CN113480543A - 2,6, 8-polysubstituted imidazo [1,2-a ] pyrazine and synthetic method and application thereof - Google Patents

2,6, 8-polysubstituted imidazo [1,2-a ] pyrazine and synthetic method and application thereof Download PDF

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CN113480543A
CN113480543A CN202110765383.1A CN202110765383A CN113480543A CN 113480543 A CN113480543 A CN 113480543A CN 202110765383 A CN202110765383 A CN 202110765383A CN 113480543 A CN113480543 A CN 113480543A
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pyrazine
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CN113480543B (en
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王鑫
邓凯元
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Wuxi No 2 Peoples Hospital
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses a 2,6, 8-polysubstituted imidazo [1,2-a ] as shown in formula (I)]Pyrazine or a pharmaceutically acceptable salt thereof. The invention also discloses the 2,6, 8-polysubstituted imidazo [1,2-a ]]Pyrazine or pharmaceutically acceptable salts thereof are used as TYK2 inhibitors and are applied to preparation of medicines for preventing and treating tumor or inflammatory diseases. The invention also provides the 2,6, 8-polysubstituted imidazo [1,2-a ]]A method for synthesizing pyrazine or pharmaceutically acceptable salts thereof.

Description

2,6, 8-polysubstituted imidazo [1,2-a ] pyrazine and synthetic method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical synthesis chemical industry, and relates to 2,6, 8-polysubstituted imidazo [1,2-a ] pyrazine and a synthesis method and application thereof, in particular to a 2,6, 8-polysubstituted imidazo [1,2-a ] pyrazine compound serving as a TYK2 inhibitor and a preparation method and application thereof.
Background
Tyrosine kinase 2(Tyrosine kinase 2, TYK2) is a member of a non-receptor protein Tyrosine kinase JAK family, is an intersection point of various signal transduction pathways, and plays an important role in normal tumor cell proliferation, differentiation and apoptosis. Downstream protein STATs can be recruited by activated JAK, and then phosphorylated by JAK to form homodimers or heterodimers, enter cell nucleus, and are combined with the promoter of downstream genes to regulate the transcription of the downstream genes. The JAK-STAT signaling pathway is closely related to the development and progression of tumors, exhibiting over-activation in many malignancies.
In recent years, more and more studies have shown that TYK2 is closely related to many tumors. In Anaplastic Large Cell Lymphoma (ALCL), TYK2 is highly expressed and promotes the growth of ALCL cells through abnormal activation of the TYK2-STAT1/3-Bcl2 pathway, and ALCL apoptosis can be promoted through the use of TYK2 inhibitors. The universal high expression of TYK2 was found in samples of patients with Malignant Peripheral Nerve Sheath Tumors (MPNSTs), cell death was significantly increased by lower TYK2 in both murine and human MPNST cells, while aberrant activation of the TYK2-STAT1/3-Bcl2 pathway was also detected in MPNST. In animal in vivo studies, it was found that the TYK2(-/-) mice had tumors that grew rapidly and had significantly stronger metastasis capacity than TYK2 (+/-) mice when 4T1 breast cancer cells were injected into TYK2(-/-) mice and TYK2(+/+) mice, respectively, and observed their tumor growth. Therefore, based on the biological function of TYK2 and the extensive research results in tumors, it can be concluded that TYK2 has an important regulatory role in the development of tumors, and TYK2 is a very potential target for tumor therapy.
In conclusion, the expression level of TYK2 is abnormal in various tumor patient samples, which is closely related to the occurrence of tumors. Although there are reported TYK2 inhibitors that have entered clinical trials, there are no TYK2 inhibitors that have been used in tumor therapy. The TYK2 is a potential drug target for anti-tumor therapy, and a targeted inhibitor of the TYK2 is very potential to be developed for anti-tumor drugs, so that the development of TYK2 inhibitors for tumor therapy is urgently needed.
Disclosure of Invention
The 2,6, 8-polysubstituted imidazo [1,2-a ] pyrazine compound provided by the invention is a TYK2 inhibitor, and can be used for treating various tumors, including lymphoma, ovarian cancer, gastric cancer, breast cancer, lung cancer and other malignant tumors.
The 2,6, 8-polysubstituted imidazo [1,2-a ] pyrazine and pharmaceutically acceptable salts thereof provided by the invention have a structural general formula shown as (I):
Figure RE-GDA0003226041140000021
wherein:
R1is selected from
Figure RE-GDA0003226041140000022
Wherein E, Y, A, Q are each independently selected from C, N, O, S, R in (1)4Selected from hydrogen radicals, amino radicals, methylamino radicals, dimethylamino radicals, hydroxyl radicals, halogen atoms, cyano radicals, hydrocarbon radicals, cycloalkyl radicals, heteroatomic cycloalkyl radicals, aryl or heteroaromatic radicals, substituted aryl radicals or substituted heteroaromatic radicals,
Figure RE-GDA0003226041140000023
In (2), L is selected from
Figure RE-GDA0003226041140000024
Figure RE-GDA0003226041140000025
Figure RE-GDA0003226041140000026
R5Selected from hydrogen radicals, aryl or heteroaromatic rings, substituted aryl or substituted heteroaromatic rings;
R2selected from cycloalkyl or substituted cycloalkyl, heteroatomic cycloalkyl or substituted heteroatomic cycloalkyl or
Figure RE-GDA0003226041140000027
When R is2When the structure is selected from the structure in (3), M, X, Z, T are independently selected from C, N, R6Selected from hydrogen, amino, substituted amino, hydroxyl, halogen, cycloalkyl or substituted cycloalkyl, heteroatomic cycloalkyl or substituted heteroatomic cycloalkyl, cyano, hydrocarbyl, aryl or heteroaromatic ring, substituted aryl or substituted heteroaromatic ring;
R3selected from the group consisting of hydrogen atoms,
Figure RE-GDA0003226041140000031
Figure RE-GDA0003226041140000032
Preferably, R1Is selected from
Figure RE-GDA0003226041140000033
Wherein E, Y, A, Q are each independently selected from C, N, R in (1)4Selected from amino, cyano, in (2) L is selected from
Figure RE-GDA0003226041140000034
R5Is selected from
Figure RE-GDA0003226041140000035
R2Selected from cyclopropane or
Figure RE-GDA0003226041140000036
Wherein M, X, Z, T are each independently selected from C, N, R6Selected from halogen atoms,
Figure RE-GDA0003226041140000037
Figure RE-GDA0003226041140000038
R3Selected from the group consisting of hydrogen atoms,
Figure RE-GDA0003226041140000039
Further preferably, R1Is selected from
Figure RE-GDA00032260411400000310
Wherein E, Y, A, Q are each independently selected from C, N, R in (1)4Selected from amino, cyano, in (2) L is selected from
