HPK1 inhibitors and uses thereof

Abstract

The invention provides an HPK1 inhibitor. The HPK1 inhibitor is a compound as shown in a formula (I) or pharmaceutically acceptable salt, stereoisomer, solvate, polymorphic substance, acid, ester, metabolite or prodrug thereof. The present application also provides pharmaceutical compositions comprising these HPK1 inhibitor compounds, and uses of these HPK1 inhibitor compounds in the preparation of medicaments for the treatment and / or prevention of diseases mediated by HPK1 activity, preferably cancers.

Description

Technical Field

[0001] This invention belongs to the field of medicine, specifically relating to a class of compounds that inhibit hematopoietic progenitor cell kinase 1 (HPK1), and methods and uses for the prevention and / or treatment of diseases mediated by HPK1 activity. Background Technology

[0002] The discovery and inhibition of immune checkpoints have emerged as a novel approach to targeting cancer by harnessing the body's own immune system to fight tumors. While checkpoint therapies such as PD1 / PDL1 have shown great promise in several tumor types, only a small percentage of cancer patients respond, and new therapies are needed to treat a wider range of patients. T cells are crucial in the cancer immune cycle; they are effector cells that recognize and kill tumor cells. In cancer patients, T cells are depleted and rendered ineffective by being driven into the tumor microenvironment through chronic exposure to antigens. Furthermore, inhibitory signals in the tumor, such as PGE2, TNFβ, and adenosine, impair the function of these cells. Therefore, therapies that enhance T cell function and revive depleted T cells thus achieve improved tumor control.

[0003] HPK1 is a hematopoietic-specific serine-threonine kinase, also known as mitogen-activated protein kinase 1 (MAP4K1), and is a member of the mammalian Ste20-associated protein kinase MAP4K family. Members of the MAP4K family include HPK1 (MAP4K1), GCK (MAP4K2), GLK (MAP4K3), HGK / NIK (MAP4K4), KHS / GCKR (MAP4K5), and MINK (MAP4K6). HPK1 is primarily expressed in immune-mediated cells such as precursor cells, T cells, B cells, and dendritic cells, and acts as a negative regulator of the immune response. HPK1 is a key kinase in the T cell receptor (TCR) signaling pathway. Studies have shown that HPK1 expression is positively correlated with T cell exhaustion; reducing HPK1 kinase activity can enhance the anti-tumor ability of T cells, specifically manifested as increased T cell proliferation due to HPK1 kinase inhibition, sustained TCR-induced calcium influx, and increased secretion of pro-inflammatory cytokines, such as persistently elevated levels of IL-2 and TNF. In T cells, when the TCR signaling pathway is activated, the Tyr369 domain of HPK1 is phosphorylated. Subsequently, the SH2 domain of HPK1 binds to the adaptor protein SLP76 and induces phosphorylation of SLP76Ser376. SLP76 then binds to the 14-3-3 dimer. The 14-3-3 dimer recruits the E3 ubiquitin (Ub) ligase to the SLP76 protein and induces SLP76 ubiquitination at Lys30, degrading SLP76, followed by TCR signal attenuation. A collaborative study in 2020 by Professor Xuebin Liao's group at Tsinghua University and Professor Lai Wei's group at Sun Yat-sen University found that HPK1 in different cancer patients is positively correlated with T cell exhaustion signals (such as CD3E, TIGIT, PDCD1, CTLA4, HAVCR2, and LAG3), and HPK1 expression is upregulated in exhausted T cells, revealing that HPK1 mediates T cell dysfunction and is a drug target for T cell immunotherapy. Furthermore, HPK1 is also a negative regulator of B cell receptor (BCR)-induced B cell activation and dendritic cell activation. Within B cells, HPK1 plays a crucial role in maintaining Treg cell function.

[0004] HPK1 activation is closely related to the induction of tumor-infiltrating T cell dysfunction and the weakening of immune responses from T cells, B cells, and dendritic cells, making it a potential target for tumor immunotherapy. Small molecule drugs targeting HPK1 (MAP4K1) kinase activity can "normalize" the immune system in the tumor microenvironment, increasing the number and killing ability of infiltrating immune cells in the tumor microenvironment. Furthermore, they can be used in combination with PD-1 / PD-L1 antibodies to improve the sensitivity of antibody drugs, enhance the efficacy of tumor treatment, and improve patient survival rates. Summary of the Invention

[0005] One object of the present invention is to provide a novel HPK1 (MAP4K1) inhibitor compound, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite or prodrug thereof, and a pharmaceutical composition comprising the thereof.

[0006] On one hand, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof.

[0007]

[0008] in,

[0009] X, Y, and Z are each -NR 5 -、-(C=O)- and -CR 6a R 6b -, provided that X is not -(C=O)- and Z is not -NR. 5 -;

[0010] R 1 Selected from hydrogen, C 3-6 Cycloalkenyl, unsubstituted, or with one or two independent R 7 Substituted heterocyclic groups, and unsubstituted or substituted groups, or those with one or two independent R groups 7 Substituted heteroaryl groups;

[0011] R 2 and R 3 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Alkylamino C 1-3 Alkyl, C 1-6 Alkylaminoyl, (C 1-3 Alkyl)(C 3-6 Cycloalkyl)aminoC 1-3 Alkyl, unsubstituted, or with one or two independent R 7 Substituted heterocyclic groups, and unsubstituted or substituted groups, or those with one or two independent R groups 7 Substituted heteroaryl groups;

[0012] Or R 1 With adjacent R 2 Or R 3 Together they form a heteroalkylene group containing one heteroatom selected from N and O and 2-4 carbon atoms, wherein when the heteroatom is an N atom, the N atom is not substituted or is replaced by R. 7 replace;

[0013] The condition is R1 R 2 and R 3 They are not both hydrogen;

[0014] R 4 Selected from C 1-6 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl;

[0015] R 5 Selected from C 1-6 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl;

[0016] R 6a and R 6b Each is independently selected from hydrogen and C. 1-6 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl, or R 6a R 6b Together with the carbon atoms bonded to them, they form C 3-6 cycloalkyl;

[0017] Or R 4 With adjacent R 6a Or R 6b Together they form C 3-5 Alkylene, or a heteroalkylene containing one heteroatom selected from N and O and 2-4 carbon atoms, wherein the C 3-5 Alkylenes are optionally further divided by one or two independent C 1-3 Alkyl substitution, and the C 3-5 Two non-adjacent carbon atoms on an alkylene group are optionally connected to form a bridging bond;

[0018] R 7 Each is independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkoxyalkyl, C 2-6 Alkyl group, C 3-6 Cycloalkylformyl, C 1-6 Alkylamino, C 1-6 alkylsulfonyl, C 1-3 Alkylaminoacyl C 1-3 Alkyl and C 3-6 Cycloalkylaminoacyl C 1-3 Alkyl group, or two adjacent R groups 7 Connect to form C 2-4 Alkylene;

[0019] R8 Each is independently selected from amino, halogen, and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Alkylamino, or two adjacent R 8 They are linked to form a heteroalkylene group containing two independent heteroatoms selected from N and O and 1-3 carbon atoms;

[0020] Each of the heterocyclic groups is independently a 5-7 member monocyclic heterocyclic group containing one or two heteroatoms independently selected from N and O, or a 7-10 member bridged bicyclic heterocyclic group containing one or two heteroatoms independently selected from N and O.

[0021] Each of the heteroaryl groups is independently a 5-6 membered monocyclic heteroaryl group containing one or two heteroatoms independently selected from N and O.

[0022] In a preferred embodiment, R 1 Selected from hydrogen, C 5-6 Cycloalkenyl, unsubstituted, or with one or two independent R 7 Substituted heterocyclic groups, and unsubstituted or substituted groups, or those with one or two independent R groups 7 Substituted heteroaryl groups; R 2 and R 3 Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-4 Alkylamino C 1-2 Alkyl, C 1-2 Alkylaminoyl, (C 1-2 Alkyl)(C 3-4 Cycloalkyl)aminoC 1-2 Alkyl, unsubstituted, or with one or two independent R 7 Substituted heterocyclic groups, and unsubstituted or substituted groups, or those with one or two independent R groups 7 Substituted heteroaryl groups; or R 1 With adjacent R 2 Or R 3 Together they form a heteroalkylene group containing one heteroatom selected from N and O and three carbon atoms, wherein when the heteroatom is an N atom, the N atom is not substituted or is replaced by R. 7 replace.

[0023] In a further embodiment, R 7 Each is independently selected from hydroxyl, halogen, C 1-3 Alkyl, C 3-6 cycloalkyl, C 1-3 Haloalkyl, C1-3 Hydroxyalkyl, C 1-3 Alkoxy C 1-3 Alkyl, C 2-4 Alkyl group, C 3-4 Cycloalkylformyl, C 1-4 Alkylamino, C 1-3 alkylsulfonyl, C 1-2 Alkylaminoacyl C 1-2 Alkyl and C 3-4 Cycloalkylaminoacyl C 1-2 Alkyl group, or two adjacent R groups 7 They connect to form propylidene.

[0024] In yet another preferred embodiment, each of the heterocyclic groups is independently selected from morpholino, piperazino, homopiperazino, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and 8-9 membered bridged bicyclic heterocyclic groups containing 2 N atoms;

[0025] In another preferred embodiment, each of the heteroaryl groups is independently selected from pyrazolyl, pyridyl, and pyrroleyl.

[0026] In yet another implementation, R 1 Selected from unsubstituted or with one selected from hydroxyl, halogen, C 1-3 Alkyl, C 3-5 cycloalkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 2-3 Alkyl group, C 3-4 Cycloalkylformyl, C 2-4 Alkylamino and C 1-2 alkylsulfonyl groups substituted with heterocyclic groups, and unsubstituted or substituted groups with 1 carbon atom. 1-3 Alkyl-substituted pyrazolyl group; R 2 and R 3 Each is independently selected from hydrogen, halogen, and C. 1-2 Alkylamino C 1-2 Alkyl groups, and unsubstituted or substituted with one carbon atom 1-3 Alkyl-substituted heteroaryl groups; or R 1 With adjacent R 2 Or R 3 Together they form a heteroalkylene group containing one heteroatom selected from N and O and three carbon atoms, wherein when the heteroatom is an N atom, the N atom is not substituted or is selected from C. 1-3 Alkyl, C 1-2 Alkoxy C 1-2 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 2-3 Alkyl group, C 1-2 Alkylaminoacyl C1-2 Alkyl and C 3-4 Cycloalkylaminoacyl C 1-2 Alkyl group substitution; wherein the heterocyclic group is selected from morpholino, piperazine, homopiperazine, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and The heteroaryl group is selected from pyrazolyl, pyridyl, and pyrroleyl.

[0027] In other embodiments, R 4 Selected from C 1-3 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl; R 5 Selected from C 1-3 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl; R 6a and R 6b Each is independently selected from hydrogen and C. 1-3 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl, or R 6a R 6b Together with the carbon atoms bonded to them, they form C 3-6 cycloalkyl; or R 4 With adjacent R 6a Or R 6b Together they form C 3-4 Alkylene, or heteroalkylene containing one oxygen atom and three carbon atoms, wherein the C 3-4 The alkylene group is optionally further substituted with two methyl groups, and the C 3-4 Two non-adjacent carbon atoms on the alkylene group are optionally connected to form a bridging bond; wherein, R 8 Each is independently selected from amino, halogen, and C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups and C 1-3 Alkylamino, or two adjacent R 8 They are linked to form a heteroalkylene group containing two heteroatoms independently selected from N and O and one to two carbon atoms.

[0028] In a further embodiment, R 4 Selected from C 1-3 Alkyl groups, and unsubstituted or with one or two independently selected from amino, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 alkylamino group-substituted phenyl groups; R 5 Selected from C 1-3Alkyl groups, and unsubstituted or with one or two independently selected from halogens, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 A phenyl group substituted with a halogenated alkoxy group; R 6a and R 6b Each is independently selected from hydrogen, and unsubstituted or by one or two independently selected from halogens and C. 1-3 Alkyl groups substituted with phenyl groups, or R 6a R 6b Together with the carbon atoms bonded to them, they form C 3-6 cycloalkyl; or R 4 With adjacent R 6a Or R 6b They connect together to form butylene.

[0029] Preferably, the present invention relates to a compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof.

[0030]

[0031] More preferably, in this embodiment, R 1 Selected from hydrogen, unsubstituted or selected by one or two independently selected hydroxyl groups, halogens, C 1-3 Alkyl, C 3-5 cycloalkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 2-3 Alkyl group, C 3-4 Cycloalkylformyl, C 2-4 Alkylamino and C 1-2 alkylsulfonyl groups substituted with heterocyclic groups, and unsubstituted or substituted groups with 1 carbon atom. 1-3 Alkyl-substituted pyrazolyl group; wherein the heterocyclic group is selected from morpholinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and R 2 and R 3 Each is independently selected from hydrogen, halogen, and C. 1-2 Alkylamino C 1-2 Alkyl groups, and unsubstituted or substituted with one carbon atom 1-3 Alkyl-substituted heteroaryl; wherein the heteroaryl group is selected from pyrazolyl, pyridyl, and pyrrolithyl; or R 1 With adjacent R 2 Or R 3 Together they form a heteroalkylene group containing one heteroatom selected from N and O and three carbon atoms, wherein when the heteroatom is an N atom, the N atom is not substituted or is selected from C. 1-3 Alkyl, C1-2 Alkoxy C 1-2 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 2-3 Alkyl group, C 1-2 Alkylaminoacyl C 1-2 Alkyl and C 3-4 Cycloalkylaminoacyl C 1-2 Alkyl groups are substituted.

[0032] Furthermore, preferably in this embodiment, R 4 Selected from unsubstituted or by one or two independently selected amino, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 alkylamino group-substituted phenyl groups; R 5 Selected from C 1-3 Alkyl; R 6a and R 6b Each is independently selected from hydrogen, and unsubstituted or halogenated phenyl groups, or R 6a R 6b Together with the carbon atoms bonded to them, they form C 3-6 cycloalkyl; or R 4 With adjacent R 6a Or R 6b They connect together to form butylene.

[0033] More preferably, R 1 Selected from unsubstituted or by one or two independently selected halogens, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 2-3 alkyl acyl and C 2-4 Alkylamino groups substituted with heterocyclic groups, and unsubstituted or substituted groups with one carbon atom. 1-3 Alkyl-substituted pyrazolyl group; wherein the heterocyclic group is selected from morpholinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and R 2 and R 3 Each is independently selected from hydrogen, halogens, and C. 1-2 Alkylamino C 1-2 Alkyl; or R 1 With adjacent R 2 Or R 3 Together they form a heteroalkylene group containing 1 nitrogen atom and 3 carbon atoms, wherein the nitrogen atom is not substituted or is replaced by a carbon atom. 1-3 Alkyl or C 1-2 Alkoxy C 1-2 Alkyl substitution; R 4 Selected from unsubstituted or one selected from halogen and C1-3 Alkyl groups substituted with phenyl groups; R 5 Methyl; R 6a and R 6b Each is independently selected from hydrogen and phenyl, or R 6a R 6b Together with the carbon atoms bonded to them, they form C 3-6 cycloalkyl; or R 4 With adjacent R 6a Or R 6b They connect together to form butylene.

[0034] In other preferred embodiments, the present invention relates to a compound of formula (III) or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof.

[0035]

[0036] Preferably, in this embodiment, R 1 Selected from unsubstituted or by 1 C 1-3 Alkyl-substituted heterocyclic group; wherein the heterocyclic group is selected from morpholino, piperazine, piperidinyl, and tetrahydropyranyl; R 2 and R 3 Each is independently selected from hydrogen and C. 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-2 Alkylamino C 1-2 Alkyl, (C 1-2 Alkyl)(C 3-4 Cycloalkyl)aminoC 1-2 Alkyl groups, and unsubstituted or substituted with one carbon atom 1-3 Alkyl-substituted pyrazolyl group; or R 1 With adjacent R 2 Or R 3 Together they form a heteroalkylene group containing one nitrogen atom and three carbon atoms, wherein the nitrogen atom is unsubstituted or selected from C. 1-3 Alkyl and C 1-3 Hydroxyl alkyl groups are substituted.

[0037] Furthermore, preferably in this embodiment, R 4 Selected from C 1-3 Alkyl; R 5 Selected from unsubstituted or one selected from halogen, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 A phenyl group substituted with a halogenated alkoxy group; R 6a and R 6b Each is hydrogen.

[0038] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

[0039] In a third aspect of the invention, a method is provided for regulating, for example, inhibiting or treating HPK1 (MAP4K1)-related conditions or diseases, including cancer, said method being implemented by using the compounds disclosed herein.

[0040] In another aspect of the invention, the use of the above-described compound, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof, in the preparation of a medicament for treating and / or preventing diseases mediated by HPK1 activity, and a method for using the above-described compound, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof, for treating and / or preventing diseases mediated by HPK1 activity.

[0041] Furthermore, the diseases are selected from Parkinson's disease, Alzheimer's disease, stroke and related memory loss, arthritis, allergies, asthma, diabetes, symptoms characterized by inflammation, liver ischemia, reperfusion injury, hearing loss or deafness, neural tube birth defects, obesity, oxidative damage to organs, heart disease, and transplant rejection.

[0042] Alternatively, the disease may be selected from the following hyperproliferative disorders: melanoma, thyroid cancer, adenocarcinoma, breast cancer, central nervous system cancer, colorectal cancer, squamous cell carcinoma, small cell and non-small cell lung cancer, ovarian cancer, endometrial cancer, pancreatic cancer, prostate cancer, sarcoma, and skin cancer; or the disease may be selected from the following hematologic cancers: leukemia, acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, megakaryoblastic leukemia, and multiple myeloma. Detailed Implementation

[0043] the term

[0044] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains.

[0045] Unless otherwise stated, this invention employs conventional methods within the scope of the art, such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology. Unless specifically defined, nomenclature and laboratory procedures and techniques related to analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry described herein are known to those skilled in the art. Generally, the foregoing techniques and steps can be practiced by conventional methods well-known in the art and described in various general and more specific documents, which are cited and discussed herein.

[0046] The term "alkyl" refers to an aliphatic hydrocarbon group, which can be branched or straight-chain alkyl. Depending on the structure, an alkyl group can be a monovalent or divalent group (i.e., an alkylene group). In this invention, the alkyl group is preferably an alkyl group having 1-8 carbon atoms, more preferably a "lower alkyl" having 1-6 carbon atoms, and even more preferably an alkyl group having 1-4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. It should be understood that "alkyl" as used herein includes all possible configurations and conformations of the alkyl group; for example, "propyl" as used herein includes n-propyl and isopropyl, "butyl" includes n-butyl, isobutyl, and tert-butyl, and "pentyl" includes n-pentyl, isopentyl, neopentyl, tert-pentyl, and pent-3-yl, etc.

[0047] The term "alkoxy" refers to an -O-alkyl group, where the alkyl group is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy.

[0048] The term "alkoxyalkyl" refers to an alkyl group as defined herein that has been substituted with an alkoxy group as defined herein.

[0049] The term "cycloalkyl" refers to a monocyclic or polycyclic group containing only carbon and hydrogen. Cycloalkyl groups include groups having 3-12 ring atoms. Depending on the structure, a cycloalkyl group can be a monovalent or bivalent group (e.g., a cycloalkylene group). In this invention, the cycloalkyl group is preferably a cycloalkyl group having 3-8 carbon atoms, more preferably a "lower cycloalkyl group" having 3-6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantyl.

[0050] The term "alkyl (cycloalkyl)" or "cycloalkylalkyl" means that an alkyl group as defined herein is substituted with a cycloalkyl group as defined herein. Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc.

[0051] The term "aromatic group" refers to a planar ring with a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. An aromatic ring can consist of five, six, seven, eight, nine, or more than nine atoms. The aromatic group can be optionally substituted. The term "aromatic group" includes carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent carbon atom pairs) groups.

[0052] As used herein, the term "aryl" refers to an aromatic ring in which every atom constituting the ring is a carbon atom. An aryl ring can consist of five, six, seven, eight, nine, or more than nine atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthraceneyl, fluorenyl, and indene. Depending on the structure, the aryl group can be a monovalent or divalent group (i.e., an arylene).

[0053] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined herein.

[0054] The term "heteroaryl" refers to an aryl group that includes one or more cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. An N-containing "heteroaryl" moiety means that at least one skeletal atom on the ring of the aryl group is a nitrogen atom. Depending on its structure, a heteroaryl can be a monovalent or bivalent group (i.e., a hypoaryl). Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indazinyl, phthalazinyl, pyridazinyl, isoydinolyl, pteridinyl, purine, oxadiazolyl, thiazolyl, furazonyl, benzofuranyl, benzothiophene, benzothiazolyl, benzooxazolyl, quinazolinyl, naphridinyl, and furanopyridinyl, etc.

[0055] The term "alkyl (aryl)" or "aralkyl" means that an alkyl group as defined herein is replaced by an aryl group as defined herein. Non-limiting alkyl (aryl) groups include benzyl, phenethyl, etc.

[0056] The term “alkyl (heteroaryl)” or “heteroarylalkyl” means that an alkyl group as defined herein is replaced by a heteroaryl group as defined herein.

[0057] As used herein, the term "heteroalkyl" means an alkyl group in which one or more skeletal chain atoms are heteroatoms, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof. The heteroatoms (one or more) may be located at any position within the heteroalkyl group or at a position where the heteroalkyl group is attached to the rest of the molecule.

[0058] As used herein, the term "heterocyclic alkyl" or "heterocyclic group" refers to a non-aromatic ring in which one or more of the constituent atoms of the ring are heteroatoms selected from nitrogen, oxygen, and sulfur. Heterocyclic alkyl rings can be monocyclic or polycyclic, consisting of three, four, five, six, seven, eight, nine, or more atoms. Heterocyclic alkyl rings may be optionally substituted. Examples of heterocyclic alkyl groups include, but are not limited to, lactams, lactones, cycloimides, cyclothioimides, cyclocarbamates, tetrahydrothiarans, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxins, 1,3-dioxanes, 1,4-dioxins, 1,4-dioxanes, piperazines, 1,3-oxothiacyclohexane, 1,4-oxothiacyclohexadiene, 1,4-oxothiacyclohexane, tetrahydro-1,4-thiazine, 2H-1,2-oxazines, maleimides, succinimides, barbiturates, and thiobarbiturates. Acids, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrrolidone, pyrrolidine, imidazoline, pyrazole, imidazoline, imidazoline, 1,3-dioxacyclopentene, 1,3-dioxacyclopentene, 1,3-dithiocyclopentene, isoxazoline, isoxazoline, oxazoline, oxazoline, oxazoline, oxazoline ketone, thiazoline, thiazoline, and 1,3-oxothiocyclopentane. Depending on the structure, heterocyclic alkyl groups can be monovalent or bivalent (i.e., heterocyclic alkylene).

[0059] The term "alkyl (heterocyclic alkyl)" or "heterocyclic alkyl alkyl" means that an alkyl group as defined herein is replaced by a heterocyclic alkyl group as defined herein.

[0060] The term "alkoxy (heterocyclic alkyl)" or "heterocyclic alkyl alkoxy" means that the alkoxy group defined herein is substituted with the heterocyclic alkyl group defined herein.

[0061] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0062] The terms "haloalkyl", "haloalkoxy", and "haloheteroalkyl" include structures of alkyl, alkoxy, or heteroalkyl groups in which at least one hydrogen atom is replaced by a halogen atom. In some embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same or different from each other.

[0063] The term "hydroxyl group" refers to the -OH group.

[0064] The term "cyano" refers to the -CN group.

[0065] The term "ester group" refers to a chemical moiety having the formula -COOR, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (linked by a ring carbon), and heterocyclic (linked by a ring carbon).

[0066] The term "amino" refers to the -NH2 group.

[0067] The term "aminoacyl" refers to the -CO-NH2 group.

[0068] The term "alkylaminoacyl" refers to the -CO-NH-R group, where R is an alkyl group as defined herein.

[0069] The term "amide group" or "amide group" refers to -NR-CO-R', where R and R' are each independently hydrogen or alkyl.

[0070] The term "alkylamino" refers to an amino substituent further replaced by one or two alkyl groups, specifically the group -NRR', where R and R' are each independently selected from hydrogen or lower alkyl groups, provided that -NRR' is not -NH2. "Alkylamino" includes groups in compounds in which the nitrogen atom of -NH2 is attached to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, etc. "Dialkylamino" includes groups in which the nitrogen atom of -NH2 is attached to at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, etc.

[0071] The terms “arylamino” and “diarylamino” refer to amino substituents that are further replaced by one or two aryl groups, specifically the group -NRR', where R and R' are each independently selected from hydrogen, lower alkyl, or aryl, and N is attached to one or two aryl groups respectively.

[0072] The term "cycloalkylamino" refers to an amino substituent that is further replaced by one or two cycloalkyl groups as defined herein.

[0073] The term "heteroalkylamino" refers to an amino substituent that is further replaced by one or two heteroalkyl groups as defined herein.

[0074] The term "arylamino" in this article refers to a group in which R is a lower aryl group and R' is a hydrogen, lower alkyl, aryl, or lower aryl group -NRR'.

[0075] The term “heteroarylamino” refers to an amino substituent that is further replaced by one or two heteroaryl groups as defined herein.

[0076] The term "heterocyclic alkylamino" refers to an amino group as defined herein that has been substituted with a heterocyclic alkyl group as defined herein.

[0077] The term "alkylaminoalkyl" means that an alkyl group as defined herein is replaced by an alkylamino group as defined herein.

[0078] The term "aminoalkyl" refers to an alkyl substituent that is further replaced by one or more amino groups.

[0079] The term "aminoalkoxy" refers to an alkoxy substituent that is further replaced by one or more amino groups.

[0080] The term "hydroxyalkyl" or "hydroxyalkyl group" refers to an alkyl substituent that is further replaced by one or more hydroxyl groups.

[0081] The term "cyanoalkyl" refers to an alkyl substituent that is further replaced by one or more cyano groups.

[0082] The term "acyl" refers to the monovalent group remaining after removing the hydroxyl group from an organic or inorganic oxyacid, with the general formula RM(O)-, where M is usually C.

[0083] The term "carbonyl" refers to an organic functional group (C=O) formed by carbon and oxygen atoms linked by a double bond.

[0084] The terms "alkanoyl" or "alkyl carbonyl" refer to a carbonyl group that is further substituted with an alkyl group. Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, and hexanoyl.

[0085] The term "aryl carbonyl" refers to a carbonyl group as defined herein that has been replaced by an aryl group as defined herein.

[0086] The term "alkoxycarbonyl" refers to a carbonyl group that is further replaced by an alkoxy group.

[0087] The term "heterocyclic alkyl carbonyl" refers to a carbonyl group that is further replaced by a heterocyclic alkyl group.

[0088] The terms “alkylaminocarbonyl”, “cycloalkylaminocarbonyl”, “arylaminocarbonyl”, “arylalkylaminocarbonyl”, and “heteroarylaminocarbonyl” refer to carbonyl groups as defined herein that have been substituted by alkylamino, cycloalkylamino, arylamino, arylalkylamino, or heteroarylamino groups as defined herein.

[0089] The terms “alkylcarbonylalkyl” or “alkanoylalkyl” refer to an alkyl group that is further replaced by an alkylcarbonyl group.

[0090] The term "alkylcarbonylalkoxy" or "alkanoylalkoxy" refers to an alkoxy group that is further substituted with an alkyl carbonyl group.

[0091] The term "heterocyclic alkyl carbonyl alkyl" refers to an alkyl group that is further replaced by a heterocyclic alkyl carbonyl group.

[0092] The term "thiol" refers to a -SH group. The term "alkathiol" refers to a thiol group as defined herein that has been substituted with an alkyl group as defined herein.

[0093] The terms "sulfonyl" or "sulfonyl" refer to the functional group of a sulfonic acid after the loss of its hydroxyl group, specifically the -S(=O)2- group.

[0094] The term "sulfonyl" or "sulfinyl" refers to -S(=O)-.

[0095] The terms "aminosulfonyl" or "aminosulfonyl" refer to the -S(=O)2-NH2 group.

[0096] The terms "alkyl sulfoxide" or "alkyl sulfinyl" refer to alkyl-S(=O)-.

[0097] The terms "alkyl sulfonyl" or "alkyl sulfonyl" refer to -S(=O)2-R, where R is an alkyl group.

[0098] The term "alkylaminosulfone" refers to a sulfone group as defined herein that has been replaced by an alkylamino group as defined herein.

[0099] The terms “alkylsulfonylamino(amine)” or “alkylsulfonylamino(amine)”, and “cycloalkylsulfonylamino(amine)” or “cycloalkylsulfonylamino(amine)”, refer to an amino group as defined herein that is substituted with an alkylsulfonyl or cycloalkylsulfonyl group as defined herein, i.e., -NH-S(=O)2-R, where R is alkyl and cycloalkyl, respectively.

[0100] The terms "cycloalkylsulfonyl" and "cycloalkylsulfonyl" refer to -S(=O)2-R, where R is cycloalkyl.

[0101] The term "quaternary ammonium group" refers to -N + RR'R", where R, R' and R" are each independently selected from alkyl groups having 1 to 8 carbon atoms.

[0102] The term "optional" means that one or more events described below may or may not occur, and includes both the events that occur and the events that do not occur. The terms "optionally substituted" or "substituted" mean that the mentioned group can be substituted by one or more additional groups, each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, hydroxyl, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methanesulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc. Preferably, the amino protecting group is selected from neopentanoyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl, etc.

[0103] As used herein, a pharmaceutically acceptable form of the disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, esters, acids, isomers, metabolites, prodrugs, and isotopically labeled derivatives of the disclosed compound.

[0104] The term "pharmaceutically acceptable salt" in this article refers to a salt that retains the desired biological activity of the subject compound while exhibiting minimal undesirable toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.

[0105] "Solvate" or "solvent compound" refers to a solvation compound containing a stoichiometric or non-stoichiometric solvent. Some compounds tend to trap solvent molecules in a fixed molar ratio in a crystalline solid state, thus forming a solvate compound. If the solvent is water, the resulting solvate compound is a hydrate; if the solvent is an alcohol, the resulting solvate compound is an alcohol. Hydrates are formed by the combination of one or more water molecules with a molecule of the substance, wherein the water retains its molecular state as H₂O.

