WO2022228489A1 - Hpk1 inhibitor and application thereof in medicine - Google Patents

Abstract

The present invention relates a novel compound having cancer treatment activity. The present invention also relates to a preparation method for the compound and a pharmaceutical composition containing the compound.

Description

HPK1 inhibitor and its application in medicine technical field

The present invention relates to an HPK1 inhibitor having cancer therapeutic activity. The present invention also relates to methods for the preparation of these compounds and pharmaceutical compositions containing them.

Background technique

Hematopoietic progenitor kinase 1 (HPK1), also known as mitogen-activated protein kinase kinase kinase 1 (mitogen-activated protein kinase kinase kinase kinase 1, MAP4K1), is a member of the serine/threonine kinase subfamily Ste20. Its family members also include MAP4K2 (GCK), MAP4K3 (GLK), MAP4K4 (HGK), MAP4K5 (KHS) and MAP4K6 (MINK). HPK1 is a negative regulator of the activation response of B cells, T cells and dendritic cells. Inhibiting its expression can specifically improve the body's anti-tumor immunity. It is mainly expressed in hematopoietic cells, such as T cells, B cells, and dendritic cells. cells, macrophages, mast cells, and neutrophils.

In T cells, HPK1 regulates T cell activation through the TCR signaling pathway. After TCR activation, HPK1 interacts with T cell receptor proteins, is phosphorylated by tyrosine kinases Zap70 and Lck, and phosphorylates SLP-76 receptor protein, which negatively regulates TCR signaling, thereby inhibiting T cell activation and proliferation. Studies have found that HPK1 can participate in many signaling cascades, including MAKP signaling pathway, Fas-induced apoptosis pathway and NF-κB signaling pathway. Moreover, HPK1 can also inhibit AP-1, which plays a role in promoting cell proliferation, inhibiting differentiation, and promoting tumor cell invasion and metastasis during tumor formation and development.

Therefore, drugs targeting HPK1 have become one of the hot areas of current drug research and development, and some varieties have entered the clinical stage. However, there are currently no drugs on the market targeting hematopoietic progenitor kinase (HPK1). The present invention will provide a small molecule HPK1 inhibitor with a novel structure, which has good antitumor activity.

SUMMARY OF THE INVENTION

The present invention provides a compound represented by the general formula (I), its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt:

in,

R ₁ is selected from H, halogen, -CN, -NO ₂ , -OR _b , -SR _b , -SO ₂ R _b , -SO ₂ NR _b R _c , -COR _b , -CO ₂ R _b , -CONR _b R _c , -NR _b R _c , -NR _b COR _c , -NR _b CO ₂ R _c , -NR _b SONR _c R _d , -NR _b SO ₂ NR _c R _d , -NR _b SO ₂ R _c , C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-12 membered aryl or 5-12 membered heteroaryl , the C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-12 cycloalkyl group, 3-12-membered heterocyclic group, C _6-12 aryl group, 5-12 A membered heteroaryl, R _b , R _c or R _d is optionally substituted with at least one R _1a ;

R ₂ , R ₃ are independently selected from H, halogen, -CN, -OH, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl or cyclopropyl, the C _1-4 Alkyl, C _2-4 alkenyl, C _2-4 alkynyl, cyclopropyl are optionally substituted with at least one R _a ;

L ₁ is selected from a bond, O, S or NR _a ;

R ₄ is selected from C _0-3 alkylene-C _3-12 cycloalkyl or C _0-3 alkylene-3-12 membered heterocyclic group, the C _0-3 alkylene-C _3-12 cycloalkyl or C _0-3 alkylene-3-12 membered heterocyclyl optionally substituted with at least one R _4a ;

X ₁ is selected from O, NR ₅ or C(R ₅ ) ₂ ;

X ₂ is selected from O, NR ₆ or C(R ₆ ) ₂ ;

_{X3 is} selected from N or _CR7 ;

_{X4 is} selected from N or _CR8 ;

_X5 is selected from N or _CR9 ;

R ₅ , R ₆ , R ₇ , R ₈ , R ₉ are each independently selected from H, halogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkane base, 3-12-membered heterocyclic group, C _6-12 -membered aryl, 5-12-membered heteroaryl, oxo, -CN, -NO ₂ , -OR _b , -SR _b , -SO ₂ R _b , -SO ₂ NR _b R _c , -COR _b , -CO ₂ R _b , -CONR _b R _c , -NR _b R _c , -NR _b COR _c , -NR _b CO ₂ R _c , -NR _b SONR _c R _d , -NR _b SO ₂ NR _c R _d or -NR _b SO ₂ R _c , the C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl , 3-12 membered heterocyclyl, _C6-12 aryl, 5-12 membered heteroaryl, R _b , R _c or R _d are optionally substituted with at least one R _a ;

Or 2 R ₆ together with the attached atoms form C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-12 aryl or 5-12 membered heteroaryl, the C _3-12 cycloalkane radical, 3-12 membered heterocyclyl, _C6-12 membered aryl or 5-12 membered heteroaryl optionally substituted with one or more _R6a substituents;

R _1a , R _4a , R _6a , R _a are independently selected from H, halogen, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _{3 -12} cycloalkyl, 3-12 membered heterocyclyl, C _6-12 aryl, 5-12 membered heteroaryl, oxo, -CN, -NO ₂ , -OR _b , -SR _b , -SO ₂ R _b , -SO ₂ NR _b R _c , -COR _b , -CO ₂ R _b , -CONR _b R _c , -NR _b R _c , -NR _b COR _c , -NR _b CO ₂ R _c , -NR _b SONR _c R _d , -NR _b SO ₂ NR _c R _d or -NR _b SO ₂ R _c , the C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _{2 -8} alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-12 membered aryl or 5-12 membered heteroaryl optionally selected from H, halogen, hydroxy, _{C1- 8} alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-12 membered aryl, 5-12 membered heteroaryl, oxygen substituted group, -CN, -NO ₂ , R _b , -OR _b , -SR _b , -SO ₂ R _b , -SO ₂ NR _b R _c , -COR _b , -CO ₂ R _b , -CONR _b R _{c at least one substitution of} , _{-NRbRc , -NRbCORc , -NRbCO2Rc , -NRbSONRcRd , -NRbSO2NRcRd , or -NRbSO2Rc} base substituted;

R _b , R _c , R _d are independently selected from H, amino, hydroxy, oxo, C _1-8 alkoxy, C _1-8 alkyl, C _1-8 hydroxyalkyl, C _1-8 amino Alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-12 aryl or 5-12 membered heteroaryl, the C _1-8 alkoxy, C _1-8 alkyl, C _1-8 hydroxyalkyl, C _1-8 aminoalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-6 ring Alkyl, 3-6 membered heterocyclyl, _C6-12 membered aryl or 5-12 membered heteroaryl optionally selected from H, halogen, hydroxy, _{C1-8 alkyl, C1-8 alkoxy} base, C _1-8 hydroxyalkyl, C _1-8 aminoalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _{6 -12} aryl, 5-12 membered heteroaryl, oxo, -CN, -NO ₂ , -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl _{) 2 ,} -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -COC _1-6 alkyl, -COO C _1-6 alkyl substituted with at least one substituent.

In some embodiments, R ₁ in formula (I) is selected from H, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-12 aryl or _5-12 A membered heteroaryl, the _C2-8 alkynyl, 3-12 membered heterocyclyl, _C6-12 membered aryl or 5-12 membered heteroaryl is optionally substituted with 1-4 R _1a .

In some embodiments, R _1a in formula (I) is selected from H, halogen, C _1-8 alkoxy, oxo, C _1-6 alkyl, C _{1-6 cyanoalkyl} , C _{1- 6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, -CONR _b R _c , -COR _b , -CO ₂ R _b , -OR _b , -SO ₂ NR _b R _c , -NR _b R _c , C _3-12 cycloalkyl, hydroxy-substituted C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _1-6 alkyl substituted heterocyclyl,

The R _b or R _c is independently selected from H, amino, hydroxy or C _1-6 alkyl.

In some embodiments, R ₂ in formula (I) is selected from H or C _1-3 alkyl, preferably H.

In some embodiments, R ₃ in formula (I) is selected from H or C _1-3 alkyl, preferably H.

In some embodiments, R4 in _formula (I) is a 3-12 membered heterocyclyl optionally further substituted with 1-4 _R4a .

In some embodiments, R _4a in formula (I) is selected from H or C _1-3 alkyl, preferably C _1-3 alkyl.

In some embodiments, L ₁ in formula (I) is a bond.

In some embodiments, X ₁ in formula (I) is selected from O, NH or CH ₂ .

