Compound with unsaturated alkane functional group as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicines, in particular to a compound with an unsaturated alkane functional group and a preparation method and application thereof, and the compound has JAK kinase inhibitory activity. The invention provides a compound as shown in a formula I or a stereoisomer, a tautomer and pharmaceutically acceptable salt thereof, and the compound with an unsaturated alkane functional group has excellent JAK3 kinase inhibition effect, high biological activity, better drug effect and higher selectivity, and can be used as a JAK3 kinase inhibitor for treating various diseases with abnormal JAK3 kinase activity. # imgabs0 #

Description

Field of the Invention

[0001] The present invention relates to the field of medical technology, and in particular to a compound having an unsaturated alkane functional group, a preparation method and application thereof. The compound has JAK kinase inhibitory activity. Background Art

[0002] Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins and are broadly classified as tyrosine and serine / threonine kinases. Abnormal kinase activity caused by mutation, overexpression or inappropriate regulation, dysregulation or imbalance, and excessive or insufficient production of growth factors or cytokines can lead to many diseases, including but not limited to cancer, cardiovascular disease, allergy, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative diseases (e.g., Alzheimer's disease). Among them, autoimmune diseases are a large class of diseases caused by tissue damage due to the body's immune response to self-antigens, including rheumatoid arthritis (RA), psoriasis, alopecia areata, etc., characterized by unclear pathogenesis, few targets, and lack of effective therapeutic drugs.

[0003] Protein kinases have become an important class of enzymes that are targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) plays an important role in cytokine signal transduction. When cytokines bind to their receptors, the cytokines activate the JAK kinase, and then the JAK phosphorylates the cytokine receptor, thereby generating docking sites for signal transduction molecules. Many cytokines are known to activate the JAK family. Currently, several JAK small molecule inhibitors are on the market for the treatment of different autoimmune diseases, but with the clinical application of JAK inhibitors, side effects such as opportunistic infections and anemia have gradually emerged, mainly due to the non-selective inhibition of different subtypes of JAK kinases. The non-selective inhibition of JAK is bound to affect the physiological effects of multiple cytokines, thereby causing corresponding side effects. There is still a need for novel compounds that effectively and selectively inhibit specific JAK enzymes (especially JAK3).

[0004] Therefore, although a series of JAK3 inhibitors have been disclosed, there is still a need to discover and develop new compounds with better selectivity.

[0005] In view of this, the present invention is proposed. Summary of the invention

[0006] The primary purpose of the present invention is to provide a compound having an unsaturated alkane functional group, as shown in general formula I, II or III, which is found to exhibit excellent JAK3 kinase inhibitory effect and is used to treat a variety of diseases related to abnormal JAK3 kinase activity.

[0007] The present invention provides a compound as shown in formula I or its stereoisomers, tautomers, and pharmaceutically acceptable salts,

[0008]

[0009] Wherein, X is an oxygen atom or -NH-;

[0010] Y is a nitrogen atom or -C(H)=;

[0011] Z is a nitrogen atom or CR 1 ;

[0012] R 0 , R 1 , R A , R B , R C , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 R is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxyl, amino, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, alkynyl; alkyl, aryl and heteroaryl are independently and optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl; or R A and R B , R B and R C Cyclization to form 4 to 8 membered rings;

[0013] n1=0, 1, 2, 3, 4;

[0014] n2=0, 1, 2, 3, 4.

[0015] The present invention also provides a compound as shown in Formula II or its stereoisomers, tautomers, and pharmaceutically acceptable salts,

[0016]

[0017] Wherein, X is an oxygen atom or -NH-;

[0018] Y is a nitrogen atom or -C(H)=;

[0019] Z is a nitrogen atom or CR 1 ;

[0020] R 0 , R 1 , R A , R B , R C , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 R is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxyl, amino, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, alkynyl; alkyl, aryl and heteroaryl are independently and optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl; or R A and R B , R B and R C The ring closure forms a 4- to 8-membered ring.

[0021] The present invention also provides a compound as shown in formula III or its stereoisomers, tautomers, and pharmaceutically acceptable salts,

[0022]

[0023] Where Z is a nitrogen atom or CR 1 ;

[0024] R 1 , R A , R B , R C , R 3 , R 13 , R 14 , R 17 , R 18 , R 19Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxyl, amino, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, alkynyl; alkyl, aryl and heteroaryl are independently and optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl;

[0025] or R A and R B , R B and R C The ring is closed to form a 4- to 8-membered ring. Includes the following structures:

[0026]

[0027] The compounds of the present invention as shown in general formula I, II or III do not include the following structures:

[0028]

[0029] The technical solution provided by the embodiment of the present invention has the following advantages compared with the prior art:

[0030] The embodiment of the present invention provides a novel compound having an unsaturated alkane functional group, which has excellent JAK3 kinase inhibitory effect, high biological activity, better efficacy, and better selectivity, and can be used as a JAK3 kinase inhibitor for treating a variety of diseases associated with abnormal JAK3 kinase activity. DETAILED DESCRIPTION

[0031] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the specification.

[0032] The detailed implementation method of the present invention is shown in the examples. The experimental methods and reagents described in the examples are conventional experimental methods and reagents unless otherwise specified. The following examples are only used to illustrate and explain the present invention, and are not intended to limit the present invention in any way.

[0033] All technical and scientific terms used in this specification have the meanings commonly understood by those of ordinary skill in the art.

[0034] Table 1:

[0035]

[0036] The term "alkyl" refers to a saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms in this article, and further refers to a saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. The term includes straight and branched hydrocarbon groups. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, etc. Alkyl described herein can be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acyloxy, amide, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkyloxy, heterocyclic oxygen, aryloxy, heteroaryloxy, aryl or heteroaryl.

