A selective TYK2 inhibitor compound and its preparation method and application

Abstract

The present invention provides a selective TYK2 inhibitor compound, its preparation method, and its application, belonging to the technical fields of medicinal chemistry and pharmacotherapy. The present invention provides a novel structural aryl pyrimidine amine compound with good safety and excellent TYK2 and JAK inhibitory activity, providing a new option for the preparation of drugs for the prevention or treatment of autoimmune diseases.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry and pharmacotherapy, and in particular to a selective TYK2 inhibitor compound, a preparation method and an application thereof. Background Art

[0002] Ulcerative colitis (UC) is a chronic, nonspecific inflammatory intestinal disease that primarily affects the mucosal layer of the colon and rectum. Its hallmark is continuous, diffuse inflammation of the colorectal mucosa. In recent years, the incidence of UC has been increasing worldwide. The pathogenesis of UC is complex, involving multiple factors, including genetic, immune, and environmental factors. Patients often experience recurrent diarrhea, abdominal pain, and bloody stools with mucus, pus, and pus, which severely impact their quality of life. Ulcerative colitis can also increase the risk of colon cancer, posing a long-term health risk. There is no cure for UC; treatment primarily relies on medication to control the disease, alleviate symptoms, prevent complications, and prevent cancer. Currently, clinically available medications for UC carry risks of relapse, drug dependence, drug resistance, and the accumulation of adverse events. Due to the chronic and recurrent nature of UC, patients require long-term, or even lifelong, medication, placing a heavy financial burden on society and their families. Therefore, finding safe, effective and novel drugs for the treatment of ulcerative colitis has become an urgent problem to be solved in the current medical field.

[0003] Research has found that the JAK-STAT signaling pathway plays a crucial role in intracellular signaling in various cellular processes under both normal and pathological conditions. TYK2 influences the phosphorylation of STAT-1 and STAT-2 by regulating signaling pathways downstream of the IL-12, IL-23, and type I interferon (IFN) receptors. IL-23 and IL-12 are considered key cytokines that initiate and maintain chronic inflammation, and tyrosine kinase 2 (TYK2) is a key intracellular signaling link between them. Inhibiting TYK2 activity can disrupt the IL23 / IL-12 connection. As an intracellular signaling kinase, TYK2 plays a key role in mediating signaling of IL-23, IL-12, and type I interferons (IFNs). In recent years, the potential of TYK2 inhibitors in the treatment of ulcerative colitis (UC) has garnered widespread attention. By specifically inhibiting TYK2 activity, TYK2 inhibitors block downstream inflammatory signaling, controlling the progression of inflammation and thus playing a therapeutic role in UC.

[0004] This mechanism of action is more precise and effective than traditional anti-inflammatory drugs. The mechanism of action of TYK2 inhibitors in treating ulcerative colitis is significantly innovative, bringing new hope and breakthroughs to the treatment of ulcerative colitis. Therefore, the design of highly selective inhibitors targeting TYK2 is of great significance for the treatment of ulcerative colitis and the study of its mechanism of action. Summary of the Invention

[0005] In view of the above deficiencies in the prior art, the present invention provides a compound with a novel structure that selectively inhibits TYK2, as well as a preparation method and application thereof.

[0006] To achieve the above object, the specific technical solutions of the present invention are as follows:

[0007] In a first aspect, the present invention provides a selective TYK2 inhibitor compound having the structure shown in Formula I:

[0008]

[0009] In formula I, X is -NH-(C=O)- or -NH-(CH2)-;

[0010] R1 is heteroaryl or substituted aryl, wherein the substituents of the aryl include but are not limited to halogen (including F, Cl, Br or I), trifluoromethyl, methoxy, hydroxyl or methyl;

[0011] R2 is an alkane (including a cycloalkane and a straight-chain alkane), an aryl group or a substituted aryl group, and the substituent of the aryl group includes but is not limited to a halogen (including F, Cl, Br or I), a trifluoromethyl group, a methoxy group, a hydroxyl group or a methyl group.

[0012] For each of the above variables, any combination and collocation outside of the above groups are also contemplated herein. It is understood that substituents and substitution patterns on the compounds provided herein can be selected by those skilled in the art to provide chemically stable compounds that can be synthesized using techniques known in the art and those described herein.

[0013] Preferably, the compound has the structure shown in Formula Ia:

[0014]

[0015] In Formula Ia, R1 is pyridine or at least one substituted aryl group at the ortho, meta or para position, and the substituent of the aryl group is halogen (including F, Cl, Br or I), trifluoromethyl, methoxy, hydroxyl or methyl; R2 is an alkane (including cycloalkane and straight-chain alkane), an aryl group or a substituted aryl group, and the substituent of the aryl group is halogen (including F, Cl, Br or I), trifluoromethyl, methoxy, hydroxyl or methyl.

[0016] Preferably, the compound has the structure shown in Formula Ib:

[0017]

[0018] In Formula Ib, R1 is 2-fluorophenyl, 2-chlorophenyl, 2-fluoro-6-chlorophenyl or 2,6-dimethylphenyl; R2 is an alkane (including a cycloalkane and a linear alkane), an aryl group or a substituted aryl group, and the substituent of the aryl group is a halogen (including F, Cl, Br or I), a trifluoromethyl group, a methoxy group, a hydroxyl group or a methyl group.

[0019] Preferably, the R2 has one of the following structures:

[0020]

[0021] Preferably, the compound has one of the following structures:

[0022]

[0023] In a second aspect, the present invention provides a method for preparing the compound. When X is -NH-(CH2)-, the compound is prepared by the following reaction route:

[0024]

[0025] The reaction process is as follows: the starting material (SM) is reacted with R1-CH2-NH2 through substitution to obtain intermediate 1; intermediate 1 is reacted with tert-butyl (4-aminophenyl)carbamate through substitution to obtain intermediate 2; intermediate 2 is deprotected by the BOC protecting group to obtain intermediate 3; intermediate 3 is acylated to obtain the target compound Ia;

[0026] When X is -NH-(C=O)-, the compound is prepared by the following reaction scheme:

[0027]

[0028] The reaction process is as follows: the starting material (SM) is acylated to obtain intermediate 4; intermediate 4 is reacted with tert-butyl (4-aminophenyl)carbamate by substitution to obtain intermediate 5; intermediate 5 is deprotected by removing the BOC protecting group to obtain intermediate 6; intermediate 6 is acylated to obtain the target compound Ib.

