Pyrazolo-ring compounds, pharmaceutical compositions containing the same, preparation methods thereof and uses thereof

Abstract

The present invention relates to a compound of formula I or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, cocrystal, solvate, metabolite, prodrug thereof, or any mixture of two or more of them, a pharmaceutical composition comprising the same, a method for preparing the same, and its use in the preparation of a drug for treating, for example, tumors.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and relates to pyrazolo-ring compounds, pharmaceutical compositions containing the same, methods for preparing the same, and their use in the preparation of drugs for treating diseases related to HPK1. Background Art

[0002] Hematopoietic progenitor kinase 1 (HPK1), also known as mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1), is a member of the Ste-20 serine / threonine family, and its family members also include MAP4K2 (GCK), MAP4K3 (GLK), MAP4K4 (HGK), MAP4K5 (KHS), and MAP4K6 (MINK). HPK1 is mainly restrictively expressed in hematopoietic system cells, including early progenitor cells and hematopoietic cell lines, such as human acute lymphoblastic leukemia cells (MOLT4), human lymphoma cells (Daudi), etc. Under physiological conditions, HPK1 functions in peripheral immune tolerance through the JNK / SAPK signaling pathway. However, in certain tumor processes, HPK1 negatively regulates T cell and B cell responses and the activation of dendritic cells. When the T cell receptor (TCR) binds to ligands (CD3 / 28), HPK1 is activated by the TCR signaling pathway. Activated HPK1 can phosphorylate serine 376 of the adaptor protein SLP-76, thereby recruiting 14-3-3 proteins, resulting in the instability of the TCR complex, and ultimately leading to weakened T cell responses and inhibited T cell proliferation. Therefore, in tumor treatment, more and more attention has been paid to exerting the anti-tumor effect of the patient's own immune system by inhibiting the immune negative regulatory effect of HPK1. Studies have shown that the antigen presentation function of mouse dendritic cells is enhanced by specifically deleting the HPK1 enzyme activity (Alzabin, Bhardwaj et al. 2009). Similarly, compared with the control group (wild-type T cells), the tumor inhibition rate of Lewis lung cancer xenograft mice was significantly increased after receiving T cell transplantation treatment with HPK1 knockout (Alzabin, Pyarajan et al. 2010). Therefore, searching for small molecule inhibitors of HPK1 can be a new direction for tumor immunotherapy. Summary of the Invention

[0003] The present invention provides novel and highly active HPK1 inhibitor compounds, which can be used alone or in combination with other drugs to treat tumor diseases.

[0004] The first aspect of the present invention relates to a compound of formula I or a stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, co-crystal, solvate, metabolite, prodrug thereof, or any mixture of two or more of them:

[0005]

[0006] wherein,

[0007] R 1 is selected from hydrogen, C(O)R a , CO2R a , C(O)NR b R c , S(O)R a , SO2R a , SO2NR b R c , C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl, 3-8 membered heterocyclic group and 5-14 membered heteroaryl, and the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl, 3-8 membered heterocyclic group and 5-14 membered heteroaryl are each optionally substituted by one or more R d ;

[0008] R 2 is selected from hydrogen, halogen, CN, NO2, C(O)R a , CO2R a , C(O)NR b R c , S(O)R a , SO2R a , SO2NR b R c , NR b R c , NHC(O)R a , NHCO2R a , OC(O)R a , C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 aryl and 5-14 membered heteroaryl, and the C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 aryl and 5-14 membered heteroaryl are each optionally substituted by one or more R d ;

[0009] R 3 is selected from hydrogen, C(O)R a , CO2R a , C(O)NR b Rc 、S(O)R a 、SO2R a 、SO2NR b R c 、C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl and 5-14 membered heteroaryl, wherein the C6-C 14 aryl and 5-14 membered heteroaryl are each optionally fused with a C3-C7 cycloalkyl or a 5-10 membered heterocyclic group, and the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl, 5-14 membered heteroaryl and 5-10 membered heterocyclic group are each optionally substituted with one or more R d ;

[0010] R a is independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl and 5-14 membered heteroaryl, wherein the C6-C 14 aryl and 5-14 membered heteroaryl are each optionally fused with a C3-C7 cycloalkyl or a 5-10 membered heterocyclic group, and the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl, 5-14 membered heteroaryl and 5-10 membered heterocyclic group are each optionally substituted with one or more R d ;

[0011] R b and R c are each independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl and 4-7 membered heterocyclic group; or, R b and R c together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group, and the C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl and 4-7 membered heterocyclic group are each optionally substituted with one or more R d ;

[0012] X is selected from CH and N;

[0013] R d is independently selected from: hydrogen, hydroxy, halogen, oxo, CN, NO2, C(O)R e 、CO2R e 、NR f SO2R g 、S(O)R e 、SO2R e 、C(O)NR f R g 、SO2NR f Rg , NR f R g , NR f C(O)R g , C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 alkoxy-C1-C6 alkoxy, C6-C 14 aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 alkoxy-C1-C6 alkoxy, C6-C 14 aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic group are each optionally substituted by one or more R j substituted;

[0014] R e is independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl and 5-14 membered heteroaryl;

[0015] R f and R g are each independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl and 4-7 membered heterocyclic group, wherein the C1-C6 alkyl is optionally substituted by C1-C6 alkoxy or NR h R i substituted; or, R b and R c together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group;

[0016] R h and R i are each independently selected from hydrogen and C1-C6 alkyl; and

[0017] R j is independently selected from halogen, hydroxy, CN, C(O)R e , NR f R g , C(O)NR b R e , NR b C(O)R e and 3-8 membered heterocyclic group.

[0018] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs or any mixture of two or more thereof, and one or more pharmaceutically acceptable carriers.

[0019] Another aspect of the present invention provides a medicine box, which comprises:

[0020] 1) The compound of the present invention or its stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, cocrystal, solvate, metabolite, prodrug or any mixture of two or more of them; and

[0021] 2) Optionally present packaging and / or instructions.

[0022] Another aspect of the present invention provides the use of the compound of the present invention or its stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, cocrystal, solvate, metabolite, prodrug or any mixture of two or more of them, or the pharmaceutical composition of the present invention in the preparation of a drug for treating diseases related to HPK1.

[0023] Another aspect of the present invention provides the compound of the present invention or its stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, cocrystal, solvate, metabolite, prodrug or any mixture of two or more of them, or the pharmaceutical composition of the present invention, or the medicine box of the present invention, which is used for treating diseases related to HPK1.

[0024] Another aspect of the present invention provides a method for treating diseases related to HPK1, the method comprising administering to an individual in need thereof an effective amount of the compound of the present invention or its stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, cocrystal, solvate, metabolite or prodrug or any mixture of two or more of them, or the pharmaceutical composition of the present invention, and optionally comprising co-administering other agents for treating diseases or disorders related to HPK1.

[0025] 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 route 1 or 2:

[0026] Reaction route 1:

[0027]

[0028] Wherein, R 1 、R 2 、R 3 、X are as defined above;

[0029] The first step: The compound I-1 undergoes a coupling, condensation or alkylation reaction to generate the compound I-2, wherein LG1 is a leaving group, such as a halogen (such as Cl, Br or I), OTs, OTf, etc.;

[0030] Step 2: Compound I-2 undergoes a coupling or nucleophilic substitution reaction to form compound I-3, where PG is an amino protecting group, such as Boc, Cbz, Bn, PMB, etc.;

[0031] Step 3: Compound I-3 undergoes a deprotection reaction to form compound I-4;

[0032] Step 4: Compound I-4 undergoes a coupling, condensation or alkylation reaction to form the target compound I.

[0033] Reaction Route 2:

[0034]

[0035] wherein, R 1 , R 2 , R 3 , X are as defined above;

[0036] Step 1: Compound I-1 undergoes a coupling, condensation or alkylation reaction to form compound I-2, where LG1 is a leaving group, such as a halogen (e.g., Cl, Br or I), OTs, OTf, etc.;

[0037] Step 2: Compound I-2 undergoes a coupling or nucleophilic substitution reaction to form the target compound I.

[0038] Compounds and Preparation Methods

[0039] An object of the present invention is to provide a compound of formula I or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs or any mixture of two or more of them:

[0040]

[0041] wherein,

[0042] R 1 is selected from hydrogen, C(O)R a , CO2R a , C(O)NR b R c , S(O)R a , SO2R a , SO2NR b R c , C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl, 3-8 membered heterocyclic group and 5-14 membered heteroaryl group, and the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl, 3-8 membered heterocyclic group and 5-14 membered heteroaryl group are each optionally substituted by one or more R dSubstituted;

[0043] R 2 Selected from hydrogen, halogen, CN, NO2, C(O)R a , CO2R a , C(O)NR b R c , S(O)R a , SO2R a , SO2NR b R c , NR b R c , NHC(O)R a , NHCO2R a , OC(O)R a , C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 aryl and 5-14 membered heteroaryl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 aryl and 5-14 membered heteroaryl are each optionally substituted by one or more R d Substituted;

[0044] R 3 Selected from hydrogen, C(O)R a , CO2R a , C(O)NR b R c , S(O)R a , SO2R a , SO2NR b R c , C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl and 5-14 membered heteroaryl, wherein the C6-C 14 aryl and 5-14 membered heteroaryl are each optionally fused to a C3-C7 cycloalkyl or a 5-10 membered heterocyclic group, and the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl, 5-14 membered heteroaryl and 5-10 membered heterocyclic group are each optionally substituted by one or more R d Substituted;