[0037] The term "aryl" herein refers to a 6-10 membered all-carbon monocyclic or fused polycyclic (i.e., a ring that shares adjacent carbon atom pairs) group, a polycyclic (i.e., a ring with adjacent carbon atom pairs) group having a conjugated π electron system. The aryl group can be covalently linked to the defined chemical structure at any carbon atom that produces a stable structure. The aryl group described herein can be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl, and cycloalkoxy.

[0038] The term "heterocyclic group" refers to a ring system containing a nitrogen atom or an oxygen atom, and the ring system can be "connected" to aromatic and non-aromatic ring systems, or linked to other ring systems through a "spiro carbon atom".

[0039] The term "heteroaryl" herein refers to an aromatic group consisting of 5 to 10 atoms and containing at least one heteroatom selected from N, O or S. The term may have a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple fused rings (non-limiting examples include benzothiophene, benzofuran, indole, isoindole, etc.), wherein the fused rings may or may not be aromatic groups containing heteroatoms, provided that the point of attachment is through the atoms of the aromatic heteroaryl group. The heteroaryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl, acyloxy, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl and cycloalkoxy.

[0040] The term "alkenyl" refers to an alkenyl group having 2 to 8 carbon atoms and having at least one alkenyl unsaturated site in this article, and further refers to an alkenyl group having 2 to 6 carbon atoms and having at least one alkenyl unsaturated site. The non-limiting examples of alkenyl include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl, etc. Alkenyl described herein can be optionally substituted with one or more of the following substituents: deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkyloxy, sulfydryl, alkyl sulfydryl, deuterated alkyl sulfydryl, sulfone, sulfoxide, amino, silicon, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester.

[0041] The term "alkynyl" herein refers to an alkyl group having 2 to 8 carbon atoms, wherein two adjacent carbon atoms are connected by a triple bond, and further refers to an alkynyl group having 2 to 6 carbon atoms and having at least one alkynyl unsaturation site. The alkyl group is as defined herein. Alkyl refers to an unsaturated alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, amide, ester, amine, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, cycloalkoxy, mercapto, alkylthiol, deuterated alkylthiol, sulfone, sulfoxide, amino, silicon, phosphono, deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, ester.

[0042] The present invention provides a compound having an unsaturated alkane functional group and exhibiting excellent selective inhibition of JAK3 kinase. Its chemical structure is as shown in Formula I or its stereoisomers, tautomers, and pharmaceutically acceptable salts.

[0043]

[0044] Wherein, X is an oxygen atom or -NH-;

[0045] Y is a nitrogen atom or -C(H)=;

[0046] Z is a nitrogen atom or CR 1 ;

[0047] R 0 , R 1 , R A , R B , RC , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxyl, amino, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, alkynyl; alkyl, aryl and heteroaryl are independently and optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl;

[0048] or R A and R B , R B and R C Cyclization to form 4 to 8 membered rings;

[0049] n1=0, 1, 2, 3, 4;

[0050] n2=0, 1, 2, 3, 4;

[0051] And does not include the following structures:

[0052]

[0053] As an improvement of the embodiment of the present invention, R 0 , R 1 , R A , R B , R C , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19Each is independently hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, C2-C5 heterocyclyl, C1-C6 alkyl substituted with C2-C5 heterocyclyl, C6-C10 aryl, C4-C9 heteroaryl, hydroxyl, amino, phosphorus carbonyl, sulfone; alkyl, aryl and heteroaryl are independently and optionally substituted with one or more of the following substituents: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl.

[0054] As an improvement of the embodiment of the present invention, R A , R B , R C Each is independently a hydrogen atom, a C1-C6 alkyl group or a deuterated C1-C6 alkyl group.

[0055] As an improvement of the embodiment of the present invention, R A , R B , R C Each is independently a hydrogen atom or a C1-C6 alkyl group.

[0056] As an improvement of the embodiment of the present invention, R A , R B , R C Each is independently a hydrogen atom, a methyl group, an ethyl group or a propyl group.

[0057] As an improvement of the embodiment of the present invention, R A It may be a hydrogen atom.

[0058] As an improvement of the embodiment of the present invention, R B It may be a hydrogen atom.

[0059] As an improvement of the embodiment of the present invention, R C It may be a hydrogen atom.

[0060] As an improvement of the embodiment of the present invention, R A , R B , R C It can also be a hydrogen atom.

[0061] As an improvement of the embodiment of the present invention, Y is a nitrogen atom.

[0062] As an improvement to the embodiment of the present invention, n1=1, 2, 3, 4, specifically 1.

[0063] As an improvement to the embodiment of the present invention, n2=1, 2, 3, 4, specifically 1.

[0064] As an improvement of the embodiment of the present invention, R13 and R 14 Among the substituents shown, one represents a C1-C6 alkyl group and the other represents a hydrogen atom;

[0065] As an improvement of the embodiment of the present invention, R 13 and R 14 Among the substituents shown, one of the substituents is a methyl group, an ethyl group or a propyl group, and the other substituent is a hydrogen atom.

[0066] As an improvement of the embodiment of the present invention, R 17 , R 18 , R 19 Each is independently a hydrogen atom, a C1-C6 alkyl group or a deuterated C1-C6 alkyl group.

[0067] As an improvement of the embodiment of the present invention, R 17 , R 18 , R 19 Each is independently a hydrogen atom or a C1-C6 alkyl group.

[0068] As an improvement of the embodiment of the present invention, R 17 , R 18 , R 19 Each is independently a hydrogen atom, a methyl group, an ethyl group or a propyl group.

[0069] As an improvement of the embodiment of the present invention, R 17 When it is a hydrogen atom, R 18 , R 19 It may be other substituents or a hydrogen atom.

[0070] As an improvement of the embodiment of the present invention, R 18 A hydrogen atom.

[0071] As an improvement of the embodiment of the present invention, R 19 A hydrogen atom.

[0072] As an improvement of the embodiment of the present invention, R 17 , R 18 , R 19 All are hydrogen atoms.

[0073] As an improvement of the embodiment of the present invention, R 0 , R 3 Each is independently a hydrogen atom, a C1-C6 alkyl group or a deuterated C1-C6 alkyl group.

