Macrocyclic nitrogen-containing crown ether compounds and their use as protein kinase inhibitors

Abstract

The present application provides a kind of macrocyclic nitrogen-containing crown ether compound shown in formula (I) and its application as protein kinase inhibitor.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a class of compounds containing macrocyclic nitrogen-containing crown ethers and their stereoisomers, tautomers, or pharmaceutically acceptable salts, methods for their preparation, and pharmaceutical compositions containing said compounds. This invention also relates to the use of these compounds as protein kinase inhibitors. Background Technology

[0002] Protein kinases are enzymes widely distributed within and on the surface of cells; to date, over 500 protein kinases have been discovered and identified. They belong to a family of structure-associated proteins, whose known members are involved in almost all cellular signal transduction activities. The catalytic function of protein kinases is to transfer the γ-phosphate group from the ATP (or GTP) molecule to a specific threonine, serine, or tyrosine group on the target protein, causing a conformational change in the target protein and leading to a transition from a resting to an activated state. Based on the specificity of the target amino acid, protein kinases are divided into two main categories: serine / threonine protein kinases and tyrosine protein kinases.

[0003] Protein kinases play a crucial role in signal transduction and regulation, essential for the normal function of cells and organs, including cell growth, differentiation, proliferation, angiogenesis, apoptosis, cytoskeleton alignment, regulation of metabolic reactions, membrane transport, and cell motility. Beyond these functions, protein kinases also play indispensable roles in non-catalytic processes, such as allosteric effects, subcellular targeting, protein complex scaffolding, protein-protein competitive interactions, and DNA binding. However, when protein kinase genes mutate or are overexpressed, dysregulated protein kinases can lead to various pathological changes, including cancer, inflammation, autoimmune diseases, cardiovascular diseases, and neurological disorders. Therefore, protein kinases have become one of the most important targets in drug development today. In recent years, protein kinase inhibitors have achieved continuous success in clinical treatment and have been approved by drug regulatory agencies worldwide, bringing significant breakthroughs to the treatment of clinical diseases.

[0004] This invention specifically relates to a class of macrocyclic nitrogen-containing crown ether compounds and their use as inhibitors of protein kinases, including but not limited to LRRK2, JAK1, JAK2, JAK3, EGFR and CDK9.

[0005] Leucine-rich repeat kinase 2 (LRRK2) is the protein product of the LRRK2 gene and belongs to the serine / threonine protein kinase class. Although the function of the LRRK2 protein is not fully understood, LRRK2 gene mutations were first identified as being associated with Parkinson's disease (PD) as early as 2004. Common LRRK2 gene mutations include G2019S and I2020T mutations in the kinase active region and R1441G / C / H and Y1699C mutations in the GTPase region. These mutations can all lead to increased LRRK2 protein kinase activity, triggering various pathological changes, including increased phosphorylation of β-synuclein and TAU proteins, neurological inflammation, and neuronal mitochondrial dysfunction.

[0006] Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, affecting over 10 million people worldwide, yet no effective treatment has been found. 10% of PD patients have a significant family history, with LRRK2 mutation being the most common cause. This mutation occurs in approximately 5% of familial PD and 1% of non-familial PD, and the clinical manifestations of these mutations are indistinguishable from sporadic PD. Furthermore, LRRK2 mutations can lead to pathological changes in the TAU protein, a key characteristic of Alzheimer's disease. Therefore, LRRK2 may be located upstream in the pathogenesis of neurodegenerative diseases and plays an important role in other neurodegenerative disorders. Thus, developing LRRK2-specific inhibitors is one of the effective approaches to treating PD and other neurodegenerative diseases.

[0007] Janus kinases (JAKs) are non-receptor tyrosine protein kinases. The JAK family includes four members: JAK1, JAK2, JAK3, and TYK2. They are cytoplasmic tyrosine kinases that transduce cytokine signals from membrane receptors to STAT transcription factors. JAK-STAT-related diseases include rheumatoid arthritis (RA), asthma, ankylosing spondylitis, lupus erythematosus, psoriasis, vitiligo, and other autoimmune diseases. While pan-JAK inhibitors have shown good efficacy in treating inflammatory and neoplastic diseases, off-target effects can occur at higher doses, leading to serious side effects and adverse reactions. Therefore, there is still a need to develop novel inhibitors that target different JAK subtypes for the treatment of autoimmune diseases. For example, highly selective JAK1 inhibitors are being studied in clinical trials for the treatment of rheumatoid arthritis (RA), asthma, and dermatitis, and may have higher safety profiles.

[0008] Cyclin-dependent kinases (CDKs) belong to the serine / threonine kinase family and are a group of protein kinases that regulate cell cycle and gene transcription. At different stages of the cell cycle, CDKs phosphorylate specific cyclins to regulate cellular activity. CDK9 is one of the most important CDKs, cooperating with four cyclins: cyclin T1, cyclin K, cyclin T2a, and T2b. CDK9 binds to cyclins to form a heterodimer of positive transcription elongation factor b (P-TEFb). P-TEFb phosphorylates the C-terminal domain (CTD) of RNA polymerase II, enabling transcription to elongate from the initiation site; it is a core molecule in transcription elongation. Dysregulation of CDK9 kinase activity can lead to a variety of diseases, including highly proliferative diseases (such as cancer), viral infectious diseases, and cardiovascular diseases.

[0009] Given the crucial role of CDK9 in disease, downregulating CDK9 offers an excellent opportunity to develop targeted therapies for cancer and other diseases. While many small-molecule CDK inhibitors have been reported, most lack selectivity for specific CDKs, resulting in low efficacy and high adverse event rates in clinical practice. Therefore, developing CDK9-specific inhibitors is essential for the treatment of human diseases.

[0010] Existing protein kinase compounds do not yet exhibit satisfactory enzyme inhibitory activity or sufficient water solubility, failing to meet the requirements of drug development. Therefore, there is still an urgent need in the current technology for compounds with good protein kinase inhibitory activity and / or good water solubility. Summary of the Invention

[0011] Through research, the inventors have discovered that the heterocyclic compounds containing macrocyclic nitrogen crown ethers of the present invention exhibit excellent inhibitory activity against protein kinases; moreover, these compounds also exhibit good water solubility.

[0012] Based on the above findings, in a first aspect, the present invention provides a compound having the structure of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0013]

[0014] in,

[0015] Z indicates the absence of (covalent bond) or -OCH2CH2-;

[0016] L indicates the absence of (covalent bond), -O-, -NH-, or -N(C). 1～4 alkyl)-;

[0017] A is an aryl group optionally substituted with one or two substituents selected from the following: 5-12 membered heteroaryl group, C 1～10 Alkyl, C 3～8 Cycloalkyl, 3-8 membered heterocyclic or 5-18 membered bridged cyclic, wherein the substituent is selected from: deuterium, C 1～4 Alkyl, C 1～10 Alkoxy, C 3～6 Cycloalkyl, 3- to 8-membered heterocyclic groups, C 1～4 Alkyl phosphoryl group, C 1～4 alkylsulfonyl, aminosulfonyl, C 1～4 Alkylaminosulfonyl, cyano C 3～6 cycloalkyl, C 2～4 alkenylformyl, C 2～4 alkenylformamide, cyanoC 1～4 Alkyl carbamoyl, cyano C 1～4 Alkyl, C 1～4 Alkylformyl-3 to 8-membered heterocyclic groups, C 3～6 Cycloalkylformyl, 3-8 membered heterocyclic sulfonyl, C 1～4 alkylsulfonyl-3 to 8-membered heterocyclic groups, amino C 3～6 Cycloalkylformamide, C 1～4 Alkylphosphorylamino, C 1～4 Alkylsulfonamide, cyano, hydroxyl, oxo, mercapto, amino, C 2～4 Alkenes and halogens;

[0018] R1 is hydrogen, or an optional substituted C. 1～4 Alkyl, C 3～6 cycloalkyl, C 1～4 Alkyl-CO-, -CO or C 1～4 alkylsulfonyl, wherein the substituent is selected from: deuterium, C 1～4 Alkyl, C 1～10 Alkoxy, C 3～6 Cycloalkyl, oxo, cyano, hydroxyl, amino, dimethylamino, hydroxylamine;

[0019] R2 is independently selected from hydrogen, C 1～3 Alkyl, trifluoromethyl, C 1～3 Alkyl groups, cyano groups, and halogens;

[0020] n is 1 or 2;

[0021] Ra is selected from hydrogen, amino, trifluoromethyl, halogen, cyano, C 1～3 Alkyl, acetyl, C 1～3 Alkyl phosphoryl and C 1～3 alkylsulfonyl;

[0022] Rb is selected from hydrogen, amino, and C. 1～3 Alkylamino;

[0023] Ra, Rb and the C atoms they are attached to can form 5-6 membered aromatic rings, 5-12 membered heteroaromatic rings or 5-8 membered heterocycles together;

[0024] More specifically, in some embodiments, the compound of formula (I) has the structure of formula (II) or formula (III):

[0025]

[0026] L, A, R1, R2, Ra, and Rb are defined as above.

[0027] In other embodiments, the compound of formula I has the structure of formula (IV):

[0028]

[0029] Among them, X and Y are each independently selected from C and N;

[0030] Z indicates the absence of a covalent bond or -OCH2CH2; -

[0031] L, A, R1, R2, and n are as defined above.

[0032] In this invention, for compounds of formula (I) or formulas (II)-(IV) above,

[0033] A can preferably have the following structure:

[0034]

[0035] The following compounds or their pharmaceutically acceptable salts are preferred in this invention:

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050] In another aspect of the invention, a pharmaceutical composition is provided comprising a compound of formula (I) as described herein, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier. In some embodiments, the compound of formula (I) has the structures (II)-(IV) described above. In other embodiments, the compound of formula (I) is the specific compound described above.

[0051] In another aspect of the invention, the use of the above-described compounds of the invention or their stereoisomers, tautomers or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the preparation of a medicament for use as a protein kinase inhibitor is provided.

[0052] In another aspect of the invention, the use of the above-described compounds of the invention, or their stereoisomers, tautomers, or pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in the preparation of a medicament for treating or preventing protein kinase-related diseases is provided. These protein kinase-related diseases are those in which protein kinases are involved in the signaling, mediation, regulation, or adjustment of disease development or symptoms. The protein kinases are selected from LRRK2, JAK1, JAK2, JAK3, EGFR, and CDK9. Examples of protein kinase-related diseases include the following disease types: cancer, autoimmune diseases, metabolic diseases, inflammation, infections (bacteria, viruses, yeasts, fungi, etc.), central nervous system diseases, degenerative nervous system diseases, allergies / asthma, skin diseases, vascularization, angiogenesis, cardiovascular diseases, etc.

[0053] In some embodiments, the protein kinase-related diseases described in this invention are selected from neurodegenerative diseases, autoimmune diseases, and tumors. In other preferred embodiments, the protein kinase-related diseases described in this invention are selected from Parkinson's disease, asthma, dermatitis, non-small cell lung cancer, acute myeloid leukemia (AML), and liver cancer.

[0054] The compounds, compositions, and methods described herein are intended for the treatment or prevention of diseases or their symptoms, including transplant rejection (e.g., allogeneic or xenografts of kidney, liver, heart, lung, pancreas (islet cells), bone marrow, cornea, small intestine, and skin), graft-versus-host disease, osteoarthritis, rheumatoid arthritis, multiple sclerosis, diabetes, diabetic retinopathy, asthma, inflammatory bowel disease (Crohn's disease, ulcerative colitis), kidney disease, cachexia, septic shock, lupus, diabetes, myasthenia gravis, psoriasis, dermatitis, eczema, seborrheic dermatitis, Alzheimer's disease, and Parkinson's disease. Stem cell protection during chemotherapy; in vitro selection or purging during autologous or allogeneic bone marrow transplantation; leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, etc.); cancer (breast cancer, lung cancer, colorectal cancer, ovarian cancer, prostate cancer, kidney cancer, squamous cell carcinoma, prostate cancer, glioblastoma, melanoma, pancreatic cancer, Kaposi's sarcoma, etc.); eye diseases; retinal diseases (e.g., macular degeneration, diabetic retinopathy); corneal diseases; glaucoma; bacterial infections; viral infections; fungal infections; and heart disease, including but not limited to restenosis. In one embodiment, the compositions and methods described herein are used to treat or prevent cancer, eye diseases, or retinal diseases. In another embodiment, the compositions and methods described herein are used to treat or prevent rheumatoid arthritis, transplant rejection, asthma, or allergies, or their symptoms. In other embodiments, the compositions and methods described herein are used to treat or prevent diseases or symptoms associated with hyperproliferative disorders or angiogenesis.

[0055] In this article, "optional substitution" means that the groups described in A, R1, etc., may or may not be substituted by substituents; that is, it is not limited to the cases where they are substituted by the listed substituents, but also includes the cases where they are not substituted by the listed substituents. This expression is similar to "R is a substituted or unsubstituted C". 1～10 Alkyl, C 3～6 Cycloalkyl or heterocycloalkyl, phenyl, naphthyl or indole, wherein the substituent is C 1～4 Alkyl, C 1～4 The expressions “alkoxy, cyano, hydroxy, sulfhydryl, amino, or halogen” are the same, but the limitation of substitution or non-substitution is not limited to the narrow sense of C. 1～10 Alkyl groups, but this applies to all the groups described. In this document, when "optional substitution" is mentioned, the substituent can be deuterium, C... 1～4 Alkyl, C 1～10 Alkoxy, C 3～6 Cycloalkyl, 3- to 8-membered heterocyclic groups, C 1～4 Alkyl phosphoryl group, C 1～4 alkylsulfonyl, aminosulfonyl, C 1～4 Alkylaminosulfonyl, cyano C3～6 cycloalkyl, C 2～4 alkenylformyl, C 2～4 alkenylformamide, cyanoC 1～4 Alkyl carbamoyl, cyano C 1～4 Alkyl, C 1～4 Alkylformyl-3 to 8-membered heterocyclic groups, C 3～6 Cycloalkylformyl, 3-8 membered heterocyclic sulfonyl, C 1～4 alkylsulfonyl-3 to 8-membered heterocyclic groups, amino C 3～6 Cycloalkylformamide, C 1～4 Alkylphosphorylamino, C 1～4 Alkylsulfonylamino, cyano, hydroxyl, oxo (=O), mercapto, amino, dimethylamino, hydroxylamine, C 2～4 Alkenyl and halogen; wherein the aryl group as a substituent can be deuterated, C 1～4 Alkyl, C 1～10 Alkoxy, C 3～6 Further substitutions are made by substituents such as cycloalkyl, cyano, hydroxyl, mercapto, amino, and halogen.

[0056] The term "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group, for example, C 1～3 Alkyl groups refer to saturated hydrocarbon groups containing 1 to 3 carbon atoms, C 1～4 Alkyl groups refer to saturated hydrocarbon groups containing 1 to 4 carbon atoms, C 1～10 Alkyl groups refer to saturated hydrocarbon groups containing 1 to 10 carbon atoms, including straight, branched, or cyclic alkyl groups.

[0057] The term "alkoxy" refers to an alkyl-O- group. 1～6 "Alkoxy" is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy. Similarly, "C 1～10 "Alkoxy" refers to an -O-alkyl group. Alkyl groups include straight-chain, branched, and cyclic alkyl groups, with 1 to 10 carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy, isopropoxy, and cyclopropoxy), tert-butoxy, etc. The preferred alkoxy group in this document is C10-20-3 ... 1～6 Alkoxy, C 1～4 Alkyl group.

[0058] The term "cycloalkyl" refers to a non-aromatic carbocyclic group, including cyclic alkyl groups. Cycloalkyl groups can include monocyclic, bicyclic, or polycyclic systems. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., C 3～8 Cycloalkyl refers to a cycloalkyl group containing 3 to 8 carbon atoms. The preferred cycloalkyl group in this paper is C10. 3～8 cycloalkyl, C3～6 Cycloalkyl.

[0059] The term "heterocyclic alkyl" or "heterocyclic group" refers to a non-aromatic heterocyclic alkyl group in which one, two, or three cyclic carbon atoms are substituted with heteroatoms such as O, N, or S atoms. Heterocyclic alkyl groups preferably have 3, 4, 5, 6, or 7 cyclic atoms. Preferred heterocyclic groups in this document are C16 and C26. 3-8 Heterocyclic group.

[0060] "Aryl" refers to an aromatic carbocyclic group, including monocyclic, bicyclic, tricyclic, or polycyclic aromatic hydrocarbons, such as phenyl, naphthyl, anthracene, phenanthrene, etc. Aryl groups are preferably monocyclic, bicyclic, or tricyclic ring systems having 6 to 14 or 6 to 12 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. "Substituted aryl" refers to an aryl group in which at least one hydrogen atom on the benzene ring is replaced by a non-hydrogen moiety; the substituents in the aryl group can be halogens, carbonyl groups ... 1～10 Alkoxy, -CN, -OH, -SH, -NH2, C 1～6 Alkyl groups. Preferred aryl groups include phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, etc. Fused aryl groups may be attached to another group at a suitable position on a cycloalkyl ring or aromatic ring.

[0061] The term "heteroaryl" refers to a stable 5-12 membered aromatic monocyclic, bicyclic, or polycyclic heterocycle that is fully or partially unsaturated and contains a carbon atom and one, two, three, or four heteroatoms independently selected from N, O, and S. It includes 5-, 6-, or 7-membered aromatic monocyclic rings or 8-, 9-, 10-, 11-, or 12-membered aromatic bicyclic or polycyclic heterocycles; preferably, any heterocycle defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or, if defined, another substituent). The heterocycle may be attached to its side group at any heteroatom or carbon atom to obtain a stable structure. If the resulting compound is stable, the heterocyclic group described herein may be substituted at the carbon or nitrogen atom. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other.Examples of aromatic heteroyl groups include, but are not limited to, acridine, aziridine, acridine, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophene, benzooxazolyl, benzooxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisooxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazole, 4aH-carbazole, carbolinyl, chromanyl, chromenyl, quinolinyl, decahydroquinolinyl, dihydrofurano[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazoalkyl, imidazolinyl, imidazolyl, 1H-inzolyl, imidazopyridyl, dihydroindole, indazinyl, indoleyl, 3H-indoleyl, iso Benzofuranyl, isochoryl, isoindazole, isodihydroindole, isoindole, isoquinolinyl, isothiazolyl, isothiazolopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, diazanaphthyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolylalkyl, oxazolyl, oxazolopyridyl, oxazolyl, naphthalene-intercalated diazaphenyl, hydroxyindole, pyrimidinyl, phenanthidyl, phenanthrololinyl, phenazinyl, phenothiazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, piperazine, piperidinyl, piperidoneyl 4-Piperidinone, Piperidin, Pteridin, Purinyl, Pyranyl, Pyrazinyl, Pyrazolyl, Pyrazolinyl, Pyrazolopyridyl, Pyrazolyl, Pyridazinyl, Pyridoxazolyl, Pyridinium-imidazolyl, Pyridinium, Pyridine, Pyrrolidinyl, Pyrrolinyl, 2-Pyrrolidone, 2H-Pyrrolyl, Pyrrolyl, Quinazolinyl, Quinolinyl, 4H-Quinazinyl, Quinoxalinyl, Quininecycloyl, Tetrazolyl, Tetrahydrofuranyl, Tetrahydroisoquinolinyl, Tetrahydroquinolinyl, 6H-1,2,5-Thiadiazinyl, 1,2,3-Thiadiazinyl, 1,2,4-Thiadiazinyl, 1,2,5-Thiadiazinyl, 1,3,4-Thiadiazinyl Thianthyl, thiazolyl, thienyl, thiazopyridyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthonyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, 1H-inzolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl. The term "heteroaryl" may also include biaryl structures formed by an "aryl" as defined above and a monocyclic "heteroaryl", such as, but not limited to, "-phenylbipyridinyl-", "-phenylbipyrimidinyl", "-pyridylbiphenyl", "-pyridylbipyrimidinyl-", and "-pyrimidinylbiphenyl-".

[0062] Term "C"1～4 "alkylphosphoryl" refers to C 1～4 An alkyl-substituted phosphoryl group, wherein the two alkyl groups on the phosphoryl group can be the same or different.

[0063] Term "C" 1～4 "alkylsulfonyl" refers to C 1～4 Alkyl-substituted sulfonyl group.

[0064] The term "halogen" includes fluorine, chlorine, bromine, and iodine.

[0065] "Bridged ring group" refers to a polycyclic group consisting of 5 to 18 members, preferably 5 to 14 members, containing two or more cyclic structures sharing two non-directly connected carbon atoms. More preferably, it is a 6 to 14-membered bridged ring group, and even more preferably, a 7 to 10-membered bridged ring group. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, pyridone, or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic, or pyridone group, and more preferably a bicyclic or tricyclic group. In this document, the bridged ring group may have one, two, or three ring atoms selected from nitrogen, oxygen, or S(O). n (where n is selected from 0, 1 and 2) heteroatoms.

[0066] In this document, unless otherwise specified, the groups or substituents are conventionally connected to the parent nucleus at their rightmost end, in a left-to-right order. For example, for cyano C 1～4 In the case of alkyl carbamoyl groups, the position where it is attached to the parent nucleus of the compound as a substituent is the rightmost "formyl group".

[0067] As used herein, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to certain salts that enable the compounds of the present invention to retain their original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds represented by formula (I) can be salts formed by a carboxyl or amino group (primarily an amino group) with a suitable base or acid, such as salts formed with a suitable base (including metal salts and ammonium salts), or salts formed with a suitable acid. The compounds of the present invention preferably form salts with a suitable acid, which may be selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid, and aspartic acid, preferably methanesulfonic acid or hydrochloric acid.

[0068] The term “treatment” as used in this article includes any effect that results in improvement of a condition, disease, disorder, etc., such as reducing, decreasing, regulating, improving or eliminating, or improving its symptoms.

[0069] As used herein, the phrase "medicinal carrier" refers to a pharmaceutical substance, composition, or medium, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate, zinc stearate, or stearic acid), or solvent encapsulation substance, relating to the transport or delivery of a subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of compatibility with other components of the formulation and harmlessness to the patient.

[0070] The term "pharmaceutical composition" means a composition comprising the compounds of the present invention and at least one other pharmaceutical carrier. "Pharmaceutical carrier" refers to a medium commonly accepted in the art for delivering a bioactive agent to an animal (specifically a mammal), including (i) adjuvants, excipients, or mediators such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form.

[0071] Terminology: “Brettphos Pd G3” is mamethanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); “TLC” refers to thin-layer chromatography;

[0072] To better illustrate the technical means and effects of the present invention, the present invention will be further described below in conjunction with non-limiting embodiments. The embodiments of the present invention, including the descriptions provided in the embodiments, are intended to illustrate the implementation of the present invention and are not intended to limit the scope of any claim. According to the present invention, those skilled in the art will understand that many changes can be made to the specific embodiments disclosed without departing from the spirit and scope of the present invention and still obtain the same or similar results.

[0073] Unless otherwise stated, all materials / reagents were obtained from commercial suppliers and were ready for use without further purification. The structures of the compounds in the following examples were characterized and determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS).

[0074] 1 ¹H NMR spectra were recorded at room temperature using a Bruker Avance 400MHz spectrometer. The solvents used for analysis were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), or deuterated water (D2O). Chemical shift values ​​(δ) are expressed in ppm, with tetramethylsilane (TMS) or the residual solvent peak used as an internal standard. Coupling constants (J) are expressed in Hertz (Hz). 1The abbreviations for the multiplicity of peaks in H NMR spectra are as follows: s (single peak), d (doublet), t (triplet), q (quartet), qn (quintet), m (multiplet), br (broad peak).

[0075] The instrument used for liquid chromatography-mass spectrometry (LC-MS) was a Shimadzu LCMS-2020, and the instrument used for preparative high-performance liquid chromatography (Prep-HPLC) was a Bonna-Agela FLEXA FL-H100G. The silica gel plates used for thin-layer chromatography (TLC) were Yantai Huanghai HSGF254 plates, with a 2.5×8cm size for reaction monitoring and a coating thickness of 0.2±0.03mm. The plates used for separation and purification were 20×20cm plates with a coating thickness of 0.4–0.5mm. For silica gel column chromatography, Qingdao Haiyang silica gel (100–200 mesh or 200–300 mesh) was used as the support.

[0076] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be used in the methods of this invention.

[0077] Synthesis Example:

[0078] Amine-1 (segment) Implementation method:

[0079]

[0080] Step 1: Synthesis of intermediate Amine-1-b(((4-nitrophenyl)sulfonyl)azadiyl)bis(ethane-2,1-diyl)bis(4-nitrobenzenesulfonate)

[0081]

[0082] A solution of tetrahydrofuran (10 ml) containing 4-nitrobenzenesulfonyl chloride (7.0 g, 31.38 mmol) was slowly added dropwise to a 5 ml solution of tetrahydrofuran containing diethanolamine (1.0 g, 9.51 mmol) and triethylamine (3.4 g, 33.28 mmol). The resulting mixture was heated to room temperature and stirred for 16 hours. The reaction was monitored by TLC until complete. The reaction solution was concentrated, and the residue was purified by recrystallization from methanol (30 ml) to give a white solid (((4-nitrophenyl)sulfonyl)aminodiyl)bis(ethylene-2,1-diol)bis(4-nitrobenzenesulfonate) (5.2 g, 83%).

[0083] 1H NMR (400MHz, DMSO-d6): δ8.46(d,J=8.8Hz,4H),8.34(d,J=8.8Hz,2H),8.13(d,J =8.8Hz, 4H), 8.04 (d, J = 8.8Hz, 2H), 4.19 (t, J = 5.2Hz, 4H), 3.50 (t, J = 4.8Hz, 4H).

[0084] Step 2: Synthesis of intermediate Amine-1-c 9-nitro-4-((4-nitrophenyl)sulfonyl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline

[0085]

[0086] A solution of N,N-dimethylformamide (20 mL) containing (((4-nitrophenyl)sulfonyl)azadiyl)bis(ethane-2,1-diyl)bis(4-nitrobenzenesulfonate) (5.2 g, 7.9 mmol), 4-nitrocatechol (1.1 g, 7.2 mmol), potassium carbonate (2.1 g, 15.1 mmol), and potassium iodide (112 mg, 0.7 mmol) was reacted at 70 °C for 12 h. The reaction was monitored by TLC until complete. The mixture was partitioned into ethyl acetate (150 mL) and water (200 mL). The organic phase was collected, washed with saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (33% dichloromethane eluted with n-hexane) to obtain a white solid 9-nitro-4-((4-nitrophenyl)sulfonyl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline (556 mg, 15%).

[0087] 1 H NMR (400MHz, DMSO-d6): δ8.35(d,J=8.8Hz,2H),8.01-8.04(m,2H),7.91(d,J=2.8Hz,1H),7.84-7. 87(m,1H),7.14(d,J=9.2Hz,1H),4.67(t,J=4.6Hz,2H),4.41(t,J=4.6Hz,2H),3.52-3.56(m,4H).

[0088] Step 3: Synthesis of intermediate Amine-1-d9-nitro-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline

[0089]

[0090] To a solution of N,N-dimethylformamide (10 mL) containing 9-nitro-4-((4-nitrophenyl)sulfonyl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline (556.0 mg, 1.36 mmol), 4-methylthiophenol (203.0 mg, 1.63 mmol) and potassium carbonate (564.0 mg, 4.08 mmol) were added. The resulting mixture was stirred at room temperature for 14 hours. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into ethyl acetate (100 mL) and water (100 mL). The organic phase was collected, washed with saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with n-hexane solution of 20%-33% ethyl acetate) to obtain a yellow solid 9-nitro-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline (267 mg, 87%).

[0091] LC_MS:(ES + ):m / z 225.15[M+H] + .

[0092] 1 H NMR (400MHz, CDCl3): δ7.74-7.77(m,1H),7.63(d,J=2.8Hz,1H),6.62(d,J=8.8Hz,1 H), 4.24 (t, J = 4.4Hz, 2H), 3.90-3.94 (m, 2H), 3.57-3.62 (m, 4H), 3.57-3.62 (m, 4H).

[0093] Step 4: Synthesis of intermediate Amine-1-e 4-methyl-9-nitro-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline

[0094]

[0095] Sodium hydride (60%, 118 mg, 2.95 mmol) and methyl iodide (457 mg, 3.22 mmol) were added to a solution containing 9-nitro-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline (600 mg, 2.68 mmol) and N,N-dimethylformamide (5 mL) at 0 °C. The resulting mixture was reacted at 0 °C for 30 min, then at room temperature for 3 h. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into ethyl acetate (50 mL) and water (50 mL). The organic layer was collected, washed with saturated sodium chloride solution (30 ml x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with 15%-20% ethyl acetate in n-hexane) to obtain a yellow solid 4-methyl-9-nitro-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline (583 mg, 91%).

[0096] LC_MS:(ES + ):m / z 239.30[M+H] + .

[0097] 1 H NMR (400MHz, CDCl3): δ7.78-7.81(m,1H),7.67(d,J=2.4Hz,1H),6.59(d,J=8.8Hz,1H),4.21(t,J=4.4Hz,2H),3.56-3.63(m,6H),3.36(s,3H).

[0098] Step 5: Synthesis of intermediate Amine-1 4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine

[0099]

[0100] A solution of 4-methyl-9-nitro-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline (583 mg, 2.45 mmol) and Pd / C (10% 60 mg) in methanol (10 mL) and ethyl acetate (10 mL) was reacted at room temperature under a hydrogen atmosphere (hydrogen balloon) for 2 hours. The reaction was monitored by TLC until complete. Pd / C was removed by filtration, and the residue was washed with methanol (10 mL x 2). The combined filtrates were concentrated under reduced pressure to give crude 4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (497 mg, 97%), which was ready for use in the next step without further purification. LC-MS:(ES) + ):m / z 208.85[M+H] + .

