A compound as a non-covalent BTK kinase inhibitor and its biological use

Abstract

The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to various types of substituted (7H-pyrrolo[2,3-d]pyrimidin-5-yl)[4-(phenyloxy)phenyl]methanone derivatives shown in formula I as compounds of non-covalent BTK kinase inhibitors or their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, pharmaceutical compositions containing these compounds, and applications of these compounds or compositions in drug preparation. The activity data of the compounds of the present invention show that they have obvious BTK kinase activity inhibition, and can be used to prepare drugs for treating B cell malignant tumor diseases and autoimmune diseases mediated by BTK kinase, and thus have clinical application value.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and relates to a class of pyrrolopyrimidine compounds and a preparation method thereof, a pharmaceutical composition and use thereof in preparing a drug for treating B-cell malignant tumor diseases and autoimmune diseases mediated by BTK kinase. Background Art

[0002] BTK kinase is a non-receptor tyrosine kinase belonging to the TEC kinase family, one of the largest kinase families in mammals. It is a membrane-bound protein present in all hematopoietic cells except T cells and natural killer (NK) cells. BTK is composed of 659 amino acids and mainly contains five domains, namely the N-terminal pleckstrin homology (PH) domain, the proline-rich Tec homology (TH) domain, the Src homology domain 3 (SH3), SH2 and the C-terminal part containing the catalytic domain.

[0003] In cells, the full activation of BTK kinase is a complex multi-step process. After the B cell receptor (BCR) is stimulated by external antigens and binds to them, Src family kinases (such as Lyn) phosphorylate the activation motif (ITAM) of CD79A and CD79B immunoreceptor tyrosine, thereby creating a docking site for spleen tyrosine kinase (SYK). At the same time, LYN phosphorylates the tyrosine residues in the cytoplasmic tail of the BCR co-receptor CD19. Tyr55l phosphorylation and Tyr223 autophosphorylation mediated by kinases such as Lyn and Syk stabilize the active conformation of BTK and finally fully activate BTK kinase. Subsequently, BTK activates phospholipase C-γ2 (phospholipase C-γ2, PLCγ2), activates nuclear factor of T cells (NFAT), regulates intracellular calcium ion levels, and activates mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways, regulating the survival, activation, proliferation, differentiation and maturation of B cells.

[0004] Since BTK kinase plays a key regulatory role in the BCR signaling pathway, targeting BTK for the treatment of various B-cell malignancies is a hot topic. Currently, six BTK inhibitors have been approved by the FDA for marketing, namely Ibrutinib, Acalabrutinib, Zanubrutinib, Zanubrutinib, Orelabrutinib and Pirtobrutinib, most of which are covalent inhibitors. In addition, several inhibitor molecules have shown effective anti-tumor effects in corresponding animal models and subsequent clinical studies. Although mainstream covalent inhibitors have substantial therapeutic effects on a variety of B-cell malignancies, these drugs often seem helpless when faced with primary or acquired drug resistance, a fact that also limits their application in clinical treatment. Therefore, the development of reversible inhibitors that resist drug resistance is currently a key focus of BTK kinase research. Summary of the invention

[0005] The main technical problem solved by the present invention is to provide a class of compounds with novel structures that can effectively inhibit mutant BTK kinases and can be used for the treatment of B cell-derived malignant tumors and autoimmune diseases.

[0006] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0007] In the first aspect of the present invention, there is provided a compound represented by formula (I),

[0008]

[0009] or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:

[0010] X1 is O, NH or S;

[0011] X2 is -O-, -S(=O)-, -S(=O)O-, -OS(=O)-, -C(=O)-, -C(=O)O-, -OC(=O)- or unsubstituted;

[0012] X3 is CH, N or unsubstituted;

[0013] X4 for O, S, CHR d or NR e ;

[0014] X5 is O, NH, S, CH2, CHR d or NR e ;

[0015] R a , R bare independently selected from: hydrogen, halogen, nitrile, nitro, hydroxyl, carboxyl, substituted or unsubstituted C 1-6 acyl, substituted or unsubstituted amino, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy may be mono-, di- or poly-substituted;

[0016] R c may be the same or different, and are each independently -(CH2) f NR 1 R 2 , R 1 -S(=O) g -, R 1 -S(=O) g O-,

[0017] R 1 -OS(=O) g -, R 1 -C(=O)-,R 1 -C(=O)O(CH2) f -, R 1 -(CH2) f OC(=O)-,R 1 -(CH2) f N(R 1 )C(=O)-,

[0018] R 1 -(CH2) f C(=O)N(R 1 )-, R 1 -(CH2) f OC(=O)N(R 1 )-, ether alkyl, hydroxy-substituted alkyl, hydrogen, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxy, alkyl, haloalkyl, heteroalkyl, alkoxy, alkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloheterocyclyl, amino, nitro, carboxyl, cyano, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, heteroarylalkyl, aminosulfonyl, carbamoyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heterocyclylamino, heterocyclylalkylamino, aryloxy, heteroaryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, heterocyclyloxy or heterocyclylalkoxy;

[0019] R d -(CH2) f NR 1 R 2 , R 1 -S(=O) g -, R 1-S(=O) g O-, R 1 -OS(=O) g -, R 1 -C(=O)-,

[0020] R 1 -C(=O)O(CH2) f -, R 1 -(CH2) f OC(=O)-,R 1 -(CH2) f N(H)C(=O)-,R 1 -(CH2) f C(=O)N(R 1 )-,

[0021] R 1 -(CH2) f OC(=O)N(R 1 )-, ether alkyl, hydroxy-substituted alkyl, hydrogen, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxy, alkyl, haloalkyl, heteroalkyl, alkoxy, alkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloheterocyclyl, amino, nitro, carboxyl, cyano, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, heteroarylalkyl, aminosulfonyl, carbamoyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heterocyclylamino, heterocyclylalkylamino, aryloxy, heteroaryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, heterocyclyloxy or heterocyclylalkoxy;

[0022] R e -(CH2) f NR 1 R 2 , R 1 -S(=O) g -, R 1 -S(=O) g O-, R 1 -OS(=O) g -, R 1 -C(=O)-,

[0023] R 1 -C(=O)O(CH2) f -, R 1 -(CH2) f OC(=O)-,R 1 -(CH2) f N(H)C(=O)-,R 1 -(CH2) f C(=O)N(R 1)-,

[0024] R 1 -(CH2) f OC(=O)N(R 1 )-, ether alkyl, hydroxy-substituted alkyl, hydrogen, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxy, alkyl, haloalkyl, heteroalkyl, alkoxy, alkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloheterocyclyl, amino, nitro, carboxyl, cyano, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, heteroarylalkyl, aminosulfonyl, carbamoyl, arylamino, heteroarylamino, arylalkylamino, heteroarylalkylamino, heterocyclylamino, heterocyclylalkylamino, aryloxy, heteroaryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, heterocyclyloxy or heterocyclylalkoxy;

[0025] Each R 1 and R 2 is independently hydrogen, alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, haloalkyl, heterocyclyl, aryl or heteroaryl;

[0026] Each g is independently 0, 1 or 2;

[0027] Each n, m, p, f is independently 0, 1, 2, 3, 4 or 5;

[0028] When m=2, and two R c are attached to the same carbon atom, then the two R c The carbon atoms to which it is attached can form a 3-8 membered heterocyclic ring.

[0029] In certain preferred embodiments, disclosed are compounds of formula (I), or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, wherein:

[0030] X1 is O, NH or S;

[0031] X2 is -O-, -S(=O)-, -S(=O)O-, -OS(=O)-, -C(=O)-, -C(=O)O-, -OC(=O)- or unsubstituted;

[0032] R a , R b independently selected from: hydrogen, halogen;

[0033] in, The structural units are selected from the following substructures:

[0034]

[0035] in,

[0036] R 3 may be the same or different and are each independently selected from substituted or unsubstituted hydroxy, methyl, ethyl, propyl, butyl, isopropyl, methoxy, ethoxy, amino, nitro, carboxyl, cyano or phenyl;

[0037] or two R on the same atom or adjacent atoms 3 The groups may together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;

[0038] R 4 is selected from hydrogen, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, methoxy, ethoxy, amino, nitro, carboxyl, cyano or phenyl;

[0039] q is 0, 1, 2, 3, 4 or 5;

[0040] The halogen is F, Cl, or Br;

[0041] The substitution refers to substitution by one or more of the following substituents: 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, C 1-5 alkoxy, halogen, nitro, cyano, hydroxy, amino, carboxyl and oxo.

[0042] In certain more preferred embodiments, the compound of the present invention is any of the following compounds or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof:

[0043]

[0044]

[0045]

[0046] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, or an optional pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combination thereof. In some embodiments, these compounds are protein kinase inhibitors, and in other embodiments, these compounds are BTK kinase inhibitors.

[0047] In another aspect, the present invention provides a method for preparing a compound as shown in formula C, wherein the reaction formula of the preparation method is as follows:

[0048]

[0049] Among them, X1, X2, X3, X4, X5, R c , m, n and p are as described in claim 1;

[0050] The preparation method specifically comprises the following steps:

[0051] First, compound A is used as a raw material, and a halogen-metal exchange reaction occurs with n-butyl lithium to form an organic lithium compound, which then undergoes a nucleophilic addition reaction with 4-phenoxybenzoate to obtain compound B; then, various weak bases are used as acid-binding agents, and compound B undergoes a nucleophilic substitution reaction with a heterocyclic substituted chain structure to obtain the target compound C.

[0052] Another aspect of the present invention provides the use of the compound of the present invention, or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug in the preparation of a protein kinase inhibitor; further, the kinase inhibitor is a BTK inhibitor

[0053] On the other hand, the present invention provides the use of the compound of the present invention or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs and pharmaceutical compositions comprising the compound of the present invention or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs in the preparation of drugs for treating any one or more of autoimmune diseases, inflammatory diseases, thromboembolic diseases, allergies, infectious diseases, proliferative diseases and cancers.

[0054] In a specific embodiment, the disease is selected from: arthritis, rheumatoid arthritis, urticaria, vitiligo, organ transplant rejection, ulcerative colitis, Crohn's disease, dermatitis, asthma, Sjögren's syndrome, systemic lupus erythematosus, multiple sclerosis, idiopathic thrombocytopenic purpura, rash, anti-neutrophil cytoplasmic antibody vasculitis, pus, pus, chronic obstructive pulmonary disease, psoriasis; breast cancer, mantle cell lymphoma, ovarian cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, hepatocellular carcinoma, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, Bladder cancer, bile duct cancer, pancreatic cancer, lymphoma, hairy cell cancer, nasopharyngeal cancer, colorectal cancer, rectal cancer, brain and central nervous system cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, lung cancer, small cell lung cancer, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, thyroid cancer, follicular carcinoma, Hodgkin's leukemia, bronchial cancer, uterine corpus cancer, cervical cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphoid leukemia, myeloid leukemia, non-Hodgkin's lymphoma, primary macroglobulinemia.