[0045] R a Independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl and 5-14 membered heteroaryl, wherein the C6-C 14 aryl and 5-14 membered heteroaryl are each optionally fused to a C3-C7 cycloalkyl or a 5-10 membered heterocyclic group, and the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14An aryl, 5- to 14-membered heteroaryl, and 5- to 10-membered heterocyclic group are each optionally substituted with one or more R d substituted;

[0046] R b and R c are each independently selected from hydrogen, C1-C6 alkyl, C 3- C7 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, and 4- to 7-membered heterocyclic group; or, R b and R c together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic group, and the C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, and 4- to 7-membered heterocyclic group are each optionally substituted with one or more R d substituted;

[0047] X is selected from CH and N;

[0048] R d is independently selected from: hydrogen, hydroxy, halogen, oxo, CN, NO2, C(O)R e CO2R e NR f SO2R g S(O)R e SO2R e C(O)NR f R g SO2NR f R g NR f R g NR f C(O)R g C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 alkoxy C1-C6 alkoxy, C6-C 14 aryl, 5- to 14-membered heteroaryl, and 3- to 8-membered heterocyclic group, and the C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 alkoxy-C1-C6 alkoxy, C6-C 14 aryl, 5- to 14-membered heteroaryl, and 3- to 8-membered heterocyclic group are each optionally substituted with one or more R j substituted;

[0049] R e is independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl, and 5- to 14-membered heteroaryl;

[0050] R f and R g are each independently selected from hydrogen, C1-C6 alkyl, C3- C7 cycloalkyl and 4-7 membered heterocyclic group, wherein said C1-C6 alkyl is optionally substituted with C1-C6 alkoxy or NR h R i ; or, R b and R c together with the nitrogen atom to which it is attached form a 4-7 membered heterocyclic group;

[0051] R h and R i are each independently selected from hydrogen and C1-C6 alkyl; and

[0052] R j is independently selected from halogen, hydroxy, CN, C(O)R e 、NR f R g 、C(O)NR b R e 、NR b C(O)R e and 3-8 membered heterocyclic group.

[0053] According to some embodiments of the present invention, R 1 is selected from hydrogen, C(O)R a 、CO2R a 、C(O)NR b R c 、S(O)R a 、SO2R a 、SO2NR b R c 、C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, 3-8 membered heterocyclic group and 5-10 membered heteroaryl, said C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, 3-8 membered heterocyclic group and 5-10 membered heteroaryl are each optionally substituted with one or more R d substituents.

[0054] In some embodiments of the present invention, R 1 is selected from hydrogen, C(O)R a 、C1-C6 alkyl, C3-C7 cycloalkyl and 3-8 membered heterocyclic group, said C1-C6 alkyl, C3-C7 cycloalkyl and 3-8 membered heterocyclic group are each optionally substituted with one or more R d substituents.

[0055] In some embodiments of the present invention, R 1 is selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl and 3-8 membered heterocyclic group, said C1-C6 alkyl, C3-C7 cycloalkyl and 3-8 membered heterocyclic group are each optionally substituted with Rd Substituted.

[0056] In some embodiments of the present invention, R 1 is selected from C1-C6 alkyl and 3-8 membered heterocyclic groups, and each of the C1-C6 alkyl and 3-8 membered heterocyclic groups is optionally substituted by R d Substituted.

[0057] In some embodiments of the present invention, R 1 is selected from C1-C6 alkyl and 5-6 membered azacycloalkyl, and the C1-C6 alkyl is optionally substituted by a group selected from the following: hydroxyl, C1-C6 alkoxy, halogen, and 5-6 membered heterocyclic group.

[0058] In some embodiments of the present invention, R 1 is selected from C1-C6 alkyl and pyrrolidinyl, and the C1-C6 alkyl is optionally substituted by a group selected from the following: hydroxyl, C1-C6 alkoxy, halogen, and morpholinyl.

[0059] In some embodiments of the present invention, R 1 is selected from C1-C6 alkyl and pyrrolidinyl, and the C1-C6 alkyl is optionally substituted by a group selected from the following: hydroxyl, methoxy, fluorine, and morpholinyl.

[0060] In some embodiments of the present invention, R 1 is selected from methyl, ethyl, isopropyl, isobutyl, sec-butyl, morpholin-2-ylmethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-fluoroethyl, and pyrrolidinyl.

[0061] In some embodiments of the present invention, R 1 is selected from isopropyl, sec-butyl, morpholin-2-ylmethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-fluoroethyl, and pyrrolidinyl.

[0062] According to some embodiments of the present invention, R 2 is selected from hydrogen, halogen, CN, NO2, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 10 aryl, and 5-10 membered heteroaryl, and each of the C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 10 aryl, and 5-10 membered heteroaryl is optionally substituted by one or more R d Substituted.

[0063] In some embodiments of the present invention, R 2 is selected from hydrogen, halogen, C1-C6 alkyl, and C3-C7 cycloalkyl, and each of the C1-C6 alkyl and C3-C7 cycloalkyl is optionally substituted by one or more R d Substituted.

[0064] In some embodiments of the present invention, R 2 is selected from hydrogen, halogen, and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with one or more R d substituents.

[0065] In some embodiments of the present invention, R 2 is hydrogen.

[0066] According to some embodiments of the present invention, R 3 is selected from hydrogen, C(O)R a , CO2R a , C(O)NR b R c , S(O)R a , SO2R a , SO2NR b R c , C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5-10 membered heteroaryl, and the C6-C 10 aryl and 5-10 membered heteroaryl are each optionally fused to a C3-C7 cycloalkyl or 5-10 membered heterocyclic group, and the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclic group are each optionally substituted with one or more R d substituents.

[0067] In some embodiments of the present invention, R 3 is selected from C(O)R a , CO2R a , C(O)NR b R c , C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, and 5-10 membered heteroaryl, and the C6-C 10 aryl and 5-10 membered heteroaryl are each optionally fused to a C3-C7 cycloalkyl or 5-10 membered heterocyclic group, and the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclic group are each optionally substituted with one or more R d substituents.

[0068] In some embodiments of the present invention, R 3 is selected from C(O)R a , CO2R a , C6-C 10 aryl, and 5-10 membered heteroaryl, and the C6-C 10An aryl and a 5- to 10-membered heteroaryl are each optionally fused with a C3-C7 cycloalkyl or a 5- to 10-membered heterocyclic group, and the C6-C 10 The aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl and 5- to 10-membered heterocyclic group are each optionally substituted by 1, 2, 3 or 4 R d substituents.

[0069] In some embodiments of the present invention, R 3 is selected from C(O)R a 、C6-C 10 aryl and 5- to 10-membered heteroaryl, the C6-C 10 aryl and 5- to 10-membered heteroaryl are each optionally fused with a C3-C7 cycloalkyl or a 5- to 10-membered heterocyclic group, and the C6-C 10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl and 5- to 10-membered heterocyclic group are each optionally substituted by 1, 2, 3 or 4 R d substituents.

[0070] In some embodiments of the present invention, R 3 is selected from C(O)R a 、phenyl and 5- to 9-membered heteroaryl, the phenyl and 5- to 9-membered heteroaryl are each optionally fused with a C5-C6 cycloalkyl or a 5- to 9-membered heterocyclic group, and the phenyl, 5- to 9-membered heteroaryl, C5-C6 cycloalkyl and 5- to 9-membered heterocyclic group are each optionally substituted by 1, 2, 3 or 4 R d substituents.

[0071] In some embodiments of the present invention, R 3 is selected from C(O)R a 、phenyl and 5- to 9-membered heteroaryl, the phenyl and 5- to 9-membered heteroaryl are each optionally fused with a C5-C6 cycloalkyl or a 5- to 9-membered heterocyclic group, and the phenyl, 5- to 9-membered heteroaryl, C5-C6 cycloalkyl and 5- to 9-membered heterocyclic group are each optionally substituted by 1, 2, 3 or 4 R d substituents;

[0072] R a is selected from cyclopropyl, cyclobutyl, isopropyl, pyrazolyl, indazolyl, indolyl and the cyclopropyl, pyrazolyl, indazolyl, indolyl and are optionally substituted by 1, 2, 3 or 4 fluorine or methyl groups;

[0073] R dIndependently selected from: fluorine, vinyl, pyrrolidinyl, ethyl, n-propyl, isopropyl, oxo, methyl, methoxy, -N(CH3)2, -NH(CH2)2-NH(CH3), isobutyl, morpholinyl, piperidinyl, -(CH2)2N(CH3)2 and amino, wherein the vinyl, methyl, ethyl, n-propyl, pyrrolidinyl are optionally substituted by one or more hydroxyl, fluorine, CN, acetyl or morpholinyl.

[0074] In some embodiments of the present invention, R 3 is selected from pyrazolyl, pyridyl, pyrimidinyl, indolyl, indazolyl or pyrimido[1,2-a]pyrazolyl, and the pyrazolyl, pyridyl, pyrimidinyl, indolyl, indazolyl or pyrimido[1,2-a]pyrazolyl is optionally substituted by 1 or 2 R d ; and R d is independently selected from oxo, amino, C1-C6 alkyl and pyrrolidinyl, and the C1-C6 alkyl and pyrrolidinyl are each optionally substituted by hydroxyl, CN or acetyl.

