2, 4-diaminopyrimidine compound and application thereof

Abstract

The invention relates to the field of medicinal chemistry, in particular to a 2, 4-diaminopyrimidine compound and application thereof in preparation of drugs for treating and / or preventing diseases mediated by a JAK family. The compound is a compound as shown in a general formula I, and a stereoisomer and pharmaceutically acceptable salt thereof, wherein substituent groups R1, R2, L and ring A have meanings given in the specification. The invention further relates to application of the compound shown in the general formula I in preparation of drugs for treating and / or preventing diseases mediated by the JAK family. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a 2,4-diaminopyrimidine compound and an application thereof in preparing a drug for treating and / or preventing diseases mediated by the JAK family. Background Art

[0002] Janus kinases (JAKs), as a cytoplasmic non-receptor tyrosine kinase, are an important component of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. The JAK-STAT signaling pathway is considered to be one of the central communication nodes of cell function, and more than 50 cytokines and growth factors such as hormones, interferon (IFN), interleukin (IL) and colony stimulating factor have been found to be involved in it, affecting a variety of downstream physiological activities including hematopoiesis, immune adaptability, tissue repair, inflammation, apoptosis and adipogenesis. The main pathway of the JAK-STAT signaling pathway is: after extracellular cytokines bind to receptors, they activate JAKs coupled to the receptors. After activation, 2-3 JAK molecules combine to form aggregates. After further enhancing the kinase activity through tyrosine residue autophosphorylation, the downstream STAT is phosphorylated. The activated STAT forms a dimer and enters the cell nucleus to regulate the transcription of the corresponding gene. Due to its wide range of cellular functions, the dysregulation of the JAK-STAT signaling pathway is associated with a variety of diseases.

[0003] The JAK family consists of four members: JAK1, JAK2, JAK3, and TYK2. JAK1, JAK2, and TYK2 are expressed in all tissues and cells of the human body, while JAK3 is mainly expressed in bone marrow cells, thymocytes, NK cells, and activated B and T lymphocytes. In the JAK-STAT signaling pathway, the JAK1 subtype is the common core of multiple pathways and is the only subtype that can form heterodimers with all three JAKs and can phosphorylate all STATs. Studies have found that JAK1 can be phosphorylated by a variety of cytokine receptor families: (1) Cytokine receptors with γ-c receptor subunits include IL-2 receptor, IL-4 receptor, IL-7 receptor, IL-9 receptor and IL-15 receptor; (2) Class II cytokine receptors include IFN-α / β receptor, IFN-γ receptor and IL-10 family cytokine receptor; (3) Receptors with gp130 subunits include IL6 receptor, IL-11 receptor, ciliary neurotrophic factor (CNTF) receptor, oncostatin M (OSM) receptor, leukemia inhibitory factor (LIF) receptor and cardiotrophic factor-1 (CT-1) receptor. JAK1 plays a major role in the signaling of γ-c receptor cytokines and proinflammatory cytokines and is closely related to diseases such as inflammation, cancer and immunity. Moreover, JAK1 dysfunction can lead to severe inflammation, autoimmune diseases, etc. Therefore, JAK1 has received extensive attention in recent years.

[0004] Early drug discovery focused on developing pan-JAK inhibitors and applying them to the treatment of inflammatory and autoimmune diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and atopic dermatitis (AD). However, recent clinical data analysis of JAK inhibitors found that long-term use of existing pan-JAK inhibitors increases the risk of thrombosis and heart-related problems as well as serious infections. For example, Tofacitinib, as a pan-JAK inhibitor, can lead to side effects such as hematopoiesis and bone marrow differentiation disorders when taken for a long time; Baricitinib, a potent inhibitor of JAK1 and JAK2, increases the risk of serious infections and thrombosis; Upadacitinib is a potent JAK1 inhibitor that only exhibits 4 times the selectivity of JAK2 in in vitro binding experiments, which may increase the risk of infections such as herpes zoster.

[0005]

[0006] Selective JAK1 inhibitors can not only specifically regulate biological functions related to JAK1, but also do not affect other JAK-dependent signals, and significantly reduce the risk of side effects compared with pan-JAK or dual-JAK inhibitors. In the present invention, the inventors have discovered a class of compounds with selective JAK1 inhibition. Summary of the invention

[0007] The present invention aims to provide a novel 2,4-diaminopyrimidine derivative and application thereof.

[0008] To achieve the above purpose, the present invention adopts the following technical solution:

[0009] A 2,4-diaminopyrimidine compound, characterized in that the compound is a compound represented by general formula I, a stereoisomer thereof and a pharmaceutically acceptable salt thereof,

[0010]

[0011] in,

[0012] L is selected from

[0013] W is N or CH;

[0014] m and n are independently selected from 1, 2 or 3;

[0015] p, q and s are each independently selected from 0, 1 or 2;

[0016] R 1 is hydrogen, halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, cyano, nitro;

[0017] R 2 is (C3-C8) cycloalkyl, 4-10 membered heterocyclic group, (C6-C 10 ) aryl, 5-10 membered heteroaryl, the cycloalkyl, heterocyclic, aryl or heteroaryl may be optionally substituted by 1-3 identical or different R 3 replace;

[0018] R 3 is hydroxy, halogen, amino, mercapto, cyano, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C1-C6)alkylacyl, (C1-C6)haloalkylacyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylamido, free, salified, esterified and amidated carboxyl, (C1-C6)alkyl or (C1-C6)alkoxy which is unsubstituted or substituted by at least one hydroxy, amino, cyano or halogen , amino substituted by 1-2 identical or different (C1-C6) alkyl or (C3-C8) cycloalkyl groups, carbamoyl unsubstituted or substituted by 1-2 identical or different (C1-C6) alkyl groups, 4-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the heterocyclyl and heteroaryl groups may be optionally substituted by 1-3 identical or different substituents selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, (C1-C4) haloalkyl, hydroxy, halogen, cyano;

[0019] A is selected from

[0020] R 4 is hydrogen, halogen, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, wherein the alkyl and alkoxy are optionally substituted by 1-3 identical or different halogens;

[0021] z is 1, 2 or 3, and when z is 2 or 3, R 4 Can be the same or different;

[0022] X is CH2, NR 5 or O;

[0023] t is selected from 1 or 2;

[0024] R 5 is hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, or 4-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted by 1-3 identical or different substituents selected from hydrogen, halogen, hydroxyl, cyano, or (C3-C6) cycloalkyl;

[0025] R 6 is hydrogen, (C1-C6) alkyl;

[0026] The heterocyclic group and heteroaryl group involved in the above substituents optionally contain 1-4 identical or different heteroatoms selected from N, O or S, wherein the heterocyclic group optionally includes 1-2 double bonds.

[0027] Preferably, the compound of formula I, its stereoisomers and pharmaceutically acceptable salts thereof,

[0028] in,

[0029] L is selected from

[0030] W is N or CH;

[0031] m and n are independently selected from 1, 2 or 3;

[0032] p, q and s are each independently selected from 0, 1 or 2;

[0033] R 1 is hydrogen, halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, cyano;

[0034] R 2 is (C3-C6) cycloalkyl, 4-10 membered heterocyclic group, (C6-C 10 ) aryl, 5-10 membered heteroaryl, the cycloalkyl, heterocyclic, aryl or heteroaryl may be optionally substituted by 1-3 identical or different R3 replace;

[0035] R 3 is hydroxy, halogen, cyano, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C7)cycloalkyl, (C1-C4)alkylacyl, (C1-C4)haloalkylacyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylamido, free, salified, esterified and amidated carboxyl, (C1-C4)alkyl or (C1-C4)alkoxy which is unsubstituted or substituted by at least one hydroxy, amino, cyano or halogen, an amino group substituted with 1-2 identical or different (C1-C4) alkyl or (C3-C7) cycloalkyl groups, a carbamoyl group which is unsubstituted or substituted with 1-2 identical or different (C1-C4) alkyl groups, a 4-10 membered heterocyclyl group or a 5-10 membered heteroaryl group, wherein the heterocyclyl group and the heteroaryl group are optionally substituted with 1-3 identical or different substituents selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, (C1-C4) haloalkyl, hydroxy, halogen, and cyano;

[0036] A is selected from

[0037] R 4 is hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, cyano, wherein the alkyl and alkoxy are optionally substituted by 1-3 identical or different halogens;

[0038] z is 1, 2 or 3, and when z is 2 or 3, R 4 Can be the same or different;

[0039] X is CH2, NR 5 or O;

[0040] t is selected from 1 or 2;

[0041] R 5 is hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, or 4-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally further substituted by 1-3 identical or different substituents selected from hydrogen, halogen, hydroxyl, cyano, or (C3-C4) cycloalkyl;

[0042] R 6 is hydrogen, (C1-C4) alkyl;

[0043] The heterocyclic group and heteroaryl group involved in the above substituents optionally contain 1-4 identical or different heteroatoms selected from N, O or S, wherein the heterocyclic group optionally includes 1-2 double bonds.