[0029] In a third aspect, the present invention provides use of the compound or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof in the preparation of a TYK2 inhibitor or a JAK inhibitor.

[0030] Preferably, the JAK includes JAK1, JAK2, and JAK3.

[0031] In a fourth aspect, the present invention provides the use of the compound or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof in the preparation of a medicament for preventing or treating an autoimmune disease, wherein the autoimmune disease includes but is not limited to rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, ulcerative colitis or autoimmune-related skin disease.

[0032] Preferably, the autoimmune-related skin disease includes alopecia areata, vitiligo, lupus erythematosus, lichen planus, lichen luster, lichen sclerosus, panniculitis, atopic dermatitis, eczema or neurodermatitis.

[0033] In a fifth aspect, the present invention provides a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0034] Compared with the prior art, the present invention is beneficial in that:

[0035] A needle inhibitor with a new structure, its preparation method, pharmaceutical composition and application

[0036] The present invention provides a novel aryl pyrimidine amine compound. In in vitro cell experiments, the aryl pyrimidine amine compound has a good inhibitory effect on TYK2 of the JAK-START signaling pathway. The aryl pyrimidine amine compound or a pharmaceutically acceptable salt thereof can be used to prepare a drug for preventing or treating ulcerative colitis, has a good preventive or therapeutic effect, and has certain drugability. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 These are the experimental results of the effect of compound I-13 on the JAK-STAT signaling pathway. DETAILED DESCRIPTION

[0038] The technical solutions of the present invention are described clearly and completely below. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. All other embodiments obtained by persons of ordinary skill in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0039] The present invention provides a selective TYK2 inhibitor compound having the structure shown in Formula I:

[0040]

[0041] In formula I, X is -NH-(C=O)- or -NH-(CH2)-;

[0042] R1 is heteroaryl or substituted aryl, wherein the substituents of the aryl include but are not limited to halogen (including F, Cl, Br or I), trifluoromethyl, methoxy, hydroxyl or methyl;

[0043] R2 is an alkane (including a cycloalkane and a straight-chain alkane), an aryl group or a substituted aryl group, and the substituent of the aryl group includes but is not limited to a halogen (including F, Cl, Br or I), a trifluoromethyl group, a methoxy group, a hydroxyl group or a methyl group.

[0044] For each of the above variables, any combination and collocation outside of the above groups are also contemplated herein. It is understood that substituents and substitution patterns on the compounds provided herein can be selected by those skilled in the art to provide chemically stable compounds that can be synthesized using techniques known in the art and those described herein.

[0045] In some examples, when X is -NH-(CH2)-, R1 is pyridine or at least one substituted aryl group at the ortho, meta, or para position, wherein the substituent of the aryl group is halogen (including F, Cl, Br, or I), trifluoromethyl, methoxy, hydroxyl, or methyl; R2 is an alkane (including a cycloalkane and a linear alkane), an aryl group, or a substituted aryl group, wherein the substituent of the aryl group is halogen (including F, Cl, Br, or I), trifluoromethyl, methoxy, hydroxyl, or methyl. When X is -NH-(C=O)-, R1 is 2-fluorophenyl, 2-chlorophenyl, 2-fluoro-6-chlorophenyl, or 2,6-dimethylphenyl; R2 is an alkane (including a cycloalkane and a linear alkane), an aryl group, or a substituted aryl group, wherein the substituent of the aryl group is halogen (including F, Cl, Br, or I), trifluoromethyl, methoxy, hydroxyl, or methyl.

[0046] In some examples, the R2 has one of the following structures:

[0047]

[0048] In some examples, the aryl pyrimidine compound has one of the following structures:

[0049]

[0050] In the following specific examples, when X is -NH-(CH2)-, the compound is prepared by the following reaction route:

[0051]

[0052] The reaction conditions are: (a) ethanol, 0-25°C; (b) HCl, 1-butanol, 80°C; (c) CF3COOH, DCM, RT; (d) Et3N, DCM, 0°C-RT;

[0053] The reaction process is as follows: the starting material (SM) is reacted with R1-CH2-NH2 through substitution reaction to obtain intermediate 1; intermediate 1 is reacted with tert-butyl (4-aminophenyl)carbamate through substitution reaction to obtain intermediate 2; intermediate 2 is deprotected by removing the BOC protecting group to obtain intermediate 3; intermediate 3 is acylated to obtain the target compound Ia.

[0054] When X is -NH-(C=O)-, the compound is prepared by the following reaction scheme:

[0055]

[0056] The reaction conditions are: (a) NaH, DMF, 0°C-RT; (b) HCl, 1-butanol, 80°C; (c) CF3COOH, DCM, RT; (d) Et3N, DCM, 0°C-RT;

[0057] The reaction process is as follows: the starting material (SM) is acylated to obtain intermediate 4; intermediate 4 is reacted with tert-butyl (4-aminophenyl)carbamate by substitution to obtain intermediate 5; intermediate 5 is deprotected by removing the BOC protecting group to obtain intermediate 6; intermediate 6 is acylated to obtain the target compound Ib.

[0058] In the following specific examples, unless otherwise specified, all materials and reagents used were purchased conventionally.

[0059] Example 1 Preparation of Compound I-1

[0060]

[0061] The specific reaction steps are as follows: (a) Dissolve 2,4-dichloropyrimidine (1 mmol) and 2-fluorobenzylamine (1.2 mmol) in ethanol (5 mL) and stir at room temperature for 5 h. After the reaction, dilute with ethyl acetate (15 mL), wash twice with saturated sodium bicarbonate (10 mL), then with saturated brine (10 mL), dry over anhydrous sodium sulfate for 30 min, filter, concentrate, and separate by column chromatography (eluent: EA:PE = 10% to 30%) to obtain intermediate 1-1.

[0062] (b) Intermediate 1-1 (1 mmol) and tert-butyl (4-aminophenyl)carbamate (1.2 mmol) were dissolved in n-butanol (5 mL). After complete dissolution by ultrasonic agitation, 1 drop of hydrochloric acid was added, and the mixture was refluxed in an oil bath at 80°C for 8 h. After completion of the reaction, ice water (15 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (eluent: PE:EA = 10% to 60%) to obtain Intermediate 2-1.