Figure RE-GDA00032260411400000311
R5Is selected from
Figure RE-GDA00032260411400000312
R2Selected from cyclopropane or
Figure RE-GDA00032260411400000313
Wherein M, X, Z, T are each independently selected from C, N, R6Selected from fluorine atoms,
Figure RE-GDA0003226041140000041
Figure RE-GDA0003226041140000042
R3Selected from the group consisting of hydrogen atoms,
Figure RE-GDA0003226041140000043
The invention also provides a pharmaceutical composition, which comprises the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof and one or more medicinal carriers and/or diluents, and is prepared into a clinical medicinal preparation. Wherein, the pharmaceutical composition is prepared into tablets, capsules, liquid preparations or the like. The compounds of the present invention may be combined with pharmaceutical carriers or excipients (e.g., pharmaceutically acceptable carriers and excipients) to form pharmaceutical formulations according to conventional pharmaceutical formulation techniques. The 2,6, 8-polysubstituted imidazo [1,2-a ] pyrazine compounds may be incorporated as the active ingredient in any of the usual oral dosage forms including tablets, capsules and liquid preparations (e.g., elixirs and suspensions) containing coloring, flavoring, stabilizing and taste-masking substances. For mixed oral dosage forms, the 2,6, 8-polysubstituted imidazo [1,2-a ] pyrazine compounds as active ingredients may be mixed with various common tablet materials (e.g., starch, calcium carbonate, lactose, sucrose, and dicalcium phosphate) to facilitate tableting and encapsulation, and the 2,6, 8-polysubstituted imidazo [1,2-a ] pyrazine compounds may be dissolved or suspended in a pharmaceutically acceptable sterile liquid carrier such as sterile water, sterile organic solvents, or a mixture of both. The liquid carrier may be a carrier suitable for injection, such as physiological saline, propylene glycol or aqueous polyethylene glycol solution. In other cases, it may also be prepared by dispersing the micronised active ingredient in an aqueous solution of starch or sodium carboxymethylcellulose or in a suitable oil, for example arachis oil. Liquid pharmaceutical formulations (referred to as sterile solutions or suspensions) can be used for intravenous, intramuscular, intraperitoneal or subcutaneous injection. The pharmaceutical composition may also comprise one or more inorganic or organic, solid or liquid pharmaceutically acceptable carriers or excipients. The term "pharmaceutically acceptable" refers to additives or compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction (e.g., dizziness, etc.) when administered to an animal such as a mammal (e.g., a human). Pharmaceutical carriers and excipients may include, but are not limited to, diluents, such as lactose, glucose, mannose, and/or glycerol; a lubricant; polyethylene glycol; binders, such as magnesium aluminum silicate, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone; and, if desired, disintegrating agents, such as starch, agar, alginic acid or a salt thereof such as sodium alginate; and/or adsorbents, colorants, preservatives, stabilizers, flavorants and sweeteners.
The invention also provides application of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing TYK2 inhibitors.
The invention also provides application of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing medicines for preventing and treating tumor or inflammatory diseases. The tumor comprises various malignant tumors such as lymphoma, ovarian cancer, gastric cancer, breast cancer, lung cancer and the like.
The compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition is used for inhibiting the proliferation, growth, infiltration and migration of tumor cells, or promoting the apoptosis of the tumor cells.
The invention also provides a preparation method of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof: obtaining 2-substituted-6, 8-dibromo-imidazo [1,2-a ] pyrazine through ring closure of 2-amino-3, 5-dibromo-pyrazine, then obtaining 2, 6-polysubstituted-8-dibromo-imidazo [1,2-a ] pyrazine through substitution reaction, and finally obtaining the target compound 2,6, 8-polysubstituted imidazo [1,2-a ] pyrazine through scouring reaction:
Figure RE-GDA0003226041140000051
the compound disclosed by the invention has the beneficial effects that a cell activity determination experiment and a TYK2 enzyme activity determination experiment are carried out on the compound, and the experiment result shows that the compound disclosed by the invention has good application in preventing and treating cancer or inflammation related diseases.
Detailed Description
The following detailed description of the preferred embodiments of the present invention is provided to enable those skilled in the art to more readily understand the advantages and features of the present invention, and to clearly and unequivocally define the scope of the present invention.
Various aspects and features of the disclosure are described further below.
Abbreviations used herein are generally well known to those skilled in the art or may be readily understood based on basic knowledge.
The starting materials employed in the preparation of the compounds of the invention are known, can be prepared according to known methods or are commercially available.
The invention also relates to novel intermediates and/or starting materials. The same or similar reaction conditions and novel intermediates as those mentioned in the examples are particularly preferred.
Both intermediates and final products can be worked up and/or purified according to conventional methods including pH adjustment, extraction, filtration, drying, concentration, chromatography, trituration, crystallization, and the like.
In addition, the compounds of the present invention may be prepared by various methods known in the art or variations of the methods described herein.
The following examples are intended to illustrate the invention and are not intended to limit it in any way.
Example 1
Preparation of 3-cyano-N- (3- (8- ((4-morpholinophenyl) amino) imidazo [1,2-a ] pyrazin-6-yl) phenyl) benzamide
Figure RE-GDA0003226041140000061
Figure RE-GDA0003226041140000071
Step 1.1: preparation of 4- (4-nitrophenyl) morpholine (1b)
Figure RE-GDA0003226041140000072
P-fluoronitrobenzene (35.44mmol) and excess morpholine (205mmol) were stirred at 80 ℃ for 5 hours in a 100mL single-neck flask. After the reaction, the reaction mixture was slowly poured into 1000mL of ice water, and a yellow solid precipitated, filtered, and dried to obtain a yellow powdery solid with a yield of 99%.1H NMR(400 MHz,CDCl3)δ8.14(d,J＝9.4Hz,2H),6.84(d,J＝9.4Hz,2H),3.90–3.83(m, 4H),3.37(dd,J＝5.9,4.0Hz,4H).13C NMR(101MHz,CDCl3)δ155.0,138.9, 125.9,112.6,66.4,47.1.