[0044] It is further preferred that the compound of formula I, its stereoisomers and pharmaceutically acceptable salts thereof,

[0045] in,

[0046] L is selected from

[0047] W is N or CH;

[0048] m and n are independently selected from 1, 2 or 3;

[0049] R 1 is hydrogen, halogen, methyl, ethyl, trifluoromethyl;

[0050] R 2 is (C3-C6) cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, phenyl or heteroaryl is optionally substituted by 1-3 identical or different R 3 replace;

[0051] R 3 is hydroxy, halogen, cyano, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C7)cycloalkyl, (C1-C4)alkylacyl, (C1-C4)haloalkylacyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylamido, free, salified, esterified and amidated carboxyl, (C1-C4)alkyl or (C1-C4)alkoxy which is unsubstituted or substituted by at least one hydroxy, amino, cyano or halogen, amino substituted by 1-2 identical or different (C1-C4) alkyl or (C3-C7) cycloalkyl groups, carbamoyl unsubstituted or substituted by 1-2 identical or different (C1-C4) alkyl groups, 4-8 membered heterocyclyl or 5-10 membered heteroaryl, wherein the heterocyclyl and heteroaryl groups are optionally substituted by 1-3 identical or different substituents selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, (C1-C4) haloalkyl, hydroxy, halogen, cyano;

[0052] A is selected from

[0053] R 4 is hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, wherein the alkyl and alkoxy are optionally substituted by 1-3 identical or different halogens;

[0054] X is CH2, NR 5 or O;

[0055] t is selected from 1 or 2;

[0056] R 5It is hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, 4-6 membered heterocyclyl, and the alkyl, cycloalkyl, heterocyclyl is optionally further substituted by 1-3 identical or different substituents selected from hydrogen, halogen, cyano, (C3-C4) cycloalkyl.

[0057] R 6 is hydrogen, (C1-C4) alkyl;

[0058] The heterocyclic group and heteroaryl group involved in the above substituents optionally contain 1-4 identical or different heteroatoms selected from N, O or S, wherein the heterocyclic group optionally includes 1-2 double bonds.

[0059] Still further preferably, the compound of formula I, its stereoisomers and pharmaceutically acceptable salts thereof,

[0060] in,

[0061] L is selected from

[0062] W is N or CH;

[0063] m and n are independently selected from 1, 2 or 3;

[0064] R 1 is hydrogen, halogen, methyl, ethyl, trifluoromethyl;

[0065] R 2 is a 4-10 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group, wherein the heterocyclic group, the phenyl group, or the heteroaryl group is optionally substituted by 1-3 identical or different R 3 replace;

[0066] R 3 is halogen, cyano, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C7)cycloalkyl, (C1-C4)alkylacyl, (C1-C4)haloalkylacyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylamido, free, salified, esterified and amidated carboxyl, (C1-C4)alkyl or (C1-C4)alkoxy which is unsubstituted or substituted by at least one hydroxyl, amino, cyano or halogen, an amino group substituted with 1-2 identical or different (C1-C4) alkyl or (C3-C7) cycloalkyl groups, a carbamoyl group which is unsubstituted or substituted with 1-2 identical or different (C1-C4) alkyl groups, a 4-6 membered heterocyclyl group or a 5-6 membered heteroaryl group, wherein the heterocyclyl group and the heteroaryl group are optionally substituted with 1-3 identical or different substituents selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, (C1-C4) haloalkyl, hydroxy, halogen, and cyano;

[0067] A is selected from

[0068] R 4 is hydrogen, halogen, (C1-C4) alkyl, the alkyl being optionally substituted by 1-3 identical or different halogens;

[0069] X is CH2, NR 5 or O;

[0070] t is selected from 1 or 2;

[0071] R 5 is hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, or 4-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally further substituted by 1-3 identical or different substituents selected from hydrogen, halogen, cyano, or (C3-C4) cycloalkyl;

[0072] R 6 is hydrogen, methyl or ethyl;

[0073] The heterocyclic group and heteroaryl group involved in the above substituents optionally contain 1-4 identical or different heteroatoms selected from N, O or S, wherein the heterocyclic group optionally includes 1-2 double bonds.

[0074] More preferably, the compound of formula I, its stereoisomers and pharmaceutically acceptable salts thereof,

[0075] in,

[0076] L is selected from

[0077] W is N or CH;

[0078] R 1 is hydrogen, halogen, methyl, ethyl, trifluoromethyl;

[0079] R 2 is a 4-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group, wherein the heterocyclic group, the phenyl group, or the heteroaryl group is optionally substituted by 1-3 identical or different R 3 replace;

[0080] R 3is halogen, cyano, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C7)cycloalkyl, (C1-C4)alkylacyl, (C1-C4)haloalkylacyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylamido, free, salified, esterified and amidated carboxyl, (C1-C4)alkyl or (C1-C4)alkoxy which is unsubstituted or substituted by at least one hydroxyl, amino, cyano or halogen, an amino group substituted with 1-2 identical or different (C1-C4) alkyl or (C3-C7) cycloalkyl groups, a carbamoyl group which is unsubstituted or substituted with 1-2 identical or different (C1-C4) alkyl groups, a 4-6 membered heterocyclyl group or a 5-6 membered heteroaryl group, wherein the heterocyclyl group and the heteroaryl group are optionally substituted with 1-3 identical or different substituents selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, (C1-C4) haloalkyl, hydroxy, halogen, and cyano;

[0081] A is selected from

[0082] R 4 is hydrogen, halogen, methyl, ethyl, trifluoromethyl;

[0083] X is CH2, NR 5 or O;

[0084] t is selected from 1 or 2;

[0085] R 5 is hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, or 4-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally further substituted by 1-3 identical or different substituents selected from hydrogen, halogen, cyano, or (C3-C4) cycloalkyl;

[0086] The heterocyclic group and heteroaryl group involved in the above substituents optionally contain 1-4 identical or different heteroatoms selected from N, O or S, wherein the heterocyclic group optionally includes 1-2 double bonds.

[0087] Still further preferably, the compound of formula I, its stereoisomers and pharmaceutically acceptable salts thereof,

[0088] in,

[0089] L is selected from

[0090] R 1 is hydrogen, halogen, methyl, trifluoromethyl;

[0091] R 2is a 4-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group, wherein the heterocyclic group, the phenyl group, or the heteroaryl group is optionally substituted by 1-3 identical or different R 3 replace;

[0092] R 3 is halogen, cyano, (C2-C4)alkynyl, (C3-C7)cycloalkyl, (C1-C4)alkylacyl, (C1-C4)haloalkylacyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylamido, free, salified, esterified and amidated carboxyl, (C1-C4)alkyl or (C1-C4)alkoxy which is unsubstituted or substituted with at least one hydroxyl, amino, cyano or halogen, substituted with 1 to 2 identical or different (C1-C4)alkyl groups. amino, unsubstituted or substituted by 1-2 identical or different (C1-C4) alkyl groups, (C3-C7) cycloalkyl groups, carbamoyl groups which are unsubstituted or substituted by 1-2 identical or different (C1-C4) alkyl groups, 4-6 membered heterocyclyl groups or 5-6 membered heteroaryl groups, wherein the heterocyclyl groups and heteroaryl groups are optionally substituted by 1-3 identical or different substituents selected from (C1-C4) alkyl groups, (C1-C4) alkoxy groups, (C3-C6) cycloalkyl groups, (C1-C4) haloalkyl groups, hydroxy groups, halogen groups, and cyano groups;

[0093] A is selected from

[0094] R 4 is hydrogen, halogen;

[0095] X is CH2, NR 5 or O;

[0096] t is selected from 1 or 2;

[0097] R 5 is hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, or 4-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally further substituted by 1-3 identical or different substituents selected from hydrogen, halogen, cyano, or (C3-C4) cycloalkyl;

[0098] The heterocyclic group and heteroaryl group involved in the above substituents optionally contain 1-4 identical or different heteroatoms selected from N, O or S, wherein the heterocyclic group optionally includes 1-2 double bonds.

[0099] Still further preferably, the compound of formula I, its stereoisomers and pharmaceutically acceptable salts thereof,

[0100] in,

[0101] L is selected from

[0102] R 1 is hydrogen, halogen, methyl;

[0103] R 2 is a 5-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group, wherein the heterocyclic group, the phenyl group, or the heteroaryl group is optionally substituted by 1-3 identical or different R 3 replace;

[0104] R 3 is halogen, cyano, (C3-C7)cycloalkyl, (C1-C4)alkylacyl, (C1-C4)haloalkylacyl, (C1-C4)alkylsulfonyl, (C1-C4)alkyl or (C1-C4)alkoxy which is unsubstituted or substituted with at least one hydroxyl, amino, cyano or halogen, amino substituted with 1-2 identical or different (C1-C4)alkyl or (C3-C7)cycloalkyl groups, carbamoyl which is unsubstituted or substituted with 1-2 identical or different (C1-C4)alkyl groups, 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the heterocyclyl and heteroaryl groups are optionally substituted with 1-3 identical or different substituents selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, halogen and cyano;

[0105] A is selected from

[0106] R 4 is hydrogen, halogen;

[0107] X is CH2, NR 5 or O;

[0108] R 5 is hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, the alkyl, cycloalkyl, optionally further substituted by 1-3 identical or different substituents selected from hydrogen and halogen;

[0109] The heterocyclic group and heteroaryl group involved in the above substituents optionally contain 1-4 identical or different heteroatoms selected from N, O or S, wherein the heterocyclic group optionally includes 1-2 double bonds.