[0055] On the other hand, the present invention provides the use of the compound of the present invention or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs and pharmaceutical compositions comprising the compound of the present invention or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs in the preparation of drugs for treating diseases that cause overexpression of BTK kinase.

[0056] On the other hand, the present invention provides the use of the compound of the present invention or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs and a pharmaceutical composition comprising the compound of the present invention or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs in the preparation of drugs for treating diseases caused by overexpression of BTK kinase.

[0057] definition

[0058] Definitions of specific functional groups and chemical terms are described in more detail below.

[0059] The term "pharmaceutically acceptable" as used herein refers to any substance that does not interfere with the effectiveness of the biological activity of the active ingredient and is non-toxic to the host to which it is administered.

[0060] The administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0061] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or solubilizers, for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffer. Solid dosage forms such as tablets, pills, capsules, pills and granules may be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions may be delayed in a certain part of the digestive tract. Examples of embedding components that may be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0062] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances. In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylate and agar or mixtures of these substances.

[0063] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0064] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0065] The compounds of the present invention can also be used in injection preparations. Wherein, the injection is selected from liquid injection (water injection), sterile powder for injection (powder injection) or tablet for injection (referring to molded tablets or machine-pressed tablets made by aseptic operation of the drug, which are dissolved in water for injection for subcutaneous or intramuscular injection). Wherein, in addition to the above-mentioned compounds, the powder for injection also contains at least an excipient. The excipient described in the present invention is a component intentionally added to the drug, which should not have pharmacological properties in the amount used, but the excipient can help the processing, dissolution or dissolution of the drug, through targeted administration routes or contribute to stability.

[0066] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the general formula compounds of the present invention, or as the specific examples, subclasses, and classes of compounds included in the present invention. It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted and unsubstituted". In general, the term "optionally", whether or not preceded by the term "substituted", means that one or more hydrogen atoms in the given structure are replaced by a specific substituent. Unless otherwise indicated, an optional substituted group may have a substituent substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted with one or more substituents selected from the specific group, the substituents may be substituted at each position the same or different. The substituents may be, but are not limited to, hydroxy, hydroxyalkyl, amino, halogen, cyano, oxo (=O), aryl, heteroaryl, alkoxy, alkyl, haloalkyl, aminoalkyl, alkylamino, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy or arylalkyl, etc.

[0067] The term "alkyl" used in the present invention includes saturated straight or branched monovalent hydrocarbon groups of 1 to 20 carbon atoms, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in the present invention. In some embodiments, the alkyl group contains 1 to 10 carbon atoms, in other embodiments, the alkyl group contains 1 to 8 carbon atoms, in other embodiments, the alkyl group contains 1 to 6 carbon atoms, and in other embodiments, the alkyl group contains 1 to 4 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl, n-heptyl, and the like. The term "alkyl" and its prefix "alkane" as used herein include both straight and branched saturated carbon chains.

[0068] The term "hydroxy-substituted alkyl" as used herein means that an alkyl group is substituted by one or more hydroxy groups, wherein alkyl has the meaning described herein, such examples include, but are not limited to, hydroxymethyl, (R)-hydroxyethyl, (S)-hydroxyethyl, (R)-hydroxypropyl, (S)-hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-2propyl, 3-hydroxy 3-pentyl and the like.

[0069] The term "ether alkyl" used in the present invention means that the alkyl group contains one or more O or S and is connected to the rest of the molecule by a carbon atom, wherein the alkyl group has the meaning described in the present invention, and such examples include, but are not limited to, methoxymethyl, ethoxyethyl, propoxypropyl, ethoxyethoxyethyl and the like.

[0070] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms, wherein at least one position is unsaturated, i.e., one CC is sp 2 Double bond, wherein the alkenyl group can be independently optionally substituted with one or more substituents described in the present invention, including groups with "anti", "normal" or "E" "Z" orientations, specific examples of which include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), propenyl (CH3CH=CH-) and the like.

[0071] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, wherein at least one position is unsaturated, i.e., one CC is a sp triple bond, wherein the alkynyl group may be independently and optionally substituted by one or more substituents described herein, specific examples include, but are not limited to, ethynyl (-C≠CH), propargyl (-CH2C≠CH), and the like.

[0072] The term "alkoxy" includes optionally substituted alkyl groups, as defined herein, attached to an oxygen atom and linked to the remainder of the molecule via the oxygen atom, such examples include, but are not limited to, methoxy, ethoxy, propoxy, and the like.

[0073] The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are independently substituted by one or two alkyl groups, wherein the alkyl groups have the meanings as described in the present invention. In some embodiments, the alkylamino group is one or two C 1-6 In some other embodiments, the alkylamino group is C 1-3 Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, and the like.

[0074] The term "heteroalkyl" means that one or more atoms on the alkyl group can be independently optionally substituted by a heteroatom, and the alkyl group is as defined in the present invention and is connected to the rest of the molecule by a carbon atom. Some embodiments are that "heteroalkyl" is a branched or straight chain of 1-10 atoms (1-9 carbon atoms and 1-3 heteroatoms selected from N, O, S, P, where S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO2, SO, PO, PO2), such examples include, but are not limited to aminomethyl, methoxyethyl and the like.

[0075] The terms "heterocycle" or "heterocyclyl" are used interchangeably herein and refer to monocyclic, bicyclic, or tricyclic ring systems, wherein one or more atoms in the ring may be independently optionally substituted with heteroatoms, the ring may be fully saturated or contain one or more unsaturations, but is never aromatic, and has one or more points of attachment to other molecules. One or more hydrogen atoms in the ring may be independently optionally substituted with one or more substituents described herein. Some embodiments of the heterocycle or heterocyclyl group are 3-7 membered monocyclic rings (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, S, P, where S or P is optionally substituted with one or more oxygen atoms to give groups such as SO2, SO, PO, PO2, and when the ring is a three-membered ring, there is only one heteroatom), or 7-10 membered bicyclic rings (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, S, P, where S or P is optionally substituted with one or more oxygen atoms to give groups such as SO2, SO, PO, PO2). Heterocyclic groups can be carbonyl or heteroatom groups. "Heterocyclic groups" also include groups formed by the fusion of heterocyclic groups with saturated or partially unsaturated rings or heterocyclic rings. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thiidine, homopiperidinyl, glycidyl, azepanyl, oxetanyl, thiidine, oxetanyl, oxetanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3- Pyrrolinyl, dihydroindolinyl, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinolinyl and N-pyridylurea. Examples of heterocyclic groups also include 1,1-dioxothiomorpholinyl, and pyrimidinedione in which two carbon atoms are replaced by oxygen atoms. And the heterocyclic group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic group, mercapto, nitro, aryloxy, arylalkyl and the like.

[0076] The term "heterocyclyloxy" includes optionally substituted heterocyclyl groups, as defined herein, attached to an oxygen atom which is attached to the rest of the molecule, such examples include, but are not limited to, pyrrol-2-oxy, pyrrol-3-oxy, piperidine-2oxy, piperidine-3-oxy, piperazine-2-oxy, piperidine-4-oxy and the like.

[0077] The term "heterocyclylamino" means an amino group substituted with one or two heterocyclyl groups, wherein the nitrogen atom is attached to the rest of the molecule and the heterocyclyl group has the meaning as described herein, such examples include, but are not limited to, pyrrole-2-amino, pyrrole-3-amino, piperidine-2-amino, piperidine-3-amino, piperidine-4-amino, piperazine-2-amino, dipyrrole-2-amino and the like.

[0078] The term "heterocyclylalkyl" includes heterocyclyl substituted alkyl groups; the term "heterocyclylalkoxy" includes heterocyclyl substituted alkoxy groups in which the oxygen atom is attached to the rest of the molecule; the term "heterocyclylalkylamino" includes heterocyclyl substituted alkylamino groups in which the nitrogen atom is attached to the rest of the molecule; wherein heterocyclyl, alkyl, alkoxy and alkylamino groups have the meanings as described herein. Such examples include, but are not limited to, pyrrole-2-methyl, morpholine-4-methyl, pyrrole-2-methoxy, piperidine-2-ethoxy, piperazine-2-ethylamino, morpholine-4-propoxy, morpholine-4-ethylamino, and the like.

[0079] The term "heteroatom" means one or more of O, S, N, P and Si, including N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring in which the hydrogen is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NR (such as NR in N-substituted pyrrolidinyl).

[0080] The term "halogen" or the prefix "halo" refers to F, Cl, Br or I.

[0081] As used herein, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0082] The term "aryl" can be used alone or as a part of "aralkyl", "aralkyloxy" or "aryloxyalkyl" to refer to monocyclic, bicyclic and tricyclic carbon ring systems containing 6-14 ring members, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 ring members and has only one point of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring", such as phenyl, naphthyl and anthracene. And the aryl group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, arylalkyl and the like.

[0083] The term "arylalkyl" means an alkyl group substituted with one or more aryl groups, wherein the alkyl and aryl groups have the meanings described herein, and examples include, but are not limited to, benzyl, phenethyl, p-tolylethyl, phenylvinyl, and the like.

[0084] The term "aryloxy" includes optionally substituted aryl groups, as defined herein, attached to an oxygen atom and connected to the rest of the molecule by the oxygen atom, wherein the aryl group has the Chinese radicals described herein, such examples include, but are not limited to, p-tolyloxy, p-ethylphenoxy, and the like.

[0085] The term "arylamino" means an amino group substituted by one or two aryl groups, wherein aryl has the meaning described in the present invention, and such examples include, but are not limited to, phenylamino, diphenylamino, ditolylamino and the like.

[0086] The term "arylalkoxy" includes alkoxy groups substituted by one or more aryl groups, wherein aryl and alkoxy have the meanings described in the present invention and are connected to the rest of the molecule by an oxygen atom. Such examples include, but are not limited to, benzyloxy, p-tolueneethoxy, p-ethylphenylethoxy, etc.

[0087] The term "arylalkylamino" means an alkylamino group substituted by one or more aryl groups, wherein aryl and alkylamino have the meanings described herein and are connected to the rest of the molecule by a nitrogen atom, such examples include, but are not limited to, phenylmethylamino, diphenylethylamino, and the like.

[0088] The term "heteroaryl" can be used alone or as a part of "heteroarylalkyl" or "heteroarylalkoxy" to refer to monocyclic, bicyclic, and tricyclic ring systems containing 5-14 ring members, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein each ring system contains 3-7 ring members, and has only one point of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the term "aromatic heterocycle" or "heteroaromatic compound". And the heteroaryl group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, arylalkyl and the like.

