Pyrimidine phosphonamide and pyrimidine amide compounds and use thereof

Abstract

The present invention relates to compounds of formula (I) or formula (II), wherein R1 to R7 are as defined in the description and claims. The compounds of formula (I) or formula (II) can be used as selective JAK3 inhibitors for treating related diseases such as autoimmune diseases.

Description

Pyrimidinephosphonamides and pyrimidine amide compounds and their applications Technical Field

[0001] This invention relates to the field of pharmaceutical compounds. Specifically, this invention provides a class of pyrimidine phosphonamides and pyrimidine amide compounds and their applications. Background Technology

[0002] JAK is a non-receptor tyrosine protein kinase composed of seven homologous domains (JH). It mediates cytokine signals and transmits them through the JAK-STAT signaling pathway. The JAK-STAT signaling pathway has a wide range of functions, participating in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation. JAK kinase is a crucial target, being the core of the entire JAK-STAT signaling pathway, which is one of the few proven immune regulatory pathways involved in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation. Many diseases, including tumors, rheumatoid arthritis, psoriasis, and hematological disorders, have been shown to require the transmission of signals through the JAK-STAT signaling pathway. JAK kinase plays a key role in immune responses by transmitting signals from more than 50 cytokines, making it an attractive therapeutic target for autoimmune diseases. However, this non-selective inhibition of JAK inevitably affects the physiological functions of various cytokines, leading to corresponding side effects. Therefore, drugs targeting a specific JAK can significantly reduce the occurrence of adverse events while controlling disease progression. Therefore, developing highly selective JAK inhibitors is the current trend and direction of drug development in this field.

[0003] The JAK kinase family of non-receptor tyrosine kinases comprises four subtypes: JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase 2), which signal via the JAK / STAT pathway. JAK1, JAK2, and TYK2 are widely expressed, while JAK3 is primarily expressed in lymphoid tissues and is a selective regulator of lymphocyte development, functioning in the immune system, making JAK3 an attractive target for treating autoimmune diseases. JAK3 selectively binds to only one cytokine receptor subunit, called the common γ-subunit or γc chain. JAK3, in conjunction with JAK1, participates in signal transduction initiated by six cytokines (interleukins 2, 4, 5, 7, 15, and 21), and JAK3 regulates only a narrow spectrum of γc cytokines, thus making it a potentially ideal target.

[0004] Therefore, selective targeting of JAK3 may have fewer adverse reactions and can be used to prevent transplant rejection and treat a variety of autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, psoriasis, arthritis and Crohn's disease, and may reduce adverse reactions caused by inhibiting JAK1 and JAK2.

[0005] Although several companies are conducting drug research targeting JAK3, the clinical application still fails to meet the needs due to adverse reactions such as hyperlipidemia, elevated creatinine, elevated transaminase, neutropenia, and lymphopenia. Therefore, it is still urgent to develop new compounds with market potential and better efficacy and pharmacokinetic results. Summary of the Invention

[0006] In light of the above background, the inventors designed pyrimidine amide or phosphonamide compounds and found that compounds with such structures exhibit excellent effects and functions (such as JAK3 inhibitory activity, selectivity of JAK3 inhibitory activity and pharmacodynamic and pharmacokinetic properties), which is of positive significance for the development of JAK3 inhibitors.

[0007] Therefore, the present invention provides, in one aspect, compounds of formula (I),

[0008] in

[0009] R1, R2, and R3 are each independently selected from: hydrogen, deuterium, halogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optional substituted C 3-10 cycloalkyl and optionally substituted C 1-6 alkoxy, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or is substituted by one or more substituents selected from: C 1-6 Alkyl, halogen, hydroxyl, mercapto, amino, and cyano groups;

[0010] R4 is selected from: hydrogen, or C with optional substitution. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optional substituted C 3-10 cycloalkyl and optionally substituted C 1-6 alkoxy, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or is substituted by one or more substituents selected from: C 1-6 Alkyl, halogen, hydroxyl, mercapto, amino, and cyano groups;

[0011] R5 and R6 are each independently selected from: hydrogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optional substituted C 3-10cycloalkyl and optionally substituted C 1-6 alkoxy, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or is substituted by one or more substituents selected from: C 1-6 Alkyl, halogen, hydroxyl, mercapto, amino, and cyano groups;

[0012] X is selected from: —(chemical bond), -N-, -CH-, -NCH2-, or not present;

[0013] Y is selected from: —(chemical bond), -N-, -CH-, -CH2N-, -CH2NMe-, or not present; and

[0014] A is selected from: C with optional substitution. 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C 4-10 Aryl and optionally substituted 5-10 membered heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or is substituted by one or more substituents selected from the following: C 1-6 Alkyl, halogen, hydroxyl, mercapto, amino, and cyano groups;

[0015] Or its stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, solvates or isotopically labeled analogs.

[0016] In one specific embodiment, R1, R2, and R3 are each independently selected from: hydrogen, deuterium, halogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl and optional substituted C 1-6 Alkoxy;

[0017] R4 is selected from: hydrogen, or C with optional substitution. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl and optional substituted C 1-6 Alkoxy;

[0018] R5 and R6 are each independently selected from: hydrogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl and optional substituted C 1-6 Alkoxy;

[0019] X is selected from: —(chemical bond), -N-, -CH-, -NCH2-, or not present;

[0020] Y is selected from: —(chemical bond), -N-, -CH-, -CH2N-, -CH2NMe-, or not present; and

[0021] A is selected from: C with optional substitution.1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C 4-10 Aryl and optionally substituted 5-10 membered heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or is substituted by one or more substituents selected from the following: C 1-6 Alkyl, halogen, hydroxyl, mercapto, amino, and cyano groups.

[0022] In one specific embodiment, A is an optionally substituted piperidine, optionally substituted pyrrolidine, piperazine, bicyclo[1.1.1]pentyl, phenyl, optionally substituted benzopiperidine, optionally substituted thiazopiperidine, optionally substituted thiophenepiperidine, optionally substituted pyrazolopiperidine, or optionally substituted pyridopiperidine, preferably methyl-substituted piperidine, pyrrolidine, bicyclo[1.1.1]pentyl, phenyl, wherein the benzene ring is optionally substituted with a hydroxyl group and / or halogen, benzopiperidine, methyl-substituted piperazine, thiazopiperidine, thiophenepiperidine, wherein the pyrazole ring is optionally substituted with a C 1-6 Alkyl-substituted pyrazolopiperidine or pyridopiperidine.

[0023] In one specific implementation, R1, R2, and R3 are each independently hydrogen or deuterium;

[0024] R4 is either hydrogen or methyl;

[0025] One of R5 and R6 is C. 2-6 Alkenyl group, and another one is C. 1-6 Alkoxy;

[0026] X is selected from: —(chemical bond), -N-, -CH-, -NCH2-, or not present;

[0027] Y is selected from: —(chemical bond), -N-, -CH-, -CH2N-, -CH2NMe-, or not present; and

[0028] A is a methyl-substituted piperidine, pyrrolidine, bicyclic [1.1.1]pentyl, phenyl, benzo[a]piperidine wherein the benzene ring is optionally substituted with a hydroxyl group and / or a halogen, methyl-substituted piperazine, thiazo[a]piperidine, thiophen[a]piperidine, wherein the pyrazole ring is optionally substituted with a C-type hydroxyl group. 1-6 Alkyl-substituted pyrazolopiperidine or pyridopiperidine.

[0029] Another aspect of the present invention provides a compound or its stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, solvates or isotopically labeled analogs thereof, said compound being selected from the following compounds:

[0030] Another aspect of the present invention provides a compound of formula (II),

[0031] in

[0032] R7 is selected from: C with optional substitution 3-6 Cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C 6- 10 Aryl and optionally substituted 5-10 membered heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or is substituted by one or more substituents selected from the following: -NHPO(R 1a (R) 1b C 1-6 Alkyl, halogen, hydroxyl, mercapto, amino, cyano, and carbonyl groups, wherein R 1a and R 1b Each was independently selected from C 1-6 Alkyl, C 1-6 Alkoxy and C 2- 6-Alkenyl;

[0033] Or its stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, solvates or isotopically labeled analogs.

[0034] In one specific implementation, R7 is the -NHPO(R 1a (R) 1b ) substituted phenyl, pyrrolidine or piperidine, and R 1a and R 1b Each is independently selected from methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and vinyl; preferably, R 1a and R 1b One of them is methyl, ethyl, isopropyl, methoxy, ethoxy, or isopropoxy, and the other is vinyl; most preferably R 1a and R 1b One is methoxy and the other is vinyl.

[0035] In one specific embodiment, R7 is a group selected from the following:

[0036] In one specific embodiment, the compound of formula (II) is selected from the following compounds:

[0037] Another aspect of the present invention provides the use of the above-described compounds in the preparation of a medicament, preferably as a selective JAK3 inhibitor, more preferably for the treatment of autoimmune diseases, and even more preferably the autoimmune diseases are selected from: rheumatoid arthritis, atopic dermatitis, amyotrophic lateral sclerosis, psoriatic arthritis, axial arthritis, ulcerative colitis, Crohn's disease, alopecia areata, ankylosing spondylitis, lupus erythematosus, psoriasis, multiple sclerosis, organ transplant rejection, type 1 diabetes, and diabetic complications.

[0038] In particular, compounds of formula (II) above (represented by compound 17) have been found to also have FLT3 (FMS-like tyrosine kinase-3) inhibitory activity. Therefore, the present invention also provides the use of the compound in the preparation of a medicament for treating FLT3 kinase-mediated diseases, preferably including leukemias such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS). Detailed Implementation

[0039] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0040] Unless otherwise indicated, the terms used herein have their general technical meanings as understood by those skilled in the art.

[0041] In this invention, the singular articles “a” and “the” cover a plurality of indicators unless the context clearly indicates otherwise. All references cited herein are incorporated herein by reference in their entirety.

[0042] As used herein, the term "stereoisomer" refers to isomers that have the same atomic bond sequence but different spatial arrangements of atoms. Stereoisomers with different optical properties are also called optical isomers.

[0043] As used in this article, the term "geometric isomerism" refers to a stereoisomerism phenomenon present in certain double-bonded or cyclic compounds, and the corresponding isomers are called geometric isomers. Due to the presence of double bonds or rings, the free rotation of these molecules is hindered, resulting in two isomers with different physical or chemical properties, called cis and trans isomers, respectively.

[0044] As used in this article, the term "tautomerism" refers to the phenomenon in which the structure of certain organic compounds undergoes an equilibrium interconversion between two functional group isomers, and the corresponding isomers are called tautomers.

[0045] As used herein, the term "medicinal salt" refers to those salts that retain the biological effectiveness and properties of a free base or free acid, and which are not biologically or otherwise unsuitable. These salts are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. Furthermore, these salts can be prepared by adding an inorganic or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of the following substances: primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyamine resins.

[0046] As used in this article, the term "prodrug" refers to a compound that can be converted into an active drug (a compound with pharmacological activity) in the body through chemical reactions or enzymatic action, and then exert its therapeutic effect.

[0047] As used herein, the term "solvent" refers to a molecular complex formed by one or more solvent molecules embedded in the crystal lattice of a drug molecule in a stoichiometric or non-stoichiometric ratio. Depending on the solvent molecules, solvates can be classified as hydrates and other organic solvent compounds.

[0048] As used herein, the term "isotope-labeled analogue" refers to an analogue obtained by substituting an isotope atom for a corresponding atom. The isotope atom includes, for example, 2 H(D, deuterium) 13 C 15 N、 17 O or 18 O、 34 S, 10 B, etc. In this invention, deuterated compounds are preferred.

[0049] As used in this article, the term "C" 1-6 "Alkyl" refers to a monovalent straight-chain or branched saturated hydrocarbon group with 1 to 6 carbon atoms. 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl.

[0050] As used in this article, the term "C"2-6 "Alkenyl" refers to a hydrocarbon group containing one or more carbon-carbon double bonds in the middle or at the end of an alkyl group containing 2 to 6 carbon atoms. Alkenyl groups can be straight-chain or branched. C 2-6 Non-limiting examples of alkenyl groups include vinyl, propenyl, 1-butenyl, 1-pentenyl, 1,3-butadienyl, etc.

[0051] As used in this article, the term "C" 3-10 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group with 3 to 10 carbon atoms. C 3-10 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0052] As used in this article, the term "C" 1-6 "Alkoxy" refers to a group of the formula -O-R', where R' is a carbon atom. 1-6 Alkyl group. C 1-6 Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particular example is methoxy.

