CN113061137A - Nitrogen-containing heterocyclic derivative or pharmaceutically acceptable salt and application thereof - Google Patents

Nitrogen-containing heterocyclic derivative or pharmaceutically acceptable salt and application thereof Download PDF

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CN113061137A
CN113061137A CN202110361324.8A CN202110361324A CN113061137A CN 113061137 A CN113061137 A CN 113061137A CN 202110361324 A CN202110361324 A CN 202110361324A CN 113061137 A CN113061137 A CN 113061137A
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nitrogen
heterocyclic derivative
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CN113061137B (en
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何林洪
姚华良
黄怀征
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Guangxi Medical University
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Abstract

The invention discloses a nitrogenous heterocyclic derivative or pharmaceutically acceptable salt thereof, wherein the nitrogenous heterocyclic derivative has a general formula shown in formula I;
Figure DDA0003005653960000011
the invention also provides the application of the nitrogenous heterocyclic derivative or the pharmaceutically acceptable salt thereof. The nitrogen-containing heterocyclic derivative can effectively and selectively silence JAK3, and has higher medication safety.

Description

Nitrogen-containing heterocyclic derivative or pharmaceutically acceptable salt and application thereof
Technical Field
The invention relates to the field of chemical medicine. More particularly, the invention relates to a nitrogenous heterocyclic derivative or a pharmaceutically acceptable salt thereof and application.
Background
Janus kinases (JAKs), including JAK1, JAK2, JAK3 and TYK2, belong to cytoplasmic protein kinases, interact with type I and type II cytokine receptors, and complete a variety of biological processes through Signal Transduction and Activator of Transcription (STAT). Among them, JAK3 is activated only by gamma-chain cytokines (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21), is specifically expressed in T lymphocytes, B lymphocytes, Natural Killer (NK) cells, bone marrow cells and thymocytes, and induces JAK1 to dimerize therewith (other JAKs can dimerize or trimerize with each other), and is activated by interactive tyrosine phosphorylation; the receptor tyrosine residue is catalyzed to generate phosphorylation modification, a docking site for recruiting STAT protein is formed by the receptor tyrosine residue and the surrounding amino acid sequence, the STAT protein is catalyzed to generate phosphorylation modification, the activated STAT protein enters a cell nucleus in a dimer form to be combined with a target gene, the transcription of the gene is regulated and controlled, and the receptor tyrosine residue is involved in the maturation and activation of leukocytes and the generation of cytokines and immunoglobulin; growth and development of lymphocytes, differentiation of T lymphocytes and NK cells, switching of B lymphocytes, and the like. Therefore, JAK3, by virtue of its specific tissue distribution and functional characteristics, is a star target for the treatment of autoimmune diseases.
With the intensive research on JAK3 targets, indications of inhibitors of the JAK3 targets are continuously excavated, and the marketed drug Tovatinib is applied to clinical treatment of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and juvenile idiopathic arthritis, and also has various indications in clinical research stages, including alopecia areata, Crohn's disease, ankylosing spondylitis, systemic lupus erythematosus and the like. However, by far the majority of JAK3 inhibitors on the market or in clinical research are pan JAK inhibitors, and their broad spectrum JAK inhibition poses a safety barrier that is difficult to break through. Tovatinib increased from a red safety warning to a black safety warning; decernotiib caused neutropenia in phase II/III clinical trials in rheumatoid arthritis was discontinued; in addition, at higher doses, pan JAK inhibitors may also carry risks of serious infections and dyslipidemia. Therefore, there is a great need to develop selective JAK3 covalent inhibitors to more efficiently and safely serve the treatment of autoimmune diseases.
Disclosure of Invention
The invention aims to provide a nitrogen-containing heterocyclic derivative or a pharmaceutically acceptable salt thereof, a preparation method and application thereof, and the obtained nitrogen-containing heterocyclic derivative can effectively and selectively silence JAK3 and has higher medication safety.