In some embodiments, X in _formula (I) is selected from O, NH, _CH or

In some embodiments, X ₃ in formula (I) is selected from N or CR ₇ , and R ₇ is selected from H, halogen or C _1-3 alkyl.

In some embodiments, X ₄ in formula (I) is selected from N or CR ₈ , and R ₈ is selected from H, halogen or C _1-3 alkyl.

In some embodiments, X ₅ in formula (I) is selected from N or CR ₉ , and R ₉ is H.

In some embodiments, the compound in formula (I) is selected from the compound shown in formula (I-1) or (I-2),

R ₁ -R ₉ are as defined in any one of formula (I).

In some embodiments, the compound represented by formula (I) is selected from,

The present invention also provides a pharmaceutical composition, characterized in that, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound represented by formula (I) and at least one pharmaceutically acceptable adjuvant.

The present invention further provides a pharmaceutical composition, characterized in that the therapeutically effective amount of at least one compound represented by formula (I) and a pharmaceutically acceptable auxiliary material are in a mass percentage of 0.0001:1-10.

The present invention provides the application of the compound represented by the structural formula (I) or the pharmaceutical composition in the preparation of medicine.

The present invention further provides the preferred technical solution of the application:

Preferably, the application is in the preparation of a drug for treating and/or preventing cancer.

Preferably, the application is for the preparation of a medicament for treating diseases mediated by HPK1. Preferably, the disease is cancer.

Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophagus Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumor, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell Carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.

The present invention also provides a method for treating and/or preventing a disease, comprising administering a therapeutically effective amount of at least any compound represented by structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.

The present invention also provides a method for treating and/or preventing diseases mediated by HPK1, comprising administering a therapeutically effective amount of at least any compound represented by structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.

The present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of at least any compound represented by the structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.

Preferably, in the above method, the HPK1-mediated disease is cancer.

Preferably, in the above method, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic Lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cells tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.

Unless otherwise indicated, general chemical terms used in the structural formulae have their ordinary meanings.

For example, unless otherwise specified, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.

In the present invention, unless otherwise specified, "alkyl" includes linear or branched monovalent saturated hydrocarbon groups. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, " _1-8 " in "C _1-8 alkyl" refers to a group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in straight or branched chain form group.

"Alkoxy" refers to the oxyether form of the aforementioned straight or branched chain alkyl groups, ie, -O-alkyl.

The term "alkylene" refers to a divalent alkyl linking group. Alkylene formally refers to an alkane in which two CH bonds are replaced with the point of attachment of the alkylene to the rest of the compound. Similarly, "C _1-3 " in C _1-3 alkylene refers to an alkylene group containing 1, 2 or 3 carbon atoms, including but not limited to methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylidene.

In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.

The term "haloalkyl" refers to an alkyl group in which one or more Hs have been replaced by halogen atoms.

The term "haloalkoxy" refers to the group -O-haloalkyl.

The term "oxo" or "oxo" refers to an oxygen atom in the form of a divalent substituent which, when attached to C, forms a carbonyl group, which, when attached to a heteroatom, forms a sulfoxide or sulfone or N-oxide group group.

In the present invention, unless otherwise specified, the terms "aromatic ring", "aromatic ring" or "aromatic heterocycle" refer to those having aromatic characteristics (having (4n+2) delocalized π electrons, where n is carbocyclic or heterocyclic polyunsaturated ring of an integer).

The term "aryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted mono- or fused-ring aromatic group comprising atoms of a carbocyclic ring. A _C6-12 aryl group is preferred, and a monocyclic or bicyclic aromatic ring group in which the aryl group is _C6-10 is more preferred. Preferred are phenyl and naphthyl. Most preferred is phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples including, but not limited to, benzocyclopentyl.

The term "heterocyclyl" refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heteroatom selected from N, O and/or S. The heterocyclyl group may include monocyclic or polycyclic rings (eg, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). A heterocyclyl group can be attached to the rest of the compound via a ring carbon atom or a ring heteroatom. A 3-12-membered heterocyclic group is preferred, and "3-12-membered" in the 3-12-membered heterocyclic group refers to a heterocyclic group consisting of 3-12 ring atoms of C, N, O or S; more preferably 3-8 membered heterocyclic group, more preferably 3-6 membered heterocyclic group. Wherein nitrogen or sulfur heteroatoms can be selectively oxidized, and nitrogen heteroatoms can be selectively quaternized. Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro oxadiazolyl. The heterocyclyl group can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl group.

The term "heteroaryl", in the present invention, unless otherwise specified, refers to a monocyclic or polycyclic (eg, fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O and/or S, and wherein the nitrogen or sulfur heteroatom can be selectively oxidized, and the nitrogen heteroatom can be selectively quaternized. A 5-18-membered heteroaryl group is preferred, wherein "5-18-membered" in the 5-18-membered heteroaryl group refers to a heteroaryl group consisting of 5-18 ring atoms of C, N, O or S. More preferred is a 5-10 membered heteroaryl; more preferred is a 5-6 membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene thiadiazolyl, benzotriazolyl adenine, quinolinyl or isoquinolinyl. The heteroaryl group can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.

The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. A C _3-12 cycloalkyl group is preferred, wherein "C 3-12 " means that the cycloalkyl group may have ₃ , 4, 5, 6, 7, 8, 9, 10, 11 or ₁₂ ring atoms. Cycloalkyl groups can include monocyclic and polycyclic rings (eg, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). In some embodiments, the cycloalkyl group includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group can also be fused to an aryl, heterocyclyl or heteroaryl ring, where it is related to the parent structure. The rings joined together are cycloalkyl groups.

The term "substituted" refers to the replacement of one or more hydrogen atoms in a group with the same or a different substituent, respectively. Typical substituents include, but are not limited to, halogen (F, Cl, Br or I), C _1-8 alkyl, C _3-12 cycloalkyl, -OR ¹ , -SR ¹ , =O, =S, -C (O)R ₁ , -C(S)R ¹ , =NR ¹ , -C(O)OR ¹ , -C(S)OR ¹ , -NR ¹ R ² , -C(O)NR ¹ R ² , cyano, nitro, -S(O) ₂ R ¹ , -OS(O ₂ )OR ¹ , -OS(O) ₂ R ¹ , -OP(O)(OR ¹ )(OR ² ); wherein R ¹ and R ² are independently selected from -H, C _1-6 alkyl, C _1-6 haloalkyl, or C _3-6 cycloalkyl. In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy, tert-butoxy, -SCH ₃ , -SC ₂ H ₅ , carboxaldehyde, -C(OCH ₃ ), cyano, nitro, -CF ₃ , -OCF ₃ , amino, dimethyl amino, methylthio, sulfonyl and acetyl groups.

Examples of substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl , phenylmethyl, dioxinylmethyl and piperazinylmethyl.

Examples of substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-di The term "pharmaceutically acceptable salt" refers to a non-toxic pharmaceutically acceptable base or salt prepared from acid.

When the compounds provided herein are acids, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low), ferric, ferrous, lithium, magnesium, manganese (high and low), potassium, sodium, zinc, and the like. The ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Nontoxic organic bases that can be derivatized into pharmaceutically acceptable salts include primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable nontoxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine Acid, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine Wait.

When the compounds provided by the present invention are bases, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, Cyclohexamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid, etc. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid.

Since the compound represented by formula (I) will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% pure, more suitably at least 75% pure, particularly suitably at least 98% pure (% by weight) Compare).

Prodrugs of the compounds of the present invention are included within the scope of the present invention. In general, the prodrugs refer to functional derivatives that are readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester or other derivative of a compound of the present application which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite thereof or Residues.

The compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers and pharmaceutically acceptable salts thereof.

When the compound represented by formula (I) exists as a tautomer, unless otherwise stated, the present invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof.

Substitution of compounds of formula (I) with heavier isotopes (eg deuterium) may provide certain therapeutic advantages due to greater metabolic stability, eg increased in vivo half-life or reduced dosage requirements.

When the compounds of formula (I) and their pharmaceutically acceptable salts exist as solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone and similar solvents can be used.

The term "composition", in the present invention, refers to a product comprising a specified amount of each of the specified ingredients, as well as any product produced directly or indirectly from a combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also within the scope of this invention.

The pharmaceutical composition provided by the present invention includes the compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or adjuvants. Although the most suitable mode of administration of the active ingredient in any given situation will depend on the particular subject being administered, the nature of the subject and the severity of the condition, the pharmaceutical compositions of the present invention include oral, rectal, topical and Pharmaceutical compositions for parenteral (including subcutaneous, intramuscular, intravenous) administration. The pharmaceutical compositions of the present invention may conveniently be presented in unit dosage form and prepared by any of the methods of preparation well known in the art of pharmacy.