[0053] As used herein, the term "4-10 membered heterocyclic alkyl" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system with 4 to 10 ring atoms, comprising 1, 2, or 3 cyclic heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. A bicyclic ring indicates a system consisting of two rings sharing a common ring atom, where the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocyclic alkyl groups are 4,5-dihydro-oxazolyl, oxazolidinyl, aziridine, pyrrolyl, 2-oxo-pyrrolidine-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazoyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, aziridine-heptyl, diaziridine-heptyl, homopiperazinyl, or oxazonicycloheptyl. Examples of bicyclic saturated heterocyclic alkyl groups are bicyclic [1.1.1]pentyl, 8-aza-bicyclo[3.2.1]octyl, quininecycloyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocyclic alkyl groups are dihydrofuranyl, imidazolinyl, dihydrooxazolyl, tetrahydropyridyl, or dihydropyranyl.

[0054] As used in this article, the term "C" 4-10 "Aryl" refers to a functional group or substituent derived from an aromatic hydrocarbon ring and containing 4 to 10 cyclic carbon atoms. 4-10 The aryl group can be a monocyclic aryl or a polycyclic aryl. C 4-10Non-limiting examples of aryl groups include phenyl, naphthyl, etc.

[0055] As used herein, the term "5-10 membered heteroaryl" refers to a monocyclic or bicyclic aromatic heterocyclic system comprising 5 to 10 ring carbon atoms, containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of heteroaryl groups include pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, and azatriylyl groups. basalt, diazoxide The aromatic compounds include pyrazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothiophenyl, indolyl, isoindolyl, benzopiperidinyl, thiazopiperidinyl, thiophenepiperidinyl, pyrazolopiperidinyl, pyridinopiperidinyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzodiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, and benzothiopheneyl. Particularly noteworthy heteroaryl groups are pyrazinyl, pyridinyl, pyrimidinyl, and thiopheneyl.

[0056] As used herein, the term “halogen” or “halogenated”, alone or in combination, refers to fluorine, chlorine, bromine or iodine, and in particular fluorine, chlorine or bromine, and even more particularly fluorine and chlorine.

[0057] The purpose of this invention is to provide pyrimidine amide or phosphonamide derivatives and their preparation methods, as well as the application of such compounds in the prevention and / or treatment of autoimmune diseases.

[0058] In a first aspect, the present invention provides compounds represented by formulas (I) and (II) below, and their stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates or isotopically labeled analogs.

[0059] in,

[0060] R1, R2, and R3 are independently selected from: hydrogen, deuterium, or optionally substituted C. 1-6 Alkyl or optionally substituted C 1-6 Alkenyl groups and optionally substituted C 3-10 cycloalkyl and optionally substituted C 1-6 Alkoxy; the optional substitution means that the hydrogen on the substituted group is not substituted or that one or more substituted sites of the substituted group are independently selected from hydrogen, alkyl, hydroxy, mercapto, amino, cyano, etc.

[0061] R4 is selected from: hydrogen, or C with optional substitution. 1-6 Alkyl or optionally substituted C 1-6 Alkenyl groups and optionally substituted C3-10 cycloalkyl and optionally substituted C 1-6 Alkoxy; the optional substitution means that the hydrogen on the substituted group is not substituted or that one or more substituted sites of the substituted group are independently selected from hydrogen, alkyl, hydroxy, mercapto, amino, cyano, etc.

[0062] R5 and R6 are independently selected from: hydrogen, or optionally substituted C. 1-6 Alkyl or optionally substituted C 1-6 Alkenyl groups and optionally substituted C 3-10 cycloalkyl and optionally substituted C 1-6 Alkoxy; the optional substitution means that the hydrogen on the substituted group is not substituted or that one or more substituted sites of the substituted group are independently selected from hydrogen, alkyl, etc.

[0063] X is selected from: —(chemical bond), -N-, -CH-, -NCH2-, or not present;

[0064] Y is selected from: —(chemical bond), -N-, -CH-, -CH2N-, -CH2NMe-, or not present;

[0065] A is selected from: C with optional substitution. 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C 4-10 One of aryl and optionally substituted 5-10-membered heteroaryl groups; wherein the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substituted sites of the substituted group are independently selected from hydrogen, alkyl, hydroxyl, halogen, etc.

[0066] R7 is selected from: C with optional substitution 3-6 Cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C 6- 10 The aryl group, or one of the optionally substituted 5-10 membered heteroaryl groups; wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that one or more substituted sites of the substituted group are independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, cyano, carbonyl, -NHPO(R) 1a (R) 1b ) replaced by, where R 1a and R 1b Each occurrence is independently selected from methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and vinyl;

[0067] In a preferred embodiment of the invention, R1, R2, and R3 are independently selected from: hydrogen, deuterium, and optionally substituted C. 1-6 Alkyl or optionally substituted C 1-6Alkenyl group. The optional substitution means that the hydrogen on the substituted group is not substituted or that one or more substituted sites of the substituted group are independently selected from hydrogen, alkyl, hydroxyl, etc.

[0068] R4 is selected from: hydrogen, or C with optional substitution. 1-6 Alkyl or optionally substituted C 1-6 Alkenyl groups and optionally substituted C 3-10 Cycloalkyl; the optional substitution means that the hydrogen on the substituted group is not substituted or that one or more substituted sites of the substituted group are independently selected from hydrogen, alkyl, hydroxyl, etc.

[0069] R5 and R6 are independently selected from: hydrogen, or optionally substituted C. 1-6 Alkyl or optionally substituted C 1-6 Alkenyl groups and optionally substituted C 1-6 Alkoxy; the optional substitution means that the hydrogen on the substituted group is not substituted or that one or more substituted sites of the substituted group are independently selected from hydrogen, alkyl, etc.

[0070] X is selected from: —(chemical bond), -N-, -CH-, -NCH2-, or not present;

[0071] Y is selected from: —(chemical bond), -N-, -CH-, -CH2N-, -CH2NMe-, or not present;

[0072] A is selected from: C with optional substitution. 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C 4-10 One of aryl and optionally substituted 5-10-membered heteroaryl groups; wherein the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substituted sites of the substituted group are independently selected from hydrogen, alkyl, hydroxyl, halogen, etc.

[0073] R7 is selected from: C with optional substitution 3-6 Cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C 6- 10 One of aryl and optionally substituted 5-10 membered heteroaryl groups; wherein the optional substitution means that the hydrogen on the substituted group is not substituted or that one or more substituted sites of the substituted group are independently selected from hydrogen, halogen, hydroxyl, carbonyl, -NHPO(R 1a (R) 1b ) replaced by, where R 1a and R 1b Each occurrence is independently selected from methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and vinyl.

[0074] In the most preferred embodiment of the invention, R1, R2 and R3 are independently selected from: hydrogen or deuterium;

[0075] R4 is selected from: hydrogen, methyl; R 5， R6 is independently selected from: hydrogen, or optionally substituted C. 1-6 Alkenyl and optional substituted C 1-6 Alkoxy; the optional substitution means that the hydrogen on the substituted group is not substituted or that one or more substituted sites of the substituted group are independently selected from hydrogen, alkyl, etc.

[0076] X is selected from: —(chemical bond), -N-, -CH-, -NCH2-, or not present;

[0077] Y is selected from: —(chemical bond), -N-, -CH-, -CH2N-, -CH2NMe-, or not present;

[0078] A is selected from: C with optional substitution. 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C 4-10 One of aryl and optionally substituted 5-10-membered heteroaryl groups; wherein the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substituted sites of the substituted group are independently selected from hydrogen, alkyl, hydroxyl, halogen, etc.

[0079] R7 is selected from: optionally substituted 4-6 membered heterocyclic alkyl groups, optionally substituted C 6-10 One of the aryl groups; the optional substitution refers to the hydrogen on the substituted group being unsubstituted or one or more substituted sites of the substituted group being independently selected from hydrogen, halogen, -NHPO(R 1a (R) 1b ) replaced by, where R 1a and R 1b Each time it appears, select independently: methoxy, ethoxy, isopropoxy, vinyl;

[0080] In a preferred embodiment of the present invention, the compounds represented by formulas (I) and (II), and their stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, hydrates, solvates, or isotopically labeled analogs are selected from the following compounds:

[0081] Furthermore, the present invention includes pharmaceutical compositions comprising compounds of formulas (I) and (II) and pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients refer to any diluent, adjuvant, and / or carrier that can be used in the pharmaceutical field. The compounds of the present invention can be used in combination with other active ingredients, provided they do not produce other adverse effects, such as allergic reactions.

[0082] The pharmaceutical combinations of the present invention can be formulated into several dosage forms, containing some excipients commonly used in the pharmaceutical field, such as oral formulations (e.g., tablets, capsules, solutions or suspensions); injectable formulations (e.g., injectable solutions or suspensions, or injectable dry powders that can be used immediately after being added to water for injection before injection); and topical formulations (e.g., ointments or solutions).

[0083] The carriers used in the pharmaceutical compositions of this invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, pigments, flavoring agents, etc., for oral formulations; preservatives, solubilizers, stabilizers, etc., for injectable formulations; and matrices, diluents, lubricants, preservatives, etc., for topical formulations. The pharmaceutical formulations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0084] Through in vitro activity screening, we found that the compounds of this invention selectively inhibit JAK3 kinase activity. Therefore, the compounds of this invention can be used to prepare drugs for the treatment and / or prevention of various autoimmune diseases, such as rheumatoid arthritis, atopic dermatitis, psoriatic arthritis, axial arthritis, ulcerative colitis, Crohn's disease, alopecia areata, ankylosing spondylitis, lupus erythematosus, psoriasis, multiple sclerosis, psoriasis, type I diabetes and diabetic complications; but are not limited thereto.

[0085] The compounds of this invention can be used as the sole agent for autoimmune diseases, or in combination with one or more other agents for autoimmune diseases. Combination therapy is achieved by administering the various therapeutic components simultaneously, sequentially, or separately.

[0086] The above only summarizes some aspects of the present invention and is not, and should not be considered as limiting the present invention in any way.

[0087] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0088] The starting materials used in the embodiments of this application are known and can be obtained from commercial suppliers, or can be synthesized according to methods known in the art.

[0089] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or high-performance liquid chromatography (HPLC). NMR determinations were performed using a Bruker AVANCE NEO 400 (or 600) MHz; LC-MS determinations were performed using LCMS Waters ACQUITY UPLC H-Class PLUS and / or SQD2; and HPLC determinations were performed using Waters ACQUITY UPLC and / or Agilent 1260.

[0090] Example 1: Preparation of 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)-2-chloro-2-fluoroacetone

[0091] Step 1: Synthesis of (2S,5R)-5-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carboxylic acid benzyl ester

[0092] (2S,5R)-5-amino-2-methylpiperidin-1-carboxylic acid benzyl ester (2.48 g, 10.0 mmol) and 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.87 g, 10.0 mmol) were dissolved in N,N-dimethylformamide (30 mL), and N,N-diisopropylethylamine (3.87 g, 30.0 mmol) was added. The mixture was heated to 100 °C, and the reaction was completed after 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate (V / V = 4 / 1)) to give the title compound (1b) (3.3 g, yield 82.5%), a yellow solid. 1 H NMR (400MHz, CDCl3, ppm): δ11.22(s,1H),7.40-7.31(m,5H),7.03(s,1H),6.38(s,1H),5.22-5.12(m,3H),4.58-4.49(m,2H), 4.15-4.07(m,1H),2.80-2.74(m,1H),2.07-2.04(m,1H),1.95-1.87(m,1H),1.72-1.66(m,2H),1.28-1.21(m,3H); LCMS[M+H] + :400.1.

[0093] Step 2: Synthesis of (3R,6S)-(6-methylpiperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl-amine

[0094] (2S,5R)-5-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-carboxylic acid benzyl ester (3.2 g, 8.0 mmol) was dissolved in methanol (30 mL), and 1.5 g of Pd / C (10%, 0.5 w / w) was slowly added. The mixture was reacted at room temperature under a hydrogen atmosphere for 16 hours. After filtration, the filter cake was washed with methanol, and the filtrate was concentrated to give 1.85 g of crude yellow solid, which was the target compound 1c. The crude product was used directly in the next reaction. LCMS [M+H] + :232.1.

[0095] Step 3: Synthesis of 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)-2-chloro-2-fluoroethyl ketone

[0096] (3R,6S)-(6-methylpiperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl-amine 1c (920 mg, 4.0 mmol), sodium chlorofluoroacetate 1d (800 mg, 6.0 mmol), and HATU (2.28 g, 6.0 mmol) were dissolved in N,N-dimethylformamide (30 mL), followed by the addition of N,N-diisopropylethylamine (1.56 g, 12.0 mmol). The reaction was stirred at room temperature, and the reaction was completed after 16 hours. The mixture was concentrated, and the crude product was prepared by reversed-phase HPLC (C18, 0.05% ammonium bicarbonate aqueous solution, acetonitrile) to give the title compound (121 mg, yield 9.3%) as a white solid. 1 H NMR (400MHz, DMSO-d6, ppm): δ11.53(s,1H),8.13-8.09(m,1H),7.42-7.09(m,3H),6.53(s,1H),4.69 -4.42(m,1H),4.22-3.78(m,2H),3.10-2.66(m,1H),1.92-1.66(m,4H),1.32-1.13(m,3H); LCMS[M+H] + :326.1.

