CN113845531A

CN113845531A - Pyrazolo ring compound, pharmaceutical composition containing same, preparation method and application thereof

Info

Publication number: CN113845531A
Application number: CN202010597780.8A
Authority: CN
Inventors: 贾兰齐; 游泽金; 孙晓阳; 冉茂盛; 陈泉龙; 朱军; 李伟; 王太津; 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: 2020-06-28
Filing date: 2020-06-28
Publication date: 2021-12-28

Description

Pyrazolo ring compound, pharmaceutical composition containing same, preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicines, and relates to a pyrazolo ring compound, a pharmaceutical composition containing the pyrazolo ring compound, a preparation method of the pyrazolo ring compound, and application of the pyrazolo ring compound in preparation of medicines for treating HPK 1-related diseases.

Background

Hematopoietic progenitor protein kinase 1 (HPK 1), also known as mitogen-activated protein kinase kinase kinase kinase kinase kinase 1 (MAP 4K1), is a member of the Ste-20 silk/threonine family, which family members also include MAP4K2(GCK), MAP4K3(GLK), MAP4K4(HGK), MAP4K5(KHS) and MAP4K6 (MINK). HPK1 is 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), HPK1 is activated by a TCR signal path, and the activated HPK1 can phosphorylate serine 376 of a joint protein SLP-76, so that 14-3-3 protein is recruited to cause instability of a TCR complex, and finally, T cell response is weakened and T cell proliferation is inhibited. 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 depleted in HPK1 enzyme activity, was enhanced (Alzabin, Bhardwaj et al 2009). Similarly, lewis lung carcinoma transplanted tumor mice had significantly increased tumor suppression rates after receiving HPK1 knockout T cell transplantation therapy compared to the control group (wild type T cells) (Alzabin, pyrajan et al 2010). Therefore, a small-molecule inhibitor of HPK1 is searched as a new direction for tumor immunotherapy.

Disclosure of Invention

The present invention provides novel, highly active HPK1 inhibitor compounds that can be used alone or in combination with other drugs for the treatment of neoplastic diseases.

A first aspect of the present invention relates to a compound of formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof:

wherein the content of the first and second substances,

R¹selected from hydrogen, C (O) R^a、CO₂R^a、C(O)NR^bR^c、S(O)R^a、SO₂R^a、SO₂NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl, 3-8 membered heterocyclyl and 5-14 membered heteroaryl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl, 3-8 membered heterocyclyl and 5-14 membered heteroaryl are each optionally substituted with one or more R^dSubstitution;

R²selected from hydrogen, halogen, CN, NO₂、C(O)R^a、CO₂R^a、C(O)NR^bR^c、S(O)R^a、SO₂R^a、SO₂NR^bR^c、NR^bR^c、NHC(O)R^a、NHCO₂R^a、OC(O)R^a、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl are each optionally substituted with one or more R^dSubstitution;

R³selected from hydrogen, C (O) R^a、CO₂R^a、C(O)NR^bR^c、S(O)R^a、SO₂R^a、SO₂NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl, said C₆-C₁₄Aryl and 5-14 membered heteroaryl are each optionally substituted with C₃-C₇Cycloalkyl or 5-10 membered heterocyclyl fused ringsAnd C is₁-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;

R^aindependently selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl, said C₆-C₁₄Aryl and 5-14 membered heteroaryl are each optionally substituted with C₃-C₇Cycloalkyl or 5-to 10-membered heterocyclyl fused, and 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;

R^band R^cEach independently selected from hydrogen and C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆alkoxy-C₁-C₆Alkyl and 4-7 membered heterocyclyl; or, R^bAnd R^cTogether with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆alkoxy-C₁-C₆Each of alkyl and 4-7 membered heterocyclyl is optionally substituted with one or more R^dSubstitution;

x is selected from CH and N;

R^dindependently selected from: hydrogen, hydroxy, halogen, oxo, CN, NO₂、C(O)R^e、CO₂R^e、NR^fSO₂R^g、S(O)R^e、SO₂R^e、C(O)NR^fR^g、SO₂NR^fR^g、NR^fR^g、NR^fC(O)R^g、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₁-C₆alkoxy-C₁-C₆Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl, said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₁-C₆alkoxy-C₁-C₆Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl are each optionally substituted with one or more R^jSubstitution;

R^eindependently selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl;

R^fand R^gEach independently selected from hydrogen and C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 4-7 membered heterocyclyl, wherein said C is₁-C₆Alkyl is optionally substituted by C₁-C₆Alkoxy or NR^hRⁱSubstitution; or, R^bAnd R^cTogether with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl;

R^hand RⁱEach independently selected from hydrogen and C₁-C₆An alkyl group; and is

R^jIndependently selected from halogen, hydroxy, CN, C (O) R^e、NR^fR^g、C(O)NR^bR^e、NR^bC(O)R^eAnd 3-8 membered heterocyclic groups.

Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, co-crystal, solvate, metabolite, prodrug or any mixture of two or more thereof, together with one or more pharmaceutically acceptable carriers.

Another aspect of the invention provides a kit comprising:

1) a compound of the invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, co-crystal, solvate, metabolite, prodrug or any mixture of two or more thereof; and

2) optionally packaging and/or instructions.

Another aspect of the invention provides the use of a compound of the invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof, or a pharmaceutical composition of the invention, for the manufacture of a medicament for the treatment of a disease associated with HPK 1.

Another aspect of the invention provides a compound of the invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof, or a pharmaceutical composition of the invention or a kit of the invention, for use in the treatment of a disease associated with HPK 1.

Another aspect of the present invention provides a method of treating a disease associated with HPK1, comprising administering to a subject in need thereof an effective amount of a compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, co-crystal, solvate, metabolite or prodrug thereof, or any mixture of two or more thereof, or a pharmaceutical composition of the present invention, and optionally comprising co-administering other agents for treating a disease or disorder associated with HPK 1.

Another aspect of the present invention provides a method for preparing the compound of the present invention, which is carried out according to the following reaction scheme 1 or 2:

scheme 1:

wherein R is¹、R²、R³X is as defined above;

the first step is as follows: the compound I-1 is subjected to coupling, condensation or alkylation reaction to form a compound I-2, wherein LG₁Is a leaving group such as halogen (e.g., Cl, Br or I), OTs, OTf, etc.;

the second step is that: carrying out coupling or nucleophilic substitution reaction on the compound I-2 to generate a compound I-3, wherein PG is an amino protecting group, such as Boc, Cbz, Bn, PMB and the like;

the third step: carrying out deprotection reaction on the compound I-3 to generate a compound I-4;

the fourth step: the compound I-4 is subjected to coupling, condensation or alkylation reaction to generate the target compound I.

Scheme 2:

wherein R is¹、R²、R³X is as defined above;

the second step is that: the compound I-2 is subjected to coupling or nucleophilic substitution reaction to generate the target compound I.

Compounds and methods of preparation

It is an object of the present invention to provide a compound of formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof:

wherein the content of the first and second substances,

R³selected from hydrogen, C (O) R^a、CO₂R^a、C(O)NR^bR^c、S(O)R^a、SO₂R^a、SO₂NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl, said C₆-C₁₄Aryl and 5-14 membered heteroaryl are each optionally substituted with C₃-C₇Cycloalkyl or 5-to 10-membered heterocyclyl fused, and 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;

R^band R^cEach independently selected from hydrogen and C₁-C₆Alkyl radical, C_3-C₇Cycloalkyl radical, C₁-C₆Alkoxy radical C₁-C₆Alkyl and 4-7 membered heterocyclyl; or, R^bAnd R^cTogether with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy radical C₁-C₆Each of alkyl and 4-7 membered heterocyclyl is optionally substituted with one or more R^dSubstitution;

x is selected from CH and N;

R^dindependently selected from: hydrogen, hydroxy, halogen, oxo, CN, NO₂、C(O)R^e、CO₂R^e、NR^fSO₂R^g、S(O)R^e、SO₂R^e、C(O)NR^fR^g、SO₂NR^fR^g、NR^fR^g、NR^fC(O)R^g、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy radical C₁-C₆Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl, said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₁-C₆alkoxy-C₁-C₆Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl are each optionally substituted with one or more R^jSubstitution;

R^fand R^gEach independently selected from hydrogen and C₁-C₆Alkyl radical, C_3-C₇Cycloalkyl and 4-7 membered heterocyclyl, wherein said C is₁-C₆Alkyl is optionally substituted by C₁-C₆Alkoxy or NR^hRⁱSubstitution; or, R^bAnd R^cTogether with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl;

According to some embodiments of the invention, R¹Selected from hydrogen, C (O) R^a、CO₂R^a、C(O)NR^bR^c、S(O)R^a、SO₂R^a、SO₂NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more R^dAnd (4) substitution.

In some embodiments of the invention, R¹Selected from hydrogen, C (O) R^a、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 3-8 membered heterocyclyl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 3-8 membered heterocyclyl are each optionally substituted with one or more R^dAnd (4) substitution.

In some embodiments of the invention, R¹Selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radicalsAnd 3-8 membered heterocyclic group, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 3-8 membered heterocyclyl are each optionally substituted with R^dAnd (4) substitution.

In some embodiments of the invention, R¹Is selected from C₁-C₆Alkyl and 3-8 membered heterocyclic group, said C₁-C₆Alkyl and 3-8 membered heterocyclyl are each optionally substituted with R^dAnd (4) substitution.

In some embodiments of the invention, R¹Is selected from C₁-C₆Alkyl and 5-6 membered azacycloalkyl, said C₁-C₆Alkyl is optionally substituted with a group selected from: hydroxy, C₁-C₆Alkoxy, halogen, and 5-6 membered heterocyclyl.