[0106] The "metabolites" of the compounds disclosed herein are derivatives of the compounds formed when the compounds are metabolized. The term "active metabolite" refers to a biologically active derivative of the compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to the sum of processes by which a particular substance is altered by an organism (including, but not limited to, hydrolysis and enzyme-catalyzed reactions, such as oxidation). Thus, enzymes can produce specific structures that are transformed into compounds. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while glucuronyl diphosphate transferases catalyze the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be obtained from *The Pharmacological Basis of Therapeutics*, 9th edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from that host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both methods are known in the art. In some embodiments, the metabolites of the compound are formed through an oxidation process and correspond to the corresponding hydroxyl-containing compounds. In some implementations, the compound is metabolized into a drug-active metabolite.

[0107] The term “modulation” as used in this article refers to direct or indirect interaction with a target to alter its activity, including, for example, enhancing, inhibiting, limiting, or prolonging the activity of a target.

[0108] The term "prodrug" or "prodrug precursor" refers to derivatives that may not be pharmacologically active, but in some cases can be administered orally or parenterally and subsequently metabolized in vivo to form the pharmacologically active compounds of the present invention. Non-limiting examples of prodrugs include esters, carbonates, hemiesters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, nitrogen-containing compounds, phosphoramides, glycosides, ethers, acetals, and ketoacetates, etc.

[0109] "Effective amount" refers to the amount of a drug or pharmaceutical preparation that will elicit a biological or medical response in an investigational tissue, system, animal, or human, such as that of an investigator or physician. Furthermore, the term "therapeutic effective amount" refers to any amount that, compared to a corresponding subject who has not received that amount, results in a treatment, cure, prevention, or relief of disease, disorder, or side effects, or a reduction in the rate of disease or disorder progression. The term also includes amounts that effectively improve normal physiological function.

[0110] As used herein, the term "treatment" refers to the relief of at least one symptom of a disease, disorder, or condition. This term includes administering medication to a subject and / or applying one or more of the compounds described herein to provide management or treatment of the condition. For the purposes of this disclosure, "treatment" may, but does not necessarily, provide a cure; rather, it means that "treatment" can be a form of management of the condition. When the compounds described herein are used to treat harmful proliferating cells (including cancer), "treatment" includes the partial or complete destruction of said harmful proliferating cells, but with minimal impact on normal cells. The desired treatment mechanism for harmful, rapidly proliferating cells (including cancer cells) is apoptosis at the cellular level.

[0111] As used in this article, “prevention” includes the initiation of joint prevention or mitigation of the development of a clinically significant disease or the initiation of a preclinically significant disease stage in an individual at risk. This includes preventative treatment of individuals at risk of disease development.

[0112] The terms "subject" or "patient" include organisms that may suffer from a condition or a condition associated with reduced or insufficient programmed cell death (apoptosis) or that may otherwise benefit from administration of the compounds of the present invention, such as humans and non-human animals. Preferred humans include human patients who suffer from or are predisposed to suffer from the condition or related condition as described herein. The term "non-human animal" includes vertebrates, such as mammals, such as non-human primates, sheep, cattle, dogs, cats, and rodents such as mice, as well as non-mammals such as chickens, amphibians, reptiles, etc.

[0113] The GI used in this article 50 This refers to the drug concentration required to inhibit the growth of 50% of cells, that is, the drug concentration at which the growth of 50% of cells (such as cancer cells) is inhibited or controlled.

[0114] IC used in this article 50 This refers to the amount, concentration, or dose of a specific test compound that achieves 50% inhibition of the maximum effect in the analysis of the measured effect.

[0115] EC used in this article 50 A dose-dependent response refers to a dose, concentration, or amount of a measured compound that elicits a specific response induced, stimulated, or enhanced by that compound at a maximum expression of 50%.

[0116] The kinase inhibitor of the present invention

[0117] This invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof.

[0118]

[0119] in,

[0120] X, Y, and Z are each -NR 5 -、-(C=O)- and -CR 6a R 6b -, provided that X is not -(C=O)- and Z is not -NR. 5 -;

[0121] R 1 Selected from hydrogen, C 3-6 Cycloalkenyl, unsubstituted, or with one or two independent R 7 Substituted heterocyclic groups, and unsubstituted or substituted groups, or those with one or two independent R groups 7 Substituted heteroaryl groups;

[0122] R 2 and R 3 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Alkylamino C 1-3 Alkyl, C 1-6 Alkylaminoyl, (C 1-3 Alkyl)(C 3-6 Cycloalkyl)aminoC 1-3 Alkyl, unsubstituted, or with one or two independent R 7 Substituted heterocyclic groups, and unsubstituted or substituted groups, or those with one or two independent R groups 7 Substituted heteroaryl groups;

[0123] Or R 1 With adjacent R 2 Or R 3Together they form a heteroalkylene group containing one heteroatom selected from N and O and 2-4 carbon atoms, wherein when the heteroatom is an N atom, the N atom is not substituted or is replaced by R. 7 replace;

[0124] The condition is R 1 R 2 and R 3 They are not both hydrogen;

[0125] R 4 Selected from C 1-6 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl;

[0126] R 5 Selected from C 1-6 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl;

[0127] R 6a and R 6b Each is independently selected from hydrogen and C. 1-6 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl, or R 6a R 6b Together with the carbon atoms bonded to them, they form C 3-6 cycloalkyl;

[0128] Or R 4 With adjacent R 6a Or R 6b Together they form C 3-5 Alkylene, or a heteroalkylene containing one heteroatom selected from N and O and 2-4 carbon atoms, wherein the C 3-5 Alkylenes are optionally further divided by one or two independent C 1-3 Alkyl substitution, and the C 3-5 Two non-adjacent carbon atoms on an alkylene group are optionally connected to form a bridging bond;

[0129] R 7 Each is independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkoxyalkyl, C 2-6 Alkyl group, C 3-6 Cycloalkylformyl, C 1-6 Alkylamino, C 1-6 alkylsulfonyl, C 1-3 Alkylaminoacyl C 1-3 Alkyl and C3-6 Cycloalkylaminoacyl C 1-3 Alkyl group, or two adjacent R groups 7 Connect to form C 2-4 Alkylene;

[0130] R 8 Each is independently selected from amino, halogen, and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Alkylamino, or two adjacent R 8 They are linked to form a heteroalkylene group containing two independent heteroatoms selected from N and O and 1-3 carbon atoms;

[0131] Each of the heterocyclic groups is independently a 5-7 member monocyclic heterocyclic group containing one or two heteroatoms independently selected from N and O, or a 7-10 member bridged bicyclic heterocyclic group containing one or two heteroatoms independently selected from N and O.

[0132] Each of the heteroaryl groups is independently a 5-6 membered monocyclic heteroaryl group containing one or two heteroatoms independently selected from N and O.

[0133] In a preferred embodiment, R 1 Selected from hydrogen, C 5-6 Cycloalkenyl, unsubstituted, or with one or two independent R 7 Substituted heterocyclic groups, and unsubstituted or substituted groups, or those with one or two independent R groups 7 Substituted heteroaryl groups; R 2 and R 3 Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-4 Alkylamino C 1-2 Alkyl, C 1-2 Alkylaminoyl, (C 1-2 Alkyl)(C 3-4 Cycloalkyl)aminoC 1-2 Alkyl, unsubstituted, or with one or two independent R 7 Substituted heterocyclic groups, and unsubstituted or substituted groups, or those with one or two independent R groups 7 Substituted heteroaryl groups; or R 1 With adjacent R 2 Or R 3 Together they form a heteroalkylene group containing one heteroatom selected from N and O and three carbon atoms, wherein when the heteroatom is an N atom, the N atom is not substituted or is replaced by R. 7 replace.

[0134] In a further embodiment, R 7 Each is independently selected from hydroxyl, halogen, C 1-3 Alkyl, C 3-6 cycloalkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy C 1-3 Alkyl, C 2-4 Alkyl group, C 3-4 Cycloalkylformyl, C 1-4 Alkylamino, C 1-3 alkylsulfonyl, C 1-2 Alkylaminoacyl C 1-2 Alkyl and C 3-4 Cycloalkylaminoacyl C 1-2 Alkyl group, or two adjacent R groups 7 They connect to form propylidene.

[0135] In yet another preferred embodiment, each of the heterocyclic groups is independently selected from morpholino, piperazino, homopiperazino, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and 8-9 membered bridged bicyclic heterocyclic groups containing 2 N atoms;

[0136] In another preferred embodiment, each of the heteroaryl groups is independently selected from pyrazolyl, pyridyl, and pyrroleyl.

[0137] In yet another implementation, R 1 Selected from unsubstituted or with one selected from hydroxyl, halogen, C 1-3 Alkyl, C 3-5 cycloalkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 2-3 Alkyl group, C 3-4 Cycloalkylformyl, C 2-4 Alkylamino and C 1-2 alkylsulfonyl groups substituted with heterocyclic groups, and unsubstituted or substituted groups with 1 carbon atom. 1-3 Alkyl-substituted pyrazolyl group; R 2 and R 3 Each is independently selected from hydrogen, halogen, and C. 1-2 Alkylamino C 1-2 Alkyl groups, and unsubstituted or substituted with one carbon atom 1-3 Alkyl-substituted heteroaryl groups; or R 1 With adjacent R 2 Or R 3 Together they form a heteroalkylene group containing one heteroatom selected from N and O and three carbon atoms, wherein when the heteroatom is an N atom, the N atom is not substituted or is selected from C. 1-3 Alkyl, C 1-2Alkoxy C 1-2 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 2-3 Alkyl group, C 1-2 Alkylaminoacyl C 1-2 Alkyl and C 3-4 Cycloalkylaminoacyl C 1-2 Alkyl group substitution; wherein the heterocyclic group is selected from morpholino, piperazine, homopiperazine, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and The heteroaryl group is selected from pyrazolyl, pyridyl, and pyrroleyl.

[0138] In other embodiments, R 4 Selected from C 1-3 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl; R 5 Selected from C 1-3 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl; R 6a and R 6b Each is independently selected from hydrogen and C. 1-3 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl, or R 6a R 6b Together with the carbon atoms bonded to them, they form C 3-6 cycloalkyl; or R 4 With adjacent R 6a Or R 6b Together they form C 3-4 Alkylene, or heteroalkylene containing one oxygen atom and three carbon atoms, wherein the C 3-4 The alkylene group is optionally further substituted with two methyl groups, and the C 3-4 Two non-adjacent carbon atoms on the alkylene group are optionally connected to form a bridging bond; wherein, R 8 Each is independently selected from amino, halogen, and C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups and C 1-3 Alkylamino, or two adjacent R 8 They are linked to form a heteroalkylene group containing two heteroatoms independently selected from N and O and one to two carbon atoms.

[0139] In a further embodiment, R 4 Selected from C 1-3 Alkyl groups, and unsubstituted or with one or two independently selected from amino, halogen, C1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 alkylamino group-substituted phenyl groups; R 5 Selected from C 1-3 Alkyl groups, and unsubstituted or with one or two independently selected from halogens, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 A phenyl group substituted with a halogenated alkoxy group; R 6a and R 6b Each is independently selected from hydrogen, and unsubstituted or by one or two independently selected from halogens and C. 1-3 Alkyl groups substituted with phenyl groups, or R 6a R 6b Together with the carbon atoms bonded to them, they form C 3-6 cycloalkyl; or R 4 With adjacent R 6a Or R 6b They connect together to form butylene.

[0140] Preferably, the present invention relates to a compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof.

[0141]

[0142] More preferably, in this embodiment, R 1 Selected from hydrogen, unsubstituted or selected by one or two independently selected hydroxyl groups, halogens, C 1-3 Alkyl, C 3-5 cycloalkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 2-3 Alkyl group, C 3-4 Cycloalkylformyl, C 2-4 Alkylamino and C 1-2 alkylsulfonyl groups substituted with heterocyclic groups, and unsubstituted or substituted groups with 1 carbon atom. 1-3 Alkyl-substituted pyrazolyl group; wherein the heterocyclic group is selected from morpholinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and R 2 and R 3 Each is independently selected from hydrogen, halogen, and C. 1-2 Alkylamino C 1-2 Alkyl groups, and unsubstituted or substituted with one carbon atom 1-3 Alkyl-substituted heteroaryl; wherein the heteroaryl group is selected from pyrazolyl, pyridyl, and pyrrolithyl; or R 1 With adjacent R 2 Or R3 Together they form a heteroalkylene group containing one heteroatom selected from N and O and three carbon atoms, wherein when the heteroatom is an N atom, the N atom is not substituted or is selected from C. 1-3 Alkyl, C 1-2 Alkoxy C 1-2 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 2-3 Alkyl group, C 1-2 Alkylaminoacyl C 1-2 Alkyl and C 3-4 Cycloalkylaminoacyl C 1-2 Alkyl groups are substituted.

[0143] Furthermore, preferably in this embodiment, R 4 Selected from unsubstituted or by one or two independently selected amino, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 alkylamino group-substituted phenyl groups; R 5 Selected from C 1-3 Alkyl; R 6a and R 6b Each is independently selected from hydrogen, and unsubstituted or halogenated phenyl groups, or R 6a R 6b Together with the carbon atoms bonded to them, they form C 3-6 cycloalkyl; or R 4 With adjacent R 6a Or R 6b They connect together to form butylene.

[0144] More preferably, R 1 Selected from unsubstituted or by one or two independently selected halogens, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 2-3 alkyl acyl and C 2-4 Alkylamino groups substituted with heterocyclic groups, and unsubstituted or substituted groups with one carbon atom. 1-3 Alkyl-substituted pyrazolyl group; wherein the heterocyclic group is selected from morpholinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and R 2 and R 3 Each is independently selected from hydrogen, halogens, and C. 1-2 Alkylamino C 1-2 Alkyl; or R 1 With adjacent R 2 Or R 3Together they form a heteroalkylene group containing 1 nitrogen atom and 3 carbon atoms, wherein the nitrogen atom is not substituted or is replaced by a carbon atom. 1-3 Alkyl or C 1-2 Alkoxy C 1-2 Alkyl substitution; R 4 Selected from unsubstituted or one selected from halogen and C 1-3 Alkyl groups substituted with phenyl groups; R 5 Methyl; R 6a and R 6b Each is independently selected from hydrogen and phenyl, or R 6a R 6b Together with the carbon atoms bonded to them, they form C 3-6 cycloalkyl; or R 4 With adjacent R 6a Or R 6b They connect together to form butylene.

[0145] In other preferred embodiments, the present invention relates to a compound of formula (III) or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof.

[0146]

[0147] Preferably, in this embodiment, R 1 Selected from unsubstituted or by 1 C 1-3 Alkyl-substituted heterocyclic group; wherein the heterocyclic group is selected from morpholino, piperazine, piperidinyl, and tetrahydropyranyl; R 2 and R 3 Each is independently selected from hydrogen and C. 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-2 Alkylamino C 1-2 Alkyl, (C 1-2 Alkyl)(C 3-4 Cycloalkyl)aminoC 1-2 Alkyl groups, and unsubstituted or substituted with one carbon atom 1-3 Alkyl-substituted pyrazolyl group; or R 1 With adjacent R 2 Or R 3 Together they form a heteroalkylene group containing one nitrogen atom and three carbon atoms, wherein the nitrogen atom is unsubstituted or selected from C. 1-3 Alkyl and C 1-3 Hydroxyl alkyl groups are substituted.

[0148] Furthermore, preferably in this embodiment, R 4 Selected from C 1-3 Alkyl; R 5Selected from unsubstituted or one selected from halogen, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 A phenyl group substituted with a halogenated alkoxy group; R 6a and R 6b Each is hydrogen.

[0149] Furthermore, the present invention relates to the preferred compounds described below:

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169] For each variable, any combination of the aforementioned groups is also considered in this paper. It is understood that the substituents and substitution patterns on the compounds presented herein can be selected by those skilled in the art to provide chemically stable compounds that can be synthesized using techniques known in the art and those described herein.

[0170] This article also describes pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, acids, esters, metabolites, or prodrugs of this compound.

[0171] In particular, the compounds described herein can be prepared and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; or formed by reacting with an organic acid such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1 - Formic acid, 2-naphthalenesulfonic acid, tert-butylacetic acid, glucoheponic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, salicylic acid, hydroxynaphthalene acid, stearic acid, mucoconic acid, etc.; (2) Base addition salts, which are formed when the acidic protons in the parent compound are replaced by metal ions, such as alkali metal ions (e.g., lithium, sodium, potassium), alkaline earth metal ions (e.g., magnesium or calcium) or aluminum ions; or coordinated with organic or inorganic bases, the acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucosamine, etc.; the acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.

[0172] The corresponding equilibrium ions of pharmaceutically acceptable salts can be analyzed and identified using a variety of methods, including but not limited to ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectrometry, mass spectrometry, or any combination thereof.

[0173] The salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, solvent evaporation, or lyophilization in the case of an aqueous solution.

[0174] Screening and characterizing pharmaceutically acceptable salts, polymorphs, and / or solvates can be accomplished using a variety of techniques, including but not limited to thermal analysis, X-ray diffraction, spectroscopy, microscopy, and elemental analysis. Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid states). Various microscopy techniques include, but are not limited to, IR microscopy and Raman microscopy.

[0175] All stereoisomers of the compounds of the present invention are considered, in mixtures or in pure or substantially pure form. Stereoisomers can include compounds that are optical isomers by having one or more chiral atoms, and compounds that are optical isomers (restricted isomers) by means of limited rotation around one or more bonds. The definition of compounds according to the invention covers all possible stereoisomers and mixtures thereof. It very specifically covers racemic forms and separated optical isomers with specified activities. Racemic forms can be resolved by physical methods, such as fractional crystallization, separation or crystallization of diastereomer derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from racemic forms by conventional methods (e.g., forming salts with optically active acids, followed by crystallization).

[0176] Prodrugs of the compounds of the present invention are also considered. The term "prodrug" means a compound that, upon administration to a subject, undergoes a metabolic or chemical transformation to produce a compound of formula (I) and / or its salts and / or solvates. Any compound that will be transformed in vivo to provide a bioactive agent is a prodrug within the scope and spirit of the present invention.

[0177] Drug Use

[0178] The compounds of formula I, II or III of the present invention, or their pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, acids, esters, metabolites or prodrugs, are capable of inhibiting HPK1 (MAP4K1) activity, thereby achieving the purpose of treating, preventing or alleviating HPK1 (MAP4K1) mediated diseases.

[0179] Therefore, this application protects the use of compounds of formula I, II or III or pharmaceutically acceptable salts, stereoisomers, solvates, polymorphs, acids, esters, metabolites or prodrugs thereof in the preparation of medicaments for inhibiting HPK1 (MAP4K1) activity, or for treating, preventing or alleviating diseases mediated by HPK1 (MAP4K1).

[0180] Compounds of formula I, II, or II as described herein are inhibitors of HPK1 (MAP4K1) kinase. The HPK1 (MAP4K1) inhibitors according to the invention can therefore be used to treat and prevent diseases associated with dysfunction of protein kinase signaling. Thus, inhibition of HPK1 (MAP4K1) can reverse or prevent cellular dysfunction, particularly in T cells and B cells, associated with disturbances in the JNK signaling pathway. Therefore, administration of HPK1 (MAP4K1) inhibitors as described herein can modulate the MAPK signaling pathway, particularly JNK phosphorylation, thereby providing therapeutic benefits for a variety of diseases and conditions, including autoimmune, neurodegenerative, nervous system, inflammatory, proliferative, and cardiovascular diseases and conditions.

[0181] Furthermore, the selective HPK1 (MAP4K1) inhibition provided by the compounds of this invention can offer a novel approach to cancer treatment. Traditional signal transduction strategies involve interfering with pathways that promote tumor cell proliferation or metastasis. This invention, in turn, provides a means to enhance the activity and effectiveness of the body's T cells, for example, to overcome immunosuppressive strategies exploited by many cancers. The U.S. Food and Drug Administration (FDA) has recently approved several monoclonal antibody-based treatments that achieve the same results by interfering with inhibitory T cell surface receptors that promote TCR activity (e.g., anti-CTLA-4 and anti-PD-1 antibodies, marketed as ipilimumab and pembrolizumab, respectively). The success of these treatments demonstrates validation of the concept that cancer can be effectively treated by interfering with pathways that inhibit TCR signaling. Targeting these pathways with small molecule inhibitors of HPK1 (MAP4K1) should yield improved results using more patient-friendly administration techniques.

[0182] This invention provides a method for treating or preventing diseases or conditions that can be improved by modulating (e.g., inhibiting) HPK1 (MAP4K1)-dependent signaling pathways (including the JNK pathway), such as autoimmune, neurodegenerative, nervous system, inflammatory, hyperproliferative, and cardiovascular diseases and conditions, the method comprising administering to a patient in need an effective amount of a compound of formula I, II, or III as described herein, in free or pharmaceutically acceptable salt form.

[0183] In certain embodiments, administration of a compound of formula I, II, or III results in enhanced T-cell receptor (TCR) signaling, such as resulting in enhanced T-cell-mediated immune responses (e.g., increased T-cell cytokine production).

[0184] In other specific embodiments, administration of a compound of formula I, II, or III results in increased resistance of T cells to PGE2-mediated T cell suppression.

[0185] The disease or condition can be selected from the following groups: neurodegenerative diseases, such as Parkinson's disease or Alzheimer's disease; stroke and related memory loss; autoimmune diseases, such as arthritis; allergies and asthma; diabetes, especially insulin-resistant diabetes; other conditions characterized by inflammation, including chronic inflammatory diseases; liver ischemia; reperfusion injury; hearing loss or deafness; neural tube birth defects; obesity; hyperproliferative conditions, including malignancies, such as leukemia, such as chronic myeloid leukemia (CML); oxidative damage to organs, such as the liver and kidneys; heart disease; and transplant rejection.

[0186] In some embodiments, the disease or condition to be treated may also be associated with impaired HPK1 (MAP4K1)-dependent signaling. Impaired HPK1 (MAP4K1) signaling leads to reduced function of immune cells (e.g., T cells and B cells), which allows or enhances the escape of newly generated cancer cells from immune surveillance. Restoring T cell and B cell function through treatment with MAP4K1 inhibitors can thus promote the clearance of oncogenic and precancerous cells from the body. Therefore, in one particular embodiment, the present invention provides a method for treating or preventing hyperproliferative diseases such as cancers, including melanoma, thyroid cancer, adenocarcinoma, breast cancer, central nervous system cancers (such as glioblastoma, astrocytoma, and ependymoma), colorectal cancer, squamous cell carcinoma, small cell and non-small cell lung cancer, ovarian cancer, endometrial cancer, pancreatic cancer, prostate cancer, sarcoma, and skin cancer.

[0187] In a particular embodiment, the present invention provides a method for treating or preventing hematologic cancers such as leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome, chronic myeloid leukemia (CML), Hodgkin lymphoma, non-Hodgkin lymphoma, megakaryoblastic leukemia, and multiple myeloma, due to the unique role of abnormal immune cell function in hematologic cancers.

[0188] According to the foregoing method, the MAP4K1 inhibitor compounds described herein for the treatment or prevention of diseases or conditions can be used as a standalone therapeutic agent or in combination with one or more other therapeutic agents that can be used to treat said diseases or conditions. These other agents include inhibitors of other protein kinases in the JNK pathway, including, for example, inhibitors of JNK (e.g., JNK1 or JNK2), MKK4, MKK7, p38, MEKK (e.g., MEKK1, MEKK2, MEKK5), and GCK.

[0189] Therefore, in one particular embodiment, the HPK1 (MAP4K1) inhibitor of the present invention can be administered in combination with inhibitors of JNK (e.g., JNK1 or JNK2), MKK4, MKK7, p38, MEKK (e.g., MEKK1, MEKK2, MEKK5) and GCK.

[0190] In another aspect, the present invention provides the following:

[0191] (i) A compound of formula I, II or III as described herein, in free or pharmaceutically acceptable salt form, used in any method as set forth herein or for the treatment or prevention of any disease or ailment as set forth herein;

[0192] (ii) The combination as described above, comprising the HPK1 (MAP4K1) inhibitor of the present invention in free or pharmaceutically acceptable salt form, such as compounds of formula I, II or III as described herein; and a second therapeutic agent that may be used to treat or prevent any disease or condition set forth herein;

[0193] (iii) Use of compounds of formula I, II or III, or combinations thereof, in free or pharmaceutically acceptable salt form (in pharmaceutical manufacturing) for the treatment or prevention of any disease or condition as set forth herein;

[0194] (iv) Compounds of formula I, II, or III in free or pharmaceutically acceptable salt form, combinations thereof, or pharmaceutical compositions of the present invention, used for the treatment or prevention of any disease or condition as described herein.

[0195] The compounds of the present invention can be administered orally or parenterally to mammals (preferably humans) in pharmaceutical form containing only the compounds of the present invention, or in mixtures with pharmacologically acceptable carriers.

[0196] Examples of dosage forms for the drugs of the present invention include: oral formulations, such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, lozenges, and rapidly disintegrating oral tablets), pills, granules, powders, capsules (including soft capsules and microcapsules), syrups, emulsions, suspensions, films (e.g., orally disintegrating films and films applied to the oral mucosa), etc. Other examples of dosage forms for the drugs of the present invention include: parenteral formulations, such as injections, infusions, transdermal formulations (e.g., iontophoresis epidermal formulations), suppositories, ointments, nasal formulations, pulmonary formulations, eye drops, etc. Alternatively, the drugs of the present invention may be controlled-release formulations, such as rapidly released formulations, sustained-release formulations (e.g., sustained-release microcapsules), etc.

[0197] The medicaments of the present invention can be prepared using methods commonly used in the pharmaceutical field and known in the art (e.g., methods described in pharmacopoeias). If desired, the medicaments of the present invention may suitably contain appropriate amounts of additives commonly used in the pharmaceutical field, such as excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers, colorants, preservatives, flavorings, corrective agents, stabilizers, viscosity modifiers, etc.

[0198] Examples of pharmacologically acceptable carriers include these additives. For example, excipients, binders, disintegrants, lubricants, etc., can be used to prepare tablets. Excipients, binders, and disintegrants can be used to prepare pills and granules. Excipients, etc., can be used to prepare powders and capsules. Sweeteners, etc., can be used to prepare syrups. Suspensions, surfactants, emulsifiers, etc., can be used to prepare emulsions or suspensions.

[0199] Examples of excipients include: lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, and calcium sulfate.

[0200] Examples of adhesives include: solutions containing 5 to 10% by weight of starch paste, solutions containing 10 to 20% by weight of gum arabic or gel, solutions containing 1 to 5% by weight of astragalus gum, carboxymethyl cellulose solutions, sodium alginate solutions, and glycerol.

[0201] Examples of disintegrants include starch and calcium carbonate.

[0202] Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, and purified talc.

[0203] Examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerol, and net sugar syrup.

[0204] Examples of surfactants include sodium lauryl sulfonate, polysorbate 80, dehydrated sorbitol monofatty acid ester, and polyhydroxy 40 stearate.

[0205] Examples of suspending agents include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, and bentonite.

[0206] Examples of emulsifiers include gum arabic, astragalus gum, gelling agents, and polysorbate 80.

[0207] For example, when the pharmaceutical product of the present invention is a tablet, the tablet can be prepared according to methods known in the art as follows: excipients (e.g., lactose, sucrose, starch), disintegrants (e.g., starch, calcium carbonate), binders (e.g., starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose), or lubricants (e.g., talc, magnesium stearate, polyethylene glycol 6000) are added to the compound of the present invention; the mixture is compressed and molded; and then, if desired, coated using methods known in the art to mask taste, enteric properties, or durability. For example, hydroxypropyl methylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, Eudragit (Rohm GmbH, Germany, methacrylic acid-acrylic acid copolymer), and dyes (e.g., iron oxide red, titanium dioxide) can be used as coating agents.

[0208] Injectable drugs include intravenous injections, as well as subcutaneous injections, intradermal injections, intramuscular injections, intraperitoneal injections, intravenous infusions, and so on.

[0209] This injectable preparation is prepared using methods known in the art, namely, by dissolving, suspending, or emulsifying the compound of the invention in a sterile aqueous or oil solution. Examples of aqueous solutions include saline, isotonic solutions containing glucose, or other adjuvants (e.g., D-sorbitol, D-mannitol, sodium chloride), etc. Aqueous solutions may contain suitable solubilizers, such as alcohols (e.g., ethanol), polyols (e.g., propylene glycol, polyethylene glycol), or nonionic surfactants (e.g., polysorbate 80, HCO-50). Examples of oil solutions include sesame oil, soybean oil, etc. Oil solutions may contain suitable solubilizers. Examples of solubilizers include benzyl benzoate, benzyl alcohol, etc. The injectable preparation may be further supplemented with buffers (e.g., phosphate buffer, sodium acetate buffer), placebos (e.g., benzalkonium chloride, procaine hydrochloride), stabilizers (e.g., human serum albumin, polyethylene glycol), preservatives (e.g., benzyl alcohol, phenol), etc. Ampoules are typically filled with the prepared injectable solution.

[0210] The combination of the compounds of this invention and the drugs used in combination is referred to as the "combination drug of this invention".

[0211] Regarding the use of the combination drug of the present invention, there are no restrictions on the timing of administration of the compound of the present invention and the combination drug; the recipient may be given the compound of the present invention and the combination drug simultaneously, or they may be administered in an alternating manner. In the case of alternating administration, the alternation method varies depending on the active ingredient, dosage form, and method of administration. The dosage of the combination drug may be in accordance with clinically used dosages and may be appropriately selected according to the recipient, route of administration, disease, combination drug, etc.

[0212] Examples of administration modes of the compound of the present invention and the combined drug used in combination therapy include: (1) administering a single formulation obtained by simultaneously formulating the compound of the present invention and the combined drug; (2) administering two formulations obtained by separately formulating the compound of the present invention and the combined drug simultaneously via the same route of administration; (3) administering two formulations obtained by separately formulating the compound of the present invention and the combined drug in an alternating manner via the same route of administration; (4) administering two formulations obtained by separately formulating the compound of the present invention and the combined drug simultaneously via different routes of administration; and (5) administering two formulations obtained by separately formulating the compound of the present invention and the combined drug in an alternating manner via different routes of administration (e.g., administering the compound of the present invention, then the combined drug, or in reverse order).