[0063] (c) Intermediate 2-1 (1 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1.3 mmol) was added. The mixture was reacted at room temperature for 3 h. The mixture was concentrated in vacuo and separated by column chromatography (eluent: DCM:MeOH = 1% to 3%) to give intermediate 3-1.

[0064] (d) Intermediate 3-1 (1 mmol) was dissolved in anhydrous dichloromethane (5 mL). Benzoyl chloride (1.2 mmol) was slowly added dropwise in an ice bath, followed by triethylamine (2 mmol). The reaction was stirred at room temperature for 2 h, and then 1-3 drops of hydrazine hydrate were added and the reaction was continued for 5 h. After the reaction was completed, the reaction solution was spin-dried and then extracted with ethyl acetate (20 mL × 3). The solution was washed twice with saturated sodium bicarbonate aqueous solution (20 mL), then washed with saturated brine (15 mL), and dried over anhydrous sodium sulfate for 30 min. The solution was filtered and concentrated, and separated by column chromatography (eluent: MeOH:DCM = 1% to 3%) to obtain compound I-1 as a white solid with a yield of 66.5% and a purity of 95%. MS (ESI) m / z (M+1) + :414.1725.

[0065] 1 H NMR(500MHz,DMSO-d6)δ10.07(s,1H),8.94(s,1H),7.98–7.94(m,2H),7.84(d ,J=5.8Hz,1H),7.68(s,1H),7.63(d,J=8.6Hz,1H),7.57(dt,J=7.3,2.7Hz,3H ),7.52(dd,J=8.2,6.5Hz,2H),7.39(td,J=7.7,1.8Hz,1H),7.31(tdd,J=7.5, 5.3,1.8Hz,1H),7.24–7.15(m,2H),6.04(d,J=5.7Hz,1H),4.67–4.56(m,2H). 13C NMR (126MHz, DMSO) δ165.51,162.98,161.68,160.16,159.73,137.73,135.65,132.74,131.7 7,129.64,129.23,128.78,128.01,126.90,124.81,121.23,118.99,115.62,115.45,37.74.

[0066] Example 2 Preparation of Compound I-2

[0067]

[0068] The preparation steps of compound I-2 are basically the same as those in Example 1, except that in step (d), intermediate 3-1 is reacted with p-methoxybenzoyl chloride as raw materials to obtain compound I-2 as a white solid with a yield of 70.9% and a purity of 96%. MS (ESI) m / z (M+1) + :444.1830.

[0069] 1 HNMR(500MHz,DMSO-d6)δ13.29(s,1H),10.31(s,1H),8.61(d,J=3.2Hz,1H),8. 21(d,J=8.5Hz,1H),7.98–7.89(m,2H),7.81(t,J=7.9Hz,2H),7.66(d,J=7.8Hz ,1H),7.57(d,J=16.4Hz,1H),7.51(d,J=7.8Hz,1H),7.47(d,J=8.0Hz,2H),7.4 2(q,J=7.8Hz,2H),7.28(dd,J=7.7,4.9Hz,1H),7.22–7.12(m,3H),3.82(s,3H). 13 C NMR (126MHz, DMSO) δ167.45,165.92,159.65,155.36,150.04,140.76,137.34,136.55,135.22,133.98,132. 00,130.05,129.15,126.83,124.05,123.13,123.08,122.19,120.36,120.33,117.92,113.41,65.50,55.81.

[0070] Example 3 Preparation of Compound I-3

[0071]

[0072] The preparation steps of compound I-3 are basically the same as those in Example 1, except that in step (d), intermediate 3-1 is reacted with 3-methylbenzoyl chloride as raw materials to obtain compound I-3 as a white solid with a yield of 71.2% and a purity of 96%. MS (ESI) m / z (M+1) + :428.1881.

[0073] 1 H NMR (500MHz, DMSO-d6) δ10.03(d,J=4.1Hz,1H),8.92(s,1H),7.85(t,J=4.8Hz,1H),7.80–7.72(m,2H),7.71–7.54(m,5H) ,7.40(dd,J=7.3,4.2Hz,3H),7.31(s,1H),7.24–7.13(m,2H),6.04(d,J=5.8Hz,1H),4.62(s,2H),2.40(d,J=4.2Hz,3H). 13 C NMR (126MHz, DMSO) δ165.62,162.98,161.67,160.22,159.73,138.08,137.71,135.65,132.77,132.34,1 29.59,129.22,129.16,128.68,128.51,127.04,125.16,124.78,121.19,118.97,115.62,115.45,21.43.

[0074] Example 4 Preparation of Compound I-4

[0075]

[0076] The preparation steps of compound I-4 are basically the same as those in Example 1, except that in step (d), intermediate 3-1 is reacted with 2-chloromethylbenzoyl chloride as raw materials to obtain compound I-4 as a white solid with a yield of 71.2% and a purity of 97%. MS (ESI) m / z (M+1) + :448.1335.

[0077] 1H NMR (500MHz, DMSO-d6) δ10.29(s,1H),9.02(s,1H),7.83(d,J=5.9Hz,2H),7.60(d,J=8.5Hz,2H),7.58–7.52(m,4H),7.49(td,J=7.7,1.9H z,1H),7.45(dd,J=7.4,1.4Hz,1H),7.41–7.36(m,1H),7.31(d,J=7.9Hz,1H),7.23–7.13(m,2H),6.05(d,J=5.9Hz,1H),4.65–4.55(m,2H). 13 C NMR (126MHz, DMSO) δ164.89,162.98,161.68,159.73,159.64,137.69,137.46,132.88,131.36,130.4 5,130.08,129.67,129.41,129.23,127.66,126.86,124.79,120.33,119.38,115.63,115.46,39.53.

[0078] Example 5 Preparation of Compound I-5

[0079]

[0080] The specific reaction steps are as follows: (a) 2-chloro-4-aminopyrimidine (1 mmol), o-fluorobenzoic acid (1.2 mmol), and NaH (2.5 mmol) were replaced with a double-row tube, flushed with nitrogen three times, and then dissolved in anhydrous DMF (5 mL) in an ice bath. The mixture was stirred and reacted at room temperature for 7 h. After the reaction, the mixture was quenched with ice water, diluted with ethyl acetate, and then washed twice with saturated sodium bicarbonate aqueous solution (20 mL) and then with saturated brine (15 mL). The mixture was then dried over anhydrous sodium sulfate for 30 min, filtered, concentrated, and separated by column chromatography (eluent: EA:PE = 10% to 30%) to obtain intermediate 4-1.