In some embodiments of the invention, R¹Is selected from C₁-C₆Alkyl and pyrrolidinyl, said C₁-C₆Alkyl is optionally substituted with a group selected from: hydroxy, C₁-C₆Alkoxy, halogen and morpholinyl.

In some embodiments of the invention, R¹Is selected from C₁-C₆Alkyl and pyrrolidinyl, said C₁-C₆Alkyl is optionally substituted with a group selected from: hydroxy, methoxy, fluoro and morpholinyl.

In some embodiments of the invention, R¹Selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, sec-butyl, morpholin-2-ylmethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-fluoroethyl and pyrrolidinyl.

In some embodiments of the invention, R¹Selected from the group consisting of isopropyl, sec-butyl, morpholin-2-ylmethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-fluoroethyl and pyrrolidinyl.

According to some embodiments of the invention, R²Selected from hydrogen, halogen, CN, NO₂、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy radical, C₆-C₁₀Aryl and 5-to 10-membered heteroaryl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy radical, C₆-C₁₀Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more R^dAnd (4) substitution.

In some embodiments of the invention, R²Selected from hydrogen, halogen, C₁-C₆Alkyl and C₃-C₇Cycloalkyl radical, said C₁-C₆Alkyl and C₃-C₇Cycloalkyl is each optionally substituted by one or more R^dAnd (4) substitution.

In some embodiments of the invention, R²Selected from hydrogen, halogen and C₁-C₆Alkyl radical, said C₁-C₆Alkyl is optionally substituted by one or more R^dAnd (4) substitution.

In some embodiments of the invention, R²Is hydrogen.

According to some embodiments of the invention, R³Selected from hydrogen, C (O) R^a、CO₂R^a、C(O)NR^bR^c、S(O)R^a、SO₂R^a、SO₂NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl and 5-to 10-membered heteroaryl, said C₆-C₁₀Aryl and 5-10 membered heteroaryl are each optionally substituted with C₃-C₇Cycloalkyl or 5-to 10-membered heterocyclyl fused, and said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are each optionally substituted with one or more R^dAnd (4) substitution.

In some embodiments of the invention, R³Selected from C (O) R^a、CO₂R^a、C(O)NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl and 5-to 10-membered heteroaryl, said C₆-C₁₀Aryl and 5-10 membered heteroaryl are each optionally substituted with C₃-C₇Cycloalkyl or 5-10 membered heterocyclyl fused ringsAnd C is₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are each optionally substituted with one or more R^dAnd (4) substitution.

In some embodiments of the invention, R³Selected from C (O) R^a、CO₂R^a、C₆-C₁₀Aryl and 5-to 10-membered heteroaryl, said C₆-C₁₀Aryl and 5-10 membered heteroaryl are each optionally substituted with C₃-C₇Cycloalkyl or 5-to 10-membered heterocyclyl fused, and said C₆-C₁₀Aryl, 5-10 membered heteroaryl, C₃-C₇Cycloalkyl and 5-10 membered heterocyclyl are each optionally substituted with 1,2,3 or 4R^dAnd (4) substitution.

In some embodiments of the invention, R³Selected from C (O) R^a、C₆-C₁₀Aryl and 5-to 10-membered heteroaryl, said C₆-C₁₀Aryl and 5-10 membered heteroaryl are each optionally substituted with C₃-C₇Cycloalkyl or 5-to 10-membered heterocyclyl fused, and said C₆-C₁₀Aryl, 5-10 membered heteroaryl, C₃-C₇Cycloalkyl and 5-10 membered heterocyclyl are each optionally substituted with 1,2,3 or 4R^dAnd (4) substitution.

In some embodiments of the invention, R³Selected from C (O) R^aPhenyl and 5-9 membered heteroaryl, each of which is optionally substituted with C₅-C₆Cycloalkyl or 5-9 membered heterocyclyl fused and said phenyl, 5-9 membered heteroaryl, C₅-C₆Cycloalkyl and 5-9 membered heterocyclyl are each optionally substituted with 1,2,3 or 4R^dAnd (4) substitution.

In some embodiments of the invention, R³Selected from C (O) R^aPhenyl and 5-9 membered heteroaryl, each of which is optionally substituted with C₅-C₆Cycloalkyl or 5-9 membered heterocyclyl fused and said phenyl, 5-9 membered heteroaryl, C₅-C₆Cycloalkyl and 5-9 membered heterocyclyl are each optionally substituted with 1,2,3 or 4R^dSubstitution;

R^aselected from the group consisting of cyclopropyl, cyclobutyl, isopropyl, pyrazolyl, indazolyl, indolyl and

the cyclopropyl, pyrazolyl, indazolyl, indolyl and

optionally substituted with 1,2,3 or 4 fluoro or methyl groups;

R^dindependently selected from: fluoro, vinyl, pyrrolidinyl, ethyl, N-propyl, isopropyl, oxo, methyl, methoxy, -N (CH)₃)₂、-NH(CH₂)₂-NH(CH₃) Isobutyl, morpholinyl, piperidinyl, - (CH)₂)₂N(CH₃)₂And amino, said vinyl, methyl, ethyl, n-propyl, pyrrolidinyl being optionally substituted with one or more hydroxy, fluoro, CN, acetyl or morpholinyl.

In some embodiments of the invention, R³Selected from pyrazolyl, pyridyl, pyrimidinyl, indolyl, indazolyl or pyrimidopyrazolyl, optionally substituted by 1 or 2R^dSubstitution; and R is^dIndependently selected from oxo, amino, C₁-C₆Alkyl and pyrrolidinyl, said C₁-C₆Alkyl and pyrrolidinyl are each optionally substituted with hydroxy, CN or acetyl.

In some embodiments of the present invention, the first and second substrates are,

R¹is selected from C₁-C₆Alkyl and pyrrolidinyl, said C₁-C₆Alkyl is optionally substituted with a group selected from: hydroxy, C₁-C₆Alkoxy, halogen and morpholinyl;

R²is hydrogen;

R³is selected from

The above-mentioned

Optionally substituted by 1 or 2 or 3 or 4R^dSubstitution;

R^dindependently selected from fluoro, oxo, amino, methyl, ethyl, N-propyl, isopropyl, isobutyl, methoxy, -N (CH)₃)₂、-NH(CH₂)₂NH₂、C₂-C₆Alkenyl, morpholinyl, piperidinyl and pyrrolidinyl, said methyl, ethyl, n-propyl, isopropyl, -NH (CH)₂)₂NH₂、C₂-C₆Alkenyl and pyrrolidinyl are each optionally substituted with one or more groups selected from hydroxy, methyl, halo, morpholinyl, -N (CH)₃)₂CN or acetyl; and is

X is selected from CH and N.

R¹selected from isopropyl, sec-butyl, morpholin-2-ylmethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-fluoroethyl and pyrrolidinyl;

R²is hydrogen;

R³is selected from

And the number of the first and second electrodes,

x is selected from CH and N.

The present invention encompasses compounds of formula I obtained by any combination of the above preferred groups.

According to some embodiments of the invention, the compounds of the invention have the structure of formula II:

wherein the content of the first and second substances,

R¹、R²x and R^aAs defined above.

In some embodiments of the invention, R^aIs selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl, said C₆-C₁₄Aryl and 5-14 membered heteroaryl are each optionally substituted with C₃-C₇Cycloalkyl or 5-to 10-membered heterocyclyl fused, and 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^dIs substituted in which R^dAs defined above.

In some embodiments of the invention, R^aIs selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl and 5-to 10-membered heteroaryl, said C₆-C₁₀Aryl and 5-10 membered heteroaryl are each optionally substituted with C₃-C₇Cycloalkyl or 5-to 10-membered heterocyclyl fused, and said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl and 5-10 membered heteroaryl are each optionally substituted by 1 or 2R^dIs substituted in which R^dAs defined above.

In the inventionIn some embodiments, R^aIs selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 5-10 membered heteroaryl, said 5-10 membered heteroaryl being optionally fused with a 5-6 membered heterocyclyl, and said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 5-10 membered heteroaryl and 5-6 membered heterocyclyl are each optionally substituted with 1 or 2 substituents independently selected from halogen and C₁-C₆Alkyl groups.

In some embodiments of the invention, R^aIs selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, pyrrolyl, pyrazolyl and imidazolyl each optionally fused to a benzene or tetrahydropyrimidine ring, and C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, pyrrolyl, pyrazolyl, imidazolyl, phenyl and tetrahydropyrimidine ring each optionally substituted by 1 or 2 substituents independently selected from halogen and C₁-C₆Alkyl groups.

In some embodiments of the invention, R^aSelected from cyclopropyl, fluorocyclopropyl, difluorocyclopropyl, cyclobutyl, isopropyl, pyrazolyl, methyl pyrazolyl, indazolyl, indolyl and tetrahydropyrimidizolyl.

R²is hydrogen;

R^ais selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, pyrrolyl, pyrazolyl and imidazolyl each optionally fused to a benzene or tetrahydropyrimidine ring, and C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, pyrrolyl, pyrazolyl, imidazolyl, phenyl and tetrahydropyrimidine rings are each optionally substituted by 1 or 2 substituents independently selected from halogenAnd C₁-C₆Radical substitution of alkyl; and is

X is CH.

R²is hydrogen;

R^aselected from cyclopropyl, fluorocyclopropyl, difluorocyclopropyl, cyclobutyl, isopropyl, pyrazolyl, methyl pyrazolyl, indazolyl, indolyl and tetrahydropyrimidizolyl pyrazolyl; and is

X is CH.

