1H), 9.13 (s, 1H), 9.00 (d, J= 4.8 Hz, 1H), 7.27 (s, 1H), 6.54 (s, 2H), 3.81 (s, 3H), 3.05 (s, 3H), 2.82 (d, J = 4.5 Hz, 3H), 2.60 (s, 3H), 2.12 - 2.04 (m, 1H), 0.83 (d, J= 6.6 Hz, 4H). MS m / z [M+H]+: 449. Example 28 Preparation of (R)-4-((6-amino-5-chloro-3-(A>S'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarbonyl)-A-(methyl-t / 3)pyridazine-3-carboxamide 6a VO(acac)2, H2O2 PhMe / DCM, RT 3N HCI(aq.) 50°C RIDA, H2NCO2NH .. MeOH, 30°C HN ,0 NH2 MeB(OH)2, Cu(OAc)2 Pyridine / DMF, 02 80°C 28c Cl 28d d°c'nh Ph 28g Pd2(dba)3, xantphos Cs2CO3, DMF 125°C, 4h Step 1: Synthesis of (R)-N-(6- chloro-3-(methylsulfinyl)pyridin-2-yl)trimethylacetamide (28b) The synthesis of (77?,2S)-l-(3,5-dichloro-2-hydroxybenzylidene)amino-2-indanol (28a) referenced Comptes Rendus Chimie, 2014, 17(5), 403 - 412. f / R,2SJH-Amino-2-indanol (61.5 g, 0.413 mmol) and3,5-dichlorosalicylaldehyde (78.8 g, 0.413 mmol) were dissolved in anhydrous methanol (1.5 L), and stirred at 70°C for 1 hour. Methanol was removed under reduced pressure, heated with petroleum ether, suction fdtered and dried to obtain f / 7?,2S)-l-(3,5-dichloro-2-hydroxybenzylidene)amino-2-indanol (28a) (131 g, yellow solid), yield 99%. 1H NMR (400 MHz, DMSO-t / 6) 5 14.79 (s, 1H), 8.70 (s, 1H), 7.56 (t, J= 2.0 Hz, 1H), 7.48 (t, J = 1.9 Hz, 1H), 7.31 (q, J = 7.7, 7.3 Hz, 2H), 7.24 (d, J = 5.8 Hz, 2H), 5.55 (d, J = 4.8 Hz, 1H), 5.06 (d, J= 5.3 Hz, 1H), 4.60 (t, J = 4.6 Hz, 1H), 3.15 (dd, J = 16.1,5.7 Hz, 1H), 2.91 (dd, J= 16.1, 4.0 Hz, 1H). MS m / z [M+H]+: 322. f / R,2S)-l-(3,5-dichloro-24iydroxybenzylidene)amino-2-indanol (28a) (4.62 g, 14.4 mmol) and alum acetylacetonate oxide (2.38 g, 9.0 mmol) were added to a solvent mixture of toluene and dichloromethane (10:1, 930 mL), and stirred for 20 min until completely dissolved. A-(6-chloro-3-(methylthio)pyridin-2-yl)trimethylacetamide (6a) (46.4 g, 179.8 mmol) was added and stirred for 20 min. Hydrogen peroxide (26.5 g, 234.0 mmol) was added dropwise in an ice bath, after the addition, and stirred at room temperature for 2 h. Hydrogen peroxide (3.6 mL, 36.0 mmol) was added and the reaction was continued for 1 hour. The reaction was quenched with saturated sodium sulfite solution (150 mL), extracted with ethyl acetate, the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The obtained was concentrated and beated with a mixture of isopropanol (40 ml) and petroleum ether (280 mL), suction filtered, and the filtrate was separated by Flash (ethyl acetate / petroleum ether = 1:1) to obtain (R)-Af-(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%. 1H NMR (400 MHz, CDC13) 5 8.59 (s, 1H), 8.11 (d,J=8.2 Hz, 1H), 7.27 (d,J = 8.2 Hz, 1H), 2.94 (s, 3H), 1.26 (s, 9H). MS m / z [M+H]+: 275. Step 2: Synthesis of (l?)-6-chloro-3-(methylsulfinyl)-pyridin-2-amine (28c) (7?)-77-(6- chloro-3-(methylsulfinyl)pyridin-2-yl)trimethylacetamide (28b) (50.2 g, 0.183 mol) was added to an aqueous 3 N hydrochloric acid solution (610 mL, 1.832 mol), and stirred at 50°C for 5 hours. In an ice bath, pH = 9 ~ 10 was adjusted with aqueous potassium carbonate (40%), the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The obtained was concentrated and beated with a mixture of dichloromethane / petroleum ether (2:3, 100 mL), suction filtered, the filter cake was washed 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%. 1H NMR (400 MHz, CDCI3) 5 7.42 (d, J= 7.8 Hz, 1H), 6.69 (d, J= 7.8 Hz, 1H), 6.07 (s, 2H), 2.89 (s, 3H). MS m / z [M+H]+: 191. Step 3: Synthesis of (l?)-6-chloro-3-(5-methylsulfoximino)pyridin-2-amine (28d) The synthesis referenced the synthesis of 3-(5-methylsulfoximino)-2-nitropyridine, yield 70%. 1H NMR (400 MHz, CDCI3) 5 7.98 (d, J= 8.1 Hz, 1H), 6.76 (d, J= 8.1 Hz, 1H), 6.35 (s, 2H), 3.11 (s, 3H), 2.46 (s, 1H). MS m / z [M+H]+: 206. Step 4: Synthesis of (l?)-6-chloro-3-(A / ,5-dimethylsulfoximino)pyridin-2-amine (28e) (R)-6-chloro-3-(S-methylsulfoximino)pyridin-2-amine (28d) (11.63 g, 56.7 mmol), methylboronic acid (8.16 g, 136.1 mmol) and copper acetate (15.5 g, 85 mmol) were dissolved in a mixture of anhydrous DMF (69 mL) and pyridine (46 mL), and the reaction was carried out under oxygen atmosphere at 80°C for 4 hours. The reaction solution was cooled to room temperature, suction filtered, and the filter cake was washed with ethyl acetate, the filtrate was added with water (200 mL) and ammonia (60 mL), extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The obtained was concentrated and separated by column chromatography (ethyl acetate / petroleum ether = 40   - 50%) to obtain (7?)-6-chloro-3-(7V,5- dimethylsulfoximino)pyridin-2- amine (28e) (8.69 g, light yellow solid), ee value 98.2%, yield 70%. 1H NMR (400 MHz, CDCI3) 5 7.91 (d, J= 8.0 Hz, 1H), 6.78 (d, J= 8.1 Hz, 1H), 6.26 (s, 2H), 3.07 (s, 3H), 2.68 (s, 3H). MS m / z [M+H]+: 220. Step 5:       Synthesis of (l?)-6-chloro-4-((6-chloro-3-(A / ,5- dimethylsulfoximino)pyridin-2-yl)amino)-AL(methyl-< / 3)pyridazine-3-carboxamide (28f) The synthesis referenced the synthesis of 6-chloro-4-((6-chloro-3-(7V,S-dimethylsulfoximino)pyridin-2-yl)amino)-7V-(methyl-£ / 5)pyridazine-3-carboxamide, yield 79%. 1HNMR(4OO MHz, DMS0-< / 6) 8 12.21 (s, 1H), 9.32 (s, 1H), 8.78 (s, 1H), 8.22 (d, J= 8.1 Hz, 1H), 7.42 (d, J= 8.1 Hz, 1H), 3.24 (s, 3H), 2.68 (s, 3H). MS m / z [M+H]+: 393. Step 6: Synthesis of (7?)-6-chloro-4-((3-(7V,5'-dimethylsulfoximino)-6-((diphenylmethykne)amino)pyridin-2-yl)amino)-7V-(methyl-4 / 3)pyridazine-3-carboxamide (28g) The synthesis referenced the synthesis of 6-chloro-4-((3-(A^lS'-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide, yield 68%. MS m / z [M+H]+: 538. Step 7: Synthesis of (7?)-6-(cyclopropylcarboxamido)-4-((3-(Az,JS'-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-7V-(methyl-* / 3)pyridazine-3-carboxamide (28h) The synthesis referenced the synthesis of 6-(cyclopropylcarboxamido)-4-((3-(7V,S,-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-JV-methylpyridazine-3-carboxamide, yield 91%. MS m / z [M+H]+: 586. Step 8: Synthesis of (7?)-4-((6-amino-3-(Az,5'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropykarboxamido)-7V-(methyl-< / 3)pyridazine-3-carboxamide (28i) The synthesis referenced the synthesis of 4-((6-amino-3-(A^S’-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-7V-methylpyridazine-3-carboxamide, yield 69%. 1HNMR(4OO MHz, DMSO-6?6) 8 11.55 (s, 1H), 11.30 (s, 1H), 9.50 (s, 1H), 8.98 (s, 1H), 7.73 (d, J= 8.6 Hz, 1H), 6.54 (s, 2H), 6.23 (d, J = 8.6 Hz, 1H), 3.05 (s, 3H), 2.61 (s, 3H), 2.14-2.05 (m, 1H), 0.90 - 0.82 (m, 4H). MS m / z [M+H]+: 422. Step 9:       Synthesis of (7f)-4-((6-amino-5-chloro-3-(A / ,5'- dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-A / -(methyl-< / 3)pyridazine-3-carboxamide (28) The synthesis referenced the synthesis of 4-(6-amino-5-chloro-3-(A^lS'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformamido)-jV-methylpyridazine-3-carboxamide with an ee value of 98.2% and a yield of 50%. 1HNMR(4OO MHz, DMSO-O 8 11.59 (s, 1H), 11.34 (s, 1H), 9.43 (s, 1H), 9.01 (s, 1H), 7.78 (s, 1H), 6.86 (s, 2H), 3.12 (s, 3H), 2.61 (s, 3H), 2.15-2.06 (m, 1H), 0.85 (d, J =6.1 Hz, 4H). MS m / z [M+H]+: 456. The asymmetric synthesis of the chiral fragment (7?)-6-chloro-3-(methylsulfinyl)-pyridin-2-amine (28c) can also be achieved by the following route: 28j VO(acac)2, H2O2 PhMe / DCM, RT Step 1: Synthesis of (l?)-3,6-dichloro-AL(l-(4-methoxyphenyl)ethyl)-2-pyridinecarboxamide (28j) 3, 6-Dichloro-2-pyridinecarboxylic acid (5 g, 26.04 mmol) was dissolved in anhydrous DMF (20 mL), and AL'V-carbonyldiimidazolc (4.64 g, 28.65 mmol) was added in batches, after the addition, and the solution was stirred at room temperature for 20 minutes. The reaction solution was cooled to 0°C, and (R)-(+)~1-(4-methoxyphenyl)ethylamine (4.33 g, 28.65 mmol) was added dropwise, the internal temperature was controlled to be less than 10°C, after the addition, and the solution was continued to be stirred at room temperature for 1.5 hours. The reaction was quenched with water (60 mL), continued to be stirred for 1 hour, suction filtered, and the filter cake was washed with distilled water. The filter cake was dissolved in dichloromethane, washed with 1% HC1, and dried over anhydrous sodium sulfate. The obtained was concentrated to obtain (7?)-3,6-dichloro-7V-(l-(4-methoxyphenyl)ethyl)-2-pyridinecarboxamide (28j) (7.77 g, white solid), yield 92%. 1H NMR (400 MHz, CDC13) 5 7.80 (d, J= 7.3 Hz, 1H), 7.76 (d, J= 8.4 Hz, 1H), 7.39 - 7.31 (m, 3H), 6.90 (d, J= 8.5 Hz, 2H), 5.28 - 5.20 (m, 1H), 3.81 (s, 3H), 1.61 (d, J =6.9 Hz, 3H). MS m / z [M+H]+: 325. Step 2: Synthesis of (l?)-6-chloro-AL(l-(4-methoxyphenyl)ethyl)-3-(methylthio)-2-pyridinecarboxamide (28k) ( / ?)