[0097] Example 2: Preparation of N-2-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)-2-oxoethyl)-2-chloro-2-fluoroacetamide

[0098] Step 1: Synthesis of 2-2-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)-2-oxoethyl)isoindoline-1,3-dione

[0099] Compound (3R,6S)-(6-methylpiperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl-amine 1c (920 mg, 4.0 mmol, 1.0 eq), compound phthaloylglycine 2a (1.23 g, 6.0 mmol, 1.5 eq), and HATU (2.28 g, 6.0 mmol) were dissolved in N,N-dimethylformamide (20 mL), followed by the addition of N,N-diisopropylethylamine (1.55 g, 12.0 mmol). The mixture was stirred at room temperature for 16 hours, and the reaction solution was concentrated under reduced pressure. The crude product was purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate (V / V = 2 / 1)) to give target compound 2b (890 mg, yield 53.2%) as a yellow solid. LCMS [M+H] + :419.1.

[0100] Step 2: Synthesis of 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)-2-aminoethyl-1-one

[0101] Compound 2-2-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)-2-oxoethyl)isoindoline-1,3-dione 2b (835 mg, 2.0 mmol) was dissolved in ethanol (10 mL), followed by the addition of hydrazine hydrate (300 mg, 6.0 mmol). The mixture was stirred at room temperature for 16 hours and concentrated to give crude product compound 2c (575 mg), a yellow solid. The crude product was used directly in the next reaction. LCMS [M+H] + :289.0.

[0102] Step 3: Synthesis of N-2-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)-2-oxoethyl)-2-chloro-2-fluoroacetamide

[0103] Compound 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)-2-aminoethyl 1-one 2c (575 mg, 2.0 mmol), sodium chlorofluoroacetate (402 mg, 3.0 mmol), and HATU (1.14 g, 3.0 mmol) were dissolved in N,N-dimethylformamide (10 mL), followed by the addition of N,N-diisopropylethylamine (780 mg, 6.0 mmol). The mixture was stirred at room temperature for 16 hours, the reaction solution was concentrated, and the crude product was prepared by reversed-phase HPLC (C18, 0.05% ammonium bicarbonate aqueous solution, acetonitrile) to give title compound 2 (143 mg, yield 18.7%), a white solid. 1 HNMR(400MHz,DMSO-d6,ppm):11.54-11.51(m,1H),8.72-8.69(m,1H),8.10(d,J=8.0Hz,1H),7.36-7.26(m,1H),7.09(s,1H),6.88(d,J= 24Hz,1H),6.56-6.54(m,1H),4.73-4.49(m,1H),4.23-3.86(m,4H),2.97-2.54(m,1H),1.85-1.65(m,4H),1.26-1.14(m,3H); LCMS[M+H] + :383.1.

[0104] Example 3: Preparation of methyl 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)-2-vinylphosphonamide

[0105] Step 1: Synthesis of methyl vinyl chlorophosphonate

[0106] Dimethyl vinylphosphonate 3a (5.44 g, 40 mmol) was dissolved in dichloromethane (100 mL), and oxalyl chloride (19.3 g, 152 mmol) was slowly added under nitrogen protection at room temperature. The reaction was carried out at room temperature for 16 hours, followed by reflux for 1 hour. The reaction solution was concentrated to give crude product compound 3b (5.5 g), a colorless oil. The crude product was used directly in the next reaction.

[0107] Step 2: Synthesis of 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)-2-vinylphosphonamide methyl ester

[0108] (3R,6S)-(6-methylpiperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl-amine 1c (531 mg, 2.3 mmol) and N,N-diisopropylethylamine (593 mg, 4.6 mmol) were dissolved in dichloromethane (15 mL), followed by the slow addition of vinylchlorophosphonate methyl 3b (354 mg, 2.53 mmol). The reaction was carried out at room temperature under nitrogen protection for 4 hours. Dichloromethane (100 mL) was added to the reaction solution, and the organic phase was washed once with water and once with saturated sodium chloride solution. The crude product was purified by rapid chromatography (Silica gel, dichloromethane:methanol (V / V = 40 / 1)) to give the title compound (146 mg, yield 19%) as a white solid. 1 H NMR (400MHz, DMSO-d6, ppm): δ11.49(s,1H),8.09(s,1H),7.19-7.17(m,1H),7.07(s,1H),6.54(s,1H),6.18-5.93(m,3H),4.06-3.48(m,5H),2.68(br s,1H),1.83-1.61(m,4H),1.20-1.15(m,4H); LCMS[M+H] + :336.1.

[0109] Example 4: Preparation of ((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)-2-vinylphosphonamide ethyl ester

[0110] Similarly, using commercially available dimethyl vinylphosphonate and (3R,6S)-(6-methylpiperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl-amine 1c as starting materials, compound 4 was prepared according to the preparation method of Example 3. 1 HNMR (400MHz, DMSO-d6, ppm): δ11.48(s,1H),8.08(d,J=6.8Hz,1H),7.17(dd,J=1.6,7.6Hz,1H),7.07(t,J=2.8Hz,1H),6.53(t,J=1.2 Hz,1H),6.39-5.90(m,3H),4.07-3.81(m,4H),3.42-3.32(m,1H),2.75-2.59(m,1H),1.82-1.60(m,4H),1.33-1.14(m,6H); LCMS[M+H] + 350.1.

[0111] Example 5: Preparation of (2S,5R)-2-methyl-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)vinylphosphonamide methyl ester

[0112] Step 1: Synthesis of (2S,5R)-2-methyl-5-((7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylic acid benzyl ester

[0113] Under nitrogen protection, 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 g, 3.52 mmol) was dissolved in n-butanol (50 mL). Then, (2S,5R)-5-amino-2-methylpiperidin-1-carboxylic acid benzyl ester (963 mg, 3.88 mmol) and N,N-diisopropylethylamine (1.37 g, 10.57 mmol) were added. The mixture was reacted at 140 °C for 12 hours, cooled to room temperature in an ice bath, and the crude product was concentrated. The crude product was then prepared by reversed-phase HPLC (C18, 0.05% ammonium bicarbonate aqueous solution, acetonitrile) to give the title compound (600 mg, 34.3%) as a white solid. LCMS [M+H] + :496.6.

[0114] Step 2: Synthesis of benzyl ((2S,5R)-2-methyl-5-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate

[0115] Under nitrogen protection, (2S,5R)-2-methyl-5-((7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylic acid benzyl ester (600 mg, 1.21 mmol) was dissolved in anhydrous DMF (15 mL) and cooled to 0 °C. Sodium hydride (73 mg, 60%, 1.82 mmol) was then added in portions, and the resulting mixture was reacted at 0 °C for 0.5 hours, followed by the slow dropwise addition of iodomethane (344 mg, 2.42 mmol). The reaction mixture was then stirred at 0 °C for 0.5 hours and gradually raised to room temperature, followed by stirring at room temperature for 1.5 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to produce a crude yellow oily substance (610 mg, 98.9%). The crude product is used directly in the next reaction. LCMS[M+H] + :510.6.

[0116] Step 3: Synthesis of N-methyl-N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine

[0117] (2S,5R)-2-methyl-5-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-carboxylic acid benzyl ester (600 mg, 1.20 mmol) was dissolved in trifluoroacetic acid (TFA) (50 mL). The reaction mixture was stirred at 60 °C for 5 hours and then concentrated. Ammonia was added to adjust the pH to 8-9, and the mixture was further concentrated to obtain the crude product. The crude product was prepared by reversed-phase HPLC (C18, 0.05% ammonium bicarbonate aqueous solution, acetonitrile) to give the title compound (290 mg, 98.2%). LCMS [M+H] + :246.2.

[0118] Step 4: Synthesis of (2S,5R)-2-methyl-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)vinylphosphonamide methyl ester

[0119] N-Methyl-N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (290 mg, 1.18 mmol) was dissolved in dichloromethane (20 mL), and then N,N-diisopropylethylamine (612 mg, 4.73 mmol) was added to this mixture and the mixture was cooled to 0 °C. Then, a solution of methyl vinylphosphoryl chloride (177 mg, 1.30 mmol) in dichloromethane (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 5 hours and then concentrated. The crude product was purified by rapid chromatography (Silica gel, dichloromethane:methanol:ammonia (V / V / V = 120 / 10 / 1)) to give the title compound (35.5 mg, 8.6%) as a light brown oil. 1 H NMR (400MHz, DMSO-d6, ppm): δ11.61(br,1H),8.11(s,1H),7.15(d,1H,J=4.0Hz),6 .57(d,1H,J=4.0Hz),6.20-5.99(m,3H),4.64(br,1H),3.80(br,1H),3.63(d,1.5H ,J=8.0Hz),3.51(d,1.5H,J=8.0Hz),3.24(s,3H),3.18-2.96(m,2H),2.09-2.04(m ,1H),1.80-1.59(m,3H),1.23(dd,2.5H,J=8.0,12.0Hz),0.94(d,0.5H,J=8.0Hz). LCMS[M+H] + 350.1.

[0120] Example 6: Preparation of ((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)-2-(vinyl)phosphonamide isopropyl ester

[0121] Similarly, using commercially available diisopropyl vinylphosphonate and (3R,6S)-(6-methylpiperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl-amine 1c as starting materials, compound 6 was prepared according to the preparation method of Example 3. 1 HNMR (400MHz, DMSO-d6, ppm): δ11.48(s,1H),8.06(d,J=6.8Hz,1H),7.25(d,J=7.6Hz,1H),7.06 -7.08(m,1H),6.53(s,1H),6.45-6.00(m,3H),4.39-4.61(m,1H),3.83-4.12(m,2H),3.43-3 .29(m,1H),2.77-2.58(m,1H),1.82-1.59(m,4H),1.38-1.13(m,9H).LCMS:364.2(M+H,ESI).

[0122] Example 7: Preparation of ((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)divinylphosphine oxide

[0123] Step 1: Synthesis of divinyl ethyl phosphate

[0124] At 25 °C, ethyl dichlorophosphate compound 7a (5.00 g, 30.8 mmol) was dissolved in tetrahydrofuran (50 mL). The reaction solution was cooled to -78 °C, and then vinyl magnesium bromide (61 mL, 61 mol) was added to the system. After the addition was complete, the reaction mixture was stirred at -78 °C for 3.5 hours. At the reaction temperature of -78 °C, a saturated ammonium chloride aqueous solution (30 mL) was slowly added dropwise to quench the reaction system. The mixture was slowly raised to room temperature, and then extracted with ethyl acetate (200 mL). The organic phase was washed twice with a saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by rapid chromatography (Silica gel, dichloromethane:methanol (V / V = 20 / 1)) to give the target compound (2.6 g, yield 57.8%) as a colorless liquid. 1H NMR (400MHz, DMSO-d6, ppm): δ6.35-6.11 (m, 6H), 3.91 (q, J = 7.2Hz, 2H), 1.22 (t, J = 7.2Hz, 3H).

[0125] Step 2: Synthesis of divinylphosphonic acid

[0126] At 0°C, 2.60 g (18 mmol) of divinyl ethyl phosphate compound 7b was dissolved in 2.68 mL of trimethylbromosilane. After the addition was complete, the reaction mixture was stirred at 0°C for 3 hours. Then, 30 mL of methanol was slowly added to the reaction mixture at 0°C, and the mixture was stirred at 0°C for 0.5 hours. The reaction mixture was concentrated to obtain crude product compound 7c (2.32 g), a colorless oil. The crude product was used directly in the next reaction step.

[0127] Step 3: Synthesis of divinylphosphonic chloride

[0128] At 0 °C, ethyl divinyl phosphate compound 7c (2.30 g, 16.9 mmol) was dissolved in dichloromethane (20 mL). Oxaloyl chloride (2.10 g, 16.5 mmol) was added to the system, and the mixture was stirred at 0 °C for 24 hours. The reaction solution was concentrated to give crude product compound 7d (2.20 g), a yellow oil. The crude product was used directly in the next reaction step. Step 4: Synthesis of ((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)divinylphosphine oxide

[0129] (3R,6S)-(6-methylpiperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl-amine 1c (461 mg, 2.0 mmol) and N,N-diisopropylethylamine (516 mg, 4.0 mmol) were dissolved in dichloromethane (15 mL), followed by the slow addition of divinylphosphonic chloride compound 7d (301 mg, 2.2 mmol). The reaction mixture was stirred at room temperature for 2 hours under nitrogen protection. Dichloromethane (100 mL) was added to the reaction mixture, and the mixture was washed once with water and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by rapid chromatography (Silica gel, dichloromethane ether: methanol (V / V = 30 / 1)) to give the target compound (166 mg, yield 26%) as a white solid. 1H NMR (400MHz, DMSO-d6, ppm): δδ11.49 (s, 1H), 8.09 (s, 1H), 7.15 (d, J = 4Hz, 1H), 7.07 (s, 1H), 6.54 (s, 1H), 6.18-5.93 (m, 6H), 4.06-4.02(m,1H),3.69-3.67(m,1H),3.36-3.32(m,1H),2.74-2.68(m,1H),1.75-1.56(m,4H),1.20-1.15(m,3H); LCMS[M+H] + :332.2.