Synthesis Scheme 1:

Step I: Compounds

Under the action of NBS, compound A-1 is obtained through bromine substitution reaction;

Step II: Compound A-1 and TosCl are added with a Tos protecting group under the action of a strong base such as sodium hydride;

Step III: Compound A-2 with

Under the action of a metal catalyst such as [PdCl ₂ (dppf)]CH ₂ Cl ₂ , it is introduced through Suzuki coupling reaction

Compound I-3 is obtained; Cyc is a C _3-12 -membered cycloalkyl group, a 3-12-membered heterocyclic group, a C _6-12 -membered aryl group or a _5-12 -membered heteroaryl group;

Step IV: Compound A-3 removes the Boc protecting group under the action of strong acid such as TFA;

Step V: Compound A-4 and formaldehyde are introduced into R _4a through reductive amination reaction under the action of a reducing agent such as NaBH(OAc) ₃ to obtain compound A-5;

Step VI: compound A-5 is hydrolyzed by ester bond under acidic conditions such as hydrochloric acid;

Step VII: Under high temperature conditions, compound A-6 is subjected to self-ring closing reaction to compound A-7 under basic conditions such as cesium carbonate;

Step VIII: Compound A-7 with

Under the action of a metal catalyst such as [PdCl ₂ (dppf)]CH ₂ Cl ₂ , the R ₁ group is introduced through the Suzuki coupling reaction;

Step IX: Compound A-8 can obtain the target compound A by removing the Tos protecting group under the action of basic conditions such as potassium carbonate.

Synthesis Scheme 2:

Step X: Compound A-7 with

Under the action of metal catalyst such as PdCl ₂ (PPh ₃ ) ₂ and CuI, it is introduced through Sonogashira coupling reaction

group;

Step XI: Compound B-1 can obtain the target compound B by removing the Tos protecting group under the action of basic conditions such as potassium carbonate.

Detailed ways

In order to make the above content clearer and clearer, the present invention will further illustrate the technical solutions of the present invention with the following examples. The following examples are only used to illustrate the specific embodiments of the present invention, so that those skilled in the art can understand the present invention, but are not intended to limit the protection scope of the present invention. In the specific embodiments of the present invention, the technical means or methods that are not specifically described are conventional technical means or methods in the field.

All parts and percentages herein are by weight and all temperatures are in degrees Celsius unless otherwise indicated.

The following abbreviations are used in the examples:

DMF: N,N-dimethylformamide;

NBS: N-bromosuccinimide;

NIS: N-iodosuccinimide;

NaH: sodium hydride;

TosCl: p-toluenesulfonyl chloride;

[PdCl ₂ (dppf)]CH ₂ Cl ₂ : [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex;

EA: ethyl acetate;

PE: petroleum ether;

DCM: dichloromethane;

NaBH(OAc) ₃ : sodium triacetoxyborohydride;

MeOH: methanol;

DMA: N,N-dimethylacetamide;

Pd(OAc) ₂ : palladium acetate;

BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine;

B2Pin2: pinacol biborate;

Pd ₂ (dba) ₃ : tris(dibenzylideneacetone)dipalladium;

Xphos: 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl;

TosCl: p-toluenesulfonyl chloride;

PdCl ₂ (PPh ₃ ) ₂ : bistriphenylphosphonium palladium dichloride;

TEA: triethylamine;

DMK: acetone;

PdCl ₂ (PPh ₃ ) ₂ : bistriphenylphosphonium palladium dichloride;

NaBH(OAc) ₃ : sodium triacetoxyborohydride;

Synthesis of Intermediate M:

Step 1: Synthesis of Compound M-1

At room temperature, methyl 3-bromobenzoate (45.00 g), tert-butyl piperazine-1-carboxylate (41.31 g), Pd(OAc) ₂ (2.35 g), BINAP (6.52 g), cesium carbonate (136.36 g) was added to toluene (500.00 mL), and then reacted at 100 °C for 1 h under N ₂ protection to stop the reaction. The reaction solution was filtered, the organic phase was concentrated, and the concentrate was separated by silica gel column chromatography (PE:EA=10:1-2:1) to obtain the target product M-1 (55.80 g, yield 83.23%) as a light gray solid. ESI-MS m/z: 321.1 [M+H] ⁺ .

Step 2: Synthesis of Compound M-2

At room temperature, compound M-1 (62.00 g) was dissolved in dichloromethane (700.00 mL), then NBS (41.33 g) was slowly added, and the reaction was performed at room temperature for 0.5 h. 300 mL of water was added to the reaction solution, followed by separation; then extracted with 150 mL*3 DCM; the combined organic phases were washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was separated by column chromatography (PE:EA=10:1-2:1) to obtain the target product M-2 (72.10 g, purity 97.00%, yield 90.51%) as a pale yellow solid. ESI-MS m/z: 399.1 [M+H] ⁺ .

Step 3: Synthesis of Compound M-3

At room temperature, compound M-2 (60.00 g) was dissolved in THF (960.00 mL), then under N ₂ protection, in an ice-water bath, NaBH ₄ (28.42 g) was added in batches, and the reaction was carried out at room temperature for 0.5 h; Methanol (150.00 mL) was added five times at intervals of half an hour. After the addition was completed, the reaction was incubated at room temperature for 1 h. Under ice-water bath conditions, saturated ammonium chloride was slowly added to the reaction solution to quench the reaction; then extracted with 200 mL*3, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the concentrate was Column chromatography (PE:EA:DCM=10:1:1～1:1:1) obtained the target product M-3 (47.50 g, yield 85.14%) as colorless transparent liquid. ESI-MS m/z: 371.1 [M+H] ⁺ .

Step 4: Synthesis of Compound M-4

At room temperature, compound M-3 (54.40 g) was dissolved in DCM (500.00 mL), under _N2 protection, under ice-water bath conditions, triethylamine (40.73 mL) was added, and then acetyl chloride (13.54 mL) was slowly added dropwise mL), slowly warmed to room temperature for 0.5 h, and stopped the reaction. To the reaction solution, 400 mL of saturated sodium bicarbonate was added to quench the reaction, then extracted with 150 mL of DCM * 3, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain the brown liquid target product M-4 ( 60.40 g, 99.74% yield). ESI-MS m/z: 413.1 [M+H] ⁺ .

Step 5: Synthesis of Compound M

Compound M-4 (10.00 g), B ₂ Pin ₂ (18.43 g), Pd ₂ (dba) ₃ (1.11 g), Xphos (1.15 g) and potassium acetate (9.50 g) were added to 1,4-di in oxane (150.00 mL), and then under N ₂ protection, the reaction was carried out at 80 °C for 7 h to stop the reaction. The reaction solution was quenched with water, filtered with celite, then extracted with 200mL*3 of EA, washed with saturated sodium chloride, the organic phase was concentrated, and the concentrate was subjected to column chromatography (PE:EA=20:1～2:1) The target product M (9.23 g, 82.86% purity) was isolated as a black oil. ESI-MS m/z: 461.3 [M+H] ⁺ .

Synthesis of Intermediate N:

Step 1: Synthesis of Compound N-1

4-Chloro-5-iodo-1H-indole (4.80 g) was added to DMF (80.00 mL) at room temperature, NBS (3.23 g) was added in portions at room temperature, and then under _N2 protection , react at room temperature for 1h, stop the reaction. In the reaction solution, 150mL of water was slowly added dropwise to separate out a white solid, then filtered, and the filtered solid was added to 500mL of water, beating, then filtered and the solid was washed with 50mL*2 water and the solid was filtered and dried to obtain a white solid target product ( 6.00 g, yield 97.06%) ie N-1. ESI-MS m/z: 356.8 [M+H] ⁺ .

Step 2: Synthesis of Compound N-2

At room temperature, NaH (0.43 g) was added to DMF (100.00 mL), then N-1 (4.90 g) dissolved in 10 mL of DMF was slowly added under ice-water bath conditions, and then reacted at room temperature for 1 h, under ice-water bath conditions , 10 mL of DMF in TosCl (2.88 g) was slowly added, and then the reaction was performed at room temperature for 2 h to stop the reaction. Under ice-water bath conditions, 100 mL of water was slowly added dropwise to quench the reaction, and then a light yellow solid was precipitated, then filtered, 50 mL of the filter cake was washed, and dried with an infrared lamp to obtain the target product N-2 (6.01 g, purity 98.00%, light yellow solid) yield 83.97%). ESI-MS m/z: 510.8 [M+H] ⁺ .