[0074] As an improvement of the embodiment of the present invention, R 0 , R 3 Each is independently a hydrogen atom or a C1-C6 alkyl group.

[0075] As an improvement of the embodiment of the present invention, R 0 , R 3 Each is independently a hydrogen atom, a methyl group, an ethyl group or a propyl group.

[0076] As an improvement of the embodiment of the present invention, R 0 A hydrogen atom.

[0077] As an improvement of the embodiment of the present invention, R 3 A hydrogen atom.

[0078] As an improvement of the embodiment of the present invention, the embodiment of the present invention provides a compound as shown in Formula II or its stereoisomers, tautomers, and pharmaceutically acceptable salts,

[0079]

[0080] Wherein, X is an oxygen atom or -NH-;

[0081] Y is a nitrogen atom or -C(H)=;

[0082] Z is a nitrogen atom or CR 1 ;

[0083] R 0 , R 1 , R A , R B , R C , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxyl, amino, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, alkynyl; alkyl, aryl and heteroaryl are independently and optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl;

[0084] or R A and R B , R B and R C Cyclization to form a 4- to 8-membered ring;

[0085] And does not include the following structures:

[0086]

[0087] As an improvement of the embodiment of the present invention, R 0 , R 1 , R A , R B , R C , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, phosphorus carbonyl, sulfone, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, C2-C5 heterocyclyl, C1-C6 alkyl substituted with C2-C5 heterocyclyl, C6-C10 aryl, C4-C9 heteroaryl; alkyl, aryl and heteroaryl are independently and optionally substituted with one or more of the following substituents: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl.

[0088] As an improvement of the embodiment of the present invention, R A , R B , R C Each is independently a hydrogen atom, a C1-C6 alkyl group or a deuterated C1-C6 alkyl group.

[0089] As an improvement of the embodiment of the present invention, R A , R B , R C Each is independently a hydrogen atom or a C1-C6 alkyl group.

[0090] As an improvement of the embodiment of the present invention, R A , R B , R C Each is independently a hydrogen atom, a methyl group, an ethyl group or a propyl group.

[0091] As an improvement of the embodiment of the present invention, R A It may be a hydrogen atom.

[0092] As an improvement of the embodiment of the present invention, R B It may be a hydrogen atom.

[0093] As an improvement of the embodiment of the present invention, R C It may be a hydrogen atom.

[0094] As an improvement of the embodiment of the present invention, R A , R B , R C It can also be a hydrogen atom.

[0095] As an improvement of the embodiment of the present invention, Y may be a nitrogen atom.

[0096] As an improvement of the embodiment of the present invention, in the above formula I and formula II, R A and R B , R B and R C The ring is closed to form a 4- to 8-membered ring. Includes the following structures:

[0097]

[0098] As an improvement of the embodiment of the present invention, R 13 and R 14 Among the substituents shown, one represents a C1-C6 alkyl group and the other represents a hydrogen atom;

[0099] As an improvement of the embodiment of the present invention, R 13 and R 14 Among the substituents shown, one of the substituents is a methyl group, an ethyl group or a propyl group, and the other substituent is a hydrogen atom.

[0100] As an improvement of the embodiment of the present invention, R 17 , R 18 , R 19 Each is independently a hydrogen atom, a C1-C6 alkyl group or a deuterated C1-C6 alkyl group.

[0101] As an improvement of the embodiment of the present invention, R 17 , R 18 , R 19 Each is independently a hydrogen atom or a C1-C6 alkyl group.

[0102] As an improvement of the embodiment of the present invention, R 17 , R 18 , R 19 Each is independently a hydrogen atom, a methyl group, an ethyl group or a propyl group.

[0103] As an improvement of the embodiment of the present invention, R 17 A hydrogen atom.

[0104] As an improvement of the embodiment of the present invention, R 18 A hydrogen atom.

[0105] As an improvement of the embodiment of the present invention, R 19 A hydrogen atom.

[0106] As an improvement of the embodiment of the present invention, R 17 , R 18 , R 19 All are hydrogen atoms.

[0107] As an improvement of the embodiment of the present invention, R 0 , R 3 Each is independently a hydrogen atom, a C1-C6 alkyl group or a deuterated C1-C6 alkyl group.

[0108] As an improvement of the embodiment of the present invention, R 0 , R 3 Each is independently a hydrogen atom or a C1-C6 alkyl group.

[0109] As an improvement of the embodiment of the present invention, R 0 , R 3 Each is independently a hydrogen atom, a methyl group, an ethyl group or a propyl group.

[0110] As an improvement of the embodiment of the present invention, R 0 A hydrogen atom.

[0111] As an improvement of the embodiment of the present invention, R 3 A hydrogen atom.

[0112] As an improvement of the embodiment of the present invention, the embodiment of the present invention provides a compound as shown in Formula III or its stereoisomers, tautomers, and pharmaceutically acceptable salts,

[0113]

[0114] Where Z is a nitrogen atom or CR 1 ;

[0115] R 1 , R A , R B , R C , R 3 , R 13 , R 14 , R 17 , R 18 , R 19R is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxyl, amino, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, alkynyl; alkyl, aryl and heteroaryl are independently and optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl; or R A and R B , R B and R C The ring is closed to form a 4- to 8-membered ring. Includes the following structures:

[0116]

[0117] And does not include the following structures:

[0118]

[0119] As an improvement of the embodiment of the present invention, R 1 , R A , R B , R C , R 3 , R 13 , R 14 , R 17 , R 18 , R 19 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, C2-C5 heterocyclyl, C1-C6 alkyl substituted with C2-C5 heterocyclyl, C6-C10 aryl, C4-C9 heteroaryl; alkyl, aryl and heteroaryl are independently and optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl.