Step 1.2: preparation of 4-morpholinoaniline (1c)
Figure RE-GDA0003226041140000073
Under the protection of argon, 4- (4-nitrophenyl) morpholine (19mmol) is dissolved in 60mL of ethanol in a two-neck bottle, 10% palladium-carbon and hydrazine hydrate are sequentially added, and the mixture is heated to 75 ℃ to react for 8 hours. After the reaction is finished, filtering by using kieselguhr, evaporating the organic solvent under reduced pressure, and carrying out column chromatography separation to obtain the target compound with the yield of 95%.1H NMR(400MHz,DMSO-d6)δ6.68(d,J＝8.8Hz,2H),6.51(d,J＝8.8Hz,2H),4.58 (s,2H),3.73–3.65(m,4H),2.88–2.85(m,4H)；13C NMR(101MHz,DMSO-d6)δ 142.8,142.8,118.0,115.2,66.8,51.1.
Step 1.3: preparation of 6-bromo-N- (4-morpholinophenyl) imidazo [1,2-a ] pyrazin-8-amine (1d)
Figure RE-GDA0003226041140000081
4-Morpholine aniline (5.6mmol) was dissolved in 60mL of isopropanol solution, and DIPEA (8.4mmol) and 6, 8-dibromo-imidazole [1,2-a ] were added in this order]Pyrazine (6.72mmol) was heated to 85 ℃ and reacted for 8 hours. After the reaction, cooled to room temperature, the organic solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and then with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and separated by column chromatography silica gel to obtain a white solid with a yield of 85%.1H NMR(400MHz,DMSO-d6)δ9.81(s, 1H),8.18(d,J＝5.7Hz,1H),7.91(d,J＝3.1Hz,1H),7.80(d,J＝9.3Hz,2H),7.60 (d,J＝2.4Hz,1H),6.92(d,J＝8.3Hz,2H),3.73(d,J＝3.1Hz,4H),3.06(dt,J＝ 8.3,4.6Hz,4H)；13C NMR(101MHz,DMSO-d6)δ147.58,144.9,132.9,132.1, 131.8,122.0,121.3,116.7,115.7,111.2,66.6,49.4.
Step 1.4: preparation of 6- (3-aminophenyl) -N- (4-morpholinophenyl) imidazo [1,2-a ] pyrazin-8-amine (1e)
Figure RE-GDA0003226041140000082
Under argon flow, 6-bromo-N- (4-morpholinophenyl) imidazole [1,2-a ] is added into a two-neck bottle in sequence]Pyrazine-8-amine (1mmol), amino boronic acid ester (1.2mmol), PdCl2(dppf) (0.1mmol) and 1M aqueous sodium carbonate solution (1.5mmol) were heated to 100 ℃ and reacted overnight. After the reaction was completed, it was cooled to room temperature, filtered through celite, and the organic solvent was distilled off. Dissolving in ethyl acetate, washing with water and saturated sodium chloride solution, and drying the organic phase with anhydrous sodium sulfate. Separating with column chromatography silica gel to obtain pure product with yield of 54%.1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.39(s,1H),8.05(d,J＝8.6Hz,2H), 7.98(s,1H),7.61(s,1H),7.22(d,J＝2.2Hz,1H),7.12(d,J＝4.7Hz,2H),6.99(d, J＝8.6Hz,2H),6.59(dt,J＝6.1,2.7Hz,1H),5.42–5.13(m,2H),3.76–3.72(m, 4H),3.07(t,J＝4.7Hz,4H)；13C NMR(101MHz,DMSO-d6)δ149.4,146.8,145.1, 138.4,137.6,133.2,132.6,132.6,129.6,121.2,116.7,116.0,114.3,113.8,111.9, 108.3,66.6,49.6.
Step 1.5: preparation of 3-cyano-N- (3- (8- ((4-morpholinophenyl) amino) imidazo [1,2-a ] pyrazin-6-yl) phenyl) benzamide (1)
Figure RE-GDA0003226041140000091
Sequentially adding the compound 6- (3-aminophenyl) -N- (4-morpholinophenyl) imidazole [1,2-a ] into a single-mouth bottle at normal temperature]Pyrazine-8-amine (0.5mmol), 3-cyanobenzoic acid (0.7mmol), EDCI (0.9mmol), HOBt (0.9mmol), DIEA (1.2mmol) and stirred overnight. After completion of the TLC monitoring reaction, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate. And separating by column chromatography silica gel to obtain the pure product with the yield of 53 percent.1H NMR(400MHz, DMSO-d6)δ10.61(s,1H),9.58(s,1H),8.70(s,1H),8.56(s,1H),8.49(s,1H), 8.34(d,J＝8.0Hz,1H),8.10(dd,J＝8.3,5.8Hz,3H),8.03(s,1H),7.81–7.72 (m,2H),7.67(d,J＝9.9Hz,2H),7.48(t,J＝7.9Hz,1H),7.03(d,J＝8.6Hz, 2H),3.74(t,J＝4.6Hz,4H),3.07(t,J＝4.8Hz,4H).13C NMR(101MHz, DMSO-d6)δ164.04,146.79,145.13,139.69,138.12,136.70,136.31,135.51, 133.08,132.96,132.43,131.88,130.31,129.45,121.52,121.48,120.55,118.83, 118.73,117.02,116.07,112.04,66.60,49.62.
Example 2
Preparation of 6- (5-aminopyridin-3-yl) -N- (4-morpholinophenyl) imidazo [1,2-a ] pyrazin-8-amine (2)
Figure RE-GDA0003226041140000101
Under argon flow, 6-bromo-N- (4-morpholinophenyl) imidazole [1,2-a ] is added into a two-neck bottle in sequence]Pyrazine-8-amine (1.5mmol), 5-aminopyridine-3-boronic acid pinacol ester (1.8mmol), PdCl2(dppf) (0.15mmol) and 1M aqueous sodium carbonate solution (3mmol), and the mixture was heated to 100 ℃ to react overnight. After the reaction, the reaction mixture was cooled to room temperature, filtered through celite, the organic solvent was removed by rotary evaporation, and the mixture was dissolved in ethyl acetate, washed with water and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate. Separating with column chromatography silica gel to obtain pure product with yield of 73%.1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.51(s, 1H),8.35(s,1H),8.07–7.91(m,4H),7.63(s,1H),7.48(t,J＝2.3Hz,1H),6.99(d, J＝8.5Hz,2H),5.51(s,2H),3.75(t,J＝4.8Hz,4H),3.08(t,J＝4.8Hz,4H).；13C NMR(101MHz,DMSO-d6)δ146.51,145.00,135.80,134.65,134.45,133.85, 132.97,132.46,132.25,132.14,120.97,116.79,116.44,115.48,108.41,66.17,49.11.