Step 3: Synthesis of Compound N-3

At room temperature, compound N-2 (5.80 g), intermediate M (6.79 g), [PdCl ₂ (dppf)]CH ₂ Cl ₂ (0.93 g), potassium carbonate (3.13 g) were added to 1,4- Dioxane (100.00 mL) and water (50.00 mL), and then under N ₂ protection, react at 80 °C for 40 min to stop the reaction. The reaction solution was filtered with celite, 50 mL of H ₂ O and 100 mL of EA were added to the reaction solution, and then extracted with EA 60 mL*3, the organic phases were combined, washed with saturated sodium chloride, and subjected to column chromatography (PE: EA=95 : 5～60:40) to obtain the target product N-3 (5.83 g, yield 71.61%) as a light yellow solid. ESI-MS m/z: 717.1 [M+H] ⁺ .

Step 4: Synthesis of Compound N-4

At room temperature, compound N-3 (5.50 g) was added to trifluoroacetic acid (15.00 mL) and dichloromethane (40.00 mL), and then reacted at room temperature for 1 h under N ₂ protection to stop the reaction. Under ice-water bath conditions, slowly add saturated sodium bicarbonate to adjust the pH to 8～9, then extract with DCM 50mL*3, combine the organic phases and wash with saturated sodium chloride, and concentrate the organic phase to obtain pale yellow solid target product N-4( 4.70 g, 99.30% yield). ESI-MS m/z: 617.1 [M+H] ⁺ .

Step 5: Synthesis of Compound N-5

The above compound N-4 (4.70 g) was added to methanol (40.00 mL) and DCM (40.00 mL) at room temperature, then glacial acetic acid (0.10 mL) and aqueous formaldehyde 37% (0.93 mL) were added under _N2 protection g, 37%), react at room temperature for 1 h, then add NaBH(OAc) ₃ (4.84 g), react at room temperature for 2 h, and stop the reaction. Concentrate to remove the reaction solvent, add 50 mL of EA to the reaction solution, then slowly add saturated sodium bicarbonate to adjust the pH to 8-9, then extract with EA 60 mL*3, wash with saturated sodium chloride, concentrate the organic phase, and the concentrate is Column chromatography (DCM:CH ₃ OH=95:5～90:10) gave the target product N-5 (4.30 g, yield 89.46%) as a pale yellow solid. ESI-MS m/z: 631.1 [M+H] ⁺ .

Step 6: Synthesis of Compound N-6

Compound N-5 (4.20 g) was added to hydrochloric acid (30.00 mL) (2M) and MeOH (30.00 mL) at room temperature, and then heated at 60 °C for 3 h under _N2 protection. Saturated sodium bicarbonate was added to the reaction solution to adjust the pH to 8-9, then extracted with EA 30 mL*3, the organic phases were combined, concentrated, and the concentrate was subjected to column chromatography (DCM: CH ₃ OH=95:5-88: 12) The target product N-6 (3.62 g, yield 92.33%) was isolated and obtained as a pale yellow solid. ESI-MS m/z: 589.1 [M+H] ⁺ .

Step 7: Synthesis of Compound N

At room temperature, compound N-6 (100.00 mg), cesium carbonate (165.68 mg) were added to DMA (2.00 mL), and then under N ₂ protection, the reaction was carried out at 100 °C for 1 h. 50 mL of H ₂ O was added to the reaction solution and 50mL (EA:THF=1:1), then extracted with 50mL*3 (EA:THF=1:1), washed with saturated sodium chloride, and the organic phase was concentrated to obtain the crude product, which was subjected to column chromatography (DCM:CH ₃ OH=97:3～85:15) was separated to obtain light yellow solid target product N (2.20g). ESI-MS m/z: 553.1 [M+H] ⁺ .

Example 1: Compound 4-(7-(4-Methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d]pyrro[2,3-b]pyridine-3- Synthesis of phenyl)benzamide

Step 1: Synthesis of Compound 1-1

At room temperature, intermediate N (100.00 mg), (4-carbamoylphenyl)boronic acid (38.75 mg), [PdCl ₂ (dppf)]CH ₂ Cl ₂ (14.78 mg), potassium carbonate (49.95 mg) It was added to 1,4-dioxane (4.00 mL) and water (2.00 mL), and then reacted at 90°C for 20 min under N ₂ protection to stop the reaction. 20 mL of H ₂ O and 20 mL of EA were added to the reaction solution, then extracted with 20 mL of EA*3, the organic phases were combined, washed with saturated sodium chloride, and subjected to column chromatography (DCM: CH ₃ OH=95:5～85:15) The desired product 1-1 (100.00 mg, 93.21% yield) was isolated as a pale yellow solid. ESI-MS m/z: 594.2 [M+H] ⁺ .

Step 2: Synthesis of Compound 1

Compound 1-1 (100.00 mg), potassium carbonate (46.55 mg) were added to tetrahydrofuran (3.00 mL) and methanol (3.00 mL) at room temperature, and then reacted at 25°C for 1 h under _N2 protection. 5mL of water was added to the reaction solution, then extracted with (EA:THF=1:1) 10mL*5, washed twice with saturated sodium chloride, and the organic phase was concentrated to obtain a crude product. The crude product was prepared and separated by Pre-HPLC to obtain a pale yellow solid. Target product 1 (20.30 mg, 27.43% yield). ESI-MS m/z: 440.2 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ )δ12.11(d, J=2.7Hz, 1H), 9.73(s, 1H), 8.74(s, 1H), 7.96(s, 1H), 7.92-7.87( m, 2H), 7.84(d, J=8.6Hz, 1H), 7.72(d, J=8.3Hz, 2H), 7.68(d, J=2.6Hz, 1H), 7.31(s, 1H), 7.08( dd,J＝8.6,2.6Hz,1H),6.95(d,J＝2.6Hz,1H),5.24(s,2H),3.91(d,J＝11.5Hz,2H),3.54(d,J＝11.5 Hz, 2H), 3.20-3.14 (m, 2H), 3.03-2.97 (m, 2H), 2.87 (d, J=3.5Hz, 2H).

Example 2: Compound 5-(7-(4-Methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d]pyrro[2,3-b]pyridine-3- Synthesis of methyl) valerate

Step 1: Synthesis of Compound 2-1

At room temperature, intermediate N (100.00 mg), cuprous iodide (3.45 mg), PdCl ₂ (PPh ₃ ) ₂ (6.32 mg), methyl pentynoate (40.52 mg), triethylamine (0.05 mL) were combined ) was added to DMF (4.00 mL) and reacted at 90°C for 1 h under N ₂ protection. 20 mL of H ₂ O and 20 mL of EA were added to the reaction solution, then extracted with 20 mL (EA:THF=1:1)*3, the combined organic phases were washed 5 times with saturated sodium chloride, and the crude product was subjected to column chromatography (DCM:MeOH). =96:4～90:10), the target product 2-1 (80.00 mg, yield 75.72%) was isolated as a pale yellow solid. ESI-MS m/z: 585.2 [M+H] ⁺ .

Step 2: Synthesis of Compound 2

Compound 2-1 (80.00 mg), potassium carbonate (56.72 mg) were added to tetrahydrofuran (3.00 mL) and methanol (3.00 mL) at room temperature, and then reacted at 25°C for 2 h under N ₂ protection. 5 mL of water was added to the reaction solution, then extracted with (EA:THF=1:1) 10 mL*5, washed twice with saturated sodium chloride, the organic phase was concentrated, and the concentrate was subjected to Pre-TLC (DCM: CH ₃ OH= 4:1) The target product 2 (11.30 mg, purity 99.71%, yield 19.13%) was isolated as a pale yellow solid. ESI-MS m/z: 431.2 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ ) δ 11.84(s, 1H), 8.62(s, 1H), 7.73(d, J=8.6Hz, 1H), 7.49(d, J=2.3Hz, 1H) ,6.96(dd,J=8.7,2.7Hz,1H),6.88(d,J=2.6Hz,1H),5.23(s,2H),3.66(s,3H),3.19-3.16(m,4H), 2.69-2.60(m, 4H), 2.47-2.44(m, 4H), 2.23(s, 3H).

Example 3: Compound 2-methyl-4-(7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d]pyrrole[2,3-b Synthesis of ]pyridin-3-yl)but-3-yn-2-ol

The specific synthesis steps of Example 3 refer to Example 2. ESI-MS m/z: 403.2 [M+H] ⁺ .

Example 4: Compound 3-(2-Fluoro-6-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d ]Pyrro[2,3-b]pyridine Synthesis

The specific synthesis steps of Example 4 refer to Example 1. ESI-MS m/z: 445.2 [M+H] ⁺ .

Example 5: Compound methyl propionate 3-(7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d]pyrrole[2,3-b] Synthesis of Pyridin-3-yl)

The specific synthesis steps of Example 5 refer to Example 2. ESI-MS m/z: 403.2 [M+H] ⁺ .

