Novel IRAK4 inhibitor, compound for inhibiting and degrading IRAK4 protein as well as preparation method and application of novel IRAK4 inhibitor

Abstract

The invention relates to a novel IRAK4 inhibitor as shown in a formula (I), a compound for inhibiting and degrading IRAK4 protein as well as a preparation method and application of the compound, and further relates to a pharmaceutical composition containing the IRAK4 inhibitor or the compound for inhibiting and degrading IRAK4 protein. # imgabs0 #

Description

Novel IRAK4 inhibitors and compounds that inhibit and degrade IRAK4 protein, as well as preparation methods and applications thereof

[0001] This application claims priority to Chinese invention patent application CN202211529378.1, filed on November 30, 2022, and incorporates the full text of the patent application into this application. Technical Field

[0002] The present application relates to novel IRAK4 inhibitors and compounds that inhibit and degrade IRAK4 protein, as well as preparation methods and uses thereof, and also relates to pharmaceutical compositions comprising the IRAK4 inhibitors or the compounds that inhibit and degrade IRAK4 protein. Background Art

[0003] IRAK4 is a serine / threonine protein kinase that belongs to the interleukin-1 receptor-associated kinase (IRAK) family. This family includes four isoforms: IRAK1, IRAK2, IRAK3 (also known as 'IRAKM'), and IRAK4. IRAK1, IRAK2, and IRAK4 promote the release of inflammatory factors, while IRAK3 is involved in suppressing inflammation. Of the four isoforms, the biological function of IRAK4 has been clearly elucidated. When TLRs or IL-1Rs perceive external signals, the Myddosome complex formed by IRAK4 activates the MAPK and NF-κB pathways, leading to the release of multiple inflammatory factors.

[0004] Research has confirmed that IRAK4 is highly expressed in various tumor cells and inflammatory models. The development of inhibitors targeting IRAK4 is becoming an increasingly important area of ​​research for the treatment of autoimmune diseases and tumors. IRAK4 possesses both kinase and scaffold activities, both of which play a crucial role in regulating downstream signaling. Conventional small-molecule IRAK4 kinase inhibitors, which inhibit kinase activity alone, are ineffective in achieving optimal therapeutic effects and pose potential risks, such as target protein mutations and drug resistance.

[0005] Protein degradation targeting chimera (PROTAC) technology is a new technology that has emerged in recent years. Since its advent in 2001, the technology has attracted much attention. At present, many drug developments based on this technology have entered the clinical research stage, and some have entered clinical phase 2. PROTAC is a heterogeneous bifunctional molecule that consists of three parts: a small molecule inhibitor that can recognize the target protein at one end, a linker, and a ligand that can recognize the E3 ubiquitin ligase at the other end. This bifunctional molecule recognizes the target protein in the body and brings the target protein and the E3 ubiquitin ligase together to form a ternary complex. The target protein is then ubiquitinated and marked, thereby initiating a degradation pathway that depends on the ubiquitin-proteasome. Compared with traditional small molecule inhibitors, PROTAC technology achieves simultaneous inhibition of the two functions of IRAK4 by degrading the IRAK4 protein, which can effectively solve the problems of insufficient activity of small molecule inhibitors or target protein mutations. At present, no PROTAC drug targeting IRAK4 has entered the clinical research stage in China.

[0006] It is necessary to develop novel small molecule inhibitors of IRAK4 and PROTAC molecules targeting IRAK4 for the treatment of diseases, disorders or conditions associated with IRAK4 protein kinase.

[0007] Summary of the Invention

[0008] The present invention provides novel small molecule inhibitors of IRAK4 and PROTAC molecules targeting IRAK4 for diseases, disorders or conditions associated with IRAK4 protein kinases. The compounds of the present invention are highly selective for IRAK4 and can inhibit, or inhibit and degrade IRAK4 protein kinases. In addition, the compounds of the present invention have better physicochemical properties (e.g., solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and / or fewer side effects), less prone to drug resistance and other more excellent properties.

[0009] In one aspect, the present invention provides a compound of formula (I) as defined below:

[0010] or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0011] In another aspect, the present invention provides a compound of formula (I) or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts for the preparation of protein degradation targeting chimeras (PROTACs).

[0012] In another aspect, the present invention provides a protein degradation targeting chimera (PROTAC) comprising a portion having IRAK4 protein kinase inhibitory activity, wherein the portion is derived from a compound of formula (I) of the present invention or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0013] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) of the present invention or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a PROTAC molecule of the present invention, and a pharmaceutically acceptable excipient, carrier or diluent. The pharmaceutical composition is preferably a solid preparation, a liquid preparation or a transdermal preparation.

[0014] In another aspect, the present invention provides a compound of formula (I) of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates or pharmaceutically acceptable salts, or a PROTAC molecule of the present invention, or a pharmaceutical composition of the present invention for the preparation of a medicament for treating a disease, disorder or condition associated with IRAK4 protein kinase.

[0015] In another aspect, the present invention provides a method for treating a disease, disorder or condition associated with IRAK4 protein kinase, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) of the present invention, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a PROTAC molecule of the present invention, or a pharmaceutical composition of the present invention.

[0016] In another aspect, the present invention provides methods of preparing compounds of formula (I) of the present invention and PROTAC molecules of the present invention. DETAILED DESCRIPTION

[0017] definition

[0018] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0019] The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps (i.e., these terms also encompass the terms "consisting essentially of and "consisting of").

[0020] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0021] As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6, carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogen (in which case the group is referred to as "haloalkyl") (e.g., CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl or -CH2CH2CF3, etc.). The term "C 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0022] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above. 1-6"Alkoxy" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy or n-hexoxy), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogen (in this case, the group is referred to as "haloalkoxy") (e.g., -OCF3, -OC2F5, -OCHF2, -OCH2F, -OCH2CF3, -OCH2Cl or -OCH2CH2CF3, etc.). The term "C 1-4 The term "alkoxy" refers to a linear or branched alkoxy group of 1 to 4 carbon atoms (eg, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy).

[0023] As used herein, the term "alkylthio" refers to an -S-alkyl group, wherein the alkyl group is as defined above. 1-6 "Alkylthio" refers to a linear or branched alkylthio group having 1 to 6 carbon atoms (e.g., methylthio, ethylthio or propylthio), which is optionally substituted by one or more (e.g., 1 to 3) suitable substituents such as halogen (in this case, the group is referred to as a "halogenated alkylthio group") (e.g., -SCF3, -SC2F5, -SCHF2, -SCH2F, -SCH2CF3, -SCH2Cl or -SCH2CH2CF3, etc.). The term "C 1-4 The term "alkylthio" refers to a linear or branched alkylthio group having 1 to 4 carbon atoms (eg, methylthio, ethylthio, propylthio).

[0024] As used herein, the terms "cycloalkyl", "hydrocarbon ring" and "cycloalkylene" refer to saturated (i.e., "cycloalkyl" and "cycloalkylene") or partially unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 3-7 or 3-6) ring carbon atoms, including but not limited to (cyclo)propyl, (cyclo)butyl, (cyclo)pentyl, (cyclo)hexyl, (cyclo)heptyl, (cyclo)octyl, (cyclo)nonyl, (cyclo)hexenyl, and the like.

[0025] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which is optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms, suitably 3 to 10 carbon atoms. For example, the term "C 3-6"Cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl). The cycloalkyl group is optionally substituted by one or more (such as one to three) suitable substituents, for example, a methyl-substituted cyclopropyl group.

[0026] As used herein, the term "heterocyclyl" refers to a saturated (i.e., "heterocycloalkyl") or partially unsaturated monovalent monocyclic or bicyclic radical having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and one or more (e.g., one, two, three, or four) carbon atoms selected from C(=O), O, S, S(=O), S(=O)2, and NR a A heteroatom-containing group, wherein R a Represents a hydrogen atom or C 1-6 Alkyl or halo-C 1-6 Alkyl. The heterocyclic group may be connected to the rest of the molecule via any one of the carbon atoms or the nitrogen atom (if present). In particular, a 3-10 membered heterocyclic group is a group having 3-10 (e.g., 3-7, 4-6, or 5-6) carbon atoms and heteroatoms in the ring, such as, but not limited to, oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

[0027] As used herein, the term "heterocyclyl" encompasses a cyclic structure, and the connection point of the cyclic structure to the other groups can be on any ring in the cyclic structure. Therefore, the heterocyclyl of the present invention also includes but is not limited to heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, such as 3-7 membered (mono) heterocyclyl and 3-7 membered (mono) heterocyclyl, 3-7 membered (mono) heterocyclyl and (mono) cycloalkyl, 3-7 membered (mono) heterocyclyl and C 4-6 (Mono)cycloalkyl, examples of which are not limited to pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl,

[0028] As used herein, the term "heterocyclyl" encompasses bridged heterocyclyls and spiro heterocyclyls.

[0029] As used herein, the term "bridged heterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, and / or sulfur atoms) formed by two saturated rings sharing two ring atoms that are not directly connected, including but not limited to 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, 7-10 membered sulfur-containing bridged heterocycles, etc., for example The "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle" and "sulfur-containing bridged heterocycle" optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.

[0030] As used herein, term " monospiro heterocyclic radical " refers to the cyclic structure containing one or more (such as 1, 2, 3 or 4) heteroatoms (such as oxygen atoms, nitrogen atoms, sulphur atoms) formed by sharing a ring atom of two or more saturated or partially unsaturated rings." monospiro heteroalkyl ring radical " is the monospiro heterocyclic radical that each ring forming spiro ring is saturated ring. Monospiro heterocycloalkyl includes but is not limited to 5-11 yuan monospiro heterocycloalkyl, 6-10 yuan monospiro heterocycloalkyl, 7-10 yuan monocyclic heterocycloalkyl, 6-10 yuan nitrogen-containing spiro heterocycloalkyl, 6-10 yuan oxygen-containing spiro heterocycloalkyl, 6-10 yuan sulfur-containing spiro heterocycloalkyl etc. Monospiro heterocycloalkyl can include for example 3 yuan / 5 yuan ring system, 4 yuan / 4 yuan ring system, 4 yuan / 5 yuan ring system, 4 yuan / 6 yuan ring system, 5 yuan / 5 yuan ring system, 5 yuan / 6 yuan ring system and 6 yuan / 6 yuan ring system, and the counting of wherein each ring includes spiral atom. Examples include, but are not limited to The "nitrogen-containing monospiro heterocycloalkyl", "oxygen-containing monospiro heterocycloalkyl" and "sulfur-containing monospiro heterocycloalkyl" optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur. The term "6-10 membered nitrogen-containing monospiro heterocycloalkyl" refers to a spiro heterocyclic group containing a total of 6-10 ring atoms, at least one of which is a nitrogen atom.

[0031] As used herein, the rings shown in the cyclic structures, such as Ring A, Ring B, Ring C, and Ring D in Formula (I), Formula (I-1), and Formula (I-2) herein are This means that each corresponding ring structure is aromatic (ie, aryl or heteroaryl).

[0032] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, as used herein, the term "C 6-14"Aryl" means an aromatic group containing 6 to 14 (e.g. 6 to 12) carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituted by one or more (e.g. 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.) substituted.

[0033] As used herein, the term "heteroaryl" refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being, for example, oxygen, nitrogen or sulfur) and, in each case, may be benzo-fused. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl), thiadiazolyl and the like, and benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and benzo derivatives thereof.

[0034] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0035] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, substituted by one or more (such as 1 to 3) the same or different halogen atoms. 1-8 Halogenated alkyl, "C 1-6 Haloalkyl" and "C 1-4 The term "haloalkyl" refers to a haloalkyl group having 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1-4 carbon atoms, respectively, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0036] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and at least one nitrogen atom in the ring, which may optionally further contain one or more (e.g., one, two, three or four) ring members selected from N, O, C=O, S, S=O and S(=O); the nitrogen-containing heterocycle is linked to the rest of the molecule via the nitrogen atom. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring. In particular, the 3- to 14-membered nitrogen-containing heterocycle is a group having 3-14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to a three-membered nitrogen-containing heterocycle (such as aziridine), a four-membered nitrogen-containing heterocycle (such as azetidinyl), a five-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidine ring), pyrrolinyl, pyrrolidonyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), a six-membered nitrogen-containing heterocycle (such as piperidinyl (piperidine ring), morpholinyl, thiomorpholinyl, piperazinyl), a seven-membered nitrogen-containing heterocycle, etc.

[0037] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0038] If a substituent is described as being "optionally substituted with," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the listed substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the listed substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0039] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0040] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0041] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0042] When a bond to a substituent is shown as passing through a bond connecting two atoms in a ring (a "floating bond"), such substituent may be bonded to any ring atom in the substitutable ring, unless otherwise indicated. Where an available ring member is shown as carrying a substitutable hydrogen atom, the substitutable hydrogen atom is substantially substituted (i.e., not present) when the floating bond is to the available ring member.

[0043] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, 2 H), tritium (T, 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13 N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0044] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0045] In this article, solid lines can be used Solid wedge or virtual wedge The chemical bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0046] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0047] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0048] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate / carbonate, bisulfate / sulfate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodide / iodide, maleate, malonate, methylsulfate, naphthoate (naphthylate), nicotinate, nitrate, orotate, oxalate, palmitate and other similar salts.

