Pyridine compound, pharmaceutical composition containing the same, preparation method and use thereof

Abstract

The present invention belongs to the field of pharmaceutical chemistry and relates to pyridine compounds, pharmaceutical compositions containing the same, preparation methods and uses thereof. Specifically, the present invention relates to a compound having a structure of formula I, which exhibits good HPK1 inhibitory activity and can be used as a highly effective HPK1 inhibitor for preventing and / or treating HPK1-related diseases.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and relates to a pyridine compound used as an HPK1 (hematopoietic progenitorkinase 1) inhibitor, a pharmaceutical composition containing the pyridine compound, a preparation method thereof, and use thereof for preventing and / or treating HPK1-related diseases. Background Art

[0002] Hematopoietic progenitor kinase 1 (HPK1), also known as mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1), is a member of the serine / threonine kinase subfamily Ste20, whose family members also include MAP4K2 (GCK), MAP4K3 (GLK), MAP4K4 (HGK), MAP4K5 (KHS) and MAP4K6 (MINK). HPK1 is mainly restrictedly expressed in hematopoietic system cells, including early progenitor cells, and hematopoietic cell lines, such as human acute lymphoblastic leukemia cells (MOLT4), human lymphoma cells (Daudi), etc.

[0003] Under physiological conditions, HPK1 functions as peripheral immune tolerance through the JNK / SAPK signaling pathway. However, in some tumor processes, HPK1 negatively regulates T cell and B cell responses and dendritic cell activation. When the T cell receptor (TCR) binds to the ligand (CD3 / 28), HPK1 is activated by the TCR signaling pathway. The activated HPK1 can phosphorylate serine 376 of the adaptor protein SLP-76, thereby recruiting 14-3-3 protein, which in turn leads to instability of the TCR complex, and ultimately leads to weakened T cell responses and inhibited T cell proliferation. Therefore, in tumor treatment, inhibiting the negative immune regulation of HPK1 to exert the anti-tumor effect of the patient's own immune system has received increasing attention.

[0004] Studies have shown that the specific loss of HPK1 enzyme activity in mouse dendritic cells enhances their antigen presentation function (Alzabin, S., N. Bhardwaj, F. Kiefer, S. Sawasdikosol and S. Burakoff (2009). "Hematopoietic progenitor kinase 1 is a negative regulator of dendritic cell activation." J Immunol 182 (10): 6187-6194). Similarly, the tumor suppression rate of Lewis lung cancer transplanted mice after receiving HPK1 knockout T cell transplantation therapy was significantly increased compared with the control group (wild-type T cell transplantation therapy) (Alzabin, S., S. Pyarajan, H. Yee, F. Kiefer, A. Suzuki, S. Burakoff and S. Sawasdikosol (2010). "Hematopoietic progenitor kinase 1 is a critical component of prostaglandin E2-mediated suppression of the anti-tumor immune response." Cancer Immunol Immunother 59 (3): 419-429). Therefore, the search for HPK1 inhibitors (especially small molecule inhibitors) can be a new direction for tumor immunotherapy. Summary of the invention

[0005] Problem that the invention aims to solve

[0006] The present invention has discovered a series of novel pyridine compounds through extensive research. These compounds have high HPK1 inhibitory activity and can be used alone or in combination with other drugs to prevent and / or treat HPK1-related diseases, especially tumor diseases, showing good application prospects.

[0007] Solutions for solving problems

[0008] In a first aspect, the present invention provides a compound having a structure of Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite, prodrug or a mixture of any two or more thereof,

[0009]

[0010] in,

[0011] A is selected from C6-C 14 Aryl and 5-14 membered heteroaryl, the C6-C 14 Aryl and 5-14 membered heteroaryl are each optionally substituted by one or more R d replace;

[0012] R 1 Selected from C1-C6 alkoxy, cyano, nitro, P(O)R b R c 、C(O)NR b R c 、S(O)2R a 、S(O)2NR b R c 、C(O)R a and NR b C(O)R a The C1-C6 alkoxy group is optionally replaced by one or more R d replace;

[0013] R 2 is selected from hydrogen and C1-C6 alkyl, the C1-C6 alkyl being optionally substituted by one or more R d replace;

[0014] R 3 is selected from hydrogen, halogen, hydroxyl, cyano, nitro, C1-C6 alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C(O)NR b R c NR b C(O)R a and NR b R c The C1-C6 alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy groups are each optionally substituted by one or more R d replace;

[0015] R 4 and R 5 are each independently selected from hydrogen, halogen, cyano, nitro, C(O)R a 、C(O)OR a 、C(O)NR b R c 、S(O)R a 、S(O)2R a 、S(O)2NR b R c 、NHC(O)R a 、NHC(O)OR a NR b Rc 、OC(O)R a , C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 14 The aryl and 5-14 membered heteroaryl groups, the C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 14 Aryl and 5-14 membered heteroaryl are each optionally substituted by one or more R d replace;

[0016] R 6 Selected from hydrogen, halogen, hydroxy, cyano, nitro, NR b R c , C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 14 The aryl and 5-14 membered heteroaryl groups, the C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 14 Aryl and 5-14 membered heteroaryl are each optionally substituted by one or more R d replace;

[0017] X is selected from CR 7 and N;

[0018] R 7 is selected from hydrogen, halogen, cyano, nitro, C(O)R a 、C(O)OR a 、C(O)NR b R c 、S(O)R a 、S(O)2R a 、S(O)2NR b R c 、NHC(O)R a 、NHC(O)OR a 、OC(O)R a NR b R c , C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 14 The aryl and 5-14 membered heteroaryl groups, the C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 14Aryl and 5-14 membered heteroaryl are each optionally substituted by one or more R d replace;

[0019] If present, each R a Each independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl, 5-14 membered heteroaryl and 5-10 membered heterocyclic group, the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl, 5-14 membered heteroaryl and 5-10 membered heterocyclyl are each optionally substituted by one or more R d replace;

[0020] If present, each R b and R c Each is independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl and 4-7 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl and 4-7 membered heterocyclyl are each optionally substituted by one or more R d Replace; or, if present, each pair of R b and R c Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group is optionally substituted by one or more R d replace;

[0021] If present, each R d are each independently selected from hydrogen, hydroxy, halogen, oxo, cyano, nitro, C(O)R e 、C(O)OR e NR f S(O)2R g 、S(O)R e 、S(O)2R e 、C(O)NR f R g 、S(O)2NR f R g NR f R g NR f C(O)R g , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 alkyleneoxy-C1-C6 alkoxy, C6-C 14 The aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic groups, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 alkyleneoxy-C1-C6 alkoxy, C6-C 14Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl are each optionally substituted by one or more R j replace;

[0022] If present, each R e Each independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 membered heteroaryl;

[0023] If present, each R f and R g are each independently selected from hydrogen, C 1- C6 alkyl, C3-C7 cycloalkyl and 4-7 membered heterocyclic group, wherein the C1-C6 alkyl is optionally substituted by one or more C1-C6 alkoxy or NR h R i Replace; or, if present, each pair of R f and R g Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic group;

[0024] If present, each R h and R i are each independently selected from hydrogen and C1-C6 alkyl; and

[0025] If present, each R j Each is independently selected from halogen, hydroxy, cyano and 3-8 membered heterocyclic group.

[0026] In a second aspect, the present invention provides specific examples of the compound having the structure of Formula I, which include:

[0027] (1) (2-((5-chloro-2-((4-(pyrrolidin-3-yl)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0028] (2) (2-((5-chloro-2-((4-(1-methylpyrrolidin-3-yl)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0029] (3) (2-((5-chloro-2-((4-(1-(2-fluoro-2-methylpropyl)pyrrolidin-3-yl)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0030] (4) (2-((5-chloro-2-((4-(1-(2-hydroxy-2-methylpropyl)pyrrolidin-3-yl)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0031] (5)(2-((5-chloro-2-((4-(piperidin-4-yl)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0032] (6) (2-((5-chloro-2-((4-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0033] (7) (2-((5-chloro-2-((4-(piperidin-3-yl)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0034] (8) (2-((5-chloro-2-((4-(piperazin-1-yl)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0035] (9) (2-((5-chloro-2-((4-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0036] (10) (2-((5-chloro-2-((4-((2-(dimethylamino)ethyl)amino)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0037] (11) (2-((5-chloro-2-((4-((2-(methylamino)ethyl)amino)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0038] (12) (2-((5-chloro-2-((4-(2-(methylamino)ethoxy)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0039] (13) (2-((5-chloro-2-((4-cyclopentyl-6-((2-(methylamino)ethyl)amino)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0040] (14) (2-((5-chloro-2-((4-cyclopropyl-6-((2-(methylamino)ethyl)amino)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0041] (15) (2-((5-chloro-2-((4-(3-hydroxycyclopentyl)-6-((2-(methylamino)ethyl)amino)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0042] (16) (2-((5-chloro-2-((6-((2-(methylamino)ethyl)amino)-4-morpholinylpyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0043] (17) (2-((5-chloro-2-((6-((2-(methylamino)ethyl)amino)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0044] (18) (2-((5-chloro-2-((4-(3-hydroxypyrrolidin-1-yl)-6-((2-(methylamino)ethyl)amino)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide;

[0045] (19) (2-((5-chloro-2-((4-(pyrrolidin-3-yl)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)diethylphosphine oxide;

[0046] (20)5-Chloro-N 4 -(2-(Methylsulfonyl)phenyl)-N 2 -(4-(Pyrrolidin-3-yl)pyridin-2-yl)pyridine-2,4-diamine;

[0047] (21)5-Chloro-N 4 -(2-(isopropylsulfonyl)phenyl)-N 2 -(4-(Pyrrolidin-3-yl)pyridin-2-yl)pyridine-2,4-diamine;

[0048] (22) 2-((5-chloro-2-((4-(pyrrolidin-3-yl)pyridin-2-yl)amino)pyridin-4-yl)amino)-N,N-dimethylbenzenesulfonamide;

[0049] (23) 2-((5-chloro-2-((4-(pyrrolidin-3-yl)pyridin-2-yl)amino)pyridin-4-yl)amino)-N-methylbenzamide; and

[0050] (24) (2-((2-((4-(Pyrrolidin-3-yl)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide.