Example 6: Compound 1-methyl-4-(7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d]pyrrole[2,3-b Synthesis of ]pyridin-3-yl)pyridin-2(1H)-one

The specific synthesis steps of Example 6 refer to Example 1. ESI-MS m/z: 428.2 [M+H] ⁺ .

Example 7: Compound 5-(7-(4-Methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d]pyrro[2,3-b]pyridine-3- Synthesis of yl)pent-4-ynonitrile

The specific synthesis steps of Example 7 refer to Example 2. ESI-MS m/z: 398.2 [M+H] ⁺ .

Example 8: Compound 3-(3-Methoxyprop-1-yn-1-yl)-7-(4-methylpiperazin-1-yl)-1,5-dihydroisochrom[3, Synthesis of 4-d]pyrro[2,3-b]pyridine

The specific synthesis steps of Example 8 refer to Example 2. ESI-MS m/z: 389.2 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ ) δ 11.98 (d, J=2.4 Hz, 1H), 8.65 (s, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.63 (d, J= 2.5Hz, 1H), 6.97(dd, J=8.6, 2.6Hz, 1H), 6.87(d, J=2.6Hz, 1H), 5.25(s, 2H), 4.32(s, 2H), 3.38(s, 3H), 3.19-3.16 (m, 4H), 2.47-2.44 (m, 4H), 2.23 (s, 3H).

Example 9: Compound 2-((3-(7-(4-Methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d]pyrrole[2,3-b] Synthesis of Pyridin-3-yl)prop-2-yn-1-yl)oxy)propanol

The specific synthesis steps of Example 9 refer to Example 2. ESI-MS m/z: 433.2 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ )δ12.05(d,J=2.5Hz,1H),8.70(s,1H),7.82(d,J=8.6Hz,1H),7.66(d,J= 2.7Hz, 1H), 7.06(dd, J=8.6, 2.7Hz, 1H), 6.94(d, J=2.5Hz, 1H), 5.29(s, 2H), 4.39(s, 2H), 3.93-3.89( m,2H),3.83-3.79(m,1H),3.56-3.52(m,2H),3.47-3.44(m,1H),3.39-3.36(m,1H),3.21-3.14(m,2H), 3.04-2.96 (m, 2H), 2.87 (d, J=4.0 Hz, 3H), 1.09 (d, J=6.3 Hz, 3H).

Example 10: Compound 4-(7-(4-Methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d]pyrro[2,3-b]pyridine-3- Synthesis of yl)but-3-yn-2-one

The specific synthesis steps of Example 10 refer to Example 2. ESI-MS m/z: 387.2 [M+H] ⁺ .

Example 11: Compound 5-(7-(4-Methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d]pyrro[2,3-b]pyridine-3- Synthesis of yl)pent-4-yn-2-ol

The specific synthesis steps of Example 11 refer to Example 2. ESI-MS m/z: 403.2 [M+H] ⁺ .

Example 12: Compound 1-(7-(4-Methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d]pyrro[2,3-b]pyridine-3- Synthesis of Hex-1-yn-3-ol

The specific synthesis steps of Example 12 refer to Example 2. ESI-MS m/z: 417.2 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ ) δ 11.90 (s, 1H), 8.63 (s, 1H), 7.74 (d, J=8.6Hz, 1H), 7.55 (d, J=2.7Hz, 1H) ,6.96(d,J＝8.5Hz,1H),6.93-6.89(m,1H),5.28(d,J＝5.6Hz,1H),5.23(s,2H),4.45(q,J＝6.2Hz, 1H), 3.20-3.17(m, 4H), 2.24(s, 3H), 1.70-1.60(m, 2H), 1.58-1.51(m, 2H), 0.97(t, J=7.3Hz, 3H).

Example 13: Compound 4-(7-(4-Methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d]pyrro[2,3-b]pyridine-3- Synthesis of yl)but-3-yn-1-ol

The specific synthesis steps of Example 13 refer to Example 2. ESI-MS m/z: 389.2 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ ) δ 11.81 (d, J=2.6 Hz, 1H), 8.61 (s, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.49 (d, J= 2.5Hz, 1H), 6.96 (dd, J=8.7, 2.6Hz, 1H), 6.86 (d, J=2.6Hz, 1H), 5.24 (s, 2H), 4.82 (t, J=5.6Hz, 1H) , 3.62-3.58(m, 2H), 3.19-3.17(m, 4H), 2.56(t, J=7.2Hz, 2H), 2.47-2.44(m, 4H), 2.23(s, 3H).

Example 14: Compound 3-(1-Methyl-1H-pyrazol-4-yl)-7-(4-methylpiperazin-1-yl)-1,5-dihydroisochrom[3,4 Synthesis of -d]pyrro[2,3-b]pyridine

The specific synthesis steps of Example 14 refer to Example 7. ESI-MS m/z: 401.2 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ )δ11.64(d, J=2.5Hz, 1H), 8.60(s, 1H), 7.93(s, 1H), 7.77-7.71(m, 2H), 7.48( d, J＝2.5Hz, 1H), 6.97(dd, J＝8.6, 2.6Hz, 1H), 6.88(d, J＝2.6Hz, 1H), 5.26(s, 2H), 3.87(s, 3H), 3.19-3.16 (m, 4H), 2.47-2.44 (m, 4H), 2.23 (s, 3H).

Example 15: Compound N,N-Dimethyl-4-(7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromeno[3,4-d]pyrrole[ Synthesis of 2,3-b]pyridin-3-yl)benzamide

The specific synthesis steps of Example 15 refer to Example 1. ESI-MS m/z: 468.2 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ )δ11.97(d,J=2.7Hz,1H),8.67(s,1H),7.76(d,J=8.6Hz,1H),7.70(d,J= 8.1Hz, 2H), 7.61(d, J＝2.7Hz, 1H), 7.42(d, J＝8.1Hz, 2H), 6.98(dd, J＝8.6, 2.6Hz, 1H), 6.87(d, J＝ 2.7Hz, 1H), 5.20(s, 2H), 3.19-3.16(m, 4H), 3.01(s, 6H), 2.47-2.45(m, 4H), 2.23(s, 3H).

Example 16: Compound 7-(4-Methylpiperazin-1-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1,5-dihydroisochrom[ Synthesis of 3,4-d]pyrro[2,3-b]pyridine

The specific synthesis steps of Example 16 refer to Example 1. ESI-MS m/z: 495.3 [M+H] ⁺ .

Example 17: Compound 3-(3-Fluoro-4-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d ]Pyrro[2,3-b]pyridine Synthesis

The specific synthesis steps of Example 17 refer to Example 1. ESI-MS m/z: 445.2 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ ) δ 11.85 (d, J=2.6Hz, 1H), 8.65 (s, 1H), 7.75 (d, J=8.7Hz, 1H), 7.51 (J=2.5Hz) ,1H),7.49-7.45(m,1H),7.42-7.40(m,1H),7.16(t,J=8.9Hz,1H),6.98(dd,J=8.6,2.6Hz,1H),6.88( d, J=2.6Hz, 1H), 5.19(s, 2H), 3.87(s, 3H), 3.19-3.16(m, 4H), 2.48-2.45(m, 4H), 2.23(s, 3H).

Example 18: Compound 7-(4-Methylpiperazin-1-yl)-3-phenyl-1,5-dihydroisochromenol[3,4-d]pyrrole[2,3-b] Synthesis of Pyridine

The specific synthesis steps of Example 18 refer to Example 1. ESI-MS m/z: 397.2 [M+H] ⁺ . ¹ H NMR(500 MHz, DMSO-d ₆ )δ11.98(s,1H),δ9.72(s,1H),δ8.72(s,1H),7.84(d,J=8.7Hz,1H) ,7.67-7.61(m,2H),7.54(d,J＝2.5Hz,1H),7.38(t,J＝7.7Hz,2H),7.25(t,J＝7.4Hz,1H),7.08(dd, J=8.6, 2.6Hz, 1H), 6.94(d, J=2.5Hz, 1H), 5.21(s, 2H), 3.90-3.88(m, 2H), 3.54-3.51(m, 2H), 3.23-3.13 (m, 2H), 3.03-2.97 (m, 2H), 2.87 (d, J=4.0 Hz, 3H).