[0049] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium and other similar salts.

[0050] For a review of suitable salts see Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0051] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acid or alcohol). The compounds of the present invention themselves may also be esters.

[0052] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0053] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0054] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, and the like of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0055] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0056] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P.GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0057] As used herein, the term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0058] Compounds that act as IRAK4 inhibitors

[0059] In one general aspect, the present invention provides compounds of formula (I) as IRAK4 inhibitors:

[0060] or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof,

[0061] in:

[0062] X1, X2, X3, X4, X5, X6, X7, X8 and X9 can each independently be C, CR or N, provided that the valences of all atoms are satisfied and X4 and X5 are not N at the same time;

[0063] R, R 1 、R 4 and R 5 Each independently selected from: hydrogen, deuterium, R 7 、Halogen、CN、NO2、C 1-6 Alkyl, -OR 1f 、-SR 1f 、-NR 1d R 1e 、-S(O)2R 1f 、-S(O)R 1f 、-S(O)2-NR 1d R 1e 、-S(O)-NR 1d R 1e 、-P(O)(OR 1f )2、-P(O)(NR 1d R 1e )2、-CF(R 1f )2、-CF2(R 1f )、-CF3、-CCl(R 1f )2、-CCl2(R 1f )、-CCl3、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)R 1f 、-C(O)OR 1f 、-C(O)NR 1d R 1e 、-C(O)NR 1f-OR 1f 、-OC(O)R 1f 、-OC(O)NR 1d R 1e 、-NR 1f -C(O)OR 1f 、-NR 1f -C(O)R 1f 、-NR 1f -C(O)NR 1d R 1e and -NR 1f -S(O)2R 1f ,

[0064] p is 1, 2, or 3;

[0065] n is 0, 1 or 2, wherein when n is 1 or 2, R 4 available ring members connected to ring D; and

[0066] R 5 Available ring members connected to ring C;

[0067] R 2 Selected from: saturated or partially unsaturated C 3-7 Cycloalkyl; 3-7 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -NR 2d R 2e 、-C(O)OR 2f and -C(O)NR 2d R 2e and in the case where two substituents are attached to the same ring carbon atom of the cycloalkyl or heterocyclyl group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form a saturated or partially unsaturated optionally substituted C 3-7 cycloalkyl or 3-7 membered saturated or partially unsaturated optionally substituted heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0068] R 3 and R 6 Each independently selected from: H, R 8 、Halogen、CN、NO2、C1-6 Alkyl, -OR 3f 、-SR 3f 、-NR 3d R 3e 、-S(O)2R 3f 、 -S(O)R 3f 、-S(O)2-NR 3d R 3e 、-S(O)-NR 3d R 3e 、-P(O)(OR 3f )2、-P(O)(NR 3d R 3e )2、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f )、-CCl3、-(CR 3a R 3b ) q -OR 3f 、-(CR 3a R 3b ) q -C(O)OR 3f 、-(CR 3a R 3b ) q -NR 3d R 3e 、-C(O)R 3f 、-C(O)OR 3f and -C(O)NR 3d R 3e ,

[0069] q is 1, 2, or 3; and

[0070] m is 0, 1, 2 or 3, wherein when m is 1, 2 or 3, R 6 Available ring members connected to ring B;

[0071] R 1a 、R 1b 、R 3a and R 3b Each independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 7d R 7e ; or R 1a and R 1b , or R3a and R 3b , together with the carbon atom to which they are attached, form R 9 ;

[0072] R 1d 、R 1e 、R 2d 、R 2e 、R 3d 、R 3e 、R 7d and R 7e are each independently selected from hydrogen, deuterium, R 11 、C 1-6 Alkyl and C 1-6 haloalkyl; or, R 1d and R 1e , or R 2d and R 2e , or R 3d and R 3e , or R 7d and R 7e , together with the nitrogen atom to which they are commonly attached, form R 10 ;

[0073] R 1f 、R 2f and R 3f independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl and R 12 ;

[0074] R 7 、R 8 、R 9 、R 11 and R 12 Each independently selected from: saturated or partially unsaturated C 3-7 Cycloalkyl; 3-10 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 8d R 8e Substituents substituted;

[0075] R 10is selected from: a 3-7 membered saturated or partially unsaturated heterocyclyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5-10 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-3 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 10d R 10e and

[0076] R 8d 、R 8e 、R 10d and R 10e are each independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0077] In some embodiments, the present invention provides compounds of formula (I), wherein R 1 and R 4 Not hydrogen or deuterium at the same time.

[0078] In some embodiments, the present invention provides compounds of formula (I), wherein R 1a 、R 1b 、R 3a and R 3b Each independently selected from hydrogen, halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio and -NR 7d R 7e ; or R 1a and R 1b , or R 3a and R 3b , together with the carbon atom to which they are attached, form R 9 .

[0079] In some embodiments, the present invention provides compounds of formula (I), wherein R 1d 、R 1e 、R 2d 、R 2e 、R 3d 、R 3e 、R 7d and R 7e are each independently selected from hydrogen, R11 、C 1-4 Alkyl and C 1-4 haloalkyl; or, R 1d and R 1e , or R 2d and R 2e , or R 3d and R 3e , or R 7d and R 7e , together with the nitrogen atom to which they are commonly attached, form R 10 .

[0080] In some embodiments, the present invention provides compounds of formula (I), wherein R 1f 、R 2f and R 3f are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl and R 12 .

[0081] In some embodiments, the present invention provides compounds of formula (I), wherein R 7 、R 8 、R 9 、R 11 and R 12 Each independently selected from: saturated or partially unsaturated C 3-6 Cycloalkyl; 3-10 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 8d R 8e substituted by a substituent.

[0082] In some embodiments, the present invention provides compounds of formula (I), wherein R 10 is selected from: a 3-6 membered saturated or partially unsaturated heterocyclyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 10d R 10e substituted by a substituent.

[0083] In some embodiments, the present invention provides compounds of formula (I), wherein R 8d 、R 8e 、R 10d and R 10e are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0084] In a first sub-aspect, the present invention provides a compound of formula (I) as described above, wherein R 1 Not hydrogen.

[0085] In some embodiments, R 1 Selected from: R 7 、Halogen、CN、NO2、C 1-4 Alkyl, -OR 1f 、-SR 1f 、-NR 1d R 1e 、-S(O)2R 1f 、-S(O)R 1f 、-S(O)2-NR 1d R 1e 、-S(O)-NR 1d R 1e 、-P(O)(OR 1f )2、-P(O)(NR 1d R 1e )2、-CF(R 1f )2、-CF2(R 1f )、-CF3、-CCl(R 1f )2、-CCl2(R 1f )、-CCl3、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)R 1f 、-C(O)OR 1f、-C(O)NR 1d R 1e 、-C(O)NR 1f -OR 1f 、-OC(O)R 1f 、-OC(O)NR 1d R 1e 、-NR 1f -C(O)OR 1f 、-NR 1f -C(O)R 1f 、-NR 1f -C(O)NR 1d R 1e or -NR 1f -S(O)2R 1f In some embodiments, R 1 Selected from: R 7 、Halogen、CN、NO2、C 1-4 Alkyl, -OR 1f 、-SR 1f 、-NR 1d R 1e 、-CF(R 1f )2、-CF2(R 1f )、-CF3、-CCl(R 1f )2、-CCl2(R 1f )、-CCl3、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)OR 1f or -C(O)NR 1d R 1e In some embodiments, R 1 Selected from: R 7 、Halogen、CN、-OR 1f 、-NR 1d R 1e 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR1f 、-C(O)OR 1f or -C(O)NR 1d R 1e In some such embodiments, R 7 Selected from: C 3-6 cycloalkyl; 4-6 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, phenyl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 8d R 8e In some such embodiments, R 7 Selected from: C 3-6 cycloalkyl; 4-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and -NR 8d R 8e In some such embodiments, R 8d and R 8e Preferably each independently selected from hydrogen and C 1-6 Preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-4 alkyl.

[0086] In some such embodiments, R 7 is selected from: a 4-6 membered heterocycloalkyl group having 1 N atom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0087] In some such embodiments, R 7 Selected from: azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0088] In some such embodiments, R 7 Selected from: azetidinyl, pyrrolidinyl and piperidinyl.

[0089] In some such embodiments, p is 1.

[0090] In some such embodiments, R 1a and R 1b are each independently selected from hydrogen and C 1-6 alkyl.

[0091] In some such embodiments, R 1a and R 1b are each independently selected from hydrogen and C 1-4 In some such embodiments, R 1a and R 1b are each independently hydrogen.

[0092] In some such embodiments, R 1a and R 1b Together with the carbon atom to which they are attached, they form R 9 .

[0093] In some such embodiments, R 9 Preferably selected from: C 3-6 Cycloalkyl; a 3-6 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio and -NR 8d R 8e In some such embodiments, R 8d and R 8ePreferably each independently selected from hydrogen and C 1-6 More preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-4 alkyl.

[0094] In some such embodiments, R 9 Preferably selected from: C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, NH2, -NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0095] In some such embodiments, R 9 Preferably selected from: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0096] In some such embodiments, R 9 Preferred is cyclopropyl.

[0097] In some such embodiments, R 1d and R 1e are each independently selected from hydrogen, R 11 and C 1-6 In some such embodiments, R 1d and R 1e are each independently selected from hydrogen, R 11 and C 1-4 In some such embodiments, R 1d and R 1e are each independently selected from hydrogen, R 11 , methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0098] In some such embodiments, R 1d and R 1e Together with the nitrogen atom to which they are attached, they form R 10 .

[0099] In some such embodiments, R 11 Preferably selected from: C3-6 Cycloalkyl; a 3-6 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio and -NR 8d R 8e In some such embodiments, R 8d and R 8e Preferably each independently selected from hydrogen and C 1-6 Preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-4 alkyl.

[0100] In some such embodiments, R 11 Selected from: C 3-6 and 3-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0101] In some such embodiments, R 11 Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0102] In some such embodiments, R 11is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from F and Cl.

[0103] In some such embodiments, R 11 Selected from cyclopropyl and

[0104] In some such embodiments, R 10 Preferably selected from: 3-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl and heteroaryl are optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0105] In some such embodiments, R 10 is selected from the group consisting of: azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0106] In some such embodiments, R 10 Selected from: Each of them is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0107] In some such embodiments, R 10 Selected from: Each of them is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0108] In some such embodiments, R 1f Selected from hydrogen and C 1-6 In some such embodiments, R 1f Selected from hydrogen and C 1-4 In some such embodiments, R 1f For hydrogen.

[0109] In some particular embodiments, R 1 Selected from: F, Cl, Br, CN, OH, NH2, -NHCH3, -C(O)OH, -C(O)NH2, -CH2NH2, -CH2OH,

[0110] In some particular embodiments, R 1 Selected from -CN, -C(O)NH2, F, -NHCH3, -C(O)OH,

[0111] In some embodiments according to the first sub-aspect, the compound of formula (I) has the structure of formula (I-1):

[0112] Where n is 0 or 1.

[0113] In a second sub-aspect, the present invention provides compounds of formula (I) as described above, wherein R 1 is selected from hydrogen and deuterium, and n is 1 or 2.

[0114] In some embodiments, R 1 is hydrogen, and n is 1.

[0115] In some embodiments according to the second sub-aspect, the compound of formula (I) has the structure of formula (I-2):

[0116] The conditions are: R 4 Not hydrogen or deuterium.

[0117] In some embodiments, the present invention provides a compound according to any of the embodiments described above, wherein R 4 Selected from: hydrogen, R 7、Halogen、CN、NO2、-OR 1f 、-SR 1f and -NR 1d R 1e ; The condition is: when R 1 When it is hydrogen or deuterium, R 4 is not hydrogen. In some such embodiments, R 1d and R 1e Preferably each independently selected from hydrogen and C 1-6 Preferably, R 1d and R 1e are each independently selected from hydrogen and C 1-4 In some such embodiments, R 1f Preferably selected from hydrogen and C 1-6 Preferably, R 1f Selected from hydrogen and C 1-4 alkyl.

[0118] In some embodiments, R 4 Selected from: hydrogen, R 7 , F, Cl, Br, CN, NO2, OH and NH2; the condition is: when R 1 When it is hydrogen or deuterium, R 4 In some embodiments, R 4 Selected from: hydrogen, R 7 and CN; the condition is: when R 1 When it is hydrogen or deuterium, R 4 Not hydrogen.

[0119] In some such embodiments, R 7 Preferably selected from: 4-6 membered saturated monocyclic heterocyclic group, 8-10 membered saturated fused bicyclic heterocyclic group, 6-11 membered saturated monospiro heterocyclic group and 7-10 membered saturated bridged heterocyclic group, each of which has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and is optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 8d R 8e In some such embodiments, R 7 Selected from: 4-6 membered saturated monocyclic heterocyclic groups and 7-10 membered saturated bridged heterocyclic groups, said monocyclic heterocyclic groups and bridged heterocyclic groups having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4Halogenated alkyl, C 1-4 Alkoxy and -NR 8d R 8e In some such embodiments, R 8d and R 8e Preferably each independently selected from hydrogen and C 1-6 Preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-4 alkyl.