[0130] Example 8: Preparation of N-(3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pent-1-yl)-N-methyl-vinylphosphonamide methyl ester

[0131] Step 1: Synthesis of tert-butyl (3-aminobicyclo[1.1.1]pent-1-yl)(methyl)carbamate

[0132] tert-butyl (3-aminobicyclo[1.1.1]pent-1-yl)carbamate (600 mg, 3.03 mmol, 1 equiv.) and potassium tert-butoxide (3.6 mL, 3.64 mmol, 1.2 equiv., 1 mol / L) were dissolved in tetrahydrofuran (10 mL). After stirring at room temperature for half an hour, iodomethane (645 mg, 4.545 mmol, 1.5 equiv.) was added to the mixture, and the reaction was stirred at room temperature for 1 hour. The reaction was monitored by LCMS until completion. The mixture was quenched with ice water (2 mL), concentrated under reduced pressure, and the crude product was prepared by reversed-phase HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, methanol) to give the title compound (490 mg, 2.31 mmol, 76.27%). LCMS [M+H] + :140.2.

[0133] Step 2: Synthesis of tert-butyl 3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate

[0134] (3-Aminobicyclo[1.1.1]pent-1-yl)(methyl)carbamate tert-butyl ester (490 mg, 2.31 mmol, 1 equiv.) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1574 mg, 7.95 mmol, 1.1 equiv.) were dissolved in dimethyl sulfoxide (5 mL). Then, N,N-diisopropylethylamine (1.20 g, 9.245 mmol, 4 equiv.) was added to this mixture. The mixture was purged with nitrogen for 15 minutes, and the reaction solution was stirred in a microwave at 150 °C for 12 hours. The reaction was monitored for completion by LCMS. The reaction solution was then subjected to reversed-phase HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, methanol) to obtain the title compound (180 mg, 0.547 mmol, 23.67%). LCMS [M+H] + :330.3.

[0135] Step 3: Synthesis of N1-methyl-N3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)bicyclo[1.1.1]pentane-1,3-diamine

[0136] 3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate tert-butyl ester (180 mg, 0.547 mmol, 1 equiv.) was dissolved in trifluoroacetic acid (4 mL) and dichloromethane (1 mL). The reaction was stirred at 25 °C for 1 hour, and the reaction was monitored by LCMS until completion. The solution was concentrated under reduced pressure, and then 2 mL of saturated potassium carbonate solution was added to neutralize the remaining trifluoroacetic acid. The mixture was directly prepared by reversed-phase HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, methanol) to give the title compound (90 mg, 0.393 mmol, 71.83%). LCMS [M+H] + :230.3.

[0137] Step 4: Synthesis of N-(3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pent-1-yl)-N-methyl-vinylphosphonamide methyl ester

[0138] N1-methyl-N3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)bicyclo[1.1.1]pentane-1,3-diamine (90 mg, 0.393 mmol, 1 equiv.) was dissolved in pyridine (2 mL) and dichloromethane (0.5 mL), and then vinylphosphonomethyl chloride (550 mg, 3.93 mmol, 10 equiv.) was added to this mixture. The reaction was stirred at 25 °C for 1 h. The reaction was monitored by LCMS until completion. The reaction was quenched with 1 mL of ice water and concentrated under reduced pressure. The residue was dissolved in water and dimethylformamide and prepared by reversed-phase HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to give the title compound (47 mg, 0.141 mmol, 35.91%). 1 H NMR (400MHz, DMSO-d6, ppm) δ11.50(s,1H),8.13(s,1H),7.95(s,1H),7.07(s,1H),6.54(d,J=2.8Hz,1 H),6.33–5.87(m,3H),3.55(d,J=12.0Hz,3H),2.64(d,J=8.8Hz,3H),2.31(d,J=8.0Hz,6H).LCMS[M+H] + :334.4.

[0139] Example 9: Preparation of N-(((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-2-yl)methyl)-N-methyl-vinylphosphonamide methyl ester:

[0140] Step 1: Synthesis of (R)-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-2-yl)tert-butyl methylcarbamate

[0141] 4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2.84 g, 10 mmol, 1.0 eq.), (R)-(piperidin-2-ylmethyl)carbamate tert-butyl ester (2.14 g, 1 mmol, 1.0 eq.), and N,N-diisopropylethylamine (1.3 g, 10 mmol, 1 eq.) were dissolved in dimethyl sulfoxide (20 mL), and the mixture was stirred at 150 °C for 1 hour. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by rapid chromatography (Silica gel, petroleum ether (60-90): ethyl acetate (V / V = 5 / 1)) to give the target compound (2.0 g, 43.3%). LCMS [M+H] + :462.3.

[0142] Step 2: Synthesis of (R)-methyl(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-2-yl)methylcarbamate tert-butyl

[0143] (R)-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-2-yl)methylcarbamate tert-butyl ester (461 mg, 1 mmol, 1.0 eq.), methyl iodoformate (142 mg, 1 mmol, 1.0 eq.), and 60% sodium hydride (40 mg, 0.1 mmol, 1 eq.) were dissolved in N,N-dimethylformamide (20 mL), and the mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by rapid chromatography (Silica gel, petroleum ether (60-90): ethyl acetate (V / V = 5 / 1)) to give the target compound (320 mg, 67.4%). LCMS[M+H] + :476.3.

[0144] Step 3: Synthesis of (R)-(4-(2-((methylamino)methyl)piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methanol

[0145] (R)-methyl(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-2-yl)methylcarbamate tert-butyl ester (47.5 mg, 0.1 mmol, 1.0 eq.) and trifluoroacetic acid (97 mg, 1.0 mol, 10 eq.) were dissolved in dichloromethane (2 mL), and the mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated to give the crude target compound (27.5 mg, 100%). LCMS [M+H] + : 276.3.

[0146] Step 4: Synthesis of N-(((R)-1-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-2-yl)methyl)-N-methyl-vinylphosphonamide ester

[0147] (R)-(4-(2-((methylamino)methyl)piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methanol (27.5 mg, 0.1 mmol, 1.0 eq) and methylvinylphosphonochloride (14.2 mg, 0.1 mmol, 1.0 eq) were dissolved in a mixture of N,N-dimethylformamide (2 mL) and triethylamine (1 mL). The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated to give the crude target compound (37.9 mg, 100%). LCMS[M+H] + 380.3.

[0148] Step 5: Synthesis of N-(((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-2-yl)methyl)-N-methyl-vinylphosphonamide methyl ester

[0149] N-(((R)-1-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-2-yl)methyl)-N-methyl-P-vinylphosphonamide ester (37.9 mg, 0.1 mmol, 1.0 eq) and potassium carbonate (138 mg, 1 mmol, 10 eq) were dissolved in acetonitrile (2 mL), and the mixture was stirred at 20 °C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to give a crude product. Two isomers were prepared by reversed-phase HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile).

[0150] P1 (7mg, 20%) 1H NMR(500MHz,MeOD,ppm)δ8.11(d,J=7.0Hz,1H),7.09(t,J=3.5Hz,1H),6.62(t,J=4.5Hz,1H),6.21–5.57(m,3H),5.46(s,1H),4.49(d,J=11.5Hz,1H),3 .91(dt,J=14.0,9.5Hz,1H),3.66–3.42(m,4H),3.31(s,2H),3.02(ddd,J=1 4.0,8.5,5.0Hz,1H),2.59(t,J=10.0Hz,3H),1.95–1.46(m,6H).LCMS[M+H] + 350.3.

[0151] P2 (7mg, 20%) 1 H NMR(500MHz,MeOD,ppm)δ8.11(d,J=7.0Hz,1H),7.09(d,J=3.5Hz,1H),6.63(d ,J=3.5Hz,1H),6.22–5.54(m,3H),5.47(s,1H),4.51(d,J=12.0Hz,1H),3.81(d t,J=14.0,9.5Hz,1H),3.82–3.72(m,1H),3.63–3.43(m,1H),3.16(d,J=11.0Hz ,3H),3.07–2.87(m,1H),2.59(t,J=10.0Hz,3H),1.97–1.46(m,6H).LCMS[M+H] + 350.3.

[0152] Example 10: Preparation of N-(3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)-vinylphosphamide methyl ester:

[0153] Similarly, using commercially available phenyl 1,3-diamine and 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 5a as starting materials, compound 10 was prepared according to steps 1, 3, and 4 of the preparation method in Example 5. 1H NMR (400MHz, DMSO-d6, ppm): δ11.72(s,1H),9.24(s,1H),8.24(s,1H),7.90( d,J=8.0Hz,1H),7.63(t,J=2.0Hz,1H),7.37(dd,J=8.0,1.2Hz,1H),7.21(dd ,J=3.2,2.4Hz,1H),7.12(t,J=8.0Hz,1H),6.78(dd,J=3.6,1.9Hz,1H),6.70 (dd,J=8.0,1.6Hz,1H),6.44–6.00(m,3H),3.64(d,J=11.2Hz,3H).LCMS[M+H] + :330.1.

[0154] Example 11: Preparation of (2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl-2-deuterium)amino)-2-methylpiperidin-1-yl)vinylphosphonamide methyl ester

[0155] Step 1: Synthesis of (2S,5R)-5-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carboxylic acid benzyl ester

[0156] Under nitrogen protection, 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.66 mmol) was dissolved in n-butanol (20 mL). Then, (2S,5R)-5-amino-2-methylpiperidin-1-carboxylic acid benzyl ester (758 mg, 2.66 mmol) and N,N-diisopropylethylamine (1.03 g, 7.98 mmol) were added. The mixture was reacted at 140 °C for 16 hours, cooled to room temperature with ice water, concentrated, and extracted with water (200 mL) and dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by Prep-TLC (Silica gel, dichloromethane:methanol (V / V = 10 / 1)) to give the target compound (745 mg, 70.2%) as a yellow solid. LCMS [M+H] + :400.0.

[0157] Step 2: Synthesis of N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-2-deuter-4-amine

[0158] (2S,5R)-5-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-carboxylic acid benzyl ester (909 mg, 2.27 mmol) was dissolved in deuterated methanol (15 mL). Pd / C (300 mg) was then added, and the mixture was reacted at room temperature for 16 hours under a deuterium atmosphere at 1 atm. The mixture was filtered, the filtrate was concentrated, and the residue was purified by Prep-TLC (Silica gel, petroleum ether (60-90): ethyl acetate (V / V = 1 / 1)) to give the target compound (200 mg, 37.97%) as a yellow solid. LCMS [M+H] + :233.2.

[0159] Step 3: Synthesis of (2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl-2-deuterium)amino)-2-methylpiperidin-1-yl)vinylphosphonamide methyl ester

[0160] N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-2-deuterium-4-amine (300 mg, 1.29 mmol) was dissolved in dichloromethane (10 mL), and then N,N-diisopropylethylamine (499 mg, 3.87 mmol) was added to this mixture. The mixture was then cooled to 0 °C. Subsequently, a dichloromethane solution of methoxyvinylphosphonate chloride (271 mg, 1.935 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The crude product was purified by reversed-phase HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to give the title compound (13.43 mg, 3.1%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6, ppm) δ11.48 (s, 1H), 7.18 (dd, J = 7.8, 4.0Hz, 1H), 7.06 (dd, J=8.4,5.6Hz,1H),6.53(dd,J=3.2,2.0Hz,1H),6.34–5.91(m,3H),4.11–3.95(m,1 H),3.82(s,1H),3.56(dd,J=52.0,11.2Hz,3H),3.43–3.35(m,1H),2.66(ddd,J=1 8.4,11.6,5.6Hz,1H),1.84–1.59(m,4H),1.18(dd,J=14.4,6.8Hz,3H).LCMS[M+H] + :337.1.

[0161] Example 12: Preparation of (2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl-5-deuterium)amino)-2-methylpiperidin-1-yl)vinylphosphonamide methyl ester

[0162] Similarly, using commercially available (2S,5R)-5-amino-2-methylpiperidin-1-carboxylate and 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as starting materials, compound 12 was prepared sequentially according to steps 1 and 2 of the preparation method in Example 11, and steps 3 and 4 of the preparation method in Example 5. 1 H NMR (400MHz, DMSO-d6, ppm): δ11.48(s,1H),8.10(d,J=7.6Hz,1H),7.20(dd,J=7.6,3.6Hz,1H),7.07(d,J=2.0Hz,1H),6.36–5.91(m,3H) ,4.05(s,1H),3.82(s,1H),3.56(dd,J=52.4,11.2Hz,3H),2.77–2.63(m,1H),1.89–1.56(m,5H),1.18(dd,J=14.4,6.8Hz,3H).LCMS[M+H] + :337.2.

