Heterocyclic compound used as SHP2 inhibitor, pharmaceutical composition containing heterocyclic compound and preparation method and application of heterocyclic compound

Abstract

The present application relates to a heterocyclic compound of formula (I), a pharmaceutical composition comprising the same, a method for preparing the same, and a use of the same as an SHP2 inhibitor.

Description

Heterocyclic compound used as SHP2 inhibitor, pharmaceutical composition containing the same, and preparation method and use thereof Technical Field

[0001] The present application relates to heterocyclic compounds, pharmaceutical compositions containing the same, preparation methods thereof, and uses thereof as SHP2 inhibitors. Background Art

[0002] SHP2 (Src homology-2 protein tyrosine phosphatase) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that catalyzes protein tyrosine dephosphorylation. It is generally believed that SHP2 contains two SH2 domains at its N-terminus, the N-Src homology 2 domain (SH2) and the C-SH2 domain, and a catalytic PTP domain at its C-terminus. In its inactive state, SHP2 is autoinhibitory, with the binding of N-SH2 and C-PTP inhibiting phosphatase activity. In the presence of extracellular stimuli, they bind to their receptors and activate multiple downstream signaling pathways, including Ras-Erk, Ras-MAPK, PI3K-AKT, Jak-Stat, Met, FGFR, EGFR, as well as the insulin receptor and NF-κB pathways, regulating cell proliferation, differentiation, apoptosis, survival, and migration.

[0003] Hyperactivation of SHP2 due to germline or somatic mutations has been found in Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, myelodysplastic syndrome, B-cell acute lymphoblastic leukemia, and acute myeloid leukemia. Furthermore, activating mutations in PTPN11 have been found in solid tumors such as lung cancer, colon cancer, melanoma, neuroblastoma, and liver cancer. Therefore, activated or upregulated SHP2 in human tumors or other diseases represents a novel therapeutic target.

[0004] In addition, studies have shown (Sci Adv. 2020.6(5):eaay 4458) that programmed death 1 (PD-1) is also involved in mediating and activating SHP2. In cancer, PD-1 inhibits T cell stimulation and mediates immune escape. After stimulation, PD-1 is phosphorylated at its immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM), then binds to SHP2 and initiates T cell inactivation. Therefore, SHP2 inhibitors can stimulate adaptive and innate immune activity in the tumor microenvironment and have the potential to restore anti-tumor immune responses that have been silenced by cancer cells.

[0005] Therefore, there is a great need for compounds that act as SHP2 inhibitors to treat and prevent diseases, disorders and conditions mediated through SHP2 activity.

[0006] Summary of the Invention

[0007] The present invention provides heterocyclic compounds that can be used as SHP2 inhibitors to prevent or treat diseases, disorders, and conditions mediated by SHP2 activity. The compounds of the present invention have high selectivity for their target sites. Furthermore, the compounds of the present invention have superior properties, including improved 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), and reduced resistance to drug resistance.

[0008] In one aspect, the present invention provides a compound of formula (I) as defined below:

[0009] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof.

[0010] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof and one or more pharmaceutically acceptable carriers, wherein the pharmaceutical composition is preferably a solid preparation, a liquid preparation or a transdermal preparation.

[0011] In another aspect, the present invention provides use of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, in the preparation of a medicament for preventing or treating a disease, disorder or condition mediated by SHP2 activity.

[0012] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention for use in preventing or treating a disease, disorder or condition mediated by SHP2 activity.

[0013] In another aspect, the present invention provides a method for preventing or treating a disease, disorder or condition mediated by SHP2 activity, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention.

[0014] In another aspect, the present invention provides methods of preparing the compounds of the present invention. DETAILED DESCRIPTION

[0015] definition

[0016] 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.

[0017] 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").

[0018] 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.

[0019] 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).

[0020] 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 of 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).

[0021] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2 to 6 carbon atoms ("C 2-6 The alkenyl group is, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compound of the present invention contains an alkenyl group, the compound may be in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof. The term "alkenylene" is a corresponding divalent group, including, for example, "C 2-6 Alkenylene", "C 2-4 Specific examples include, but are not limited to, -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, butenylene, pentenylene, hexenylene, cyclopentenylene, cyclohexenylene, etc.

[0022] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon radical containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. The alkynyl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents. The term "alkynylene" is a corresponding divalent radical, including, for example, "C 2-8 Alkynylidene", "C2-6 alkynylene", "C 2-4 Examples include, but are not limited to, The alkynylene group is optionally substituted with one or more (such as 1 to 3) identical or different substituents.

[0023] As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene" and "cycloalkyl") or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) monocyclic or polycyclic (e.g., bicyclic or tricyclic) hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 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, etc. Cycloalkyl groups include monocyclic, spirocyclic, fused or bridged systems.

[0024] As used herein, "fused ring" means that two rings in a ring system share two adjacent ring atoms (e.g., in the case of cycloalkyl, the two ring atoms are both C; or in the case of heterocyclyl, the two ring atoms can be both C or N, or one is C and the other is N). "Spirocyclic" means that two rings in a ring system share one ring atom (e.g., C). "Bridged ring" means that two rings in a ring system share two ring atoms that are not directly connected (e.g., in the case of cycloalkyl, the two ring atoms are both C; or in the case of heterocyclyl, the two ring atoms can be both C or N, or one is C and the other is N).

[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 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] The term "monospirocycloalkyl" refers to two monocyclic cycloalkyl groups that have only one carbon atom in common. Monospirocycloalkyl groups may have 6 to 14 (C 6-14 ), such as 6-11(C 6-11 ) or 7-10(C 7-10 ) carbon atoms. Monospirocycloalkyl can include, for example, a 3-membered / 5-membered ring system, a 4-membered / 4-membered ring system, a 4-membered / 5-membered ring system, a 4-membered / 6-membered ring system, a 5-membered / 5-membered ring system, a 5-membered / 6-membered ring system, and a 6-membered / 6-membered ring system, wherein the count of each ring includes the spiro atom. Non-limiting examples of monospirocycloalkyl include: The monospirocycloalkyl group is optionally substituted with one or more (such as 1 to 3) suitable substituents.

[0027] 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., 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.

[0028] As used herein, the term "heterocyclyl" encompasses fused ring structures, and the connection point of the fused ring structure to the other groups can be on any ring in the fused ring 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,

[0029] As used herein, the term "heterocyclyl" encompasses bridged heterocyclyls and spiro heterocyclyls.

[0030] 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 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. In some embodiments, the two rings forming the bridged heterocycle are both saturated rings. In other embodiments, one of the two rings forming the bridged heterocycle is a saturated ring and the other is a partially unsaturated ring. In some embodiments, the two rings forming the bridged heterocycle are both partially unsaturated rings. Examples of bridged heterocycles include but are not limited to 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.

[0031] As used herein, the term "monospiroheterocycloalkyl" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, sulfur atoms) formed by two or more saturated rings sharing a ring atom, including but not limited to 5-11 membered monospiroheterocycloalkyl, 6-10 membered monospiroheterocycloalkyl, 7-10 membered monocyclic heterocycloalkyl, 6-10 membered nitrogen-containing spiroheterocycloalkyl, 6-10 membered oxygen-containing spiroheterocycloalkyl, 6-10 membered sulfur-containing spiroheterocycloalkyl, etc. Monospiroheterocycloalkyl can include, for example, 3-membered / 5-membered ring systems, 4-membered / 4-membered ring systems, 4-membered / 5-membered ring systems, 4-membered / 6-membered ring systems, 5-membered / 5-membered ring systems, 5-membered / 6-membered ring systems, and 6-membered / 6-membered ring systems, wherein the count of each ring includes the spiro 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 heteroatoms selected from oxygen, nitrogen and sulfur. The term "6-10 membered nitrogen-containing monospiro heterocycloalkyl" refers to a spiro heterocycloalkyl containing a total of 6-10 ring atoms, at least one of which is a nitrogen atom.

[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] The term "aralkyl" preferably refers to an alkyl group substituted with an aryl group, wherein the aryl group and the alkyl group are as defined herein. Typically, the aryl group may have 6 to 14 carbon atoms, and the alkyl group may have 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0034] 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.

[0035] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0036] 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 1-4The 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.

[0037] The term "alkylthio" as used herein, means an alkyl group, as defined above, appended to the parent molecular moiety through a sulfur atom. 1-6 Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.