[0120] In some such embodiments, R 7 is selected from: a 4-6 membered saturated monocyclic heterocyclic group (e.g., azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl or thiomorpholinyl) and a 7-10 membered saturated bridged heterocyclic group, wherein the monocyclic heterocyclic group and the bridged heterocyclic group have 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and are optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0121] In some such embodiments, R 7 Selected from: Each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2, and wherein X 10 is CH2, (CH2)2 or (CH2)3.

[0122] In some such embodiments, R 7 Selected from:

[0123] In some particular embodiments, R 4 Selected from: hydrogen, CN, The condition is: when R 1 When it is hydrogen or deuterium, R 4 Not hydrogen.

[0124] In some embodiments, the present invention provides a compound according to any of the embodiments described above, wherein:

[0125] R and R 5 are each independently selected from hydrogen.

[0126] In some embodiments, the present invention provides a compound according to any of the embodiments described above, wherein:

[0127] R 2 Selected from: C 3-6 Cycloalkyl; a 4-6 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -NR 2d R 2e 、-C(O)OR 2f and -C(O)NR 2d R 2e and in the case where two substituents are attached to the same ring carbon atom of the cycloalkyl or heterocyclyl group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 In some such embodiments, R 2d and R 2e Preferably each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 In some such embodiments, R 2f Selected from hydrogen and C 1-6 alkyl.

[0128] In some embodiments, R 2 Selected from: C 3-6 cycloalkyl; 4-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; and 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, NH2, NO2, C 1-4Alkyl, -C(O)OH, -C(O)OC 1-4 Alkyl, -C(O)NH2, -C(O)NH(C 1-4 alkyl) and -C(O)NH(C 1-4 alkyl)2, and in the case where two substituents are attached to the same ring carbon atom of the cycloalkyl or heterocycloalkyl, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl.

[0129] In some embodiments, R 2 is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, each of which is optionally substituted by 1, 2 or more independently selected from F, Cl, Br, CN, OH, NH2, NO2, methyl, ethyl, isopropyl, tert-butyl, C(O )OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)NH2, -C(O)NHCH3 and -C(O)N(CH3)2, and in the case where two substituents are attached to the same ring carbon atom of the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, morpholinyl or thiomorpholinyl group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl.

[0130] In some embodiments, R 2 is selected from the group consisting of cyclohexyl, pyrrolidinyl, piperidinyl, phenyl and pyridinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, OH, NH2 and methyl, and in the case where two substituents are attached to the same ring carbon atom of the pyrrolidinyl or piperidinyl, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl.

[0131] In some embodiments, R 2 Selected from:

[0132] In some embodiments, R 2 Selected from:

[0133] In some embodiments, the present invention provides a compound according to any of the embodiments described above, wherein R 3 Selected from: halogen, CN, NO2, C 1-6 Alkyl, -OR 3f 、-SR 3f 、-NR 3d R 3e 、-S(O)2-NR 3d R 3e 、-S(O)-NR 3d R 3e 、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f )、-CCl3、-C(O)OR 3f and -C(O)NR 3d R 3e In some embodiments, R 3 Selected from: halogen, CN, C 1-4 Alkyl, -OR 3f 、-NR 3d R 3e 、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f )、-CCl3、-C(O)OR 3f and -C(O)NR 3d R 3e .

[0134] In some embodiments, R 3 Selected from: halogen, CN, C 1-4 Alkyl, -OR 3f 、-NR 3d R 3e 、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f ), -CCl3 and -C(O)NR 3d R 3e .

[0135] In some such embodiments, R 3d and R 3e Preferably each independently selected from hydrogen, deuterium, R 11 、C 1-4 Alkyl and C 1-4Halogenated alkyl.

[0136] In some such embodiments, R 11 Preferably selected from: C 3-6 Cycloalkyl; a 4-6 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio and -NR 8d R 8e substituted by a substituent.

[0137] In some such embodiments, R 8d and R 8e Preferably each independently selected from hydrogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

[0138] In some particular embodiments, R 3d and R 3e are each independently selected from hydrogen, methyl and ethyl.

[0139] In some such embodiments, R 3f Selected from hydrogen and C 1-6 Preferably, R 3f Selected from hydrogen and C 1-4 alkyl.

[0140] In some such embodiments, R 3d and R 3e Together with the nitrogen atom to which they are attached, they form R 10 .

[0141] In some such embodiments, R 10 Preferably selected from: 3-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl and heteroaryl are optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0142] In some particular embodiments, R 3 Selected from: halogen, OH, SH, NH2, CN, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2、-CHF2、-CH2F、-CF3、-CH2Cl、-CHCl2、-CCl3、-C(O)NH2、-C(O)NH(C 1-4 alkyl) and -C(O)N(C 1-4 Alkyl)2.

[0143] In some particular embodiments, R 3 Selected from: F, Cl, Br, OH, NH2, CN, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, -N(CH3)2, -CHF2, -CHCl2 and -C(O)NH2.

[0144] In some embodiments, the present invention provides a compound according to any of the embodiments described above, wherein R 6 Selected from: halogen, CN, NO2, C 1-4 Alkyl, -OR 3f 、-SR 3f 、-NR 3d R 3e 、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f ) and -CCl3. In some such embodiments, R 3f Preferably selected from hydrogen and C 1-6 Preferably, R 3f Selected from hydrogen and C 1-4 alkyl.

[0145] In some embodiments, R 6 Selected from: F, Cl, Br, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2 and -CCl3.

[0146] In some embodiments, the present invention provides a compound according to any of the embodiments described above, wherein m is 0.

[0147] In some embodiments, the present invention provides a compound according to any of the embodiments described above, wherein at least two of X1, X2, X3, X4 and X5 are N, provided that X4 and X5 are not N at the same time.

[0148] In some embodiments, three of X1, X2, X3, X4 and X5 are N, provided that X4 and X5 are not N at the same time.

[0149] In some embodiments, four of X1, X2, X3, X4, and X5 are N, provided that X4 and X5 are not N at the same time.

[0150] In some embodiments, X1 is N.

[0151] In some embodiments, the present invention provides a compound according to any of the embodiments described above, wherein at least two of X6, X7, X8 and X9 are N.

[0152] In some embodiments, at least three of X6, X7, X8 and X9 are N.

[0153] In some embodiments, at least four of X6, X7, X8 and X9 are N.

[0154] In some embodiments, X8 and X9 are each N.

[0155] In some embodiments, the present invention provides a compound according to any of the embodiments described above, wherein 2 or 3 of X1, X2, X3, X4 and X5 are N, and X1 is N, provided that X4 and X5 are not N at the same time; and

[0156] Three or four of X6, X7, X8, and X9 are N, and X8 and X9 are each N.

[0157] In a third sub-aspect, the present invention provides compounds according to formula (I), formula (I-1) and formula (I-2) as described above, wherein X1 and X2 are each N; X3 is CH; X4 and X5 are each C; X6, X8 and X9 are each N; and X7 is CH.

[0158] In some embodiments, the compounds of the present invention have the structure of Formula (Ii) or Formula (I-ii):

[0159] where R 1 、R 2 、R 3 and R 4Each is as defined above in any of the embodiments of the compounds of formula (I), formula (I-1) and formula (I-2), provided that: R 1 Not hydrogen or deuterium;

[0160] where R 2 、R 3 and R 4 Each is as defined above in any of the embodiments of the compounds of formula (I), formula (I-1) and formula (I-2), provided that: R 4 Not hydrogen or deuterium.

[0161] In some embodiments, R 1 Selected from: halogen, CN, NO2, -OR 1f 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)OR 1f or -C(O)NR 1d R 1e .

[0162] In some embodiments, R 1 Selected from: halogen, CN, -(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-C(O)OR 1f or -C(O)NR 1d R 1e .

[0163] In some such embodiments, p is preferably 1.

[0164] In some such embodiments, R 1a and R 1b Preferably each independently selected from hydrogen and C 1-4 The alkyl groups are preferably each independently hydrogen.

[0165] In some such embodiments, R1a and R 1b Together with the carbon atom to which they are attached, they form R 9 .

[0166] In some such embodiments, R 9 Preferably selected from: C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0167] In some such embodiments, R 9 Selected from: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0168] In some such embodiments, R 9 It is cyclopropyl.

[0169] In some such embodiments, R 1d and R 1e Preferably each independently selected from hydrogen and R 11 ; or R 1d and R 1e Together with the nitrogen atom to which they are attached, they form R 10 .

[0170] In some such embodiments, R 11 Preferably selected from: C 3-6 Cycloalkyl, and 3-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0171] In some such embodiments, R 11is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2 and NH2.

[0172] In some such embodiments, R 11 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2 and NH2.

[0173] In some such embodiments, R 11 Selected from cyclopropyl and

[0174] In some such embodiments, R 10 Preferably selected from: 3-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0175] In some such embodiments, R 10 Selected from: azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more groups independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0176] In some such embodiments, R 10 Selected from: Each of them is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0177] In some such embodiments, R 1f Selected from hydrogen and C 1-4 Alkyl, preferably hydrogen.

[0178] In some particular embodiments, R 1 Selected from: F, Cl, Br, CN, OH, NH2, C(O)OH, -C(O)NH2,

[0179] In some particular embodiments, R 1 Selected from CN and -C(O)NH2.

[0180] In some embodiments, R 2 Selected from: C 3-6 cycloalkyl; 4-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; and 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, NH2, NO2, C 1-6 Alkyl and C 1-6 In the case where two substituents are attached to the same ring carbon atom of the cycloalkyl or heterocycloalkyl group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl.

[0181] In some embodiments, R 2Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, each of which is optionally substituted by 1 or 2 independently selected from F, Cl, Br, C N, OH, NH2, NO2 and C1-C4 alkyl substituents, and in the case where two substituents are attached to the same ring carbon atom of the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl or thiomorpholinyl, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C1-C4 alkyl group. 3-6 Cycloalkyl.

[0182] In some embodiments, R 2 is selected from cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, phenyl and pyridinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, CN, OH, NH2, NO2, methyl, ethyl and isopropyl, and in the case where two substituents are attached to the same ring carbon atom of the pyrrolidinyl or piperidinyl, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl.

[0183] In some embodiments, R 2 Selected from:

[0184] In some embodiments, R 2 Selected from

[0185] In some embodiments, R 2 for

[0186] In some embodiments, R 3 Selected from: halogen, CN, NO2, C 1-6 Alkyl, OH, NH2, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2 and -CCl3.

[0187] In some embodiments, R 3 is -CHF2.

[0188] In some embodiments, R 4 Selected from: hydrogen, R7 , halogens, CN, NO2, OH and NH2.

[0189] In some embodiments, R 4 Selected from: hydrogen, R 7 , F, Cl, Br, CN, NO2, OH and NH2.

[0190] In some such embodiments, R 7 Preferably selected from: 4-6 membered saturated monocyclic heterocyclic groups having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0191] In some such embodiments, R 7 Selected from:

[0192] In some particular embodiments, R 4 Selected from: hydrogen, CN and The condition is: when R 1 When it is hydrogen, R 4 Not hydrogen.

[0193] In a fourth sub-aspect, the present invention provides compounds according to formula (I), formula (I-1) and formula (I-2) as described above, wherein X1 and X5 are each N; X2 and X4 are C; X3 is CH; X6, X8 and X9 are each N; and X7 is CH.

[0194] In some embodiments, the compounds of the present invention have the structure of Formula (I-iii):

[0195] where R 1 、R 2 and R 3 Each is as defined above in any of the embodiments of the compounds of formula (I), formula (I-1) and formula (I-2), provided that: R 1 Not hydrogen or deuterium.

[0196] In some embodiments, R 1 Selected from: R 7 、Halogen、NO2、-OR 1f、-NR 1d R 1e 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)OR 1f or -C(O)NR 1d R 1e .

[0197] In some embodiments, R 1 Selected from: R 7 , halogen, -NR 1d R 1e 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-C(O)OR 1f or -C(O)NR 1d R 1e .

[0198] In some such embodiments, p is 1.

[0199] In some such embodiments, R 7 is selected from: a 4-6 membered heterocycloalkyl group having 1 N atom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0200] In some such embodiments, R 7Selected from: azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0201] In some such embodiments, R 7 It is a piperidinyl group.

[0202] In some such embodiments, R 1a and R 1b are each independently selected from hydrogen and C 1-4 The alkyl groups are preferably each independently hydrogen.

[0203] In some such embodiments, R 1a and R 1b Together with the carbon atom to which they are attached, they form R 9 .

[0204] In some such embodiments, R 9 Selected from: C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0205] In some such embodiments, R 9 Selected from: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0206] In some such embodiments, R 1d and R 1e are each independently selected from hydrogen, C 1-4 Alkyl and R 11 ; or R 1d and R 1eTogether with the nitrogen atom to which they are attached, they form R 10 .

[0207] In some such embodiments, R 11 Selected from: C 3-6 Cycloalkyl, and 3-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0208] In some such embodiments, R 11 is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2 and NH2.

[0209] In some such embodiments, R 10 is selected from: a 3-6 membered heterocycloalkyl group having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0210] In some such embodiments, R 10 Selected from: azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more groups independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0211] In some such embodiments, R 1f Selected from hydrogen and C1-4 Alkyl, preferably hydrogen.

[0212] In some particular embodiments, R 1 Selected from: F, Cl, Br, OH, NH2, -NHCH3, C(O)OH, -C(O)NH2, -CH2OH,

[0213] In some particular embodiments, R 1 Selected from -CN and -C(O)NH2.