[0089] In some other embodiments, the aromatic heterocycle includes the following monocyclic rings, but is not limited to these monocyclic rings: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl , 3-thienyl, pyrazolyl, (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3,-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic rings, but are by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl) and the like.

[0090] The term "heteroarylalkyl" means an alkyl group substituted by one or more heteroaryl groups, wherein the alkyl group and the heteroaryl group have the meanings as described herein, such examples include, but are not limited to, pyridine-2-ethyl, thiazole-2-methyl, imidazole-2-ethyl, pyrimidine-2-propyl and the like.

[0091] The term "heteroaryloxy" includes optionally substituted heteroaryl groups, as defined herein, attached to an oxygen atom and connected to the rest of the molecule via the oxygen atom, wherein the heteroaryl group has the meaning defined herein, such examples include, but are not limited to, pyridin-2-oxy, thiazole-2-oxy, imidazole-2-oxy, pyrimidine-2-oxy and the like.

[0092] The term "heteroarylamino" means an amino group substituted by one or two heteroaryl groups, wherein the heteroaryl group has the meaning as described herein, such examples include, but are not limited to, pyridine-2-amino, thiazole-2-amino, imidazole-2-amino, pyrimidine-2-amino and the like.

[0093] The term "heteroarylalkoxy" includes heteroarylalkyl groups containing an oxygen atom connected to the rest of the molecule through the oxygen atom, wherein heteroaryl and alkoxy groups have the meanings as described herein. Such examples include, but are not limited to, pyridyl-2-methoxy, pyridyl-4-ethoxy, thiazolyl-2-ethoxy, imidazole-3-propoxy, and the like.

[0094] The term "heteroarylalkylamino" means an alkylamino group substituted by one or more heteroaryl groups, wherein heteroaryl and alkylamino have the meanings as described herein, and are connected to the rest of the molecule by a nitrogen atom, such examples include, but are not limited to, pyridyl-2-methylamino, pyridyl-4-ethylamino, thiazolyl-2-ethylamino, imidazole-3-propylamino, and the like.

[0095] The term "aminosulfonyl" refers to a sulfonyl group substituted with an amino group, forming a sulfamoyl group (-SO2NH2).

[0096] The term "carbamoyl" refers to a formyl group substituted with an amino group, forming a carbamoyl group (-CONH2).

[0097] The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", refers to -COOH.

[0098] As described in the present invention, the substituent is connected to the central ring by a bond to form a ring system (as shown in a) to represent R c Any substitutable position on the ring can be substituted. For example, a represents W and any possible substitutable position on the ring can be replaced by R c replace.

[0099]

[0100] Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)); for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) are all within the scope of the present invention.

[0101] The term "prodrug" as used in the present invention refers to a compound that is converted in vivo to a compound of formula I. Such conversion is affected by the prodrug being hydrolyzed in the blood or being converted to the parent structure by enzymes in the blood or tissues. The prodrug compounds of the present invention may be esters. In the prior invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphates, such as these phosphate compounds obtained by phosphorylation of the hydroxyl group on the parent.

[0102] Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are included within the scope of the present invention. In addition, unless otherwise indicated, the structural formulas of the compounds described in the present invention include enriched isotopes of one or more different atoms.

[0103] "Metabolite" refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques known in the art. Such products can be obtained by administering a compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of a compound, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

[0104] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist as different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefix d, l or (+), (-) is used to name the sign of rotation of the plane polarized light of the compound, the prefix (-) or l means that the compound is levorotatory, and the prefix (+) or d means that the compound is dextrorotatory. The chemical structures of these stereoisomers are the same, but their stereostructures are different. Specific stereoisomers can be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

[0105] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. Such examples include, but are not limited to, proton tautomers (i.e., prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0106] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association formed by the solvent molecule being water.

[0107] The present invention provides a series of compounds capable of inhibiting BTK activity. Experiments show that the compounds have a significant inhibitory effect on BTK, providing a new solution for the treatment of diseases with BTK as a therapeutic target, such as malignant tumor diseases or autoimmune diseases, and can be used to prepare drugs for treating related diseases. At the same time, some compounds have a strong inhibitory effect on wild-type and mutant BTK kinases, with considerable cell activity and kinase activity, and can be used to prepare drugs for treating diseases caused by overexpression of BTK kinase, and have broad application prospects. DETAILED DESCRIPTION

[0108] The following examples are provided so as to provide those skilled in the art with a complete disclosure and description of how to perform, prepare and evaluate the methods and compounds claimed herein and are intended to merely illustrate the invention and not to limit the scope of the invention.

[0109] In the present invention, the structure of the compound is determined by mass spectrometry (MS) and / or nuclear magnetic resonance ( 1 H NMR) equipment. The chemical abbreviations have the following meanings: DMF: N,N-dimethylformamide; n-BuLi: n-butyllithium; THF: tetrahydrofuran; TEA: triethylamine; PE: petroleum ether; EA: ethyl acetate; DCM: dichloromethane; MeOH: methanol; TFA: trifluoroacetic acid; EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBT: 1-hydroxybenzotriazole

[0110] Synthesis method

[0111] The compounds of the present invention can be prepared according to conventional methods in the art, and using suitable reagents, raw materials and purification methods known to those skilled in the art. The preparation method of the compounds of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such a combination can be easily carried out by a technician in the field to which the present invention belongs.

[0112] Example 1 Preparation of [2-chloro-4-(phenyloxy)phenyl]{4-[(3-hydroxypropyl)amino]-7H-pyrrolo[2, 3-d]pyrimidin-5-yl}methanone (Compound 1)

[0113]

[0114] Step 1: Synthesis of Compound 1-3

[0115] Compound 1-1 (10.00 g, 53.03 mmol), 1-2 (5.99 g, 63.63 mmol), DMF (80 mL) were added to the reaction bottle, potassium carbonate (14.66 g, 106.05 mmol) was added during stirring, and the reaction was stirred at 90°C for 3 hours. TLC showed that the reaction was complete. The reaction system was poured into water, extracted twice with ethyl acetate, the ethyl acetate layers were combined, washed twice with water, washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA=20:1) to obtain 12 g of product 1-3 as a colorless transparent oily liquid, with a yield of 86.15%.

[0116] Step 2: Synthesis of Compound 1-5

[0117] Compound 1-4 (5.00 g, 21.51 mmol) was added to a three-necked reaction bottle, replaced with nitrogen, anhydrous tetrahydrofuran (20 mL) was added, the reaction solution was cooled to -78 ° C, n-BuLi tetrahydrofuran solution (17.90 mL, 2.4 M) was added dropwise to the reaction bottle, stirred for 1 hour, 1-3 (6.22 g, 23.66 mmol) tetrahydrofuran solution was added, and the reaction was continued at -78 ° C for 2 hours. TLC showed that the reaction was complete. The reaction solution was warmed to room temperature, saturated ammonium chloride solution was added to quench the reaction, ethyl acetate was added to extract twice, the ethyl acetate layer was combined, washed twice with water, washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE: EA = 5: 1) to obtain 5.00 g of white solid product 1-5, yield: 60.50%.

[0118] Step 3: Synthesis of compound 1

[0119] Compound 1-5 (150.00 mg, 0.39 mmol), compound 1-6 (43.99 mg, 0.59 mmol), triethylamine (79.01 mg, 0.78 mmol) and dichloromethane (3 mL) were added to the reaction bottle, stirred at room temperature overnight, and TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM: MeOH = 40: 1) and then freeze-dried to obtain 63.1 mg of white solid, which was product 1, with a yield of 38.22%. 1HNMR (300MHz, DMSO-d6) δ12.69(brs,1H),8.73(d,J=5.6Hz,1H),8.24(s,1H),7.61(s,1H),7.58(d,J=8.5Hz,1H),7.48(t,J=7.6H z,2H),7.26(t,J=7.9Hz,1H),7.19(d,J=6.6Hz,3H),7.03(d,J=8.2Hz,1H),4.62(s,1H),3.65–3.54(m,4H),1.80(p,J=6.5Hz,2H).

[0120] Example 2 Preparation of [2-chloro-4-(phenyloxy)phenyl](4-{[2-(tetrahydro-1H-pyrrol-1-yl)ethyl]amino 7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 2)

[0121]

[0122] Referring to the method of Example 1, intermediates 1-5 and 2-1 were used as raw materials to obtain a white solid, compound 2, with a yield of 51.73%. 1 HNMR(300MHz,DMSO-d6)δ8.81(t,J=5.4Hz,1H),8.24(s,1H),7.59(s,1H),7. 57(d,J=8.4Hz,1H),7.48(dd,J=8.5,7.3Hz,2H),7.25(t,J=7.4Hz,1H),7.22– 7.15(m,3H),7.03(dd,J=8.4,2.4Hz,1H),3.66(q,J=6.3Hz,2H),2.70(t,J=6 .5Hz,2H),2.53(d,J=2.6Hz,4H),1.74–1.61(m,4H).LC / MS: m / z=462.11[M+H] + .

[0123] Example 3 Preparation of 2-(5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino 1-Morpholinoethyl-1-one (Compound 3)

[0124]

[0125] Step 1: Synthesis of compound 3-2

[0126] Compound 1-5 (1.5 g, 3.90 mmol), 3-1 (586.13 mg, 7.81 mmol), anhydrous sodium carbonate (475.85 mg, 4.49 mmol) and anhydrous ethanol (30 mL) were added to the reaction bottle and refluxed at 70°C for 3 h. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, water was added, and the pH was adjusted to 5-6 with glacial acetic acid. Solid precipitated, which was filtered and dried to obtain 1.57 g of white solid, which was the product 3-2. The yield was 95.11%.1 HNMR(300MHz,DMSO-d6)δ12.78(brs,1H),8.94(t,J=5.6Hz,1H),8.26(s,1H),7.66(s,1H),7.59(d,J=8.5Hz,1H),7.4 9(dd,J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.23–7.17(m,3H),7.04(dd,J=8.5,2.4Hz,1H),4.27(d,J=5.6Hz,2H).

[0127] Step 2: Synthesis of compound 3

[0128] Compound 3-2 (100 mg, 0.24 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 90.68 mg, 0.47 mmol), 1-hydroxybenzotriazole (HOBT, 47.94 mmol, 0.36 mmol), triethylamine (47.87 mg, 0.47 mmol) and DMF (3 mL) were added to the reaction bottle, stirred at room temperature for 1 h, and then compound 3-3 (41.21 mg, 0.47 mmol) was added, and stirring was continued overnight. TLC showed that the reaction was complete. The reaction system was poured into water, extracted twice with ethyl acetate, the ethyl acetate layers were combined, washed twice with water, washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM: MeOH = 20: 1) to obtain 51.2 mg of white solid, which was compound 3, with a yield of 44.01%. 1HNMR (300MHz, DMSO-d6) δ12.73(brs,1H),9.08(t,J=4.9Hz,1H),8.25(s,1H),7.63(s,1H),7.58(d,J=8.5Hz,1H),7.49(t,J=7.9Hz,2H),7.26( t,J=7.4Hz,1H),7.23–7.16(m,3H),7.04(dd,J=8.4,2.4Hz,1H),4.46(d,J=4.9Hz,2H),3.66–3.57(m,4H),3.51(s,4H).LC / MS: m / z=492.09[M+H] + .