-3,6-dichloro-'V-( l-(4-mcthoxyphcnyl (ethyl )-2-pyridinccarboxam ide (28j) (7.2 g, 22.15 mmol) was dissolved in DMF (35 mL), and 20% aqueous sodium methyl mercaptide (11.6 g, 33.23 mmol) was slowly added dropwise at room temperature, after the addition, and the solution was continued to be stirred at room temperature for 1 hour. The reaction was quenched with water (100 mL) and stirred for 2 h at room temperature, suction filtered and the filter cake was washed with distilled water. The filter cake was dissolved in dichloromethane, washed with saturated brine and dried over anhydrous sodium sulfate. The obtained was concentrated and separated by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain (R)-6-chloro-Af-(l-(4-methoxyphenyl)ethy 1)-3-(methylthio)-2-pyridinecarboxamide (28k) (4.84 g, white solid), yield 65%. 1H NMR (400 MHz, CDCI3) 5 8.03 (d, J= 7.5 Hz, 1H), 7.58 (d, J= 8.4 Hz, 1H), 7.41 - 7.29 (m, 3H), 6.89 (d, J = 8.0 Hz, 2H), 5.31 - 5.19 (m, 1H), 3.80 (s, 3H), 2.40 (s, 3H), 1.60 (d, J = 7.6 Hz, 3H). MS m / z [M+H]+: 337. Step 3: Synthesis of 6-chloro-AL((l?)-l-(4-methoxyphenyl)ethyl)-3-((l?)-methylsulfinyl)-2-pyridinecarboxamide (281) The synthesis referenced the synthesis of (R)-7V-(6-chloro-3-(methylsulfinyl)pyridin-2-yl)trimethylacetamide, ethanol was used for recrystallization in post-treatment, yield 64% and d.e. value 99.9%. 1H NMR (400 MHz, CDC13) 5 8.55 (d, J= 8.3 Hz, 1H), 7.97 (d, J= 8.0 Hz, 1H), 7.63 (d, J= 8.2 Hz, 1H), 7.24 (d, J= 8.5 Hz, 2H), 6.83 (d, J= 8.4 Hz, 2H), 5.17 - 5.07 (m, 1H), 3.73 (s, 3H), 2.87 (s, 3H), 1.55 (d, J= 6.9 Hz, 3H). MS m / z [M+H]+: 353. Step 4: Synthesis of (l?)-6-chloro-3-(methylsulfinyl)-2-pyridinecarboxamide (28m) 6-Chloro-N-((R)-l-(4-methoxyphenyl)ethyl)-3-((R)-methylsulfinyl)-2-pyridinecarboxamide (281) (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 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. The obtained was concentrated, beated with a mixture of dichloromethane / petroleum ether (1:10, 100 mL) and suction filtered to obtain (R)-6-chloro-3-(methylsulfinyl)-2-pyridinecarboxamide (281) (3.4 g, white solid), yield 92%. 1H NMR (400 MHz, CDCI3) 5 8.65 (d, J= 8.3 Hz, 1H), 7.81 - 6.76 (m, 2H), 6.03 (s, 1H), 2.92 (s, 3H). MS m / z [M+H]+: 219. Step 5: Synthesis of (7?)-6-chloro-3-(methylsulfinyl)-pyridin-2-amine (28c) (R)-6-chloro-3-(methylsulfmyl)-2-pyridinecarboxamide (281) (55 g, 0.252 mol) was dissolved in dioxane (250 mL), 10% aqueous sodium hydroxide (250 mL) precooled to 0°C was added, 7.5% aqueous sodium hypochlorite (180 g, 0.378 mol) was added dropwise at room temperature, after the addition, and stirred for 1 hour at 70°C. The reaction solution was cooled to room temperature and quenched by dropwise addition of saturated sodium sulfite solution (10 mL) until the starch potassium iodide test paper did not change color, and diluted by adding saturated saline. The obtained was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The obtained was concentrated and beated by adding dichloromethane (100 mL) and petroleum ether (100 mL), suction filtered and washed with petroleum ether, dried to obtain (7?)-6-chloro-3-(methylsulfinyl)-pyridin-2-yl-amine (28c) (39.4 g, white solid), yield 82%. 1H NMR (400 MHz, CDCI3) 5 7.42 (d, J= 7.8 Hz, 1H), 6.69 (d, J= 7.8 Hz, 1H), 6.07 (s, 2H), 2.89 (s, 3H). MS m / z [M+H]+: 191. Example 29 Preparation of (7?)-4-((6-amino-5-chloro-3-(S-methylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A^-(methyl-f / 3)pyridazine-3-carboxamide HN O N(Boc)2 6d ci 1)Py, NsCI RT, 1h 2) HCI / dioxane DCM, RT, 1 h 29a 2a NaH, THF, 60 °C, 2 h 29b Pd2(dba)3, XantPhos Cs2CO3, dioxane MW (130°C, 120W) 1 h Pd2(dba)3, Xantphos Cs2CO3, dioxane 110°C,1 h Step 1: Synthesis of 6-chloro-3-(S-methyl-7V-(4-nitrophenylsulfonyl)-sulfoximino)pyridin-2-amine (29a) A^A^(di-tert-butoxycarbonyl)-6-chloro-3-(S-methylsulfoximino)pyridin-2-amine (6d) (2.05 g, 5.06 mmol) was dissolved in anhydrous pyridine (30 mL), and p-nitrobenzenesulfonyl chloride (1.34 g, 6.07 mmol) was added slowly at room temperature, and stirred for 2 hours. The reaction was quenched with water (60 mL), extracted with ethyl acetate, the organic phases were combined, washed with IN hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product (yellow solid, 3.3 g). The crude product was dissolved in dichloromethane (10 mL), 4 M hydrogen chloride in dioxane (10 mL) was added in an ice-water bath, and stirred for 1 hour at room temperature. The obtained was concentrated and diluted with water, pH = 8~9 was adjusted 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-7V-(4-nitrophenylsulfonyl)-sulfoximino)pyridin-2-amine (29a) (1.68 g, yellow solid), yield 85%. 1H NMR (400 MHz, DMSO-^6) 8 8.34 (d, J= 8.8 Hz, 2H), 8.00 (d, J= 8.8 Hz, 2H), 7.89 (d, J= 8.3 Hz, 1H), 7.28 (s, 2H), 6.82 (d, J= 8.3 Hz, 1H), 3.65 (s, 3H). MS m / z [M+H]+: 391. Step 2:     Synthesis of 6-chloro-4-((6-chloro-3-(S-methyl-AL(4- nitrobenzenesulfonyl)sulfoximino)pyridin-2-yl)amino)-. / V-(methyl-< / 3)pyridazine-3-carboxamide (29b) The synthesis referenced the synthesis of 6-chloro-4-((6-chloro-3-(A^5'-dimethylsulfoximino)pyridin-2-yl)amino)-7V-(methyl-d3)pyridazine-3-carboxamide, yield 50%. 1HNMR (400 MHz, DMSO-t / 6) 5 12.29 (s, 1H), 9.50 (s, 1H), 8.71 (s, 1H), 8.38 (d, J= 8.4 Hz, 1H), 8.20 (d, J= 8.6 Hz, 2H), 7.93 (d, J= 8.7 Hz, 2H), 7.54 (d, J= 8.3 Hz, 1H), 3.82 (s, 3H). MS m / z [M+H]+: 563. Step 3: Synthesis of 6-chloro-4-((6-((diphenylmethylene)amino)-3-(S-methyl-AL((4-nitrobenzenesulfonyl)sulfoximino)pyridin-2-yl)amino)-AL(methyl-< / 3)pyridazine-3-carboxamide (29c) The synthesis referenced the synthesis of 6-chloro-4-((3-(A^5'-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl)amino)-7V-methylpyridazine-3-carboxamide, dioxane was used as the solvent instead of DMF, reaction temperature was 110 °C, yield 25%. 1H NMR (400 MHz, DMSO-^6) 5 11.89 (s, 1H), 9.40 (s, 1H), 8.27 (s, 1H), 8.21 (d, J= 8.5 Hz, 1H), 8.03 (d, J= 8.4 Hz, 2H), 7.68 (d, J= 8.4 Hz, 2H), 7.59 - 7.45 (m, 10H), 6.98 (d, J= 8.5 Hz, 1H), 3.76 (s, 3H). MS m / z [M+H]+: 708. Step 4:      Synthesis of 6-(cyclopropylcarboxamido)-4-((6- ((diphenylmethylene)amino)-3-(5'-methyl-AL((4-nitrophenylsulfonyl)sulfoximino)pyridin-2-yl)amino)-AL(methyl-< / 3)pyridazine-3-carboxamide (29d) The synthesis referenced the synthesis of 6-(cyclopropylcarboxamido)-4-((3-(A^5'-dimethylsulfoximino)pyridin-2-yl)amino)-7V-(methyl-£ / 3)pyridazine-3-carboxamide, the reaction was completed and processed without separation, and the crude product was used directly in the next step. MS m / z [M+H]+: 757. Step 5: Synthesis of 4-((6-amino-3-(S-methyl-AL(4-nitrobenzenesulfonyl)-sulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-< / 3)pyridazine-3-carboxamide (29e) The synthesis referenced the synthesis of 4-((6-amino-3-(A^>S'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-7V-methylpyridazine-3-carboxamide using the crude product 29d instead of 6-(cyclopropylcarboxamido)-4-((3-(Af,S-dimethylsulfoximino)-6-((diphenylmethylene)amino)pyridin-2-yl )amino)-7V-methylpyridazine-3-carboxamide, two-step yield 43%. MS m / z [M+H]+: 593. Step 6:       Synthesis of (l?)-4-((6-amino-5-chloro-3-(S- methylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-AL(methyl-< / 3)pyridazine-3-carboxamide (29) NCS (248 mg, 1.86 mmol) was added to 4-((6-amino-3-(S-methyl-7V-(4-nitrobenzenesulfonyl)-sulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)- A-(methyl-53)pyridazine-3-carboxamide (29e) (1.1 g, 1.86 mmol) in anhydrous DMF (20 mL), and stirred at 60°C for 1 hour. After cooled to room temperature, the reaction was quenched by adding saturated aqueous sodium sulfite solution (10 mL) and water (80 mL) to the reaction solution, stirred for 10 minutes and then suction filtered. The filter cake was washed with water, dried and then beated with dichloromethane and filtered to obtain the chlorinated crude product (380 mg, earthy yellow solid). Aqueous potassium hydroxide (851 mg, 15.2 mmol) (1 mL) was added to p-methoxybenzenethiol (2.18 g, 15.6 mmol) in acetonitrile (5 mL), stirred for 5 minutes, and the chlorinated crude product (380 mg) was added, and continued to be stirred for 1 hour at room temperature. The reaction was quenched by the addition of saturated potassium carbonate solution, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. The obtained was concentrated and Flash separated (methanol: dichloromethane = 1:10) to obtain the racemic compound 4-((6-amino-5-chloro-3-(S-methylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-(methyl-53)pyridazine-3-carboxamide (250 mg, yellow solid), yield 30%. The racemic compound was subjected to SFC chiral splitting to afford (5)-4-((6-amino-5 -chloro-3-(5-mcthy I sul fox i m i no )py ri di n-2-y I )am i no )-6-(cyclopropylcarboxamido)-A-(methyl-53)pyridazine-3-carboxamide (29f) (85 mg, white solid, yield 10%) and     (5)-4-((6-amino-5-chloro-3-(5- methylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-(methyl-53)pyridazine-3-carboxamide (29) (85 mg, pale yellow solid, yield 10%). 