Sulfonamide compound and use thereof

Abstract

Disclosed in the present invention are a sulfonamide compound and the use thereof, and specifically provided are a compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, which has good inhibitory activity on JAK1 kinase and good selectivity for JAK2 kinase.

Description

A sulfonamide compound and its application

[0001] This application claims the benefit of Chinese patent application No. 2023107956104, filed June 30, 2023. The entire text of the aforementioned Chinese patent application is incorporated herein by reference. Technical Field

[0002] The present invention relates to a sulfonamide compound and application thereof. Background Art

[0003] Janus kinases (JAKs) are a class of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals through the JAK-STAT pathway. The human JAK kinase family consists of four members: JAK1, JAK2, JAK3, and TYK2. This family is defined by the presence of two adjacent kinase domains, JH1 and JH2. JH1 performs the phosphorylation involved in pathway activation, while JH2 regulates the function of JH1 (Thomas et al., 2015 British Journal of Cancer 113, 365–371).

[0004] After cytokine stimulation, these cytoplasmic tyrosine kinases can bind to membrane cytokine receptors, such as the common γ-chain receptor and glycoprotein 130 (gp130) transmembrane protein. (Murray et al., 2007 Immunol. 178(5):2623-2629). Approximately 40 cytokine receptors signal through a combination of these four JAKs and their seven downstream substrates, the STAT family members (Ghoreschi et al., 2009 Immunol Rev. 228(1):273-287).

[0005] The JAK-STAT signaling pathway activates regulatory genes through signal transduction between cytokines outside the cell and the cell nucleus, and plays an important role in many biological processes, such as apoptosis and inflammation. Therefore, a dysfunctional JAK-STAT pathway may cause a wide range of diseases, such as cancer and immune system-related diseases.

[0006] Studies have shown that although blocking JAK targets can effectively control and alleviate the disease, first-generation JAK inhibitors (such as tofacitinib and baricitinib) have limited their dosage due to safety and tolerability issues, preventing them from fully realizing their therapeutic potential. (Fleischmann et al., Curr. Opin. Rheumatol. 24:335-341, 2012; Riese et al., Best Pract. Res. Clin. Rheumatol. 24:513-526, 2010). Even though these two drugs have higher selectivity for JAK kinases compared to other kinase families, these inhibitors do not have good selectivity for kinases within the JAK family. These adverse safety side effects may be caused by the inhibition of EPO and IL-15 signaling mediated by JAK2 and JAK3. (Jost et al., 2013 Annu. Rev. Immunol. 31:163-194; Kennedy et al., 2000 J. Exp. Med. 191:771-780; Richmond et al., 2005 Trends Cell Biol. 15:146-155). The development of highly selective JAK1 inhibitors has important clinical significance. By inhibiting JAK1 kinase activity to modulate immune activity, they can be demonstrated to play a role in the treatment of various immune diseases while avoiding the adverse side effects and usage limitations associated with the inhibition of JAK2-dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling. (Murray 2007 J. Immunol. 178, 2623-2629; Kisseleva et al., 2002 Gene, 285, 1-24; O'Shea et al., 2002 Cell 109, S121-S131; Neubauer et al., 1998 Cell 93(3), 397-409; Parganas et al., 1998 Cell 93(3), 385-95).

[0007] Summary of the Invention

[0008] The technical problem to be solved by the present invention is that the existing selective JAK1 inhibitors have a relatively simple structure, and provide a sulfonamide compound and its application, which has good JAK1 kinase inhibitory activity and selectivity for JAK2 kinase.

[0009] The present invention provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof,

[0010] Where R1 is C 1-6 Alkyl, C 3-6Cycloalkyl, one or more R 1-1 Substituted C 1-6 Alkyl or one or more R 1-2 Substituted C 3-6 Cycloalkyl;

[0011] Each R 1-1 are independently halogen, C 1-6 alkoxy or deuterium;

[0012] Each R 1-2 are each independently halogen or deuterium.

[0013] In certain preferred embodiments of the present invention, certain groups in the compound of formula (I) or a pharmaceutically acceptable salt thereof are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in some embodiments").

[0014] In some embodiments, the R1 is C 1-6 Alkyl, C 3-6 Cycloalkyl or one or more R 1- 1 substituted C 1-6 alkyl.

[0015] In some embodiments, the R1 is C 1-6 Alkyl or one or more R 1-1 Substituted C 1- 6 alkyl.

[0016] In some embodiments, the R1 is C 1-6 alkyl.

[0017] In some embodiments, each R 1-1 are independently halogen or C 1-6 Alkoxy, preferably halogen.

[0018] In some embodiments, each R 1-2 are each independently halogen.

[0019] In some embodiments, in the R1, the "C 1-6 Alkyl" and the " 1-1 Substituted C 1-6 C in "alkyl" 1-6 The alkyl groups are each independently C 1-4 The alkyl group is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably ethyl, n-propyl, n-butyl or isobutyl, more preferably n-propyl.

[0020] In some embodiments, in the R1, the "C 3-6 Cycloalkyl" and the "1-2 Substituted C 3-6 The "C" in "cycloalkyl" 3-6 The "cycloalkyl" groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclobutyl.

[0021] In some embodiments, the R 1-1 In the above, the "halogen" is independently fluorine, chlorine, bromine or iodine, preferably fluorine.

[0022] In some embodiments, the R 1-2 In the above, the "halogen" is independently fluorine, chlorine, bromine or iodine, preferably fluorine.

[0023] In some embodiments, the R 1-1 In the 1-6 "alkoxy" are each independently C 1- 4 Alkoxy, for example methoxy or ethoxy.

[0024] In some embodiments, the R1 is Preferably

[0025] In some embodiments, the compound represented by formula (I) is selected from any one of the following compounds:

[0026] The present invention also provides a pharmaceutical composition comprising:

[0027] (1) the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and (2) a pharmaceutically acceptable excipient.