[0075] In some embodiments of the present invention,

[0076] R 1 is selected from C1-C6 alkyl and pyrrolidinyl, and the C1-C6 alkyl is optionally substituted by a group selected from: hydroxyl, C1-C6 alkoxy, halogen and morpholinyl;

[0077] R 2 is hydrogen;

[0078] R 3 is selected from the is optionally substituted by 1 or 2 or 3 or 4 R d ;

[0079] R d is independently selected from fluorine, oxo, amino, methyl, ethyl, n-propyl, isopropyl, isobutyl, methoxy, -N(CH3)2, -NH(CH2)2NH2, C2-C6 alkenyl, morpholinyl, piperidinyl and pyrrolidinyl, and the methyl, ethyl, n-propyl, isopropyl, -NH(CH2)2NH2, C2-C6 alkenyl and pyrrolidinyl are each optionally substituted by one or more substituents selected from hydroxyl, methyl, halogen, morpholinyl, -N(CH3)2, CN or acetyl; and

[0080] X is selected from CH and N.

[0081] In some embodiments of the present invention,

[0082] R1 selected from isopropyl, sec-butyl, morpholin-2-ylmethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-fluoroethyl and pyrrolidinyl;

[0083] R 2 is hydrogen;

[0084] R 3 is selected from

[0085] and,

[0086] X is selected from CH and N.

[0087] The present invention encompasses compounds of formula I obtained by any combination of the above preferred groups.

[0088] According to some embodiments of the present invention, the compounds of the present invention have the structure of formula II:

[0089]

[0090] wherein,

[0091] R 1 、R 2 、X and R a are as defined above.

[0092] In some embodiments of the present invention, R a is selected from C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl and 5-14-membered heteroaryl, wherein the C6-C 14 aryl and 5-14-membered heteroaryl are each optionally fused with C3-C7 cycloalkyl or 5-10-membered heterocyclic group, and the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl, 5-14-membered heteroaryl and 5-10-membered heterocyclic group are each optionally substituted by one or more R d wherein R d is as defined above.

[0093] In some embodiments of the present invention, R a is selected from C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl and 5-10-membered heteroaryl, wherein the C6-C 10 aryl and 5-10-membered heteroaryl are each optionally fused with C3-C7 cycloalkyl or 5-10-membered heterocyclic group, and the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 10 aryl and 5-10-membered heteroaryl are each optionally substituted by 1 or 2 R d wherein Rd As defined above.

[0094] In some embodiments of the present invention, R a is selected from C1-C6 alkyl, C3-C7 cycloalkyl, and 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally fused to a 5-6 membered heterocyclic group, and each of the C1-C6 alkyl, C3-C7 cycloalkyl, 5-10 membered heteroaryl, and 5-6 membered heterocyclic group is optionally substituted with 1 or 2 groups independently selected from halogen and C1-C6 alkyl.

[0095] In some embodiments of the present invention, R a is selected from C1-C6 alkyl, C3-C7 cycloalkyl, pyrrolyl, pyrazolyl, and imidazolyl, wherein each of the pyrrolyl, pyrazolyl, and imidazolyl is optionally fused to a benzene ring or a tetrahydropyrimidine ring, and each of the C1-C6 alkyl, C3-C7 cycloalkyl, pyrrolyl, pyrazolyl, imidazolyl, benzene ring, and tetrahydropyrimidine ring is optionally substituted with 1 or 2 groups independently selected from halogen and C1-C6 alkyl.

[0096] In some embodiments of the present invention, R a is selected from cyclopropyl, fluorocyclopropyl, difluorocyclopropyl, cyclobutyl, isopropyl, pyrazolyl, methylpyrazolyl, indazolyl, indolyl, and tetrahydropyrimidinopyrazolyl.

[0097] In some embodiments of the present invention,

[0098] R 1 is selected from C1-C6 alkyl and pyrrolidinyl, wherein the C1-C6 alkyl is optionally substituted with a group selected from: hydroxy, C1-C6 alkoxy, halogen, and morpholinyl;

[0099] R 2 is hydrogen;

[0100] R a is selected from C1-C6 alkyl, C3-C7 cycloalkyl, pyrrolyl, pyrazolyl, and imidazolyl, wherein each of the pyrrolyl, pyrazolyl, and imidazolyl is optionally fused to a benzene ring or a tetrahydropyrimidine ring, and each of the C1-C6 alkyl, C3-C7 cycloalkyl, pyrrolyl, pyrazolyl, imidazolyl, benzene ring, and tetrahydropyrimidine ring is optionally substituted with 1 or 2 groups independently selected from halogen and C1-C6 alkyl; and

[0101] X is CH.

[0102] In some embodiments of the present invention,

[0103] R 1 is selected from isopropyl, sec-butyl, morpholin-2-ylmethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-fluoroethyl, and pyrrolidinyl;

[0104] R 2 is hydrogen;

[0105] R a is selected from cyclopropyl, fluorocyclopropyl, difluorocyclopropyl, cyclobutyl, isopropyl, pyrazolyl, methylpyrazolyl, indazolyl, indolyl, and tetrahydropyrimidinopyrazolyl; and

[0106] X is CH.

[0107] According to some embodiments of the present invention, the compounds of the present invention have the structure of Formula III:

[0108]

[0109] wherein,

[0110] R 4 is selected from hydrogen, C(O)R e , CO2R e , C(O)NR f R g , S(O)R e , SO2R e , SO2NR f R g , C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C 14 aryl, and 5-14 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C6-C 14 aryl, and 5-14 membered heteroaryl are each optionally substituted by 1 or 2 R j ;

[0111] R 5 is selected from hydrogen, NR f R g , C1-C6 alkyl, C3-C7 cycloalkyl, 3-8 membered heterocyclic group, C6-C 14 aryl, and 5-14 membered heteroaryl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl, 3-8 membered heterocyclic group, C6-C 14 aryl, and 5-14 membered heteroaryl are each optionally substituted by 1 or 2 R j ; and

[0112] R 1 , R 2 , X, R f , R g , R e and R j are as defined above.

[0113] In some embodiments of the present invention, R 4Selected from C1-C6 alkyl and C2-C6 alkenyl, each of the C1-C6 alkyl and C2-C6 alkenyl being optionally substituted by 1 or 2 groups independently selected from halogen, NR f R g and 5- to 6-membered heterocyclic groups.

[0114] In some embodiments of the present invention, R 4 is selected from C1-C6 alkyl and C2-C6 alkenyl, each of the C1-C6 alkyl and C2-C6 alkenyl being optionally substituted by 1 or 2 groups independently selected from halogen, N(C1-C6 alkyl)2, and morpholinyl.

[0115] In some embodiments of the present invention, R 4 is selected from 2-fluoro vinyl, 2,2-difluoro ethyl, isopropyl, isobutyl, and 2-(N,N-dimethylamino)ethyl.

[0116] In some embodiments of the present invention,

[0117] R 5 is selected from hydrogen, NR f R g and 5- to 6-membered heterocyclic groups;

[0118] R f and R g are each independently selected from hydrogen and C 1- C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by NR h R i ; and

[0119] R h and R i are each independently selected from hydrogen and C1-C6 alkyl.

[0120] In some embodiments of the present invention,

[0121] R 5 is selected from hydrogen, NR f R g , pyrrolidinyl, morpholinyl, and piperidinyl;

[0122] R f and R g are each independently selected from hydrogen and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by NR h R i ; and;

[0123] R h and R i are each independently selected from hydrogen and C1-C6 alkyl.

[0124] In some embodiments of the present invention, R 5 is selected from hydrogen, pyrrolidinyl, morpholinyl, piperidinyl, 2-(N-methylamino)ethylamino, and 2-(N,N-dimethylamino)ethylamino.

[0125] In some embodiments of the present invention,

[0126] R 1 is a C1-C6 alkyl group;

[0127] R 2 is hydrogen;

[0128] R 4 is selected from C1-C6 alkyl groups and C2-C6 alkenyl groups, and each of the C1-C6 alkyl groups and C2-C6 alkenyl groups is optionally substituted with 1 or 2 groups independently selected from halogen, N(C1-C6 alkyl)2, and morpholinyl;

[0129] R 5 is selected from hydrogen, NR f R g , pyrrolidinyl, morpholinyl, and piperidinyl;

[0130] R f and R g are each independently selected from hydrogen and C1-C6 alkyl groups, where the C1-C6 alkyl group is optionally substituted with NR h R i ;

[0131] R h and R i are each independently selected from hydrogen and C1-C6 alkyl groups; and

[0132] X is CH.

[0133] In some embodiments of the present invention, R 5 is selected from hydrogen, pyrrolidinyl, morpholinyl, piperidinyl, 2-(N-methylamino)ethylamino, and 2-(N,N-dimethylamino)ethylamino.

[0134] In some embodiments of the present invention,

[0135] R 1 is a C1-C6 alkyl group;

[0136] R 2 is hydrogen;

[0137] R 4 is selected from 2-fluoro vinyl, 2,2-difluoroethyl, isopropyl, isobutyl, and 2-(N,N-dimethylamino)ethyl;

[0138] R 5 is selected from hydrogen, pyrrolidinyl, morpholinyl, piperidinyl, 2-(N-methylamino)ethylamino, and 2-(N,N-dimethylamino)ethylamino; and,

[0139] X is CH.

[0140] According to some embodiments of the present invention, the compounds of the present invention have the structure of Formula IV:

[0141]

[0142] wherein,

[0143] R 6 and R 7 are each independently selected from hydrogen, halogen, CN, NO2, C(O)R e 、CO2R e 、C(O)NR f R g 、S(O)R e 、SO2R e 、SO2NR f R g 、NR f R g 、C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 aryl, and 5-14-membered heteroaryl, and the C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 aryl, and 5-14-membered heteroaryl are each optionally substituted with one or more R j ;

[0144] R 8 and R 9 are each independently selected from hydrogen, NR f R g and C1-C6 alkyl; or, R 8 and R 9 together with the carbon atom to which they are attached form C3-C7 cycloalkyl or carbonyl, and the C1-C6 alkyl and C3-C7 cycloalkyl are each optionally substituted with one or more R j ;

[0145] Y is selected from CH and N;

[0146] U and V are each independently selected from CR f R g 、NR e 、O、S(O), and SO2;

[0147] 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

[0148] R 1 、R 2 、X、R e 、R f 、R g and R j are as defined above.