[0038] 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 also optionally 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). In some embodiments, the nitrogen-containing heterocycle is connected to the rest of the molecule via a carbon atom. In some embodiments, the nitrogen-containing heterocycle is connected to the rest of the molecule via a 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0043] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0044] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0045] 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 13N) 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.

[0046] 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%).

[0047] 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).

[0048] 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.

[0049] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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)).

[0058] 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.

[0059] As used herein, the term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0060] Compound

[0061] In a first aspect, the present invention provides a compound of formula (I):

[0062] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof,

[0063] in:

[0064] X 1 and X 2 Each independently is N or CR 9 , and X 1 and X 2 At least one of them is N;

[0065] X 3 is N;

[0066] X 4 N or CR 10 ;

[0067] L is selected from O, S, CR 7a R 7b , C(O) and S(O) p ;

[0068] p is 1 or 2;

[0069] R 1 and R 10Each independently selected from H, D, halogen, OH, NH2, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl, -COC 1-6 Substitution of alkyl groups;

[0070] R 2 Selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 The alkyl group is substituted with a substituent; or

[0071] R 2 Together with L and the carbon atoms indicated by "a" and "b" to which they are attached, they form a ring B represented by the following formula:

[0072] The ring B is selected from a partially unsaturated C 3-10 Cyclic hydrocarbon group, partially unsaturated 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl, wherein the C3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, COOH, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-NHCOR 8a 、-N(R 8a )COR 8b 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 Substitution of aryl and 5-14 membered heteroaryl substituents;

[0073] R 3 and R 5 Each independently selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 Substitution of alkyl groups;

[0074] R 4 and R 9Each independently selected from H, D, halogen, OH, NH2, CN, NO2, COOH, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-NHCOR 8a 、-N(R 8a )COR 8b 、-COC 1-6 Alkyl-OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, saturated or partially unsaturated monocyclic or condensed ring C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated monocyclic or condensed 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-11 Monospirocycloalkyl and 6-11 membered monospiroheterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-11 The monospirocycloalkyl and 6-11 membered monospiroheterocycloalkyl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, -NR 8a R 8b 、CN、NO2、oxo、C 1-6 Alkyl, C 1-6 Alkoxy, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 Substitution of aryl and 5-14 membered heteroaryl substituents;

[0075] U is selected from O, S, CR 11a R 11b and NR 12 ;as well as

[0076] Ring A is present or absent,

[0077] When ring A is absent, V and W are each independently selected from O, S, CR13a R 13b and NR 12 , and m is 0;

[0078] or

[0079] Wherein when ring A exists, ring A is selected from saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl,

[0080] V and W are each independently selected from C, N or CR 11a ,

[0081] R 6 Selected from H, D, halogen, OH, NH2, CN, NO2, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOH、-S(O) n C 1-6 Alkyl, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the -S(O) n C 1-6 Alkyl, C 1-6 Alkyl and C 1-6 The alkoxy groups are optionally each independently substituted with one or more groups independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 Alkyl substituents are substituted,

[0082] m is 1, 2, 3, or 4, and

[0083] n is 0, 1, or 2;

[0084] R 7a 、R 7b 、R 11a 、R 11b 、R 12 、R 13a and R 13b , at each occurrence, are independently selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, saturated or partially unsaturated C3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 Substitution of alkyl groups;

[0085] R 8a and R 8b , at each occurrence, are independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, CN, NO2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 aryl and 5-14 membered heteroaryl substituents; and

[0086] represents a single bond or a double bond; and

[0087] The conditions are:

[0088] (1) the valences of all atoms are satisfied; and

[0089] (2) The compound of formula (I) does not include the following compounds:

[0090] In some embodiments, the present invention provides compounds of formula (I), wherein when ring A is absent, R 2 Together with L and the carbon atoms indicated by "a" and "b" to which they are attached, they form the ring B.

[0091] In other embodiments, the present invention provides compounds of formula (I), wherein when ring A is present, R 2 Together with L and the carbon atoms indicated by "a" and "b" to which they are attached, they form the ring B.

[0092] In some embodiments, the present invention provides compounds of formula (I), wherein:

[0093] X 1 is N, and X 2 CR 9 ;or

[0094] X 1 CR 9 , and X 2 is N.

[0095] In some such embodiments, at each occurrence, R 9 Independently selected from H, D, halogen, OH, NH2, CN, NO2, COOH, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-NHCOR 8a 、-N(R 8a )COR 8b 、-COC 1-6 Alkyl-OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, monocyclic or condensed ring C 3-10 Cycloalkyl, monocyclic or condensed ring 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 6-11 Monospirocycloalkyl and 6-11 membered monospiroheterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6Alkynyl, monocyclic or condensed ring C 3-10 Cycloalkyl, monocyclic or condensed ring 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 6-11 The monospirocycloalkyl and 6-11 membered monospiroheterocycloalkyl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, -NR 8a R 8b 、CN、NO2、oxo、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl substituents; wherein the monospirocycloalkyl and monospiroheterocycloalkyl optionally include 3-membered / 5-membered ring systems, 4-membered / 4-membered ring systems, 4-membered / 5-membered ring systems, 4-membered / 6-membered ring systems, 5-membered / 5-membered ring systems, 5-membered / 6-membered ring systems, and 6-membered / 6-membered ring systems, wherein the count of each ring includes the spiro atom; and wherein R 8a and R 8b , at each occurrence, are independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein R 8a and R 8b The C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, CN, NO2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 The substituents of the aryl and 5-10 membered heteroaryl groups are substituted.

[0096] In some preferred embodiments, at each occurrence, R 9 Independently selected from H, D, F, Cl, OH, NH2, CN, NO2, COOH, -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-COC 1-4Alkyl-OC 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, monocyclic C 3-6 Cycloalkyl, monocyclic 4-6 membered heterocycloalkyl, C 7-10 Monospirocycloalkyl and 7-10 membered monospiroheterocycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, monocyclic C 3-6 Cycloalkyl, monocyclic 4-6 membered heterocycloalkyl, C 7-10 The monospirocycloalkyl and 7-10 membered monospiroheterocycloalkyl are optionally each independently substituted by one or more independently selected from F, Cl, OH, NH2, -NR 8a R 8b , CN and NO2 substituents; wherein the monospirocycloalkyl and monospiroheterocycloalkyl optionally include 3-membered / 5-membered ring systems, 4-membered / 4-membered ring systems, 4-membered / 5-membered ring systems, 4-membered / 6-membered ring systems, 5-membered / 5-membered ring systems and 5-membered / 6-membered ring systems, wherein the count of each ring includes spiro atoms; and wherein R 8a and R 8b , at each occurrence, are independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and phenyl, wherein R 8a and R 8b The C 1-4 The alkyl group is optionally substituted with one or more independently selected from F, Cl, OH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)2, CN, NO2, C 3-6 The substituents of cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are substituted.

[0097] In some more preferred embodiments, at each occurrence, R 9 Independently selected from H, D, F, Cl, CN, COOH, -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-COC 1-4 Alkyl-OC 1-4 Alkyl, C 2-4 Alkenyl, monocyclic C 3-6 Cycloalkyl, monocyclic 4-6 membered heterocycloalkyl, C7 monospirocycloalkyl, 7 membered monospiro heterocycloalkyl and C substituted by OH 1-4alkyl, wherein the monospirocycloalkyl and monospiroheterocycloalkyl include 4-membered / 4-membered ring systems, wherein the number of each ring includes the spiro atom; and wherein R 8a and R 8b , at each occurrence, are independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and phenyl, wherein R 8a and R 8b The C 1-4 The alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, OH, NH2, NHCH3, N(CH3)2, cyclopropyl, azetidinyl, and phenyl.

[0098] In some more preferred embodiments, at each occurrence, R 9 independently selected from H, D, F, Cl, CN, -CH2OH, vinyl, cyclopropyl, COOH, -COOCH3, -COOCH2CH3, -CONH2, -COCH3, -COCH2OCH3, -COCH2F, -COCH2OH, -COCH2NH2, -COCH2N(CH3)2,

[0099] In some more preferred embodiments, at each occurrence, R 9 are independently H.

[0100] In some embodiments, the present invention provides compounds of formula (I), wherein X 1 and X 2 Both are N.