[0028] The present invention also provides the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof in the preparation of a JAK1 inhibitor;

[0029] In the application, the JAK1 inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: a kit can be prepared according to conventional methods in the art to provide rapid detection of JAK1 inhibitory effects.

[0030] The present invention also provides the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition, in the preparation of a medicament for treating and / or preventing JAK1-related diseases, such as rheumatoid arthritis, psoriasis, ankylosing spondylitis, inflammatory bowel disease, or atopic dermatitis.

[0031] Definition and Description

[0032] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0033] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids, including but not limited to acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977) or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0034] In the present invention, the term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions, and refers to all substances contained in pharmaceutical preparations other than the active ingredient. For details, see the Pharmacopoeia of the People's Republic of China (2015 Edition), Part IV, or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009, Sixth Edition).

[0035] In the present invention, the term "plurality" refers to 2, 3, 4 or 5, preferably 2 or 3.

[0036] When any variable (such as R 1-1 ) occurs more than once in the composition or structure of a compound, its definition is independent on each occurrence. Thus, for example, if a group is replaced by one or more R 1-1 substituted, the group may optionally be substituted with at least one R 1-1 is replaced, and in each case R 1-1 Also, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0037] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0038] The reagents and raw materials used in the present invention are commercially available.

[0039] The positive progress of the present invention is that the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has good JAK1 kinase inhibitory activity and selectivity against JAK2 kinase. DETAILED DESCRIPTION

[0040] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0041] Representative method for preparative HPLC: Flow rates and mobile phase gradients may vary.

[0042] An exemplary method for preparing a high performance liquid chromatograph is as follows:

[0043] Method A: Ammonium bicarbonate:

[0044] Chromatographic column: Gilson 2Xbrige C18 19*150 mm, 5 μm; mobile phase: acetonitrile aqueous solution (0.1% ammonium bicarbonate) 20% to 60% gradient elution, flow rate 15 mL / min.

[0045] Method B: Formic acid:

[0046] Chromatographic column: Waters Xbridge C18 10*190 mm, 5 μm; mobile phase: acetonitrile aqueous solution (0.1% formic acid) 15% to 40% gradient elution, flow rate 15 mL / min.

[0047] Representative methods of HPLC-MS analysis:

[0048] Method 1:

[0049] Instrument: Agilent 1200_series HPLC-6120MS; chromatographic column: Waters Xbridge C18 column (1.8 μm, 4.6*50 mm); column temperature: 40°C; mobile phase: acetonitrile in water (containing 0.02% ammonium acetate) with a gradient elution from 5% to 95%, run time: 6.5 minutes; flow rate: 1.5 mL / min.

[0050] Method 2:

[0051] Instrument: Agilent 1200_series HPLC-6120MS; chromatographic column: Waters Xbridge C18 column (1.8 μm, 4.6*50 mm); column temperature: 40°C; mobile phase: acetonitrile in water (containing 0.1% trifluoroacetic acid) with a gradient elution from 5% to 95%, run time: 6.5 minutes; flow rate: 1.5 mL / min.

[0052] Method 3:

[0053] Instrument: Agilent 1260_ Series HPLC-6120MS; Chromatographic column: Diamonsil Plus C18 column (1.8 μm, 4.6*30 mm); Column temperature: 40°C; Mobile phase: Acetonitrile in water (containing 0.02% ammonium acetate) with a gradient elution from 5% to 95%, run time: 2.5 minutes; Flow rate: 1.5 mL / min.

[0054] Example 1: Preparation of target compound 1

[0055] The synthetic route is as follows:

[0056] Step 1. Synthesis of Intermediate 1-2

[0057] Compound 1-1 (4.1 g, 18.0 mmol) and 8 drops of N,N-dimethylformamide were dissolved in 40 mL of anhydrous dichloromethane and cooled to 0°C. Oxalyl chloride (2.7 g, 21.6 mmol) was added dropwise at 0°C. After the addition was complete, the reaction was stirred at 0°C for 1.5 hours. Trimethylsilylated diazomethane (22.5 mL, 45 mmol, in a 2 mol / L n-hexane solution) was slowly added to the reaction mixture. The reaction was stirred at 0°C for 2 hours, followed by the addition of 18 mL of ethyl acetate hydrochloride. Stirring was continued at 0°C for 30 minutes, followed by the addition of saturated sodium bicarbonate solution to adjust the pH to ≥7. The reaction mixture was extracted with ethyl acetate (150 mL x 3). The combined extracts were washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound 1-2 (2.8 g, 60% yield) as a brown solid. This product was used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ4.57(s,2H),2.07(s,6H),1.33(s,9H).

[0058] Step 2. Synthesis of Intermediates 1-3

[0059] Compound 1-2 (1.0 g, 3.85 mmol) and sodium iodide (1.16 g, 7.70 mmol) were dissolved in 20 mL of acetone and stirred at room temperature overnight. The solid was filtered out, and the filtrate was concentrated under reduced pressure to yield compound 1-3 (1.25 g, 92% yield) as a yellow solid. This product was used directly in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ4.93(br s,1H),3.77(s,2H),2.29(s,6H),1.38(s,9H).

[0060] Step 3. Synthesis of Intermediate 1-5

[0061] A mixture of compound 1-4 (4.0 g, 20.2 mmol) and sodium hydroxide (1.21 g, 30.2 mmol) in acetone (40 mL) and water (4 mL) was cooled to 0°C, and p-toluenesulfonyl chloride (4.6 g, 24.1 mmol) was added dropwise. After the addition was complete, the reaction temperature was raised to room temperature and stirred overnight. The reaction mixture was filtered, and the filter cake was dried under reduced pressure to afford compound 1-5 (4.3 g, 61% yield) as a brown solid. The crude product was used directly in the next step without further purification. 1H NMR (400MHz, DMSO-d6) δ8.59(s,1H),8.37(d,J=4.0Hz,1H),8.00(d,J=8.0Hz,2H),7.45(d,J=8.0Hz,2H),7.02(d,J=4.0Hz,1H),2.36(s,3H).