To achieve these objects and other advantages in accordance with the present invention, according to one aspect of the present invention, there is provided a nitrogen-containing heterocyclic derivative having a general formula as shown in formula I;
Figure BDA0003005653940000021
wherein Z is C or N;
R1selected from phenyl, substituted phenyl, heterocyclic and substituted heterocyclic;
x is selected from
Figure BDA0003005653940000022
Figure BDA0003005653940000023
X1Selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 halogen substituted alkyl, C3-C8 cycloalkyl, X2Selected from H, C1-C8 alkyl, C1-C8 halogen substituted alkyl, C3-C8 cycloalkyl;
R2is selected from
Figure BDA0003005653940000024
R3Selected from C2-C8 alkenyl, substituted C2-C8 alkenyl, C2-C8 alkynyl, substituted C2-C8 alkynyl, halogen substituted C1-C8 alkyl, cyano substituted C1-C8 alkyl and halogen substituted C3-C8 cycloalkyl.
Further, R1Is selected from
Figure BDA0003005653940000025
Figure BDA0003005653940000031
Wherein R is11Comprising H, C1-C8 alkyl, C1-C8 alkoxy and C1-C8 halogen substituted alkylA C3-C8 cycloalkyl group,
Figure BDA0003005653940000032
Phenoxy, -NO2、
Figure BDA0003005653940000033
R12Is H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 halogen substituted alkyl, C3-C8 cycloalkyl, -NO2And n is 0 to 2.
According to another aspect of the invention, there is provided the use of a nitrogen-containing heterocyclic derivative, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting a JAK kinase.
According to another aspect of the present invention there is provided the use of a nitrogen-containing heterocyclic derivative, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of transplant rejection.
According to another aspect of the present invention, there is provided the use of a nitrogen-containing heterocyclic derivative or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of arthritis.
The invention at least comprises the following beneficial effects:
the nitrogenous heterocyclic derivative can effectively and selectively silence JAK3, and has higher medication safety (LD50 is more than 2 g/kg); the compound preparation shows better foot swelling relieving effect than that of the Tovatinib in an ICR (experimental model for arthritis) mouse, and shows better effect of resisting immunological rejection in a mouse allogeneic heart transplantation model, thereby greatly prolonging the survival period of the mouse.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
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FIG. 1 shows the effect of A-1 on survival in a mouse allogeneic heart transplant model;
figures 2 and 3 show carrageenan-induced foot swelling in ICR mice and the therapeutic effect of each compound (n-8).
Detailed Description
The present invention is described in further detail below to enable those skilled in the art to practice the invention with reference to the description.
It will be understood that terms such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or groups thereof.
The embodiments of the present application provide nitrogen-containing heterocyclic derivatives, or pharmaceutically acceptable salts thereof, that are meant to be those salts that retain the biological effectiveness and properties of the parent compound, the nitrogen-containing heterocyclic derivatives having the general formula shown in formula I;
Figure BDA0003005653940000041
wherein Z is C or N; r1Is selected from phenyl, substituted phenyl, heterocyclic radical and substituted heterocyclic radical, such as five-membered heterocyclic radical and six-membered N, O, S heterocyclic radical;
x is selected from
Figure BDA0003005653940000042
Figure BDA0003005653940000043
X1Selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 halogen substituted alkyl, C3-C8 cycloalkyl, X2Selected from H, C1-C8 alkyl, C1-C8 halogen substituted alkyl, C3-C8 cycloalkyl;
R2is selected from
Figure BDA0003005653940000044
R3Selected from C2-C8 alkenyl, substituted C2-C8 alkenyl, C2-C8 alkynyl, substituted C2-C8 alkynyl, halogen substituted C1-C8 alkyl, cyano substituted C1-C8 alkyl and halogen substituted C3-C8 cycloalkyl.
In other embodiments, R1Is selected from
Figure BDA0003005653940000051
Figure BDA0003005653940000052
Wherein R is11Comprising H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 halogen substituted alkyl, C3-C8 cycloalkyl,
Figure BDA0003005653940000053
Phenoxy, -NO2、
Figure BDA0003005653940000054
R12Is H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 halogen substituted alkyl, C3-C8 cycloalkyl, -NO2And n is 0 to 2.
In other embodiments, the nitrogen-containing heterocyclic derivative has the formula shown in Table 1.