[0101] In some embodiments, the present invention provides compounds of formula (I), wherein L is selected from O, S or CR 7a R 7b , where R 7a and R 7b Each independently selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 The alkyl group is substituted with a substituent.

[0102] In some preferred embodiments, L is selected from O, S or CR 7a R 7b , where R 7a and R 7b Each independently selected from H, D, F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl are optionally each independently substituted by one or more independently selected from F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl and -COC 1-4 The alkyl group is substituted with a substituent.

[0103] In some preferred embodiments, L is selected from O, S, and CH. In some more preferred embodiments, L is S.

[0104] In some embodiments, the present invention provides compounds of formula (I), wherein R 2 Selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 The alkyl group is substituted with a substituent.

[0105] In some preferred embodiments, R 2 Selected from H, D, halogen, OH, NH2, CN, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-4 Alkyl and -COC 1-4 The alkyl group is substituted with a substituent.

[0106] In some more preferred embodiments, R 2 Selected from H, D, F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 3-6 The cycloalkyl groups are optionally each independently substituted with one or more radicals independently selected from F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl and -COC 1-4 The alkyl group is substituted with a substituent.

[0107] In some more preferred embodiments, R 2 Selected from H, D, OH, NH2 and C 1-4 alkyl.

[0108] In some more preferred embodiments, R2 Selected from H, OH, NH2 and CH3.

[0109] In some more preferred embodiments, R 2 For H.

[0110] In some embodiments, the present invention provides compounds of formula (I), wherein R 2 Together with L and the carbon atoms indicated by "a" and "b" to which they are attached, they form a ring B represented by the following formula:

[0111] The ring B is selected from a partially unsaturated C 3-6 Cyclic hydrocarbon group, partially unsaturated 4-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 3-6 Cyclic hydrocarbon group, 4-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, COOH, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-NHCOR 8a 、-N(R 8a )COR 8b 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl substituents, and wherein R 8a and R 8b , at each occurrence, are independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein R 8a and R 8b The C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10Aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, CN, NO2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 The substituents of the aryl and 5-10 membered heteroaryl groups are substituted.

[0112] In some preferred embodiments, the ring B is selected from phenyl and 5-6 membered heteroaryl, more preferably selected from 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, COOH, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-NHCOR 8a 、-N(R 8a )COR 8b 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 aryl and 5-6 membered heteroaryl substituents, and wherein R 8a and R 8b , at each occurrence, are independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl, wherein R 8a and R 8b The C 1-4 Alkyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-4 alkyl), N(C 1-4 alkyl)2, CN, NO2, oxo, C1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 The substituents of the aryl and 5-6 membered heteroaryl groups are substituted.

[0113] In some more preferred embodiments, the ring B is selected from pyrrolyl, pyrazolyl, 1,2,3-triazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, more preferably pyrazolyl, each of the above groups is optionally independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, COOH, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-NHCOR 8a 、-N(R 8a )COR 8b 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 aryl and 5-6 membered heteroaryl substituents, and wherein R 8a and R 8b , at each occurrence, are independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl, wherein R 8a and R 8b The C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)2, CN, NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 The substituents of the aryl and 5-6 membered heteroaryl groups are substituted.

[0114] In some embodiments, the bond indicated by "c" in the above structures is attached to an available ring atom of Ring B.

[0115] In some preferred embodiments, R 2 Together with L and the carbon atoms indicated by "a" and "b" to which they are attached, they form a structure represented by the following formula:

[0116] where R 14 Selected from H, halogen, OH, NH2, CN, NO2, COOH, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-NHCOR 8a 、-N(R 8a )COR 8b 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-4 alkyl), N(C 1-4 alkyl)2, CN, NO2, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 The substituents of the aryl and 5-6 membered heteroaryl groups are substituted.

[0117] In some preferred embodiments, R 14 For H.

[0118] In some embodiments, the present invention provides compounds of formula (I), wherein Selected from:

[0119]

[0120] In some preferred embodiments, for

[0121] In other embodiments, the present invention provides compounds of formula (I), wherein R 2 Together with L and the carbon atoms indicated by "a" and "b" to which they are attached, form a ring such that A structure represented by the following formula is formed:

[0122] In some embodiments, the present invention provides compounds of formula (I), wherein R 5 Selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 The alkyl group is substituted with a substituent.

[0123] In some preferred embodiments, R 5 Selected from H, D, F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the C1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl are optionally each independently substituted by one or more independently selected from F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl and -COC 1-4 The alkyl group is substituted with a substituent.

[0124] In some preferred embodiments, R 5 Selected from OH and NH2.

[0125] In some more preferred embodiments, R 5 For OH.

[0126] In some embodiments, the present invention provides compounds of formula (I), wherein R 6 Selected from H, D, halogen, OH, NH2, CN, NO2, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOH、-S(O) n C 1-6 Alkyl, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the -S(O) n C 1-6 Alkyl, C 1-6 Alkyl and C 1-6 The alkoxy groups are optionally each independently substituted with one or more groups independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 The alkyl group is substituted with a substituent, and wherein R 8a and R 8b , at each occurrence, are independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-10 Aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, CN, NO2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 The substituents of the aryl and 5-10 membered heteroaryl groups are substituted.

[0127] In some preferred embodiments, R 6 Selected from H, D, halogen, OH, NH2, CN, NO2, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOH、-S(O) n C 1-4 Alkyl, C 1-4 Alkyl and C 1-4 Alkoxy, wherein the -S(O) n C 1-4 Alkyl, C 1-4 Alkyl and C 1-4 The alkoxy groups are optionally each independently substituted with one or more groups independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-4 Alkyl and -COC 1-4 The alkyl group is substituted with a substituent, and wherein R 8a and R 8b , at each occurrence, are independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)2, CN, NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C6-10 The substituents of the aryl and 5-6 membered heteroaryl groups are substituted.

[0128] In some embodiments, m is 1, 2, or 3.

[0129] In some embodiments, n is 0, 1, or 2.

[0130] In some preferred embodiments, R 6 is H, and m is 1;

[0131] In some embodiments, the present invention provides compounds of formula (I), wherein X 4 is N.

[0132] In some embodiments, the present invention provides compounds of formula (I), wherein X 4 CR 10 , where R 10 Selected from H, D, halogen, OH, NH2, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl, -COC 1-6 The alkyl group is substituted with a substituent.

[0133] In some preferred embodiments, R 10 Selected from H, D, F, Cl, OH, NH2, CN, NO2, COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10Aryl and 5-6 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, C 1-4 Alkyl, -COC 1-4 The alkyl group is substituted with a substituent.

[0134] In some more preferred embodiments, R 10 For H.

[0135] In some embodiments, the present invention provides a compound of formula (I), wherein the compound has a structure of formula II:

[0136] In some preferred embodiments, Ring A is present.

[0137] In some embodiments, the present invention provides a compound of formula (I), wherein the compound has a structure of formula III:

[0138] wherein ring A is present or absent.

[0139] In some embodiments, the present invention provides compounds of formula (I), wherein R 1 Each independently selected from H, D, halogen, OH, NH2, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl, -COC 1-6 The alkyl group is substituted with a substituent.

[0140] In some preferred embodiments, R 1 Selected from H, D, F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 3-6 Cycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C3-6 The cycloalkyl groups are optionally substituted each independently with one or more substituents independently selected from F, Cl, OH, NH2, CN and NO2.

[0141] In some more preferred embodiments, R 1 Selected from F, Cl, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, CH2F, CHF2 and CF3.

[0142] In some more preferred embodiments, R 1 Selected from Cl and CF3.

[0143] In some embodiments, the present invention provides compounds of formula (I), wherein R 3 Selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 The alkyl group is substituted with a substituent.

[0144] In some preferred embodiments, R 3 Selected from H, D, F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl are optionally each independently substituted by one or more independently selected from F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl and -COC 1-4 The alkyl group is substituted with a substituent.

[0145] In some more preferred embodiments, R 3 Selected from H, D, F, Cl, OH, NH2, CN, NO2 and C 1-4 alkyl.

[0146] In some more preferred embodiments, R 3 For H.