Example 3
Preparation of N- (5- (8- ((4-morpholinophenyl) amino) imidazo [1,2-a ] pyrazin-6-yl) -pyridin-3-yl) -3- (trifluoromethyl) benzamide (3)
Figure RE-GDA0003226041140000111
Sequentially adding the compound 6- (3-aminophenyl) -N- (4-morpholinophenyl) imidazole [1,2-a ] into a single-mouth bottle at normal temperature]Pyrazine-8-amine (0.26mmol), 3-trifluoromethylbenzoic acid (0.28mmol), EDCI (0.39mmol), HOBt (0.39mmol) and DIEA (0.52mmol) were stirred at room temperature overnight. After completion of the TLC monitoring reaction, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate. Separating with column chromatography silica gel to obtain pure product with yield of 66%.1H NMR(400 MHz,DMSO-d6)δ10.83(s,1H),9.64(s,1H),9.04(s,1H),8.95(s,1H),8.85(d, J＝2.4Hz,1H),8.71(s,1H),8.44–8.32(m,2H),8.11–7.99(m,4H),7.83(t,J ＝7.8Hz,1H),7.66(s,1H),7.02(d,J＝8.6Hz,2H),3.77–3.69(m,4H),3.11– 3.02(m,4H).13C NMR(101MHz,DMSO-d6)δ164.48,146.58,145.12,141.87, 141.08,135.71,135.23,133.55,132.88,132.47,132.41,132.21,131.93,129.89, 125.37,124.59,124.46,124.42,121.29,116.71,115.52,108.97,66.17,49.56, 49.08.
Example 4
Preparation of N- (5- (8- (cyclopropylamino) imidazo [1,2-a ] pyrazin-6-yl) -pyridin-3-yl) -3-fluorobenzamide (4)
Figure RE-GDA0003226041140000121
Step 4.1: preparation of 6-bromo-N-cyclopropylimidazo [1,2-a ] pyrazin-8-amine (4b)
Figure RE-GDA0003226041140000122
Adding 6, 8-dibromo-imidazole [1,2-a ] into a 100mL two-mouth bottle]Pyrazine (9.1mmol) was dissolved in 20mL of isopropanol, and cyclopropylamine (13.6mmol) and DIPEA (13.6mmol) were added in this order, and the mixture was heated to 80 ℃ and reacted for 3 hours. After the reaction is finished, cooling to room temperature, removing the organic solvent under reduced pressure, adding ethyl acetate into the residue to dissolve the residue, precipitating yellow solid, and filtering to obtain a pure product with the yield of 92%.1H NMR(400MHz, DMSO-d6)δ8.13(d,J＝4.3Hz,1H),8.04(s,1H),7.83(s,1H),7.49(s,1H), 2.91(tt,J＝8.1,3.8Hz,1H),0.75–0.63(m,4H).13C NMR(101MHz,DMSO-d6) δ148.47,132.03,131.47,122.16,115.81,109.40,23.85,6.16.
Step 4.2: preparation of 6- (5-aminopyridin-3-yl) -N-cyclopropylimidazo [1,2-a ] pyrazin-8-amine (4c)
Figure RE-GDA0003226041140000123
Under argon flow, 6-bromo-N-cyclopropyl imidazole [1,2-a ] is added into a two-neck bottle in sequence]Pyrazine-8-amine (2.1mmol), 5-aminopyridine-3-boronic acid pinacol ester (2.5mmol), PdCl2(dppf) (0.2mmol) and 1M aqueous sodium carbonate solution (4.2mmol) were heated to 100 ℃ and reacted overnight. After the reaction was completed, it was cooled to room temperature, filtered through celite, and the organic solvent was distilled off. Dissolving in ethyl acetate, washing with water and saturated sodium chloride solution, and drying the organic phase with anhydrous sodium sulfate. By column chromatographyThe product was isolated on silica gel in 81% yield.1H NMR(400MHz,DMSO-d6)δ8.37(s,2H),8.03–7.84(m,2H),7.75 (d,J＝4.2Hz,1H),7.56–7.49(m,2H),5.41(s,2H),3.07(tq,J＝7.7,4.0Hz,1H), 0.77(dh,J＝8.1,3.9Hz,2H),0.69(hept,J＝4.1Hz,2H).13C NMR(101MHz, DMSO-d6)δ148.72,135.72,135.03,134.62,131.87,116.99,115.87,113.79,111.51, 109.58,107.07,23.68,6.23.
Step 4.3: preparation of N- (5- (8- (cyclopropylamino) imidazo [1,2-a ] pyrazin-6-yl) -pyridin-3-yl) -3-fluorobenzamide (4)
Figure RE-GDA0003226041140000131
At normal temperature, the compound 6- (5-aminopyridin-3-yl) -N-cyclopropyl imidazole [1,2-a ] is added into a single-mouth bottle in sequence]Pyrazine-8-amine (0.4mmol), 3-fluorobenzoic acid (0.4mmol), EDCI (0.6mmol), HOBt (0.6mmol) and DIPEA (0.6mmol) were stirred at room temperature overnight. After completion of the TLC monitoring reaction, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate. Separating with column chromatography silica gel to obtain pure product with yield of 28%.1H NMR(400MHz, DMSO-d6)δ10.63(s,1H),8.96(d,J＝2.0Hz,1H),8.91(d,J＝2.4Hz,1H), 8.83(t,J＝2.3Hz,1H),8.53(s,1H),7.94(s,1H),7.85(dd,J＝16.8,7.9Hz, 3H),7.63(td,J＝8.0,5.8Hz,1H),7.54(s,1H),7.49(td,J＝8.6,2.7Hz,1H), 3.11(tq,J＝7.6,4.0Hz,1H),0.80(dt,J＝6.7,3.2Hz,2H),0.72(q,J＝4.1Hz, 2H).13C NMR(101MHz,DMSO-d6)δ164.68,163.16,160.73,148.88,142.14, 141.21,135.55,134.05,133.09,132.10,132.08,130.76,130.68,124.47,124.05, 124.02,118.71,116.14,114.75,114.53,107.69,23.73,6.26.