According to some embodiments of the invention, the compounds of the invention have the structure of formula III:

wherein the content of the first and second substances,

R⁴selected from hydrogen, C (O) R^e、CO₂R^e、C(O)NR^fR^g、S(O)R^e、SO₂R^e、SO₂NR^fR^g、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl, said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl are each optionally substituted with 1 or 2R^jSubstitution;

R⁵selected from hydrogen, NR^fR^g、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₄Aryl and 5-14 membered heteroaryl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₄Aryl and 5-14 membered heteroaryl are each optionallyGround is 1 or 2R^jSubstitution; and is

R¹、R²、X、R^f、R^g、R^eAnd R^jAs defined above.

In some embodiments of the invention, R⁴Is selected from C₁-C₆Alkyl and C₂-C₆Alkenyl radical, said C₁-C₆Alkyl and C₂-C₆Each alkenyl group is optionally substituted by 1 or 2 substituents independently selected from halogen, NR^fR^gAnd 5-6 membered heterocyclyl.

In some embodiments of the invention, R⁴Is selected from C₁-C₆Alkyl and C₂-C₆Alkenyl radical, said C₁-C₆Alkyl and C₂-C₆Each alkenyl group is optionally substituted with 1 or 2 substituents independently selected from halogen, N (C)₁-C₆Alkyl radical)₂And morpholinyl.

In some embodiments of the invention, R⁴Selected from 2-fluorovinyl, 2-difluoroethyl, isopropyl, isobutyl, and mixtures thereof,

And 2- (N, N-dimethylamino) ethyl.

R⁵selected from hydrogen, NR^fR^gAnd 5-6 membered heterocyclyl;

R^fand R^gEach independently selected from hydrogen and C_1-C₆Alkyl radical, wherein said C₁-C₆Alkyl is optionally substituted by NR^hRⁱSubstitution; and is

R^hAnd RⁱEach independently selected from hydrogen and C₁-C₆An alkyl group.

R⁵selected from hydrogen,NR^fR^gPyrrolidinyl, morpholinyl, and piperidinyl;

R^fand R^gEach independently selected from hydrogen and C₁-C₆Alkyl radical, wherein said C₁-C₆Alkyl is optionally substituted by NR^hRⁱSubstitution; and;

In some embodiments of the invention, R⁵Selected from the group consisting of hydrogen, pyrrolidinyl, morpholinyl, piperidinyl, 2- (N-methylamino) ethylamino, and 2- (N, N-dimethylamino) ethylamino.

R¹is C₁-C₆An alkyl group;

R²is hydrogen;

R⁴is selected from C₁-C₆Alkyl and C₂-C₆Alkenyl radical, said C₁-C₆Alkyl and C₂-C₆Each alkenyl group is optionally substituted with 1 or 2 substituents independently selected from halogen, N (C)₁-C₆Alkyl radical)₂And morpholinyl;

R⁵selected from hydrogen, NR^fR^gPyrrolidinyl, morpholinyl, and piperidinyl;

R^fand R^gEach independently selected from hydrogen and C₁-C₆Alkyl radical, wherein said C₁-C₆Alkyl is optionally substituted by NR^hRⁱSubstitution;

X is CH.

R¹is C₁-C₆An alkyl group;

R²is hydrogen;

R⁴selected from the group consisting of 2-fluorovinyl, 2-difluoroethyl, isopropyl, isobutyl, and mixtures thereof,

And 2- (N, N-dimethylamino) ethyl;

R⁵selected from hydrogen, pyrrolidinyl, morpholinyl, piperidinyl, 2- (N-methylamino) ethylamino, and 2- (N, N-dimethylamino) ethylamino; and the number of the first and second electrodes,

x is CH.

According to some embodiments of the invention, the compounds of the invention have the structure of formula IV:

wherein the content of the first and second substances,

R⁶and R⁷Each independently selected from hydrogen, halogen, CN, NO₂、C(O)R^e、CO₂R^e、C(O)NR^fR^g、S(O)R^e、SO₂R^e、SO₂NR^fR^g、NR^fR^g、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl are each optionally substituted with one or more R^jSubstitution;

R⁸and R⁹Each independently selected from hydrogen, NR^fR^gAnd C₁-C₆An alkyl group; or, R⁸And R⁹Together with the carbon atom to which they are attached form C₃-C₇Cycloalkyl or carbonyl, said C₁-C₆Alkyl and C₃-C₇Cycloalkyl is each optionally substituted by one or more R^jSubstitution;

y is selected from CH and N;

u and V are each independently selected from CR^fR^g、NR^eO, S (O) and SO₂；

m and n are each independently selected from 0, 1 and 2, and the sum of m and n is 0, 1 or 2; and is

R¹、R²、X、R^e、R^f、R^gAnd R^jAs defined above.

In some embodiments of the invention, R⁶And R⁷Each independently selected from hydrogen, halogen and C₁-C₆An alkoxy group.

In some embodiments of the invention, R⁶And R⁷Each independently selected from hydrogen, fluoro and methoxy.

In some embodiments of the invention, R⁸And R⁹Each independently selected from hydrogen and NR^fR^gWherein R is^fAnd R^gAs defined above; or, R⁸And R⁹Together with the carbon atom to which it is attached form a carbonyl group.

R⁸is hydrogen;

R⁹selected from hydrogen and NR^fR^g(ii) a And is

R^fAnd R^gEach independently is C₁-C₆An alkyl group;

or, R⁸And R⁹Together with the carbon atom to which it is attached form a carbonyl group.

R⁸is hydrogen; and is

R⁹Selected from hydrogen and N, N-dimethylamino;

In some embodiments of the invention, Y is CH.

u and V are each independently selected from CR^fR^gAnd NR^e；

R^eIndependently selected from hydrogen and C₁-C₆An alkyl group; and is

R^fAnd R^gEach independently selected from hydrogen and C₁-C₆An alkyl group.

In some embodiments of the invention, U and V are each independently selected from CH₂And N (C)₁-C₆Alkyl groups).

u is CH₂(ii) a And V is selected from CH₂And N (C)₁-C₆Alkyl groups).

u is CH₂(ii) a And is

V is selected from CH₂、NCH(CH₃)₂And N (CH)₃)。

R¹is C₁-C₆An alkyl group;

R²is hydrogen;

R⁶and R⁷Each independently selected from hydrogen, halogen and C₁-C₆An alkoxy group;

R⁸is hydrogen;

R⁹selected from hydrogen and NR^fR^g；

R^fAnd R^gEach independently is C₁-C₆An alkyl group;

or, R⁸And R⁹Together with the carbon atom to which it is attached form a carbonyl group;

y is CH;

u is CH₂；

V is selected from CH₂And N (C)_1-C₆Alkyl groups);

X is selected from CH and N.

R¹is isopropyl;

R²is hydrogen;

R⁶and R⁷Each independently selected from hydrogen, fluoro and methoxy;

R⁸is hydrogen;

R⁹selected from hydrogen and NR^fR^g；

R^fAnd R^gEach independently is methyl;

y is CH;

u is CH₂；

V is selected from CH₂、NCH(CH₃)₂And N (CH)₃)；

X is selected from CH and N.

According to some embodiments of the invention, the compounds of the invention have the structure of formula V:

wherein the content of the first and second substances,

R¹⁰selected from hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl, said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl are each optionally substituted with one or moreR^jSubstitution;

R¹¹、R¹²、R¹³、R¹⁴each independently selected from hydrogen, halogen, hydroxy, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl, said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl are each optionally substituted with one or more R^jSubstitution; or, R¹¹、R¹²Together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl group; or, R¹³、R¹⁴Together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl group; and is

R¹、R²X and R^jAs defined above.

In some embodiments of the invention, R¹⁰Is C₁-C₆An alkyl group.

In some embodiments of the invention, R¹⁰Selected from methyl and isopropyl.

In some embodiments of the invention, R¹¹、R¹²、R¹³、R¹⁴Each independently selected from hydrogen and C₁-C₆An alkyl group; or, R¹¹、R¹²Together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl group; or, R¹³、R¹⁴Together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl group.

In some embodiments of the invention, R¹¹、R¹²、R¹³、R¹⁴Each independently selected from hydrogen and methyl; or, R¹¹、R¹²Together with the carbon atom to which it is attached form a cyclopropyl group; or, R¹³、R¹⁴Together with the carbon atom to which it is attached, form a cyclopropyl group.

In some embodiments of the inventionIn, R¹¹、R¹²Each independently selected from hydrogen and C₁-C₆Alkyl, and R¹³、R¹⁴Together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl group.

In some embodiments of the invention, R¹¹、R¹²Each independently selected from hydrogen and methyl, and R¹³、R¹⁴Together with the carbon atom to which it is attached, form a cyclopropyl group.

R¹is C₁-C₆An alkyl group;

R²is hydrogen;

R¹⁰is C₁-C₆An alkyl group;

R¹¹、R¹²、R¹³、R¹⁴each independently selected from hydrogen and C₁-C₆An alkyl group; or, R¹¹、R¹²Together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl group; or, R¹³、R¹⁴Together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl group; and is

X is CH.

R¹is C₁-C₆An alkyl group;

R²is hydrogen;

R¹⁰is C₁-C₆An alkyl group;

R¹¹、R¹²、R¹³、R¹⁴each independently selected from hydrogen and C₁-C₆An alkyl group; or, R¹¹、R¹²Each independently selected from hydrogen and C₁-C₆Alkyl radical, R¹³、R¹⁴Together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl group; and is

X is CH.