[0081] (b) Intermediate 4-1 (1 mmol) and tert-butyl (4-aminophenyl)carbamate (1.2 mmol) were dissolved in n-butanol (5 mL). After complete dissolution by ultrasonic agitation, 1 drop of hydrochloric acid was added, and the mixture was refluxed in an oil bath at 80°C for 8 h. After completion of the reaction, ice water (15 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (eluent: EA:PE = 10% to 60%) to obtain Intermediate 5-1.

[0082] (c) Intermediate 5-1 (1 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1.3 mmol) was added. The mixture was reacted at room temperature for 3 h. After completion of the reaction, the mixture was concentrated in vacuo and separated by column chromatography (eluent: MeOH:DCM = 1% to 3%) to obtain intermediate 6-1.

[0083] (d) Intermediate 6-1 (1 mmol) was dissolved in anhydrous dichloromethane. Cyclohexanecarboxyl chloride (1.2 mmol) was slowly added dropwise in an ice bath, followed by triethylamine (2 mmol). The reaction was stirred at room temperature for 2 h, and then 1-3 drops of hydrazine hydrate were added. The reaction was continued for 5 h. After completion of the reaction, the reaction solution was spin-dried and extracted with ethyl acetate (20 ml x 3). The solution was washed twice with saturated sodium bicarbonate aqueous solution (20 mL) and then with saturated brine (15 ml). The solution was dried over anhydrous sodium sulfate for 30 min, filtered, concentrated, and separated by column chromatography (eluent: MeOH:DCM = 1% to 3%) to obtain compound I-5 as a white solid with a yield of 66.5% and a purity of 97%. MS (ESI) m / z (M+1) + :434.1987.

[0084] 1 H NMR (500MHz, DMSO-d6) δ10.85(s,1H),9.79(s,1H),9.38(s,1H),8.39(d,J=5.5Hz,1H),7.71(t,J=9.8Hz,3H),7.66–7.58(m,1H),7.51(d d,J=11.0,6.4Hz,3H),7.36(dd,J=13.6,6.1Hz,2H),1.76(t,J=15.7Hz,4H),1.64(s,1H),1.40(q,J=10.9,9.3Hz,2H),1.29–1.20(m,3H). 13 C NMR (126MHz, DMSO) δ174.37,164.82,160.12,160.07,158.62,158.22,136.09,134.08,133. 64,130.62,125.09,125.06,119.83,119.47,116.75,116.57,101.21,45.17,29.67,25.74.

[0085] Example 6 Preparation of Compound I-6

[0086]

[0087] The preparation steps of compound I-6 are basically the same as those in Example 5, except that in step (a), 2-chloro-4-aminopyrimidine and o-chlorobenzoic acid are reacted as raw materials to obtain intermediate 4-2; correspondingly, intermediate 5-2 is obtained in step (b); intermediate 6-2 is obtained in step (c); and finally, compound I-6 is obtained as a white solid in step (d) with a yield of 71.7% and a purity of 92%. MS (ESI) m / z (M+1) + :450.1691.

[0088] 1 H NMR (500MHz, DMSO-d6) δ11.04(s,1H),9.58(s,1H),9.32(s,1H),8.33(d,J=5.5Hz,1H),7.67(d,J=8.8Hz ,2H),7.57–7.37(m,7H),2.21(s,1H),1.74–1.50(m,6H),1.33(d,J=15.2Hz,2H),1.19(d,J=9.2Hz,2H). 13 C NMR (126MHz, DMSO) δ174.41,174.37,167.09,160.10,158.29,136.64,136.20,133.88,131 .93,130.30,130.08,129.46,127.71,119.91,119.46,101.26,45.30,29.66,25.88,25.72.

[0089] Example 7 Preparation of Compound I-7

[0090]

[0091] The preparation steps of compound I-7 are basically the same as those in Example 5, except that in step (a), 2-chloro-4-aminopyrimidine and 2-chloro-6-fluorobenzoic acid are used as raw materials to react to obtain intermediate 4-3; correspondingly, intermediate 5-3 is obtained in step (b); intermediate 6-3 is obtained in step (c); and finally, compound I-7 is obtained as a white solid in step (d) with a yield of 74.2% and a purity of 93%. MS (ESI) m / z (M+1) + :454.1804.

[0092] 1H NMR (500MHz, DMSO) δ11.35(s,1H),9.64(s,1H),9.41(s,1H),8.42(d,J=5.6Hz, 1H),7.70(d,J=8.6Hz,2H),7.57(d,J=7.3Hz,1H),7.50(t,J=9.3Hz,3H),7.46(d ,J=8.1Hz,1H),7.38(t,J=8.7Hz,1H),2.29(t,J=11.6Hz,1H),1.76(t,J=13.1Hz ,4H),1.64(d,J=12.3Hz,1H),1.46–1.35(m,2H),1.24(dt,J=30.6,15.3Hz,3H). 13 C NMR (126MHz, DMSO) δ174.34,162.47,160.37,160.15,158.17,157.90,136.06,134.05,132 .61,131.32,126.04,125.89,119.89,119.60,115.21,101.17,45.30,29.66,25.89,25.73.

[0093] Example 8 Preparation of Compound I-8

[0094]

[0095] The preparation steps of compound I-8 are basically the same as those in Example 5, except that in step (a), 2-chloro-4-aminopyrimidine and 2,6-dichlorobenzoic acid are used as raw materials to react to obtain intermediate 4-4; correspondingly, intermediate 5-4 is obtained in step (b); intermediate 6-4 is obtained in step (c); and finally, compound I-8 is obtained as a white solid in step (d) with a yield of 73.9% and a purity of 95%. MS (ESI) m / z (M+1) + :484.1302.

[0096] 1H NMR (500MHz, DMSO) δ11.33(d,J=7.6Hz,1H),9.64(s,1H),9.38(d,J=15.3Hz,1H),8.40(dd,J=10.3,5.4Hz,1H),7.70(d,J=8.6Hz,2H),7.58(d,J=7.9H z,2H),7.53(t,J=4.1Hz,2H),7.50(t,J=6.1Hz,2H),2.29(tt,J=11.8,3.5H z,1H),1.80–1.72(m,4H),1.41(td,J=12.3,3.0Hz,2H),1.29–1.19(m,4H). 13 C NMR (126MHz, DMSO) δ174.39,164.35,160.30,160.16,158.03,136.08,134.03,13 2.12,131.42,128.69,119.61,101.24,45.30,42.43,29.66,29.51,25.88,25.73.

