CN114181257A

CN114181257A - Pyridine compound, pharmaceutical composition containing pyridine compound, preparation method and application of pyridine compound

Info

Publication number: CN114181257A
Application number: CN202010961910.1A
Authority: CN
Inventors: 贾兰齐; 游泽金; 孙晓阳; 朱军; 陈泉龙; 李伟; 冉茂盛; 姚昊; 田强; 宋宏梅; 薛彤彤; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2020-09-14
Filing date: 2020-09-14
Publication date: 2022-03-15

Abstract

The invention belongs to the field of pharmaceutical chemistry, and relates to a pyridine compound, a pharmaceutical composition containing the pyridine compound, a preparation method and application of the pyridine compound. In particular, the invention relates to a compound with a structure shown in a formula I, which shows better HPK1 inhibition activity and can be used as a high-efficiency HPK1 inhibitor for preventing and/or treating HPK1 related diseases.

Description

Pyridine compound, pharmaceutical composition containing pyridine compound, preparation method and application of pyridine compound

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and relates to a pyridine compound used as an HPK1(hematopoietic promoter kinase 1) inhibitor, a pharmaceutical composition containing the same, a preparation method of the pyridine compound, and application of the pyridine compound in preventing and/or treating HPK1 related diseases.

Background

Hematopoietic progenitor kinase 1(HPK1), also known as mitogen-activated protein kinase kinase kinase kinase kinase 1 (MAP 4K1), is a member of the serine/threonine kinase subfamily Ste20, which family members also include MAP4K2(GCK), MAP4K3(GLK), MAP4K4(HGK), MAP4K5(KHS) and MAP4K6 (MINK). HPK 1is primarily expressed restrictively in hematopoietic cells, including early progenitor cells, as well as hematopoietic cell lines, such as human acute lymphoblastic leukemia cells (MOLT4), human lymphoma cells (Daudi), and the like.

Under physiological conditions, HPK1 functions as peripheral immune tolerance via the JNK/SAPK signaling pathway. However, in certain tumor progression, HPK1 down-regulates T cell, B cell responses, and activation of dendritic cells. When a T Cell Receptor (TCR) binds to a ligand (CD3/28), HPK 1is activated by a TCR signal path, and the activated HPK1 can phosphorylate serine 376 of a joint protein SLP-76 so as to recruit 14-3-3 protein, further to cause instability of a TCR complex, and finally to cause weakening of T cell response and inhibition of T cell proliferation. Therefore, it has been increasingly appreciated that the inhibition of the immune down-regulation of HPK1 in tumor therapy exerts an anti-tumor effect on the immune system of the patient himself.

It has been shown that the antigen presentation of mouse dendritic cells, which had been specifically deleted for HPK1 enzyme activity, was enhanced (Alzabin, S., N.Bhardwaj, F.Kiefer, S.Sawass dikosol and S.Burrakoff (2009). "hepatogenic promoter kinase 1is a negative regulator of dendritic cell activation." J Immunol 182(10): 6187-. Similarly, Lewis lung carcinoma transplanted tumor mice received a T cell transplantation therapy with HPK1 knockout, and the tumor suppression rate was significantly increased over the control (wild-type T cell transplantation therapy) (Alzabin, S. Parajan, H.Yee, F.Kiefer, A.Suzuki, S.Burrakoff and S.Sawasdsikol (2010)' hematopic prognosticator kinase 1is a critical component of prostaglandin E2-mediated rendering of the anti-tumor immunity. Cancer immunity 59(3): 419) 429). Therefore, the HPK1 inhibitor (especially small molecule inhibitor) can be searched as a new direction for tumor immunotherapy.

Disclosure of Invention

Problems to be solved by the invention

A large number of researches discover a series of novel pyridine compounds, which have high HPK1 inhibitory activity, can be used independently or combined with other medicines, are used for preventing and/or treating HPK1 related diseases, especially tumor diseases, and show good application prospects.

Means for solving the problems

In a first aspect, the present invention provides a compound having the structure of formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, prodrug, or mixture of any two or more thereof,

wherein the content of the first and second substances,

a is selected from C₆-C₁₄Aryl and 5-14 membered heteroaryl, said C₆-C₁₄Aryl and 5-14 membered heteroaryl are each optionally substituted with one or more R^dSubstitution;

R¹is selected from C₁-C₆Alkoxy, cyano, nitro, P (O) R^bR^c、C(O)NR^bR^c、S(O)₂R^a、S(O)₂NR^bR^c、C(O)R^aAnd NR^bC(O)R^aSaid C is₁-C₆Alkoxy is optionally substituted by one or more R^dSubstitution;

R²selected from hydrogen and C₁-C₆Alkyl radical, said C₁-C₆Alkyl is optionally substituted by one or more R^dSubstitution;

R³selected from hydrogen, halogen, hydroxy, cyano, nitro, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy, C (O) NR^bR^c、NR^bC(O)R^aAnd NR^bR^cSaid C is₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl and C₁-C₆Each alkoxy group is optionally substituted with one or more R^dSubstitution;

R⁴and R⁵Each independently selected from hydrogen, halogen, cyano, nitro, C (O) R^a、C(O)OR^a、C(O)NR^bR^c、S(O)R^a、S(O)₂R^a、S(O)₂NR^bR^c、NHC(O)R^a、NHC(O)OR^a、NR^bR^c、OC(O)R^a、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-7 membered heterocyclic group, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-7 membered heterocyclic group, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl are each optionally substituted with one or more R^dSubstitution;

R⁶selected from hydrogen, halogen, hydroxy, cyano, nitro, NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-7 membered heterocyclic group, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-7 membered heterocyclic group, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl are each optionally substituted with one or more R^dSubstitution;

x is selected from CR⁷And N;

R⁷selected from hydrogen, halogen, cyano, nitro, C (O) R^a、C(O)OR^a、C(O)NR^bR^c、S(O)R^a、S(O)₂R^a、S(O)₂NR^bR^c、NHC(O)R^a、NHC(O)OR^a、OC(O)R^a、NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-7 membered heterocyclic group, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-7 membered heterocyclic group, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl are each optionally substituted with one or more R^dSubstitution;

if present, each R^aEach independently selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 5-10 membered heterocyclyl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 5-10 membered heterocyclyl are each optionally substituted with one or more R^dSubstitution;

if present, each R^bAnd R^cEach independently selected from hydrogen and C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 4-7 membered heterocyclyl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 4-7 membered heterocyclyl are each optionally substituted with one or more R^dSubstitution; or, if present, each pair R^bAnd R^cTogether with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl, said 4-7 membered heterocyclyl being optionally substituted with one or more R^dSubstitution;

if present, each R^dEach independently selected from hydrogen, hydroxy, halogen, oxo, cyano, nitro, C (O) R^e、C(O)OR^e、NR^fS(O)₂R^g、S(O)R^e、S(O)₂R^e、C(O)NR^fR^g、S(O)₂NR^fR^g、NR^fR^g、NR^fC(O)R^g、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₁-C₆alkyleneoxy-C₁-C₆Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl, said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₁-C₆alkyleneoxy-C₁-C₆Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl are each optionally substituted with one or more R^jSubstitution;

if present, each R^eEach independently selected from hydrogen and C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl;

if present, each R^fAnd R^gEach independently selected from hydrogen and C_1-C₆Alkyl radical, C₃-C₇Cycloalkyl and 4-7 membered heterocyclyl, said C₁-C₆Alkyl optionally substituted by one or more C₁-C₆Alkoxy or NR^hRⁱSubstitution; or, if present, each pair R^fAnd R^gTogether with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl;

if present, each R^hAnd RⁱEach independently selected from hydrogen and C₁-C₆An alkyl group; and is

If present, each R^jEach independently selected from halogen, hydroxy, cyano and 3-8 membered heterocyclyl.