[0149] In some embodiments of the present invention, R 6 and R 7 are each independently selected from hydrogen, halogen, and C1-C6 alkoxy.

[0150] In some embodiments of the present invention, R 6 and R 7 are each independently selected from hydrogen, fluorine, and methoxy.

[0151] In some embodiments of the present invention, R 8 and R 9 are each independently selected from hydrogen and NR f R g wherein R f and R g are as defined above; or, R 8 and R 9 together with the carbon atom to which they are attached form a carbonyl group.

[0152] In some embodiments of the present invention,

[0153] R 8 is hydrogen;

[0154] R 9 is selected from hydrogen and NR f R g ; and

[0155] R f and R g are each independently C1-C6 alkyl;

[0156] Or, R 8 and R 9 together with the carbon atom to which they are attached form a carbonyl group.

[0157] In some embodiments of the present invention,

[0158] R 8 is hydrogen; and

[0159] R 9 is selected from hydrogen and N,N-dimethylamino;

[0160] Or, R 8and R 9 Together with the carbon atom to which it is attached, form a carbonyl group.

[0161] In some embodiments of the present invention, Y is CH.

[0162] In some embodiments of the present invention,

[0163] U and V are each independently selected from CR f R g and NR e ;

[0164] R e is independently selected from hydrogen and C1-C6 alkyl; and

[0165] R f and R g are each independently selected from hydrogen and C1-C6 alkyl.

[0166] In some embodiments of the present invention, U and V are each independently selected from CH2 and N(C1-C6 alkyl).

[0167] In some embodiments of the present invention,

[0168] U is CH2; and V is selected from CH2 and N(C1-C6 alkyl).

[0169] In some embodiments of the present invention,

[0170] U is CH2; and

[0171] V is selected from CH2, NCH(CH3)2 and N(CH3).

[0172] In some embodiments of the present invention,

[0173] R 1 is C1-C6 alkyl;

[0174] R 2 is hydrogen;

[0175] R 6 and R 7 are each independently selected from hydrogen, halogen and C1-C6 alkoxy;

[0176] R 8 is hydrogen;

[0177] R 9 is selected from hydrogen and NR f R g ;

[0178] R f and R g are each independently C1-C6 alkyl;

[0179] Or, R 8 and R 9 together with the carbon atom to which it is attached form a carbonyl group;

[0180] Y is CH;

[0181] U is CH2;

[0182] V is selected from CH2 and N(C 1- C6 alkyl);

[0183] 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

[0184] X is selected from CH and N.

[0185] In some embodiments of the present invention,

[0186] R 1 is isopropyl;

[0187] R 2 is hydrogen;

[0188] R 6 and R 7 are each independently selected from hydrogen, fluorine, and methoxy;

[0189] R 8 is hydrogen;

[0190] R 9 is selected from hydrogen and NR f R g ;

[0191] R f and R g are each independently methyl;

[0192] Or, R 8 and R 9 together with the carbon atom to which they are attached form a carbonyl group;

[0193] Y is CH;

[0194] U is CH2;

[0195] V is selected from CH2, NCH(CH3)2, and N(CH3);

[0196] 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

[0197] X is selected from CH and N.

[0198] According to some embodiments of the present invention, the compounds of the present invention have the structure of formula V:

[0199]

[0200] Wherein,

[0201] R 10 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C6-C 14 aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic group, and the C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C6-C 14 aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic group are each optionally substituted with one or more R j substituents;

[0202] R 11 、R 12 、R 13 、R 14 are each independently selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C6-C 14 aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic group, and the C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C6-C 14 aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic group are each optionally substituted with one or more R j substituents; or, R 11 、R 12 together with the carbon atom to which it is attached form a 3-7 membered cycloalkyl; or, R 13 、R 14 together with the carbon atom to which it is attached form a 3-7 membered cycloalkyl; and

[0203] R 1 、R 2 、X and R j are as defined above.

[0204] In some embodiments of the present invention, R 10 is C1-C6 alkyl.

[0205] In some embodiments of the present invention, R 10 is selected from methyl and isopropyl.

[0206] In some embodiments of the present invention, R 11 、R 12 、R 13 、R 14 are each independently selected from hydrogen and C1-C6 alkyl; or, R 11 、R12 Together with the carbon atom to which it is attached, form a 3- to 7-membered cycloalkyl group; or, R 13 , R 14 Together with the carbon atom to which it is attached, form a 3- to 7-membered cycloalkyl group.

[0207] In some embodiments of the present invention, R 11 , R 12 , R 13 , R 14 Are each independently selected from hydrogen and methyl; or, R 11 , R 12 Together with the carbon atom to which it is attached, form a cyclopropyl group; or, R 13 , R 14 Together with the carbon atom to which it is attached, form a cyclopropyl group.

[0208] In some embodiments of the present invention, R 11 , R 12 Are each independently selected from hydrogen and C1-C6 alkyl, and R 13 , R 14 Together with the carbon atom to which it is attached, form a 3- to 7-membered cycloalkyl group.

[0209] In some embodiments of the present invention, R 11 , R 12 Are each independently selected from hydrogen and methyl, and R 13 , R 14 Together with the carbon atom to which it is attached, form a cyclopropyl group.

[0210] In some embodiments of the present invention,

[0211] R 1 Is C1-C6 alkyl;

[0212] R 2 Is hydrogen;

[0213] R 10 Is C1-C6 alkyl;

[0214] R 11 , R 12 , R 13 , R 14 Are each independently selected from hydrogen and C1-C6 alkyl; or, R 11 , R 12 Together with the carbon atom to which it is attached, form a 3- to 7-membered cycloalkyl group; or, R 13 , R 14 Together with the carbon atom to which it is attached, form a 3- to 7-membered cycloalkyl group; and

[0215] X is CH.

[0216] In some embodiments of the present invention,

[0217] R 1 is a C1-C6 alkyl group;

[0218] R 2 is hydrogen;

[0219] R 10 is a C1-C6 alkyl group;

[0220] R 11 R 12 R 13 R 14 are each independently selected from hydrogen and C1-C6 alkyl groups; or, R 11 R 12 are each independently selected from hydrogen and C1-C6 alkyl groups, R 13 R 14 together with the carbon atom to which it is attached forms a 3-7 membered cycloalkyl group; and

[0221] X is CH.

[0222] In some embodiments of the present invention,

[0223] R 1 is isopropyl;

[0224] R 2 is hydrogen;

[0225] R 10 is selected from methyl and isopropyl;

[0226] R 11 R 12 are each independently hydrogen, R 13 R 14 together with the carbon atom to which it is attached forms a 3-7 membered cycloalkyl group; and

[0227] X is CH.

[0228] According to some embodiments of the present invention, the compounds of the present invention are selected from:

[0229]

[0230]

[0231]

[0232] Another object of the present invention is to provide a method for preparing the compounds of the present invention, which is carried out according to the following reaction route 1 or 2:

[0233] Reaction route 1:

[0234]

[0235] Among them, R 1 、R 2 、R 3 、X are defined as above;

[0236] Step 1: Compound I-1 undergoes a coupling, condensation or alkylation reaction to form compound I-2, where LG1 is a leaving group, such as a halogen (e.g., Cl, Br or I), OTs, OTf, etc.;

[0237] Step 2: Compound I-2 undergoes a coupling or nucleophilic substitution reaction to form compound I-3, where PG is a nitrogen atom protecting group, such as Boc, Cbz, Bn, PMB, etc.;

[0238] Step 3: Compound I-3 undergoes a deprotection reaction to form compound I-4;

[0239] Step 4: Compound I-4 undergoes a coupling, condensation or alkylation reaction to form the target compound I.

[0240] Reaction route 2:

[0241]

[0242] Among them, R 1 、R 2 、R 3 、X are defined as above;

[0243] Step 1: Compound I-1 undergoes a coupling, condensation or alkylation reaction to form compound I-2, where LG1 is a leaving group, such as a halogen (e.g., Cl, Br or I), OTs, OTf, etc.;

[0244] Step 2: Compound I-2 undergoes a coupling or nucleophilic substitution reaction to form the target compound I.

[0245] Pharmaceutical Compositions and Therapeutic Methods

[0246] Another object of the present invention is to provide a pharmaceutical composition, which comprises the compound of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs or any mixture of two or more of them, and one or more pharmaceutically acceptable carriers.

[0247] Another object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, which method comprises combining a compound of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs or any mixture of two or more thereof with one or more pharmaceutically acceptable carriers.

[0248] Another object of the present invention is to provide a pharmaceutical preparation comprising a compound of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs or any mixture of two or more thereof, or the pharmaceutical composition of the present invention.

[0249] Another object of the present invention is to provide a kit, which comprises:

[0250] 1) a compound of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs or any mixture of two or more thereof, or the pharmaceutical composition of the present invention; and

[0251] 2) optionally present packaging and / or instructions.

[0252] Another object of the present invention is to provide the use of a compound of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs or any mixture of two or more thereof or the pharmaceutical composition of the present invention in the preparation of a medicament for treating a disease related to HPK1. In particular, the disease is a tumor.

[0253] Another object of the present invention is to provide a compound of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs or any mixture of two or more thereof or the pharmaceutical composition of the present invention or the kit of the present invention for treating a disease related to HPK1. In particular, the disease is a tumor.