[0163] Example 13: Preparation of (4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3,4-dihydroisoquinoline-2(1H))vinylphosphonamide methyl ester

[0164] Similarly, using commercially available 4-amino-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester and 5-bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as starting materials, two isomers of compound 13 were prepared sequentially according to step 1 of the preparation method in Example 11 and steps 3 and 4 of the preparation method in Example 5.

[0165] P1 1 H NMR (400MHz, DMSO-d6, ppm): δ11.53(s,1H),8.20(dd,J=25.6,3.6Hz,1H),7.68(dd,J=17.6,8.4Hz,1H),7.32–7.20(m,4H),7. 09–7.03(m,1H),6.61(t,J=3.6Hz,1H),6.27–5.78(m,3H),5.59–5.41(m,1H),4.47–4.15(m,2H),3.63–3.34(m,5H).LCMS[M+H] + : 370.0.

[0166] P2 1 H NMR (400MHz, DMSO-d6, ppm): δ11.53(s,1H),8.17(d,J=3.6Hz,1H),7.68(dd,J=17.6,8.0Hz,1H),7.26(ddd,J=11.6,8.0,4.8Hz,4H ),7.11–6.96(m,1H),6.61(t,J=3.6Hz,1H),6.37–5.73(m,3H),5.57–5.43(m,1H),4.42–4.15(m,2H),3.70–3.33(m,5H).LCMS[M+H] + : 370.0.

[0167] Examples 14 and 15

[0168] Similarly, compounds 14 and 15 were prepared sequentially using commercially available starting materials according to the preparation methods described in the above embodiments.

[0169] Example 16: Preparation of (2S)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)-2-methylpiperidin-1-yl)vinylphosphonamide methyl ester

[0170] Step 1: Synthesis of (S)-(1-oxopropyl-2-yl)carbamate tert-butyl ester

[0171] Under nitrogen protection, (S)-(1-hydroxypropyl-2-yl)carbamate tert-butyl ester (10 g, 57.07 mmol) was dissolved in anhydrous dichloromethane (350 mL) and cooled to 0 °C. Then, Dietrich Martin's reagent (25.42 g, 59.92 mmol) was added in portions, and the mixture was stirred overnight at room temperature before adding saturated sodium bicarbonate aqueous solution (100 mL). The resulting suspension was filtered, and the filtrate was separated. The aqueous phase was extracted with dichloromethane (2 x 100 mL), the organic phases were combined, and the mixture was washed with saturated sodium thiosulfate aqueous solution (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound (319 mg, 16.0%). 1 H NMR (400MHz, DMSO-d6, ppm): δ9.43 (s, 1H), 7.32 (d, 1H, J = 8.0Hz), 3.89-3.82 (m, 2H), 1.40 (s, 9H), 1.03 (d, 3H, J = 4.0Hz).

[0172] Step 2: Synthesis of (S)-4-((tert-Butoxycarbonyl)amino)pent-2-enoic acid methyl ester

[0173] (S)-(1-oxopropyl-2-yl)carbamate tert-butyl ester (9.36 g, 54.04 mmol) was dissolved in dichloromethane (350 mL) and cooled to 0 °C. Then, a dichloromethane (150 mL) solution of methoxyformylmethylenetriphenylphosphine (19.87 g, 59.44 mmol) was added to this mixture. The reaction mixture was stirred at room temperature for 16 hours and then concentrated. The crude product was purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate (V / V = 5 / 1)) to give the target compound (11.8 g, 95.2%) as a clear, colorless, oily liquid. 1 H NMR (400MHz, CDCl3, ppm) δ6.81 (dd, 1H, J = 4.0, 16.0Hz), 5.84 (d, 1H, J = 16.0Hz), 4.47 (br, 1H), 4.33 (br 1H), 3.67 (s, 3H), 1.38 (s, 9H), 1.20 (d, 3H, J = 8.0Hz).

[0174] Step 3: Synthesis of methyl (S)-4-((tert-Butoxycarbonyl)amino)valerate

[0175] Methyl (S)-4-((tert-Butoxycarbonyl)amino)pent-2-enoate (11.8 g, 51.47 mmol) was dissolved in methanol (400 mL), and then Pd / C (2.3 g) was added to the mixture under a nitrogen atmosphere. The reaction mixture was then stirred at room temperature under a hydrogen atmosphere at 1 atm for 20 hours and filtered. The filtrate was concentrated to give the crude title compound (11.5 g, 96.6%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃, ppm) δ 4.38 (br, 1H), 3.67 (s, 4H), 2.30 (t, 2H, J = 8.0 Hz), 1.77–1.66 (m, 2H), 1.37 (s, 9H), 1.07 (d, 3H, J = 8.0 Hz).

[0176] Step 4: Synthesis of (S)-(6-(dimethyl(oxo)-16-thionyl)-5-oxohexane-2-yl)tert-butyl carbamate

[0177] At room temperature, trimethyl sulfoxide (17.51 ​​g, 79.55 mmol) was added fractionally to a solution of potassium tert-butoxide (9.21 g, 82.05 mmol) in tetrahydrofuran (100 mL). Under nitrogen protection, the mixture was stirred at 65 °C for 2 hours and then cooled to room temperature. Subsequently, a solution of (S)-4-((tert-butoxycarbonyl)amino)valerate (11.5 g, 49.72 mmol) in tetrahydrofuran (30 mL) was slowly added to this mixture. The reaction mixture was stirred at room temperature for 16 hours and then filtered. The filtrate was concentrated, and the crude product was purified by rapid chromatography (Silica gel, dichloromethane ether:methanol (V / V = 10 / 1)) to give the title compound (6.3 g, 43.5%) as a pale white solid. LCMS [M+H] + :292.3.

[0178] Step 5: Synthesis of (S)-2-methyl-5-oxoperidin-1-carboxylic acid tert-butyl ester

[0179] Under nitrogen protection, [Ir(COD)Cl2]2 (35 mg, 54.3 μmol) was dissolved in anhydrous dichloroethane (40 mL) and stirred at 65 °C for 30 min. Then, a solution of (S)-(6-(dimethyl(oxo)-16-thionyl)-5-oxohexane-2-yl)carbamate (1.5 g, 5.43 mmol) in dichloroethane (20 mL) was added dropwise over 2 hours. The reaction mixture was then cooled to room temperature and stirred at room temperature for 16 hours before concentration. The crude product was purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate (V / V = 4 / 1)) to give the title compound (670 mg, 60.9%). 1 H NMR (400MHz, CDCl3, ppm) δ4.34 (d, 1H, J = 20.0Hz), 4.22 (s, 1H), 3.50 (d, 1H, J = 20.0Hz), 2. 43-2.31(m,2H),2.20-2.08(m,1H),1.58-1.43(m,1H),1.40(s,9H),1.17(d,3H,J=8.0Hz).

[0180] Step 6: Synthesis of (S)-2-methyl-5-enylpiperidine-1-carboxylic acid tert-butyl ester

[0181] Under nitrogen protection, triphenylmethylphosphine bromide (1.51 g, 4.22 mmol) was dissolved in anhydrous toluene (10 mL), and the mixture was cooled to 0 °C. Potassium tert-butoxide (395 mg, 3.52 mmol) was then added in portions, and the mixture was stirred at 0 °C for 1 hour. Subsequently, a toluene solution of (S)-2-methyl-5-oxopiperidin-1-carboxylic acid tert-butyl ester (500 mg, 2.34 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours and quenched with a saturated ammonium chloride aqueous solution (30 mL). The mixture was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate (V / V = 5 / 1)) to give the title compound (312 mg, 63.0%). 1 H NMR (400MHz, CDCl3, ppm) δ4.74 (s, 1H), 4.67 (s, 1H), 4.28 (br, 1H), 4.24 (d, 1H, J = 16.0Hz), 3.43 (d, 1H, J = 16.0Hz) ,2.32-2.24(m,1H),2.15-2.09(m,1H),2.11(d,3H,J=8.0Hz),1.71-1.66(m,1H),1.52-1.47(m,1H),1.39(s,9H).

[0182] Step 7: Synthesis of (2S)-2-methyl-5-((7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl ester)piperidine-1-carboxylic acid tert-butyl ester

[0183] Under nitrogen protection, (S)-2-methyl-5-enylpiperidin-1-carboxylic acid tert-butyl ester (313 mg, 1.48 mmol) was dissolved in anhydrous tetrahydrofuran (7 mL), followed by the slow dropwise addition of a tetrahydrofuran solution of 9-BBN (0.5 M, 6 mL, 3 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours, quenched with water (5 mL), and then 10 mL of tetrahydrofuran was added. Then, 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (280 mg, 0.99 mmol), tetrakis(triphenylphosphine)palladium (114 mg, 0.01 mmol), and potassium carbonate (409 mg, 2.96 mmol) were added to the mixture. The reaction mixture was refluxed for 2 hours, cooled to room temperature, and diluted with 15 mL of water. The mixture was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, concentrated, and the crude product was purified by reversed-phase HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to give the title compound (385 mg, 84.6%). LCMS [M+H] +:461.3.

[0184] Step 8: Synthesis of 4-(((6S)-6-methylpiperidin-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine

[0185] (2S)-2-methyl-5-((7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl ester)piperidin-1-carboxylic acid tert-butyl ester (3.13 g, 6.79 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of trifluoroacetic acid (10 mL). The mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in acetonitrile (15 mL) and ammonia water (15 mL) was added. The reaction mixture was stirred at room temperature for 16 hours and then concentrated. The crude product was purified by reversed-phase HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to give the title compound (720 mg, 46.2%). LCMS [M+H] + :231.3.

[0186] Step 9: Synthesis of (2S)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl)-2-methylpiperidin-1-yl)vinylphosphonamide methyl ester

[0187] Under nitrogen atmosphere, 4-(((6S)-6-methylpiperidin-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine (720 mg, 313 μmol) was dissolved in anhydrous dichloromethane (30 mL) and cooled to 0 °C. Then, N,N-diisopropylethylamine (404 mg, 9.38 mmol) and methylvinylphosphonic chloride (659 mg, 4.69 mmol) were added sequentially. The reaction mixture was brought to room temperature and stirred for 1 hour, then concentrated. The crude product was purified by Prep-HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to obtain two isomers.

[0188] P1 (28 mg, 2.7%). 1 H NMR (400MHz, DMSO-d6, ppm) δ12.02(s,1H),8.64(s,1H),7.48(d,1H,J=4.0Hz),6.65(d,1H,J=4.0Hz),6.11-5.85(m,3H),3.80-3.70(m,1H),3.43( d,3H,J=12.0Hz),3.13-3.06(m,1H),2.90-2.80(m,2H),2.74-2.64(m,1H) ),1.98-1.91(m,1H),1.51-1.43(m,4H),1.14(d,3H,J=8.0Hz); LCMS[M+H] +:335.1.

[0189] P2 (32mg, 3.1%). 1 H NMR (400MHz, DMSO-d6, ppm) δ11.94(br,1H),8.65(s,1H),7.48(d,1H,J=4.0Hz),6.64(d,1H,J=4.0Hz),6.11-5.85(m,3H),3.80-3.70(m,1H),3.43( d,3H,J=12.0Hz),3.13-3.06(m,1H),2.90-2.80(m,2H),2.74-2.64(m,1H) ),1.99-1.91(m,1H),1.51-1.43(m,4H),1.14(d,3H,J=8.0Hz); LCMS[M+H] + :335.1.

[0190] Example 17: Preparation of N-(4-(2-((4-morpholinylphenyl)amino)pyrimidin-4-yl)phenyl)vinyl)phosphonamide methyl ester

[0191] Step 1: Synthesis of 2-((4-morpholinylphenyl)amino)pyrimidin-4-ol

[0192] A mixture of 2-methylthio-4-pyrimidinone (20 g, 140 mmol) and 4-(4-morpholino)aniline (25 g, 140 mmol) was heated to 160 °C and stirred for 4 h. After cooling to room temperature, the reaction mixture was washed three times with methanol (50 mL x 3) and dried under vacuum to give the title compound 17b (38.3 g, 100% yield). LCMS [M+H] + :273.2.

[0193] Step 2: Synthesis of 4-chloro-N-(4-morpholinylphenyl)pyrimidine-2-amine

[0194] 2-((4-morpholinylphenyl)amino)pyrimidin-4-ol (38 g, 140 mmol) was dissolved in phosphorus oxychloride (500 mL), and the reaction mixture was heated to 120 °C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was poured into ice water (500 mL). The mixture was adjusted to pH 9 with sodium hydroxide (1 M). The precipitate was filtered and dried under vacuum to give the title compound 17c (38 g, 100% yield). LCMS [M+H] + :291.2.