[0213] Based on clinically used dosages, the dosage of the concurrent drugs can be appropriately selected. The mixing ratio between the compounds of this invention and the concurrent drugs can be appropriately selected according to the recipient, route of administration, targeted disease, symptoms, combination drugs, etc.

[0214] The medicament comprising the compound of the present invention may be administered to a patient via at least one of injection, oral, inhalation, rectal, and transdermal administration. When treating a patient according to the present invention, the amount of the given medicament depends on many factors, such as the specific dosing regimen, the type and severity of the disease or condition, and the unique characteristics of the patient or host requiring treatment (e.g., weight). However, depending on the specific surrounding circumstances, including, for example, the specific medicament used, the route of administration, the condition being treated, and the patient or host being treated, the dosage may be conventionally determined by methods known in the art. Typically, for adult treatment, the dosage is typically in the range of 0.02-5000 mg / day, for example, about 1-1500 mg / day. This required dosage can conveniently be expressed as a single dose, or concurrent (or over a short period of time) or fractions at appropriate intervals, such as two, three, four, or more doses per day. Those skilled in the art will understand that although the above dosage ranges are given, the specific effective amount may be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.

[0215] Preparation of compounds

[0216] The compounds of the present invention can be synthesized using standard synthetic techniques known to those skilled in the art, or by combining methods known in the art with those described herein. Furthermore, the solvents, temperatures, and other reaction conditions given herein can be varied according to the art. As further guidance, the following synthetic methods can also be utilized.

[0217] The reactions may be used sequentially to provide the compounds described herein; or they may be used to synthesize fragments subsequently added by the methods described herein and / or methods known in the art.

[0218] In some embodiments, this document provides methods for preparing and using the inhibitor compounds described herein. In some embodiments, the compounds described herein can be synthesized using the following synthetic schemes. The compounds can be synthesized using methods similar to those described below, employing suitable, selectable starting materials.

[0219] The starting materials used to synthesize the compounds described herein may be synthesized or are available from commercial sources. Commercially purchased starting materials have not undergone further purification unless otherwise stated. The compounds described herein and other related compounds with different substituents can be synthesized using techniques and starting materials known to those skilled in the art. General methods for preparing the compounds disclosed herein can be derived from reactions known in the art, and these reactions can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various moieties provided herein.

[0220] If necessary, the reaction products can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography. These products can be characterized using conventional methods, including physical constants and spectral data.

[0221] Column chromatography used silica gel (200-300 mesh) produced by Qingdao Chemical Co., Ltd., thin-layer chromatography used silica gel plates produced by Qingdao Chemical, nuclear magnetic resonance chromatography used a Bruker nuclear magnetic resonance instrument, and liquid chromatography-mass spectrometry (LCMS) used an Agilent 1200 series liquid chromatograph.

[0222] Example 1: 2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5-methyl-8-phenyl-7,8-dihydropterin-6(5H)-one

[0223]

[0224] Step 1: Ethyl phenylglycine (A1): Aniline (2 g, 21.5 mmol, 1.0 eq), ethyl bromoacetate (4.31 g, 25.8 mmol, 1.2 eq), and potassium carbonate (4.45 g, 32.2 mmol, 1.5 eq) were added to a round-bottom flask and dissolved in acetonitrile (30 mL). The reaction mixture was stirred overnight at 70 °C. After the reaction was complete, the solvent was removed from the mixture under reduced pressure. The residue was purified by pressurized silica gel column chromatography to give compound A1 (3.19 g, 83% yield). MS (ESI) M / Z [M+H] + : 180.21.

[0225] Step 2: N-(2-chloro-5-nitropyrimidin-4-yl)-N-phenylglycine ethyl ester (A2): Phenylacetic glycine ethyl ester (2 g, 11.2 mmol, 1.0 eq), 2,4-dichloro-5-nitropyrimidin (3.24 g, 16.8 mmol, 1.5 eq), and potassium carbonate (3.09 g, 22.4 mmol, 1.5 eq) were added to a round-bottom flask and dissolved in acetone (50 mL). The reaction mixture was stirred at 0 °C for 5 hours. After the reaction was complete, the solvent was removed from the mixture under reduced pressure. The residue was purified by pressurized silica gel column chromatography to give compound A2 (2.74 g, 73% yield). MS (ESI) M / Z [M+H] + 337.07.

[0226] Step 3: 2-Chloro-8-phenyl-7,8-dihydropterin-6(5H)-one (A3): In a round-bottom flask, N-(2-chloro-5-nitropyrimidin-4-yl)-N-phenylglycine ethyl ester (3 g, 8.9 mmol, 1.0 eq) dissolved in glacial acetic acid (60 mL) was added, followed by the addition of iron powder (5 g, 89.1 mmol, 10.0 eq) with stirring. The reaction system was stirred at 80 °C for two hours. After the reaction was complete, the solvent was evaporated under reduced pressure, and the product was neutralized to alkaline with saturated sodium bicarbonate solution. Extraction with ethyl acetate was performed, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. The organic phase was filtered, evaporated under reduced pressure to obtain a crude product, and washed with diethyl ether to give compound A3 (1.37 g, 59% yield). MS (ESI) M / Z [M+H] + : 261.68.

[0227] Step 4: 2-Chloro-5-methyl-8-phenyl-7,8-dihydropterin-6(5H)-one (A4): 2-Chloro-8-phenyl-7,8-dihydropterin-6(5H)-one (1 g, 3.8 mmol, 1.0 eq) and N,N-dimethylformamide (10 mL) were added to a round-bottom flask. Iodimethane (655 mg, 4.6 mmol, 1.2 eq) was added under ice bath conditions, followed by sodium hydride (185 mg, 4.6 mmol, 1.2 eq). The reaction mixture was stirred under ice bath conditions for 1 hour. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. The organic phase was filtered, evaporated under reduced pressure to obtain a crude product, and washed with diethyl ether to give compound A4 (800 mg, 76% yield). MS(ESI)M / Z[M+H] + : 275.70.

[0228] Step 5: 2-Morpholine-5-nitrobenzaldehyde (A5): 2-fluoro-5-nitrobenzaldehyde (2 g, 11.8 mmol, 1.0 eq), morpholine (1.24 g, 14.2 mmol, 1.2 eq), and potassium carbonate (2.44 g, 17.7 mmol, 1.5 eq) were added to a round-bottom flask and dissolved in N,N-dimethylformamide (30 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and purified by pressurized silica gel column chromatography to give compound A5 (2.46 g, 88% yield). MS (ESI) M / Z [M+H] + : 237.22.

[0229] Step 6: N,N-Dimethyl-1-(2-morpholino-5-nitrophenyl)methylamine (A6): In a round-bottom flask, 1.5 g of 2-morpholino-5-nitrobenzaldehyde (6.4 mmol, 1.0 eq) dissolved in 20 mL of N,N-dimethylformamide was added. Then, 6.5 mL of 2 M dimethylamine THF solution (12.8 mmol, 2.0 eq) and glacial acetic acid (2 mL) were added. At 0 °C, sodium triacetylborohydride (2.71 g, 12.8 mmol, 2.0 eq) was added to the reaction system, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was quenched with water, adjusted to a weakly alkaline state with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered, concentrated, and purified by pressurized silica gel column chromatography to obtain compound A6 (1.42 g, 84% yield). MS(ESI)M / Z[M+H] + : 266.31.

[0230] Step 7: 3-((dimethylamino)methyl)-4-morpholinoaniline (A7): In a round-bottom flask, add N,N-dimethyl-1-(2-morpholino-5-nitrophenyl)methylamine (1 g, 3.8 mmol, 1.0 eq), 10% reducing palladium on carbon (100 mg), dissolved in methanol (10 mL). The reaction system was reacted at room temperature under a hydrogen atmosphere for 2 hours. After the reaction, the mixture was filtered through diatomaceous earth, concentrated, and purified by pressurized silica gel column chromatography to obtain compound A7 (807 mg, 91% yield). MS (ESI) M / Z [M+H] + : 236.33.

[0231] Step 8: 2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5-methyl-8-phenyl-7,8-dihydropterin-6(5H)-one: 2-chloro-5-methyl-8-phenyl-7,8-dihydropterin-6(5H)-one (100 mg, 0.36 mmol, 1.0 eq), 3-((dimethylamino)methyl)-4-morpholinoaniline (76 mg, 0.32 mmol, 0.9 eq), p-toluenesulfonic acid (186 mg, 1.1 mmol, 3.0 eq), and sec-butanol (5 mL) were added to a sealed tube. The reaction mixture was stirred overnight at 120 °C. After the reaction was complete, the mixture was quenched with water, adjusted to a weakly alkaline state with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with water and saturated brine respectively, and dried over anhydrous sodium sulfate. The organic phase was filtered, concentrated, and purified by thin-layer chromatography to obtain compound 1 (40 mg, yield 26%).

[0232] The synthesis of the compound in Example 1 was completed using the steps described above. 1 H NMR (500MHz, DMSO-d6) δ8.89(s,1H),7.95(s,1H),7.50-7.37(m,6H),7.32(t,J=6.9Hz,1H),6.78(d,J= 8.7Hz,1H),4.49(s,2H),3.70-3.68(m,4H),3.30(s,3H),3.26(s,2H),2.81-2.79(m,4H),2.09(s,6H). MS(ESI)m / z[M+H] + : 474.58.

[0233] Example 2: 2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-8-phenyl-7,8-dihydropterin-6(5H)-one

[0234]

[0235] The synthesis of the compound in Example 2 was carried out using steps similar to those described in Example 1, except that methylpiperazine was used instead of morpholine in step 5 of Example 1, while the remaining steps were the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ8.87(s,1H),7.95(s,1H),7.49-7.40(m,6H),7.33-7.30(m,1H),6.78(d,J=9. 0Hz,1H),4.49(s,2H),3.30(s,3H),3.29(s,2H),2.80(s,4H),2.45(s,4H),2.23(s,3H),2.12(s,6H). MS(ESI)m / z[M+H] + : 487.29.

[0236] Example 3: 2-((3-((dimethylamino)methyl)-4-(4-isopropylpiperazin-1-yl)phenyl)amino)-5-methyl-8-phenyl-7,8-dihydropterin-6(5H)-one

[0237]

[0238] The synthesis of the compound in Example 3 was carried out using steps similar to those described in Example 1, except that isopropylpiperazine was used instead of morpholine in step 5 of Example 1; the remaining steps were the same as in Example 1. MS (ESI) m / z [M+H] + : 515.32.

[0239] Example 4: 2-((4-(4-acetylpiperazin-1-yl)-3-((dimethylamino)methyl)phenyl)amino)-5-methyl-8-phenyl-7,8-dihydropterin-6(5H)-one

[0240]

[0241] The synthesis of the compound in Example 4 was carried out using steps similar to those described in Example 1, except that in step 5 of Example 1, N-acetylpiperazine was used instead of morpholine, and the remaining steps were the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ8.94 (s, 1H), 7.96 (s, 1H), 7.53-7.37 (m, 6H), 7.33 (t, J = 7.0Hz, 1H), 6.81 (s, 1H), 4. 50(s,2H),3.52(d,J=13.6Hz,4H),3.30(s,5H),2.77(d,J=37.6Hz,4H),2.18(d,J=24.5Hz,6H),2.03(s,3H). MS(ESI)m / z[M+H] +: 515.28.

[0242] Example 5: (R)-2-((3-((dimethylamino)methyl)-4-(3-(dimethylamine)pyrrolidone-1-yl)phenyl)amino)-5-methyl-8-phenyl-7,8-dihydropterin-6(5H)-one

[0243]

[0244] The synthesis of the compound in Example 5 was carried out using steps similar to those described in Example 1, except that in step 5 of Example 1, (R)-N,N-dimethylpyrrolidine-3-amine was used instead of morpholine, and the remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.76(s,1H),7.94(s,1H),7.49-7.42(m,4H),7.35(d,J=7.7Hz, 2H),7.32-7.28(m,1H),6.66(d,J=8.6Hz,1H),4.48(s,2H),3.34(s,3H),3.28-3.16(m,2 H),3.09(dtd,J=8.9,7.5,6.8,2.1Hz,2H),2.99-2.91(m,2H),2.76(t,J=7.3Hz,1H),2.1 6(s,6H),2.09(s,6H),1.99(dtt,J=11.9,7.5,3.8Hz,1H),1.70(dq,J=12.0,7.9Hz,1H). MS(ESI)m / z[M+H] + : 501.31.

[0245] Example 6: 2-((3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-5-methyl-8-phenyl-7,8-dihydropterin-6(5H)-one

[0246]

[0247] Step 1: 1-Bromo-2-(dimethoxymethyl)-4-nitrobenzene (A8): 2-Bromo-5-nitrobenzaldehyde (2 g, 8.7 mmol, 1.0 eq) and trimethyl orthoformate (1.38 g, 13.1 mmol, 1.5 eq) were added to a round-bottom flask and dissolved in methanol (20 mL). The system was stirred at 60 °C for 4 hours. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain crude product A8, which can be directly used in the next step. MS(ESI)M / Z[M+H] + 275.97.

[0248] Step 2: 4-(2-(dimethoxymethyl)-4-nitrophenyl)-3,6-dihydro-2H-pyran (A9): In a round-bottom flask, add 1-bromo-2-(dimethoxymethyl)-4-nitrobenzene (2 g, 7.2 mmol, 1.0 eq), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (1.81 g, 8.6 mmol, 1.2 eq), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (512 mg, 0.7 mmol, 0.1 eq), and potassium carbonate (1.49 g, 10.8 mmol, 1.5 eq). Dissolve the above reagents in 20 mL of 1,4-dioxane and heat to 100 °C under an argon atmosphere with stirring for 6 hours. After the reaction was complete, the solvent was removed from the mixture under reduced pressure, and the residue was purified by pressurized silica gel column chromatography to give compound A9 (1.39 g, 69% yield). MS(ESI)M / Z[M+H) + :280.11.

[0249] Step 3: 2-(3,6-dihydro-2H-pyran-4-yl)-5-nitrobenzaldehyde (A10): 4-(2-(dimethoxymethyl)-4-nitrophenyl)-3,6-dihydro-2H-pyran (500 mg, 1.8 mmol, 1.0 eq) was added to a round-bottom flask, dissolved in 1,4-dioxane (5 mL). Then, 2M hydrochloric acid solution (5 mL) was added dropwise with stirring at room temperature. After the reaction was complete, the mixture was quenched with water, adjusted to alkalinity with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. The organic phase was filtered, concentrated, and the crude product A10 was obtained, which could be directly used in the next reaction. MS(ESI)M / Z[M+H] + : 234.07

[0250] Step 4: N,N-Dimethyl-1-(2-(3,6-dihydro-2H-pyran-4-yl)-5-nitrophenyl)methylamine (A11): In a round-bottom flask, 2-(3,6-dihydro-2H-pyran-4-yl)-5-nitrobenzaldehyde (1 g, 4.3 mmol, 1.0 eq) was added and dissolved in N,N-dimethylformamide (20 mL). Dimethylamine (THF solution (2 M), 4.5 mL) and glacial acetic acid (2 mL) were then added. At 0 °C, sodium triacetylborohydride (1.82 g, 8.6 mmol, 2.0 eq) was added to the reaction system, and the reaction system was stirred overnight at 0 °C to room temperature. After the reaction was completed, the mixture was quenched with water, adjusted to alkalinity with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with water and saturated brine respectively, and dried over anhydrous sodium sulfate. The organic phase was filtered, concentrated, and purified by pressurized silica gel column chromatography to give compound A11 (933 mg, 83% yield). MS (ESI) M / Z [M+H] + :263.13.

[0251] Step 5: 3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)aniline (A12): In a round-bottom flask, add N,N-dimethyl-1-(2-(3,6-dihydro-2H-pyran-4-yl)-5-nitrophenyl)methylamine (1 g, 3.8 mmol, 1.0 eq), 10% reducing palladium on carbon (100 mg), dissolved in methanol (10 mL). The reaction system was reacted at room temperature under a hydrogen atmosphere for 2 hours. After the reaction, the mixture was filtered through diatomaceous earth, concentrated, and purified by pressurized silica gel column chromatography to obtain compound A12 (723 mg, yield 81%). MS (ESI) M / Z [M+H] + :235.18.

[0252]

[0253] The synthesis of the compound in Example 6 was carried out using A12 synthesized in the above steps and steps similar to those described in Example 1. The difference is that in step 8 of Example 1, 3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Example 1. 1HNMR(500MHz,DMSO-d6)δ8.91(s,1H),7.96(s,1H),7.47(dt,J=8.5,7.7Hz,4H),7. 38(dd,J=8.5,2.2Hz,1H),7.33(t,J=7.1Hz,1H),7.30(d,J=2.2Hz,1H),6.92(d,J= 8.5Hz,1H),4.49(s,2H),3.92(dd,J=10.9,3.4Hz,2H),3.37(dd,J=11.5,9.9Hz,2H ), 3.13 (s, 2H), 3.04 (ddd, J = 11.7, 8.1, 3.9Hz, 1H), 2.05 (s, 6H), 1.67-1.44 (m, 4H). MS(ESI)m / z[M+H] + : 473.26.

[0254] Example 7: 2-((4-(4,4-difluoropiperidin-1-yl)-3-((dimethylamino)methyl)phenyl)amino)-5-methyl-8-phenyl-7,8-dihydropterin-6(5H)-one

[0255]

[0256] The synthesis of the compound in Example 7 was carried out using steps similar to those described in Example 1, except that morpholine was replaced with 4,4-difluoropiperidine in step 5 of Example 1, and the remaining steps were the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ8.94 (s, 1H), 7.96 (s, 1H), 7.46 (dq, J = 12.8, 6.9, 5.6Hz, 6H), 7.32 (t,J=7.0Hz,1H),6.84(s,1H),4.50(s,2H),3.30(s,3H),2.91(s,6H),2.32-1.84(m,10H). MS(ESI)m / z[M+H] + : 508.26.

[0257] Example 8: 5-Methyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-8-phenyl-7,8-dihydropterin-6(5H)-one

[0258]

[0259] The synthesis of the compound in Example 8 was carried out using steps similar to those described in Example 1, except that in step 8 of Example 1, 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine, and the remaining steps were the same as in Example 1.1 H NMR (500MHz, DMSO-d6) δ8.99(s,1H),7.96(s,1H),7.51(t,J=7.8Hz,2H),7.45(d,J=7.3Hz,2H),7.35(t,J=7.3Hz,1H),7.24(s,1H) ,7.12(d,J=8.2Hz,1H),6.78(d,J=8.3Hz,1H),4.49(s,2H),3.30(s,3H),3.22(s,2H),2.72-2.66(m,2H),2.63(s,2H),2.39(s,3H). MS(ESI)m / z[M+H] + :401.20.

[0260] Example 9: 2-((3-((dimethylamino)methyl)-4-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)amino)-5-methyl-8-phenyl-7,8-dihydropterin-6(5H)-one

[0261]

[0262] The synthesis of the compound in Example 9 was carried out using steps similar to those described in Example 1, except that in step 5 of Example 1, morpholine was replaced with 8-methyl-3,8-diazabicyclo[3.2.1]octane, and the remaining steps were the same as in Example 1. 1 HNMR (500MHz, DMSO-d6) δ8.88(s,1H),7.95(s,1H),7.50-7.41(m,4H),7.39(d,J=9.0Hz,2H),7.32(t,J=7.0Hz,1H),6.81(d,J=8.5Hz,1H),4. 49(s,2H),3.30(s,3H),3.28(s,2H),3.08(s,2H),2.84(d,J=10.0Hz,2 H), 2.61 (d, J = 8.4Hz, 2H), 2.21 (s, 3H), 2.08 (s, 6H), 1.96-1.85 (m, 4H). MS(ESI)m / z[M+H] + : 513.30.

[0263] Example 10: 2-((3-((dimethylamino)methyl)-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5-methyl-8-phenyl-7,8-dihydropterin-6(5H)-one

[0264]

[0265] The synthesis of the compound in Example 10 was carried out using steps similar to those described in Example 1, except that in step 5 of Example 1, N-hydroxyethylpiperazine was used instead of morpholine, and the remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.51-7.43(m,5H),7.40(d,J=8.9Hz,2H),7.35-7.28(m,2H),6.77(d,J=8.4Hz,1H),4.49(s, 2H), 4.39 (s, 1H), 3.52 (q, J = 6.0Hz, 2H), 3.30 (s, 3H), 3.27 (s, 2H), 2.79 (s, 4H), 2.53 (s, 3H), 2.44 (t, J = 6.1Hz, 3H), 2.10 (s, 6H). MS(ESI)m / z[M+H] + : 517.30.

[0266] Example 11: 2-((3-((dimethylamino)methyl)-4-(piperidin-1-yl)phenyl)amino)-5-methyl-8-phenyl-7,8-dihydropterin-6(5H)-one

[0267]

[0268] The synthesis of the compound in Example 11 was carried out using steps similar to those described in Example 1, except that piperidine was used instead of morpholine in step 5 of Example 1, and the remaining steps were the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ8.84(s,1H),7.95(s,1H),7.49-7.42(m,4H),7.39(d,J=7.2Hz,2H),7.31(t,J=6.8Hz,1H),6.73 (d,J=9.2Hz,1H),4.49(s,2H),3.30(s,3H),3.26(s,2H),2.72(s,4H),2.09(s,6H),1.60(p,J=5.6Hz,4H),1.48(s,2H). MS(ESI)m / z[M+H] + : 472.28.

[0269] Example 12: 2-((3-((dimethylamino)methyl)-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-methyl-8-phenyl-7,8-dihydropterin-6(5H)-one

[0270]

[0271] The synthesis of the compound in Example 12 was carried out using steps similar to those described in Example 6, except that in step 2 of Example 6, 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine was used instead of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane, and the remaining steps were the same as in Example 6. 1 H NMR(500MHz,DMSO-d6)δ8.93(s,1H),7.96(s,1H),7.47(dt,J=14.4,7.7Hz,4H) ,7.37(dd,J=8.5,2.0Hz,1H),7.33(t,J=7.1Hz,1H),7.28(d,J=1.9Hz,1H),6.8 9(d,J=8.5Hz,1H),4.49(s,2H),3.30(s,3H),3.11(s,2H),2.93(d,J=7.9Hz,2H ), 2.78 (s, 1H), 2.28 (s, 3H), 2.09 (s, 2H), 2.05 (s, 6H), 1.61 (d, J = 10.7Hz, 4H). MS(ESI)m / z[M+H] + : 486.29.

[0272] Example 13: 2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5-methyl-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0273]

[0274] The synthesis of the compound in Example 13 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3-methylaniline in step 1 of Example 1, and the remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.89(s,1H),7.94(s,1H),7.45(dd,J=8.7,2.7Hz,1H), 7.40(d,J=2.7Hz,1H),7.36(t,J=7.7Hz,1H),7.26(d,J=1.9Hz,1H),7.23(dd,J =7.9,2.2Hz,1H),7.14(d,J=7.2Hz,1H),6.78(d,J=8.7Hz,1H),4.47(s,2H),3. 71-3.68(m,4H),3.29(s,5H),2.80(t,J=4.5Hz,5H),2.34(s,3H),2.10(s,6H). MS(ESI)m / z[M+H] +: 488.27.

[0275] Example 14: 2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0276]

[0277] The synthesis of the compound in Example 14 was carried out using steps similar to those described in Example 1, except that 3-methylaniline was used instead of aniline in step 1 of Example 1, and methylpiperazine was used instead of morpholine in step 5 of Example 1. The remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.86(s,1H),7.94(s,1H),7.43(dd,J=8.6,2.7Hz,1H),7.38 (d,J=2.7Hz,1H),7.35(t,J=7.7Hz,1H),7.26(d,J=2.0Hz,1H),7.23(dd,J=7.9,2.2 Hz,1H),7.13(d,J=7.6Hz,1H),6.76(d,J=8.7Hz,1H),4.47(s,2H),3.29(s,4H),3.2 5(s,2H),2.80(t,J=4.8Hz,4H),2.44(s,4H),2.34(s,3H),2.22(s,3H),2.09(s,6H). MS(ESI)m / z[M+H] + : 501.30.

[0278] Example 15: 2-((3-((dimethylamino)methyl)-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0279]

[0280] The synthesis of the compound in Example 15 was carried out using steps similar to those described in Example 1, except that 3-methylaniline was used instead of aniline in step 1 of Example 1, and ethylpiperazine was used instead of morpholine in step 5 of Example 1, with the remaining steps being the same as in Example 1. 1H NMR(500MHz,DMSO-d6)δ8.87(s,1H),7.94(s,1H),7.43(dd,J=8.7,2.7Hz,1H),7.40- 7.32(m,2H),7.26(d,J=2.0Hz,1H),7.23(dd,J=8.0,2.2Hz,1H),7.14(d,J=7.5Hz,1H ),6.76(d,J=8.7Hz,1H),4.47(s,2H),3.28(d,J=16.3Hz,5H),2.80(t,J=4.8Hz,4H), 2.47 (s, 4H), 2.37 (q, J = 7.1Hz, 2H), 2.34 (s, 3H), 2.09 (s, 6H), 1.02 (t, J = 7.2Hz, 3H). MS(ESI)m / z[M+H] + : 514.32.

[0281] Example 16: 2-((3-((dimethylamino)methyl)-4-(4-isopropylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0282]

[0283] The synthesis of the compound in Example 16 was carried out using steps similar to those described in Example 1, except that 3-methylaniline was used instead of aniline in step 1 of Example 1, and isopropylpiperazine was used instead of morpholine in step 5 of Example 1. The remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.86(s,1H),7.94(s,1H),7.43(dd,J=8.7,2.7Hz,1H),7.39 -7.32(m,2H),7.26(d,J=2.0Hz,1H),7.23(dd,J=7.8,2.2Hz,1H),7.14(d,J=7.6Hz,1 H),6.76(d,J=8.7Hz,1H),4.47(s,2H),3.29(s,3H),3.26(s,2H),2.79(t,J=4.7Hz,4 H), 2.70-2.63 (m, 1H), 2.55 (s, 4H), 2.34 (s, 3H), 2.10 (s, 6H), 1.01 (d, J = 6.6Hz, 6H). MS(ESI)m / z[M+H] + : 529.34.

[0284] Example 17: 2-((4-(4-acetylpiperazin-1-yl)-3-((dimethylamino)methyl)phenyl)amino)-5-methyl-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0285]

[0286] The synthesis of the compound in Example 17 was carried out using steps similar to those described in Example 1, except that 3-methylaniline was used instead of aniline in step 1 of Example 1, and 1-acetylpiperazine was used instead of morpholine in step 5 of Example 1, with the remaining steps following the steps in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.93(s,1H),7.95(s,1H),7.44(dd,J=8.7,2.7Hz,1H),7.41(d,J =2.6Hz,1H),7.35(t,J=7.7Hz,1H),7.26(d,J=2.0Hz,1H),7.23(dd,J=7.7,2.2Hz,1H),7 .14(d,J=7.5Hz,1H),6.76(d,J=8.6Hz,1H),4.48(s,2H),3.53(d,J=5.4Hz,4H),3.29(s, 5H), 2.81 (t, J = 5.0Hz, 2H), 2.74 (t, J = 5.1Hz, 2H), 2.34 (s, 3H), 2.11 (s, 6H), 2.03 (s, 3H). MS(ESI)m / z[M+H] + : 529.30.

[0287] Example 18: 2-((3-((dimethylamino)methyl)-4-(4-methyl-1,4-azaphen-1-yl)phenyl)amino)-5-methyl-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0288]

[0289] The synthesis of the compound in Example 18 was carried out using steps similar to those described in Example 1, except that 3-methylaniline was used instead of aniline in step 1 of Example 1, and N-methylperiperazine was used instead of morpholine in step 5 of Example 1, with the remaining steps being the same as in Example 1. 1H NMR(500MHz,DMSO-d6)δ8.86(s,1H),7.94(s,1H),7.41(dd,J=8.7,2.7Hz,1H),7.38- 7.32(m,2H),7.26(d,J=1.9Hz,1H),7.23(dd,J=7.7,2.2Hz,1H),7.13(d,J=7.5Hz,1H) ,6.79(d,J=8.7Hz,1H),4.47(s,2H),3.29(s,5H),3.03-2.94(m,4H),2.68(t,J=5.8H z, 2H), 2.63-2.57 (m, 2H), 2.33 (d, J = 10.8Hz, 6H), 2.09 (s, 6H), 1.81 (d, J = 6.0Hz, 2H). MS(ESI)m / z[M+H] + : 515.32.

[0290] Example 19: 2-((3-((dimethylamino)methyl)-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-methyl-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0291]

[0292] The synthesis of the compound in Example 19 was carried out using steps similar to those described in Examples 1 and 6, except that aniline was replaced with 3-methylaniline in step 1 of Example 1, and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine was replaced with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine in step 2 of Example 6. The remaining steps were the same as in Examples 1 and 6. 1 H NMR (500MHz, DMSO-d6) δ8.92 (s, 1H), 7.95 (s, 1H), 7.42-7.34 (m, 2H), 7.27 (d, J = 2. 3Hz,2H),7.23(dd,J=7.9,2.2Hz,1H),7.15(d,J=7.5Hz,1H),6.88(d,J=8.5Hz,1H), 4.47(s,2H),3.29(s,3H),3.10(s,2H),2.87(d,J=11.0Hz,2H),2.76(p,J=8.2Hz,1H ), 2.35 (s, 3H), 2.22 (s, 3H), 2.04 (s, 6H), 1.97 (s, 2H), 1.57 (dt, J = 8.0, 4.7Hz, 4H). MS(ESI)m / z[M+H] +: 500.31.