29f: 1H NMR (400 MHz, DMSO-56) 8 11.70 (s, 1H), 11.36 (s, 1H), 9.41 (s, 1H), 9.04 (s, 1H), 7.87 (s, 1H), 6.83 (s, 2H), 4.50 (s, 1H), 3.09 (s, 3H), 2.17 - 2.06 (m, 1H), 0.85 (d, J =6.0 Hz, 4H). MS m / z [M+H]+: 442. 29: 1H NMR (400 MHz, DMSO-56) 5 11.71 (s, 1H), 11.36 (s, 1H), 9.41 (s, 1H), 9.04 (s, 1H), 7.87 (s, 1H), 6.83 (s, 2H), 4.50 (s, 1H), 3.09 (s, 3H), 2.17 - 2.06 (m, 1H), 0.85 (d, 5=5.2 Hz, 4H). MS m / z [M+H]+: 442. Example 30 Preparation of (5)-4-((6-amino-5-bromo-3-(A,5-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-A-(methyl-53)pyridazine-3-carboxamide (30) (7?)-4-((6-amino-3-(A5-dimethylsulfoximino)pyridin-2-yl)amino)-6- (cyclopropylcarboxamido)-A-(methyl-£ / 3)pyridazine-3-carboxamide (28i) (7.95 g, 18.9 mmol) was dissolved in NMP (48 mL), and NBS (3.38 g, 19 mmol) was added in batches in an ice bath, and stirred for half an hour in an ice bath. After the reaction was completed, Na2SO3 saturated aqueous solution (6.5 mL) was added in an ice bath, stirred for 10 minutes, ice water (500 mL) was added in batches, solids was precipitated, stirred for 1 hour. The obtained was suction filtered, and the filter cake was washed 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 obtained was beated with EtOH / DCM (1 / 10, 30 mL) to obtain 5.2 g of off-white solid. The mother liquor was mixed with silica gel and subjected to column chromatography (methanol / dichloromethane = 2—5%) to obtain 4.3 g of white solid. The obtained solids in two batches were combined, EA (97 mL) was added, heated for half an hour in oil bath at 75 degrees, slowly cooled to room temperature, suction filtered to obtain 8.15 g of gray-white solid, yield 86%. 1HNMR(4OO MHz, DMSO-^6) 8 11.60 (s, 1H), 11.35 (s, 1H), 9.46 (s, 1H), 9.02 (s, 1H), 7.89 (s, 1H), 6.77 (s, 2H), 3.12 (s, 3H), 2.60 (s, 3H), 2.14-2.06 (m, 1H), 0.85 (d, J =6.5 Hz, 4H). MS m / z [M+H]+: 500. Example 31 Preparation of 6-(cyclopropylcarboxamido)-4-((5-(A,>S'-dimethylsulfoximino)-lH-pyrrolo[2,3-b]pyridin-6-yl)amino)-A-methylpyridazine-3-carboxamide ^NH Br 24 Pd(dppf)CI2 LiOH.H2O DMF, 70 °C then HCI (25%), 50 °C Step 1: Synthesis of 6-(cyclopropylcarboxamido)-4-((5-(A,5-dimethylsulfoximino)-lH-pyrrolo[2,3-b]pyridin-6-yl)amino)-A-methylpyridazine-3-carboxamide (31) The synthesis of 2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxacyclopentaborane referenced WO2012 / 010538, 2012, A2. 4-((6-amino-5-bromo-3-(A,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-methylpyridazine-3-carboxamide (24) (12 mg, 0.0241 mmol), 2-(2-ethoxyethenyl)-4,4,5,5-tetramethyl-l,3,2-dioxacyclopentaborane (5.7 mg , 0.0290 mmol), Pd(dppf)Ch (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 nitrogen atmosphere. The reaction solution was cooled to room temperature, 25% aqueous hydrochloric acid (53 mg) was added, and the reaction was carried out 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 being concentrated, the obtained was Flash separated (methanol / dichloromethane = 4 - 7%), prep-HPLC prepared to obtain 6-(cyclopropylcarboxamido)-4-((5-(A,S-dimethylsulfoximino)-l H-pyrrolo[2,3-b]pyridin-6-yl)amino)-A-methylpyridazine-3-carboxamide (31) (1.2 mg, yellow solid), yield 11%. 1HNMR(4OO MHz, DMS0-< / 6) 8 11.93 (s, 1H), 11.66 (s, 1H), 11.33 (s, 1H),9.11 (s, 1H), 9.04 (d, J= 5.0 Hz, 1H), 8.48 (s, 1H), 7.48 (d, J= 3.4 Hz, 1H), 6.62 (d, J= 3.4 Hz, 1H), 3.14 (s, 3H), 2.84 (d, J= 4.6 Hz, 3H), 2.67 (s, 3H), 2.12 - 2.04 (m, 1H), 0.90 - 0.73 (m, 4H). MS m / z [M+H]+: 443. Example 32 Preparation of 4-((3<hloro-5-(A,5'-dimethylsulfoximino)-lH-pyrrolo[2,3-b]pyridin-6-yl)amino)-6-(cyclopropylamido)-A-methylpyridazine-3-carboxamide 6-(Cyclopropylcarboxamido)-4-((5-(A5'-dimethylsulfoximino)-lH-pyrrolo[2,3-b]pyridin-6-yl)amino)-A-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, stirred at 80°C for 1.5 hours, cooled down to room temperature, the reaction solution was subjected to direct prep-HPLC to obtain 4-((3-chloro-5-(A5'-dimethylsulfoximino)-lH-pyrrolo[2,3-b]pyridin-6-yl)amino)-6-(cyclopropylamido)-A-methylpyridazine-3-carboxamide (32) (5.3 mg, light yellow solid), yield 31%. 1HNMR(4OO MHz, DMSO-< / 6) 8 12.24 (s, 1H), 11.74 (s, 1H), 11.38 (s, 1H),9.14 (s, 1H), 9.09 (d, J= 4.6 Hz, 1H), 8.35 (s, 1H), 7.71 (s, 1H), 3.19 (s, 3H), 2.84 (d, J = 4.5 Hz, 3H), 2.67 (s, 3H), 2.13 - 2.05 (s, 1H), 0.92 - 0.74 (m, 4H). MS m / z [M+H]+: 477. Example 33 Preparation          of         6-(cyclopropylamido)-4-((2,3-dichloro-5-(A>S'- dimethylsulfoximino)-lH-pyrrolo[2,3-b]pyridin-6-yl)amino)-A-methylpyridazine-3-carboxamide 6-(Cyclopropylcarboxamido)-4-((5-(A(S-dimethylsulfoximino)-lH-pyrrolo[2,3-b]pyridin-6-yl)amino)-7V-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, stirred at 80°C for 1 hour, and cooled to room temperature. The reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and then Flash separated (methanol / dichloromethane = 3~5%), and prep-HPLC prepared to obtain 6-(cyclopropylamido)-4-((2,3-dichloro-5-(A / 8'-dimethylsulfoximino)-lH-pyrrolo[2,3-b]pyridin-6-yl)amino)- 7V-methylpyridazine-3-carboxamide (33) (1.0 mg, brown solid), yield 4%. 1HNMR(4OO MHz, DMSO-< / 6) 8 13.29 (s, 1H), 11.74 (s, 1H), 11.37 (s, 1H),9.O5 (s, 2H), 8.27 (s, 1H), 3.18 (s, 3H), 2.84 (d, J = 4.7 Hz, 3H), 2.66 (s, 3H), 2.09 (s, 1H), 0.90 - 0.79 (m, 4H). MS m / z [M+H]+: 511. Example 34 Preparation of    4-((3 -bromo-5 -(N, .S’-di methyl sul fox i m i no)-1 H-pyrrolo [2,3 - b]pyridin-6-yl)amino)-6-(cyclopropylamido)-'V-mcthylpyridazinc-3-carboxamidc 6-(Cyclopropylcarboxamido)-4-((5-(A(>S'-dimethylsulfoximino)-lH-pyrrolo[2,3-b]pyridin-6-yl)amino)-7V-methylpyridazine-3-carboxamide (31) (67 mg, 0.151 mmol) was dissolved in dichloromethane (2 mL), andNBS (26.6 mg, 0.151 mmol) was added at room temperature, stirred at room temperature for 2 hours, the solvent was spin-dried, Flash separated (methanol / dichloromethane = 2~5%) to obtain 4-((3-bromo-5-(N,S-dimethylsulfoximino)-lH-pyrrolo[2,3-b]pyridin-6-yl)amino)-6-(cyclopropylamido)-N-methylpyridazine-3-carboxamide (34) (60 mg, yellow solid), yield 76%. 1HNMR(4OO MHz, DMSO-^6) 8 12.29 (s, 1H), 11.73 (s, 1H), 11.37 (s, 1H),9.14 (s, 1H), 9.08 (d, J= 4.7 Hz, 1H), 8.27 (s, 1H), 7.73 (s, 1H), 3.19 (s, 3H), 2.84 (d, J = 4.7 Hz, 3H), 2.67 (s, 3H), 2.18 - 2.02 (m, 1H), 0.89 - 0.75 (m, 4H). MS m / z [M+H]+: 521. Example 35 Preparation of (7?)-4-((6-amino-5-chloro-3-(AfS-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-7V-(methyl-£ / 3)pyridazine-3-carboxamide oxalate Cl        COOH 35 (l?)-4-((6-amino-5-chloro-3-(. / V,5'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-AL(methyl-< / 3)pyridazine-3-carboxamide (28) (100 mg, 0.22 mmol) was dissolved in DCM / MeOH (9:1, 6 mL), and oxalic acid dihydrate (27 mg, 0.22 mmol) in methanol (0.2 mL) was added, and stirred for 10 min at room temperature. The solvent was evaporated under reduced pressure, and DCM / THF (1:1, 3 mL) was added. The solid was precipitated, suction fdtered, washed with DCM / THF (1:1, 1 mL) and rinsed with PE (3 mL). 72 mg of light yellow solid was obtained, yield 56.7%. *HNMR(400 MHz, DMSO-t / 6) 5 11.61 (s, 1H), 11.36 (s, 1H), 9.43 (s, 1H), 9.04 (s, 1H), 7.79 (s, 1H), 6.90 (s, 2H), 3.14 (s, 3H), 2.62 (s, 3H), 2.15-2.07 (m, 1H), 0.86 (d, J =6.4 Hz, 4H). Example 36 Preparation of (7?)-4-((6-amino-5-chloro-3-(A(>S'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylcarbonyl)-'V-(mcthyl-<73)pyridazinc-3-carboxamidc hydrochloride Cl 36 (R)-4-((6-amino-5-chloro-3-(A(S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-7V-(methyl-£ / 3)pyridazine-3-carboxamide (28) (500 mg, 1.10 mmol) was added to MeCN (5 mL) in suspension state. 37% HC1 aq. (271 mg, 2.75 mmol) was added dropwise at room temperature, heated to reflux in an oil bath at 85 °C, water (2 mL) was added dropwise, and dissolved to be clear in reflux state. Then the solution was stirred at room temperature for 1 h. The solid was precipitated, suction filtered, the filter cake was washed with MeCN (1 mL*2), and the filter cake was dried under reduced pressure at 50 °C to obtain 336 mg of yellow solid, yield 57.9%. ‘HNMR (400 MHz, DMSO-t / 6) 5 12.03 (s, 1H), 11.92 (s, 1H), 9.49 (s, 1H), 9.23 (s, 1H), 7.92 (s, 1H), 7.86 (s, 2H), 3.92 (s, 3H), 2.83 (s, 3H), 2.21-2.14 (m, 1H), 0.90 (d, J =6.7 Hz, 4H). Example 37 Preparation of (R)-4-((6-amino-5-chloro-3-(A(>S'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropyl formyl)-;'V-(mcthyl-<73)pyridazinc-3-carboxamidc sulfate Cl 37 (R)-4-((6-amino-5-chloro-3-(A(S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-7V-(methyl-t / 3)pyridazine-3-carboxamide (28) (500 mg, 1.10 mmol) was added to THF (5 mL) in suspension state. 