[0129] Example 4 Preparation of 3-(5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino 1-Morpholinopropan-1-one (Compound 4)

[0130]

[0131] Step 1: Synthesis of compound 4-2

[0132] Compound 1-5 (1.5 g, 3.90 mmol), 4-1 (695.66 mg, 7.81 mmol), anhydrous sodium carbonate (475.85 mg, 4.49 mmol) and anhydrous ethanol (30 mL) were added to the reaction bottle and refluxed at 70°C for 3 h. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure, water was added, and the pH was adjusted to 5-6 with glacial acetic acid. Solid precipitated, which was filtered and dried to obtain 1.68 g of white solid, which was the product 4-2. The yield was 98.51%. 1 H NMR (300MHz, DMSO-d6) δ12.66(s,1H),8.82(t,J=5.8Hz,1H),8.27(s,1H),7.62(s,1H),7.57(d,J=8.5Hz,1H),7.48(dd,J=8.4, 7.3Hz,2H),7.24(d,J=7.4Hz,1H),7.22–7.16(m,3H),7.02(dd,J=8.4,2.4Hz,1H),3.77(q,J=6.3Hz,2H),2.63(t,J=6.4Hz,2H).

[0133] Step 2: Synthesis of compound 4

[0134] Compound 4-2 (100 mg, 0.23 mmol), EDCI (87.77 mg, 0.46 mmol), HOBT (46.40 mg, 0.34 mmol), triethylamine (46.33 mg, 0.46 mmol) and DMF (3 mL) were added to the reaction bottle, stirred at room temperature for 1 h, and then compound 3-3 (23.93 mg, 0.27 mmol) was added, and stirring was continued overnight. TLC showed that the reaction was complete. The reaction system was poured into water, extracted twice with ethyl acetate, the ethyl acetate layers were combined, washed twice with water, washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM: MeOH = 20: 1) to obtain 63.3 mg of white solid, which was compound 4, with a yield of 54.65%. 1HNMR(300MHz,DMSO-d6)δ12.70(brs,1H),8.80(t,J=5.9Hz,1H),8.26(s,1H),7.6 0(s,1H),7.56(d,J=8.5Hz,1H),7.48(t,J=7.9Hz,2H),7.26(t,J=7.3Hz,1H),7.19( dd,J=5.2,2.8Hz,3H),7.03(dd,J=8.5,2.4Hz,1H),3.80(q,J=6.1Hz,2H),3.53(d,J =5.2Hz, 4H), 3.46 (d, J = 5.1Hz, 4H), 2.71 (t, J = 6.5Hz, 2H). LC / MS: m / z = 506.23 [M+H] + .

[0135] Example 5 Preparation of 4-(5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino 1-Morpholinobutan-1-one (Compound 5)

[0136]

[0137] Step 1: Synthesis of compound 5-2

[0138] Referring to the method of Example 3, intermediate 1-5 and compound 5-1 were used as raw materials to prepare compound 5-2 with a yield of 98.00%. 1H NMR (300MHz, DMSO-d6) δ12.51(s,1H),8.75(t,J=5.5Hz,1H),8.25(s,1H),7.63(s,1H),7.59(d,J=8.4Hz,1H),7.48(dd,J=8.5,7.3Hz,2H ),7.26(t,J=7.4Hz,1H),7.23–7.16(m,3H),7.03(dd,J=8.4,2.4Hz,1H),3.60–3.53(m,2H),2.36(t,J=7.4Hz,2H),1.88(p,J=7.2Hz,2H).

[0139] Step 2: Synthesis of compound 5

[0140] Referring to the method of Example 3, intermediate 5-2 and compound 3-3 were used as raw materials to obtain compound 5 with a yield of 42.66%. 1 H NMR(300MHz,DMSO-d6)δ12.74(s,1H),8.74(t,J=5.2Hz,1H),8.24(s,1H),7.6 2(s,1H),7.58(d,J=8.5Hz,1H),7.49(t,J=7.8Hz,2H),7.26(t,J=7.4Hz,1H), 7.22-7.16(m,3H),7.03(dd,J=8.4,2.4Hz,1H),3.57-3.49(m,8H),2.45(t,J= 7.3Hz, 2H), 1.96-1.84 (m, 2H), 1.35 (t, J=6.1Hz, 2H). LC / MS: m / z=520.27[M+H] + .

[0141] Example 6 Preparation of 5-(5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino 1-Morpholinopentan-1-one (Compound 6)

[0142]

[0143] Step 1: Synthesis of compound 6-2

[0144] Referring to the method of Example 3, intermediate 1-5 and compound 6-1 were used as raw materials to prepare compound 6-2 with a yield of 80.83%. 1H NMR (300MHz, DMSO-d6) δ8.74(t,J=5.5Hz,1H),8.24(s,1H),7.61(s,1H),7.58(d,J=8.5Hz,1H),7.48(dd,J=8.5,7.3Hz,2H),7.26(t,J= 7.4Hz,1H),7.19(ddt,J=6.5,3.8,2.3Hz,3H),7.02(dd,J=8.5,2.4Hz,1H),3.56(t,J=5.8Hz,2H),2.33–2.24(m,2H),1.72–1.59(m,4H).

[0145] Step 2: Synthesis of compound 6

[0146] Referring to the method of Example 3, intermediate 6-2 and compound 3-3 were used as raw materials to prepare compound 6 with a yield of 56.85%. 1 H NMR(300MHz,DMSO-d6)δ12.74(brs,1H),8.74(t,J=5.6Hz,1H),8.32(s,1H),8.24(s,1H ),7.62(s,1H),7.58(d,J=8.4Hz,1H),7.49(dd,J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1H) ,7.22-7.15(m,3H),7.03(dd,J=8.4,2.4Hz,1H),3.52(d,J=4.4Hz,4H),3.42(d,J=6.4Hz ,4H),3.19–3.09(m,4H),2.42-2.35(m,2H),1.67–1.65(m,2H).LC / MS: m / z=534.31[M+H] + .

[0147] Example 7 Preparation of 2-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- [4-yl)amino]-1-(4-methylpiperazin-1-yl)ethan-1-one (Compound 7)

[0148]

[0149] Referring to the method of Example 3, intermediate 3-2 and compound 7-1 were used as raw materials to prepare compound 7 with a yield of 37.09%. 1H NMR(300MHz,DMSO-d6)δ9.08(t,J=4.9Hz,1H),8.23(s,1H),7.59(s,1H),7.5 6(d,J=8.5Hz,1H),7.51–7.44(m,2H),7.27(d,J=7.4Hz,1H),7.18(dd,J=7.7, 1.7Hz, 3H), 7.03 (dd, J=8.4, 2.4Hz, 1H), 4.42 (d, J=5.0Hz, 2H), 3.48 (q, J=5. 0Hz, 4H), 2.33 (dt, J=22.8, 4.9Hz, 4H), 2.19 (s, 3H). LC / MS: m / z=505.46[M+H] + .

[0150] Example 8 Preparation of 3-(5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino 1-(4-methylpiperazin-1-yl)propan-1-one (Compound 8)

[0151]

[0152] Referring to the method of Example 3, intermediate 4-2 and compound 7-1 were used as raw materials to prepare compound 8 with a yield of 52.78%. 1 H NMR(300MHz,DMSO-d6)δ12.74(brs,1H),8.79(t,J=5.9Hz,1H),8.26(s,1H),7.61 (s,1H),7.56(d,J=8.5Hz,1H),7.48(dd,J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1H), 7.23–7.16(m,3H),7.03(dd,J=8.4,2.4Hz,1H),3.79(q,J=6.4Hz,2H),3.55–3.46 (m,4H),2.72(t,J=6.6Hz,2H),2.43(s,4H),2.27(s,3H).LC / MS: m / z=519.05[M+H] + .

[0153] Example 9 Preparation of 4-(5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino 1-(4-methylpiperazin-1-yl)butan-1-one (Compound 9)

[0154]

[0155] Referring to the method of Example 3, intermediate 5-2 and compound 7-1 were used as raw materials to prepare compound 9 with a yield of 36.96%. 1H NMR(300MHz,DMSO-d6)δ12.76(brs,1H),8.74(t,J=5.6Hz,1H),8.24(s,1H),7.63 (s,1H),7.58(d,J=8.4Hz,1H),7.49(dd,J=8.5,7.4Hz,2H),7.26(t,J=7.4Hz,1H), 7.22-7.17(m,3H),7.03(dd,J=8.5,2.4Hz,1H),3.57(q,J=6.6Hz,2H),3.48(s,4H ),2.48-2.40(m,6H),2.27(s,3H),1.88(p,J=7.2Hz,2H).LC / MS: m / z=533.25[M+H] + .

[0156] Example 10 Preparation of 5-(5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino 1-(4-methylpiperazin-1-yl)pentan-1-one (Compound 10)

[0157]

[0158] Referring to the method of Example 3, intermediate 6-2 and compound 7-1 were used as raw materials to prepare compound 10 with a yield of 42.85%. 1 H NMR (300MHz, DMSO-d6) δ12.75(brs,1H),8.74(t,J=5.5Hz,1H),8.24(s,1H),7.62(s,1H),7. 58(d,J=8.5Hz,1H),7.48(dd,J=8.6,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.21–7.17(m,3H),7. 03(dd,J=8.4,2.4Hz,1H),3.56(q,J=6.1,5.4Hz,2H),3.41(d,J=5.2Hz,4H),2.37(t,J=6.8Hz ,2H),2.21(dt,J=10.5,4.9Hz,4H),2.12(s,3H),1.72–1.60(m,4H).LC / MS: m / z=547.49[M+H] + .

[0159] Example 11 Preparation of 2-(5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino 1-(3-hydroxypiperidin-1-yl)ethan-1-one (Compound 11)

[0160]

[0161] Referring to the method of Example 3, intermediate 3-2 and compound 11-1 were used as raw materials to prepare compound 11 with a yield of 57.98%. 1H NMR (300MHz, DMSO-d6) δ12.74(brs,1H),9.25–8.98(m,1H),8.26(d,J=3.7Hz,1H),7.62(s,1H),7.58(d ,J=8.4Hz,1H),7.49(dd,J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.23–7.17(m,3H),7.04(dd,J=8.5,2 .4Hz,1H),4.64(d,J=40.9Hz,1H),4.43(d,J=4.7Hz,2H),4.38–4.06(m,1H),3.79(t,J=12.4Hz,1H),3. 20–2.69(m,2H),2.42(d,J=11.7Hz,1H),1.82–1.42(m,4H),1.24–1.15(m,2H).LC / MS: m / z=520.49[M+H] + .