[0110] Most preferably, the compound of general formula I is the following compound and its stereoisomers and pharmaceutically acceptable salts:

[0111] N-(4-acetylphenyl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0112] N-(4-acetylphenyl)-3-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)pyrrolidine-1-carboxamide;

[0113] N-(4-acetylphenyl)-3-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)azetidine-1-carboxamide;

[0114] N-(4-acetylphenyl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)azepane-1-carboxamide;

[0115] N-(4-acetylphenyl)-3-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)-8-azabicyclo[3.2.1]octane-8-carboxamide;

[0116] N-(4-methoxyphenyl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0117] N-(4-chlorophenyl)-4-(5-chloro-2-((1-oxoisoindol-5-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxamide;

[0118] N-cyclohexyl-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0119] N-(4-acetylphenyl)-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0120] N-(4-acetylphenyl)-4-({5-chloro-2-[(2-ethyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0121] N-(4-acetylphenyl)-4-({5-chloro-2-[(2-cyclopropyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0122] N-[4-(1H-1,2,4-triazol-1-yl)phenyl]-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0123] N-[4-(1H-imidazol-1-yl)phenyl]-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0124] N-[4-(Methylsulfonyl)phenyl]-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)-piperidine-1-carboxamide;

[0125] N-(4-cyanophenyl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0126] N-(5-acetylpyridin-2-yl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0127] N-[1-(2,2,2-trifluoroacetyl)piperidin-4-yl]-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0128] N-(1-methyl-1H-pyrazol-4-yl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0129] N-(thiazol-2-yl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0130] N-(2-aminobenzo[d]thiazol-6-yl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0131] N-(4-acetyl-2-fluorophenyl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0132] N-(4-acetyl-2-methylphenyl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0133] N-(4-acetyl-2-chlorophenyl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0134] N-(4-acetyl-2-fluorophenyl)-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0135] N-(4-acetyl-2-fluorophenyl)-4-({5-fluoro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0136] N-(4-Acetyl-2-fluorophenyl)-4-({5-methyl-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide

[0137] N-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0138] N-(1-methylpiperidin-4-yl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0139] N-[1-(Cyclopropylmethyl)piperidin-4-yl]-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0140] N-(1-methylpiperidin-4-yl)-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0141] N-[1-(2-fluoroethyl)piperidin-4-yl]-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0142] N-[1-(2-fluoroethyl)piperidin-4-yl]-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0143] (S)-N-[1-(2-fluoroethyl)pyrrolidin-3-yl]-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0144] (R)-N-[1-(2-fluoroethyl)pyrrolidin-3-yl]-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0145] (R)-N-[1-(2-fluoroethyl)pyrrolidin-3-yl]-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0146] N-[1-(2-fluoroethyl)azepan-4-yl]-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0147] N-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0148] N-((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)-piperidine-1-carboxamide;

[0149] N-((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)-piperidine-1-carboxamide;

[0150] N-((3S,4R)-3-fluoro-1-ethylpiperidin-4-yl)-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0151] N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-((5-chloro-2-{[2-(2,2,2-trifluoroethyl)-1-oxoisoindol-5-yl]amino}pyrimidin-4-yl)amino)piperidine-1-carboxamide;

[0152] N-(4-acetylphenyl)-4-({5-chloro-2-[(2-methyl-1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0153] N-[1-(2-fluoroethyl)piperidin-4-yl]-4-({5-chloro-2-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0154] N-(4-acetylphenyl)-4-({5-chloro-2-[(2-methyl-1,3-dioxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0155] N-(4-acetylphenyl)-4-({5-chloro-2-[(2-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0156] N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-({5-chloro-2-[(1-oxo-2,3-dihydro-1H-inden-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0157] N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-({5-chloro-2-[(1-oxo-1,3-dihydroisobenzofuran-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0158] N-((3S,4R)-3-fluoro-1-ethylpiperidin-4-yl)-4-({5-chloro-2-[(6-fluoro-2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide;

[0159] cis-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)cyclohexane-1-carboxamide;

[0160] trans-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)cyclohexane-1-carboxamide;

[0161] cis-N-(4-acetyl-2-fluorophenyl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)cyclohexane-1-carboxamide.

[0162] Unless otherwise indicated, the term "halogen" used in the present invention refers to fluorine, chlorine or bromine; "alkyl" refers to straight-chain or branched alkyl; "cycloalkyl" refers to substituted or unsubstituted cycloalkyl; "alkoxy" refers to straight-chain or branched alkoxy; "aryl" refers to phenyl or naphthyl with no or substituted groups; "heteroaryl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, and the ring system is aromatic, such as pyridyl, pyrazolyl, imidazolyl, furanyl, thienyl , pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, etc.; "heterocyclic group" refers to a monocyclic or bridged ring system containing one or more heteroatoms selected from N, O, and S, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, etc.

[0163] The salt of the compound of general formula I is a salt formed by the compound of general formula I and an acid, wherein the acid is selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid or aspartic acid.

[0164] A pharmaceutical composition comprising the compound of general formula I, its stereoisomers and pharmaceutically acceptable salts thereof.

[0165] The present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the present invention are derivatives of general formula I, which may themselves have weak activity or even no activity, but after administration, are converted into the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis or other means).

[0166] The present invention also includes a pharmaceutical composition comprising a compound of formula I and their pharmaceutically acceptable salts and / or solvates as an active ingredient and a pharmaceutically acceptable carrier; the compounds of the present invention may also be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.

[0167] The carriers used in the pharmaceutical composition of the present invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, cosolvents, diluents, stabilizers, suspending agents, pigments, flavoring agents, etc. for oral preparations; pH regulators, osmotic pressure regulators, solubilizers, stabilizers, etc. for injectable preparations; bases, diluents, lubricants, preservatives, etc. for local preparations. The pharmaceutical preparations can be administered orally, parenterally (e.g., intravenously, subcutaneously, intraperitoneally, etc.) or topically (e.g., ocular, nasal, sublingual, skin, etc.), and if some drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0168] The exact amount of the compound of the invention required to treat a disease mediated by the JAK family will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the disease being treated, the specific compound used and the mode of administration, such as the route and frequency of administration, etc. An appropriate effective amount can be determined by one of ordinary skill in the art using only routine experimentation.

[0169] The diseases include immune system diseases, autoimmune diseases, skin diseases, allergic diseases, viral diseases, type I diabetes and diabetic complications, Alzheimer's disease, dry eye disease, non-infectious uveitis, myelofibrosis, thrombocytosis, polycythemia, leukemia and cancer. The immune system disease is organ transplant rejection, such as allogeneic rejection or graft-versus-host disease; the autoimmune disease is selected from systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, ankylosing spondylitis, ulcerative colitis, Crohn's disease or autoimmune The present invention relates to an immunomodulatory agent comprising: an immunomodulatory agent comprising: an immunomodulatory agent comprising: an immunomodulatory agent comprising: an immunomodulatory agent comprising: a psoriasis, a rash, alopecia areata or atopic dermatitis; the allergic disease is selected from asthma or rhinitis; the viral disease is selected from hepatitis B, hepatitis C, varicella, and herpes zoster virus; the cancer is selected from solid tumors, blood cancers or skin cancers, the solid tumors are selected from prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma or melanoma, the blood cancer is selected from lymphoma or leukemia, and the skin cancer is selected from cutaneous T-cell lymphoma or cutaneous B-cell lymphoma.

[0170] The dosage of the compound can be from about 0.1 to 100 mg / kg body weight per day, preferably 1 to 50 mg / kg body weight per day. It is understood that the dosage can vary depending on the patient's needs, the severity of the immune system, autoimmunity and other diseases being treated, and the specific compound used. Moreover, it is understood that the initial dose administered can be increased beyond the upper limit in order to quickly reach the required blood level, or the initial dose can be less than the optimal value, and the daily dose can be gradually increased during treatment, depending on the specific situation. If necessary, the daily dose can also be divided into multiple doses, for example 2-4 times a day.

[0171] Mammal means a human or an animal.