20% H2SO4 aq. (646 mg, 1.32 mmol) was added dropwise at room temperature, placed in an oil bath at 70 °C, water (0.5 mL) was added dropwise in the reflux state, dissolved to be clear in the reflux state, and then placed in the environment at room temperature and stirred for Ih, the solid was precipitated, suction filtered, the filter cake was washed with THF (1 mL*2), the filter cake was dried at 50 °C under reduced pressure to obtain 495 mg of yellow solid. Y=81.5%, HPLC:99.0%. ‘HNMR (400 MHz, DMSO-t / 6) 5 11.81 (s, IH), 11.45 (s, IH), 9.33 (s, IH), 9.29 (s, IH), 7.89 (s, IH), 7.62 (s, 2H), 3.90 (s, 3H), 2.85 (s, 3H), 2.16-2.08 (m, IH), 0.87 (d, J =6.7 Hz, 4H). Example 38 Preparation of (7?)-4-((6-amino-5-chloro-3-(A(>S'-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropyl formyl )-;'V-(mcthyl-<73)pyridazinc-3-carboxamidc methanesulfonate Cl 38 (R)-4-((6-Amino-5-chloro-3-(A,S-dimethylsulfoximino)pyridin-2-yl)amino)-6-(cyclopropylformyl)-A-(methyl-t / 5)pyridazine-3-carboxamide (28) (100 mg, 0.22 mmol) was dissolved in DCM / MeOH (9:1, 6 mL), and methylsulfonic acid (42 mg, 0.44 mmol) was added, stirred at room temperature for 10 min. The solvent was evaporated under reduced pressure and DCM / THF (1:1, 3 mL) was added. The solid was precipitated, suction fdtered, washed with DCM / THF (1:1, 1 mL) and washed with PE (3 mL). 110 mg of yellow solid was obtained. Yield: 77.4%. *HNMR(400 MHz, DMSO-t / 6) 5 11.82 (s, 1H), 11.47 (s, 1H), 9.34 (s, 1H), 9.30 (s, 1H), 7.90 (s, 1H), 7.63 (s, 2H), 3.91 (s, 3H), 2.86 (s, 3H), 2.35 (d, J= 1.0 Hz, 6H), 2.12 (d, J= 5.7 Hz, 1H), 0.88 (d, J= 6.7 Hz, 4H). Example 39 Preparation of 6-(cyclopropylcarboxamido)-A-(methyl-t / 3)-4-((3-(S'-methyl-A- (methyl-t / 3)sulfoximino)pyridin-2-yl)amino)pyridazine-3-carboxamide pida, h2nco2nh4 MeOH, 0 °C to RT HN ,O NO2 CP3I, KOH t DMSO, RT, 3 h d3c-n o no2 's' .A , d3c-n Fe, NH4CI 3 "c EtOH / H2O (2 / 1) 70 °C, 1 h 39b 1a                            1b                        39a Pd2(dba)3, XantPhos Cs2CO3, dioxane MW (110°C, 100W) 45 min 39 The syntheses were prepared using CD3I instead of Mel referenced Example 1 and Example 2. 1H NMR (400 MHz, dmso) 8 11.86 (s, 1H), 11.37 (s, 1H), 9.46 (s, 1H), 9.06 (s, 1H), 8.53 (d, J = 4.0 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 7.32-7.24 (m, 1H), 3.21 (s, 3H), 2.09 (dd, J = 13.2, 7.3 Hz, 1H), 0.85 (d, J = 6.7 Hz, 4H). MS m / z [M+H]+: 410. Example 40 Preparation of (R)-4-((6-amino-5-chloro-3-(S-methyl-7V-(methyl- 6k)sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-7V-(methyl-t / 3)pyridazine-3-carboxamide THF,20°C-25°C, overnight Cl t-BuONa,CD3l,Nal CD CD3X NH 28d                                    40a                                  40b CD3x NH Ph^NH 120°C~125°C DMAC,K2C03 Pd2(dba)3,XantPhos 40c 40d THF, HCI( 12N) 40e                                                        40 Step 1:     Synthesis of (l?)-6-chloro-3-(5'-methyl-A^-(methyl-< / 3) sulfonylimino)pyridin-2-amine (40a) (R)-6-Chloro-3-(S-methylsulfoximino)pyridin-2-amine (28d) (29.7 g, 144.88 mmol) was dissolved in 600 mL of tetrahydrofuran, Nai (2.18 g, 14.5 mmol) was added, sodium tert-butanolate (13.91 g, 144.88 mmol) was added in batches n a water bath, and stirred for 20 min. CD3I (21 g, 144.88 mmol) dissolved in tetrahydro furan (50 mL) was added dropwise, after the addition, and stirred at room temperature overnight. The reaction solution was quenched with saturated ammonium chloride solution, diluted with water, the liquid was separated, the aqueous layer was extracted with ethyl acetate, the organic phases were combined, concentrated and dissolved with ethyl acetate, the liquid was separated, the aqueous layer was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography (petroleum ether: ethyl acetate=2:l) to obtain (R)-6-chloro-3-(S-methyl-7V-(methyl -<7j)sulfonylimino)pyridin-2-amine (22.5 g, off-white solid), yield 70%. *H NMR (400 MHz, DMSO-^) 5 7.84 (d, J = 8.0 Hz, 1H), 7.24 (s, 2H), 6.78 (d,J=8.0Hz 1H), 3.09 (s,3H). MS m / z [M+H]+: 223. Step 2: Synthesis of (^)-6-06101-0-4-((6-06101-0-3-(5-016^1-^-(016^1-^) sulfooylioiioo)pyridio-2-yl)amioo)-AL(methyl-< / 5)pyridazioe-3-carboxamide (40b) (R)-6-Chloro-3-(S-methyl-N-(methyl-t / 3)sulfonylimino) pyridin -2-amine (40a) (36.7 g, 0.165 mol) was dissolved in 1 L of tetrahydro furan, and cooled down to 0~5 °C under N2 protection, NaH (19.8 g, 60% w / w, 0.496 mol) was added in batches and then stirred for 25 min, and 4,6-dichloro-N-(methyl-t / 3)pyridazine-3-carboxamide (41.3 g, 0.198 mol) was added in batches, stirred for 15 min and then heated to 70 °C and reacted for 2 h. The reaction was quenched with saturated ammonium chloride solution in an ice bath, diluted with water, extracted with ethyl acetate, the liquid was separated, and the organic phases were combined and washed with saturated brine, and dried over anhydrous sodium sulfate. The obtained was concentrated, and ethanol was added for cold beating for 30 min, suction filtered, the filter cake was washed with ethanol, drained to obtain (R)-6-chloro-4-((6-chloro-3-(S-methyl-X-(methyl-J0sulfonylimino)pyridin-2-yl)amino)-'V-('mcthyl-<7,')pyridazinc-3-carboxamidc (40.25 g, 61.8%). 1HNMR (400 MHz, DMSO-< / 6) 8 12.23 (s, 1H), 9.33 (s, 1H), 8.79 (d, J = 1.4 Hz, 1H), 8.23 (dd, J = 8.0, 1.4 Hz, 1H), 7.43 (dd, J = 8.1, 1.4 Hz, 1H),3.24 (s, 3H). MS m / z [M+H]+: 395 Step 3: Synthesis of (l?)-6-chloro-4-((6-((diphenylmethylene)amino)-3-(S-methyl-AL(methyl-< / j)sulfonylimino)pyridin-2-yl)amino)-AL(methyl-< / j)pyridazine-3-carboxamide (40c) Pd2(dba)s (4.6 g, 0.005 mol), XantPhos (5.78 g, 0.01 mol), (R)-6-chloro-4-((6-chloro-3-(5-methyl-X-(methyl-6?3)sulfonylimino)pyridin-2-yl)amino)-N-(methyl-r / 3)pyridazin- 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) under N2 atmosphere, and reacted at 130 °C for 5 h. After being cooled, the reaction was quenched with saturated ammonium chloride solution, diluted with water, solubilized with ethyl acetate, filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The liquid was separated, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and beated with MTBE for 30 min, suction filtered, and the filter cake was washed with MTBE, and drained to obtain (R)-6-chloro-4-((6-((diphenylmethylene)amino)-3-(5-methyl-X-(methyl-f / 3)sulfonylimino)pyridin-2-yl)amino)-A-(methyl - J,■ )pyridazinc-3-carboxamide (38 g, 69.5%). ‘HNMR (400 MHz, DMSO-< / 6) 8 11.96 (s, 1H), 9.24 (s, 1H), 8.48 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.43 (m, 10H), 6.79 (d, J = 8.0 Hz, 1H), 3.16 (s, 3H). MS m / z [M+H]+: 540 Step 4:     Synthesis of (l?)-6-(cyclopropylcarboxamide)-4-((6- ((diphenylmethylene)amino)-3-(5-methyl-A-(methyl-< / 3)sulfonylimino)pyridin-2-yl)amino)-A-(methyl-< / 3)pyridazine-3-carboxamide (40d) Pd2(dba)3 (238 mg, 0.26 mmol), XantPhos (300 mg,0.52 mol), (R)-6-chloro-4-((6-((dibenzylidene)amino)-3-(S-methyl-X-(methyl-6?3)sulfonylimino)pyridin-2         - yl)amino)-A-(methyl-6?3)pyridazine-3-carboxamide (40c) (2.8 g, 5.19 mmol), K2CO3 (1.79 g, 12.98 mmol) and cyclopropylamide (882 mg, 10.38 mmol) were added to xylene: DMAC=1O:1 (33 mL) under N2 atmosphere, and the reaction was carried out at 130 °C for 2 h. After being cooled, the reaction was quenched with saturated ammonium chloride solution, diluted with water, and dissolved with dichloromethane, and filtered through diatomaceous earth, the filter cake was washed with dichloromethane. The liquid was separated, the aqueous phase was extracted with dichloromethane, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and beated with petroleum ether for 10 min, suction filtered, and the filter cake was washed with petroleum ether, and drained to obtain (7?)-6-(cyclopropylcarboxamido)-4-((6-((dibenzylidene)amino)-3-(S-methyl-A-(methyl-£ / 3)sulfonylimino)pyridin-2-yl)amino)-A-(methyl-t / 3)pyridazine-3-carboxamide in crude form, which was directly used in the next step of the reaction without separation. MS m / z [M+H]+: 589 Step 5: Synthesis of (l?)-4-((6-amino-3-(5'-methyl-A-(methyl-< / j)sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-A-(methyl-< / j)pyridazine-3-carboxamide (40e) Crude (7?)