[0101] 1 H NMR (400MHz, CDCl3): δ6.53-6.56(m,1H), 6.23-6.25(m,2H), 4.19(t,J=4.4Hz,2H), 3.57(t,J=5.8Hz,2H), 3.30-3.36(m,9H).

[0102] Amine-2 clip

[0103] Implementation method:

[0104]

[0105] Implementation method:

[0106] Step 1: Synthesis of intermediate Amine-2-b-2-(2-hydroxyethoxy)-5-nitrophenol

[0107]

[0108] 5-Nitrobenzo[d][1,3]dioxazole (2 g, 12 mmol) was added to a 10 mL solution of ethylene glycol containing 551 mg (24 mmol) of metallic sodium at 0 °C. The resulting mixture was stirred at 120 °C for 3 hours. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature, acidified to pH 3–4 with 2N hydrochloric acid, the suspension was filtered, the solid was collected, washed with water, and dried under reduced pressure to give a brown solid 2-(2-hydroxyethoxy)-5-nitrophenol (2.1 g, 88%).

[0109] LC_MS:(ES+):m / z 199.9[M+H] + .

[0110] 1 H NMR (400MHz, DMSO-d6): δ9.86(s,1H),7.75-7.72(m,1H),7.62-7.61(m,1H),7.14-7.12(m,1H),4.90(s,1H),4.13-4.11(m,2H),3.78-3.76(m,2H).

[0111] Step 2: Synthesis of intermediate Amine-2-c 2-(2-(2-(2-hydroxyethoxy)-5-nitrophenoxy)ethoxy)ethanol

[0112]

[0113] A solution of N,N-dimethylformamide (20 mL) containing 2-(2-hydroxyethoxy)-5-nitrophenol (2.15 g, 10.75 mmol), 2-(2-chloroethoxy)ethane-1-ol (2 g, 16.13 mmol), potassium iodide (1.8 g, 10.75 mmol), and potassium carbonate (4.45 g, 32.25 mmol) was stirred at 70 °C for 2 days. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature and partitioned into water (200 mL) and ethyl acetate (100 mL). The organic layer was collected, and the aqueous phase was extracted with ethyl acetate (50 mL). The organic layers were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an orange oil, 2-(2-(2-(2-hydroxyethoxy)-5-nitrophenoxy)ethoxy)ethanol (2.1 g, 67%), which could be used in the next step without further purification.

[0114] LC_MS:(ES+):m / z 288.2[M+H] + .

[0115] 1 HNMR (400MHz, CDCl3): δ7.95-7.92(m,1H),7.77-7.76(m,1H),6.94-6.92(m,1H),4.24-4 .22(m,2H),4.16-4.14(m,2H),4.04-4.01(m,2H),3.96-4.00(m,2H),3.84-3.76(m,4H).

[0116] Step 3: Synthesis of intermediate Amine-2-d4-(4-nitro-2-(2-(2-(toluenesulfonyloxy)ethoxy)ethoxy)phenoxy)4-methylbenzenesulfonate ethyl ester

[0117]

[0118] 4-Toluenesulfonyl chloride (3.5 g, 18.25 mmol) was added to a dichloromethane solution containing 2-(2-(2-(2-hydroxyethoxy)-5-nitrophenoxy)ethoxy)ethanol (2.1 g, 7.3 mmol) and triethylamine (3.3 g, 21.9 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 14 h. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into dichloromethane (10 ml) and water (20 ml). The organic layer was collected, washed with saturated sodium chloride solution (20 ml x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: 50% ethyl acetate in petroleum ether to 1.6% ethyl acetate in dichloromethane) to give a brown oily ethyl 4-(4-nitro-2-(2-(2-(toluenesulfonyloxy)ethoxy)ethoxy)phenoxy)4-methylbenzenesulfonate (3.5 g, 80%).

[0119] LC_MS:(ES+):m / z 596.1[M+H] + .

[0120] 1 H NMR (400MHz, CDCl3): δ7.86-7.72(m,6H),7.34-7.29(m,4H),6.86-6.84(m,1H),4.42-4.39(m,2H),4. 31-4.29(m,2H),4.20-4.18(m,2H),4.15-4.13(m,2H),3.85-3.79(m,4H),2.44-2.42(d,J=8.4Hz,6H).

[0121] Step 4: Synthesis of intermediate Amine-2-e-7-(4-methoxybenzyl)-13-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane

[0122]

[0123] A solution of acetonitrile (100 mL) containing 2-(4-nitro-2-(2-(2-(toluenesulfonyloxyethoxy)ethoxy)phenoxy)ethyl (3.5 g, 5.9 mmol), (4-methoxyphenyl)methylamine (806 mg, 5.9 mmol), potassium iodide (488 mg, 2.94 mmol), and potassium carbonate (4.05 g, 29.38 mmol) was refluxed for 16 hours. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature and partitioned into water (100 mL) and ethyl acetate (50 mL). The organic layer was collected, and the aqueous layer was separated into ethyl acetate (50 mL x 100 mL). 2) Extraction. Combine the organic layers, wash with saturated sodium chloride solution (80 ml), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (eluent: petroleum ether solution of 33% ethyl acetate) to obtain a yellow solid 7-(4-methoxybenzyl)-13-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane (1.6 g, 70%).

[0124] LC_MS:(ES+):m / z 389.5[M+H] + .

[0125] Step 5: Synthesis of intermediate Amine-2-f13-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane

[0126]

[0127] A solution of 1,2-dichloroethane (30 mL) containing 7-(4-methoxybenzyl)-13-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxaza

[10] azacyclododecane (1.6 g, 4.12 mmol) and 1-chloroethyl chloroformate (883 mg, 6.18 mmol) was stirred at room temperature for 13 h. The reaction was monitored by TLC until complete. The reaction mixture was concentrated, and the residue was dissolved in methanol (8 mL). The resulting mixture was refluxed for 1 h. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into water (20 mL) and dichloromethane (30 mL). The organic layer was collected, and the aqueous layer was extracted with dichloromethane (10 mL x 5). The organic layers were combined, washed with saturated sodium chloride solution (30 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with 5%-10% methanol in dichloromethane solution) to obtain a yellow solid 13-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azadodecyl (620 mg, 56%).

[0128] LC_MS:(ES+):m / z 269.2[M+H] + .

[0129] 1 H NMR (400MHz, CDCl3): δ7.93-7.91(m,1H),7.86-7.85(m,1H),7.12-7.10(d,J=8.8Hz,1H),4. 31-4.28(m,4H),3.81-3.79(m,2H),3.72-3.69(m,2H),3.00-2.98(m,2H),2.82-2.79(m,2H).

[0130] Step 6: Synthesis of intermediate Amine-2-g 7-methyl-13-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane

[0131]

[0132] A solution of N,N-dimethylformamide containing 13-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azadodecyl (515 mg, 1.9 mmol), triethylamine (567 mg, 3.8 mmol), and methyl iodide (409 mg, 2.88 mmol) was reacted in a sealed tube at 70 °C for three hours. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature and partitioned into water (50 mL) and ethyl acetate (30 mL). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (20 mL x 2). The organic layers were combined, washed with saturated sodium chloride solution (30 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with 5%-10% methanol in dichloromethane solution) to obtain a yellow solid 7-methyl-13-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane (267 mg, 49%).

[0133] LC_MS:(ES+):m / z 283.2[M+H] + .

[0134] 1 H NMR (400MHz, DMSO-d6): δ7.96-7.92(m,2H),7.28-7.26(d,J=8.8Hz,1H),4 .34-4.25(m,4H),3.71-3.70(m,4H),3.05-2.84(m,4H),2.48-2.40(m,3H).

[0135] Step 7: Synthesis of Amine-2,7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-amine

[0136]

[0137] At room temperature, zinc powder (870 mg, 13.3 mmol) and acetic acid (1.6 g, 26.6 mmol) were added to a solution of 7-methyl-13-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxazacyclododecane (267 mg, 0.95 mmol) in dichloromethane (3 mL). The reaction mixture was stirred for 10 min at room temperature under a nitrogen atmosphere. The reaction was monitored by TLC until complete. The reaction mixture was alkalized to pH 7-8 with saturated sodium bicarbonate solution and filtered. The filtrate was partitioned into a solution of 10% methanol in dichloromethane (20 mL) and water (10 mL). The organic layer was collected, and the aqueous layer was extracted with a solution of 10% methanol in dichloromethane (20 mL x 3). The organic layers were combined, washed with saturated sodium chloride solution (30 ml), dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily crude product, 7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxaza

[10] azacyclododecane-13-amine (230 mg, 96%).

[0138] LC_MS:(ES+):m / z 252.8[M+H] + .

[0139] Amine-3 clip

[0140] Implementation method:

[0141]

[0142] Step 1: Synthesis of intermediate Amine-3-b-2-(allyloxy)-1-chloro-4-nitrobenzene

[0143]

[0144] 2-Chloro-5-nitrophenol (5.0 g, 28.8 mmol), 3-bromopropene (3.5 g, 28.8 mmol), and potassium carbonate (6 g, 43.2 mmol) were added to a reaction flask, followed by 20 mL of N,N-dimethylformamide. The mixture was heated to 70 °C and reacted for 12 hours. The reaction was monitored by LTC until complete. The reaction solution was cooled to room temperature and extracted with water (200 mL) and ethyl acetate (100 mL). The aqueous phase was then extracted again with ethyl acetate (50 mL). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was recrystallized to give a brown solid, 2-(allyloxy)-1-chloro-4-nitrobenzene (5.5 g, 90%).

[0145] 1 H NMR (400MHz, CDCl3): δ7.78-7.82(m,2H),7.53(d,J=8.4Hz,1H),6.03-6.12(m,1H),5.49-5.54(m,1H),5.37-5.40(m,1H),4.71-4.73(m,2H).

[0146] Step 2: Synthesis of intermediate Amine-3-c 2-(2-(2-(allyloxy)-4-nitrophenoxy)ethoxy)ethanol-1-ol

[0147]

[0148] Diethylene glycol (10 g, 93.6 mmol) was added to a reaction flask containing 10 mL of N,N-dimethylformamide at 0 °C, followed by sodium hydride (60%, 562 mg, 14 mmol). The reaction mixture was brought to room temperature and reacted for 1 hour, then cooled to 0 °C. 2-(allyloxy)-1-chloro-4-nitrobenzene (2 g, 9.36 mmol) was added dropwise, and the reaction mixture was stirred at 50 °C under nitrogen protection for 2 days. The reaction was monitored by TLC until complete. The reaction mixture was extracted with ethyl acetate (100 mL) and water (100 mL). The organic phase was washed twice with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (eluent: 20%-50% ethyl acetate in n-hexane) to give a brown oily substance, 2-(2-(2-(allyloxy)-4-nitrophenoxy)ethoxy)ethanol-1-ol (2 g, 75%).

[0149] 1H NMR (400MHz, CDCl3): δ7.88-7.91(m,1H),7.76(d,J=2.8Hz,1H),6.94(d,J=8.8Hz,1H),6.04-6.13(m,1H),5.44-5.49(m, 1H),5.33-5.36(m,1H),4.66-4.68(m,2H),4.27(t,J=4.6Hz,2H),3.96(t,J=4.8Hz,2H),3.69-3.78(m,4H),2.28(s,1H).

[0150] Step 3: Synthesis of intermediate Amine-3-d2-(2-(2-hydroxy-4-nitrophenoxy)ethoxy)ethyl acetate

[0151]

[0152] Under nitrogen protection at room temperature, tetrakis(triphenylphosphine)palladium (408 mg, 0.35 mmol) was added to a suspension of acetic acid (5 mL) containing 2-(2-(2-(allyloxy)-4-nitrophenoxy)ethoxy)ethyl-1-ol (1 g, 3.53 mmol). The resulting mixture was purged with nitrogen three times, and the mixture was heated to 120 °C and stirred for 2 hours. The reaction was monitored by TLC until complete. The reaction mixture was concentrated under reduced pressure and partitioned into water (20 mL) and ethyl acetate (10 mL). The organic layer was collected, and the aqueous phase was extracted with ethyl acetate (10 mL x 2). The organic layers were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a brown oily crude product of 2-(2-(2-hydroxy-4-nitrophenoxy)ethoxy)ethyl acetate (860 mg, crude product), which could be used for the next step without further purification.

[0153] LC_MS:(ES + ):m / z 286.10[M+H] + .

[0154] 1 H NMR (400MHz, CDCl3): δ7.77-7.80(m,2H),6.92(d,J=9.6Hz,1H),6.86(s,1H),4.26-4.33(m,4H),3.88-3.90(m,2H),3.76-3.78(m,2H),2.11(s,3H).

[0155] Step 4: Synthesis of intermediate Amine-3-e-2-(2-(2-(2-hydroxyethoxy)-4-nitrophenoxy)ethoxy)ethanol-1-ol

[0156]

[0157] A solution of N,N-dimethylformamide (10 mL) containing ethyl acetate (860 mg, 3 mmol), 2-bromoethanol (1.5 g, 12 mmol), and potassium carbonate (3.7 g, 27.1 mmol) was stirred at 70 °C for 14 h. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature and partitioned into water (100 mL) and ethyl acetate (50 mL). The organic layer was collected, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The organic layers were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (5 mL), and potassium carbonate (416 mg, 3 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 30 min. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into dichloromethane (30 mL) and water (20 mL). The organic layer was collected, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (eluting with 2-5% methanol and dichloromethane solution) to obtain a pale yellow oily substance 2-(2-(2-(2-hydroxyethoxy)-4-nitrophenoxy)ethoxy)ethanol (500 mg, 57%).

[0158] 1 H NMR (400MHz, CDCl3): δ7.91-7.94(m,1H),7.78(d,J=2.4Hz,1H),6.92(d,J=8.8Hz,1H),4.75(s,1H),4.24( t,J=4.2Hz,2H),4.15(t,J=4.2Hz,2H),4.02(t,J=4.2Hz,2H),3.96(s,2H),3.75-3.82(m,4H),1.74(s,1H).

[0159] Step 5: Synthesis of intermediate Amine-3-f 2-(5-nitro-2-(2-(2-(toluenesulfonyloxy)ethoxy)ethoxy)phenoxy)ethyl-4-toluenesulfonate

[0160]

[0161] p-Toluenesulfonyl chloride (730 mg, 3.83 mmol) was added to a solution of 2-(2-(2-(2-hydroxyethoxy)-4-nitrophenoxy)ethoxy)ethanol-1-ol (500 mg, 1.74 mmol), triethylamine (528 mg, 5.22 mmol), and 4-dimethylaminopyridine (21 mg, 0.17 mmol) in dichloromethane (5 mL) at 0 °C. The resulting mixture was heated to room temperature and stirred for 2 hours, and the reaction was monitored by TLC until complete. The reaction mixture was partitioned into dichloromethane (20 mL) and water (20 mL). The organic phase was collected, washed with saturated sodium chloride solution (10 ml x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (eluting with hexane solution of 50-100% ethyl acetate) to obtain a brown oily substance 2-(5-nitro-2-(2-(2-(toluenesulfonyloxy)ethoxy)ethoxy)phenoxy)ethyl-4-toluenesulfonate (830 mg, 80%).

[0162] 1 H NMR (400MHz, CDCl3): δ7.88-7.91(m,1H),7.76-7.81(m,4H),7.64(d,J=2.8Hz,1H),7.30-7.35(m,4H),6.91(d,J=9.2Hz,1H),4 .19(t,J=4.6Hz,4H),4.38-4.40(m,2H),4.23-4.26(m,2H),3.86(t,J=4.6Hz,2H),3.81(t,J=4.6Hz,2H),2.43(d,J=8.0Hz,6H).

[0163] Step 6: Synthesis of intermediate Amine-3-g 7-(4-methoxybenzyl)-12-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane

[0164]

[0165] A solution of acetonitrile (30 mL) containing 2-(5-nitro-2-(2-(2-(toluenesulfonyloxy)ethoxy)phenoxy)ethyl-4-toluenesulfonate (630 mg, 1.06 mmol), 4-methoxybenzylamine (145 mg, 1.06 mmol), potassium carbonate (731 mg, 5.3 mmol), and potassium iodide (88 mg, 0.53 mmol) was refluxed for 14 hours. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature and partitioned into water (30 mL) and ethyl acetate (10 mL). The organic layer was collected, and the aqueous phase was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (30 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (eluting with hexane solution of 20%-50% ethyl acetate) to obtain a yellow oily substance 7-(4-methoxybenzyl)-12-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane (210 mg, 51%).

[0166] 1 H NMR (400MHz, CDCl3): δ7.90-7.93(m,1H),7.75(d,J=2.0Hz,1H),7.13(s,2H),7.00(d,J=8.8Hz,1H),6.78(d,J=7.2 Hz,2H),4.31(t,J=4.0Hz,2H),4.17(s,2H),3.87(t,J=3.8Hz,2H),3.78(s,5H),3.64(s,2H),2.87(d,J=6.8Hz,4H).

[0167] Step 7: Synthesis of intermediate Amine-3-h 12-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azadodecyl

[0168]

[0169] A solution containing 7-(4-methoxybenzyl)-12-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane (1.08 g, 2.78 mmol) and 1-chloroethyl chloroformate (596 mg, 4.17 mmol) in 1,2-dichloroethane (15 mL) was stirred at room temperature for 3 hours. The reaction was monitored by TLC until complete. The reaction mixture was concentrated, and methanol (3 mL) was added to the residue. The resulting mixture was heated under reflux for 1 hour. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into water (20 mL) and dichloromethane (30 mL). The organic layer was collected, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (eluting with 2%-5% methanol dichloromethane solution) to obtain a yellow solid 12-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane (479 mg, 64%).

[0170] 1 H NMR (400MHz, DMSO-d6): δ8.03(t,J=5.4Hz,2H),7.44(s,1H),7.35(d,J=8.8Hz,1H), 4.30-4.35(m,4H),3.81(t,J=4.0Hz,2H),3.70(t,J=4.6Hz,2H),3.05-3.12(m.4H).

[0171] Step 8: Synthesis of intermediate Amine-3-i 7-methyl-12-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane

[0172]

[0173] Sodium hydride (60%, 43 mg, 1.08 mmol) was added to N,N-dimethylformamide (5 ml) containing 12-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane (265 mg, 0.98 mmol) and iodomethane (167 mg, 1.18 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then heated to room temperature and stirred for another 3 h. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into ethyl acetate (30 ml) and water (50 ml). The organic layer was collected, and the aqueous phase was extracted with ethyl acetate (20 ml x 4). The organic layers were combined, washed with saturated sodium chloride solution (50 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (eluting with 2%-10% methanol dichloromethane solution) to obtain a yellow oily substance 7-methyl-12-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane (153 mg, 56%).

[0174] LC_MS:(ES + ):m / z 283.20[M+H] + .

[0175] 1 H NMR (400MHz, CDCl3): δ7.89-7.91(m,1H),7.85(d,J=2.4Hz,1H),6.99(d,J=8.8Hz,1H),4.28(t,J=4.2Hz,2H),4.21(t ,J=4.8Hz,2H),3.88(t,J=4.2Hz,2H),3.74(t,J=5Hz,2H),2.82(t,J=4.6Hz,2H),2.68(t,J=4.8Hz,2H),2.37(s,3H).

[0176] Step 9: Synthesis of Amine-3-7-methyl-12-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-amine

[0177]

[0178] Zinc powder (574 mg, 8.78 mmol) and acetic acid (1.05 g, 17.55 mmol) were added to a solution of 7-methyl-12-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azadodecane (153 mg, 0.63 mmol) in dichloromethane (7 mL) at room temperature. The resulting mixture was stirred for 30 min at room temperature under nitrogen protection. The reaction was monitored by TLC until complete. The reaction mixture was filtered, and the filtrate was partitioned into dichloromethane (20 mL) and water (10 mL). The organic layer was collected, and the aqueous phase was extracted with a 10% methanol solution in dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude light brown oily product 7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxaza

[10] azacyclododecane-12-amine (123 mg, 90%), which can be used in the next step without further purification.

[0179] LC_MS:(ES + ):m / z 253.20[M+H] + .

[0180] Example 1

[0181] N-(tert-butyl)-3-((5-fluoro-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)pyrimidin-4-yl)amino)benzenesulfonamide

[0182]

[0183] Implementation steps (Implementation Method 1):

[0184]

[0185] Step 1: Synthesis of fragment 1-c N-(tert-butyl)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)benzenesulfonamide

[0186]

[0187] A methanol (10 mL) solution containing 2,4-dichloro-5-fluoropyrimidine (500 mg, 3 mmol) and 3-amino-N-(tert-butyl)benzenesulfonamide (685 mg, 3 mmol) was heated to 50 °C and stirred for 3 hours. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with 15%-25% ethyl acetate in n-hexane) to obtain a white solid N-(tert-butyl)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)benzenesulfonamide (362 mg, 33%).

[0188] LC_MS:(ES + ):m / z 360.0[M+H] + .

[0189] 1 H NMR (400MHz, DMSO-d6): δ10.27(s,1H),8.38(d,J=3.6Hz,1H),8.21(t,J=2.4Hz,1H),7.88-7.91(m,1H),7.55-7.59(m,3H),1.14(s,9H),

[0190] Step 2: Synthesis of compound 1N-(tert-butyl)-3-((5-fluoro-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)pyrimidin-4-yl)amino)benzenesulfonamide

[0191]

[0192] BrettPhos PdG3 (10 mg, 0.011 mmol) was added to a suspension of 1,4-dioxane (1 mL) containing N-(tert-butyl)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)benzenesulfonamide (40 mg, 0.11 mmol), 4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (23 mg, 0.11 mmol) and potassium phosphate (70 mg, 0.33 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was purged with nitrogen three times and heated to 110 °C with stirring for 14 hours. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature and partitioned into water (10 mL) and ethyl acetate (10 mL). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (10 mL). The organic layers were combined, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (eluting with dichloromethane solution of 5% methanol) to obtain the target compound as a yellow solid (21.1 mg, 35%).

[0193] LC_MS:(ES+ ):m / z 531.5[M+H] + .

[0194] 1 H NMR (400MHz, CDCl3): δ8.27(s,1H),7.95(d,J=2.8Hz,1H),7.76(d,J=8.0Hz,1H),7.59(d,J=7.6Hz,1H),7.41(t,J=8.0Hz,1H),6.94-6.99(m,2H),6 .86-6.90(m,1H),6.69(d,J=8.0Hz,1H),4.65(brs,1H),4.24(t,J=4.4Hz ,2H),3.62(t,J=5.6Hz,2H),3.42-3.48(m,4H),3.37(s,3H),1.20(s,9H).

[0195] Example 2

[0196] N-(cyanomethyl)-4-(2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide

[0197]

[0198] Implementation steps (Implementation Method Two):

[0199]

[0200] Step 1: Synthesis of fragment 2-b(4-((cyanomethyl)carbamoyl)phenyl)boronic acid

[0201]

[0202] Oxaloyl chloride (2.4 ml, 26.5 mmol) was added to a solution of dichloromethane (80 ml) containing 4-carboxyphenylboronic acid (2.0 g, 12.0 mmol) and N,N-dimethylformamide (2 ml) at 0 °C. The resulting mixture was heated under reflux for 3 hours. The reaction was monitored by TLC until complete. The reaction mixture was concentrated, and the residue was dissolved in N,N-dimethylformamide (5 ml), and added dropwise to a solution of N,N-dimethylformamide (10 ml) containing aminoacetonitrile hydrochloride (1.23 g, 13.2 mmol) and N,N-diisopropylethylamine (3.9 g, 30.1 mmol) under nitrogen protection at 0 °C. The resulting mixture was stirred and reacted at room temperature for 12 hours. The reaction was monitored by TLC until complete. Water (150 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 ml x 5). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was recrystallized in ethyl acetate to give a pale yellow solid (4-((cyanomethyl)carbamoyl)phenyl)boronic acid (950 mg, 38%).

[0203] 1 H NMR (400MHz, DMSO-d6): δ9.18(t,J=5.4Hz,1H),8.23(s,2H),7.81-7.90(m,4H),4.31(d,J=5.6Hz,2H).

[0204] Step 2: Synthesis of fragment 2-d 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

[0205]

[0206] Sodium hydride (60%, 1.3 g, 31.9 mmol) was added to a solution of N,N-dimethylformamide (50 mL) containing 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (5 g, 26.6 mmol) at 0 °C. The resulting mixture was heated to room temperature and stirred for 1 hour, then cooled to 0 °C, and 2-(trimethylsilyl)ethoxymethyl chloride (4.9 g, 29.3 mmol) was added dropwise. The mixture was heated to room temperature and stirred under nitrogen protection for 14 hours. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into ethyl acetate (150 mL) and water (300 mL). The organic layer was collected, washed with saturated sodium chloride solution (100 ml x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with 1.5% ethyl acetate in n-hexane) to obtain a colorless oily substance 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2.3 g, 27%).

[0207] 1 H NMR (400MHz, CDCl3): δ7.37 (d, J = 3.6 Hz, 1H), 6.66 (d, J = 3.6 Hz, 1H), 5.60 (s, 2H), 3.53 (t, J = 8.2 Hz, 2H), 0.92 (t, J = 8.4 Hz, 2H), -0.04 (s, 9H).

[0208] Step 3: Synthesis of fragment 2-e 4-(2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(cyanomethyl)benzamide

[0209]

[0210] Tetra(triphenylphosphine)palladium (113 mg, 0.1 mmol) was added to acetonitrile (2 ml) containing (4-(cyanomethyl)carbamoylphenylboronic acid (200 mg, 0.98 mmol), 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (624 mg, 1.96 mmol) and sodium carbonate aqueous solution (1 ml, 2N) at room temperature under a nitrogen atmosphere. The resulting reaction mixture was purged with nitrogen three times, heated to 90 °C, and stirred for 12 hours. The reaction was monitored by LC until complete. The reaction mixture was partitioned into ethyl acetate (10 ml) and water (10 ml). The organic phase was collected, washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with 0.5-2% methanol in dichloromethane) to give a white solid 4-(2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(cyanomethyl)benzamide (300 mg, 34%).

[0211] LC_MS:(ES + ):m / z 442.1[M+H] + .

[0212] 1 H NMR (400MHz, DMSO-d6): δ9.41(t,J=5.4Hz,1H),8.28(d,J=8.4Hz,2H),8.08(d,J=8.4Hz,2H),7.92(d,J=3.6Hz,1H),7 .10(d,J=3.6Hz,1H),5.64(s,2H),4.37(d,J=5.6Hz,2H),3.56(d,J=8.0Hz,2H),0.86(t,J=8.0Hz,2H),-0.08(s,9H).

[0213] Step 4: Synthesis of fragment 2-f N-(cyanomethyl)-4-(2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide

[0214]

[0215] Under a nitrogen atmosphere at room temperature, BrettPhos Pd G3 (9.1 mg, 0.01 mmol) was added to a solution of 1,4-dioxane (1 mL) containing 4-(2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(cyanomethyl)benzamide (60.0 mg, 0.1 mmol), 4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (35.4 mg, 0.2 mmol), and potassium phosphate (89.0 mg, 0.4 mmol). The resulting mixture was purged with nitrogen three times, and the mixture was heated to 110 °C and stirred for 13 hours. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature, partitioned into water (20 mL), and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative TLC (eluting with 5% methanol in dichloromethane) to obtain a yellow solid N-(cyanomethyl)-4-(2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide (62 mg, 72%).

[0216] LC_MS:(ES + ):m / z 614.4[M+H] + .

[0217] Step 5: Synthesis of N-(cyanomethyl)-4-(2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide

[0218]

[0219] A solution of tetrahydrofuran (0.5 ml) containing N-(cyanomethyl)-4-(2-(((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide (60 mg, 0.1 mmol) and tetrabutylammonium fluoride (0.5 ml, 1 M tetrahydrofuran solution) was heated to 70 °C and stirred for 5 hours. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature and partitioned into water (10 ml). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (10 ml x 2). The organic phases were combined, washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (eluting with dichloromethane solution of 10% methanol) to obtain a yellow solid target compound (16.5 mg, 34%).

[0220] LC_MS:(ES + ):m / z 484.3[M+H] + .

[0221] 1 H NMR (400MHz, DMSO-d6): δ11.63(s,1H),9.35(t,J=5.6Hz,1H),8.83-9.23(m,1H),8.24(d,J=7.6Hz,2H),8.05(d,J=8.4Hz,2H),7.07-7. 68(m,3H),6.68(s,2H),4.36(d,J=5.2Hz,2H),3.92-4.28(m,2H),3.49-3.59(m,2H),3.32-3.41(m,2H),3.29-3.31(m,2H),3.28(s,3H).

[0222] Example 3

[0223] 1-(3-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one

[0224]

[0225] Implementation steps (Implementation Method 3):

[0226]

[0227] Step 1: Synthesis of fragment 3-b tert-butyl 3-((2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylic acid

[0228]

[0229] An ethanol (2 mL) solution containing the fragment 2-d:2,4-dichloro-7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.315 mmol), tert-butyl 3-aminopiperidine-1-carboxylate (94.6 mg, 0.473 mmol), and N-ethyl-N-isopropylpropyl-2-amine (61 mg, 0.473 mmol) was stirred at 90 °C for 18 h. The reaction was monitored by TLC until complete. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with petroleum ether containing 25% ethyl acetate) to obtain a white solid tert-butyl 3-(((2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)piperidine-1-carboxylate (130 mg, 85%).