[0162] Example 12 Preparation of 3-(5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino 1-(3-hydroxypiperidin-1-yl)propan-1-one (Compound 12)

[0163]

[0164] Referring to the method of Example 3, intermediate 4-2 and compound 11-1 were used as raw materials to prepare compound 12 with a yield of 40.33%. 1 HNMR(300MHz,DMSO-d6)δ12.90(brs,1H),9.00(s,1H),8.30(s,1H),7.67(s,1H),7.57(d,J=8.4Hz, 1H),7.49(dd,J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.23–7.16(m,3H),7.03(dd,J=8.4,2.4Hz, 1H),4.28(dd,J=82.8,12.8Hz,1H),3.86–3.73(m,3H),3.32–3.18(m,3H),2.97–2.77(m,1H),2.72( t,J=6.7Hz,2H),2.42–2.16(m,1H),1.71–1.54(m,2H),1.47–1.06(m,3H).LC / MS: m / z=534.31[M+H] + .

[0165] Example 13 Preparation of 4-(5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino 1-(3-hydroxypiperidin-1-yl)butan-1-one (Compound 13)

[0166]

[0167] Referring to the method of Example 3, intermediate 5-2 and compound 11-1 were used as raw materials to prepare compound 13 with a yield of 39.08%. 1 HNMR(300MHz,DMSO-d6)δ12.77(brs,1H),8.79(s,1H),8.25(s,1H),7.63(s,1H),7.59(d,J=8.5Hz,1H),7.49(d d,J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.22–7.16(m,3H),7.03(dd,J=8.5,2.4Hz,1H),4.25(dd,J=79.4,12 .7Hz,1H),3.77(d,J=10.3Hz,1H),3.56(q,J=6.5Hz,2H),3.30–3.16(m,2H),3.07–2.57(m,2H),2.45(t,J=7.4H z,2H),2.40–2.26(m,1H),1.89(q,J=7.4Hz,2H),1.72–1.52(m,2H),1.51–1.01(m,3H).LC / MS: m / z=548.03[M+H] + .

[0168] Example 14 Preparation of 5-(5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino 1-(3-hydroxypiperidin-1-yl)pentan-1-one (Compound 14)

[0169]

[0170] Referring to the method of Example 3, intermediate 6-2 and compound 11-1 were used as raw materials to prepare compound 14 with a yield of 39.08%. 1H NMR (300MHz, DMSO-d6) δ12.72(s,1H),8.74(t,J=5.4Hz,1H),8.24(s,1H),7.62(s,1H),7.59(d,J=8.4Hz,1H),7.48(dd, J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.22–7.16(m,3H),7.03(dd,J=8.4,2.4Hz,1H),4.55(dt,J=22.7,5.2Hz,1H), 4.23(dd,J=79.2,13.1Hz,1H),3.78(t,J=12.7Hz,1H),3.56(d,J=5.3Hz,2H),3.32–3.15(m,2H),2.97–2.79(m,1H),2.7 9–2.58(m,1H),2.38(d,J=6.3Hz,2H),2.33–2.20(m,1H),1.71–1.59(m,5H),1.44–1.03(m,3H).LC / MS: m / z=562.40[M+H] + .

[0171] Example 15 Preparation of 2-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-(hydroxypyrrolidin-1-yl)ethan-1-one (Compound 15)

[0172]

[0173] Referring to the method of Example 3, intermediate 3-2 and compound 15-1 were used as raw materials to prepare compound 15 with a yield of 55.74%. 1 H NMR (400MHz, DMSO-d6) δ12.71(brs,1H),9.09(dt,J=12.8,4.8Hz,1H),8.25(d,J=2.3Hz,1H),7.61(s, 1H),7.57(d,J=8.4Hz,1H),7.49(t,J=7.9Hz,2H),7.26(t,J=7.4Hz,1H),7.20(dd,J=5.3,2.8Hz,3H),7 .04(dd,J=8.4,2.4Hz,1H),4.94(dd,J=7.8,4.1Hz,1H),4.43(t,J=5.5Hz,2H),4.16–3.60(m,2H),3.5 7(d,J=13.2Hz,1H),3.22–2.66(m,2H),1.92–1.65(m,2H),1.56–1.30(m,2H).LC / MS: m / z=506.48[M+H] + .

[0174] Example 16 Preparation of 3-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- [4-yl)amino]-1-(hydroxypyrrolidin-1-yl)propan-1-one (Compound 16)

[0175]

[0176] Referring to the method of Example 3, intermediate 4-2 and compound 15-1 were used as raw materials to prepare compound 16 with a yield of 37.81%. 1 H NMR (400MHz, DMSO-d6) δ12.68(brs,1H),8.77(t,J=5.9Hz,1H),8.26(s,1H),7.59(s,1H),7.56(dd,J= 8.4,2.5Hz,1H),7.48(t,J=7.9Hz,2H),7.26(t,J=7.4Hz,1H),7.20(s,1H),7.20–7.17(m,2H),7.03(dd ,J=8.4,2.4Hz,1H),4.96–4.10(m,2H),3.78(q,J=6.4Hz,2H),3.67–3.52(m,2H),3.21–2.92(m,2H),2. 70(t,J=7.4Hz,2H),1.87–1.72(m,1H),1.69–1.59(m,1H),1.48–1.21(m,2H).LC / MS: m / z=520.49[M+H] + .

[0177] Example 17 Preparation of 4-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- [4-yl)amino]-1-(hydroxypyrrolidin-1-yl)butan-1-one (Compound 17)

[0178]

[0179] Referring to the method of Example 3, intermediate 5-2 and compound 15-1 were used as raw materials to prepare compound 17 with a yield of 37.92%. 1H NMR (400MHz, DMSO-d6) δ12.72(brs,1H),8.74(t,J=5.5Hz,1H),8.24(s,1H),7.61(s,1H),7.58(d,J=8 .5Hz,1H),7.48(dd,J=8.6,7.4Hz,2H),7.26(t,J=7.4Hz,1H),7.21–7.17(m,3H),7.03(dd,J=8.5,2.4H z,1H),4.90–4.09(m,2H),3.65–3.49(m,4H),3.22–2.89(m,2H),2.45(td,J=7.4,4.0Hz,2H),1.87(td ,J=7.2,3.6Hz,2H),1.84–1.73(m,1H),1.70–1.58(m,1H),1.45–1.22(m,2H).LC / MS: m / z=534.31[M+H] + .

[0180] Example 18 Preparation of 5-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- [4-yl)amino]-1-(hydroxypyrrolidin-1-yl)pentan-1-one (Compound 18)

[0181]

[0182] Referring to the method of Example 3, intermediate 6-2 and compound 15-1 were used as raw materials to prepare compound 18 with a yield of 40.12%. 1 H NMR(300MHz,DMSO-d6)δ12.73(brs,1H),8.74(t,J=5.5Hz,1H),8.24(s,1H),7.61(s,1H),7 .58(dd,J=8.5,1.9Hz,1H),7.48(t,J=7.9Hz,2H),7.26(t,J=7.4Hz,1H),7.22–7.16(m,3H) ,7.03(dd,J=8.4,2.4Hz,1H),4.86(s,1H),4.21–3.62(m,1H),3.62–3.47(m,4H),3.20–2.8 6(m,2H),2.42–2.32(m,2H),1.87–1.55(m,6H),1.48–1.19(m,2H).LC / MS: m / z=548.51[M+H] + .

[0183] Example 19 Preparation of (R)-2-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d] [pyrimidin-4-yl)amino]-1-[3-(hydroxymethyl)pyrrolidin-1-yl]ethan-1-one (Compound 19)

[0184]

[0185] Referring to the method of Example 3, intermediate 3-2 and compound 19-1 were used as raw materials to prepare compound 19 with a yield of 39.87%. 1 H NMR(400MHz,DMSO-d6)δ12.72(brs,1H),9.08–9.03(m,1H),8.26(s,1H),7.62(s,1H),7.58(d, J=8.5Hz,1H),7.48(dd,J=8.6,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.21(d,J=1.3Hz,1H),7.20– 7.18(m,2H),7.04(dd,J=8.5,2.4Hz,1H),5.03(dd,J=39.4,3.5Hz,1H),4.34(dq,J=24.8,5.9, 5.2Hz,3H),3.67–3.46(m,2H),3.44–3.36(m,2H),2.04–1.74(m,2H).LC / MS: m / z=492.41[M+H] + .

[0186] Example 20 Preparation of (R)-3-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d] [pyrimidin-4-yl)amino]-1-[3-(hydroxymethyl)pyrrolidin-1-yl]propan-1-one (Compound 20)

[0187]

[0188] Referring to the method of Example 3, intermediate 4-2 and compound 19-1 were used as raw materials to prepare compound 20 with a yield of 45.21%. 1 H NMR(400MHz,DMSO-d6)δ12.69(brs,1H),8.81–8.76(m,1H),8.26(s,1H),7.59(s,1H),7.56(d,J=8.5Hz,1 H),7.48(dd,J=8.6,7.4Hz,2H),7.26(t,J=7.4Hz,1H),7.20(d,J=1.3Hz,1H),7.20–7.17(m,2H),7.03(dd ,J=8.5,2.4Hz,1H),4.95(dd,J=29.9,3.5Hz,1H),4.26(d,J=23.8Hz,1H),3.79(dtd,J=9.2,6.4,2.3Hz,2 H),3.54–3.42(m,2H),3.31–3.23(m,2H),2.71–2.58(m,2H),1.96–1.68(m,2H).LC / MS: m / z=506.42[M+H] + .

[0189] Example 21 Preparation of (R)-4-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d] [pyrimidin-4-yl)amino]-1-[3-(hydroxymethyl)pyrrolidin-1-yl]butan-1-one (Compound 21)

[0190]

[0191] Referring to the method of Example 3, intermediate 5-2 and compound 19-1 were used as raw materials to prepare compound 21 with a yield of 45.21%. 1 H NMR(300MHz,DMSO-d6)δ12.72(brs,1H),8.82–8.70(m,1H),8.24(s,1H),7.62(s,1H),7.59(d,J= 8.5Hz,1H),7.49(dd,J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.22–7.17(m,3H),7.03(dd,J=8.5 ,2.4Hz,1H),5.03–4.88(m,1H),4.25(d,J=19.3Hz,1H),3.61–3.53(m,2H),3.52–3.44(m,2H),3.2 9–3.21(m,2H),2.43–2.31(m,2H),1.92–1.85(m,2H),1.84–1.65(m,2H).LC / MS: m / z=520.27[M+H] + .