[0254] Another object of the present invention is to provide a method for treating a disease related to HPK1, which method comprises administering to an individual in need thereof an effective amount of a compound of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs or any mixture of two or more thereof or the pharmaceutical composition of the present invention, and optionally comprises co-administering other agents for treating a disease or disorder related to HPK1. In particular, the disease is a tumor.

[0255] As used herein, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or vehicle 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 undue toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0256] Pharmaceutically acceptable carriers that can be used 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, etc. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, especially for injectable solutions. Examples of suitable pharmaceutically acceptable carriers are described in Remington’s Pharmaceutical Sciences (1990).

[0257] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by suitable routes, such as by injection, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly, or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations, or by inhalation.

[0258] For these routes of administration, the pharmaceutical compositions of the present invention can be administered in suitable dosage forms.

[0259] The pharmaceutical compositions of the present invention can optionally be co-administered with other agents that are at least somewhat effective in the treatment of various diseases. In some embodiments, the present invention provides combination preparations of the compounds of the present invention and additional therapeutic agents for simultaneous, separate, or sequential use in treatment.

[0260] As used herein, the term "effective amount" refers to an amount of a compound that, when administered, will, to some extent, alleviate one or more symptoms of the disorder being treated.

[0261] The dosage regimen can be adjusted to provide the optimum desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of the treating situation. It should be noted that the dosage values can vary with the type and severity of the condition to be alleviated, and can include single or multiple doses. It is further to be understood that for any particular individual, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the compositions.

[0262] The amount of the compound of the present invention administered will depend on the individual 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 about 0.0001 to about 50 mg per kg of body weight per day, for example about 0.01 to about 10 mg / kg / day (administered singly or in divided doses). For a 70 kg person, this would amount to about 0.007 mg / day to about 3500 mg / day, for example about 0.7 mg / day to about 700 mg / day. In some cases, a dose level not higher than the lower limit of the foregoing range may be sufficient, while in other cases, larger doses may still be employed without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.

[0263] The content or dosage of the compound of the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg.

[0264] Unless otherwise specified, as used herein, the term "treating" means reversing, alleviating, inhibiting the progression of a disorder or condition to which such term applies or one or more symptoms of such disorder or condition, or preventing such disorder or condition or one or more symptoms of such disorder or condition.

[0265] As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and / or domesticated animals (such as sheep, dogs, cats, cows, pigs, etc.).

[0266] Definitions

[0267] Unless otherwise defined below, the meanings of all technical terms and scientific terms used herein are intended to be the same as those commonly understood by those of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those techniques that are obvious to those of ordinary skill in the art or substitutions of equivalent techniques. Although the following terms are believed to be well understood by those of ordinary skill in the art, the following definitions are set forth to better explain the present invention.

[0268] As used herein, the terms "comprises", "comprising", "has", "having", "includes" or "involving" and other variant forms thereof herein are inclusive or open-ended and do not exclude other unrecited elements or method steps.

[0269] As used herein, the term "alkyl" is defined as a straight-chain or branched-chain saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 10 carbon atoms, such as 1 to 8 carbon atoms (C1-C8 alkyl), 1 to 6 carbon atoms (C1-C6 alkyl), 1 to 4 carbon atoms (C1-C4 alkyl), 1 to 3 carbon atoms (C1-C3 alkyl), 2 to 6 carbon atoms (C2-C6 alkyl), 2 to 4 carbon atoms (C2-C4 alkyl), or 3 to 4 carbon atoms (C3-C4 alkyl). For example, as used herein, the term "C1-C6 alkyl" refers to a straight-chain or branched-chain group having 1 to 6 carbon atoms (such as 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 (in which case the group is referred to as "haloalkyl", such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3, etc.).

[0270] As used herein, the term "alkenyl" refers to a hydrocarbon group containing at least one C═C double bond. The alkenyl group can be a straight-chain or branched-chain alkenyl group and contains 2 to 15 carbon atoms. For example, herein, "C 2-6 alkenyl" is an alkenyl group containing 2 to 6 carbon atoms. Non-limiting examples of alkenyl groups include vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl, and decenyl. The alkenyl group can be unsubstituted or substituted with one or more identical or different substituents.

[0271] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (for example, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring including a spiro ring, a fused or bridged system (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, etc.), which is optionally substituted with one or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15, for example 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, etc. For example, as used herein, the term "C3-C7 cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having 3 to 7 ring-forming carbon atoms (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as a methyl-substituted cyclopropyl.

[0272] As used herein, the term "aryl" refers to a monocyclic or fused polycyclic aromatic group of all carbon atoms having a conjugated π electron system. For example, as used herein, the term "C6-C 14 aryl" means an aromatic group containing 6 to 14 carbon atoms, and the term "C6-C 10 aryl" means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituted with one or more (such as 1 to 3) suitable substituents (such as halogen, -OH, -CN, -NO2, C1-C6 alkyl, etc.).

[0273] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic aromatic ring system having 5-14 ring atoms, particularly having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, particularly 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and containing at least one heteroatom (such as oxygen, nitrogen or sulfur) which may be the same or different. Also, the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, where the ring connected to the parent structure is the heteroaryl ring. For example, as used herein, the term "5-14-membered heteroaryl" means a heteroaryl containing 5 to 14 ring atoms. Specific examples of heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, etc., or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., or azaindolyl, pyrimidinopyrazolyl, pyrrolopyridyl, pyrazolopyrimidine, etc., and their benzo derivatives such as indazolyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, etc.

[0274] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br or I.

[0275] As used herein, the term "alkoxy" means an alkyl group as defined above attached to the parent molecular moiety through an oxygen atom. Representative examples of C1-C6 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, etc.

[0276] As used herein, the term "heterocyclic group" refers to a monocyclic or polycyclic group which, for example, has 2, 3, 4, 5, 6, 7, 8, 9 carbon atoms in the ring and one or more (e.g., 1, 2, 3 or 4) groups selected from C(=O), O, S, S(=O), S(=O)2 and NR (where R represents a hydrogen atom or a substituent, such as but not limited to an alkyl or cycloalkyl group). The heterocyclic group can be saturated or unsaturated. The saturated heterocyclic group can be referred to as a heterocycloalkyl group, such as a 3- to 8-membered heterocycloalkyl group, a 5- to 6-membered heterocycloalkyl group, etc. Unless otherwise specifically indicated in this specification, the heterocyclic group can be a monocyclic, bicyclic, tricyclic or more-ring ring system, which can include a fused ring system, a spirocyclic ring system, a bridged ring system or a spirocyclic ring system. In particular, a 3- to 10-membered heterocyclic group is a group having 3 to 10 carbon atoms and heteroatoms in the ring. For example, it has 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-membered, 4- to 7-membered, 4- to 6-membered, 5- to 10-membered, 5- to 7-membered and 5- to 6-membered heterocyclic groups respectively), such as but not limited to oxiranyl, aziridinyl, azetidinyl, azepanyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidone, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, azetidinyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, etc.; and their spirocyclic derivatives, such as but not limited to groups, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, etc.; and their fused ring derivatives, such as but not limited to pyrrolidinyl-fused cyclopropyl, cyclopentyl-fused aziridinyl, pyrrolidinyl-fused cyclobutyl, pyrrolidinyl-fused pyrrolidinyl, pyrrolidinyl-fused piperidinyl, pyrrolidinyl-fused piperazinyl, pyrrolidinyl-fused morpholinyl, piperidinyl-fused morpholinyl; or benzo derivatives or heteroaryl-fused derivatives; or spirocyclic derivatives, such as but not limited to etc.

[0277] The term "substituted" means that one or more (e.g., 1, 2, 3 or 4) hydrogens on the designated atom are replaced by a selection from the indicated groups, provided that the normal valence of the designated atom in the current case is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are only permitted when such combinations form a stable compound.

[0278] If a substituent is described as "optionally substituted with...", the substituent can (1) be unsubstituted or (2) be substituted. If a carbon of a substituent is described as optionally substituted with one or more of a list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) can be replaced by independently selected optional substituents, either individually and / or together. If a nitrogen of a substituent is described as optionally substituted with one or more of a list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) can each be replaced by independently selected optional substituents.

[0279] If a substituent is described as "independently selected from" a group, each substituent is selected independently of the others. Thus, each substituent can be the same as or different from another (other) substituent.

[0280] If a variable or substituent is optionally selected from different alternatives and the variable or substituent occurs more than once, then each alternative can be the same as or different from the others.

[0281] As used herein, the term "one or more" means 1 or more than 1 under reasonable conditions, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.

[0282] Unless specified otherwise, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent.

[0283] The present invention also includes all pharmaceutically acceptable isotopic compounds which are identical to the compounds of the present invention except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include (but are not limited to) isotopes of hydrogen (e.g. 2 H, 3 H); isotopes of carbon (e.g. 11 C, 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (e.g. 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); isotopes of oxygen (e.g. 15 O, 17 O and 18 O); isotopes of phosphorus (e.g. 32 P); and isotopes of sulfur (e.g. 35 S).

[0284] The term "stereoisomer" refers to isomers formed due to at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, it can give rise to racemic mixtures, single enantiomers, mixtures of diastereomers, and individual diastereomers. A particular individual molecule can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms that are in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. For example, dihydropyrimidine groups, 2(1H)-pyridone groups, etc. can exist in solution in equilibrium in the following tautomeric forms. It is to be understood that the scope of the present application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0285] Unless otherwise specified, the compounds of the present invention are intended to exist in the form of stereoisomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present invention can exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0286] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which can be a single polymorph or a mixture of more than one polymorph in any proportion. It should also be understood that certain compounds of the present invention can exist in free form for therapeutic use, or, when appropriate, in the form of their pharmaceutically acceptable derivatives. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to: pharmaceutically acceptable salts, solvates, metabolites, or prodrugs, which, after administration to a patient in need thereof, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Thus, when referring to "the compounds of the present invention" herein, it is also intended to cover the above various derivative forms of the compounds.