[0172] The amount of active ingredient, i.e. the compound according to the invention, in the pharmaceutical composition and its unit dosage form may vary, depending on the specific application, the efficacy of the specific compound and the desired concentration. Generally speaking, the content of the active ingredient will be between 0.5% and 90%, based on the total weight of the composition.

[0173] In combination therapy, the compound of the present invention and other compounds may be administered simultaneously or separately. When administered simultaneously, the compound of the present invention and other compounds may be combined in a single pharmaceutical composition or in separate compositions.

[0174] The examples and preparations provided below further illustrate and illustrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparations does not limit the scope of the present invention in any way.

[0175] The following synthetic routes describe the preparation of the derivatives of formula I of the present invention, all starting materials being prepared by the methods described in these schemes, by methods well known to those skilled in the art of organic chemistry, or commercially available. All final compounds of the present invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those skilled in the art of organic chemistry. All variables used in these schemes are as defined below or as defined in the claims.

[0176] According to the general formula I derivatives of the present invention, in this synthetic route, the following compounds are taken as examples: 1 , R 2 , R 4 , R 5 , m, n, z and ring A are as defined in the claims.

[0177] When L is Ring A is The key intermediate G can be synthesized according to route 1, some compounds II-i in the general formula can be synthesized through route 2, and some compounds III-i in the general formula can be synthesized through route 3:

[0178]

[0179] Route 1: Synthesis of key intermediate G

[0180] In route 1, intermediate A is subjected to esterification, bromination, cyclization and reduction to obtain intermediate E; intermediate H and K are subjected to nucleophilic substitution to obtain intermediate L, and intermediate E is further subjected to nucleophilic substitution and de-Boc protection to obtain intermediate G.

[0181]

[0182] Route 2 Synthesis of Compound Ⅱ-i

[0183] In route 2, intermediate Ⅱ-1 is substituted with phenyl chloroformate to obtain intermediate Ⅱ-2, which is then reacted with intermediate G to form urea to obtain the target compound Ⅱ-i.

[0184]

[0185] Route 3 Synthesis of Compound III-i

[0186] In route three, intermediate III-1 and G are directly reacted with CDI to form urea to obtain the target compound III-i.

[0187] When L is When ring A is other heterocyclic rings, some compounds IV-i in the general formula can be synthesized according to route 4:

[0188]

[0189] Route 4 Synthesis of Compound IV-i

[0190] In route 4, intermediate Ⅳ-1 is subjected to nucleophilic substitution to obtain intermediate Ⅳ-2, which is then subjected to Buchwald-Hartwig coupling, de-Boc protection, and urea formation to obtain the target compound Ⅳ-i.

[0191] When L is Some compounds V-i in the general formula can be synthesized according to route 5:

[0192]

[0193] Route 5 Synthesis of Compound Ⅴ-i

[0194] In route five, intermediate V-1 undergoes two-step substitution or Buchwald-Hartwig coupling to obtain intermediate V-3, which is then subjected to ester hydrolysis and amide condensation to obtain the target compound V-i. DETAILED DESCRIPTION

[0195] In the following examples, methods for preparing some of the compounds are described. It should be understood that the following methods and other methods known to those of ordinary skill in the art can be applied to the preparation of all compounds described in the present invention. The examples are intended to illustrate rather than limit the scope of the present invention. The H NMR spectra of the compounds were measured using a Bruker ARX-600, and the mass spectra were measured using an Agilent 1100 LC / MSD; all reagents used were analytically pure or chemically pure.

[0196] Example 1. Preparation of N-(4-acetylphenyl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide

[0197] 1.1 Synthesis of N-(4-acetylphenyl)phenylcarbamate (Ⅱ-2)

[0198] At room temperature, 4-aminoacetophenone (20 g, 148 mmol) and sodium carbonate (9.42 g, 88.8 mmol) were added to a mixed solution of ethyl acetate-tetrahydrofuran-water (V:V:V=3:1:1, 200 mL), and phenyl chloroformate (21.3 mL, 178 mmol) was added dropwise under ice bath, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, water (100 mL) was added to the residue, the pH was adjusted to 5 with 1 M hydrochloric acid solution, and the filter cake was washed with water (100 mL) and dried to obtain 30 g of a white solid with a yield of 81.1%.

[0199] 1.2 Synthesis of methyl 4-nitro-2-methylbenzoate (B)

[0200] At room temperature, 4-nitro-2-methylbenzoic acid (50g, 276.1mmol) was added to 400mL methanol, and 50mL concentrated sulfuric acid was slowly added dropwise under ice bath. After the addition, the mixture was stirred evenly and heated to reflux for 12h. After the reaction was completed, the reaction solution was cooled to room temperature and slowly poured into 1.2L ice water. The pH was adjusted to 6-7 with saturated sodium carbonate aqueous solution, stirred for 30min, filtered, and the filter cake was washed with ice water (50mL×2) and dried to obtain 51.3g of white solid with a yield of 95.2%.

[0201] 1.3 Synthesis of methyl 2-(bromomethyl)-4-nitrobenzoate (C)

[0202] At room temperature, add 4-nitro-2-methylbenzoic acid methyl ester (30g, 153.7mmol), NBS (32.8g, 184.4mmol) and AIBN (5g, 30.7mmol) to 400mL carbon tetrachloride, stir evenly, and heat to reflux for 12h. After the reaction is completed, the reaction solution is cooled to room temperature, the carbon tetrachloride in the reaction solution is evaporated, and the residue is dissolved in 300mL methanol. Diethyl phosphite (10.9mL, 84.5mmol) and DIPEA (14.5mL, 92.2mmol) are added to the reaction solution, stirred evenly, and heated to 40℃ for overnight reaction. After the reaction is completed, the reaction solution is cooled to room temperature, poured into 1L ice water, and stirred for 30min. Extract with ethyl acetate (3×600mL), combine the organic phases, wash with saturated brine (2×400mL), and dry with anhydrous Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography to obtain 27.4 g of a white solid with a yield of 65%.

[0203] 1.4 Synthesis of 5-nitroisoindolin-1-one (D)

[0204] At room temperature, methyl 2-(bromomethyl)-4-nitrobenzoate (5g, 18.2mmol) and methanolic ammonia solution (20mL, 7.0M, 140mmol) were added to 20mL 1,4-dioxane, stirred evenly, and heated to 65°C for 4h. After the reaction was completed, the reaction solution was cooled to room temperature, the excess solvent in the reaction solution was evaporated under reduced pressure, 30mL of ether was added to the residue, stirred for 5h, filtered, and the filter cake was washed with ether and dried to obtain 2.75g of a white solid with a yield of 85%.

[0205] 1.5 Synthesis of 5-aminoisoindolin-1-one (E)

[0206] At room temperature, 5-nitroisoindolin-1-one (3.0 g, 16.8 mmol) and palladium-carbon (0.3 g) were added to 40 mL of anhydrous methanol and reacted at room temperature for 8 h under a hydrogen atmosphere. After the reaction, the mixture was filtered and the solvent was evaporated under reduced pressure to obtain 2.27 g of a light white powder with a yield of 91.2%.

[0207] 1 H NMR(600MHz, DMSO-d6)δ7.87(s,1H),7.28(d,J=8.7Hz,1H),6.65-6.56(m,2H),5.70(s,2H),4.16(s,2H).MS(ESI)m / z:149.0[M+H] + .

[0208] 1.6 Synthesis of tert-butyl 4-[(2,5-dichloropyrimidin-4-yl)amino]piperidine-1-carboxylate (L)

[0209] At room temperature, 4-amino-N-Boc-piperidine (10 g, 50 mmol) and 2,4,5-trichloropyrimidine (9.17 g, 50 mmol) were added to 70 mL of DMF, and DIPEA (11.8 mL, 75 mmol) was slowly added dropwise at -5 °C. After the addition, the reaction was maintained at -5 °C for 14 h. After the reaction was completed, the reaction solution was poured into 300 mL of ice water, stirred for 30 min, filtered, and the filter cake was washed with ice water (50 mL × 2) and dried to obtain 15.6 g of white solid, with a yield of 90%.

[0210] 1 H NMR (600MHz, DMSO-d6) δ8.17 (s, 1H), 7.64 (d, J = 8.2Hz, 1H), 4.27-4.05 (m, 1H), 3.97 (s, 2H), 2.91-2.72 ( m,2H),1.75(dd,J=12.8,3.8Hz,2H),1.53(qd,J=12.3,4.4Hz,2H),1.41(s,9H).MS(ESI)m / z:347.0[M+H] + .

[0211] 1.7 Synthesis of tert-butyl 4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxylate (F)

[0212] At room temperature, tert-butyl 4-[(2,5-dichloropyrimidin-4-yl)amino]piperidine-1-carboxylate (3g, 8.64mmol) and 5-aminoisoindolin-1-one (1.28g, 8.64mmol) were added to isopropanol, and trifluoroacetic acid (1.93mL, 25.9mmol) was added dropwise under ice bath, stirred evenly, and heated to 85°C for 6h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with isopropanol and dried to obtain 3.33g of white solid with a yield of 84%.