In a second aspect, the present invention provides specific examples of the compounds having the structure of formula I, including:

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

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

(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;

(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;

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

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

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

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

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

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

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

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

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

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

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

(16) (2- ((5-chloro-2- ((6- ((2- (methylamino) ethyl) amino) -4-morpholinopyridin-2-yl) amino) pyridin-4-yl) amino) phenyl) dimethylphosphine oxide;

(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;

(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;

(19) (2- ((5-chloro-2- ((4- (pyrrolidinyl-3-yl) pyridin-2-yl) amino) pyridin-4-yl) amino) phenyl) diethylphosphine oxide;

(20) 5-chloro-N⁴- (2- (methylsulfonyl) phenyl) -N²- (4- (pyrrolidin-3-yl) pyridin-2-yl) pyridine-2, 4-diamine;

(21) 5-chloro-N⁴- (2- (isopropylsulfonyl) phenyl) -N²- (4- (pyrrolidin-3-yl) pyridin-2-yl) pyridine-2, 4-diamine;

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

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

(24) (2- ((2- ((4- (pyrrolidin-3-yl) pyridin-2-yl) amino) pyridin-4-yl) amino) phenyl) dimethyl phosphine oxide.

In a third aspect, the present invention provides a process for preparing the compound having the structure of formula I, comprising the steps of:

1) reacting the compound I-1 with the compound I-2 to obtain a compound I-3;

2) reacting the compound I-3 with a compound I-4 to obtain a compound with a structure shown in a formula I;

wherein the content of the first and second substances,

R¹、R²、R³、R⁴、R⁵、R⁶and X is as defined above;

LG₁and LG₂Represents a leaving group, each independently selected from a halogen atom (e.g. Cl, Br or I), a p-toluenesulfonate group and a trifluoromethanesulfonate group.

In a fourth aspect, the present invention provides a pharmaceutical composition comprising at least one of the compounds having the structure of formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, prodrug, or a mixture of any two or more thereof, and one or more pharmaceutically acceptable carriers.

In a fifth aspect, the present invention provides a pharmaceutical product comprising:

a) a container;

b) at least one of said compounds having the structure of formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, prodrug, or mixture of any two or more thereof, located in said container; and

c) optionally packaging and/or instructions.

In a sixth aspect, the present invention provides the use of a compound having the structure of formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, prodrug, or a mixture of any two or more thereof, or of a pharmaceutical composition, or of a pharmaceutical product, in the manufacture of a medicament for the prevention and/or treatment of a disease or condition mediated at least in part by HPK1, particularly a tumor.

In a seventh aspect, the present invention provides the use of a compound having the structure of formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, prodrug, or a mixture of any two or more thereof, or of a pharmaceutical composition, or of a medicament, as an inhibitor of HPK 1. Preferably, the HPK1 inhibitor is for use in the prevention and/or treatment of a disease or condition (in particular a tumor) mediated at least in part by HPK 1.

In an eighth aspect, the present invention provides a method for the prevention and/or treatment of a disease or condition mediated at least in part by HPK1 (in particular a tumour), comprising the steps of: administering to an individual in need thereof a prophylactically and/or therapeutically effective amount of the compound having the structure of formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, prodrug, or a mixture of any two or more thereof, or the pharmaceutical composition, or the pharmaceutical product.

ADVANTAGEOUS EFFECTS OF INVENTION

The compound of the invention has strong inhibitory activity on HPK1, good physicochemical properties (such as solubility, physical and/or chemical stability), good pharmacokinetic properties (such as good bioavailability, proper blood drug concentration, half-life and action duration), good safety (lower toxicity, such as lower cardiac and hepatic toxicity and/or fewer side effects and wider therapeutic window) and the like.

Detailed Description

General terms and definitions

Unless otherwise defined, terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The technical intent used herein is to refer to techniques commonly understood in the art, including variations or equivalents of techniques that are apparent to those skilled in the art. Although the following terms are readily understood by those skilled in the art, they are set forth below in order to better explain the present invention.

The terms "comprising," "including," "having," or "involving," and other variations thereof herein, refer to an inclusive or open-ended collection of concepts and do not exclude additional unrecited elements or method steps. It will be understood by those skilled in the art that terms such as "including" and "comprising" encompass the meaning of "consisting of ….

The term "one or more" or similar expressions "at least one" mean, for example, 1,2, 3, 4,5, 6, 7, 8, 9, 10 or more(s).

When the lower and upper limits of a range of values are disclosed, any value or any sub-range falling within the range is specifically disclosed. In particular, each numerical range of parameters disclosed herein (e.g., in the form of "about a to b," or equivalently "about a-b") is to be understood to encompass each number and subrange therein. For example, "C₁-C₆"is to be understood to cover any subrange therein as well as each point value, e.g. C₂-C₅、C₃-C₄、C₁-C₂、C₁-C₃、C₁-C₄、C₁-C₅Etc. and C₁、C₂、C₃、C₄、C₅、C₆And the like. Also for example, "3-10 membered" is understood to encompass any subrange therein as well as each point value, e.g., 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 4-5, 4-6, 4-7, 4-8, 5-7, 5-8, 6-7, etc., as well as 3, 4,5, 6, 7, 8, 9, 10, etc.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting a compound of the invention with a pharmaceutically acceptable inorganic acid/organic acid/acidic amino acid or inorganic base/organic base/basic amino acid, such salts also being referred to as acid addition salts or base addition salts. 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 present invention are known to those skilled in the art.

The term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to an organism and that hydrolyzes in vivo to a compound of the invention or a salt thereof. Pharmaceutically acceptable esters generally include, but are not limited to, esters of the compounds of the present invention with pharmaceutically acceptable carboxylic or sulfonic acids, such esters also being referred to as carboxylic or sulfonic esters. In addition, the compounds of the present invention may themselves be esters.

The term "isomers" refers to compounds having the same molecular weight, but differing in the spatial arrangement or configuration of the atoms, due to the same number and type of atoms.

The term "stereoisomer" (or "optical isomer") refers to a stable isomer having a perpendicular plane of asymmetry due to having at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.) that enables rotation of plane polarized light. Since the compounds of the present invention have asymmetric centers as well as other chemical structures that may lead to stereoisomers, the present invention also includes such 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, mixtures of enantiomers and diastereomers. Generally, these compounds can be prepared in the form of racemates. However, if desired, such compounds may be prepared or isolated to give pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in single stereoisomers (purity ≥ 99%, ≥ 98%, ≥ 97%, ≥ 96%, ≥ 95%, ≥ 90%, > 85%, ≥ 80%, ≥ 75%, > 70%, > 65% or ≥ 60%). As described hereinafter, individual stereoisomers of compounds are prepared synthetically from optically active starting materials containing the desired chiral center, or by preparation of mixtures of enantiomeric products followed by separation or resolution, e.g., conversion to mixtures of diastereomers followed by separation or recrystallization, chromatography, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. The starting compounds of a particular stereochemistry are either commercially available or may be prepared according to the methods described hereinafter 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 the 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.

Solid lines are used herein

Solid wedge shape

Or virtual wedge shape

To depict the covalent chemical bonds of the compounds of the present invention. When a solid line is used to depict a bond to a chiral atom, it is meant to include all possible stereoisomers (e.g., particular enantiomers, racemic mixtures, etc.) at that chiral atom. When a solid or dotted wedge is used to depict the bond to the chiral atom, it indicates that 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 proportion.

The term "tautomer" (or "tautomeric form") refers to structural isomers having different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-iminoalcohol isomerization, nitroso-oxime isomerization, and the like. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

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 a number of 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 using 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), among others. 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 polymorphs mixed in any ratio.

The term "solvate" refers to a substance formed by the binding of a compound of the present invention (or a pharmaceutically acceptable salt thereof) to at least one solvent molecule by non-covalent intermolecular forces. Common solvates include, but are not limited to, hydrates (including hemihydrate, monohydrate, dihydrate, trihydrate, etc.), ethanolates, acetonates, and the like. The compounds according to the invention can be present in the form of solvates, preferably hydrates, which contain polar solvents (in particular water, methanol or ethanol) as lattice structural element. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.

The term "isotopic label" refers to a derivatized compound formed by replacing a particular atom in a compound of the invention with its isotopic atom. Unless otherwise indicated, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, Cl, such as²H(D)、³H(T)、¹³C、¹⁴C、¹³N、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁴S、³⁵S、³⁶S、³⁷Cl and¹²⁵I. for example,¹²c can be covered¹²C、¹³C or¹⁴C, replacing;¹h can be covered²H (D, deuterium) or³H (T, tritium) substitution;¹⁶o can be¹⁸O substitution, and the like.