[0293] Example 20: 2-((3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-5-methyl-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0294]

[0295] The synthesis of the compound in Example 20 was carried out using steps similar to those described in Examples 1 and 6, except that aniline was replaced with 3-methylaniline in step 1 of Example 1, and the remaining steps were the same as those in Examples 1 and 6. 1 HNMR(500MHz,DMSO-d6)δ8.94(s,1H),7.96(s,1H),7.43-7.34(m,2H),7.32-7.25(m ,2H),7.23(dd,J=7.8,2.2Hz,1H),7.15(d,J=7.5Hz,1H),6.91(d,J=8.5Hz,1H),4.47 (s,2H),3.92(dd,J=11.1,3.7Hz,2H),3.38(td,J=11.6,2.3Hz,2H),3.30(s,3H),3.1 3(s,2H),3.04(td,J=11.5,5.7Hz,1H),2.35(s,3H),2.05(s,6H),1.64-1.49(m,4H). MS(ESI)m / z[M+H] + : 487.28.

[0296] Example 21: 2-((3-((dimethylamino)methyl)-4-(piperidin-1-yl)phenyl)amino)-5-methyl-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0297]

[0298] The synthesis of the compound in Example 21 was carried out using steps similar to those described in Example 1, except that 3-methylaniline was used instead of aniline in step 1 of Example 1, and piperidine was used instead of morpholine in step 5 of Example 1, with the remaining steps being the same as in Example 1. 1H NMR (500MHz, DMSO-d6) δ8.85 (s, 1H), 7.94 (s, 1H), 7.42 (dd, J = 8.7, 2.7Hz, 1H), 7. 39-7.31(m,2H),7.26(t,J=1.9Hz,1H),7.23(dd,J=7.9,2.2Hz,1H),7.13(d,J=7.5 Hz,1H),6.74(d,J=8.7Hz,1H),4.47(s,2H),3.29(s,3H),3.26(s,2H),2.72(t,J=5 .1Hz, 4H), 2.34 (s, 3H), 2.10 (s, 6H), 1.61 (p, J = 5.6Hz, 4H), 1.49 (d, J = 8.0Hz, 2H). MS(ESI)m / z[M+H] + : 486.29.

[0299] Example 22: 2-((3-((dimethylamino)methyl)-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)amino)-5-methyl-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0300]

[0301] The synthesis of the compound in Example 22 was carried out using steps similar to those described in Example 1, except that 3-methylaniline was used instead of aniline in step 1 of Example 1, and 1-(methanesulfonyl)piperazine was used instead of morpholine in step 5 of Example 1, with the remaining steps following the steps in Example 1. 1 H NMR (500MHz, DMSO-d6) δ8.93(s,1H),7.95(s,1H),7.48-7.40(m,2H),7.36(t,J=7.8Hz,1H),7.29-7.20(m,2H),7.14(d,J=7.5Hz, 1H), 6.81 (d, J = 8.7Hz, 1H), 4.48 (s, 2H), 3.30 (s, 5H), 3.22 (d, J = 5.0Hz, 4H), 2.94 (s, 3H), 2.91 (s, 4H), 2.34 (s, 3H), 2.11 (s, 6H). MS(ESI)m / z[M+H] + 565.27.

[0302] Example 23: 2-((3-((dimethylamino)methyl)-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5-methyl-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0303]

[0304] The synthesis of the compound in Example 23 was carried out using steps similar to those described in Example 1, except that 3-methylaniline was used instead of aniline in step 1 of Example 1, and N-hydroxyethylpiperazine was used instead of morpholine in step 5 of Example 1, with the remaining steps following the steps in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.88(s,1H),7.94(s,1H),7.44(dd,J=8.7,2.7Hz,1H),7.40- 7.32(m,2H),7.26(d,J=2.0Hz,1H),7.23(dd,J=7.9,2.2Hz,1H),7.14(d,J=7.5Hz,1H) ,6.77(d,J=8.7Hz,1H),4.47(s,2H),4.40(s,1H),3.52(q,J=5.8Hz,2H),3.29(s,5H) ,2.79(d,J=4.9Hz,4H),2.54(s,4H),2.46(d,J=6.8Hz,2H),2.34(s,3H),2.12(s,6H). MS(ESI)m / z[M+H] + : 531.31.

[0305] Example 24: 2-((3-((dimethylamino)methyl)-4-(4-methylpiperidin-1-yl)phenyl)amino)-5-methyl-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0306]

[0307] The synthesis of the compound in Example 24 was carried out using steps similar to those described in Example 1, except that 3-methylaniline was used instead of aniline in step 1 of Example 1, and 4-methylpiperidine was used instead of morpholine in step 5 of Example 1, with the remaining steps following the steps in Example 1. 1H NMR(500MHz,DMSO-d6)δ8.85(s,1H),7.94(s,1H),7.42(dd,J=8.7,2.7Hz,1H),7.40-7 .30(m,2H),7.28-7.20(m,2H),7.13(d,J=7.5Hz,1H),6.75(d,J=8.7Hz,1H),4.47(s,2H ),3.29(s,5H),2.97(d,J=11.0Hz,2H),2.53(d,J=2.3Hz,1H),2.34(s,3H),2.11(s,6H ), 1.66 (d, J = 11.9Hz, 2H), 1.48-1.39 (m, 1H), 1.32-1.21 (m, 3H), 0.95 (d, J = 6.4Hz, 3H). MS(ESI)m / z[M+H] + : 500.31.

[0308] Example 25: 2-((3-((dimethylamino)methyl)-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-methyl-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0309]

[0310] The synthesis of the compound in Example 25 was carried out using steps similar to those described in Example 1, except that 3-methylaniline was used instead of aniline in step 1 of Example 1, and morpholine was used instead of octahydropyrrolo[1,2-a]pyrazine in step 5 of Example 1, with the remaining steps following the steps in Example 1. 1 H NMR (500MHz, DMSO-d6) δ8.88(s,1H),7.94(s,1H),7.43(dd,J=8.7,2.7Hz,1H),7.41-7.33(m,2H),7.26( d,J=1.9Hz,1H),7.23(dd,J=7.8,2.2Hz,1H),7.13(d,J=7.5Hz,1H),6.79(d,J=8.7Hz,1H),4.47(s,2H), 3.29(s,6H),3.08(d,J=10.3Hz,1H),2.97(dt,J=20.4,9.0Hz,3H),2.69(td,J=11.2,3.0Hz,1H),2.41(s ,1H),2.34(s,3H),2.28(d,J=10.4Hz,1H),2.10(s,7H),1.78-1.63(m,3H),1.33(td,J=10.9,6.2Hz,1H). MS(ESI)m / z[M+H] +: 527.32.

[0311] Example 26: 2-((3-((dimethylamino)methyl)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-methyl-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0312]

[0313] The synthesis of the compound in Example 26 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3-methylaniline in step 1 of Example 1, and 3-((dimethylamino)methyl)-4-(1-methyl-1H-pyrazol-4-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline in step 8 of Example 1, with the remaining steps referring to Example 1. 1 H NMR (500MHz, DMSO-d6) δ9.07(s,1H),7.98(s,1H),7.81(s,1H),7.57(d,J=5.9Hz,1H),7.51-7.45(m,2H),7.37(t,J=7.7Hz,1H),7.29-7 .22(m,2H),7.14(d,J=7.6Hz,1H),7.02(d,J=8.3Hz,1H),4.49(s,2H),3.86(s,3H),3.09(s,2H),2.34(s,3H),2.11(s,2H),2.08(s,6H). MS(ESI)m / z[M+H] + : 483.26.

[0314] Example 27: 5-Methyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0315]

[0316] The synthesis of the compound in Example 27 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3-methylaniline in step 1 of Example 1, and 3-((dimethylamino)methyl)-4-morpholineaniline was replaced with 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine in step 8 of Example 1, with the remaining steps following those in Example 1. 1H NMR(500MHz,DMSO-d6)δ8.96(s,1H),7.95(s,1H),7.38(t,J=7.7Hz,1H),7.2 6(d,J=2.0Hz,1H),7.22(q,J=3.4,2.8Hz,2H),7.16(d,J=7.5Hz,1H),7.09(dd ,J=8.2,2.3Hz,1H),6.76(d,J=8.3Hz,1H),4.46(s,2H),3.30(s,3H),3.06(s ,2H),2.64(t,J=5.8Hz,2H),2.48(d,J=6.0Hz,2H),2.35(s,3H),2.30(s,3H). MS(ESI)m / z[M+H] + :415.22.

[0317] Example 28: 5-Methyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0318]

[0319] Step 1: 2-Isopropyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (A13): 7-nitro-1,2,3,4-tetrahydroisoquinoline (2 g, 11.2 mmol, 1.0 eq), 2-iodopropane (3.81 g, 22.4 mmol, 2.0 eq), and potassium carbonate (3.1 g, 22.4 mmol, 2.0 eq) were added to a round-bottom flask and dissolved in N,N-dimethylformamide (25 mL). The mixture was stirred overnight at 80 °C. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. The organic phase was filtered, concentrated, and purified by pressurized silica gel column chromatography to give compound A13 (1.81 g, 73% yield). MS (ESI) M / Z [M+H] + :221.12.

[0320] Step 2: 2-Isopropyl-1,2,3,4-Tetrahydroisoquinoline-7-amine (A14): 2-Isopropyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (1 g, 4.5 mmol, 1.0 eq), 10% reducing palladium on carbon (100 mg), and methanol (10 mL) were added to a round-bottom flask. The reaction mixture was reacted at room temperature under a hydrogen atmosphere for 2 hours. After the reaction, the mixture was filtered through diatomaceous earth, concentrated, and purified by pressurized silica gel column chromatography to obtain compound A14 (760 mg, 88% yield). MS (ESI) M / Z [M+H] + :191.14.

[0321]

[0322] The synthesis of the compound in Example 28 was carried out using A14 synthesized by the above steps and steps similar to those described in Example 1, except that aniline was replaced with 3-methylaniline in step 1 of Example 1, and 3-((dimethylamino)methyl)-4-morpholineaniline was replaced with 2-isopropyl-1,2,3,4-tetrahydroisoquinoline-7-amine in step 8 of Example 1. The remaining steps were the same as those in Example 1 and this Example. 1 H NMR(500MHz,DMSO-d6)δ8.96(s,1H),7.96(s,1H),7.38(t,J=7.8Hz,1H),7.27(t,J=2.0Hz,2H),7.24(dd,J=7.6,2.2Hz,1H),7.14(d,J=7.5Hz,1H), 7.08(d,J=8.2Hz,1H),6.76(d,J=8.3Hz,1H),4.46(s,2H),3.30(s,4H),3 .24(s,2H),2.63(s,3H),2.35(s,3H),1.24(s,1H),1.07(d,J=6.2Hz,6H). MS(ESI)m / z[M+H] + : 415.25.

[0323] Example 29: 2-((2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5-methyl-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0324]

[0325] The synthesis of the compound in Example 29 was carried out using steps similar to those described in Examples 1 and 28, except that 3-methylaniline was used instead of aniline in step 1 of Example 1, and 1-bromo-2-methoxyethane was used instead of 2-iodopropane in step 1 of Example 28, with the remaining steps being the same as in Examples 1 and 28. 1 HNMR(500MHz,DMSO-d6)δ8.94(s,1H),7.95(s,1H),7.38(t,J=7.7Hz,1H),7.29-7.20(m,3H),7.17-7.08(m,2H),6.75(d,J= 8.3Hz,1H),4.46(s,2H),3.51(t,J=5.9Hz,2H),3.30(s,3H),3.29(s,3H),3.20(s,2H),2.61(d,J=7.2Hz,6H),2.35(s,3H). MS(ESI)m / z[M+H]+ : 459.25.

[0326] Example 30: 2-((2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5-methyl-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0327]

[0328] The synthesis of the compound in Example 30 was carried out using steps similar to those described in Examples 1 and 28, except that aniline was replaced with 3-methylaniline in step 1 of Example 1 and 2-iodopropane was replaced with 2-bromoethane-1-ol in step 1 of Example 28, with the remaining steps being the same as in Examples 1 and 28. 1 H NMR(500MHz,DMSO-d6)δ8.95(s,1H),7.95(s,1H),7.38(t,J=7.7Hz,1H),7.2 6(d,J=1.9Hz,1H),7.23(q,J=3.3,2.4Hz,2H),7.16(d,J=7.5Hz,1H),7.10(dd ,J=8.5,2.3Hz,1H),6.75(d,J=8.3Hz,1H),4.46(s,3H),3.58(q,J=6.0Hz,2H ), 3.30 (s, 3H), 3.21 (s, 2H), 2.63 (s, 4H), 2.53 (d, J = 6.5Hz, 2H), 2.35 (s, 3H). MS(ESI)m / z[M+H] + : 445.23.

[0329] Example 31: 2-((2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5-methyl-8-(m-tolyl)-7,8-dihydropterin-6(5H)-one

[0330]

[0331] The synthesis of the compound in Example 31 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3-methylaniline in step 1 of Example 1, and 3-((dimethylamino)methyl)-4-morpholineaniline was replaced with 2-acetyl-7-amino-1,2,3,4-tetrahydroisoquinoline in step 8 of Example 1, with the remaining steps referring to Example 1. 1H NMR(500MHz,DMSO-d6)δ9.04(d,J=30.2Hz,1H),7.96(d,J=6.2Hz,1H),7.38(s ,1H),7.33-7.15(m,5H),6.83(d,J=8.4Hz,1H),4.47(d,J=2.4Hz,2H),4.23(d, J=3.3Hz,2H),3.57(dt,J=9.7,5.9Hz,2H),3.30(d,J=1.8Hz,3H),2.70(t,J=5 .9Hz, 1H), 2.59 (t, J = 6.0Hz, 1H), 2.35 (d, J = 5.5Hz, 3H), 2.06 (d, J = 2.0Hz, 3H). MS(ESI)m / z[M+H] + : 443.21.

[0332] Example 32: 8-(3-chlorophenyl)-2-((3-((dimethylamino)methyl)-4-morpholinylphenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one

[0333]

[0334] The synthesis of the compound in Example 32 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3-chloroaniline in step 1 of Example 1, and the remaining steps were the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ9.07(s,1H),8.00(s,1H),7.57(t,J=2.1Hz,1H),7.50(t,J=8.0Hz,2H),7.42(dd,J=7.7,2.1Hz,2H),7.3 9(dt,J=7.9,1.7Hz,1H),6.93(s,1H),4.52(s,2H),3.71(t,J=4.5Hz,4H),3.30(s,5H),2.79(t,J=4.5Hz,4H),2.43-2.10(m,6H). MS(ESI)m / z[M+H] + : 508.22.

[0335] Example 33: 8-(3-chlorophenyl)-2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one

[0336]

[0337] The synthesis of the compound in Example 33 was carried out using steps similar to those described in Example 1, except that 3-chloroaniline was used instead of aniline in step 1 of Example 1, and methylpiperazine was used instead of morpholine in step 5 of Example 1, with the remaining steps being the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ9.04(s,1H),7.99(s,1H),7.57(t,J=2.1Hz,1H),7.52-7.45(m,2H),7.42(dd,J=7.5,2.2Hz,2H),7 .38(dd,J=8.0,2.1Hz,1H),6.90(d,J=8.8Hz,1H),4.52(s,2H),3.30(s,5H),2.85(s,4H),2.60(s,3H),2.38-2.14(m,10H). MS(ESI)m / z[M+H] + 521.25.

[0338] Example 34: 2-((4-(4,4-difluoropiperidin-1-yl)-3-((dimethylamino)methyl)phenyl)amino)-8-(3-fluorophenyl)-5-methyl-7,8-dihydropterin-6(5H)-one

[0339]

[0340] The synthesis of the compound in Example 34 was carried out using steps similar to those described in Example 1, except that 3-chloroaniline was used instead of aniline in step 1 of Example 1, and 4,4-difluoropiperidine was used instead of morpholine in step 5 of Example 1, with the remaining steps following the steps in Example 1. 1 H NMR (500MHz, DMSO-d6) δ9.04(s,1H),8.00(s,1H),7.54-7.47(m,3H),7.36(d,J=10.7Hz,1H),7.30(d,J=7 .9Hz,1H),7.15(td,J=8.6,2.6Hz,1H),6.92(s,1H),4.51(s,2H),2.91(s,2H),2.23(s,6H),2.10(s,4H). MS(ESI)m / z[M+H] + 526.25.

[0341] Example 35: 2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-8-(3-fluorophenyl)-5-methyl-7,8-dihydropterin-6(5H)-one

[0342]

[0343] The synthesis of the compound in Example 35 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3-fluoroaniline in step 1 of Example 1, and the remaining steps were the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ8.95(s,1H),8.00(s,1H),7.52-7.43(m,3H),7.35(dt,J=10.7,2.3Hz,1H),7.29(dd,J=7.9,1.9Hz,1H ),7.14(td,J=8.5,2.6Hz,1H),6.83(d,J=9.3Hz,1H),4.50(s,2H),3.70(t,J=4.5Hz,4H),2.81(t,J=4.5Hz,4H),2.11(s,6H). MS(ESI)m / z[M+H] + : 492.25.

[0344] Example 36: 2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(3-fluorophenyl)-5-methyl-7,8-dihydropterin-6(5H)-one

[0345]

[0346] The synthesis of the compound in Example 36 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3-fluoroaniline in step 1 of Example 1, and morpholine was replaced with methylpiperazine in step 5 of Example 1, with the remaining steps being the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.98(s,1H),8.00(s,1H),7.51-7.47(m,1H),7.44-7.42(m,2H),7.37-7.34(m,1H),7.29(dd,J=7.8,2.0Hz,1 H),7.14(td,J=8.5,2.5Hz,1H),6.83(d,J=9.4Hz,1H),4.51(s,2H),3.30(s,2H),2.82(s,4H),2.48(s,4H),2.25(s,3H),2.13(s,6H). MS(ESI)m / z[M+H] + : 505.28.

[0347] Example 37: 2-((3-((dimethylamino)methyl)-4-(4-isopropylpiperazin-1-yl)phenyl)amino)-8-(3-fluorophenyl)-5-methyl-7,8-dihydropterin-6(5H)-one

[0348]

[0349] The synthesis of the compound in Example 37 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3-fluoroaniline in step 1 of Example 1, and morpholine was replaced with isopropylpiperazine in step 5 of Example 1. The remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ9.06(s,1H),8.00(s,1H),7.53-7.48(m,2H),7.45(s, 1H),7.37(d,J=10.8Hz,1H),7.30(dd,J=7.5,2.1Hz,1H),7.15(td,J=8.5,2.5 Hz,1H),6.90(d,J=8.8Hz,1H),4.52(s,2H),3.51(s,2H),3.33(s,4H),2.90(s ,4H),2.79(s,3H),2.28(s,6H),2.02-1.97(m,1H),1.11(s,3H),1.10(s,3H). MS(ESI)m / z[M+H] + : 533.31.

[0350] Example 38: 2-((4-(4-cyclopropylpiperazin-1-yl)-3-((dimethylamino)methyl)phenyl)amino)-8-(3-fluorophenyl)-5-methyl-7,8-dihydropterin-6(5H)-one

[0351]

[0352] The synthesis of the compound in Example 38 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3-fluoroaniline in step 1 of Example 1, and morpholine was replaced with 1-cyclopropylpiperazine in step 5 of Example 1, with the remaining steps being the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ9.02(s,1H),7.99(s,1H),7.53-7.44(m,3H),7.36(dt,J=10.8,2.3Hz,1H),7.29(dd,J=8.0,1.9Hz,1H),7.15(td . MS(ESI)m / z[M+H] + : 531.29.

[0353] Example 39: 8-(3-fluorophenyl)-5-methyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-7,8-dihydropterin-6(5H)-one

[0354]

[0355] The synthesis of the compound in Example 39 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3-fluoroaniline in step 1 of Example 1, and 3-((dimethylamino)methyl)-4-morpholineaniline was replaced with 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine in step 8 of Example 1, with the remaining steps referring to Example 1. 1 H NMR(500MHz,DMSO-d6)δ9.04(s,1H),8.01(s,1H),7.53(q,J=7.8Hz,1H),7.37(d,J=10.6Hz,1H),7.31-7.25(m,2H), 7.20-7.11(m,2H),6.79(d,J=8.3Hz,1H),4.50(s,2H),3.30(s,3H),3.13(s,2H),2.66(t,J=5.9Hz,2H),2.30(s,3H). MS(ESI)m / z[M+H] + :419.19.

[0356] Example 40: 8-(3-fluorophenyl)-5-methyl-2-((3-(1-methyl-1H-pyrazol-5-yl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-7,8-dihydropterin-6(5H)-one

[0357]

[0358] Step 1: 1-(2-Bromo-4-nitrophenyl)-4-methylpiperazine (A15): In a round-bottom flask, add 2-bromo-1-fluoro-4-nitrobenzene (2 g, 9.1 mmol, 1.0 eq), 1-methylpiperazine (1.09 g, 10.9 mmol, 1.2 eq), and potassium carbonate (1.88 g, 13.7 mmol, 1.5 eq), dissolved in N,N-dimethylformamide (30 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and purified by pressurized silica gel column chromatography to give compound A15 (2.29 g, 84% yield). MS (ESI) M / Z [M+H] + 300.02.

[0359] Step 2: 1-Methyl-4-(2-(1-methyl-1H-pyrazol-5-yl)-4-nitrophenyl)piperazine (A16): Add 1-(2-bromo-4-nitrophenyl)-4-methylpiperazine (1 g, 3.3 mmol, 1.0 eq), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (808 mg, 4.0 mmol, 1.2 eq), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (242 mg, 0.3 mmol, 0.1 eq), and potassium carbonate (690 mg, 5.0 mmol, 1.5 eq) to a round-bottom flask. Dissolve the above reagents in 1,4-dioxane (20 mL) and heat to 100 °C under an argon atmosphere with stirring for 6 hours. After the reaction was complete, the solvent was removed from the mixture under reduced pressure, and the residue was purified by pressurized silica gel column chromatography to give compound A16 (632 mg, yield 63%). MS(ESI)M / Z[M+H) + :302.15.

[0360] Step 3: 3-(1-Methyl-1H-pyrazol-5-yl)-4-(4-methylpiperazin-1-yl)aniline (A17): 1-Methyl-4-(2-(1-methyl-1H-pyrazol-5-yl)-4-nitrophenyl)piperazine (500 mg, 1.7 mmol, 1.0 eq), 10% reducing palladium on carbon (50 mg), dissolved in methanol (10 mL) were added to a round-bottom flask. The reaction mixture was reacted at room temperature under a hydrogen atmosphere for 2 hours. After the reaction, the mixture was filtered through diatomaceous earth, concentrated, and purified by pressurized silica gel column chromatography to obtain compound A17 (396 mg, yield 88%). MS (ESI) M / Z [M+H] + :272.17.

[0361]

[0362] The synthesis of the compound in Example 40 was carried out using A17 synthesized by the above steps and steps similar to those described in Example 1, except that aniline was replaced with 3-fluoroaniline in step 1 of Example 1, and 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 3-(1-methyl-1H-pyrazol-5-yl)-4-(4-methylpiperazin-1-yl)aniline in step 8 of Example 1. The remaining steps were the same as those in Example 1 and this example. 1H NMR (500MHz, DMSO-d6) δ9.01(s,1H),8.05(s,1H),7.41(d,J=1.8Hz,1H),7.28(dt,J=11.3,1.9Hz,1H),7.24(q,J=4.2,2.9Hz,2H),7.23-7.19(m,2 H),6.92-6.86(m,1H),6.47(t,J=1.8Hz,1H),6.18(d,J=1.9Hz,1H),4.50 (s,2H),3.70(s,3H),3.30(s,4H),3.02(s,4H),2.45(s,3H),2.26(s,3H). MS(ESI)m / z[M+H] + 528.26.

[0363] Example 41: 2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(3-(methylamino)phenyl)-7,8-dihydropterin-6(5H)-one

[0364]

[0365] The synthesis of the compound in Example 41 was carried out using steps similar to those described in Example 1, except that in step 1 of Example 1, N-methyl-m-phenylenediamine was used instead of aniline, and in step 5 of Example 1, methylpiperazine was used instead of morpholine. The remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.84(s,1H),7.91(s,1H),7.50(dd,J=8.7,2.7Hz,1H), 7.40(d,J=2.7Hz,1H),7.16(t,J=8.3Hz,1H),6.79(d,J=8.7Hz,1H),6.59-6.54( m,2H),6.53-6.47(m,1H),5.78(q,J=5.0Hz,1H),4.42(s,2H),3.28(s,5H),2.80 (d, J=4.9Hz, 4H), 2.66 (d, J=5.0Hz, 3H), 2.44 (s, 3H), 2.22 (s, 3H), 2.11 (s, 6H). MS(ESI)m / z[M+H] + : 516.31.

[0366] Example 42: 2-((3-((dimethylamino)methyl)-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)amino)-5-methyl-8-(3-(methylamino)phenyl)-7,8-dihydropterin-6(5H)-one

[0367]

[0368] The synthesis of the compound in Example 42 was carried out using steps similar to those described in Example 1, except that in step 1 of Example 1, N-methyl-m-phenylenediamine was used instead of aniline, and in step 5 of Example 1, 8-methyl-3,8-diazabicyclo[3.2.1]octane was used instead of morpholine, with the remaining steps following those in Example 1. 1 H NMR (500MHz, DMSO-d6) δ8.85 (s, 1H), 7.90 (s, 1H), 7.50 (dd, J = 8.7, 2.7Hz, 1H), 7.38 (d, J = 2. 8Hz,1H),7.16(s,1H),6.83(d,J=8.8Hz,1H),6.59-6.54(m,2H),6.51(dd,J=8.2,2.2Hz,1H), 5.77(q,J=5.0Hz,1H),4.42(s,2H),3.30(s,3H),3.28(s,3H),3.09(s,2H),2.84(d,J=10.1Hz ,2H),2.66(d,J=5.0Hz,3H),2.65-2.58(m,2H),2.22(s,3H),2.08(s,6H),1.97-1.84(m,4H). MS(ESI)m / z[M+H] + : 542.33.

[0369] Example 43: 2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5-methyl-8-(3-(methylamino)phenyl)-7,8-dihydropterin-6(5H)-one

[0370]

[0371] The compound in Example 43 was synthesized using steps similar to those described in Example 1, except that in step 1 of Example 1, aniline was replaced with N-methyl-m-phenylenediamine; the remaining steps were the same as in Example 1. MS (ESI) m / z [M+H] + : 503.28.

[0372] Example 44: 2-((3-((dimethylamino)methyl)-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-methyl-8-(3-(methylamino)phenyl)-7,8-dihydropterin-6(5H)-one

[0373]

[0374] The synthesis of the compound in Example 44 was carried out using steps similar to those described in Examples 1 and 6, except that in step 1 of Example 1, aniline was replaced with N-methyl-m-phenylenediamine, and in step 2 of Example 6, 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine was replaced with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine. The remaining steps were the same as in Examples 1 and 6. MS (ESI) m / z [M+H] + : 515.32.

[0375] Example 45: 5-Methyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-8-(3-(methylamino)phenyl)-7,8-dihydropterin-6(5H)-one

[0376]

[0377] The synthesis of the compound in Example 45 was carried out using steps similar to those described in Example 1, except that in step 1 of Example 1, N-methyl-m-phenylenediamine was used instead of aniline, and in step 8 of Example 1, 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine was used instead of 3-((dimethylamino)methyl)-4-morpholine aniline, and the remaining steps were the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ8.91(s,1H),7.91(s,1H),7.35(d,J=2.3Hz,1H),7.22-7.15(m,1H),7.10(dd,J=8.3,2.3Hz,1H),6.77(d,J=8.3Hz,1H),6.59 -6.54(m,2H),6.52(dt,J=8.2,1.7Hz,1H),5.79(q,J=5.0Hz,1H),4.41(s, 2H), 3.29 (s, 4H), 3.14 (s, 2H), 2.66 (dd, J = 17.7, 5.4Hz, 5H), 2.31 (s, 2H). MS(ESI)m / z[M+H] + : 430.23.

[0378] Example 46: 2-((2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5-methyl-8-(3-(methylamino)phenyl)-7,8-dihydropterin-6(5H)-one

[0379]

[0380] The synthesis of the compound in Example 46 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3-methylaniline in step 1 of Example 1, and 3-((dimethylamino)methyl)-4-morpholineaniline was replaced with 2-acetyl-7-amino-1,2,3,4-tetrahydroisoquinoline in step 8 of Example 1, with the remaining steps following those in Example 1. 1 H NMR(500MHz,DMSO-d6)δ9.03(d,J=38.3Hz,1H),7.94(d,J=6.1Hz,1H),7.60-7.36(m,1H),7.21(dt,J=8.0,4.8Hz,1H),6.85(dd,J=8.4,4.7Hz,1H),6.62 -6.53(m,3H),5.90-5.67(m,1H),4.43(s,2H),4.28(d,J=23.4Hz,2H),3.61-3.54(m,2H),3.29(d,J =2.1Hz, 3H), 2.70 (t, J = 5.9Hz, 1H), 2.65 (dd, J = 5.0, 3.4Hz, 3H), 2.58 (t, J = 5.9Hz, 1H), 2.06 (s, 3H). MS(ESI)m / z[M+H] + : 458.23.

[0381] Example 47: 2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5-methyl-8-(3-(trifluoromethyl)phenyl)-7,8-dihydropterin-6(5H)-one

[0382]

[0383] The synthesis of the compound in Example 47 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3-trifluoromethylaniline in step 1 of Example 1, and the remaining steps were the same as in Example 1. 1 HNMR(500MHz,DMSO-d6)δ9.04(s,1H),8.02(s,1H),7.81(s,1H),7.77(d,J=7.9Hz,1H),7.70(dd,J=14.4,6.6Hz,2H),7.44 -7.33(m,2H),6.80(d,J=8.3Hz,1H),4.57(s,2H),3.70(t,J=4.4Hz,4H),3.31(s,3H),2.78(t,J=4.3Hz,4H),2.16(s,6H). MS(ESI)m / z[M+H] + : 542.24.