[0192] Example 22 Preparation of (R)-5-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d] [pyrimidin-4-yl)amino]-1-[3-(hydroxymethyl)pyrrolidin-1-yl]pentan-1-one (Compound 22)

[0193]

[0194] Referring to the method of Example 3, intermediate 6-2 and compound 19-1 were used as raw materials to prepare compound 22 with a yield of 39.56%. 1 H NMR (300MHz, DMSO-d6) δ12.71(brs,1H),8.74(t,J=5.5Hz,1H),8.24(s,1H),7.62(s,1H),7.59(d,J=8 .5Hz,1H),7.48(dd,J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.23–7.16(m,3H),7.03(dd,J=8.5,2.4 Hz,1H),4.94(d,J=29.6Hz,1H),4.24(d,J=21.5Hz,1H),3.56(q,J=5.8Hz,2H),3.52–3.42(m,2H),3.2 6(t,J=3.2Hz,2H),2.35–2.23(m,2H),1.97–1.72(m,2H),1.71–1.60(m,4H).LC / MS: m / z=534.38[M+H] + .

[0195] Example 23 Preparation of 2-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-[3-(hydroxymethyl)pyrrolidin-1-yl]ethan-1-one (Compound 23)

[0196]

[0197] Referring to the method of Example 3, intermediate 3-2 and compound 23-1 were used as raw materials to prepare compound 23 with a yield of 44.86%. 1 H NMR (400MHz, DMSO-d6) δ12.72(s,1H),9.05(t,J=4.9Hz,1H),8.25(s,1H),7.61(s,1H),7.58(d,J=8.5Hz,1H),7.48(t,J=7.9 Hz,2H),7.26(t,J=7.4Hz,1H),7.20(dd,J=5.4,2.9Hz,3H),7.04(dd,J=8.4,2.4Hz,1H),4.74(d,J=19.6Hz,1H),4.34(d,J=4. 4Hz, 2H), 3.60 (ddd, J=14.2, 9.1, 6.2Hz, 1H), 3.49 (dq, J=13.4, 6.3, 5.8Hz, 2H), 3.42 (t, J=6.3Hz, 1H), 3.21 (ddd, J=58.4, 10. 8,6.9Hz,2H),2.34(dp,J=56.5,7.0Hz,1H),2.05–1.84(m,1H),1.67(ddq,J=57.9,12.3,7.9Hz,1H).LC / MS: m / z=506.42[M+H] + .

[0198] Example 24 Preparation of 3-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-[3-(hydroxymethyl)pyrrolidin-1-yl]propan-1-one (Compound 24)

[0199]

[0200] Referring to the method of Example 3, intermediate 4-2 and compound 23-1 were used as raw materials to prepare compound 24 with a yield of 50.07%. 1H NMR (400MHz, DMSO-d6) δ12.69(brs,1H),8.81–8.74(m,1H),8.26(s,1H),7.59(s,1H),7.56(d,J=8.4Hz,1H),7.48(dd,J=8.6,7.3 Hz,2H),7.26(t,J=7.4Hz,1H),7.22–7.16(m,3H),7.03(dd,J=8.4,2.4Hz,1H),4.67(q,J=5.7Hz,1H),3.78(q,J=6.4Hz,2H),3.51( td,J=10.0,7.1Hz,1H),3.43(ddt,J=12.2,8.5,4.5Hz,3H),3.25(dt,J=11.7,7.6Hz,1H),3.10(ddd,J=42.4,11.0,7.0Hz,1H),2.6 2(t,J=6.6Hz,2H),2.26(dp,J=40.4,7.0Hz,1H),1.95–1.79(m,1H),1.59(ddq,J=39.9,12.4,7.9Hz,1H).LC / MS: m / z=520.49[M+H] + .

[0201] Example 25 Preparation of 4-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-[3-(hydroxymethyl)pyrrolidin-1-yl]butan-1-one (Compound 25)

[0202]

[0203] Referring to the method of Example 3, intermediate 5-2 and compound 23-1 were used as raw materials to prepare compound 25 with a yield of 53.46%. 1 H NMR (400MHz, DMSO-d6) δ12.72(s,1H),8.74(t,J=5.5Hz,1H),8.24(s,1H),7.61(s,1H),7.58(d,J=8. 5Hz,1H),7.48(dd,J=8.5,7.4Hz,2H),7.26(t,J=7.3Hz,1H),7.21–7.16(m,3H),7.03(dd,J=8.4,2.4H z,1H),4.67(dt,J=10.0,5.3Hz,1H),3.57(q,J=6.6Hz,2H),3.53–3.37(m,4H),3.27–2.99(m,2H),2.3 7(t,J=7.3Hz,2H),2.34–2.15(m,1H),1.94–1.78(m,3H),1.70–1.48(m,1H).LC / MS: m / z=534.37[M+H] + .

[0204] Example 26 Preparation of 5-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-[3-(hydroxymethyl)pyrrolidin-1-yl]pentan-1-one (Compound 26)

[0205]

[0206] Referring to the method of Example 3, intermediate 6-2 and compound 23-1 were used as raw materials to prepare compound 26 with a yield of 54.38%. 1 H NMR(300MHz,DMSO-d6)δ8.15(s,1H),7.49(d,J=8.5Hz,2H),7.44(dd,J=8.5,7.3Hz, 2H),7.22(t,J=7.4Hz,1H),7.11(s,1H),7.10–7.05(m,2H),6.98(d,J=2.4Hz,1H),3. 54–3.41(m,3H),3.37–3.28(m,3H),3.28–2.91(m,2H),2.31–2.12(m,3H),1.83(dtd ,J=17.4,12.5,7.1Hz,1H),1.61(s,4H),1.57–1.44(m,1H).LC / MS: m / z=548.45[M+H] + .

[0207] Example 27 Preparation of (S)-2-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d] [pyrimidin-4-yl)amino]-1-[2-(hydroxymethyl)pyrrolidin-1-yl]ethan-1-one (Compound 27)

[0208]

[0209] Referring to the method of Example 3, intermediate 3-2 and compound 27-1 were used as raw materials to prepare compound 27 with a yield of 33.92%. 1 HNMR(400MHz,DMSO-d6)δ12.72(brs,1H),9.07(t,J=4.7Hz,1H),8.26(d,J=2.6Hz,1H),7.61(d,J =2.7Hz,1H),7.58(d,J=8.4Hz,1H),7.49(dd,J=8.6,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.22–7.1 8(m,3H),7.04(dd,J=8.5,2.4Hz,1H),4.91(dt,J=128.6,5.7Hz,1H),4.56–4.28(m,2H),4.11–3. 96(m,1H),3.56–3.44(m,3H),3.40(d,J=6.4Hz,1H),2.03–1.79(m,4H).LC / MS: m / z=506.42[M+H] + .

[0210] Example 28 Preparation of (S)-3-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d] [pyrimidin-4-yl)amino]-1-[2-(hydroxymethyl)pyrrolidin-1-yl]propan-1-one (Compound 28)

[0211]

[0212] Referring to the method of Example 3, intermediate 4-2 and compound 27-1 were used as raw materials to prepare compound 28 with a yield of 33.92%. 1 H NMR (300MHz, DMSO-d6) δ12.64(brs,1H),8.78(dt,J=9.2,5.9Hz,1H),8.25(d,J=1.6Hz,1H),7.60(d,J=1.9Hz ,1H),7.56(dd,J=8.5,1.3Hz,1H),7.48(dd,J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.22–7.17(m,3H),7.03 (dd,J=8.4,2.4Hz,1H),4.83(d,J=46.4Hz,1H),3.99–3.85(m,1H),3.79(q,J=6.9Hz,2H),3.52(d,J=10.4Hz, 2H),3.28–3.17(m,2H),2.82–2.67(m,1H),2.63(t,J=6.6Hz,1H),1.92–1.70(m,4H).LC / MS: m / z=520.36[M+H] + .

[0213] Example 29 Preparation of (S)-4-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d] [pyrimidin-4-yl)amino]-1-[2-(hydroxymethyl)pyrrolidin-1-yl]butan-1-one (Compound 29)

[0214]

[0215] Referring to the method of Example 3, intermediate 5-2 and compound 27-1 were used as raw materials to prepare compound 29 with a yield of 38.21%. 1HNMR(400MHz,Chloroform-d)δ13.34(brs,1H),9.09(t,J=5.6Hz,1H),8.33(s,1H),7.48–7.42(m,3H),7. 39(s,1H),7.25(t,J=7.4Hz,1H),7.16–7.11(m,2H),7.10(d,J=2.4Hz,1H),6.98(dd,J=8.4,2.3Hz,1H),4. 23(tdd,J=8.0,5.5,3.1Hz,1H),3.78–3.66(m,3H),3.65–3.59(m,1H),3.58–3.48(m,2H),2.55(dd,J=8.2 ,6.6Hz,2H),2.19–2.11(m,2H),2.07–1.82(m,4H),1.66(dt,J=12.1,6.2Hz,1H).LC / MS:m / z=534.31[M+H] + .

[0216] Example 30 Preparation of (S)-5-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d] [pyrimidin-4-yl)amino]-1-[2-(hydroxymethyl)pyrrolidin-1-yl]pentan-1-one (Compound 30)

[0217]

[0218] Referring to the method of Example 3, intermediate 6-2 and compound 27-1 were used as raw materials to prepare compound 30 with a yield of 44.26%. 1 H NMR (300MHz, DMSO-d6) δ12.73(brs,1H),8.74(t,J=5.5Hz,1H),8.24(s,1H),7.62(s,1H),7.58(d,J=8.4Hz, 1H),7.48(dd,J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.22–7.16(m,3H),7.03(dd,J=8.4,2.4Hz,1H),4.8 4(d,J=46.5Hz,1H),3.97–3.85(m,1H),3.56(t,J=4.2Hz,2H),3.46(dd,J=9.4,5.2Hz,1H),3.41(d,J=3.4Hz ,1H),3.30–3.15(m,2H),2.45–2.26(m,2H),1.89–1.73(m,4H),1.70–1.61(m,4H).LC / MS: m / z=548.36[M+H] + .

[0219] Example 31 Preparation of 2-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-(2-hydroxymorpholino)ethan-1-one (Compound 31)

[0220]

[0221] Referring to the method of Example 3, intermediate 3-2 and compound 31-1 were used as raw materials to prepare compound 31 with a yield of 43.78%. 1 H NMR (300MHz, DMSO-d6) δ9.13(s,1H),8.19(s,1H),7.52(d,J=8.8Hz,2H),7.46(dd,J=8.5,7.4Hz,2H),7.24(t,J=7.4Hz,1H),7.14(s,1H),7.13–7.08( m,2H),7.02(dd,J=8.4,2.4Hz,1H),4.91–4.66(m,1H),4.38(s,2H),3.96–3 .82(m,1H),3.80–3.56(m,1H),3.53–3.00(m,4H).LC / MS: m / z=508.47[M+H] + .