[0214] In some embodiments, R 2 Selected from: C 3-6 cycloalkyl; 4-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; and 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, NH2, NO2, C 1-6 Alkyl and C 1-6 In the case where two substituents are attached to the same ring carbon atom of the cycloalkyl or heterocycloalkyl group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl.

[0215] In some embodiments, R 2 Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, each of which is optionally substituted by 1 or 2 independently selected from F, Cl, Br, C N, OH, NH2, NO2 and C1-C4 alkyl substituents, and in the case where two substituents are attached to the same ring carbon atom of the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl or thiomorpholinyl, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C1-C4 alkyl group. 3-6 Cycloalkyl.

[0216] In some embodiments, R 2is selected from the group consisting of cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, phenyl and pyridinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F, Cl, Br, CN, OH, NH2, NO2, methyl, ethyl and isopropyl, and in the case where two substituents are attached to the same ring carbon atom of the pyrrolidinyl or piperidinyl, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl.

[0217] In some embodiments, R 2 Selected from:

[0218] In some embodiments, R 2 Selected from:

[0219] In some embodiments, R 3 Selected from: halogen, CN, C 1-4 Alkyl, -OR 3f 、-SR 3f 、-NR 3d R 3e 、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f ), -CCl3 and -C(O)NR 3d R 3e In some such embodiments, R 3d and R 3e are each independently selected from hydrogen and C 1-4 Alkyl, preferably hydrogen and methyl. In some such embodiments, R 3f Selected from hydrogen and C 1-4 Alkyl groups, preferably hydrogen and methyl.

[0220] In some particular embodiments, R 3 Selected from: halogen, OH, SH, NH2, CN, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2、-CHF2、-CH2F、-CF3、-CH2Cl、-CHCl2、-CCl3、-C(O)NH2、-C(O)NH(C 1-4 alkyl) and -C(O)N(C 1-4 Alkyl)2.

[0221] In some embodiments, R 3Selected from: F, OH, NH2, CN, methyl, ethyl, isopropyl, tert-butyl, methoxy, -N(CH3)2, -CHF2 and -C(O)NH2.

[0222] In some embodiments, R 3 Selected from: F, CN, methyl, isopropyl, methoxy, -N(CH3)2, -CHF2 and -C(O)NH2.

[0223] In a fifth sub-aspect, the present invention provides compounds according to formula (I), formula (I-1) and formula (I-2) as described above, wherein X1, X3 and X4 are each N; X2 and X5 are C; X6, X8 and X9 are each N; and X7 is CH.

[0224] In some embodiments, the compounds of the present invention have the structure of Formula (I-iv):

[0225] where R 1 、R 2 and R 3 Each is as defined above in any of the embodiments of the compounds of formula (I), formula (I-1) and formula (I-2), provided that: R 1 Not hydrogen or deuterium.

[0226] In some embodiments, R 1 Selected from: halogen, CN, NO2, -OR 1f 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e or-C(O)OR 1f .

[0227] In some embodiments, R 1 Selected from: halogen, CN, -(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f , or -C(O)OR 1f .

[0228] In some such embodiments, p is 1.

[0229] In some such embodiments, R 1a and R 1b are each independently selected from hydrogen and C 1-4 alkyl, preferably each independently hydrogen; or R 1a and R 1b Together with the carbon atom to which they are attached, they form R 9 .

[0230] In some such embodiments, R 9 Selected from: C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0231] In some such embodiments, R 9 Selected from: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0232] In some such embodiments, R 1d and R 1e are each independently selected from hydrogen and R 11 ; or R 1d and R 1e Together with the nitrogen atom to which they are attached, they form R 10 .

[0233] In some such embodiments, R 11 Selected from: C 3-6 Cycloalkyl, and 3-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4alkyl)2 is substituted with a substituent.

[0234] In some such embodiments, R 11 is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2 and NH2.

[0235] In some such embodiments, R 10 is selected from: a 3-6 membered heterocycloalkyl group having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0236] In some such embodiments, R 10 Selected from: azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more groups independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0237] In some such embodiments, R 1f Selected from hydrogen and C 1-4 Alkyl, preferably hydrogen.

[0238] In some particular embodiments, R 1 Selected from: F, Cl, Br, CN, OH, NH2, C(O)OH, In some particular embodiments, R 1 For CN.

[0239] In some embodiments, R 2 Selected from: C 3-6cycloalkyl; 4-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; and 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, NH2, NO2 and C 1-4 The alkyl group is substituted with a substituent.

[0240] In some embodiments, R 2 Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, each of which is optionally substituted by 1 or 2 independently selected from F, Cl, Br, C N, OH, NH2, NO2 and C1-C4 alkyl substituents, and in the case where two substituents are attached to the same ring carbon atom of the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl or thiomorpholinyl, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C1-C4 alkyl group. 3-6 Cycloalkyl.

[0241] In some embodiments, R 2 Selected from:

[0242] In some embodiments, R 2 Selected from:

[0243] In some embodiments, R 2 for

[0244] In some embodiments, R 3 Selected from: halogen, CN, NO2, C 1-6 Alkyl, OH, NH2, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2 and -CCl3.

[0245] In some embodiments, R 3 is -CHF2.

[0246] In a sixth sub-aspect, the present invention provides compounds according to formula (I), formula (I-1) and formula (I-2) described above, wherein X1 and X5 are each N; X2 and X4 are C; X3 is CH; X6 is CH; and X7, X8 and X9 are each N.

[0247] In some embodiments, the compounds of the present invention have the structure of Formula (IV):

[0248] where R 1 、R 2 and R 3 Each is as defined above in any of the embodiments of the compounds of formula (I), formula (I-1) and formula (I-2), provided that: R 1 Not hydrogen or deuterium.

[0249] In some embodiments, R 1 、R 2 and R 3 Each is as defined in any of the embodiments according to the third, fourth and / or fifth sub-aspects.

[0250] In some embodiments, R 1 is -C(O)NH2; and / or, in some embodiments, R 2 for And / or, in some embodiments, R 3 is -CHF2.

[0251] In a seventh aspect, the present invention provides compounds according to formula (I), formula (I-1) and formula (I-2) as described above, wherein X1 and X5 are each N; X2 and X4 are C; X3 is CH; and X6, X7, X8 and X9 are each N.

[0252] In some embodiments, the compounds of the present invention have the structure of Formula (I-vi):

[0253] where R 1 、R 2 and R 3 Each is as defined above in any of the embodiments of the compounds of formula (I), formula (I-1) and formula (I-2), provided that: R 1 Not hydrogen or deuterium.

[0254] In some embodiments, R 1 、R 2 and R 3 Each is as defined in any of the embodiments according to the third, fourth and / or fifth sub-aspects.

[0255] In some embodiments, R 1 is -C(O)NH2; and / or, in some embodiments, R 2 for And / or, in some embodiments, R 3 is -CHF2.

[0256] In a seventh aspect, the present invention provides compounds according to formula (I), formula (I-1) and formula (I-2) as described above, wherein X1 and X2 are each N; X3 is CH; X4 and X5 are each C; and X6, X7, X8 and X9 are each N.

[0257] In some embodiments, the compounds of the present invention have the structure of Formula (I-vii):

[0258] where R 1 、R 2 and R 3 Each is as defined above in any of the embodiments of the compounds of formula (I), formula (I-1) and formula (I-2), provided that: R 1 Not hydrogen or deuterium.

[0259] In some embodiments, R 1 、R 2 and R 3 Each is as defined in any of the embodiments according to the third, fourth and / or fifth sub-aspects.

[0260] In some embodiments, R 1 is -CN; and / or, in some embodiments, R 2 for And / or, in some embodiments, R 3 is -CHF2.

[0261] In an eighth sub-aspect, the present invention provides compounds according to formula (I), formula (I-1) and formula (I-2) described above, wherein X1, X3 and X4 are each N; X2 and X5 are C; and X6, X7, X8 and X9 are each N.

[0262] In some embodiments, the compounds of the present invention have the structure of Formula (I-viii):

[0263] where R 2 、R 3 and R 4Each is as defined above in any of the embodiments of the compounds of formula (I), formula (I-1) and formula (I-2), provided that: R 4 Not hydrogen or deuterium.

[0264] In some embodiments, R 2 and R 3 Each is as defined in any of the embodiments according to the third, fourth and / or fifth sub-aspects.

[0265] In some embodiments, R 2 for And / or, in some embodiments, R 3 is -CHF2.

[0266] In some embodiments, R 4 Selected from: R 7 , halogen, CN, NO2, OH and NH2. In some embodiments, R 4 Selected from: R 7 , F, Cl, Br, CN, NO2, OH and NH2. In some such embodiments, R 7 Selected from: 7-10 membered saturated bridged heterocyclic groups having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 In some such embodiments, R 7 Selected from: where X 10 is CH2, (CH2)2 or (CH2)3.

[0267] In some particular embodiments, R 4 Selected from: CN and More preferred

[0268] The present invention encompasses compounds resulting from any combination of the various embodiments.

[0269] In some embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0270] PROTAC molecules that inhibit and degrade IRAK4

[0271] In another aspect, the present invention provides a compound of the present invention as described above, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof for the preparation of a protein degradation targeting chimera (PROTAC).

[0272] In another aspect, the present invention provides a protein degradation targeting chimera (PROTAC) comprising a portion having IRAK4 protein kinase inhibitory activity, wherein the portion is derived from a compound of the present invention as described above, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0273] Pharmaceutical compositions and methods of treatment

[0274] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or its stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt, or a PROTAC molecule of the present invention, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition is preferably a solid preparation, a liquid preparation or a transdermal preparation.

[0275] In another aspect, the present invention provides a compound of the present invention or its stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt, or a PROTAC molecule of the present invention, or a pharmaceutical composition of the present invention for the preparation of a medicament.

[0276] In some embodiments, the compounds of the invention, the PROTAC molecules of the invention, the pharmaceutical compositions of the invention, or the medicaments are used to treat a disease, disorder, or condition associated with IRAK4 protein kinase.

[0277] In another aspect, the present invention also provides a method for treating a disease, disorder or condition associated with IRAK4 protein kinase, alleviating its symptoms, delaying its development or onset, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, PROTAC molecules of the present invention, or pharmaceutical compositions of the present invention.

[0278] In another aspect, the present invention provides a compound of the present invention or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, a PROTAC molecule of the present invention, or a pharmaceutical composition of the present invention for use in treating a disease, disorder or condition associated with IRAK4 protein kinase.

[0279] In another aspect, the present invention also provides a compound of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, PROTAC molecules of the present invention, or pharmaceutical compositions of the present invention for the preparation of a medicament as an IRAK4 inhibitor.

[0280] In another aspect, the present invention provides a method of inhibiting IRAK4 activity in a subject, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates or pharmaceutically acceptable salts, PROTAC molecules of the present invention, or pharmaceutical compositions of the present invention.

[0281] In some embodiments, the disease, disorder or condition associated with IRAK4 protein kinase is selected from the group consisting of: an autoimmune disorder, an inflammatory disorder, cancer, transplant rejection, thromboembolism, atherosclerosis, myocardial infarction, and metabolic syndrome.

[0282] In some embodiments, the inflammatory disorder is selected from the group consisting of osteoarthritis, gout, gouty arthritis, chronic obstructive pulmonary disease, periodic fevers, atopic dermatitis, allergic eczema, lymphadenopathy, sepsis, irritable bowel syndrome (IBD), ulcerative colitis, asthma, and allergies.

[0283] In some embodiments, the autoimmune disorder is selected from the group consisting of: Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, psoriatic arthritis, multiple sclerosis, neuropathic pain, ankylosing spondylitis, reactive arthritis, and systemic juvenile idiopathic arthritis.

[0284] In some embodiments, the transplant rejection is selected from graft-versus-host disease and allograft rejection.

[0285] In some embodiments, the cancer is selected from the group consisting of brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, stomach tumors, breast cancer, bladder and colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, testicular cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck and head tumors, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin and non-Hodgkin lymphoma, breast cancer, follicular carcinoma, papillary carcinoma, seminoma Myeloma, melanoma, acute myeloid leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, activated B-cell-like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and multiple myeloma.

[0286] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0287] As used herein, unless otherwise indicated, the terms "treat," ...

[0288] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0289] In another embodiment, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.

[0290] Example

[0291] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are intended only to illustrate the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all commercially available conventional products.

[0292] NMR was measured using a Bruker Avance III 400 NMR spectrometer, and the chemical shift (δ) was measured at 10 -6 The unit is ppm. The solvent is deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard is tetramethylsilane (TMS).

[0293] MS was measured using an Agilent (ESI) mass spectrometer (Agilent 1260, Agilent 6125B).

[0294] High-performance liquid chromatography (HPLC) assay conditions: Gilson GX-281, C18 column (10 μM, 19 mm x 250 mm), UV detection at 220 and 254 nm, elution with a gradient of 5–95% acetonitrile (containing 0.05% v / v formic acid or ammonium bicarbonate) over 15 min.

[0295] Reverse phase purification was performed using the Biotage Isolera Rapid Purification System.

[0296] Thin layer chromatography separation and purification were performed using thin layer chromatography silica gel plates (aluminum plates (20 cm x 20 cm x 1 mm) produced by Meck, or GF 254 produced in Yantai).