[0287] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts. A review of suitable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0288] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, in particular, for example, water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of the polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0289] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by a method of contacting the compounds of the present invention with a mammal for a time sufficient to produce its metabolites.

[0290] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and which, when administered to or on the body, may be converted, for example, by hydrolytic cleavage into the compounds of the present invention having the desired activity. Generally, such prodrugs will be functional group derivatives of the compounds that are readily convertible in vivo into the desired therapeutically active compound. Other information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987 (edited by E. B. Roche, American Pharmaceutical Association). The prodrugs of the present invention may be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as “pro-moieties” (as described, for example, in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0291] The present invention also encompasses compounds of the present invention containing protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive groups or reactive groups on any relevant molecule, thereby forming chemically protected forms of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those 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 groups can be removed at appropriate subsequent stages using methods known in the art. As used herein, the term "about" when used to modify a numerical value or a numerical range means including the numerical value or numerical range and the error range acceptable to those skilled in the art for that numerical value or numerical range, for example, the error range is ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, etc.

[0292] Advantages of the Invention

[0293] The compounds of the present invention have strong inhibitory activity against HPK1 and have excellent properties such as good physicochemical properties (e.g., solubility, physical and / or chemical stability), good pharmacokinetic properties (e.g., good bioavailability, appropriate blood drug concentration, half-life and duration of action), and good safety (low toxicity (e.g., low cardiac and liver toxicity) and / or few side effects, wide therapeutic window), etc. Detailed Description of the Invention

[0294] Examples

[0295] The present invention will be further described below in conjunction with examples, but providing these examples is not intended to limit the scope of the present invention.

[0296] The abbreviations in the present invention have the following meanings:

[0297]

[0298]

[0299] The structure of the compounds of the present invention is confirmed by nuclear magnetic resonance spectroscopy ( 1 H NMR) or mass spectrometry (MS).

[0300] The progress of the reaction is monitored by thin layer chromatography (TLC) or LCMS.

[0301] The microwave reaction was carried out using a Biotage Initiator + microwave reactor.

[0302] Column chromatography generally used silica gel (Qingdao Marine) with 200 - 300 mesh as the stationary phase. The eluent systems included: A: petroleum ether / ethyl acetate; B: dichloromethane / methanol, and the volume ratio of the solvents was adjusted according to the polarity of the compound.

[0303] In the following examples, unless otherwise specified, the reaction temperature was room temperature (20 °C - 30 °C).

[0304] The reagents used in this application were purchased from companies such as Acros Organics, Aldrich Chemical Company, or TCI Chemicals.

[0305] Intermediate Int.1: 1 - isopropyl - 1H - pyrazolo[4,3 - c]pyridin - 6 - amine

[0306]

[0307] First step: 6 - chloro - 1 - isopropyl - 1H - pyrazolo[4,3 - c]pyridine (Int.1b)

[0308] 6 - chloro - 1H - pyrazolo[4,3 - c]pyridine (Int.1a, 6 g, 39.07 mmol) was dissolved in 50 mL of DMF. NaH (3.13 g, 78.14 mmol, 60% purity) was added under an ice bath, and then stirred for 0.5 h. Then 2 - iodopropane (9.96 g, 58.61 mmol) was added, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, extracted with EA (50 mL * 3), the organic phases were combined, and dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness and purified by flash column chromatography (eluent system A) to obtain compound Int.1b (4.58 g).

[0309] MS(ESI, m / z): 196.0 [M + H] + .

[0310] Second step: tert - butyl (1 - isopropyl - 1H - pyrazolo[4,3 - c]pyridin - 6 - yl)carbamate (Int.1c)

[0311] Dissolve Int.1b (4.45 g, 22.74 mmol), tert-butyl carbamate (13.32 g, 113.72 mmol), Pd2(dba)3 (2.08 g, 2.27 mmol), Brettphos (2.44 g, 4.55 mmol) and Cs2CO3 (18.53 g, 56.86 mmol) in 50 mL of 1,4-dioxane, heat to 110 °C under N2 protection, and react for 5 h. After the reaction, filter through diatomaceous earth, rotary evaporate the filtrate, and purify by flash column chromatography (eluent system A) to obtain compound Int.1c (4.8 g).

[0312] MS(ESI,m / z):277.1[M+H] + .

[0313] Step 3: 1-Isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine (Int.1)

[0314] Dissolve Int.1c (800 mg, 2.90 mmol) in 10 mL of DCM and 10 mL of TFA, stir at room temperature overnight. After the reaction, quench the reaction with saturated sodium bicarbonate solution and adjust the pH to basic. Extract with EA (50 mL × 3), combine the organic phases, and dry with anhydrous sodium sulfate. Rotary evaporate the organic phase and purify by flash column chromatography (eluent system A) to obtain compound Int.1 (200 mg).

[0315] MS(ESI,m / z):177.1[M+H] + .

[0316] Intermediate Int.2: 4,6-Dichloro-1-(2,2-difluoroethyl)-1H-pyrrolo[2,3-b]pyridine

[0317]

[0318] Dissolve 4,6-dichloro-1H-pyrrolo[2,3-b]pyridine (Int.2a, 1 g, 5.35 mmol), Cs2CO3 (3.49 g, 10.69 mmol) and 1,1-difluoro-2-iodoethane (1.54 g, 8.02 mmol) in 10 mL of DMF, heat to 70 °C, and react for 1 h. After the reaction, quench the reaction with water, extract with EA (50 mL × 3), combine the organic phases, and dry with anhydrous sodium sulfate. Rotary evaporate the organic phase and purify by flash column chromatography (eluent system A) to obtain compound Int.2 (1.1 g).

[0319] MS(ESI,m / z):251.0[M+H] + .

[0320] Intermediate Int.3: 2-Bromo-5,5,6-trimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin -7(8H)-one

[0321]

[0322] First step: 2-(3,5-Dibromo-1H-pyrazol-1-yl)acetonitrile (Int.3b)

[0323] Dissolve 3,5-dibromo-1H-pyrazole (Int.3a, 1.5 g, 6.64 mmol) in 20 mL of DMF, add chloroacetonitrile (750 mg, 9.96 mmol) and potassium carbonate (1.84 g, 13.28 mmol), heat to 40 °C, and react for 2 h. After the reaction is completed, quench the reaction with water, extract with EA (50 mL * 3), combine the organic phases, dry with anhydrous sodium sulfate, evaporate the organic phase to dryness, and purify by flash column chromatography (eluent system A) to obtain compound Int.3b (1.5 g).

[0324] MS(ESI,m / z): 265.0 [M+H] + .

[0325] Second step: (3-Bromo-5-(2-methylprop-1-enyl)-1H-pyrazol-1-yl)acetonitrile (Int.3c)

[0326] Add compound 1b (1.5 g, 5.56 mmol), 2-methyl-1-propenylboronic acid pinacol ester (1.03 g, 5.56 mmol), Pd(dppf)Cl2 (413 mg, 0.56 mmol) and K2CO3 (3.13 g, 21.65 mmol) to a mixed solvent of 10 mL of 1,4-dioxane and 10 mL of water, heat to 100 °C under N2 protection, and react for 2 h. After the reaction is completed, filter through diatomaceous earth, evaporate the filtrate to dryness, and purify by flash column chromatography (eluent system A) to obtain compound Int.3c (1 g).

[0327] MS(ESI,m / z): 240.0 [M+H] + .

[0328] Third step: 2-Bromo-5,5-dimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin -7(8H)-one (Int.3d)

[0329] Int.3c (1 g, 4.16 mmol) was added to 20 mL of methanesulfonic acid, and the mixture was heated to 65 °C and reacted for 72 h. After the reaction was completed, the pH was adjusted to 8 - 9 with 1 N sodium hydroxide solution. The mixture was extracted with EA (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness. The compound was separated by preparative high performance liquid chromatography (preparation method: Prep-HPLC (instrument model: Agilent 1260, chromatographic column: Waters SunFire Prep C 18 OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 °C; 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% formic acid aqueous solution. The retention time of the compound R t = 5.6 min) to obtain compound Int.3d (200 mg).

[0330] MS (ESI, m / z): 258.0 [M + H] + .

[0331] Step 4: 2-Bromo-5,5,6-trimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin -7(8H)-one (Int.3)

[0332] Int.3d (100 mg, 387.42 μmol) was dissolved in 10 mL of THF, and potassium tert-butoxide (52 mg, 464.91 μmol) was added. After stirring at room temperature for 0.5 h, methyl iodide (110 mg, 774.85 μmol) was added, and stirring was continued for 1 h. After the reaction was completed, 2 mL of methanol was added to the reaction solution, and the organic phase was evaporated to dryness. The compound was separated by preparative high performance liquid chromatography (preparation method: Prep-HPLC (instrument model: Agilent 1260, chromatographic column: Waters SunFire Prep C 18 OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 °C; 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% formic acid aqueous solution. The retention time of the compound R t = 6.1 min) to obtain compound Int.3 (45 mg).

[0333] MS (ESI, m / z): 272.0 [M + H] + .