[0051] In a third aspect, the present invention provides a method for preparing the compound having the structure of formula I, comprising the following steps:

[0052] 1) Compound I-1 reacts with compound I-2 to obtain compound I-3;

[0053]

[0054] 2) Compound I-3 reacts with compound I-4 to obtain a compound having a structure of formula I;

[0055]

[0056] in,

[0057] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and X is as defined above;

[0058] LG1 and LG2 represent leaving groups, each independently selected from a halogen atom (eg, Cl, Br or I), a p-toluenesulfonate group and a trifluoromethanesulfonate group.

[0059] In a fourth aspect, the present invention provides a pharmaceutical composition comprising at least one compound having a structure of Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite, prodrug or a mixture of any two or more thereof, and one or more pharmaceutically acceptable carriers.

[0060] In a fifth aspect, the present invention provides a medicine comprising:

[0061] a) Container;

[0062] b) at least one compound having the structure of Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled compound, metabolite, prodrug or a mixture of any two or more thereof in the container; and

[0063] c) optional packaging and / or instructions.

[0064] In a sixth aspect, the present invention provides the compound having the structure of Formula I or its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled substances, metabolites, prodrugs or a mixture of any two or more thereof, or the pharmaceutical composition, or the drug, for use in the preparation of a medicament for preventing and / or treating a disease or condition (especially a tumor) at least partially mediated by HPK1.

[0065] In a seventh aspect, the present invention provides the compound having the structure of Formula I or its pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotope-labeled substances, metabolites, prodrugs or mixtures of any two or more thereof, or the pharmaceutical composition, or the pharmaceutical product, for use as an HPK1 inhibitor. Preferably, the HPK1 inhibitor is used to prevent and / or treat a disease or condition (especially a tumor) at least partially mediated by HPK1.

[0066] In an eighth aspect, the present invention provides a method for preventing and / or treating a disease or condition (especially a tumor) at least partially mediated by HPK1, comprising the following steps: administering a preventive and / or therapeutically effective amount of the compound having the structure of Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite, prodrug or a mixture of any two or more thereof, or the pharmaceutical composition, or the drug to an individual in need thereof.

[0067] Effects of the Invention

[0068] The compounds of the present invention have strong inhibitory activity on HPK1, and have excellent properties such as good physicochemical properties (such as solubility, physical and / or chemical stability), good pharmacokinetic properties (such as good bioavailability, appropriate blood drug concentration, half-life and duration of action), and good safety (lower toxicity, such as lower cardiac and liver toxicity, and / or fewer side effects, and a wider therapeutic window). DETAILED DESCRIPTION

[0069] General Terms and Definitions

[0070] Unless otherwise defined, the meaning of the terms used herein is the same as that commonly understood by those skilled in the art. The technical intent used herein refers to the technology commonly understood in the art, including changes or equivalent replacements of the technology that are obvious to those skilled in the art. Although the following terms are easily understood by those skilled in the art, they are still described below to better explain the present invention.

[0071] The terms "include", "comprising", "having" or "involving" and other variant forms thereof in this article refer to inclusive or open-ended collective concepts and do not exclude other unlisted elements or method steps. It should be understood by those skilled in the art that the above terms such as "comprising" include the meaning of "consisting of..."

[0072] The term "one or more" or the similar expression "at least one" means, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0073] When the lower and upper limits of a numerical range are disclosed, any value or any sub-range falling within the range is specifically disclosed. In particular, each numerical range of a parameter disclosed herein (e.g., in the form of "about a to b", or equivalently "about a to b", or equivalently "about ab") should be understood to include each value and sub-range therein. For example, "C1-C6" should be understood to include any sub-range and each point value therein, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, etc., as well as C1, C2, C3, C4, C5, C6, etc. For example, "3-10 yuan" should be understood as covering any sub-range and every point value therein, such as 3-4 yuan, 3-5 yuan, 3-6 yuan, 3-7 yuan, 3-8 yuan, 3-9 yuan, 4-5 yuan, 4-6 yuan, 4-7 yuan, 4-8 yuan, 5-7 yuan, 5-8 yuan, 6-7 yuan, etc., as well as 3, 4, 5, 6, 7, 8, 9, 10 yuan, etc.

[0074] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is substantially non-toxic to an organism. Pharmaceutically acceptable salts generally include (but are not limited to) salts formed by reacting a compound of the present invention with a pharmaceutically acceptable inorganic acid / organic acid / acidic amino acid or inorganic base / organic base / basic amino acid, and such salts are also referred to as acid addition salts or base addition salts. For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0075] The term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to an organism and is hydrolyzed in vivo to form a compound of the present invention or a salt thereof. Pharmaceutically acceptable esters generally include (but are not limited to) esters formed between a compound of the present invention and a pharmaceutically acceptable carboxylic acid or sulfonic acid, which are also referred to as carboxylic acid esters or sulfonic acid esters. In addition, the compound of the present invention itself may also be an ester.

[0076] The term "isomers" refers to compounds that have the same number of atoms and types of atoms and therefore the same molecular weight, but differ in the arrangement or configuration of the atoms in space.

[0077] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a vertical asymmetric plane due to at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane polarized light. Since the compounds of the present invention have asymmetric centers and other chemical structures that may cause stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Since the compounds of the present invention (or pharmaceutically acceptable salts thereof) include asymmetric carbon atoms, they can exist in the form of single stereoisomers, racemates, enantiomers, and mixtures of diastereomers. Generally, these compounds can be prepared in the form of racemates. However, if desired, such compounds may be prepared or isolated as pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in a single stereoisomer (purity ≥99%, ≥98%, ≥97%, ≥96%, ≥95%, ≥90%, ≥85%, ≥80%, ≥75%, ≥70%, ≥65%, or ≥60%). As described below, single stereoisomers of a compound may be prepared synthetically from optically active starting materials containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatography, use of a chiral resolving agent, or direct separation of the enantiomers on a chiral chromatographic column. Starting compounds of a particular stereochemistry may be either commercially available or prepared as described below and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that have non-superimposable mirror images of each other. The term "diastereomer" or "diastereomer" refers to optical isomers that do not form mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.

[0078] In this paper, solid lines are used Solid wedge Virtual wedge To depict the covalent chemical bonds of the compounds of the invention. When a solid line is used to depict a bond to a chiral atom, all possible stereoisomers (e.g., a specific enantiomer, a racemic mixture, etc.) at that chiral atom are included. When a solid or dashed wedge is used to depict a bond to a chiral atom, the stereoisomer shown is present. Unless otherwise indicated, stereoisomers of the compounds of the invention may encompass specific enantiomers, diastereomers, racemates, or mixtures thereof in any ratio.

[0079] The term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (or prototransfer tautomers) include (but are not limited to) interconversions through proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-imino alcohol isomerization, nitroso-oxime isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0080] The term "polymorph" (or "polymorphic form") refers to a solid crystalline form of a compound or complex. Polymorphs of a molecule can be obtained by many known methods by those skilled in the art. These methods include (but are not limited to) melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion and sublimation. In addition, polymorphs can be detected, classified and identified by well-known techniques, including (but not limited to) differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single crystal X-ray diffraction (SCXRD), solid-state nuclear magnetic resonance (NMR), infrared spectroscopy (IR), Raman spectroscopy and scanning electron microscopy (SEM), etc. The present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which can be a single polymorph or a mixture of multiple polymorphs in any proportion.