R¹is isopropyl;

R²is hydrogen;

R¹⁰selected from methyl and isopropyl;

R¹¹、R¹²each independently is hydrogen, R¹³、R¹⁴Together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl group; and is

X is CH.

According to some embodiments of the invention, the compound of the invention is selected from:

another object of the present invention is to provide a method for preparing the compound of the present invention, which is carried out according to the following reaction scheme 1 or 2:

scheme 1:

wherein R is¹、R²、R³X is as defined above;

the second step is that: carrying out coupling or nucleophilic substitution reaction on the compound I-2 to generate a compound I-3, wherein PG is an N atom protecting group, such as Boc, Cbz, Bn, PMB and the like;

Scheme 2:

wherein R is¹、R²、R³X is as defined above;

Pharmaceutical compositions and methods of treatment

It is another object of the present invention to provide a pharmaceutical composition comprising a compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof, together with one or more pharmaceutically acceptable carriers.

It is another object of the present invention to provide a process for preparing a pharmaceutical composition of the present invention, said process comprising combining a compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof, with one or more pharmaceutically acceptable carriers.

It is another object of the present invention to provide a pharmaceutical formulation comprising a compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof, or a pharmaceutical composition of the present invention.

It is another object of the present invention to provide a kit comprising:

1) a compound of the invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, co-crystal, solvate, metabolite, prodrug or any mixture of two or more thereof, or a pharmaceutical composition of the invention; and

2) optionally packaging and/or instructions.

Another object of the present invention is to provide the use of a compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof, or a pharmaceutical composition of the present invention, for the manufacture of a medicament for the treatment of a disease related to HPK 1. In particular, the disease is a tumor.

It is another object of the present invention to provide a compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof or a pharmaceutical composition of the present invention or a kit of the present invention for use in the treatment of a disease associated with HPK 1. In particular, the disease is a tumor.

It is another object of the present invention to provide a method of treating a disease associated with HPK1, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof, or a pharmaceutical composition of the present invention, and optionally comprising co-administering other agents for treating a disease or disorder associated with HPK 1. In particular, the disease is a tumor.

By "pharmaceutically acceptable carrier" in the context of the present invention is meant a diluent, adjuvant, excipient, or vehicle that is administered together 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 employed in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

The pharmaceutical compositions of the present invention may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms.

The pharmaceutical compositions of the present invention may optionally be administered in combination with other agents that have at least some effect in the treatment of various diseases. In some embodiments, the present invention provides a combination preparation of a compound of the invention and an additional therapeutic agent for simultaneous, separate or sequential use in therapy.

The term "effective amount" as used herein 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 desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition being alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering the composition or supervising the administration of the composition.

The amount of a compound of the invention administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. Generally, an effective dose is from about 0.0001 to about 50mg per kg body weight per day, e.g., from about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70kg human, this may amount to about 0.007 mg/day to about 3500 mg/day, e.g., about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforesaid range may be sufficient, while in other cases still larger doses may be employed without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

The compound of the invention may be present in the pharmaceutical composition in an amount or amount of about 0.01mg to about 1000 mg.

As used herein, unless otherwise specified, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing such a disorder or condition, or one or more symptoms of such a disorder or condition, to which such term applies.

As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) having a disease (e.g., a disease described herein) or normal individuals. "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

Definition of

Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. Reference to the techniques used herein is intended to refer to those techniques commonly understood in the art, including those variations of or alternatives to those techniques that would be apparent to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

As used herein, the terms "comprises," "comprising," "has," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

The term "alkyl" as used herein is defined as 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, as used herein, the term "C₁-C₆Alkyl "refers to a straight or branched chain group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl). In some embodiments, the alkyl group is optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogen (when this group is referred to as "haloalkyl", e.g., -CF)₃、-C₂F₅、-CHF₂、-CH₂F、-CH₂CF₃、-CH₂Cl or-CH₂CH₂CF₃Etc.).

As used herein, the term "alkenyl" refers to a hydrocarbon group containing at least one C ═ C double bond. The alkenyl group may be a straight or branched chain alkenyl group and contains 2 to 15 carbon atoms. E.g. "C" herein_2-6Alkenyl "is alkenyl containing 2 to 6 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. An alkenyl radical may be unsubstituted or substituted by one or more identical or different substituentsAnd (4) substitution.

As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo [ 1.1.1)]Pentyl, bicyclo [2.2.1]Heptyl, etc.), optionally substituted with one or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15, such as 3 to 10 carbon atoms, 3 to 7 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, 5 to 7 carbon atoms, 4 to 6 carbon atoms, or 5 to 6 carbon atoms, and the like. For example, as used herein, the term "C₃-C₇Cycloalkyl "refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) having 3 to 7 ring carbon atoms, optionally substituted with one or more (such as 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl.

As used herein, the term "aryl" refers to an all-carbon monocyclic or fused ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term "C₆-C₁₄Aryl "means an aromatic radical containing from 6 to 14 carbon atoms, the term" C₆-C₁₀Aryl "means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. Aryl is optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO)₂、C₁-C₆Alkyl, etc.).

As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic aromatic ring system having 5 to 14 ring atoms, in particular having 5,6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1,2,3,4, 5,6, 7, 8, 9 or 10 carbon atoms, and which contains at least one heteroatom (e.g. oxygen, nitrogen or sulfur) which may be the same or different. And, the heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring linked together with the parent structure is a heteroaryl ring. For example, as used herein, the term "5-14 membered heteroaryl" means a heteroaryl group containing 5 to 14 ring atoms. Specific examples of heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl and the like, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, or azaindolyl, pyrimidopyrazolyl, pyrrolopyridyl, pyrazolopyrimidine and the like, and their benzo derivatives such as indazolyl, indolyl, isoindolyl, quinolyl, isoquinolyl and the like.

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

The term "alkoxy," as used herein, means an alkyl group, as defined above, appended to the parent molecular moiety through an oxygen atom. C₁-C₆Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

As used herein, the term "heterocyclyl" refers to a monocyclic or polycyclic group having, for example, 2,3,4, 5,6, 7, 8, 9 carbon atoms in the ring and one or more (e.g., 1,2,3, or 4) selected from C (═ O), O, S, S (═ O), S (═ O)₂And NR (R represents a hydrogen atom or a substituent such as, but not limited to, an alkyl group or a cycloalkyl group). The heterocyclic group may be saturated or unsaturated. Saturated heterocyclyl groups can be referred to as heterocycloalkyl groups, such as 3-8 membered heterocycloalkyl groups, 5-6 membered heterocycloalkyl groups, and the like. Unless otherwise specifically indicated in the specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or higher ring system, which may include fused, bridged or spiro ring systems. In particular, a 3-10 membered heterocyclyl is a group having 3-10 carbon atoms and heteroatoms in the ring, e.g., having 4 to 10, 4 to 7, 4 to 6, 5 to 10, 5 to 7, or 5 to 6 carbon atoms and heteroatoms (referred to as 4 to 10, 4 to 7, 4 to 6, 5 to 10, 5 to 7, and 5 to 6 membered heterocyclyl, respectively), such as, but not limited to, oxiranyl, aziridinyl, azetidinylAzepinyl, oxetanyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, azacycloheptyl

Mesityl, piperidyl, morpholinyl, dithianyl (dithianyl), thiomorpholinyl, piperazinyl, trithianyl (trithianyl), and the like; and bicyclic derivatives thereof, such as, but not limited to, pyrrolidinyl-cyclopropyl, cyclopent-aziridinyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, pyrrolidinyl-morpholinyl, piperidinyl-morpholinyl; or a benzo derivative or a heteroaryl and derivative; or spiro derivatives, e.g. but not limited to

And the like.

The term "substituted" means that one or more (e.g., 1,2,3, or 4) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency at the present time is not exceeded and the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

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

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

If a variable or substituent can be selected from different variations and the variable or substituent occurs more than once, then the variations can be the same or different.

As used herein, the term "one or more" means 1 or more than 1, such as 2,3,4, 5,6, 7, 8, 9, 10, etc., under reasonable conditions.

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

The invention also includes all pharmaceutically acceptable isotopic compounds, which are identical to those of the present invention, except that one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g. hydrogen)²H、³H) (ii) a Isotopes of carbon (e.g. of¹¹C、¹³C and¹⁴C) (ii) a Isotopes of chlorine (e.g. of chlorine)³⁶Cl); isotopes of fluorine (e.g. of fluorine)¹⁸F) (ii) a Isotopes of iodine (e.g. of iodine)¹²³I and¹²⁵I) (ii) a Isotopes of nitrogen (e.g. of¹³N and¹⁵n); isotopes of oxygen (e.g. of¹⁵O、¹⁷O and¹⁸o); isotopes of phosphorus (e.g. of phosphorus)³²P); and isotopes of sulfur (e.g. of³⁵S)。

The term "stereoisomer" denotes an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., 1,2,3, or 4) asymmetric centers, they can result in racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as mixtures of two or more structurally different forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, dihydropyrimidine groups, 2(1H) -pyridonyl groups, and the like may exist in solution in equilibrium in the following tautomeric forms. It is understood that the scope of this application encompasses all such isomers or mixtures thereof in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerization and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio. It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to: pharmaceutically acceptable salts, solvates, metabolites or prodrugs thereof, which upon administration to a patient in need thereof are capable of providing, directly or indirectly, a compound of the present invention or a metabolite or residue thereof. Thus, when reference is made herein to "a compound of the invention," it is also intended to encompass the various derivative forms of the compounds described above.

Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. 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 compounds of the invention may be present in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.

Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by the process of contacting the compounds of the present invention with a mammal for a time sufficient to produce a metabolite thereof.