[0120] As an improvement of the embodiment of the present invention, R A , R B , R C Each independently represents a hydrogen atom, a C1-C6 alkyl group or a deuterated C1-C6 alkyl group. As an improvement to the embodiment of the present invention, R A , R B , R C Each is independently a hydrogen atom or a C1-C6 alkyl group.

[0121] As an improvement of the embodiment of the present invention, RA , R B , R C Each is independently a hydrogen atom, a methyl group, an ethyl group or a propyl group.

[0122] As an improvement of the embodiment of the present invention, R A A hydrogen atom.

[0123] As an improvement of the embodiment of the present invention, R B A hydrogen atom.

[0124] As an improvement of the embodiment of the present invention, R C A hydrogen atom.

[0125] As an improvement of the embodiment of the present invention, Z is a nitrogen atom.

[0126] As an improvement of the embodiment of the present invention, R 13 and R 14 Among the substituents shown, one represents a C1-C6 alkyl group and the other represents a hydrogen atom.

[0127] As an improvement of the embodiment of the present invention, R 13 and R 14 Among the substituents shown, one of the substituents is a methyl group, an ethyl group or a propyl group, and the other substituent is a hydrogen atom.

[0128] As an improvement of the embodiment of the present invention, R 17 , R 18 , R 19 Each is independently a hydrogen atom, a C1-C6 alkyl group or a deuterated C1-C6 alkyl group.

[0129] As an improvement of the embodiment of the present invention, R 17 , R 18 , R 19 Each is independently a hydrogen atom or a C1-C6 alkyl group.

[0130] As an improvement of the embodiment of the present invention, R 17 , R 18 , R 19 Each is independently a hydrogen atom, a methyl group, an ethyl group or a propyl group.

[0131] As an improvement of the embodiment of the present invention, R 17 A hydrogen atom.

[0132] As an improvement of the embodiment of the present invention, R 18 A hydrogen atom.

[0133] As an improvement of the embodiment of the present invention, R 19 A hydrogen atom.

[0134] As an improvement of the embodiment of the present invention, R 17 , R 18 , R 19 All are hydrogen atoms.

[0135] The present invention also provides a compound as shown in the following structural formula or its stereoisomers, tautomers, and pharmaceutically acceptable salts,

[0136]

[0137] The present invention also provides a method for preparing the above-mentioned compound. For example, a halogen-substituted 7H-pyrrolo[2,3-D]pyrimidine or 1H-pyrazolo[3,4-d]pyrimidine can be coupled with a substituted piperidine, and then further coupled with a compound having an unsaturated alkane functional group to obtain the compound of the present invention.

[0138] Specifically, the synthetic route of the compound of formula III in the embodiment of the present invention is as follows:

[0139]

[0140]

[0141] SM-1 is used as a starting material, and a coupling reaction is carried out with SM-2 to obtain an intermediate as shown in IM-1, and then a coupling reaction is carried out with SM-3 to obtain an intermediate as shown in IM-2, and deprotection is carried out to obtain an intermediate as shown in IM-3, and finally a coupling reaction is carried out with SM-4 to obtain a compound as shown in III;

[0142] Among them, Z, R 3 , R 13 , R 14 , R 17 , R 18 , R 19 , R A , R B , R C As defined above.

[0143] In the embodiments of the present invention, compounds of the present invention having the same molecular formula but different properties or sequences of their atomic bonds or different spatial arrangements of their atoms are referred to as "isomers". Isomers with different spatial arrangements of atoms are referred to as "stereoisomers". All isomers of the compounds described herein (e.g., cis-, trans-, or diastereomers) alone or in any mixture thereof are included within the scope of the embodiments of the present invention. All of these forms include enantiomers, diastereomers, cis, trans, syn, anti, tautomers, and mixtures thereof. Stereoisomeric mixtures (e.g., mixtures of diastereomers) can be separated into their corresponding isomers in a known manner using suitable separation methods.

[0144] In an embodiment of the present invention, the pharmaceutically acceptable salt of the compound of formula I can include acid addition salts and basic salts. Suitable acid addition salts are formed by the acid that can form non-toxic salts. For example, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclohexanesulfonate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, sucrose acid salt, stearate, succinate, tannate, tartrate. Suitable basic salts are formed by the alkali that forms non-toxic salts. Examples thereof include salts of aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc.

[0145] The present invention also proposes a pharmaceutical composition, which includes a therapeutically effective dose of the above-mentioned compound or its stereoisomer, tautomer or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention can be prepared by methods known in the art. The pharmaceutical composition used in the present invention can be prepared using one or more pharmaceutically acceptable carriers according to conventional methods, and the carrier includes excipients and adjuvants, which are conducive to processing the active compound into a pharmaceutically usable preparation. Suitable preparations depend on the selected route of administration. Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in the scope of the present invention. The pharmaceutical composition of the embodiment of the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and the compounds of the embodiment of the present invention can be present in suitable solid or liquid carriers or diluents. The pharmaceutical composition of the present invention can also be stored in suitable sterile equipment for injection or infusion. Usually, the amount of active ingredient in the pharmaceutical composition is 0.01% by weight to 99% by weight of the pharmaceutical composition.

[0146] The compounds of the embodiments of the present invention or pharmaceutical compositions comprising the compounds of the embodiments of the present invention can be used clinically in mammals (including humans) through oral, nasal, skin, lung or gastrointestinal administration routes. The preferred route of administration is oral. The preferred daily dose is 0.5-200 mg / kg body weight, taken once or in divided doses. Regardless of the method of administration, the optimal dose for an individual should be determined according to the specific treatment. Usually, it starts with a small dose and gradually increases the dose until the most suitable dose is found. The effective dose of the active ingredient used may vary with the compound used, the mode of administration and the severity of the disease to be treated. However, generally, when the compound of the present invention is administered at a dose of about 1-300 mg / kg animal body weight per day, satisfactory results can be obtained, preferably administered in 1-3 divided doses per day, or administered in a sustained release form. For most large mammals, the total daily dose is about 5-1000 mg, preferably about 10-500 mg. A dosage form suitable for oral administration comprises about 1-200 mg of an active compound intimately mixed with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as required by the exigencies of the therapeutic situation.