-6-(cyclopropylcarboxamide)-4-((6-((dibenzylidene)amino)-3-(S-mcthylAAmcthyl-J0sull'onylimino)pyridin-2-yl)amino)-''V-(mcthyl-<A)pyridazinc-3-carboxamide (40d) was dissolved in tetrahydrofuran (30 mL), and 12N HC1 (0.6 mL) was added in an ice bath, and the solution was heated to room temperature and stirred for 1.5 h. The solution was diluted with water, and extracted with ethyl acetate, the organic phase was washed with water, the aqueous layer was combined, 10% potassium carbonate solution was slowly added to adjust the pH to be 9—10, extracted with methanol: dichloromethane = 10:1, the liquid was separated,, the organic phases were combined, and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, ethanol was added, heated to reflux, beated for 20 min in an ice bath, suction filtered, and the filter cake was washed with ethanol, and drained to obtain (R)-4T(6-aminoAASuncthyl-''V-(mcthyl-<A)sull'onylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-A-(methyl-t / 3)pyridazine-3-carboxamide (1.4 g, 65%). *HNMR(400 MHz, DMSO-^) 5 11.56 (s, 1H), 11.32 (s, 1H), 9.51 (s, 1H), 9.00 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 6.55 (s, 2H), 6.24 (d, J = 8.6 Hz, 1H), 3.06 (s, 3H), 2.15 -2.03 (m, 1H), 0.86 (m, 4H). MS m / z [M+H]+: 425 Step 6: Synthesis of (l?)-4-((6-amino-5-chloro-3-(5'-methyl-A-(methyl-< / j)sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-A-(methyl-< / j)pyridazine-3-carboxamide (40) (R)-4-((6-Amino-3-(S-methyl-A-(methyl-£ / 3)sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-A-(methyl-t / 3)pyridazine-3-carboxamide (40e) (1.4 g, 3.30 mmol) was dissolved in DMAC (14 mL), cooled down in an ice bath under the protection ofN2 (0-5 °C), 1,3-dichloro-5,5-dimethylhydantoin (683 mg, 3.47 mmol) was added in batches, and the reaction was carried out for 15 min. The reaction was quenched with ice water and saturated sodium sulfite solution, suction filtered, the filter cake was washed with water, and dissolved with dichloromethane: methanol = 10:1, and the liquid was separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and separated by Flash (methanol / dichloromethane = 3%) to obtain (R)-4-((6-amino-5-chloro-3-(>S,-methyl-7V-(methyl-6?3)sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-7V-(methyl-t / 3)pyridazine-3-carboxamide (669 mg, off-white solid), yield 44%. *HNMR(400 MHz, DMSO-^) 5 11.62 (s, 1H), 11.37 (s, 1H), 9.43 (s, 1H), 9.04 (s, 1H), 7.79 (s, 1H), 6.89 (s, 2H), 3.13 (s, 3H), 2.16 - 2.07 (m, 1H), 0.87 (m, 4H). MS m / z [M+H]+: 459 Example 41 Preparation of (R)-4-((6-amino-5-bromo-3-(S-methyl-N-(methyl- <7,')sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamidc)-N-(mcthyl- t / 3)pyridazine-3-carboxamide 40e                                                   41 (R)-4-((6-Amino-3-(S-mcthyl-N-(mcthyl-<7,')sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-t / 3)pyridazine-3-carboxamide (40e) (113 mg, 0.26 mmol) was dissolved in DMF (1.4 mL), cooled down to 0~5 °C in an ice bath under the protection of N2, and NBS ( 50 mg, 0.28 mmol) was added, reacted for 30 min. The reaction was quenched with saturated sodium sulfite solution, diluted with water, extracted with ethyl acetate, the liquid was separated, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and Flash separated (methanol / dichloromethane = 3%) to obtain (R)-4-((6-amino-5-bromo-3-(S-mcthyl-N-(mcthyl-<7,')sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-(methyl-t / 3)pyridazine-3-carboxamide (62 mg, light yellow solid), yield 46%. *HNMR(400 MHz, DMSO-^) 5 11.62 (s, 1H), 11.37 (s, 1H), 9.48 (s, 1H), 9.04 (s, 1H), 7.91 (s, 1H), 6.79 (s, 2H), 3.13 (s, 3H), 2.12 (s, 1H), 0.88 (m, 4H). MS m / z [M+H]+: 503 Example 42 Preparation of (R)-4-((6-amino-5-iodo-3-(S-methyl-N-(methyl- <7,')sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamidc)-N-(mcthyl- t / 3)pyridazine-3-carboxamide 40e                                                  42 (R)-4-((6-amino-3-(S-methyl-N-(methyl-f / 3)sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-t / 3)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 in batches, reacted at 50°C for 1 h. The reaction was quenched with saturated sodium sulfite solution in an ice bath, diluted with water, extracted with dichloromethane: methanol=10:l, the liquid was separated, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and Flash separated (methanol / dichloromethane = 3%) to obtain (R)-4-((6-Amino-5-iodo-3-(S-methyl-N-(methyl-t / 3)sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-t / 3)pyridazin-3-carboxamide (912 mg, pale yellow solid), yield 64%. *HNMR(400 MHz, DMSO-^) 5 11.61 (s, 1H), 11.37 (s, 1H), 9.54 (s, 1H), 9.04 (s, 1H), 8.06 (s, 1H), 6.60 (s, 2H), 3.12 (s, 3H), 2.17 - 2.07 (m, 1H), 0.87 (d, J = 6.0 Hz, 4H). MS m / z [M+H]+: 551 Example 43 Preparation of (R)-4-((6-amino-5-cyclopropyl-3-(S-methyl-N-(methyl-f / i)sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-(methyl-t / i)pyridazine-3-carboxamide 42                                                     43 Under N2 atmosphere, (R)-4-((6-amino-5-iodo-3-(S-methyl-N-(methyl-f / i)sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-t / i)pyridazine-3-carboxamide (42) (203 mg, 0. 367 mmol) was dissolved in anhydrous 1,4-dioxane (4 mL), cyclopropylboronic acid (63 mg, 0.734 mmol), Pd(PPhs)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, the reaction solution was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane: methanol=10:l, and the filtrate was concentrated and Flash separated (methanol / dichloromethane = 7%) to obtain (R)-4-((6-amino-5-cyclopropyl-3-(S-methyl-N-(methyl-t / 5)sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-t / 5)pyridazine-3-carboxamide (32 mg, light yellow solid), yield 18.7%. *HNMR(400 MHz,DMS0-t / 6) 5 11.55 (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 = 4.4 Hz, 2H). MS m / z [M+H]+: 465 Example 44 Preparation of (R)-4-((6-amino-3-(S-methyl-N-(methyl-t / 3)sulfonylimino)-5-vinylpyridin-2-yl)amino)-6-(cyclopropylcarboxamidc)-N-(mcthyl-<7,')pyridazinc-3-carboxamide 42                                                   44 Under N2 atmosphere, (R)-4-((6-amino-5-iodo-3-(S-methyl-N-(methyl-6?3)sulfonyfimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-<7,')pyridazinc-3-carboxamide (42) (103 mg, 0. 187 mmol) was dissolved in anhydrous 1,4-dioxane (2 mL), potassium ethylenetrifluoroborate (50 mg, 0.37 mmol), Pd(PPhs)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, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with dichloromethane, and the filtrate was concentrated and Flash separated (methanol / dichloromethane = 3%) to obtain (R)-4-((6-amino-3-(S-mcthyl-N-(mcthyl-<7,')sulfonylimino)-5-vinylpyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-t / 3)pyridazine-3-carboxamide (40 mg, light yellow solid), yield 47%. *HNMR(400 MHz, DMSO-^) 5 11.68 (s, 1H), 11.36 (s, 1H), 9.67 (s, 1H), 9.02 (s, 1H), 7.92 (s, 1H), 6.81 (dd, J = 17.6, 10.6 Hz, 1H), 6.59 (s, 2H), 5.63 (d, J = 16.9 Hz, 1H), 5.25 (d, J = 10.2 Hz, 1H), 3.12 (s, 3H), 2.12 (s, 1H), 0.87 (m, 4H). MS m / z [M+H]+: 451 Example 45 Preparation of (R)-4-((6-amino-3-(S-methyl-N-(methyl-t / 3)sulfonylimino)-5-(propynyl         -1 -yl)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-(methyl- t / 3)pyridazine-3-carboxamide Pd(PPh3)2CI2,Cul TEA, KF, rt, overnight 42 TMS (R)-4-((6-Amino-54odo-3-(S-methyl-N-(methyl< / 3)sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-r / 3)pyridazine-3-carboxamide (42) (100 mg, 0. 182 mmol) was dissolved in DMF (2 mL), Cui (4 mg, 0.0182 mmol ), Pd(PPhs)2C12 (13 mg, 0.0182 mmol), KF (16 mg, 0.273 mmol), and triethylamine (0.7 mL) were added, and l-(trimethylsilyl)propyne (31 mg, 0.273 mmol) in DMF (0.5 mL) was added under N2 atmosphere, reacted at 50 °C for 1 h. The reaction solution was cooled to room temperature and then quenched with saturated ammonium chloride solution, diluted with water, extracted with dichloromethane, the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After being concentrated, the obtained was Flash separated (methanol / dichloromethane = 3%) to obtain (R)-4-((6-amino-3-(S-mcthyl-N-(mcthyl-<7,')sulfonylimino)-5-(propynyl -l-yl)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(mcthyl-<7,')pyridazinc-3-carboxamide (64 mg, yellow solid), yield 76%. *HNMR(400 MHz, DMSO-< / 6) 5 11.67 (s, 1H), 11.36 (s, 1H), 9.55 (s, 1H), 9.02 (s, 1H), 7.71 (s, 1H), 6.67 (s, 2H), 3.10 (s, 3H), 2.10 (m„ 4H), 0.87 (m, 4H). MS m / z [M+H]+: 463 Example 46 Preparation of (R)-4-((6-amino-5-(cyclopropylethynyl)-3-(S-methyl-N-(methyl-6?3)sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-(methyl-t / 3)pyridazine-3-carboxamide —--TMS Pd(PPh3)2CI2,Cul TEA,KF,rt,overnight 42 46 (R)-4-((6-Amino-5-iodo-3-(S-mcthyl-N-(mcthyl-<7,')sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-6?3)pyridazine-3-carboxamide (42) (100 mg, 0. 