[0147] In some embodiments, the present invention provides compounds of formula (I), wherein R 4 Selected from H, D, halogen, OH, NH2, CN, NO2, COOH, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-NHCOR 8a 、-N(R 8a )COR 8b 、C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, monocyclic or condensed ring C 3-10 Cycloalkyl, monocyclic or condensed ring 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 7-10 Monospirocycloalkyl and 7-10 membered monospiroheterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, monocyclic or condensed ring C 3-10 Cycloalkyl, monocyclic or condensed ring 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 7-10 The monospirocycloalkyl and 7-10 membered monospiroheterocycloalkyl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, -NR 8a R 8b 、CN、NO2、oxo、C 1-6 Alkyl, C1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl substituents, and wherein R 8a and R 8b , at each occurrence, are independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, wherein R 8a and R 8b The C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-6 alkyl), N(C 1-6 Alkyl)2, CN, NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The substituents of cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are substituted.

[0148] In some preferred embodiments, R 4 Selected from H, D, F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl and C 3-6 Cycloalkyl.

[0149] In some more preferred embodiments, R 4 For H.

[0150] In some embodiments, the present invention provides compounds of formula (I), wherein R 12 , at each occurrence, is independently selected from H, D, F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-10 Aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from F, Cl, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 The alkyl group is substituted with a substituent.

[0151] In some embodiments, the present invention provides compounds of formula (I), wherein U is selected from O, S and CR 11a R 11b , where R 11a and R 11b Each independently selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 In some preferred embodiments, R 11a and R 11b Each is H.

[0152] In some preferred embodiments, U is O or CH2.

[0153] In some embodiments, the present invention provides compounds of formula (I), wherein:

[0154] When ring A is absent, V and W are each independently selected from O, S and CR 13a R 13b , where R 13a and R 13b Each independently selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 In some preferred embodiments, R 13a and R 13b are each independently selected from H, halogen, C 1-4 In some more preferred embodiments, R 13a and R 13b Each is independently selected from H, F, Cl, methyl and ethyl. In some preferred such embodiments, V and W are each independently selected from O, CH2, CHCH3, CHCH2CH3, CHF2 and CH2F.

[0155] In some more preferred embodiments, when ring A is absent, V is selected from O, CH2, CHF2, and CHCH3, preferably O. In some more preferred embodiments, W is selected from CH2, CH2F, CHCH3, and CHCH2CH3, preferably CHCH3.

[0156] In some more preferred embodiments, when Ring A is absent, The part has the following structure:

[0157] In other embodiments, the present invention provides compounds of formula (I), wherein:

[0158] When ring A is present, V and W are each C, and the ring A is selected from phenyl and 5-6 membered heteroaryl.

[0159] In some preferred embodiments, the ring A is selected from phenyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl. In some more preferred embodiments, the ring A is phenyl or pyridinyl.

[0160] In some more preferred embodiments, when Ring A is present, The part has the following structure:

[0161] In some embodiments, the present invention provides compounds of formula (I), wherein The part has the following structure:

[0162] In other embodiments, the present invention provides compounds of formula (I), wherein The part has the following structure:

[0163] The present invention encompasses compounds resulting from any combination of the various embodiments.

[0164] In a preferred embodiment, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound is selected from:

[0165] Pharmaceutical compositions and methods of treatment

[0166] In another aspect, the present invention provides a pharmaceutical composition comprising a preventive or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof and one or more pharmaceutically acceptable carriers. The pharmaceutical composition is preferably a solid preparation, a liquid preparation or a transdermal preparation.

[0167] In another aspect, the present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention for preparing a medicament.

[0168] In some embodiments, the compound of the present invention, the pharmaceutical composition of the present invention, or the medicament is used to prevent or treat cancer, cancer metastasis, cardiovascular disease, immune disorder, or visual disorder.

[0169] In another aspect, the present invention also provides a method for preventing or treating a disease, disorder or condition, alleviating its symptoms, delaying its development or onset, which comprises administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, wherein the disease, disorder or condition is cancer, cancer metastasis, cardiovascular disease, immune disorder or visual disorder.

[0170] In another aspect, the present invention also provides the use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention for the preparation of a medicament as a SHP2 inhibitor.

[0171] In another aspect, the present invention provides a method of inhibiting SHP2 activity in a subject, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention.

[0172] In another aspect, the present invention provides use of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, in the preparation of a medicament for preventing or treating a disease, disorder or condition mediated by SHP2 activity.

[0173] In yet another aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, for use in preventing or treating a disease, disorder or condition mediated by SHP2 activity.

[0174] In another aspect, the present invention provides a method for preventing or treating a disease, disorder or condition mediated by SHP2 activity, alleviating the symptoms thereof, delaying the development or onset thereof, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention.

[0175] In some embodiments, the disease, disorder, or condition mediated by SHP2 activity is selected from Noonan's syndrome, Leopard syndrome, and cancer.

[0176] In some embodiments, the cancer includes solid cancers and blood cancers. In some embodiments, the solid cancers include neuroblastoma, melanoma, head cancer, head and neck squamous cell carcinoma, breast cancer, esophageal cancer, liver cancer, pancreatic cancer, gastric cancer, colon cancer, lung cancer (preferably non-small cell lung cancer), anaplastic large cell lymphoma and glioblastoma. In some embodiments, the blood cancer includes leukemia, preferably juvenile myelomonocytic leukemia, acute myeloid leukemia.

[0177] 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.

[0178] As used herein, unless otherwise indicated, the terms "treat," ...

[0179] 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.).

[0180] In another embodiment, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.

[0181] Example

[0182] The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0183] Example 1: Synthesis of Compound A1

[0184] A1-1 (100 mg, 0.22 mmol, synthesized according to the synthesis method of patent CN111647000A), A1-2 (79 mg, 0.29 mmol), and potassium phosphate (190 mg, 0.88 mmol) were added to N,N-dimethylformamide (3 mL) and stirred at 80°C under nitrogen for 12 hours. LC-MS showed the formation of the product. The reaction solution was returned to room temperature, silica gel was added, and column chromatography (dichloromethane:methanol = 0-15%) was used for purification. Concentration gave a white solid, which was purified by preparative HPLC (water / acetonitrile = 80%) to give A1 (37 mg, yield 27%). ESI m / z [M+1] + =631.2. 1H NMR(400MHz,Chloroform-d)δ8.33(d,J=5.0Hz,1H),8.20(dt,J=8.2,1.4Hz,1H),8.15–8 .04(m,3H),7.13(ddd,J=17.5,8.4,6.4Hz,2H),6.76(dt,J=7.8,1.4Hz,1H),4.20(s,2H) ,4.04(s,1H),3.92(t,J=5.9Hz,2H),3.34–3.20(m,2H),3.19–3.11(m,2H),2.89(dd,J=1 1.7,5.2Hz,2H),1.95(d,J=6.0Hz,4H),1.80–1.67(m,2H),1.51(dd,J=59.4,13.4Hz,2H).

[0185] Biological activity test

[0186] Experimental Example 1. Enzyme activity assay

[0187] An enzyme activity assay was used to evaluate the inhibitory activity of the compounds of the present application against SHP2. The test compound was prepared with DMSO and diluted serially so that the final starting concentration in the reaction system was 1000 nM (1:5 serial dilutions, 9 gradients in total). The test compounds at different concentrations were transferred to a 384-well plate. An assay buffer (60 mM HEPES, pH 7.2, 75 mM NaCl, 75 mM KCl, 1 mM EDTA, 0.05% Tween-20, 5 mM DTT) was prepared. 4 × SHP2 recombinant protein, 4 × IRS1 peptide, and 4 × DiFMUP were prepared in the buffer solution, respectively, and added to a 384-well plate so that the final concentrations in the reaction system were 2.5 nM, 0.5 μM, and 200 μM, respectively. The reaction was allowed to proceed at room temperature for 45 minutes. The reaction was terminated by adding 5 μL of bpV (Phen) reagent to a final concentration of 32 μM. Fluorescence emission intensity was measured at 450 nm under excitation at 340 nm. The inhibition rate of the compound on enzyme activity was calculated. The inhibition rate and the logarithm of the compound concentration were fitted using nonlinear regression (dose-response - variable slope) to obtain the IC50 value of the test compound.