[0081] The term "solvate" refers to a substance formed by the combination of a compound of the present invention (or a pharmaceutically acceptable salt thereof) and at least one solvent molecule through non-covalent intermolecular forces. Common solvates include (but are not limited to) hydrates (including hemihydrates, monohydrates, dihydrates, trihydrates, etc.), ethanolates, acetoneates, etc. The compounds of the present invention may exist in the form of a solvate (preferably a hydrate), which contains a polar solvent (especially water, methanol or ethanol) as a lattice structural element. The amount of the polar solvent (especially water) may exist in a stoichiometric ratio or a non-stoichiometric ratio.

[0082] The term "isotopically labeled" refers to a derivative compound formed by replacing a specific atom in the compound of the present invention with an isotope atom thereof. Unless otherwise indicated, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, and Cl, such as 2 H(D), 3 H(T), 13 C. 14 C. 13 N. 15 N. 17 O.18 O. 18 F. 31 P. 32 P. 34 S. 35 S. 36 S. 37 Cl and 125 I. For example, 12 C can be 12 C. 13 C or 14 C substitution; 1 H can be 2 H (D, deuterium) or 3 H (T, tritium) substitution; 16 O can be 18 O substitution, etc.

[0083] The term "metabolite" refers to a derivative compound formed after the metabolism of the compound of the present invention, for example, produced by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis and the like. For further information on metabolism, see Goodman and Gilman's: The Pharmacological Basis of Therapeutics [M], McGraw-Hill International Editions, 1996. The present invention encompasses all possible metabolite forms of the compounds of the present invention, i.e., substances formed in the body of an individual to whom the compounds of the present invention are administered. Metabolites of the compounds can be identified by known techniques in the art, and their activity can be characterized by tests.

[0084] The term "prodrug" refers to a derivative compound that can directly or indirectly provide a compound of the present invention after being applied to an individual. Particularly preferred derivative compounds or prodrugs are compounds that can improve the bioavailability of the compound of the present invention when applied to an individual (e.g., more easily absorbed into the blood), or compounds that promote the delivery of the parent compound to the site of action (e.g., lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are known in the art, for example, see T.Higuchi, V.Stella, Pro-drugs as Novel Drug Delivery Systems [J], American Chemical Society, Vol.14, 1975. In addition, the present invention also encompasses compounds of the present invention containing protecting groups. In any process of preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive groups or reactive groups on any related molecules, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, such as the protecting groups described in TWGreene, PGM Wuts, Protective Groups in Organic Synthesis [M], John Wiley & Sons, 2006. These protecting groups may be removed at an appropriate subsequent stage using methods known in the art.

[0085] The term "chemical bond" refers to the strong force between two or more adjacent atoms (or ions) in a pure molecule or crystal that binds them together, mainly including covalent bonds, ionic bonds, metallic bonds, coordination bonds, etc. Unless otherwise specified, the chemical bonds in the compounds of the present invention that exist in free form are mostly covalent bonds.

[0086] When used alone or in combination with other groups herein, the term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 10 carbon atoms, such as 1 to 8 carbon atoms (C1-C8 alkyl), 1 to 6 carbon atoms (C1-C6 alkyl), 1 to 4 carbon atoms (C1-C4 alkyl), 1 to 3 carbon atoms (C1-C3 alkyl), 2 to 6 carbon atoms (C2-C6 alkyl), 2 to 4 carbon atoms (C2-C4 alkyl) or 3 to 4 carbon atoms (C3-C4 alkyl). For example, the term "C1-C6 alkyl" as used herein refers to an alkyl group having 1-6 carbon atoms (such as 1, 2, 3, 4, 5 or 6 carbon atoms) (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, etc.), which is optionally substituted with one or more (such as 1-3) substituents described herein (such as when substituted with halogen, the group is a "C1-C6 haloalkyl" such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, -CH2CH2CF3, etc.).

[0087] When used alone or in combination with other groups herein, the term "cycloalkyl" refers to saturated and partially saturated aliphatic monocyclic or polycyclic (such as bicyclic) hydrocarbon groups (including cycloalkyl, cycloalkenyl, cycloalkynyl, etc., for example, monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc., or bicyclic, including spiro, fused or bridged rings, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, etc.), which are optionally substituted with one or more (such as 1-3) suitable substituents.

[0088] When used alone or in combination with other groups herein, the term "cycloalkyl" refers to a saturated aliphatic monocyclic or polycyclic (such as bicyclic) hydrocarbon group (e.g., monocyclic cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.; or bicyclic cycloalkyl, including fused rings, bridged rings or spiro rings, such as decahydronaphthyl, bicyclo[2.2.1]heptyl, spiro[4.5]decyl, etc.). In some embodiments, the cycloalkyl group has 3 to 15 carbon atoms, for example, 3 to 10 carbon atoms (C3-C 10The term "C3-C7 cycloalkyl" as used herein refers to a cycloalkyl group having 3 to 7 carbon atoms (C3-C7 cycloalkyl), 3 to 6 carbon atoms (C3-C6 cycloalkyl), 3 to 5 carbon atoms (C3-C5 cycloalkyl), 5 to 7 carbon atoms (C5-C7 cycloalkyl), 4 to 6 carbon atoms (C4-C6 cycloalkyl) or 5 to 6 carbon atoms (C5-C6 cycloalkyl), etc. For example, the term "C3-C7 cycloalkyl" as used herein refers to a cycloalkyl group having 3 to 7 ring-forming carbon atoms, which is optionally substituted with one or more (such as 1 to 3) substituents described herein (such as when substituted with halogen, the group is a "C3-C7 halocycloalkyl", such as 2-fluorocyclopropyl, 3-chlorocyclobutyl, 4-bromocyclohexyl, etc.).

[0089] When used alone or in combination with other groups herein, the term "heterocyclyl" refers to an aliphatic monocyclic or polycyclic (such as bicyclic, tricyclic or more) hydrocarbon group, which has one or more carbon atoms (such as 1, 2, 3, 4, 5, 6, 7, 8 or 9) in the ring and one or more (such as 1, 2, 3 or 4) independently selected from C (=O), O, S, S (=O), S (=O) 2 and NR (R represents a hydrogen atom or a substituent, such as an alkyl or cycloalkyl) fragment (such as a 3-7-membered heterocyclyl, a 4-7-membered heterocyclyl, a 3-8-membered heterocyclyl, a 5-10-membered heterocyclyl, etc.). The heterocyclyl may be saturated (containing no double or triple bonds) or unsaturated (containing at least one double or triple bond), and a saturated heterocyclyl may also be referred to as a heterocycloalkyl, such as a 3-8-membered heterocycloalkyl, a 5-6-membered heterocycloalkyl, etc. For example, the term "3-7 membered heterocyclyl" as used herein refers to a heterocyclyl group having 3-7 ring atoms (including one or more heteroatoms), which is optionally substituted with one or more (e.g., 1 to 3) substituents described herein (e.g., oxirane, thioethane, cyclonitrilo, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dioxolanyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, azepine, thiazolin ... 1,4-dioxanyl, 1,4-dithianyl, piperazinyl, trioxanyl, trithianyl, thiazinyl, etc.; or its cyclopentaneaziridine, pyrrolidinocyclopropyl, pyrrolidinocyclobutyl, pyrrolidinopyrrolidinyl, pyrrolidinopiperidinyl, pyrrolidinopiperazinyl, pyrrolidinomorpholinyl, piperidinomorpholinyl, etc.; or its spiro derivatives, such as wait).

[0090] When used alone or in combination with other groups herein, the term "alkoxy" refers to the above-mentioned alkyl group connected to the parent molecular part by an oxygen atom, i.e., -O-alkyl. For example, the term "C1-C6 alkoxy" used herein refers to an alkoxy group (such as methoxy, ethoxy, isopropoxy, tert-butoxy, etc.) having 1-6 carbon atoms (such as 1, 2, 3, 4, 5 or 6 carbon atoms), which is optionally substituted with one or more (such as 1-3) substituents described herein (such as when substituted with halogen, the group is a "C1-C6 haloalkoxy group", such as -OCF3, -OC2F5, -OCHF2, -OCH2Cl, etc.).

[0091] When used alone or in combination with other groups herein, the term "alkyleneoxy" refers to a divalent group formed by removing a hydrogen atom from the above-mentioned alkoxy group, i.e., -O-alkylene-. For example, the term "C1-C6 alkyleneoxy" used herein refers to an alkyleneoxy group (such as methyleneoxy, ethyleneoxy, etc.) having 1-6 carbon atoms (such as 1, 2, 3, 4, 5 or 6 carbon atoms), which is optionally substituted with one or more (such as 1-3) substituents described herein (such as when substituted with halogen, the group is a "C1-C6 haloalkyleneoxy group", such as -OCF2-, -OC2F4-, -OCHF-, -OCHCl-, etc.).

[0092] When used alone or in combination with other groups herein, the term "aryl" refers to a monocyclic or condensed aromatic hydrocarbon group having a conjugated π electron system. 14 The term "aryl" refers to an aromatic group having 6 to 14 carbon atoms (such as phenyl, naphthyl, etc.), which is optionally substituted by one or more substituents described herein (such as tolyl substituted by C1-C6 alkyl, chlorophenyl substituted by halogen, etc.).