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

The invention also encompasses compounds of the invention containing a protecting group. 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, for example, as described in Protective Groups in Organic Chemistry, ed.j.f.w.mcomie, Plenum Press, 1973; and T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons,1991, which are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art. As used herein, the term "about" when used in reference to a value or range of values means that the value or range of values and the range of errors acceptable to one skilled in the art for that value or range of values, for example, the range of errors is ± 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, etc.

Advantageous effects of the 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, wider therapeutic window) and other excellent properties.

Detailed Description

Examples

The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.

The abbreviations in the present invention have the following meanings:

the structure of the compound of the invention is determined by nuclear magnetic resonance spectrum (¹H NMR) or Mass Spectrometry (MS).

The reaction was monitored by Thin Layer Chromatography (TLC) or LCMS.

The microwave reaction was performed using a BiotageInitiator + microwave reactor.

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

In the following examples, the reaction temperature was room temperature (20 ℃ C. to 30 ℃ C.), unless otherwise specified.

Reagents used in this application were purchased from Acros Organics, Aldrich Chemical Company, or Tereber Chemical, among others.

Intermediate int.1: 1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-6-amine

The first step is as follows: 6-chloro-1-isopropyl-1H-pyrazolo [4,3-c ] pyridine (int.1b)

6-chloro-1H-pyrazolo [4,3-c ] pyridine (int.1a,6g,39.07mmol) is dissolved in 50mL DMF, NaH (3.13g,78.14mmol, 60% purity) is added under ice-bath, and then stirred for 0.5H. Then 2-iodopropane (9.96g,58.61mmol) was added and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was quenched by adding saturated ammonium chloride solution, extracted with EA (50mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was spin-dried and purified by flash column chromatography (eluent system a) to yield compound int.1b (4.58 g).

MS(ESI,m/z):196.0[M+H]⁺.

The second step is that: (1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-6-yl) carbamic acid tert-butyl ester (int.1c)

Int.1b (4.45g,22.74mmol), tert-butyl carbamate (13.32g,113.72mmol), Pd₂(dba)₃(2.08g,2.27mmol), Brettphos (2.44g,4.55mmol) and Cs₂CO₃(18.53g,56.86mmol) was dissolved in 50mL of 1, 4-dioxane, N₂Heating to 110 ℃ under protection, and reacting for 5 h. After the reaction was completed, the reaction mixture was filtered through celite, and the filtrate was dried by spin-drying and purified by flash column chromatography (eluent system a) to obtain compound int.1c (4.8 g).

MS(ESI,m/z):277.1[M+H]⁺.

The third step: 1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-6-amine (int.1)

Int.1c (800mg,2.90mmol) was dissolved in 10mL DCM and 10mL TFA and stirred at RT overnight. After the reaction is finished, adding saturated sodium bicarbonate solution to quench the reaction, and adjusting the pH value to be alkaline. Extracted with EA (50mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was spin-dried and purified by flash column chromatography (eluent system a) to yield compound int.1(200 mg).

MS(ESI,m/z):177.1[M+H]⁺.

Intermediate int.2: 4, 6-dichloro-1- (2, 2-difluoroethyl) -1H-pyrrolo [2,3-b ] pyridine

4, 6-dichloro-1H-pyrrolo [2,3-b ]]Pyridine (int.2a,1g,5.35mmol), Cs₂CO₃(3.49g,10.69mmol) and 1, 1-difluoro-2-iodoethane (1.54g,8.02mmol) were dissolved in 10mL of DMF and heated to 70 ℃ for 1 h. After the reaction was completed, the reaction was quenched by adding water, extracted with EA (50mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was spin-dried and purified by flash column chromatography (eluent system a) to yield compound int.2(1.1 g).

MS(ESI,m/z):251.0[M+H]⁺.

Intermediate int.3: 2-bromo-5, 5, 6-trimethyl-5, 6-dihydro-4H-pyrazoline [1,5-d ]][1,4]Diaza derivatives

-7(8H) -one

The first step is as follows: 2- (3, 5-dibromo-1H-pyrazol-1-yl) acetonitrile (Int.3b)

3, 5-dibromo-1H-pyrazole (int.3a,1.5g,6.64mmol) was dissolved in 20mL of DMF, and chloroacetonitrile (750mg,9.96mmol) and potassium carbonate (1.84g,13.28mmol) were added, followed by heating to 40 ℃ for 2H. After the reaction was completed, the reaction was quenched by addition of water, extracted with EA (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the organic phases were dried and purified by flash column chromatography (eluent system a) to yield compound int.3b (1.5 g).

MS(ESI,m/z):265.0[M+H]⁺.

The second step is that: (3-bromo-5- (2-methylprop-1-enyl) -1H-pyrazol-1-yl) acetonitrile (int.3c)

Compound 1b (1.5g, 5.56mmol), 2-methyl-1-propenylboronic acid pinacol ester (1.03g, 5.56mmol), Pd (dppf) Cl₂(413mg, 0.56mmol) and K₂CO₃(3.13g, 21.65mmol) was added to a mixed solvent of 10mL of 1, 4-dioxane and 10mL of water, and N was added₂Heating to 100 ℃ under protection, and reacting for 2 h. After the reaction was completed, the reaction mixture was filtered through celite, and the filtrate was dried by spin-drying and purified by flash column chromatography (eluent system a) to obtain compound int.3c (1 g).

MS(ESI,m/z):240.0[M+H]⁺.

The third step: 2-bromo-5, 5-dimethyl-5, 6-dihydro-4H-pyrazoline [1,5-d ]][1,4]Diaza derivatives

-7(8H) -one (int.3d)

Int.3c (1g,4.16mmol) was added to 20mL of methanesulfonic acid, heated to 65 ℃ and reacted for 72 h. After the reaction is finished, adjusting the pH to 8-9 by using a 1N sodium hydroxide solution. Extracting with EA (50 mL. multidot.3), mixing the organic phases, drying with anhydrous sodium sulfate, spin-drying the organic phase, and subjecting to preparative high performance liquid chromatography (preparation method: Prep-HPLC (instrument model: Agilent 1260, chromatography column: Waters SunAire Prep C)₁₈OBD (19 mm. times.150 mm. times.5.0. mu.m); temperature of the chromatographic column: 25 ℃; flow rate: 20.0 mL/min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid. Compound retention time R_t5.6min) to yield compound int.3d (200 mg).

MS(ESI,m/z):258.0[M+H]⁺.

The fourth step: 2-bromo-5, 5, 6-trimethyl-5, 6-dihydro-4H-pyrazoline [1,5-d ]][1,4]Diaza derivatives

-7(8H) -one (int.3)

Int.3d (100mg, 387.42. mu. mol) was dissolved in 10mL THF, and potassium tert-butoxide (52mg, 464.91. mu. mol) was added. After stirring at room temperature for 0.5h, iodomethane (110mg, 774.85. mu. mol) was added and stirring was continued for 1 h. After the reaction, 2mL of methanol was added to the reaction solution, the organic phase was spin-dried, and subjected to preparative high performance liquid chromatography (preparation method: Prep-HPLC (Instrument model: Agilent 1260, chromatography column: Waters SunAire Prep C)₁₈OBD (19 mm. times.150 mm. times.5.0. mu.m); temperature of the chromatographic column: 25 ℃; flow rate: 20.0 mL/min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid. Compound retention time R_t6.1min) to yield compound int.3(45 mg).

MS(ESI,m/z):272.0[M+H]⁺.

Example 1: (Z) -N- (1- (2-fluorovinyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-6-amine (Compound 1)

Int.1(42.74mg, 170.24. mu. mol), Int.2(30mg, 170.24. mu. mol), tBuONa (49.08mg, 510.73. mu. mol), xantphos (9.85mg, 17.02. mu. mol) and Pd₂(dba)₃(15.59mg, 17.02. mu. mol) was added to a 10mL microwave tube. 3mL of DMF was added, and the mixture was heated to 100 ℃ by microwave for 2 hours. After the reaction, the reaction mixture was filtered through celite, and the filtrate was dried by preparative high performance liquid chromatography (preparation method: Prep-HPLC (Instrument model: Agilent 1260, chromatography column: Waters SunAire Prep C)₁₈OBD (19 mm. times.150 mm. times.5.0. mu.m); temperature of the chromatographic column: 25 ℃; flow rate: 20.0 mL/min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; flow ofPhase B: 0.05% aqueous formic acid. Compound retention time R_t9.3min) to give compound 1(2.11 mg).

MS(ESI,m/z):371.1[M+H]⁺.

¹H NMR(400MHz,MeOD)δ8.74(s,1H),8.52(s,1H),8.08(s,1H),7.84(d,J＝8.4Hz,1H),7.59(dd,J＝3.7,1.8Hz,1H),7.07–6.98(dd,J＝35.4,4.2Hz,1H),6.95–6.93(d,J＝8.4Hz,1H),6.95–6.74(dd,J＝74.0,4.3Hz,1H),6.56–6.55(d,J＝3.7Hz,1H),4.88–4.85(m,1H)1.63–1.62(d,J＝6.7Hz,6H).

Example 2: n- (1- (2, 2-difluoroethyl) -4- (pyrrolidin-3-yl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-6-amine (Compound 2)

The first step is as follows: n- (4-chloro-1- (2, 2-difluoroethyl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-6-amine (Compound 2a)

Compounds int.1(400mg,2.27mmol), int.2(570mg,2.27mmol), Cs₂CO₃(1.48g,4.54mmol), Xantphos (131.34mg, 226.99. mu. mol) and Pd₂(dba)₃(207.86mg, 226.99. mu. mol) was dissolved in 10mL1, 4-dioxane, heated to 90 ℃ and reacted overnight. After the reaction was completed, the mixture was filtered through celite, and the filtrate was spin-dried and purified by flash column chromatography (eluent system a) to give compound 2a (220 mg).