182 mmol) was dissolved in DMF (2 mL), Cui (4 mg, 0.0182 mmol ), Pd(PPhs)2C12 (13 mg, 0.0182 mmol), KF (16 mg, 0.273 mmol), and triethylamine (0.7 mL) were added. Cyclopropyl (trimethylsilyl) acetylene (38 mg, 0.273 mmol) dissolved in DMF (0.5 mL) was added under N2 atmosphere, and stirred overnight at room temperature. The reaction solution was quenched with saturated ammonium chloride solution, diluted with water, extracted with dichloromethane, the liquid was separated, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The obtained was concentrated and Flash separated (methanol / dichloromethane = 3%) to obtain (R)-4-((6-amino-5-(cyclopropylethynyl)-3-(S-methyl-N-(methyl-t / 3)sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-t / 3)pyridazine-3-carboxamide (74 mg, light yellow solid), yield 83%. *HNMR(400 MHz, DMSO-< / 6) 5 11.68 (s, 1H), 11.36 (s, 1H), 9.56 (s, 1H), 9.02 (s, 1H), 7.70 (s, 1H), 6.59 (s, 2H), 3.10 (s, 3H), 2.12 (s, 1H), 1.56 (s, 1H), 0.96 -0.74 (m, 8H). MS m / z [M+H]+: 489 Example 47 Synthesis of (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-6?3)sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-(methyl-t / 3)pyridazine-3-carboxamide hydrochloride 40                                         47 (R)-4-((6-amino-5-chloro-3-(S-mcthyl-N-(mcthyl-<7,')sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamide)-N-(methyl-t / 3)pyridazine-3-carboxamide (200 mg, 0. 44 mmol) was added into DMF (2 mL) and stirred at room temperature, concentrated HC1 (108 mg, 1.09 mmol) was added. The obtained was placed in 90 °C oil bath and stirred for 5 min, became turbid, acetonitrile (10 mL) was added, reflux for 5 min, the suspension was stirred for 1.5 h at room temperature, suction filtered, washed with acetonitrile (0.5 mL * 2), the filter cake was dried at 50 °C under reduced pressure for Ih to obtain the dihydrochloride, light yellow solid: 230 mg, yield: 99.2%. ‘HNMR(400 MHz, DMStW5) 8 11.88 (s, IH), 11.82 (s, IH), 9.44 (d, J=2.2Hz, IH), 9.24 (s, IH), 7.91 (d, J= 2.6 Hz, IH), 7.77 (s, 2H), 3.91 (s, 3H), 2.21-2.11 (m, IH), 0.94-0.86 (m, 4H). MS m / z [M+H]+: 459 Example 48 Synthesis of (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-<7,')sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamidc)-N-(mcthyl-t / 3)pyridazine-3-carboxamide sulfate 40 48 (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl-£ / 3)sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-f / 3)pyridazine-3-carboxamide (200 mg, 0. 44 mmol) was added to DMF (1 mL), stirred at room temperature, became a suspension, concentrated H2SO4 (109 mg, 1.09 mmol) was added, and dissolved with acetonitrile (1 mL) with stirring at room temperature. The obtained was placed in 90 °C oil bath and stirred for 5 min, acetonitrile (6 mL) was added, reflux for 5 min, solid was precipitated, stirred for 1.5 h at room temperature, suction fdtered, washed with acetonitrile (0.5 mL * 2), the filter cake was dried at 50 °C for 1 h under reduced pressure to obtain disulfate, white solid: 268 mg, yield: 93.8%. ‘HNMR(400 MHz, DMS(W) 5 11.82 (s, 1H), 11.46 (s, 1H), 9.34 (s, 1H), 9.30 (s, 1H), 8.92 (s, 4H), 7.90 (s, 1H), 7.64 (s, 2H), 3.92 (s, 3H), 2.15-2.08 (m, 1H), 0.900.82 (m, 4H). MS m / z [M+H]+: 459 Example 49 Synthesis of (R)-4-((6-amino-5-chloro-3-(S-methyl-N-(methyl- <7,')sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(mclhyl- t / 3)pyridazine-3-carboxamide methanesulfonate MeSO3H 40                                            49 (R)-4-((6-amino-5-chloro-3-(S-mcthyl-N-(mcthyl-<7,')sulfonylimino)pyridin-2-yl)amino)-6-(cyclopropylcarboxamido)-N-(methyl-t / 3)pyridazine-3-carboxamide (200 mg, 0. 44 mmol) was added to DMF (0.5 mL), stirred at room temperature, became a suspension. Methanesulfonic acid (105 mg, 1.09 mmol) was added, dissolved with acetonitrile (1 mL) at room temperature with stirring, placed in 90 °C oil bath and stirred for 5 min, acetonitrile (8 mL) was added, reflux for 5 min, the solid was precipitated, stirred for 1.5 h at room temperature, suction filtered, washed with acetonitrile (0.5 mL * 2), the filter cake was dried at 50°C for 1 h under reduced pressure to obtain dimethylsulfonate, off-white solid: 268 mg, yield: 94.4%. *HNMR(400 MHz, DMS(W) 5 11.82 (s, 1H), 11.46 (s, 1H), 9.34 (s, 1H), 9.30 (s, 1H), 7.90 (s, 1H), 7.63 (s, 2H), 3.92 (s, 3H), 2.35 (s, 6H), 2.17-2.09 (m„ 1H), 0.900.82 (m, 4H). MS m / z [M+H]+: 459 Biological Evaluation Test Example 1: TYK2 kinase activity inhibition assay 1.1 Principle and purpose of the experiment The TYK2 kinase gene was introduced into wild-type murine-derived B lymphocytes (BaF3) to construct the Ba / F3-FL -TYK2-E957D stable cell line. The growth and proliferation of Ba / F3 -FL -TYK2-E957D were independent of IL-3, and dependent on exogenously transferred TYK2 kinase. If the compound selectively inhibited the activity of TYK2 kinase, it would inhibit the proliferation of this cell line. In this experiment, the inhibitory effect of the compounds on the proliferation of Ba / F3-FL-TYK2-E957D cells were tested, apoptosis was detected, and the IC50 value was calculated. The inhibitory activity of the compounds against TYK2 kinase was evaluated based on the IC50 value. 1.2 Experimental Methods 1.2. 1 Preparation of stock solution The tested compounds, powder and stored at room temperature, were prepared into 10 mM stock solution with DMSO and stored at -20°C away from light for use. 1.2. 2 Experimental steps Preparation of compounds Compounds were prepared into dilute solutions which was 1000 times of the final concentration. The compound was prepared into 20-times of the final concentration by diluting the compound with culture medium. 2ul of 1000-times compound was added to per well to 98ul of culture medium. Plating Cells (provided by Sundia Pharmaceutical Technology (Shanghai) Co., Ltd.) were resuspended and counted using an automated cell counter. The cell suspension was diluted to the desired density based on BaF3 seeding density of 2000 cells per well. Each well was plated with 95ul of cells and incubated at 37°C for stable equilibrium. 5ul of 20-times compound was added to each well, with the wells to which the same volume of DMSO was added as a control. The cells were incubated for 72h at 37°C with 5% CO2. Detection The cell plate was equilibrated to room temperature. 40ul CellTiter-Glo® Reagent was added to each well, shaken for 2 minutes and allowed to stand for 10 minutes. Detected with SpectraMax Paradigm. Data Analysis (1) IC50 was calculated using GraphPad Prism 5. (2) %Inh = (Max signal - Compound signal) / (Max signal - Min signal) x 100. (3) Max signal was the positive control well with only the same volume of DMSO as the compound. (4) Min signal was the negative control well with only the culture medium. The results are shown in Table 1 below. Table 1 Inhibitory activity of representative compounds of the present invention against TYK2 kinase Example No. Ba / F3 -FL -TYK2-E957D cell IC5o(nM) BMS-986165 2.3 2 2.4 13 3.9 14 3.7 16 3.5 23 2.0 24 1.3 28 0.60 29 1.1 31 1.1 32 0.62 33 1.2 40 0.4 41 0.4 42 0.4 43 1.1 44 0.3 45 0.1 46 0.1 Wherein, the structural formula of compound BMS-986165 is The test results show that the compounds provided in the present invention have excellent TYK2 inhibitory activity, and most of the compounds have TYK2 inhibitory activity superior to that of the positive control BMS-986165, with IC50 values of pM level. In particular, Example 28, Example 32, Example 40, Example 41, Example 42 and Example 44 show a 4- to 7-fold increase in TYK2 inhibitory activity over BMS-986165, and Example 45 and Example 46 show a more than 20-fold increase in TYK2 inhibitory activity over BMS-986165. Test Example 2: JAK family kinase selectivity assay 2.1 Principle and purpose of the experiment There are four kinases in the JAK family, respectively TYK2, JAKI, JAK2 and JAK3. JAK family kinase genes were introduced into the wild-type murine B lymphocytes (BaF3), and four BaF3 engineered cell lines were constructed respectively (Ba / F3 -FL -TYK2-E957D, Ba / F3-TEL-JAK1, Ba / F3-TEL-JAK2, Ba / F3-TEL-JAK3). The growth and proliferation of these engineered cell lines were not dependent on IL-3, but on exogenously transferred JAK family kinases. If a compound selectively inhibited the activity of a JAK kinase, it would inhibit the proliferation of the corresponding cell line. In this experiment, the inhibitory effects of the compounds on the proliferation of four cell types, Ba / F3 -FL -TYK2-E957D, Ba / F3-TEL-JAK1, Ba / F3-TEL-JAK2, and Ba / F3-TEL-JAK3 were tested, and apoptosis was detected, and the IC50 values were calculated. The inhibitory activities of the compounds against TYK2, JAKI, JAK2, and JAK3 kinases were evaluated based on the IC50 value, thus assessing the JAK family kinase selectivity of the compounds. 2.2 Experimental Methods 2.2. 1 Preparation of stock solution The tested compounds, powder and stored at room temperature, were prepared into 10 mM stock solution with DMSO and stored at -20°C away from light for use. 2.2. 