[0213] 1.8 Synthesis of 5-{[5-chloro-4-(piperidin-4-ylamino)pyrimidin-2-yl]amino}isoindol-1-one (G)

[0214] At room temperature, tert-butyl 4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxylate (4g, 8.72mmol) was added to 25mL DCM, 4mL trifluoroacetic acid was added dropwise under ice bath, stirred evenly, and the temperature was raised to reflux for 3h. After the reaction was completed, the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, 15mL cold water was added to the residue, 3.0M NaOH solution was used to adjust the pH to 8-9, and the filter cake was washed with 10mL cold water and dried to obtain 2.6g of white solid, with a yield of 83%. MS (ESI) m / z: 359.0 [M + H] + .

[0215] 1.9 Synthesis of N-(4-acetylphenyl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide

[0216] At room temperature, add intermediate II-2 (0.25 g, 1.0 mmol), TEA (0.25 mL, 2.0 mmol) and intermediate G (0.35 g, 1.0 mmol) to 6 mL 1,4-dioxane, and heat to 80 ° C for 4 h. After the reaction is completed, cool to room temperature, concentrate the solvent under reduced pressure, add water (5 mL) to the residue, filter and dry to obtain a crude product. The crude product is purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain 0.34 g of a white solid with a yield of 65.6%.

[0217] According to the synthesis method of Example 1, substituted aromatic amines were used as raw materials, and intermediate II-2 was synthesized according to the synthesis method of 1.1 in Example 1. The key intermediate G was synthesized according to the synthesis methods of 1.2-1.8 in the examples. Finally, a series of compounds were synthesized according to the synthesis method of 1.9 in Example 1. The structural formulas, MS, 1 The H-NMR data are shown in Table 1.

[0218] Table 1

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226] Example 29. Preparation of N-(1-methylpiperidin-4-yl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide

[0227] 3.1 Synthesis of key intermediate G

[0228] Using 4-nitro-2-methylbenzoic acid, ammonia methanol solution, 4-amino-N-Boc-piperidine and 2,4,5-trichloropyrimidine as raw materials, the key intermediate G was synthesized according to the synthesis method 1.2-1.8 in Example 1.

[0229] 3.2 Synthesis of N-(1-methylpiperidin-4-yl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide

[0230] At room temperature, N-Boc-4-aminopiperidine (1.8 g, 8.9 mmol), CDI (1.57 g, 9.7 mmol) and TEA (2.06 mL, 16 mmol) were added to 18 mL DMF, stirred at 30 ° C for 30 min, and G (3.0 g, 8.36 mmol) was added to continue stirring and reacting for 4 h. After the reaction was completed, the reaction solution was slowly poured into 100 mL ice water, stirred for 10 min, extracted with ethyl acetate (3×50 mL), the organic phases were combined, washed with saturated brine (2×50 mL), and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain an oily residue. The above residue was added to 20 mL DCM, 6 mL trifluoroacetic acid was added dropwise under ice bath, stirred evenly, and reacted at room temperature for 6 h. After the reaction is completed, the solvent is evaporated under reduced pressure and 20 mL of cold water is added to the residue. The pH is adjusted to 8-9 with 3.0 M NaOH solution, and the filter cake is washed with 10 mL of cold water and dried to obtain 3.2 g of a white solid with a yield of 79%. 0.3 g of the above white solid, 0.05 mL of iodomethane and 0.156 mL of triethylamine are added to 3 mL of DMF, stirred evenly, and reacted at room temperature for 5 h. After the reaction is completed, the reaction solution is slowly poured into 15 mL of ice water and stirred for 10 min. Extract with ethyl acetate (3×20 mL), combine the organic phases, wash with saturated brine, and dry with anhydrous Na2SO4. The solvent is evaporated under reduced pressure, and thin layer chromatography is purified to obtain 0.102 g of a white solid with a yield of 33.1%.

[0231] According to the synthesis method of Example 29, a series of compounds were synthesized using heterocyclic amines and different halogenated hydrocarbons as raw materials. The structures of some of the compounds in the examples, MS, 1 The H-NMR data are shown in Table 2.

[0232] Table 2

[0233]

[0234]

[0235]

[0236]

[0237]

[0238] Example 45. N-[1-(2-fluoroethyl)piperidin-4-yl]-4-({5-chloro-2-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide

[0239] 3.1 tert-Butyl 4-[(2-amino-5-chloropyrimidin-4-yl)amino]piperidine-1-carboxylate (IV-2)

[0240] At room temperature, N-Boc-4-aminopiperidine (10g, 50mmol), 2-amino-4,5-dichloropyrimidine (6.82g, 41.6mmol) and TEA (10.5mL, 83.2mmol) were added to 50mL methanol, stirred evenly, and heated to reflux for 24h. After the reaction was completed, the reaction solution was poured into 150mL ice water, stirred for 30min, extracted with ethyl acetate (3×80mL), the organic phases were combined, washed with saturated brine (2×50mL), and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and column chromatography was used for purification to obtain 10.9g of a white solid with a yield of 80%.

[0241] 1 H NMR (600MHz, DMSO-d6) δ7.70(s,1H),6.49(d,J=8.3Hz,1H),6.18(s,2H),4.11(dtd,J=11.5,7.5,4.1Hz,1H),3.96(s ,2H),2.73(s,2H),1.74(dd,J=12.7,4.2Hz,2H),1.47(qd,J=12.3,4.2Hz,2H),1.41(s,9H).MS(ESI)m / z:328.1[M+H] + .

[0242] 3.2 tert-Butyl 4-({5-chloro-2-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxylate (IV-3)

[0243] At room temperature, IV-2 (1g, 3.05mmol), 6-bromo-3,4-dihydro-2H-isoquinolin-1-one (0.69g, 3.05mmol), Xantphos-Pd-G3 (0.145g, 0.153mmol) and cesium carbonate (1.99g, 6.1mmol) were added to 15mL 1,4-dioxane, stirred evenly, and heated to 100℃ under nitrogen protection for 8h. After the reaction was completed, the reaction solution was slowly poured into 30mL ice water and stirred for 10min. Extracted with ethyl acetate (3×50mL), the organic phases were combined, washed with saturated brine, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and purified by column chromatography to obtain 1g of a white solid with a yield of 70%.

[0244] 3.3 6-{[5-chloro-4-(piperidin-4-ylamino)pyrimidin-2-yl]amino}-3,4-dihydroisoquinolin-1(2H)-one (IV-4)

[0245] At room temperature, IV-3 (1 g, 2.1 mmol) was added to 8 mL of DCM, and 3.0 mL of trifluoroacetic acid was added dropwise under ice bath, stirred evenly, and heated to reflux for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, 5 mL of cold water was added to the residue, and the pH was adjusted to 8-9 with 3.0 M NaOH solution, filtered, and the filter cake was washed with 10 mL of cold water and dried to obtain 0.67 g of white solid, with a yield of 85%.

[0246] 3.4 N-[1-(2-fluoroethyl)piperidin-4-yl]-4-({5-chloro-2-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide

[0247] At room temperature, N-Boc-4-aminopiperidine (0.295 g, 1.48 mmol), CDI (0.26 g, 1.61 mmol) and TEA (0.37 mL, 2.68 mmol) were added to 5 mL DMF, stirred at 30 ° C for 30 min, and IV-4 (0.5 g, 1.34 mmol) was added and continued to stir for 4 h. After the reaction was completed, the reaction solution was slowly poured into 25 mL ice water, stirred for 10 min, extracted with ethyl acetate (3×50 mL), the organic phases were combined, washed with saturated brine (2×20 mL), and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain an oily residue. The above residue was added to 6 mL DCM, 2 mL trifluoroacetic acid was added dropwise under ice bath, stirred evenly, and reacted at room temperature for 6 h. After the reaction was completed, the solvent was evaporated under reduced pressure and 5 mL cold water was added to the residue, and the pH was adjusted to 8-9 with 3.0 M NaOH solution, filtered, and the filter cake was washed with 10 mL cold water and dried to obtain a white solid. Next, add the white solid, 1-fluoro-2-iodoethane and triethylamine to 3 mL of DMF, stir evenly, and react at room temperature for 5 h. After the reaction is complete, slowly pour the reaction solution into 15 mL of ice water and stir for 10 min. Extract with ethyl acetate (3×20 mL), combine the organic phases, wash with saturated brine, and dry over anhydrous Na2SO4. Evaporate the solvent under reduced pressure, and purify with thin layer chromatography to obtain 0.16 g of a white solid with a total yield of 21.9%.

[0248] According to the synthesis method of Example 45, a series of compounds were synthesized using heterocyclic amine and brominated aromatic heterocycle as raw materials. The structural formula, MS, 1 The H-NMR data are shown in Table 3.