[0062] Step 4. Synthesis of Intermediate 1-6

[0063] Compound 1-5 (1.0 g, 2.84 mmol), ethyl carbamate (303 mg, 3.41 mol), tris(dibenzylideneacetone)dipalladium (260 mg, 0.28 mmol), X-Phos (270 mg, 0.57 mmol), and cesium carbonate (1.85 g, 5.68 mmol) were dissolved in 15 mL of 1,4-dioxane. The reaction was stirred at 120°C under nitrogen for 10 hours. After cooling, the solution was poured into 50 mL of water and extracted twice with 50 mL of ethyl acetate. The combined extracts were washed with 100 mL of saturated brine and dried over anhydrous sodium sulfate. The filtered filtrate was evaporated to dryness under reduced pressure. The crude product was purified using a silica gel column (eluent: petroleum ether / ethyl acetate) to obtain compound 1-6 (600 mg, 59% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.82(s,1H),8.19(d,J=4.0Hz,1H),7.98(d,J=8.8Hz,2H),7.4 4(d,J=8.8Hz,2H),6.85(d,J=4.0Hz,1H),4.17(q,J=6.8Hz,2H),2.53(s,3H),1.25(t,J=7.2Hz,3H).

[0064] Step 5. Synthesis of Intermediate 1-7

[0065] Compound 1-6 (400 mg, 1.11 mmol) was dissolved in 10 mL of N, N-dimethylacetamide solution and cooled to -10 ° C. Lithium tert-butoxide (178 mg, 2.22 mmol) and 1 mL of N, N-dimethylacetamide were prepared into a solution and added dropwise to the above reaction solution. The reaction was stirred at room temperature for 1 hour and then quenched by adding 30 mL of water. The reaction solution was extracted 3 times with 50 mL of ethyl acetate. The extracts were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated and purified using a silica gel column (eluent: petroleum ether / ethyl acetate) to obtain a yellow oily compound 1-7 (503 mg, yield 78%). LC-MS (ESI, method 3) t R =1.75min,m / z(M+H) +=584.5.

[0066] Step 6. Synthesis of Intermediate 1-8

[0067] Sodium hydroxide (400 mg, 1 mmol) was added to a 4 mL ethanol solution of compound 1-7 (180 mg, 0.31 mmol). The reaction was stirred at room temperature for 1.5 hours and then adjusted to pH = 8 with 2N aqueous hydrochloric acid. The reaction solution was extracted three times with 30 mL of dichloromethane, the combined extracts were washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 1-8 (110 mg, yield 99%) as a yellow oil. This product was used directly in the next step without further purification. LC-MS (ESI, method 3) t R =1.40min,m / z(M+H) + =358.3.

[0068] Step 7. Synthesis of Intermediate 1-9

[0069] A 3 mL acetonitrile solution of compound 1-8 (110 mg, 0.31 mmol) and trifluoroacetic anhydride (260 mg, 1.24 mmol) was stirred at 70 ° C for 2 hours. After the reaction was cooled, it was concentrated under reduced pressure. The obtained product was dissolved in methanol and saturated sodium carbonate solution (12 mL, v / v = 1 / 2), stirred at room temperature for 1 hour, and then 2N hydrochloric acid aqueous solution was added to adjust the pH to 2. The crude product obtained after the reaction solution was concentrated under reduced pressure was separated and purified using preparative high performance liquid chromatography (method A) to obtain yellow solid compound 1-9 (50 mg, yield 47%). LC-MS (ESI, method 1) t R =0.32min,m / z(M+H) + =240.1.

[0070] Step 8. Synthesis of target compound 1

[0071] Compound 1-9 (50 mg, 0.14 mmol) and N,N-diisopropylethylamine (108 mg, 0.84 mmol) were dissolved in a mixed solution of dimethyl sulfoxide / tetrahydrofuran (1.5 mL, v / v = 2 / 1). After cooling to 0°C, propane-1-sulfonyl chloride (20 mg, 0.14 mmol) was added dropwise and stirring continued for 3 hours. The reaction was diluted with 5 mL of water and then extracted three times with 25 mL of ethyl acetate. The extracts were combined and concentrated under reduced pressure to obtain a crude product, which was separated and purified using preparative high performance liquid chromatography (method A) to obtain yellow solid compound 1 (2.5 mg, yield 5%). LC-MS (ESI, method 2) t R =2.43min,m / z(M+H) + =346.1. 1H NMR(400MHz,MeOD-d4)δ8.55(s,1H),7.57(s,1H),7.45(s,1H),6.93(d,J=2.8Hz, 1H),3.13(t,J=7.6Hz,2H),2.65(s,6H),1.91-1.85(m,2H),1.12(t,J=7.6Hz,3H).

[0072] Example 2: Preparation of target compound 2

[0073] The synthetic route is as follows:

[0074] Step 1. Synthesis of Intermediate 2-1

[0075] At 0°C, 0.3 mL of trifluoroacetic acid was added to a solution of compound 1-8 (30 mg, 0.08 mmol) in 0.1 mL of dichloromethane. The reaction was stirred at 0°C for 1 hour, and the reaction solution was slowly blown dry with a stream of nitrogen to obtain compound 2-1 (31 mg, 99% yield) as a brown oil. This crude product was used directly in the next step without further purification. LC-MS (ESI, Method 3) revealed that the product was 1-8 (30 mg, 0.08 mmol) and 1-8 (0.1 mL). R =0.24min,m / z(M+H) + =258.3.