Example 5
Preparation of N- (3- (8-cyclopropylamino) imidazo [1,2-a ] pyrazin-6-yl) phenyl) -1H-1,2, 4-triazole-3-carboxamide (5)
Figure RE-GDA0003226041140000141
Step 5.16- (3-aminophenyl) -N-cyclopropylimidazo [1,2-a ] pyrazin-8-amine (5a) preparation
Figure RE-GDA0003226041140000142
Under the protection of argon, 6-bromine-N-cyclopropyl imidazole [1,2-a ] is added into a two-mouth bottle in sequence]Pyrazine-8-amine (4.0mmol), 3-aminophenylboronic acid pinacol ester (4.8mmol), PdCl2(dppf) (0.4mmol) and 1M aqueous sodium carbonate (8.0mmol) were heated to 100 ℃ and reacted overnight. After the reaction was completed, it was cooled to room temperature, filtered through celite, and the organic solvent was distilled off. Dissolving in ethyl acetate, washing with water and saturated sodium chloride solution, and drying the organic phase with anhydrous sodium sulfate. Separating with column chromatography silica gel to obtain pure product with yield of 69%.1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),7.88(s,1H),7.64(d,J＝4.2Hz, 1H),7.49(s,1H),7.26(t,J＝1.9Hz,1H),7.09(dt,J＝15.3,7.7Hz,2H),6.56(dt,J ＝7.8,1.6Hz,1H),5.12(s,2H),3.08(tq,J＝7.7,4.0Hz,1H),0.77(td,J＝7.1,4.6 Hz,2H),0.68(q,J＝4.0Hz,2H).13C NMR(101MHz,DMSO)δ148.71,148.39, 138.04,137.42,132.03,131.71,128.88,115.69,113.66,113.43,111.54,106.46, 23.68,6.24.
Step 5.2 preparation of N- (3- (8-cyclopropylamino) imidazo [1,2-a ] pyrazin-6-yl) phenyl) -1H-1,2, 4-triazole-3-carboxamide (5)
Figure RE-GDA0003226041140000151
Sequentially adding the compound 6- (3-aminophenyl) -N-cyclopropyl imidazole [1,2-a ] into a single-mouth bottle at normal temperature]Pyrazine-8-amine (0.4mmol), 1H-1,2, 4-triazole-3-carboxylic acid (0.5mmol), EDCI (0.7mmol), HOBt (0.7mmol) and DIPEA (1.02mmol), and stirring at room temperature overnight. After completion of the TLC monitoring reaction, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate. Separating with column chromatography silica gel to obtain pure product with yield of 35%.1H NMR(400MHz, DMSO-d6)δ14.81(s,1H),10.56(s,1H),8.59(d,J＝34.5Hz,2H),8.38(s,1H), 7.93(s,1H),7.82–7.72(m,3H),7.52(s,1H),7.43(t,J＝7.9Hz,1H),3.13(tq, J＝7.9,4.1Hz,1H),0.80(dq,J＝6.9,4.3Hz,2H),0.70(p,J＝4.4Hz,2H).13C NMR(101MHz,DMSO)δ148.57,146.87,138.48,138.01,136.56,132.05, 131.91,131.43,128.75,121.44,120.21,118.18,115.94,112.74,106.98,23.71, 6.26.
Example 6
Preparation of N- (3- (8-cyclopropylamino) imidazo [1,2-a ] pyrazin-6-yl) phenyl) -3- (methylthio) benzamide (6)
Figure RE-GDA0003226041140000161
Sequentially adding the compound 6- (3-aminophenyl) -N-cyclopropyl imidazole [1,2-a ] into a single-mouth bottle at normal temperature]Pyrazine-8-amine (0.6mmol), 3- (methylthio) benzoic acid (0.9mmol), EDCI (1.2mmol), HOBt (1.2mmol) and DIPEA (1.6mmol) were stirred at room temperature overnight. After completion of the TLC monitoring reaction, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate. Separating with column chromatography silica gel to obtain pure product with yield of 72%.1H NMR(400MHz, DMSO-d6)δ10.41(s,1H),8.49–8.42(m,1H),8.38(s,1H),7.97–7.91(m, 1H),7.84(s,1H),7.76(q,J＝5.7,3.9Hz,4H),7.54–7.42(m,4H),3.13(tt,J＝ 7.5,3.7Hz,1H),2.56(s,3H),0.80(dh,J＝7.8,3.5Hz,2H),0.71(q,J＝3.9Hz, 2H).13C NMR(101MHz,DMSO)δ165.18,148.59,139.28,138.74,137.97, 136.63,135.67,132.06,131.89,128.99,128.72,124.71,124.19,121.24,120.23, 120.19,118.08,115.95,106.93,23.73,14.62,6.28.
Example 7
Preparation of N- (3- (8-cyclopropylamino) imidazo [1,2-a ] pyrazin-6-yl) phenyl) -3- (methylthio) benzamide (7)
Figure RE-GDA0003226041140000171
At 0 ℃, adding N- (3- (8-cyclopropylamino) imidazole [1,2-a ]]Pyrazin-6-yl) phenyl) -3- (methylthio) benzamide (0.4mmol) was dissolved in dichloromethane and excess m-chloroperoxybenzoic acid (1.6mmol) was added with stirring. After the reaction, a sodium sulfite saturated solution was added, liquid separation was performed, the organic phase was dried over anhydrous sodium sulfate, and column analysis separation was performed to obtain a white solid with a yield of 65%.1H NMR(400MHz,DMSO-d6)δ 10.64(s,1H),8.51(t,J＝1.8Hz,1H),8.45(t,J＝2.0Hz,1H),8.39(s,1H),8.33 (dt,J＝7.8,1.4Hz,1H),8.15(dt,J＝7.7,1.4Hz,1H),7.94(d,J＝1.1Hz,1H), 7.85(t,J＝7.8Hz,1H),7.80–7.74(m,3H),7.52(d,J＝1.1Hz,1H),7.46(t,J ＝7.9Hz,1H),3.13(tt,J＝7.2,3.9Hz,1H),0.80(td,J＝7.1,4.7Hz,2H),0.73– 0.67(m,2H).13C NMR(101MHz,DMSO)δ164.09,148.61,141.13,139.01, 138.07,136.53,135.99,132.75,132.06,131.93,129.86,129.83,128.85,126.20, 121.48,120.35,118.23,115.99,107.00,43.50,23.74,6.29.