[0384] Example 48: 2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(3-(trifluoromethyl)phenyl)-7,8-dihydropterin-6(5H)-one

[0385]

[0386] The synthesis of the compound in Example 48 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3-trifluoromethylaniline in step 1 of Example 1, and morpholine was replaced with methylpiperazine in step 5 of Example 1. The remaining steps were the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ9.04(s,1H),8.01(s,1H),7.81(s,1H),7.76(d,J=7.9Hz,1H),7.74-7.63(m,2H),7.45-7.33(m, 2H), 6.80 (d, J = 8.2Hz, 1H), 4.57 (s, 2H), 3.42 (s, 1H), 3.31 (s, 3H), 2.82 (s, 4H), 2.59 (s, 4H), 2.32 (s, 3H), 2.21 (s, 6H). MS(ESI)m / z[M+H] + : 555.28.

[0387] Example 49: 2-((3-((dimethylamino)methyl)-4-(piperidin-1-yl)phenyl)amino)-8-(4-fluorophenyl)-5-methyl-7,8-dihydropterin-6(5H)-one

[0388]

[0389] The synthesis of the compound in Example 49 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 4-fluoroaniline in step 1 of Example 1, and morpholine was replaced with piperidine in step 5 of Example 1. The remaining steps were the same as in Example 1. MS (ESI) m / z [M+H] + : 490.27.

[0390] Example 50: 2-((3-((dimethylamino)methyl)-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-8-(4-fluorophenyl)-5-methyl-7,8-dihydropterin-6(5H)-one

[0391]

[0392] The compound of Example 50 was synthesized using steps similar to those described in Example 1, except that 4-fluoroaniline was used instead of aniline in step 1 of Example 1, and N-hydroxyethylpiperazine was used instead of morpholine in step 5 of Example 1. The remaining steps were the same as in Example 1. MS (ESI) m / z [M+H] + : 535.29.

[0393] Example 51: 2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(4-fluorophenyl)-5-methyl-7,8-dihydropterin-6(5H)-one

[0394]

[0395] The compound of Example 51 was synthesized using steps similar to those described in Example 1, except that 4-fluoroaniline was used instead of aniline in step 1 of Example 1, and methylpiperazine was used instead of morpholine in step 5 of Example 1. The remaining steps were the same as in Example 1. MS (ESI) m / z [M+H] + : 505.28.

[0396] Example 52: 2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-8-(4-fluorophenyl)-5-methyl-7,8-dihydropterin-6(5H)-one

[0397]

[0398] The synthesis of the compound in Example 52 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 4-fluoroaniline in step 1 of Example 1, and the remaining steps were the same as in Example 1. MS (ESI) m / z [M+H] + : 492.25.

[0399] Example 53: 8-(4-fluorophenyl)-5-methyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-7,8-dihydropterin-6(5H)-one

[0400]

[0401] The synthesis of the compound in Example 53 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 4-fluoroaniline in step 1 of Example 1, and 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine in step 8 of Example 1. The remaining steps were the same as in Example 1. MS (ESI) m / z [M+H] + :419.19.

[0402] Example 54: 2-((3-((dimethylamino)methyl)-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)amino)-8-(4-fluorophenyl)-5-methyl-7,8-dihydropterin-6(5H)-one

[0403]

[0404] The compound of Example 54 was synthesized using steps similar to those described in Example 1, except that aniline was replaced with 4-fluoroaniline in step 1 of Example 1, and morpholine was replaced with 1-(methanesulfonyl)piperazine in step 5 of Example 1. The remaining steps were the same as in Example 1. MS (ESI) m / z [M+H] + : 569.24.

[0405] Example 55: 2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydropterin-6(5H)-one

[0406]

[0407] The synthesis of the compound in Example 55 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 4-trifluoromethylaniline in step 1 of Example 1, and morpholine was replaced with methylpiperazine in step 5 of Example 1, with the remaining steps being the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ9.00(s,1H),8.04(s,1H),7.80(d,J=8.6Hz,2H),7.65(d,J=8.4Hz,2H),7.38(s,2H),6. 77(d,J=9.3Hz,1H),4.56(s,2H),3.31(s,4H),3.27(s,3H),2.80(s,4H),2.48(s,2H),2.25(s,3H),2.11(s,6H). MS(ESI)m / z[M+H] + : 555.28.

[0408] Example 56: 2-((3-((dimethylamino)methyl)-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydropterin-6(5H)-one

[0409]

[0410] The synthesis of the compound in Example 56 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 4-trifluoromethylaniline in step 1 of Example 1, and morpholine was replaced with ethylpiperazine in step 5 of Example 1, with the remaining steps being the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ9.01(s,1H),8.04(s,1H),7.80(d,J=8.6Hz,2H),7.66(d,J=8.4Hz,2H),7.39(s,2H),6.79(d,J=8. 7Hz,1H),4.56(s,2H),3.31(d,J=2.6Hz,10H),2.82(s,4H),2.64(s,2H),2.44(s,2H),2.13(s,6H),1.04(t,J=7.0Hz,3H). MS(ESI)m / z[M+H] + : 569.29.

[0411] Example 57: 2-((3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-5-methyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydropterin-6(5H)-one

[0412]

[0413] The synthesis of the compound in Example 57 was carried out using steps similar to those described in Examples 1 and 6, except that aniline was replaced with 4-trifluoromethylaniline in step 1 of Example 1, and the remaining steps were the same as those in Examples 1 and 6. 1 H NMR(500MHz,DMSO-d6)δ9.02(s,1H),8.04(s,1H),7.80(d,J=8.6Hz,2H),7.66(d,J=8.5Hz,2H),7.40(s,2H),6.80 (d,J=8.4Hz,1H),4.56(s,2H),3.76-3.63(m,5H),3.31(s,4H),2.88-2.76(m,4H),2.76-2.67(m,1H),2.11(s,6H). MS(ESI)m / z[M+H] + 541.25.

[0414] Example 58: 2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5-methyl-8-(p-tolyl)-7,8-dihydropterin-6(5H)-one

[0415]

[0416] The synthesis of the compound in Example 58 was carried out using steps similar to those described in Example 1, except that 4-methylaniline was used instead of aniline in step 1 of Example 1, and the remaining steps were the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ8.85(s,1H),7.92(s,1H),7.42(d,J=2.7Hz,1H),7.38(dd,J=8.8,2.6Hz,1H),7.34-7.30(m,2H),7.27(d,J=8 .3Hz,2H),6.79(d,J=8.7Hz,1H),4.46(s,2H),3.70(t,J=4.4Hz,4H),3.29(s,5H),2.84-2.77(m,4H),2.38(s,3H),2.20-2.01(m,6H). MS(ESI)m / z[M+H] + : 488.27.

[0417] Example 59: 2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(p-tolyl)-7,8-dihydropterin-6(5H)-one

[0418]

[0419] The synthesis of the compound in Example 59 was carried out using steps similar to those described in Example 1, except that 4-methylaniline was used instead of aniline in step 1 of Example 1, and methylpiperazine was used instead of morpholine in step 5 of Example 1, with the remaining steps being the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ8.84(s,1H),7.91(s,1H),7.40(d,J=2.7Hz,1H),7.36(dd,J=8.7,2.7Hz,1H),7.31(d,J=8.4Hz,2H),7.27(d,J= 8.3Hz,2H),6.77(d,J=8.7Hz,1H),4.46(s,2H),3.29(s,6H),2.81(t,J=4.8Hz,4H),2.47(s,3H),2.38(s,3H),2.24(s,3H),2.12(s,6H). MS(ESI)m / z[M+H] + : 501.30.

[0420] Example 60: 2-((3-((dimethylamino)methyl)-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(p-tolyl)-7,8-dihydropterin-6(5H)-one

[0421]

[0422] The synthesis of the compound in Example 60 was carried out using steps similar to those described in Example 1, except that 4-methylaniline was used instead of aniline in step 1 of Example 1, and ethylpiperazine was used instead of morpholine in step 5 of Example 1, with the remaining steps following the steps in Example 1. 1 H NMR (500MHz, DMSO) δ8.82(s,1H),7.91(s,1H),7.39(d,J=2.7Hz,1H),7.35(dd,J=8.6,2.7Hz,1H),7.31(d,J=8.4Hz,2H),7.27(d,J=8.3Hz,2H),6 .76(d,J=8.7Hz,1H),4.46(s,2H),3.29(s,4H),3.23(s,2H),2.81(t,J=4 .5Hz, 4H), 2.49 (s, 3H), 2.38 (s, 5H), 2.09 (s, 6H), 1.02 (t, J = 7.1Hz, 3H). MS(ESI)m / z[M+H] + : 515.32.

[0423] Example 61: 2-((3-((dimethylamino)methyl)-4-(4-isopropylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(p-tolyl)-7,8-dihydropterin-6(5H)-one

[0424]

[0425] The synthesis of the compound in Example 61 was carried out using steps similar to those described in Example 1, except that 4-methylaniline was used instead of aniline in step 1 of Example 1, and isopropylpiperazine was used instead of morpholine in step 5 of Example 1, with the remaining steps being the same as in Example 1. 1 H NMR(500MHz,DMSO)δ8.81(s,1H),7.91(s,1H),7.40(d,J=2.7Hz,1H),7.35(d d,J=8.7,2.7Hz,1H),7.33-7.29(m,2H),7.27(d,J=8.4Hz,2H),6.75(d,J=8. 7Hz,1H),4.46(s,2H),3.29(s,3H),3.24(s,2H),2.80(t,J=4.6Hz,4H),2.69 -2.63(m,1H),2.55(s,4H),2.38(s,3H),2.09(s,6H),1.01(d,J=6.6Hz,6H). MS(ESI)m / z[M+H] + : 529.34.

[0426] Example 62: 5-Methyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-8-(p-tolyl)-7,8-dihydropterin-6(5H)-one

[0427]

[0428] The synthesis of the compound in Example 62 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 4-methylaniline in step 1 of Example 1, and 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine in step 8 of Example 1. The remaining steps were the same as in Example 1. MS (ESI) m / z [M+H] + :415.22.

[0429] Example 63: 2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-8-(o-tolyl)-7,8-dihydropterin-6(5H)-one

[0430]

[0431] The synthesis of the compound in Example 63 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 2-methylaniline in step 1 of Example 1, and morpholine was replaced with methylpiperazine in step 5 of Example 1. The remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.80(s,1H),7.87(s,1H),7.43-7.35(m,2H),7.37- 7.31(m,2H),7.30(d,J=2.7Hz,1H),7.27(dd,J=8.6,2.7Hz,1H),6.69(d,J=8 .7Hz,1H),4.61(d,J=16.5Hz,1H),4.23(d,J=16.5Hz,1H),3.30(s,5H),2.8 1-2.76(m,4H),2.44(d,J=15.8Hz,3H),2.23(s,3H),2.14(d,J=5.0Hz,10H). MS(ESI)m / z[M+H] + : 501.31.

[0432] Example 64: 2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5-methyl-8-(o-tolyl)-7,8-dihydropterin-6(5H)-one

[0433]

[0434] The synthesis of the compound in Example 64 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 2-methylaniline in step 1 of Example 1, and the remaining steps were the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ8.81(s,1H),7.88(s,1H),7.40(s,2H),7.34(dd,J=5.8,3.5Hz,2H),7.31(d,J=2.7Hz,2H),6.69(d,J=8.7Hz,1H), 4.61(d,J=16.4Hz,1H), 4.23(d,J=16.4Hz,1H), 3.68(t,J=4.5Hz,4H), 3.30(s,5H), 2.78(dd,J=7.7,4.1Hz,4H), 2.15(s,3H), 2.12(s,6H). MS(ESI)m / z[M+H] + : 488.27.

[0435] Example 65: 2-((3-((dimethylamino)methyl)-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5-methyl-8-(o-tolyl)-7,8-dihydropterin-6(5H)-one

[0436]

[0437] The synthesis of the compound in Example 65 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 2-methylaniline in step 1 of Example 1, and morpholine was replaced with N-hydroxyethylpiperazine in step 5 of Example 1. The remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.78(s,1H),7.87(s,1H),7.42-7.35(m,2H),7.33(dd,J=5.7,3.5Hz,2 H),7.29(d,J=2.7Hz,1H),7.26(dd,J=8.8,2.6Hz,1H),6.67(d,J=8.7Hz,1H),4.61(d,J=16.4H z,1H),4.39(t,J=5.4Hz,1H),4.23(d,J=16.3Hz,1H),3.52(q,J=6.0Hz,2H),3.30(s,6H),3.22 (s,1H),2.80-2.75(m,4H),2.58-2.51(m,2H),2.43(t,J=6.3Hz,2H),2.14(s,3H),2.11(s,6H). MS(ESI)m / z[M+H] + : 531.31.

[0438] Example 66: 2-((3-((dimethylamino)methyl)-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-methyl-8-(o-tolyl)-7,8-dihydropterin-6(5H)-one

[0439]

[0440] The synthesis of the compound in Example 66 was carried out using steps similar to those described in Examples 1 and 6, except that aniline was replaced with 2-methylaniline in step 1 of Example 1, and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine was replaced with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine in step 2 of Example 6, with the remaining steps being the same as in Examples 1 and 6. 1 H NMR (500MHz, DMSO-d6) δ8.84(s,1H),7.88(s,1H),7.40(tt,J=9.6,3.8Hz,2H),7.35(dp,J=7.3, 3.6Hz,2H),7.22(dd,J=8.5,2.4Hz,1H),7.18(d,J=2.4Hz,1H),6.81(d,J=8.5Hz,1H),4.61(d,J =16.3Hz,1H),4.23(d,J=16.3Hz,1H),3.31(s,5H),3.15-3.00(m,2H),2.87(d,J=10.9Hz,2H),2 .73(d,J=8.0Hz,1H),2.22(s,3H),2.15(s,3H),2.06(s,6H),1.97(s,2H),1.55(p,J=5.0Hz,2H). MS(ESI)m / z[M+H] + : 500.31.

[0441] Example 67: 2-((3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-5-methyl-8-(o-tolyl)-7,8-dihydropterin-6(5H)-one

[0442]

[0443] The synthesis of the compound in Example 67 was carried out using steps similar to those described in Examples 1 and 6, except that aniline was replaced with 2-methylaniline in step 1 of Example 1, and the remaining steps were the same as those in Examples 1 and 6. 1HNMR(500MHz,DMSO-d6)δ8.85(s,1H),7.89(s,1H),7.45-7.38(m,2H),7.37-7.32( m,2H),7.23(dd,J=8.6,2.4Hz,1H),7.20(d,J=2.4Hz,1H),6.84(d,J=8.5Hz,1H),4 .61(d,J=16.3Hz,1H),4.23(d,J=16.3Hz,1H),3.94-3.88(m,2H),3.36(d,J=2.5Hz ,2H),3.31(s,3H),3.19-2.97(m,3H),2.15(s,3H),2.06(s,6H),1.61-1.43(m,4H). MS(ESI)m / z[M+H] + : 487.28.

[0444] Example 68: 2-((3-((dimethylamino)methyl)-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)amino)-5-methyl-8-(o-tolyl)-7,8-dihydropterin-6(5H)-one

[0445]

[0446] The synthesis of the compound in Example 68 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 2-methylaniline in step 1 of Example 1, and morpholine was replaced with 8-methyl-3,8-diazabicyclo[3.2.1]octane in step 5 of Example 1, with the remaining steps following those in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.80(s,1H),7.87(s,1H),7.41-7.36(m,2H),7.36-7.31(m,2H),7 .28(d,J=2.7Hz,1H),7.24(dd,J=8.7,2.7Hz,1H),6.71(d,J=8.7Hz,1H),4.61(d,J=16.4Hz ,1H),4.23(d,J=16.4Hz,1H),3.30(s,3H),3.25(d,J=19.4Hz,2H),3.10(s,2H),2.82(d,J= 10.1Hz,2H),2.66-2.57(m,2H),2.22(s,3H),2.14(s,3H),2.09(s,6H),1.98-1.82(m,4H). MS(ESI)m / z[M+H] + : 527.32.

[0447] Example 69: 5-Methyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-8-(o-tolyl)-7,8-dihydropterin-6(5H)-one

[0448]

[0449] The synthesis of the compound in Example 69 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 2-methylaniline in step 1 of Example 1, and 3-((dimethylamino)methyl)-4-morpholineaniline was replaced with 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine in step 8 of Example 1, with the remaining steps referring to Example 1. 1 H NMR (500MHz, DMSO-d6) δ8.90 (s, 1H), 7.89 (s, 1H), 7.41 (ddd, J = 7.1, 5.5, 2.5Hz, 2H), 7 .35(ddd,J=6.2,3.6,2.1Hz,2H),7.11(d,J=2.3Hz,1H),6.97(dd,J=8.3,2.3Hz,1H),6 .70(d,J=8.3Hz,1H),4.61(d,J=16.4Hz,1H),4.24(d,J=16.4Hz,1H),3.31(s,3H),3.1 1-2.93(m,2H),2.62(t,J=6.0Hz,2H),2.47(t,J=5.7Hz,2H),2.30(s,3H),2.15(s,3H). MS(ESI)m / z[M+H] + :415.22.

[0450] Example 70: 2-((2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5-methyl-8-(o-tolyl)-7,8-dihydropterin-6(5H)-one

[0451]

[0452] The synthesis of the compound in Example 70 was carried out using steps similar to those described in Examples 1 and 28, except that aniline was replaced with 2-methylaniline in step 1 of Example 1 and 2-iodopropane was replaced with 2-bromoethane-1-ol in step 1 of Example 28, and the remaining steps were the same as those in Examples 1 and 28. 1H NMR (500MHz, DMSO)-d6δ8.90(s,1H),7.89(s,1H),7.42(td,J=7.2,6.6,1.9H z,2H),7.39-7.31(m,2H),7.10(d,J=2.2Hz,1H),6.97(dd,J=8.5,2.3Hz,1H), 6.69(d,J=8.4Hz,1H),4.61(d,J=16.4Hz,1H),4.24(d,J=16.3Hz,1H),3.52(t ,J=5.9Hz,2H),3.31(s,3H),3.30(s,3H),2.61(d,J=6.6Hz,6H),2.16(s,3H). MS(ESI)m / z[M+H] + : 445.23.

[0453] Example 71: 8-(3-chloro-2-methylphenyl)-2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one

[0454]

[0455] The compound of Example 71 was synthesized using steps similar to those described in Example 1, except that aniline was replaced with 3-chloro-2-methylaniline in step 1 of Example 1; the remaining steps were the same as in Example 1. MS (ESI) m / z [M+H] + : 522.23.

[0456] Example 72: 8-(3-chloro-2-methylphenyl)-2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one

[0457]

[0458] The synthesis of the compound in Example 72 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3-chloro-2-methylaniline in step 1 of Example 1, and morpholine was replaced with methylpiperazine in step 5 of Example 1. The remaining steps were the same as in Example 1. 1H NMR (500MHz, DMSO-d6) δ8.90(s,1H),7.91(s,1H),7.32(tq,J=27.5,8.9,8.4Hz,5H),6.78(d,J=7.7Hz,1H),4.65(d,J=16. 2Hz,1H),4.25(d,J=16.2Hz,1H),3.32(s,6H),2.83(s,4H),2.57(s,3H),2.32(s,3H),2.24(s,6H),2.03(d,J=1.5Hz,3H). MS(ESI)m / z[M+H] + : 535.27.

[0459] Example 73: 8-(3,4-difluorophenyl)-2-((3-((dimethylamino)methyl)-4-morpholinylphenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one

[0460]

[0461] The synthesis of the compound in Example 73 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3,4-difluoroaniline in step 1 of Example 1, and the remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.96(s,1H),7.98(s,1H),7.64-7.59(m,1H),7.56-7.51(m,1H),7.44(d,J=2.6Hz,1H),7.39(d,J=8.6Hz,1 H),7.32-7.29(m,1H),6.85(d,J=8.7Hz,1H),4.49(s,2H),3.70(t,J=4.5Hz,4H),3.29(s,3H),2.81(t,J=4.5Hz,4H),2.11(s,6H). MS(ESI)m / z[M+H] + : 510.24.

[0462] Example 74: 8-(3,4-difluorophenyl)-2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one

[0463]

[0464] The synthesis of the compound in Example 74 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3,4-difluoroaniline in step 1 of Example 1, and morpholine was replaced with methylpiperazine in step 5 of Example 1, with the remaining steps being the same as in Example 1.1 H NMR (500MHz, DMSO-d6) δ8.93(s,1H),7.97(s,1H),7.63-7.59(m,1H),7.56-7.50(m,1H),7.41(d,J=2.6Hz,1H),7.36(dd,J=8.7,2.7Hz,1 H),7.31-7.28(m,1H),6.82(d,J=8.7Hz,1H),4.49(s,2H),3.29(s,3H),3.24(s,2H),2.81(s,4H),2.44(s,4H),2.22(s,3H),2.09(s,6H). MS(ESI)m / z[M+H] + 523.27.

[0465] Example 75: 8-(3,5-difluorophenyl)-2-((3-((dimethylamino)methyl)-4-morpholinylphenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one

[0466]

[0467] The synthesis of the compound in Example 75 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3,5-difluoroaniline in step 1 of Example 1, and the remaining steps were the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ9.10(s,1H),8.04(s,1H),7.53(d,J=6.5Hz,1H),7.49(d,J=2.1Hz,1H),7.25(dd,J=8.9,2.1Hz,2H) ,7.21-7.12(m,1H),6.96(s,1H),4.51(s,2H),3.75-3.69(m,4H),3.57(s,1H),3.30(s,4H),2.83-2.78(m,4H),2.31(s,6H). MS(ESI)m / z[M+H] + : 510.24.

[0468] Example 76: 8-(3,5-difluorophenyl)-2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one

[0469]

[0470] The synthesis of the compound in Example 76 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3,5-difluoroaniline in step 1 of Example 1, and morpholine was replaced with methylpiperazine in step 5 of Example 1, with the remaining steps being the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ9.04(s,1H),8.04(s,1H),7.47(d,J=7.7Hz,2H),7.25(dd,J=8.9,2.1Hz,2H),7.19-7.11(m,1 H), 6.89 (d, J = 8.2Hz, 1H), 4.51 (s, 2H), 3.38 (s, 2H), 3.29 (s, 4H), 2.84 (s, 4H), 2.53 (s, 3H), 2.28 (s, 3H), 2.17 (s, 6H). MS(ESI)m / z[M+H] + 523.27.

[0471] Example 77: 8-(3,5-difluorophenyl)-2-((3-((dimethylamino)methyl)-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one

[0472]

[0473] The compound of Example 77 was synthesized using steps similar to those described in Example 1, except that aniline was replaced with 3,5-difluoroaniline in step 1 of Example 1, and morpholine was replaced with ethylpiperazine in step 5 of Example 1. The remaining steps were the same as in Example 1. MS (ESI) m / z [M+H] + : 537.29.

[0474] Example 78: 2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-(3-fluoro-4-methylphenyl)-5-methyl-7,8-dihydropterin-6(5H)-one

[0475]

[0476] The compound of Example 78 was synthesized using steps similar to those described in Example 1, except that aniline was replaced with 3-fluoro-4-methylaniline in step 1 of Example 1, and morpholine was replaced with methylpiperazine in step 5 of Example 1. The remaining steps were the same as in Example 1. MS (ESI) m / z [M+H] + : 519.29.

[0477] Example 79: 2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-8-(3-fluoro-2-methylphenyl)-5-methyl-7,8-dihydropterin-6(5H)-one

[0478]

[0479] The synthesis of the compound in Example 79 was carried out using steps similar to those described in Example 1, except that aniline was replaced with 3-fluoro-2-methylaniline in step 1 of Example 1; the remaining steps were the same as in Example 1. MS (ESI) m / z [M+H] + 506.26.

[0480] Example 80: 2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-8-(3-fluoro-2-methylphenyl)-5-methyl-7,8-dihydropterin-6(5H)-one

[0481]

[0482] Step 1: (3-Bromophenyl)glycine ethyl ester (A18): 3-Bromoaniline (3 g, 17.4 mmol, 1.0 eq), ethyl bromoaniline (3.49 g, 20.9 mmol, 1.2 eq), and potassium carbonate (3.6 g, 26.1 mmol, 1.5 eq) were added to a round-bottom flask and dissolved in acetonitrile (30 mL). The reaction mixture was stirred overnight at 70 °C. After the reaction was complete, the solvent was removed from the mixture under reduced pressure. The residue was purified by pressurized silica gel column chromatography to give compound A18 (3.64 g, 81% yield). MS (ESI) M / Z [M+H] + 258.00.

[0483] Step 2: N-(3-bromophenyl)-N-(2-chloro-5-nitropyrimidin-4-yl)glycine ethyl ester (A19): In a round-bottom flask, add (3-bromophenyl)glycine ethyl ester (2 g, 7.7 mmol, 1.0 eq), 2,4-dichloro-5-nitropyrimidin (2.25 g, 11.6 mmol, 1.5 eq), and potassium carbonate (2.13 g, 15.4 mmol, 2.0 eq), dissolved in cyclohexane (50 mL). The reaction mixture is stirred overnight at 80 °C. After the reaction is complete, the solvent is removed from the mixture under reduced pressure. The residue is purified by pressurized silica gel column chromatography to give compound A19 (2.48 g, 77% yield). MS (ESI) M / Z [M+H] + : 414.97.

[0484] Step 3: 8-(3-Bromophenyl)-2-chloro-7,8-dihydropterin-6(5H)-one (A20): In a round-bottom flask, ethyl N-(3-bromophenyl)-N-(2-chloro-5-nitropyrimidin-4-yl)glycine (2 g, 4.8 mmol, 1.0 eq) was dissolved in glacial acetic acid (60 mL). Iron powder (2.69 g, 48 mmol, 10.0 eq) was added with stirring. The reaction mixture was stirred at 80 °C for two hours. After the reaction was complete, the solvent was evaporated under reduced pressure, and the product was neutralized to alkalinity with saturated sodium bicarbonate solution. Extraction with ethyl acetate was performed, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain the crude product. The crude product was washed with diethyl ether to give compound A20 (800 mg, yield 49%). MS (ESI) M / Z [M+H] + 338.95.

[0485] Step 4: 8-(3-Bromophenyl)-2-chloro-5-methyl-7,8-dihydropterin-6(5H)-one (A21): 8-(3-Bromophenyl)-2-chloro-7,8-dihydropterin-6(5H)-one (500 mg, 1.5 mmol, 1.0 eq) and N,N-dimethylformamide (10 mL) were added to a round-bottom flask. Iodomethane (256 mg, 1.8 mmol, 1.2 eq) was added under ice bath conditions, followed by sodium hydride (72 mg, 1.8 mmol, 1.2 eq). The reaction mixture was stirred under ice bath conditions for 1 hour. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain the crude product. The crude product was washed with diethyl ether to obtain compound A21 (390 mg, 75% yield). MS(ESI)M / Z[M+H] + 352.97.

[0486] Step 5: 8-(3-bromophenyl)-2-((3-(((dimethylamino)methyl)-4-morpholinphenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one (A22): Add 100 mg (0.28 mmol, 1.0 eq), 60 mg (0.25 mmol, 0.9 eq), 145 mg (0.84 mmol, 3.0 eq), and 5 mL of sec-butanol to a sealed tube. Stir the reaction mixture overnight at 120 °C. After the reaction is complete, quench with water, adjust to a weakly alkaline pH with saturated sodium bicarbonate solution, extract with ethyl acetate, wash the organic phase with water and saturated brine, and dry with anhydrous sodium sulfate. The organic phase was filtered, concentrated, and purified by thin-layer chromatography to give compound A22 (32 mg, yield 23%). MS (ESI) M / Z [M+H) + : 552.16.

[0487] Step 6: 2-((3-((dimethylamino)methyl)-4-(morpholin-4-yl)phenyl)amino)-8-(3-((diphenylmethylene)amino)phenyl)-5-methyl-7,8-dihydropterin-6(5H)-one (A23): Add 200 mg, 0.36 mg of 8-(3-bromophenyl)-2-((3-((dimethylamino)methyl)-4-morpholinphenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one to a round-bottom flask. The following reagents were added: benzophenone imine (98 mg, 0.54 mmol, 1.5 eq), BINAP (45 mg, 0.08 mmol, 0.2 eq), tris(dibenzylacetone) palladium (35 mg, 0.04 mmol, 0.1 eq), and cesium carbonate (234 mg, 0.72 mmol, 2.0 eq). These reagents were dissolved in 1,4-dioxane (20 mL), and the mixture was heated to 100 °C and stirred for 6 hours under an argon atmosphere. After the reaction, the solvent was removed from the mixture under reduced pressure, and the residue was purified by pressurized silica gel column chromatography to give compound A23 (137 mg, 58% yield). MS (ESI) M / Z [M+H] + : 623.32.

[0488] Step 7: 8-(3-aminophenyl)-2-((3-(((dimethylamino)methyl)-4-morpholinylphenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one: Add 2-((3-((dimethylamino)methyl)-4-(morpholin-4-yl)phenyl)amino)-8-(3-((diphenylmethylene)amino)phenyl)-5-methyl-7,8-dihydropterin-6(5H)-one (100 mg, 0.15 mmol, 1.0 eq) to a round-bottom flask, dissolve in methanol (5 mL), and then add 1M hydrochloric acid solution (2 mL) dropwise with stirring at room temperature. After the reaction is complete, quench with water, adjust to alkalinity with saturated sodium bicarbonate solution, extract with ethyl acetate, wash the organic phase with water and saturated brine respectively, and dry with anhydrous sodium sulfate. The organic phase was filtered, concentrated, and purified by thin-layer chromatography to obtain compound 80 (45 mg, yield 61%).

[0489]

[0490] The synthesis of the compound in Example 80 was accomplished using the steps described above. 1 H NMR (500MHz, DMSO-d6) δ8.87(s,1H),7.91(s,1H),7.52(dd,J=8.7,2.7Hz,1H),7.45(s,1H),7.10(t,J=7.9Hz,1H),6.87(d,J=8.6Hz,1 H), 6.59 (s, 1H), 6.55-6.52 (m, 2H), 5.19 (s, 2H), 4.39 (s, 2H), 3.70 (t, J = 4.4Hz, 4H), 3.28 (s, 3H), 2.81 (t, J = 4.4Hz, 4H), 2.15 (s, 6H). MS(ESI)m / z[M+H] + : 489.27.