[0093] When used alone or in combination with other groups herein, the term "heteroaryl" refers to an aromatic group of a monocyclic or condensed ring with a conjugated π electron system. As used herein, "5-14 membered heteroaryl" has 5-14 ring atoms, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and one or more (e.g., 1, 2, 3 or 4) heteroatoms independently selected from N, O, P and S. If the valence bond requirements are met, the heteroaryl can be connected to the parent molecular part by any one of the ring atoms. If the valence bond requirements are met, the heteroaryl can be connected to other groups (or fragments) by any one of the carbon atoms or heteroatoms (such as N atoms) in the ring. In addition, the heteroaryl can be optionally fused to an aryl, a heterocyclic radical (e.g., a heterocycloalkyl) or a cycloalkyl (e.g., a cycloalkyl) ring, wherein the ring connected to the parent structure is a heteroaryl ring. For example, the term "5-14 membered heteroaryl" as used herein refers to a heteroaryl group having 5-14 ring atoms (such as thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, triazolyl, tetrazolyl, etc., or such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., or benzo derivatives thereof, such as indazolyl, indolyl, isoindolyl, quinolyl, isoquinolyl, etc., or such as pyrazolopyridine, pyrrolopyrimidine, pyrrolopyridinyl, pyrazolopyrimidine, etc.), which is optionally substituted with one or more substituents described herein (such as methylpyridyl substituted with C1-C6 alkyl, chloropyridyl substituted with halogen, etc.).

[0094] When used alone or in combination with other groups herein, the term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group with one or more carbon-carbon double bonds. In some embodiments, alkenyl has 2 to 15 carbon atoms. For example, the term "C2-C6 alkenyl" used herein refers to an alkenyl (such as vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl etc.) with 2-6 carbon atoms and one, two or three carbon-carbon double bonds, which is optionally substituted by one or more (such as 1-3) substituents described herein.

[0095] When used alone or in combination with other groups herein, the term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group with one or more carbon-carbon triple bonds. For example, the term "C2-C6 alkynyl" as used herein refers to an alkynyl (such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.) with 2-6 carbon atoms and one, two or three carbon-carbon triple bonds, which is optionally substituted with one or more (such as 1-3) substituents described herein.

[0096]

[0046] The term "halogen" as used herein alone or in combination with other groups refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0097]

[0046] The term "hydroxy" as used herein alone or in combination with other groups refers to -OH.

[0098]

[0046] The term "cyano," as used herein alone or in combination with other groups, refers to -CN.

[0099] The term "nitro" as used herein alone or in combination with other groups refers to -NO2.

[0100] The term "amino" as used herein alone or in combination with other groups refers to -NH2.

[0101] The term "oxo," as used herein alone or in combination with other groups, refers to =0.

[0102] The term "independently" as used herein means that at least two groups (or fragments) with the same or similar value ranges in the structure may have the same or different meanings in specific circumstances. For example, substituent X and substituent Y are independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl, then when substituent X is hydrogen, substituent Y may be either hydrogen, or halogen, hydroxyl, cyano, alkyl or aryl; similarly, when substituent Y is hydrogen, substituent X may be either hydrogen, or halogen, hydroxyl, cyano, alkyl or aryl.

[0103] The term "substituted" and its other variant forms in this article refer to one or more (such as 1, 2, 3 or 4) atoms or atomic groups (such as hydrogen atoms) on the specified atom are replaced by other equivalents, provided that the normal valence of the specified atom or atomic group in the current situation is not exceeded, and a stable compound can be formed. If an atom or atomic group is described as "optionally substituted by...", it can be substituted or unsubstituted. Unless otherwise specified, the attachment site of the substituent in this article can be from any suitable position of the substituent. When the connecting bond in the substituent is shown as a chemical bond between two atoms connected to each other in the ring system, it means that the substituent can be connected to any ring-forming atom in the ring system.

[0104] General formula compound

[0105] The present invention provides a compound of formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled substance, metabolite, prodrug or a mixture of any two or more thereof,

[0106]

[0107] in,

[0108] A is selected from C6-C 14 Aryl and 5-14 membered heteroaryl, the C6-C 14 Aryl and 5-14 membered heteroaryl are each optionally substituted by one or more R d replace;

[0109] R 1 Selected from C1-C6 alkoxy, cyano, nitro, P(O)R b R c 、C(O)NR b R c 、S(O)2R a 、S(O)2NR b R c 、C(O)R a and NR b C(O)R a The C1-C6 alkoxy group is optionally replaced by one or more R d replace;

[0110] R 2 is selected from hydrogen and C1-C6 alkyl, the C1-C6 alkyl being optionally substituted by one or more R d replace;

[0111] R 3is selected from hydrogen, halogen, hydroxyl, cyano, nitro, C1-C6 alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C(O)NR b R c NR b C(O)R a and NR b R c The C1-C6 alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl and C1-C6 alkoxy groups are each optionally substituted by one or more R d replace;

[0112] R 4 and R 5 are each independently selected from hydrogen, halogen, cyano, nitro, C(O)R a 、C(O)OR a 、C(O)NR b R c 、S(O)R a 、S(O)2R a 、S(O)2NR b R c 、NHC(O)R a 、NHC(O)OR a NR b R c 、OC(O)R a , C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 14 The aryl and 5-14 membered heteroaryl groups, the C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 14 Aryl and 5-14 membered heteroaryl are each optionally substituted by one or more R d replace;

[0113] R 6 Selected from hydrogen, halogen, hydroxy, cyano, nitro, NR b R c , C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 14 The aryl and 5-14 membered heteroaryl groups, the C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 14 Aryl and 5-14 membered heteroaryl are each optionally substituted by one or more R d replace;

[0114] X is selected from CR 7 and N;

[0115] R 7 is selected from hydrogen, halogen, cyano, nitro, C(O)R a 、C(O)OR a 、C(O)NR b R c 、S(O)R a 、S(O)2R a 、S(O)2NR b R c 、NHC(O)R a 、NHC(O)OR a 、OC(O)R a NR b R c , C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 14 The aryl and 5-14 membered heteroaryl groups, the C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 14 Aryl and 5-14 membered heteroaryl are each optionally substituted by one or more R d replace;

[0116] If present, each R a Each independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl, 5-14 membered heteroaryl and 5-10 membered heterocyclic group, the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl, 5-14 membered heteroaryl and 5-10 membered heterocyclyl are each optionally substituted by one or more R d replace;

[0117] If present, each R b and R c Each is independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl and 4-7 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl and 4-7 membered heterocyclyl are each optionally substituted by one or more R d Replace; or, if present, each pair of R b and R c Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group is optionally substituted by one or more R d replace;

[0118] If present, each Rd are each independently selected from hydrogen, hydroxy, halogen, oxo, cyano, nitro, C(O)R e 、C(O)OR e NR f S(O)2R g 、S(O)R e 、S(O)2R e 、C(O)NR f R g 、S(O)2NR f R g NR f R g NR f C(O)R g , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 alkyleneoxy-C1-C6 alkoxy, C6-C 14 The aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic groups, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 alkyleneoxy-C1-C6 alkoxy, C6-C 14 Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl are each optionally substituted by one or more R j replace;

[0119] If present, each R e Each independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 membered heteroaryl;

[0120] If present, each R f and R g are each independently selected from hydrogen, C 1- C6 alkyl, C 3- C7 cycloalkyl and 4-7 membered heterocyclic group, the C1-C6 alkyl group is optionally replaced by one or more C 1- C6 alkoxy or NR h R i Replace; or, if present, each pair of R f and R g Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic group;

[0121] If present, each R h and R i are each independently selected from hydrogen and C 1- C6 alkyl; and

[0122] If present, each R jEach is independently selected from halogen, hydroxy, cyano and 3-8 membered heterocyclic group.

[0123] In some preferred embodiments of the present invention, A in the above-mentioned compound of formula I is C6-C 14 Aryl, preferably C6-C 10 Aryl.

[0124] In some preferred embodiments of the present invention, R 1 Selected from C1-C6 alkoxy, cyano, nitro, P(O)R b R c 、C(O)NR b R c 、S(O)2R a and S(O)2NR b R c , preferably P(O)R b R c 、C(O)NR b R c 、S(O)2R a and S(O)2NR b R c .

[0125] In some preferred embodiments of the present invention, R 2 Selected from hydrogen and C1-C6 alkyl, preferably hydrogen.

[0126] In some preferred embodiments of the present invention, R 3 Selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C3-C7 cycloalkyl and C1-C6 alkoxy, preferably hydrogen and halogen.

[0127] In some preferred embodiments of the present invention, R 4 and R 5 are each independently selected from hydrogen, halogen, cyano, nitro, NHC(O)R a 、NHC(O)OR a NR b R c , C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy, wherein the C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy are each optionally substituted by one or more R d Substitution; preferably hydrogen, NR b R c, C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy, wherein the C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy are each optionally substituted by one or more R d substituted; more preferably hydrogen, NR b R c , C3-C7 cycloalkyl, 3-7 membered heterocyclyl and C1-C6 alkoxy, wherein the C3-C7 cycloalkyl, 3-7 membered heterocyclyl and C1-C6 alkoxy are each optionally substituted by one or more R d replace.