Example 8
Preparation of 6- (5-aminopyridin-3-yl) -N- (4- ((1R,4R) -5-isopropyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) imidazo [1,2-a ] pyrazin-8-amine (8)
Figure RE-GDA0003226041140000181
Under argon flow, 6-bromo-N- (4- ((1R,4R) -5-isopropyl-2, 5-diazabicyclo [2.2.1] was added sequentially to a two-necked flask]Heptane-2-yl) phenyl) imidazole [1,2-a]Pyrazine-8-amine (1.0mmol), 5-aminopyridine-3-boronic acid pinacol ester (1.2mmol), PdCl2(dppf) (0.1mmol) and 1M aqueous sodium carbonate solution (2.0mmol) were heated to 100 ℃ and reacted overnight. After the reaction was completed, it was cooled to room temperature, filtered through celite, and the organic solvent was distilled off. Dissolving in ethyl acetate, washing with water and saturated sodium chloride solution, and drying the organic phase with anhydrous sodium sulfate. Separating with column chromatography silica gel to obtain pure product with yield of 30%.1H NMR(400 MHz,DMSO-d6)δ9.43(s,1H),8.47(s,1H),8.34(s,1H),7.98–7.92(m,4H),7.62 (s,1H),7.45(d,J＝2.7Hz,1H),6.68(d,J＝8.5Hz,2H),5.48(s,2H),4.40(s,1H), 3.21(s,5H),2.89–2.59(m,2H),1.97(s,1H),1.12–1.01(m,6H).13C NMR(101 MHz,DMSO)δ145.05,144.73,142.50,142.32,135.96,134.81,134.68,133.01, 132.21,132.17,121.61,116.71,116.45,112.85,108.16,59.81,58.55,57.98,56.40, 55.02,20.82,14.13.
Example 9
Preparation of 6- (3-aminophenyl) -N- (5-fluoropyrimidin-2-yl) imidazo [1,2-a ] pyrazin-8-amine (9)
Figure RE-GDA0003226041140000191
Step 9.16 preparation of bromo-N- (5-fluoropyrimidin-2-yl) imidazo [1,2-a ] pyrazin-8-amine (9b)
Figure RE-GDA0003226041140000192
Under argon flow, 6, 8-dibromo-imidazole [1,2-a ] is sequentially added into a two-mouth bottle]Pyrazine (3.6mmol), 2-amino-5-fluoro-pyridine (5.4mmol), Pd2(dba)3(0.36mmol), Xantphos (0.72mmol) and cesium carbonate (7.2mmol) were heated to 100 ℃ for reaction overnight. After the reaction was completed, it was cooled to room temperature, filtered through celite, and the organic solvent was distilled off. Dissolving in ethyl acetate, washing with water and saturated sodium chloride solution, and drying the organic phase with anhydrous sodium sulfate. Separating with column chromatography silica gel to obtain pure product with yield of 45%.1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.41(s,1H),8.38(d,J＝3.1Hz,1H), 8.33(dd,J＝9.2,4.1Hz,1H),8.01(d,J＝1.1Hz,1H),7.87(td,J＝8.7,3.1Hz,1H), 7.68(d,J＝1.1Hz,1H).13C NMR(101MHz,DMSO)δ147.95,143.08,135.76, 135.51,133.42,131.35,125.58,125.38,119.71,116.84,114.32,113.32.
Step 9.26 preparation of (3-aminophenyl) -N- (5-fluoropyrimidin-2-yl) imidazo [1,2-a ] pyrazin-8-amine (9)
Figure RE-GDA0003226041140000201
Under argon flowSequentially adding 6-bromo-N- (5-fluoropyrimidin-2-yl) imidazole [1,2-a ] into a two-mouth bottle]Pyrazine-8-amine (2.0mmol), 3-aminophenylboronic acid pinacol ester (2.4mmol), PdCl2(dppf) (0.2mmol) and 1M aqueous sodium carbonate solution (4.0mmol) were heated to 100 ℃ and reacted overnight. After the reaction was completed, it was cooled to room temperature, filtered through celite, and the organic solvent was distilled off. Dissolving in ethyl acetate, washing with water and saturated sodium chloride solution, and drying the organic phase with anhydrous sodium sulfate. Separating with column chromatography silica gel to obtain pure product with yield of 45%.1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.74(dd,J＝9.2, 4.0Hz,1H),8.58(s,1H),8.37(d,J＝3.1Hz,1H),8.06(d,J＝1.1Hz,1H),7.89(td, J＝8.7,3.1Hz,1H),7.68(d,J＝1.1Hz,1H),7.24(t,J＝1.9Hz,1H),7.16–7.09(m, 2H),6.61(dt,J＝7.5,1.9Hz,1H),5.27(s,2H).13C NMR(101MHz,DMSO)δ 156.42,153.97,149.05,148.66,143.08,137.27,136.70,135.63,135.38,133.07, 131.69,129.31,125.61,125.42,116.85,113.97,113.74,113.70,113.21,111.42, 109.89.