[0147] The present invention also provides the use of a compound or a pharmaceutical salt thereof or a pharmaceutical composition in the preparation of a drug for treating a disease associated with abnormal JAK kinase activity. Wherein, the JAK kinase is JAK3 kinase, that is, the compound of the embodiment of the present invention can inhibit JAK3 kinase and is used for diseases caused by abnormal activation of JAK3 kinase, and the diseases include autoimmune diseases. Specifically, the diseases include rheumatoid arthritis, alopecia areata, vitiligo, asthma, chronic obstructive pulmonary disease, tumors, Crohn's disease, inflammatory bowel disease of ulcerative colitis, proctitis, eosinophilic gastroenteritis or mastocytosis.

[0148] The present invention also provides a JAK3 kinase inhibitor, which is the compound described in the present invention, such as the above-mentioned compounds 1, 2, and 3.

[0149] The embodiments of the present invention also provide methods for treating or preventing a disease or condition, which include administering an effective amount of a compound comprising an embodiment of the present invention or a pharmaceutically acceptable salt thereof to an individual. The compound of the present invention or its pharmaceutical composition can be administered orally, parenterally, topically, rectally, mucosally or intestinally. Parenteral administration includes indirect injection to produce systemic effects or direct injection to the diseased site. Topical administration includes treatment of the skin or organs (e.g., eyes or ears) that can be easily reached by topical application. Transdermal delivery is also included to produce systemic effects. Rectal administration includes the form of suppositories. Preferred routes of administration are oral and parenteral.

[0150] Preparation Example 1:

[0151]

[0152] first step:

[0153] SM-1 (2.0 g), diisopropylethylamine DMAP (87.4 mg), triethylamine (2.17 g), and 40 mL of dichloromethane were added to the reaction flask in sequence, and p-toluenesulfonyl chloride (1.64 g) was added at room temperature for 2 hours after the addition. The resulting reaction solution was concentrated to dryness under reduced pressure, and then 10 mL of ethanol was added. The mixture was first slurried at room temperature for 0.5 hours, and then slurried in an ice-water bath for 0.5 hours before filtering. The filter cake was washed with petroleum ether, and the filter cake was dried to obtain 3.2 g of a yellow solid, which was the intermediate 1-1. m / z: 433.85 (M+H), 431.95 (MH).

[0154] Step 2:

[0155] Add intermediate 1-1, SM-2 (2.65 g), triethylamine (2.17 g), and 31 mL of acetonitrile to a reaction flask, and heat to 95°C for 4 hours. After the obtained reaction solution was concentrated to dryness under reduced pressure, 50 mL of ethyl acetate was added, stirred for 0.5 hours, and filtered. The filtrate was washed with 1M hydrochloric acid 30 mL×2, 30 mL of saturated sodium chloride, dried with sodium sulfate, and purified by silica gel column after drying to obtain 3.6 g of white solid. m / z: 646.20 (M+H), 644.20 (MH).

[0156] Step 3:

[0157] Intermediate 1-2 (0.7 g), 3-methylbut-2-ene-1,1-diol (162.4 mg), Pd(dppf)Cl 2 (80 mg), potassium phosphate (692 mg), toluene (14 mL), added in one pot, reacted at 90°C for 2.5 hours under nitrogen protection, filtered, the filtrate was concentrated and purified by silica gel column chromatography and thin layer preparation to obtain 440 mg of yellow solid. m / z: 574.20 (M+H), 572.25 (MH).

[0158] Step 4:

[0159] Intermediate 1-3 (440 mg) was dissolved in acetonitrile (4.4 mL), trimethylsilyl iodide (61.4 mg) was added, and the mixture was reacted at room temperature for 1 hour. Triethylamine (201.65 mg) was added, and the mixture was stirred at room temperature for 15 min, and the solvent was removed by concentration, and ethyl acetate (15 mL) was added, and the mixture was washed with saturated sodium bicarbonate solution (15 mL×2), saturated sodium chloride solution (15 mL×1), and dried over anhydrous sodium sulfate. After concentration, 315 mg of yellow solid was obtained by thin layer preparation and purification, which was intermediate 1-4, m / z: 440.35 (M+H), 438.15 (MH).

[0160] Step 5:

[0161] Dissolve intermediate 1-4 (315 mg) in N-methylpyrrolidone (NMP) (0.63 mL), and add potassium hydroxide aqueous solution (KOH 80.36 mg, water 0.315 mL) dropwise. React at 70°C for 15 min. Cool to room temperature, add the system dropwise into 25 mL of water, extract with dichloromethane (25 mL×3), dry with anhydrous sodium sulfate, and concentrate to obtain a NMP solution of the product. m / z: 286.15 (M+H).

[0162] Step 6:

[0163] Add dimethylformamide (0.2 mL), diisopropylethylamine (DIPEA) (111 mg), and acryloyl chloride (26.4 μL) to the NMP solution of intermediate 1-5. React at room temperature for 15 min. Pour into water, precipitate solid, filter, and rinse. Dissolve the filter cake in dichloromethane and purify by thin layer preparation to obtain 14 mg of off-white solid compound 1.

[0164] m / z: 340.20(M+H), 338.20(MH). 1 H NMR (DMSO-d6, 600MHz) δ = 11.60 (s, 1H), 8.12 (s, 1H),

[0165] 6.965~6.963(d,J=1.2Hz,1H),6.82~6.77(dd,J=16.8Hz,J=10.2Hz,1H),6.47(d,J= 1.2Hz, 1H), 6.11~6.08 (dd, J=16.8Hz, J=1.8Hz, 1H), 5.866~5.864 (d, J=1.2Hz, 1H), 5 .68~5.66(dd,J=14.4Hz,J=1.8Hz,1H),4.79~4.09(m,2H),4.03(s,1H),3.18~2.65( m,1H),1.94(s,3H),1.89~1.82(m,2H),1.79(s,3H),1.70~1.60(m,2H),1.21(s,3H).