The term "metabolite" refers to a derivative compound formed by the metabolism of a compound of the present invention, for example, 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 proportions, 1996. The present invention encompasses all possible metabolite forms of the compounds of the invention, i.e. substances formed in the body of the individual to whom the compounds of the invention are administered. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized by assays.

The term "prodrug" refers to a derivative compound that is capable of providing, directly or indirectly, a compound of the invention upon administration to a subject. Particularly preferred derivative compounds or prodrugs are those that increase the bioavailability of the compounds of the invention when administered to a subject (e.g., more readily absorbed into the blood), or facilitate delivery of the parent compound to the site of action (e.g., the 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, see, e.g., T.Higuchi, V.Stella, Pro-drugs as Novel Drug Delivery Systems [ J ], American Chemical Society, Vol.14, 1975. Furthermore, the present invention also encompasses compounds of the present invention containing protecting groups. In 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 concerned, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting Groups, such as those described in t.w.greene, p.g.m.wuts, Protective Groups in Organic Synthesis [ M ], John Wiley & Sons, 2006. These protecting groups may be removed at a suitable subsequent stage using methods known in the art.

The term "chemical bond" refers to the strong force that binds two or more adjacent atoms (or ions) within a pure molecule or crystal to each other, and includes mainly covalent bonds, ionic bonds, metallic bonds, coordination bonds, and the like. Unless otherwise indicated, the chemical bonds in the compounds of the invention in free form are mostly covalent bonds.

The term "alkyl", when used herein alone or in combination with other groups, refers to a straight or branched chain saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 10 carbon atoms, e.g., 1 to 8 carbon atoms (C)₁-C₈Alkyl), 1 to 6 carbon atoms (C)₁-C₆Alkyl), 1 to 4 carbon atoms (C)₁-C₄Alkyl), 1 to 3 carbon atoms (C)₁-C₃Alkyl), 2 to 6 carbon atoms (C)₂-C₆Alkyl), 2 to 4 carbon atoms (C)₂-C₄Alkyl) or 3 to 4 carbon atoms (C)₃-C₄Alkyl groups). For example, the term "C" as used herein₁-C₆Alkyl "refers to an alkyl group having 1 to 6 carbon atoms (e.g., 1,2, 3, 4,5, or 6 carbon atoms) (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like), which is optionally substituted with one or more (e.g., 1 to 3) substituents described herein (e.g., when substituted with halogen, the group is" C₁-C₆Haloalkyl radicals ", e.g. -CF₃、-C₂F₅、-CHF₂、-CH₂F、-CH₂CF₃、-CH₂Cl、-CH₂CH₂CF₃Etc.).

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

The term "cycloalkyl" as used herein, alone or in combination with other groups, refers to a saturated aliphatic monocyclic or polycyclic (e.g., bicyclic) hydrocarbon group (e.g., monocyclic cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and the like; or bicyclic cycloalkyl, including fused, bridged or spiro rings, such as decahydronaphthyl, bicyclo [2.2.1] or]Heptyl, spiro [4.5 ]]Decyl, etc.). In some embodiments, cycloalkyl groups have 3 to 15 carbon atoms, e.g., 3 to 10 carbon atoms (C)₃-C₁₀Cycloalkyl), 3 to 7 carbon atoms (C)₃-C₇Cycloalkyl), 3 to 6 carbon atoms (C)₃-C₆Cycloalkyl), 3 to 5 carbon atoms (C)₃-C₅Cycloalkyl), 5 to 7 carbon atoms (C)₅-C₇Cycloalkyl), 4 to 6 carbon atoms (C)₄-C₆Cycloalkyl) or 5 to 6 carbon atoms (C)₅-C₆Cycloalkyl), and the like. For example, the term "C" as used herein₃-C₇Cycloalkyl "refers to a cycloalkyl group having 3 to 7 ring-forming carbon atoms, optionally substituted with one or more (e.g., 1 to 3) substituents described herein (e.g., when substituted with halogen, the group is" C₃-C₇Halocycloalkyl radicals "such as 2-fluorocyclopropyl, 3-chlorocyclobutyl, 4-bromocyclohexyl, etc.).

The term "heterocyclyl" as used herein, alone or in combination with other groups, refers to an aliphatic monocyclic or polycyclic (e.g., bicyclic, tricyclic, or higher polycyclic) hydrocarbon group having one or more carbon atoms in the ring (e.g., 1,2, 3, 4,5, 6, 7, 8, or 9) and one or more (e.g., 1,2, 3, or 4) each independently selected from C (═ O), O, S, S (═ O), S (═ O)₂And NR (R represents a hydrogen atom or a substituent such as an alkyl group or a cycloalkyl group) (e.g., a 3-7-membered heterocyclic group, a 4-7-membered heterocyclic group, a 3-8-membered heterocyclic group, a 5-10-membered heterocyclic group, etc.). The heterocyclyl group may be saturated (containing no double or triple bonds) or unsaturated (containing at least one double or triple bond), and saturated heterocyclyl groups may also be referred to asIs heterocycloalkyl, such as 3-to 8-membered heterocycloalkyl, 5-to 6-membered heterocycloalkyl, and the like. For example, the term "3-7 membered heterocyclyl" as used herein refers to a heterocyclyl having 3-7 ring atoms (including one or more heteroatoms) that is optionally substituted with one or more (e.g., 1 to 3) substituents described herein (e.g., oxirane, thietane, cycloazethane, azetidine, oxetane, thietane, tetrahydrofuranyl, dioxolane, tetrahydrothienyl, pyrrolidinyl, pyrrolidinone, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, azathiopyranyl

A group such as morpholinyl, thiomorpholinyl, 1, 4-thiaxalkyl, 1, 4-dioxane, 1, 4-dithianyl, piperazinyl, trioxane, trithianyl, thiazinoalkyl, and the like; or a fused ring derivative thereof, such as cyclopentazacyclopropyl, pyrrolidinocyclopropyl, pyrrolidinocyclobutyl, pyrrolidinopyrrolidinyl, pyrrolidinopiperidinyl, pyrrolidinopiperazinyl, pyrrolidinomomorpholinyl, piperidinomomorpholinyl, and the like; or spiro derivatives thereof, e.g.

Etc.).

The term "alkoxy", as used herein, alone or in combination with other groups, means an alkyl group as described above attached to the parent molecular moiety through an oxygen atom, i.e., -O-alkyl. For example, the term "C" as used herein₁-C₆Alkoxy "refers to an alkoxy group (e.g., methoxy, ethoxy, isopropoxy, tert-butoxy, etc.) having 1 to 6 carbon atoms (e.g., 1,2, 3, 4,5, or 6 carbon atoms) optionally substituted with one or more (e.g., 1 to 3) substituents described herein (e.g., when substituted with halogen, the group is" C₁-C₆Haloalkoxy ", e.g. -OCF₃、-OC₂F₅、-OCHF₂、-OCH₂Cl, etc.).

The term "alkyleneoxy", as used herein, alone or in combination with other groups "Refers to a divalent group formed by removing one hydrogen atom from the above alkoxy group, i.e., -O-alkylene-. For example, the term "C" as used herein₁-C₆Alkyleneoxy "refers to an alkyleneoxy group (e.g., methyleneoxy, ethyleneoxy, etc.) having 1-6 carbon atoms (e.g., 1,2, 3, 4,5, or 6 carbon atoms) that is optionally substituted with one or more (e.g., 1-3) substituents described herein (e.g., when substituted with a halogen, the group is" C₁-C₆Haloalkyleneoxy radicals ", e.g. -OCF₂-、-OC₂F₄-, -OCHF-, -OCHCl-, etc.).

The term "aryl" as used herein alone or in combination with other groups refers to a monocyclic or fused-ring aromatic hydrocarbon group having a conjugated pi-electron system. For example, the term "C" as used herein₆-C₁₄Aryl "refers to an aryl group having 6 to 14 carbon atoms (e.g., phenyl, naphthyl, etc.), optionally substituted with one or more substituents described herein (e.g., with C)₁-C₆Alkyl-substituted tolyl, chlorophenyl substituted with halogen, etc.).