[0128] In some preferred embodiments of the present invention, R 6 Selected from hydrogen, halogen, cyano, nitro, NR b R c , C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy, preferably hydrogen, halogen, cyano, nitro, NR b R c , C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy, more preferably hydrogen and NR b R c .

[0129] In some preferred embodiments of the present invention, X in the above-mentioned compound of formula I is CR 7 .

[0130] In some preferred embodiments of the present invention, R 7 Selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C3-C7 cycloalkyl and C1-C6 alkoxy, preferably hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C3-C7 cycloalkyl and C1-C6 alkoxy, more preferably hydrogen.

[0131] In some preferred embodiments of the present invention, each R a Each independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclic group, preferably C1-C6 alkyl, C3-C7 cycloalkyl and C6-C 10 Aryl.

[0132] In some preferred embodiments of the present invention, each R b and R c Each is independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl and 4-7 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl and 4-7 membered heterocyclyl are each optionally substituted by one or more R dSubstituted; preferably hydrogen and C1-C6 alkyl, the C1-C6 alkyl optionally by one or more R d Replace; or, each pair of R b and R c Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group, preferably a 5-6 membered heterocyclic group.

[0133] In some preferred embodiments of the present invention, each R d are each independently selected from hydrogen, hydroxy, halogen, cyano, nitro, NR f S(O)2R g NR f R g NR f C(O)R g , C1-C6 alkyl, C1-C6 alkoxy and C3-C7 cycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy and C3-C7 cycloalkyl are each optionally substituted by one or more R j Substitution; preferably hydroxyl, halogen, NR f R g and C1-C6 alkyl, the C1-C6 alkyl being optionally substituted by one or more R j replace.

[0134] In some preferred embodiments of the present invention, each R e Each independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 Aryl and 5-10 membered heteroaryl, preferably hydrogen, C1-C6 alkyl and C3-C7 cycloalkyl.

[0135] In some preferred embodiments of the present invention, each R f and R g are each independently selected from hydrogen, C 1- C6 alkyl and C 3- C7 cycloalkyl, the C1-C6 alkyl is optionally substituted by one or more NR h R i Substituted; preferably hydrogen and C1-C6 alkyl, the C1-C6 alkyl optionally by one or more NR h R i Replace; or, each pair of R f and R g Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group.

[0136] In some preferred embodiments of the present invention, each R h and R i Each is independently selected from hydrogen and C1-C4 alkyl.

[0137] In some preferred embodiments of the present invention, each R j Each is independently selected from halogen, hydroxy, cyano and 3-6 membered heterocyclic group, preferably halogen and hydroxy.

[0138] In some more preferred embodiments of the present invention, the compound of formula I has a structure as shown in formula II,

[0139]

[0140] in,

[0141] Each Y is independently selected from CR 7 and N;

[0142] X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined above.

[0143] In some more preferred embodiments of the present invention, the compound of formula I has a structure as shown in formula III,

[0144]

[0145] in,

[0146] Each Y is independently selected from CR 7 and N;

[0147] X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined above.

[0148] In some more preferred embodiments of the present invention, the compound of formula I has a structure as shown in formula IV,

[0149]

[0150] Among them, X, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 As defined above.

[0151] In some more preferred embodiments of the present invention, the compound of formula I has a structure as shown in formula V,

[0152]

[0153] Among them, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 As defined above.

[0154] In some more preferred embodiments of the present invention, the compound of formula I has a structure as shown in formula VI,

[0155]

[0156] Among them, R 1 , R 3 , R 4 , R 5 and R 6 As defined above.

[0157] In some more preferred embodiments of the present invention, the compound of formula I has a structure as shown in formula VII,

[0158]

[0159] Among them, R 1 , R 3 and R 5 As defined above.

[0160] In some preferred embodiments of the present invention, in the above-mentioned compounds of formula I, II, III, IV, V, VI and VII, R 1 Selected from C1-C6 alkoxy, cyano, nitro, P(O)R b R c 、C(O)NR b R c 、S(O)2R a and S(O)2NR b R c Preferably, R 1 Selected from P(O)R b R c 、C(O)NR b R c 、S(O)2R a and S(O)2NR b R c More preferably, R 1 Selected from S(O)2CH3, S(O)2CH(CH3)2, S(O)2N(CH3)2 and C(O)NHCH3.

[0161] In some preferred embodiments of the present invention, in the above-mentioned compounds of formula I, formula II, formula III, formula IV and formula V, R 2 is selected from hydrogen and C1-C6 alkyl; preferably, R 2 For hydrogen.

[0162] In some preferred embodiments of the present invention, in the above-mentioned compounds of formula I, II, III, IV, V, VI and VII, R 3 is selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C3-C7 cycloalkyl and C1-C6 alkoxy; preferably, R 3 is selected from hydrogen and halogen; more preferably, R 3 Selected from hydrogen and chlorine.

[0163] In some preferred embodiments of the present invention, in the above-mentioned compounds of formula I, II, III, IV, V and VI, R 4 and R 5 are each independently selected from hydrogen, halogen, cyano, nitro, NHC(O)R a 、NHC(O)OR a NR b R c , C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy, wherein the C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy are each optionally substituted by one or more R d Substituted; preferably, R 4 and R 5 are each independently selected from hydrogen, NR b R c , C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy, wherein the C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy are each optionally substituted by one or more R d More preferably, R 4 and R 5 are each independently selected from hydrogen, NR b R c , C3-C7 cycloalkyl, 3-7 membered heterocyclyl and C1-C6 alkoxy, wherein the C3-C7 cycloalkyl, 3-7 membered heterocyclyl and C1-C6 alkoxy are each optionally substituted by one or more R d More preferably, R 4 and R 5 are each independently selected from hydrogen,

[0164] In some more preferred embodiments of the present invention, in the above-mentioned compounds of formula I, II, III, IV, V and VI, R 4 is hydrogen, R 5 Selected from NR b R c , C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy, wherein the C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy are each optionally substituted by one or more R d Substitution, the R d Selected from hydroxyl, halogen, NR f R g and C1-C6 alkyl, the C1-C6 alkyl being optionally substituted by one or more R j Substitution, the R j is selected from halogen and hydroxyl; said R b and R c are each independently selected from hydrogen and C1-C6 alkyl, the C1-C6 alkyl being optionally substituted by one or more NR f R g Substitution, the R f and R g are each independently selected from hydrogen and C1-C6 alkyl; preferably, R 4 is hydrogen, R 5 Selected from

[0165] In some preferred embodiments of the present invention, in the above-mentioned compounds of formula I, II, III, IV, V and VI, R 6 Selected from hydrogen, halogen, cyano, nitro, NR b R c , C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy; preferably, R 6 Selected from hydrogen, halogen, cyano, nitro, NR b R c , C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy; more preferably, R 6 Selected from hydrogen and NR b R c , preferably hydrogen and -NHCH2CH2NHCH3.

[0166] In some preferred embodiments of the present invention, in the above-mentioned compounds of formula I, formula II, formula III and formula IV, X is CR 7 .

[0167] In some preferred embodiments of the present invention, in the above-mentioned compounds of formula I, formula II, formula III and formula IV, R 7 is selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C3-C7 cycloalkyl and C1-C6 alkoxy; preferably, R 7 is selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C3-C7 cycloalkyl and C1-C6 alkoxy; more preferably, R 7 For hydrogen.

[0168] In some preferred embodiments of the present invention, in the above-mentioned compounds of formula I, II, III, IV, V, VI and VII, each R a Each independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl; preferably, each R a Each independently selected from C1-C6 alkyl, C3-C7 cycloalkyl and C6-C 10 Aryl.

[0169] In some preferred embodiments of the present invention, in the above-mentioned compounds of formula I, II, III, IV, V, VI and VII, each R b and R c Each is independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl and 4-7 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl and 4-7 membered heterocyclyl are each optionally substituted by one or more R d Preferably, each R b and R c are each independently selected from hydrogen and C1-C6 alkyl, the C1-C6 alkyl being optionally substituted by one or more R d Replace; or, each pair of R b and R c Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group, preferably a 5-6 membered heterocyclic group.

[0170] In some preferred embodiments of the present invention, in the above-mentioned compounds of formula I, II, III, IV, V, VI and VII, each R d are each independently selected from hydrogen, hydroxy, halogen, cyano, nitro, NR f S(O)2R g NR f R g NR f C(O)R g, C1-C6 alkyl, C1-C6 alkoxy and C3-C7 cycloalkyl; the C1-C6 alkyl, C1-C6 alkoxy and C3-C7 cycloalkyl are each optionally substituted by one or more R j Preferably, each R d Each independently selected from hydroxyl, halogen, NR f R g and C1-C6 alkyl, the C1-C6 alkyl being optionally substituted by one or more R j replace.