Example 10
Preparation of 3-cyano-N- (3- (8- ((5-fluoropyrimidin-2-yl) amino) imidazo [1,2-a ] pyrazin-6-yl) phenyl) benzamide
Figure RE-GDA0003226041140000202
Figure RE-GDA0003226041140000211
At normal temperature, the compound 6- (3-aminophenyl) -N- (5-fluoropyrimidin-2-yl) imidazole [1,2-a ] is added into a single-mouth bottle in sequence]Pyrazine-8-amine (0.5mmol), 3-cyanobenzoic acid (0.7mmol), EDCI (0.9mmol), HOBt (0.9mmol), and DIPEA (1.2mmol) were stirred at room temperature overnight. After completion of the TLC monitoring reaction, the reaction mixture was diluted with ethyl acetate, washed with water and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate. Separating with column chromatography silica gel to obtain pure product with yield of 77%.1H NMR(400 MHz,DMSO-d6)δ10.54(s,1H),8.96(s,1H),8.86(dd,J＝9.2,4.1Hz,1H), 8.73(s,1H),8.68(s,1H),8.47(s,1H),8.33(dd,J＝9.5,5.4Hz,2H),8.08(d,J ＝8.9Hz,2H),7.83(ddd,J＝21.8,10.9,5.5Hz,2H),7.67(td,J＝11.3,9.2,4.8 Hz,3H),7.46(t,J＝7.9Hz,1H).13C NMR(101MHz,DMSO)δ163.78,156.46, 154.01,148.55,143.15,139.40,137.13,135.96,135.70,135.56,135.31,135.02, 133.14,132.58,131.70,131.35,129.87,129.05,125.54,125.35,120.91,119.96, 118.39,117.84,117.04,114.08,111.55,110.31.
Example 11
Preparation of 6- (3-cyanophenyl) -N-methyl-8- ((4-morpholinophenyl) amino) imidazo [1,2-a ] pyrazine-2-benzamide (11)
Figure RE-GDA0003226041140000221
Step 11.preparation of 16, 8-dibromoimidazo [1,2-a ] pyrazine-2-carboxylic acid ethyl ester (11b)
Figure RE-GDA0003226041140000222
In a 100mL single-necked flask, 2-amino-3, 5-dibromopyrazine (20mmol) and ethyl 3-bromopyruvate (24mmol) were dissolved in 40mL of ethylene glycol dimethyl ether and stirred at 100 ℃ overnight. After the reaction, the reaction mixture was added with ether, filtered and dried to obtain a brown solid with a yield of 47%.1H NMR(400MHz, CDCl3)δ8.31(dd,J＝7.2,1.7Hz,2H),4.48(qd,J＝7.1,1.6Hz,2H),1.43(td,J＝ 7.1,1.7Hz,3H).13C NMR(101MHz,CDCl3)δ161.81,139.73,138.31,135.93, 121.68,119.55,119.32,62.14,14.46.
Step 11.2: preparation of ethyl 6-bromo-8- ((4-morpholinophenyl) amino) imidazo [1,2-a ] pyrazine-2-carboxylate (11c)
Figure RE-GDA0003226041140000231
4-Morpholine aniline (7.2mmol) is dissolved in 30mL acetonitrile solution, DIPEA (16.2mmol) and 6, 8-dibromoImidazole [1,2-a ]]Ethyl pyrazine-2-carboxylate (6.0mmol) was heated to 85 ℃ and reacted overnight. After the reaction, the reaction mixture was cooled to room temperature, the organic solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and then with saturated brine in this order, the organic phase was dried over anhydrous sodium sulfate, filtered, and separated by column chromatography silica gel to obtain a yellow solid with a yield of 39%.1H NMR(400MHz,CDCl3) δ8.13(s,1H),8.00(s,1H),7.70(d,J＝8.6Hz,2H),7.60(s,1H),6.92(d,J＝ 8.5Hz,2H),4.44(q,J＝7.1Hz,2H),3.85(t,J＝4.5Hz,5H),3.12(t,J＝4.6Hz, 4H),1.41(d,J＝14.1Hz,3H).13C NMR(101MHz,CDCl3)δ162.31,148.02, 144.66,136.04,132.43,130.76,123.83,121.06,118.96,116.32,110.01,66.94, 61.57,49.68,14.47.
Step 11.3: preparation of 6-bromo-N-methyl-8- ((4-morpholinophenyl) amino) imidazo [1,2-a ] pyrazine-2-carboxamide (11d)
Figure RE-GDA0003226041140000232
Mixing 6-bromo-8- ((4-morpholinophenyl) amino) imidazole [1,2-a]Pyrazine-2-carboxylic acid ethyl ester (2.35mmol) was dissolved in 10mL of tetrahydrofuran solution, and 12mL of 30% methylamine aqueous solution was added and stirred at room temperature overnight. After the reaction was completed, filtration was carried out to obtain a pale yellow solid with a yield of 85%.1H NMR(400MHz, CDCl3)δ8.01(s,1H),7.79(s,1H),7.74(d,J＝8.5Hz,2H),7.67(s,1H),7.23(d,J ＝5.6Hz,1H),7.00(s,2H),3.90(s,4H),3.17(t,J＝4.8Hz,4H),3.05(d,J＝5.0Hz, 3H).13C NMR(101MHz,CDCl3)δ162.84,149.54,144.59,137.06,133.61,130.59, 123.82,121.06,119.08,116.31,110.76,77.48,77.16,76.84,66.92,61.67,26.07.
Step 11.4: preparation of 6- (3-cyanophenyl) -N-methyl-8- ((4-morpholinophenyl) amino) imidazo [1,2-a ] pyrazine-2-benzamide (11)
Figure RE-GDA0003226041140000241
Under the flow of argon, the mixture is poured into a two-mouth bottleAdding 6-bromo-N-methyl-8- ((4-morpholinophenyl) amino) imidazole [1,2-a ] for a time]Pyrazine-2-carboxamide (0.23mmol), 3-cyanophenylboronic acid pinacol ester (0.27mmol), PdCl2(dppf) (0.02mmol) and 1M aqueous sodium carbonate (0.46mmol) were heated to 100 ℃ and reacted overnight. After the reaction was completed, it was cooled to room temperature, filtered through celite, and the organic solvent was distilled off. Dissolving in ethyl acetate, washing with water and saturated sodium chloride solution, and drying the organic phase with anhydrous sodium sulfate. Separating with column chromatography silica gel to obtain pure product with yield of 42%.1H NMR(400MHz,DMSO-d6)δ9.41(s, 1H),8.72(s,1H),8.35(d,J＝1.8Hz,1H),8.32–8.28(m,2H),8.14(q,J＝4.8Hz, 1H),7.92–7.88(m,2H),7.85(dt,J＝7.7,1.4Hz,1H),7.71(t,J＝7.8Hz,1H),7.02 –6.97(m,2H),3.77–3.73(m,4H),3.12–3.07(m,4H),2.86(d,J＝4.8Hz,3H). 13C NMR(101MHz,DMSO-d6)δ161.85,147.01,145.19,139.32,138.14,135.12, 131.70,131.62,131.55,130.22,130.13,128.96,121.36,118.83,117.14,115.38, 111.88,109.47,66.17,48.95,25.60.