TABLE 1 structural formula of nitrogen-containing heterocyclic derivatives
Figure BDA0003005653940000055
Figure BDA0003005653940000061
Figure BDA0003005653940000071
Figure BDA0003005653940000081
Figure BDA0003005653940000091
Figure BDA0003005653940000101
Figure BDA0003005653940000111
Figure BDA0003005653940000121
Figure BDA0003005653940000131
Figure BDA0003005653940000141
Figure BDA0003005653940000151
Figure BDA0003005653940000161
Figure BDA0003005653940000171
Embodiments of the present application also provide the use of a nitrogen-containing heterocyclic derivative or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting JAK kinase, preferably, the medicament comprises each compound described above and a pharmaceutically acceptable carrier, excipient or diluent.
The embodiments of the present application also provide the use of a nitrogen-containing heterocyclic derivative or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of transplant rejection, preferably, the medicament comprises each of the compounds described above and a pharmaceutically acceptable carrier, excipient or diluent.
The embodiments of the present application also provide the use of the nitrogen-containing heterocyclic derivative or the pharmaceutically acceptable salt thereof for preparing a medicament for treating arthritis, preferably, the medicament comprises each compound described above and a pharmaceutically acceptable carrier, excipient or diluent.
This is further illustrated by the following specific examples.
Example 1: a process for producing a nitrogen-containing heterocyclic derivative or a pharmaceutically acceptable salt thereof.
To facilitate the description of the example synthetic routes and methods that follow, the following table will now be prepared with abbreviations for the starting materials or reagents used.
TABLE 2 reagents and abbreviations
Figure BDA0003005653940000181
Figure BDA0003005653940000182
Figure BDA0003005653940000191
At room temperature, adding the raw material 1(1.0eq) and a proper amount of THF into a reaction flask, adding NIS (1.2eq) into the reaction solution for a plurality of times in a small amount, continuing stirring until the suspension becomes clear, and stopping the reaction. The reaction solution was spin-dried to recover the reaction solvent THF. Adding the dispersed concentrated residue, filtering and collecting the filter cake, washing the filter cake with water for multiple times, and drying to obtain an intermediate 2 which is brown solid and does not need purification.
Figure BDA0003005653940000192
Under the ice-bath condition, adding the intermediate 2(1.0eq) and a proper amount of DMF (dimethyl formamide) and NaH (1.2eq) into a reaction bottle for a plurality of times in a small amount, and continuously stirring at low temperature for 1h after the addition is finished. 2- (trimethylsilyl) ethoxymethyl chloride (1.2eq) was slowly added dropwise and the reaction was continued for 2 h. Stopping the reaction, pouring the reaction solution into a large amount of ice water, separating out solids, filtering and collecting the solids, washing filter cakes with water and drying to obtain an intermediate 3 which is brown solid and does not need purification.
Figure BDA0003005653940000193
The intermediate 3(1.0eq), DIEA (1.5eq), (R) -3-Boc-aminopiperidine (1.2eq) and a suitable amount of n-BuOH were added to a reaction flask as a solvent, and the reaction was stopped by heating to 80 ℃ and stirring for 3 hours. EA/H2And (3) extracting the reaction solution, collecting an oil layer, washing the oil layer for multiple times by using saturated saline solution, drying the oil layer by using anhydrous sodium sulfate, spin-drying the oil layer, and purifying by using a silica gel column to collect the intermediate 4 which is brownish red oily.
Figure BDA0003005653940000194
The intermediate 4(1.0eq), boric acid derivative (1.1eq), Pd (PPh) were added to a three-necked flask3)4(0.05eq) and K2CO3(3.0eq) by passage through N2After replacing air in the three-mouth bottle for many times, injecting mixed solvent 1, 4-dioxane/H into the three-mouth bottle by using injection2O (7/3, v/v). Heating under reflux overnight, filtering with celite to remove insoluble material, collecting filtrate, rotary evaporating, extracting filtrate with EtOAc and water, collecting oil layer, washing oil layer with saturated saline solution for 3 times, and collecting anhydrous Na2SO4The oil layer was dried, the oil layer was spin dried and purified with silica gel column to collect product 5.
Figure BDA0003005653940000201
Adding the intermediate 5 and a proper amount of EA into a reaction bottle, dropwise adding a little saturated HCl solution at room temperature, stirring overnight, monitoring by TLC to obtain a solid after the deprotection of the raw material is finished, and filtering and collecting the solid to obtain an intermediate 6.