[0188] The reagent information used in this experiment is shown in the following table:

[0189] Experimental Example 2. Anti-tumor cell proliferation activity test

[0190] The CCL method was used to evaluate the anti-proliferative activity of the compounds of the present application on human non-small cell lung cancer NCI-H358 (ATCC: CRL-5807) and human oral squamous tumor cells HSC-2 (Kebai: CBP60260). Take the above-mentioned normally grown cells, digest them with trypsin cell digestion solution, centrifuge, count, and plate them into 96-well plates (3000 cells / well) at a suitable cell density, 180 μL per well. After 24 hours, the test compound is first prepared with DMSO and then diluted with culture medium so that the final starting concentration in the reaction system is 1000 nM, 1:5 doubling dilution, and a total of 9 gradients. The above-mentioned prepared compound is added to each well, three replicates are set for each concentration point, and a corresponding DMSO negative treatment control group is also set. After 120 hours of drug treatment, all the liquid in the adherent cultured 96-well plate was swiped out, and 100 μL of a solution of a 1:1 mixture of the cell proliferation detection reagent CellCounting-Lite (CCL) and the culture medium was added to each well. After shaking for 3 minutes, the cells were allowed to stand for 10 minutes. The chemiluminescence value was read using a Thermo Varioskan LUX-3020 multifunctional microplate reader and converted into a proliferation index to calculate the inhibition rate of the compound on tumor cell proliferation. The inhibition rate value and the logarithm of the compound concentration were fitted using nonlinear regression (dose response-variable slope) using GraphPad Prism 7.0 software to obtain the IC50 value of the compound.

[0191] The enzymatic activity and cell proliferation inhibitory activity of compound A1 are shown in the following table:

[0192] From the above data, it can be seen that compound A1 has excellent enzyme activity and cell proliferation inhibitory activity, which is far superior to the known SHP2 inhibitor TNO-155 (Batoprotafib).

[0193] Experimental Example 3. Liver microsome stability test

[0194] The test compounds were assessed for their first-phase metabolic stability in liver microsomes of CD-1 mice, Sprague-Dawley rats, beagle dogs, cynomolgus monkeys, and humans.

[0195] Experimental system:

[0196] The animal and human liver microsomes used in this test system were purchased from Xenotech, Corning or other qualified suppliers and stored in a freezer below -60°C before use.

[0197] Experiment Introduction:

[0198] Test and control compounds were incubated with animal and human liver microsomes at 37 ± 1°C for a specified period of time, with a maximum incubation time of 60 minutes. Samples were removed at designated time points and the reaction was terminated with acetonitrile or other organic solvent containing an internal standard. After centrifugation, the resulting supernatant was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0199] Experimental methods:

[0200] 1. Preparation of Buffer

[0201] Dissolve 73.21 g of potassium phosphate dibasic trihydrate and 10.78 g of potassium dihydrogen phosphate in 4000 mL of ultrapure water. Adjust the pH of the solution to 7.40 ± 0.10 using 10% phosphoric acid or 1 M potassium hydroxide, for a final concentration of 100 mM.

[0202] 2. Preparation of working solution

[0203] The test sample powder is prepared into a stock solution of a certain concentration using DMSO or other organic solvents, and then further diluted with a suitable organic solvent.

[0204] The control compounds testosterone, diclofenac, and propafenone were prepared as 10 mM stock solutions in DMSO and then further diluted in appropriate organic solvents.

[0205] 3. Preparation of Liver Microsome Solution

[0206] Dilute each microsome to a 2x working solution using 100 mM potassium phosphate buffer. The final concentration of microsomes in the reaction system is 0.5 mg / mL.

[0207] 4. Preparation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) regeneration system

[0208] Weigh an appropriate amount of nicotinamide adenine dinucleotide phosphate (NADP) and isocitrate (ISO) powder, dissolve in magnesium chloride solution, and vortex to mix thoroughly. Add an appropriate amount of isocitrate dehydrogenase (IDH) and gently invert to mix thoroughly. The final concentrations in the reaction system are: 1 mM NADP, 1 mM magnesium chloride, 6 mM ISO, and 1 unit / mL IDH.

[0209] 5. Preparation of Stop Solution

[0210] The stop solution is prepared with acetonitrile or other organic solvent containing an internal standard (tolbutamide or other suitable compound). The prepared stop solution is stored in a refrigerator at 2-8°C.

[0211] 6. Incubation Process

[0212] Incubations will be performed in 96-well plates. Prepare eight incubation plates, designated T0, T5, T15, T30, T45, T60, Blank60, and NCF60. The first six plates correspond to reaction time points of 0, 5, 15, 30, 45, and 60 minutes, respectively. In the Blank60 plate, no test or control compound is added, and a sample is taken after 60 minutes of incubation. In the NCF60 plate, potassium phosphate buffer is used instead of the NADPH regeneration system solution and incubated for 60 minutes. All conditions are replicated in triplicate.

[0213] Mix the microsomes with the test article or control compound, then preincubate the Blank60, T5, T15, T30, T45, and T60 plates (excluding T0 and NCF60) in a 37°C waterbath for approximately 10 minutes. Add the stop solution to the T0 plate, followed by the NADPH regeneration system working solution. In the NCF60 plate, 98 μL of potassium phosphate buffer was added to each well to initiate the reaction. After the preincubation period, 98 μL of the NADPH regeneration system working solution was added to each well of the Blank60, T5, T15, T30, T45, and T60 plates to initiate the reaction. The reaction temperature was 37 ± 1°C, and the final reaction volume was 200 μL. The reaction system contained 0.5 mg / mL microsomes, 1.0 μM substrate, 1 mM NADP, 6 mM ISO, and 1 unit / mL IDH.

[0214] The reaction was terminated by adding cold stop solution containing internal standard to the reaction plate at 5, 15, 30, 45 and 60 minutes, respectively.

[0215] All reaction plates were shaken and centrifuged at 3220 × g for 20 minutes at 4°C. The supernatant was diluted to a certain ratio and analyzed by LC-MS / MS.

[0216] Sample analysis

[0217] Sample analysis was performed using liquid chromatography-tandem mass spectrometry (LC-MS / MS) without a standard curve or quality control samples. Semiquantitative determination was performed using the ratio of the analyte peak area to the internal standard peak area. Analyst software (Sciex, Framingham, Massachusetts, USA) was used for analyte and internal standard retention times, chromatogram acquisition, and chromatogram integration.

[0218] The CV of the internal standard peak area in each matrix should be within 20% for each analytical run.

[0219] Data Analysis

[0220] The in vitro elimination rate constant ke of the compound was obtained by converting the ratio of the compound to the internal standard peak area into a residual rate using the following formula:

[0221] when hour,

[0222] CL int(mic) =0.693 / T 1 / 2 / Microsomal protein content (microsomal concentration during incubation mg / mL)

[0223] CL int(liver) =CL int(mic) × amount of microsomal protein in the liver (mg / g) × liver weight to body weight ratio

[0224] According to the well stir model, the hepatic intrinsic clearance and hepatic clearance can be converted using the following formula.

[0225] CL (liver) =(CL int(liver) *Q h ) / (CL int(liver) +Q h )

[0226] The parameters in the formula are shown in Table 3.

[0227] Table 3. Parameters in the data analysis formula

[0228] Experimental Example 4. Hepatocyte metabolic stability test

[0229] This experiment was used to test the metabolic stability of compounds in hepatocytes.

[0230] Prepare 0.5 x 10 6 / mL of hepatocyte suspension, then 198μL of preheated cell suspension was added to a 96-well plate. 2μL of the test compound was added to each well of the 96-well plate to a final concentration of 1μM, and 2 replicates were set. For samples at T=0 minutes, the compound and cells were thoroughly mixed for 1 minute, and then 25μL of sample was immediately taken and added to 125μL of stop solution (containing 200ng / mL tolbutamide and 200ng / mL labetalol in acetonitrile) in an ice bath and mixed. At the same time, all plates were placed in an incubator at 37°C and 5% CO2, and the shaker was set to 600rpm. The samples were mixed at 15, 30, 60, and 90 minutes of incubation, and 25μL of sample was added to 125μL of stop solution (containing 200ng / mL tolbutamide and 200ng / mL labetalol in acetonitrile) in an ice bath, and shaken at 500rpm for 10 minutes after mixing. The plates were then centrifuged at 3220 × g for 20 minutes at 4°C. After centrifugation, 80 μL of supernatant was transferred from each well to another 96-well plate containing 240 μL of ultrapure water. The intrinsic clearance (CLint) and half-life (T1 / 2) were then calculated using LC-MS / MS.