Example 19: Compound 3-(3-Fluoro-5-methoxyphenyl)-7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d ]Pyrro[2,3-b]pyridine Synthesis

The specific synthesis steps of Example 19 refer to Example 1. ESI-MS m/z: 445.2 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ )δ11.98(d,J=2.6Hz,1H),8.67(s,1H),7.76(d,J=8.6Hz,1H),7.68(d,J= 2.6Hz, 1H), 7.16(t, J=1.9Hz, 1H), 7.07(dt, J=10.4, 1.9Hz, 1H), 6.98(dd, J=8.6, 2.6Hz, 1H), 6.89(d, J=2.6Hz, 1H), 6.67-6.64(m, 1H), 5.24(s, 2H), 3.83(s, 3H), 3.22-3.15(m, 4H), 2.48-2.45(m, 4H), 2.25 (s, 2H).

Example 20: Compound 7-(4-Methylpiperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)-1,5-dihydroisochromo[3,4-d] Synthesis of Pyrro[2,3-b]pyridine

The specific synthesis steps of Example 20 refer to Example 1. ESI-MS m/z: 465.2 [M+H] ⁺ .

Example 21: Compound N-(2-(dimethylamino)ethyl)-N-methyl-4-(7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromatic Synthesis of [3,4-d]pyrro[2,3-b]pyridin-3-yl)benzamide

The specific synthesis steps of Example 21 refer to Example 1. ESI-MS m/z: 525.3 [M+H] ⁺ .

Example 22: Compound 4-(7-(4-Methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d]pyrro[2,3-b]pyridine-3- Synthesis of phenyl)benzenesulfonamide

The specific synthesis steps of Example 22 refer to Example 1. ESI-MS m/z: 476.2 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ )δ12.06(d,J=2.6Hz,1H),8.69(s,1H),7.83-7.79(m,4H),7.77(d,J=8.7Hz, 1H), 7.68(d, J=2.6Hz, 1H), 7.33(s, 2H), 6.98(dd, J=8.7, 2.6Hz, 1H), 6.87(d, J=2.7Hz, 1H), 5.21( s, 2H), 3.19-3.16 (m, 4H), 2.47-2.44 (m, 4H), 2.23 (s, 3H).

Example 23: Compound 4-(7-(4-Methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d]pyrro[2,3-b]pyridine-3- Synthesis of methyl) benzoate

The specific synthesis steps of Example 23 refer to Example 1. ESI-MS m/z: 455.2 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ )δ12.07(d,J=2.7Hz,1H),8.69(s,1H),7.96(d,J=8.0Hz,2H),7.80(d,J= 8.0Hz, 2H), 7.77(d, J=8.0Hz, 1H), 7.72(d, J=2.6Hz, 1H), 6.99(dd, J=8.0, 2.6Hz, 1H), 6.87(d, J= 2.6Hz, 1H), 5.21(s, 2H), 3.88(s, 3H), 3.20-3.17(m, 4H), 2.48-2.46(m, 4H), 2.24(s, 3H).

Example 24: Compound 4-(7-(4-Methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d]pyrro[2,3-b]pyridine-3- Synthesis of base) benzonitrile

The specific synthesis steps of Example 24 refer to Example 1. ESI-MS m/z: 422.2 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.14 (d, J=2.8Hz, 1H), 8.69 (s, 1H), 7.87 (d, J=8.5Hz, 2H), 7.84-7.72 (m, 4H), 6.98(dd, J=8.6, 2.6Hz, 1H), 6.88(d, J=2.6Hz, 1H), 5.21(s, 2H), 3.20-3.17(m, 4H), 2.48-2.45(m , 4H), 2.23(s, 3H).

Example 25: Compound (1-methylazetidin-3-yl)(4-(7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromo[3, Synthesis of 4-d]pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanone

Step 1: Synthesis of Compound 25-1

(4-Bromophenyl)-(1-chloroazetidin- ₃ -yl)methanone (900.00 mg) was added to methanol (20.00 mL) at room temperature, then N protected Under the conditions, 37% aqueous formaldehyde solution (118.01 mg) and glacial acetic acid (1.00 mL) were added, the reaction was carried out at room temperature for 1 h, and then NaBH(OAc) ₃ (2084.35 mg) was added, and the reaction was stopped at room temperature for 1 h. Saturated sodium bicarbonate was adjusted to pH 8-9, then combined with EA (25mL*3) and the organic phase was washed with saturated sodium chloride, and separated by column chromatography (DCM:MeOH=96:4～90:10) to obtain a yellow liquid target Product 25-1 (750.00 mg, 90.03% yield). ESI-MS m/z: 254.0 [M+H] ⁺ .

Step 2: Synthesis of Compound 25-2

At room temperature, the above compound 25-1 (0.30 g), B ₂ Pin ₂ (0.39 g), [PdCl ₂ (dppf)]CH ₂ Cl ₂ (0.06 g), potassium acetate (0.35 g), were added to 1 , 4-dioxane (6.00 mL), and then under N ₂ protection, the reaction was carried out at 90 °C for 1.5 h, and the reaction was stopped. The organic phase was concentrated, and the concentrate was separated by silica gel column chromatography (DCM:MeOH=95:5～88:12) to obtain the target product 25-2 (0.17 g, yield 47.81%) as a gray oily liquid. ESI-MS m/z: 302.2 [M+H] ⁺ .

The subsequent specific synthesis steps of Example 25 refer to Example 1. ESI-MS m/z: 494.3 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ )δ12.07(s,1H),8.67(s,1H),7.85(d,J=8.0Hz,2H),7.80(d,J=8.0Hz,2H) ,7.76(d,J＝8.0Hz,1H),7.71(s,1H),6.98(dd,J＝8.0,2.7Hz,1H),6.87(d,J＝2.6Hz,1H),5.20(s, 2H), 4.22-4.16(m, 1H), 3.58(t, J=7.5Hz, 2H), 3.20-3.16(m, 6H), 2.47-2.45(m, 4H), 2.23(s, 3H), 2.20 (s, 3H).

Example 26: Compound (1-methylnonazin-3-yl)(4-(7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromenol[3,4 Synthesis of -d]pyrro[2,3-b]pyridin-3-yl)phenyl)methanol

The specific synthesis steps of Example 26 refer to Example 1. ESI-MS m/z: 496.3 [M+H] ⁺ .

Example 27: Compound N,N-Dimethyl-3-(7-(4-methylpiperazin-1-yl)-1,5-dihydroisochromo[3,4-d]pyrrole[2, Synthesis of 3-b]pyridin-3-yl)propionamide

The specific synthesis steps of Example 27 refer to Example 1 and Example 2. ESI-MS m/z: 416.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.34 (d, J=2.6 Hz, 1H), 8.70 (s, 1H), 7.97 (d, J=2.3 Hz, 1H), 7.77 (d, J= 8.7Hz, 1H), 6.98(dd, J=8.8, 2.6Hz, 1H), 6.87(d, J=2.7Hz, 1H), 5.28(s, 2H), 3.34(s, 3H), 3.21-3.18( m, 4H), 2.92 (s, 3H), 2.47-2.44 (m, 4H), 2.23 (s, 3H).

Example 28: Synthesis of compound 7-(piperazin-1-yl)-1,5-dihydroisochromo[3,4-d]pyrro[2,3-b]pyridine

Step 1: Synthesis of Compound 28-1

At room temperature, the raw materials, methyl 3-bromobenzoate (9.00 g), and tert-butyl piperazine-1-carboxylate (8.18 g) were dissolved in toluene (10.00 mL), and Pd(OAc) ₂ (0.94 g) was added. ), Binap (2.61 g), Cs ₂ CO ₃ (27.27 g), replaced by N ₂ three times, heated at 90° C. for 6 hours. Cooled to room temperature, filtered, the filter cake was washed with EA, the filtrate was concentrated, separated and purified by silica gel column (PE:EA=10:1-5:1) to obtain off-white solid target product 28-1 (11.60 g, yield 86.51%) ). ESI-MS m/z: 321.2 [M+H] ⁺ .

Step 2: Synthesis of Compound 28-2

At room temperature, compound 28-1 (10.60 g) was dissolved in dichloromethane (150.00 mL), N-bromosuccinimide (7.07 g) was added, and the reaction was carried out at RT for 0.5 hours. Water (200ml) was added, the organic phase was separated, the organic phase was washed with saturated sodium bicarbonate (100ml), washed with water (100ml), the organic phase was dried with anhydrous sodium sulfate, concentrated, and the concentrate was passed through a silica gel column (PE:EA=10: 1-5:1) was purified to obtain the target product 28-2 (10.10 g, yield 76.46%). ESI-MS m/z: 399.1 [M+H] ⁺ .