[0249] Table 3

[0250]

[0251]

[0252] Example 52. cis-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)cyclohexane-1-carboxamide

[0253] 4.1 cis-4-[(2,5-dichloropyrimidin-4-yl)amino]cyclohexanecarboxylic acid methyl ester (V-2)

[0254] At room temperature, cis-4-aminocyclohexanecarboxylic acid methyl ester (1.714 g, 10.9 mmol) and 2,4,5-trichloropyrimidine (2 g, 10.9 mmol) were added to 15 mL of DMF, and DIPEA (2.6 mL, 16.35 mmol) was slowly added dropwise at -10°C. After the addition, the reaction was maintained at -5°C. After the reaction was completed, the reaction solution was poured into 50 mL of ice water, stirred for 30 min, and filtered. The filter cake was washed with ice water (10 mL × 2) and dried to obtain 2.72 g of a white solid with a yield of 82%.

[0255] 4.2 cis-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)cyclohexanecarboxylic acid methyl ester (V-3)

[0256] At room temperature, V-2 (1.5 g, 4.93 mmol) and 5-amino-2-methylisoindolin-1-one (0.8 g, 4.93 mmol) were added to isopropanol, and trifluoroacetic acid (1.1 mL, 14.8 mmol) was added dropwise under ice bath, stirred evenly, and heated to 85°C for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with isopropanol and dried to obtain 1.73 g of white solid with a yield of 81.8%.

[0257] 4.3 cis-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)cyclohexanecarboxylic acid (V-4)

[0258] At room temperature, V-3 (1.5 g, 3.49 mmol) was added to 15 mL MeOH / H2O (V:V=4:1), and sodium hydroxide (0.69 g, 17.4 mmol) was added under ice bath, and the mixture was stirred evenly and heated to 30°C to continue the reaction. After the reaction was completed, the excess methanol was evaporated, 5 mL of water was added to the residue, and 1.0 M hydrochloric acid was used to adjust the pH to 3-4, and DCM (20 mL*3) was used for extraction, and the organic phases were combined, washed with saturated brine, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain 1.25 g of a white solid with a yield of 86.1%.

[0259] 4.4 cis-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)cyclohexane-1-carboxamide

[0260] At room temperature, intermediate V-4 (0.3 g, 0.72 mmol), EDCI (0.21 g, 0.108 mmol) and HOBT (0.075 g, 0.108 mmol) were added to DMF (6 mL) and reacted at 30 °C for 1 h. After 1 h, (3S, 4R)-3-fluoro-N-Boc-4-aminopiperidine (0.19 g, 0.86 mmol) and TEA (0.183 mL, 1.44 mmol) were added and the reaction was continued with stirring. After the reaction was completed, the reaction solution was slowly poured into 15 mL of ice water and stirred for 10 min. The organic phases were extracted with ethyl acetate (3×20 mL), the organic phases were combined, washed with saturated brine, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain an oil. The above residue was added to 6 mL of DCM, 2 mL of trifluoroacetic acid was added dropwise under ice bath, stirred evenly, and reacted at room temperature for 6 h. After the reaction was completed, the solvent was evaporated under reduced pressure and 5 mL of cold water was added to the residue. The pH was adjusted to 8-9 with 3.0 M NaOH solution, and the filter cake was washed with 10 mL of cold water and dried to obtain 0.28 g of white solid with a yield of 75.1%. Next, the above white solid, 0.05 mL of iodomethane and 0.14 mL of triethylamine were added to 3 mL of DMF, stirred evenly, and reacted at room temperature for 5 h. After the reaction was completed, the reaction solution was slowly poured into 15 mL of ice water and stirred for 10 min. Ethyl acetate (3×20 mL) was extracted, the organic phases were combined, washed with saturated brine, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and thin layer chromatography was used for purification to obtain 0.15 g of white solid with a total yield of 39.3%.

[0261] According to the synthesis method of Example 52, a series of compounds were synthesized using heterocyclic amine and brominated aromatic heterocycle as raw materials. The structural formula, MS, 1 The H-NMR data are shown in Table 4.

[0262] Table 4

[0263]

[0264]

[0265] The in vitro enzyme activity and IL-6-JAK / STAT3 phosphorylation of some compounds prepared by the present invention were studied, and the results are as follows.

[0266] Studies have found that JAK2 is mainly involved in regulating red blood cell and myeloid hematopoiesis, and its inhibition will produce side effects such as hematopoietic dysfunction, anemia and thromboembolism, which need to be avoided. Therefore, the compound of the 2,4-diaminopyrimidine skeleton of the general formula I of the present invention was tested for in vitro JAK1 and JAK2 kinase activity using ADP-Glo ​​Kinase Assay.

[0267] The starting concentration of the compound was set to 10 μM. First, the test compound was vortexed and thoroughly mixed, and DMSO was used to dilute it continuously to 100 times the test concentration, and 40 nL of the compound was transferred to a 384-well plate. Then, 2 times the kinase (JAK1, JAK2) solution was prepared with 1 times kinase reaction buffer (50mM Hepes, 10mM MgCl2, 0.01% Brij35, 1mM EGTA, 2mM DTT, H2O), and 2 μL of the kinase solution was transferred to a 384-well plate, centrifuged briefly to mix, and incubated at 25°C for 10 min. A 2-fold mixture of substrate (IRS1 tide: 0.05mg / mL) and ATP (1mM) was prepared with kinase reaction buffer, and then 2 μL of the mixture was transferred to a 384-well plate, centrifuged briefly to mix, and incubated at 25°C for 60 min. Next, 4 μL of ADP-Glo ​​Reagent was transferred to a 384-well plate and mixed briefly by centrifuge, and incubated at 25°C for 40 min. Finally, 8 μL of the test solution was transferred to a 384-well plate, mixed briefly by centrifuge, incubated at 25°C for 40 min, and the chemiluminescence signal was read by a multifunctional microplate reader. The reading value of the negative control was set to 0% inhibition rate, and the reading value of the positive control was set to 100% inhibition rate, and the inhibition rate of each test solution was calculated.

[0268] Percent inhibition = 100*(negative control reading - compound well reading) / (negative control reading - positive control reading).

[0269] Compound IC 50 (half-maximal inhibitory concentration) was obtained by nonlinear fitting formula of GraphPad 8 software:

[0270] IC 50 The calculation formula is: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0271] Table 5 In vitro kinase assay results of some examples

[0272]

[0273]

[0274] Furthermore, the above-described 2,4-diaminopyrimidine skeleton compounds were selected to conduct an in vitro IL-6-JAK / STAT3 assay.

[0275] First, after obtaining HEK-Blue-IL6 cells, resuspend the cells in DMEM cell culture medium containing 10% FBS and calculate the cell density. According to the cell density, remove the appropriate amount of resuspended cells from the centrifuge tube to adapt to 10,000 / 40μL per well. Then, in a 384-well plate, distribute 40μL of resuspended HEK-Blue-IL6 cells per well. Next, add the test compound to the test well plate. After 30min, hIL-6 (at a concentration of 1ng / mL) is also added to the test well plate. The 384-well plate is placed in a cell culture incubator at 37°C and 5% CO2 for 24 hours. Subsequently, 18μL of the pre-prepared Quanti-Blue solution is added to each well of the new 384-well plate, and 2μL of the supernatant is transferred to the 384-well plate containing the Quanti-Blue solution, incubated at room temperature for 60min, and finally read the value using a multifunctional microplate reader.

[0276] Inhibition rate % = (blank reading - compound well reading) / (blank reading - control reading)

[0277] Data analysis, curve fitting, and reporting were performed using IDBS XLfit software and the Dose-response one-site 205 model.

[0278] IC 50 The calculation formula is: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0279] Table 6 IC of IL-6-JAK / STAT3 phosphorylation in some examples 50 data

[0280] Example <![CDATA[HEK Blue IL-6IC 50 (nM)]]> Example <![CDATA[HEK Blue IL-6IC 50 (nM)]]> Example 1 290.31 Example 9 37.11 Embodiment 22 27.97 Embodiment 24 72.60 Embodiment 25 45.55 Embodiment 40 139.6 Embodiment 42 89.8 Embodiment 43 125.05 Embodiment 49 38.96 Embodiment 54 46.59 Tofacitinib 395.48 Filgotinib 2356.4

[0281] The results of the cell activity test of the compound showed that the compound can effectively inhibit the phosphorylation of JAK / STAT3 induced by IL-6, and the compound with better activity than the reference Tofacitinib and Filgotinib was found. The results of the in vitro kinase and cell activity test showed that the compound involved in the present invention has good JAK1 inhibitory activity and excellent cell activity, and the activity of some compounds is better than the positive control drug.