The term "heteroaryl" as used herein alone or in combination with other groups refers to a monocyclic or fused ring aromatic group having a conjugated pi-electron system. As used herein, a "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 is 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 each independently selected from N, O, P and S. A heteroaryl group may be attached to the parent molecular moiety through any one of the ring atoms if the valency requirements are met. Heteroaryl groups may be attached to other groups (or moieties) through any one of the carbon atoms or heteroatoms (e.g., N atoms) in the ring if the valence requirement is met. Also, heteroaryl groups may be optionally fused to an aryl, heterocyclyl (e.g., heterocycloalkyl), or cycloalkyl (e.g., cycloalkyl) ring, wherein the ring to which the parent structure is attached is a heteroaryl ring. For example, the term "5-14 membered heteroaryl" as used herein refers to heteroaryl having 5-14 ring atoms (e.g., thienyl, furyl, pyrrolyl, indolyl, heterocyclyl, or heterocyclyl,Thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, triazolyl, tetrazolyl and the like, or such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, or benzo derivatives thereof, such as indazolyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl and the like, or such as pyrazolopyridine, pyrrolopyrimidine, pyrrolopyridyl, pyrazolopyrimidine and the like), optionally substituted with one or more substituents described herein (such as by C)₁-C₆Alkyl-substituted methylpyridyl, halogen-substituted chloropyridyl, etc.).

The term "alkenyl", as used herein alone or in combination with other groups, refers to a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds. In some embodiments, alkenyl groups have 2 to 15 carbon atoms. For example, the term "C" as used herein₂-C₆Alkenyl "refers to alkenyl groups having 2 to 6 carbon atoms and one, two, or three carbon-carbon double bonds (e.g., ethenyl, 1-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, and the like), which are optionally substituted with one or more (e.g., 1 to 3) substituents described herein.

The term "alkynyl", as used herein alone or in combination with other groups, refers to a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. For example, the term "C" as used herein₂-C₆Alkynyl "refers to alkynyl groups having 2 to 6 carbon atoms and one, two, or three carbon-carbon triple bonds (e.g., ethynyl, 1-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like), which are optionally substituted with one or more (e.g., 1 to 3) substituents described herein.

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

The term "hydroxy" when used herein alone or in combination with other groups means-OH.

The term "cyano," when used herein alone or in combination with other groups, refers to — CN.

The term "nitro" as used herein, alone or in combination with other groups, refers to-NO₂。

The term "amino" as used herein, alone or in combination with other groups, refers to-NH₂。

The term "oxo", when used herein alone or in combination with other groups, refers to ═ O.

The term "independently" as used herein means that at least two groups (or fragments) present in a structure in the same or similar range of values can have the same or different meanings in a particular instance. For example, substituent X and substituent Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl, and when substituent X is hydrogen, substituent Y may be either hydrogen, halogen, hydroxy, cyano, alkyl or aryl; similarly, when the substituent Y is hydrogen, the substituent X may be hydrogen, or may be halogen, hydroxy, cyano, alkyl or aryl.

The term "substituted" and other variations thereof herein mean that one or more (e.g., 1,2, 3, or 4) atoms or groups of atoms (e.g., hydrogen atoms) on the designated atom is replaced with other equivalents, provided that the designated atom or group of atoms does not exceed the normal valence under the current circumstances and that a stable compound can be formed. If an atom or group of atoms is described as "optionally substituted with … …," it may be substituted or unsubstituted. Unless otherwise indicated, the attachment site of a substituent herein may be from any suitable position of the substituent. When a linkage in a substituent is shown across a chemical bond between two atoms attached to each other in a ring system, it means that the substituent may be attached to any one of the ring atoms in the ring system.

A compound of the formula

The present invention provides a compound of formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, prodrug, or a mixture of any two or more thereof,

wherein the content of the first and second substances,

x is selected from CR⁷And N;

R⁷selected from hydrogen, halogen, cyano, nitro, C (O) R^a、C(O)OR^a、C(O)NR^bR^c、S(O)R^a、S(O)₂R^a、S(O)₂NR^bR^c、NHC(O)R^a、NHC(O)OR^a、OC(O)R^a、NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-7 membered heterocyclic group, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl radical、C₁-C₆Alkoxy radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-7 membered heterocyclic group, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl are each optionally substituted with one or more R^dSubstitution;

if present, each R^fAnd R^gEach independently selected from hydrogen and C_1-C₆Alkyl radical, C_3-C₇Cycloalkyl and 4-7 membered heterocyclyl, said C₁-C₆Alkyl optionally substituted by one or more C_1-C₆Alkoxy or NR^hRⁱSubstitution; or, if present, each pair R^fAnd R^gTogether with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl;

if present, each R^hAnd RⁱEach independently selected from hydrogen and C_1-C₆An alkyl group; and is

In some preferred embodiments of the invention, A in the above-described compounds of formula I is C₆-C₁₄Aryl, preferably C₆-C₁₀And (4) an aryl group.

In some preferred embodiments of the invention, R in the above-described compounds of formula I¹Is selected from C₁-C₆Alkoxy, cyano, nitro, P (O) R^bR^c、C(O)NR^bR^c、S(O)₂R^aAnd S (O)₂NR^bR^cPreferably P (O) R^bR^c、C(O)NR^bR^c、S(O)₂R^aAnd S (O)₂NR^bR^c。

In some preferred embodiments of the invention, R in the above-described compounds of formula I²Selected from hydrogen and C₁-C₆Alkyl, preferably hydrogen.

In some preferred embodiments of the invention, R in the above-described compounds of formula I³Selected from hydrogen, halogen, cyano, nitro, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and C₁-C₆Alkoxy, preferably hydrogen and halogen.

In some preferred embodiments of the invention, R in the above-described compounds of formula I⁴And R⁵Each independently selected from hydrogen, halogen, cyano, nitro, NHC (O) R^a、NHC(O)OR^a、NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Alkoxy radical, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Each alkoxy group is optionally substituted with one or more R^dSubstitution; preferably hydrogen, NR^bR^c、C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Alkoxy radical, said C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Each alkoxy group is optionally substituted with one or more R^dSubstitution; more preferably hydrogen, NR^bR^c、C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Alkoxy radical, said C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Each alkoxy group is optionally substituted with one or more R^dAnd (4) substitution.

In some preferred embodiments of the invention, R in the above-described compounds of formula I⁶Selected from hydrogen, halogen, cyano, nitro, NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇A cycloalkyl group,3-7 membered heterocyclic group and C₁-C₆Alkoxy, preferably hydrogen, halogen, cyano, nitro, NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Alkoxy, more preferably hydrogen and NR^bR^c。

In some preferred embodiments of the invention, X in the above-described compounds of formula I is CR⁷。

In some preferred embodiments of the invention, R in the above-described compounds of formula I⁷Selected from hydrogen, halogen, cyano, nitro, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and C₁-C₆Alkoxy, preferably hydrogen, halogen, cyano, nitro, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and C₁-C₆Alkoxy, more preferably hydrogen.

In some preferred embodiments of the invention, each R is^aEach independently selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, preferably C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and C₆-C₁₀And (4) an aryl group.

In some preferred embodiments of the invention, each R is^bAnd R^cEach independently selected from hydrogen and C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 4-7 membered heterocyclyl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 4-7 membered heterocyclyl are each optionally substituted with one or more R^dSubstitution; preferably hydrogen and C₁-C₆Alkyl radical, said C₁-C₆Alkyl is optionally substituted by one or more R^dSubstitution; or, each pair R^bAnd R^cTogether with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, preferably a 5-6 membered heterocyclic group.

In some preferred embodiments of the invention, each R is^dEach independentlySelected from hydrogen, hydroxy, halogen, cyano, nitro, NR^fS(O)₂R^g、NR^fR^g、NR^fC(O)R^g、C₁-C₆Alkyl radical, C₁-C₆Alkoxy and C₃-C₇Cycloalkyl radical, said C₁-C₆Alkyl radical, C₁-C₆Alkoxy and C₃-C₇Cycloalkyl is each optionally substituted by one or more R^jSubstitution; preferably hydroxy, halogen, NR^fR^gAnd C₁-C₆Alkyl radical, said C₁-C₆Alkyl is optionally substituted by one or more R^jAnd (4) substitution.