[0097] Example 9 Preparation of Compound I-9

[0098]

[0099] The preparation steps of compound I-9 are basically the same as those in Example 5, except that in step (a), 2-chloro-4-aminopyrimidine and 2,6-dimethylbenzoic acid are used as raw materials to react to obtain intermediate 4-5; correspondingly, intermediate 5-5 is obtained in step (b); intermediate 6-5 is obtained in step (c); and finally, compound I-9 is obtained as a white solid in step (d) with a yield of 70.5% and a purity of 95%. MS (ESI) m / z (M+1) + :444.2394.

[0100] 1 H NMR(500MHz,DMSO)δ11.03(s,1H),9.59(s,1H),9.35(s,1H),8.38(d,J=5.5Hz ,1H),7.76(d,J=8.6Hz,2H),7.60(d,J=5.6Hz,1H),7.51–7.45(m,2H),7.26(d d,J=9.6,5.6Hz,1H),7.13(d,J=7.6Hz,2H),2.28(s,7H),1.76(t,J=12.8Hz,4 H), 1.64 (s, 1H), 1.40 (dd, J = 22.9, 10.9Hz, 2H), 1.23 (dd, J = 25.2, 12.5Hz, 3H).13 C NMR (126MHz, DMSO) δ174.25,170.27,160.13,159.93,158.38,138.19,136.28,134.10 ,133.83,129.19,127.77,119.85,119.36,101.24,45.30,29.68,25.90,25.75,19.35.

[0101] Example 10 Preparation of Compound I-10

[0102]

[0103] The preparation steps of compound I-10 are basically the same as those in Example 1, except that in step (a), 2,4-dichloropyrimidine and 2-chlorobenzylamine are reacted as raw materials to obtain intermediate 1-2; correspondingly, intermediate 2-2 is obtained in step (b); intermediate 3-2 is obtained in step (c); and finally, in step (d), intermediate 3-2 and cyclohexanecarboxyl chloride are reacted as raw materials to obtain compound I-10 as a white solid with a yield of 66.5% and a purity of 94%. MS (ESI) m / z (M+1) + :436.1899.

[0104] 1 H NMR (500MHz, DMSO-d6) δ9.58 (s, 1H), 8.83 (s, 1H), 7.83 (d, J = 5.8Hz, 1H), 7. 71(s,1H),7.48(s,2H),7.47(d,J=2.1Hz,1H),7.36(dd,J=9.2,2.1Hz,2H),7 .32–7.26(m,2H),6.05(s,1H),4.61(s,2H),2.28(t,J=11.6Hz,1H),1.75(t, J=9.7Hz,4H),1.64(d,J=11.8Hz,1H),1.47–1.35(m,2H),1.31–1.13(m,4H). 13 C NMR (126MHz, DMSO) δ174.16,162.97,160.19,155.62,137.28,136.96,133.20,132.50,13 0.12,129.57,128.87,127.61,119.79,118.92,45.23,41.80,29.68,29.47,25.91,25.76.

[0105] Example 11 Preparation of Compound I-11

[0106]

[0107] The preparation steps of compound I-11 are basically the same as those in Example 1, except that in step (a), 2,4-dichloropyrimidine and 2-bromobenzylamine are reacted as raw materials to obtain intermediate 1-3; correspondingly, intermediate 2-3 is obtained in step (b); intermediate 3-3 is obtained in step (c); and finally, in step (d), intermediate 3-3 and cyclohexanecarboxyl chloride are reacted as raw materials to obtain compound I-11 as a white solid with a yield of 71.6% and a purity of 95%. MS (ESI) m / z (M+1) + :480.1393.

[0108] 1 H NMR(500MHz,DMSO-d6)δ9.55(s,1H),8.85(s,1H),7.84(d,J=5.8Hz,1H),7.70(dt,J= 8.0,3.7Hz,1H),7.64(d,J=7.7Hz,1H),7.49(s,1H),7.38(s,1H),7.36–7.33(m,3H),7 .32(d,J=5.7Hz,1H),7.23–7.19(m,1H),6.05(s,1H),4.57(s,2H),2.28(t,J=11.5Hz ,1H),1.76(s,3H),1.64(d,J=12.0Hz,2H),1.40(d,J=12.0Hz,2H),1.26–1.21(m,3H). 13 C NMR (126MHz, DMSO) δ175.17,174.15,162.96,160.15,136.94,133.19,132.81,132.59,129 .20,128.86,128.16,122.81,122.51,119.83,118.92,45.24,42.72,29.68,25.91,25.76.

[0109] Example 12 Preparation of Compound I-12

[0110]

[0111] The preparation steps of compound I-12 are basically the same as those in Example 1, except that in step (a), 2,4-dichloropyrimidine and 2-hydroxybenzylamine are reacted as raw materials to obtain intermediate 1-4; correspondingly, intermediate 2-4 is obtained in step (b); intermediate 3-4 is obtained in step (c); and finally, in step (d), intermediate 3-4 and cyclohexanecarboxyl chloride are reacted as raw materials to obtain compound I-12 as a white solid with a yield of 72.8% and a purity of 96%. MS (ESI) m / z (M+1) + :418.2238.

[0112] 1 H NMR(500MHz,DMSO-d6)δ9.58(d,J=9.7Hz,2H),8.89(s,1H),7.78(d,J=5.9Hz,1H),7.74–7.65( m,1H),7.59(d,J=8.6Hz,2H),7.41(d,J=8.6Hz,2H),7.15(d,J=7.6Hz,1H),7.06(t,J=7.7Hz,1 H),6.84(d,J=8.0Hz,1H),6.74(t,J=7.4Hz,1H),6.01(s,1H),4.47(s,1H),4.22(t,J=6.5Hz,1 H),2.28(s,1H),1.76(s,2H),1.67–1.61(m,2H),1.38(s,1H),1.23(s,3H),0.94–0.85(m,2H). 13 C NMR (126MHz, DMSO) δ174.18,167.42,163.11,159.68,155.49,136.79,133.38,131.96,12 9.12,128.23,119.92,119.38,115.39,65.48,45.24,30.48,29.68,25.75,19.11,13.99.