[0230] LC_MS:(ES + ):m / z 482.2[M+H] + .

[0231] Step 2: Synthesis of fragment 3-c 3-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0232]

[0233] BrettPhos Pd G3 (16 mg, 0.017 mmol) was added to a suspension of 1,4-dioxane (2 ml) containing 3-(((2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (84 mg, 0.17 mmol), 4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (36 mg, 0.17 mmol) and potassium phosphate (111 mg, 0.53 mmol) under a nitrogen atmosphere at room temperature. The reaction mixture was purged with nitrogen three times, and the mixture was stirred at 110 °C for 20 hours. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature and partitioned into water (10 ml) and ethyl acetate (10 ml). The organic layer was collected, and the aqueous layer was separated into ethyl acetate (10 ml x 10 ml). 2) Extraction. The organic layers were combined, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (eluting with petroleum ether containing 6% methanol and 50% ethyl acetate) to obtain brown solid tert-butyl3-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylic acid (60 mg, 47%).

[0234] LC_MS:(ES + ):m / z 654.9[M+H] + .

[0235] Step 3: Fragment 3-d N 2 -(4-Methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)-N 4 Synthesis of -(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[0236]

[0237] A solution of tert-butyl piperidine-1-carboxylate (75 mg, 0.11 mmol) containing 3-((2-(4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (2 ml) was stirred at room temperature for 5 hours. The reaction was monitored by TLC until complete. The reaction mixture was concentrated, and the residue was added to ammonia (5 ml) and ethyl acetate (5 ml). The reaction mixture was stirred at 40 °C for 16 hours. The reaction was monitored by TLC until complete. The organic layer was collected, washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (eluting with dichloromethane containing 10% methanol) to obtain a yellow solid N. 2 -(4-Methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)-N 4 -(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (40 mg, 82%).

[0238] LC_MS:(ES + ):m / z 424.0[M+H] + .

[0239] Step 4: Synthesis of 1-(3-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one

[0240]

[0241] At 0℃, to contain N 2 -(4-Methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)-N 4Acrylyl chloride (8.5 mg, 0.09 mmol) was added to a solution of 40 mg (40 mg, 0.09 mmol) and 28 mg (2.28 mmol) of pyrimidine-2,4-diamine and triethylamine (28 mg, 0.28 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into water (5 mL) and dichloromethane (10 mL) containing 10% methanol. The organic layer was collected, and the aqueous layer was extracted with dichloromethane (10 mL x 3) containing 10% methanol. The organic layers were combined, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (eluting with dichloromethane containing 10% methanol) to obtain a brown solid 1-(3-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (12.1 mg, 26%).

[0242] LC_MS:(ES + ):m / z 478.5[M+H] + .

[0243] 1 H NMR (400MHz, DMSO-d6): δ11.06(s,1H),8.49(brs,1H),7.23-7.35(m,2H),7.10(brs,1H),6.83-7 .01(m,2H),6.65-6.74(m,1H),6.52(s,1H),6.06-6.20(m,1H),5.57-5.77(m,1H),4.54(d,J=10. 8Hz,1H),4.04-4.17(m,5H),3.57(t,J=5.6Hz,2H),3.41(brs,2H),3.32(s,3H),3.20-3.26(m,1H ),3.08-3.16(m,1H),2.73-2.98(m,1H),2.05-2.11(m,1H),1.88-1.90(m,1H),1.52-1.70(m,2H).

[0244] Example 4

[0245] N-(tert-butyl)-3-((6-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)benzenesulfonamide

[0246]

[0247] Implementation steps (Implementation Method 4):

[0248]

[0249] Step 1: Synthesis of fragment 4-b N-(tert-butyl)-3-((6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)benzenesulfonamide

[0250]

[0251] A solution of isopropanol (10 mL) containing 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (196 mg, 0.83 mmol), fragment 1-b: 3-amino-N-(tert-butyl)benzenesulfonamide (189 mg, 0.83 mmol), and N,N-diisopropylethylamine (128 mg, 0.99 mmol) was heated to reflux and stirred for 6 hours. The reaction was monitored by TLC until complete. The reaction solution was concentrated, and the residue was partitioned into ethyl acetate (15 mL) and water (20 mL). The organic layer was collected, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with n-hexane solution of 20%-33% ethyl acetate) to obtain a white solid N-(tert-butyl)-3-((6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)benzenesulfonamide (150 mg, 45%).

[0252] LC_MS:(ES + ):m / z 465.4[M+H] + .

[0253] 1 H NMR (400MHz, DMSO-d6): δ10.77(s,1H),8.34(s,1H),8.19(s,1H),8.02-8.11(m,1H),7.61-7.66(m,3H),5.81-5.84(m,1H),3.94,3.97(two singles,1H),3.67-3.73(m,1H),2.33-2.44(m,1H),1.74-2.03(m,3H),1.50-1.62(m,2H),1.15(s,9H).

[0254] Step 2: Synthesis of fragment 4-c N-(tert-butyl)-3-((6-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)benzenesulfonamide

[0255]

[0256] BrettPhos Pd G3 (8.7 mg, 0.009 mmol) was added to a suspension of 1,4-dioxane (1 ml) containing N-(tert-butyl)-3-((6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)benzenesulfonamide (44.6 mg, 0.096 mmol), 4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (20 mg, 0.096 mmol) and potassium phosphate (61 mg, 0.29 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was purged with nitrogen three times and heated to 110 °C with stirring for 16 hours. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature and dispensed into water (10 ml) and ethyl acetate (10 ml). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (10 ml x 2). The organic layers were combined, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (eluting with dichloromethane solution of 5% methanol) to obtain a yellow solid N-(tert-butyl)-3-((6-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)benzenesulfonamide (52 mg, 80%).

[0257] LC_MS:(ES + ):m / z 637.2[M+H] + .

[0258] Step 3: Synthesis of N-(tert-butyl)-3-((6-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)benzenesulfonamide

[0259]

[0260] A solution of N-(tert-butyl)-3-((6-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)benzenesulfonamide (52 mg, 0.082 mmol) and trifluoroacetic acid (0.5 mL) in dichloromethane (1.5 mL) was stirred at room temperature for 2 hours. The reaction was monitored by TLC until complete. The organic solvent was concentrated under reduced pressure, and the residue was adjusted to pH 7-8 with sodium carbonate solution, followed by extraction with dichloromethane (10 mL × 2). The organic layers were combined, washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (eluting with 7.5% methanol and dichloromethane solution) to obtain a yellow solid N-(tert-butyl)-3-((6-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)benzenesulfonamide (20 mg, 46%).

[0261] LC_MS:(ES + ):m / z 553.4[M+H] + .

[0262] 1 H NMR (400MHz, DMSO-d6): δ12.96(s,1H),9.90(s,1H),8.81(s,1H),8.46(d,J=7.6Hz,1 H),8.28(brs,1H),8.11(s,1H),7.68(s,1H),7.47-7.53(m,2H),7.31(brs,1H),7.06 -7.09(m,1H),6.66(d,J=8.8Hz,1H),4.15(t,J=4.2Hz,2H),3.53(t,J=5.6Hz,2H),3. 40(t,J=5.4Hz,2H),3.33-3.35(m,1H),3.29-3.30(m,1H),3.27(s,3H),1.14(s,9H).

[0263] Example 5

[0264] 4-Methyl-N-(4-(1-methyl-1H-indol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine

[0265]

[0266] Implementation steps (Implementation Method 5):

[0267]

[0268] Step 1: Synthesis of fragment 5-c 6-chloro-4-(1-methyl-1H-indol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine

[0269]

[0270] A solution containing 4,6-dichloro-pyrazolo[3,4-d]pyrimidine (500 mg, 2.64 mmol), N-methylindole (347 mg, 2.64 mmol), and aluminum trichloride in 1,2-dichloroethane (10 mL) was heated under reflux for 12 hours. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into dichloromethane (10 mL) and water (20 mL). The organic layer was collected, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a pale yellow crude product of 6-chloro-4-(1-methyl-1H-indole-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (1.4 g), which could be used in the next step without further purification.

[0271] Step 2: Synthesis of fragment 5-d 6-chloro-4-(1-methyl-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine

[0272]

[0273] Sodium hydride (60%, 294 mg, 7.3 mmol) was added to a solution of N,N-dimethylformamide (10 mL) containing 6-chloro-4-(1-methyl-1H-indol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (1.4 g, 4.9 mmol) at 0 °C. The mixture was heated to room temperature and stirred for 1 h, then cooled to 0 °C, and 2-(trimethylsilyl)ethoxymethyl chloride (980 g, 5.8 mmol) was added dropwise to the reaction mixture. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 14 h. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into ethyl acetate (100 mL) and water (100 mL). The organic layer was collected, washed with saturated sodium chloride solution (100 ml x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with 0.5-1% methanol in dichloromethane solution) to obtain a white solid 6-chloro-4-(1-methyl-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (245 mg, 22% in two steps).

[0274] LC_MS:(ES + ):m / z 414.4[M+H] + .

[0275] 1 H NMR (400MHz, DMSO-d6): δ8.90 (d, J=2.8Hz, 2H), 8.62-8.64 (m, 1H), 7.61-7.63 (m, 1H), 7.31-7.3 8(m,2H),5.70(s,2H),3.98(s,3H),3.64(t,J=8.0Hz,2H),0.86(t,J=8.0Hz,2H),-0.08(s,9H).

[0276] Step 3: Synthesis of fragment 5-e 4-methyl-N-(4-(1-methyl-1H-indol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine

[0277]

[0278] Under nitrogen protection at room temperature, BrettPhos Pd G3 (22 mg, 0.024 mmol) was added to a solution of 1,4-dioxane (2 mL) containing 6-chloro-4-(1-methyl-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.24 mmol), 4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (55 mg, 0.24 mmol) and potassium phosphate (154 mg, 0.72 mmol). The resulting mixture was purged with nitrogen three times, and the mixture was heated to 110 °C and stirred for 12 hours. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature and partitioned into water (20 mL) and ethyl acetate (10 mL). The organic layer was collected, and the aqueous phase was extracted with ethyl acetate (10 mL x 2). The organic layers were combined, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative TLC (eluting with 5% methanol in dichloromethane) to obtain a yellow solid 4-methyl-N-(4-(1-methyl-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (38 mg, 27%).

[0279] LC_MS:(ES+ ):m / z 586.5[M+H] + .

[0280] Step 4: Synthesis of 4-methyl-N-(4-(1-methyl-1H-indol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine

[0281]

[0282] A solution of 4-methyl-N-(4-(1-methyl-1H-indol-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (38 mg, 0.065 mmol) and trifluoroacetic acid (0.5 mL) in dichloromethane (0.5 mL) was stirred for 3 hours at room temperature. The reaction was monitored by TLC until complete. The reaction solution was concentrated, and the residue was added to a mixed solution containing ammonia (2 mL) and ethyl acetate (4 mL). The resulting mixture was stirred at 30 °C for 16 hours. The reaction was monitored by TLC until complete. The organic layer was collected, washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (eluting with dichloromethane solution of 10% methanol) to obtain a yellow solid 4-methyl-N-(4-(1-methyl-1H-indol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (18.5 mg, 62%).

[0283] LC_MS:(ES + ):m / z 456.2[M+H] + .

[0284] 1 H NMR (400MHz, CDCl3): δ8.62(d,J=7.6Hz,1H),8.14(s,1H),7.91(s,1H),7.28-7.41(m,6H),7.06-7.08(m,1H),6 .68(d,J=8.4Hz,1H),4.26(t,J=4.2Hz,2H),3.93(s,3H),3.61(t,J=5.6Hz,2H),3.42-3.55(m,4H),3.38(s,3H).

[0285] Example 6

[0286] 1-Methyl-4-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)cyclohexanol

[0287]

[0288] Implementation steps (Implementation Method Six):

[0289]

[0290] Step 1: Synthesis of fragment 6-b-8-methyl-1,4-dioxaspiro[4,5]dec-8-ol

[0291]

[0292] At -60°C, methyl magnesium bromide (3M dissolved in tetrahydrofuran, 7.7 ml, 23 mmol) was added to a suspension of anhydrous tetrahydrofuran (20 ml) containing 1,4-cyclohexanedione monoethylene glycol ketal (2 g, 12.8 mmol). The reaction mixture was stirred at -60°C for 20 min, then heated to -30°C and stirred for 30 min, and finally stirred at 0°C for 30 min. The reaction was monitored by TLC until complete. The reaction mixture was quenched with saturated ammonium chloride solution (10 ml) and extracted with ethyl acetate (20 ml). The organic layer was collected, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a colorless oily substance, 8-methyl-1,4-dioxaspiro[4.5]dec-8-ol (1.4 g, 63%), which was used directly for the next step without further purification.

[0293] Step 2: Synthesis of fragment 6-C 4-hydroxy-4-methylcyclohexanone

[0294]

[0295] A suspension of acetone (16 ml) and water (8 ml) containing 8-methyl-1,4-dioxaspiro[4.5]dec-8-ol (1.4 g, 8.1 mmol) and pyridinium p-toluenesulfonate (408.6 mg, 1.63 mmol) was stirred at 60 °C under nitrogen protection for 13 h. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature, quenched with water (50 ml), and extracted with ethyl acetate (30 ml x 2). The organic layers were combined, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with n-hexane containing 15% ethyl acetate) to obtain a yellow oily substance, 4-hydroxy-4-methylcyclohexanone (630 mg, 57%).

[0296] Step 3: Synthesis of fragments 6-d(1r,4r)-1-methylcyclohexane-1,4-diol and 6-e(1s,4s)-1-methylcyclohexane-1,4-diol

[0297]

[0298] Sodium borohydride (372.1 mg, 9.5 mmol) was added to a methanol (6 mL) suspension containing 4-hydroxy-4-methylcyclohexanone (630 mg, 4.9 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC until complete. The reaction mixture was quenched with water (0.5 mL), concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with dichloromethane containing 4% methanol) to obtain a white solid 6-d(1r,4r)-1-methylcyclohexane-1,4-diol (80 mg, 12%).

[0299] 1 H NMR (400MHz, CDCl3): δ4.04–3.71(m,1H),1.89(dq,J=16.0,9.6,6.7Hz,2H),1.89(dq,J=16.0,9.6,6.7Hz,2H),1.59–1.36(m,6H),1.26(s,3H).

[0300] And white solid 6-e(1s,4s)-1-methylcyclohexane-1,4-diol (400 mg, 60%);

[0301] 1 H NMR (400MHz, CDCl3): δ3.60(tt,J=9.7,4.1Hz,1H),1.81–1.72(m,2H),1.72–1.58(m,4H),1.55–1.37(m,4H),1.22(s,3H).

[0302] Step 4: Synthesis of fragment 6-f(1s,4s)-4-((2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-1-methylcyclohexane-1-ol

[0303]

[0304] Under nitrogen protection at 0 °C, potassium tert-butoxide (70.7 mg, 0.6 mmol) was added to an anhydrous tetrahydrofuran (5 mL) solution containing (1s,4s)-1-methylcyclohexane-1,4-diol (40.4 mg, 0.3 mmol) and 2,4-dichloro-7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 13 hours. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into water (20 mL) and ethyl acetate (20 mL). The aqueous phase was separated into ethyl acetate (10 mL x 10 mL). 2) Extraction. Combine the organic layers, wash with saturated sodium chloride solution (30 ml), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (eluting with n-hexane containing 25% ethyl acetate) to obtain a colorless oily substance (1s,4s)-4-((2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-1-methylcyclohexane-1-ol (100 mg, 79%).

[0305] LC_MS:(ES + ):m / z 412.2[M+H] + .

[0306] Step 5: Synthesis of fragment 6-g(1s,4s)-1-methyl-4-((2-((7-methyll-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecyl-12-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)cyclohexyl-1-ol

[0307]

[0308] BrettPhos Pd was added to a suspension of 1,4-dioxane (2 ml) containing (1s,4s)-4-((2-chloro-7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-1-methylcyclohexanol (100 mg, 0.24 mmol), Amine-3: 6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxaza

[10] azacyclododecane-12-amine (61.2 mg, 0.24 mmol), and potassium phosphate (154.8 mg, 0.73 mmol) under a nitrogen atmosphere at room temperature. G3 (21.8 mg, 0.02 mmol), the reaction mixture was purged with nitrogen three times, and the mixture was stirred at 110 °C for 14 hours. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature and partitioned into water (20 ml) and ethyl acetate (10 ml). The organic layer was collected, and the aqueous layer was separated into ethyl acetate (10 ml x 10 ml). 2) Extraction. Combine the organic layers, wash with saturated sodium chloride solution (20 ml), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and the crude product is subjected to preparative TLC (eluted with dichloromethane containing 10% methanol and 1% ammonia) to obtain a yellow solid (1s,4s)-1-methyl-4-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)-7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)hexanol (70 mg, 46%).

[0309] LC_MS:(ES + ):m / z 628.3[M+H] + .

[0310] Step 6: Synthesis of (1s,4s)-1-methyl-4-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecyl-12-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)cyclohexyl-1-ol

[0311]

[0312] A solution of (1s,4s)-1-methyl-4-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)-7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)hexanol (70 mg, 0.11 mmol) and trifluoroacetic acid (1 ml) in dichloromethane (1 ml) was stirred at 0 °C for 3 hours. The reaction was monitored by TLC until complete. The volatiles were removed under reduced pressure, and the residue was adjusted to pH 7-8 with saturated sodium carbonate solution. Dichloromethane (10 ml x 2) Extraction. The organic layers were combined, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was added to a mixed solvent containing ammonia (2 ml) and ethyl acetate (4 ml). The reaction mixture was stirred at 30 °C for 12 hours. The reaction was monitored by TLC until complete. The organic layer was collected, washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (eluting with dichloromethane containing 10% methanol) to obtain an orange solid 1-methyl-4-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)cyclohexanol (42.6 mg, 76%).

[0313] LC_MS:(ES + ):m / z 498.2[M+H] + .

[0314] 1 H NMR (400MHz, DMSO-d6): δ11.33(s,1H),8.90(s,1H),7.66(s,1H),7.35(brs,1H),6.95-6.98(m,2H),6.25-6.27(m,1H),5.16-5.22(m,1H ),4.08-4.22(m,5H),3.72(s,4H),3.29(s,3H),2.82-3.05(m,4H),1.86-1.87(m,4H),1.66-1.69(m,2H),1.41-1.48(m,2H),1.17(s,3H).

[0315] Example 7

[0316] (1s,4s)-1-methyl-4-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecyl-12-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)oxy)cyclohexyl-1-ol

[0317]

[0318] Implementation steps (Implementation Method Seven):

[0319]

[0320] Step 1: Synthesis of fragment 7-b(1s,4s)-4-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-1-methylcyclohexane-1-ol and fragment 7-c(1s,4s)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)oxy)-1-methylcyclohexane-1-ol

[0321]

[0322] Sodium hydride (60%, 68 mg, 1.69 mmol) was added to a 3 mL solution of tetrahydrofuran containing (1s,4s)-1-methylcyclohexane-1,4-diol (100 mg, 0.77 mmol). The mixture was slowly heated to room temperature and stirred for 30 min. The reaction mixture was then added dropwise to a 2 mL solution of tetrahydrofuran containing 2,4-dichloro-5-(trifluoromethyl)pyrimidine (334 mg, 1.54 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC until complete. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic layer was collected, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (eluting with n-hexane containing 6%-12.5% ​​ethyl acetate) to obtain two groups of compounds: colorless oily 7-b (first elution fraction) (1s,4s)-4-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-1-methylcyclohexane-1-ol (28 mg, 12%);

[0323] LC_MS:(ES + ):m / z 311.0[M+H] + .

[0324] And colorless oily substance 7-c (second effluent component) (1s,4s)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)oxy)-1-methylcyclohexyl-1-ol (52 mg, 21%).

[0325] LC_MS:(ES + ):m / z 311.0[M+H] + .

[0326] Step 2: Synthesis of (1s,4s)-1-methyl-4-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecyl-12-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)oxy)cyclohexyl-1-ol

[0327]

[0328] BrettPhos Pd G3 (21.8 mg, 0.02 mmol) was added to a suspension of 1,4-dioxane (2 ml) containing (1s,4s)-4-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-1-methylcyclohexane-1-ol (20.0 mg, 0.064 mmol), 6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxaza

[10] azacyclododecane-12-amine (19.4 mg, 0.077 mmol), and potassium phosphate (154.8 mg, 0.73 mmol). The reaction mixture was purged with nitrogen three times and stirred at 110 °C for 12 h. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature and partitioned into water (10 ml) and ethyl acetate (10 ml). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (10 ml x 2). The organic layers were combined, washed with saturated sodium chloride solution (20 ml), dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was subjected to preparative TLC (eluted with dichloromethane containing 10% methanol and 1% ammonia) to obtain a grayish-white solid (1s,4s)-1-methyl-4-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecyl-12-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)oxy)cyclohexyl-1-ol (10 mg, 30%).

[0329] LC_MS:(ES + ):m / z 527.5[M+H] + .

[0330] 1H NMR (400MHz, CD3OD): δ8.34(s,1H),7.54(brs,1H),7.28-7.30(m,1H),7.09(d,J=8.8Hz,1H),5.18-5.22(m,1H),4.35(t,J=4.8Hz,2H),4.1 9(t,J=4Hz,2H),3.82-3.97(m,4H),3.43-3.53(m,2H),2.91(s,3H),1.90-1.96(m,4H),1.77-1.81(m,2H),1.50-1.57(m,2H),1.25(s,3H).

[0331] Example 8

[0332] 2-Methyl-1-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)prop-2-ol

[0333]

[0334] Implementation steps (Implementation Method 8):

[0335]

[0336] Step 1: Synthesis of fragment 8-a N-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine

[0337]

[0338] A solution of tetrahydrofuran (30 mL) containing 2,4-dichloro-5-(trifluoromethyl)pyrimidine (800 mg, 3.69 mmol), 4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (768 mg, 3.69 mmol), and triethylamine (750 mg, 7.40 mmol) was stirred at room temperature for 16 hours. The reaction was monitored by TLC until complete. The reaction solution was concentrated, and the residue was partitioned into ethyl acetate (15 mL) and water (20 mL). The organic layer was collected, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting with 20-33% ethyl acetate in n-hexane) to obtain a yellow solid. Then, it was separated by preparative HPLC (mobile phase: gradient elution of 30%-90% acetonitrile aqueous solution for 25 min) to obtain the first eluting fraction as a yellow solid N-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (430 mg, 30%).

[0339] LC_MS:(ES + ):m / z 389.0[M+H] + .

[0340] 1 H NMR (400MHz, CDCl3): δ8.34(d,J=1.2Hz,1H),6.97(d,J=2.5Hz,1H),6.93(dd,J=8.7,2.6Hz,1H),6.87(s,1H ),6.65(d,J=8.6Hz,1H),4.27–4.18(m,2H),3.60(t,J=5.6Hz,2H),3.46(dt,J=8.9,5.0Hz,4H),3.37(s,3H).

[0341] The second effluent component was a yellow solid N-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (406 mg, 28%).

[0342] LC_MS:(ES + ):m / z 389.0[M+H] + .

[0343] 1H NMR (400MHz, CDCl3): δ8.48(s,1H),7.35(s,1H),7.03(d,J=2.5Hz,1H),6.93(d,J=7.8Hz,1H),6.64(d, J=8.7Hz,1H),4.30–4.17(m,2H),3.59(t,J=5.6Hz,2H),3.45(dq,J=11.9,6.1,4.5Hz,4H),3.36(s,3H).

[0344] Step 2: Synthesis of 2-methyl-1-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)prop-2-ol

[0345]

[0346] A solution of 1,4-dioxane (1 ml) containing N-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (30 mg, 77.2 μmol), 1-amino-2-methylprop-2-ol (14 mg, 155 μmol), and triethylamine (16 mg, 155 μmol) was stirred at 80 °C for 16 hours. The reaction was monitored by TLC until complete. The reaction solution was concentrated, and the residue was partitioned into ethyl acetate (15 ml) and water (20 ml). The reaction was monitored by TLC until complete. The organic layer was collected, washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (eluting with petroleum ether containing 50% ethyl acetate) to obtain orange solid 2-methyl-1-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)prop-2-ol (18 mg, 52%).

[0347] LC_MS:(ES + ):m / z 442.1[M+H] + .

[0348] Example 9

[0349] N-(tert-butyl)-3-((5-fluoro-2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecyl-13-yl)amino)pyrimidin-4-yl)amino)benzenesulfonamide

[0350]

[0351] The implementation method is the same as Method 1, except that fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound. LC_MS:(ES + ):m / z 575.9[M+H] + .

[0352] 1 H NMR (400MHz, DMSO-d6): δ9.67(s,1H),9.10(s,1H),8.19-8.14(m,3H),7.60(s,1H),7.52-7.49(m,2H),7.43(s,1H),7.22-7.19 (m,1H),6.96-6.94(d,J=8.4Hz,1H),4.13-4.09(m,2H),3.96(s,2H),3.73(s,4H),3.30(s,3H),3.18-2.85(m,4H),1.12(s,9H).

[0353] Example 10

[0354] N 4 -(2-(isopropylsulfonyl)phenyl)-N 2 -(7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[0355]

[0356] The implementation method is the same as in Method 4, except that fragment 4-a is replaced with fragment 2-d, fragment 1-b is replaced with fragment 10-a: 2-(isopropylsulfonyl)aniline, and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0357] LC_MS:(ES + ):m / z 567.9[M+H] + .

[0358] 1H NMR (400MHz, DMSO-d6): δ11.43(s,1H),9.48(s,1H),8.88-8.93(m,2H),7.82(d,J=8.0H z,1H),7.73(t,J=7.8Hz,1H),7.58(s,1H),7.27-7.31(m,2H),7.04(d,J=3.2Hz,1H),6. 91(d,J=8.4Hz,1H),6.25(d,J=2.8Hz,1H),4.01-4.12(m,4H),3.61-3.77(m,4H),3.42- 3.51(m,1H),3.29(s,3H),2.72-2.87(m,2H),2.26-2.38(m,2H),1.18(d,J=6.8Hz,6H).

[0359] Example 11

[0360] N 4 -(2-(isopropylsulfonyl)phenyl)-N 6 -(7-Methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

[0361]

[0362] The same method as Method 4 was used, except that fragment 4-a was replaced with fragment 2-d, fragment 1-b was replaced with fragment 2-(isopropylsulfonyl)aniline, and fragment Amine-1 was replaced with fragment Amine-2 to obtain the title compound.

[0363] LC_MS:(ES + ):m / z 568.6[M+H] + .

[0364] 1 H NMR(400MHz, CDCl3): δ9.86(s,1H),8.75-8.77(m,1H),7.89-7.92(m,2H), 7.66-7.70(m,1H),7.56(s,1H),7.25-7.29(m,1H),7.08-7.11(m,1H),6.9 4-6.96(m,1H),4.41(s,2H),4.14-4.16(m,2H),4.07(s,2H),3.90(s,2H), 3.62(s,4H),3.22-3.29(m,1H),2.96(s,3H),1.30-1.32(d,J=6.8Hz,6H).

[0365] Example 12

[0366] N 4 -(2-(isopropylsulfonyl)phenyl)-N 6 -(7-Methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

[0367]

[0368] The implementation method is the same as in Method 4, except that fragment 4-a is replaced with fragment 2-d, fragment 1-b is replaced with fragment 2-(isopropylsulfonyl)aniline, and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0369] LC_MS:(ES + ):m / z 568.5[M+H] + .

[0370] 1 H NMR (400MHz, DMSO-d6): δ13.11(s,1H),9.65(s,1H),9.15(s,1H),8.34-8.50(m ,1H),7.90-7.92(m,1H),7.78-7.82(m,2H),7.44-7.48(m,2H),7.25-7.28(m,1 H),6.90(d,J=8.4Hz,1H),3.98-4.10(m,4H),3.62-3.74(m,4H),3.41-3.46(m, 1H), 3.30 (s, 3H), 2.73-2.92 (m, 2H), 2.31-2.46 (m, 2H), 1.14 (d, J = 6.4Hz, 6H).

[0371] Example 13

[0372] N-(5-fluoro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine

[0373]

[0374] The implementation method is the same as in Method 5, except that fragment 5-a is replaced with fragment 1-a to obtain the title compound.

[0375] LC_MS:(ES + ):m / z 434.3[M+H] + .

[0376] 1 HNMR (400MHz, CDCl3): δ8.69(d,J=8.0Hz,1H),8.15(d,J=4.0Hz,1H),7.93(d,J=2.4Hz,1H),7.30-7.38(m,2H),7.23-7.26(m,1H),7.13(d,J=2.4Hz,1 H),7.02-7.04(m,1H),6.83(s,1H),6.68(d,J=8.4Hz,1H),4.26(t,J=4.4H z,2H),3.88(s,3H),3.62(t,J=5.6Hz,2H),3.42-3.48(m,4H),3.38(s,3H).

[0377] Example 14

[0378] 2-(1-(ethylsulfonyl)-3-(4-(5-fluoro-2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile

[0379]

[0380] The implementation method is the same as Method 2, except that fragment 2-d is replaced with fragment 1-a, fragment 2-b is replaced with fragment 14-e, and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0381] LC_MS:(ES + ):m / z 601.6[M+H] + .