[0076] Step 2. Synthesis of Intermediate 2-2

[0077] Compound 2-1 (31 mg, 0.08 mmol) and N,N-diisopropylethylamine (65 mg, 0.50 mmol) were dissolved in 0.3 mL of tetrahydrofuran. After cooling to 0°C, 1-butanesulfonyl chloride (39 mg, 0.25 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was slowly dried with a stream of nitrogen to obtain a brown oily compound 2-2 (20 mg, 48% yield). This crude product was used directly in the next step without further purification. LC-MS (ESI, Method 3) R =1.27min,m / z(M+H) + =498.3.

[0078] Step 3. Synthesis of target compound 2

[0079] Compound 2-2 (20 mg, 0.05 mmol) was added dropwise to an acetonitrile solution of trifluoroacetic anhydride (0.3 mL, v / v = 1 / 1) and stirred at 100 ° C for 2 hours. After the reaction cooled to room temperature, the reaction solution was slowly blown dry with a stream of nitrogen. The crude product was dissolved in 2 mL of ethyl acetate and saturated sodium carbonate solution was added to adjust the pH to greater than or equal to 7. The reaction solution was extracted three times with 3 mL of ethyl acetate, the extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a brown solid compound. The crude product was separated and purified using preparative high performance liquid chromatography (method B) to obtain white solid compound 2 (3.5 mg, yield 18%). LC-MS (ESI, method 2) t R =0.90min,m / z(M+H) + =360.1. 1 H NMR (400MHz, DMSO-d6) δ12.32(s,1H),8.58(s,1H),8.28(s,1H),7.54(s,1H),7.47(t,J=2.8Hz,1H),6.78(d,J =2.8Hz,1H),3.08(t,J=7.6Hz,2H),2.55(s,6H),1.71-1.65(m,2H),1.47-1.42(m,2H),0.92(t,J=7.6Hz,3H).

[0080] Example 3: Preparation of target compound 3

[0081] The synthetic route is as follows:

[0082] Step 1. Synthesis of Intermediate 3-1

[0083] Compound 2-1 (31 mg, 0.08 mmol) and N,N-diisopropylethylamine (65 mg, 0.50 mmol) were dissolved in 0.3 mL of tetrahydrofuran. After cooling to 0°C, 3,3,3-trifluoropropane-1-sulfonyl chloride (49 mg, 0.25 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was slowly dried with a stream of nitrogen to obtain a brown oily compound 3-1 (15 mg, 43% yield). This crude product was used directly in the next step without further purification. LC-MS (ESI, Method 3) revealed that the reaction mixture had a brown oily substance. R =0.96min,m / z(M+H) + =418.2.

[0084] Step 2. Synthesis of target compound 3

[0085] Compound 3-1 (15 mg, 0.04 mmol) was added dropwise to an acetonitrile solution of trifluoroacetic anhydride (0.3 mL, v / v = 1 / 1) and stirred at 100 ° C for 2 hours. After the reaction cooled to room temperature, the reaction solution was slowly blown dry with a stream of nitrogen. The crude product was dissolved in 2 mL of ethyl acetate and saturated sodium carbonate solution was added to adjust the pH to greater than or equal to 7. The reaction solution was extracted three times with 3 mL of ethyl acetate, the extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a brown solid compound. The crude product was separated and purified by preparative high performance liquid chromatography (method B) to obtain a white solid compound 3 (1.5 mg, yield 10%). LC-MS (ESI, method 2) t R =0.92min,m / z(M+H) + =400.0. 1 H NMR (400MHz, CD3OD-d4) δ8.53(s,1H),7.55(s,1H),7.42(d,J=3.6Hz,1H),6.92(d,J=3.6Hz,1H),3.39-3.31(m,2H),2.76-2.69(m,2H),2.65(s,6H).

[0086] Example 4: Preparation of target compound 4

[0087] The synthetic route is as follows:

[0088] Step 1. Synthesis of Intermediate 4-1

[0089] Compound 2-1 (31 mg, 0.08 mmol) and N,N-diisopropylethylamine (65 mg, 0.50 mmol) were dissolved in 0.3 mL of tetrahydrofuran and cooled to 0°C before adding ethylsulfonyl chloride (46 mg, 0.36 mmol) dropwise. The reaction mixture was slowly heated to room temperature and stirred for 1 hour. After the reaction, the reaction solution was slowly dried with a stream of nitrogen to obtain compound 4-1 as a brown oil (20 mg, 48% yield). This crude product was used directly in the next step without further purification. LC-MS (ESI, Method 3) revealed that the reaction mixture was quenched with ethanol and then dried with a stream of nitrogen. R =0.75min,m / z(M+H) + =350.2.

[0090] Step 2. Synthesis of target compound 4

[0091] Compound 4-1 (20 mg, 0.06 mmol) was added dropwise to an acetonitrile solution of trifluoroacetic anhydride (0.3 mL, v / v = 1 / 1) and stirred at 100 ° C for 2 hours. After the reaction cooled to room temperature, the reaction solution was slowly blown dry with a stream of nitrogen. The crude product was dissolved in 2 mL of ethyl acetate and saturated sodium carbonate solution was added to adjust the pH to greater than or equal to 7. The reaction solution was extracted three times with 3 mL of ethyl acetate, the extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a brown solid compound. The crude product was separated and purified by preparative high performance liquid chromatography (method B) to obtain a white solid compound 3 (3.4 mg, yield 18%). LC-MS (ESI, method 2) t R =0.80min,m / z(M+H) + =332.0. 1 H NMR(400MHz,DMSO-d6)δ12.39(s,1H),8.61(s,1H),8.29(s,1H),7.60(s,1H),7.51-7.4 9(m,1H),6.84-6.82(m,1H),3.09(q,J=6.8Hz,2H),2.58(s,6H),1.26(t,J=7.2Hz,3H).