[0334] Example 1: (Z)-N-(1-(2-fluoroethenyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-amine (Compound 1)

[0335]

[0336] Int.1 (42.74 mg, 170.24 μmol), Int.2 (30 mg, 170.24 μmol), tBuONa (49.08 mg, 510.73 μmol), xantphos (9.85 mg, 17.02 μmol) and Pd2(dba)3 (15.59 mg, 17.02 μmol) were added to a 10 mL microwave tube. 3 mL of DMF was added and the mixture was heated to 100 °C by microwave for 2 h. After the reaction, it was filtered through diatomaceous earth. After the filtrate was evaporated to dryness, it was separated by preparative high performance liquid chromatography (preparation method: Prep-HPLC (instrument model: Agilent 1260, chromatographic column: Waters SunFire Prep C 18 OBD (19 mm×150 mm×5.0 μm); column temperature: 25 °C; 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% formic acid aqueous solution. The retention time R t = 9.3 min) to obtain Compound 1 (2.11 mg).

[0337] MS (ESI, m / z): 371.1 [M+H] + .

[0338] 1 H NMR (400 MHz, MeOD) δ 8.74 (s, 1H), 8.52 (s, 1H), 8.08 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.59 (dd, J = 3.7, 1.8 Hz, 1H), 7.07–6.98 (dd, J = 35.4, 4.2 Hz, 1H), 6.95–6.93 (d, J = 8.4 Hz, 1H), 6.95–6.74 (dd, J = 74.0, 4.3 Hz, 1H), 6.56–6.55 (d, J = 3.7 Hz, 1H), 4.88–4.85 (m, 1H) 1.63–1.62 (d, J = 6.7 Hz, 6H).

[0339] 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)

[0340]

[0341] First step: 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)

[0342] Dissolve Compound Int.1 (400 mg, 2.27 mmol), Int.2 (570 mg, 2.27 mmol), Cs2CO3 (1.48 g, 4.54 mmol), Xantphos (131.34 mg, 226.99 μmol) and Pd2(dba)3 (207.86 mg, 226.99 μmol) in 10 mL of 1,4-dioxane, heat to 90 °C, and react overnight. After the reaction is completed, filter through diatomaceous earth. After the filtrate is evaporated to dryness, purify by flash column chromatography (eluent system A) to obtain Compound 2a (220 mg).

[0343] MS(ESI, m / z): 391.0 [M+H] + .

[0344] Second 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)-2,5-dihydro-1H-pyrrole-1-carboxylate (Compound 2b)

[0345] Dissolve Compound 2a (100 mg, 266.10 μmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (117.82 mg, 399.15 μmol), Pd(dppf)Cl2 (19.47 mg, 26.61 μmol) and Cs2CO3 (173.50 mg, 532.19 μmol) in 10 mL of 1,4-dioxane and 1 mL of water. Heat to 90 °C under N2 protection and react for 2 h. After the reaction is completed, filter through diatomaceous earth. After the filtrate is evaporated to dryness, purify by flash column chromatography (eluent system A) to obtain Compound 2b (38 mg).

[0346] MS(ESI, m / z): 524.2 [M+H] + .

[0347] Step 3: 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-carboxylate (Compound 2c)

[0348] Dissolve Compound 2b (10.00 mg, 19.10 μmol) and 10% Pd / C (2.32 mg, 19.10 μmol) in 10 mL of MeOH, and react overnight under H2 protection. After the reaction is completed, filter the reaction solution. After the filtrate is concentrated to dryness, Compound 2c (8 mg) is obtained and directly used for the next step of the reaction.

[0349] MS(ESI, m / z): 526.2 [M+H] + .

[0350] Step 4: 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)

[0351] Dissolve Compound 2c (8 mg, 15.22 μmol) in 10 mL of DCM, add 10 mL of TFA, and react at room temperature for 2 h. After the reaction is completed, concentrate the reaction solution, and separate it by preparative high-performance liquid chromatography (preparation method: Prep-HPLC (instrument model: Agilent 1260, chromatographic column: Waters SunFire Prep C 18 OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 °C; 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% formic acid aqueous solution. The retention time R of the compound t = 3.8 min) to obtain Compound 2 (3.57 mg).

[0352] MS(ESI, m / z): 426.2 [M+H] + .

[0353] 11H NMR (400 MHz, MeOD) δ 8.76 (s, 1H), 8.64 (s, 1H), 8.10 (s, 1H), 7.26–7.25 (d, J = 3.5 Hz, 1H), 6.84 (s, 1H), 6.59–6.58 (d, J = 3.6 Hz, 1H), 6.47–6.17 (tt, J = 55.6, 3.9 Hz, 1H), 4.92–4.90 (m, 1H), 4.78–4.70 (td, J = 14.6, 4.0 Hz, 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 = 9.3 Hz, 6H).

[0354] Example 3: N-(1-(Morpholin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropanecarboxamide (Compound 3)

[0355]

[0356] First step: 6-Chloro-1-trityl-1H-pyrazolo[4,3-c]pyridine (Compound 3a)

[0357] Dissolve Int.1a (4 g, 26.05 mmol) in 60 mL of THF. Add NaH (1.80 g, 46.88 mmol, 60% purity) to the reaction system at 0 °C and stir for 0.5 h. Then add trityl chloride (18.88 g, 67.72 mmol) to the reaction system, stir at 0 °C for 0.5 h and then raise the temperature to room temperature, and react for 2 h. After the reaction is completed, extract with EA (50 mL * 3), combine the organic phases, and dry with anhydrous sodium sulfate. Concentrate the organic phase by rotary evaporation and purify by flash column chromatography (eluent system A) to obtain Compound 3b (8.4 g).

[0358] MS (ESI, m / z): 396.1 [M + H] + .

[0359] Second step: tert-Butyl (1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)carbamate (Compound 3b)

[0360] Compound 3b (8.4 g, 21.22 mmol), tert-butyl carbamate (12.43 g, 106.09 mmol), Pd2(dba)3 (1.94 mg, 2.12 mmol), Brettphos (2.28 g, 4.24 mmol) and Cs2CO3 (17.28 g, 53.05 mmol) were dissolved in 100 mL of 1,4-dioxane, and heated to 110 °C under N2 protection for 6 h. After the reaction, it was filtered through diatomaceous earth. After the filtrate was evaporated to dryness, it was purified by flash column chromatography (eluent system A) to obtain compound 3b (7.2 g).

[0361] MS(ESI,m / z):477.0[M+H] + .

[0362] Step 3: tert-Butyl (cyclopropanecarbonyl)(1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)carbamate (Compound 3c)

[0363] Compound 3b (7.1 g, 14.90 mmol) and DIPEA (7.7 g, 59.59 mmol) were dissolved in 100 mL of DCM. At 0 °C, cyclopropanecarbonyl chloride (3.11 g, 29.80 mmol) was slowly added dropwise to the reaction solution, and the reaction was carried out at room temperature for 2 h. After the reaction, the reaction solution was directly concentrated to obtain compound 3c (8 g).

[0364] MS(ESI,m / z):545.0[M+H] + .

[0365] Step 4: N-(1H-Pyrazolo[4,3-c]pyridin-6-yl)cyclopropanecarboxamide (Compound 3d)

[0366] Compound 3c (8.0 g, 14.69 mmol) was dissolved in 80 mL of DCM and 20 mL of TFA, and the reaction was carried out at room temperature for 5 h. After the reaction, the pH was adjusted to about 8 - 9 with saturated sodium bicarbonate. It was extracted with EA (50 mL * 3), the organic phases were combined, and dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness and purified by flash column chromatography (eluent system A) to obtain compound 3d (2.3 g).

[0367] MS(ESI,m / z):203.1[M+H] + .

[0368] Step 5: tert-Butyl 2-((6-(cyclopropanecarboxamido)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)morpholine-4-carboxylate (Compound 3e)

[0369] Compound 3d (200 mg, 989.06 μmol) and tert-butyl 2-(bromomethyl)morpholine-4-carboxylate (415.64 mg, 1.48 mmol) were dissolved in 8 mL of DMF, and then K2CO3 (272.98 mg, 1.98 mmol) was added. The mixture was heated to 60 °C and stirred for 15 h. After the reaction was completed, it was extracted with EA (50 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness and purified by flash column chromatography (eluent system A) to obtain compound 3e (300 mg).

[0370] MS(ESI,m / z):402.0[M+H] + .

[0371] Step 6: N-(1-(morpholin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropanecarboxamide (Compound 3)

[0372] Compound 3e (300 mg, 747.28 μmol) was added to 12 mL of DCM and 3 mL of TFA, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the pH was adjusted to about 8 - 9 with saturated sodium bicarbonate, and then separated by preparative high performance liquid chromatography (preparation method: Prep-HPLC (instrument model: Agilent 1260, chromatographic column: Waters SunFire Prep C 18 OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 °C; 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. The retention time R of the compound t = 7.12 min) to obtain compound 3 (130 mg).

[0373] MS(ESI,m / z):302.0[M+H] + .

[0374] 11H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.84 (d, J = 0.7 Hz, 1H), 8.21 (d, J = 3.4 Hz, 2H), 4.37–4.22 (m, 2H), 3.82–3.73 (m, 1H), 3.64 (d, J = 11.0 Hz, 1H), 3.31 (td, J = 11.0, 4.2 Hz, 1H), 2.76 (d, J = 11.8 Hz, 1H), 2.66–2.53 (m, 2H), 2.45 (t, J = 11.0 Hz, 1H), 2.11–2.00 (m, 1H), 0.89–0.77 (m, 4H).