[0113] Example 13 Preparation of Compound I-13

[0114]

[0115] The preparation steps of compound I-13 are basically the same as those in Example 1, except that in step (a), 2,4-dichloropyrimidine and 2-methoxybenzylamine are reacted as raw materials to obtain intermediate 1-5; correspondingly, intermediate 2-5 is obtained in step (b); intermediate 3-5 is obtained in step (c); and finally, in step (d), intermediate 3-5 and cyclohexanecarboxyl chloride are reacted as raw materials to obtain compound I-13 as a white solid with a yield of 70.7% and a purity of 96%. MS (ESI) m / z (M+1) + :432.2374.

[0116] 1 H NMR(500MHz,DMSO-d6)δ9.56(s,1H),8.80(s,1H),7.79(d,J=5.8Hz,1H),7.51(s,3H) ,7.37(d,J=8.5Hz,2H),7.22(dd,J=16.4,8.0Hz,2H),7.01(d,J=8.1Hz,1H),6.89(t, J=7.4Hz,1H),6.00(s,1H),4.49(s,2H),3.86(s,3H),2.28(t,J=11.6Hz,1H),1.86(d ,J=36.9Hz,1H),1.79–1.73(m,4H),1.64(s,1H),1.40(d,J=14.3Hz,2H),1.23(s,2H). 13 CNMR(126MHz,DMSO)δ174.33,163.11,159.58,157.29,155.49,136.66,133.44,128.44,127.9 6,120.58,119.79,119.41,115.46,113.30,110.94,55.82,47.81,45.28,29.67,25.74,14.00.

[0117] Example 14 Preparation of Compound I-14

[0118]

[0119] The preparation steps of compound I-14 are basically the same as those in Example 1, except that in step (a), 2,4-dichloropyrimidine and 2-methylbenzylamine are reacted as raw materials to obtain intermediate 1-6; correspondingly, intermediate 2-6 is obtained in step (b); intermediate 3-6 is obtained in step (c); and finally, in step (d), intermediate 3-6 and cyclohexanecarboxyl chloride are reacted as raw materials to obtain compound I-14 as a white solid with a yield of 75.0% and a purity of 94%. MS (ESI) m / z (M+1) +:416.2445.

[0120] 1 H NMR(500MHz,DMSO-d6)δ9.64(s,1H),8.88(s,1H),7.85(d,J=5.7Hz,1H),7.59(s,3H),7.43(d,J=8.6Hz,2H),7.34–7.15(m,4H), 6.06(s,1H),4.56(s,2H),2.37(s,4H),1.81(d,J=11.7Hz,4H),1.67(d,J=10.0Hz,2H),1.50–1.36(m,3H),1.31(d,J=3.0Hz,1H). 13 C NMR (126MHz, DMSO) δ174.23,167.46,162.99,160.19,137.06,135.97,133.16,130.39,127. 17,126.22,119.80,119.06,65.50,45.27,42.73,29.68,29.59,25.91,25.75,19.14,13.99.

[0121] Example 15 Preparation of Compound I-15

[0122]

[0123] The preparation steps of compound I-15 are basically the same as those in Example 1, except that in step (a), 2,4-dichloropyrimidine and 2-trifluoromethylbenzylamine are reacted as raw materials to obtain intermediate 1-7; correspondingly, intermediate 2-7 is obtained in step (b); intermediate 3-7 is obtained in step (c); and finally, in step (d), intermediate 3-7 and cyclohexanecarboxyl chloride are reacted as raw materials to obtain compound I-15 as a white solid with a yield of 74.2% and a purity of 94%. MS (ESI) m / z (M+1) + :470.2162.

[0124] 1H NMR(500MHz,DMSO-d6)δ9.55(s,1H),8.87(s,1H),7.85(d,J=5.8Hz,1H),7.76(d,J=7.8Hz ,1H),7.72(s,1H),7.64(t,J=7.6Hz,1H),7.53(d,J=7.8Hz,1H),7.47(t,J=7.5Hz,3H),7. 33(d,J=7.5Hz,2H),6.06(s,1H),4.76(s,2H),2.27(t,J=11.6Hz,1H),1.75(t,J=10.4Hz, 4H),1.64(d,J=11.6Hz,1H),1.44–1.35(m,2H),1.24(d,J=6.0Hz,2H),0.93–0.81(m,1H). 13 CNMR(126MHz,DMSO)δ174.16,163.05,160.10,142.63,138.43,136.81,133.11,130.96,128.69 ,127.70,127.16,126.74,126.51,126.29,119.73,118.93,48.77,45.24,29.67,25.91,25.75.

[0125] Example 16 Preparation of Compound I-16

[0126]

[0127] The preparation steps of compound I-16 are basically the same as those in Example 1, except that in step (a), 2,4-dichloropyrimidine and 2-picolylamine are reacted as raw materials to obtain intermediate 1-8; correspondingly, intermediate 2-8 is obtained in step (b); intermediate 3-8 is obtained in step (c); and finally, in step (d), intermediate 3-8 and cyclohexanecarboxyl chloride are reacted as raw materials to obtain compound I-16 as a white solid with a yield of 67.7% and a purity of 90%. MS (ESI) m / z (M+1) + :403.2241.

[0128] 1H NMR(500MHz,DMSO)δ9.56(s,1H),8.83(s,1H),8.54(d,J=4.9Hz,1H),7.82(d,J=5.8H z,1H),7.74(d,J=1.8Hz,2H),7.49(s,2H),7.37(d,J=8.5Hz,2H),7.32(d,J=7.9Hz,1 H),7.28–7.23(m,1H),6.03(s,1H),4.62(d,J=2.2Hz,2H),2.28(s,1H),1.76(t,J=13 .7Hz,4H),1.65(d,J=12.0Hz,1H),1.45–1.34(m,2H),1.24(dt,J=28.4,14.2Hz,3H). 13 C NMR (126MHz, DMSO) δ175.18,174.17,163.03,160.14,159.67,155.56,149.36,137.13 ,136.93,133.20,122.47,121.30,119.82,119.11,45.93,45.27,29.69,25.91,25.76.

[0129] Example 17 Preparation of Compound I-17

[0130]

[0131] The preparation steps of compound I-17 are basically the same as those in Example 1, except that in step (a), 2,4-dichloropyrimidine and 3-methoxybenzylamine are reacted as raw materials to obtain intermediate 1-9; correspondingly, intermediate 2-9 is obtained in step (b); intermediate 3-9 is obtained in step (c); and finally, in step (d), intermediate 3-9 and cyclohexanecarboxyl chloride are reacted as raw materials to obtain compound I-17 as a white solid with a yield of 65.7% and a purity of 97%. MS (ESI) m / z (M+1) + :432.2374.