In some preferred embodiments of the invention, each R is^eEach independently selected from hydrogen and C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl and 5-to 10-membered heteroaryl, preferably hydrogen, C₁-C₆Alkyl and C₃-C₇A cycloalkyl group.

In some preferred embodiments of the invention, each R is^fAnd R^gEach independently selected from hydrogen and C_1-C₆Alkyl and C_3-C₇Cycloalkyl radical, said C₁-C₆Alkyl optionally substituted by one or more NR^hRⁱSubstitution; preferably hydrogen and C₁-C₆Alkyl radical, said C₁-C₆Alkyl optionally substituted by one or more NR^hRⁱSubstitution; or, each pair R^fAnd R^gTogether with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group.

In some preferred embodiments of the invention, each R is^hAnd RⁱEach independently selected from hydrogen and C₁-C₄An alkyl group.

In some preferred embodiments of the invention, each R is^jEach independently selected from halogen, hydroxy, cyano and 3-6 membered heterocyclyl, preferably halogen and hydroxy.

In some more preferred embodiments of the present invention, the above-described compound of formula I has a structure as shown in formula II,

wherein the content of the first and second substances,

each Y is independently selected from CR⁷And N;

X、R¹、R²、R³、R⁴、R⁵、R⁶and R⁷As defined above.

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

wherein the content of the first and second substances,

each Y is independently selected from CR⁷And N;

X、R¹、R²、R³、R⁴、R⁵、R⁶and R⁷As defined above.

In some more preferred embodiments of the present invention, the above-described compound of formula I has the structure shown in formula IV,

wherein, X, R¹、R²、R³、R⁴、R⁵And R⁶As defined above.

In some more preferred embodiments of the present invention, the above-described compound of formula I has the structure shown in formula V,

wherein R is¹、R²、R³、R⁴、R⁵And R⁶As defined above.

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

wherein R is¹、R³、R⁴、R⁵And R⁶As defined above.

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

wherein R is¹、R³And R⁵As defined above.

In some preferred embodiments of the present invention, in the compounds of formula I, formula II, formula III, formula IV, formula V, formula VI and formula VII described above, R is¹Is selected from C₁-C₆Alkoxy, cyano, nitro, P (O) R^bR^c、C(O)NR^bR^c、S(O)₂R^aAnd S (O)₂NR^bR^c(ii) a Preferably, R¹Selected from P (O) R^bR^c、C(O)NR^bR^c、S(O)₂R^aAnd S (O)₂NR^bR^c(ii) a More preferably, R¹Is selected from

S(O)₂CH₃、S(O)₂CH(CH₃)₂、S(O)₂N(CH₃)₂And C (O) NHCH₃。

In some preferred embodiments of the present invention, R in the compounds of formula I, formula II, formula III, formula IV, and formula V described above²Selected from hydrogen and C₁-C₆An alkyl group; preferably, R²Is hydrogen.

In some preferred embodiments of the present invention, in the compounds of formula I, formula II, formula III, formula IV, formula V, formula VI and formula VII described above, R is³Selected from hydrogen, halogen, cyano, nitro, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and C₁-C₆An alkoxy group; preferably, R³Selected from hydrogen and halogen; more preferably, R³Selected from hydrogen and chlorine.

In some preferred embodiments of the present invention, R in the compounds of the structures of formula I, formula II, formula III, formula IV, formula V, and formula VI described above⁴And R⁵Each independently selected from hydrogen, halogen, cyano, nitro, NHC (O) R^a、NHC(O)OR^a、NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Alkoxy radical, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Each alkoxy group is optionally substituted with one or more R^dSubstitution; preferably, R⁴And R⁵Each independently selected from hydrogen, NR^bR^c、C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Alkoxy radical, said C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Each alkoxy group is optionally substituted with one or more R^dSubstitution; more preferably, R⁴And R⁵Each independently selected from hydrogen, NR^bR^c、C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Alkoxy radical, said C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Each alkoxy group is optionally substituted with one or more R^dSubstitution; more preferably, R⁴And R⁵Each independently selected from hydrogen,

In some more preferred embodiments of the present invention, R in the compounds of the structures of formula I, formula II, formula III, formula IV, formula V, and formula VI described above⁴Is hydrogen, R⁵Selected from NR^bR^c、C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Alkoxy radical, said C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Each alkoxy group is optionally substituted with one or more R^dSubstituted, said R^dSelected from hydroxy, halogen, NR^fR^gAnd C₁-C₆Alkyl radical, said C₁-C₆Alkyl is optionally substituted by one or more R^jSubstituted, said R^jSelected from halogen and hydroxyl; the R is^bAnd R^cEach independently selected from hydrogen and C₁-C₆Alkyl radical, said C₁-C₆Alkyl optionally substituted by one or more NR^fR^gSubstituted, said R^fAnd R^gEach independently selected from hydrogen and C₁-C₆An alkyl group; preferably, R⁴Is hydrogen, R⁵Is selected from

In some preferred embodiments of the present invention, R in the compounds of the structures of formula I, formula II, formula III, formula IV, formula V, and formula VI described above⁶Selected from hydrogen, halogen, cyano, nitro, NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆An alkoxy group; preferably, R⁶Selected from hydrogen, halogen, cyano, nitro, NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆An alkoxy group; more excellentOptionally, R⁶Selected from hydrogen and NR^bR^cHydrogen and-NHCH are preferred₂CH₂NHCH₃。

In some preferred embodiments of the present invention, in the compounds of formula I, formula II, formula III and formula IV above, X is CR⁷。

In some preferred embodiments of the present invention, in the compounds of the structures of formula I, formula II, formula III and formula IV described above, R⁷Selected from hydrogen, halogen, cyano, nitro, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and C₁-C₆An alkoxy group; preferably, R⁷Selected from hydrogen, halogen, cyano, nitro, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and C₁-C₆An alkoxy group; more preferably, R⁷Is hydrogen.

In some preferred embodiments of the present invention, in the compounds of formula I, formula II, formula III, formula IV, formula V, formula VI and formula VII described above, each R is^aEach independently selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl; preferably, each R^aEach independently selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and C₆-C₁₀And (4) an aryl group.

In some preferred embodiments of the present invention, in the compounds of formula I, formula II, formula III, formula IV, formula V, formula VI and formula VII described above, each R is^bAnd R^cEach independently selected from hydrogen and C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 4-7 membered heterocyclyl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 4-7 membered heterocyclyl are each optionally substituted with one or more R^dSubstitution; preferably, each R^bAnd R^cEach independently selected from hydrogen and C₁-C₆Alkyl radical, said C₁-C₆Alkyl is optionally substituted by one or more R^dSubstitution; or, each pair R^bAnd R^cTogether with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, preferably a 5-6 membered heterocyclic group.

In some preferred embodiments of the present invention, in the compounds of formula I, formula II, formula III, formula IV, formula V, formula VI and formula VII described above, each R is^dEach independently selected from hydrogen, hydroxy, halogen, cyano, nitro, NR^fS(O)₂R^g、NR^fR^g、NR^fC(O)R^g、C₁-C₆Alkyl radical, C₁-C₆Alkoxy and C₃-C₇A cycloalkyl group; said C is₁-C₆Alkyl radical, C₁-C₆Alkoxy and C₃-C₇Cycloalkyl is each optionally substituted by one or more R^jSubstitution; preferably, each R^dEach independently selected from hydroxy, halogen, NR^fR^gAnd C₁-C₆Alkyl radical, said C₁-C₆Alkyl is optionally substituted by one or more R^jAnd (4) substitution.

In some preferred embodiments of the present invention, in the compounds of formula I, formula II, formula III, formula IV, formula V, formula VI and formula VII described above, each R is^eEach independently selected from hydrogen and C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl and 5-10 membered heteroaryl; preferably, each R^eEach independently selected from hydrogen and C₁-C₆Alkyl and C₃-C₇A cycloalkyl group.