[0171] In some preferred embodiments of the present invention, in the above-mentioned compounds of formula I, II, III, IV, V, VI and VII, each R e Each independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 Aryl and 5-10 membered heteroaryl; preferably, each R e Each is independently selected from hydrogen, C1-C6 alkyl and C3-C7 cycloalkyl.

[0172] In some preferred embodiments of the present invention, in the above-mentioned compounds of formula I, II, III, IV, V, VI and VII, each R f and R g are each independently selected from hydrogen, C1-C6 alkyl and C3-C7 cycloalkyl, the C1-C6 alkyl being optionally substituted by one or more NR h R i Preferably, each R f and R g are each independently selected from hydrogen and C1-C6 alkyl, the C1-C6 alkyl being optionally substituted by one or more NR h R i Replace; or, each pair of R f and R g Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group.

[0173] In some preferred embodiments of the present invention, in the above-mentioned compounds of formula I, II, III, IV, V, VI and VII, each R h and R i are each independently selected from hydrogen and C 1- C4 alkyl.

[0174] In some preferred embodiments of the present invention, in the above-mentioned compounds of formula I, II, III, IV, V, VI and VII, each R j Each is independently selected from halogen, hydroxyl, cyano and 3-6 membered heterocyclic group; preferably, each Rj Each is independently selected from halogen and hydroxy.

[0175] In some embodiments, in the above compound of formula I,

[0176] A is C6-C 14 Aryl, preferably C6-C 10 Aryl;

[0177] R 4 and R 5 are each independently selected from hydrogen, halogen, cyano, nitro, NHC(O)R a 、NHC(O)OR a NR b R c , C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy, wherein the C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy are each optionally substituted by one or more R d Substitution; preferably hydrogen, NR b R c , C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy, wherein the C3-C7 cycloalkyl, 3-7 membered heterocyclic group and C1-C6 alkoxy are each optionally substituted by one or more R d replace.

[0178] In some embodiments, in the above-mentioned compounds of formula I, formula II, formula III, formula IV and formula V,

[0179] R 1 Selected from C1-C6 alkoxy, cyano, nitro, P(O)R b R c 、C(O)NR b R c 、S(O)2R a and S(O)2NR b R c ;

[0180] R 2 is selected from hydrogen and C1-C6 alkyl;

[0181] R 3 Selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C3-C7 cycloalkyl and C1-C6 alkoxy.

[0182] In some embodiments, in the above-mentioned compounds of formula I, formula II, formula III, formula IV, formula V, formula VI and formula VII,

[0183] Every R aEach independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclic group, preferably C1-C6 alkyl, C3-C7 cycloalkyl and C6-C 10 Aryl;

[0184] Every R b and R c Each is independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl and 4-7 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl and 4-7 membered heterocyclyl are each optionally substituted by one or more R d Substituted; preferably hydrogen and C1-C6 alkyl, the C1-C6 alkyl optionally by one or more R d Replace; or, each pair of R b and R c Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group;

[0185] Every R d are each independently selected from hydrogen, hydroxy, halogen, cyano, nitro, NR f S(O)2R g NR f R g NR f C(O)R g , C1-C6 alkyl, C1-C6 alkoxy and C3-C7 cycloalkyl.

[0186] In some embodiments, in the above-mentioned compounds of formula I, formula II, formula III and formula IV,

[0187] X is CR 7 ;

[0188] R 7 Selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C3-C7 cycloalkyl and C1-C6 alkoxy.

[0189] The present invention provides the following compounds encompassed by the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI or Formula VII:

[0190]

[0191] Preparation method of compound

[0192] The present invention provides a method for preparing a compound of formula I, comprising the following steps:

[0193] 1) Compound I-1 reacts with compound I-2 to obtain compound I-3;

[0194]

[0195] 2) Compound I-3 reacts with compound I-4 to obtain a compound having a structure of formula I;

[0196]

[0197] in,

[0198] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and X is as defined above;

[0199] LG1 and LG2 represent leaving groups, each independently selected from a halogen atom (eg, Cl, Br or I), a toluenesulfonate group (OTs) and a triflate group (OTf).

[0200] In some embodiments of the invention, LG 1 is a halogen leaving group (such as chlorine, bromine or iodine).

[0201] In some embodiments of the invention, LG 2 is a halogen leaving group (such as chlorine, bromine or iodine).

[0202] In some embodiments of the present invention, the reaction in the above step (1) is carried out in the presence of a base and a metal catalyst. In some preferred embodiments of the present invention, the base is an inorganic base, such as cesium carbonate. In other preferred embodiments of the present invention, the metal catalyst is a palladium catalyst, such as tetrakis(triphenylphosphine)palladium, palladium acetate, tris(dibenzylideneacetone)dipalladium, 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride, 1,2-bis(diphenylphosphino)ethanepalladium dichloride, bis(triphenylphosphine)palladium dichloride, etc.

[0203] In some embodiments of the present invention, the reaction in the above step (2) is carried out in the presence of a base and a metal catalyst. In some preferred embodiments of the present invention, the base is an inorganic base, such as cesium carbonate. In other preferred embodiments of the present invention, the metal catalyst is a palladium catalyst, such as tetrakis(triphenylphosphine)palladium, palladium acetate, tris(dibenzylideneacetone)dipalladium, 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride, 1,2-bis(diphenylphosphino)ethanepalladium dichloride, bis(triphenylphosphine)palladium dichloride, etc.

[0204] Those skilled in the art will appreciate that, depending on the desired product structure, one or more steps in the above-described preparation method may be omitted, and the order of the reaction steps may be appropriately adjusted as well as protection / deprotection reaction steps may be added or omitted as needed.

[0205] The compounds of formula II, formula III, formula IV, formula V, formula VI and formula VII of the present invention can be synthesized by similar methods.

[0206] Pharmaceutical composition

[0207] The term "pharmaceutical composition" refers to a composition that can be used as a drug, which contains an active pharmaceutical ingredient (API) (or therapeutic agent) and optionally one or more pharmaceutically acceptable carriers, with the purpose of facilitating administration to an organism, facilitating the absorption of the active ingredient, and thus exerting biological activity. The term "pharmaceutically acceptable carrier" refers to an excipient that is administered together with a therapeutic agent and is suitable for contact with human and / or other animal tissues within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications corresponding to a reasonable benefit / risk ratio. Pharmaceutically acceptable carriers that can be used in the present invention include (but are not limited to) a) diluents; b) lubricants; c) binders; d) disintegrants; e) absorbents, colorants, flavorings and sweeteners; f) emulsifiers or dispersants; and / or g) agents that enhance the absorption of compounds.

[0208] The present invention provides a pharmaceutical composition comprising at least one compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI or Formula VII of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (such as hydrate), isotope-labeled substance, metabolite, prodrug or a mixture of any two or more thereof.

[0209] In some embodiments of the present invention, the above-mentioned pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

[0210] In some embodiments of the present invention, the above-mentioned pharmaceutical composition can act systemically and / or locally. For this purpose, they can be administered by suitable routes, for example, by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular, inhalation routes or all methods known to medical and pharmaceutical technical personnel. The above-mentioned pharmaceutical composition can be administered in combination with at least one other therapeutic agent with disease or condition therapeutic effect.

[0211] In some embodiments of the present invention, the above-mentioned route of administration can be achieved by suitable dosage forms. The dosage forms that can be used in the present invention include (but are not limited to) tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, etc.

[0212] In some embodiments of the present invention, the pharmaceutical composition may contain 0.01 mg to 1000 mg of at least one compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI or Formula VII of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (such as hydrate), isotope label, metabolite, prodrug or a mixture of any two or more thereof.

[0213] The present invention also provides a method for preparing the above-mentioned pharmaceutical composition or its corresponding formulation, which comprises combining at least one compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI or Formula VII of the present invention or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (such as hydrate), isotope label, metabolite, prodrug or a mixture of any two or more thereof with one or more pharmaceutically acceptable carriers.

[0214] drug

[0215] The term "pharmaceutical" refers to a combination product comprising a therapeutic agent, optionally other therapeutic agents, and optionally packaging and / or instructions.

[0216] The terms "pharmaceutically active ingredient," "pharmaceutically active substance," "pharmaceutically active agent," or "therapeutic agent" refer to a chemical entity that is effective in preventing and / or treating a target disease or one or more symptoms thereof.

[0217] The present invention provides a medicine comprising:

[0218] a) Container;

[0219] b) at least one compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI or Formula VII of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (such as hydrate), isotope-labeled substance, metabolite, prodrug, or a mixture of any two or more thereof, or a pharmaceutical composition, located in a container; and

[0220] c) optional packaging and / or instructions.