2 Experimental steps Preparation of compounds Compounds were formulated into dilute solutions which was 1000 times of the final concentration. The compound was prepared into 20-times of final concentration by diluting the compound with culture medium. 2ul of 1000-times compound was added per well to 98ul of culture medium. Plating Cells (provided by Sundia Pharmaceutical Technology (Shanghai) Co., Ltd.) were resuspended and counted using an automated cell counter. The cell suspension was diluted to the desired density based on BaF3 seeding density of 2000 cells per well. Each well was plated with 95ul of cells and incubated at 37°C for stable equilibrium. 5ul of 20-times compound was added to each well, with the wells to which the same volume of DMSO was added as a control. The cells were incubated at 37°C with 5% CO2 for 72h. Detection The cell plate was equilibrated to room temperature. 40ul CellTiter-Glo® Reagent was added to each well, shaken for 2 minutes and allowed to stand for 10 minutes. Detected with SpectraMax Paradigm. Data Analysis (1) IC50 was calculated using GraphPad Prism 5. (2) %Inh = (Max signal - Compound signal) / (Max signal - Min signal) x 100. (3) Max signal was the positive control well with only the same volume of DMSO as the compound. (4) Min signal was the negative control well with only the culture medium. The results are shown in Table 2 below. Table 2 Selectivity of representative compounds of the present invention against TYK2 kinase Compound No. Ba / F3 Cell IC50 (nM) TYK2 JAKI JAK2 JAK3 BMS-986165 1.37 >1000 >1000 >1000 28 0.6 >1000 >1000 >1000 29 1.1 >1000 >1000 >1000 The test results show that the compounds in the present invention have excellent TYK2 inhibitory activity, as well as no inhibitory activity against JAKI, JAK2, and JAK3 kinases, and the JAK family kinases selectivity is very high. The basic research and clinical results of existing JAK kinase inhibitors show that non-selective kinase inhibitors bring serious side effects, including thrombosis, anemia and serious infections, thus, poor kinase subtype selectivity is a difficulty to be overcome in the development of next-generation JAK inhibitors. In contrast, the compounds of the present invention have excellent kinase selectivity and exhibit high safety of drug use. Test Example 3: IFN-a-induced STAT phosphorylation in human whole blood 3.1 Principle and purpose of the experiment The cytokine receptor attached to TYK2 mediates the signaling of type 1 interferon (IFN-a), which has been identified as the most important inflammatory factor of the autoimmune system. Human whole blood is induced with IFN-a, and TYK2 from lymphocytes in whole blood triggered STAT phosphorylation, which mediated subsequent inflammatory signaling. Therefore, TYK2 inhibitors have an inhibitory effect on IFN-a signaling, and the stronger the TYK2 inhibitory activity, the lower the level of STAT phosphorylation, and the stronger the corresponding anti-inflammatory effect. In this experiment, the ability of the compounds to inhibit IFN-a-induced STAT phosphorylation in human whole blood were tested, and the IC50 values were calculated. The anti-inflammatory activity of the compounds was evaluated at the tissue level and evaluation of the inhibitory activity of compounds on the IFN-a inflammatory pathway based on the IC50 value. 3.2 Experimental process 3.2. 1 Preparation of stock solution The tested compound, powder and stored at room temperature, prepared into 10 mM stock solution with DMSO and stored at -80°C in the refrigerator. Positive control compound, BMS-986165, powder and stored at room temperature, prepared into 10 mM stock solution with DMSO and stored at -80°C in a refrigerator. 3.2. 2 Preparation of solution IX Fix / Lysis solution preparation: 5X Fix / Lysis and ddH2O were diluted according to 1:4 and preheated in 37°C incubator, waiting for use. Flow cytometric staining buffer preparation: 1 g of bovine serum albumin (BSA) and 1 mL of ED TA (0.5 M) solution were added to 500 mL of phosphate buffer solution (PBS) and stored at 4°C in the refrigerator. Compound dilution solution: 0.5 g of bovine serum albumin (BSA) was added to 500 mL of phosphate buffer solution (PBS), and stored at 4°C in the refrigerator. 3.2. 3 Experimental steps Preparation of compounds and cytokines 10 rnM of the test compound and the positive compound BMS-986165 were diluted with DMSO into 5 mM of working solution , which was further diluted with DMSO in a 3-fold gradient to eight concentrations. The eight concentrations gradient of the test compound and each concentration point of BMS-986165 were diluted 25fold with compound diluent and set aside. 50 pg / mL IFN-alpha was diluted to 400 ng / mL with Compound Diluent and set aside. Processing of human whole blood 67.5 pL of human whole blood was added to a 96-well plate using a 300 pL electric volley gun. 3.5 pL of prepared test compound was added, mixed well and placed in the cell culture incubator. After 60 min incubation, 400 ng / mL IFN-a (Biolegend 592702, final concentration 20 ng / ml) was added. The obtained was mixed well and placed in the cell culture incubator to continue incubation for 15 min. After cytokine stimulation, 5 pl of PE-CD3 (BD 555333) antibody was added to each well, mixed and incubation was continued at 4 °C in the refrigerator. At the end, whole blood was transferred to a 96-well deep-well plate using a volley gun, prewarmed IX Fix / Lysis solution was added, and cells were lysed and fixed for 12 minutes at 37°C in an incubator. After being washed, 400 pL of Perm III solution was added, vortexed and incubated on ice for 30 minutes. Cells were then stained by 100 pL of APC-pSTAT5 (1:100) antibody for 50 min at room temperature. This was followed by flow-through instrumentation. The expression of pSTAT5 was quantified by median fluorescence intensity after gating the CD3-positive signaling cluster. The results are shown in Table 3 below. Table 3 Inhibitory activity of representative compounds of the present invention on IFN-a inflammatory pathway Example No. IC5o(nM) BMS-986165(Deucravacitinib) 23.2 7 22.1 15 18.0 22 13.0 23 8.1 24 7.5 26 9.4 28 4.0 29 3.7 32 16.1 The test results show that the compounds provided in the present invention have high inhibitory activity against IFN-a-induced STAT phosphorylation in human whole blood, indicating that the compounds of the present invention strongly inhibit the IFN-a inflammatory pathway at the tissue level. Compared to the control BMS-986165, the present invention exhibits better IFN-a inflammatory pathway inhibitory activity, and, in particular, Example 28 and Example 29 have about 6-fold higher anti-inflammatory activity. Test Example 4: hERG potassium channel inhibition assay with compounds of the invention 4.1 Purpose of the experiment The blocking effect of the compounds in the present invention on hERG potassium currents on stable cell lines transfected with hERG potassium channels was tested by applying a fully automated membrane clamp. 4.2, Experimental method 4.2.1 Cell preparation CHO-hERG cells were cultured in 175 cm2 culture flasks, and when the cell density grew to 60-80%, the culture medium was removed and washed with 7 ml of PBS (Phosphate Buffered Saline), and then 3 ml of Detachin was added for digestion. When digestion was completed, 7 ml of culture medium was added to neutralize the cells, then centrifuged, the supernatant was removed, and 5 ml of culture medium was added to resuspend the cells to ensure that the cell density is 2-5x106 / ml. 4.2.2 Solution preparation Reagent Extracellular fluid(mM) Intracellular fluid(mM) CaCl2 2 5.374 MgCl2 1 1.75 KC1 4 120 NaCl 145 - Glucose 10 - HEPES 10 10 EGTA - 5 Na2ATP - 4 pH 7.4 7.25 4.2.3 Electrophysiological recording process The single-cell high-impedance sealing and whole-cell pattern formation processes were all automated with the Qpatch instrument. After obtaining the recording pattern, the cells were clamped at -80 mV, and a -50 mV preconditioning voltage was given for 50 ms prior to giving a +40 mV depolarizing stimulus for 5 s. The cell was then repolarized to -50 mV to be maintained for 5 s and then returned to -80 mV. This voltage stimulus was applied every 15 s. After recording for 2 min, extracellular fluid were given, recording for 5 min, and then the drug administration process was started, with compound concentrations starting from the lowest tested concentration, and each tested concentration was given for 2.5 min, and after giving all the concentrations consecutively, the positive control compound 3 pM Cisapride was given. At least 3 cells were tested for each concentration (n > 3). 