Figure BDA0003005653940000202
In a reaction flaskThe intermediate 6(1.0eq) and an appropriate amount of dry DMF were added, DIEA (5.0eq) and the acid chloride derivative (1.0eq) were added dropwise in this order, and the mixture was allowed to react overnight at room temperature. Extracting the reaction solution with DCM and water, collecting the oil layer, washing the oil layer with saturated brine for 3 times, and removing anhydrous Na2SO4The oil layer was dried, the oil layer was spin-dried and purified with silica gel column to collect the objective product 7.
The acidic material (1.0eq) and an appropriate amount of dry DCM were added to a reaction flask, stirred at room temperature, followed by the addition of PyBOP (1.0eq) and DIEA (3.0eq) in sequence, reacted for 30min, followed by the addition of intermediate 6(1.0eq) and reacted at room temperature overnight. Spin-drying the reaction solution, extracting the filtrate with DCM and water, collecting the oil layer, washing the oil layer with saturated brine for 3 times, anhydrous Na2SO4The oil layer was dried, the oil layer was spin-dried and purified by silica gel column to collect the product 7 (corresponding to A-1 to A-12 of Table 1).
Of compounds A11H NMR(600MHz,DMSO)δ12.07(s,1H),8.39(d,J＝37.4Hz,1H),8.04(s,1H),7.47(d,J＝61.6Hz,1H),7.09(d,J＝14.8Hz,1H),7.00(s,2H),6.25(dd,J＝15.9,8.3Hz,1H),6.17–6.08(m,3H),5.62(s,2H),3.94(s,1H),3.77(s,1H),3.59(d,J＝12.4Hz,1H),2.73(dd,J＝48.3,11.2Hz,2H),1.82(s,1H),1.43(s,1H),1.37–1.30(m,2H).13C NMR(151MHz,DMSO)δ164.38,160.10,153.36,151.95,150.57,147.78,146.29,132.22,129.74,125.53,124.62,121.96,116.37,108.90,103.17,101.37,66.98(s,0H),52.88,50.53,45.91,23.19.MS(ESI),m/z:392.20[M+H]+。
Other compounds in table 1 can be prepared by similar methods and are not described in detail herein.
Example 2: in vitro biochemical level JAK kinase activity inhibition experiment.
Materials: JAK1, JAK2, JAK3 and TYK2 kinase (Carna); polypeptide FAM-P22 and polypeptide FAM-P30(GL Biochem); ATP, DMSO, and edta (sigma); 96-well plates (Corning), positive control staurosporine (sigma).
The method comprises the following steps:
1.1 Xkinase in alkaline buffer and stop buffer.
1) The 1x kinase base buffer of JAK1 and JAK3 contained 50Mm HEPES, Ph 7.5; 0.0015% Brij-35; 10Mm MgCl 2; 2Mm DTT.
2) The 1x kinase base buffer of JAK2 and TYK2 contained 25Mm HEPES, Ph 7.5; 0.001% Brij-35; 0.01% Triton; 0.5Mm EGTA; 10Mm MgCl 2; 2Mm DTT.
3) The stop buffer contained 100Mm HEPES, Ph 7.5; 0.015% Brij-35; 0.2% Coating Reagent # 3; 50Mm EDTA.
2. And (4) preparing the compound.
1) Test compounds were formulated with 100% DMSO at 50-fold the highest concentration tested. Transfer 100 μ l of compound dilution to well plate.
2) Add 100 μ l of 100% DMSO to 2 wells and mark the plate as the original plate. Transfer 10. mu.l of compound from the original plate to a new 96-well plate and record as the intermediate plate, add 90. mu.l of 1 Xkinase base buffer to each well of the intermediate plate and place the plate on a shaker to mix the compound solution with the 1 Xkinase base buffer. Further, duplicate wells were formed by taking 5. mu.l of each mixture from the intermediate plate to a 384-well plate, and the plate was designated as a detection plate.
3. And (4) carrying out enzyme reaction.
1) Prepare 2.5x enzyme solution and add kinase to 1x kinase base buffer.
2) Prepare 2.5x polypeptide buffer, add FAM-marker polypeptide and ATP to 1x kinase base buffer.