[0297] Microwave reaction was carried out using Biotage Initiator+ (400W, RT-300°C) microwave reactor.

[0298] Reaction monitoring is usually performed by TLC or LCMS. Common developing solvent systems include: dichloromethane / methanol, n-hexane / ethyl acetate, petroleum ether / ethyl acetate. The volume ratio of the solvent is adjusted according to the polarity of the compound or by adding triethylamine.

[0299] The silica gel used in column chromatography is generally 100-200 mesh. Common eluent systems include dichloromethane / methanol and petroleum ether / ethyl acetate. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0300] The reagents and solvents of the present invention were purchased from Aldrich Chemical Company, Anage, J&K Technology, Shanghai Bid Pharmaceutical Technology Co., Ltd., Yaoshi Technology, and Shanghai Titan Technology Co., Ltd.

[0301] In conventional synthesis methods and synthesis examples of compounds and intermediates of the present invention, the meanings of the abbreviations are as shown below.

[0302] Synthesis Example

[0303] Example 1: Preparation of Compound C1

[0304] Synthesis route

[0305] (1) Preparation of compound 1-1

[0306] Compound 1-1 was prepared with reference to the following patent applications and literature: 1) WO2012156334A1; and 2) Storz, Thomas, et al., Synthesis (2008), (2), 201-214.

[0307] (2) Preparation of Compound 1-2

[0308] At room temperature, NaH (882.0 mg, 22.0 mmol) and N,N-dimethylformamide (20 mL) were added to a single-necked flask and stirred under nitrogen. Compound 1-3 (5.00 g, 18.4 mmol) was dissolved in N,N-dimethylformamide (20 mL) and slowly added dropwise to the NaH suspension at 0°C under nitrogen. After the addition, the reaction was continued at 0°C for 30 minutes. Compound 1a (9.72 g, 44.0 mmol) was added, and the reaction solution was stirred at 25°C for 16 hours. Water (4 mL) was added to the reaction solution. After stirring for 5 minutes, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (0-5% ethyl acetate / petroleum ether) to obtain compound 1-2 (3.0 g).

[0309] LC-MS: m / z: 356.1 (M+H) + , RT=0.983min.

[0310] (3) Preparation of Compound C1

[0311] Compound 1-1 (200 mg, 0.98 mmol) and N,N-dimethylformamide (8 mL) were stirred until dissolved, and compound 1-2 (325 mg, 0.98 mmol), tris(dibenzylideneacetone)dipalladium (45.1 mg, 0.05 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (41.8 mg, 0.10 mmol), and potassium phosphate (626.60 mg, 2.95 mmol) were added in sequence. The atmosphere was purged with nitrogen three times, and the reaction solution was stirred at 90°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (formic acid / acetonitrile / water system) to obtain compound C1 (11.2 mg). LC-MS: m / z: 453.1 (M+H) + , RT=1.169min.

[0312] Example 2: Preparation of Compound C2

[0313] Synthesis route

[0314] (1) Preparation of Compound 2-1

[0315] Compound 2-1 was prepared with reference to the method disclosed in WO2021254493A1.

[0316] (2) Preparation of Compound 2-2

[0317] At room temperature, potassium carbonate (3.99 g, 28.89 mmol) was added to a DMF (30 mL) solution of compound 2-1 (2.7 g, 9.63 mmol) and bromocyclohexane (2.36 mL, 19.26 mmol), and the resulting mixture was stirred at 80 ° C for 18 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10: 1 to 1: 1) to give compound 2-2 (1.00 g, 2.76 mmol). LC-MS: m / z: 363 (M + H) + , RT=2.925min.

[0318] (3) Preparation of Compound 2-3

[0319] At room temperature, bis(triphenylphosphine)palladium dichloride (0.97 g, 1.38 mmol) was added to a solution of compound 2-2 (1.00 g, 2.76 mmol) and tributyl(vinyl)tin (1.62 mL, 5.52 mmol) in 1,4-dioxane (20 mL). The mixture was replaced with nitrogen and stirred at 100 ° C for 18 hours under nitrogen protection. The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10: 1 to 1: 1) to give compound 2-3 (500 mg, 1.90 mmol). LC-MS: m / z: 262.9 (M + H) + , RT=1.042min.

[0320] (4) Preparation of Compound 2-4

[0321] A solution of compound 2-3 (500 mg, 1.90 mmol) in dichloromethane (10 mL) and methanol (10 mL) was replaced with nitrogen at -78 ° C. The mixture was continuously purged with ozone at -78 ° C and stirred for 1 hour. The reaction solution was quenched with dimethyl sulfide (355 mg, 5.71 mmol) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give compound 2-4 (540 mg, 2.04 mmol).

[0322] LC-MS: m / z: 265 (M+H) + , RT=2.017min.

[0323] (5) Preparation of Compound 2-5

[0324] DAST (0.81 mL, 6.12 mmol) was added to a dichloromethane solution (10 mL) of compound 2-4 (540 mg, 2.04 mmol) at -30 ° C, and the mixture was stirred at -30 ° C for 18 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10: 1 to 1: 1) to give compound 2-5 (180 mg, 0.63 mmol).

[0325] 1 H NMR (400MHz, DMSO-d6) δ9.68 (s, 1H), 7.46 (t, J = 52.0Hz, 1H), 4.98–4.86 (m, 1H), 2.10–2 .05(m,2H),1.90–1.86(m,3H),1.73–1.70(m,1H),1.55–1.44(m,2H),1.35–1.23(m,2H).

[0326] (6) Preparation of Compound C2

[0327] To a solution of compound 2-5 (70 mg, 0.24) and 5a in DMA (4 mL) at room temperature were added 2-amidinopyridine hydrochloride (76.0 mg, 0.48 mmol), zinc powder (62.0 mg, 0.95 mmol), tetrabutylammonium iodide (87.6 mg, 0.24 mmol), and nickel chloride in dimethoxyethane (208 mg, 0.95 mmol). The atmosphere was purged with nitrogen three times and stirred at 65°C under nitrogen for 16 hours. The mixture was cooled to room temperature and filtered. The filtrate was diluted with water (50 mL) and extracted with ethyl acetate (40 mL x 2). The organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water) to afford compound C2 (5.5 mg).

[0328] 1H NMR(400MHz, DMSO-d6)δ9.59(s,1H),8.73(d,J=7.7Hz,1H),8.52(s,1H),7.39(t,J=53.4Hz,1H),7.06(s,1H),4.99–4.70(m,2H) ,3.81(t,J=12.6Hz,2H),3.60(d,J=9.8Hz,2H),2.10-1.70(m,9H),1.73(d,J=12.4Hz,1H),1.57-1.46(m,2H),1.36-1.24(m,1H).

[0329] LC-MS: m / z: 467.2 (M+H) + , RT=2.889min.

[0330] Example 3: Preparation of Compounds C3i and C3ii

[0331] Synthesis route:

[0332] (1) Preparation of compound 3-2

[0333] At room temperature, NaH (882.0 mg, 22.0 mmol) and N,N-dimethylformamide (20 mL) were added to a 100 mL single-necked flask and stirred under nitrogen. Compound 3-1 (5.00 g, 18.4 mmol) was dissolved in N,N-dimethylformamide (20 mL) and slowly added dropwise to the NaH suspension at 0°C under nitrogen. After the addition was complete, the reaction was continued at 0°C for 30 minutes. Compound 3a (9.72 g, 44.0 mmol) was added, and the reaction solution was stirred at 25°C for 16 hours. Water (4 mL) was added to the reaction solution. After stirring for 5 minutes, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (0-5% ethyl acetate / petroleum ether) to obtain compound 3-2 (3.0 g).

[0334] LC-MS: m / z: 356.1 (M+H) + , RT=0.983min.

[0335] (2) Preparation of compound 3-3

[0336] At room temperature, compound 3-2 (3.20 g, 9.03 mmol), acetic acid (50 mL) and water (10 mL) were added to a 100 mL single-necked bottle, and the reaction solution was stirred at 80 ° C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (60 mL) and washed with saturated sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain product 3-3 (2.50 g). The crude product was used directly in the next reaction. LC-MS: m / z: 307.9 (M+H) + .

[0337] (3) Preparation of Compound 3-4

[0338] Compound 3-3 (1.70 g, 5.52 mmol) and dichloromethane (40 mL) were added to a 100 mL single-necked flask at room temperature and stirred to dissolve. Diethylaminosulfur trifluoride (4.45 g, 27.6 mmol) was added at 0°C, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into ice water (30 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound 3-4 (0.90 g).

[0339] 1 H NMR(400MHz, CDCl3)δ8.80(d,J=1.1Hz,1H),7.99(s,1H),6.95(t,J=54.3Hz,1H),4.54–4 .47(m,1H),2.14-1.95(m,7H),1.87-1.74(m,1H),1.57-1.45(m,2H),1.42-1.25(m,1H).

[0340] LC-MS: m / z: 331.8 (M+H) + , RT=1.025min.

[0341] (4) Preparation of Compound 3-5

[0342] At room temperature, compound 3-4 (1.90 g, 5.75 mmol) and dioxane (50 mL) were added to a 100 mL single-necked flask and stirred until dissolved. Hexabutyltin (4.00 g, 6.91 mmol), tris(dibenzylideneacetone)dipalladium (263.5 mg, 0.29 mmol), tricyclohexylphosphine (161.5 mg, 0.58 mmol), and lithium chloride (1.46 g, 34.5 mmol) were added. The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (0-5% ethyl acetate / petroleum ether) to obtain compound 3-5 (2.20 g). LC-MS: m / z: 542.1 (M+H) + , RT=1.083min.

[0343] (5) Preparation of compound C3i

[0344] At room temperature, compound 3b (300.0 mg, 1.35 mmol) and toluene (10 mL) were added to a 40 mL single-necked flask and stirred thoroughly. Compound 3-5 (727 mg, 1.35 mmol) and tetrakis(triphenylphosphine)palladium (155 mg, 0.13 mmol) were added. The reaction solution was stirred at 120°C under nitrogen for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain product C3i (120.0 mg).

[0345] 1 H NMR(400MHz, CDCl3)δ9.16-9.04(m,3H),8.82(s,1H),8.75-8.68(m,1H),7.18–6.90(m,1H),4 .66-4.51(m,1H),2.20-1.98(m,6H),1.87-1.79(m,1H),1.56–1.47(m,2H),1.43–1.34(m,1H).

[0346] LC-MS: m / z: 394.1 (M+H) + , RT=1.01min.

[0347] (6) Preparation of Compound C3ii

[0348] At room temperature, compound C3I (70.0 mg, 0.18 mmol) and sulfuric acid (1.5 mL) were added to an 8 mL single-necked flask. The reaction mixture was stirred at 25°C under nitrogen for 1 hour. LC-MS indicated the reaction was complete. The reaction mixture was poured into ice water (50 mL) and the pH was adjusted to 9-10 with saturated sodium carbonate solution. Extraction was performed with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain product C3ii (18.9 mg).

[0349] 1 H NMR(400MHz,DMSO-d6)δ9.70-9.61(m,1H),9.50-9.41(m,1H),9.21-9.12(m,1H),9.04–8.96(m,1H),8.86-8.78(m,1H),8.32-8.20(m,1H) ),7.87-7.76(m,1H),7.63-7.33(m,1H),2.14-2.04(m,2H),1.97-1.85(m,4H),1.79-1.71(m,1H),1.61-1.48(m,2H),1.38-1.30(m,1H).

[0350] LC-MS: m / z: 412.1 (M+H) + , RT=0.908min.

[0351] Example 4: Preparation of Compounds C4i and C4ii

[0352] Synthesis route

[0353] (1) Preparation of compound 4-1

[0354] Compound 4-1 was prepared by referring to the method disclosed in WO2015117563A1.

[0355] (2) Preparation of compound 4-2

[0356] Compound 4-1 (300 mg, 2.10 mmol) and N-iodosuccinimide (707 mg, 3.14 mmol) were added to acetonitrile (10 ml) at room temperature. The reaction solution was stirred at 60°C for 1 hour. TLC monitored the reaction to confirm completion. Sodium sulfite solution (10 ml) was carefully added to the reaction solution. The mixture was then extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (10% ethyl acetate in petroleum ether) to afford compound 4-2 (270 mg, 1.00 mmol).

[0357] 1 H NMR (400MHz, CDCl3) δ8.27(d,J=2.1Hz,1H),8.05(d,J=2.1Hz,1H),7.24(d,J=4.7Hz,1H),6.95(d,J=4.7Hz,1H).

[0358] (3) Preparation of C4i

[0359] At room temperature, compound 4-2 (50 mg, 0.19 mmol) and toluene (1 mL) were added to a 40 mL IKA vial. Compound 4-3 (110.46 mg, 0.20 mmol) and tetrakis(triphenylphosphine)palladium (21.48 mg, 0.02 mmol) were then added to the reaction flask. The atmosphere was then purged with nitrogen for 1 minute. The reaction mixture was stirred at 120°C for 16 hours. LC-MS monitoring confirmed the completion of the reaction. 2 mL of water and 2 mL of ethyl acetate were added to the reaction mixture, followed by extraction with 15 mL of ethyl acetate three times. The organic phase was concentrated under reduced pressure, and the residue was purified by HPLC (water / ammonia / acetonitrile) to afford C4i (3.87 mg, 0.01 mmol).