[0382] 1 HNMR (400MHz, DMSO-d6): δ9.57 (s, 1H), 8.72 (s, 1H), 8.56 (d, J = 2.0Hz, 1H), 8.25 (s, 1H),7.59(s,1H),7.33(d,J=8.8Hz,1H),7.03(d,J=8.4Hz,1H),4.53(d,J=9.2Hz,2H) ,4.24(d,J=8.8Hz,2H),4.21-4.10(m,4H),3.89-3.74(m,4H),3.69(s,2H),3.30(s, 3H),3.26-3.21(m,2H),3.14-2.91(m,2H),2.67-2.56(m,2H),1.24(t,J=7.2Hz,3H).

[0383] The synthesis method of fragment 14-e is as follows:

[0384]

[0385] Step 1: Synthesis of fragment 14-a 2-(azacyclobutane-3-alkylene)acetonitrile trifluoroacetate

[0386]

[0387] A solution of tert-butyl 3-(cyanomethylene)-azacyclobutane-1-carboxylate (5 g, 25.7 mmol) and trifluoroacetic acid (20 mL) in 20 mL of dichloromethane was stirred at room temperature for 2.5 h. The reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure to obtain a brown oily substance, 2-(3-azacyclobutylene)acetonitrile trifluoroacetate (5 g, crude product), which could be used in the next step without further purification.

[0388] Step 2: Synthesis of fragment 14-C 2-(1-(ethylsulfonyl)-3-azacyclobutanediol)acetonitrile

[0389]

[0390] Ethylsulfonyl chloride (4 g, 31.4 mmol) was added to a solution of 2-(3-azacyclobutylidene)acetonitrile trifluoroacetate (5 g, 26.2 mmol) and N,N-diisopropyldiamine (11.8 g, 91.6 mmol) in dichloromethane (50 mL) at 0 °C. The resulting mixture was heated to room temperature and reacted for 14 h. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into dichloromethane (50 mL) and water (100 mL). The organic layer was collected, washed with saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with 20%–33% ethyl acetate in hexane) to obtain a yellow solid 2-(1-(ethylsulfonyl)-3-azacyclobutylidene)acetonitrile (3 g, combined yield 62%).

[0391] 1 H NMR (400MHz, DMSO-d6): δ5.89-5.92(m,1H),4.77-4.79(m,2H),4.68-4.70(m,2H),3.20-3.25(q,2H),1.23(t,J=7.4Hz,3H).

[0392] Step 3: Synthesis of fragment 14-e 2-(1-(ethylsulfonyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile

[0393]

[0394] A solution of acetonitrile (40 mL) containing 2-(1-(ethylsulfonyl)-3-azacyclobutanediyl)acetonitrile (2.9 g, 15.6 mmol), pinacol 4-pyrazoloborate (3.02 g, 15.6 mmol), and 1,8-diazabicycloundec-7-ene (2.37 g, 15.6 mmol) was heated to reflux for 2 hours. The reaction was monitored by TLC until complete. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with 30%–50% ethyl acetate in hexane) to obtain a white solid 2-(1-(ethylsulfonyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile (3 g, 51%).

[0395] 1 H NMR (400MHz, DMSO-d6): δ8.36(s,1H),7.78(s,1H),4.45(d,J=8.8Hz,2H),4.15(d, J=9.2Hz,2H),3.60(s,2H),3.17-3.23(q,2H),1.28(s,12H),1.23(t,J=7.4Hz,3H).

[0396] Example 15

[0397] N-(cyanomethyl)-4-(5-fluoro-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)pyrimidin-4-yl)benzamide

[0398]

[0399] The implementation method is the same as Method 2, except that fragment 2-d is replaced with fragment 1-a to obtain the title compound.

[0400] LC_MS:(ES + ):m / z 463.3[M+H] + .

[0401] 1H NMR (400MHz, CDCl3): δ8.31(d,J=3.2Hz,1H),8.18(d,J=8.4Hz,2H),7.89(d,J=8.4Hz,2H),7.14(d,J=2.4Hz,1H),6.94-7.05( m,2H),6.65-6.74(m,2H),4.41(d,J=5.6Hz,2H),4.24(t,J=4.4Hz,2H),3.60(t,J=5.6Hz,2H),3.41-3.48(m,4H),3.37(s,3H).

[0402] Example 16

[0403] N-(cyanomethyl)-4-(5-fluoro-2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)amino)pyrimidin-4-yl)benzamide

[0404]

[0405] The implementation method is the same as Method 2, except that fragment 2-d is replaced with fragment 1-a and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0406] LC_MS:(ES+):m / z 507.8[M+H] + .

[0407] 1 H NMR (400MHz, DMSO-d6): δ9.68(s,1H),8.40-8.37(m,1H),8.66-8.65(m,1H),8.16-8.14(m,2H),8.06-8.04(m,2H),7.60(m,1H),7.24-7.22(m,1 H),6.97-6.94(m,1H),4.37-4.36(m,2H),4.14-4.12(m,2H),4.07-4.04 (m,2H),3.74(m,2H),3.64-3.63(m,2H),2.73-2.62(m,4H),2.28(s,3H).

[0408] Example 17

[0409] N-(cyanomethyl)-4-(2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide

[0410]

[0411] The implementation method is the same as Method 2, except that fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0412] LC_MS:(ES + ):m / z 528.5[M+H] + .

[0413] 1 H NMR (400MHz, DMSO-d6): δ11.71(s,1H),9.41-9.38(m,1H),9.27(s,1H),8.28-8.26,(m,2H),8.08-8.06(m,2H),7.81(s,1H),7.33-7.32(m,2H) ,6.96-6.94(m,1H),6.73(m,1H),4.38-4.36(m,2H),4.17-4.08(m,4H) ,3.78-3.68(m,4H),3.31(s,3H),2.71-2.62(m,2H),2.37-2.30(m,2H).

[0414] Example 18

[0415] N-(cyanomethyl)-4-(2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide

[0416]

[0417] The implementation method is the same as Method 2, except that fragment 2-d is replaced with fragment 4-a and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0418] LC_MS:(ES + ):m / z 529.9[M+H] + .

[0419] 1H NMR (400MHz, DMSO-d6): δ9.74(s,1H),9.44(t,J=1.6Hz,1H),8.43-8.36(m,3H),8.10(d,J=8.4Hz,2H),7.73(s,1H),7.39(d,J=8.8Hz ,1H),7.00(d,J=8.8Hz,1H),4.37(d,J=4.8Hz,2H),4.17-4.10(m,4H),3.73(d,J=32.8Hz,4H),2.82-2.68(m,4H),2.37-2.33(m,3H).

[0420] Example 19

[0421] N-(tert-butyl)-3-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)benzenesulfonamide

[0422]

[0423] The implementation method is the same as in Method 4, except that fragment 4-a is replaced with fragment 2-d and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0424] LC_MS:(ES + ):m / z 596.5[M+H] + .

[0425] 1 H NMR (400MHz, DMSO-d6): δ11.27(s,1H),9.42(s,1H),8.71(s,1H),8.44(d,J= 7.2Hz,1H),8.28(s,1H),7.65(s,1H),7.61(brs,1H),7.51-7.42(m,2H),7.3 5(d,J=8.0Hz,1H),7.00-6.90(m,2H),6.70(s,1H),4.16-3.99(m,4H),3.77- 3.61(m,4H),3.29(s,3H),2.88-2.74(m,2H),2.38-2.23(m,2H),1.15(s,9H).

[0426] Example 20

[0427] N-(tert-butyl)-3-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)benzenesulfonamide

[0428]

[0429] The implementation method is the same as in Method 4, except that fragment 4-a is replaced with fragment 2-d and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0430] LC_MS:(ES + ):m / z 596.7[M+H] + .

[0431] 1 H NMR (400MHz, DMSO-d6): δ11.31(s,1H),9.48(s,1H),8.82(s,1H),8.44(d,J=8.0Hz,1H),8.28(s,1H),7.77(s,1H),7.66(s,1H),7.51-7.43(m,2 H),7.36-7.33(m,1H),7.02-6.96(m,2H),6.72-6.71(m,1H),4.23(s,2H ),4.07(s,2H),3.82(brs,4H),3.32(s,3H),2.80(brs,4H),1.14(s,9H).

[0432] Example 21

[0433] N-(tert-butyl)-3-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)benzenesulfonamide

[0434]

[0435] The implementation method is the same as in Method 4, except that fragment 4-a is replaced with fragment 2-d to obtain the title compound.

[0436] LC_MS:(ES + ):m / z 552.2[M+H] + .

[0437] 1H NMR (400MHz, DMSO-d6): δ11.24(s,1H),9.42(brs,1H),8.41-8.62(m,2H),8.34(s,1H),7.66(s,1H),7.41-7.49(m,2H),7.27-7.35(m,1H),7 .01-7.14(m,1H),6.82-6.99(m,1H),6.54-6.78(m,2H),4.02-4.28(m ,2H),3.52-3.58(m,2H),3.34-3.48(m,4H),3.27(s,3H),1.15(s,9H).

[0438] Example 22

[0439] N-(tert-butyl)-3-((6-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)benzenesulfonamide

[0440]

[0441] The implementation method is the same as in Method 4, except that fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound. LC_MS:(ES + ):m / z 597.6[M+H] + .

[0442] 1 H NMR (400MHz, DMSO-d6): δ13.04(s,1H),10.00(s,1H),9.08(s,1H),8.50-8.48 (m,1H),8.22(brs,1H),8.13(s,1H),7.70(s,1H),7.56-7.49(m,3H),7.35-7. 32(m,1H),6.95(d,J=8.8Hz,1H),4.09-4.05(m,4H),3.72-3.65(m,4H),3.32( m,3H),2.77-2.74(m,1H),2.64-2.60(m,1H),2.33-2.29(m,2H),1.14(s,9H).

[0443] Example 23

[0444] 7-Methyl-N-(4-(1-methyl-1H-indol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-amine

[0445]

[0446] The procedure is the same as in Method 5, except that fragment 5-a is replaced with fragment 2-c and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0447] LC_MS:(ES + ):m / z 499.6[M+H] + .

[0448] 1 H NMR (400MHz, DMSO-d6): δ11.44(s,1H),9.03(brs,1H),8.87(d,J=8.0Hz,1H),8.41 (s,1H),7.83(brs,1H),7.53(d,J=8.0Hz,1H),7.46-7.43(m,1H),7.30-7.26(m,1H ),7.22-7.18(m,2H),7.00(d,J=8.0Hz,1H),6.87-6.86(m,1H),4.22-4.10(m,4H), 3.95(s,3H),3.85-3.70(m,4H),3.31(s,3H),3.13-2.93(m,2H),2.76-2.54(m,2H).

[0449] Example 24

[0450] 7-Methyl-N-(4-(1-methyl-1H-indol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-amine

[0451]

[0452] The implementation method is the same as in Method 5, except that fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0453] LC_MS:(ES + ):m / z 500.8[M+H] + .

[0454] 1H NMR (400MHz, DMSO-d6): δ13.17(s,1H),9.38(s,1H),8.90(d,J=8.0Hz,1H),8 .66(s,1H),8.50(s,1H),7.69(brs,1H),7.56(d,J=8.0Hz,1H),7.46(d,J=8. 4Hz,1H),7.33-7.23(m,2H),6.99(d,J=8.4Hz,1H),4.21-4.06(m,4H),3.97( s,3H),3.81-3.63(m,4H),3.29(s,3H),2.85-2.71(m,2H),2.39-2.30(m,2H).

[0455] Example 25

[0456] 3-Cyclopentyl-3-(4-(5-fluoro-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl))amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile

[0457]

[0458] The implementation method is the same as Method 2, except that fragment 2-b is replaced with fragment 25-b and fragment 2-d is replaced with fragment 1-a to obtain the title compound.

[0459] LC_MS:(ES + ):m / z 492.3[M+H] + .

[0460] 1 H NMR (400MHz, CDCl3): δ8.26(s,1H),8.21(brs,1H),8.17(s,1H),7.14(brs,1 H),6.84-7.02(m,2H),6.58-6.73(m,1H),4.19-4.25(m,3H),3.60(t,J=5.6H z,2H),3.38-3.45(m,2H),3.37(s,3H),3.09-3.15(m,1H),2.91-2.96(m,1H) ,2.51-2.62(m,1H),1.92-2.00(m,1H),1.48-1.75(m,6H),1.19-1.31(m,3H).

[0461] The synthesis method for fragment 25-b is as follows:

[0462]

[0463] Step 1: Synthesis of fragment 25-b 3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)propionitrile

[0464]

[0465] An acetonitrile (1 mL) solution containing 3-cyclopentylacrylonitrile (100 mg, 0.8 mmol) and pyrazolium borate pyrrolyl ester (161 mg, 0.8 mmol) was stirred at 0 °C for 10 min, followed by the addition of 1,8-diazabicycloundec-7-ene (126 mg, 0.8 mmol) at 0 °C. The reaction mixture was heated to 100 °C and stirred for 12 h. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting with 30% ethyl acetate in petroleum ether) to obtain a colorless oily substance, 3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl)propionitrile (85 mg, 32%).

[0466] 1 H NMR (400MHz, CDCl3): δ7.83(s,1H),7.78(s,1H),4.11-4.18(m,1H),3.03-.309(m,1H),2.85-2.91(m,1H),2.45-2.56(m,1H),1 .88-1.96(m,1H),1.61-1.72(m,2H),1.56-1.59(m,1H),1.43-1.54(m,2H),1.32(s,12H),1.25-1.29(m,1H),1.08-1.16(m,1H).

[0467] Example 26

[0468] 3-Cyclopentyl-3-(4-(2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile

[0469]

[0470] The implementation method is the same as Method 2, except that fragment 2-b is replaced with fragment 25-b and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0471] LC_MS:(ES + ):m / z 557.6[M+H]+ .

[0472] 1 HNMR (400MHz, DMSO-d6): δ11.50(s,1H),9.02(s,1H),8.68(s,1H),8.29(s,1H),7.7 7(s,1H),7.38-7.36(m,1H),7.23-7.22(m,1H),6.98-6.96(m,1H),6.79-6.78(m,1H ),4.58-4.52(m,1H),4.16-4.12(m,4H),3.79-3.72(m,4H),3.29(s,3H),3.25-3.16 (m,2H),2.97-2.81(m,2H),2.43-2.42(m,2H),1.85-1.82(m,1H),1.25-1.23(m,8H).

[0473] Example 27

[0474] 3-Cyclopentyl-3-(4-(2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile

[0475]

[0476] The implementation method is the same as Method 2, except that fragment 2-b is replaced with fragment 25-b to obtain the title compound.

[0477] LC_MS:(ES + ):m / z 513.5[M+H] + .

[0478] 1H NMR (400MHz, DMSO-d6): δ11.45(s,1H),8.72(s,1H),8.66(s,1H),8.26(s,1H),7.40(d,J=2.4Hz,1H),7.14-7. 20(m,2H),6.74(d,J=2.8Hz,1H),6.65(d,J=8.8Hz,1H),4.50-4.57(m,1H),4.15(t,J=3.4Hz,2H),3.53(t,J=5. 6Hz,2H),3.38(t,J=5.4Hz,2H),3.28-3.30(m,1H),3.27(s,3H),3.24(d,J=9.2Hz,1H),3.17-3.22(m,1H),2.3 8-2.46(m,1H),1.78-1.86(m,1H),1.51-1.65(m,3H),1.39-1.46(m,1H),1.29-1.38(m,2H),1.14-1.23(m,2H),

[0479] Example 28

[0480] 2-(1-(ethylsulfonyl)-3-(4-(2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile

[0481]

[0482] The procedure is the same as in Method 2, except that fragment 2-b is replaced with fragment 14-a to obtain the title compound.

[0483] LC_MS:(ES + ):m / z 578.6[M+H] + .

[0484] 1 H NMR (400MHz, CDCl3): δ9.36(s,1H),8.37(s,1H),8.27(s,1H),7.26-7.28(m,2H),6.93-7.14(m,2H),6.77-6.88(m,1H),6.66(d,J=8.4Hz,1H),6. 47-6.59(m,1H),4.62(d,J=9.2Hz,2H),4.24(d,J=8.8Hz,4H),3.60(t,J= 5.4Hz,2H),3.37-3.51(m,8H),3.06-3.11(q,2H),1.41(t,J=7.4Hz,3H).

[0485] Example 29

[0486] 2-(1-(ethylsulfonyl)-3-(4-(6-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile

[0487]

[0488] The implementation method is the same as Method 2, except that fragment 2-b is replaced with fragment 14-a and fragment 2-d is replaced with fragment 4-a to obtain the title compound.

[0489] LC_MS:(ES + ):m / z 579.4[M+H] + .

[0490] 1 H NMR (400MHz, DMSO-d6): δ13.26(s,1H),9.31(s,1H),8.94(s,1H),8.44,8.51(two singles,2H),7.39(brs,1H),7.19(d,J=7.2Hz,1H),6.66-6.69(m,1H),4.59(d,J=9.2Hz,2H),4.26(d,J=8.8Hz,2H) ,4.11-4.20(m,2H),3.71(brs,2H),3.49-3.57(m,2H),3.37-3.45(m,2H),3.23-3.32(m,7H),1.25(t,J=7.0Hz,3H).

[0491] Example 30

[0492] 5-Fluoro-N 4 -(1H-indol-5-yl)-N 2 -(7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)pyrimidin-2,4-diamine

[0493]

[0494] The procedure is the same as in Method 1, except that fragment 1-b is replaced with fragment 1H-indole-5-amine, and fragment Amine-1 is replaced with fragment Amine-2, to obtain the title compound.

[0495] LC_MS:(ES +):m / z 479.3[M+H] + .

[0496] 1 H NMR (400MHz, DMSO-d6): δ11.07(s,1H),9.14(s,1H),8.96(s,1H),8.00(d,J=4.0Hz,1H),7.82(s,1H),7.43(s,1H),7.34-7.36(m,2H),7.27- 7.30(m,1H),7.11-7.13(m,1H),6.79(d,J=8.0Hz,1H),6.39(s,1H),4 .01(s,2H),3.62(s,4H),3.47(s,2H),2.67-2.95(m,4H),2.33(s,3H).

[0497] Example 31

[0498] N-(4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-amine

[0499]

[0500] The implementation method is the same as Method 2, except that fragment 2-b is replaced with fragment 31-b and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0501] LC_MS:(ES + ):m / z 560.5[M+H] + .

[0502] 1 H NMR (400MHz, DMSO-d6): δ11.69(s,1H),9.23(s,1H),8.16(s,1H),7.81(s,1 H),7.74(d,J=12.0Hz,1H),7.38-7.41(m,1H),7.32-7.33(m,1H),6.97(d,J= 8.4Hz,1H),6.67-6.68(m,1H),4.82-4.93(m,1H),4.13-4.17(m,4H),3.74-3 .80(m,4H),3.32(s,3H),2.94(brs,4H),2.65(s,3H),1.64(d,J=7.2Hz,6H).

[0503] The implementation method for 31-b is as follows:

[0504]

[0505] Step 1: Synthesis of fragment 31-b 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-benzo[d]imidazole

[0506]

[0507] Under a nitrogen atmosphere at room temperature, 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (II) (80 mg, 0.11 mmol) was added to a suspension containing 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (300 mg, 1.11 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (338 mg, 1.33 mmol) and potassium acetate (5 mL). The reaction mixture was purged with nitrogen three times, and the mixture was stirred at 100 °C for 14 hours. The reaction was monitored by TLC until complete. The reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (eluting with hexane containing 50% ethyl acetate) to obtain a white solid 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-benzo[d]imidazole (300 mg, 85%).

[0508] LC_MS:(ES + ):m / z 319.1[M+H] + .

[0509] Example 32

[0510] Dimethyl(2-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide

[0511]

[0512] The implementation method is the same as in Method 4, except that fragment 4-a is replaced with fragment 2-d, fragment 1-b is replaced with fragment (2-aminophenyl)dimethylphosphine oxide, and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0513] LC_MS:(ES + ):m / z 537.6[M+H] + .

[0514] 1 H NMR (400MHz, DMSO-d6): δ11.62(s,1H),11.27(s,1H),9.10-9.13(m,1H),8.81(s,1H),7 .48-7.59(m,3H),7.32-7.35(m,1H),7.06(t,J=7.2Hz,1H),6.90-6.94(m,2H),6.35-6.3 7(m,1H),4.11(t,J=3.8Hz,2H),4.04(t,J=5.0Hz,2H),3.72(t,J=3.8Hz,2H),3.64(t,J =4.8Hz,2H),2.26(s,3H),2.68-2.76(m,2H),2.58-2.65(m,2H),1.83(d,J=13.6Hz,6H).

[0515] Example 33

[0516] Dimethyl(2-((6-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide

[0517]

[0518] The procedure is the same as in Method 4, except that fragment 1-b is replaced with fragment (2-aminophenyl)dimethylphosphine oxide, and fragment Amine-1 is replaced with fragment Amine-2, to obtain the title compound.

[0519] LC_MS:(ES + ):m / z 538.2[M+H] + .

[0520] 1 H NMR (400MHz, DMSO-d6): δ13.05(s,1H),12.06(s,1H),9.19(s,1H),9.02(s,1H),7.75(s,1H),7.52-7.66(m,3H),7.35(d,J=8Hz,1H),7.15(t,J=7. 2Hz,1H),6.96(d,J=8.8Hz,1H),4.09-4.11(m,4H),3.67-3.74(m,4H),3. 29(s,3H),2.67-2.82(m,2H),2.32-2.33(m,2H),1.85(d,J=13.6Hz,6H).

[0521] Example 34

[0522] N 4 -(4-bromo-2-fluorophenyl)-N 6 -(7-Methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine

[0523]

[0524] The procedure is the same as in Method 4, except that fragment 1-b is replaced with fragment 4-bromo-2-fluoroaniline, and fragment Amine-1 is replaced with fragment Amine-2, to obtain the title compound.

[0525] LC_MS:(ES + ):m / z 558.4[M+H] + .

[0526] 1 H NMR (400MHz, DMSO-d6): δ12.99(s,1H),9.76(s,1H),9.05(s,1H),8.07(s,1H),7.80(t,J=8.2Hz,1H),7.64-7.69(m,2H),7.44(d ,J=8.8Hz,1H),7.27-7.29(m,1H),6.97(d,J=8.8Hz,1H),4.17-4.33(m,2H),3.75-4.01(m,6H),3.31(s,3H),2.66-3.05(m,4H).

[0527] Example 35

[0528] N 4 -(2-(isopropylsulfonyl)phenyl)-N 2 -(4-Methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)-7H-pyrrolo[2,3-d]pyrimidin-2,4-diamine

[0529]

[0530] The same method as Method 4 was used, except that fragment 4-a was replaced with fragment 2-d and fragment 1-b was replaced with fragment 2-(isopropylsulfonyl)aniline to obtain the title compound.

[0531] LC_MS:(ES + ):m / z 523.6[M+H] + .

[0532] 1 H NMR (400MHz, CDCl3): δ9.58(brs,1H),9.16(brs,1H),8.87(d,J=8.4Hz,1H),7.84- 7.86(m,1H),7.59-7.64(m,1H),7.13-7.19(m,2H),6.89-7.00(m,1H),6.77-6.86(m ,1H),6.64-6.72(m,2H),6.41(d,J=3.6Hz,1H),4.24(t,J=4.2Hz,2H),3.60(t,J=5. 8Hz,2H),3.41-3.52(m,4H),3.37(s,3H),3.22-3.29(m,1H),1.30(d,J=7.2Hz,6H).

[0533] Example 36

[0534] N 4 -(2-(isopropylsulfonyl)phenyl)-N 6 -(4-Methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)-1H-pyrazolo[3,4-d]pyrimidin-4,6-diamine

[0535]

[0536] The procedure is the same as in Method 4, except that fragment 1-b is replaced with fragment 2-(isopropylsulfonyl)aniline to obtain the title compound.

[0537] LC_MS:(ES + ):m / z 524.6[M+H] + .

[0538] 1 H NMR (400MHz, CDCl3): δ9.83(brs,1H),8.78(d,J=8.4Hz,1H),7.87-7.91(m,2H),7.64(t,J=7.8Hz,1H),7.21-7.26(m,1H),7.17(brs,1H),6.85- 7.05(m,1H),6.52-6.78(m,1H),4.25(brs,2H),3.61(t,J=5.4Hz,2H),3 .41-3.56(m,4H),3.38(s,3H),3.20-3.27(m,1H),1.31(d,J=6.8Hz,6H),

[0539] Example 37

[0540] 2-(1-(ethylsulfonyl)-3-(4-(5-fluoro-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile

[0541]

[0542] The implementation method is the same as Method 2, except that fragment 2-b is replaced with fragment 14-a and fragment 2-d is replaced with fragment 1-a to obtain the title compound.

[0543] LC_MS:(ES + ):m / z 557.1[M+H] + .

[0544] 1 H NMR (400MHz, DMSO-d6): δ8.22-8.30(m,3H),7.17(s,1H),4.59(d,J=9.2Hz,2H),4.23(d,J=9.6Hz,4H),3.60(t,J=5.2Hz,1H),3.37,3.38(two singles,5H),3.05-3.11(q,2H),1.53-1.70(m,2H),1.41(t,J=7.4Hz,3H),1.19-1.34(m,2H).

[0545] Example 38

[0546] N-(cyanomethyl)-4-(6-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamide

[0547]

[0548] The implementation method is the same as Method 2, except that fragment 2-d is replaced with fragment 4-a to obtain the title compound.

[0549] LC_MS:(ES + ):m / z 484.9[M+H] + .

[0550] 1H NMR (400MHz, DMSO-d6): δ13.39(s,1H),9.51(s,1H),9.43(t,J=5.6Hz,1H),8.37 (s,1H),8.34(d,J=8.4Hz,2H),8.10(d,J=8.4Hz,2H),7.39(d,J=2.0Hz,1H),7.1 8-7.20(m,1H),6.69(d,J=8.8Hz,1H),4.37(t,J=2.8Hz,2H),4.16(t,J=4.2Hz,2 H),3.53(t,J=5.6Hz,2H),3.41(t,J=5.6Hz,2H),3.32-3.35(m,2H),3.28(s,3H).

[0551] Example 39

[0552] 4-Methyl-N-(4-(1-methyl-1H-indol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine

[0553]

[0554] The procedure is the same as in Method 5, except that fragment 5-a is replaced with fragment 2-c to obtain the title compound.

[0555] LC_MS:(ES + ):m / z 455.4[M+H] + .

[0556] 1 H NMR (400MHz, CDCl3): δ9.21 (s, 1H), 8.51 (d, J = 4.8Hz, 1H), 7.91 (s, 1H), 7.38 (d,J=8.0Hz,1H),7.30-7.34(m,1H),7.27-7.29(m,2H),7.07(d,J=6.8Hz,1H ),6.77(brs,1H),6.66(d,J=8.4Hz,1H),6.60(d,J=2.4Hz,1H),4.24(t,J=4. 4Hz, 2H), 3.91 (s, 3H), 3.60 (t, J = 5.6Hz, 2H), 3.38-3.51 (m, 4H), 3.36 (s, 3H).

[0557] Example 40

[0558] N-(tert-butyl)-3-((5-fluoro-2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecyl-12-yl)amino)pyrimidin-4-yl)amino)benzenesulfonamide

[0559]

[0560] The implementation method is the same as Method 1, except that fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0561] LC_MS:(ES + ):m / z 575.2[M+H] + .

[0562] 1 H NMR (400MHz, DMSO-d6): δ9.68(s,1H),9.11(s,1H),8.20-8.16(m,3H),7.63(s,1H),7.52-7.41(m,3H),7.23(d,J =8.8Hz,1H),6.96(d,J=8.4Hz,1H),4.07-4.03(m,4H),3.70(s,4H),3.32(s,3H),3.17-2.67(m,4H),1.12(s,9H).

[0563] Example 41

[0564] N-(5-fluoro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-amine

[0565]

[0566] The implementation method is the same as in Method 5, except that fragment 5-a is replaced with fragment 1-a and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0567] LC_MS:(ES + ):m / z 478.6[M+H] + .

[0568] 1H NMR (400MHz, DMSO-d6): δ9.38(s,1H),9.74(d,J=8.0Hz,1H),8.40(d,J=3.6Hz,1H),8.23(d,J=2.8Hz,1H),7.58-7.54(m,2H),7.32(t,J=7. 2Hz,2H),7.22(t,J=7.6Hz,1H),7.03(d,J=8.8Hz,1H),4.23-4.04(m,4H),3.93(s,3H),3.83-3.64(m,4H),3.31(s,3H),3.18-2.70(m,4H).

[0569] Example 42

[0570] 3-Cyclopentyl-3-(4-(5-fluoro-2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecyl-12-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile

[0571]

[0572] The implementation method is the same as Method 2, except that fragment 2-b is replaced with fragment 25-b, fragment 1-a is replaced with fragment 2-d, and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0573] LC_MS:(ES + ):m / z 536.9[M+H] + .

[0574] 1 H NMR (400MHz, DMSO-d6): δ9.57(s,1H),8.57(d,J=1.6Hz,1H),8.52(d,J=2.8Hz,1H),8.18(s,1 H),7.59(d,J=1.6Hz,1H),7.40(d,J=8.8Hz,1H),7.08(d,J=8.8Hz,1H),4.66-4.60(m,1H),4.2 9(s,2H),4.10(brs,2H),3.82-3.72(m,4H),3.32(s,3H),3.23-3.20(m,2H),2.79(brs,2H),2 .43-2.36(m,2H),1.85-1.79(m,1H),1.65-1.52(m,4H),1.33-1.25(m,2H),1.20-1.11(m,2H).

[0575] Example 43

[0576] 2-(1-(ethylsulfonyl)-3-(4-(5-fluoro-2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile

[0577]

[0578] The implementation method is the same as Method 2, except that fragment 2-b is replaced with fragment 14-a, fragment 2-d is replaced with fragment 1-a, and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0579] LC_MS:(ES + ):m / z 601.6[M+H] + .