4.2.4 Compound preparation 20 mM compound stock solution was diluted with extracellular fluid, 5 pL of 20 mM compound stock solution was added to 2495 pL of extracellular fluid, 500-fold diluted to 40 pM, and then 3-fold serial dilution was sequentially carried out in extracellular fluid containing 0.2% DMSO to obtain the final concentration to be tested. The highest tested concentration was 40 pM, and there were six concentrations of 40, 13.33, 4.44, 1.48, 0.49, and 0.16 pM, respectively. 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. 4.3 Data analysis The experimental data was analyzed by XLFit software. 4.4 Experimental results The results are shown in Table 4 below. Table 4 Inhibitory activity of representative compounds of the present invention on hERG potassium channel Example No. ICso(pM) 28 >30 29 >30 The test results show that the compounds of the present invention have no hERG potassium channel inhibitory activity and low risk of cardiotoxicity. Test Example 5: In vivo pharmacokinetics assay of the compounds of the present invention 5.1 In vivo pharmacokinetic experiment in rats Experimental method: Healthy male SD rats were randomly grouped into 3 rats in each group and given the test compound orally. The rats were fasted for 12 h before the gavage experiment, and drank water freely, and were fed uniformly for 4 h after the administration of the compounds. Before (0 h) and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after the administration of the test compounds, 0.2 mL of blood was collected from the jugular vein at the above set time points and placed in EDTA-K2 tubes, and the whole blood was collected and stored temporarily in an ice-water bath, and then centrifuged at 11,000 rpm for 5 min within 30 min, the plasma was separated, and frozen at -70° C in a refrigerator for testing. Test Example 5.1 Results: see Table 5.1 below. Table 5.1 Metabolic parameters of representative compounds of the invention in rats Example No. Dose Tl / 2 (h) Cmax (ng / mL) AUC (ngh / mL) MRT (h) F (%) BMS-986165 5mg / kg 3.68 229 2804 6.43 28.5 28 5mg / kg 2.48 651 2644 3.54 103.8 40 20mg / kg 2.65 2953 22029 4.7 109 5.2 In vivo pharmacokinetic experiments in Beagle dogs Experimental Methods: Healthy male Beagle dogs were randomly grouped into 3 rats in each group, and were given the test compounds orally. Before the gavage experiment, the dogs were fasted for 12 h, drank water freely, and were uniformly fed for 4 h after the administration of the drug. 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10 and 24 h after administration; about 600 pL of blood was collected from the forelimb or hindlimb at the above set time points and placed in EDTA-K2 tubes, and the whole blood was collected and stored temporarily in an ice-water bath, and then centrifuged at least 3500 rpm for 10 min within 30 min, and the plasma was separated and frozen in a -70°C refrigerator for testing. Test Example 5.2 Results: see Table 5.2 below. Table 5.2 dogs metabolic parameters of representative compounds of the inventions Example No. Dose Tl / 2 (h) Cmax (ng / mL) AUC (ngh / mL) MRT (h) F (%) BMS-986165(literature values) 2mg / kg 6.21 222 1312 35.5 28 2mg / kg 7.26 485 6684 10.68 117 30 2mg / kg 8.61 625 8454 11.8 40 lOmg / kg 9.28 4853 79882 12.7 136.6 The test results show that the compounds in the present invention have good drug metabolizing properties, good drug-forming properties and their plasma exposure (AUC) is high. The oral bioavailability (F%) and plasma exposure of the compounds of the present invention in rats and dogs have significant advantages over BMS-986165, showing excellent oral absorption properties and excellent metabolic profiles. Test Example 6: Solubility of the compounds of the invention in water (at pH=7) Test Example 6 results: see Table 6 below. Table 6 Solubility of representative compounds of the present invention Example No. Solubility (pg / ml) BMS-986165 8.2 28 22 38 47 The test results show that the water solubility properties of the compounds provided by the present invention are significantly better than that of BMS-986165. Water solubility is an important indicator for evaluating the drug ability of small molecule oral drugs. Only when the drug is dissolved can it be absorbed into the body circulation through the stomach and intestines. Drugs with poor water solubility are slowly absorbed and have low bioavailability, affecting the blood drug concentration and pharmacological effects, which directly leads to a high clinical failure rate. The compounds in the present invention have higher solubility compared to BMS-986165, and thus have better oral absorption properties and drug-forming properties. All literatures mentioned in the present invention are incorporated by reference herein, as though individually incorporated by reference. Additionally, it should be understood that after reading the above teaching, many variations and modifications may be made by the skilled in the art, and these equivalents also fall within the scope as defined by the appended claims.

Claims

1. A compound of formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:wherein,R1 is selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl and substituted or unsubstituted C3-C6 cycloalkyl, the substitution refers to be substituted by one or more substituents selected from the group consisting of deuterium and halogen;A is NH or CH2;Bis CH orN;R2 is selected from the group consisting of H, -CDs, C1-C6 alkyl and C3-C6 cycloalkyl;Xis CH orN;Y is NH, O or S;R3, R4, R5 are each independently selected from the group consisting of H, -NH2, -OH, C1-C6 alkoxy, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, -CONH2, -CN, halogen, -O(CH2)nR9, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkylsubstituted C2-C6 alkynyl and -NR8(CH2)nR9;n is 1, 2, 3, 4 or 5;R9 is selected from the group consisting of -OH, C1-C6 alkoxy, C4-C6 cycloalkoxy, 4-8-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S and -CN;R8isHorCl-C6 alkyl;R6, R7 are each independently selected from the group consisting of H, C1-C6 alkyl and halogen2. The compound or the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is a fully deuterated C1-C6 alkyl;A is NH;Bis CH orN3. The compound or the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, or the mixture thereof, or the pharmaceutically acceptable salt thereofR20 'n -ppS^y^R3according to claim 1, wherein L is R4 ;R2 is selected from the group consisting of H, -CDs, and C1-C6 alkyl;Xis N;R3, R4, R5 are each independently selected from the group consisting of H, -NH2, -OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, -CONH2, -CN, halogen, -O(CH2)nR9, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl-substituted C2-C6 alkynyl and -NR8(CH2)nR9;n is 1, 2, 3, 4 or 5;R9 is selected from the group consisting of C1-C6 alkoxy, C4-C6 cycloalkoxy, 48-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S and -CN;R8isHorCl-C6 alkyl.

4. The compound or the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is a fully deuterated C1-C6 alkyl;A is NH;Bis N;R2ON -y-I £ r5Y^xr3L is R4 ;R2 is selected from the group consisting of H, -CDs and C1-C6 alkyl;Xis N;R3 is -NH2;R4 is selected from the group consisting of halogen, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl and C3-C6 cycloalkyl-substituted C2-C6 alkynyl;R5 is H.

5. The compound or the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is a fully deuterated C1-C6 alkyl;A is NH;Bis N;R2R2 is -CD3;Xis N;R3 is -NH2;R4 is selected from the group consisting of halogen, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl and C3-C6 cycloalkyl-substituted C2-C6 alkynyl;R5 is H.

6. The compound or the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of:9243444748497. A preparation method for the compound or the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, or the mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 comprising the following steps:l-creacting formula I-c with cyclopropyl amide to obtain the compound of formula (i);wherein,R1, A, B, L are as defined in claim 1;G is halogen.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound or the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, or the mixture thereof, or the pharmaceutically acceptable salt thereof of claim 1.

9. A use of the compound or the tautomer, the mesomer, the racemate, the enantiomer, the diastereoisomer, or the mixture thereof, or the pharmaceutically acceptable salt thereof of claim 1 for the preparation of a medicament, the medicament is used for the prevention and / or treatment of a disease mediated by TYK2.

10. The use according to claim 9, wherein the disease mediated by TYK2 is an inflammatory or autoimmune disease in mammals.

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