[0231] Experimental Example 5. Pharmacokinetic test in rats

[0232] In this experiment, the pharmacokinetic behavior of the test compound was investigated in SD rats after intravenous (IV) and oral (PO) administration.

[0233] On the day of administration, the actual body weight of the rats was weighed and the administration volume was calculated. There were 3 rats in each group, and two groups of tests were performed for each compound, one group was administered with a single intravenous injection, and the other group was administered with a single oral gavage. Whole blood samples were collected at the specified time (0.25, 0.5, 1, 2, 4, 8, 24h after administration) by blood sampling from the jugular vein. After blood sample collection, it was immediately transferred to a labeled commercial sample tube containing K2-EDTA (0.85-1.15mg), followed by centrifugation (3200xg, 4°C, 10 minutes) and plasma was collected. The plasma was transferred to a pre-cooled centrifuge tube, quick-frozen in dry ice, and then stored in an ultra-low temperature freezer at -60°C or lower until LC-MS / MS analysis.

[0234] Plasma concentrations were determined using LC-MS / MS. Plasma concentration data were analyzed using WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software using a non-compartmental model. Pharmacokinetic parameters were calculated using the linear-log trapezoidal method.

[0235] Table 4. Pharmacokinetic results of compound A1 in rats

[0236] As shown in Table 4, the compound of the present invention has a good oral exposure and oral bioavailability in rats, which is significantly better than the control compound C. The structure of the control compound C is It is compound 1 in international patent application WO2022089389 and is synthesized according to the method of the patent application.

[0237] Experimental Example 6. Pharmacokinetic test in mice

[0238] In this experiment, the pharmacokinetic behavior of the test compound was investigated in BALB / c mice after intravenous (IV) and oral (PO) administration.

[0239] On the day of administration, the actual body weight of the mice was weighed and the administration volume was calculated. There were 9 mice in each group, and two groups of tests were performed for each compound, one group was administered with a single intravenous injection, and the other group of mice was administered with a single oral gavage. Whole blood samples were collected at the specified time (0.25, 0.5, 1, 2, 4, 8, 24h after administration) by orbital bleeding. After blood sample collection, it was immediately transferred to a labeled commercial sample tube containing K2-EDTA (0.85-1.15mg), followed by centrifugation (3200xg, 4°C, 10 minutes) and plasma was collected. The plasma was transferred to a pre-cooled centrifuge tube, quick-frozen in dry ice, and then stored in an ultra-low temperature freezer at -60°C or lower until LC-MS / MS analysis.

[0240] Plasma concentrations were determined using LC-MS / MS. Plasma concentration data were analyzed using WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software using a non-compartmental model. Pharmacokinetic parameters were calculated using the linear-log trapezoidal method.

[0241] Experimental Example 7. hERG inhibition test

[0242] HEK293 cells were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418 at 37°C and 5% CO2. TM After express digestion, centrifugation was performed and the cell density was adjusted to 2 × 10 6cells / mL, then gently mix the cells on a room temperature balanced shaker for 15-20 minutes, and perform patch clamp detection on the machine. Replace the culture medium of the prepared cells with extracellular fluid. Aspirate the intracellular and extracellular fluids from the liquid pool and add them to the intracellular fluid pool, cell and test substance pool of the QPlate chip respectively. The whole-cell patch clamp records the voltage stimulation of the whole-cell hERG potassium current, and the experimental data is collected and stored by Qpatch. The compound starts at 30μM, is diluted 3 times, and 6 concentration points are set. Each drug concentration is set to be administered twice for at least 5 minutes. The current detected in the compound-free extracellular fluid of each cell is used as its own control group, and at least two cells are used for each concentration to repeat the test twice independently. All electrophysiological experiments were performed at room temperature.

[0243] Data analysis: First, the current after each drug concentration is normalized with the blank control current. Then calculate the inhibition rate corresponding to each drug concentration For each concentration, calculate the mean and standard error, and calculate the half-inhibitory concentration for each compound: The above equation was used to perform nonlinear fitting of the dose-dependent effect, where Y represents the inhibition rate, C represents the concentration of the test substance, and IC 50 is the half-inhibitory concentration, and HillSlope represents the Hill coefficient. Curve fitting and IC 50 The calculations were completed using Graphpad software.

[0244] Table 5. hERG inhibition results of Compound A1

[0245] As shown in Table 5, the compounds of the present invention have no significant inhibitory risk on hERG and are significantly better than the control compound B. The structure of the control compound B is It is the compound of Example 30 in patent application CN110143949A, and is synthesized according to the method of the patent application.

[0246] Experimental Example 8. Cytochrome oxidase P450 inhibition test

[0247] 1) Preparation of buffer solution:

[0248] 100mM K-Buffer: Mix 9.5mL of stock solution A with 40.5mL of stock solution B, adjust the total volume to 500mL with ultrapure water, and titrate the buffer to pH 7.4 with KOH or H3PO4.

[0249] Raw material A (1M potassium dihydrogen phosphate): 136.5 g potassium dihydrogen phosphate in 1 L water;

[0250] Stock B (1M KH2PO4): 174.2 g KH2PO4 in 1 L water.

[0251] 2) Preparation of test substance

[0252] The test substance powder is prepared into a stock solution of a certain concentration using DMSO or other organic solvents, and then further diluted with a suitable organic solvent.

[0253] 3) In vitro incubation

[0254] The in vitro incubation system of liver microsomes for CYP450 enzyme metabolic phenotype studies is a biochemical reaction carried out under conditions simulating physiological temperature and physiological environment, with the prepared liver microsomes supplemented with redox coenzymes and enzyme-specific selective inhibitors.

[0255] 4) Detection of parent drug or metabolites

[0256] The concentration of parent drug or its metabolites in the incubation solution was determined by LC-MS / MS.

[0257] Experimental Example 9. Compound Tissue Distribution Test

[0258] Animals were randomly divided into groups and dosed at 10 ml / kg of body weight. Whole blood and tissue samples were collected at the time points specified in the experimental protocol. Whole blood was placed in a centrifuge tube containing anticoagulant, placed on wet ice, and centrifuged (8000 rpm / 10 min / 4°C). The supernatant was collected to obtain plasma and stored at -80°C for drug concentration analysis. After each tissue was collected, it was thoroughly rinsed with normal saline, blotted dry with filter paper, weighed, and quickly frozen in liquid nitrogen. Tissue samples were stored at -80°C for drug concentration analysis. Tissue samples were added to a volume of 2 mL / g of tissue homogenate and homogenized by grinding at 60 Hz for 10 min. 20 μL of tissue homogenate was transferred to a 96-well plate, 80 μL of acetonitrile containing an internal standard was added, the plate was vortexed for 10 min, and the supernatant was collected for LC-MS / MS analysis.