[0580] 1 H NMR (400MHz, DMSO-d6): δ9.61 (s, 1H), 8.74 (s, 1H), 8.57 (d, J = 2.4Hz, 1H), 8.26(s,1H),7.59(s,1H),7.36(d,J=7.6Hz,1H),7.07(d,J=7.6Hz,1H),4.5 4(d,J=9.2Hz,2H),4.25(d,J=9.2Hz,4H),4.10-4.09(m,2H),3.74-3.69(m, 6H),3.31(s,3H),3.26-3.21(m,2H),2.82(brs,4H),1.24(t,J=7.2Hz,3H).

[0581] Example 44

[0582] N-(cyanomethyl)-4-(5-fluoro-2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)pyrimidin-4-yl)benzamide

[0583]

[0584] The implementation method is the same as Method 2, except that fragment 1-a replaces fragment 2-d, and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0585] LC_MS:(ES + ):m / z 507.8[M+H] + .

[0586] 1 H NMR (400MHz, DMSO-d6): δ9.79 (s, 1H), 9.52-9.50 (m, 1H), 8.68 (d, J = 3.2Hz, 1H), 8.17-8.15 (m, 2H), 8.10-8.07 (m, 2H), 7.65 (s, 1H), 7.33-7 .31(m,1H),7.08-7.06(m,1H),4.37-4.35(m,2H),4.28-4.22(m,2H), 4.17-4.09(m,2H),3.83-3.70(m,4H),3.32(s,3H),2.92-2.66(m,4H).

[0587] Example 45

[0588] N-(tert-butyl)-3-((6-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)benzenesulfonamide

[0589]

[0590] The implementation method is the same as in Method 4, except that fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0591] LC_MS:(ES + ):m / z 597.6[M+H] + .

[0592] 1 H NMR (400MHz, DMSO-d6): δ13.08-13.06(m,1H),10.04(s,1H),9.13(s,1H),8.50-8.48(m,1H),8.22-8.16(m,2H),7.70(s,1H),7.61(s,1H) ),7.56-7.50(m,2H),7.40-7.39(m,1H),7.05-7.03(m,1H),4.17-4.11(m,4H),3.73(s,4H),3.32(s,3H),2.94-2.62(m,4H),1.14(s,9H).

[0593] Example 46

[0594] 7-Methyl-N-(4-(1-methyl-1H-indol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-amine

[0595]

[0596] The procedure is the same as in Method 5, except that fragment 5-a is replaced with fragment 2-c and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0597] LC_MS:(ES + ):m / z 499.8[M+H] + .

[0598] 1 H NMR (400MHz, DMSO-d6): δ11.43(s,1H),9.00(s,1H),8.87(d,J=7.6Hz,1H),8.41(s,1H),7.76(s,1H),7.30-7.18(m,3H) ,7.00(d,J=8.8Hz,2H),6.87(s,1H),4.17-4.11(m,4H),3.95(s,3H),3.76-3.71(m,4H),3.12-2.87(m,4H),2.67(s,3H).

[0599] Example 47

[0600] 7-Methyl-N-(4-(1-methyl-1H-indol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-amine

[0601]

[0602] The implementation method is the same as in Method 5, except that fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0603] LC_MS:(ES + ):m / z 500.7[M+H] + .

[0604] 1H NMR (400MHz, DMSO-d6): δ13.18(s,1H),9.37(s,1H),8.91(d,J=7.6Hz,1H) ,8.66(s,1H),8.50(s,1H),7.65-7.64(m,1H),7.56(d,J=8.0Hz,1H),7.47- 7.45(m,1H),7.34-7.23(m,2H),7.00(d,J=8.8Hz,1H),4.12-4.09(m,4H),3 .96(s,3H),3.71-3.64(m,4H),3.30(s,3H),2.78(brs,2H),2.63(brs,2H).

[0605] Example 48

[0606] 3-Cyclopentyl-3-(4-(2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile

[0607]

[0608] The implementation method is the same as Method 2, except that fragment 2-b is replaced with fragment 25-b and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0609] LC_MS:(ES + ):m / z 557.8[M+H] + .

[0610] 1 HNMR (400MHz, DMSO-d6): δ11.51(s,1H),9.04(s,1H),8.69(s,1H),8.30(s,1H),7.74(s,1H) ,7.73-7.40(m,1H),7.24-7.22(m,1H),7.00-6.98(m,1H),6.80-6.79(m,1H),4.59-4.53(m, 1H),4.26-4.09(m,4H),3.71(s,4H),3.31(s,3H),3.26-3.21(m,2H),2.95-2.75(m,2H),2.4 6-2.40(m,2H),1.85-1.81(m,1H),1.63-1.51(m,3H),1.47-1.43(m,1H),1.35-1.17(m,4H).

[0611] Example 49

[0612] 2-(1-(ethylsulfonyl)-3-(4-(2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile

[0613]

[0614] The procedure is the same as in Method 2, except that fragment 2-b is replaced with fragment 14-a and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0615] LC_MS:(ES + ):m / z 622.6[M+H] + .

[0616] 1 H NMR (400MHz, DMSO-d6): δ11.55(s,1H),9.08(s,1H),8.82(s,1H),8.39(s,1H),7.72( s,1H),7.40(d,J=8.0Hz,1H),7.26-7.25(m,1H),6.98(d,J=8.4Hz,1H),6.89(d,J=3.2 Hz,1H),4.59(d,J=9.2Hz,2H),4.25(d,J=8.8Hz,2H),4.16-4.08(m,4H),3.70(s,6H), 3.31(s,3H),3.28-3.22(m,2H),2.82(brs,2H),2.39(brs,2H),1.25(t,J=7.2Hz,3H).

[0617] Example 50

[0618] 2-(1-(ethylsulfonyl)-3-(4-(6-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile

[0619]

[0620] The implementation method is the same as Method 2, except that fragment 2-b is replaced with fragment 14-a, fragment 2-d is replaced with fragment 4-a, and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0621] LC_MS:(ES + ):m / z 623.6[M+H] + .

[0622] 1 H NMR (400MHz, DMSO-d6): δ13.37(s,1H),9.62(s,1H),8.98(s,1H),8.58(s, 1H),8.47(s,1H),7.74(s,1H),7.50(d,J=8.0Hz,1H),7.09(d,J=8.0Hz,1H ),4.60(d,J=9.2Hz,2H),4.44-4.26(m,4H),4.12(brs,2H),3.92-3.72(m, 6H),3.32(s,3H),3.28-3.23(m,2H),2.85(brs,4H),1.26(t,J=7.6Hz,3H).

[0623] Example 51

[0624] N-(cyanomethyl)-4-(2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide

[0625]

[0626] The implementation method is the same as Method 2, except that fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0627] LC_MS:(ES + ):m / z 528.8[M+H] + .

[0628] 1 H NMR (400MHz, DMSO-d6): δ11.74(s,1H),9.45(t,J=5.2Hz,1H),9.34(s,1H),8. 27(d,J=8.4Hz,2H),8.09(d,J=8.4Hz,2H),7.84(s,1H),7.43(d,J=8.0Hz,1H), 7.34(d,J=3.2Hz,1H),7.04(d,J=8.4Hz,1H),6.74(d,J=2.8Hz,1H),4.37-4.29 (m,4H),4.13-4.10(m,2H),3.81-3.74(m,4H),3.31(s,3H),3.02-2.62(m,4H).

[0629] Example 52

[0630] N-(cyanomethyl)-4-(6-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzamide

[0631]

[0632] The implementation method is the same as Method 2, except that fragment 2-d is replaced with fragment 4-a and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0633] LC_MS:(ES + ):m / z 529.7[M+H] + .

[0634] 1 H NMR (400MHz, DMSO-d6): δ13.48(s,1H),9.75(s,1H),9.44(t,J=5.6Hz,1H),8.43-8.36(m,3H),8.11(d,J=8.4Hz,2H),7.71(d,J=1.6Hz,1H),7.4 2(d,J=8.4Hz,1H),7.03(d,J=8.4Hz,1H),4.38-4.37(m,2H),4.17-4.09 (m,4H),3.71(s,4H),3.30(s,3H),2.97-2.79(m,2H),2.45-2.33(m,2H).

[0635] Example 53

[0636] N 4 -(2-(isopropylsulfonyl)phenyl)-N 2 -(7-Methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)-7H-pyrrolo[2,3-d]pyrimidin-2,4-diamine

[0637]

[0638] The procedure is the same as in Method 4, except that fragment 1-b is replaced with fragment 2-(isopropylsulfonyl)aniline, fragment 4-a is replaced with fragment 2-d, and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0639] LC_MS:(ES +):m / z 567.6[M+H] + .

[0640] 1 H NMR (400MHz, DMSO-d6): δ11.45(s,1H),9.48(s,1H),8.89-8.93(m,2H),7.81-7.84( m,1H),7.72-7.76(m,1H),7.56(s,1H),7.28-7.31(m,2H),7.04-7.05(m,1H),6.92-6 .94(m,1H),6.25-6.26(m,1H),4.03-4.08(m,4H),3.67-3.69(m,4H),3.44-3.48(m, 1H),3.31(s,3H),2.75-2.90(m,2H),2.33-2.36(m,2H),1.17-1.19(d,J=6.8Hz,6H).

[0641] Example 54

[0642] N-(3-((5-chloro-2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide

[0643]

[0644] The implementation method is the same as in Method 3, except that fragment 3-a is replaced with fragment (3-aminophenyl)carbamate tert-butyl ester, fragment 2-d is replaced with fragment 1-a, and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0645] LC_MS:(ES + ):m / z 525.2[M+H] + .

[0646] 1 H NMR (400MHz, DMSO-d6): δ10.35(s,1H),9.33(s,1H),8.89(s,1H),8.13(s,1H),7.96(s,1H),7.56-7.57(m,1H),7.42(s,1H),7.20-7.29(m,3 H),6.81-6.83(m,1H),6.48-6.55(m,1H),6.22-6.27(m,1H),5.73-5.7 6(m,1H),4.06(s,2H),3.68-3.81(m,6H),3.32(s,3H),2.91(brs,4H).

[0647] Example 55

[0648] N-(3-((5-chloro-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide

[0649]

[0650] The procedure is the same as in Method 3, except that fragment 3-a is replaced with fragment (3-aminophenyl)carbamate tert-butyl ester and fragment 2-d is replaced with fragment 1-a to obtain the title compound.

[0651] LC_MS:(ES + ):m / z 481.2[M+H] + .

[0652] 1 H NMR (400MHz, DMSO-d6): δ10.12(s,1H),8.91(s,1H),8.80(s,1H),8.06(s,1H),7.84(s,1H),7.49(d,J=8.0Hz,1H),7.36(d,J=7.6Hz,1H),7. 29-7.25(m,1H),7.00-6.97(m,2H),6.49-6.42(m,2H),6.28-6.23(m,1 H),5.76-5.74(m,1H),4.07(s,2H),3.51-3.46(m,2H),3.25(brs,7H).

[0653] Example 56

[0654] N-(3-((5-chloro-2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide

[0655]

[0656] The same method as Method 3 was used, except that fragment 3-a was replaced with fragment (3-aminophenyl)carbamate tert-butyl ester, fragment 2-d was replaced with fragment 1-a, and fragment Amine-1 was replaced with fragment Amine-3 to obtain the title compound.

[0657] LC_MS:(ES + ):m / z 526.0[M+H] + .

[0658] 1 H NMR (400MHz, DMSO-d6): δ10.37(s,1H),9.34(s,1H),8.89(s,1H),8.77(s,1H),8.13(s,1H),7.97(s,1H),7.59(s,1H),7.43(s,1H),7 .29(s,2H),6.56-6.48(m,1H),6.27-6.22(m,1H),5.76-5.73(m,1H),4.14-3.95(m,4H),3.77-3.69(m,4H),3.31(s,3H),2.77(m,4H).

[0659] Example 57

[0660] N-(3-((5-chloro-2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)amino)pyrimidin-4-yl)amino)phenyl)propionamide

[0661]

[0662] The implementation method is the same as in Method 3, except that fragment 3-a is replaced with fragment (3-aminophenyl)carbamate tert-butyl ester, fragment 2-d is replaced with fragment 1-a, fragment 3-e is replaced with fragment propionyl chloride, and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0663] LC_MS:(ES + ):m / z 527.2[M+H] + .

[0664] 1 H NMR (400MHz, DMSO-d6): δ10.01(s,1H),9.34(s,1H),8.87(s,1H),8.13(s,1H),7.87(s,1H),7.46(s,2H),7.19-7.25(m,3H), 6.86-6.88(m,1H),4.14(s,2H),3.70-3.79(m,6H),3.32(s,3H),2.50-2.79(m,4H),2.29-2.35(m,2H),1.07(t,J=7.6Hz,3H).

[0665] Example 58

[0666] N-(3-((5-chloro-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)pyrimidin-4-yl)amino)phenyl)propionamide

[0667]

[0668] The same method as Method 3 was used, except that fragment 3-a was replaced with fragment (3-aminophenyl)carbamate tert-butyl ester, fragment 2-d was replaced with fragment 1-a, and fragment 3-e was replaced with fragment propionyl chloride, to obtain the title compound.

[0669] LC_MS:(ES + ):m / z 483.8[M+H] + .

[0670] 1 HNMR (400MHz, DMSO-d6): δ9.83(s,1H),8.89(s,1H),8.75(s,1H),8.06(s,1H ),7.78(s,1H),7.38-7.34(m,2H),7.25-7.21(m,1H),7.02-6.97(m,2H),6.4 9(d,J=8.4Hz,1H),4.10-4.08(m,2H),3.48(t,J=5.4Hz,2H),3.41-3.34(m,2 H),3.29-3.28(m,2H),3.25(s,3H),2.34-2.29(m,2H),1.07(t,J=7.4Hz,3H).

[0671] Example 59

[0672] N-(3-((5-chloro-2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)pyrimidin-4-yl)amino)phenyl)propionamide

[0673]

[0674] The implementation method is the same as in Method 3, except that fragment 3-a is replaced with fragment (3-aminophenyl)carbamate tert-butyl ester, fragment 2-d is replaced with fragment 1-a, fragment 3-e is replaced with fragment propionyl chloride, and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0675] LC_MS:(ES + ):m / z 527.2[M+H] + .

[0676] 1HNMR (400MHz, DMSO-d6): δ9.87(s,1H),9.17(s,1H),8.86(s,1H),8.11(s,1H ),7.77(s,1H),7.42-7.40(m,1H),7.32-7.25(m,3H),7.15(d,J=8.8Hz,1H), 6.78(d,J=8.4Hz,1H),4.05-3.98(m,2H),3.83-3.73(m,2H),3.69-3.56(m,4 H),3.33(s,3H),2.67-2.59(m,2H),2.33-2.28(m,4H),1.07(t,J=7.6Hz,3H).

[0677] Example 60

[0678] N 6 -(2-(isopropylsulfonyl)phenyl)-N 2 -(7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)-9H-purine-2,6-diamine

[0679]

[0680] The procedure is the same as in Method 4, except that fragment 1-b is replaced with fragment 2-(isopropylsulfonyl)aniline, fragment 4-a is replaced with fragment 60-b, and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0681] LC_MS:(ES + ):m / z 568.3[M+H] + .

[0682] 1 H NMR (400MHz, DMSO-d6): δ12.80(s,1H),9.84(s,1H),9.14(s,1H),9.02(d,J=8.4 Hz,1H),8.00(s,1H),7.82-7.84(m,1H),7.74(t,J=7.2Hz,1H),7.56(s,1H),7.28 -7.32(m,2H),6.96(d,J=8.8Hz,1H),4.05-4.10(m,4H),3.70-3.73(m,4H),3.41- 3.48(m,1H),3.31(s,3H),2.84(s,2H),2.33-2.41(m,2H),1.19(d,J=6.8Hz,6H).

[0683] The synthesis method for fragment 60-b is as follows:

[0684]

[0685] Step 1: Synthesis of fragment 60-b 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

[0686]

[0687] An ethyl acetate solution containing 2,6-dichloro-9H-purine (1 g, 5.32 mmol), 3,4-dihydro-2H-pyran (1.2 g, 14.36 mmol), and p-toluenesulfonic acid (27 mg, 0.16 mmol) was stirred at 50 °C for 2 hours. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting with petroleum ether containing 2% ethyl acetate) to give a white solid 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (1 g, 68%).

[0688] LC_MS:(ES + ):m / z 272.9[M+H] + .

[0689] 1 H NMR (400MHz, CDCl3): δ8.33(s,1H),5.75-5.78(m,1H),4.17-4.21(m,1H),3.75-3.82 (m,1H),2.15-2.19(m,1H),2.08-2.11(m,1H),1.92-2.02(m,1H),1.66-1.85(m,3H).

[0690] Example 61

[0691] N-(2-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)methanesulfonamide

[0692]

[0693] The procedure is the same as in Method 4, except that fragment 1-b is replaced with fragment N-(2-aminophenyl)methanesulfonamide, fragment 4-a is replaced with fragment 2-d, and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0694] LC_MS:(ES + ):m / z 554.6[M+H]+ .

[0695] 1 H NMR (400MHz, DMSO-d6): δ11.26(s,1H),9.24(s,1H),8.84(s,1H),8.73(s,1H),7.85-7. 87(d,J=8Hz,1H),7.61(s,1H),7.39-7.41(d,J=8Hz,1H),7.28-7.32(t,J=8.0Hz,1H),7. 18-7.23(m,2H),6.95(s,1H),6.85-6.87(d,J=8.0Hz,1H),6.43(s,1H),4.07(s,2H),3.9 0(s,2H),3.70(s,4H),3.28(s,3H),2.97(s,1H),2.86(s,3H),2.75(s,1H),2.42(s,2H).

[0696] Example 62

[0697] N-(4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-amine

[0698]

[0699] The procedure is the same as in Method 2, except that fragment 2-b is replaced with fragment 14-e and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0700] LC_MS:(ES + ):m / z 436.6[M+H] + .

[0701] 1 H NMR (400MHz, DMSO-d6): δ13.30(s,1H),11.45(s,1H),8.96(s,1H),8.26-8.53(m,2H),7.72(s,1H),7.36-7.38(m,1H),7.17-7.19(m,1H) ,6.93(d,J=8.8Hz,1H),6.79(d,J=3.2Hz,1H),4.06-4.16(m,4H),3.66-3.76(m,4H),3.30(s,3H),2.67-2.77(m,2H),2.31-2.33(m,2H).

[0702] Example 63

[0703] 7-Methyl-N-(4-(1-(methanesulfonyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-amine

[0704]

[0705] The procedure is the same as in Method 2, except that fragment 2-b is replaced with fragment 63-a and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0706] LC_MS:(ES + ):m / z 514.5[M+H] + .

[0707] 1 H NMR (400MHz, DMSO-d6): δ11.68(s,1H),9.28(s,1H),8.87(s,1H),8.70(s,1H),7 .96-7.97(m,1H),7.20-7.32(m,2H),7.06-7.08(m,1H),6.90-6.91(m,1H),4.26 -4.30(m,3H),4.11-4.15(m,3H),3.98-4.07(m,2H),3.79-3.83(m,2H),3.70(s, 3H),3.55-3.61(m,1H),3.43-3.48(m,2H),3.19-3.23(m,1H),2.91-2.92(m,3H).

[0708] The synthesis method of fragment 63-a is as follows:

[0709]

[0710] Step 1: Synthesis of fragment 63-a 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborcycloalkyl-2-yl)-1H-pyrazole

[0711]

[0712] Methanesulfonyl chloride (212 mg, 1.86 mmol) was added to dichloromethane (5 mL) containing 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)-1H-pyrazole (300 mg, 1.55 mmol) and triethylamine (470 mg, 4.65 mmol) at 0 °C. The reaction mixture was brought to room temperature and stirred for 3 hours. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into water (20 mL) and extracted with dichloromethane (10 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (using petroleum ether containing 30% ethyl acetate) to obtain a colorless oily substance, 1-(methanesulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)-1H-pyrazole (200 mg, 47%).

[0713] 1 H NMR (400MHz, DMSO-d6): δ8.35(s,1H),8.04(s,1H),3.57(s,3H),1.29(s,12H).

[0714] Example 64

[0715] N 4 -Methyl-N 2 -(4-Methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)-7H-pyrrolo[2,3-d]pyrimidin-2,4-diamine

[0716]

[0717] The procedure is the same as in Method 4, except that fragment 1-b is replaced with fragment methylamine hydrochloride and fragment 4-a is replaced with fragment 2-d to obtain the title compound.

[0718] LC_MS:(ES + ):m / z 355.1[M+H] + .

[0719] 1H NMR (400MHz, DMSO-d6): δ10.96(s,1H),8.36(s,1H),7.38(s,1H),7.22-7.26(m,1H),7.10(d,J=8.0Hz,1H),6.73(s,1H),6.60(d,J=8 .8Hz,1H),6.36(s,1H),4.11-4.13(m,2H),3.51(t,J=5.6Hz,2H),3.34-3.37(m,2H),3.29(s,2H),3.26(s,3H),2.96(d,J=4.4Hz,3H).

[0720] Example 65

[0721] N 4 -(3-(isopropylsulfonyl)phenyl)-N 2 -(7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[0722]

[0723] The same method as Method 4 was used, except that fragment 1-b was replaced with fragment 3-(isopropylsulfonyl)aniline, fragment 4-a was replaced with fragment 2-d, and fragment Amine-1 was replaced with fragment Amine-2 to obtain the title compound.

[0724] LC_MS:(ES + ):m / z 567.6[M+H] + .

[0725] 1 H NMR (400MHz, DMSO-d6): δ11.28(s,1H),9.53(s,1H),8.90-8.92(m,1H),8.76(s,1H) ),7.94-7.95(m,1H),7.57-7.61(m,2H),7.43(d,J=8.0Hz,1H),7.29-7.32(m,1H), 6.92-6.96(m,2H),6.67-6.68(m,1H),4.05-4.10(m,4H),3.70-3.74(m,4H),3.36- 3.43(m,1H),3.30(s,3H),2.88(brs,2H),2.39-2.46(m,2H),1.19(d,J=6.8Hz,6H).

[0726] Example 66

[0727] Dimethyl(3-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide

[0728]

[0729] The same method as Method 4 was used, except that fragment 1-b was replaced with fragment (3-aminophenyl)dimethylphosphine oxide, fragment 4-a was replaced with fragment 2-d, and fragment Amine-1 was replaced with fragment Amine-2 to obtain the title compound.

[0730] LC_MS:(ES + ):m / z 537.2[M+H] + .

[0731] 1 H NMR (400MHz, DMSO-d6): δ11.22(s,1H),9.37(s,1H),8.74-8.80(m,1H),8.46-8 .52(m,1H),7.90(d,J=12.4Hz,1H),7.65-7.73(m,1H),7.44-7.48(m,1H),7.29- 7.38(m,2H),6.93-6.96(m,2H),6.68(s,1H),4.14-4.18(m,2H),3.94-4.03(m, 2H),3.65-3.80(m,4H),3.31(s,3H),2.74-3.08(m,4H),1.64(d,J=13.2Hz,6H).

[0732] Example 67

[0733] 3-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecyl-13-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)benzenesulfonamide

[0734]

[0735] The procedure is the same as in Method 4, except that fragment 1-b is replaced with fragment 3-aminobenzenesulfonamide, fragment 4-a is replaced with fragment 2-d, and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0736] LC_MS:(ES + ):m / z 540.3[M+H] + .

[0737] 1 H NMR (400MHz, DMSO-d6): δ11.31(s,1H),9.52(s,1H),8.93-8.94(m,1H),8.48(s,1H),8 .47(d,J=8.0Hz,1H),8.17(s,1H),7.78-7.79(m,1H),7.35-7.52(m,4H),7.03(d,J=8. 8Hz,1H),6.96-6.97(m,1H),6.71-6.72(m,1H),4.25-4.30(m,2H),3.92-4.11(m,4H), 3.77-3.80(m,2H),3.56(brs,1H),3.43-3.46(m,1H),3.16-3.23(m,2H),2.91(s,3H).

[0738] Example 68

[0739] N 4 -((1s,3s)-3-(azacyclobutane-1-ylsulfonyl)cyclobutyl)-N 4 -Methyl-N 2 -(4-Methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)-7H-pyrrolo[2,3-d]pyrimidin-2,4-diamine

[0740]

[0741] The implementation method is the same as in Method 4, except that fragment 1-b is replaced with fragment 68-h, and fragment 4-a is replaced with fragment 2-d, to obtain the title compound.

[0742] LC_MS:(ES + ):m / z 528.3[M+H] + .

[0743] 1 H NMR (400MHz, DMSO-d6): δ11.19(s,1H),8.43(brs,1H),7.27(brs,1H),6.99-7.14(m,1H),6.81-6.92(m,1H),6.47-6.73(m,2H),5.14-5.23(m, 1H),4.09-4.17(m,1H),3.87(t,J=7.6Hz,4H),3.46-3.55(m,2H),3.29 -3.44(m,6H),3.17-3.25(m,6H),2.55-2.69(m,4H),2.17-2.25(m,2H).

[0744] The synthesis method for fragment 68-h is as follows:

[0745]

[0746] Step 1: Synthesis of fragment 68-b(1r,3r)-3-(methylamino)cyclobut-1-ol

[0747]

[0748] Lithium aluminum hydride (812 mg, 21.36 mmol) was added dropwise to an anhydrous tetrahydrofuran (15 mL) solution containing ((1r,3r)-3-hydroxycyclobutyl)carbamate (1 g, 5.34 mmol) at 0 °C. The resulting mixture was stirred at 65 °C for 18 h. The reaction was monitored by TLC until complete. The reaction mixture was quenched at 0 °C with water (0.8 mL), sodium hydroxide (0.8 mL, 15% aqueous solution), and water (2.4 mL), and the reaction was continued to be stirred at room temperature for 10 min. The solid was removed by filtration, and the filter cake was washed with dichloromethane (20 mL × 3) containing 10% methanol. The filtrates were combined and concentrated under reduced pressure to give a colorless oily substance (1r,3r)-3-(methylamino)cyclobut-1-ol (540 mg, crude product), which was used directly in the next reaction.

[0749] Step 2: Synthesis of fragment 68-c benzyl((1r,3r)-3-hydroxycyclobutyl)(methyl)carbamate

[0750]

[0751] Benzyl chloroformate was added to a solution of tetrahydrofuran (10 ml) and water (2.5 ml) containing crude (1r,3r)-3-(methylamino)cyclobut-1-ol (540 mg, 5.34 mmol) and sodium carbonate (1.1 g, 10.7 mmol) at 0 °C. The resulting mixture was heated to room temperature and stirred for 15 hours. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into ethyl acetate (10 ml) and water (15 ml). The organic layer was collected, washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with n-hexane containing 20%–100% ethyl acetate) to obtain a colorless oily benzyl ((1r,3r)-3-hydroxycyclobutyl)(methyl)carbamate (1.1 g, 87% two-step).

[0752] LC_MS:(ES + ):m / z 236.1[M+H] + .

[0753] 1H NMR (400MHz, DMSO-d6): δ7.31-7.39(m,5H),5.05(s,2H),4.97(d,J=4.4Hz,1H),4.71 -4.80(m,1H),4.15-4.17(m,1H),2.82(s,3H),2.30-2.37(m,2H),1.95-2.01(m,2H).

[0754] Step 3: Synthesis of fragment 68-d(1r,3r)-3-(((benzyloxy)carbonyl)(methyl)amino)cyclobutyl4-methylbenzenesulfonic acid

[0755]

[0756] 4-Toluenesulfonyl chloride (977 mg, 5.13 mmol) was added to a solution of benzyl ((1r,3r)-3-hydroxycyclobutyl)(methyl)carbamate (1.1 g, 4.66 mmol), triethylamine (944 mg, 9.32 mmol), and 4-dimethylaminopyridine (57 mg, 0.47 mmol) in 15 mL of dichloromethane at 0 °C. The resulting mixture was heated to room temperature and stirred for 16 hours. The reaction was monitored by TLC until complete. The reaction mixture was diluted with dichloromethane (10 ml), washed with water (20 ml x 2), washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with n-hexane containing 10%-15% ethyl acetate) to obtain a colorless oily substance (1r,3r)-3-(((benzyloxy)carbonyl)(methyl)amino)cyclobutyl4-methylbenzenesulfonic acid (1.63 g, 89%).

[0757] 1 H NMR (400MHz, CDCl3): δ7.76 (d, J = 8.4Hz, 2H), 7.31-7.36 (m, 7H), 5.09 (s, 2H), 4.87-4.97 ( m,1H),4.71-4.79(m,1H),2.84(s,3H),2.48-2.58(m,2H),2.44(s,3H),2.39-2.45(m,2H).

[0758] Step 4: Synthesis of fragment 68-e S-((1s,3s)-3-(((benzyloxy)carbonyl)(methyl)amino)cyclobutyl)ethanethiol ester

[0759]

[0760] A solution of dimethyl sulfoxide (16 mL) containing (1r,3r)-3-(((benzyloxy)carbonyl)(methyl)amino)cyclobutyl 4-methylbenzenesulfonic acid (1.63 g, 4.58 mmol) and potassium thioacetate (2.62 g, 22.93 mmol) was stirred at 60 °C for 17 h. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into ethyl acetate (10 mL) and water (15 mL). The aqueous layer was extracted with ethyl acetate (10 mL x 2). The organic layers were combined, washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with n-hexane containing 10-20% ethyl acetate) to obtain a colorless oily substance S-((1s,3s)-3-(((benzyloxy)carbonyl)(methyl)amino)cyclobutyl)ethanethiol ester (1 g, 81%).