Step 3: Synthesis of Compound 28-3

Compound 28-2 (8.00 g) was dissolved in dioxane (160.00 mL) at room temperature, pinacol diboronate (6.11 g), [PdCl ₂ (dppf)]CH ₂ Cl ₂ (0.82 g), AcOK (4.92 g), replaced by N ₂ 3 times, heated at 80°C for overnight reaction. The reaction solution was cooled to room temperature, filtered through celite, the filter cake was washed with EA, the filtrate was concentrated, and the concentrate was purified by silica gel column (PE:EA=10%-17%-30%) to obtain a white solid, which was slurried with PE to obtain the target product 28-3 (7.12 g, 79.62% yield). ESI-MS m/z: 447.3 [M+H] ⁺ .

Step 4: Synthesis of Compound 28-4

At room temperature, the starting compound 28-3 (5.00 g) was dissolved in dichloromethane (75.00 mL), protected by _N2 , cooled to 0 °C, and diisobutylaluminum hydride (1M/dioxane) was added dropwise ( 33.61 mL), then incubated for 1 hour. The temperature was lowered to -10°C, and 1N HCl (150ml) was added dropwise to quench the reaction. Then extracted with DCM (200ml), washed with saturated brine (50ml*2), dried over anhydrous sodium sulfate, and concentrated to obtain the target product 28-4 (1.82g, yield 38.84%) as a foamy solid. ESI-MS m/z: 419.3 [M+H] ⁺ .

Step 5: Synthesis of Compound 28-5

At room temperature, compound 28-4 (0.36 g) and 4-bromo-5-chloro-9-(4-methylphenyl)sulfonyl-2,9-diazabicyclo[4.3.0]nonane were combined -1,3,5,7-tetraene (0.30 g) and [PdCl ₂ (dppf)]CH ₂ Cl ₂ (0.06 g) were dissolved in 1,4-dioxane (6.00 mL) and H ₂ O ( 1.00 mL), K ₂ CO ₃ (0.32 g) was added, and the mixture was heated at 80° C. to react for 2 hours. Cooled to room temperature, filtered, washed with EA, the filtrate was concentrated, and the concentrate was purified by silica gel column (PE:EA=3:1-1:1) to obtain the target compound 28-5 (0.15 g, yield 32.00%). ESI-MS m/z: 597.2 [M+H] ⁺ .

Step 6: Synthesis of Compound 28-6

Compound 28-5 (0.15 g) was dissolved in N,N-dimethylacetamide (5.00 mL) at room temperature, cesium carbonate (0.33 g) was added, and the reaction was heated at 100° C. for 1 hour. Water was added to the reaction mixture, EA/THF=1/1 was added for extraction (10ml*3), the organic phases were combined, washed with saturated brine (5ml*4), dried over anhydrous sodium sulfate, spin-dried, dissolved in DCM, and passed through column ( PE:EA=1:1) was purified to obtain the target compound 28-6 as a white solid (83 mg, yield 55.40%). ESI-MS m/z: 561.2 [M+H] ⁺ .

Step 7: Synthesis of Compound 28-7

At room temperature, compound 28-6 (0.05 g) was dissolved in tetrahydrofuran (2.00 mL) and methanol (2.00 mL), potassium carbonate (0.04 g) was added, and the reaction was carried out overnight at RT. The reaction solution was concentrated, water was added and vigorously stirred, the solid Filter, wash with water, and dry to obtain the target product 28-7 (31 mg, yield 83.78%). ESI-MS m/z: 407.2 [M+H] ⁺ .

Step 8: Synthesis of Compound 28

Compound 28-7 (31 mg) was dissolved in 1,4-dioxane (1.00 mL) at room temperature, 4N-hydrochloric acid methanol solution (0.56 mL) was added, and the reaction was heated at 50° C. for 1 hour. Spin-dried, washed with EA, filtered, and the filter cake was prepared by Pre-HPLC to obtain the hydrochloride salt 28 of the target product as a white solid (9.1 mg, 38.89% yield). ESI-MS m/z: 307.2 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ ) δ 11.91(s, 1H), 8.86(s, 1H), 8.71(s, 1H), 7.83(d, J=8.6Hz, 1H), 7.39(d, J=3.3Hz, 1H), 7.06(dd, J=8.6, 2.7Hz, 1H), 6.94(d, J=2.6Hz, 1H), 6.50(s, 1H), 5.34(s, 2H), 3.42- 3.40 (m, 4H).

Example 29: Compound 4-(7-(piperazin-1-yl)-1,5-dihydroisochromo[3,4-d]pyrro[2,3-b]pyridin-3-yl)benzenesulfone amide synthesis

The specific synthesis steps of Example 29 refer to Example 1 and Example 28. ESI-MS m/z: 462.2 [M+H] ⁺ .

Example intermediate list:

The following examples were synthesized using the methods described above, or analogously using the corresponding intermediates.

Example 44: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.59 (d, J=2.6 Hz, 1H), 8.59 (s, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.26 ( d,J＝2.6Hz,1H),6.97(dd,J＝8.6,2.6Hz,1H),6.87(d,J＝2.6Hz,1H),6.13-6.08(m,1H),5.19(s,2H) ),3.19-3.16(m,4H),3.01-2.98(m,2H),2.56-2.54(m,2H),2.47-2.44(m,4H),2.28(s,3H),2.23(s,3H ).

Example 74: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.26 (d, J=2.7 Hz, 1 H), 8.69 (s, 1 H), 7.87-7.80 (m, 2H), 7.76 (d, J =8.7Hz,1H),7.47(s,1H),6.98(dd,J=8.7,2.7Hz,1H),6.88(d,J=

2.6Hz, 1H), 5.29(s, 2H), 3.21-3.19(m, 4H), 2.55-2.53(m, 4H), 2.27(s, 3H).

Example 75: ¹ H NMR (500 MHz, DMSO d ₆ ) δ 11.94 (d, J=2.7 Hz, 1H), 8.63 (s, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.59 (d , J=2.3Hz, 1H), 6.96(dd, J=8.7, 2.6Hz, 1H), 6.87(d, J=2.5Hz, 1H), 5.25(s, 2H), 5.23(t, J=5.9Hz) ,1H),4.31(d,J＝5.9Hz,2H),3.19-3.16(m,4H),2.47-2.44(m,4H),2.23(s,3H).

Pharmacological experiments

Pharmacological Experiment 1: Detection of Enzymatic Activity

(1) Prepare 4× Kinase Buffer (Promega, Cat.No.V9102)

(2) Compound gradient dilution: the compound to be tested was diluted 3 times, and 11 gradient concentrations were set, and each concentration was set up for duplicate well detection. In a 384-well preparation plate, the solution was serially diluted to the corresponding 100-fold final concentration, and then 0.1 μL was transferred to a 384-well reaction plate with Echo for testing. Transfer 0.1 μL of 100% DMSO to Min and Max wells.

(3) Prepare HPK1 enzyme working solution with 4x kinase buffer.

(4) Add 5 μL of HPK1 enzyme working solution to each well, add 5 μL of 1× kinase buffer to Min well, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 15 min.

(5) During the incubation period, prepare the substrate working solution with 4x Kinase Buffer.

(6) Add 5 μL of substrate working solution to each well of the reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at 25° C. for 60 min.

(7) After the incubation, 5 μL of ADP Glo reagent (Promega, Cat. No. V9102) was added to each well. Centrifuge at 1000 rpm for 1 min and incubate at 25°C for 60 min.

(8) Add 10 μL of detection solution to each well, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 60 min.

(9) Reading with EnVision.

Inhibition rate calculation formula:

Signal_max: reading of DMSO control wells

Signal value_min: No enzyme well reading

signal_sample: sample well reading

Taking the log value of the concentration as the X-axis and the percentage inhibition rate as the Y-axis, the log(inhibitor) vs.response-Variable slope of the analysis software GraphPad Prism 5 was used to fit the dose-response curve to obtain the _IC50 of the compound for kinase binding inhibition value.

See Table 1 for the enzymatic _IC50 data of the example compounds against HPK1.

Table 1

Compound name	IC50 (nM)
1	0.4
2	7.0
8	5.5
12	0.4
13	2.2
14	0.8
15	2.7
16	11.2
17	0.7
18	2.5
19	3.1

twenty two	2.1
twenty three	6.9
twenty four	8.1
25	0.2
27	0.1
28	41.8
29	7.0
44	25.3
50	32.0
51	9.8
74	0.1
75	4.6

Although the present invention has been fully described in terms of its embodiments, it is worth noting that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications are intended to be included within the scope of the appended claims of the present invention.