[0195] Step 3: Synthesis of 4-(4-aminophenyl)-N-(4-morpholinylphenyl)pyrimidine-2-amine

[0196] 4-Chloro-N-(4-morpholinylphenyl)pyrimidin-2-amine 17c (3 g, 10.3 mmol), 4-aminophenylboronic acid (2.83 g, 20.7 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (757 mg, 1.03 mmol), and potassium carbonate (4.18 g, 30.3 mmol) were dissolved in dioxane / water (50 mL / 10 mL). The reaction mixture was heated to 100 °C and stirred for 3 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the crude product was purified by rapid chromatography (Silica gel, dichloromethane ether:methanol (V / V = 20 / 1)) to give the target compound (2.5 g, 70% yield) as a yellow solid. LCMS [M+H] + :347.2.

[0197] Step 4: Synthesis of N-(4-(2-((4-morpholinylphenyl)amino)pyrimidin-4-yl)phenyl)vinyl)phosphonamide methyl ester

[0198] At -78°C, a solution of methyl vinyl chlorophosphonate (3.02 g, 21.6 mmol) in dichloromethane (20 mL) was added to a solution of 4-(4-aminophenyl)-N-(4-morpholinylphenyl)pyrimidin-2-amine (1.5 g, 4.32 mmol) and N,N-diisopropylethylamine (5.57 g, 43.2 mmol) in dichloromethane (50 mL). The reaction mixture was slowly heated to room temperature and stirred for 3 hours, then poured into water. The mixture was extracted three times with dichloromethane (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by rapid chromatography (Silica gel, dichloromethane ether:methanol (V / V = 30 / 1)) to give the target compound (70 mg, yield 4%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6, ppm): δ9.31(s,1H),8.40(d,J=5.2Hz,1H),8.01(d,J=8.4Hz,2H),7.67(d,J=8.4Hz,2H),7.21(d,J=5.2Hz,1H),7 .16(d,J=8.4Hz,2H),6.93(d,J=8.4Hz,2H),6.16-6.08(m,3H),3.75–3.73(m,4H),3.65(d,J=12.0Hz,3H),2.51–2.49(m,4H); LCMS[M+H] + :452.1.

[0199] Example 18: Preparation of N-(3-(2-((4-morpholinylphenyl)amino)pyrimidin-4-yl)phenyl)vinyl)phosphonamide methyl ester

[0200] Similarly, using commercially available 3-aminophenylboronic acid and 4-chloro-N-(4-morpholinylphenyl)pyrimidine-2-amine 17c as starting materials, compound 18 was prepared according to steps 3-4 of the preparation method in Example 17. 1 H NMR (400MHz, DMSO-d6, ppm): δ9.40(s,1H),8.47(d,J=5.2Hz,1H),8.15–8.13(m,1H),7.82(s,1H),7.70(d,J=8.4Hz,2H),7.60(d,J=5.2Hz,1H),7. 37–7.35(m,1H),7.20–7.18(m,1H),7.16–7.15(m,1H),6.35-6.05(m,3H) ,3.75–3.73(m,4H),3.65(d,J=12.0Hz,3H),2.51–2.49(m,4H); LCMS[M+H] + :452.1.

[0201] Example 19: Preparation of N-(1-(2-((4-morpholinylphenyl)amino)pyrimidin-4-yl)pyrrole-3-yl-vinylphosphonamide methyl ester

[0202] Step 1: Synthesis of 4-(1-(2-((4-morpholinylphenyl)amino)pyrimidin-4-yl)pyrrolo-3-yl)tert-butyl carbonate

[0203] 4-Chloro-N-(4-morpholinylphenyl)pyrimidin-2-amine 17c (1.8 g, 6.2 mmol) and 3-(Boc-amino)pyrrolidine (2.06 g, 10.3 mmol) were dissolved in N,N-dimethylformamide (30 mL), followed by the addition of potassium carbonate (4.27 g, 30.9 mmol). The reaction mixture was stirred at 110 °C for 16 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (30 mL x 3). The organic phase was washed once with water and saturated brine, then dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was washed with methanol and dried under vacuum to give the target compound (1.4 g, 51% yield). LC-MS [M+H] + :441.2.

[0204] Step 2: Synthesis of 4-(3-aminopyrrolo-1-yl)-N-(4-morpholinylphenyl)pyrimidine-2-amine

[0205] 1.4 g (3.1 mmol) of 4-(1-(2-((4-morpholinylphenyl)amino)pyrimidin-4-yl)pyrrolo-3-yl)tert-butyl carbonate 19a was dissolved in 20 mL of N-dichloromethane, followed by the addition of 5 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated to give crude compound 19b (1.2 g, 51% yield). LC-MS [M+H] + 341.2. The crude product is used directly in the next reaction step.

[0206] Step 3: Synthesis of N-(1-(2-((4-morpholinylphenyl)amino)pyrimidin-4-yl)pyrrole-3-yl-vinylphosphonamide methyl ester

[0207] At -78°C, a solution of methyl vinylchlorophosphonate (3.02 g, 21.6 mmol) in dichloromethane (20 mL) was added to a solution of 4-(3-aminopyrrolo-1-yl)-N-(4-morpholinophenyl)pyrimidin-2-amine (1.5 g, 4.32 mmol) and N,N-diisopropylethylamine (5.57 g, 43.2 mmol) in dichloromethane (50 mL). The reaction mixture was slowly heated to room temperature and stirred for 3 hours, then poured into water. The mixture was extracted three times with dichloromethane (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by rapid chromatography (Silica gel, dichloromethane ether:methanol (V / V = 30 / 1)) to give the target compound (110 mg, yield 6%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6, ppm): δ8.75(s,1H),7.86(d,J=5.2Hz,1H),7.63(d,J=8.4Hz,2 H),6.83(d,J=8.4Hz,2H),6.24–5.95(m,3H),5.85(d,J=5.2Hz,1H),5.24–5.19(m,1H ),3.79–3.78(m,2H),3.73–3.71(m,4H),3.55(d,J=12.0Hz,3H),3.43–3.40(m,1H),3 .29–3.24(m,1H),3.04–2.99(m,4H),2.20–2.13(m,1H),1.86–1.79(m,1H); LCMS[M+H] + :445.2.

[0208] Example 20: Preparation of N-(1-(2-((4-morpholinylphenyl)amino)pyrimidin-4-yl)pyrrole-3-yl-vinylphosphonamide methyl ester

[0209] Step 1: N 2-(4-morpholinophenyl)-N 4 Synthesis of 3-nitrobenzyl)pyrimidine-2,4-diamine

[0210] 4-Chloro-N-(4-morpholinylphenyl)pyrimidin-2-amine 17c (7.0 g, 24.1 mmol) and 3-nitrobenzylamine (7.34 g, 48.3 mmol) were dissolved in N,N-dimethylformamide (30 mL), followed by the addition of potassium carbonate (8.54 g, 61.9 mmol). The reaction mixture was stirred at 110 °C for 3 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (30 mL x 3). The organic phase was washed once with water and saturated brine, then dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude target compound (10 g, 94% yield). LC-MS [M+H] + :407.2.

[0211] Step 2: N 2 -(4-morpholinophenyl)-N 4 Synthesis of 3-(aminobenzyl)pyrimidine-2,4-diamine

[0212] N 2 -(4-morpholinophenyl)-N 4 -(3-nitrobenzyl)pyrimidine-2,4-diamine 20a (10.0 g, 22.7 mmol) was dissolved in methanol / water (100 mL / 100 mL), followed by the addition of ammonium chloride (6.4 g, 113.5 mmol) and iron powder (6.5 g, 113.5 mmol). The mixture was reacted and stirred at 80°C for 3 hours. The reaction mixture was poured into water (100 mL), and the mixture was extracted three times with ethyl acetate (30 mL x 3). The organic phase was washed once with water and saturated brine, then dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by rapid chromatography (Silica gel, dichloromethane ether:methanol (V / V = 30 / 1)) to give the title compound (2 g, yield 21%). LCMS [M+H] + :377.2.

[0213] Step 3: Synthesis of N-(1-(2-((4-morpholinylphenyl)amino)pyrimidin-4-yl)pyrrole-3-yl-vinylphosphonamide methyl ester

[0214] At -78℃, to N 2 -(4-morpholinophenyl)-N 4A solution of methyl vinylchlorophosphonate (3.02 g, 21.6 mmol) in dichloromethane (20 mL) was added to a solution of (3-aminobenzyl)pyrimidine-2,4-diamine 20b (1.5 g, 3.98 mmol) and N,N-diisopropylethylamine (5.57 g, 43.2 mmol). The reaction mixture was slowly heated to room temperature and stirred for 3 hours, then poured into water. The mixture was extracted three times with dichloromethane (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by rapid chromatography (Silica gel, dichloromethane ether:methanol (V / V = 30 / 1)) to give the title compound (30 mg, yield 2%) as a white solid. 1 H NMR (400MHz, DMSO-d6, ppm): δ7.76-7.69(m,2H),6.98-6.89(m,5H),6.43-6.34(m,3H),6.09-6.02(m,3H) ,5.01(s,1H),4.27-4.25(m,2H),3.75–3.71(m,4H),3.50(d,J=12.0Hz,3H),3.11–3.07(m,4H); LCMS[M+H] + :481.2.

[0215] Example 21: Preparation of N-(1-(2-((4-morpholinylphenyl)amino)pyrimidin-4-yl)piperidin-3-yl)vinylphosphonamide methyl ester

[0216] Similarly, using commercially available 3-tert-butoxycarbonylaminopiperidine and 4-chloro-N-(4-morpholinylphenyl)pyrimidine-2-amine 17c as starting materials, compound 21 was prepared according to steps 1-3 of the preparation method in Example 19. 1 H NMR (400MHz, DMSO-d6, ppm): δ8.74 (s, 1H), 7.88 (d, J = 5.2Hz, 1H), 7.55–7.52 (m, 2H ),6.85–6.83(m,2H),6.17–5.91(m,4H),4.99–4.95(m,1H),4.31–4.25(m,1H),4.0 7–4.02(m,1H),3.73–3.71(m,4H),3.51(d,J=12.0Hz,3H),3.00–2.93(m,4H),2.88 –2.73(m,3H),1.91–1.89(m,1H),1.73–1.70(m,1H),1.43–1.41(m,2H); LCMS[M+H] + :459.2.

[0217] Example 22: Preparation of N-(1-(2-((4-morpholinylphenyl)amino)pyrimidin-4-yl)piperidin-4-yl)vinylphosphonamide methyl ester

[0218] Similarly, using commercially available 4-tert-butoxycarbonylaminopiperidine and 4-chloro-N-(4-morpholinylphenyl)pyrimidine-2-amine 17c as starting materials, compound 22 was prepared according to steps 1-3 of the preparation method in Example 19. 1 H NMR (400MHz, DMSO-d6, ppm): δ8.75(s,1H),7.88(d,J=5.2Hz,1H),7.54(d,J=9.2Hz,2H),6.85(d,J=9.2Hz,2H),6.27–5.93(m,4H),4.89–4.84(m,1H), 4.25–4.22(m,1H),3.73–3.71(m,4H),3.51(d,J=12.0Hz,3H),3.19–3.15( m,1H),3.01–2.93(m,6H),1.81–1.78(m,2H),1.38–1.27(m,2H); LCMS[M+H] + :459.2.

[0219] Example 23: Preparation of (2S,4R)-4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpyrrolidine-1-yl)vinylphosphonamide methyl ester

[0220] Similarly, using commercially available (2S,4R)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester and 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as starting materials, compound 23 was prepared sequentially according to step 1 of the preparation method in Example 11 and steps 3 and 4 of the preparation method in Example 5. 1 H NMR (400MHz, DMSO-d6, ppm): δ11.51(br,1H),8.11(s,1H),7.38(d,1H,J=4. 0Hz),7.08(s,1H),6.56(s,1H),6.16-5.99(m,3H),4.60-4.44(m,1H),3.61 -3.54(m,5H),2.98-2.83(m,1H),2.51-2.40(m,1H),1.62-1.53(m,1H),1.2 9(d,1H,J=8.0Hz),1.24(d,1H,J=8.0Hz),0.94(d,1H,J=4.0Hz); LCMS[M+H] +:322.1.

[0221] Example 24: Preparation of (2S,4R)-2-methyl-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidine-1-yl)vinylphosphonamide methyl ester:

[0222] Similarly, using commercially available (2S,4R)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester and 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as starting materials, compound 24 was prepared according to steps 1-4 of the preparation method in Example 5. 1 H NMR (400MHz, DMSO-d6, ppm): δ11.66(br,1H),8.12(s,1H),7.16(s,1H),6.57( s,1H),6.33-6.02(m,3H),5.35-5.23(m,1H),3.77-3.59(m,1H),3.58(d,3H,J =12.0Hz),3.32-3.20(m,4H),3.15-3.07(m,1H),2.33-2.24(m,1H),1.74-1.6 7(m,1H),1.31(dd,2.5H,J=8.0,16.0Hz),0.95(d,0.5H,J=4.0Hz); LCMS[M+H] + :336.1.