MS(ESI,m/z):391.0[M+H]⁺.

The second step is that: tert-butyl 3- (1- (2, 2-difluoroethyl) -6- (((1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-6-yl) amino ] -1H-pyrrolo [2,3-b ] pyridin-4-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylate (Compound 2b)

Compound 2a (100mg, 266.10. mu. mol), 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydropyrrole-1-carboxylic acid tert-butyl ester (117.82mg, 399.15. mu. mol), Pd (dppf) Cl₂(19.47mg, 26.61. mu. mol) and Cs₂CO₃(173.50mg, 532.19. mu. mol) was dissolved in 10mL of 1, 4-dioxoSix rings and 1mL water. N is a radical of₂Heating to 90 ℃ under protection, and reacting for 2 h. After the reaction was completed, the mixture was filtered through celite. The filtrate was spin-dried and purified by flash column chromatography (eluent system a) to give compound 2b (38 mg).

MS(ESI,m/z):524.2[M+H]⁺.

The third step: tert-butyl 3- (1- (2, 2-difluoroethyl) -6- (((1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-6-yl) amino ] -1H-pyrrolo [2,3-b ] pyridin-4-yl) pyrrolidine-1-carboxylic acid ester (Compound 2c)

Compound 2b (10.00mg, 19.10. mu. mol), 10% Pd/C (2.32mg, 19.10. mu. mol) was dissolved in 10mL MeOH, H₂The reaction was carried out overnight under protection. After the reaction was completed, the reaction solution was filtered. The filtrate was spun dry to give compound 2c (8mg) which was used directly in the next reaction.

MS(ESI,m/z):526.2[M+H]⁺.

The fourth step: n- (1- (2, 2-difluoroethyl) -4- (pyrrolidin-3-yl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-6-amine (Compound 2)

Compound 2c (8mg, 15.22. mu. mol) was dissolved in 10mL DCM, 10mL TFA was added, and the reaction was carried out at room temperature for 2 h. After the reaction, the reaction mixture was concentrated and subjected to preparative high performance liquid chromatography (preparation method: Prep-HPLC (Instrument model: Agilent 1260, chromatography column: Waters SunAire Prep C)₁₈OBD (19 mm. times.150 mm. times.5.0. mu.m); temperature of the chromatographic column: 25 ℃; flow rate: 20.0 mL/min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid. Compound retention time R_t3.8min) to give compound 2(3.57 mg).

MS(ESI,m/z):426.2[M+H]⁺.

¹H NMR(400MHz,MeOD)δ8.76(s,1H),8.64(s,1H),8.10(s,1H),7.26–7.25(d,J＝3.5Hz,1H),6.84(s,1H),6.59–6.58(d,J＝3.6Hz,1H),6.47–6.17(tt,J＝55.6,3.9Hz,1H),4.92–4.90(m,1H),4.78–4.70(td,J＝14.6,4.0Hz,2H),3.93–3.82(m,2H),3.70–3.58(m,1H),3.51–3.41(m,2H),2.66–2.49(m,1H),2.42–2.28(m,1H),1.60–1.58(t,J＝9.3Hz,6H).

Example 3: n- (1- (morpholin-2-ylmethyl) -1H-pyrazolo [4,3-c ] pyridin-6-yl) cyclopropanecarboxamide (Compound 3)

The first step is as follows: 6-chloro-1-trityl-1H-pyrazolo [4,3-c ] pyridine (Compound 3a)

Int.1a (4g,26.05mmol) was dissolved in 60mL THF, NaH (1.80g,46.88mmol, 60% purity) was added to the reaction at 0 deg.C and stirred for 0.5 h. Triphenylchloromethane (18.88g,67.72mmol) was added to the reaction system, stirred at 0 ℃ for 0.5h, warmed to room temperature, and reacted for 2 h. After the reaction was completed, extraction was performed with EA (50mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was spin dried and purified by flash column chromatography (eluent system a) to give compound 3b (8.4 g).

MS(ESI,m/z):396.1[M+H]⁺.

The second step is that: (1-trityl-1H-pyrazolo [4,3-c ] pyridin-6-yl) carbamic acid tert-butyl ester (Compound 3b)

Compound 3b (8.4g, 21.22mmol), tert-butylcarbamate (12.43g, 106.09mmol), Pd₂(dba)₃(1.94mg, 2.12mmol), Brettphos (2.28g, 4.24mmol) and Cs₂CO₃(17.28g, 53.05mmol) was dissolved in 100mL of 1, 4-dioxane, N₂Heating to 110 ℃ under protection, and reacting for 6 h. After the reaction was completed, the mixture was filtered through celite. The filtrate was spin dried and purified by flash column chromatography (eluent system a) to give compound 3b (7.2 g).

MS(ESI,m/z):477.0[M+H]⁺.

The third step: (Cyclopropanecarbonyl) (1-trityl-1H-pyrazolo [4,3-c ] pyridin-6-yl) carbamic acid tert-butyl ester (Compound 3c)

Compound 3b (7.1g,14.90mmol) and DIPEA (7.7g,59.59mmol) were dissolved in 100mL DCM, cyclopropanecarbonyl chloride (3.11g,29.80mmol) was slowly added dropwise to the reaction mixture at 0 deg.C, and the reaction was carried out at room temperature for 2 h. After completion of the reaction, the reaction mixture was directly concentrated to obtain compound 3c (8 g).

MS(ESI,m/z):545.0[M+H]⁺.

The fourth step: n- (1H-pyrazolo [4,3-c ] pyridin-6-yl) cyclopropanecarboxamide (Compound 3d)

Compound 3c (8.0g,14.69mmol) was dissolved in 80mL DCM and 20mL TFA and reacted at room temperature for 5 h. After the reaction is finished, the pH is adjusted to about 8-9 by using saturated sodium bicarbonate. Extracted with EA (50mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was spin dried and purified by flash column chromatography (eluent system a) to give compound 3d (2.3 g).

MS(ESI,m/z):203.1[M+H]⁺.

The fifth step: tert-butyl 2- ((6- (cyclopropanecarboxamido) -1H-pyrazolo [4,3-c ] pyridin-1-yl) methyl) morpholine-4-carboxylate (compound 3e)

Compound 3d (200mg, 989.06. mu. mol) and tert-butyl 2- (bromomethyl) morpholine-4-carboxylate (415.64mg,1.48mmol) were dissolved in 8mL DMF and K was added₂CO₃(272.98mg,1.98mmol), the temperature was raised to 60 ℃ and the reaction was stirred for 15 h. After the reaction was completed, extraction was performed with EA (50mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was spin dried and purified by flash column chromatography (eluent system a) to give compound 3e (300 mg).

MS(ESI,m/z):402.0[M+H]⁺.

And a sixth step: n- (1- (morpholin-2-ylmethyl) -1H-pyrazolo [4,3-c ] pyridin-6-yl) cyclopropanecarboxamide (Compound 3)

Compound 3e (300mg, 747.28. mu. mol) was added to 12mL DCM and 3mL TFA and reacted at room temperature with stirring for 2 h. After the reaction is finished, the pH is adjusted to about 8-9 by saturated sodium bicarbonate, and the mixture is subjected to preparative high performance liquid chromatography (preparation method: Prep-HPLC (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; elution gradient: (2 min: 8% A, 92% B; 15.0 min: 40% A, 60% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous ammonium bicarbonate solution. Compound retention time R_t7.12min) compound 3(130mg) was isolated.

MS(ESI,m/z):302.0[M+H]⁺.

¹H NMR(400MHz,DMSO-d₆)δ10.91(s,1H),8.84(d,J＝0.7Hz,1H),8.21(d,J＝3.4Hz,2H),4.37–4.22(m,2H),3.82–3.73(m,1H),3.64(d,J＝11.0Hz,1H),3.31(td,J＝11.0,4.2Hz,1H),2.76(d,J＝11.8Hz,1H),2.66–2.53(m,2H),2.45(t,J＝11.0Hz,1H),2.11–2.00(m,1H),0.89–0.77(m,4H).

Example 4: 2- ((1-isopropyl-1H-pyrazolo [4, 3-c)]Pyridin-6-yl) amino) -5,5, 6-trimethyl-5, 6-dihydro-4H-pyrazoline [1,5-d][1,4]Diaza derivatives

-7(8H) -one (Compound 4)

Int.3(15mg, 56.75. mu. mol), Int.1(15mg, 56.75. mu. mol), cesium carbonate (37mg, 113.50. mu. mol), Xantphos (3.3mg, 5.67. mu. mol) and Pd₂(dba)₃(5.2mg, 5.67. mu. mol) in 10mL1, 4-dioxane, N₂Heating to 100 ℃ under protection, and reacting for 2 h. After the reaction was completed, the mixture was filtered through celite. The filtrate was spin-dried and subjected to preparative high performance liquid chromatography (preparation method: Prep-HPLC (instrument model: Agilent 1260, column: Waters SunAire Prep C)₁₈OBD (19 mm. times.150 mm. times.5.0. mu.m); temperature of the chromatographic column: 25 ℃; flow rate: 20.0 mL/min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous formic acid. Compound retention time R_t4.2min) to give compound 4(1.37 mg).

MS(ESI,m/z):368.2[M+H]⁺.