Claims

1. A 2,4-diaminopyrimidine compound, characterized in that: The compound is a compound represented by general formula I, its stereoisomers and pharmaceutically acceptable salts thereof, in, L is selected from W is N or CH; m and n are independently selected from 1, 2 or 3; p, q and s are each independently selected from 0, 1 or 2; R 1 is hydrogen, halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, cyano, nitro; R 2 is (C3-C8) cycloalkyl, 4-10 membered heterocyclic group, (C6-C 10 ) aryl, 5-10 membered heteroaryl, the cycloalkyl, heterocyclic, aryl or heteroaryl may be optionally substituted by 1-3 identical or different R 3 replace; R 3 is hydroxy, halogen, amino, mercapto, cyano, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C1-C6)alkylacyl, (C1-C6)haloalkylacyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylamido, free, salified, esterified and amidated carboxyl, (C1-C6)alkyl or (C1-C6)alkoxy which is unsubstituted or substituted by at least one hydroxy, amino, cyano or halogen , amino substituted by 1-2 identical or different (C1-C6) alkyl or (C3-C8) cycloalkyl groups, carbamoyl unsubstituted or substituted by 1-2 identical or different (C1-C6) alkyl groups, 4-10 membered heterocyclyl or 5-10 membered heteroaryl, wherein the heterocyclyl and heteroaryl groups may be optionally substituted by 1-3 identical or different substituents selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, (C1-C4) haloalkyl, hydroxy, halogen, cyano; A is selected from R 4 is hydrogen, halogen, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, wherein the alkyl and alkoxy are optionally substituted by 1-3 identical or different halogens; z is 1, 2 or 3, and when z is 2 or 3, R 4 Can be the same or different; X is CH2, NR 5 or O; t is selected from 1 or 2; R 5 is hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, or 4-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted by 1-3 identical or different substituents selected from hydrogen, halogen, hydroxyl, cyano, or (C3-C6) cycloalkyl; R 6 is hydrogen, (C1-C6) alkyl; The heterocyclic group and heteroaryl group involved in the above substituents optionally contain 1-4 identical or different heteroatoms selected from N, O or S, wherein the heterocyclic group optionally includes 1-2 double bonds.

2. The 2,4-diaminopyrimidine compound according to claim 1, characterized in that: The compound of general formula I, its stereoisomers and pharmaceutically acceptable salts thereof, in, L is selected from W is N or CH; m and n are independently selected from 1, 2 or 3; p, q and s are each independently selected from 0, 1 or 2; R 1 is hydrogen, halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, cyano; R 2 is (C3-C6) cycloalkyl, 4-10 membered heterocyclic group, (C6-C 10 ) aryl, 5-10 membered heteroaryl, the cycloalkyl, heterocyclic, aryl or heteroaryl may be optionally substituted by 1-3 identical or different R 3 replace; R 3 is hydroxy, halogen, cyano, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C7)cycloalkyl, (C1-C4)alkylacyl, (C1-C4)haloalkylacyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylamido, free, salified, esterified and amidated carboxyl, (C1-C4)alkyl or (C1-C4)alkoxy which is unsubstituted or substituted by at least one hydroxy, amino, cyano or halogen, an amino group substituted with 1-2 identical or different (C1-C4) alkyl or (C3-C7) cycloalkyl groups, a carbamoyl group which is unsubstituted or substituted with 1-2 identical or different (C1-C4) alkyl groups, a 4-10 membered heterocyclyl group or a 5-10 membered heteroaryl group, wherein the heterocyclyl group and the heteroaryl group are optionally substituted with 1-3 identical or different substituents selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, (C1-C4) haloalkyl, hydroxy, halogen, and cyano; A is selected from R 4 is hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, cyano, wherein the alkyl and alkoxy are optionally substituted by 1-3 identical or different halogens; z is 1, 2 or 3, and when z is 2 or 3, R 4 Can be the same or different; X is CH2, NR 5 or O; t is selected from 1 or 2; R 5 is hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, or 4-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally further substituted by 1-3 identical or different substituents selected from hydrogen, halogen, hydroxyl, cyano, or (C3-C4) cycloalkyl; R 6 is hydrogen, (C1-C4) alkyl; The heterocyclic group and heteroaryl group involved in the above substituents optionally contain 1-4 identical or different heteroatoms selected from N, O or S, wherein the heterocyclic group optionally includes 1-2 double bonds.

3. The 2,4-diaminopyrimidine compound according to claim 2, characterized in that: The compound of general formula I, its stereoisomers and pharmaceutically acceptable salts thereof, in, L is selected from W is N or CH; m and n are independently selected from 1, 2 or 3; R 1 is hydrogen, halogen, methyl, ethyl, trifluoromethyl; R 2 is (C3-C6) cycloalkyl, 4-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, phenyl or heteroaryl is optionally substituted by 1-3 identical or different R 3 replace; R 3 is hydroxy, halogen, cyano, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C7)cycloalkyl, (C1-C4)alkylacyl, (C1-C4)haloalkylacyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylamido, free, salified, esterified and amidated carboxyl, (C1-C4)alkyl or (C1-C4)alkoxy which is unsubstituted or substituted by at least one hydroxy, amino, cyano or halogen, amino substituted by 1-2 identical or different (C1-C4) alkyl or (C3-C7) cycloalkyl groups, carbamoyl unsubstituted or substituted by 1-2 identical or different (C1-C4) alkyl groups, 4-8 membered heterocyclyl or 5-10 membered heteroaryl, wherein the heterocyclyl and heteroaryl groups are optionally substituted by 1-3 identical or different substituents selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, (C1-C4) haloalkyl, hydroxy, halogen, cyano; A is selected from R 4 is hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, wherein the alkyl and alkoxy are optionally substituted by 1-3 identical or different halogens; X is CH2, NR 5 or O; t is selected from 1 or 2; R 5 is hydrogen, (C1-C4) alkyl, (C3-C7) cycloalkyl, or 4-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally further substituted by 1-3 identical or different substituents selected from hydrogen, halogen, cyano, or (C3-C4) cycloalkyl; R 6 is hydrogen, (C1-C4) alkyl; The heterocyclic group and heteroaryl group involved in the above substituents optionally contain 1-4 identical or different heteroatoms selected from N, O or S, wherein the heterocyclic group optionally includes 1-2 double bonds.

4. The 2,4-diaminopyrimidine compound according to claim 3, characterized in that: The compound of general formula I, its stereoisomers and pharmaceutically acceptable salts thereof, in, L is selected from W is N or CH; m and n are independently selected from 1, 2 or 3; R 1 is hydrogen, halogen, methyl, ethyl, trifluoromethyl; R 2 is a 4-10 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group, wherein the heterocyclic group, the phenyl group, or the heteroaryl group is optionally substituted by 1-3 identical or different R 3 replace; R 3 is halogen, cyano, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C7)cycloalkyl, (C1-C4)alkylacyl, (C1-C4)haloalkylacyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylamido, free, salified, esterified and amidated carboxyl, (C1-C4)alkyl or (C1-C4)alkoxy which is unsubstituted or substituted by at least one hydroxyl, amino, cyano or halogen, an amino group substituted with 1-2 identical or different (C1-C4) alkyl or (C3-C7) cycloalkyl groups, a carbamoyl group which is unsubstituted or substituted with 1-2 identical or different (C1-C4) alkyl groups, a 4-6 membered heterocyclyl group or a 5-6 membered heteroaryl group, wherein the heterocyclyl group and the heteroaryl group are optionally substituted with 1-3 identical or different substituents selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, (C1-C4) haloalkyl, hydroxy, halogen, and cyano; A is selected from R 4 is hydrogen, halogen, (C1-C4) alkyl, the alkyl being optionally substituted by 1-3 identical or different halogens; X is CH2, NR 5 or O; t is selected from 1 or 2; R 5 is hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, or 4-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally further substituted by 1-3 identical or different substituents selected from hydrogen, halogen, cyano, or (C3-C4) cycloalkyl; R 6 is hydrogen, methyl or ethyl; The heterocyclic group and heteroaryl group involved in the above substituents optionally contain 1-4 identical or different heteroatoms selected from N, O or S, wherein the heterocyclic group optionally includes 1-2 double bonds.

5. The 2,4-diaminopyrimidine compound according to claim 4, characterized in that: The compound of general formula I, its stereoisomers and pharmaceutically acceptable salts thereof, in, L is selected from W is N or CH; R 1 is hydrogen, halogen, methyl, ethyl, trifluoromethyl; R 2 is a 4-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group, wherein the heterocyclic group, the phenyl group, or the heteroaryl group is optionally substituted by 1-3 identical or different R 3 replace; R 3 is halogen, cyano, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C7)cycloalkyl, (C1-C4)alkylacyl, (C1-C4)haloalkylacyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylamido, free, salified, esterified and amidated carboxyl, (C1-C4)alkyl or (C1-C4)alkoxy which is unsubstituted or substituted by at least one hydroxyl, amino, cyano or halogen, an amino group substituted with 1-2 identical or different (C1-C4) alkyl or (C3-C7) cycloalkyl groups, a carbamoyl group which is unsubstituted or substituted with 1-2 identical or different (C1-C4) alkyl groups, a 4-6 membered heterocyclyl group or a 5-6 membered heteroaryl group, wherein the heterocyclyl group and the heteroaryl group are optionally substituted with 1-3 identical or different substituents selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, (C1-C4) haloalkyl, hydroxy, halogen, and cyano; A is selected from R 4 is hydrogen, halogen, methyl, ethyl, trifluoromethyl; X is CH2, NR 5 or O; t is selected from 1 or 2; R 5 is hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, or 4-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally further substituted by 1-3 identical or different substituents selected from hydrogen, halogen, cyano, or (C3-C4) cycloalkyl; The heterocyclic group and heteroaryl group involved in the above substituents optionally contain 1-4 identical or different heteroatoms selected from N, O or S, wherein the heterocyclic group optionally includes 1-2 double bonds.