[0222] Example 32 Preparation of 3-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-(2-hydroxymorpholino)propan-1-one (Compound 32)

[0223]

[0224] Referring to the method of Example 3, intermediate 4-2 and compound 31-1 were used as raw materials to prepare compound 32 with a yield of 30.06%. 1 H NMR (300MHz, DMSO-d6) δ12.69(s,1H),8.79(t,J=5.9Hz,1H),8.25(s,1H),7.60(s,1H),7.56(d,J=8 .5Hz,1H),7.48(dd,J=8.6,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.19(td,J=3.3,1.5Hz,3H),7.03(dd ,J=8.4,2.4Hz,1H),6.67(dd,J=9.2,5.6Hz,1H),4.79–4.58(m,1H),3.87–3.75(m,3H),3.59–3.46( m,2H),3.43(dd,J=7.5,4.5Hz,1H),3.26–2.84(m,2H),2.78–2.63(m,2H).LC / MS: m / z=522.29[M+H] + .

[0225] Example 33 Preparation of 4-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-(2-hydroxymorpholino)butan-1-one (Compound 33)

[0226]

[0227] Referring to the method of Example 3, intermediate 5-2 and compound 31-1 were used as raw materials to prepare compound 33 with a yield of 29.73%. 1 H NMR (400MHz, DMSO-d6) δ12.72(brs,1H),8.74(t,J=5.6Hz,1H),8.24(s,1H),7.61(s,1H),7.58(d,J=8 .4Hz,1H),7.48(dd,J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.22–7.16(m,3H),7.03(dd,J=8.5,2.4H z,1H),6.64(s,1H),4.68(d,J=48.3Hz,1H),3.83(dq,J=8.7,3.3,2.9Hz,1H),3.56(q,J=6.5Hz,3H),3. 50–3.40(m,2H),3.25–2.85(m,2H),2.49–2.40(m,2H),1.88(p,J=7.3Hz,2H).LC / MS: m / z=536.36[M+H] + .

[0228] Example 34 Preparation of 5-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-(2-hydroxymorpholino)pentan-1-one (Compound 34)

[0229]

[0230] Referring to the method of Example 3, intermediate 6-2 and compound 31-1 were used as raw materials to prepare compound 34 with a yield of 29.73%. 1 H NMR (400MHz, DMSO-d6) δ12.68(brs,1H),8.73(t,J=5.5Hz,1H),8.24(s,1H),7.60(s,1H),7.58(d,J=8 .4Hz,1H),7.48(dd,J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.22–7.17(m,3H),7.03(dd,J=8.5,2.4H z,1H),6.63(s,1H),4.67(dd,J=53.8,3.5Hz,1H),3.86–3.80(m,1H),3.61–3.51(m,3H),3.50–3.41(m ,2H),3.24–2.82(m,2H),2.46–2.32(m,2H),1.65(qd,J=8.9,7.8,4.2Hz,4H).LC / MS: m / z=550.43[M+H] + .

[0231] Example 35 Preparation of 2-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-[3-(hydroxymethyl)morpholino]ethan-1-one (Compound 35)

[0232]

[0233] Referring to the method of Example 3, intermediate 3-2 and compound 35-1 were used as raw materials to prepare compound 35 with a yield of 51.07%. 1 H NMR (400MHz, DMSO-d6) δ12.71(s,1H),9.13(t,J=4.9Hz,1H),8.25(s,1H),7.62(s,1H),7.58(d, J=8.5Hz,1H),7.49(dd,J=8.6,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.23–7.17(m,3H),7.04(dd,J =8.4,2.4Hz,1H),5.00(d,J=92.0Hz,1H),4.59–4.29(m,2H),4.16–3.95(m,1H),3.89–3.75(m,3 H),3.69–3.53(m,2H),3.48–3.40(m,2H),2.95(td,J=13.2,3.7Hz,1H).LC / MS:m / z=522.54[M+H] + .

[0234] Example 36 Preparation of 3-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-[3-(hydroxymethyl)morpholino]propan-1-one (Compound 36)

[0235]

[0236] Referring to the method of Example 3, intermediate 4-2 and compound 35-1 were used as raw materials to prepare compound 36 with a yield of 44.39%. 1 H NMR (300MHz, DMSO-d6) δ12.56(s,1H),8.79(t,J=5.9Hz,1H),8.25(s,1H),7.60(s,1H),7.56(d,J=8 .5Hz,1H),7.48(dd,J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.19(ddt,J=4.2,2.3,1.4Hz,3H),7. 03(dd,J=8.4,2.4Hz,1H),4.90(d,J=34.1Hz,1H),4.04(dd,J=47.3,11.7Hz,1H),3.88–3.48(m,8H) ,3.21(d,J=10.7Hz,1H),2.86(dd,J=15.0,7.6Hz,1H),2.81–2.55(m,2H).LC / MS: m / z=536.06[M+H] + .

[0237] Example 37 Preparation of 4-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-[3-(hydroxymethyl)morpholino]butan-1-one (Compound 37)

[0238]

[0239] Referring to the method of Example 3, intermediate 5-2 and compound 35-1 were used as raw materials to prepare compound 37 with a yield of 41.33%. 1 H NMR (300MHz, DMSO-d6) δ12.73(brs,1H),8.74(t,J=5.5Hz,1H),8.24(s,1H),7.62(s,1H),7.58(d,J=8 .5Hz,1H),7.49(dd,J=8.5,7.4Hz,2H),7.26(t,J=7.4Hz,1H),7.22–7.17(m,3H),7.03(dd,J=8.4,2.4H z,1H),4.89(d,J=31.3Hz,1H),4.24–3.70(m,4H),3.57(dt,J=13.2,6.0Hz,4H),3.45–3.39(m,1H),3. 30-3.16(m,2H),2.89–2.55(m,1H),2.48–2.36(m,1H),1.91(q,J=6.9Hz,2H).LC / MS: m / z=550.49[M+H] + .

[0240] Example 38 Preparation of 5-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-[3-(hydroxymethyl)morpholino]pentan-1-one (Compound 38)

[0241]

[0242] Referring to the method of Example 3, intermediate 6-2 and compound 35-1 were used as raw materials to prepare compound 38 with a yield of 47.56%. 1 H NMR (300MHz, DMSO-d6) δ8.77(t,J=5.4Hz,1H),8.16(s,1H),7.54–7.48(m,2H),7.45(t,J=7.9Hz,2H),7.23(t,J=7.4Hz,1H),7.13(s,1H),7.12– 7.06(m,2H),7.00(dd,J=8.5,2.4Hz,1H),3.89–3.12(m,10H),2.39–2.26(m,1H),1.62(s,4H),1.28(d,J=32.5Hz,2H).LC / MS: m / z=564.57[M+H] + .

[0243] Example 39 Preparation of 2-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-[2-(hydroxymethyl)morpholino]ethan-1-one (Compound 39)

[0244]

[0245] Referring to the method of Example 3, intermediate 3-2 and compound 39-1 were used as raw materials to prepare compound 39 with a yield of 44.25%. 1 H NMR(300MHz,DMSO-d6)δ9.10(q,J=4.9Hz,1H),8.23(d,J=2.3Hz,1H),7.58(s ,1H),7.56(d,J=8.5Hz,1H),7.51–7.44(m,2H),7.25(t,J=7.4Hz,1H),7.20– 7.14(m,3H),7.03(dd,J=8.4,2.4Hz,1H),4.56–4.12(m,3H),3.85(dd,J=13. 1,9.3Hz,2H),3.57–3.30(m,5H),3.28–2.71(m,2H).LC / MS: m / z=522.48[M+H] + .

[0246] Example 40 Preparation of 3-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-[2-(hydroxymethyl)morpholino]propan-1-one (Compound 40)

[0247]

[0248] Referring to the method of Example 3, intermediate 4-2 and compound 39-1 were used as raw materials to prepare compound 40 with a yield of 39.77%. 1 H NMR (300MHz, DMSO-d6) δ12.70(s,1H),8.80(t,J=5.9Hz,1H),8.26(d,J=1.2Hz,1H),7.61(s,1H),7.56(d ,J=8.4Hz,1H),7.48(dd,J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.19(ddt,J=4.5,2.4,1.4Hz,3H),7.0 3(dd,J=8.5,2.4Hz,1H),4.78(q,J=6.0Hz,1H),4.28(dd,J=50.1,13.5Hz,1H),3.88–3.71(m,4H),3.42(d d,J=11.4,5.9Hz,2H),3.31–3.04(m,2H),2.95–2.58(m,3H),2.48–2.27(m,1H).LC / MS: m / z=536.00[M+H] + .

[0249] Example 41 Preparation of 4-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-[2-(hydroxymethyl)morpholino]butan-1-one (Compound 41)

[0250]

[0251] Referring to the method of Example 3, intermediate 5-2 and compound 39-1 were used as raw materials to prepare compound 41 with a yield of 44.25%. 1 H NMR(300MHz,Chloroform-d)δ13.29(s,1H),9.07(d,J=6.1Hz,1H),8.35(s,1H),7.50–7.38(m,4H),7.28–7.22(m ,1H),7.16–7.09(m,3H),6.98(dd,J=8.4,2.3Hz,1H),4.44(t,J=11.3Hz,1H),3.94(d,J=6.0Hz,1H),3.73(q,J=6 .1Hz,3H),3.62(t,J=6.1Hz,1H),3.57(d,J=10.9Hz,1H),3.51(d,J=3.4Hz,1H),3.33–3.06(m,1H),2.89–2.59(m ,2H),2.56(t,J=7.9Hz,1H),2.14(t,J=7.0Hz,2H),1.27(s,1H),0.88(d,J=7.0Hz,1H).LC / MS: m / z=550.31[M+H] + .

[0252] Example 42 Preparation of 5-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-[2-(hydroxymethyl)morpholino]pentan-1-one (Compound 42)

[0253]

[0254] Referring to the method of Example 3, intermediate 6-2 and compound 39-1 were used as raw materials to prepare compound 42 with a yield of 41.92%. 1H NMR (400MHz, DMSO-d6) δ8.18(s,1H),7.53(t,J=4.2Hz,2H),7.46(t,J=7.9Hz,2H),7.24(t, J=7.4Hz,1H),7.15(s,1H),7.14–7.10(m,2H),7.01(dd,J=8.5,2.4Hz,1H),4.16(dd,J=51.9 ,13.2Hz,1H),3.83–3.65(m,2H),3.57–3.45(m,2H),3.39–3.27(m,3H),3.25–3.03(m,1H),2 .92–2.60(m,1H),2.39(tt,J=14.9,5.6Hz,3H),1.70–1.55(m,4H).LC / MS:m / z=564.50[M+H] + .