In some preferred embodiments of the present invention, in the compounds of formula I, formula II, formula III, formula IV, formula V, formula VI and formula VII described above, each R is^fAnd R^gEach independently selected from hydrogen and C₁-C₆Alkyl and C₃-C₇Cycloalkyl radical, said C₁-C₆Alkyl optionally substituted by one or more NR^hRⁱSubstitution; preferably, each R^fAnd R^gEach independently selected from hydrogen and C₁-C₆Alkyl radical, said C₁-C₆Alkyl optionally substituted by one or more NR^hRⁱSubstitution; or, each pair R^fAnd R^gTogether with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group.

In some preferred embodiments of the present invention, in the compounds of formula I, formula II, formula III, formula IV, formula V, formula VI and formula VII described above, each R is^hAnd RⁱEach independently selected from hydrogen and C_1-C₄An alkyl group.

In some preferred embodiments of the present invention, in the compounds of formula I, formula II, formula III, formula IV, formula V, formula VI and formula VII described above, each R is^jEach independently selected from halogen, hydroxy, cyano and 3-6 membered heterocyclyl; preferably, each R^jEach independently selected from halogen and hydroxyl.

In some embodiments, in the compounds of formula I above,

a is C₆-C₁₄Aryl, preferably C₆-C₁₀An aryl group;

R⁴and R⁵Each independently selected from hydrogen, halogen, cyano, nitro, NHC (O) R^a、NHC(O)OR^a、NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Alkoxy radical, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Each alkoxy group is optionally substituted with one or more R^dSubstitution; preferably hydrogen, NR^bR^c、C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Alkoxy radical, said C₃-C₇Cycloalkyl, 3-7 membered heterocyclyl and C₁-C₆Each alkoxy group is optionally substituted with one or more R^dAnd (4) substitution.

In some embodiments, in the compounds of the structures of formula I, formula II, formula III, formula IV, and formula V described above,

R¹is selected from C₁-C₆Alkoxy, cyano, nitro, P (O) R^bR^c、C(O)NR^bR^c、S(O)₂R^aAnd S (O)₂NR^bR^c；

R²Selected from hydrogen and C₁-C₆An alkyl group;

R³selected from hydrogen, halogen, cyano, nitro, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and C₁-C₆An alkoxy group.

In some embodiments, in the compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, and formula VII described above,

each R^aEach independently selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl, preferably C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and C₆-C₁₀An aryl group;

each R^bAnd R^cEach independently selected from hydrogen and C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 4-7 membered heterocyclyl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 4-7 membered heterocyclyl are each optionally substituted with one or more R^dSubstitution; preferably hydrogen and C₁-C₆Alkyl radical, said C₁-C₆Alkyl is optionally substituted by one or more R^dSubstitution; or, each pair R^bAnd R^cTogether with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl;

each R^dEach independently selected from hydrogen, hydroxy, halogen, cyano, nitro, NR^fS(O)₂R^g、NR^fR^g、NR^fC(O)R^g、C₁-C₆Alkyl radical, C₁-C₆Alkoxy and C₃-C₇A cycloalkyl group.

In some embodiments, in the compounds of the structures of formula I, formula II, formula III, and formula IV described above,

x is CR⁷；

R⁷Selected from hydrogen, halogen, cyano, nitro,C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and C₁-C₆An alkoxy group.

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:

process for the preparation of compounds

The present invention provides a process for the preparation of a compound of formula I, comprising the steps of:

1) reacting the compound I-1 with the compound I-2 to obtain a compound I-3;

wherein the content of the first and second substances,

R¹、R²、R³、R⁴、R⁵、R⁶and X is as defined above;

LG₁and LG₂Represents a leaving group, each independently selected from a halogen atom (e.g. Cl, Br or I), p-toluenesulfonate (OTs) and trifluoromethanesulfonate (OTf).

In some embodiments of the invention, LG is¹Is a halogen leaving group (e.g., chloro, bromo, or iodo).

In some embodiments of the invention, LG is²Is a halogen leaving group (e.g., chloro, bromo, or iodo).

In some embodiments of the present invention, the reaction in step (1) above is carried out in the presence of a base and a metal catalyst. In some preferred embodiments of the 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' -bis (diphenylphosphino) ferrocene dichloropalladium, 1, 2-bis (diphenylphosphino) ethane dichloropalladium, bis (triphenylphosphine) palladium dichloride, and the like.

In some embodiments of the present invention, the reaction in step (2) above is carried out in the presence of a base and a metal catalyst. In some preferred embodiments of the 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' -bis (diphenylphosphino) ferrocene dichloropalladium, 1, 2-bis (diphenylphosphino) ethane dichloropalladium, bis (triphenylphosphine) palladium dichloride, and the like.

It will be appreciated by those skilled in the art that one or more steps of the above-described production method may be omitted, the order of reaction steps may be appropriately adjusted, and protection/deprotection reaction steps may be added or omitted as necessary, depending on the structure of the product desired to be obtained.

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

Pharmaceutical composition

The term "pharmaceutical composition" refers to a composition that can be used as a medicament, comprising a pharmaceutically active ingredient (API) (or therapeutic agent) and optionally one or more pharmaceutically acceptable carriers, with the purpose of facilitating administration to an organism, facilitating absorption of the active ingredient, and thereby exerting biological activity. The term "pharmaceutically acceptable carrier" refers to an excipient that is administered with a therapeutic agent, and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable carriers that may be used in the present invention include, but are not limited to, a) diluents; b) a lubricant; c) a binder; d) a disintegrant; e) absorbents, coloring, flavoring and sweetening agents; f) an emulsifier or dispersant; and/or g) an agent that enhances absorption of the compound.

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 (e.g., hydrate), isotopic label, metabolite, prodrug, or a mixture of any two or more thereof.

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

In some embodiments of the invention, the above pharmaceutical compositions may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular, inhalation routes or by all means well known to those skilled in the art of medicine. The pharmaceutical compositions described above may be administered in combination with at least one other therapeutic agent having a therapeutic effect on a disease or condition.

In some embodiments of the invention, the above routes of administration may be achieved by suitable dosage forms. Dosage forms that may 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, and the like.

In some embodiments of the present invention, the above pharmaceutical composition may comprise 0.01mg to 1000mg 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 (e.g., hydrate), isotopic label, metabolite, prodrug, or mixture of any two or more thereof.

The present invention also provides a process for the preparation of the above pharmaceutical composition or corresponding formulation forms thereof, 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 a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (e.g. hydrate), isotopic label, metabolite, prodrug or mixture of any two or more thereof, with one or more pharmaceutically acceptable carriers.

Medicine and food additive

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

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 disease of interest or one or more symptoms thereof.

The present invention provides a pharmaceutical product comprising:

a) a container;

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 (e.g., hydrate), isotopic label, metabolite, prodrug, or mixture of any two or more thereof, or a pharmaceutical composition, in a container; and

c) optionally packaging and/or instructions.

The specification lists the relevant information of the active pharmaceutical ingredients or the pharmaceutical compositions in the medicine, and preferably specifically lists the indications that the active pharmaceutical ingredients or the pharmaceutical compositions are approved to be used. The instructions are printable materials (e.g., paper, plastic, metal foil, adhesive paper, etc.) on which the desired information can be formed (e.g., printed or applied).

In some embodiments of the present invention, the above pharmaceutical product may comprise 0.01mg to 1000mg 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 (e.g., hydrate), isotopic label, metabolite, prodrug, or mixture of any two or more thereof.

The present invention also provides a process for the preparation of the above mentioned pharmaceutical product, 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 a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate (e.g. hydrate), isotopic label, metabolite, prodrug, or mixture of any two or more thereof, or a pharmaceutical composition, with a container and optionally packaging and/or instructions.

Medical application

The compound of the invention can show strong inhibition effect on HPK1, and can be used as an HPK1 inhibitor. Accordingly, the present invention provides a 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 (e.g. hydrate), isotopic label, metabolite, prodrug, or mixture of any two or more thereof, or a pharmaceutical composition, or a medicament, for use as an inhibitor of HPK 1. Preferably, the HPK1 inhibitor may be used for the prevention and/or treatment of a disease or condition (especially a tumor) mediated at least in part by HPK 1.

In addition, the present invention provides a use of a 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 (e.g., hydrate), isotopic label, metabolite, prodrug, or a mixture of any two or more thereof, or a pharmaceutical composition, or a pharmaceutical product, in the manufacture of a medicament for the prevention and/or treatment of a disease or condition mediated at least in part by HPK1 (or an HPK 1-related disease, particularly a tumor).