¹H NMR(400MHz,MeOD)δ8.65(s,1H),8.03(s,1H),7.57(s,1H),6.09(s,1H),5.05(s,2H),4.82–4.79(m,1H),3.24(s,2H),2.92(s,3H),1.55–1.53(d,J＝6.7Hz,6H).

Example 5: n- (1-isopropyl-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine (compound 5)

The first step is as follows: 2, 4-dichloropyrimidine-5-carbaldehyde (Compound 5b)

Compound 5a (3g,13.17mmol) was dissolved in 30mL of THF, and isopropyl magnesium chloride-lithium chloride (11.14mL,14.48mmol) was added to the reaction system at-78 deg.C, followed by reaction for 40 minutes with stirring. Then a solution of morpholine-4-aldehyde (4.55g,39.50mmol) in 30mL of THF was added to the reaction, stirred at-78 deg.C for 10min, then raised to-40 deg.C and reacted for 1 h. After the reaction was completed, the reaction was quenched with 1N hydrochloric acid. Extracted with EA (50mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was spin dried and purified by flash column chromatography (eluent system a) to give compound 5b (830 mg).

MS(ESI,m/z):177.0[M+H]⁺.

The second step is that: 6-chloro-1H-pyrazolo [3,4-d ] pyrimidine (compound 5c)

Compound 5b (800mg,4.52mmol) was dissolved in 10mL THF, and a solution of hydrazine hydrate (452.55mg,9.04mmol) in 10mL THF was added to the reaction at 0 deg.C, followed by reaction for 1h with stirring at room temperature. After the reaction was completed, extraction was performed with EA (50mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was spin dried and purified by flash column chromatography (eluent system a) to give compound 5c (190 mg).

MS(ESI,m/z):155.1[M+H]⁺.

The third step: 6-chloro-1-isopropyl-1H-pyrazolo [3,4-d ] pyrimidine (compound 5d)

Compound 5c (180mg,1.16mmol) was dissolved in 5mL of DMF, the system was left at 0 ℃ and NaH (55.9mg,46.88mmol, 60% purity) was added to the reaction system and reacted for 0.5h with stirring. Finally, 2-iodopropane (296.96mg,1.75mmol) was added to the reaction system, and the reaction was allowed to warm to room temperature for 1 hour. After the reaction was completed, extraction was performed with EA (50mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was spin dried and purified by flash column chromatography (eluent system a) to give compound 5d (120 mg).

MS(ESI,m/z):197.1[M+H]⁺.

The fourth step: n- (1-isopropyl-1H-pyrazolo [3,4-d ] pyrimidin-6-yl) -6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine (compound 5)

Compound 5d (49.09mg, 249.67. mu. mol) and 6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine (40mg, 208.05. mu. mol) were added to 3mL of isopropanol and 0.02mL of concentrated hydrochloric acid, and the mixture was heated to 80 ℃ and reacted with stirring for 15 hours. After the reaction, the reaction mixture was cooled, concentrated, and subjected to preparative high performance liquid chromatography (preparation method: Prep-HPLC (instrument model: Agilent 1260, 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; elution gradient: (3 min: 10% A, 90% B; 16.0 min: 70% A, 30% B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous ammonium bicarbonate solution. Compound retention time R_t8.1min) compound 5(10mg) was isolated.

MS(ESI,m/z):353.1[M+H]⁺.

¹H NMR(400MHz,CDCl₃)δ8.80(s,1H),8.35(s,1H),7.90(d,J＝3.4Hz,2H),6.64(s,1H),5.10–4.98(m,1H),3.89(s,3H),3.62(s,2H),2.91(t,J＝5.8Hz,2H),2.71(t,J＝5.9Hz,2H),2.51(s,3H),1.62(d,J＝6.7Hz,6H).

The compounds in the following table were synthesized according to the corresponding methods in the above examples:

biological evaluation

The following experimental examples further describe and explain the present invention, but these examples are not intended to limit the scope of the present invention.

Experimental example 1: inhibition assay of HPK1 enzymatic activity by Compounds

Compounds were tested for HPK1 enzymatic activity using an ATP-glossay assay, reagents (HPK1,5x kinase buffer, substrate (mbp), ATP) were purchased from Promega corporation, and protocol and optimization were recommended based on the instructions for the reagents.

Mu.l 2.5 XHPK 1(2 ng/. mu.l) was added to the 384 well plates followed by 1. mu.l of the 5 Xrange of concentrations of the test compound, and after incubation for 10min at room temperature 2. mu.l 2.5 XMBP (0.25. mu.g/. mu.l)/ATP (25. mu.M) was added and incubated for 1h at room temperature. After completion of the incubation, 5. mu.l of ATP-Glo reagent (ATP-Glo reagent) was added to each well of the 384-well plate, 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 reacted at room temperature for 1 hour. After the reaction was completed, the 384 well plates were transferred to BMG LABTECH (PHERAstar) for reading, and the mode was selected: luminescence, data presentation: relative chemiluminescence values RLU (relative Luminescence units).

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

compound 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}The values are relative chemiluminescence values of the group treated with no compound; RLU_{Blank space}Relative chemiluminescence values for the group without HPK1 and without compound treatment; RLU_{Treatment of}Is the relative chemiluminescence value of the compound treatment group. IC was calculated by Graphpad Prism software log (inhibitor) vs. response-variable slope (four parameter) fitting₅₀。

Compound (I)	HPK1 IC₅₀(nM)
		1	60.79
2	4.22
		3	175.07
4	60.87
		5	15.91

Therefore, the compounds (such as the compounds 1-5) have better inhibition effect on the enzymatic activity of HPK 1.

Claims

1. A compound of formula I or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, co-crystal, solvate, metabolite, prodrug or any mixture of two or more thereof:

wherein the content of the first and second substances,

R¹selected from hydrogen, C (O) R^a、CO₂R^a、C(O)NR^bR^c、S(O)R^a、SO₂R^a、SO₂NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl, 3-8 membered heterocyclyl and 5-14 membered heteroaryl, said C₁-C₆Alkyl radical, C₃-C₇CycloalkanesBase, C₆-C₁₄Aryl, 3-8 membered heterocyclyl and 5-14 membered heteroaryl are each optionally substituted with one or more R^dSubstitution;

R^band R^cEach independently selected from hydrogen and C_1-C₆Alkyl radical, C_3-C₇Cycloalkyl radical, C_1-C₆Alkoxy radical C₁-C₆Alkyl and 4-7 membered heterocyclyl; or, R^bAnd R^cTogether with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy radical C₁-C₆Each of alkyl and 4-7 membered heterocyclyl is optionally substituted with one or more R^dSubstitution;

x is selected from CH and N;

R^dindependently selected from: hydrogen, hydroxy, halogen, oxo, CN, NO₂、C(O)R^e、CO₂R^e、NR^fSO₂R^g、S(O)R^e、SO₂R^e、C(O)NR^fR^g、SO₂NR^fR^g、NR^fR^g、NR^fC(O)R^g、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy radical C₁-C₆Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl, said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy radical C₁-C₆Alkoxy radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl are each optionally substituted with one or more R^jSubstitution;

2. A compound of claim 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug, or any mixture of two or more thereof,

R¹selected from hydrogen, C (O) R^a、CO₂R^a、C(O)NR^bR^c、S(O)R^a、SO₂R^a、SO₂NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more R^dSubstitution;

preferably, R¹Selected from hydrogen, C (O) R^a、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 3-8 membered heterocyclyl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 3-8 membered heterocyclyl are each optionally substituted with one or more R^dSubstitution;

more preferably, R¹Selected from hydrogen, C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 3-8 membered heterocyclyl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 3-8 membered heterocyclyl are each optionally substituted with R^dSubstitution;

more preferably, R¹Is selected from C₁-C₆Alkyl and 5-6 membered azacycloalkyl, said C₁-C₆Alkyl is optionally substituted with a group selected from: hydroxy, C₁-C₆Alkoxy, halogen, and 5-6 membered heterocyclyl;

more preferably, R¹Is selected from C₁-C₆Alkyl and pyrrolidinyl, said C₁-C₆Alkyl is optionally substituted with a group selected from: hydroxy, C₁-C₆Alkoxy, halogen and morpholinyl;

more preferably, R¹Is selected from C₁-C₆Alkyl and pyrrolidinyl, said C₁-C₆Alkyl is optionally substituted with a group selected from: hydroxy, methoxy, fluoro and morpholinyl;

particularly preferably, R¹Selected from the group consisting of isopropyl, sec-butyl, morpholin-2-ylmethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-fluoroethyl and pyrrolidinyl.

3. A compound of claim 1 or 2, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof,

R²selected from hydrogen, halogen, CN, NO₂、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy radical, C₆-C₁₀Aryl and 5-to 10-membered heteroaryl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₁-C₆Alkoxy radical, C₆-C₁₀Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more R^dSubstitution;

preferably, R²Selected from hydrogenHalogen, C₁-C₆Alkyl and C₃-C₇Cycloalkyl radical, said C₁-C₆Alkyl and C₃-C₇Cycloalkyl is each optionally substituted by one or more R^dSubstitution;

more preferably, R²Selected from hydrogen, halogen and C₁-C₆Alkyl radical, said C₁-C₆Alkyl is optionally substituted by one or more R^dSubstitution;

particularly preferably, R²Is hydrogen.