[0360] 1 H NMR (400MHz, DMSO-d6) δ9.51(br s,1H),9.11(br s,1H),8.89-8.70(m,2H),7.91(br s,1H),7.72-7.33(m,1H),7.15(br s,1H),4.93(br s,1H),2.08(br s,2H),1.91(br s,4H),1.73(br s,1H),1.55(br d,J=8.6Hz,2H),1.29(br s,1H).

[0361] LC-MS: m / z: 393.1 (M+H) + , RT=1.051min.

[0362] (4) Preparation of C4ii

[0363] To a 40 mL IKA vial at room temperature, compound C4i (50 mg, 0.13 mmol) was added and dissolved in hydrochloric acid (0.5 mL) and acetic acid (0.5 mL). The reaction was stirred at 20°C for 16 hours. LC-MS confirmed the completion of the reaction. 10 mL of water and 5 mL of ethyl acetate were added to the reaction mixture, followed by extraction with 30 mL of ethyl acetate three times. The organic phase was concentrated under reduced pressure, and the residue was purified by HPLC (water / ammonia / acetonitrile) to afford C4ii (6.8 mg, 0.02 mmol).

[0364] 1 H NMR (400MHz, DMSO-d6) δ9.49(s,1H),9.19(s,1H),8.89(d,J=2.2Hz,1H),8.64(d,J=2.2Hz,1H),8.11(br s,1H),7.83(d,J=4.6Hz,1H),7.65-7.34(m,2H),7.04(d,J=4.6Hz,1H),5.07-4.78(m,1H),2.10(br d,J=9.8Hz,2H),1.99-1.85(m,4H),1.74(br d,J=11.9Hz,1H),1.63-1.46(m,2H),1.44-1.24(m,1H).

[0365] LC-MS:XT221418-51-P1A1,m / z:411.3(M+H) + , RT=0.954min.

[0366] Example 5: Preparation of Compounds C5i and C5ii

[0367] Synthesis route:

[0368] (1) Preparation of C5i

[0369] To a 40 mL IKA vial at room temperature, compound 5-1 (346.84 mg, 2.42 mmol) and N,N-dimethylformamide (5 mL) were added sequentially and stirred until dissolved. Compound 5-2 (800.0 mg, 2.42 mmol), N,N-dimethylethylenediamine (2.14 mg, 0.02 mmol), cuprous iodide (4.61 mg, 0.02 mmol), and potassium phosphate (1028.58 mg, 4.85 mmol) were then added. The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at 110°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (0-50% petroleum ether and tetrahydrofuran) to afford C5i (150 mg).

[0370] LC-MS: m / z: 393.3 (M+H) + , RT=1.108min.

[0371] (2) Preparation of C5ii

[0372] To an 8 mL IKA vial at room temperature, compound C5i (120 mg, 0.31 mmol) and concentrated sulfuric acid (2 mL) were added sequentially and stirred until dissolved. The reaction mixture was stirred at 25°C for 1 hour. The reaction was detected to be complete. In an ice-water bath, the reaction mixture was slowly added dropwise to a saturated sodium carbonate solution and extracted three times with ethyl acetate. The reaction mixture was concentrated under reduced pressure, and the residue was added to water and acetonitrile and lyophilized to afford C5ii (55.68 mg).

[0373] 1 H NMR (400MHz, DMSO-d6) δ9.50-9.37(m,1H),9.14(s,1H),8.97(d,J=1.9Hz,1H),8.61(d,J=2.0Hz,1H),8.50(d,J=3.8Hz,1H),8.12(br s,1H),7.68-7.30(m,2H),6.89(d,J=3.9Hz,1H),5.01-4.89(m,1H),2.16-2.06(m,2H),1.98-1.87(m,3H),1.75(br d,J=12.5Hz,1H),1.63-1.46(m,2H),1.37-1.17(m,2H).

[0374] LC-MS: m / z: 411.0 (M+H) + , RT=3.558min.

[0375] Other compounds of the present invention can be prepared by methods similar to those described in the above examples (with appropriate modifications, if necessary).

[0376] Biological tests:

[0377] Experimental Example 1: IRAK4 kinase inhibition assay

[0378] This experiment used the Cisbio HTRF KinEASE-STK SI kit (62S1PEB). The kit includes assay / detection buffer, STK Substrate 1-biotin, Streptavidin-XL665, and STK Antibody-Cryptete.

[0379] Using an Echo 665, compound / DMSO was added to a 384-well plate (PerkinElmer 6008280). After addition of 5 μL of assay buffer (1 volume of 5X kinase buffer + 20 mM magnesium chloride (Sigma) solution + 1 mM DTT (Alfa Aesar) solution + 4 volumes of deionized water) at a 2x reaction concentration of IRAK4 kinase protein (final concentration: 10 nM), the plate was sealed, shaken, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 5 minutes. Then, 5 μL of a 1:1 mixture of STK Substrate 1-biotin (final concentration: 1 μM) and ATP (Sigma A1852) (final concentration: 200 μM) prepared in assay buffer at a 2x reaction concentration was added. Seal the shallow well plate, shake it and centrifuge it at 1000 rpm for 1 minute. After incubation at 37°C for 2 hours, add 10 μL of a 1:1 mixture of Streptavidin-XL665 (final concentration: 62.5 nM) and STK-antibody-cryptate dissolved in detection buffer. Seal the shallow well plate, shake it and centrifuge it at 1000 rpm for 1 minute. After incubation at room temperature for 1 hour, use a microplate reader to read the value at a wavelength of 620 nm / 665 nm. Data were analyzed using Prism 9.3 software, and the four-parameter logistic equation was used to fit the IC of IRAK4 kinase inhibition. 50 The test results are shown in Table 1:

[0380] Table 1: IRAK4 inhibitory activity of compounds

[0381] Note: A<1uM; 1uM≤B≤5uM; 5uM<C≤10uM; 10uM<D.

[0382] Experimental Example 2: HiBit fluorescence detection of protein degradation

[0383] Using HiBiT tag technology, the tag containing HiBiT was connected to the IRAK4 plasmid (Beijing Qingke Biotechnology Co., Ltd.), and the plasmid was transfected into HEK293T cells (Chinese Academy of Sciences, 1101HUM-PUMC000212). The HiBiT fluorescence level was detected to characterize the degradation level of IRAK4 by the compound. 1 mL of fresh culture medium and 300,000 HEK293T cells were seeded into a 6-well plate (Corning 3516) and placed in a constant temperature incubator at 37°C and 5% CO2 overnight. 3 μL X-tremeGENE TM9DNA Transfection Reagent (Roche #06365787001) and 1 μg of pcDNA3.1-IRAK4-HiBiT (Beijing Qingke Biotechnology Co., Ltd.) were added to 200 μL of Opti-MEM (Gibico 31985062) and gently mixed. The 6-well plate, which had been incubated overnight, was removed and allowed to stand at room temperature for 15 minutes before being added dropwise to the 6-well plate. Six hours after transient transfection, the cells were trypsinized and centrifuged at 1000 rpm for 3 minutes. 5000 HEK293T cells were seeded into 384-well plates (Corning 3765) with 40 μL of fresh culture medium and placed in a 37°C, 5% CO2 incubator overnight. Then, 40 nL of compound was added to the 384-well plate using an Echo 655 Liquid Handler. A maximum final concentration of 10 μM was achieved, and a 1:3 serial dilution was performed for a total of 10 concentrations. Incubate at 37°C, 5% CO2 for 24 hours. Remove the 384-well plate and equilibrate to room temperature. Add 40 μL of HiBiT Lytic Detection System (Promega N3030) was used for incubation at room temperature for 15 minutes, and fluorescence values ​​were recorded using EnVision Xcite Multilabel Reader (PerkinElmer 2105-0020). Data were analyzed using Prism 9.3 software, and a four-parameter logistic equation was used to fit the DC degradation of IRAK4. 50 value.

[0384] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. Compounds of formula (I): or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, in: X1, X2, X3, X4, X5, X6, X7, X8 and X9 can each independently be C, CR or N, provided that the valences of all atoms are satisfied and X4 and X5 are not N at the same time; R, R 1 、R 4 and R 5 Each independently selected from: hydrogen, deuterium, R 7 、Halogen、CN、NO2、C 1-6 Alkyl, -OR 1f 、-SR 1f 、-NR 1d R 1e 、-S(O)2R 1f 、-S(O)R 1f 、-S(O)2-NR 1d R 1e 、-S(O)-NR 1d R 1e 、-P(O)(OR 1f )2、-P(O)(NR 1d R 1e )2、-CF(R 1f )2、-CF2(R 1f )、-CF3、-CCl(R 1f )2、-CCl2(R 1f )、-CCl3、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)R 1f 、-C(O)OR 1f 、-C(O)NR 1d R 1e 、-C(O)NR 1f -OR 1f 、-OC(O)R 1f 、-OC(O)NR 1d R 1e 、-NR 1f -C(O)OR 1f 、-NR 1f -C(O)R 1f 、-NR 1f -C(O)NR 1d R 1e and -NR 1f -S(O)2R 1f , p is 1, 2, or 3; n is 0, 1 or 2, wherein when n is 1 or 2, R 4 available ring members connected to ring D; and R 5 Available ring members connected to ring C; R 2 Selected from: saturated or partially unsaturated C 3-7 Cycloalkyl; 3-7 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -NR 2d R 2e 、-C(O)OR 2f and -C(O)NR 2d R 2e and in the case where two substituents are attached to the same ring carbon atom of the cycloalkyl or heterocyclyl group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form a saturated or partially unsaturated optionally substituted C 3-7 cycloalkyl or 3-7 membered saturated or partially unsaturated optionally substituted heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 3 and R 6 Each independently selected from: H, R 8 、Halogen、CN、NO2、C 1-6 Alkyl, -OR 3f 、-SR 3f 、-NR 3d R 3e 、-S(O)2R 3f 、-S(O)R 3f 、-S(O)2-NR 3d R 3e 、-S(O)-NR 3d R 3e 、-P(O)(OR 3f )2、-P(O)(NR 3d R 3e )2、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f )、-CCl3、-(CR 3a R 3b ) q -OR 3f 、-(CR 3a R 3b ) q -C(O)OR 3f 、-(CR 3a R 3b ) q -NR 3d R 3e 、-C(O)R 3f 、-C(O)OR 3f and -C(O)NR 3d R 3e , q is 1, 2, or 3; and m is 0, 1, 2 or 3, wherein when m is 1, 2 or 3, R 6 Available ring members connected to ring B; R 1a 、R 1b 、R 3a and R 3b Each independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 7d R 7e ; or R 1a and R 1b , or R 3a and R 3b , together with the carbon atom to which they are attached, form R 9 ; R 1d 、R 1e 、R 2d 、R 2e 、R 3d 、R 3e 、R 7d and R 7e are each independently selected from hydrogen, deuterium, R 11 、C 1-6 Alkyl and C 1-6 haloalkyl; or, R 1d and R 1e , or R 2d and R 2e , or R 3d and R 3e , or R 7d and R 7e , together with the nitrogen atom to which they are commonly attached, form R 10 ; R 1f 、R 2f and R 3f independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl and R 12 ; R 7 、R 8 、R 9 、R 11 and R 12 Each independently selected from: saturated or partially unsaturated C 3-7 Cycloalkyl; 3-10 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or A plurality of independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 8d R 8e Substituents substituted; R 10 is selected from: a 3-7 membered saturated or partially unsaturated heterocyclyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5-10 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-3 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 10d R 10e and R 8d 、R 8e 、R 10d and R 10e are each independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

2. The compound according to claim 1, wherein: R 1 and R 4 Not simultaneously hydrogen or deuterium; and / or R 1a 、R 1b 、R 3a and R 3b Each independently selected from hydrogen, halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio and -NR 7d R 7e ; or R 1a and R 1b , or R 3a and R 3b , together with the carbon atom to which they are attached, form R 9 ; and / or R 1d 、R 1e 、R 2d 、R 2e 、R 3d 、R 3e 、R 7d and R 7e are each independently selected from hydrogen, R 11 、C 1-4 Alkyl and C 1-4 haloalkyl; or, R 1d and R 1e , or R 2d and R 2e , or R 3d and R 3e , or R 7d and R 7e , together with the nitrogen atom to which they are commonly attached, form R 10 ; and / or R 1f 、R 2f and R 3f are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl and R 12 ; and / or R 7 、R 8 、R 9 、R 11 and R 12 Each independently selected from: saturated or partially unsaturated C 3-6 Cycloalkyl; 3-10 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 8d R 8e Substituents substituted; and / or R 10 is selected from: a 3-6 membered saturated or partially unsaturated heterocyclyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 10d R 10e Substituents substituted; and / or R 8d 、R 8e 、R 10d and R 10e are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

3. The compound according to claim 1 or 2, wherein: R 1 is not hydrogen; or R 1 Selected from: R 7 , halogen, CN, NO2, C 1-4 alkyl, -OR 1f , -SR 1f , -NR 1d R 1e , -S(O)2R 1f , -S(O)R 1f , -S(O)2-NR 1d R 1e , -S(O)-NR 1d R 1e , -P(O)(OR 1f )2, -P(O)(NR 1d R 1e , -CF(R 1f )2, -CF2(R 1f ), -CF3, -CCl(R 1f )2, -CCl2(R 1f ), -CCl?3, -(CR 1a R 1b ) p -OR 1f , -(CR 1a R 1b ) p -C(O)OR 1f , -(CR 1a R 1b ) p -NR 1d R 1e , -C(O)R 1f , -C(O)OR 1f , -C(O)NR 1d R<` 1e , -C(O)NR 1f -OR 1f , -OC(O)R 1f , -OC(O)NR 1d R 1e , -NR 1f -C(O)OR 1f , -NR 1f -C(O)R 1f , -NR 1f -C(O)NR 1d R 1e or -NR 1f -S(O)2R 1f ; or R 1 Selected from: R 7 、Halogen、CN、NO2、C 1-4 Alkyl, -OR 1f 、-SR 1f 、-NR 1d R 1e 、-CF(R 1f )2、-CF2(R 1f )、-CF3、-CCl(R 1f )2、-CCl2(R 1f )、-CCl3、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)OR 1f or -C(O)NR 1d R 1e ;or R 1 Selected from: R 7 、halogen, CN, -OR 1f 、-NR 1d R 1e 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-C(O)OR 1f or -C(O)NR 1d R 1e 。 4. The compound according to any one of claims 1 to 3, wherein: R 7 Selected from: C 3-6 cycloalkyl; 4-6 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, phenyl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 8d R 8e or R 7 Selected from: C 3-6 cycloalkyl; 4-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are Aryl is optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and -NR 8d R 8e Substituents substituted; Wherein: Preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-6 Alkyl; or, preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-4 alkyl; or R 7 is selected from: a 4-6 membered heterocycloalkyl group having 1 N atom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or R 7 is selected from the group consisting of: azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, and NH2; or R 7 Selected from: azetidinyl, pyrrolidinyl and piperidinyl.