6. The 2,4-diaminopyrimidine compound according to claim 5, characterized in that: The compound of general formula I, its stereoisomers and pharmaceutically acceptable salts thereof, in, L is selected from R 1 is hydrogen, halogen, methyl, trifluoromethyl; R 2 is a 4-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group, wherein the heterocyclic group, the phenyl group, or the heteroaryl group is optionally substituted by 1-3 identical or different R 3 replace; R 3 is halogen, cyano, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C7)cycloalkyl, (C1-C4)alkylacyl, (C1-C4)haloalkylacyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylamido, free, salified, esterified and amidated carboxyl, (C1-C4)alkyl or (C1-C4)alkoxy which is unsubstituted or substituted by at least one hydroxyl, amino, cyano or halogen, substituted by 1 to 2 identical or amino substituted with different (C1-C4) alkyl or (C3-C7) cycloalkyl groups, carbamoyl unsubstituted or substituted with 1-2 identical or different (C1-C4) alkyl groups, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the heterocyclyl and heteroaryl groups are optionally substituted with 1-3 identical or different substituents selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, (C1-C4) haloalkyl, hydroxy, halogen, cyano; A is selected from R 4 is hydrogen, halogen; X is CH2, NR 5 or O; t is selected from 1 or 2; R 5 is hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, or 4-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally further substituted by 1-3 identical or different substituents selected from hydrogen, halogen, cyano, or (C3-C4) cycloalkyl; The heterocyclic group and heteroaryl group involved in the above substituents optionally contain 1-4 identical or different heteroatoms selected from N, O or S, wherein the heterocyclic group optionally includes 1-2 double bonds.

7. The 2,4-diaminopyrimidine compound according to claim 6, characterized in that: The compound of general formula I, its stereoisomers and pharmaceutically acceptable salts thereof, in, L is selected from R 1 is hydrogen, halogen, methyl; R 2 is a 5-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group, wherein the heterocyclic group, the phenyl group, or the heteroaryl group is optionally substituted by 1-3 identical or different R 3 replace; R 3 is halogen, cyano, (C3-C7)cycloalkyl, (C1-C4)alkylacyl, (C1-C4)haloalkylacyl, (C1-C4)alkylsulfonyl, (C1-C4)alkyl or (C1-C4)alkoxy which is unsubstituted or substituted with at least one hydroxyl, amino, cyano or halogen, amino substituted with 1-2 identical or different (C1-C4)alkyl or (C3-C7)cycloalkyl groups, carbamoyl which is unsubstituted or substituted with 1-2 identical or different (C1-C4)alkyl groups, 5-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the heterocyclyl and heteroaryl groups are optionally substituted with 1-3 identical or different substituents selected from (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, halogen and cyano; A is selected from R 4 is hydrogen, halogen; X is CH2, NR 5 or O; R 5 is hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, and the alkyl or cycloalkyl is optionally further substituted by 1-3 identical or different substituents selected from hydrogen and halogen; The heterocyclic group and heteroaryl group involved in the above substituents optionally contain 1-4 identical or different heteroatoms selected from N, O or S, wherein the heterocyclic group optionally includes 1-2 double bonds.

8. The 2,4-diaminopyrimidine compound according to claim 7, characterized in that: The compound of general formula I is the following compound and its stereoisomers and pharmaceutically acceptable salts: N-(4-acetylphenyl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-(4-acetylphenyl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)azepane-1-carboxamide; N-(4-acetylphenyl)-3-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)-8-azabicyclo[3.2.1]octane-8-carboxamide; N-(4-methoxyphenyl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-(4-chlorophenyl)-4-(5-chloro-2-((1-oxoisoindol-5-yl)amino)pyrimidin-4-yl)amino)piperidine-1-carboxamide; N-(4-acetylphenyl)-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-(4-acetylphenyl)-4-({5-chloro-2-[(2-ethyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-(4-acetylphenyl)-4-({5-chloro-2-[(2-cyclopropyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-[4-(1H-1,2,4-triazol-1-yl)phenyl]-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-[4-(1H-imidazol-1-yl)phenyl]-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-[4-(Methylsulfonyl)phenyl]-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)-piperidine-1-carboxamide; N-(4-cyanophenyl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-(5-acetylpyridin-2-yl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-[1-(2,2,2-trifluoroacetyl)piperidin-4-yl]-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-(1-methyl-1H-pyrazol-4-yl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-(thiazol-2-yl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-(4-acetyl-2-fluorophenyl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-(4-acetyl-2-chlorophenyl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-(4-acetyl-2-fluorophenyl)-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-(1-methylpiperidin-4-yl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-(1-methylpiperidin-4-yl)-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-[1-(2-fluoroethyl)piperidin-4-yl]-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-[1-(2-fluoroethyl)piperidin-4-yl]-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; (S)-N-[1-(2-fluoroethyl)pyrrolidin-3-yl]-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; (R)-N-[1-(2-fluoroethyl)pyrrolidin-3-yl]-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-[1-(2-fluoroethyl)azepan-4-yl]-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-[1-(3,3,3-trifluoropropyl)piperidin-4-yl]-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)-piperidine-1-carboxamide; N-((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)-piperidine-1-carboxamide; N-((3S,4R)-3-fluoro-1-ethylpiperidin-4-yl)-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-((5-chloro-2-{[2-(2,2,2-trifluoroethyl)-1-oxoisoindol-5-yl]amino}pyrimidin-4-yl)amino)piperidine-1-carboxamide; N-(4-acetylphenyl)-4-({5-chloro-2-[(2-methyl-1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-[1-(2-fluoroethyl)piperidin-4-yl]-4-({5-chloro-2-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-({5-chloro-2-[(1-oxo-2,3-dihydro-1H-inden-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-({5-chloro-2-[(1-oxo-1,3-dihydroisobenzofuran-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; N-((3S,4R)-3-fluoro-1-ethylpiperidin-4-yl)-4-({5-chloro-2-[(6-fluoro-2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)piperidine-1-carboxamide; cis-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-4-({5-chloro-2-[(2-methyl-1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)cyclohexane-1-carboxamide; cis-N-(4-acetyl-2-fluorophenyl)-4-({5-chloro-2-[(1-oxoisoindol-5-yl)amino]pyrimidin-4-yl}amino)cyclohexane-1-carboxamide.

9. The 2,4-diaminopyrimidine compound according to any one of claims 1 to 8, characterized in that: The salt of the compound of general formula I is a salt formed by the compound of general formula I and an acid, wherein the acid is selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid or aspartic acid.

10. A pharmaceutical composition, characterized in that: The composition contains the compound of general formula I according to any one of claims 1 to 8, its stereoisomers and pharmaceutically acceptable salts thereof.

11. Use of the compound according to claim 1, characterized in that: Use of the compound according to any one of claims 1 to 8, its stereoisomers and pharmaceutically acceptable salts thereof in the preparation of drugs for preventing or treating diseases mediated by the JAK family.

12. The use according to claim 11, characterized in that: The diseases include immune system diseases, autoimmune diseases, skin diseases, allergic diseases, viral diseases, type I diabetes and diabetic complications, Alzheimer's disease, dry eye disease, non-infectious uveitis, myelofibrosis, thrombocytosis, polycythemia, leukemia and cancer. The immune system disease is organ transplant rejection, such as allogeneic rejection or graft-versus-host disease; the autoimmune disease is selected from systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, ankylosing spondylitis, ulcerative colitis, Crohn's disease or autoimmune The present invention relates to an immunomodulatory agent comprising: an immunomodulatory agent comprising: an immunomodulatory agent comprising: an immunomodulatory agent comprising: an immunomodulatory agent comprising: a psoriasis, a rash, alopecia areata or atopic dermatitis; the allergic disease is selected from asthma or rhinitis; the viral disease is selected from hepatitis B, hepatitis C, varicella, and herpes zoster virus; the cancer is selected from solid tumors, blood cancers or skin cancers, the solid tumors are selected from prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma or melanoma, the blood cancer is selected from lymphoma or leukemia, and the skin cancer is selected from cutaneous T-cell lymphoma or cutaneous B-cell lymphoma.

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