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

R³selected from hydrogen, C (O) R^a、CO₂R^a、C(O)NR^bR^c、S(O)R^a、SO₂R^a、SO₂NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl and 5-to 10-membered heteroaryl, said C₆-C₁₀Aryl and 5-10 membered heteroaryl are each optionally substituted with C₃-C₇Cycloalkyl or 5-to 10-membered heterocyclyl fused, and said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are each optionally substituted with one or more R^dSubstitution;

preferably, R³Selected from C (O) R^a、CO₂R^a、C(O)NR^bR^c、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl and 5-to 10-membered heteroaryl, said C₆-C₁₀Aryl and 5-10 membered heteroaryl are each optionally substituted with C₃-C₇Cycloalkyl or 5-to 10-membered heterocyclyl fused, and said C₁-C₆Alkyl radical, C₃-C₇A cycloalkyl group, a,C₆-C₁₀Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are each optionally substituted with one or more R^dSubstitution;

more preferably, R³Selected from C (O) R^a、CO₂R^a、C₆-C₁₀Aryl and 5-to 10-membered heteroaryl, said C₆-C₁₀Aryl and 5-10 membered heteroaryl are each optionally substituted with C₃-C₇Cycloalkyl or 5-to 10-membered heterocyclyl fused, and said C₆-C₁₀Aryl, 5-10 membered heteroaryl, C₃-C₇Cycloalkyl and 5-10 membered heterocyclyl are each optionally substituted with 1,2,3 or 4R^dSubstitution;

more preferably, R³Selected from C (O) R^a、C₆-C₁₀Aryl and 5-to 10-membered heteroaryl, said C₆-C₁₀Aryl and 5-10 membered heteroaryl are each optionally substituted with C₃-C₇Cycloalkyl or 5-to 10-membered heterocyclyl fused, and said C₆-C₁₀Aryl, 5-10 membered heteroaryl, C₃-C₇Cycloalkyl and 5-10 membered heterocyclyl are each optionally substituted with 1,2,3 or 4R^dSubstitution;

more preferably, R³Selected from C (O) R^aPhenyl and 5-9 membered heteroaryl, each of which is optionally substituted with C₅-C₆Cycloalkyl or 5-9 membered heterocyclyl fused and said phenyl, 5-9 membered heteroaryl, C₅-C₆Cycloalkyl and 5-9 membered heterocyclyl are each optionally substituted with 1,2,3 or 4R^dAnd (4) substitution.

5. A compound of claim 4, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug, or any mixture of two or more thereof,

R³selected from pyrazolyl, pyridyl, pyrimidinyl, indolyl, indazolyl or pyrimidopyrazolyl, optionally substituted by 1 or 2R^dSubstitution; and is

R^dIndependently selected from oxo, amino, C₁-C₆Alkyl and pyrrolidinyl, said C₁-C₆Alkyl and pyrrolidinyl are each optionally substituted with hydroxy, CN or acetyl.

6. A compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof, wherein the compound is a compound of formula II:

wherein the content of the first and second substances,

R^ais selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl, said C₆-C₁₄Aryl and 5-14 membered heteroaryl are each optionally substituted with C₃-C₇Cycloalkyl or 5-to 10-membered heterocyclyl fused, and 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;

preferably, R^aIs selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl and 5-to 10-membered heteroaryl, said C₆-C₁₀Aryl and 5-10 membered heteroaryl are each optionally substituted with C₃-C₇Cycloalkyl or 5-to 10-membered heterocyclyl fused, and said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₀Aryl and 5-10 membered heteroaryl are each optionally substituted by 1 or 2R^dSubstitution;

more preferably, R^aIs selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl and 5-to 10-membered heteroaryl, said5-10 membered heteroaryl optionally fused with 5-6 membered heterocyclyl, and said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 5-10 membered heteroaryl and 5-6 membered heterocyclyl are each optionally substituted with 1 or 2 substituents independently selected from halogen and C₁-C₆Radical substitution of alkyl;

more preferably, R^aIs selected from C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, pyrrolyl, pyrazolyl and imidazolyl each optionally fused to a benzene or tetrahydropyrimidine ring, and C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, pyrrolyl, pyrazolyl, imidazolyl, phenyl or tetrahydropyrimidine ring each optionally substituted by 1 or 2 substituents independently selected from halogen and C₁-C₆Radical substitution of alkyl;

particularly preferably, R^aSelected from cyclopropyl, fluorocyclopropyl, difluorocyclopropyl, cyclobutyl, isopropyl, pyrazolyl, methyl pyrazolyl, indazolyl, indolyl and tetrahydropyrimidizolyl.

7. A compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof, wherein the compound is of formula III:

wherein the content of the first and second substances,

R⁴selected from hydrogen, C (O) R^e、CO₂R^e、C(O)NR^fR^g、S(O)R^e、SO₂R^e、SO₂NR^fR^g、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl, said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl and 5-14 membered heteroaryl are each optionally substituted with 1 or 2R^jSubstitution; and is

R⁵Selected from hydrogen, NR^fR^g、C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₄Aryl and 5-14 membered heteroaryl, said C₁-C₆Alkyl radical, C₃-C₇Cycloalkyl, 3-8 membered heterocyclyl, C₆-C₁₄Aryl and 5-14 membered heteroaryl are each optionally substituted with 1 or 2R^jSubstitution;

preferably, the first and second electrodes are formed of a metal,

R⁴is selected from C₁-C₆Alkyl and C₂-C₆Alkenyl radical, said C₁-C₆Alkyl and C₂-C₆Each alkenyl group is optionally substituted by 1 or 2 substituents independently selected from halogen, NR^fR^gAnd 5-6 membered heterocyclyl;

R⁵selected from hydrogen, NR^fR^gAnd 5-6 membered heterocyclyl;

R^fand R^gEach independently selected from hydrogen and C_1-C₆Alkyl radical, wherein said C₁-C₆Alkyl is optionally substituted by NR^hRⁱSubstitution; and;

R^hand RⁱEach independently selected from hydrogen and C_1-C₆An alkyl group;

it is particularly preferred that,

R⁴selected from 2-fluorovinyl, 2-difluoroethyl, isopropyl, isobutyl, and mixtures thereof,

And 2- (N, N-dimethylamino) ethyl; and is

R⁵Selected from the group consisting of hydrogen, pyrrolidinyl, morpholinyl, piperidinyl, 2- (N-methylamino) ethylamino, and 2- (N, N-dimethylamino) ethylamino.

8. A compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof, wherein the compound is of formula IV:

wherein the content of the first and second substances,

y is selected from CH and N;

u and V are each independently selected from CR^fR^g、NR^eO, S (O) and SO₂(ii) a And is

m and n are each independently selected from 0, 1 and 2, and the sum of m and n is 0, 1 or 2;

preferably, the first and second electrodes are formed of a metal,

R⁸and R⁹Each independently selected from hydrogen and NR^fR^g(ii) a Or, R⁸And R⁹Together with the carbon atom to which it is attached form a carbonyl group;

y is CH;

u and V are each independently selected from CR^fR^gAnd NR^e；

R^eIndependently selected from hydrogen and C₁-C₆An alkyl group;

R^fand R^gEach independently selected from hydrogen and C₁-C₆An alkyl group; and is

it is particularly preferred that,

R⁶and R⁷Each independently selected from hydrogen, fluoro and methoxy;

R⁸is hydrogen;

R⁹selected from hydrogen and N, N-dimethylamino;

y is CH;

u is CH₂；

V is selected from CH₂、NCH(CH₃)₂And N (CH)₃) (ii) a And is

m and n are each independently selected from 0, 1 and 2, and the sum of m and n is 0, 1 or 2.

9. A compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof, wherein the compound is of formula V:

wherein the content of the first and second substances,

R¹⁰selected from hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl, said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl are each optionally substituted with one or more R^jSubstitution; and is

R¹¹、R¹²、R¹³、R¹⁴Each independently selected from hydrogen, halogen, hydroxy, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl, said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl radical, C₆-C₁₄Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl are each optionally substituted with one or more R^jSubstitution; or, R¹¹、R¹²Together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl group; or, R¹³、R¹⁴Together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl group;

preferably, the first and second electrodes are formed of a metal,

R¹⁰is C₁-C₆An alkyl group; and is

R¹¹、R¹²、R¹³、R¹⁴Each independently selected from hydrogen and C₁-C₆An alkyl group; or, R¹¹、R¹²Together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl group; or, R¹³、R¹⁴Together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl group;

it is particularly preferred that,

R¹⁰selected from methyl and isopropyl; and is

R¹¹、R¹²、R¹³、R¹⁴Each independently selected from hydrogen and methyl; or, R¹¹、R¹²Together with the carbon atom to which it is attached form a cyclopropyl group; or, R¹³、R¹⁴Together with the carbon atom to which it is attached, form a cyclopropyl group.

10. The compound of claim 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug, or any mixture of two or more thereof, wherein the compound is selected from the group consisting of:

11. a pharmaceutical composition comprising a compound of any one of claims 1 to 10, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug, or any mixture of two or more thereof, and one or more pharmaceutically acceptable carriers.

12. A kit, comprising:

1) a compound according to any one of claims 1 to 10 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof, or a pharmaceutical composition according to claim 11; and

2) optionally packaging and/or instructions.

13. Use of a compound according to any one of claims 1 to 10, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof, for the manufacture of a medicament for the treatment of a disease associated with HPK1, in particular a tumor.

14. The use of claim 13, wherein the medicament further comprises an additional agent for treating a disease or disorder associated with HPK 1.

15. A process for the preparation of a compound according to any one of claims 1 to 10, according to the following scheme 1 or 2:

scheme 1:

wherein R is¹、R²、R³X is as defined in any one of claims 1 to 10;

the fourth step: carrying out coupling, condensation or alkylation reaction on the compound I-4 to generate a target compound I;

scheme 2:

wherein R is¹、R²、R³X is as defined in any one of claims 1 to 10;