The term "a disease or condition mediated at least in part by HPK1 (or HPK1 related disease)" refers to a disease whose pathogenesis includes at least a portion of the factors associated with HPK1, including, but not limited to, neoplastic diseases.

Method of treatment

The present invention provides a method for the prevention and/or treatment of a disease mediated at least in part by HPK1, in particular a tumour, comprising the steps of: administering to an individual in need thereof a prophylactically 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 (e.g., hydrate), isotopic label, metabolite, prodrug, or mixture of any two or more thereof, or a pharmaceutical composition, or a pharmaceutical product.

The term "effective amount" refers to an amount of a compound that, when administered, will alleviate one or more symptoms of the condition being treated to some extent. The dosing regimen may be adjusted to provide the best response. For example, it may be administered in a single dose, may be administered in divided doses over time, or may be administered after proportionally decreasing or increasing the dose as the case may be. It will be appreciated that for any particular individual, the specific dosage regimen will be adjusted as required and at the discretion of the attendant person. In addition, a distinction is also made between prophylactic and therapeutic applications. In prophylactic applications, relatively low doses are typically administered chronically at relatively long intervals. In therapeutic applications, then, relatively high doses are typically administered at relatively short intervals until the progression of the disease is delayed or halted, preferably until the individual exhibits a partial or complete improvement in symptoms.

In the present invention, suitable in vitro or in vivo assays are performed to determine the efficacy of the compounds, pharmaceutical compositions and/or medicaments and whether administration is suitable for treating a disease or condition in an individual. Examples of such assays are described in the non-limiting examples below. Typically, an effective amount of a compound sufficient to achieve a prophylactic and/or therapeutic effect is from about 0.001 mg/kg body weight/day to about 10,000 mg/kg body weight/day. Where appropriate, an effective amount is from about 0.01 mg/kg body weight/day to about 1,000 mg/kg body weight/day. In more general terms, an effective amount is about 0.01 to 1,000 mg/kg body weight per day, every second day, or every third day, preferably about 0.1 to 500 mg/kg body weight. Exemplary treatment regimens are once every two days or once a week or once a month.

The term "treating" refers to reversing, alleviating or eliminating the disease or disorder in question. A subject is successfully "treated" if the subject receives a therapeutic amount of a compound of the invention or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the invention, and the subject exhibits an observable and/or detectable remission and/or improvement of at least one of the indications and symptoms. It is understood that treatment includes not only complete treatment, but also less than complete treatment, but achieves some biologically or medically relevant result. In particular, "treatment" means that the compound of the invention or a pharmaceutically acceptable form thereof or the pharmaceutical composition of the invention can achieve at least one of the following effects: (1) preventing disease from occurring in an animal that may be predisposed to the disease but has not yet experienced or exhibited disease pathology or symptomology; (2) inhibiting disease in an animal experiencing or exhibiting disease pathology or symptomatology (i.e., arresting further development of pathology and/or symptomatology); (3) ameliorating the disease (i.e., reversing pathology and/or symptomatology) in an animal experiencing or exhibiting disease pathology or symptomatology.

The term "administering" refers to the process of applying a pharmaceutically active ingredient (such as a compound of the invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (e.g., a pharmaceutical composition of the invention) to an individual or a cell, tissue, organ, biological fluid, etc. site thereof, such that the pharmaceutically active ingredient or pharmaceutical composition contacts the individual or a cell, tissue, organ, biological fluid, etc. site thereof. Common modes of administration include, but are not limited to, oral administration, subcutaneous administration, intramuscular administration, intraperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, and the like.

The term "in need thereof" refers to a judgment by a physician or other caregiver that an individual needs or will benefit from a prophylactic and/or therapeutic procedure, the judgment being made based on various factors within the physician's or other caregiver's expertise.

The term "individual" (or subject) refers to a human or non-human animal. The subject of the invention includes both subjects (patients) suffering from a disease and/or disorder and normal subjects. Non-human animals of the invention include all vertebrates, e.g., non-mammals, such as birds, amphibians, reptiles, and the like, and mammals, e.g., non-human primates, livestock, and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, and the like).

In order to make the objects and technical solutions of the present invention clearer, embodiments of the present invention will be described in detail below with reference to examples. It will be understood by those skilled in the art that the following examples are illustrative of the present invention only and should not be taken as limiting the scope of the invention.

The reagents and instruments used in the examples are not indicated by the manufacturer, and are all conventional products commercially available. Those who do not have specific conditions noted are conducted under conventional conditions or conditions recommended by the manufacturer. The term "room temperature" as used herein means 20 ℃. + -. 5 ℃. As used herein, the term "about" when used to modify a value or range of values refers to the range of error that is acceptable to one skilled in the art including the value or range of values and the value or range of values, for example, the range of error is ± 10%, ± 5%, ± 4%, ± 3%, ± 2%, ± 1%, ± 0.5%, etc. Unless otherwise stated, concentrations are by weight and ratios (including percentages) are by mole.

In the conventional syntheses as well as in the examples and intermediate syntheses, the meanings of the abbreviations are shown in the following table.

The structures of the compounds described in the following examples were confirmed by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS).

NMR) was measured using a Bruker 400MHz NMR spectrometer, and the solvent was deuteratedMethanol (CD)₃OD), deuterated chloroform (CDCl)₃) Deuterated dimethyl sulfoxide (DMSO-d)₆) Or heavy water (D)₂O), internal standard substance Tetramethylsilane (TMS).

Abbreviations in the Nuclear Magnetic Resonance (NMR) data in the following examples represent the following meanings:

s: unimodal (singlet), d: doublet (doublt), t: triplet (triplet), q: quartet (quartz), dd: doublet (doubledoubledoublet), qd: quartet doubtet, ddd: double doublet (double doublet), ddt: double double triplet (double double triple), dddd: double double doublet (double double doublet), m: multiplet (multiplex), br: broad (broad), J: coupling constant, Hz: hertz, δ: chemical shift.

All chemical shift (δ) values are given in parts per million (ppm).

The reaction was monitored by Thin Layer Chromatography (TLC) or liquid chromatography-mass spectrometry (LC/MS). TLC was performed using silica GF 254 as the stationary phase and LC/MS was performed using an Aglient 1260Infinity/Aglient 6120 Quadrupole.

The microwave reaction was carried out using a BiotageInitiator + microwave synthesizer.

The column chromatography uses 200-300 mesh silica gel (Qingdao ocean chemical Co., Ltd.) as a stationary phase, and the system of the eluent comprises: a: petroleum ether/ethyl acetate; b: dichloromethane/methanol, the volume ratio of the solvent can be adjusted according to the polarity of the compound.

Preparative high performance liquid chromatography (Prep-HPLC) was performed using Agilent model 1260, Waters model 2489 or GeLai model 3500 chromatography.

Unless otherwise stated, the reaction temperature in the following examples is room temperature (20 to 30 ℃ C.)

Unless otherwise indicated, the reagents in the following examples were purchased from Acros Organics, Aldrich Chemical Company, Tex Chemical, and the like.

[ preparation of Compound ]

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

The first step is as follows: 3- (2-Aminopyridin-4-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (1b)

4-Bromopyridin-2-amine (1a,1.5g,8.67mmol), 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (3.07g,10.40mmol), Pd (dppf) Cl₂·CH₂Cl₂(707.47mg, 867. mu. mol) and K₂CO₃(2.99g,21.67mmol) was added to 1, 4-dioxane (50mL) and water (10mL) in N₂Heating to 90 ℃ under protection, and reacting for 5 h. After the reaction was completed, the reaction mixture was filtered through celite, 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).

MS(ESI):m/z 262.0[M+H]⁺。

The second step is that: 3- (2-Aminopyridin-4-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (1c)

Compound 1b (2.1g,8.04mmol) was dissolved in methanol (50mL) and 10% Pd/C (975.99mg,8.04mmol) was added in H₂And reacting for 7h at room temperature under protection. After the reaction was completed, the reaction solution was filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain a crude product of compound 1c (2.0g), which was used in the next reaction without purification.