[0761] LC_MS:(ES + ):m / z 294.1[M+H] + .

[0762] Step 5: Synthesis of fragment 68-f benzyl((1s,3s)-3-(chlorosulfonyl)cyclobutyl)(methyl)carbamate

[0763]

[0764] At room temperature, a solution of acetonitrile (5 ml) containing S-((1s,3s)-3-(((benzyloxy)carbonyl)(methyl)amino)cyclobutyl)ethiocyanate (1 g, 3.4 mmol) was slowly added dropwise to a solution of N-chlorosuccinimide (983 mg, 7.15 mmol), acetic acid (0.12 ml), and water (0.12 ml) in acetonitrile (5 ml) under stirring. The addition rate was kept constant and slow to keep the temperature of the reaction mixture below 30°C. The resulting mixture was stirred at room temperature for 15 minutes. The reaction was monitored by TLC until complete. The reaction mixture was diluted with ethyl acetate (10 ml), washed with saturated sodium bicarbonate solution (20 ml), washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oily product, benzyl((1s,3s)-3-(chlorosulfonyl)cyclobutyl)(methyl)carbamate (622 mg, crude product). The crude product was used directly in the next reaction without purification.

[0765] Step 6: Synthesis of fragment 68-g benzyl((1s,3s)-3-(azacyclobutane-1-ylsulfonyl)cyclobutyl)(methyl)carbamate

[0766]

[0767] A solution containing crude benzyl((1s,3s)-3-(chlorosulfonyl)cyclobutyl)(methyl)carbamate (622 mg, 1.96 mmol), aziridine (112 mg, 1.96 mmol), and N,N-diisopropylethylamine (505 mg, 3.91 mmol) in dichloromethane (3 mL) was stirred at room temperature for 16 hours. The reaction was monitored by TLC until complete. The reaction mixture was diluted with dichloromethane (15 mL), washed with water (10 mL x 2), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with dichloromethane containing 1%–1.5% methanol) to obtain a colorless oily product benzyl((1s,3s)-3-(aziridine-1-ylsulfonyl)cyclobutyl)(methyl)carbamate (120 mg, 10% two-step).

[0768] 1 H NMR (400MHz, CDCl3): δ7.32-7.37(m,5H),5.12(s,2H),4.69-4.81(m,1H),3.96(t,J=7.6Hz,4 H),3.33-3.39(m,1H),2.94(s,1H),2.57-2.65(m,2H),2.42-2.53(m,2H),2.22-2.30(m,2H).

[0769] Step 7: Synthesis of fragment 68-h(1s,3s)-3-(azacyclobutane-1-ylsulfonyl)-N-methylcyclobut-1-amine

[0770]

[0771] A methanol (4 mL) solution containing benzyl((1s,3s)-3-(azacyclobutane-1-ylsulfonyl)cyclobutyl)(methyl)carbamate (90 mg, 0.26 mmol) and palladium / carbon (100%, 90 mg) was stirred and reacted for 24 hours at room temperature under a hydrogen atmosphere (hydrogen balloon). The reaction was monitored by TLC until complete. The palladium / carbon was removed by filtration, and the mixture was washed with methanol (5 mL x 2). The filtrates were combined and concentrated under reduced pressure to give a brown oily substance (1s,3s)-3-(azacyclobutane-1-ylsulfonyl)-N-methylcyclobut-1-amine (55 mg, crude product). The crude product was used directly in the next reaction without purification.

[0772] Example 69

[0773] 4-Methyl-N-(4-(1-(1-(methanesulfonyl)azacyclobutane-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine

[0774]

[0775] Implementation method:

[0776]

[0777] Step 1: Synthesis of fragment 69-b 3-(toluenesulfonyloxy)azacyclobutane-1-carboxylic acid tert-butyl ester

[0778]

[0779] 4-Toluenesulfonyl chloride (606.4 mg, 3.2 mmol) was added to a solution of tert-butyl 3-(toluenesulfonyloxy)azacyclobutane-1-carboxylic acid (tert-butyl ester) containing 500 mg (2.9 mmol), triethylamine (862.4 mg, 5.78 mmol), and 4-dimethylaminopyridine (36.7 mg, 0.3 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into dichloromethane (20 mL) and water (20 mL). The organic layer was collected, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with n-hexane containing 30% ethyl acetate) to obtain a colorless oily substance, tert-butyl 3-(toluenesulfonyloxy)azacyclobutane-1-carboxylic acid (700 mg, 74%).

[0780] 1 H NMR (400MHz, CDCl3): δ7.78-7.80(m,2H),7.37(d,J=8.0Hz,2H),4.98-5.03(m,1H),4.08-4.11(m,2H),3.87-3.97(m,2H),2.47(s,3H),1.41(s,9H).

[0781] Step 2: Synthesis of fragment 69-c 2-chloro-4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

[0782]

[0783] Tetra(triphenylphosphine)palladium (184.8 mg, 0.16 mmol) was added to a solution containing 2,4-dichloro-7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.57 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborborane-2-yl)-1H-pyrazole (304.6 mg, 1.57 mmol), sodium carbonate (2N, 1 ml), and acetonitrile (5 ml) under a nitrogen atmosphere at room temperature. The reaction mixture was purged with nitrogen three times. The reaction mixture was stirred at 55°C for 12 hours. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into ethyl acetate (20 ml) and water (20 ml). The organic layer was collected, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with n-hexane containing 50% ethyl acetate) to obtain a grayish-white solid 2-chloro-4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 36%).

[0784] LC_MS:(ES + ):m / z 350.4[M+H] + .

[0785] Step 3: Synthesis of fragment 69-d-tert-butyl-3-(4-(2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid

[0786]

[0787] A solution of N,N-dimethylformamide (2 mL) containing 2-chloro-4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.57 mmol), 3-(toluenesulfonyloxy)azacyclobutane-1-carboxylic acid tert-butyl ester (282 mg, 0.86 mmol), and cesium carbonate (371 mg, 1.14 mmol) was stirred at 60 °C for 13 h under a nitrogen atmosphere. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature and extracted with water (20 mL) and ethyl acetate (20 mL x 2). The organic layer was collected, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting with dichloromethane containing 2% methanol) to obtain a white solid tert-butyl3-(4-(2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid (200 mg, 65%).

[0788] Step 4: Synthesis of fragment 69-e-tert-butyl-3-(4-(2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid

[0789]

[0790] BrettPhos Pd G3 (18 mg, 0.02 mmol) was added to a solution of 1,4-dioxane (1 mL) containing 3-(4-(2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid (100 mg, 0.2 mmol), 4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (42 mg, 0.2 mmol), and potassium phosphate (127 mg, 0.6 mmol). The reaction mixture was purged with nitrogen three times, and the mixture was stirred at 110 °C for 13 h. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature and extracted with water (20 mL) and ethyl acetate (10 mL x 2). The organic layer was collected, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative TLC (eluting with n-hexane containing 4% methanol and 38% ethyl acetate) to obtain a yellow solid tert-butyl-3-(4-(2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid (100 mg, 74%).

[0791] LC_MS:(ES + ):m / z 677.7[M+H] + .

[0792] Step 5: Synthesis of fragment 69-f N-(4-(1-(azacyclobutane-3-yl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine

[0793]

[0794] At room temperature, a solution of hydrochloric acid / dioxane (4M, 1 ml) was added to a solution of dichloromethane containing tert-butyl-3-(4-(2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid (100 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC until complete. The volatiles were removed under reduced pressure, and the residue was alkalized to pH 7-8 with sodium carbonate solution. 2) Extraction. The organic layer was collected, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (eluting with dichloromethane containing 10% methanol) to obtain a yellow solid N-(4-(1-(azacyclobutane-3-yl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (62 mg, 70%).

[0795] LC_MS:(ES + ):m / z 577.6[M+H] + .

[0796] Step 6: Synthesis of fragment 69-g 4-methyl-N-(4-(1-(1-(1-(methanesulfonyl)azacyclobutane-3-yl)-1H-pyrazol-4-yl)-7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine

[0797]

[0798] Methylsulfonyl chloride (12.6 mg, 0.11 mmol) was added to a solution of N-(4-(1-(azacyclobutan-3-yl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (62 mg, 0.11 mmol) and triethylamine (16.2 mg, 0.16 mmol) in dichloromethane (2 mL). The resulting mixture was heated to room temperature and stirred for 3 hours. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into dichloromethane (10 mL) and water (10 mL). The organic layer was collected, washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (eluting with dichloromethane containing 5% methanol) to obtain a yellow solid 4-methyl-N-(4-(1-(1-(1-(methanesulfonyl)azacyclobutane-3-yl)-1H-pyrazol-4-yl)-7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (60 mg, 80%).

[0799] LC_MS:(ES + ):m / z 655.3[M+H] + .

[0800] 1 H NMR (400MHz, DMSO-d6): δ8.96(s,1H),8.69(s,1H),8.35(s,1H),7.41(d,J=2.0Hz,1H ),7.33-7.34(m,1H),7.28-7.30(m,1H),6.87(d,J=3.6Hz,1H),6.65(d,J=8.8Hz,1H) ,5.50(s,2H),5.39-5.46(m,1H),4.32-4.39(m,4H),4.13-4.14(m,2H),3.51-3.57(m ,4H),3.27-3.38(m,4H),3.27(s,3H),3.16(s,3H),0.84-0.89(m,2H),-0.11(s,9H).

[0801] Step 7: Synthesis of 4-methyl-N-(4-(1-(1-(methanesulfonyl)azacyclobutane-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine

[0802]

[0803] A solution of N-(4-(1-(azacyclobutan-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (60 mg, 0.13 mmol) and tetrabutylammonium fluoride (0.5 mL, 1 M tetrahydrofuran solution) was stirred at 50 °C for 48 h. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature and partitioned into water (10 mL) and ethyl acetate (10 mL). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (10 mL x 2). The organic layers were combined, washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (eluting with dichloromethane containing 10% methanol and 1% ammonia) to obtain 4-methyl-N-(4-(1-(1-(methanesulfonyl)azacyclobutane-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-amine (10 mg, 14%).

[0804] LC_MS:(ES + ):m / z 525.2[M+H] + .

[0805] 1 H NMR (400MHz, CDCl3): δ8.83(s,1H),8.28-7.32(m,2H),6.92-7.02(m,2H),6.59-6.66(m,2H),5.19-5.22(m ,1H),4.43-4.51(m,4H),4.24(s,2H),3.60(t,J=5.6Hz,2H),3.41-3.53(m,4H),3.37(s,3H),3.07(s,3H).

[0806] Example 70

[0807] 1-(3-(4-(2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7H)-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azacyclobutane-1-yl)ethane-1-one

[0808]

[0809] Implementation method:

[0810]

[0811] Step 1: Synthesis of 1-(3-(4-(2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azacyclobut-1-yl)acetone

[0812]

[0813] A solution of tert-butyl-3-(4-(2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid (56 mg, 0.08 mmol) and trifluoroacetic acid (1 ml) in 2 ml of dichloromethane was stirred at room temperature for 4 hours. The reaction was monitored by TLC until complete. The reaction mixture was concentrated under reduced pressure, and the residue was added to ammonia (3 ml) and ethyl acetate (2 ml). The solution was stirred at 30°C for 16 hours. The reaction was monitored by TLC until complete. The organic layer was collected, washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (eluting with dichloromethane containing 10% methanol) to obtain a yellow solid 1-(3-(4-(2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azacyclobut-1-yl)acetone (11 mg, 27%).

[0814] LC_MS:(ES + ):m / z 489.3[M+H] + .

[0815] 1 H NMR (400MHz, CDCl3): δ8.81(brs,1H),8.28(s,2H),7.28(s,1H),6.93-7.02(m,2H),6.57-6.67(m,2H),5.17-5.2 3(m,1H),4.59-4.67(m,2H),4.45-4.56(m,2H),4.24(s,2H),3.58-3.61(m,2H),3.37-3.44(m,6H),1.97(s,3H).

[0816] Example 71

[0817] (1s,3s)-3-amino-N-(3-((5-chloro-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)pyrimidin-4-yl)amino)phenyl)cyclobutane-1-carboxamide

[0818]

[0819] Implementation method:

[0820]

[0821] Step 1: Synthesis of fragment 71-c tert-butyl((1s,3s)-3-((3-((5-chloro-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)pyrimidin-4-yl)amino)phenyl)carbamoyl)cyclobutyl)carbamate

[0822]

[0823] At 0℃, to contain N 4 -(3-aminophenyl)-5-chloro-N 2 A solution of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (53 mg, 0.14 mmol) was prepared in N,N-dimethylformamide (1 mL) of (4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)pyrimidine-2,4-diamine (30 mg, 0.07 mmol), (1s,3s)-3-((tert-butoxycarbonyl)amino)cyclobutanecarboxylic acid (15 mg, 0.07 mmol), and N,N-diisopropylethylamine (36 mg, 0.28 mmol). The mixture was stirred at room temperature for 30 min. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into water (10 mL) and ethyl acetate (10 mL). The organic layer was collected, washed with saturated sodium chloride solution (20 ml x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (eluting with dichloromethane containing 5% methanol) to obtain a white solid tert-butyl((1s,3s)-3-((3-((5-chloro-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazolone-9-yl)amino)pyrimidin-4-yl)amino)phenyl)carbamoyl)cyclobutyl)carbamate (35 mg, 79%).

[0824] LC_MS:(ES + ):m / z 624.4[M+H]+ .

[0825] Step 2: Synthesis of (1s,3s)-3-amino-N-(3-((5-chloro-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)pyrimidin-4-yl)amino)phenyl)cyclobutane formamide

[0826]

[0827] A mixture of 4M hydrochloric acid / dioxane (1 ml) and dichloromethane (1 ml) containing tert-butyl((1s,3s)-3-((3-((5-chloro-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)pyrimidin-4-yl)amino)phenyl)carbamoyl)cyclobutyl)carbamate (35 mg, 0.056 mmol) was stirred at room temperature for 3 hours. The reaction was monitored by TLC until complete. The mixture was concentrated under reduced pressure, and the residue was adjusted to pH 8-9 with sodium carbonate solution and then extracted with dichloromethane (10 ml × 2). The organic layers were combined, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (eluting with dichloromethane containing 10% methanol and 1% ammonia) to obtain a gray solid (1s,3s)-3-amino-N-(3-((5-chloro-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)pyrimidin-4-yl)amino)phenyl)cyclobutanecarboxamide (20.4 mg, 69%).

[0828] LC_MS:(ES + ):m / z 524.2[M+H] + .

[0829] 1H NMR (400MHz, DMSO-d6): δ9.90(s,1H),8.94(s,1H),8.71(s,1H),8.06(s,1H),7.86(s,1H), 7.34(d,J=8.0Hz,1H),7.34(d,J=7.2Hz,1H),7.21-7.25(m,1H),7.00-7.03(m,2H),6.49(d ,J=8.4Hz,1H),5.10(s,2H),4.08(t,J=4.0Hz,2H),3.49(t,J=5.6Hz,2H),3.34-3.41(m,4H ),3.27-3.29(m,1H),3.26(s,3H),2.82-2.86(m,1H),2.32-2.39(m,2H),1.98-2.06(m,2H).

[0830] Example 72

[0831] (1r,3r)-3-amino-N-(3-((5-chloro-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)pyrimidin-4-yl)amino)phenyl)cyclobutane-1-carboxamide

[0832]

[0833] The same implementation method as in Example 71 was used, except that fragment 71-b was replaced with (1r,3r)-3-((tert-butoxycarbonyl)amino)cyclobutanecarboxylic acid to obtain the title compound.

[0834] LC_MS:(ES + ):m / z 524.7[M+H] + .

[0835] 1 H NMR (400MHz, DMSO-d6): δ9.90(s,1H),8.94(s,1H),8.71(s,1H),8.06(s,1H),7.86(s,1H), 7.34(d,J=8.0Hz,1H),7.34(d,J=7.2Hz,1H),7.21-7.25(m,1H),7.00-7.03(m,2H),6.49(d ,J=8.4Hz,1H),5.10(s,2H),4.08(t,J=4.0Hz,2H),3.49(t,J=5.6Hz,2H),3.34-3.41(m,4H ),3.27-3.29(m,1H),3.26(s,3H),2.82-2.86(m,1H),2.32-2.39(m,2H),1.98-2.06(m,2H).

[0836] Example 73

[0837] Dimethyl(2-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)phosphine oxide

[0838]

[0839] The procedure is the same as in Method 4, except that fragment 1-b is replaced with fragment (2-aminophenyl)dimethylphosphine oxide and fragment 4-a is replaced with fragment 2-d to obtain the title compound.

[0840] LC_MS:(ES + ):m / z 493.4[M+H] + .

[0841] 1 H NMR (400MHz, DMSO-d6): δ11.59(s,1H),11.20(s,1H),9.14-9.11(m,1H),8.57(s,1H),7.57-7.46(m,1H),7.32(s,1H),7.07-7.05(m,2H ),6.88(s,1H),6.65-6.64(m,1H),6.34(s,1H),4.15(s,2H),3.55-3.53(m,2H),3.38-3.32(m,4H),3.28(s,3H),1.83(d,J=13.6Hz,6H).

[0842] Example 74

[0843] (R)-3-cyclopentyl-3-(4-(2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecyl-13-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile

[0844]

[0845] The implementation method is the same as Method 2, except that fragment 2-b is replaced with fragment 74-a(R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)propionitrile (Shanghai Bid Pharmaceutical Technology Co., Ltd.), and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[0846] LC_MS:(ES + ):m / z 557.7[M+H] + .

[0847] 1 H NMR (400MHz, CDCl3): δ9.31(s,1H),8.27(s,2H),7.49(s,1H),7.11-7.07( m,2H),6.95-6.92(m,2H),4.27-4.25(m,1H),4.19-4.14(m,4H),3.80-3.7 5(m,4H),3.16-3.10(m,1H),2.97-2.92(m,1H),2.82(d,J=8.0Hz,4H),2.5 8(m,1H),2.42(s,3H),1.97(m,2H),1.72(m,2H),1.56(m,2H),1.26(m,2H).

[0848] Example 75

[0849] (S)-3-cyclopentyl-3-(4-(2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecyl-13-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile

[0850]

[0851] The implementation method is the same as Method 2, except that fragment 2-b is replaced with fragment 75-a(S)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)propionitrile (Shanghai Bid Pharmaceutical Technology Co., Ltd.), and fragment 1-a is replaced with fragment 2-d to obtain the title compound.

[0852] LC_MS:(ES + ):m / z 557.7[M+H] + .

[0853] 1H NMR (400MHz, CDCl3): δ9.06 (s, 1H), 8.27 (d, J = 1.8Hz, 2H), 7.49 (s, 1H), 7.12-7.09 (m, 1H), 7.02(s,1H),6.96-6.94(m,2H),6.61(m,1H),4.27-4.25(m,1H),4.20-4.15(m,4H),3.82-3 .77(m,4H),3.16-3.10(m,1H),2.97-2.92(m,1H),2.85(d,J=16.2Hz,4H),2.60-2.58(m,1H ),2.44(s,3H),1.98-1.96(m,1H),1.73-1.68(m,2H),1.58-1.56(m,2H),1.33-1.26(m,2H).

[0854] Example 76

[0855] (R)-3-cyclopentyl-3-(4-(2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile

[0856]

[0857] The procedure is the same as in Method 2, except that fragment 2-b is replaced with fragment 74-a to obtain the title compound.

[0858] LC_MS:(ES + ):m / z 513.4[M+H] + .

[0859] 1 H NMR (400MHz, DMSO-d6): δ11.42(s,1H),8.72(s,1H),8.66(s,1H),8.26(s,1H),7.40(d,J=2. 8Hz,1H),7.20-7.15(m,2H),6.75-6.74(m,1H),6.65(d,J=8.8Hz,1H),4.58-4.52(m,1H),4.1 5(d,J=4.4Hz,2H),3.53(t,J=5.6Hz,2H),3.38(t,J=5.6Hz,2H),3.29(s,2H),3.27(s,3H),3. 22-3.20(m,1H),2.46-2.39(m,1H),1.83-1.80(m,1H),1.63-1.43(m,4H),1.36-1.19(m,4H).

[0860] Example 77

[0861] (S)-3-cyclopentyl-3-(4-(2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile

[0862]

[0863] The procedure is the same as in Method 2, except that fragment 2-b is replaced with fragment 75-a to obtain the title compound.

[0864] LC_MS:(ES + ):m / z 513.4[M+H] + .

[0865] 1 H NMR (400MHz, DMSO-d6): δ11.42(s,1H),8.72(s,1H),8.66(s,1H),8.26(s,1H),7.40-7.39(m,1H) ,7.20-7.15(m,2H),6.75-6.74(m,1H),6.65(d,J=8.8Hz,1H),4.57-4.52(m,1H),4.15(d,J=4.0H z,2H),3.53(t,J=5.6Hz,2H),3.38(t,J=5.6Hz,2H),3.29(s,2H),3.27(s,3H),3.25-3.20(m,1H) ,2.46-2.39(m,1H),1.86-1.79(m,1H),1.63-1.51(m,3H),1.46-1.43(m,1H),1.36-1.28(m,4H).

[0866] Example 78

[0867] Dimethyl(2-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)phosphine oxide

[0868]

[0869] The procedure was the same as in Method 7, except that fragment 6-d was replaced with fragment (2-aminophenyl)dimethylphosphine oxide to obtain the title compound.

[0870] LC_MS:(ES +):m / z 566.20[M+H] + .

[0871] 1 H NMR (400MHz, CD3OD): δ8.34(s,1H),8.06-7.92(m,1H),7.76-7.71(m,1H),7.62(t,J=7.8Hz,1H),7.42-7.31(m,2H),7.12-7.0 9(m,1H),6.94(d,J=8.4Hz,1H),4.19-4.08(m,4H),3.96-3.79(m,4H),3.52-3.34(m,4H),2.92(s,3H),1.79(d,J=13.6Hz,6H).

[0872] Example 79

[0873] Cyclopropyl((1R,5S)-3-(2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-yl) methyl ketone

[0874]

[0875] The implementation method is the same as in Method 4, except that fragment 1-b is replaced with fragment 79-d and fragment 4-a is replaced with fragment 2-d to obtain the title compound.

[0876] LC_MS:(ES + ):m / z 504.4[M+H] + .

[0877] 1 H NMR (400MHz, DMSO-d6): δ11.31(s,1H),8.32(brs,1H),7.27(s,1H),7.11-7.06(m, 1H),6.84(s,1H),6.61(brs,1H),6.44-6.43(m,1H),4.76-4.63(m,2H),4.54-4.41( m,2H),4.13(s,2H),3.52(t,J=5.2Hz,2H),3.32(brs,5H),3.26(s,3H),3.21-3.16( m,1H),2.04-1.96(m,2H),1.80-1.77(m,2H),1.71-1.69(m,1H),0.79-0.72(m,4H).

[0878] The implementation method for segment 79-d is as follows:

[0879]

[0880] Step 1: Synthesis of fragment 79-c 8-(cyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester

[0881]

[0882] 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.79 g, 4.72 mmol) was added to a stirred reaction solution of N,N-dimethylformamide containing 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (500 mg, 2.35 mmol), cyclopropanecarboxylic acid (203 mg, 2.35 mmol), and N,N-diisopropylethylamine (1.22 g, 9.44 mmol) at 0 °C. The resulting mixture was heated to room temperature and stirred for 30 min. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into water (20 mL) and ethyl acetate (20 mL). The organic layer was collected, washed with saturated sodium chloride solution (10 ml x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily substance, 8-(cyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (600 mg, crude product). The crude product was used directly in the next step of the reaction without purification.

[0883] Step 2: Synthesis of fragment 79-d 3,8-diazabicyclo[3.2.1]oct-8-yl(cyclopropyl)methyl ketone

[0884]

[0885] A solution of tert-butyl octane-3-carboxylic acid (600 mg, 2.14 mmol) and trifluoroacetic acid (1.5 mL) in dichloromethane (3 mL) was stirred at room temperature for 5 hours. The reaction was monitored by TLC until complete. The volatiles were removed under pressure, and the residue was adjusted to pH 7-8 with sodium carbonate solution and then extracted with dichloromethane (10 mL × 3). The organic layers were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oily product, 3,8-diazabicyclo[3.2.1]oct-8-yl(cyclopropyl) methyl ketone (350 mg, crude).

[0886] Example 80

[0887] N 4 -(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-N 2-(4-Methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)-7H-pyrrolo[2,3-d]pyrimidin-2,4-diamine

[0888]

[0889] The procedure is the same as in Method 4, except that fragment 1-b is replaced with fragment 80-f: 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline, and fragment 4-a is replaced with fragment 2-d, to obtain the title compound.

[0890] LC_MS:(ES + ):m / z 528.4[M+H] + .

[0891] 1 H NMR (400MHz, DMSO-d6): δ11.14(s,1H),8.54(s,1H),8.34-8.38(m,1H),8.26 (d,J=4.0Hz,1H),7.55(d,J=3.8Hz,1H),7.27(s,1H),7.19(t,J=8.0Hz,1H),7 .09(s,1H),6.86(s,1H),6.56-6.58(m,1H),6.51(s,1H),4.13(s,2H),3.95(s ,3H),3.72(s,3H),3.50-3.53(m,2H),3.36(s,2H),3.30(s,2H),3.27(s,3H).

[0892] The implementation method for segment 80-f is as follows:

[0893]

[0894] Step 1: Fragment 80-b methyl 2-methoxy-3-nitrobenzene

[0895]

[0896] A solution of N,N-dimethylformamide (20 mL) containing methyl 3-nitrosalicylate (2 g, 10.15 mmol), methyl iodoformate (2.9 g, 20.29 mmol), and potassium carbonate (2.8 g, 20.29 mmol) was stirred at 60 °C for 1 h. The reaction was monitored by TLC until complete. The reaction mixture was quenched with ice water (20 mL) and then extracted with ethyl acetate (10 mL x 2). The organic layer was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a pale yellow solid, methyl 2-methoxy-3-nitrobenzoate (2.09 g, crude product).

[0897] LC_MS:(ES + ):m / z 212.0[M+H] + .

[0898] 1 H NMR (400MHz, DMSO-d6): δ8.11-8.14(m,1H),8.03-8.05(m,1H),7.44(t,J=4.0Hz,1H),3.89(d,J=7.2Hz,6H).

[0899] Step 2: Fragment 80-C 2-methoxy-3-nitrobenzamide

[0900]

[0901] A solution of methylamino alcohol (35 ml) was added to an ammonium hydroxide solution (20 ml) containing methyl 2-methoxy-3-nitrobenzene (2.09 g, 9.90 mmol) at 0 °C; the reaction mixture was stirred at room temperature for 15 hours. The reaction was monitored by TLC until complete. The reaction mixture was concentrated under reduced pressure to give a yellow solid, 2-methoxy-3-nitrobenzeneamide (2 g, crude product).

[0902] LC_MS:(ES + ):m / z 196.9[M+H] + .

[0903] 1 H NMR (400MHz, DMSO-d6): δ7.95-7.98(m,2H),7.76-7.78(m,2H),7.37(t,J=4.0Hz,1H),3.88(s,3H).

[0904] Step 3: Fragment 80-d 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole

[0905]

[0906] A solution of N,N-dimethylformamide dimethyl acetal (11.9 g, 100 mmol) containing 2-methoxy-3-nitrobenzamide (2 g, 10 mmol) was stirred at 90 °C for 30 min. The reaction was monitored by TLC until complete. A large amount of N,N-dimethylformamide dimethyl acetal was removed by concentration under reduced pressure. The residue was dissolved in ethanol (10 mL), and then a mixture of ethanol (50 mL) and acetic acid (12 mL) containing hydrazine hydrate (6.25 g, 100 mmol) was added dropwise at 0 °C. The resulting mixture was heated to room temperature and stirred for 4 h. The reaction was monitored by TLC until complete. The reaction mixture was concentrated, and the residue was partitioned into water (50 mL) and ethyl acetate (20 mL). The aqueous layer was washed with ethyl acetate (10 mL x 3). The organic layers were combined, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was added to 30 ml of 2% ethyl acetate in petroleum ether solution at room temperature and stirred for 3 hours. The mixture was filtered, the solid was collected, and dried under vacuum to give a yellow solid 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.56 g, 71%).

[0907] LC_MS:(ES + ):m / z 221.1[M+H] + .

[0908] Step 4: Fragment 80-e 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole

[0909]

[0910] A solution of N,N-dimethylformamide (10 mL) containing 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole (1.56 g, 7.085 mmol), potassium carbonate (1.31 g, 9.49 mmol), and iodomethane (1.31 g, 9.21 mmol) was stirred at room temperature for 3 hours. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into ethyl acetate (30 mL) and water (30 mL). The organic layer was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was added to ethanol (3 mL) and stirred at 45 °C until the solid disappeared. The mixture was cooled to room temperature; the solid was collected by filtration, the filter cake was washed with ethanol (2 mL) at -30 °C, dried under vacuum, and a yellow solid of 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole (255 mg, 15%) was given.

[0911] LC_MS:(ES + ):m / z 235.1[M+H] + .

[0912] 1 H NMR (400MHz, DMSO-d6): δ8.53(s,1H),8.12-8.14(m,1H),7.86-7.88(m,1H),7.40(t,J=4.0Hz,1H),4.05(s,3H),3.85(s,3H).