Claims (24)

1. A compound represented by general formula (I), its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt:

   

   in,

   R ₁ is selected from H, halogen, -CN, -NO ₂ , -OR _b , -SR _b , -SO ₂ R _b , -SO ₂ NR _b R _c , -COR _b , -CO ₂ R _b , -CONR _b R _c , -NR _b R _c , -NR _b COR _c , -NR _b CO ₂ R _c , -NR _b SONR _c R _d , -NR _b SO ₂ NR _c R _d , -NR _b SO ₂ R _c , C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-12 membered aryl or 5-12 membered heteroaryl , the C _1-8 alkyl group, C _2-8 alkenyl group, C _2-8 alkynyl group, C _3-12 cycloalkyl group, 3-12-membered heterocyclic group, C _6-12 aryl group, 5-12 A membered heteroaryl, R _b , R _c or R _d is optionally substituted with at least one R _1a ;

   R ₂ , R ₃ are independently selected from H, halogen, -CN, -OH, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl or cyclopropyl, the C _1-4 Alkyl, C _2-4 alkenyl, C _2-4 alkynyl, cyclopropyl are optionally substituted with at least one R _a ;

   L ₁ is selected from a bond, O, S or NR _a ;

   R ₄ is selected from C _0-3 alkylene-C _3-12 cycloalkyl or C _0-3 alkylene-3-12 membered heterocyclic group, the C _0-3 alkylene-C _3-12 cycloalkyl or C _0-3 alkylene-3-12 membered heterocyclyl optionally substituted with at least one R _4a ;

   X ₁ is selected from O, NR ₅ or C(R ₅ ) ₂ ;

   X ₂ is selected from O, NR ₆ or C(R ₆ ) ₂ ;

   _{X3 is} selected from N or _CR7 ;

   _{X4 is} selected from N or _CR8 ;

   _X5 is selected from N or _CR9 ;

   R ₅ , R ₆ , R ₇ , R ₈ , R ₉ are each independently selected from H, halogen, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkane base, 3-12-membered heterocyclic group, C _6-12 -membered aryl, 5-12-membered heteroaryl, oxo, -CN, -NO ₂ , -OR _b , -SR _b , -SO ₂ R _b , -SO ₂ NR _b R _c , -COR _b , -CO ₂ R _b , -CONR _b R _c , -NR _b R _c , -NR _b COR _c , -NR _b CO ₂ R _c , -NR _b SONR _c R _d , -NR _b SO ₂ NR _c R _d or -NR _b SO ₂ R _c , the C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl , 3-12 membered heterocyclyl, _C6-12 aryl, 5-12 membered heteroaryl, R _b , R _c or R _d are optionally substituted with at least one R _a ;

   Or 2 R ₆ together with the attached atoms form C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-12 aryl or 5-12 membered heteroaryl, the C _3-12 cycloalkane radical, 3-12 membered heterocyclyl, _C6-12 membered aryl or 5-12 membered heteroaryl optionally substituted with one or more _R6a substituents;

   R _1a , R _4a , R _6a , R _a are independently selected from H, halogen, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _{3 -12} cycloalkyl, 3-12 membered heterocyclyl, C _6-12 aryl, 5-12 membered heteroaryl, oxo, -CN, -NO ₂ , -OR _b , -SR _b , -SO ₂ R _b , -SO ₂ NR _b R _c , -COR _b , -CO ₂ R _b , -CONR _b R _c , -NR _b R _c , -NR _b COR _c , -NR _b CO ₂ R _c , -NR _b SONR _c R _d , -NR _b SO ₂ NR _c R _d or -NR _b SO ₂ R _c , the C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _{2 -8} alkynyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-12 membered aryl or 5-12 membered heteroaryl optionally selected from H, halogen, hydroxy, _{C1- 8} alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-12 membered aryl, 5-12 membered heteroaryl, oxygen substituted group, -CN, -NO ₂ , R _b , -OR _b , -SR _b , -SO ₂ R _b , -SO ₂ NR _b R _c , -COR _b , -CO ₂ R _b , -CONR _b R _{c at least one substitution of} , _{-NRbRc , -NRbCORc , -NRbCO2Rc , -NRbSONRcRd , -NRbSO2NRcRd , or -NRbSO2Rc} base substituted;

   R _b , R _c , R _d are independently selected from H, amino, hydroxy, oxo, C _1-8 alkoxy, C _1-8 alkyl, C _1-8 hydroxyalkyl, C _1-8 amino Alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-12 aryl or 5-12 membered heteroaryl, the C _1-8 alkoxy, C _1-8 alkyl, C _1-8 hydroxyalkyl, C _1-8 aminoalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-6 ring Alkyl, 3-6 membered heterocyclyl, _C6-12 membered aryl or 5-12 membered heteroaryl optionally selected from H, halogen, hydroxy, _{C1-8 alkyl, C1-8 alkoxy} base, C _1-8 hydroxyalkyl, C _1-8 aminoalkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _{6 -12} aryl, 5-12 membered heteroaryl, oxo, -CN, -NO ₂ , -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl _{) 2 ,} -CONH ₂ , -CONHC _1-6 alkyl, -CON(C _1-6 alkyl) ₂ , -COC _1-6 alkyl, -COO C _1-6 alkyl substituted with at least one substituent.
2. The compound according to claim 1, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein R ₁ is selected from H, C _2-8 alkynyl, C _3-12 ring Alkyl, 3-12-membered heterocyclyl, _C6-12 -membered aryl or 5-12-membered heteroaryl, the _C2-8 alkynyl, 3-12-membered heterocyclyl, _C6-12 -aryl or The 5-12 membered heteroaryl is optionally substituted with 1-4 R _1a .
3. The compound according to claim 1 or 2, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein R _1a is selected from H, halogen, C _1-8 alkoxy, Oxo, C _1-6 alkyl, C _1-6 cyanoalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, -CONR _b R _c , - COR _b , -CO ₂ R _b , -OR _b , -SO ₂ NR _b R _c , -NR _b R _c , C _3-12 cycloalkyl, hydroxy-substituted C _3-12 cycloalkyl, 3-12 membered Heterocyclyl, C _1-6 alkyl substituted heterocyclyl,

   

   

   The R _b or R _c is independently selected from H, amino, hydroxy or C _{1-6 alkyl} .
4. The compound according to any one of claims 1-3, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein R ₂ is selected from H or C _1-3 alkyl , preferably H.
5. The compound according to any one of claims 1-4, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein R ₃ is selected from H or C _1-3 alkyl , preferably H.
6. The compound according to any one of claims 1-5, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein R ₄ is a 3-12-membered heterocyclic group, and the The 3-12 membered heterocyclyl is optionally further substituted with 1-4 _R4a .
7. The compound according to any one of claims 1-6, its stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt, wherein R _4a is selected from H or C _1-3 alkyl , preferably C _1-3 alkyl.
8. The compound, stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein L ₁ is a bond.
9. The compound, stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein X ₁ is selected from O, NH or CH ₂ .
10. The compound according to any one of claims 1-9, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein X ₂ is selected from O, NH, CH ₂ or

    
11. The compound according to any one of claims 1-10, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein X ₃ is selected from N or CR ₇ , and R ₇ is selected from from H, halogen or C _1-3 alkyl.
12. The compound according to any one of claims 1-11, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein X ₄ is selected from N or CR ₈ , and R ₈ is selected from from H, halogen or C _1-3 alkyl.
13. The compound according to any one of claims 1-12, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein X ₅ is selected from N or CR ₉ , and R ₉ is H.
14. The compound according to any one of claims 1-13, its stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt, which is selected from the group consisting of formula (I-1) or (I-2) compounds shown,

    

    

    R ₁ -R ₉ are as defined in any one of claims 1-13.
15. A compound, a stereoisomer, tautomer, deuterated or pharmaceutically acceptable salt thereof selected from,

    

    
16. A pharmaceutical composition, characterized in that the pharmaceutical composition contains a therapeutically effective amount of the compound according to any one of claims 1-15 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof and at least a A pharmaceutically acceptable excipient.
17. Use of the compound according to any one of claims 1 to 15 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 16 in the preparation of a medicine.
18. The use according to claim 17, wherein the preparation of a medicine is an application in the preparation of a medicine for treating and/or preventing cancer.
19. The use according to claim 17 or 18, wherein the preparation of the medicine is the use in the preparation of a medicine for the treatment and/or prevention of diseases mediated by HPK1.
20. The use according to claim 18 or 19, wherein the cancer or disease is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer , small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer , thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.
21. A method for treating and/or preventing a disease, comprising administering a therapeutically effective amount of the compound according to any one of claims 1 to 15 or a stereoisomer, tautomer or drug thereof to a subject to be treated Use a salt or the pharmaceutical composition of claim 16.
22. The method of claim 21, wherein the disease to be treated and/or prevented is cancer.
23. The method according to claim 21 or 22, wherein the disease to be treated and/or prevented is a disease mediated by HPK1
24. The method according to claim 22 or 23, wherein the cancer or disease is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell Lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck cancer, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate carcinoma, thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.