[0491] Example 81: 8-(3-amino-2-methylphenyl)-2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one

[0492]

[0493] The synthesis of the compound in Example 81 was carried out by a procedure similar to that described in Example 80, except that 3-bromo-2-methylaniline was replaced with 3-bromoaniline in step 1 of Example 80, and the remaining steps were the same as in Example 80. 1H NMR(500MHz,DMSO-d6)δ8.79(s,1H),7.84(s,1H),7.41-7.32(m,2H),7.01(t,J =7.9Hz,1H),6.81(s,1H),6.70(dd,J=8.1,1.2Hz,1H),6.58(dd,J=7.8,1.2Hz, 1H),5.04(s,2H),4.52(d,J=16.5Hz,1H),4.16(d,J=16.6Hz,1H),3.69(t,J=4. 5Hz, 4H), 3.29 (s, 5H), 2.80 (qt, J = 11.5, 4.5Hz, 4H), 2.17 (s, 6H), 1.85 (s, 3H). MS(ESI)m / z[M+H] + : 503.28.

[0494] Example 82: 8-(3-amino-2-methylphenyl)-2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one

[0495]

[0496] The synthesis of the compound in Example 82 was carried out through steps similar to those described in Example 80, except that in step 1 of Example 80, 3-bromo-2-methylaniline was used instead of 3-bromoaniline, and in step 5 of Example 80, 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Example 80. MS (ESI) 1 H NMR (500MHz, DMSO-d6) δ8.73(s,1H),7.83(s,1H),7.36(dd,J=8.7,2.7Hz,1H),7.33(d,J=2 .7Hz,1H),7.00(t,J=7.9Hz,1H),6.76(d,J=8.7Hz,1H),6.69(dd,J=8.1,1.2Hz,1H),6.57(d d,J=7.8,1.2Hz,1H),5.02(s,2H),4.51(d,J=16.5Hz,1H),4.16(d,J=16.5Hz,1H),3.29(s, 5H), 2.79 (dq, J = 12.2, 7.2, 6.0Hz, 4H), 2.43 (s, 4H), 2.22 (s, 3H), 2.12 (s, 6H), 1.84 (s, 3H). MS(ESI)m / z[M+H] + : 516.31.

[0497] Example 83: 8-(3-amino-2-methylphenyl)-2-((3-((dimethylamino)methyl)-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one

[0498]

[0499] The synthesis of the compound in Example 83 was carried out by a method similar to that described in Example 80, except that 3-bromo-2-methylaniline was used instead of 3-bromoaniline in step 1 of Example 80, and 3-((dimethylamino)methyl)-4-(4-ethylpiperazin-1-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline in step 5 of Example 80, and the remaining steps were the same as in Example 80. 1 H NMR(500MHz,DMSO-d6)δ8.73(s,1H),7.83(s,1H),7.36(dd,J=8.7,2.7Hz,1H),7.32(d,J=2.7Hz ,1H),7.00(t,J=7.9Hz,1H),6.76(d,J=8.7Hz,1H),6.69(dd,J=7.9,1.2Hz,1H),6.57(dd,J=7.8 ,1.2Hz,1H),5.02(s,2H),4.52(d,J=16.6Hz,1H),4.16(d,J=16.6Hz,1H),3.29(s,6H),2.84-2. 76(m,5H),2.43(s,2H),2.36(q,J=7.2Hz,2H),2.12(s,6H),1.84(s,3H),1.02(t,J=7.1Hz,3H). MS(ESI)m / z[M+H] + : 530.33.

[0500] Example 84: 8-(3-amino-2-methylphenyl)-2-((3-((dimethylamino)methyl)-4-(4-isopropylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one

[0501]

[0502] The synthesis of the compound in Example 84 was carried out by a method similar to that described in Example 80, except that in step 1 of Example 80, 3-bromo-2-methylaniline was used instead of 3-bromoaniline, and in step 5 of Example 80, 3-((dimethylamino)methyl)-4-(4-isopropylpiperazin-1-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Example 80. 1H NMR (500MHz, DMSO-d6) δ8.74(s,1H),7.83(s,1H),7.36(dd,J=8.7,2.7Hz,1H),7.32(d,J= 2.7Hz,1H),7.00(t,J=7.9Hz,1H),6.76(d,J=8.7Hz,1H),6.69(dd,J=8.0,1.1Hz,1H),6.5 7(dd,J=7.8,1.2Hz,1H),5.03(s,2H),4.52(d,J=16.5Hz,1H),4.16(d,J=16.6Hz,1H),3.2 9(s,6H),2.79(s,4H),2.55(s,4H),2.15-2.11(m,6H),1.85(s,3H),1.01(d,J=6.5Hz,6H). MS(ESI)m / z[M+H] + 544.35.

[0503] Example 85: 2'-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5'-methyl-8'-phenyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0504]

[0505] Step 1: 1-(phenylamino)cyclopropane-1-carboxylic acid (A24): In a round-bottom flask, add 1-aminocyclopropane-1-carboxylic acid (7.43 g, 73.5 mmol, 1.5 eq), iodobenzene (10 g, 49 mmol, 1.0 eq), cuprous chloride (970 mg, 9.8 mmol, 0.2 eq), 2-acetylcyclohexane-1-one (274 mg, 1.96 mmol, 0.2 eq), and potassium carbonate (17 g, 123.2 mmol, 2.5 eq). Dissolve the above reagents in N,N-dimethylformamide (50 mL). Heat to 105 °C under an argon atmosphere and stir overnight. After the reaction is complete, dilute with water and extract with ethyl acetate. Adjust the aqueous phase to weakly acidic with saturated citric acid solution, and then extract with n-butanol. Wash the organic phase with saturated brine and dry with anhydrous sodium sulfate. The organic phase was filtered and evaporated to dryness under reduced pressure to obtain crude product A24, which can be directly used in the next reaction. MS(ESI)M / Z[M+H] + : 178.07.

[0506] Step 2: Methyl 1-(phenylamino)cyclopropane-1-carboxylate (A25): In a round-bottom flask, 2 g (11.3 mmol, 1.0 eq) of 1-(phenylamino)cyclopropane-1-carboxylic acid was added, followed by 30 mL of methanol, and then 2 mL of thionyl chloride was added dropwise under ice bath conditions. The reaction system was reacted overnight at 80 °C. After the reaction was complete, the solvent was evaporated under reduced pressure, the pH was adjusted to alkaline with saturated sodium bicarbonate, and the mixture was extracted three times with ethyl acetate. The organic phase was then purified under reduced pressure to remove the solvent. The crude product was separated by column chromatography to obtain A25. MS (ESI) M / Z [M+H] + : 192.09.

[0507] Step 3: Methyl 1-((2-chloro-5-nitropyrimidin-4-yl)(phenyl)amino)cyclopropane-1-carboxylate (A26): In a round-bottom flask, methyl 1-(phenylamino)cyclopropane-1-carboxylate (2 g, 10.5 mmol, 1.0 eq), 2,4-dichloro-5-nitropyrimidin (3.06 g, 15.8 mmol, 1.0 eq), and potassium carbonate (2.89 g, 21 mmol, 2.0 eq) were added and dissolved in cyclohexane (50 mL). The reaction mixture was stirred overnight at 80 °C. After the reaction was complete, the solvent was removed from the mixture under reduced pressure. The residue was purified by pressurized silica gel column chromatography to give compound A26 (2.44 g, 67% yield). MS (ESI) M / Z [M+H] + 349.06.

[0508] Step 4: 2'-Chloro-8'-phenyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one (A27): methyl 1-((2-chloro-5-nitropyrimidin-4-yl)(phenyl)amino)cyclopropane-1-carboxylate (2 g, 5.73 mmol, 1.0 eq) was dissolved in glacial acetic acid (50 mL) in a round-bottom flask. Iron powder (3.21 g, 57.3 mmol, 10.0 eq) was added with stirring. The reaction system was stirred at 70 °C for two hours. After the reaction was complete, the solvent was evaporated to dryness under reduced pressure, and the product was neutralized to alkalinity with saturated sodium bicarbonate solution. Extraction with ethyl acetate was performed, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. The organic phase was filtered, evaporated to dryness under reduced pressure to obtain a crude product, and washed with diethyl ether to give compound A27 (904 mg, 55% yield). MS(ESI)M / Z[M+H] + : 287.06.

[0509] Step 5: 2'-Chloro-5'-methyl-8'-phenyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one (A28): In a round-bottom flask, add 2'-chloro-8'-phenyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one (1 g, 3.5 mmol, 1.0 eq) and N,N-dimethylformamide (10 mL). Add iodomethane (596 mg, 4.2 mmol, 1.2 eq) under ice bath conditions, followed by sodium hydride (168 mg, 4.2 mmol, 1.2 eq). Continue stirring the reaction mixture in an ice bath for 1 hour. After the reaction is complete, quench with water, extract with ethyl acetate, wash the organic phase with water and saturated brine respectively, and dry with anhydrous sodium sulfate. The organic phase was filtered and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was washed with diethyl ether to give compound A28 (744 mg, 71% yield). MS(ESI)M / Z[M+H] + 301.07.

[0510] Step 6: 2'-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5'-methyl-8'-phenyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one: Add 2'-chloro-5'-methyl-8'-phenyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one (100 mg, 0.33 mmol, 1.0 eq), 3-((dimethylamino)methyl)-4-morpholinoaniline (71 mg, 0.3 mmol, 0.9 eq), p-toluenesulfonic acid (172 mg, 0.99 mmol, 3.0 eq), and sec-butanol (5 mL) to a sealed tube. Stir the reaction mixture overnight at 120 °C. After the reaction was completed, the mixture was quenched with water, adjusted to a weakly alkaline state with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, respectively, and dried with anhydrous sodium sulfate. The organic phase was filtered, concentrated, and purified by thin-layer chromatography to give compound 85 (39 mg, yield 26%).

[0511] The synthesis of the compound in Example 85 was accomplished using the steps described above. 1H NMR (500MHz, DMSO-d6) δ8.84(s,1H),7.89(s,1H),7.52(m,J=7.6Hz,3H),7.35-7.29(m,2H),7.23(d,J=7.1Hz,2H),6.66(d,J=8.6Hz, 1H),3.69(t,J=4.5Hz,4H),3.31(s,4H),2.78(t,J=4.5Hz,4H),2.16-2.12(m,6H),1.32-1.26(m,2H),1.23(s,1H),0.82-0.76(m,2H). MS(ESI)m / z[M+H] + 500.26.

[0512] Example 86: 2'-((3-((dimethylamino)methyl)-4-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)phenyl)amino)-5'-methyl-8'-phenyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0513]

[0514] The synthesis of the compound in Example 86 was carried out by a method similar to that described in Example 85, except that in step 6 of Example 85, 3-((dimethylamino)methyl)-4-(-8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Example 85. 1 HNMR(500MHz,DMSO-d6)δ8.89(s,1H),7.89(s,1H),7.57-7.46(m,3H),7.33(dd,J=7.0,1.9Hz,2H),7.23(dt,J=9.5,2.7Hz,2H),6.74(d,J= 8.7Hz,1H),3.31(s,7H),3.06(s,2H),2.76(d,J=11.1Hz,2H),2.13(s,6H),2.11-1.99(m,4H),1.29(s,2H),1.23(s,1H),0.82-0.76(m,2H). MS(ESI)m / z[M+H] + : 539.32.

[0515] Example 87: 2'-((3-((dimethylamino)methyl)-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)amino)-5'-methyl-8'-phenyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0516]

[0517] The synthesis of the compound in Example 87 was carried out by a method similar to that described in Example 85, except that in step 6 of Example 85, 3-((dimethylamino)methyl)-4-(4-(methanesulfonyl)piperazin-1-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Example 85. 1 H NMR(500MHz,DMSO-d6)δ8.92(s,1H),7.90(s,1H),7.53(qd,J=7.8,6.9,3.7Hz,3H),7.36-7.29(m,2H),7.26(s,2H),6.75(s,1H ),3.31(s,4H),3.23(s,4H),2.94(s,3H),2.87(t,J=4.8Hz,4H),2.30(d,J=65.0Hz,6H),1.33-1.26(m,3H),0.82-0.76(m,2H). MS(ESI)m / z[M+H] + : 577.27.

[0518] Example 88: 2'-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5'-methyl-8'-phenyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0519]

[0520] The synthesis of the compound in Example 88 was carried out through steps similar to those described in Example 85, except that in step 6 of Example 85, 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline; the remaining steps were the same as in Example 85. MS (ESI) m / z [M+H] + : 513.30.

[0521] Example 89: 2'-((3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-8'-(4-fluorophenyl)-5'-methyl-5',8'-dihydro-6'-pyran[cyclopropane-7'-pterin]-6'-one

[0522]

[0523] The synthesis of the compound in Example 89 was carried out by a method similar to that described in Example 85, except that in step 6 of Example 85, 3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Example 85. 1 H NMR(500MHz,DMSO-d6)δ8.88(s,1H),7.90(s,1H),7.53(ddd,J=14.0,8.0,6 .3Hz,3H),7.36-7.30(m,2H),7.23(s,1H),7.12(s,1H),6.81(d,J=8.6Hz,1H ),3.92(dd,J=10.6,4.1Hz,2H),3.39(t,J=11.0Hz,3H),3.31(s,3H),2.10(s ,6H),1.67-1.42(m,5H),1.32-1.26(m,2H),1.23(s,1H),0.82-0.75(m,2H). MS(ESI)m / z[M+H] + : 499.28.

[0524] Example 90: 5'-Methyl-2'-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-8'-phenyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0525]

[0526] The synthesis of the compound in Example 90 was carried out by a method similar to that described in Example 85, except that in step 6 of Example 85, 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine, and the remaining steps were the same as in Example 85. 1 H NMR (500MHz, DMSO-d6) δ8.92(s,1H),7.90(s,1H),7.57-7.46(m,3H),7.36-7.30(m,2H),7.00(d,J=2.3Hz,1H),6.95(dd,J=8.3,2.3Hz,1H ),6.68(d,J=8.3Hz,1H),3.31(s,4H),3.07(s,2H),2.63(t,J=6.0Hz,2H),2.32(s,3H),1.31-1.25(m,2H),1.23(s,1H),0.81-0.75(m,2H). MS(ESI)m / z[M+H] + :427.22.

[0527] Example 91: 2'-((2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5'-methyl-8'-phenyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0528]

[0529] The synthesis of the compound in Example 91 was carried out by a procedure similar to that described in Example 85, except that in step 6 of Example 85, 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 2-acetyl-7-amino-1,2,3,4-tetrahydroisoquinoline, and the remaining steps were the same as in Example 85. 1 H NMR(500MHz,DMSO-d6)δ8.99(d,J=24.2Hz,1H),7.91(d,J=4.3Hz,1H),7.60-7.50(m,3H) ,7.38-7.31(m,2H),7.11(d,J=10.5Hz,1H),7.05-6.98(m,1H),6.79-6.74(m,1H),4.20( d,J=4.8Hz,2H),3.55(dt,J=9.6,6.0Hz,2H),2.67(t,J=5.9Hz,1H),2.56(t,J=5.9Hz,1H ), 2.09 (s, 1H), 2.06 (s, 1H), 1.37-1.27 (m, 3H), 1.24 (d, J = 4.2Hz, 3H), 0.89-0.72 (m, 2H). MS(ESI)m / z[M+H] + :455.22.

[0530] Example 92: 2'-((2-isopropyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5'-methyl-8'-phenyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0531]

[0532] The synthesis of the compound in Example 92 was carried out by a method similar to that described in Example 85, except that in step 6 of Example 85, 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 2-isopropyl-1,2,3,4-tetrahydroisoquinoline-7-amine, and the remaining steps were the same as in Example 85. 1H NMR(500MHz,DMSO-d6)δ8.90(s,1H),7.91(s,1H),7.61-7.44(m,3H),7.37-7.31(m,2H),7.04-7.00(m,1H),6.94(d,J=8.3Hz,1H),6. 68(d,J=8.3Hz,1H),3.22(s,2H),2.86(s,1H),2.60(s,3H),1.30-1.26(m,2H),1.24(s,1H),1.07(d,J=6.5Hz,6H),0.80-0.74(m,2H). MS(ESI)m / z[M+H] + : 455.25.

[0533] Example 93: 2'-((2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5'-methyl-8'-phenyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0534]

[0535] The synthesis of the compound in Example 93 was carried out by steps similar to those described in Examples 85 and 28, except that in step 1 of Example 28, 2-bromoethane-1-ol was used instead of 2-iodopropane, and in step 6 of Example 85, 3-((dimethylamino)methyl)-4-morpholinoaniline was used instead of 2-(7-amino-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-ol. The remaining steps were the same as in Examples 85 and 28. 1 H NMR(500MHz,DMSO-d6)δ8.91(s,1H),7.90(s,1H),7.55(t,J=7.5Hz,2H),7.49(t ,J=7.3Hz,1H),7.33(d,J=7.3Hz,2H),6.99(s,1H),6.95(d,J=8.4Hz,1H),6.67(d ,J=8.3Hz,1H),4.47(t,J=5.4Hz,1H),3.59(q,J=6.0Hz,2H),3.31(s,3H),3.17( s,2H),2.60(s,4H),2.53(t,J=6.0Hz,2H),1.29-1.27(m,2H),0.78-0.76(m,2H). MS(ESI)m / z[M+H] + : 457.23.

[0536] Example 94: 2'-((2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5'-methyl-8'-phenyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0537]

[0538] The synthesis of the compound in Example 94 was carried out by steps similar to those described in Examples 85 and 28, except that in step 1 of Example 28, 1-bromo-2-methoxyethane was used instead of 2-iodopropane, and in step 6 of Example 85, 2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-amine was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Examples 85 and 28. 1 H NMR(500MHz,DMSO-d6)δ8.90(s,1H),7.90(s,1H),7.60-7.45(m,3H),7.36-7.30(m,2H),7.01-6.94(m,2H),6.67(d,J=8.3Hz,1H ), 3.53(t,J=6.1Hz,3H),3.29(s,4H),3.26(s,1H),3.21(s,1H),2.62(s,6H),1.31-1.25(m,2H),1.23(s,1H),0.81-0.75(m,2H). MS(ESI)m / z[M+H] + : 471.25.

[0539] Example 95: 2'-((2-(3-hydroxypropyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5'-methyl-8'-phenyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0540]

[0541] The synthesis of the compound in Example 95 was carried out by steps similar to those described in Examples 85 and 28, except that in step 1 of Example 28, 2-iodopropane was replaced with 3-bromoprop-1-ol, and in step 6 of Example 85, 3-(7-amino-3,4-dihydroisoquinoline-2(1H)-yl)prop-1-ol was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Examples 85 and 28. 1H NMR(500MHz,DMSO-d6)δ8.90(s,1H),7.90(s,1H),7.56-7.47(m,3H),7.34(d,J=7.3Hz ,2H),7.00(s,1H),6.94(dd,J=8.3,2.2Hz,1H),6.68(d,J=8.3Hz,1H),4.52(s,1H),3.5 0(t,J=6.3Hz,2H),3.31(s,3H),3.11(s,2H),2.61(t,J=5.8Hz,2H),2.53(t,J=5.9Hz,2 H), 2.47 (d, J = 7.2Hz, 2H), 1.68 (p, J = 6.6Hz, 2H), 1.29-1.27 (m, 2H), 0.79-0.76 (m, 2H). MS(ESI)m / z[M+H] + : 471.25.

[0542] Example 96: 5'-Methyl-8'-phenyl-2'-((2-(3,3,3-trifluoropropyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5',8'-dihydro-6'-spiro[cyclopropane-7'-pterin]-6'-one

[0543]

[0544] The synthesis of the compound in Example 96 was carried out by steps similar to those described in Examples 85 and 28, except that in step 1 of Example 28, 1-iodo-3,3,3-trifluoropropane was used instead of 2-iodopropane, and in step 6 of Example 85, 2-(3,3,3-trifluoropropyl)-1,2,3,4-tetrahydroisoquinoline-7-amine was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Examples 85 and 28. 1 H NMR (500MHz, DMSO-d6) δ8.92(s,1H),7.90(s,1H),7.54(t,J=7.6Hz,2H),7.45(t,J=7.4Hz,1H),7.34(d,J=7.3Hz,1H),7.01-6.97(m ,2H),6.68(d,J=8.3Hz,1H),3.31(s,3H),3.19(s,2H),2.68-2.65(m,2H),2.61-2.53(m,6H),1.29-1.27(m,2H),0.79-0.76(m,2H). MS(ESI)m / z[M+H] + : 509.22.

[0545] Example 97: 2'-((2-(2-fluoroethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5'-methyl-8'-phenyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0546]

[0547] The synthesis of the compound in Example 97 was carried out by steps similar to those described in Examples 85 and 28, except that in step 1 of Example 28, 1-fluoro-2-iodoethane was used instead of 2-iodopropane, and in step 6 of Example 85, 2-(2-fluoroethyl)-1,2,3,4-tetrahydroisoquinoline-7-amine was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Examples 85 and 28. 1 H NMR(500MHz,DMSO-d6)δ8.91(s,1H),7.90(s,1H),7.54(t,J=7.5Hz,2H),7.48(t, J=7.3Hz,1H),7.33(d,J=7.4Hz,2H),6.99-6.96(m,2H),6.68(d,J=8.3Hz,1H),4.6 7(t,J=4.9Hz,1H),4.57(t,J=4.9Hz,1H),3.31(s,3H),3.22(s,2H),2.79(t,J=4.9 Hz, 1H), 2.74 (t, J = 4.9Hz, 1H), 2.63 (s, 4H), 1.29-1.27 (m, 2H), 0.79-0.77 (m, 2H). MS(ESI)m / z[M+H] + : 459.23.

[0548] Example 98: 5'-Methyl-2'-((3-(1-methyl-1H-pyrazol-5-yl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-8'-phenyl-5',8'-dihydro-6'-spiro[cyclopropane-7'-pterin]-6'-one

[0549]

[0550] The synthesis of the compound in Example 98 was carried out by a method similar to that described in Examples 85 and 40, except that in step 6 of Example 85, 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 3-(1-methyl-1H-pyrazol-5-yl)-4-(4-methylpiperazin-1-yl)aniline; the remaining steps were the same as in Examples 85 and 40. MS (ESI) m / z [M+H] + : 536.28.

[0551] Example 99: 5'-Methyl-2'-((4-(4-methylpiperazin-1-yl)-3-(1H-pyrazol-5-yl)phenyl)amino)-8'-phenyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0552]

[0553] The synthesis of the compound in Example 99 was carried out by steps similar to those described in Examples 85 and 40, except that in step 2 of Example 40, 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole was replaced with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole, and in step 6 of Example 85, 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 4-(4-methylpiperazin-1-yl)-3-(1H-pyrazole-5-yl)aniline. The remaining steps were the same as in Examples 85 and 40. 1 H NMR(500MHz,DMSO-d6)δ12.72(s,1H),8.86(s,1H),7.90(s,1H),7.68-7.42(m,5H),7.31(d,J=6.8Hz,2H),7.2 6(d,J=7.8Hz,1H),6.68(s,1H),3.31(s,3H),2.70(s,4H),2.28(s,3H),1.31-1.28(m,2H),0.80-0.78(m,2H). MS(ESI)m / z[M+H] + : 522.27.

[0554] Example 100: 2'-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-8'-(4-fluorophenyl)-5-methyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0555]

[0556] The synthesis of the compound in Example 100 was carried out by a method similar to that described in Example 85, except that iodobenzene was replaced with 4-fluoroiodobenzene in step 1 of Example 85, and 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline in step 6 of Example 85, and the remaining steps were the same as in Example 85. 1HNMR(500MHz,DMSO-d6)δ8.82(s,1H),7.88(s,1H),7.39-7.33(m,4H),7.21-7.20(m,2H),6.67(d,J=8.8Hz,1H),3. 31(s,3H),3.25(s,2H),2.79(s,4H),2.44(s,4H),2.22(s,3H),2.12(s,6H),1.31-1.28(m,2H),0.81-0.78(m,2H). MS(ESI)m / z[M+H] + : 531.29.

[0557] Example 101: 2'-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-8'-(4-fluorophenyl)-5'-methyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0558]

[0559] The synthesis of the compound in Example 101 was carried out through a procedure similar to that described in Example 85, except that iodobenzene was replaced with 4-fluoroiodobenzene in step 1 of Example 85, while the remaining steps were the same as in Example 85. MS (ESI) m / z [M+H] + 518.26.

[0560] Example 102: 2'-((3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-8'-(4-fluorophenyl)-5'-methyl-5',8'-dihydro-6'-pyran[cyclopropane-7'-pterin]-6'-one

[0561]

[0562] The synthesis of the compound in Example 102 was carried out by steps similar to those described in Examples 85 and 6, except that iodobenzene was replaced with 4-fluoroiodobenzene in step 1 of Example 85, and 3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline in step 6 of Example 85. The remaining steps were the same as those in Examples 85 and 6. 1H NMR (500MHz, DMSO-d6) δ8.87(s,1H),7.90(s,1H),7.41-7.33(m,4H),7.19(dd,J=8.4,2.4Hz,1H),7.10(s,1H),6.84(d,J=8.5Hz,1H),3.92(dd,J=10 .5,4.2Hz,2H),3.38(td,J=11.5,2.4Hz,2H),3.12(s,2H),3.06-2.99(m,1 H),2.07(s,6H),1.61-1.50(m,4H),1.31-1.28(m,2H),0.81-0.78(m,2H). MS(ESI)m / z[M+H] + : 517.27.

[0563] Example 103: 8'-(4-fluorophenyl)-5'-methyl-2'-((4-(4-methylpiperazin-1-yl)-3-(1H-pyrazol-5-yl)phenyl)amino)-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0564]

[0565] The synthesis of the compound in Example 103 was carried out by steps similar to those described in Examples 85 and 40, except that in step 1 of Example 85, iodobenzene was replaced with 4-fluoroiodobenzene; in step 2 of Example 40, 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole was replaced with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole; and in step 6 of Example 85, 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 4-(4-methylpiperazin-1-yl)-3-(1H-pyrazole-5-yl)aniline. The remaining steps were the same as in Examples 85 and 40. 1 H NMR(500MHz,DMSO-d6)δ12.74(s,1H),8.90(s,1H),7.90(s,1H),7.72-7.54(m,2H),7.38-7.35(m,2H),7. 26-7.21(m,3H),6.85-6.54(m,2H),2.76-2.63(m,7H),2.40(s,3H),1.32-1.29(m,2H),0.81-0.78(m,2H). MS(ESI)m / z[M+H] + 540.26.

[0566] Example 104: 8'-(4-fluorophenyl)-5'-methyl-2'-((4-morpholin-3-(1H-pyrazol-5-yl)phenyl)amino)-5',8'-dihydro-6'-spiro[cyclopropane-7'-pterin]-6'-one

[0567]

[0568] The synthesis of the compound in Example 104 was carried out by steps similar to those described in Examples 85 and 40, except that in step 1 of Example 85, iodobenzene was replaced with 4-fluoroiodobenzene; in step 1 of Example 40, 1-methylpiperazine was replaced with morpholine; in step 2 of Example 40, 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole was replaced with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole was replaced with 4-morpholine-3-(1H-pyrazole-5-yl)aniline; and in step 6 of Example 85, 3-((dimethylamino)methyl)-4-morpholineaniline was replaced with 4-morpholine-3-(1H-pyrazole-5-yl)aniline. The remaining steps were the same as in Examples 85 and 40. 1 H NMR(500MHz,DMSO-d6)δ12.72(s,1H),8.88(s,1H),7.90(s,1H),7.75-7.34(m,4H),7.29-7.1 9(m,3H),6.90-6.51(m,2H),3.64(s,4H),2.66(s,4H),1.31-1.29(m,2H),0.81-0.78(m,2H). MS(ESI)m / z[M+H] + : 527.23.

[0569] Example 105: 8'-(4-fluorophenyl)-5'-methyl-2'-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0570]

[0571] The synthesis of the compound in Example 105 was carried out by a method similar to that described in Example 85, except that iodobenzene was replaced with 4-fluoroiodobenzene in step 1 of Example 85, and 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine in step 6 of Example 85, and the remaining steps were the same as in Example 85. 1H NMR (500MHz, DMSO-d6) δ8.94(s,1H),7.90(s,1H),7.42-7.35(m,4H),7.00(s,1H),6.92(dd,J=8.3,2.3Hz,1H),6.73(d,J= 8.3Hz,1H),3.04(s,2H),2.63(t,J=5.9Hz,2H),2.47(t,J=5.9Hz,2H),2.31(s,3H),1.30-1.28(m,2H),0.80-0.77(m,2H). MS(ESI)m / z[M+H] + :445.21.

[0572] Example 106: 8'-(4-fluorophenyl)-2'-((2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5'-methyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0573]

[0574] The synthesis of the compound in Example 106 was carried out by steps similar to those described in Examples 85 and 28, except that in step 1 of Example 28, 1-bromo-2-methoxyethane was used instead of 2-iodopropane, in step 1 of Example 85, 4-fluoroiodobenzene was used instead of iodobenzene, and in step 6 of Example 85, 2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-amine was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Examples 85 and 28. 1 H NMR(500MHz,DMSO-d6)δ8.93(s,1H),7.90(s,1H),7.42-7.35(m,4H),7.00(s,1H),6.94(dd,J=8.3,2.2Hz,1H),6.71(d, J=8.3Hz,1H),3.51(t,J=5.9Hz,2H),3.28(s,3H),3.18(s,2H),2.62-2.60(m,6H),1.30-1.27(m,2H),0.80-0.77(m,2H). MS(ESI)m / z[M+H] + : 489.24.