[0913] Step 5: Fragment 80-f 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline

[0914]

[0915] In a hydrogen atmosphere (hydrogen balloon), 5 ml of ethanol containing 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole (255 mg, 1.08 mmol) and palladium / carbon (10%, 100 mg) was stirred at room temperature for 1 hour. The reaction was monitored by TLC until complete. The palladium / carbon was removed by filtration, and the mixture was washed with ethanol (5 ml x 2). The filtrates were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting with dichloromethane containing 3% methanol) to obtain a grayish-white solid 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (140 mg, 63%).

[0916] LC_MS:(ES + ):m / z 205.2[M+H] + .

[0917] 1 H NMR (400MHz, DMSO-d6): δ8.08(s,1H),7.33-7.35(m,1H),6.99(t,J=3.8Hz,1H),6.80-6.82(m,1H),3.99(s,3H),3.77(s,3H).

[0918] Example 81

[0919] N 4 -Ethyl-N 2 -(4-Methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)-5-(trifluoromethyl)pyrimidin-2,4-diamine

[0920]

[0921] The procedure is the same as in Method 8, except that fragment 8-b is replaced with fragment ethylamine hydrochloride to obtain the title compound.

[0922] LC_MS:(ES +):m / z 398.3[M+H] + .

[0923] 1 H NMR (400MHz, DMSO-d6): δ8.10-8.17(m,1H),7.18-7.23(m,1H),6.96-7.10(m,2H),6.84-6.86(m,1H),6.63-6.66(m,1H),4.13(t,J= 4.4Hz,2H),3.52(t,J=5.6Hz,2H),3.41(t,J=5.4Hz,2H),3.34-3.36(m,2H),3.26(s,3H),3.10-3.26(m,2H),1.05(t,J=7.0Hz,3H).

[0924] Example 82

[0925] N 4 -(2-(isopropylsulfonyl)phenyl)-N 2 -(4-Methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)-5-(trifluoromethyl)pyrimidin-2,4-diamine

[0926]

[0927] The procedure is the same as in Method 8, except that fragment 8-b is replaced with fragment 2-(isopropylsulfonyl)aniline to obtain the title compound.

[0928] LC_MS:(ES + ):m / z 552.1[M+H] + .

[0929] 1 H NMR (400MHz, CDCl3): δ9.34(s,1H).8.42-8.44(d,J=4.2Hz,1H),8.32(s,1H),7.8 9-7.91(d,J=4.0Hz,1H),7.58(t,J=3.8Hz,1H),7.00(s,1H),6.83-6.86(d,J=4.4 Hz,1H),6.59-6.61(d,J=4.2Hz,1H),4.23(t,J=2.2Hz,2H),3.60(t,J=3.0Hz,2H) ,3.42-3.46(m,4H),3.37(s,1H),3.16-3.23(m,1H),1.28-1.30(d,J=3.4Hz,6H).

[0930] Example 83

[0931] Dimethyl(2-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)phosphine oxide

[0932]

[0933] The procedure is the same as in Method 8, except that fragment 8-b is replaced with fragment (2-aminophenyl)dimethylphosphine oxide to obtain the title compound.

[0934] LC_MS:(ES + ):m / z 522.30[M+H] + .

[0935] 1 H NMR (400MHz, DMSO-d6): δ10.62(s,1H),9.43(s,1H),8.34(s,1H),7.90-7.92(m,1H),7.55-7.57(m,1H),7.49(s,1H),7.19(t,J=8.0Hz,1H),6. 93(s,2H),6.59(d,J=8.8Hz,1H),4.13(s,2H),3.51(t,J=5.6Hz,2H),3.39(t,J=5.6Hz,2H),3.30(s,2H),3.26(s,3H),1.74(d,J=13.2Hz,6H),

[0936] Example 84

[0937] N 2 -(4-Methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)-N 4 -(2-(methylsulfonyl)ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[0938]

[0939] The procedure is the same as in Method 4, except that fragment 1-b is replaced with fragment 2-(methanesulfonyl)ethane-1-amine and fragment 4-a is replaced with fragment 2-d to obtain the title compound.

[0940] LC_MS:(ES + ):m / z 447.2[M+H] + .

[0941] 1H NMR (400MHz, DMSO-d6): δ10.96(s,1H),8.25(s,1H),7.41(s,1H),7.30(s,1H),7.11(s,1H),6.74(s,1H),6. 61(s,1H),6.34(s,1H),4.12(s,2H),3.81(d,J=5.2Hz,2H),3.49(d,J=6.1Hz,5H),3.26(s,6H),3.02(s,3H).

[0942] Example 85

[0943] Dimethyl(2-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)phosphine oxide

[0944]

[0945] The procedure is the same as in Method 4, except that fragment 1-b is replaced with fragment (2-aminoethyl)dimethylphosphine oxide and fragment 4-a is replaced with fragment 2-d to obtain the title compound.

[0946] LC_MS:(ES + ):m / z 445.3[M+H] + .

[0947] 1 H NMR (400MHz, DMSO-d6): δ10.92(s,1H),8.23(s,1H),7.39-7.27(m,2H),7.10-7.08(m,1H),6.76-6.69(m,1H),6.61-6.58(m,1H),6.35(brs ,1H),4.18-4.06(m,2H),3.75-3.63(m,2H),3.55-3.48(m,2H),3.29-3.23(m,4H),2.12-2.06(m,2H),1.76(s,3H),1.43(d,J=12.8Hz,6H).

[0948] Example 86

[0949] Dimethyl(2-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)ethyl)phosphine oxide

[0950]

[0951] The procedure is the same as in Method 8, except that fragment 8-b is replaced with fragment (2-aminoethyl)dimethylphosphine oxide to obtain the title compound.

[0952] LC_MS:(ES + ):m / z 474.2[M+H] + .

[0953] 1 H NMR (400MHz, DMSO-d6): δ9.29(s,1H),8.12(s,1H),7.21(s,1H),7.11-7.07(m,2H),6.64(d,J=8.8Hz,1H),4.12(t,J=4.4Hz,2H),3.73 -3.65(m,2H),3.50(t,J=5.2Hz,2H),3.37(t,J=5.6Hz,2H),3.32-3.30(m,2H),3.26(s,3H),2.07-2.00(m,2H),1.40(d,J=12.8Hz,6H).

[0954] Example 87

[0955] (1r,4r)-1-methyl-4-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecyl-12-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)cyclohexyl-1-ol

[0956]

[0957] The procedure is the same as in Method 6, except that fragment 6-e is replaced with fragment 6-d to obtain the title compound.

[0958] LC_MS:(ES + ):m / z 498.20[M+H] + .

[0959] 1H NMR (400MHz, DMSO-d6): δ11.31(s,1H),8.87(s,1H),7.60(m,1H),7.32-7.30(m,1H),6.95-6.91(m,1H),6.27-6.26(m,1H),5.37(m,1H),4.25(s, 2H),4.10-4.06(m,4H),3.68(m,4H),3.00-2.64(m,4H),2.35-2.33(m,3H ),2.03-1.96(m,2H),1.76-1.63(m,4H),1.51-1.45(m,2H),1.19(s,3H).

[0960] Example 88

[0961] (S)-N 2 -(7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecyl-12-yl)-N 4 -(oxetane-2-ylmethyl)-5-(trifluoromethyl)pyrimidin-2,4-diamine

[0962]

[0963] The procedure is the same as in Method 8, except that fragment 8-b is replaced with fragment (S)-oxetane-2-ylmethylamine and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[0964] LC_MS:(ES + ):m / z 484.30[M+H] + .

[0965] 1 H NMR (400MHz, DMSO-d6): δ9.60(s,1H),8.95(s,1H),8.19(s,1H),7.62(s,1H),7.37-7.27(m,2H),7.16-7.05(m,2H),4.95-4.92(m,1H),4.5 2-4.41(m,2H),4.29-4.02(m,4H),3.85-3.62(m,6H),3.51-3.44(m,1 H),3.33-3.18(m,1H),2.88(s,3H),2.63-2.57(m,1H),2.41(brs,1H).

[0966] Example 89

[0967] N 2-(7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecyl-12-yl)-N 4 -(2-(methylsulfonyl)ethyl)-5-(trifluoromethyl)pyrimidin-2,4-diamine

[0968]

[0969] The procedure is the same as in Method 8, except that fragment 8-b is replaced with fragment 2-(methanesulfonyl)ethane-1-amine, and fragment Amine-1 is replaced with fragment Amine-3, to obtain the title compound.

[0970] LC_MS:(ES + ):m / z 520.20[M+H] + .

[0971] 1 H NMR (400MHz, DMSO-d6): δ9.64(s,1H),8.99(s,1H),8.22(s,1H),7.52(s,1H),7.38(brs,1H),7.25-7.0 8(m,1H),4.31(s,2H),4.16-3.83(m,6H),3.70-3.47(m,6H),3.18(brs,2H),3.02(s,3H),2.90(s,3H).

[0972] Example 90

[0973] 2-Methyl-1-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)prop-2-ol

[0974]

[0975] The implementation method is the same as in Method 3, except that fragment 3-a is replaced with fragment 1-amino-2-methylprop-2-ol, and fragment Amine-1 is replaced with fragment Amine-3, to obtain the title compound.

[0976] LC_MS:(ES + ):m / z 457.25[M+H] + .

[0977] 1H NMR (400MHz, DMSO-d6): δ10.93(s,1H),8.43(s,1H),7.70(d,J=2.4Hz,1H),7.25 -7.23(m,1H),6.95(brs,1H),6.86(d,J=8.8Hz,1H),6.76(t,J=2.0Hz,1H),6.50 -6.49(m,1H),4.69(s,1H),4.08-4.03(m,4H),3.67-3.62(m,4H),3.50(d,J=5.6 Hz,2H),2.76(t,J=4.4Hz,2H),2.61(t,J=4.4Hz,2H),2.28(s,3H),1.16(s,6H).

[0978] Example 91

[0979] N 2 -(4-Methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)-N 4 -Phenylacetyl-5-(trifluoromethyl)pyrimidin-2,4-diamine

[0980]

[0981] The procedure is the same as in Method 7, except that fragment 6-d is replaced with fragment aniline and fragment Amine-3 is replaced with fragment Amine-1 to obtain the title compound.

[0982] LC_MS:(ES + ):m / z 446.1[M+H] + .

[0983] Example 92

[0984] (S)-N 2 -(4-Methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)-N 4 -(oxetane-2-ylmethyl)-5-(trifluoromethyl)pyrimidin-2,4-diamine

[0985]

[0986] The procedure is the same as in Method 8, except that fragment 8-b is replaced with fragment (S)-oxetane-2-ylmethylamine to obtain the title compound.

[0987] LC_MS:(ES + ):m / z 440.0[M+H] + .

[0988] Example 93

[0989] (1s,4s)-1-methyl-4-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)oxy)cyclohexyl-1-ol

[0990]

[0991] The procedure is the same as in Method 7, except that fragment Amine-3 is replaced with fragment Amine-1 to obtain the title compound.

[0992] LC_MS:(ES + ):m / z 483.20[M+H] + .

[0993] 1 H NMR (400MHz, CDCl3): δ8.29(s,1H),7.16(s,1H),6.85(d,J=8.4Hz,1H),6.62(d,J=8.8Hz,1H),5.15-5.12(m,1H),4.22(t,J=4.4Hz ,2H),3.59(t,J=5.6Hz,2H),3.46-3.40(m,4H),3.37(s,3H)1.97-1.92(m,4H),1.79-1.76(m,3H),1.63-1.56(m,2H),1.28(s,3H).

[0994] Example 94

[0995] N 4 -(2-(methoxymethyl)phenyl)-N 2 -(4-Methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)-5-(trifluoromethyl)pyrimidin-2,4-diamine

[0996]

[0997] The procedure is the same as in Method 7, except that fragment 6-d is replaced with fragment 2-(methoxymethyl)aniline and fragment Amine-3 is replaced with fragment Amine-1 to obtain the title compound.

[0998] LC_MS:(ES + ):m / z 490.1[M+H] + .

[0999] 1H NMR (400MHz, CDCl3): δ8.50(s,1H),8.27(s,1H),8.19(d,J=8.2Hz,1H),7.33( t,J=7.8Hz,1H),7.22(dd,J=7.6,1.7Hz,1H),7.08(td,J=7.5,1.2Hz,1H),7.00 (d,J=2.5Hz,1H),6.91(dd,J=8.6,2.5Hz,2H),6.58(d,J=8.7Hz,1H),4.49(s, 2H), 4.28–4.16 (m, 2H), 3.59 (t, J = 5.7Hz, 2H), 3.47–3.39 (m, 7H), 3.36 (s, 3H).

[1000] Example 95

[1001] N 4 -(2-Methoxyphenyl)-N 2 -(4-Methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)-5-(trifluoromethyl)pyrimidin-2,4-diamine

[1002]

[1003] The procedure is the same as in Method 7, except that fragment 6-d is replaced with fragment 2-methoxyaniline and fragment Amine-3 is replaced with fragment Amine-1 to obtain the title compound.

[1004] LC_MS:(ES + ):m / z 476.1[M+H] + .

[1005] 1 H NMR (400MHz, CDCl3): δ8.31(d,J=8.0Hz,1H),8.16(s,1H),7.14–7.05(m,1H),7.01(d,J=2.5Hz,1H),6.95–6.88(m,3H), 6.62(d,J=8.7Hz,1H),4.27–4.21(m,2H),3.92(s,3H),3.61(t,J=5.6Hz,2H),3.46(dt,J=8.8,4.9Hz,4H),3.38(s,3H).

[1006] Example 96

[1007] 1-(((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)methyl)cyclopropane-1-carboxynitrile

[1008]

[1009] The procedure is the same as in Method 8, except that fragment 8-b is replaced with fragment 1-(aminomethyl)cyclopropane-1-carboxynitrile to obtain the title compound.

[1010] LC_MS:(ES + ):m / z 449.1[M+H] + .

[1011] 1 H NMR (400MHz, CDCl3): δ8.11(s,1H),7.00(d,J=2.5Hz,1H),6.82(d,J=8.6Hz,1H),6.61(d,J=8.7Hz,1H),4.27–4.17(m,2H), 3.72(d,J=6.0Hz,2H),3.58(t,J=5.6Hz,2H),3.47–3.39(m,4H),3.36(s,3H),1.25(d,J=2.0Hz,2H),1.05(q,J=5.1Hz,2H).

[1012] Example 97

[1013] N 2 -(2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)-N 4 -(2-(isopropylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[1014]

[1015] Implementation method:

[1016]

[1017] Step 1: Synthesis of intermediate 97-a 13-nitro-2,3,5,6,8,9-hexahydro-7H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-7-carboxylic acid tert-butyl ester

[1018]

[1019] A solution of 13-nitro-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxazacyclododecane (140 mg, 0.52 mmol), di-tert-butyl dicarbonate (170 mg, 0.78 mmol), N,N-dimethylpyridin-4-amine (6 mg, 0.05 mmol), and triethylamine (105 mg, 1.0 mmol) in dichloromethane (2 mL) was stirred at room temperature for 12 hours. The reaction was monitored by TLC until complete. The reaction mixture was partitioned into water (20 mL) and dichloromethane (10 mL). The organic layer was collected, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The organic layers were combined, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (eluting with dichloromethane containing 1% methanol) to obtain a white solid 13-nitro-2,3,5,6,8,9-hexahydro-7H-benzo[b][1,4,7]trioxaza

[10] azacyclododecane-7-carboxylic acid tert-butyl ester (146 mg, 76%).

[1020] Step 2: Synthesis of intermediate 97-b 13-amino-2,3,5,6,8,9-hexahydro-7H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-7-carboxylic acid tert-butyl ester

[1021]

[1022] A solution of 13-nitro-2,3,5,6,8,9-hexahydro-7H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-7-carboxylic acid tert-butyl ester (146 mg, 0.4 mmol), iron powder (224 mg, 4.0 mmol), ammonium chloride (107 mg, 2.0 mmol), and water (0.2 mL) in ethanol (2 mL) was refluxed for 12 hours. The reaction was monitored by TLC until complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a black oily substance of 13-amino-2,3,5,6,8,9-hexahydro-7H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-7-carboxylic acid tert-butyl ester (100 mg, 73%), which was used directly for the next step without further purification.

[1023] Step 3: Synthesis of intermediate 97-c 13-((4-((2-(isopropylsulfonyl)phenyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-2,3,5,6,8,9-hexahydro-7H-benzo[b][1,4,7]trioxaza

[10] azacyclododecane-7-carboxylic acid tert-butyl ester

[1024]

[1025] BrettPhos Pd G3 (13.6 mg, 0.015 mmol) was added to 1,4-dioxane (1 ml) containing 2-chloro-N-(2-(isopropylsulfonyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (71.1 mg, 0.15 mmol), 13-amino-2,3,5,6,8,9-hexahydro-7H-benzo[b][1,4,7]trioxaza

[10] azacyclododecane-7-carboxylic acid tert-butyl ester (50 mg, 0.15 mmol) and potassium phosphate (95.4 mg, 0.45 mmol) under a nitrogen atmosphere at room temperature. The reaction mixture was purged with nitrogen three times, and the mixture was stirred at 110 °C for 12 hours. The reaction was monitored by TLC until complete. The reaction mixture was cooled to room temperature and partitioned into water (20 ml) and ethyl acetate (10 ml). The organic layer was collected, and the aqueous phase was extracted with ethyl acetate (10 ml x 2). The organic layer was collected, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative TLC (eluting with dichloromethane containing 3% methanol) to obtain a yellow solid 13-((4-((2-(isopropylsulfonyl)phenyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-2,3,5,6,8,9-hexahydro-7H-benzo[b][1,4,7]trioxaza

[10] azacyclododecane-7-carboxylic acid tert-butyl ester (70 mg, 59%).

[1026] LC_MS:(ES + ):m / z 783.7[M+H] + .

[1027] Step 4: N 2 -(2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl-N 4 Synthesis of -(2-(isopropylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[1028]

[1029] A solution containing 13-((4-((2-(isopropylsulfonyl)phenyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-2,3,5,6,8,9-hexahydro-7H-benzo[b][1,4,7]trioxazacyclododecane-7-carboxylic acid tert-butyl ester (70 mg, 0.09 mmol) and trifluoroacetic acid (2 ml) in dichloromethane (2 ml) was stirred at room temperature for 3 hours. The reaction was monitored by TLC until complete. The reaction mixture was concentrated, and the residue was added to a mixture of ammonia (2 ml) and ethyl acetate (4 ml). The reaction mixture was stirred at 30 °C for 16 hours. The reaction was monitored by TLC until complete. The organic layer was collected, washed with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative TLC (eluting with dichloromethane containing 10% methanol) to obtain a yellow solid N. 2 -(2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl-N 4 -(2-(isopropylsulfonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (18.7 mg, 37%).

[1030] LC_MS:(ES + ):m / z 553.9[M+H] + .

[1031] 1 H NMR (400MHz, CDCl3): δ9.58(s,1H),9.10(s,1H),8.79-8.81(m,1H),7.86-7.88(m,1H),7.60-7 .64(m,1H),7.48-7.49(m,1H),7.16-7.20(m,1H),7.00-7.05(m,2H),6.92(s,1H),6.84-6.85( d,J=3.6Hz,1H),6.44-6.45(d,J=3.6Hz,1H),4.18-4.21(m,2H),4.09-4.11(m,2H),3.77-3.81 (m,4H),3.24-3.30(m,1H),3.00-3.02(m,2H),2.92-2.94(m,2H),1.30-1.32(d,J=7.2Hz,6H).

[1032] Example 98

[1033] 1-(13-((4-((2-(isopropylsulfonyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-2,3,5,6,8,9-hexahydro-7H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-7-yl)ethyl-1-one

[1034]

[1035] The method is the same as in Example 97, except that acetyl chloride is used to replace di-tert-butyl dicarbonate to obtain the title compound.

[1036] LC_MS:(ES + ):m / z 595.6[M+H] + .

[1037] 1 H NMR (400MHz, CDCl3): δ9.60(s,1H),8.74-8.80(m,2H),7.85-7.88(m,1H),7.60-7.65(m ,1H),7.41-7.47(m,1H),7.09-7.20(m,2H),6.84-6.97(m,3H),6.45-6.46(m,1H),4.24- 4.33(m,2H),4.12-4.15(m,1H),4.06-4.10(m,2H),3.80-3.82(m,1H),3.72-3.76(m,4H ),3.55-3.63(m,2H),3.22-3.29(m,1H),2.17-2.23(m,3H),1.29-1.31(d,J=6.8Hz,6H).

[1038] Example 99

[1039] N 4 -(2-(isopropylsulfonyl)phenyl)-N 2 -(7-(methylsulfonyl)-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[1040]

[1041] The method is the same as in Example 97, except that di-tert-butyl dicarbonate is replaced with methanesulfonyl chloride to obtain the title compound.

[1042] LC_MS:(ES + ):m / z 632.0[M+H] + .

[1043] 1 H NMR (400MHz, DMSO-d6): δ11.44(s,1H),9.48(s,1H),8.88-8.93(m,2H),7.81-7.84(m,1H),7.7 2-7.76(m,1H),7.62-7.63(d,J=2.4Hz,1H),7.28-7.34(m,2H),7.03-7.04(m,1H),6.92-6.94(d ,J=8.4Hz,1H),6.25-6.26(m,1H),4.07-4.13(m,4H),3.72-3.76(m,4H),3.51-3.54(t,J=2.6Hz ,2H),3.44-3.49(m,1H),3.38-3.41(t,J=2.4Hz,2H),2.95(s,3H),1.17-1.19(d,J=6.8Hz,6H).

[1044] Example 100

[1045] (1s,4s)-4-((5-fluoro-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazolin-9-yl)amino)pyrimidin-4-yl)oxy)-1-methylcyclohexyl-1-ol

[1046]

[1047] The procedure is the same as in Method 1, except that fragment 1-b is replaced with fragment 6-e to obtain the title compound.

[1048] LC_MS:(ES + ):m / z 433.2[M+H] + .

[1049] 1 H NMR (400MHz, CDCl3): δ8.07–7.88(m,1H),7.23–7.09(m,1H),7.23–7.09(m,1H),7.09–6.33(m,3H),5.07(tt,J=9.3,5.2Hz,1H),4.21(t,J=4.4Hz,2 H),3.59(t,J=5.5Hz,2H),3.49–3.27(m,4H),3.36(s,3H),2.05–1.82(m, 4H),1.82–1.71(m,2H),1.60(ddd,J=13.9,10.7,5.7Hz,2H),1.28(s,3H).

[1050] Example 101

[1051] (1s,4s)-1-methyl-4-((5-methyl-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)pyrimidin-4-yl)oxy)cyclohexyl-1-ol

[1052]

[1053] The procedure is the same as in Method 1, except that fragment 1-a is replaced with fragment 2,4-dichloro-5-methylpyrimidine and fragment 1-b is replaced with fragment 6-e to obtain the title compound.

[1054] LC_MS:(ES + ):m / z 429.2[M+H] + .

[1055] 1 H NMR (400MHz, CDCl3): δ7.90 (s, 1H), 7.22 (d, J = 2.4Hz, 1H), 7.01–6.74 (m, 2H) ,6.60(d,J=8.6Hz,1H),5.06(tt,J=9.2,4.3Hz,1H),4.21(t,J=4.4Hz,2H),3 .59(t,J=5.7Hz,2H),3.50–3.37(m,4H),3.36(s,3H),1.96–1.82(m,4H),1.7 7(dd,J=12.8,3.9Hz,2H),1.61(ddd,J=14.3,11.5,4.5Hz,2H),1.28(s,3H).

[1056] Example 102

[1057] (1s,4s)-4-((5-chloro-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)pyrimidin-4-yl)oxy)-1-methylcyclohexyl-1-ol

[1058]

[1059] The procedure is the same as in Method 1, except that fragment 1-a is replaced with fragment 2,4,5-trichloropyrimidine and fragment 1-b is replaced with fragment 6-e to obtain the title compound.

[1060] LC_MS:(ES + ):m / z 449.1[M+H] + .

[1061] 1H NMR (400MHz, CDCl3): δ8.06 (s, 1H), 7.16 (d, J = 2.5Hz, 1H), 6.82 (dd, J = 8.6, 2.5Hz, 2H),6.61(d,J=8.7Hz,1H),5.15–4.99(m,1H),4.22(dd,J=5.2,3.6Hz,2H),3.59(t ,J=5.7Hz,2H),3.43(t,J=5.7Hz,2H),3.41–3.37(m,2H),3.36(s,3H),1.95(td,J= 10.2, 8.7, 4.4Hz, 4H), 1.78 (dh, J=9.6, 2.5Hz, 2H), 1.62–1.55 (m, 2H), 1.28 (s, 3H).

[1062] Example 103

[1063] (1s,4s)-4-((5-fluoro-2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)pyrimidin-4-yl)oxy)-1-methylcyclohexyl-1-ol

[1064]

[1065] The procedure is the same as in Method 1, except that fragment 1-b is replaced with fragment 6-e and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[1066] LC_MS:(ES + ):m / z 477.55[M+H] + .

[1067] 1 H NMR (400MHz, DMSO-d6): δ9.37(s,1H),8.24(d,J=2.8Hz,1H),7.48(d,J=2.4Hz,1H),7.21-7.19(m,1H),6.97(d,J=8.8Hz,1H),5.08-5.01(m,1H),4. 25(s,1H),4.12-4.06(m,4H),3.70(brs,4H),2.99-2.85(m,4H),2.46(s,3 H),1.88-1.84(m,4H),1.67-1.64(m,2H),1.46-1.41(m,2H),1.15(s,3H).

[1068] Example 104

[1069] (1s,4s)-4-((5-chloro-2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)pyrimidin-4-yl)oxy)-1-methylcyclohexyl-1-ol

[1070]

[1071] The procedure is the same as in Method 1, except that fragment 1-a is replaced with fragment 2,4,5-trichloropyrimidine, fragment 1-b is replaced with fragment 6-e, and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[1072] LC_MS:(ES + ):m / z 493.40[M+H] + .

[1073] 1 H NMR (400MHz, DMSO-d6): δ9.54(s,1H),8.26(s,1H),7.48(d,J=1.2Hz,1H),7.25-7.23(m,1H),7.01(d,J=8.8Hz,1H),5.09-5.02(m,1H),4.26(s ,1H),4.17-4.08(m,4H),3.72(brs,4H),3.07-2.87(m,4H),2.57(s,3H) ,1.85-1.84(m,4H),1.68-1.64(m,2H),1.46-1.40(m,2H),1.16(s,3H).

[1074] Example 105

[1075] (1s,4s)-1-methyl-4-((5-methyl-2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)pyrimidin-4-yl)oxy)cyclohexyl-1-ol

[1076]

[1077] The procedure is the same as in Method 1, except that fragment 1-a is replaced with fragment 2,4-dichloro-5-methylpyrimidine, fragment 1-b is replaced with fragment 6-e, and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[1078] LC_MS:(ES+):m / z 473.3[M+H] + .

[1079] 1HNMR (400MHz, DMSO-d6): δ9.15(s,1H),8.00(s,1H),7.55(d,J=2.0Hz,1H),7.29-7.27(m,1H),6.99(d,J=8.8Hz,1H),5.06-4.99(m,1H),4.22-4. 08(m,5H),3.78-3.67(m,4H),3.10-2.58(m,4H),2.50(s,3H),1.96(s,3H) ),1.83-1.80(m,4H),1.70-1.62(m,2H),1.46-1.39(m,2H),1.16(s,3H).

[1080] Example 106

[1081] Cyclopropyl((1R,5S)-3-(5-fluoro-2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl) methyl ketone

[1082]

[1083] The procedure is the same as in Method 1, except that fragment 1-b is replaced with fragment 79-d to obtain the title compound.

[1084] LC_MS:(ES + ):m / z 483.4[M+H] + .

[1085] 1 H NMR (400MHz, DMSO-d6): δ8.77(s,1H),7.94(d,J=6.8Hz,1H),7.01-7.06(m,2H),6.61(d, J=8.8Hz,1H),4.73-4.74(m,1H),4.57-4.58(m,1H),4.10-4.22(m,4H),3.56(t,J=5.6Hz, 2H),3.35(t,J=5.6Hz,2H),3.29(s,2H),3.26(s,3H),3.21(d,J=12.4Hz,1H),3.09(d,J= 12.4Hz,1H),1.96-2.01(m,2H),1.70-1.82(m,2H),1.26-1.34(m,1H),0.70-0.79(m,4H).

[1086] Example 107

[1087] (1s,4s)-1-methyl-4-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)-6-(methylamino)pyrimidin-4-yl)oxy)cyclohexyl-1-ol

[1088]

[1089] The procedure is the same as in Method 7, except that fragment 7-a is replaced with fragment 2,6-dichloro-N-methylpyrimidine-4-amine to obtain the title compound.

[1090] LC_MS:(ES + ):m / z 488.35[M+H] + .

[1091] 1 H NMR (400MHz, DMSO-d6): δ8.71(s,1H),7.66(s,1H),7.17(d,J=8.4Hz,1H),6.89( d,J=8.8Hz,1H),6.71(d,J=8.4Hz,1H),6.24(d,J=2.0Hz,1H),5.16(s,1H),4.89 -4.85(m,1H),4.06-4.05(m,2H),3.98-3.94(m,2H),3.66-3.62(m,4H),2.84-2. 67(m,7H),2.37-2.33(m,3H),1.75-1.60(m,6H),1.42-1.36(m,2H),1.13(s,3H).