[0259] 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 pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, in: X 1 and X 2 Each independently is N or CR 9 , and X 1 and X 2 At least one of them is N; X 3 is N; X 4 N or CR 10 ; L is selected from O, S, CR 7a R 7b , C(O) and S(O) p ; p is 1 or 2; R 1 and R 10 Each independently selected from H, D, halogen, OH, NH2, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 The aryl and 5-14 membered heteroaryl groups are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl, -COC 1-6 Substitution of alkyl groups; R 2 Selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 The aryl and 5-14 membered heteroaryl groups are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 The alkyl group is substituted with a substituent; or R 2 Together with L and the carbon atoms indicated by "a" and "b" to which they are attached, form a ring B represented by the following formula: The ring B is selected from a partially unsaturated C 3-10 Cyclic hydrocarbon group, partially unsaturated 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl, wherein the C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, COOH, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-NHCOR 8a 、-N(R 8a )COR 8b , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 Substitution of aryl and 5-14 membered heteroaryl groups; R 3 and R 5 Each is independently selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl are optionally each independently substituted with one or more is selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 Substitution of alkyl groups; R 4 and R 9 Each independently selected from H, D, halogen, OH, NH2, CN, NO2, COOH, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-NHCOR 8a 、-N(R 8a )COR 8b 、-COC 1-6 Alkyl-OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, saturated or partially unsaturated monocyclic or condensed ring C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered monocyclic or condensed heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-11 Monospirocycloalkyl and 6-11 membered monospiroheterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-11 The monospirocycloalkyl and 6-11 membered monospiroheterocycloalkyl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, -NR 8a R 8b 、CN、NO2、oxygen group、C 1-6 Alkyl, C 1-6 Alkoxy, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 Substitution of aryl and 5-14 membered heteroaryl groups; U is selected from O, S, CR 11a R 11b and NR 12 ;as well as The presence or absence of ring A, When ring A is absent, V and W are each independently selected from O, S, CR 13a R 13b and NR 12 , and m is 0; or Wherein when ring A exists, ring A is selected from saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, V and W are each independently selected from C, N or CR 11a , R 6 Selected from H, D, halogen, OH, NH2, CN, NO2, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOH、-S(O) n C 1-6 Alkyl, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the -S(O) n C 1-6 Alkyl, C 1-6 Alkyl and C 1-6 The alkoxy groups are optionally each independently substituted with one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 Alkyl substituents are substituted, m is 1, 2, 3, or 4, and n is 0, 1 or 2; R 7a , R 7b , R 11a , R 11b , R 12 , R 13a and R 13b , at each occurrence, is independently selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 The aryl and 5-14 membered heteroaryl groups are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 Substitution of alkyl groups; R 8a and R 8b , at each occurrence, independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, CN, NO2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclic group, C 6-10 Substitution of aryl and 5-14 membered heteroaryl groups by substituents; and represents a single bond or a double bond; and The conditions are: (1) the valences of all atoms are satisfied; and (2) The compound of formula (I) does not include the following compounds:

2. The compound according to claim 1, wherein when ring A is absent, R 2 Together with L and the carbon atoms indicated by "a" and "b" to which they are attached, form said ring B; or When ring A is present, R 2 Together with L and the carbon atoms indicated by "a" and "b" to which they are attached, form the ring B.

3. The compound according to claim 1 or 2, wherein: X 1 is N, and X 2 CR 9 ; or X 1 CR 9 , and X 2 is N; in: Preferably, at each occurrence, R 9 Independently selected from H, D, halogen, OH, NH2, CN, NO2, COOH, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-NHCOR 8a 、-N(R 8a )COR 8b 、-COC 1-6 Alkyl-OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, monocyclic or condensed ring C 3-10 Cycloalkyl, monocyclic or condensed 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 6-11 Monospirocycloalkyl and 6-11 membered monospiroheterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, monocyclic or condensed ring C 3-10 Cycloalkyl, monocyclic or condensed 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 6-11 The monospirocycloalkyl and 6-11 membered monospiroheterocycloalkyl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, -NR 8a R 8b 、CN、NO2、oxygen group、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl substituents; wherein the monospirocycloalkyl and monospiroheterocycloalkyl optionally include 3-membered / 5-membered ring systems, 4-membered / 4-membered ring systems, 4-membered / 5-membered ring systems, 4-membered / 6-membered ring systems, 5-membered / 5-membered ring systems, 5-membered / 6-membered ring systems, and 6-membered / 6-membered ring systems, wherein the count of each ring includes the spiro atom; and wherein R 8a and R 8b , at each occurrence, independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein R 8a and R 8b The C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, CN, NO2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Substitution of aryl and 5-10 membered heteroaryl; More preferably, at each occurrence, R 9 independently selected from H, D, F, Cl, OH, NH2, CN, NO2, COOH, -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-COC 1-4 Alkyl-OC 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, monocyclic C 3-6 Cycloalkyl, monocyclic 4-6 membered heterocycloalkyl, C 7-10 Monospirocycloalkyl and 7-10 membered monospiroheterocycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, monocyclic C 3-6 Cycloalkyl, monocyclic 4-6 membered heterocycloalkyl, C 7-10 The monospirocycloalkyl and 7-10 membered monospiroheterocycloalkyl are optionally each independently substituted by one or more independently selected from F, Cl, OH, NH2, -NR 8a R 8b , CN and NO2; wherein the monospirocycloalkyl and monospiroheterocycloalkyl optionally include 3-membered / 5-membered ring systems, 4-membered / 4-membered ring systems, 4-membered / 5-membered ring systems, 4-membered / 6-membered ring systems, 5-membered / 5-membered ring systems and 5-membered / 6-membered ring systems, wherein the count of each ring includes spiro atoms; and wherein R 8a and R 8b , at each occurrence, independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and phenyl, wherein R 8a and R 8b The C 1-4 The alkyl group is optionally substituted with one or more independently selected from F, Cl, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)2, CN, NO2, C 3-6 Substitution by substituents of cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; More preferably, at each occurrence, R 9 Independently selected from H, D, F, Cl, CN, COOH, -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-COC 1-4 Alkyl-OC 1-4 Alkyl, C 2-4 Alkenyl, monocyclic C 3-6 Cycloalkyl, monocyclic 4-6 membered heterocycloalkyl, C7 monospirocycloalkyl, 7 membered monospiro heterocycloalkyl and C7 substituted by OH 1-4 alkyl, wherein the monospirocycloalkyl and monospiroheterocycloalkyl include 4-membered / 4-membered ring systems, wherein the count of each ring includes the spiro atom; and wherein R 8a and R 8b , at each occurrence, independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl and phenyl, wherein R 8a and R 8b The C 1-4 Alkyl is optionally substituted with one or more substituents independently selected from F, Cl, OH, NH2, NHCH3, N(CH3)2, cyclopropyl, azetidinyl and phenyl; More preferably, at each occurrence, R 9 independently selected from H, D, F, Cl, CN, -CH2OH, vinyl, cyclopropyl, COOH, -COOCH3, -COOCH2CH3, -CONH2, -COCH3, -COCH2OCH3, -COCH2F, -COCH2OH, -COCH2NH2, -COCH2N(CH3)2, More preferably, at each occurrence, R 9 independently H; or X 1 and X 2 Both are N.

4. The compound according to any one of claims 1 to 3, wherein; L is selected from O, S or CR 7a R 7b , where R 7a and R 7b Each is independently selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 The aryl and 5-10 membered heteroaryl groups are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 Substitution of alkyl groups; Preferably, L is selected from O, S or CR 7a R 7b , where R 7a and R 7b Each independently selected from H, D, F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 The aryl and 5-6 membered heteroaryl groups are optionally each independently substituted with one or more independently selected from F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl and -COC 1-4 Substitution of alkyl groups; Preferably, L is selected from O, S and CH2, more preferably S; and / or R 2 Selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 The aryl and 5-10 membered heteroaryl groups are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 Substitution of alkyl groups; Preferably, R 2 Selected from H, D, halogen, OH, NH2, CN, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-4 Alkyl and -COC 1-4 Substitution of alkyl groups; More preferably, R 2 Selected from H, D, F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 3-6 The cycloalkyl groups are optionally each independently substituted with one or more independently selected from F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl and -COC 1-4 Substitution of alkyl groups; More preferably, R 2 Selected from H, D, OH, NH2 and C 1-4 alkyl; More preferably, R 2 is selected from the group consisting of H, OH, NH2 and CH3; More preferably, R 2 is H; or R 2 Together with L and the carbon atoms indicated by "a" and "b" to which they are attached, form a ring B represented by the following formula: The ring B is selected from a partially unsaturated C 3-6 Cyclic hydrocarbon group, partially unsaturated 4-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, COOH, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-NHCOR 8a 、-N(R 8a )COR 8b , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, and wherein R 8a and R 8b , at each occurrence, independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein R 8a and R 8b The C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 Heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, CN, NO2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Substitution of aryl and 5-10 membered heteroaryl; Preferably, the ring B is selected from phenyl and 5-6 membered heteroaryl, more preferably selected from 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, COOH, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-NHCOR 8a 、-N(R 8a )COR 8b , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 aryl and 5-6 membered heteroaryl substituents, and wherein R 8a and R 8b , at each occurrence, independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl, wherein R 8a and R 8b The C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)2, CN, NO2, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Substitution of aryl and 5-6 membered heteroaryl groups; More preferably, the ring B is selected from pyrrolyl, pyrazolyl, 1,2,3-triazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, more preferably pyrazolyl, each of the above groups is optionally independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, COOH, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-NHCOR 8a 、-N(R 8a )COR 8b , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 aryl and 5-6 membered heteroaryl substituents, and wherein R 8a and R 8b , at each occurrence, independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl, wherein R 8a and R 8b The C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)2, CN, NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Substitution of aryl and 5-6 membered heteroaryl groups; and / or The bond indicated by "c" is connected to an available ring atom of said ring B; Preferably, R 2 Together with L and the carbon atoms indicated by "a" and "b" to which they are attached, they form a structure represented by the following formula: Where R 14 Selected from H, halogen, OH, NH2, CN, NO2, COOH, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-NHCOR 8a 、-N(R 8a )COR 8b , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)2, CN, NO2, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Substitution of aryl and 5-6 membered heteroaryl groups; Preferably, R 14 For H.