5. The compound according to any one of claims 1 to 4, wherein: p is 1; and / or R 1a and R 1b are each independently selected from hydrogen and C 1-6 Alkyl; or R 1a and R 1b are each independently selected from hydrogen and C 1-4 Alkyl; or R 1a and R 1b are each independently hydrogen; or R 1a and R 1b Together with the carbon atom to which they are attached, they form R 9 ; in: Preferably, R 9 Selected from: C 3-6 Cycloalkyl; a 3-6 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio and -NR 8d R 8e Substituents substituted; Wherein: Preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-6 Alkyl; or preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-4 alkyl; or Preferably, R 9 Selected from: C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, NH2, -NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or Preferably, R 9 is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, and NH2; or Preferably, R 9 It is cyclopropyl.

6. The compound according to any one of claims 1 to 5, wherein: R 1d and R 1e are each independently selected from hydrogen, R 11 and C 1-6 Alkyl; or R 1d and R 1e are each independently selected from hydrogen, R 11 and C 1-4 Alkyl; or R 1d and R 1e are each independently selected from hydrogen, R 11 , methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; or R 1d and R 1e Together with the nitrogen atom to which they are attached, they form R 10 ; in: Preferably, R 11 Selected from: C 3-6 Cycloalkyl; a 3-6 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio and -NR 8d R 8e Substituents substituted; Wherein: Preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-6 Alkyl; or preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-4 alkyl; or Preferably, R 11 Selected from: C 3-6 and 3-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or Preferably, R 11 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, and NH2; or Preferably, R 11 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from F and Cl; or Preferably, R 11 Selected from cyclopropyl and and / or Preferably, R 10 is selected from: 3-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl and heteroaryl are optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or Preferably, R 10 is selected from the group consisting of: azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or Preferably, R 10 Selected from: Each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2; or Preferably, R 10 Selected from: Each of them is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

7. The compound according to any one of claims 1 to 6, wherein: R 1f Selected from hydrogen and C 1-6 Alkyl; or R 1f Selected from hydrogen and C 1-4 Alkyl; or R 1f For hydrogen.

8. A compound according to any one of claims 1 to 7, wherein R 1 Selected from: F, Cl, Br, CN, OH, NH2, -NHCH3, -C(O)OH, -C(O)NH2, -CH2NH2, -CH2OH, Or, R 1 Selected from -CN, -C(O)NH2, F, -NHCH3, -C(O)OH, 9. The compound according to any one of claims 2 to 8, wherein the compound has the structure of formula (I-1): Where n is 0 or 1.

10. The compound according to claim 1 or 2, wherein: R 1 is selected from hydrogen and deuterium, and n is 1 or 2; or R 1 is hydrogen, and n is 1; or The compound has the structure of formula (I-2): The conditions are: R 4 Not hydrogen or deuterium.

11. The compound according to any one of claims 1 to 10, wherein: R 4 Selected from: hydrogen, R 7 、Halogen、CN、NO2、-OR 1f 、-SR 1f and -NR 1d R 1e ; in: Preferably, R 1d and R 1e are each independently selected from hydrogen and C 1-6 Alkyl; or Preferably, R 1d and R 1e are each independently selected from hydrogen and C 1-4 alkyl; and / or in: Preferably, R 1f Selected from hydrogen and C 1-6 Alkyl; or Preferably, R 1f Selected from hydrogen and C 1-4 alkyl; or R 4 Selected from: hydrogen, R 7 , F, Cl, Br, CN, NO2, OH and NH2; or R 4 Selected from: hydrogen, R 7 and CN; in: Preferably, R 7 is selected from: 4-6 membered saturated monocyclic heterocyclic group, 8-10 membered saturated fused bicyclic heterocyclic group, 6-11 membered saturated monospiro heterocyclic group and 7-10 membered saturated bridged heterocyclic group, each of which has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and is optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 8d R 8e or Preferably, R 7 Selected from: 4-6 membered saturated monocyclic heterocyclic groups and 7-10 membered saturated bridged heterocyclic groups, said monocyclic heterocyclic groups and bridged heterocyclic groups having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and -NR 8d R 8e Substituents substituted; Wherein: Preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-6 Alkyl; or preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-4 alkyl; or Preferably, R 7 is selected from: a 4-6 membered saturated monocyclic heterocyclic group (e.g., azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl or thiomorpholinyl) and a 7-10 membered saturated bridged heterocyclic group, wherein the monocyclic heterocyclic group and the bridged heterocyclic group have 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and are optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or Preferably, R 7 Selected from: Each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2, and wherein X 10 is CH2, (CH2)2 or (CH2)3; or Preferably, R 7 Selected from: Preferably, R 4 Selected from: hydrogen, CN, The condition is: when R 1 When it is hydrogen or deuterium, R 4 Not hydrogen.

12. The compound according to any one of claims 1 to 11, wherein: R and R 5 are each independently selected from hydrogen; and / or R 2 Selected from: C 3-6 Cycloalkyl; a 4-6 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -NR 2d R 2e 、-C(O)OR 2f and -C(O)NR 2d R 2e and in the case where two substituents are attached to the same ring carbon atom of the cycloalkyl or heterocyclyl group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl or optionally substituted 4-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein preferably, R 2d and R 2e are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl, and / or R 2f Selected from hydrogen and C 1-6 Alkyl; or R 2 Selected from: C 3-6 cycloalkyl; 4-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; and 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, NH2, NO2, C 1-4 Alkyl, -C(O)OH, -C(O)OC 1-4 Alkyl, -C(O)NH2, -C(O)NH(C 1-4 alkyl) and -C(O)NH(C 1-4 alkyl)2, and in the case where two substituents are attached to the same ring carbon atom of the cycloalkyl or heterocycloalkyl, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 cycloalkyl; or R 2 is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, each of which is optionally substituted by 1, 2 or more independently selected from F, Cl, Br, CN, OH, NH2, NO2, methyl, ethyl, isopropyl, tert-butyl, C(O )OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)NH2, -C(O)NHCH3 and -C(O)N(CH3)2, and in the case where two substituents are attached to the same ring carbon atom of the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, morpholinyl or thiomorpholinyl group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 cycloalkyl; or R 2 is selected from the group consisting of cyclohexyl, pyrrolidinyl, piperidinyl, phenyl and pyridinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, OH, NH2 and methyl, and in the case where two substituents are attached to the same ring carbon atom of the pyrrolidinyl or piperidinyl, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 cycloalkyl; or R 2 Selected from: or R 2 Selected from: and / or R 3 Selected from: halogen, CN, NO2, C 1-6 Alkyl, -OR 3f 、-SR 3f 、-NR 3d R 3e 、-S(O)2-NR 3d R 3e 、-S(O)-NR 3d R 3e 、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f )、-CCl3、-C(O)OR 3f and -C(O)NR 3d R 3e ;or R 3 Selected from: halogen, CN, C 1-4 Alkyl, -OR 3f 、-NR 3d R 3e 、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f )、-CCl3、-C(O)OR 3f and -C(O)NR 3d R 3e ;or R 3 Selected from: halogen, CN, C 1-4 Alkyl, -OR 3f 、-NR 3d R 3e 、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f ), -CCl3 and -C(O)NR 3d R 3e ; in: Preferably, R 3d and R 3e are each independently selected from hydrogen, deuterium, R 11 、C 1-4 Alkyl and C 1-4 Haloalkyl, where R 11 Preferably selected from: C 3-6 Cycloalkyl; a 4-6 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio and -NR 8d R 8e substituted by a substituent, wherein preferably, R 8d and R 8e are each independently selected from hydrogen, C 1-4 Alkyl and C 1-4 haloalkyl; or Preferably, R 3d and R 3e are each independently selected from hydrogen, methyl and ethyl; and / or in: Preferably, R 3f Selected from hydrogen and C 1-6 Alkyl; or Preferably, R 3f Selected from hydrogen and C 1-4 alkyl; or in: Preferably, R 3d and R 3e Together with the nitrogen atom to which they are attached, they form R 10 , where R 10 Preferably selected from: 3-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl and heteroaryl are optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or R 3 Selected from: halogen, OH, SH, NH2, CN, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2、-CHF2、-CH2F、-CF3、-CH2Cl、-CHCl2、-CCl3、-C(O)NH2、-C(O)NH(C 1-4 alkyl) and -C(O)N(C 1-4 Alkyl)2; or R 3 Selected from: F, Cl, Br, OH, NH2, CN, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, -N(CH3)2, -CHF2, -CHCl2 and -C(O)NH2; and / or R 6 Selected from: halogen, CN, NO2, C 1-4 Alkyl, -OR 3f 、-SR 3f 、-NR 3d R 3e 、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f ) and -CCl3, where R 3f Preferably selected from hydrogen and C 1-6 Alkyl, or R 3f Preferably selected from hydrogen and C 1-4 Alkyl; or R 6 Selected from: F, Cl, Br, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2 and -CCl3; and / or m is 0.

13. The compound according to any one of claims 1 to 12, wherein: At least two of X1, X2, X3, X4, and X5 are N, provided that X4 and X5 are not both N; or Three of X1, X2, X3, X4, and X5 are N, provided that X4 and X5 are not both N; or Four of X1, X2, X3, X4, and X5 are N, provided that X4 and X5 are not N at the same time; Preferably, X1 is N; and / or At least two of X6, X7, X8, and X9 are N; or At least three of X6, X7, X8 and X9 are N; At least four of X6, X7, X8 and X9 are N; Preferably, X8 and X9 are each N; Preferably, 2 or 3 of X1, X2, X3, X4 and X5 are N, and X1 is N, provided that X4 and X5 are not N at the same time; and Three or four of X6, X7, X8, and X9 are N, and X8 and X9 are each N.