[0575] Example 107: 8'-(4-fluorophenyl)-2'-((2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5'-methyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0576]

[0577] The synthesis of the compound in Example 107 was carried out by steps similar to those described in Examples 85 and 28, except that in step 1 of Example 28, 2-bromoethane-1-ol was used instead of 2-iodopropane, in step 1 of Example 85, 4-fluoroiodobenzene was used instead of iodobenzene, and in step 6 of Example 85, 3-((dimethylamino)methyl)-4-morpholinoaniline was used instead of 2-(7-amino-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-ol. The remaining steps were the same as in Examples 85 and 28. 1 H NMR (500MHz, DMSO-d6) δ8.93(s,1H),7.90(s,1H),7.42-7.34(m,4H),6.99(s,1H),6.94(dd,J=8.4,2.2Hz,1H),6.71(d,J=8.3Hz,1H),4.43(t, J=5.4Hz,1H),3.58(q,J=6.0Hz,2H),3.32(s,3H),3.19(s,2H),2.64-259(m,4H),2.53(t,J=6.2Hz,2H),1.30-1.28(m,2H),0.80-0.77(m,2H). MS(ESI)m / z[M+H] + : 475.22.

[0578] Example 108: 8'-(4-fluorophenyl)-2'-((2-(3-hydroxypropyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5'-methyl-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0579]

[0580] The synthesis of the compound in Example 108 was carried out by steps similar to those described in Examples 85 and 28, except that in step 1 of Example 28, 2-iodopropane was replaced with 3-bromopropane-1-ol, in step 1 of Example 85, iodobenzene was replaced with 4-fluoroiodobenzene, and in step 6 of Example 85, 3-(7-amino-3,4-dihydroisoquinoline-2(1H)-yl)propane-1-ol was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Examples 85 and 28. 1H NMR(500MHz,DMSO-d6)δ8.93(s,1H),7.90(s,1H),7.43-7.34(m,4H),7.00(s,1 H),6.94(d,J=8.2Hz,1H),6.71(d,J=8.3Hz,1H),4.48(s,1H),3.49(t,J=6.3Hz, 2H),3.30(s,3H),3.14(s,2H),2.62(t,J=5.9Hz,2H),2.54(t,J=5.8Hz,2H),2.4 7(d,J=7.2Hz,2H),1.67(p,J=6.6Hz,2H),1.31-1.28(m,2H),0.80-0.77(m,2H). MS(ESI)m / z[M+H] + : 489.24.

[0581] Example 109: 2'-((2-(3,3,3-trifluoropropyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-8'-(4-fluorophenyl)-5'-methyl-5',8'-dihydro-6'-spiro[cyclopropane-7'-pterin]-6'-one

[0582]

[0583] The synthesis of the compound in Example 109 was carried out by steps similar to those described in Examples 85 and 28, except that in step 1 of Example 28, 1-iodo-3,3,3-trifluoropropane was used instead of 2-iodopropane, in step 1 of Example 85, 4-fluoroiodobenzene was used instead of iodobenzene, and in step 6 of Example 85, 2-(3,3,3-trifluoropropyl)-1,2,3,4-tetrahydroisoquinoline-7-amine was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Examples 85 and 28. 1 H NMR(500MHz,DMSO-d6)δ8.96(s,1H),7.90(s,1H),7.42-7.34(m,4H),7.00(s,1H),6.94(dd,J=8.3,2.2Hz,1H),6.73(d ,J=8.3Hz,1H),3.31(s,3H),3.18(s,2H),2.72-2.65(m,2H),2.64-2.52(m,6H),1.31-1.28(m,2H),0.80-0.77(m,2H). MS(ESI)m / z[M+H] + : 527.21.

[0584] Example 110: 2'-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5'-methyl-8'-(m-tolyl)-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0585]

[0586] The synthesis of compound 110 in Example 1 was carried out by a procedure similar to that described in Example 85, except that iodobenzene was replaced with 3-methyliodobenzene in step 1 of Example 85, and 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline in step 6 of Example 85. The remaining steps were the same as in Example 85. MS (ESI) m / z [M+H] + : 527.32.

[0587] Example 111: 5'-Methyl-2'-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-8'-(m-tolyl)-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0588]

[0589] The synthesis of the compound in Example 111 was carried out by a method similar to that described in Example 85, except that 3-methyliodobenzene was used instead of iodobenzene in step 1 of Example 85, and 3-((dimethylamino)methyl)-4-morpholinoaniline was used instead of 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine in step 6 of Example 85, with the remaining steps being the same as in Example 85. 1 H NMR(500MHz,DMSO-d6)δ8.90(s,1H),7.89(s,1H),7.42(t,J=7.7Hz,1H),7.30( d,J=7.6Hz,1H),7.15(s,1H),7.11(d,J=8.2Hz,1H),7.00(s,1H),6.96(dd,J=8. 4,2.2Hz,1H),6.69(d,J=8.3Hz,1H),3.03(s,2H),2.62(t,J=5.9Hz,2H),2.47(t ,J=5.8Hz,2H),2.37(s,3H),2.31(s,3H),1.28-1.26(m,2H),0.81-0.78(m,2H). MS(ESI)m / z[M+H] + :441.24.

[0590] Example 112: 5'-Methyl-2'-((1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-8'-(m-tolyl)-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0591]

[0592] The synthesis of the compound in Example 112 was carried out by a method similar to that described in Example 85, except that 3-methyliodobenzene was used instead of iodobenzene in step 1 of Example 85, and 3-((dimethylamino)methyl)-4-morpholinoaniline was used instead of 1,2,3,4-tetrahydroisoquinoline-7-amine in step 6 of Example 85, and the remaining steps were the same as in Example 85. 1 HNMR(500MHz,DMSO-d6)δ8.91(s,1H),7.89(s,1H),7.41(t,J=7.7Hz,1H),7.30(d,J=7.5Hz,1H),7.14(s,1H),7.11(d,J=8.1Hz,1H),7.04-7.0 1(m,2H),6.69(d,J=8.3Hz,1H),3.58(s,2H),2.98(t,J=6.0Hz,2H),2. 60(t,J=6.0Hz,2H),2.36(s,3H),1.29-1.26(m,2H),0.82-0.79(m,2H). MS(ESI)m / z[M+H] + :427.22.

[0593] Example 113: 2'-((2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5'-methyl-8'-(m-tolyl)-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0594]

[0595] The synthesis of compound 113 in Example 1 was carried out by a procedure similar to that described in Example 85, except that iodobenzene was replaced with 3-methyliodobenzene in step 1 of Example 85, and 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 2-acetyl-7-amino-1,2,3,4-tetrahydroisoquinoline in step 6 of Example 85. The remaining steps were the same as in Example 85. MS (ESI) m / z [M+H] + : 469.23.

[0596] Example 114: 2'-((2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5'-methyl-8'-(m-tolyl)-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0597]

[0598] The synthesis of compound 114 in Example 1 was carried out by steps similar to those described in Examples 85 and 28, except that in step 1 of Example 28, 2-bromoethane-1-ol was used instead of 2-iodopropane; in step 1 of Example 85, 3-methyliodobenzene was used instead of iodobenzene; and in step 6 of Example 85, 3-((dimethylamino)methyl)-4-morpholinoaniline was used instead of 2-(7-amino-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-ol. The remaining steps were the same as in Examples 85 and 28. MS (ESI) m / z [M+H] + : 471.25.

[0599] Example 115: 2'-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5'-methyl-8'-(p-tolyl)-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0600]

[0601] The synthesis of the compound in Example 115 was carried out by a procedure similar to that described in Example 85, except that iodobenzene was replaced with 4-methyliodobenzene in step 1 of Example 85, and the remaining steps were the same as in Example 85. 1 H NMR (500MHz, DMSO-d6) δ8.83(s,1H),7.86(s,1H),7.33(d,J=8.1Hz,2H),7.23-7.15(m,4H),6.62(d,J=8.5Hz,1H),3.72-3 .66(m,4H),3.30(s,3H),3.27(s,2H),2.81-2.76(m,4H),2.42(s,3H),2.12(s,6H),1.31-1.25(m,2H),0.83-0.77(m,2H). MS(ESI)m / z[M+H] + : 514.29.

[0602] Example 116: 2'-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-8'-(p-tolyl)-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0603]

[0604] The synthesis of the compound in Example 116 was carried out by a method similar to that described in Example 85, except that iodobenzene was replaced with 4-methyliodobenzene in step 1 of Example 85, and 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline in step 6 of Example 85, and the remaining steps were the same as in Example 85. 1 H NMR (500MHz, DMSO-d6) δ8.82(s,1H),7.85(s,1H),7.32(d,J=8.0Hz,2H),7.18(d,J=8.1Hz,4H),6.60(d,J=8.4Hz,1H) ,3.29(s,5H),2.79(s,4H),2.46(s,3H),2.42(s,4H),2.24(s,3H),2.14(s,6H),1.31-1.22(m,2H),0.83-0.77(m,2H). MS(ESI)m / z[M+H] + : 527.32.

[0605] Example 117: 2'-((3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-5'-methyl-8'-(p-tolyl)-5',8'-dihydro-6'-pyran[cyclopropane-7'-pterin]-6'-one

[0606]

[0607] The synthesis of the compound in Example 117 was carried out by steps similar to those described in Examples 85 and 6, except that iodobenzene was replaced with 4-methyliodobenzene in step 1 of Example 85, and 3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline in step 6 of Example 85, and the remaining steps were the same as in Examples 85 and 6. 1H NMR (500MHz, DMSO-d6) δ8.86(s,1H),7.87(s,1H),7.33(d,J=8.1Hz,2H),7.19(d,J=8.1Hz,3H),7.10(s ,1H),6.78(d,J=8.5Hz,1H),3.95-3.88(m,2H),3.38(t,J=10.3Hz,2H),3.30(s,3H),3.11(s,2H),3.05 -2.96(m,1H),2.43(s,3H),2.07(s,6H),1.55(dt,J=19.7,7.6Hz,4H),1.31-1.22(m,2H),0.83-0.76(m,2H). MS(ESI)m / z[M+H] + : 513.29.

[0608] Example 118: 5'-Methyl-2'-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-8'-(p-tolyl)-5',8'-dihydro-6'-H-spiro[cyclopropane-7'-pterin]-6'-one

[0609]

[0610] The synthesis of the compound in Example 118 was carried out by a method similar to that described in Example 85, except that iodobenzene was replaced with 4-methyliodobenzene in step 1 of Example 85, and 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine in step 6 of Example 85, and the remaining steps were the same as in Example 85. 1 H NMR (500MHz, DMSO-d6) δ8.90(s,1H),7.88(s,1H),7.34(d,J=8.0Hz,2H),7.19(d,J=8.1Hz,2H),7.04(s,1H),6.95(d,J=8.2Hz,1H),6.70(d,J=8 .3Hz,1H),3.30(s,3H),3.07(s,2H),2.64(t,J=5.6Hz,2H),2.51(s,2H) ,2.42(s,3H),2.34(s,3H),1.26(q,J=5.1Hz,2H),0.77(q,J=5.1Hz,2H). MS(ESI)m / z[M+H] + :441.23.

[0611] Example 119: 2'-((2-(2-fluoroethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5-methyl-8'-(p-tolyl)-5',8'-dihydro-6'-spiro[cyclopropane-7'-pterin]-6'-one

[0612]

[0613] The synthesis of the compound in Example 119 was carried out by steps similar to those described in Examples 85 and 28, except that in step 1 of Example 28, 1-fluoro-2-iodoethane was used instead of 2-iodopropane, in step 1 of Example 85, 4-methyliodobenzene was used instead of iodobenzene, and in step 6 of Example 85, 2-(2-fluoroethyl)-1,2,3,4-tetrahydroisoquinoline-7-amine was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Examples 85 and 28. 1 H NMR (500MHz, DMSO-d6) δ8.88(s,1H),7.88(s,1H),7.33(d,J=7.9Hz,2H),7.19(d,J=8 .2Hz,2H),7.05(s,1H),6.98(dd,J=8.2,2.2Hz,1H),6.68(d,J=8.3Hz,1H),4.66(t,J= 4.9Hz,1H),4.56(t,J=4.9Hz,1H),3.30(s,3H),3.26(s,2H),2.79(t,J=5.0Hz,1H),2 .73(t,J=5.0Hz,1H),2.64(s,4H),2.40(s,3H),1.28-1.25(m,2H),0.78-0.75(m,2H). MS(ESI)m / z[M+H] + : 473.23.

[0614] Example 120: 2'-((2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5'-methyl-8'-(p-tolyl)-5',8'-dihydro-6'-spiro[cyclopropane-7'-pterin]-6'-one

[0615]

[0616] The synthesis of the compound in Example 120 was carried out by steps similar to those described in Examples 85 and 28, except that in step 1 of Example 28, 2-bromoethane-1-ol was used instead of 2-iodopropane, in step 1 of Example 85, 4-methyliodobenzene was used instead of iodobenzene, and in step 6 of Example 85, 3-((dimethylamino)methyl)-4-morpholinoaniline was used instead of 2-(7-amino-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-ol. The remaining steps were the same as in Examples 85 and 28. 1 H NMR(500MHz,DMSO-d6)δ8.87(s,1H),7.88(s,1H),7.32(d,J=8.1Hz,2H),7.19( d,J=8.1Hz,2H),7.04(s,1H),6.96(dd,J=8.4,2.2Hz,1H),6.68(d,J=8.3Hz,1H) ,4.46(t,J=5.4Hz,1H),3.57(q,J=6.0Hz,2H),3.30(s,3H),3.19(s,2H),2.61(s ,4H),2.53(t,J=6.3Hz,2H),2.41(s,3H),1.27-1.25(m,2H),0.79-0.74(m,2H). MS(ESI)m / z[M+H] + : 471.25.

[0617] Example 121: 2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7,7-trimethyl-8-phenyl-7,8-dihydropterin-6(5H)-one

[0618]

[0619] The synthesis of the compound in Example 121 was carried out by a method similar to that described in Example 85, except that in step 1 of Example 85, 1-aminocyclopropane-1-carboxylic acid was replaced with 2-aminoisobutyric acid, and in step 6 of Example 85, 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Example 85. 1H NMR(500MHz,DMSO-d6)δ8.80(s,1H),7.93(s,1H),7.55-7.48(m,3H),7.34-7.31(m,2H),7.1-7.15(m,2H),6.5 7(d,J=8.5Hz,1H),3.33(s,3H),3.24(s,2H),2.77(s,4H),2.43(s,4H),2.22(s,3H),2.11(s,6H),1.34(s,6H). MS(ESI)m / z[M+H] + : 515.32.

[0620] Example 122: 5,7,7-Trimethyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-8-phenyl-7,8-dihydropterin-6(5H)-one

[0621]

[0622] The synthesis of the compound in Example 122 was carried out by a method similar to that described in Example 85, except that in step 1 of Example 85, 1-aminocyclopropane-1-carboxylic acid was replaced with 2-aminoisobutyric acid, and in step 6 of Example 85, 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine. The remaining steps were the same as in Example 85. 1 H NMR (500MHz, DMSO-d6) δ8.93(s,1H),7.96(s,1H),7.55(t,J=7.5Hz,2H),7.50(t,J=7.3Hz,1H),7.35(d,J=7.5Hz,2H),6.97(s,1H),6.93( d,J=8.1Hz,1H),6.66(d,J=8.3Hz,1H),3.34(s,3H),3.03(s,2H),2.62(t,J=5.9Hz,2H),2.47(t,J=5.9Hz,2H),2.32(s,3H),1.34(s,6H). MS(ESI)m / z[M+H] + : 429.23.

[0623] Example 123: 5'-Methyl-2'-((3-(1-methyl-1H-pyrazol-5-yl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-8'-phenyl-5',8'-dihydro-6'-spiro[cyclohexane-7'-pterin]-6'-one

[0624]

[0625] The synthesis of the compound in Example 123 was carried out by steps similar to those described in Examples 85 and 40, except that in step 1 of Example 85, 1-amino-1-cyclohexylcarboxylic acid was used instead of 1-aminocyclopropane-1-carboxylic acid, and in step 6 of Example 85, 3-(1-methyl-1H-pyrazol-5-yl)-4-(4-methylpiperazin-1-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Examples 85 and 40. 1 HNMR(500MHz,DMSO-d6)δ9.10(s,1H),7.85(s,1H),7.70(s,2H),7.45(d,J=1.7Hz,1H),7.06(d,J=8.8Hz,1H),6.25(d,J=1.7Hz,1 H),3.68(s,3H),3.22(s,3H),3.10(s,3H),2.71(t,J=4.1Hz,4H),2.25(s,4H),2.16(s,3H),1.81-1.66(m,7H),1.62-1.56(m,3H). MS(ESI)m / z[M+H] + : 578.32.

[0626] Example 124: 5'-Methyl-2'-((3-(1-methyl-1H-pyrazol-5-yl)-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)phenyl)amino)-8'-phenyl-5',8'-dihydro-6'-spiro[cyclohexane-7'-pterin]-6'-one

[0627]

[0628] The synthesis of the compound in Example 124 was carried out by steps similar to those described in Examples 85 and 40, except that in step 1 of Example 85, 1-amino-1-cyclohexylcarboxylic acid was used instead of 1-aminocyclopropane-1-carboxylic acid; in step 1 of Example 40, 1-(2,2,2-trifluoroethyl)piperazine was used instead of 1-methylpiperazine; and in step 6 of Example 85, 3-(1-methyl-1H-pyrazol-5-yl)-4-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Examples 85 and 40. 1H NMR (500MHz, DMSO-d6) δ9.11(s,1H),7.85(s,1H),7.72-7.69(m,2H),7.45(d,J=1.8Hz,1H),7.07(d,J=9.5Hz,1H),6.25(d,J=1.8Hz,1H), 3.68(s,3H),3.22(s,3H),3.14(q,J=10.2Hz,2H),3.10(s,3H),2.72(t,J=4.7Hz,4H),2.52(s,4H),1.82-1.67(m,7H),1.63-1.56(m,3H). MS(ESI)m / z[M+H] + : 646.30.

[0629] Example 125: (S)-5-methyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-7,8,9-10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0630]

[0631] The synthesis of the compound in Example 125 was carried out by a method similar to that described in Example 1, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 8 of Example 1, 3-((dimethylamino)methyl)-4-morpholinoaniline was used instead of 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine. The remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.92(s,1H),7.75(s,1H),7.48(d,J=2.2Hz,1H),7.39(dd,J= 8.4,2.2Hz,1H),6.94(d,J=8.3Hz,1H),4.65(d,J=13.0Hz,1H),4.11(dd,J=12.0,2.8 Hz,1H),3.41(s,2H),3.21(s,3H),2.78-2.71(m,3H),2.56(t,J=5.9Hz,2H),2.32(s, 3H), 2.08-2.04 (m, 1H), 1.88 (d, J = 13.1Hz, 1H), 1.69-1.54 (m, 2H), 1.49-1.42 (m, 1H). MS(ESI)m / z[M+H] + : 379.21.

[0632] Example 126: (S)-2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5-methyl-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0633]

[0634] The synthesis of the compound in Example 126 was carried out by a procedure similar to that described in Example 1, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and the remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.94(s,1H),7.90(d,J=2.6Hz,1H),7.74(s,1H),7.44(dd,J=8.6,2.6 Hz,1H),7.00(d,J=8.7Hz,1H),4.74(d,J=13.1Hz,1H),4.10(dd,J=11.9,2.8Hz,1H),3.71(t,J =4.4Hz,4H),3.43-3.37(m,2H),3.21(s,3H),2.84-2.82(m,4H),2.74(td,J=13.0,2.8Hz,1H), 2.18(s,6H),2.10-2.05(m,1H),1.88(d,J=13.0Hz,1H),1.70-1.54(m,2H),1.50-1.41(m,2H). MS(ESI)m / z[M+H] + : 452.26.

[0635] Example 127: (S)-2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0636]

[0637] The synthesis of the compound in Example 127 was carried out by a procedure similar to that described in Example 1, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 5 of Example 1, methylpiperazine was used instead of morpholine. The remaining steps were the same as in Example 1. 1H NMR(500MHz,DMSO-d6)δ8.91(s,1H),7.89(d,J=2.7Hz,1H),7.74(s,1H),7.41(dd,J=8.7,2.7 Hz,1H),6.97(d,J=8.6Hz,1H),4.74(d,J=13.0Hz,1H),4.10(dd,J=12.0,2.8Hz,1H),3.41-3. 34(m,2H),3.20(s,3H),2.82(s,4H),2.74(td,J=13.0,2.8Hz,1H),2.45(s,4H),2.22(s,3H), 2.17(s,6H),2.09-2.06(m,1H),1.88(d,J=13.0Hz,1H),1.70-1.55(m,2H),1.50-1.41(m,2H). MS(ESI)m / z[M+H] + : 465.30.

[0638] Example 128: (S)-2-((3-((dimethylamino)methyl)-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-methyl-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0639]

[0640] The synthesis of the compound in Example 128 was carried out by steps similar to those described in Examples 1 and 6, except that in step 2 of Example 1, methyl (S)-piperidin-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 2 of Example 6, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,2,3,6-tetrahydropyridine was used instead of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborane. The remaining steps were the same as in Examples 1 and 6. 1H NMR (500MHz, DMSO-d6) δ8.93(s,1H),7.76(d,J=2.5Hz,1H),7.42(dd,J=8.4,2.4Hz,1H),7.10(d,J=8.5Hz,1H),4.72(d,J=11.3Hz,1H),4.10(dd,J=12.0 ,2.8Hz,1H),3.21(s,3H),2.89(d,J=10.8Hz,2H),2.82-2.71(m,2H),2.23(s ,3H),2.15(s,6H),2.10-1.85(m,5H),1.70-1.55(m,7H),1.51-1.40(m,2H). MS(ESI)m / z[M+H] + : 464.30.

[0641] Example 129: (S)-2-((3-((dimethylamino)methyl)-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0642]

[0643] The synthesis of the compound in Example 129 was carried out by a method similar to that described in Example 1, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 8 of Example 1, 3-((dimethylamino)methyl)-5-fluoro-4-(4-methylpiperazin-1-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ9.16(s,1H),7.77(s,1H),7.60(d,J=2.4Hz,1H),7.47(dd,J= 15.7,2.5Hz,1H),4.70(d,J=13.0Hz,1H),4.12(dd,J=11.9,2.9Hz,1H),3.46-3.41(m ,2H),3.21(s,3H),2.95(s,4H),2.76(td,J=12.9,2.8Hz,1H),2.22(s,3H),2.17(s,6 H), 2.11-2.04 (m, 1H), 1.88 (d, J = 13.1Hz, 1H), 1.70-1.55 (m, 2H), 1.50-1.41 (m, 2H). MS(ESI)m / z[M+H] + : 483.29.

[0644] Example 130: (S)-2-((3-((dimethylamino)methyl)-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0645]

[0646] The synthesis of the compound in Example 130 was carried out by a method similar to that described in Example 1, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 8 of Example 1, 3-((dimethylamino)methyl)-5-methyl-4-(4-methylpiperazin-1-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ8.88(s,1H),7.74(s,1H),7.71(d,J=2.7Hz,1H),7.27(d,J=2.7Hz,1H),4. 73(d,J=13.1Hz,1H),4.10(dd,J=11.9,2.6Hz,1H),3.42-3.36(m,2H),3.20(s,3H),3.05(t,J=8.9 Hz,2H),2.93-2.90(m,2H),2.75(td,J=12.9,2.8Hz,1H),2.46(s,2H),2.36-2.34(m,2H),2.23(s, 6H), 2.16 (s, 6H), 2.10-2.06 (m, 1H), 1.88 (d, J = 13.0Hz, 1H), 1.68-1.55 (m, 2H), 1.50-1.42 (m, 2H). MS(ESI)m / z[M+H] + : 479.32.

[0647] Example 131: (S)-N-methyl-3-(7-((5-methyl-6-oxo-6,6a,7,8,9,10-hexahydro-5H-pyrido[2,1-h]pterin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)yl)propionamide

[0648]

[0649] Step 1: Methyl 3-(7-nitro-3,4-dihydroisoquinoline-2(1H)-yl)propionate (A29): 7-nitro-1,2,3,4-tetrahydroisoquinoline (3 g, 16.8 mmol, 1.0 eq) and methyl acrylate (4.34 g, 50.4 mmol, 3.0 eq) were added to a round-bottom flask and dissolved in methanol (30 mL). The reaction mixture was reacted overnight at 60 °C. After the reaction was complete, the solvent was removed from the mixture under reduced pressure, and the residue was purified by pressurized silica gel column chromatography to give compound A29 (3.8 g, 85% yield). MS (ESI) M / Z [M+H] + :265.11.

[0650] Step 2: 3-(7-nitro-3,4-dihydroisoquinoline-2(1H)-yl)propionic acid (A30): Methyl 3-(7-nitro-3,4-dihydroisoquinoline-2(1H)-yl)propionic acid (1 g, 3.8 mmol, 1.0 eq) and lithium hydroxide (910 mg, 38 mmol, 10.0 eq) were added to a round-bottom flask and dissolved in a methanol / tetrahydrofuran / water mixture (5 mL / 5 mL / 5 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the solvent was evaporated under reduced pressure, diluted with water, and the result was neutralized to weakly acidic pH with 1 M hydrochloric acid solution. The resulting solid was filtered and dried to obtain crude product A30, which can be directly used in the next step of the reaction. MS(ESI)M / Z[M+H] + : 251.09.

[0651] Step 3: N-Methyl-3-(7-nitro-3,4-dihydroisoquinoline-2(1H)-yl)propionamide (A31): In a round-bottom flask, add 3-(7-nitro-3,4-dihydroisoquinoline-2(1H)-yl)propionic acid (300 mg, 1.2 mmol, 1.0 eq), methylamine (56 mg, 1.8 mmol, 1.5 eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (684 mg, 1.8 mmol, 1.5 eq), and N,N-diisopropylethylamine (DIEA) (619 mg, 4.8 mmol, 4.0 eq), dissolved in N,N-dimethylformamide (10 mL). The system is stirred overnight at room temperature. After the reaction is complete, quench with water, extract with ethyl acetate, wash the organic phase with water and saturated brine respectively, and dry with anhydrous sodium sulfate. The organic phase was filtered, concentrated, and purified by pressurized silica gel column chromatography to give compound A31 (211 mg, yield 67%). MS (ESI) M / Z [M+H) + : 264.12.

[0652] Step 4: 3-(7-amino-3,4-dihydroisoquinoline-2(1H)-yl)-N-methylpropionamide (A32): In a round-bottom flask, add N-methyl-3-(7-nitro-3,4-dihydroisoquinoline-2(1H)-yl)propionamide (500 mg, 1.9 mmol, 1.0 eq), 10% reducing palladium on carbon (50 mg), dissolved in methanol (10 mL). The reaction system was reacted at room temperature under a hydrogen atmosphere for 2 hours. After the reaction, the mixture was filtered through diatomaceous earth, concentrated, and purified by pressurized silica gel column chromatography to obtain compound A32 (358 mg, yield 81%). MS (ESI) M / Z [M+H] + :234.15.

[0653]

[0654] The synthesis of compound 131 in Example 1 was carried out by the steps described above for A32 and similar to those in Example 1, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine. The remaining steps were the same as in Example 1 and this Example. 1 H NMR(500MHz,DMSO-d6)δ8.95(s,1H),7.87(s,1H),7.76(s,1H),7.50(s,1H),7.41(d,J= 8.4Hz,1H),6.95(d,J=8.3Hz,1H),4.65(d,J=13.0Hz,1H),4.12(dd,J=12.0,2.8Hz,1H) ,3.59-3.46(m,6H),3.21(s,3H),2.79-2.64(m,7H),2.57(d,J=4.6Hz,3H),2.35(s,2H) ,2.06(d,J=13.2Hz,1H),1.88(d,J=13.3Hz,1H),1.72-1.55(m,2H),1.50-1.42(m,2H). MS(ESI)m / z[M+H] + : 450.26.

[0655] Example 132: (S)-N-cyclopropyl-3-(7-((5-methyl-6-oxo-6,6a,7,8,9,10-hexahydro-5H-pyrido[2,1-h]pterin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)propionamide

[0656]

[0657] The synthesis of the compound in Example 132 was carried out through steps similar to those described in Examples 1 and 131, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 3 of Example 131, cyclopropylamine was used instead of methylamine. The remaining steps were the same as in Examples 1 and 131. MS (ESI) m / z [M+H] + : 476.27.

[0658] Example 133: (S)-5-methyl-2-((3-(1-methyl-1H-pyrazol-4-yl)-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)phenyl)amino)-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0659]

[0660] The synthesis of the compound in Example 133 was carried out by steps similar to those described in Examples 1 and 40, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, in step 1 of Example 40, 1-(2,2,2-trifluoroethyl)piperazine was used instead of 1-methylpiperazine, and in step 8 of Example 1, 3-(1-methyl-1H-pyrazol-4-yl)-4-(4-(2,2,2-trifluoroethyl)piperazine-1-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Examples 1 and 40. 1 H NMR (500MHz, DMSO-d6) δ9.07 (s, 1H), 7.75 (s, 1H), 7.64 (dd, J = 8.8, 2.6Hz, 1H), 7. 45(d,J=1.8Hz,1H),7.06(d,J=8.8Hz,1H),6.23(d,J=1.8Hz,1H),4.62(d,J=12.9 Hz,1H),4.10(dd,J=11.9,2.8Hz,1H),3.67(s,3H),3.19-3.11(m,5H),2.75-2.69 (m,5H),2.52(s,3H),2.06(d,J=12.7Hz,1H),1.86(d,J=12.7Hz,1H),1.62-1.54(m 2H),1.48-1.39(m,2H). MS(ESI)m / z[M+H] + : 556.27.

[0661] Example 134: (S)-2-((4-(4-(cyclopropanecarbonyl)piperazin-1-yl)-3-(1-methyl-1H-pyrazole-4-yl)phenyl)amino)-5-methyl-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0662]

[0663] The synthesis of the compound in Example 134 was carried out by steps similar to those described in Examples 1 and 40, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenyl glycine, in step 1 of Example 40, cyclopropyl (piperazin-1-yl) methyl ketone was used instead of 1-methylpiperazine, and in step 8 of Example 1, (4-(4-amino-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)(cyclopropyl) methyl ketone was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Examples 1 and 40. 1 H NMR(500MHz,DMSO-d6)δ9.10(s,1H),7.77(d,J=2.6Hz,1H),7.75(s,1H),7.66(dd,J=8.8,2.6Hz,1H),7.48 (d,J=1.8Hz,1H),7.06(d,J=8.8Hz,1H),6.27(d,J=1.8Hz,1H),4.62(d,J=13.1Hz,1H),4.10(dd,J=12.0,2 .8Hz,1H),3.70(s,3H),3.55(s,2H),3.40-3.35(m,2H),3.20(s,3H),2.75-2.70(m,5H),2.06(d,J=12.8Hz ,1H),1.97-1.91(m,1H),1.87(d,J=12.7Hz,1H),1.64-1.54(m,2H),1.49-1.37(m,2H),0.72-0.66(m,4H). MS(ESI)m / z[M+H] + 542.29.