[0166] Preparation Example 2:

[0167]

[0168] first step:

[0169] Intermediate 1-2 (1.10 g), vinylboronic acid pinacol ester (394 mg), Pd(dppf)Cl 2 (126 mg), potassium phosphate (1.08 mg), toluene (22 mL), added in one pot, reacted at 90°C for 3.5 hours under nitrogen protection, filtered, the filtrate was concentrated and purified by silica gel column chromatography to obtain 650 mg of red solid. m / z: 546.15 (M+H), 544.25 (MH).

[0170] Step 2:

[0171] Intermediate 2-3 (650 mg) was dissolved in acetonitrile (6.5 mL), and trimethylsilyl iodide (525 mg) was added, and the mixture was reacted at room temperature for 1 hour. Triethylamine (349 mg) was added, and the mixture was stirred at room temperature for 10 min. After concentration, the mixture was purified by silica gel column chromatography to obtain 340 mg of a yellow solid. m / z: 412.15 (M+H), 410.15 (MH).

[0172] Step 3:

[0173] Intermediate 2-4 (340 mg) was dissolved in NMP (2 mL), and potassium hydroxide aqueous solution (KOH 93 mg, water 1 mL) was added dropwise, and the mixture was reacted at 70°C for 30 min. The mixture was cooled to room temperature, extracted with dichloromethane (6 mL × 3), washed with saturated sodium chloride aqueous solution (6 mL × 3), dried with anhydrous sodium sulfate, and concentrated to obtain a solution of the product in N-methylpyrrolidone (NMP). m / z: 258.15 (M+H), 256.20 (MH).

[0174] Step 4:

[0175] Add DMF (1 mL), N,N-diisopropylethylamine (356 mg), and acryloyl chloride (9.1 μL) to the NMP solution of intermediate 2-5. React at room temperature for 15 min. Add water to quench, extract with dichloromethane (10 mL × 3), wash with saturated sodium chloride solution (6 mL × 3), dry with anhydrous sodium sulfate, filter, and purify by thin layer preparation to obtain 30 mg of off-white solid compound 2.

[0176] m / z: 312.15(M+H), 310.15(MH). 1 H NMR (DMSO-d6, 600MHz) δ = 11.74 (s, 1H), 8.15 ~ 8.12 (d, J = 18.6Hz, 1H), 7.42 (s, 1H), 7.16 ~ 7.11 ( dd, J=16.8Hz, J=10.8Hz, 1H), 6.80 (s, 1H), 6.20~6.19 (d, J=6.6Hz, 1H), 6.10~6.06 (dd, J=16.8 Hz, J=1.8Hz, 1H), 5.68~5.66 (dd, J=10.8Hz, J=1.8Hz, 1H), 5.59~5.56 (d, J=11.4Hz, 1H), 5.14~ 5.12(d,J=11.4Hz,1H),4.88~4.02(m,3H),3.18~2.76(m,1H),1.85~1.50(m,4H),1.24(s,3H).

[0177] Example: Biological Activity Experiment

[0178] 1. Compound kinase JAK3 activity inhibition test

[0179] The test method is the same as that in the literature (reference: “Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans”, Journal Medicinal Chemistry. 2017, 60, 5, 1971-1993).

[0180] Test method:

[0181] (1) The formulation of the test buffer is shown in Table 2.

[0182] Table 2

[0183] Reagents concentration Hepes 50mM <![CDATA[MgCl 2 ]]> 10mM Brij35 0.01％ EGTA 1mM DTT 2mM <![CDATA[H 2 The]]> /

[0184] (2) The formula of kinase and substrate information is shown in Table 3:

[0185] Table 3

[0186]

[0187] (3) Test process:

[0188] Prepare 2× ATP and substrate solutions and 2× kinase and metal solutions using assay buffer;

[0189] 40 nL of compound was transferred to the 384 assay plate by Echo 655. 2 μL of 2× kinase and metal solution was added, mixed and incubated in the 384 assay plate at 25°C for 10 min;

[0190] 2 μL of 2× substrate and ATP solution was added to the wells and incubated at 25°C for 60 min;

[0191] Add 4 μL of ADP-Glo ​​reagent to the wells and incubate at 25°C for 40 min;

[0192] Add 8 μL of kinase assay reagent to the wells and incubate at 25°C for 40 min;

[0193] Luminescent signals were recorded on a microtiter plate reader.

[0194] Calculation method:

[0195] The inhibition percentage was calculated as follows:

[0196] Inhibition percentage = 100% - (positive control) / (negative control - positive control) × 100%

[0197] Calculation IC 50 And draw the effect-dose curve of the compound:

[0198] IC50s were calculated by fitting the % inhibition values ​​and the logarithm of compound concentration to a non-linear regression (dose response - variable slope) using GraphPad 8.0.

[0199] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×hillslope))

[0200] X: logarithmic value of inhibition concentration; Y: inhibition percentage.

[0201] The test results are shown in Table 4:

[0202] Table 4: IC inhibitory activity of the compounds of the present invention on JAK3 kinase 50 value

[0203] Example Compound No. <![CDATA[IC 50 (nM)]]> 1 2.0 2 3.4 3 5.0

[0204] The above data show that compounds 1, 2, and 3 of the present invention have a good inhibitory effect on JAK3 kinase, and their inhibitory activity on JAK3 kinase is significantly better than the JAK3 inhibitory activity (IC 50 =33 nM). In addition, the activity of compounds 1, 2, and 3 of the present invention against JAK3 is also significantly better than that of compound No. 40 described in WO2015083028A1 (JAK3, IC 50 >10000nM).

[0205] 2. Inhibitory effect of compounds on the activity inhibition of kinase JAK family subtypes

[0206] Test method:

[0207] (1) Prepare 2× ATP / substrate solution and 2× kinase solution using kinase reaction buffer.