[0375] Example 4: 2 - ((1-Isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-5,5,6-trimethyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin -7(8H)-one (Compound 4)

[0376]

[0377] Dissolve Int.3 (15 mg, 56.75 μmol), Int.1 (15 mg, 56.75 μmol), cesium carbonate (37 mg, 113.50 μmol), Xantphos (3.3 mg, 5.67 μmol) and Pd2(dba)3 (5.2 mg, 5.67 μmol) in 10 mL of 1,4-dioxane, heat to 100 °C under N2 protection and react for 2 h. After the reaction, filter through diatomaceous earth. After the filtrate is evaporated to dryness, it is separated by preparative high performance liquid chromatography (preparation method: Prep-HPLC (instrument model: Agilent 1260, chromatographic column: Waters SunFire PrepC 18 OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 °C; 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% formic acid aqueous solution. The retention time of the compound R t = 4.2 min) to obtain Compound 4 (1.37 mg).

[0378] MS (ESI, m / z): 368.2 [M + H] + .

[0379] 11H NMR (400 MHz, MeOD) δ 8.65 (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 = 6.7 Hz, 6H).

[0380] 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)

[0381]

[0382] First step: 2,4-Dichloropyrimidine-5-carbaldehyde (Compound 5b)

[0383] Dissolve Compound 5a (3 g, 13.17 mmol) in 30 mL of THF. Add isopropylmagnesium chloride-lithium chloride (11.14 mL, 14.48 mmol) to the reaction system at -78 °C and stir for 40 minutes. Then add a 30 mL THF solution of morpholine-4-carbaldehyde (4.55 g, 39.50 mmol) to the reaction system, stir at -78 °C for 10 minutes, then warm to -40 °C and react for 1 h. After the reaction is completed, quench the reaction with 1 N hydrochloric acid. Extract with EA (50 mL × 3), combine the organic phases, and dry over anhydrous sodium sulfate. Rotavaporize the organic phase and purify by flash column chromatography (eluent system A) to obtain Compound 5b (830 mg).

[0384] MS (ESI, m / z): 177.0 [M+H] + .

[0385] Second step: 6-Chloro-1H-pyrazolo[3,4-d]pyrimidine (Compound 5c)

[0386] Dissolve Compound 5b (800 mg, 4.52 mmol) in 10 mL of THF. Add a 10 mL THF solution of hydrazine hydrate (452.55 mg, 9.04 mmol) to the reaction system at 0 °C and stir at room temperature for 1 h. After the reaction is completed, extract with EA (50 mL × 3), combine the organic phases, and dry over anhydrous sodium sulfate. Rotavaporize the organic phase and purify by flash column chromatography (eluent system A) to obtain Compound 5c (190 mg).

[0387] MS (ESI, m / z): 155.1 [M+H] + .

[0388] Step 3: 6-Chloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine (Compound 5d)

[0389] Dissolve Compound 5c (180 mg, 1.16 mmol) in 5 mL of DMF. Place the system at 0 °C, then add NaH (55.9 mg, 46.88 mmol, 60% purity) to the reaction system and stir for 0.5 h. Finally, add 2-iodopropane (296.96 mg, 1.75 mmol) to the reaction system, raise the temperature to room temperature, and react for 1 h. After the reaction is completed, extract with EA (50 mL * 3), combine the organic phases, and dry with anhydrous sodium sulfate. Rotavaporize the organic phase and purify by flash column chromatography (eluent system A) to obtain Compound 5d (120 mg).

[0390] MS (ESI, m / z): 197.1 [M+H] + .

[0391] Step 4: N-(1-Isopropyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (Compound 5)

[0392] Add Compound 5d (49.09 mg, 249.67 μmol) and 6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-amine (40 mg, 208.05 μmol) to 3 mL of isopropanol and 0.02 mL of concentrated hydrochloric acid, raise the temperature to 80 °C, and stir for 15 h. After the reaction is completed, cool, concentrate, and separate by preparative high performance liquid chromatography (preparation method: Prep-HPLC (instrument model: Agilent1260, chromatographic column: Waters SunFire Prep C 18 OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25 °C; 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 t = 8.1 min) to obtain Compound 5 (10 mg).

[0393] MS (ESI, m / z): 353.1 [M+H] + .

[0394] 11H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.35 (s, 1H), 7.90 (d, J = 3.4 Hz, 2H), 6.64 (s, 1H), 5.10–4.98 (m, 1H), 3.89 (s, 3H), 3.62 (s, 2H), 2.91 (t, J = 5.8 Hz, 2H), 2.71 (t, J = 5.9 Hz, 2H), 2.51 (s, 3H), 1.62 (d, J = 6.7 Hz, 6H).

[0395] The compounds in the following table were all synthesized according to the corresponding methods in the above examples:

[0396]

[0397]

[0398]

[0399] Biological evaluation

[0400] 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.

[0401] Experimental Example 1: Inhibition test of the enzymatic activity of compound on HPK1

[0402] The inhibition of the enzymatic activity of the compound on HPK1 was tested by ATP-Glo assay. The reagents (HPK1, 5x kinase buffer, Substrate (MBP), ATP) were purchased from Promega corporation, and the experimental operation and optimization were based on the recommendations in the reagent instructions.

[0403] Add 2 μl of 2.5x HPK1 (2 ng / μl) to a 384-well plate, then add 1 μl of 5x a series of concentrations of the compound to be tested. After incubating at room temperature for 10 min, add 2 μl of 2.5x MBP (0.25 μg / μl) / ATP (25 μM), and incubate at room temperature for 1 h. After incubation, add 5 μl of ATP-Glo reagent to each well of the 384-well plate, incubate at room temperature to terminate the reaction and remove the remaining ATP. After 40 min, add 10 μl of ATP-Glo detection buffer to each well and react at room temperature for 1 h. After the reaction, transfer the 384-well plate to BMG LABTECH (PHERAstar) for reading, select the mode: Luminescence, and the data presentation method: relative chemiluminescence value RLU (Relative Luminescence units).

[0404] Data processing: Calculate the inhibition rate of the compound on the enzymatic activity of HPK1 according to the following formula:

[0405] Compound inhibition rate (%) = ((RLU 最大 - RLU 空白 ) - (RLU 处理 - RLU 空白 )) / (RLU 最大 - RLU 空白 ) × 100%

[0406] Among them, the RLU 最大 value is the relative chemiluminescence value of the group without compound treatment; RLU 空白 is the relative chemiluminescence value of the group without HPK1 and without compound treatment; RLU 处理 is the relative chemiluminescence value of the compound treatment group. Calculate IC 50 by fitting with Graphpad Prism software log (inhibitor) vs. response – variable slope (four-parameter).

[0407] Compounds <![CDATA[HPK1 IC 50 (nM)]]> 1 60.79 2 4.22 3 175.07 4 60.87 5 15.91

[0408] It can be seen that the compounds of the present application (such as compounds 1-5) all have good inhibitory effects on the enzymatic activity of HPK1.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula III: Among them, X is selected from CH and N; R 1 selected from C1-C6 alkyl; R 2 is hydrogen; R 4 selected from C1-C6 alkyl and C2-C6 alkenyl, each of said C1-C6 alkyl and C2-C6 alkenyl being optionally substituted with 1 or 2 R j substituents; and R 5 selected from hydrogen and a 3- to 8-membered heterocyclic group, wherein the 3- to 8-membered heterocyclic group is optionally substituted with 1 or 2 R j substituents; R j Each is independently optionally selected from halogen, hydroxyl, and CN.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 4 selected from 2-fluoro vinyl and 2,2-difluoro ethyl; and R 5 Selected from hydrogen, pyrrolidinyl, morpholinyl and piperidinyl.

3. The compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof, wherein, R 5 Selected from hydrogen and pyrrolidinyl.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from:

5. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, and one or more pharmaceutically acceptable carriers.

6. A kit, comprising: 1) The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, or the pharmaceutical composition according to claim 5; and 2) Optionally present packaging and / or instructions.

7. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the preparation of a medicament for the treatment of a disease associated with HPK1, wherein the disease associated with HPK1 is a tumor.

8. The use according to claim 7, wherein the medicament further comprises other agents for the treatment of a disease associated with HPK1.

9. A method for preparing a compound of formula I, which is carried out according to the following reaction route 1 or 2: Reaction route 1: Among them, The compound of formula I is the compound of formula III: X is selected from CH and N; R 1 selected from C1-C6 alkyl; R 2 is hydrogen; R 3 as shown in the compound of formula III; R 4 selected from C1-C6 alkyl and C2-C6 alkenyl, each of the C1-C6 alkyl and C2-C6 alkenyl being optionally substituted by 1 or 2 R j substituents; R j are each independently optionally selected from halogen, hydroxy and CN; R 5 selected from hydrogen and a 3- to 8-membered heterocyclic group, the 3- to 8-membered heterocyclic group being optionally substituted with 1 or 2 R j substituents; First step: The compound I-1 undergoes an alkylation reaction to form the compound I-2, wherein LG1 is a leaving group; Second step: The compound I-2 undergoes a nucleophilic substitution reaction to form the compound I-3, wherein PG is an amino protecting group; Third step: The compound I-3 undergoes a deprotection reaction to form the compound I-4; Fourth step: The compound I-4 undergoes a coupling reaction to form the compound I; Reaction route 2: wherein, R 1 , R 2 , X, R 3 and LG1 are as described in Reaction Route 1; First step: The compound I-1 undergoes an alkylation reaction to form the compound I-2, wherein LG1 is a leaving group; Second step: The compound I-2 undergoes a nucleophilic substitution reaction to form the compound I.

10. The method for preparing the compound of formula I according to claim 9, wherein, LG1 is selected from halogen, OTs and OTf, and PG is selected from Boc, Cbz, Bn and PMB.

11. The method for preparing a compound of formula I according to any one of claims 9-10, wherein, The halogen is selected from Cl, Br or I.

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