14. The compound according to any one of claims 1 to 13, wherein: X1 and X2 are each N; X3 is CH; X4 and X5 are each C; X6, X8 and X9 are each N; and X7 is CH; and / or The compound has the structure of formula (Ii) or formula (I-ii): Where: R 1 、R 2 、R 3 and R 4 Each as defined in any one of claims 1 to 13, provided that: R 1 Not hydrogen or deuterium; Where: R 2 、R 3 and R 4 Each as defined in any one of claims 1 to 13, provided that: R 4 Not hydrogen or deuterium; in: Preferably, R 1 Selected from: halogen, CN, NO2, -OR 1f 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)OR 1f or -C(O)NR 1d R 1e ;or R 1 Selected from: halogen, CN, -(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-C(O)OR 1f or -C(O)NR 1d R 1e ; in: Preferably, p is 1; and / or Preferably, R 1a and R 1b are each independently selected from hydrogen and C 1-4 alkyl, preferably each independently hydrogen; or R 1a and R 1b Together with the carbon atom to which they are attached, they form R 9 ; in: Preferably, R 9 Selected from: C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or R 9 is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, and NH2; or Preferably, R 9 is cyclopropyl; and / or in: Preferably, R 1d and R 1e are each independently selected from hydrogen and R 11 ; or R 1d and R 1e Together with the nitrogen atom to which they are attached, they form R 10 ; in: Preferably, R 11 Selected from: C 3-6 Cycloalkyl, and 3-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or R 11 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, and NH2; or R 11 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2 and NH2; or R 11 Selected from cyclopropyl and and / or Preferably, R 10 is selected from: a 3-6 membered heterocycloalkyl group having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or Preferably, R 10 is selected from the group consisting of: azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, and thiomorpholinyl, each of which is optionally substituted with one or more groups independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, and NH2; or Preferably, R 10 Selected from: Preferred each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2; and / or in: R 1f Selected from hydrogen and C 1-4 Alkyl, preferably hydrogen; or R 1 Selected from: F, Cl, Br, CN, OH, NH2, C(O)OH, -C(O)NH2, Preferably, R 1 Selected from CN and -C(O)NH2; and / or in: Preferably, R 2 Selected from: C 3-6 cycloalkyl; 4-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; and 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, NH2, NO2, C 1-6 Alkyl and C 1-6 In the case where two substituents are attached to the same ring carbon atom of the cycloalkyl or heterocycloalkyl group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 cycloalkyl; or R 2 Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, each of which is optionally substituted by 1 or 2 independently selected from F, Cl, Br, C N, OH, NH2, NO2 and C1-C4 alkyl substituents, and in the case where two substituents are attached to the same ring carbon atom of the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl or thiomorpholinyl, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C1-C4 alkyl group. 3-6 cycloalkyl; or R 2 is selected from cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, phenyl and pyridinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, CN, OH, NH2, NO2, methyl, ethyl and isopropyl, and in the case where two substituents are attached to the same ring carbon atom of the pyrrolidinyl or piperidinyl, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 cycloalkyl; or R 2 Selected from: or R 2 Selected from or R 2 for and / or in: Preferably, R 3 Selected from: halogen, CN, NO2, C 1-6 Alkyl, OH, NH2, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, and -CCl3; or R 3 is -CHF2; and / or in: Preferably, R 4 Selected from: hydrogen, R 7 , halogens, CN, NO2, OH and NH2; or R 4 Selected from: hydrogen, R 7 , F, Cl, Br, CN, NO2, OH and NH2; in: Preferably, R 7 Selected from: 4-6 membered saturated monocyclic heterocyclic groups having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or R 7 Selected from: Preferably, R 4 Selected from: hydrogen, CN and The condition is: when R 1 When it is hydrogen, R 4 Not hydrogen.

15. The compound according to any one of claims 1 to 13, wherein: X1 and X5 are each N; X2 and X4 are C; X3 is CH; X6, X8 and X9 are each N; and X7 is CH; and / or The compound has the structure of formula (I-iii): Where: R 1 、R 2 and R 3 Each as defined in any one of claims 1 to 13, provided that: R 1 Not hydrogen or deuterium; Preferably, R 1 Selected from: R 7 、Halogen、NO2、-OR 1f 、-NR 1d R 1e 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)OR 1f or -C(O)NR 1d R 1e ;or R 1 Selected from: R 7 , halogen, -NR 1d R 1e 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-C(O)OR 1f or -C(O)NR 1d R 1e ; in: Preferably, p is 1; and / or in: Preferably, R 7 is selected from: a 4-6 membered heterocycloalkyl group having 1 N atom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or R 7 is selected from the group consisting of: azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, and NH2; or R 7 is piperidinyl; and / or in: Preferably, R 1a and R 1b are each independently selected from hydrogen and C 1-4 alkyl, preferably each independently hydrogen; or R 1a and R 1b Together with the carbon atom to which they are attached, they form R 9 ; in: Preferably, R 9 Selected from: C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or R 9 Selected from: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2; and / or in: Preferably, R 1d and R 1e are each independently selected from hydrogen, C 1-4 Alkyl and R 11 ; or R 1d and R 1e The nitrogen atoms that are connected to them Together they form R 10 ; in: Preferably, R 11 Selected from: C 3-6 Cycloalkyl, and 3-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or R 11 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, and NH2; and / or Preferably, R 10 is selected from: a 3-6 membered heterocycloalkyl group having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or Preferably, R 10 is selected from the group consisting of: azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, and thiomorpholinyl, each of which is optionally substituted with one or more groups independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, and NH2; and / or in: R 1f Selected from hydrogen and C 1-4 Alkyl, preferably hydrogen; Preferably, R 1 Selected from: F, Cl, Br, OH, NH2, -NHCH3, C(O)OH, -C(O)NH2, -CH2OH, More preferably, R 1 Selected from -CN and -C(O)NH2; and / or in: Preferably, R 2 Selected from: C 3-6 cycloalkyl; 4-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; and 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, NH2, NO2, C 1-6 Alkyl and C 1-6 In the case where two substituents are attached to the same ring carbon atom of the cycloalkyl or heterocycloalkyl group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 cycloalkyl; or R 2 Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, each of which is optionally substituted by 1 or 2 independently selected from F, Cl, Br, C N, OH, NH2, NO2 and C1-C4 alkyl substituents, and in the case where two substituents are attached to the same ring carbon atom of the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl or thiomorpholinyl, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C1-C4 alkyl group. 3-6 cycloalkyl; or R 2 is selected from the group consisting of cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, phenyl and pyridinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F, Cl, Br, CN, OH, NH2, NO2, methyl, ethyl and isopropyl, and in the case where two substituents are attached to the same ring carbon atom of the pyrrolidinyl or piperidinyl, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 cycloalkyl; or R 2 Selected from: or R 2 Selected from: and / or in: Preferably, R 3 Selected from: halogen, CN, C 1-4 Alkyl, -OR 3f 、-SR 3f 、-NR 3d R 3e 、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f ), -CCl3 and -C(O)NR 3d R 3e ; Wherein: Preferably, R 3d and R 3e are each independently selected from hydrogen and C 1-4 Alkyl, preferably hydrogen and methyl; and / or Preferably, R 3f Selected from hydrogen and C 1-4 Alkyl, preferably hydrogen and methyl; Preferably, R 3 Selected from: halogen, OH, SH, NH2, CN, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2、-CHF2、-CH2F、-CF3、-CH2Cl、-CHCl2、-CCl3、-C(O)NH2、-C(O)NH(C 1-4 alkyl) and -C(O)N(C 1-4 alkyl)2; or R 3 is selected from the group consisting of: F, OH, NH2, CN, methyl, ethyl, isopropyl, tert-butyl, methoxy, -N(CH3)2, -CHF2, and -C(O)NH2; or R 3 Selected from: F, CN, methyl, isopropyl, methoxy, -N(CH3)2, -CHF2 and -C(O)NH2.

16. A compound according to any one of claims 1 to 13, wherein: X1, X3 and X4 are each N; X2 and X5 are C; X6, X8 and X9 are each N; and X7 is CH; and / or The compound has the structure of formula (I-iv): Where: R 1 、R 2 and R 3 Each as defined in any one of claims 1 to 13, provided that: R 1 Not hydrogen or deuterium; Preferably, R 1 Selected from: halogen, CN, NO2, -OR 1f 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e or-C(O)OR 1f ;or R 1 Selected from: halogen, CN, -(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f , or -C(O)OR 1f ; in: Preferably, p is 1; and / or Preferably, R 1a and R 1b are each independently selected from hydrogen and C 1-4 alkyl, preferably each independently hydrogen; or R 1a and R 1b Together with the carbon atom to which they are attached, they form R 9 ; in: Preferably, R 9 Selected from: C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or R 9 Selected from: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2; and / or in: Preferably, R 1d and R 1e are each independently selected from hydrogen and R 11 ; or R 1d and R 1e Together with the nitrogen atom to which they are attached, they form R 10 ; in: Preferably, R 11 Selected from: C 3-6 Cycloalkyl, and 3-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or R 11 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, and NH2; and / or Preferably, R 10 is selected from: a 3-6 membered heterocycloalkyl group having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or Preferably, R 10 is selected from the group consisting of: azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, and thiomorpholinyl, each of which is optionally substituted with one or more groups independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, and NH2; and / or in: R 1f Selected from hydrogen and C 1-4 Alkyl, preferably hydrogen; or R 1 Selected from: F, Cl, Br, CN, OH, NH2, C(O)OH, or R 1 For CN; and / or in: Preferably, R 2 Selected from: C 3-6 cycloalkyl; 4-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; and 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, NH2, NO2, C 1-6 Alkyl and C 1-6 In the case where two substituents are attached to the same ring carbon atom of the cycloalkyl or heterocycloalkyl group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 cycloalkyl; or R 2 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, thiomorpholinyl, phenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, each of which is optionally substituted by 1 or 2 independently selected from F, C 1, Br, CN, OH, NH2, NO2 and C1-C4 alkyl, and in the case where two substituents are attached to the same ring carbon atom of the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl or thiomorpholinyl, the two substituents are optionally substituted with the ring carbon atom to which they are attached. The sub-groups together form an optionally substituted C 3-6 cycloalkyl; or R 2 Selected from: or R 2 Selected from: or R 2 for and / or in: Preferably, R 3 Selected from: halogen, CN, NO2, C 1-6 Alkyl, OH, NH2, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, and -CCl3; or R 3 is -CHF2.

17. A compound according to any one of claims 1 to 13, wherein: X1 and X5 are each N; X2 and X4 are C; X3 is CH; X6 is CH; and X7, X8 and X9 are each N; and / or The compound has the structure of formula (IV): Where: R 1 、R 2 and R 3 Each as defined in any one of claims 1 to 13, provided that: R 1 Not hydrogen or deuterium; Preferably, R 1 、R 2 and R 3 as defined in claim 14, 15 or 16 respectively; or R 1 is -C(O)NH2; and / or R 2 for and / or R 3 is -CHF2; or in: X1 and X5 are each N; X2 and X4 are C; X3 is CH; and X6, X7, X8 and X9 are each N; and / or The compound has the structure of formula (I-vi): R 1 、R 2 and R 3 Each as defined in any one of claims 1 to 13, provided that: R 1 Not hydrogen or deuterium; in: Preferably, R 1 、R 2 and R 3 as defined in claim 14, 15 or 16 respectively; or R 1 is -C(O)NH2; and / or R 2 for and / or R 3 is -CHF2; or in: X1 and X2 are each N; X3 is CH; X4 and X5 are each C; and X6, X7, X8 and X9 are each N; and / or The compound has the structure of formula (I-vii): Where: R 1 、R 2 and R 3 Each as defined in any one of claims 1 to 13, provided that: R 1 Not hydrogen or deuterium; Preferably, R 1 、R 2 and R 3 as defined in claim 14, 15 or 16 respectively; or R 1 is -CN; and / or R 2 for and / or R 3 is -CHF2.

18. A compound according to any one of claims 1 to 13, wherein: X1, X3 and X4 are each N; X2 and X5 are C; and X6, X7, X8 and X9 are each N; and / or The compound has the structure of formula (I-viii): Where: R 2 、R 3 and R 4 Each as defined in any one of claims 1 to 13, provided that: R 4 Not hydrogen or deuterium; Preferably, R 2 and R 3 as defined in claim 14, 15 or 16 respectively; or R 2 for and / or R 3 is -CHF2; and / or Preferably, R 4 Selected from: R 7 , halogens, CN, NO2, OH and NH2; or R 4 Selected from: R 7 , F, Cl, Br, CN, NO2, OH and NH2; among which: in: Preferably, R 7 Selected from: 7-10 membered saturated bridged heterocyclic groups having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or R 7 Selected from: where X 10 is CH2, (CH2)2 or (CH2)3; Preferably, R 4 Selected from: CN and More preferred 19. The compound according to claim 1, wherein the compound is selected from:

20. A compound according to any one of claims 1 to 19, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, for use in the preparation of a protein degradation targeting chimera (PROTAC).

21. A protein degradation targeting chimera (PROTAC) comprising a portion having IRAK4 protein kinase inhibitory activity, wherein the portion is derived from a compound according to any one of claims 1 to 19, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, or the protein degradation targeting chimera according to claim 21, and a pharmaceutically acceptable excipient, carrier or diluent.

23. Use of a compound according to any one of claims 1 to 19, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a protein degradation targeting chimera according to claim 21, or a pharmaceutical composition according to claim 22, in the preparation of a medicament for treating a disease, disorder or condition associated with IRAK4 protein kinase.

24. A method for treating a disease, disorder or condition associated with IRAK4 protein kinase, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 19, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a protein degradation targeting chimera according to claim 21, or a pharmaceutical composition according to claim 22.

25. The pharmaceutical composition of claim 22, the use of claim 23, or the method of claim 24, wherein the disease, disorder or condition associated with IRAK4 protein kinase is selected from the group consisting of: autoimmune disorders, inflammatory disorders, cancer, transplant rejection, thromboembolism, atherosclerosis, myocardial infarction and metabolic syndrome; in: Preferably, the inflammatory disorder is selected from: Osteoarthritis, gout, gouty arthritis, chronic obstructive pulmonary disease, periodic fevers, atopic dermatitis, atopic eczema, lymphadenopathy, sepsis, irritable bowel syndrome (IBD), ulcerative colitis, asthma, and allergies; and / or Preferably, the autoimmune disorder is selected from the group consisting of: Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, psoriatic arthritis, multiple sclerosis, neuropathic pain, ankylosing spondylitis, reactive arthritis and Systemic juvenile idiopathic arthritis; and / or Preferably, the transplant rejection is selected from graft-versus-host disease and allograft rejection; and / or Preferably, the cancer is selected from the group consisting of brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, gastric tumors, breast cancer, bladder and colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, testicular cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck and head tumors, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin and non-Hodgkin lymphoma, breast cancer, follicular carcinoma, papillary carcinoma, seminoma tumors, melanoma, acute myeloid leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, activated B-cell-like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and multiple myeloma.

Images