[0092] Example 5: Preparation of target compound 5

[0093] The synthetic route is as follows:

[0094] Step 1. Synthesis of Intermediate 5-1

[0095] Compound 2-1 (31 mg, 0.08 mmol) and N,N-diisopropylethylamine (65 mg, 0.50 mmol) were dissolved in 0.5 mL of tetrahydrofuran. After cooling to 0°C, 2-methylpropanesulfonyl chloride (46 mg, 0.30 mmol) was added dropwise. The reaction mixture was slowly heated to room temperature and stirred for 45 minutes. After the reaction was completed, the reaction solution was slowly dried with a stream of nitrogen to obtain a brown oily compound 5-1 (37 mg, 99% yield). This crude product was used directly in the next step without further purification. LC-MS (ESI, Method 3) R =0.93min,m / z(M+H) + =378.3.

[0096] Step 2. Synthesis of target compound 5

[0097] Compound 5-1 (35 mg, 0.092 mmol) was added dropwise to an acetonitrile solution of trifluoroacetic anhydride (0.3 mL, v / v = 1 / 2) and stirred at 100 ° C for 2 hours. After the reaction cooled to room temperature, the reaction solution was slowly blown dry with a nitrogen stream. The obtained crude product was dissolved in 1 mL of methanol, 2 mL of 0.5 M potassium carbonate aqueous solution was added, and stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was purified by thin layer chromatography (developing solvent: dichloromethane / methanol) to obtain a yellow solid compound 5 (3.2 mg, yield 10%). LC-MS (ESI, method 2) t R =0.89min,m / z(M+H) + =360.0. 1 H NMR (400MHz, DMSO-d6) δ12.31(s,1H),8.57(s,1H),8.28(s,1H),7.54(s,1H),7.47(t,J=2.8Hz,1H ),6.79-6.77(m,1H),2.99(d,J=6.4Hz,2H),2.51(s,6H),2.17-2.11(m,1H),1.26(d,J=6.8Hz,6H).

[0098] Preparation of target compound 6

[0099] The synthetic route is as follows:

[0100] Step 1. Synthesis of Intermediate 6-2

[0101] Compound 6-1 (900 mg, 5.07 mmol) and sodium hydroxide (304 mg, 7.60 mmol) were dissolved in 3 mL of acetone. After cooling to 0°C, 2-(trimethylsilyl)ethoxymethyl chloride (1.3 g, 7.60 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6-2 (1.56 g, 98% yield) as a brown oil. The crude product was used directly in the next reaction without further purification. 1 H NMR (400MHz, DMSO-d6) δ8.86 (s, 1H), 8.09 (d, J = 4.0Hz, 1H), 6.90 (d, J = 4.0Hz ,1H),5.89(s,2H),3.62(t,J=8.0Hz,2H),0.94(t,J=8.0Hz,2H),0.01(s,9H).

[0102] Step 2. Synthesis of Intermediate 6-3

[0103] Compound 6-2 (1.4 g, 7.07 mmol), tert-butyl N-{3-aminobicyclo[1.1.1]pentan-1-yl}carbamate (1.4 g, 4.55 mmol), and N,N-diisopropylethylamine (1.76 g, 13.6 mmol) were dissolved in 5 mL of N-methylpyrrolidone and stirred at 110°C overnight. After cooling to room temperature, an additional portion of tert-butyl N-{3-aminobicyclo[1.1.1]pentan-1-yl}carbamate (500 mg, 2.52 mmol) was added and stirring continued at 120°C for 6 hours. The reaction mixture was cooled to room temperature, poured into 100 mL of water, and extracted three times with 100 mL of ethyl acetate. The extract was washed three times with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel column (eluent: petroleum ether / ethyl acetate) to obtain a yellow solid compound 6-3 (1.1 g, yield 33%). 1 H NMR(400MHz,DMSO-d6)δ8.32(s,1H),7.81(s,1H),7.71(br s,1H),7.54(d,J=3.2Hz,1H),7.03(d,J=3.6Hz,1H),5.60(s,2H),3.57(t,J =8.0Hz,2H),2.51(s,6H),1.49(s,9H),0.89(t,J=8.0Hz,2H),0.02(s,9H).

[0104] Step 3. Synthesis of Intermediate 6-4

[0105] Compound 6-3 (1.0 g, 2.13 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran and cooled to 0°C using an ice-water bath. A 1 M n-hexane solution of diisobutylaluminum hydride (5.3 mL, 5.3 mmol) was slowly added to the reaction solution at 0°C. After the reaction was stirred at room temperature for 2 hours, it was quenched with a saturated sodium potassium tartrate solution and stirred at room temperature for 20 minutes. The resulting solution was extracted three times with 100 mL of ethyl acetate. The extract was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated and purified using a silica gel column (eluent: petroleum ether / ethyl acetate) to give a white solid compound 6-4 (490 mg, yield 49%). LC-MS (ESI, method 3) t R =1.87min,m / z(M+H) + =473.5.

[0106] Step 4. Synthesis of Intermediate 6-5

[0107] (Methoxymethyl)triphenylphosphonium bromide (551 mg, 1.61 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran and cooled to 0°C under nitrogen protection. At 0°C, a 2.5 M n-butyllithium (0.6 mL, 4.0 mmol) n-hexane solution was slowly added dropwise to the reaction solution. After the addition was complete, the reaction was stirred at room temperature for 1 hour. Compound 6-4 (380 mg, 0.80 mmol) was dissolved in 1 mL of anhydrous tetrahydrofuran and added dropwise to the reaction solution, and then the reaction was stirred at room temperature overnight. 20 mL of water was added to the reaction solution and extracted three times with 50 mL of ethyl acetate. The extracts were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated and purified using a silica gel column (eluent: petroleum ether / ethyl acetate) to obtain a white solid compound 6-5 (85 mg, yield 21%). LC-MS (ESI, method 3) t R =1.84min,m / z(M+H) + =501.5.