[0223] Example 25: Preparation of (R)-3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)vinylphosphonamide methyl ester

[0224] Similarly, using commercially available (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine as starting materials, compound 25 was prepared sequentially according to steps 2-4 of the preparation method in Example 8. 1H NMR (400MHz, DMSO-d6, ppm): δ11.52(br,1H),8.12(s,1H),7.39(d,1H,J=4.0Hz),7.08(t,1H,J=4.0Hz),6.59(br,1H),6.27-5.93(m,3H),4.6 6-4.60(m,1H),3.57-3.52(m,3H),3.49-3.43(m,1H),3.22-3.18(m,1H ),3.07-3.01(m,2H),2.23-2.15(m,1H),1.99-1.91(m,1H); LCMS[M+H] + :308.2.

[0225] Example 26: Preparation of (R)-2-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-methylpyrrolidine-1-yl)vinylphosphonamide methyl ester

[0226] Similarly, using commercially available (R)-2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester and 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as starting materials, compound 26 was prepared sequentially according to steps 1, 3 and 4 of the preparation method in Example 5. 1 H NMR (400MHz, DMSO-d6, ppm): δ11.46 (br, 1H), 8.07 (s, 1H), 7.05 (d, 1H, J = 4.0Hz), 6.51 (s, 1H), 6.31-5.96 (m, 3H), 3.95(d,0.5H,J=8.0Hz),3.80(d,0.5H,J=8.0Hz),3.57-3.32(m,5H),3.09(br,2H),1.97-1.74(m,4H); LCMS[M+H] + :322.1.

[0227] Example 27: Preparation of (R)-2-((methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-methylpyrrolidine-1-yl)vinylphosphonamide methyl ester

[0228] Similarly, using commercially available (R)-2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester and 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as starting materials, compound 27 was prepared sequentially according to steps 1-4 of the preparation method in Example 5. 1H NMR (400MHz, DMSO-d6, ppm): δ11.59 (br, 1H), 8.07 (s, 1H), 7.11 (s, 1H), 6.69 (d, 1H, J = 16.0Hz), 6.16-6.85 (m, 3H) ,4.09-3.70(m,3H),3.46(q,3H,J=8.0Hz),7.36(d,3H,J=8.0Hz),3.15-2.05(m,2H),1.96-1.67(m,4H); LCMS[M+H] + :336.2.

[0229] Example 28: Preparation of N-(((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidine-2-yl)methyl)-N-methyl-vinylphosphonamide methyl ester

[0230] Similarly, using commercially available (R)-(pyrrolidine-2-ylmethyl)carbamate tert-butyl ester and 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as starting materials, Example 28 was prepared by following steps 1-4 of the preparation method in Example 5. 1 H NMR (400MHz, DMSO-d6, ppm): δ11.57 (s, 1H), 8.09 (d, J = 1.6Hz, 1H), 7.20–6.98 (m, 1H), 6 .59(d,J=7.6Hz,1H),6.31–5.86(m,3H),4.67(dd,J=7.1,4.2Hz,1H),3.90(s,1H),3.71 (dd,J=17.0,8.9Hz,1H),3.50(dd,J=34.0,11.1Hz,3H),3.21–2.99(m,2H),2.70(dd,J= 9.7,3.3Hz,3H),2.07(dd,J=27.2,16.2Hz,3H),1.86(dd,J=16.6,8.6Hz,1H); LCMS[M+H] + :336.1.

[0231] Example 29: Preparation of N-(3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pent-1-yl)vinylphosphonamide methyl ester

[0232] Similarly, using commercially available tert-butyl ((3-aminobicyclo[1.1.1]pent-1-yl)carbamate and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine as starting materials, compound 29 was prepared sequentially according to steps 2-4 of the preparation method in Example 8. 1 H NMR (400MHz, DMSO-d6, ppm): δ11.48(s,1H),8.15–8.07(m,1H),7.90(s,1H),7.09–7.00(m,1H),6.52(dd,J =3.6,2.0Hz,1H),6.28–5.93(m,3H),5.88(d,J=9.4Hz,1H),3.54(d,J=11.2Hz,3H),2.23(s,6H); LCMS[M+H] + :320.1.

[0233] Example 30: Preparation of N-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pent-1-yl)vinylphosphonamide methyl ester

[0234] Step 1: Synthesis of tert-butyl (3-((7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate

[0235] 4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1.5 g, 5.3 mmol, 1 equiv.) and (3-aminobicyclo[1.1.1]pent-1-yl)carbamate tert-butyl ester (1.57 g, 7.95 mmol, 1.5 equiv.) were dissolved in dimethyl sulfoxide (8 mL). Then, N,N-diisopropylethylamine (2.74 g, 21.2 mmol, 4 equiv.) was added to this mixture. The mixture was purged with nitrogen for 15 minutes, and then stirred under microwave at 150 °C for 1 hour. The reaction was monitored for completion by LCMS. The reaction mixture was poured into water (100 mL), and the mixture was extracted three times with ethyl acetate (30 mL x 3). The organic phase was washed once with water and saturated brine, then dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate (V / V = 3 / 1)) to give the title compound (1.38 g, yield 58.5%). LCMS [M+H] + :446.3.

[0236] Step 2: Synthesis of tert-butyl (3-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate (30C) and tert-butyl (30d) methyl(3-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate (30d)

[0237] (3-((7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate tert-butyl ester (850 mg, 1.91 mmol, 1 equiv.) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (153 mg, 3.82 mmol, 2 equiv, 60% purity) was added. The reaction was stirred at 0 °C for half an hour. Iodimethane (407 mg, 2.87 mmol, 1.5 equiv) was added at 0 °C and the mixture was stirred at 0 °C for 1 hour. The reaction was monitored by LCMS until completion. The reaction solution was quenched with ice water (30 mL), extracted with ethyl acetate (30 mL x 3), and the organic phase was washed once with water and saturated brine. The mixture was then dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by rapid chromatography (Silica gel, petroleum ether:ethyl acetate (V / V = 3 / 1)) to give the title compound 30C (83 mg, yield 9.5%). LCMS [M+H] + : 460.4 and title compound 30d (530mg, yield 58.7%), LCMS [M+H] + :474.4.

[0238] Step 3: N 1 -Methyl-N 1 Synthesis of 7H-pyrrolo[2,3-d]pyrimidin-4-yl)bicyclo[1.1.1]pentane-1,3-diamine

[0239] (3-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)tert-butyl carbamate (83 mg, 0.18 mmol, 1 equiv.) was dissolved in trifluoroacetic acid (2 mL) and dichloromethane (0.5 mL). The reaction was stirred at 25 °C for 1 hour, then concentrated under reduced pressure. Acetonitrile (2 mL) and water (4 mL) were added, followed by potassium carbonate (249 mg, 1.8 mmol, 10 equiv.). The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS until completion. The reaction solution was filtered off with water (5 mL), and the solid was removed. The filtrate was purified by reversed-phase HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, methanol) to obtain the title compound (41 mg, 0.18 mmol, 99%). LCMS [M+H] + :230.4.

[0240] Step 4: Synthesis of N-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pent-1-yl)vinylphosphonamide methyl ester

[0241] N 1 -Methyl-N 1 -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)bicyclo[1.1.1]pentane-1,3-diamine (41 mg, 0.18 mmol, 1 equiv.) was dissolved in pyridine (2 mL) and dichloromethane (0.5 mL), and then vinylphosphonomethyl chloride (504 mg, 3.6 mmol, 20 equiv.) was added to this mixture. The reaction was stirred at 25 °C for 1 h. The reaction was monitored by LCMS until completion. The reaction solution was concentrated under reduced pressure, and the crude product was purified by reversed-phase HPLC (C18, 10 mmol / L ammonium bicarbonate aqueous solution, acetonitrile) to give the title compound (7 mg, 0.021 mmol, 11.67%). 1 H NMR (400MHz, DMSO-d6, ppm): δ11.64(s,1H),8.03(d,J=68.6Hz,1H),7.14(s,1H),6.56(t,J= 6.8Hz,1H),6.31–5.72(m,4H),3.54(d,J=11.2Hz,3H),3.27(s,3H),2.31(s,6H).LCMS[M+H] + :334.4.

[0242] Example 31: Preparation of N-methyl-N-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pent-1-yl)vinylphosphonamide methyl ester

[0243] Similarly, starting with methyl(3-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[1.1.1]pentan-1-yl)carbamate tert-butyl ester (30d), compound 31 was prepared according to steps 3-4 of the preparation method in Example 30. 1 H NMR (400MHz, DMSO-d6, ppm): δ11.66(s,1H),8.13(s,1H),7.16(s,1H),6.59(s,1H),6.40–5.7 7(m,3H),3.55(d,J=11.2Hz,3H),3.30(s,3H),2.63(d,J=8.8Hz,3H),2.39(s,6H); LCMS[M+H] + :348.1.

[0244] Examples 32-43:

[0245] Similarly, using commercially available starting materials, intermediate amines were synthesized according to the method described in the reference (Journal of Medicinal Chemistry 2025, 68, 13, 13268-13294), and then each compound was prepared according to the final step of the preparation method in Example 5 or Example 7.

[0246] Example 32:

[0247] 1 H NMR (400MHz, DMSO-d6, ppm) δ11.51(s,1H),8.17-8.16(m,1H),7.69-7.62(m,1H),7.34-7.31(m,1H),7.13-7.05( m,3H),6.61-6.58(m,1H),6.27-5.73(m,3H),5.48-5.45(m,1H),4.37-4.19(m,2H),3.58-3.38(m,5H); LCMS[M+H] + :388.2.

[0248] Example 33:

[0249] 1H NMR (400MHz, DMSO-d6, ppm) δ11.61(s,1H),9.03(d,J=5.4Hz,1H),8.20(s,1H),7.82(dd,J=18.4,7.9Hz,1H) ,7.10(s,1H),6.57(s,1H),6.44-5.77(m,3H),5.62(s,1H),4.47-4.15(m,2H),3.82-3.34(m,5H); LCMS[M+H] + :377.1.

[0250] Example 34:

[0251] 1 H NMR (400MHz, DMSO-d6, ppm) δ11.57(s,1H),8.18(d,J=2.0Hz,1H),7.77(dd,J=16.4,8.3Hz,1H),7.45(t,J=5.4Hz,1H),7.07-7.08(m,1H),6.93 -6.94(m,1H),6.60-6.61(m,1H),6.41–5.76(m,3H),5.58(d,J=6.0Hz,1 H),4.33–4.05(m,2H),3.77–3.42(m,4H),3.37-3.26(m,1H); LCMS[M+H] + :376.1.

[0252] Example 35:

[0253] 1 H NMR (400MHz, DMSO-d6, ppm) δ11.56 (s, 1H), 8.19 (d, J = 2.8Hz, 1H), 7.73 (dd, J = 24.7, 7.3Hz, 1H), 7.34 (s, 1H), 7.06 (t, J = 5.1Hz, 1H), 6.6 4(m,1H),6.08-5.96(m,3H),5.50-5.48(m,1H),4.24–4.20(m,1H),3.94–3.90(m,1H),3.55–3.40(m,7H),3.22–3.19(m,1H); LCMS[M+H] + :374.1.

[0254] Example 36:

[0255] 1H NMR (400MHz, DMSO-d6, ppm) δ11.47(s,1H),8.14(s,1H),7.48-7.41(m,1H),7.37-7.36(m,1H),7.03-7.01(m,1H),6.61-6.60(m,1H),6. 30-5.60(m,3H),5.27-5.26(m,1H),4,41-4.33(m,1H),4.22-4.13(m,1H),3.73(s,3H),3.57-3.41(m,4H),3.26-3.17(m,1H); LCMS[M+H] + :374.2.

[0256] Example 37:

[0257] 1 H NMR (400MHz, DMSO-d6, ppm) δ11.73(s,1H),8.17(s,1H),7.18-7.02(m,4H),6.61(s,1H),6.31-5. 96(m,4H),4.31-4.29(m,2H),3.66-3.48(m,4H),3.42-3.35(m,1H),3.00-2.99(m,3H); LCMS[M+H] + :402.2.

[0258] Example 38:

[0259] 1 H NMR(400MHz,DMSO-d6,ppm)δ11.76(s,1H),8.18(s,1H),7.34-7.30(m,1H),7.20-7.19(m,1H),7.13-7.08(m,1H),6.85-6.82( LCMS[M+H] + :402.2.

[0260] Example 39:

[0261] 1H NMR(400MHz,DMSO-d6,ppm)δ11.75(s,1H),8.18-8.17(m,1H),7.30-7.25(m,1H),7.18-7.10(m,2H),6.94-6.92(m,1H), 6.62(s,1H),6.35-5.98(m,4H),4.35-4.23(m,2H),3.65-3.51(m,4H),3.41-3.37(m,1H),3.02-3.01(m,3H); LCMS[M+H] + :402.2.