MS(ESI):m/z 264.1[M+H]⁺。

The third step: 3- (2- ((4, 5-dichloropyridin-2-yl) amino) pyridin-4-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (1d)

Compound 1c (1.21g,4.60mmol), 2,4, 5-trichloropyridine (700mg,3.84mmol) and Pd₂(dba)₃(351.36mg, 383.70. mu. mol), Xantphos (444.03mg, 767.40. mu. mol) and Cs₂CO₃(3.13g,959mmol) was added to 1, 4-dioxane (100mL) under N₂Heating to 75 ℃ under protection, and reacting for 18 h. After the reaction was completed, the reaction mixture was filtered through celite, 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).

MS(ESI):m/z 408.9[M+H]⁺。

The fourth step: 3- (2- ((5-chloro-4- ((2- (dimethylphosphoryl) phenyl) amino) pyridin-2-yl) amino) pyridin-4-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (1e)

Compound 1d (300mg, 732.94. mu. mol), (2-aminophenyl) dimethylphosphine oxide (247.97mg,1.47mmol), Pd₂(dba)₃(67.12mg, 73.29. mu. mol), Brettphos (78.67mg, 146.59. mu. mol) and Cs₂CO₃(597.02mg,1.83mmol) was added to toluene (5mL) under N₂Heating to 120 ℃ under protection, and reacting for 6 h. After the reaction was completed, the reaction mixture was filtered through celite, 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).

MS(ESI):m/z 541.9[M+H]⁺。

The fifth step: (2- ((5-chloro-2- ((4- (pyrrolidin-3-yl) pyridin-2-yl) amino) pyridin-4-yl) amino) phenyl) dimethylphosphine oxide (Compound 1)

Compound 1e (230mg, 424.35. mu. mol) was added to a 4N solution of hydrochloric acid in 1, 4-dioxane (15mL), and the reaction was stirred at room temperature for 4 h. After the reaction is finished, K is used₂CO₃Adjusting the pH value of a system to be 8-9 by using an aqueous solution, evaporating to dryness under reduced pressure to obtain a crude product, and purifying by using a preparative high performance liquid chromatography (instrument model: Agilent 1260; chromatographic column: Waters SunAire Prep C)₁₈OBD (19 mm. times.150 mm. times.5.0. mu.m); temperature of the chromatographic column: 25 ℃; flow rate: 28.0 mL/min; detection wavelength: 214 nm; mobile phase A: acetonitrile; mobile phase B: 0.05% w/v aqueous ammonium bicarbonate; elution gradient: at 0min, 10% v/v A, 90% v/v B; at 16.0min, 90% v/v A, 10% v/v B) to give compound 1(125 mg).

MS(ESI):m/z 441.9[M+H]⁺。

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)。

[ biological evaluation ]

The present invention will be further described and explained below by means of experimental examples, which are not intended to limit the scope of the present invention.

Experimental example 1: compounds were tested for inhibition of HPK1 enzymatic activity.

Reagents and instruments:

MBP(Promega corporation)

ATP-Glo reagent (Promega corporation)

ATP-Glo detection buffer (Promega corporation)

BMG LABTECH (model PHERAStar-FS)

The compounds of the invention were tested for inhibition of HPK1 enzymatic activity using an ATP-Glo assay kit, reagents (HPK1, 5 xkinase buffer, Myelin Basic Protein (MBP), ATP) were purchased from Promega corporation, and the protocol and optimization was recommended based on the instructions for the reagents.

Mu.l of 2.5 XHPK 1(2 ng/. mu.l) was added to the 384 well plates followed by 1. mu.l of the 5 Xseries of concentrations of the test compound, and after the end of the incubation at room temperature, 2. mu.l of 2.5 XMBP (0.25. mu.g/. mu.l)/ATP (25. mu.M) was added and the plates were incubated at room temperature for 1 h. After completion of the incubation, 5. mu.l of ATP-Glo reagent (ATP-Glo reagent) was added to each well, incubated at room temperature, the reaction was terminated, and the remaining ATP was removed. After 40min, 10. mu.l of ATP-Glo detection buffer (ATP-Glo detection buffer) was added to each well, and the reaction was carried out at room temperature for 1 h. After the reaction, the 384-well plate was transferred to a PHERAStar-FS microplate reader (BMG LABTECH) for reading, and the mode was selected: luminescence, data presentation: relative chemiluminescence values RLU (relative Luminescence units).

The inhibition of HPK1 enzymatic activity by the compound was calculated according to the following formula:

inhibition ratio (%) ((RLU)_{Maximum of}-RLU_{Blank space})-(RLU_{Treatment of}-RLU_{Blank space}))÷(RLU_{Maximum of}-RLU_{Blank space})×100％

Wherein, RLU_{Maximum of}Relative chemiluminescence values for the non-compound treated group; RLU_{Blank space}Is not added with HPK1 and compoundRelative chemiluminescence values of the physical groups; RLU_{Treatment of}Is the relative chemiluminescence value of the compound treatment group.

IC was calculated using Graphpad Prism software by fitting the data to a log (inhibitor concentration) versus normalized response (variable slope) equation₅₀

Compound (I)	IC for HPK1₅₀(nM)
		1	2.01

The test result shows that the compound 1 has higher inhibition on the HPK1 enzymatic activity.

Various modifications of the invention in addition to those described herein 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, including all patents, patent applications, journal articles, books, and any other publications, cited in this application is hereby incorporated by reference in its entirety.

Claims

1. A compound having the structure of formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, prodrug, or a mixture of any two or more thereof,

wherein the content of the first and second substances,

x is selected from CR⁷And N;

if present, eachR is^aEach independently selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 5-10 membered heterocyclyl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 5-10 membered heterocyclyl are each optionally substituted with one or more R^dSubstitution;

if present, each R^dEach independently selected from hydrogen, hydroxy, halogen, oxo, cyano, nitro, C (O) R^e、C(O)OR^e、NR^fS(O)₂R^g、S(O)R^e、S(O)₂R^e、C(O)NR^fR^g、S(O)₂NR^fR^g、NR^fR^g、NR^fC(O)R^g、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₁-C₆alkyleneoxy-C₁-C₆Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl, said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₁-C₆alkyleneoxy-C₁-C₆Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl each independentlyOptionally substituted by one or more R^jSubstitution;

2. A compound according to claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, prodrug, or mixture of any two or more thereof,

wherein the content of the first and second substances,

a is C₆-C₁₄Aryl, preferably C₆-C₁₀An aryl group;

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, prodrug, or a mixture of any two or more thereof,

wherein the content of the first and second substances,

R²Selected from hydrogen and C₁-C₆An alkyl group;

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, prodrug, or mixture of any two or more thereof,

wherein the content of the first and second substances,

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, prodrug, or a mixture of any two or more thereof,

wherein the content of the first and second substances,

x is CR⁷；

R⁷Selected from hydrogen, halogen, cyano, nitro, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and C₁-C₆An alkoxy group.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, prodrug, or mixture of any two or more thereof, which is a compound having the structure of formula IV,

wherein, X, R¹、R²、R³、R⁴、R⁵And R⁶As defined in any one of claims 1 to 5.

7. The compound of claim 6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, prodrug, or a mixture of any two or more thereof, which is a compound having the structure of formula V,

wherein R is¹、R²、R³、R⁴、R⁵And R⁶As defined in claim 6.

8. The compound of claim 7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, prodrug, or mixture of any two or more thereof, which is a compound having the structure VI,

wherein R is¹、R³、R⁴、R⁵And R⁶As defined in claim 7.

9. A compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, prodrug, or mixture of any two or more thereof,

10. a process for the preparation of a compound having the structure of formula I according to claim 1, comprising the steps of:

1) reacting the compound I-1 with the compound I-2 to obtain a compound I-3;

wherein the content of the first and second substances,

R¹、R²、R³、R⁴、R⁵、R⁶and X is as defined in claim 1;

LG₁and LG₂Represents a leaving group, each independently selected from a halogen atom, a p-toluenesulfonate group and a trifluoromethanesulfonate group.

11. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, prodrug, or mixture of any two or more thereof, in the manufacture of a medicament for the prevention and/or treatment of a disease or condition mediated at least in part by HPK 1.