3) Transfer 2.5x enzyme solution to assay plate. Each well of the assay plate was filled with 5. mu.l of a compound solution containing 10% DMSO, and 10. mu.l of a 2.5 Xenzyme solution was added and incubated at 25 ℃ for 10 min.
4) To each well of the assay plate was added 2.5 Xpolypeptide solution and incubated at 28 ℃ for an appropriate period of time followed by addition of 25. mu.l of stop buffer to stop the enzyme reaction.
4. Reading and recording the raw data of each hole, and performing corresponding conversion on the raw data.
1) Inhibition rate (max-compound conversion)/(max-min) × 100, where the maximum is DMSO control group data and the minimum is blank without enzyme addition.
2) Calculation of median inhibitory concentration IC50Value in log [ administration concentration ]]On the abscissa, the inhibition ratio is on the ordinate, at GFitting a dose response curve in raphpad Prism 5 to obtain the drug concentration of the compound at 50% inhibition rate, namely the IC of the compound at the level of kinase50The value is obtained.
The following table provides the average IC of the compounds in table 1 for JAK1, JAK2, JAK3 and TYK250Range, wherein "A" represents IC50Values less than 10nM, "B" indicates IC50Values between 10nM and 100nM, "C" denotes IC50Values between 100nM and 1000nM, "D" denotes IC50Values greater than 1000 nM.
TABLE 3 inhibitory Effect on kinases
Figure BDA0003005653940000221
Figure BDA0003005653940000231
Figure BDA0003005653940000241
Figure BDA0003005653940000251
Example 3: heart transplantation experiments.
Spleen lymphocytes from C57BL6 mice were extracted at 1X 10 per well6The individual cells were cultured in 96-well plates, drug intervention was performed at different concentrations after stimulating cell proliferation with concanavalin (ConA), and Brdu detection was performed after 72h of culture. The following table provides the inhibitory effect of compounds of this patent on spleen lymphocytes from C57BL6 mice, where "A" represents IC50The value is less than 1.0. mu.M, and "B" represents IC50The value is between 1.0 and 10. mu.M, "C" denotes IC50The value is between 10 and 50. mu.M, "D" denotes IC50The value is greater than 50. mu.M.
TABLE 4 inhibitory Effect on mouse spleen lymphocytes
Figure BDA0003005653940000252
Figure BDA0003005653940000261
Compound A-1 was tested for its immunomodulatory effects on host and graft in vivo in a mouse allogeneic heart transplant model, with female C57BL/6 mice as recipient and female BALB/C mice as heart donor, and the survival results after drug treatment are shown in the following figure. The survival time of the postoperative heart transplant is an important standard for measuring the effect of the immunosuppressant, the survival time of each group is shown in figure 1, the survival time of a control group is respectively 7, 7 and 7 days, and the average survival time is 6.8 +/-0.8 days; survival of the A-1 low dose group was 8, 9, 10, 11, 14 days, respectively, with an average survival of 9.5 days; survival in the A-1 high dose group was 27, 29, 30, 31, 35 days, respectively, with an average survival of 30.5 days; the survival of tofacitinib group was 8, 9, 10, 11 days, respectively, with an average survival of 10.5 days. The a-1 high dose group alone significantly prolonged the survival of the cardiac grafts compared to the control group, as shown in figure 1.
Example 4: foot swelling experiments.
An ICR mouse acute foot swelling inflammation model is established, and the in-vivo anti-inflammatory effects of compounds A-1, A-6, K-13, K-14 and M-13 are selected. After each treatment group takes the compound with the dose of 30mg/kg for 1h, the swelling of feet is relieved to different degrees, wherein the effects of A-1, A-6, K-13, K-14 and M-13 are obviously better than those of the Tovatinib, the inflammation inhibition effect is released smoothly, and compared with a model group, the statistical difference (p <0.01) is shown in figure 2 and figure 3. The method can guide the long-term animal model of the later arthritis, provide reference basis including CIA, and provide a thought path for designing and developing arthritis drugs.
Example 5: acute toxicity test.