5. The compound according to any one of claims 1 to 4, wherein: Selected from Preferably or R 2 Together with L and the carbon atoms indicated by "a" and "b" to which they are attached, form a ring such that A structure represented by the following formula is formed:

6. A compound according to any one of claims 1 to 5, wherein: R 5 Selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 The aryl and 5-10 membered heteroaryl groups are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 Substitution of alkyl groups; Preferably, R 5 Selected from H, D, F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 The aryl and 5-6 membered heteroaryl groups are optionally each independently substituted with one or more independently selected from F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl and -COC 1-4 Substitution of alkyl groups; Preferably, R 5 Selected from OH and NH2, more preferably OH; and / or R 6 Selected from H, D, halogen, OH, NH2, CN, NO2, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOH、-S(O) n C 1-6 Alkyl, C 1-6 Alkyl and C 1-6 Alkoxy, wherein the -S(O) n C 1-6 Alkyl, C 1-6 Alkyl and C 1-6 The alkoxy groups are optionally each independently substituted with one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 The alkyl group is substituted with a substituent, and wherein R 8a and R 8b , at each occurrence, independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, CN, NO2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Substitution of aryl and 5-10 membered heteroaryl; Preferably, R 6 Selected from H, D, halogen, OH, NH2, CN, NO2, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOH、-S(O) n C 1-4 Alkyl, C 1-4 Alkyl and C 1-4 Alkoxy, wherein the -S(O) n C 1-4 Alkyl, C 1-4 Alkyl and C 1-4 The alkoxy groups are optionally each independently substituted with one or more independently selected from halogen, OH, NH2, CN, NO2, oxygen Generation base, C 1-4 Alkyl and -COC 1-4 The alkyl group is substituted with a substituent, and wherein R 8a and R 8b , at each occurrence, independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-4 Alkyl), N(C 1-4 Alkyl)2, CN, NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Substitution of aryl and 5-6 membered heteroaryl groups; m is 1, 2, or 3, and n is 0, 1 or 2; Preferably, R 6 is H, and m is 1; and / or X 4 is N; or X 4 CR 10 , Where R 10 Selected from H, D, halogen, OH, NH2, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 The aryl and 5-10 membered heteroaryl groups are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl, -COC 1-6 Substitution of alkyl groups; Preferably, R 10 Selected from H, D, F, Cl, OH, NH2, CN, NO2, COOH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 The aryl and 5-6 membered heteroaryl groups are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, C 1-4 Alkyl, -COC 1-4 Substitution of alkyl groups; More preferably, R 10 For H.

7. The compound according to any one of claims 1 to 6, wherein the compound has a structure of Formula II or Formula III: Wherein preferably, in the compound of formula (II), ring A is present; Wherein in the compound of formula (III), ring A is present or absent.

8. A compound according to any one of claims 1 to 7, wherein: R 1 Selected from H, D, halogen, OH, NH2, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 The aryl and 5-10 membered heteroaryl groups are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl, -COC 1-6 Substitution of alkyl groups; Preferably, R 1 Selected from H, D, F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 3-6 Cycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl and C 3-6 The cycloalkyl groups are optionally substituted each independently with one or more substituents independently selected from F, Cl, OH, NH2, CN and NO2; More preferably, R 1 is selected from the group consisting of F, Cl, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, CH2F, CHF2 and CF3, more preferably selected from the group consisting of Cl and CF3; and / or R 3 Selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 The aryl and 5-10 membered heteroaryl groups are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 Substitution of alkyl groups; Preferably, R 3 Selected from H, D, F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 The aryl and 5-6 membered heteroaryl groups are optionally each independently substituted with one or more independently selected from F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl and -COC 1-4 Substitution of alkyl groups; More preferably, R 3 Selected from H, D, F, Cl, OH, NH2, CN, NO2 and C 1-4 Alkyl, more preferably H; and / or R 4 Selected from H, D, halogen, OH, NH2, CN, NO2, COOH, -NHR 8a 、-NR 8a R 8b , -CONH2, -CONHR 8a 、-CONR 8a R 8b 、-COR 8a 、-COOR 8a 、-NHCOR 8a 、-N(R 8a )COR 8b , C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, monocyclic or condensed ring C 3-10 Cycloalkyl, monocyclic or condensed 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 7-10 Monospirocycloalkyl and 7-10 membered monospiroheterocycloalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, monocyclic or condensed ring C 3-10 Cycloalkyl, monocyclic or condensed 3-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 7-10 The monospirocycloalkyl and 7-10 membered monospiroheterocycloalkyl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, -NR 8a R 8b 、CN、NO2、oxygen group、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, and wherein R 8a and R 8b , at each occurrence, independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, wherein R 8a and R 8b The C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, NH(C 1-6 Alkyl), N(C 1-6 Alkyl)2, CN, NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substitution by substituents of cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; Preferably, R 4 Selected from H, D, F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl and C 3-6 Cycloalkyl; More preferably, R 4 is H; and / or R 12 , at each occurrence, is independently selected from H, D, F, Cl, OH, NH2, CN, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 The aryl and 5-10 membered heteroaryl groups are optionally each independently substituted with one or more independently selected from F, Cl, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 Substitution of alkyl groups; and / or U is selected from O, S and CR 11a R 11b , where R 11a and R 11b Each is independently selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 The aryl and 5-10 membered heteroaryl groups are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 The alkyl group is substituted with a substituent, preferably R 11a and R 11b Each is H; Preferably, U is O or CH2; and / or When ring A is absent, V and W are each independently selected from O, S and CR 13a R 13b , where R 13a and R 13b Each is independently selected from H, D, halogen, OH, NH2, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 The aryl and 5-10 membered heteroaryl groups are optionally each independently substituted by one or more independently selected from halogen, OH, NH2, CN, NO2, oxo, C 1-6 Alkyl and -COC 1-6 The alkyl group is substituted with a substituent; preferably, R 13a and R 13b are each independently selected from H, halogen, C 1-4 More preferably, R 13a and R 13b Each independently selected from H, F, Cl, methyl and ethyl; Preferably, when ring A is absent, V is selected from O, CH2, CHF2 and CHCH3, preferably O; and / or W is selected from CH2, CH2F, CHCH3 and CHCH2CH3, preferably CHCH3; More preferably, when ring A is absent, The part has the following structure: or When ring A is present, V and W are each C, and the ring A is selected from phenyl and 5-6 membered heteroaryl, more preferably selected from phenyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, more preferably phenyl or pyridinyl; More preferably, when ring A is present, The part has the following structure: and / or The part has the following structure:

9. The compound according to any one of claims 1 to 8, wherein the compound:

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, and one or more pharmaceutically acceptable carriers, wherein the pharmaceutical composition is preferably a solid preparation, a liquid preparation or a transdermal preparation.

11. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition according to claim 10 in the preparation of a medicament for preventing and / or treating a disease, disorder or condition mediated by SHP2 activity, alleviating its symptoms, delaying its development or onset; preferably, the disease, disorder or condition is selected from Noonan syndrome, Leopard syndrome and cancer, wherein preferably, the cancer comprises solid cancer and blood cancer, the solid cancer is preferably selected from neuroblastoma, melanoma, head cancer, head and neck squamous cell carcinoma, breast cancer, esophageal cancer, liver cancer, pancreatic cancer, gastric cancer, colon cancer, lung cancer (preferably non-small cell lung cancer), anaplastic large cell lymphoma and glioblastoma, and the blood cancer is preferably leukemia, preferably juvenile myelomonocytic leukemia or acute myeloid leukemia.

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