[0262] Example 40:

[0263] 1 H NMR(400MHz,DMSO-d6,ppm)δ11.76(s,1H),8.18(s,1H),7.23-7.18(m,2H),6.78-6.76(m,1H),6.64-6.63(m,1 H),6.35-5.99(m,4H),4.32-4.18(m,2H),3.66-3.51(m,4H),3.40-3.36(m,1H),3.05-3.04(m,3H); LCMS[M+H] + :420.2.

[0264] Example 41:

[0265] 1 H NMR(400MHz,DMSO-d6,ppm)δ11.71(s,1H),8.17(s,1H),7.39-7.33(m,1H),7.17-7.15(m,2H),7.09-7.05(m,1H),6.60-6.58(m,1 LCMS[M+H] + :402.2.

[0266] Example 42:

[0267] 1H NMR(400MHz,DMSO-d6,ppm)δ11.76(s,1H),8.49(s,1H),8.37-8.36(m,1H),8.18(s,1H),7.21-7.20(m,1H),7.06-7.05(m,1H) ,6.65-6.63(m,1H),6.31-6.01(m,4H),4.37-4.31(m,2H),3.71-3.50(m,4H),3.39-3.36(m,1H),3.04-3.03(m,3H); LCMS[M+H] + :385.2.

[0268] Example 43:

[0269] 1 H NMR(400MHz,DMSO-d6,ppm)δ11.54(s,1H),8.17(s,1H),7.77 -7.75(m,1H),7.38-7.35(m,1H),7.11-7.02(m,3H),6.57-6.56(m,1H),6.41-6.25(m,2H),6.20-6 .14(m,2H),6.10-6.04(m,2H),5.52-5.50(m,1H),4,34-4.17(m,2H),3.45-3.35(m,2H); LCMS[M+H] + :384.2.

[0270] Bioactivity / Uses

[0271] Inhibitory activity of compounds against JAK kinase, etc.

[0272] Experimental Methods: Enzyme activity was detected using various JAK kinase kits. The test compound was initially 50 μM and serially diluted 100-fold to 10 different final concentrations in a 384-well plate. 250 nmol of each solution was then transferred to a 384-well plate using an Echo 550 pipette. 250 nmol of 100% DMSO was added to each negative and positive control well. 10 μl of 2.5-fold final concentration kinase solution was added to each compound and positive control well; 10 μl of 1×Kinase buffer was added to each negative control well. The plates were centrifuged at 1000 rpm for 30 seconds, vortexed to mix, and incubated at room temperature for 10 minutes. A 25 / 15-fold final concentration mixture of ATP and kinase substrate was prepared using 1×Kinase buffer. 15 μl of this 25 / 15-fold final concentration mixture was added to initiate the reaction. The 384-well plate was centrifuged at 1000 rpm for 30 seconds, vortexed to mix, and incubated at room temperature for the appropriate time. Add 30 μl of stop assay solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and vortex to mix. Read the conversion rate using a microplate reader (PerkinElmer: cat.no.caliper ez reader ii). Plot the concentration log value as the X-axis and the percentage inhibition rate as the Y-axis, and use GraphPad Prism 5 software to fit a dose-response curve to obtain the IC50 of each compound on the enzyme activity. 50 value.

[0273] The names of kits for various JAK kinases and their commercial sources are shown in Table 1 below.

[0274] Table 1

[0275] Table 2: Enzymatic data on the inhibition of JAK and other compounds by the compounds in the embodiments of the present invention (Note: Tofacitinib was purchased from Shanghai Haoyuan Biopharmaceutical Technology Co., Ltd., catalog number HY-40354)

[0276] The above results indicate that the compounds of the present invention have excellent inhibitory effects on JAK3 and good selectivity.

[0277] Pharmacokinetic studies of compound concentrations in mice using LC-MS / MS

[0278] Test principle: The plasma concentration of the target drug at different time points was determined by LC-MS / MS to investigate the pharmacokinetic characteristics of mice after a single oral administration of 30 mpk (drug mass mg / animal weight kg).

[0279] Test method: Accurately weigh an appropriate amount of the compound, dissolve the above compound in 0.5% MC (dichloromethane) / deionized water / 1mol / L HCl to obtain a drug formulation with a concentration of 1mg / mL. Male C57BL mice (Shanghai Experimental Animal Center) were used in the experiment. Six mice were administered the drug by gavage at a dose of 30 mpk. Blood samples were collected at 0.083 hr, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 8 hr, and 24 hr (N ​​= 3 / time point). Approximately 50 μL of whole blood (K2EDTA anticoagulated) was collected at each time point and placed on wet ice. 40 μL of whole blood was added to a tube containing 4 μL of stabilizer AEBSF / NaF (100 mM / 40 mg / mL in H2O). The sample was immediately centrifuged at 3000 g at 4℃ for 5 minutes to obtain plasma. 20 μL of plasma was added to a tube containing 2 μL of stabilizer PMSF (benzyl sulfonyl fluoride) (100 mM). The sample was first frozen on dry ice and then stored at a temperature below -60℃ for long-term preservation until sample analysis. The entire sample processing was carried out under wet ice conditions. Blood drug concentrations were determined using a Triple-quadrupole MS system (6500+, SCIEX). Standard curve and quality control preparation: Working solution was prepared by diluting with DMSO. 3 μL of the above standard curve and quality control working solution was added to 57 μL of blank plasma (containing stabilizer). Sample preparation: 150 μL of internal standard solution (Diclofenac, 60 ng / mL in ACN) was added to 20 μL of plasma sample. The mixture was stirred for 10 minutes, centrifuged at 12000 rpm for 10 minutes, and 90 μL of the supernatant was transferred to a fresh plate for analysis. Chromatographic conditions were optimized according to the sample, including mobile phase composition, elution gradient, flow rate, and retention time. A Waters ACQUITY UPLC HSS T3 column (2.1 × 50 mm, 1.8 μm) was used, with an injection volume of 2 μL. Mass spectrometry was performed using an electrospray ionization source (Turbo spray) in positive ion detection mode, with multichannel reaction monitoring (MRM) mode selected for secondary mass spectrometry analysis. Based on drug concentration-time data, pharmacokinetic parameters, including peak concentration C, were calculated using a non-compartmental model using WinNonlin 8.2 software. max Peak time T max Area under the drug-time curve (AUC) and elimination half-life (t) 1 / 2 The AUC is calculated using the linear trapezoidal rule (linear up log down).

[0280] Table 3: Pharmacokinetic parameters of preferred compounds

[0281] The experimental results show that the compound of the present invention has good in vivo exposure in mice after oral administration, moderate half-life, good in vivo pharmacokinetics, and has the potential to become a drug.

[0282] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0283] It should also be noted that the various specific technical features described in the above embodiments can be combined in any suitable manner without contradiction. To avoid unnecessary repetition, the present invention will not describe the various possible combinations separately. Furthermore, various different embodiments of the present invention can also be arbitrarily combined, as long as they do not violate the spirit of the present invention, and should also be regarded as the content disclosed by the present invention.

Claims

1. Compounds of formula (I), in R1, R2, and R3 are each independently selected from: hydrogen, deuterium, halogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optional substituted C 3-10 cycloalkyl and optionally substituted C 1-6 alkoxy, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or is substituted by one or more substituents selected from: C 1-6 Alkyl, halogen, hydroxyl, mercapto, amino, and cyano groups; R4 is selected from: hydrogen, or C with optional substitution. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optional substituted C 3-10 cycloalkyl and optionally substituted C 1-6 alkoxy, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or is substituted by one or more substituents selected from: C 1-6 Alkyl, halogen, hydroxyl, mercapto, amino, and cyano groups; R5 and R6 are each independently selected from: hydrogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optional substituted C 3-10 cycloalkyl and optionally substituted C 1-6 alkoxy, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or is substituted by one or more substituents selected from: C 1-6 Alkyl, halogen, hydroxyl, mercapto, amino, and cyano groups; X is selected from: —(chemical bond), -N-, -CH-, -NCH2-, or not present; Y is selected from: —(chemical bond), -N-, -CH-, -CH2N-, -CH2NMe-, or not present; and A is selected from: C with optional substitution. 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C 4-10 Aryl and optionally substituted 5-10 membered heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or is substituted by one or more substituents selected from the following: C 1-6 Alkyl, halogen, hydroxyl, mercapto, amino, and cyano groups; Or its stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, solvates or isotopically labeled analogs.

2. The compound according to claim 1, wherein... R1, R2, and R3 are each independently selected from: hydrogen, deuterium, halogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl and optional substituted C 1-6 Alkoxy; R4 is selected from: hydrogen, or C with optional substitution. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl and optional substituted C 1-6 Alkoxy; R5 and R6 are each independently selected from: hydrogen, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 Alkenyl and optional substituted C 1-6 Alkoxy; X is selected from: —(chemical bond), -N-, -CH-, -NCH2-, or not present; Y is selected from: —(chemical bond), -N-, -CH-, -CH2N-, -CH2NMe-, or not present; and A is selected from: C with optional substitution. 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C 4-10 Aryl and optionally substituted 5-10 membered heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or is substituted by one or more substituents selected from the following: C 1-6 Alkyl, halogen, hydroxyl, mercapto, amino, and cyano groups.

3. The compound according to claim 1 or 2, wherein... A is optionally substituted piperidine, optionally substituted pyrrolidine, piperazine, bicyclo[1.1.1]pentyl, phenyl, optionally substituted benzopiperidine, optionally substituted thiazopiperidine, optionally substituted thienopiperidine, optionally substituted pyrazolopiperidine, or optionally substituted pyridopiperidine, preferably methyl-substituted piperidine, pyrrolidine, bicyclo[1.1.1]pentyl, phenyl, wherein the benzene ring is optionally substituted with a hydroxyl group and / or a halogen ... 1-6 Alkyl-substituted pyrazolopiperidine or pyridopiperidine.

4. The compound according to any one of claims 1 to 3, wherein R1, R2, and R3 are each independently hydrogen or deuterium; R4 is either hydrogen or methyl; One of R5 and R6 is C. 2-6 Alkenyl group, and another one is C. 1-6 Alkoxy; X is selected from: —(chemical bond), -N-, -CH-, -NCH2-, or not present; Y is selected from: —(chemical bond), -N-, -CH-, -CH2N-, -CH2NMe-, or not present; and A is a methyl-substituted piperidine, pyrrolidine, bicyclic [1.1.1]pentyl, phenyl, benzo[a]piperidine wherein the benzene ring is optionally substituted with a hydroxyl group and / or a halogen, methyl-substituted piperazine, thiazo[a]piperidine, thiophen[a]piperidine, wherein the pyrazole ring is optionally substituted with a C-type hydroxyl group. 1-6 Alkyl-substituted pyrazolopiperidine or pyridopiperidine.

5. A compound or its stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, solvates, or isotopically labeled analogs, wherein the compound is selected from the following:

6. Compounds of formula (II), in R7 is selected from: C with optional substitution. 3-6 Cycloalkyl, optionally substituted 4-10 membered heterocyclic alkyl, optionally substituted C 6- 10 Aryl and optionally substituted 5-10 membered heteroaryl groups, wherein the optional substitution means that the hydrogen on the substituted group is not substituted or is substituted by one or more substituents selected from the following: -NHPO(R 1a (R) 1b C 1-6 Alkyl, halogen, hydroxyl, mercapto, amino, cyano, and carbonyl groups, among which, R 1a and R 1b Each was independently selected from C 1-6 Alkyl, C 1-6 Alkoxy and C 2- 6-Alkenyl; Or its stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, solvates or isotopically labeled analogs.

7. The compound according to claim 6, wherein R7 is -NHPO(R 1a (R) 1b ) substituted phenyl, pyrrolidine or piperidine, and R 1a and R 1b Each is independently selected from methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and vinyl; preferably, R 1a and R 1b One of them is methyl, ethyl, isopropyl, methoxy, ethoxy, or isopropoxy, and the other is vinyl; most preferably R 1a and R 1b One is methoxy and the other is vinyl.

8. The compound according to claim 6 or 7, wherein R7 is a group selected from:

9. The compound according to any one of claims 6 to 8, wherein the compound is selected from the group consisting of:

10. Use of the compound according to any one of claims 1 to 9 in the preparation of a medicament, preferably as a selective JAK3 inhibitor, more preferably for the treatment of autoimmune diseases, and even more preferably the autoimmune diseases are selected from: rheumatoid arthritis, atopic dermatitis, amyotrophic lateral sclerosis, psoriatic arthritis, axial arthritis, ulcerative colitis, Crohn's disease, alopecia areata, ankylosing spondylitis, lupus erythematosus, psoriasis, multiple sclerosis, organ transplant rejection, type 1 diabetes, and diabetic complications.

11. Use of the following compound or its stereoisomers, geometric isomers, tautomers, pharmaceutical salts, prodrugs, solvates or isotopically labeled analogs in the preparation of medicaments for treating FLT3 kinase-mediated diseases.

12. The use according to claim 11, wherein the compound is a compound of the following formula:

13. The use according to claim 11 or 12, wherein the FLT3 kinase-mediated diseases include leukemia, preferably acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS).

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