[0221] The instructions list the relevant information of the active pharmaceutical ingredients or pharmaceutical compositions in the above-mentioned drugs, preferably specifically list the indications for which the active pharmaceutical ingredients or pharmaceutical compositions are approved for use. The instructions are printable materials (such as paper, plastic, metal foil, adhesive paper, etc.) on which the required information can be formed (such as printed or applied).

[0222] In some embodiments of the present invention, the above-mentioned drug may contain 0.01 mg to 1000 mg of at least one compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI or Formula VII of the present invention or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (such as hydrate), isotope label, metabolite, prodrug or a mixture of any two or more thereof.

[0223] The present invention also provides a method for preparing the above-mentioned medicine, which comprises combining at least one compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI or Formula VII of the present invention or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (such as hydrate), isotope label, metabolite, prodrug or a mixture of any two or more thereof, or a pharmaceutical composition, with a container and optional packaging and / or instructions.

[0224] Medical Uses

[0225] The compounds of the present invention can exhibit a strong inhibitory effect on HPK1 and can be used as HPK1 inhibitors. Therefore, the present invention provides the use of the compounds of formula I, formula II, formula III, formula IV, formula V, formula VI or formula VII of the present invention or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates (such as hydrates), isotope labels, metabolites, prodrugs or any mixture of two or more thereof, or pharmaceutical compositions, or medicines, as HPK1 inhibitors. Preferably, the HPK1 inhibitor can be used to prevent and / or treat diseases or conditions (especially tumors) at least partially mediated by HPK1.

[0226] In addition, the present invention also provides the use of the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI or Formula VII of the present invention or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates (such as hydrates), isotope-labeled substances, metabolites, prodrugs or mixtures of any two or more thereof, or pharmaceutical compositions, or medicines, in the preparation of drugs for preventing and / or treating diseases or conditions at least partially mediated by HPK1 (or HPK1-related diseases, especially tumors).

[0227] The term "disease or condition mediated at least in part by HPK1 (or HPK1-related disease)" refers to a disease whose pathogenesis at least partially involves factors related to HPK1, and these diseases include (but are not limited to) tumor diseases.

[0228] Treatment

[0229] The present invention provides a method for preventing and / or treating a disease (especially a tumor) at least partially mediated by HPK1, comprising the following steps: administering a preventive and / or therapeutically effective amount of at least one compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI or Formula VII of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (such as hydrate), isotope label, metabolite, prodrug, or a mixture of any two or more thereof, or a pharmaceutical composition, or a medicine to an individual in need thereof.

[0230] The term "effective amount" refers to the amount of a compound that, after being administered, will relieve one or more symptoms of the treated condition to a certain extent. The dosage regimen can be adjusted to provide the best response. For example, a single dose can be administered, divided doses can be administered over time, or the dosage can be reduced or increased in proportion to the actual situation. It is understood that for any particular individual, the specific dosage regimen should be adjusted according to the needs and the professional judgment of the person administering the drug. In addition, it is also necessary to distinguish whether it is a preventive application or a therapeutic application. In preventive applications, relatively low doses are usually administered for a long time at relatively long intervals. In therapeutic applications, relatively high doses are usually administered at relatively short intervals until the progression of the disease is delayed or stopped, preferably until the individual shows partial or complete improvement of symptoms.

[0231] In the present invention, suitable in vitro or in vivo assays are performed to determine whether the effects of compounds, pharmaceutical compositions and / or medicines and administration are suitable for treating diseases or conditions suffered by individuals. Examples of these assays will be described in the non-limiting examples below. Typically, the effective amount of a compound sufficient to achieve preventive and / or therapeutic effects is from about 0.001 mg / kg body weight / day to about 10,000 mg / kg body weight / day. In suitable cases, the effective amount is from about 0.01 mg / kg body weight / day to about 1,000 mg / kg body weight / day. In more general cases, the effective amount is about 0.01 to 1,000 mg / kg body weight per day, every two days or every three days, preferably about 0.1 to 500 mg / kg body weight. An exemplary treatment regimen is administration once every two days or once a week or once a month.

[0232] The term "treat" refers to reversing, alleviating or eliminating the targeted disease or condition. If a subject receives a therapeutic amount of a compound of the present invention or a pharmaceutically acceptable form thereof or a pharmaceutical composition of the present invention, and at least one indicator and symptom of the subject shows observable and / or detectable relief and / or improvement, it indicates that the subject has been successfully "treated". It is understood that treatment includes not only complete treatment, but also includes not achieving complete treatment but achieving some biological or medically relevant results. Specifically, "treat" means that the compound of the present invention or a pharmaceutically acceptable form thereof or a pharmaceutical composition of the present invention can achieve at least one of the following effects: (1) preventing the occurrence of disease in animals that may have a tendency to the disease but have not yet experienced or shown disease pathology or symptoms; (2) inhibiting the disease in animals that are experiencing or showing disease pathology or symptoms (i.e., preventing further development of pathology and / or symptoms); (3) improving the disease in animals that are experiencing or showing disease pathology or symptoms (i.e., reversing pathology and / or symptoms).

[0233] The term "administer" refers to the process of applying a pharmaceutically active ingredient (such as a compound of the present invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (such as a pharmaceutical composition of the present invention) to an individual or its cells, tissues, organs, biological fluids, etc., so as to bring the pharmaceutically active ingredient or pharmaceutical composition into contact with the individual or its cells, tissues, organs, biological fluids, etc. Common administration methods include (but are not limited to) oral administration, subcutaneous administration, intramuscular administration, subperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, etc.

[0234] The term "in need of" refers to the physician's or other caregiver's judgment that an individual needs or will benefit from a preventive and / or therapeutic procedure, which judgment is based on a variety of factors within the physician's or other caregiver's area of ​​expertise.

[0235] The term "individual" (or subject) refers to a human or non-human animal. The individual of the present invention includes individuals (patients) suffering from diseases and / or disorders and normal individuals. The non-human animals of the present invention include all vertebrates, such as non-mammals, such as birds, amphibians, reptiles, etc., and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0236] In order to make the purpose and technical solution of the present invention clearer, the embodiments of the present invention are described in detail below in conjunction with examples. However, it will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.

[0237] The reagents or instruments used in the examples without indicating the manufacturer are all conventional products that can be obtained commercially. If the specific conditions are not indicated, they are all carried out according to the normal conditions or the conditions recommended by the manufacturer. The term "room temperature" used herein refers to 20°C ± 5°C. When used to modify a certain numerical value or numerical range, the term "about" used herein refers to an acceptable error range for those skilled in the art including the numerical value or numerical range and the numerical value or numerical range, for example, the error range is ± 10%, ± 5%, ± 4%, ± 3%, ± 2%, ± 1%, ± 0.5%, etc. Unless otherwise stated, concentrations are by weight and ratios (including percentages) are by molar amount.

[0238] In conventional synthesis methods, examples and intermediate synthesis examples, the meanings of the abbreviations are shown in the following table.

[0239]

[0240] The structures of the compounds described in the following examples were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0241] The nuclear magnetic resonance (NMR) was measured using a Bruker 400 MHz nuclear magnetic resonance instrument, the measuring solvent was deuterated methanol (CD3OD), deuterated chloroform (CDCl3), deuterated dimethyl sulfoxide (DMSO-d6) or heavy water (D2O), and the internal standard substance was tetramethylsilane (TMS).

[0242] The abbreviations in the nuclear magnetic resonance (NMR) data in the following examples represent the following meanings:

[0243] s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: quartet doublet, ddd: double double doublet, ddt: double double triplet, dddd: double double double doublet, m: multiplet, br: broad, J: coupling constant, Hz: Hertz, δ: chemical shift.

[0244] All chemical shift (δ) values ​​are given in parts per million (ppm).

[0245] The reaction was monitored by thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC / MS). TLC used silica gel GF254 as the stationary phase, and LC / MS was performed using Aglient 1260 Infinity / Aglient 6120 Quadrupole.

[0246] Microwave reactions were performed using a BiotageInitiator+ microwave synthesizer.

[0247] Column chromatography used 200-300 mesh silica gel (Qingdao Ocean Chemical Co., Ltd.) as the stationary phase, and the eluent system included: A: petroleum ether / ethyl acetate; B: dichloromethane / methanol. The volume ratio of the solvents could be adjusted according to the polarity of the compounds.

[0248] Preparative high performance liquid chromatography (Prep-HPLC) was performed using an Agilent 1260, Waters 2489 or GeLai 3500 chromatograph.

[0249] Unless otherwise stated, the reaction temperature in the following examples is room temperature (20-30°C).

[0250] Unless otherwise stated, the reagents in the following examples were purchased from Acros Organics, Aldrich Chemical Company, Teber Chemical and other companies.