BALB/c mice were selected, half each male and female, 6 mice per groupAnd (5) carrying out an acute toxicity test. Mice were given 2g/kg of each of A-1 and A-6 orally in a single dose after 6h of fasting, and fasting was continued for about 3h without water deprivation after administration. After 14 days of continuous observation, the mice did not show any adverse reaction, and the body weight continued to increase steadily, so that half of the lethal dose LD of the compounds A-1 and A-650>2g/kg。
The number of apparatuses and the scale of the process described herein are intended to simplify the description of the present invention. Applications, modifications and variations of the nitrogen-containing heterocyclic derivatives or pharmaceutically acceptable salts and uses thereof of the present invention will be apparent to those skilled in the art.
While embodiments of the invention have been described above, it is not limited to the applications set forth in the description and the embodiments, which are fully applicable to various fields of endeavor for which the invention may be embodied with additional modifications as would be readily apparent to those skilled in the art, and the invention is therefore not limited to the details given herein and to the embodiments shown and described without departing from the generic concept as defined by the claims and their equivalents.

Claims (10)

1. The nitrogenous heterocyclic derivative or pharmaceutically acceptable salt thereof is characterized in that the nitrogenous heterocyclic derivative has a general formula shown in formula I;
Figure FDA0003005653930000011
wherein Z is C or N;
R1selected from phenyl, substituted phenyl, heterocyclic and substituted heterocyclic;
x is selected from
Figure FDA0003005653930000012
Figure FDA0003005653930000013
X1Selected from H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 halogen substituted alkyl and C3-C8 cycloalkyl, X2Selected from H, C1-C8 alkyl, C1-C8 halogen substituted alkyl, C3-C8 cycloalkyl;
R2is selected from
Figure FDA0003005653930000014
R3Selected from C2-C8 alkenyl, substituted C2-C8 alkenyl, C2-C8 alkynyl, substituted C2-C8 alkynyl, halogen substituted C1-C8 alkyl, cyano substituted C1-C8 alkyl and halogen substituted C3-C8 cycloalkyl.
2. The nitrogen-containing heterocyclic derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein R is1Is selected from
Figure FDA0003005653930000015
Figure FDA0003005653930000021
Wherein R is11Comprising H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 halogen substituted alkyl, C3-C8 cycloalkyl,
Figure FDA0003005653930000022
Phenoxy, -NO2、
Figure FDA0003005653930000023
R12Is H, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 halogen substituted alkyl, C3-C8 cycloalkyl, -NO2And n is 0 to 2.
3. The nitrogen-containing heterocyclic derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein when
Figure FDA0003005653930000024
Is composed of
Figure FDA0003005653930000025
When the nitrogen-containing heterocyclic derivative has a structural formula selected from:
Figure FDA0003005653930000026
Figure FDA0003005653930000031
Figure FDA0003005653930000041
4. the nitrogen-containing heterocyclic derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein when
Figure FDA0003005653930000042
Is composed of
Figure FDA0003005653930000043
When the nitrogen-containing heterocyclic derivative has a structural formula selected from:
Figure FDA0003005653930000044
Figure FDA0003005653930000051
5. the nitrogen-containing heterocyclic derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein when
Figure FDA0003005653930000061
Is composed of
Figure FDA0003005653930000062
When the nitrogen-containing heterocyclic derivative has a structural formula selected from:
Figure FDA0003005653930000063
6. the nitrogen-containing heterocyclic derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein when
Figure FDA0003005653930000064
Is composed of
Figure FDA0003005653930000065
When the nitrogen-containing heterocyclic derivative has a structural formula selected from:
Figure FDA0003005653930000071
7. the nitrogen-containing heterocyclic derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein when
Figure FDA0003005653930000072
Is composed of
Figure FDA0003005653930000073
When the nitrogen-containing heterocyclic derivative has a structural formula selected from:
Figure FDA0003005653930000074
Figure FDA0003005653930000081
8. use of the nitrogen-containing heterocyclic derivative or the pharmaceutically acceptable salt thereof according to claim 1 for the preparation of a medicament for inhibiting JAK kinase.
9. Use of a nitrogen-containing heterocyclic derivative or a pharmaceutically acceptable salt thereof according to claim 1 for the preparation of a medicament for the treatment of transplant rejection.
10. Use of the nitrogen-containing heterocyclic derivative or the pharmaceutically acceptable salt thereof according to claim 1 for the preparation of a medicament for the treatment of arthritis.
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