[0108] Step 5. Synthesis of Intermediate 6-6

[0109] Compound 6-5 (85 mg, 0.17 mmol) was dissolved in 2 mL of methanol and acetyl chloride (40 mg, 0.51 mmol) was added dropwise at 0 ° C. After the addition was complete, the reaction was stirred at 80 ° C for 2 hours, then 0.2 mL of water was added and stirring was continued for 4 hours. The reaction was cooled to room temperature, the reaction solution was poured into 3 mL of saturated sodium bicarbonate solution, and extracted twice with 30 mL of ethyl acetate. The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a colorless oily compound 6-6 (50 mg, yield 80%). This product was used directly in the next step without further purification. LC-MS (ESI, method 3) t R =1.64min,m / z(M-100+H) + =369.4.

[0110] Step 6. Synthesis of Intermediate 6-7

[0111] 1 mL of trifluoroacetic acid was added dropwise to 1 mL of a dichloromethane solution of compound 6-6 (50 mg, 0.14 mmol) at 0°C. The reaction mixture was slowly warmed to room temperature, stirred for 2 hours, concentrated under reduced pressure, and redissolved in 2 mL of a 2M ammonia methanol solution and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain compound 6-7 (31 mg, 99% yield) as a brown oil. The crude product was used directly in the next step without further purification. LC-MS (ESI, Method 3) revealed that the product was soluble in water and soluble in water. R =1.17min,m / z(M+H) + =239.1.

[0112] Step 7. Synthesis of target compound 6

[0113] Compound 6-7 (32 mg, 0.13 mmol) and N,N-diisopropylethylamine (52 mg, 0.40 mmol) were dissolved in 0.8 mL of a mixed solution of dimethyl sulfoxide / tetrahydrofuran (v / v=1 / 1), cooled to 0°C, and propane-1-sulfonyl chloride (19 mg, 0.13 mmol) was added dropwise and stirred for 3 hours. The reaction solution was diluted with 3 mL of water and then extracted twice with 4 mL of ethyl acetate. The extracts were combined and concentrated under reduced pressure to obtain a crude product, which was separated and purified using preparative high performance liquid chromatography (method A) to obtain a white solid compound 6 (2.0 mg, yield 4.3%). LC-MS (ESI, method 1) t R =3.15min,m / z(M+H) + =345.1. 1 H NMR (400MHz, CD3OD) δ8.44(s,1H),7.35(d,J=2.8Hz,1H),7.13(d,J=2.4Hz,1H),6.82(d,J=2.8Hz,1H) ,6.67(d,J=2.4Hz,1H),3.13(t,J=7.6Hz,2H),2.77(s,6H),1.91-1.86(m,2H),1.12(t,J=7.6Hz,3H).

[0114] Preparation of target compound 7

[0115] The synthetic route is as follows:

[0116] Step 1. Synthesis of Intermediate 7-2

[0117] Compound 7-1 (1.0 g, 4.4 mmol), dimethylhydroxylamine hydrochloride (553 mg, 5.70 mmol) and N,N-diisopropylethylamine (1.7 g, 13.2 mmol) were dissolved in 10 mL of N,N-dimethylformamide, and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.5 g, 6.6 mmol) was added in portions at 0°C. After stirring at room temperature for 2 hours, the reaction was diluted with 50 mL of ethyl acetate and washed three times with 30 mL of saturated brine. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 7-2 (1.1 g, yield 93%) as a yellow oil. The crude product was used directly in the next reaction without further purification. LC-MS (ESI, method 3) t R =1.35min,m / z(M+H) + =271.1.

[0118] Step 2. Synthesis of Intermediate 7-3

[0119] Compound 7-2 (500 mg, 1.9 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran and cooled to -60°C under nitrogen. A 1 M solution of lithium bistrimethylsilylamide in tetrahydrofuran (2.8 mL, 2.8 mmol) was slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was warmed to 0°C. After stirring at this temperature for 1 hour, 1-propylsulfonyl chloride (392 mg, 2.8 mmol) was added. The reaction mixture was stirred at room temperature for another 2 hours and quenched by adding 30 mL of water. The reaction mixture was extracted three times with 30 mL of ethyl acetate, and the separated organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified using preparative HPLC (Method A) to obtain compound 7-3 (1.0 g, 60% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ3.65(s,3H),3.88-3.34(m,2H),3.17(s,3H),2.56(s,6H),1.86-1.77(m,2H),1.52(s,9H),1.06(t,J=7.6Hz,3H).

[0120] Step 3. Synthesis of Intermediate 7-4

[0121] Compound 4-iodo-7H-pyrrolo[2,3-d]pyrimidine (652 mg, 2.7 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran. The reaction mixture was cooled to -78°C, and a 1.3 M solution of isopropylmagnesium bromide in tetrahydrofuran (6.1 mL, 8.0 mmol) was slowly added dropwise. The reaction mixture was stirred at -78°C for 1 hour, followed by the addition of a 1 M solution of 2,6-dimethylphenylmagnesium bromide in tetrahydrofuran (8 mL, 8.0 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour, followed by the addition of a solution of 7-3 (1.0 g, 2.7 mmol) in tetrahydrofuran. The reaction mixture was stirred at room temperature overnight, followed by the addition of 30 mL of water and extraction with 30 mL of ethyl acetate three times. The extract was concentrated under reduced pressure, and the crude product was purified using preparative HPLC (Method A) to afford compound 7-4 as a yellow oil (357 mg, 40% yield). 1 H NMR(400MHz,DMSO-d6)δ12.47(br s,1H),8.94(s,1H),8.19(br s,1H),6.93(d,J=3.2Hz,1H),7.82(d,J=3.6Hz,1H),3.07-2.98(m,2H),2.51(s,6H),1.70-1.68(m,2H),1.00(t,J=7.2Hz,3H).