[0132] 1H NMR (500MHz, DMSO) δ9.58(s,1H),8.82(s,1H),7.80(d,J=5.6Hz,1H),7.62(d,J=21.2Hz,1H ),7.57(d,J=7.4Hz,2H),7.40(d,J=8.8Hz,2H),7.24(t,J=8.0Hz,1H),6.91(d,J=7.5Hz,2H ),6.82–6.77(m,1H),5.97(s,1H),4.50(s,2H),3.71(s,3H),2.28(ddd,J=11.7,7.6,3.2Hz ,1H),1.76(t,J=12.5Hz,4H),1.65(d,J=11.8Hz,1H),1.45–1.35(m,2H),1.31–1.19(m,3H). 13 C NMR (126MHz, DMSO) δ174.24,162.09,159.97,159.87,157.90,156.82,136.60,133.37 ,127.79,119.73,118.98,116.46,112.49,112.30,97.32,45.25,29.67,25.90,25.75.

[0133] Example 18 Preparation of Compound I-18

[0134]

[0135] The preparation steps of compound I-18 are basically the same as those in Example 1, except that in step (a), 2,4-dichloropyrimidine and 3-hydroxybenzylamine are reacted as raw materials to obtain intermediate 1-10; correspondingly, intermediate 2-10 is obtained in step (b); intermediate 3-10 is obtained in step (c); and finally, in step (d), intermediate 3-10 and cyclohexanecarboxyl chloride are reacted as raw materials to obtain compound I-18 as a white solid with a yield of 64.3% and a purity of 94%. MS (ESI) m / z (M+1) + :418.2238.

[0136] 1H NMR (500MHz, DMSO) δ9.57 (s, 1H), 9.31 (s, 1H), 8.84 (s, 1H), 7.80 (d, J = 5.4Hz, 1H), 7.63 ( dd,J=45.1,6.5Hz,3H),7.40(d,J=8.7Hz,2H),7.12(t,J=7.8Hz,1H),6.77–6.71(m,2H), 6.63(dd,J=8.0,1.5Hz,1H),5.97(s,1H),4.47(s,2H),3.35(s,2H),2.32–2.24(m,1H),1 .76(t,J=13.2Hz,4H),1.64(d,J=11.7Hz,1H),1.46–1.34(m,2H),1.23(s,J=13.1Hz,3H). 13 CNMR(126MHz,DMSO)δ175.00,174.16,162.97,160.14,157.91,155.05,141.82,137.03,13 3.17,129.68,119.85,119.12,118.14,114.21,114.12,97.93,45.25,29.69,25.91,25.76.

[0137] Example 19 Preparation of Compound I-19

[0138]

[0139] The preparation steps of compound I-19 are basically the same as those in Example 1, except that in step (a), 2,4-dichloropyrimidine and 4-methoxybenzylamine are reacted as raw materials to obtain intermediate 1-11; correspondingly, intermediate 2-11 is obtained in step (b); intermediate 3-11 is obtained in step (c); and finally, in step (d), intermediate 3-11 and cyclohexanecarboxyl chloride are reacted as raw materials to obtain compound I-19 as a white solid with a yield of 66.6% and a purity of 98%. MS (ESI) m / z (M+1) + :432.2734.

[0140] 1H NMR (500MHz, DMSO) δ9.58(s,1H),8.86(s,1H),7.78(d,J=5.5Hz,1H),7.59(d,J= 8.1Hz,3H),7.41(d,J=8.7Hz,2H),7.26(d,J=8.5Hz,2H),6.91–6.86(m,2H),5.94 (d,J=4.1Hz,1H),4.45(s,2H),2.32–2.25(m,1H),2.04(tt,J=11.7,3.4Hz,2H),1 .75(dd,J=18.5,7.9Hz,4H),1.69(dt,J=20.2,6.9Hz,4H),1.23(t,J=3.9Hz,3H). 13 C NMR (126MHz, DMSO) δ175.16,174.15,160.18,158.65,137.06,133.17,128.8 9,119.81,119.12,114.17,55.50,45.25,42.72,29.68,29.60,25.89,25.74.

[0141] Example 20 Preparation of Compound I-20

[0142]

[0143] The preparation steps of compound I-20 are basically the same as those in Example 1, except that in step (a), 2,4-dichloropyrimidine and 4-hydroxybenzylamine are reacted as raw materials to obtain intermediate 1-12; correspondingly, intermediate 2-12 is obtained in step (b); intermediate 3-12 is obtained in step (c); and finally, in step (d), intermediate 3-12 and cyclohexanecarboxyl chloride are reacted as raw materials to obtain compound I-20 as a white solid with a yield of 64.5% and a purity of 95%. MS (ESI) m / z (M+1) + :418.2238.

[0144] 1H NMR (500MHz, DMSO) δ9.57 (s, 1H), 9.31 (s, 1H), 8.84 (s, 1H), 7.80 (d, J = 5.4Hz, 1H), 7.63(dd,J=45.1,6.5Hz,3H),7.40(d,J=8.7Hz,2H),7.12(t,J=7.8Hz,1H),6.77–6 .71(m,2H),6.63(dd,J=8.0,1.5Hz,1H),5.97(s,1H),4.47(s,2H),2.32–2.24(m,1 H),1.76(t,J=13.2Hz,4H),1.64(d,J=11.7Hz,1H),1.46–1.34(m,2H),1.23(s,3H). 13 C NMR (126MHz, DMSO) δ174.19,172.52,162.87,159.97,156.73,136.95,133.29,13 0.30,128.97,119.83,119.26,115.52,45.26,29.69,26.81,25.92,25.76,21.53.

[0145] Example 21 Preparation of Compound I-21

[0146]

[0147] The preparation steps of compound I-21 are basically the same as those in Example 1, except that in step (a), 2,4-dichloropyrimidine and 4-(trifluoromethyl)benzylamine are reacted as raw materials to obtain intermediate 1-13; correspondingly, intermediate 2-13 is obtained in step (b); intermediate 3-13 is obtained in step (c); and finally, in step (d), intermediate 3-13 and cyclohexanecarboxyl chloride are reacted as raw materials to obtain compound I-21 as a white solid with a yield of 74.7% and a purity of 95%. MS (ESI) m / z (M+1) + :470.2162.