[0208] (2) Use Echo 655 to transfer 20 nL of compound dilution to the 384 assay plate; after centrifugation, add 2 μL of 2× kinase and metal ion solution to the 384 assay plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes;

[0209] (3) Add 2 μL of 2× substrate and ATP solution to the 384 assay plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 60 min.

[0210] (4) Transfer 4 μL of ADP-Glo ​​to the 384 assay plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 40 min.

[0211] (5) Transfer 8 μL of the detection solution to a 384-well detection plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 40 min.

[0212] (6) Use a multifunctional microplate reader to read the luminescence signal.

[0213] Data processing method:

[0214] The negative control reading was set as 0% inhibition rate, and the 10000nM Tofacitinib reading was set as 100% inhibition rate.

[0215] The inhibition rate of each test solution was calculated.

[0216]

[0217] Average value of 10000nM Tofacitinib control well ratio

[0218] Average value of negative control well ratio

[0219] The IC of the compound was obtained using the following nonlinear fitting formula: 50 (half inhibitory concentration):

[0220] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope));

[0221] X: log value of compound concentration;

[0222] Y: compound inhibition rate (%inh);

[0223] Z' factor calculation equation:

[0224] Z'=1-3(SDmin+SDmax) / (AVEmax-AVEmin)

[0225] in:

[0226] Min is the positive control Data value, and Max is the negative control DMSO Data value.

[0227] SD is standard error and AVE is mean.

[0228] The test results are shown in Table 5:

[0229] Table 5: IC inhibitory effects of the compounds of the present invention on different kinases 50 Value (nM)

[0230]

[0231] The above data show that Compound 1 and Compound 2 of the present invention have no inhibitory effect on other subtypes of the JAK family (JAK1, JAK2 and TYK2), but the marketed drug Tofacitinib has an inhibitory effect on other subtypes of the JAK family (JAK1, JAK2 and TYK2). The above research results show that Compound 1 and Compound 2 of the present invention have a selective inhibitory effect on the kinase JAK3 of the JAK family, but have no inhibitory effect on other subtypes of the JAK family (JAK1, JAK2 and TYK2), and the marketed drugs do not have the above selectivity. This shows that the compounds of the present invention have potential safety characteristics that are superior to the marketed drug Tofacitinib in future clinical use.

[0232] The above description is only a specific embodiment of the present invention, so that those skilled in the art can understand or implement the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments described herein, but should conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A compound as shown in formula I or its stereoisomers, tautomers, and pharmaceutically acceptable salts, in, X is an oxygen atom or -NH-; Y is a nitrogen atom or -C(H)=; Z is a nitrogen atom or CR 1 ; R 0 , R 1 , R A , R B , R C , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxy, amino, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, alkynyl; The alkyl, aryl and heteroaryl are independently and optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl; or R A and R B , R B and R C Cyclization to form 4 to 8 membered rings; n1＝0、1、2、3、4； n2＝0、1、2、3、4； And does not include the following structures:

2. The compound according to claim 1 or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: R 0 , R 1 , R A , R B , R C , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, phosphorus carbonyl, sulfone, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, C2-C5 heterocyclyl, C2-C5 heterocyclyl-substituted C1-C6 alkyl, C6-C10 aryl, C4-C9 heteroaryl; The alkyl group, the aryl group and the heteroaryl group are independently and optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl.

3. The compound according to claim 1 or 2, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: R A , R B , R C Each is independently a hydrogen atom, a C1-C6 alkyl group or a deuterated C1-C6 alkyl group; Optional, R A , R B , R C Each is independently a hydrogen atom or a C1-C6 alkyl group; Optional, R A , R B , R C are each independently a hydrogen atom, a methyl group, an ethyl group or a propyl group; Optional, R A is a hydrogen atom; Optional, R B is a hydrogen atom; Optional, R C is a hydrogen atom; Optionally, Y is a nitrogen atom; Optionally, X is a nitrogen atom; Optional, n1=1; Optionally, n2=1.

4. The compound according to claim 1 or 2, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: R 13 and R 14 Among the substituents shown, one of the substituents represents a C1-C6 alkyl group and the other substituent is a hydrogen atom; Optional, R 13 and R 14 Among the substituents shown, one of the substituents is a methyl group, an ethyl group or a propyl group, and the other substituent is a hydrogen atom; Optional, R 17 , R 18 , R 19 Each is independently a hydrogen atom, a C1-C6 alkyl group or a deuterated C1-C6 alkyl group; Optional, R 17 , R 18 , R 19 Each is independently a hydrogen atom or a C1-C6 alkyl group; Optional, R 17 , R 18 , R 19 are each independently a hydrogen atom, a methyl group, an ethyl group or a propyl group; Optional, R 17 is a hydrogen atom; Optional, R 18 is a hydrogen atom; Optional, R 19 is a hydrogen atom; Optional, R 0 , R 3 Each is independently a hydrogen atom, a C1-C6 alkyl group or a deuterated C1-C6 alkyl group; Optional, R 0 , R 3 Each is independently a hydrogen atom or a C1-C6 alkyl group; Optional, R 0 , R 3 are each independently a hydrogen atom, a methyl group, an ethyl group or a propyl group; Optional, R 0 is a hydrogen atom; Optional, R 3 A hydrogen atom.

5. A compound as shown in formula II or its stereoisomers, tautomers, and pharmaceutically acceptable salts, in, X is an oxygen atom or -NH-; Y is a nitrogen atom or -C(H)=; Z is a nitrogen atom or CR 1 ; R 0 , R 1 , R A , R B , R C , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxy, amino, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, alkynyl; The alkyl, aryl and heteroaryl are independently and optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl; or R A and R B , R B and R C Cyclization to form 4 to 8 membered rings; And does not include the following structures:

6. The compound according to claim 5 or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: R 0 , R 1 , R A , R B , R C , R 3 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, phosphorus carbonyl, sulfone, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, C2-C5 heterocyclyl, C2-C5 heterocyclyl-substituted C1-C6 alkyl, C6-C10 aryl, C4-C9 heteroaryl; The alkyl group, the aryl group and the heteroaryl group are independently and optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl.