[0122] Step 4. Synthesis of Intermediate 7-5

[0123] To a 2 mL ethanol solution of compound 7-4 (100 mg, 0.30 mmol) and hydroxylamine hydrochloride (100 mg, 1.43 mmol) was added 0.5 mL of 4N aqueous sodium hydroxide solution. The reaction was stirred at room temperature for 2 hours. The reaction solution was directly separated and purified using preparative HPLC (Method A) to obtain a yellow solid compound 7-5 (104 mg, 99% yield). LC-MS (ESI, Method 3) revealed that the product was a yellow solid. R =1.15min,m / z(M+H) + =350.4.

[0124] Step 5. Synthesis of Intermediate 7-6

[0125] A solution of compound 7-5 (104 mg, 0.30 mmol), zinc powder (80 mg, 1.23 mmol), and ammonium chloride (64 mg, 1.19 mmol) in 4 mL of methanol was stirred at room temperature for 2 hours. A 1 mL aqueous solution of formic acid (206 mg, 4.4 mmol) was added to the reaction mixture. The reaction was stirred at room temperature for another 2 hours. The reaction mixture was filtered, and the filtrate was diluted with 10 mL of ethyl acetate and washed with 5 mL of saturated brine. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified using a thin-layer chromatography preparative plate (developing solvent: dichloromethane / methanol) to obtain compound 7-6 (40 mg, 39% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.22-8.21(m,2H),7.92(br s,1H),7.68(d,J=3.6Hz,1H),6.81(d,J=3.2Hz,1H),4.90(s,1H),2.83-2. 80(m,2H),1.82(d,J=9.2Hz,3H),1.73(d,J=9.6Hz,3H),1.60-1.54(m,2H), 0.91(t,J=7.2Hz,3H).

[0126] Step 6. Synthesis of Intermediate 7-7

[0127] Compound 7-6 (40 mg, 0.12 mmol) was dissolved in 1 mL of formic acid, and the reaction mixture was stirred at 100°C for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a yellow solid compound 7-7 (40 mg, yield 92%). LC-MS (ESI, method 2) R =1.12min,m / z(M+H) + =364.3.

[0128] Step 7. Synthesis of target compound 7

[0129] The reaction solution of compound 7-7 (40 mg, 0.11 mmol) and 1 mL of polyphosphoric acid was stirred at 80°C for 2 hours. After the reaction was cooled to 40-50°C, it was poured into ice water and adjusted to pH = 7 using saturated sodium bicarbonate aqueous solution. The resulting mixture was extracted twice with 10 mL of dichloromethane, the extracts were combined, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using a thin layer chromatography preparative plate (developing solvent: dichloromethane / methanol) to obtain an off-white solid compound 7 (11.5 mg, yield 29%). LC-MS (ESI, method 1) t R =2.89min,m / z(M+H) + =346.1. 1 H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.85(s,1H),8.33(s,1H),8.11(s,1H),7.20-7.19(m,1H), 6.52-6.51(m,1H),3.03(t,J=7.2Hz,2H),2.35(s,6H),1.73-1.70(m,2H),1.02(t,J=7.2Hz,3H).

[0130] Effect Example: JAK1, JAK2 and TYK2 Kinase Activity IC 50 Evaluation experiment

[0131] Method I

[0132] 1. Experimental Purpose

[0133] Detection of IC of test compounds on JAK1, JAK2 and TYK2 kinases 50 The assay method was mobility shift assay, with a starting compound concentration of 5000 nM, 3-fold dilution, 10 concentration points, duplicate well detection, and a final ATP concentration of 1 mM.

[0134] 2. Reagents and consumables

[0135] 3. Instruments

[0136] Centrifuge (manufacturer: Eppendorf, model: 5430 )

[0137] Microplate reader (Manufacturer: Perkin Elmer, Model: Caliper EZ Reader II )

[0138] Echo 550 (Manufacturer: Labcyte, Model: Echo 550)

[0139] 4. Experimental methods

[0140] 1) Compound preparation

[0141] Prepare compound powder into 10 mM or 20 mM DMSO stock solution and store in a nitrogen cabinet away from light.

[0142] 2) Kinase reaction process

[0143] (1) Prepare 1X kinase buffer

[0144] (2) Preparation of compound concentration gradient: The compound starting concentration was 5000 nM, and the compound was diluted 3-fold over 10 concentration points in a 100% DMSO solution in a 384-well source plate to a 100-fold final concentration. 250 nL of the compound at 100-fold final concentration was transferred to the destination 384-well plate using an Echo550 dispenser.

[0145] (3) Prepare a kinase solution with a final concentration of 2.5 times using 1X kinase buffer (final enzyme concentration: JAK 15 nM, JAK2 0.25 nM, TYK2 2.5 nM).

[0146] (4) Add 10 μL of kinase solution at 2.5 times the final concentration to the test compound wells and positive control wells, respectively, and add an equal volume of 1X kinase buffer to the negative control wells.

[0147] (5) Centrifuge at 1000 rpm for 30 seconds, shake the reaction plate to mix, and incubate at room temperature for 10 minutes.

[0148] (6) Prepare a mixed solution of 5 times the final concentration of ATP (5 mM) and 3 times the final concentration of kinase substrate solution (3 μM) using 1X kinase buffer.

[0149] (7) Add 15 μL of a mixed solution of ATP and substrate at 5 / 3 times the final concentration to start the reaction.

[0150] (8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake to mix, and incubate at room temperature for the corresponding time (JAK1 90 minutes, JAK2 15 minutes, TYK2 30 minutes).

[0151] (9) Add 30 μL of stop detection solution (50 mM EDTA) to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and shake to mix.

[0152] (10) Read the conversion rate using Caliper EZ Reader.