[0255] Example 43 Preparation of 4-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-[3-(hydroxymethyl)pyrrolidin-1-yl]butan-1-one (Compound 43)

[0256]

[0257] Referring to the method of Example 3, intermediate 5-2 and compound 43-1 were used as raw materials to prepare compound 43 with a yield of 38.87%. 1 H NMR(400MHz,DMSO-d6)δ12.70(brs,1H),8.75(td,J=5.5,2.5Hz,1H),8.24(s,1H),7.61(s,1H),7.59 (d,J=8.5Hz,1H),7.48(dd,J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.22–7.17(m,3H),7.03(dd,J=8 .5, 2.4Hz, 1H), 4.94 (d, J = 33.6Hz, 1H), 4.25 (d, J = 24.1Hz, 1H), 3.57 (q, J = 7.0Hz, 2H), 3.49 (td, J = 9. 5,8.9,4.9Hz,2H),3.30–3.22(m,2H),2.43–2.32(m,2H),1.94–1.69(m,4H).LC / MS: m / z=520.30[M+H] + .

[0258] Example 44 Preparation of 4-[(5-{[2-chloro-4-(phenyloxy)phenyl]carbonyl}-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]-1-[2-(hydroxymethyl)pyrrolidin-1-yl]butan-1-one (Compound 44)

[0259]

[0260] Referring to the method of Example 3, intermediate 5-2 and compound 44-1 were used as raw materials to prepare compound 44 with a yield of 38.92%. 1 H NMR (400MHz, DMSO-d6) δ12.71(s,1H),8.74(t,J=5.5Hz,1H),8.24(s,1H),7.61(s,1H),7.58(d,J=8.5 Hz,1H),7.48(dd,J=8.6,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.22–7.17(m,3H),7.03(dd,J=8.4,2.4Hz ,1H),4.81(d,J=51.0Hz,1H),3.98–3.85(m,1H),3.57(q,J=6.8Hz,2H),3.48(dd,J=10.3,3.8Hz,1H), 3.43–3.40(m,1H),3.28–3.20(m,2H),2.49–2.33(m,2H),1.96–1.69(m,6H).LC / MS: m / z=534.31[M+H] + .

[0261] Example 45 Preparation of [2-chloro-4-(phenyloxy)phenyl](4-{[2-(1,4-oxazepine-4-yl)ethyl 1-(4-(2-(4-yl)-1-(2-(4-nitrophenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Compound 45)

[0262]

[0263] Referring to the method of Example 1, intermediate 1-5 and compound 45-1 were used as raw materials to prepare compound 45 with a yield of 37.38%. 1 H NMR(300MHz,DMSO-d6)δ12.66(s,1H),8.87(t,J=5.3Hz,1H),8.24(s,1H),7.5 8(d,J=8.8Hz,2H),7.48(dd,J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1H),7.22–7 .17(m,3H),7.03(dd,J=8.4,2.4Hz,1H),3.67(q,J=6.1Hz,2H),3.61(t,J=4.6 Hz, 4H), 2.59 (t, J = 6.4Hz, 2H), 2.46 (d, J = 4.7Hz, 4H). LC / MS: m / z = 478.16 [M+H] + .

[0264] Example 46 Preparation of [2-chloro-4-(phenyloxy)phenyl](4-{[3-(1,4-oxazepine-4-yl)propane 1-(4-(2-(4-yl)-1-(2-(4-pyridin-5-yl)-2-yl)-1-(4-(2-(4-yl)-1-nitrophenyl)-2-nitrophenyl ...

[0265]

[0266] Referring to the method of Example 1, intermediate 1-5 and compound 46-1 were used as raw materials to prepare compound 46 with a yield of 47.09%. 1 H NMR(300MHz,DMSO-d6)δ12.71(s,1H),8.76(t,J=5.6Hz,1H),8.24(s,1H),7.61 (s,1H),7.58(d,J=8.5Hz,1H),7.48(dd,J=8.5,7.3Hz,2H),7.26(t,J=7.4Hz,1 H),7.19(qd,J=3.4,2.3Hz,3H),7.03(dd,J=8.4,2.4Hz,1H),3.63–3.54(m,6H) ,2.40(dd,J=14.1,7.0Hz,6H),1.80(p,J=6.8Hz,2H).LC / MS: m / z=492.18[M+H] + .

[0267] Biological activity test

[0268] (I) Determination of the inhibitory activity of compounds on cell proliferation (SU-DHL-4) in vitro

[0269] 1: SU-DHL-4 diffuse large B-cell lymphoma cell line was purchased from Guangzhou Geneo Biotechnology Co., Ltd. and cultured in RPMI-1640 plus 10% fetal bovine serum (Gibcol) at 37°C, 5% CO2, and 95% humidity.

[0270] Table 1

[0271] Cell lines Cell Type Number of cells / well Culture medium SU-DHL-4 Suspension 10000 RPMI-1640 + 10% FBS

[0272] 2: The following are general experimental steps

[0273] The cells in the logarithmic growth phase were harvested and the cell viability was detected by trypan blue staining, and the cells were counted by a cell counter (thermo countness II). The appropriate amount of cells was taken, the cell concentration was adjusted, and 50 μL of the cell suspension was added to the 96-well plate, 5000 cells per well, and cultured overnight; the test compound solution was prepared, and 50 μL of the test compound solution was added to each well of cells, the final concentration of each test compound was 0.5 μM, and three replicates were set for each compound concentration, and the culture was continued in the incubator for 72 hours; after culturing for 72 hours after administration, 10 μL of CCK-8 solution was added to each well, and then the 96-well plate was placed in the incubator, and the culture was continued for 2 hours, the absorbance was read at 450 nm, and the relative inhibition rate was calculated. The results are shown in Table 2 below.

[0274] Table 2. Inhibitory activity of some compounds of the present invention on SU-DHL-4 cell proliferation

[0275]

[0276]

[0277] (II) In vitro wild-type and mutant BTK kinase activity inhibition assay

[0278] 1: Compound preparation

[0279] The compound powder was dissolved in 100% DMSO to prepare a 10 mM stock solution, and stored at -20°C in the dark.

[0280] 2: Kinase reaction process

[0281] (1) Prepare 4X kinase buffer and 1X kinase buffer; (2) Preparation of compounds: The concentration of the tested compound is 50 μM. It is first diluted to 100 times the final concentration of 100% DMSO solution, and then diluted to 5 times the final concentration of 5% DMSO solution using 4X kinase buffer. Transfer 1 μL to a 384-well plate with a dispenser, with duplicate wells for each compound; (3) Use 4X kinase buffer to prepare a kinase solution with a concentration of 2.5 times the final concentration; (4) Add 2 μL of the kinase solution with a concentration of 2.5 times the final concentration to the compound and positive control wells, and add 3 μL of 1X kinase buffer to the negative control wells; (5) Vortex the reaction plate to mix well and incubate at room temperature for 10 minutes; (6) Use 4X kinase buffer to prepare a mixed solution of ATP and Kinase substrate with a concentration of 2.5 times the final concentration; (7) Add 2 μL of ATP and Kinase The reaction was started by adding a mixed solution of substrate; (8) shaking and mixing, and incubating at room temperature for 60 minutes; (9) adding 5 μL of ADP-Glo ​​reagent, shaking and mixing, stopping the reaction, and incubating at room temperature for 60 minutes to consume residual ATP; (10) adding 10 μL of kinase detection reagent, shaking and mixing, and incubating at room temperature for 40 minutes; (11) reading the data with an ELISA reader and calculating the inhibition rate.

[0282] 3: Data Analysis

[0283] Calculation formula:

[0284] Where: Conversion%_sample is the conversion rate reading of the sample; Conversion%_min: the mean value of the negative control wells, representing the conversion rate reading of the wells without enzyme activity; Conversion%_max: the mean value of the negative control well ratio, representing the conversion rate reading of the wells without compound inhibition. The results are shown in Table 3.

[0285] Table 3. Inhibitory activity of some compounds of the present invention on BTK kinase

[0286]

[0287] It can be seen from the above examples that some compounds of the present invention as BTK protein kinase inhibitors have a strong inhibitory effect on wild-type and mutant BTK kinases, with considerable cell activity and kinase activity, and some of the compounds are even equivalent to the positive drug ARQ531, and can therefore be used to prepare drugs for treating diseases caused by overexpression of BTK kinase.

[0288] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A compound as a non-covalent BTK kinase inhibitor, characterized in that The compound structure is selected from one of the following:

2. A pharmaceutical composition, characterized in that The active ingredient of the pharmaceutical composition is selected from the compound described in claim 1.

3. Use of the compound as a non-covalent BTK kinase inhibitor according to claim 1 or the pharmaceutical composition according to claim 2 in the preparation of a protein kinase inhibitor; the kinase inhibitor is a BTK inhibitor.

4. Use of the compound as a non-covalent BTK kinase inhibitor according to claim 1 or the pharmaceutical composition according to claim 2 in the preparation of a medicament for treating any one or more of autoimmune diseases, inflammatory diseases, thromboembolic diseases, allergies, infectious diseases, proliferative diseases and cancer.

5. The use according to claim 4, characterized in that The disease is selected from the group consisting of arthritis, rheumatoid arthritis, urticaria, vitiligo, organ transplant rejection, ulcerative colitis, Crohn's disease, dermatitis, asthma, Sjögren's syndrome, systemic lupus erythematosus, multiple sclerosis, idiopathic thrombocytopenic purpura, rash, anti-neutrophil cytoplasmic antibody vasculitis, pus, pus, chronic obstructive pulmonary disease, psoriasis; breast cancer, mantle cell lymphoma, ovarian cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, hepatocellular carcinoma, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, gallbladder cancer, Cancer of the uterine tract, pancreatic cancer, lymphoma, hairy cell carcinoma, nasopharyngeal cancer, colorectal cancer, rectal cancer, brain and central nervous system cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, lung cancer, small cell lung cancer, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, thyroid cancer, follicular carcinoma, Hodgkin's leukemia, bronchial cancer, uterine corpus cancer, cervical cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphoid leukemia, myeloid leukemia, non-Hodgkin's lymphoma, primary macroglobulinemia.

6. Use of the compound according to claim 1 or the pharmaceutical composition according to claim 2 in the preparation of a medicament for treating a disease causing overexpression of BTK kinase.

7. Use of the compound according to claim 1 or the pharmaceutical composition according to claim 2 in the preparation of a medicament for treating a disease caused by overexpression of BTK kinase.

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