7. The compound according to claim 5 or 6, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: R A , R B , R C Each is independently a hydrogen atom, a C1-C6 alkyl group or a deuterated C1-C6 alkyl group; Optional, R A , R B , R C Each is independently a hydrogen atom or a C1-C6 alkyl group; Optional, R A , R B , R C are each independently a hydrogen atom, a methyl group, an ethyl group or a propyl group; Optional, R A is a hydrogen atom; Optional, R B is a hydrogen atom; Optional, R C is a hydrogen atom; Optionally, Y is a nitrogen atom; Optionally, X is a nitrogen atom.

8. The compound according to claim 6 or 7, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: R 13 and R 14 Among the substituents shown, one represents a C1-C6 alkyl group and the other represents a hydrogen atom; Optional, R 13 and R 14 Among the substituents shown, one of the substituents is a methyl group, an ethyl group, or a propyl group, and the other substituent is a hydrogen atom; Optional, R 17 , R 18 , R 19 Each is independently a hydrogen atom, a C1-C6 alkyl group or a deuterated C1-C6 alkyl group; Optional, R 17 , R 18 , R 19 Each is independently a hydrogen atom or a C1-C6 alkyl group; Optional, R 17 , R 18 , R 19 are each independently a hydrogen atom, a methyl group, an ethyl group or a propyl group; Optional, R 17 is a hydrogen atom; Optional, R 18 is a hydrogen atom; Optional, R 19 is a hydrogen atom; Optional, R 0 , R 3 Each is independently a hydrogen atom, a C1-C6 alkyl group or a deuterated C1-C6 alkyl group; Optional, R 0 , R 3 Each is independently a hydrogen atom or a C1-C6 alkyl group; Optional, R 0 , R 3 are each independently a hydrogen atom, a methyl group, an ethyl group or a propyl group; Optional, R 0 is a hydrogen atom; Optional, R 3 A hydrogen atom.

9. The compound according to any one of claims 1, 2, 6 and 7 or its stereoisomer, tautomer, pharmaceutically acceptable salt, characterized in that: R A and R B , R B and R C The ring is closed to form a 4- to 8-membered ring. Includes the following structures:

10. A compound of formula III or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in, Z is a nitrogen atom or CR 1 ; R 1 , R A , R B , R C , R 3 , R 13 , R 14 , R 17 , R 18 , R 19 Each is independently hydrogen, deuterium, halogen, alkyl, deuterated alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, hydroxy, amino, sulfone, phosphorus carbonyl, substituted silicon, alkenyl, alkynyl; The alkyl, aryl and heteroaryl are independently and optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl; or R A and R B , R B and R C The ring is closed to form a 4- to 8-membered ring. Includes the following structures: And does not include the following structures:

11. The compound according to claim 10 or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: R 1 , R A , R B , R C , R 3 , R 13 , R 14 , R 17 , R 18 , R 19 Each is independently hydrogen, deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, C2-C5 heterocyclyl, C1-C6 alkyl substituted with C2-C5 heterocyclyl, C6-C10 aryl, C4-C9 heteroaryl; The alkyl group, the aryl group and the heteroaryl group are independently and optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl.

12. The compound according to claim 10 or 11, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, characterized in that: R A , R B , R C Each is independently a hydrogen atom, a C1-C6 alkyl group or a deuterated C1-C6 alkyl group; Optional, R A , R B , R C Each is independently a hydrogen atom or a C1-C6 alkyl group; Optional, R A , R B , R C are each independently a hydrogen atom, a methyl group, an ethyl group or a propyl group; Optional, R A is a hydrogen atom; Optional, R B is a hydrogen atom; Optional, R C A hydrogen atom.

13. The compound according to claim 10 or 11, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, characterized in that: R 13 and R 14 Among the substituents shown, one represents a C1-C6 alkyl group and the other represents a hydrogen atom; Optional, R 13 and R 14 Among them, one is a methyl, ethyl or propyl group and the other is a hydrogen atom; Optional, R 17 , R 18 , R 19 Each is independently a hydrogen atom, a C1-C6 alkyl group or a deuterated C1-C6 alkyl group; Optional, R 17 , R 18 , R 19 Each is independently a hydrogen atom or a C1-C6 alkyl group; Optional, R 17 , R 18 , R 19 are each independently a hydrogen atom, a methyl group, an ethyl group or a propyl group; Optional, R 17 is a hydrogen atom; Optional, R 18 is a hydrogen atom; Optional, R 19 A hydrogen atom.

14. A compound represented by the following structural formula or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:

15. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 14 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

16. Use of the compound according to any one of claims 1 to 14, its stereoisomer, tautomer, pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating a disease associated with abnormal JAK kinase activity; Optionally, the JAK kinase is JAK3 kinase; Optionally, the disease is an autoimmune disease; Optionally, the disease includes rheumatoid arthritis, alopecia areata, vitiligo, asthma, chronic obstructive pulmonary disease, tumors, Crohn's disease, inflammatory bowel disease of ulcerative colitis, proctitis, eosinophilic gastroenteritis and mastocytosis. 17 . A JAK3 kinase inhibitor, which is a compound according to any one of claims 1 to 14.

18. A method for preparing the compound according to any one of claims 1 to 4, characterized in that: The following steps are involved: SM-1 is used as a starting material, and a coupling reaction is carried out with SM-2 to obtain an intermediate as shown in IM-1, and then a coupling reaction is carried out with SM-3 to obtain an intermediate as shown in IM-2, and deprotection is carried out to obtain an intermediate as shown in IM-3, and finally a coupling reaction is carried out with SM-4 to obtain a compound as shown in III; Among them, Z, R 3 , R 13 , R 14 , R 17 , R 18 , R 19 , R A , R B , R C As defined above.

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