[0153] 3) Data Analysis

[0154] Calculation formula:

[0155] % Inhibition rate = (maximum conversion rate % - sample conversion rate %) * 100 / (maximum conversion rate % - minimum conversion rate %)

[0156] Where: Sample conversion rate is the conversion rate reading of the sample, minimum conversion rate is the mean of the negative control wells, representing the conversion rate reading of the wells without enzyme activity; maximum conversion rate refers to the conversion rate reading of the wells without compound inhibition.

[0157] 4) Fitting the dose-effect curve

[0158] The Log value of the concentration was used as the X-axis and the percentage inhibition rate was used as the Y-axis. The Log (inhibitor) vs. response-Variable slope of the analysis software Graphpad Prism 5 was used to fit the dose-effect curve to obtain the IC value of each compound on the enzyme activity. 50 The calculation formula is Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * Hill slope)).

[0159] Method II

[0160] 1. Purpose of the experiment

[0161] Detection of IC of test compounds on JAK1, JAK2 and TYK2 kinases 50 The test method was HTRF method, the starting concentration of the compound was 5000 nM, 3-fold dilution, 10 concentration points, duplicate well detection, and the final ATP concentration was 1 mM.

[0162] 2. Reagents and consumables

[0163] 3. Instruments and software

[0164] 4. Experimental Methods

[0165] 1) Compound preparation

[0166] Prepare compound powder into 10 mM or 20 mM DMSO stock solution and store in a nitrogen cabinet away from light.

[0167] 2) Kinase reaction process

[0168] (1) Prepare 1X kinase buffer

[0169] (2) Preparation of compound concentration gradient: The compound starting concentration was 5000 nM. The compound was diluted 3-fold over 10 concentration points in a 100% DMSO solution in a 384-well source plate to a 100-fold final concentration. 100 nL of the compound at the 100-fold final concentration was transferred to the destination 384-well plate using an Echo dispenser.

[0170] (3) 2.5 μL of each kinase mixture was added to the test plate (final concentration of each enzyme: JAK1 10 nM, JAK2 1.5 nM, TYK2 20 nM), centrifuged at 1000 rpm for 30 seconds, and then pre-incubated at 25°C for 15 minutes.

[0171] (4) 5 μL of enzyme-substrate mixture was added to the test plate to initiate the reaction (final concentration of each enzyme substrate: JAK1 1000 nM, JAK2 550 nM, TYK2 110 nM), centrifuged at 1000 rpm for 30 seconds, and then incubated at 25°C for 120 minutes.

[0172] (5) After 120 minutes of reaction, add 10 μL of detection antibody mixture, centrifuge at 1000 rpm for 30 seconds, and continue incubation at 25°C for 120 minutes.

[0173] (6) After the reaction is completed, the TR-FRET 665 / 612 wavelength signal value is read using Envision.

[0174] The test results are as follows:

[0175] a Compound 3 was tested using Method II, with the kinase concentrations shown in Method II. All other compounds were tested using Method I.

[0176] From the above data, it can be seen that the compounds of the present application have good JAK1 kinase inhibitory activity and selectivity against JAK2 kinase.

Claims

1. A compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, in, R1 is C 1-6 Alkyl, C 3-6 Cycloalkyl, with one or more R 1-1 Substituted C 1-6 Alkyl or one or more R 1-2 Substituted C 3-6 Cycloalkyl; Each R 1-1 are independently halogen, C 1-6 Alkoxy or deuterium; Each R 1-2 are each independently halogen or deuterium.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R1 is C 1-6 Alkyl, C 3-6 Cycloalkyl or one or more R 1-1 Substituted C 1- 6 alkyl; preferably C 1-6 Alkyl or one or more R 1-1 Substituted C 1-6 Alkyl; more preferably C 1- 6 alkyl.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) Each R 1-1 are independently halogen or C 1-6 Alkoxy, preferably halogen; and (2) Each R 1-2 are each independently halogen.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) In the R1, the "C 1-6 Alkyl" and the "is replaced by one or more R 1-1 Substituted C 1-6 C in "alkyl" 1-6 The alkyl groups are each independently C 1-4 alkyl; (2) In the R1, the "C 3-6 Cycloalkyl" and said" is replaced by one or more R 1-2 Substituted C 3-6 The "C" in "cycloalkyl" 3-6 "Cycloalkyl" are independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (3) R 1-1 In the above, the "halogen" is independently fluorine, chlorine, bromine or iodine; (4) R 1-2 wherein the "halogen" is independently fluorine, chlorine, bromine or iodine; and (5) R 1-1 In the above, the "C 1-6 "alkoxy" are each independently C 1-4 Alkoxy.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) In the R1, the "C 1-6 Alkyl" and the "is replaced by one or more R 1-1 Substituted C 1-6 C in "alkyl" 1-6 The alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably ethyl, n-propyl, n-butyl or isobutyl, more preferably n-propyl; (2) In the R1, the "C 3-6 Cycloalkyl" and said" is replaced by one or more R 1-2 Substituted C 3-6 The "C" in "cycloalkyl" 3-6 "cycloalkyl" are each independently cyclobutyl; (3) R 1-1 In the above, the "halogen" is independently fluorine; (4) R 1-2 wherein the "halogen" is independently fluorine; and (5) R 1-1 In the above, the "C 1-6 "Alkoxy" are each independently methoxy or ethoxy.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R1 is Preferably 7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula (I) is selected from any of the following compounds:

8. A pharmaceutical composition comprising: (1) a compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and (2) a pharmaceutically acceptable excipient.

9. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 8 in the preparation of a JAK1 inhibitor; In the application, the JAK1 inhibitor can be used in mammals in vivo; it can also be used in vitro, mainly for experimental purposes.

10. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing JAK1-related diseases, such as rheumatoid arthritis, psoriasis, ankylosing spondylitis, inflammatory bowel disease or atopic dermatitis.

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