Example 12
Biological assay
TYK2 enzyme Activity assay
A384-well microplate TR-FRET (time resolved fluorescence energy transfer) endpoint assay was used for the TYK2 kinase activity assay. Same assay for IC of Small molecule inhibitors50And (4) measuring. In general, the kinase reaction is carried out in a volume of 25. mu.L of a reaction solution containing: mu.L of compound (in 10% DMSO), 20. mu.L of a mixture of TYK2, polypeptide, and ATP in assay buffer (25mM HEPES, pH 7.5, 0.001% Brij-35, 0.01% Triton,0.5 mM EGTA). All reactions were performed in 384-well white flat-bottom optical density plates (Perkin Elmer) at room temperature for 60min, then 25. mu.L of stop reaction solution (100mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3,50mM EDTA) was added. Read on an Evison Multilabel reader (Perkin Elmer, Envision 2102- & 0010).
TABLE 1
Example numbering Inhibition against TYK2 at 1μM(％)
1 76％(IC50＝0.2μM)
2 55％
3 3％
4 10％
5 8％
6 6％
7 3％
Cell activity assay
And (3) inoculating cells in logarithmic growth phase into a 96-well plate according to the density of 3000 cells per 100 mu L, adding 100 mu L of compounds to be detected with different concentrations after the cells adhere to the wall, and taking 6-8 concentration gradients. Each group was provided with five parallel wells, and a control group was provided. After 72 hours of co-incubation of compound and tumor cells, 10. mu.L of CCK-8 solution was added per well. After incubation for 1-2 hours in a cell incubator, absorbance (OD value) of each well was measured with an enzyme-linked immunosorbent assay, and inhibition rate was calculated: inhibition (IR%) (1-TOD/COD) x 100%, TOD: administration group OD mean value; COD: OD mean of solvent control group.
TABLE 2
Figure RE-GDA0003226041140000251
Figure RE-GDA0003226041140000261
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the present invention is not limited thereto, and any equivalent changes or modifications made according to the spirit of the present invention should be included in the scope of the present invention.

Claims (9)

1. A compound represented by the general formula (I):
Figure FDA0003151293360000011
wherein:
R1is selected from
Figure FDA0003151293360000012
Wherein E, Y, A, Q are each independently selected from C, N, O, S, R in (1)4Selected from hydrogen radicals, amino radicals, methylamino radicals, dimethylamino radicals, hydroxyl radicals, halogen atoms, cyano radicals, hydrocarbon radicals, cycloalkyl radicals, heteroatomic cycloalkyl radicals, aryl or heteroaromatic radicals, substituted aryl radicals or substituted heteroaromatic radicals,
Figure FDA0003151293360000013
In (2), L is selected from
Figure FDA0003151293360000014
Figure FDA0003151293360000015
Figure FDA0003151293360000016
R5Selected from hydrogen radicals, aryl or heteroaromatic rings, substituted aryl or substituted heteroaromatic rings;
R2selected from cycloalkyl or substituted cycloalkyl, heteroatomic cycloalkyl or substituted heteroatomic cycloalkyl or
Figure FDA0003151293360000017
When R is2When the structure is selected from the structure in (3), M, X, Z, T are independently selected from C, N, R6Selected from hydrogen, amino, substituted amino, hydroxyl, halogen, cycloalkyl or substituted cycloalkyl, heteroatomic cycloalkyl or substituted heteroatomic cycloalkyl, cyano, hydrocarbyl, aryl or heteroaromatic ring, substituted aryl or substituted heteroaromatic ring;
R3selected from the group consisting of hydrogen atoms,
Figure FDA0003151293360000018
Figure FDA0003151293360000019
2. A compound of formula (I) according to claim 1, R1Is selected from
Figure FDA0003151293360000021
Figure FDA0003151293360000022
Wherein E, Y, A, Q are each independently selected from C, N, R in (1)4Selected from amino, cyano, in (2) L is selected from
Figure FDA0003151293360000023
R5Is selected from
Figure FDA0003151293360000024
Figure FDA0003151293360000025
R2Selected from cyclopropane or
Figure FDA0003151293360000026
Wherein M, X, Z, T are each independently selected from C, N, R6Selected from halogen atoms,
Figure FDA0003151293360000027
R3Selected from the group consisting of hydrogen atoms,
Figure FDA0003151293360000028
3. A compound of formula (I) according to claim 1, R1Is selected from
Figure FDA0003151293360000029
Figure FDA00031512933600000210
Wherein E, Y, A, Q are each independently selected from C, N, R in (1)4Selected from amino, cyano, in (2) L is selected from
Figure FDA00031512933600000211
R5Is selected from
Figure FDA00031512933600000212
Figure FDA00031512933600000213
R2Selected from cyclopropane or
Figure FDA00031512933600000214
Wherein M, X, Z, T are each independently selected from C, N, R6Is selected fromA fluorine atom,
Figure FDA0003151293360000031
R3Selected from the group consisting of hydrogen atoms,
Figure FDA0003151293360000032
4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers and/or diluents, in a clinically acceptable pharmaceutical formulation.
5. The pharmaceutical composition of claim 4, wherein the pharmaceutical formulation is selected from a tablet, a capsule, or a liquid formulation.
6. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 4, for the manufacture of an inhibitor of TYK 2.
7. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 4 for the preparation of a medicament for the prevention or treatment of a neoplastic or inflammatory disease.
8. The use of claim 7, wherein said compound or pharmaceutically acceptable salt thereof, or said pharmaceutical composition is used to inhibit proliferation, growth, infiltration and migration of tumor cells, or to promote apoptosis of tumor cells.
9. A process for producing a compound according to any one of claims 1 to 3, wherein 2-amino-3, 5-dibromopyrazine is subjected to ring closure to give 2-substituted-6, 8-dibromoimidazo [1,2-a ] pyrazine, which is then subjected to substitution reaction to give 2, 6-polysubstituted-8-dibromoimidazo [1,2-a ] pyrazine, and which is finally subjected to coupling reaction to give the target compound, 2,6, 8-polysubstituted imidazo [1,2-a ] pyrazine:
Figure FDA0003151293360000033
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