[0251] [Compound Preparation]

[0252] Example 1: (2-((5-chloro-2-((4-(pyrrolidin-3-yl)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide (Compound 1)

[0253]

[0254] Step 1: tert-butyl 3-(2-aminopyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1b)

[0255] 4-Bromopyridin-2-amine (1a, 1.5 g, 8.67 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (3.07 g, 10.40 mmol), Pd(dppf)Cl2·CH2Cl2 (707.47 mg, 867 μmol) and K2CO3 (2.99 g, 21.67 mmol) were added to 1,4-dioxane (50 mL) and water (10 mL), and heated to 90°C under N2 protection for 5 h. After the reaction was completed, the mixture was filtered with diatomaceous earth, and the filtrate was evaporated to dryness under reduced pressure and purified by flash column chromatography (eluent system A) to obtain compound 1b (2.2 g).

[0256] MS (ESI): m / z 262.0 [M+H] + .

[0257] Step 2: tert-Butyl 3-(2-aminopyridin-4-yl)pyrrolidine-1-carboxylate (1c)

[0258] Compound 1b (2.1 g, 8.04 mmol) was dissolved in methanol (50 mL), and then 10% Pd / C (975.99 mg, 8.04 mmol) was added, and the mixture was reacted at room temperature for 7 h under H2 protection. After the reaction, the reaction solution was filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a crude compound 1c (2.0 g), which was directly used in the next step without purification.

[0259] MS (ESI): m / z 264.1 [M+H] + .

[0260] Step 3: tert-Butyl 3-(2-((4,5-dichloropyridin-2-yl)amino)pyridin-4-yl)pyrrolidine-1-carboxylate (1d)

[0261] Compound 1c (1.21 g, 4.60 mmol), 2,4,5-trichloropyridine (700 mg, 3.84 mmol), Pd2(dba)3 (351.36 mg, 383.70 μmol), Xantphos (444.03 mg, 767.40 μmol) and Cs2CO3 (3.13 g, 959 mmol) were added to 1,4-dioxane (100 mL), heated to 75°C under N2 protection, and reacted for 18 h. After the reaction was completed, the mixture was filtered with diatomaceous earth, and the filtrate was evaporated to dryness under reduced pressure and purified by flash column chromatography (eluent system A) to obtain compound 1d (1.1 g).

[0262] MS (ESI): m / z 408.9 [M+H] + .

[0263] Step 4: tert-butyl 3-(2-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyridin-2-yl)amino)pyridin-4-yl)pyrrolidine-1-carboxylate (1e)

[0264] Compound 1d (300 mg, 732.94 μmol), (2-aminophenyl) dimethylphosphine oxide (247.97 mg, 1.47 mmol), Pd2(dba)3 (67.12 mg, 73.29 μmol), Brettphos (78.67 mg, 146.59 μmol) and Cs2CO3 (597.02 mg, 1.83 mmol) were added to toluene (5 mL), heated to 120°C under N2 protection, and reacted for 6 h. After the reaction was completed, the mixture was filtered with diatomaceous earth, and the filtrate was evaporated to dryness under reduced pressure and purified by flash column chromatography (eluent system B) to obtain compound 1e (230 mg).

[0265] MS (ESI): m / z 541.9 [M+H] + .

[0266] Step 5: (2-((5-chloro-2-((4-(pyrrolidin-3-yl)pyridin-2-yl)amino)pyridin-4-yl)amino)phenyl)dimethylphosphine oxide (Compound 1)

[0267] Compound 1e (230 mg, 424.35 μmol) was added to a 4N hydrochloric acid solution of 1,4-dioxane (15 mL) and stirred at room temperature for 4 h. After the reaction, the pH of the system was adjusted to 8-9 with K2CO3 aqueous solution, and the crude product was obtained after evaporation under reduced pressure and purified by preparative HPLC (instrument model: Agilent 1260; chromatographic column: Waters SunFire Prep C 18 OBD (19mm×150mm×5.0μm); column temperature: 25°C; flow rate: 28.0mL / min; detection wavelength: 214nm; mobile phase A: acetonitrile; mobile phase B: 0.05% w / v aqueous ammonium bicarbonate solution; elution gradient: 0min, 10% v / v A, 90% v / v B; 16.0min, 90% v / v A, 10% v / v B), to obtain compound 1 (125mg).

[0268] MS (ESI): m / z 441.9 [M+H] + .

[0269] 1H-NMR (400MHz, DMSO-d6): δ9.89 (s, 1H), 9.52 (d, J = 27.3Hz, 1H), 8.09 (s, 1H), 8.07-8.01 (m, 2H), 7.66-7.57(m,3H),7.40(d,J=29.7Hz,1H),7.17(t,J=8.8Hz,1H),6.78-6.75(m,1H),3.70-3.66( m,1H),3.58-3.40(m,1H),3.30-3.28(m,1H),3.23-3.17(m,1H),3.06-2.89(m,2H),2.67-2.59(m ,0.5H),2.26-2.18(m,0.5H),2.15-2.06(m,0.5H),1.75(d,J=13.5Hz,6H),1.71-1.55(m,0.5H).

[0270] [Biological evaluation]

[0271] The present invention will be further described and explained below through experimental examples, but these experimental examples are not intended to limit the scope of the present invention.

[0272] Experimental Example 1: Test on the inhibition of HPK1 enzymatic activity by compounds.

[0273] Reagents and instruments:

[0274] MBP (Promega corporation)

[0275] ATP-Glo ​​reagent (Promega corporation)

[0276] ATP-Glo ​​Assay Buffer (Promega corporation)

[0277] BMG LABTECH (model PHERAstar-FS)

[0278] The ATP-Glo ​​assay kit was used to test the inhibitory effect of the compounds of the present invention on HPK1 enzymatic activity. The reagents (HPK1, 5X kinase buffer, myelin basic protein (MBP), ATP) were purchased from Promega corporation. The experimental operation and optimization were based on the recommendations in the reagent manual.

[0279] Add 2 μl of 2.5X HPK1 (2 ng / μl) to the 384-well plate, then add 1 μl of a series of 5X test compounds. After incubation at room temperature, add 2 μl of 2.5X MBP (0.25 μg / μl) / ATP (25 μM) and incubate at room temperature for 1 h. After incubation, add 5 μl of ATP-Glo ​​reagent to each well, incubate at room temperature, terminate the reaction, and remove the remaining ATP. After 40 min, add 10 μl of ATP-Glo ​​detection buffer to each well and react at room temperature for 1 h. After the reaction, move the 384-well plate into the PHERAstar-FS microplate reader (BMG LABTECH) for reading, select the mode: Luminescence, and the data presentation method: relative chemiluminescence value RLU (Relative Luminescence units).

[0280] The inhibition rate of the compound on HPK1 enzymatic activity was calculated according to the following formula:

[0281] Inhibition rate (%) = ((RLU 最大 -RLU 空白 )-(RLU 处理 -RLU 空白 ))÷(RLU 最大 -RLU 空白 )×100%

[0282] Among them, RLU 最大 RLU is the relative chemiluminescence value of the group without compound treatment. 空白 RLU is the relative chemiluminescence value of the group without HPK1 and compound treatment; 处理 is the relative chemiluminescence value of the compound treatment group.

[0283] IC was calculated by fitting the data to the equation log(inhibitor concentration) versus normalized response (variable slope) using Graphpad Prism software. 50

[0284] Compound <![CDATA[IC against HPK1 50 (nM)]]> 1 2.01

[0285] The test results showed that compound 1 had a high inhibitory effect on HPK1 enzymatic activity.

[0286] In addition to those embodiments described herein, various modifications of the present invention will be apparent to those skilled in the art based on 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. A compound having structure VI or a pharmaceutically acceptable salt thereof, in, R 1 Selected from P(O)R b R c , R b and R c Each independently selected from hydrogen and C1-C6 alkyl; R 3 is selected from halogen; R 4 Selected from hydrogen; R 5 is selected from 3-7 membered heterocyclic groups, wherein the 3-7 membered heterocyclic groups are optionally substituted by one or more R d Replacement, R d is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more R j Substitution, the R j is selected from halogen and hydroxy; R 6 Selected from hydrogen.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in, R 1 Selected from 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in, R 3 Selected from chlorine.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in, R 5 Selected from 5. The following compounds or pharmaceutically acceptable salts thereof, 6. A method for preparing a compound having a structure of formula I, comprising the following steps: 1) Compound I-1 reacts with compound I-2 to obtain compound I-3; 2) Compound I-3 reacts with compound I-4 to obtain a compound having a structure of formula I; in, R 1 Selected from P(O)R b R c , R b and R c Each independently selected from hydrogen and C1-C6 alkyl; R 2 Selected from hydrogen; R 3 is selected from halogen; R 4 Selected from hydrogen; R 5 is selected from 3-7 membered heterocyclic groups, wherein the 3-7 membered heterocyclic groups are optionally substituted by one or more R d Replacement, R d is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more R j Substitution, the R j is selected from halogen and hydroxy; R 6 Selected from hydrogen; X is selected from CH; A is a benzene ring; LG1 and LG2 represent leaving groups, and are each independently selected from a halogen atom, a p-toluenesulfonate group and a trifluoromethanesulfonate group.

7. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating a disease or condition at least partly mediated by HPK1.

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