[0148] 1H NMR(500MHz,DMSO)δ9.57(s,1H),8.82(d,J=4.3Hz,1H),7.82(d,J=5.7Hz,1 H),7.76(s,1H),7.69(d,J=8.0Hz,2H),7.53(dd,J=18.5,8.0Hz,4H),7.38(d ,J=8.5Hz,2H),5.99(s,1H),4.62(s,2H),2.28(t,J=11.6Hz,1H),1.77(d,J =11.3Hz,4H),1.65(d,J=11.8Hz,1H),1.47–1.35(m,2H),1.31–1.16(m,3H). 13 C NMR (126MHz, DMSO) δ174.30,174.25,162.94,160.23,145.48,136.92,133.23,128.14, 128.01,127.76,125.92,125.60,123.76,119.88,119.23,45.26,29.67,25.90,25.73.

[0149] The following activity and selectivity studies were conducted on the compounds prepared in Examples 1 to 21:

[0150] 1. Inhibitory effects of the compounds prepared in Examples 1 to 21 on BaF3 cells

[0151] 1) The cell density is about 4×10 4 BaF3 cells / mL were mixed evenly with test compounds at different concentrations, and 100 μL was placed in 96-well plates;

[0152] 2) Place the 96-well plate in a cell culture incubator and incubate at 37°C for 72 hours;

[0153] 3) CellTiter-Glo assay was used to test viable BaF3 cells. During the CellTiter-Glo assay, fluorescence data were read using a multi-label reader (Envision, PerkinElmer, USA). DMSO was used as a reference for all test data.

[0154] 4) Calculate IC using data processing software 50 The experimental results are shown in Table 1.

[0155] 2. Inhibitory effects of the compounds prepared in Examples 1 to 21 on BaF3-TYK2 cells

[0156] The in vitro inhibitory activity of the compound BaF3-TYK2 cells was detected using the ADP-Glo ​​kit (Promega). The reaction system included: 4.95 μL protein, 0.55 μL gradient dilution of the compound, 5.5 μL substrate and peptide (4:1 Gly, Tyr, 0.2) and 100 μM ATP. After adding ATP, the reaction was incubated at 37°C for 1 hour and cooled at room temperature for 5 minutes. 5 μL of the reaction solution was added to a 384-well plate, and then 5 μL of ADP-Glo ​​reagent was added to terminate the reaction. Finally, 10 μL of kinase detection reagent was added and incubated for 30 minutes. The fluorescence value of the experimental results was read using Perkin-Elmer Envision, and the IC was calculated. 50 The experimental results are shown in Table 1.

[0157] Table 1: Experimental results of the inhibitory effects of the compounds prepared in Examples 1 to 21 on BaF3 and BaF3-TYK2 cells

[0158]

[0159] The compounds prepared in Examples 1 to 21 were tested for safety in BaF3 and BaF3-TYK2 cells using Cerdulatinib as a positive control. The results showed that most of the compounds were safe for BaF3 cells and significantly inhibited the growth of BaF3-TYK2 cells at a concentration of 1 μM.

[0160] 3. Effect of compound I-13 on the JAK-STAT signaling pathway

[0161] TYK2 is a key member of the JAK-STAT signaling pathway, primarily mediating type I interferon, IL-12, and IL-23 signaling, regulating immune and inflammatory responses. To confirm that I-13 can inhibit activation of the JAK-STAT signaling pathway by inhibiting TYK2 protein activity, Western blotting was used to examine the expression of STAT3 phosphorylation, a component of this pathway.

[0162] 3.1 Experimental methods

[0163] Logarithmically growing RAW 264.7 cells were prepared into 8×10 cells using DMEM medium containing 10% fetal bovine serum. 4The suspension was inoculated into 6-well plates at 1 mL / well. A total of 6 groups were set up, namely, Control group, IFN-α group, I-13 + IFN-α group (I-13 concentrations were 2.5 μM, 5 μM, and 10 μM, respectively), and Cerdulatinib group. After being cultured in an incubator for 24 hours, 5 μL of 20 μg / mL IFN-α was added to each group except the Control group to stimulate the cells. At the same time, 1 mL of compound I-13 solution with concentrations of 2.5, 5, and 10 μM was added to each well of the drug-treated group except the Control group and the IFN-α group, and 1 mL of 1 μM Cerdulatinib solution was added to the Cerdulatinib group. After being incubated for 24 hours, proteins were extracted and Western Blot experiments were performed to detect the phosphorylation of STAT3 protein.

[0164] 3.2 Experimental Results

[0165] Western Blot results showed that (see Figure 1 Compound I-13 began to inhibit the JAK-STAT signaling pathway at a concentration of 2.5 μM. The inhibitory effect was strongest at a concentration of 10 μM, indicating that within a safe concentration range, compound I-13's inhibitory effect on the JAK-STAT3 signaling pathway gradually increased with increasing concentration. In summary, compound I-13 can inhibit p-STAT3 protein expression, thereby blocking JAK-STAT pathway signaling.

[0166] The above results indicate that compound I-13 of the present invention has good TYK2 inhibitory activity. Furthermore, experimental verification by the inventors indicates that the 21 compounds prepared in Examples 1 to 21 have good TYK2 inhibitory activity and can all be used as TYK2 selective inhibitors for the treatment of autoimmune diseases, particularly rheumatoid arthritis, ulcerative colitis, psoriasis, skin inflammation, and other inflammatory and autoimmune diseases.

[0167] The above specific embodiments describe the implementation of the present invention in detail, but the present invention is not limited to the specific details of the above embodiments. Within the scope of the claims and technical concept of the present invention, various simple modifications and changes can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

Claims

1. A selective TYK2 inhibitor compound, characterized in that It has the following general structural formula: ； Wherein, X is -NH-(C=O)- or -NH-(CH2)-; The compound has one of the following structures: ； 。 2. The method for preparing a selective TYK2 inhibitor compound according to claim 1, characterized in that: When X is -NH-(CH2)-, the compound is prepared by the following reaction scheme: ； Wherein, R1 and R2 are as shown in claim 1; Alternatively, when X is -NH-(C=O)-, the compound is prepared by the following reaction scheme: ； Wherein, R1 and R2 are as shown in claim 1.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a TYK2 inhibitor.

4. A pharmaceutical composition, characterized in that The invention comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

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