[1092] Example 108

[1093] (1s,4s)-1-methyl-4-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-6-(methylamino)pyrimidin-4-yl)oxy)cyclohexyl-1-ol

[1094]

[1095] The procedure is the same as in Method 7, except that fragment 7-a is replaced with fragment 2,6-dichloro-N-methylpyrimidin-4-amine, and fragment Amine-3 is replaced with fragment Amine-1, to obtain the title compound.

[1096] LC_MS:(ES + ):m / z 444.55[M+H] + .

[1097] 1H NMR (400MHz, CDCl3): δ7.24 (d, J = 2.4Hz, 1H), 6.86-6.84 (m, 1H), 6.75 (brs, 1H), 6.5 9(d,J=8.8Hz,1H),5.18(s,1H),4.99-4.94(m,1H),4.84(brs,1H),4.22-4.20(m,2H) ,3.59(t,J=5.6Hz,2H),3.43-3.37(m,4H),3.36(s,3H),2.85(d,J=5.2Hz,3H),1.95 -1.91(m,2H),1.88-1.81(m,2H),1.78-1.74(m,2H),1.63-1.55(m,2H),1.27(s,3H).

[1098] Example 109

[1099] (1s,4s)-1-methyl-4-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)quinazolin-4-yl)oxy)cyclohexyl-1-ol

[1100]

[1101] The procedure was the same as in Method 7, except that fragment 7-a was replaced with fragment 2,4-dichloroquinazoline to obtain the title compound. LC-MS:(ES) + ):m / z 509.40[M+H] + .

[1102] 1 H NMR (400MHz, DMSO-d6): δ9.35 (s, 1H), 7.93 (d, J = 8.0Hz, 1H), 7.77-7.69 (m, 2H), 7.52 ( d,J=8.4Hz,1H),7.37(d,J=8.4Hz,1H),7.26(t,J=7.6Hz,1H),6.98(t,J=8.8Hz,1H),5 .29-5.27(m,1H),4.30(s,1H),4.13-4.08(m,4H),3.68-3.66(m,4H),2.86-2.67(m,4H ),2.35(s,3H),1.93-1.91(m,4H),1.73-1.70(m,2H),1.50-1.43(m,2H),1.17(s,3H).

[1103] Example 110

[1104] (1s,4s)-1-methyl-4-((2-((7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)amino)quinoline-4-yl)oxy)cyclohexyl-1-ol

[1105]

[1106] The procedure is the same as in Method 7, except that fragment 7-a is replaced with fragment 2,4-dichloroquinoline to obtain the title compound.

[1107] LC_MS:(ES + ):m / z 508.35[M+H] + .

[1108] 1 H NMR (400MHz, DMSO-d6): δ9.16 (s, 1H), 7.96 (s, 1H), 7.90 (d, J = 8.4Hz, 1H), 7.60-7. 52(m,2H),7.30-7.21(m,2H),7.00(d,J=8.8Hz,1H),6.50(s,1H),4.48-4.42(m,1H) ,4.31(s,1H),4.20(brs,2H),4.12-4.09(m,2H),3.70(brs,4H),3.03-2.77(m,4H), 2.49(s,3H),1.93-1.89(m,4H),1.73-1.69(m,2H),1.51-1.44(m,2H),1.18(s,3H).

[1109] Example 111

[1110] N-(5-methyl-2-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)acrylamide

[1111]

[1112] The procedure is the same as in Method 3, except that fragment 3-a is replaced with fragment (2-amino-5-methylphenyl)carbamate tert-butyl ester, and fragment Amine-1 is replaced with fragment Amine-3, to obtain the title compound.

[1113] LC_MS:(ES + ):m / z 500.2[M+H] + .

[1114] 1H NMR(400MHz, CDCl3)δ8.95(s,1H),8.57(s,1H),7.74(s,1H),6.95(dd,J=48.3,41.0Hz, 2H),6.80(d,J=26.0Hz,1H),6.60(d,J=33.7Hz,2H),6.30(d,J=16.8Hz,1H),6.11(dd,J =29.9,19.3Hz,1H),5.94(s,1H),5.64(d,J=9.9Hz,1H),5.34(s,1H),4.12(dd,J=21.4, 14.4Hz,2H),3.59(d,J=30.4Hz,2H),3.35(s,5H),2.33(d,J=17.2Hz,2H),1.75(s,3H).

[1115] Example 112

[1116] N-(5-methyl-2-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide

[1117]

[1118] The procedure is the same as in Method 3, except that fragment 3-a is replaced with fragment (2-amino-5-methylphenyl)carbamate tert-butyl ester and fragment 2-d is replaced with fragment 7-a to obtain the title compound.

[1119] LC_MS:(ES + ):m / z 529.0[M+H] + .

[1120] 1H NMR (400MHz, MeOD) δ8.13(s,1H),7.53(d,J=8.0Hz,1H),7.15(d,J=8.5Hz,2H),6.77(ddd,J=18.1,15.6,11.2Hz,3H),6.37(dd,J=5 .9,3.9Hz,2H),5.77(dd,J=8.4,3.5Hz,1H),4.17–4.12(m,2H),3.58(t,J=5.6Hz,2H),3.49–3.36(m,4H),3.35(s,3H),2.39(s,3H).

[1121] Example 113

[1122] N-(2-((2-((4-methyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4,7]dioxazoline-9-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

[1123]

[1124] The procedure was the same as in Method 7, except that fragment 6-d was replaced with fragment N-(2-aminophenyl)methanesulfonamide and fragment Amine-3 was replaced with fragment Amine-1 to obtain the title compound.

[1125] LC_MS:(ES + ):m / z 539.20[M+H] + .

[1126] 1 H NMR (500MHz, DMSO-d6): δ9.14(s,1H),8.60(s,1H),8.51(s,1H),8.28(s,1 H),7.82(d,J=7.0Hz,1H),7.28(dd,J=7.6,1.6Hz,1H),7.11–7.03(m,2H),6 .82–6.74(m,2H),6.67(d,J=8.7Hz,1H),4.19–4.13(m,2H),3.54(t,J=5.5H z,2H),3.45(t,J=5.4Hz,2H),3.41–3.37(m,2H),3.28(s,3H),2.89(s,3H).

[1127] Example 114

[1128] N-(5-fluoro-4-(5-fluoro-2-methoxyphenyl)pyrimidin-2-yl)-7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-amine

[1129]

[1130] The procedure is the same as in Method 2, except that fragment 2-b is replaced with fragment 5-fluoro-2-methoxyphenylboronic acid, fragment 2-d is replaced with fragment 1-a, and fragment Amine-1 is replaced with fragment Amine-3 to obtain the title compound.

[1131] LC_MS:(ES + ):m / z 473.5[M+H] + .

[1132] 1H NMR (400MHz, DMSO-d6): δ9.66 (s, 1H), 8.54 (d, J = 2.0Hz, 1H), 7.58 (brs, 1H), 7.39-7.36 (m, 2H), 7.23-7.19 (m,2H),6.97-6.95(m,1H),4.08(brs,4H),3.80(s,3H),3.73-3.69(m,4H),3.29(s,3H),2.89-2.52(m,4H).

[1133] Example 115

[1134] N-(5-fluoro-4-(5-fluoro-2-methoxyphenyl)pyrimidin-2-yl)-7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-13-amine

[1135]

[1136] The procedure is the same as in Method 2, except that fragment 2-b is replaced with fragment 5-fluoro-2-methoxyphenylboronic acid, fragment 2-d is replaced with fragment 1-a, and fragment Amine-1 is replaced with fragment Amine-2 to obtain the title compound.

[1137] LC_MS:(ES + ):m / z 473.6[M+H] + .

[1138] 1 H NMR (400MHz, CDCl3): δ9.67(s,1H),8.55(d,J=2.0Hz,1H),7.57(d,J=2.4Hz,1H),7.41-7.36(m,2H),7.23-7.20( m,2H),6.99(d,J=8.8Hz,1H),4.13-4.07(m,4H),3.80(s,3H),3.70-3.62(m,4H),3.30(s,3H),3.08-2.75(m,4H).

[1139] Example 116

[1140] N 4 -(2-(methoxymethyl)phenyl)-N 2 -(7-methyl-2,3,6,7,8,9-hexahydro-5H-benzo[b][1,4,7]trioxa

[10] azacyclododecane-12-yl)-5-(trifluoromethyl)pyrimidin-2,4-diamine

[1141]

[1142] The procedure is the same as in Method 7, except that fragment 6-d is replaced with fragment 2-(methoxymethyl)aniline to obtain the title compound.

[1143] LC_MS:(ES + ):m / z 534.75[M+H] + .

[1144] 1 H NMR (400MHz, CD3OD): δ8.28(s,1H),7.94-7.91(m,1H),7.85-7.79(m,1H),7.47-7.33(m,4H),7.21-7.19(m,1H),7.08-7.06(m,1H),6 .92-6.90(m,1H),4.50(s,2H),4.15-4.13(m,2H),3.98-3.95(m,2H),3.81-3.78(m,4H),3.39(s,3H),3.09-2.92(m,4H),2.58(s,3H).

[1145] Example 117: Determination of the solubility of the compound in water and dilute hydrochloric acid

[1146] Preparation of standard samples:

[1147] The compound was dissolved in acetonitrile (LCMS pure) to prepare standard samples with the following concentration gradient: 1000 μg / mL, 500 μg / mL, 250 μg / mL, 125 μg / mL, 62.5 μg / mL, and 31.25 μg / mL.

[1148] Preparation of test samples in water:

[1149] Weigh approximately 1.0 mg of the analyte powder and add it to 0.3 mL of ultrapure water (pH ~6). Shake thoroughly at room temperature overnight, centrifuge, collect the supernatant, and dilute it 10 times with acetonitrile. Mix thoroughly and then inject for analysis.

[1150] Preparation of the test sample in dilute hydrochloric acid:

[1151] Take 153.8 μL of 6M HCl, add 20 mL of water, and mix well to prepare dilute hydrochloric acid solution A (pH ~ 1.5). Weigh approximately 1.0 mg of the analyte powder, add 0.3 mL of dilute hydrochloric acid solution A, shake thoroughly at room temperature for 1 h, centrifuge, collect the supernatant, and dilute 10 times with acetonitrile. Mix thoroughly and then inject for analysis.

[1152] Analysis method:

[1153] Standard samples and test samples were analyzed using a Shimadzu LCMS-2020 chromatographic column: Skim-psck GIST 5μm C182.1*50nm; mobile phase: A: water, B: methanol; flow rate: 0.3mL / min. The gradient of B was: 0min: 10%; 0-1.0min: 10%; 1.0-2.5min: 95%; 3.0-4.0min: 95%; 4.0-4.1min: 10%; 4.1-6.0min: 10%.

[1154] Data processing:

[1155] A standard curve is created by analyzing the concentration / peak area relationship of the standard sample, and this standard curve is used to calibrate the concentration of the sample to be tested.

[1156] Compound solubility = concentration of the sample to be tested × 10

[1157] The solubility of the compounds is shown in the table below:

[1158] 6 368μg / mL >3070μg / mL 7 680μg / mL >3770μg / mL 54 886μg / mL >3730μg / mL 75 120μg / mL >3500μg / mL 86 688μg / mL >3830μg / mL 97 180μg / mL >4330μg / mL

[1159] The results above show that the compound of the present invention has good solubility in water, and even better solubility in dilute hydrochloric acid that simulates gastric acid.

[1160] Bioactivity testing examples:

[1161] Biological Test Example 1: Kinase Activity Inhibition Experiment

[1162] The inhibitory rates of the test compounds on JAK1, JAK2, JAK3, TYK2, CDK7, CDK9, EGFR (T790M), and LRRK2 kinases were determined. Compounds were tested at concentrations of 10 nM and 100 nM, with replicates, or starting at 10 μM, with 3-fold dilutions and 10 replicates.

[1163] The inhibitory effects of the compounds on the activity of JAK1, JAK2, JAK3, CDK7, and CDK9 kinases were detected using the Caliper mobility shift assay. 250 nL of the compound at a final concentration of 100x was transferred to a 384-well plate using an Echo 550 dispenser. A kinase solution at a final concentration of 2.5x was prepared using 1× kinase buffer. 10 μL of the 2.5x final concentration kinase solution was added to the compound wells and the positive control wells; 10 μL of 1× kinase buffer was added to the negative control wells. After centrifugation at 1000 rpm for 30 seconds, the mixture was incubated at room temperature for 10 minutes. A mixture of ATP and kinase substrate at a final concentration of 5 / 3x was prepared using 1× kinase buffer, and 15 μL of this mixture was added to initiate the reaction. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, vortex to mix, and incubate at room temperature for the appropriate time. Add 30 μL of stop assay solution to terminate the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and vortex to mix. Read the conversion rate using a Caliper EZ Reader. The conversion rate of inhibition (%) is calculated as follows: (Mean conversion rate of positive control % - Sample conversion rate % / (Mean conversion rate of positive control % - Mean conversion rate of negative control %). Where: negative control wells represent the conversion rate readings of the kinase buffer background wells; positive control wells represent the conversion rate readings of the wells without compound inhibition. Using the logarithm of concentration as the x-axis and the percentage inhibition rate as the y-axis, a dose-response curve was fitted using the log(inhibitor) vs. response-variable slope function in GraphPad Prism5 to obtain the IC50 value of each compound on the enzyme activity. The calculation formula is: y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - x) × hillslope)), where x is the logarithm of the inhibitor concentration and y is the percentage inhibition rate.

[1164] Table 1 below provides the inhibition rates of some compounds on the activities of certain kinases at 100 nM:

[1165] (Intervals: A > 80%; B: 40-79%; C: 25-39%)

[1166]

[1167]

[1168]

[1169] Table 2 below provides the inhibition rates of some compounds on the activity of certain kinases at 10 nM:

[1170] (Intervals: A > 80%; B: 40-79%; C: 25-39%)

[1171]

[1172]

[1173]

[1174] Table 3 below provides the IC50 values ​​of some compounds in certain kinase activity assays. 50 Interval:

[1175] (IC 50 Intervals: A: <0.05 μM; B: 0.05-0.2 μM; C: 0.2-1 μM

[1176]

[1177]

[1178] Biological Testing Example 2: LRRK2 Kinase Activity Inhibition Experiment

[1179] The inhibitory effect of the compound on LRRK2 kinase activity was detected using the ADP-Glo ​​method. The compound dilution was transferred to a 384-well plate (784075, Greiner), the plate was sealed, and centrifuged at 1000g for 1 minute. A 2-fold final concentration of kinase solution was prepared using 1× kinase buffer, and 2.5 μL of this solution was added. The plate was centrifuged at 1000g for 30 seconds and incubated at room temperature for 10 minutes. A 2-fold final concentration mixture of ATP and kinase substrate was prepared using 1× kinase buffer, and 2.5 μL of this mixture was added to initiate the reaction. The plate was centrifuged at 1000g for 30 seconds, the plate was sealed, and incubated at room temperature for 2 hours. 4 μL of ADP-Glo ​​reagent was added, and the plate was incubated at room temperature for 40 minutes; then 8 μL of kinase assay reagent was added, and the plate was incubated at room temperature for 40 minutes. The luminescence signal was detected using an Envision 2104 microplate reader. Conversion inhibition rate % = 100 - (compound signal value - positive control signal value) / (blank control signal value - positive control signal value) × 100

[1180] Calculate IC50 and plot the dose-response curve of the compound using GraphPad 6.0: y=Bottom+(Top-Bottom) / (1+10^((logic50-x)ⅹhillslope)), where x: logarithm of inhibitor concentration; y: % inhibition rate.

[1181] Table 4 below provides the IC50 values ​​of some compounds in the LRRK2 kinase activity assay.50 Interval:

[1182] (IC 50 Intervals: A: <0.1 μM; B: 0.1-0.5 μM; C: 0.5-1 μM

[1183] 7 A 86 A 87 A 91 A 92 A 93 A 95 A 100 B 102 A 103 B 104 A 105 A 108 C 109 B 116 A

[1184] Biological Testing Example 3: EGFR Kinase Activity Inhibition Experiment

[1185] The inhibitory effect of the compounds on EGFR kinase activity was detected using the TR-FRET method. The compound dilutions were transferred to 384-well plates (784075, Greiner), the plates were sealed, and centrifuged at 1000g for 1 minute. 2×EGFR wt was prepared in 1× kinase buffer, and 5 μL of 2×EGFR wt was added to each 384-well plate. The plates were centrifuged at 1000g for 30 seconds and incubated at room temperature for 10 minutes. A mixture of 2×TK-substrate-biotin (2 μM) and ATP was prepared in 1× kinase buffer. 5 μL of the 2×TK-substrate-biotin and ATP mixture was added to initiate the reaction. The plates were centrifuged at 1000g for 30 seconds, the plates were sealed, and incubated at room temperature for 40 minutes. Prepare 4×Sa-XL 665 in HTRF detection buffer. Add 5 μL of Sa-XL 665 and 5 μL of TK-antibody-Cryptate to the well plate. Centrifuge the well plate at 1000g for 30 seconds and incubate at room temperature for 1 hour. Detect fluorescence signal values ​​at 615 nm (Cryptate) and 665 nm (XL665) using an Envision 2104 microplate reader. Calculate the inhibition rate % = 100 - (compound signal value - positive control signal value) / (blank control signal value - positive control signal value) × 100. Calculate the IC50 using GraphPad 8.0 and plot the dose-response curve of the compound: y = Bottom + (Top - Bottom) / (1 + 10^((logic50 - x) × hillslope)), where x: logarithm of inhibitor concentration; y: % inhibition rate.

[1186] Table 5 below provides the IC50 values ​​of some compounds in EGFR kinase activity assays. 50 Interval:

[1187] IC 50 Interval: A<0.05μM; B:0.05-1μM; C:1-5μM):

[1188] 54 A 56 A

[1189] Biological Testing Example 4:

[1190] CDK9 cell viability test

[1191] The cell lines used in the experiment were: MV-4-11, cultured in IMDM medium containing 10% fetal bovine serum (containing 100 U / mL penicillin and 0.1 g / L streptomycin); HCC1187, cultured in RPMI-1640 medium containing 10% fetal bovine serum (containing 100 U / mL penicillin and 0.1 g / L streptomycin); Mia Paca-2, cultured in DMEM medium containing 10% fetal bovine serum and 2.5% horse serum (containing 100 U / mL penicillin and 0.1 g / L streptomycin); and A375, cultured in RPMI-1640 medium containing 10% fetal bovine serum (containing 100 U / mL penicillin and 0.1 g / L streptomycin). All cells were cultured in a saturated humidity incubator at 37°C and 5% CO2.

[1192] MV-4-11 cells, HCC1187 cells, Mia Paca-2 cells, and A375 cells were trypsinized, resuspended, counted, and diluted to a specific cell density with complete culture medium. 100 μL of each cell was seeded into a 96-well plate, using complete culture medium as a background control. The plates were incubated overnight at 37°C with 5% CO2. The compound was diluted 200 times with DMSO. 3 μL of the DMSO stock solution of the compound was added to 197 μL of complete culture medium, and 50 μL of the diluted compound was added to each well. The plates were incubated at 37°C with 5% CO2 for 72 hours. After 72 hours, the plates were brought to room temperature to equilibrate, and 40 μL of CellTiter-1 was added to each well. Reagents were mixed with a shaker for 2 minutes to lyse cells, and incubated at room temperature for 60 minutes to stabilize the chemiluminescence signal. The chemiluminescence was read using a PE EnVision microplate reader. The cell growth inhibition rate Inh% was calculated as (DMSO wells - compound treatment wells) / (DMSO wells - background wells) × 100, and the IC50 value of cell growth was obtained by fitting the data with GraphPad Prism 5.

[1193] Table 6 below provides the IC50 values ​​of some compounds in cell viability assays. 50 Interval:

[1194] (IC 50 Intervals: A: <0.1 μM; B: 0.1-1 μM; C: 1-5 μM), NT not measured.

[1195]

[1196] Biological Testing Example 5:

[1197] JAKs cell viability test

[1198] Detection of pSTAT6 in JAK1_IL-4-induced THP1 cells

[1199] THP1 cells were collected by centrifugation, resuspended in 1×HBSS, counted, and diluted to a specific cell density. They were seeded in 384-well plates and cultured at 37°C with 5% CO2. Compound (DMSO, final volume 0.3%) was added to THP1 cells (10 doses, two replicates), and the cells were cultured at 37°C with 5% CO2. hIL-4 was added to stimulate the cells, and the cells were cultured at 37°C with 5% CO2. Lysis buffer was added, and the cells were incubated at room temperature. Following the instructions of the AlphaLISASureFire Ultra p-STAT6 assay kit, the lysis buffer was transferred to the pSTAT6 detection system. The ALPHA signal was read using a PEEnvision microplate reader, and the inhibition rate Inh% was calculated as ((DMSO - sample) / (DMSO - background)) × 100, IC50. 50 The Graphpad Prism nonlinear regression equation was used to obtain y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - x) × hillslope)), where x is the compound concentration and y is the inhibition rate. JAK2_pSTAT5 was detected in IL-3-induced BAF3 cells following the same procedure, and JAK3_pSTAT5 was detected in IL-2-induced CTLL-2 cells (serum-free) following the same procedure.

[1200] Table 7 below provides the IC50 values ​​of some compounds in cell activity assays. 50 Interval:

[1201] (IC 50 Intervals: A: <0.05 μM; B: 0.05-0.5 μM; C: 0.5-5 μM), NT not measured.

[1202] 2 A NT NT 16 B NT 26 A C C 27 A B A 28 A B A 54 B 55 B

[1203] Biological Testing Example 6:

[1204] Detection of HEK293T overexpression of full-length LRRK2 (G2019S) or wild-type LRRK2 phosphorylation of S935

[1205] HEK293T cells were seeded in 6-well plates and cultured overnight. The next day, pcDNA5-FRT / TO-FLAG LRRK2 (G2019S, full-length) or pCMV-flag-WT LRRK2 (full-length) plasmids were transiently transfected using Superfect transfection reagent and cultured at 37°C and 5% CO2 for 20-24 hours. The following day, cells were collected and resuspended at a density of 0.48 × 10^6 cells / mL, and seeded in 50 μL per well of 384-well plates. Tecan was used to add the compound or DMSO (0.5% v / v). The plates were cultured at 37°C and 5% CO2 for 1.5 hours. After 1.5 hours, the supernatant was discarded, and cells were fixed with 50 μL of 8% PFA per well and incubated at room temperature for 1 hour. The plates were washed three times with an EL406 washer, and 115 μL of PBST was added to each well. The plates were then blotted dry. Cells were blocked with 50 μL of Licor Odyssey blocking buffer (0.1% Tween 20) per well and incubated at room temperature for 1.5 hours. The blocking buffer was discarded and the culture plate was dried. 20 μL of primary antibody (1:1000 (pS935) primary antibody, diluted with Licor Odyssey buffer (0.1% Tween 20)) was added to each well and incubated overnight at 4°C. The next day, the primary antibody was discarded and the cells were washed five times with PBST. 20 μL of secondary antibody (1:500 diluted with Licor Odyssey buffer (0.1% Tween 20), 1:2000 for DNA staining) was added to each well and incubated at room temperature for 1 hour. The secondary antibody was discarded and the cells were washed three times with PBST. Cumulative intensity was measured using a Licor Odyssey imager scanner, and the data were analyzed.

[1206] Table 8 below provides the IC50 values ​​of some compounds in LRRK2 (G2019S) or wild-type LRRK2 cell viability assays. 50 Interval:

[1207] (IC 50 Intervals: A: <0.5 μM; B: 0.5-1 μM; C: 1-5 μM

[1208] 2 A NT 6 A A 28 A NT 73 A A 82 A A 83 A A 84 C NT

[1209] Biological Testing Example 7:

[1210] Detection of endogenously phosphorylated LRRK2 (S935) in A549 cells

[1211] A549 cells were resuspended at a density of 1×10^6 cells / mL in serum-free 1640 medium, and 1 mL was seeded per well in a 6-well plate. The plates were incubated at 37°C and 5% CO2 for 6–8 hours. 1 μL of DMSO stock solution or 0.1% DMSO (v / v) was added, mixed, and incubated at 37°C and 5% CO2 for 15 hours. Cells were collected, and each sample was lysed with 50 μL of RIPA III lysis buffer on ice for 15 minutes. The cells were then centrifuged at 13,000 rpm for 30 minutes at 4°C. The supernatant was collected, and the cell lysis concentration was determined by BCA analysis. All sample concentrations were normalized. 5× loading buffer was added, and the plates were incubated at 95°C for 10 minutes. Western blotting was performed to detect the content of endogenous LRRK2 phosphorylated S935. The antibody for phosphorylated LRRK2 (S935) was Abcam#133450. Image J statistical analysis was performed on the phosphorylated LRRK2 (S935) signal intensity, and beta-actin was used to normalize the phosphorylated LRRK2 (S935) signal in the sample.

[1212] Table 9 below provides the inhibition rates of some compounds on LRRK2 (S935) activity in A549 cells at a concentration of 2 μM:

[1213] (Intervals: A: >80%; B: 40-79%; C: 25-39%)

[1214]

[1215]

[1216] Table 10 below provides the inhibition rates of some compounds on LRRK2 (S935) activity in A549 cells at a concentration of 1 μM:

[1217] (Intervals: A: >80%; B: 40-79%; C: 25-39%)

[1218] 94 A 96 A 100 B 101 B 102 A

[1219] Table 11 below provides the IC50 inhibitory activity (IC50) of some compounds on LRRK2 (S935) activity in A549 cells. 50 Interval:

[1220] (IC 50 Intervals: A: <0.1 μM; B: 0.1-0.5 μM; C: 0.5-5 μM

[1221] 91 A 93 B 103 A

Claims

1. A compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: (I) in, Z indicates the absence of a covalent bond or -OCH2CH2-; L indicates the absence of (covalent bond), -O-, -NH-, or -N(C) 1~4 alkyl)-; A is C, which is optionally substituted with one or two substituents selected from the following. 6~14 Aryl, 5-12 heteroaryl, C 1~10 Alkyl, C 3~8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the substituents are selected from: deuterium, C 1~4 Alkyl, C 1~10 Alkoxy, C 3~6 Cycloalkyl, 3-8 membered heterocyclic groups, C 1~4 Alkyl phosphoryl group, C 1~4 alkylsulfonyl, aminosulfonyl, C 1~4 Alkylaminosulfonyl, cyano C 3~6 cycloalkyl, C 2~4 alkenylformyl, C 2~4 alkenylformamide, cyanoC 1~4 Alkyl carbamoyl, cyano C 1~4 Alkyl, C 1~4 alkylformyl-3~8-membered heterocyclic group, C 3~6 Cycloalkylformyl, 3-8 membered heterocyclic sulfonyl, C 1~4 Alkylsulfonyl-3~8-membered heterocyclic group, amino C 3~6 Cycloalkylformamide, C 1~4 Alkylphosphorylamino, C 1~4 Alkylsulfonamide, cyano, hydroxyl, oxo, mercapto, amino, C 2~4 Alkenes and halogens; R1 is hydrogen, or C. 1~4 Alkyl, C 3~6 cycloalkyl, C 1~4 Alkyl-CO-, -CHO or C 1-4 alkylsulfonyl; R2 is independently selected from hydrogen, C 1~3 Alkyl, trifluoromethyl, C 1~3 Alkyl groups, cyano groups, and halogens; n is 1 or 2; Ra is selected from hydrogen, amino, trifluoromethyl, halogen, cyano, C 1~3 Alkyl, acetyl, C 1~3 Alkyl phosphoryl and C 1~3 alkylsulfonyl; Rb is selected from hydrogen, amino, and C. 1~3 Alkylamino.

2. The compound of formula (I) according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the structure shown in formula (II): (II) in, L, A, R1, R2, Ra, Rb, and n have the definitions as described in claim 1.

3. The compound of formula (I) according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the structure shown in formula (III): (III) in, L, A, R1, R2, Ra, Rb, and n have the definitions as described in claim 1.

4. Compounds of formula (IV) or their stereoisomers, tautomers, or pharmaceutically acceptable salts: (IV) in, L, A, R1, R2, and n have the definitions as described in claim 1; X and Y are each independently selected from C and N; Z indicates that there is no covalent bond or -OCH2CH2-.

5. A compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: (I) in, Z indicates the absence of a covalent bond or -OCH2CH2-; L indicates the absence of (covalent bond), -O-, -NH-, or -N(C) 1~4 alkyl)-; A is selected from the following structure: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； R1 is hydrogen, or C. 1~4 Alkyl, C 3~6 cycloalkyl, C 1~4 Alkyl-CO-, -CHO or C 1-4 alkylsulfonyl; R2 is independently selected from hydrogen, C 1~3 Alkyl, trifluoromethyl, C 1~3 Alkyl groups, cyano groups, and halogens; n is 1 or 2; Ra is selected from hydrogen, amino, trifluoromethyl, halogen, cyano, C 1~3 Alkyl, acetyl, C 1~3 Alkyl phosphoryl and C 1~3 alkylsulfonyl; Rb is selected from hydrogen, amino, and C. 1~3 Alkylamino.

6. A compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein the compound is selected from: 。 7. A pharmaceutical composition comprising the compound of any one of claims 1 to 6 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

8. Use of the compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in the preparation of a medicament for use as a protein kinase inhibitor, wherein the protein kinase is selected from LRRK2, JAK1, JAK2, JAK3, EGFR, and CDK9.

9. The use of the compound of any one of claims 1 to 6, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing protein kinase-related diseases, wherein the protein kinase is selected from LRRK2, JAK1, JAK2, JAK3, EGFR, and CDK9, and the diseases are selected from Parkinson's disease, asthma, dermatitis, non-small cell lung cancer, acute myeloid leukemia (AML), liver cancer, and glioblastoma.

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