[0664] Example 135: (S)-2-((8-((dimethylamino)methyl)isocyano-6-yl)amino)-5-methyl-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0665]

[0666] The synthesis of the compound in Example 135 was carried out by a method similar to that described in Example 1, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 8 of Example 1, 3-((dimethylamino)methyl)benzodihydroisopyran-6-amine was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.95(s,1H),7.76(s,1H),7.54(d,J=2.2Hz,1H),7.35(d,J=2 .2Hz,1H),4.71-4.67(m,3H),4.11(dd,J=11.9,2.8Hz,1H),3.82(t,J=5.7Hz,2H),3. 21(s,3H),3.17(d,J=3.1Hz,2H),2.80-2.70(m,3H),2.12(s,6H),2.09-2.04(m,1H), 1.88(d,J=13.1Hz,1H), 1.67(d,J=13.4Hz,1H), 1.63-1.56(m,1H), 1.52-1.42(m,2H). MS(ESI)m / z[M+H] + : 423.25.

[0667] Example 136: (S)-2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-methyl-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0668]

[0669] The synthesis of compound 136 in Example 1 was carried out by steps similar to those described in Example 1 and Example 40, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenyl glycine, in step 1 of Example 40, 2-(piperazin-1-yl)ethane-1-ol was used instead of 1-methylpiperazine, and in step 8 of Example 1, 2-(4-(4-amino-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethane-1-ol was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Example 1 and Example 40. 1H NMR (500MHz, DMSO-d6) δ9.05 (s, 1H), 7.76-7.71 (m, 2H), 7.64 (dd, J = 8.8, 2.7Hz, 1H), 7.45 (d, J = 1.7 Hz,1H),7.04(d,J=8.8Hz,1H),6.23(d,J=1.8Hz,1H),4.62(d,J=12.5Hz,1H),4.34(t,J=5.3Hz,1H) ,4.10(dd,J=11.9,2.9Hz,1H),3.67(s,3H),3.46(q,J=6.0Hz,2H),3.19(s,3H),2.80-2.67(m,5H), 2.36-2.32(m,6H),2.07-2.05(m,1H),1.86(d,J=12.7Hz,1H),1.62-1.54(m,2H),1.46-1.38(m,2H). MS(ESI)m / z[M+H] + : 518.29.

[0670] Example 137: (S)-2-((4-(4-hydroxypiperidin-1-yl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-methyl-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0671]

[0672] The synthesis of the compound in Example 137 was carried out by steps similar to those described in Examples 1 and 40, except that in step 2 of Example 1, methyl (S)-piperidin-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, in step 1 of Example 40, piperidine-4-ol was used instead of 1-methylpiperazine, and in step 8 of Example 1, 1-(4-amino-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-ol was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Examples 1 and 40. 1H NMR (500MHz, DMSO-d6) δ9.04(s,1H),7.74(s,1H),7.72(d,J=2.6Hz,1H),7.62(dd,J=8.8,2.7Hz,1H),7.46(d,J=1.8 Hz,1H),7.04(d,J=8.9Hz,1H),6.23(d,J=1.8Hz,1H),4.62(d,J=11.4Hz,1H),4.55(d,J=4.4Hz,1H),4.10(dd,J=12. 0,2.9Hz,1H),3.67(s,3H),3.47-3.41(m,1H),3.19(s,3H),2.91-2.87(m,2H),2.72(td,J=13.0,2.6Hz,1H),2.54-2 .51(m,2H),2.06(d,J=12.4Hz,1H),1.86(d,J=12.8Hz,1H),1.66-1.51(m,4H),1.49-1.35(m,2H),1.28-1.24(m,2H). MS(ESI)m / z[M+H] + : 489.26.

[0673] Example 138: (S)-5-methyl-2-((3-((methylamino)methyl)-4-morpholinylphenyl)amino)-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0674]

[0675] The synthesis of the compound in Example 138 was carried out in a manner similar to that described in Example 1, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 6 of Example 1, methylamine was used instead of dimethylamine. The remaining steps were the same as in Example 1. 1H NMR(500MHz,DMSO-d6)δ8.93(s,1H),7.82(d,J=2.6Hz,1H),7.74(s,1H),7.48(dd,J=8.7 ,2.6Hz,1H),7.01(d,J=8.6Hz,1H),4.72(d,J=13.3Hz,1H),4.10(dd,J=11.9,2.8Hz,1H), 3.72-3.68(m,6H),3.21(s,3H),2.81(t,J=4.5Hz,4H),2.74(td,J=12.9,2.8Hz,1H),2.34 (s,3H),2.09-2.06(m,1H),1.88(d,J=13.1Hz,1H),1.70-1.56(m,2H),1.50-1.43(m,2H). MS(ESI)m / z[M+H] + : 438.25.

[0676] Example 139: (S)-N,N-dimethyl-5-((5-methyl-6-oxo-6,6a,7,8,9,10-hexahydro-5H-pyrido[2,1-h]pterin-2-yl)amino)-2-(4-methylpiperazin-1-yl)benzamide

[0677]

[0678] The synthesis of the compound in Example 139 was carried out by a procedure similar to that described in Example 1, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 8 of Example 1, 3-((dimethylamino)methyl)-4-morpholinoaniline was used instead of 5-amino-N,N-dimethyl-2-(4-methylpiperazin-1-yl)benzamide. The remaining steps were the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ9.03 (s, 1H), 7.76 (s, 1H), 7.61 (d, J = 7.5Hz, 2H), 6.96 (d ,J=9.0Hz,1H),4.64(d,J=12.6Hz,1H),4.11(d,J=11.8Hz,1H),3.20(s,3H),3.0 5-3.01(m,2H),2.97(s,3H),2.76-2.70(s,6H),2.37(s,4H),2.20(s,3H),2.07( d,J=12.7Hz,1H),1.87(d,J=13.1Hz,1H),1.66-1.55(m,2H),1.50-1.40(m,2H). MS(ESI)m / z[M+H] + : 479.28.

[0679] Example 140: (6aS)-2-((3-(1-(dimethylamino)ethyl)-4-morpholinophenyl)amino)-5-methyl-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0680]

[0681] Step 1: 1-(2-morpholino-5-nitrophenyl)ethane-1-one (A33): In a round-bottom flask, add 1-(2-fluoro-5-nitrophenyl)ethane-1-one (1 g, 5.5 mmol, 1.0 eq), morpholine (575 mg, 6.6 mmol, 1.2 eq), and potassium carbonate (1.13 g, 8.2 mmol, 1.5 eq), dissolved in N,N-dimethylformamide (20 mL). The reaction mixture was stirred overnight at 100 °C. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and purified by pressurized silica gel column chromatography to give compound A33 (1.05 g, 77% yield). MS (ESI) M / Z [M+H] + : 251.09.

[0682] Step 2: N,N-Dimethyl-1-(2-morpholino-5-nitrophenyl)ethane-1-amine (A34): In a round-bottom flask, 1-(2-morpholino-5-nitrophenyl)ethane-1-one (300 mg, 1.2 mmol, 1.0 eq) dissolved in dichloromethane (10 mL) was added. Then, a THF solution of (2 M) dimethylamine (1.2 mL, 2.4 mmol, 2.0 eq) and tetraisopropyl titanate (341 mg, 1.2 mmol, 1.0 eq) were added, and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (151 mg, 2.4 mmol, 2.0 eq) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered, concentrated, and purified by pressurized silica gel column chromatography to give compound A34 (200 mg, 59% yield). MS (ESI) M / Z [M+H] + : 280.15.

[0683] Step 3: 3-(1-(dimethylamino)ethyl)-4-morpholinoaniline (A35): In a round-bottom flask, add N,N-dimethyl-1-(2-morpholino-5-nitrophenyl)ethane-1-amine (500 mg, 1.8 mmol, 1.0 eq), 10% reducing palladium on carbon (50 mg), dissolved in methanol (10 mL). The reaction system is incubated at room temperature under a hydrogen atmosphere for 2 hours. After the reaction, the mixture is filtered through diatomaceous earth, concentrated, and purified by pressurized silica gel column chromatography to obtain compound A35 (397 mg, yield 89%). MS (ESI) M / Z [M+H] + : 250.18.

[0684]

[0685] The synthesis of compound 140 in Example 1 was carried out by the steps described above for A35 and similar to those in Example 1, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and the remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.93(d,J=2.1Hz,1H),7.95(dd,J=13.2,2.7Hz,1H),7.74(s,1H ),7.39(dd,J=8.7,2.6Hz,1H),7.06(d,J=8.7Hz,1H),4.78(d,J=13.4Hz,1H),4.10(dt, J=11.8,2.1Hz,1H),3.92(s,1H),3.72-3.68(m,4H),3.21(s,3H),2.94-2.63(m,5H),2. 12-2.07(m,7H),1.89(d,J=13.2Hz,1H),1.68-1.43(m,4H),1.20(dd,J=6.8,2.0Hz,3H). MS(ESI)m / z[M+H] + : 466.28.

[0686] Example 141: (6aS)-2-((3-(1-(cyclopropyl(methyl)amino)ethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0687]

[0688] The synthesis of the compound in Example 141 was carried out by steps similar to those described in Examples 1 and 140, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, in step 1 of Example 140, 4-methylpiperazine was used instead of morpholine, and in step 2 of Example 140, N-methylcyclopropaneamine was used instead of dimethylamine. The remaining steps were the same as in Examples 1 and 140. 1 H NMR (500MHz, DMSO-d6) δ8.87(s,1H),7.73(s,1H),7.71(d,J=2.7Hz,1H),7.47(dd,J=8.7,2.7Hz,1H),7.00(d,J= 8.7Hz,1H),4.73-4.64(m,1H),4.09(dd,J=11.9,2.9Hz,1H),3.63(d,J=5.2Hz,2H),3.20(s,3H),2.79(t,J=4.8H z,4H),2.73(td,J=13.0,2.9Hz,1H),2.45(s,3H),2.23(s,3H),2.16(s,3H),2.07(dd,J=13.0,3.6Hz,1H),1.88( d,J=13.0Hz,1H),1.77-1.73(m,1H),1.77-1.55(m,2H),1.49-1.41(m,2H),0.48-0.44(m,2H),0.35-0.32(m,2H). MS(ESI)m / z[M+H] + : 505.33.

[0689] Example 142: (S)-5-methyl-2-((3-(1-methyl-1H-pyrazol-5-yl)-5-(4-methylpiperazin-1-yl)phenyl)amino)-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0690]

[0691] The synthesis of the compound in Example 142 was carried out by steps similar to those described in Examples 1 and 40, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine; in step 1 of Example 40, 1-bromo-3-fluoro-5-nitrobenzene was used instead of 2-bromo-1-fluoro-4-nitrobenzene; and in step 8 of Example 1, 3-(1-methyl-1H-pyrazol-5-yl)-5-(4-methylpiperazin-1-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Examples 1 and 40. 1H NMR (500MHz, DMSO-d6) δ9.04(s,1H),7.78(s,1H),7.56(t,J=2.1Hz,1H),7.43(d,J=1.8Hz,1H),7. 27(s,1H),6.54(s,1H),6.30(d,J=1.8Hz,1H),4.69(d,J=12.8Hz,1H),4.12(dd,J=11.9,2.7Hz,1H ),3.84(s,3H),3.21(s,3H),3.17-3.16(m,4H),2.77(td,J=13.0,2.4Hz,1H),2.47-2.45(m,4H),2 .23(s,3H),2.08(d,J=13.0Hz,1H),1.89(d,J=12.8Hz,1H),1.64-1.57(m,2H),1.49-1.44(m,2H). MS(ESI)m / z[M+H] + : 488.28.

[0692] Example 143: (S)-5-methyl-2-((4-(4-methylpiperazin-1-yl)-3-(1H-pyrazol-5-yl)phenyl)amino)-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0693]

[0694] The synthesis of compound 143 in Example 1 was carried out by steps similar to those described in Examples 1 and 40, except that in step 2 of Example 1, methyl (S)-piperidin-2-carboxylate hydrochloride was used instead of ethyl phenylglycine; in step 2 of Example 40, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole was used instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole was used instead of 3-methyl-4-morpholinoaniline; and in step 8 of Example 1, 4-(4-methylpiperazin-1-yl)-3-(1H-pyrazole-5-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Examples 1 and 40. MS (ESI) m / z [M+H] + : 474.26.

[0695] Example 144: (S)-5-methyl-2-((3-(4-methylpiperazin-1-yl)-5-(1H-pyrrolo-2-yl)phenyl)amino)-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0696]

[0697] The synthesis of the compound in Example 144 was carried out by steps similar to those described in Examples 1 and 40, except that in step 2 of Example 1, methyl (S)-piperidin-2-carboxylate hydrochloride was used instead of ethyl phenylglycine; in step 1 of Example 40, 1-bromo-3-fluoro-5-nitrobenzene was used instead of 2-bromo-1-fluoro-4-nitrobenzene; in step 2 of Example 40, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole was used instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline; and the remaining steps were the same as in Examples 1 and 40. MS(ESI)m / z[M+H] + : 473.27.

[0698] Example 145: (S)-5-methyl-2-((3-(1-methyl-1H-pyrazol-5-yl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0699]

[0700] The synthesis of the compound in Example 145 was carried out by steps similar to those described in Examples 1 and 40, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 8 of Example 1, 3-(1-methyl-1H-pyrazol-5-yl)-4-(4-methylpiperazin-1-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Examples 1 and 40. 1H NMR (500MHz, DMSO-d6) δ9.06 (s, 1H), 7.76-7.72 (m, 2H), 7.65 (dd, J = 8.8, 2.7Hz, 1H), 7.45 ( d,J=1.9Hz,1H),7.05(d,J=8.8Hz,1H),6.23(d,J=1.8Hz,1H),4.62(d,J=13.5Hz,1H),4.10 (dd,J=11.9,2.8Hz,1H),3.67(s,3H),3.20(s,3H),2.75-2.70(m,5H),2.24(s,4H),2.15(s ,3H),2.06(d,J=12.8Hz,1H),1.86(d,J=12.7Hz,1H),1.64-1.53(m,2H),1.49-1.36(m,2H). MS(ESI)m / z[M+H] + : 488.28.

[0701] Example 146: (S)-5-methyl-2-((3-(1-methyl-1H-pyrazol-5-yl)-4-morpholinophenyl)amino)-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0702]

[0703] The synthesis of compound 146 in Example 1 was carried out by steps similar to those described in Examples 1 and 40, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine; in step 1 of Example 40, morpholine was used instead of 1-methylpiperazine; and in step 8 of Example 1, 3-(1-methyl-1H-pyrazol-5-yl)-4-morpholinoaniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Examples 1 and 40. MS (ESI) m / z [M+H] + : 475.24.

[0704] Example 147: (S)-5-methyl-2-((4-(4-methylpiperazin-1-yl)-3-(pyridin-2-yl)phenyl)amino)-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0705]

[0706] The synthesis of the compound in Example 147 was carried out by steps similar to those described in Examples 1 and 40, except that in step 2 of Example 1, methyl (S)-piperidin-2-carboxylate hydrochloride was used instead of ethyl phenylglycine; in step 2 of Example 40, 2-pyridineboronic acid was used instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole; and in step 8 of Example 1, 4-(4-methylpiperazin-1-yl)-3-(pyridin-2-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Examples 1 and 40. 1 HNMR(500MHz,DMSO-d6)δ9.02(s,1H),8.63-8.62(m,1H),8.14(d,J=2.7Hz,1H),8.04(d,J=7.9Hz,1H),7 .79(td,J=7.7,1.9Hz,1H),7.73(s,1H),7.53(dd,J=8.7,2.7Hz,1H),7.28(ddd,J=7.5,4.8,1.2Hz,1H),7 .01(d,J=8.7Hz,1H),4.77-4.70(m,1H),4.09(dd,J=11.9,2.8Hz,1H),3.20(s,3H),2.77-2.66(m,5H),2. 26(s,4H),2.14(s,3H),2.09-2.04(m,1H),1.86(d,J=12.7Hz,1H),1.62-1.54(m,2H),1.49-1.37(m,2H). MS(ESI)m / z[M+H] + : 485.26.

[0707] Example 148: (S)-5-methyl-2-((3-(1-methyl-1H-pyrrolo-2-yl)-5-(4-methylpiperazin-1-yl)phenyl)amino)-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0708]

[0709] The synthesis of the compound in Example 148 was carried out by steps similar to those described in Examples 1 and 40, except that in step 2 of Example 1, methyl (S)-piperidin-2-carboxylate hydrochloride was used instead of ethyl phenylglycine; in step 1 of Example 40, 1-bromo-3-fluoro-5-nitrobenzene was used instead of 2-bromo-1-fluoro-4-nitrobenzene; in step 2 of Example 40, 1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrrole was used instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline; and the remaining steps were the same as in Examples 1 and 40. 1 H NMR(500MHz,DMSO-d6)δ8.99(s,1H),7.78(s,1H),7.49(s,1H),7.21(s,1H),6.79(t,J=2 .3Hz,1H),6.50(s,1H),6.08(dd,J=3.6,1.8Hz,1H),6.04-6.01(m,1H),4.70(d,J=13.8Hz ,1H),4.13(dd,J=11.9,2.9Hz,1H),3.64(s,3H),3.21(s,6H),2.80-2.70(m,5H),2.40(s, 3H), 2.08 (d, J = 13.1Hz, 1H), 1.89 (d, J = 12.6Hz, 1H), 1.66-1.57 (m, 2H), 1.5-1.43 (m, 2H). MS(ESI)m / z[M+H] + : 487.29.

[0710] Example 149: (S)-5-methyl-2-((3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)amino)-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0711]

[0712] The synthesis of the compound in Example 149 was carried out by a method similar to that described in Example 1, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 8 of Example 1, 3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Example 1. 1H NMR(500MHz,DMSO-d6)δ9.25(s,1H),7.81(s,1H),7.67(s,1H),7.55(s,1H),6. 70(s,1H),4.65(d,J=12.9Hz,1H),4.14(dd,J=12.0,2.9Hz,1H),3.22(s,3H),3 .17(t,J=5.1Hz,4H),2.79(td,J=12.9,2.6Hz,1H),2.47(s,4H),2.24(s,3H),2 .09-2.06(m,1H),1.88(d,J=12.8Hz,1H),1.65-1.56(m,2H),1.51-1.44(m,2H). MS(ESI)m / z[M+H] + : 476.23.

[0713] Example 150: (S)-N-methyl-5-((5-methyl-6-oxo-6,6a,7,8,9,10-hexahydro-5H-pyrido[2,1-h]pterin-2-yl)amino)-2-(4-methylpiperazin-1-yl)benzamide

[0714]

[0715] The synthesis of the compound in Example 150 was carried out by a method similar to that described in Example 1, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 8 of Example 1, 3-((dimethylamino)methyl)-4-morpholinoaniline was used instead of 5-amino-N-methyl-2-(4-methylpiperazin-1-yl)benzamide. The remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ9.52(q,J=4.2Hz,1H),9.11(s,1H),8.30(d,J=2.8Hz,1H),7.75(s,1H),7.7 1(dd,J=8.7,2.8Hz,1H),7.16(d,J=8.8Hz,1H),4.73(d,J=13.2Hz,1H),4.11(dd,J=12.0,2.8Hz,1H) ,3.21(s,3H),2.87-2.83(m,8H),2.74(td,J=13.0,2.8Hz,1H),2.48(s,3H),2.24(s,3H),2.07(d,J =12.8Hz,1H),1.88(d,J=13.1Hz,1H),1.68(d,J=13.3Hz,1H),1.62-1.55(m,1H),1.50-1.41(m,2H). MS(ESI)m / z[M+H] +: 465.27.

[0716] Example 151: (R)-2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5-methyl-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0717]

[0718] The synthesis of the compound in Example 151 was carried out by a procedure similar to that described in Example 1, except that in step 2 of Example 1, methyl (R)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and the remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.94(s,1H),7.90(d,J=2.7Hz,1H),7.74(s,1H),7.45(dd,J=8.7,2.6Hz,1H),7.0 1(d,J=8.7Hz,1H),4.73(ddd,J=11.5,4.4,2.4Hz,1H),4.10(dd,J=11.9,2.8Hz,1H),3.71(t,J=4.4Hz,4H) ,3.43(s,2H),3.21(s,3H),2.83(dd,J=6.1,3.4Hz,4H),2.74(td,J=13.0,2.8Hz,1H),2.20(s,6H),2.08(d d,J=13.2,3.6Hz,1H),1.88(d,J=13.0Hz,1H),1.72-1.53(m,2H),1.45(tdq,J=12.8,8.5,4.4,3.9Hz,2H). MS(ESI)m / z[M+H] + : 452.26.

[0719] Example 152: (R)-2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0720]

[0721] The synthesis of the compound in Example 152 was carried out by a method similar to that described in Example 1, except that in step 2 of Example 1, methyl (S)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 8 of Example 1, 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Example 1.1 H NMR(500MHz,DMSO-d6)δ8.92(s,1H),7.89(d,J=2.6Hz,1H),7.74(s,1H),7.43(dd,J=8.7,2.7Hz ,1H),6.99(d,J=8.6Hz,1H),4.77-4.70(m,1H),4.10(dd,J=11.9,2.8Hz,1H),3.41(s,2H),3.21 (s,3H),2.83(t,J=4.9Hz,4H),2.78-2.69(m,1H),2.47(s,3H),2.24(s,3H),2.19(s,6H),2.11- 2.04(m,1H),1.88(d,J=13.0Hz,1H),1.72-1.54(m,2H),1.45(tdq,J=12.9,8.6,4.5,4.0Hz,2H). MS(ESI)m / z[M+H] + : 465.30.

[0722] Example 153: (R)-5-methyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-7,8,9-10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0723]

[0724] The synthesis of the compound in Example 153 was carried out by a method similar to that described in Example 1, except that in step 2 of Example 1, methyl (R)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 8 of Example 1, 3-((dimethylamino)methyl)-4-morpholinoaniline was used instead of 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine. The remaining steps were the same as in Example 1. 1H NMR (500MHz, DMSO-d6) δ8.93(s,1H),7.75(s,1H),7.48(d,J=2.3Hz,1H),7.39(dd,J=8.4,2.2 Hz,1H),6.95(d,J=8.3Hz,1H),4.65(dq,J=11.7,2.5Hz,1H),4.11(dd,J=12.0,2.8Hz,1H),3.4 2(s,2H),3.20(s,3H),2.79-2.69(m,3H),2.57(t,J=5.9Hz,2H),2.33(s,3H),2.06(dd,J=13. 3,3.2Hz,1H),1.87(d,J=13.2Hz,1H),1.72-1.53(m,2H),1.45(dtt,J=19.1,13.0,6.7Hz,2H). MS(ESI)m / z[M+H] + : 379.21.

[0725] Example 154: (R)-2-((2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5-methyl-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0726]

[0727] The synthesis of the compound in Example 154 was carried out by steps similar to those described in Examples 1 and 28, except that in step 2 of Example 1, methyl (R)-piperidine-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 8 of Example 1, 2-(7-amino-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-ol was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Examples 1 and 28. 1H NMR(500MHz,DMSO-d6)δ8.93(s,1H),7.76(s,1H),7.50(d,J=2.3Hz,1H),7.39(dd,J=8.3,2.3Hz ,1H),6.94(d,J=8.3Hz,1H),4.65(ddd,J=13.3,4.2,2.2Hz,1H),4.49(s,1H),4.11(dd,J=11.9,2 .8Hz,1H),3.62-3.54(m,4H),3.20(s,3H),2.79-2.69(m,5H),2.57(t,J=6.2Hz,2H),2.06(dd,J= 13.3, 3.0Hz, 1H), 1.88 (d, J = 13.1Hz, 1H), 1.71-1.54 (m, 2H), 1.45 (qdd, J = 12.9, 9.3, 5.0Hz, 2H). MS(ESI)m / z[M+H] + : 409.22.

[0728] Example 155: (R)-2-((2-(dimethylamino)methyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)amino)-5-methyl-7,8,9,10-tetrahydro-5H-pyrido[2,1-h]pterin-6(6aH)-one

[0729]

[0730] The synthesis of the compound in Example 155 was carried out by steps similar to those described in Examples 1 and 6, except that in step 2 of Example 1, methyl (R)-piperidin-2-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 2 of Example 6, 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane was used instead of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborane. The remaining steps were the same as in Examples 1 and 6. 1H NMR(500MHz,DMSO-d6)δ9.02(s,1H),7.97(d,J=2.6Hz,1H),7.75(s,1H),7.37(dd,J=8.3,2.4Hz,1H ),6.90(d,J=8.3Hz,1H),5.46(p,J=1.9Hz,1H),4.75(dt,J=12.8,2.7Hz,1H),4.11(dd,J=11.9,2.9 Hz,1H),3.29(s,3H),3.23(s,3H),2.75(td,J=13.0,2.8Hz,1H),2.13(s,6H),2.11(d,J=8.3Hz,3H) ,1.88(d,J=13.0Hz,1H),1.69(ddd,J=12.4,8.8,5.9Hz,4H),1.65-1.54(m,3H),1.52-1.39(m,2H). MS(ESI)m / z[M+H] + : 447.27.

[0731] Example 156: (S)-2-((3-((dimethylamino)methyl)-4-morpholinylphenyl)amino)-5-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pterin-6(5H)-one

[0732]

[0733] The synthesis of the compound in Example 156 was carried out by a procedure similar to that described in Example 1, except that in step 2 of Example 1, methyl morpholine-3-carboxylate hydrochloride was used instead of ethyl phenylglycine, and the remaining steps were the same as in Example 1. 1 HNMR(500MHz,DMSO-d6)δ9.04(s,1H),7.90(d,J=2.6Hz,1H),7.83(s,1H),7.49-7.43(m,1 H),7.01(d,J=8.6Hz,1H),4.40-4.33(m,1H),4.25(dd,J=10.6,3.8Hz,1H),4.18(dd,J=11 .3,3.8Hz,1H),3.96(dd,J=11.6,3.5Hz,1H),3.71(t,J=4.4Hz,4H),3.57-3.47(m,2H),3. 42(s,2H),3.21(s,3H),2.97(td,J=12.8,3.6Hz,1H),2.82(t,J=4.5Hz,4H),2.18(s,6H). MS(ESI)m / z[M+H] + :454.24.

[0734] Example 157: (S)-2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-6a,7,9,10-tetrahydro-[1,4]oxazinro[3,4-h]pterin-6(5H)-one

[0735]

[0736] The synthesis of the compound in Example 157 was carried out by a method similar to that described in Example 1, except that in step 2 of Example 1, methyl morpholine-3-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 8 of Example 1, 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholineaniline, and the remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO)δ9.01(s,1H),7.89(d,J=2.7Hz,1H),7.83(s,1H),7.44(dd,J=8.6,2.7Hz,1 H),6.99(d,J=8.7Hz,1H),4.36(dd,J=13.3,2.5Hz,1H),4.24(dd,J=10.6,3.8Hz,1H),4.18(dd ,J=11.3,3.8Hz,1H),3.96(dd,J=11.5,3.5Hz,1H),3.57-3.47(m,2H),3.40(s,2H),3.21(s,3H ), 2.96(td,J=12.8,3.7Hz,1H),2.82(t,J=4.8Hz,4H),2.46(s,3H),2.23(s,3H),2.18(s,6H). MS(ESI)m / z[M+H] + : 467.28.

[0737] Example 158: (S)-2-((3-((dimethylamino)methyl)-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)amino)-5-methyl-6a,7,9,10-tetrahydro-[1,4]oxazin[3,4-h]pterin-6(5H)-one

[0738]

[0739] The synthesis of compound 158 in Example 1 was carried out by a procedure similar to that described in Example 1, except that in step 2 of Example 1, methyl morpholine-3-carboxylate hydrochloride was used instead of ethyl phenyl glycine, and in step 8 of Example 1, 3-((dimethylamino)methyl)-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholine aniline. The remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ9.02(s,1H),7.91(d,J=2.7Hz,1H),7.82(s,1H),7.39(dd,J=8.7,2.7Hz,1 H),7.03(d,J=8.7Hz,1H),4.37(dd,J=13.5,2.5Hz,1H),4.21(ddd,J=34.0,10.9,3.8Hz,2H),3.96 (dd,J=11.5,3.5Hz,1H),3.58-3.48(m,2H),3.42(s,2H),3.21(s,3H),3.09(s,2H),2.96(td,J=12 .8,3.7Hz,1H),2.92-2.86(m,2H),2.65-2.59(m,2H),2.22(s,3H),2.16(s,6H),1.97-1.87(m,4H). MS(ESI)m / z[M+H] + : 493.29.

[0740] Example 159: (S)-5-methyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pterin-6(5H)-one

[0741]

[0742] The synthesis of the compound in Example 159 was carried out by a method similar to that described in Example 1, except that in step 2 of Example 1, methyl morpholine-3-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 8 of Example 1, 3-((dimethylamino)methyl)-4-morpholine aniline was used instead of 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine. The remaining steps were the same as in Example 1. 1H NMR(500MHz,DMSO-d6)δ9.01(s,1H),7.84(s,1H),7.43(d,J=7.8Hz,2H),6.96( d,J=8.2Hz,1H),4.25(td,J=10.4,3.2Hz,2H),4.17(dd,J=11.3,3.8Hz,1H),3.9 7(dd,J=11.5,3.5Hz,1H),3.56-3.46(m,2H),3.43(s,2H),3.21(s,3H),2.96(td ,J=12.8,3.7Hz,1H),2.73(t,J=5.9Hz,2H),2.57(t,J=5.9Hz,2H),2.33(s,3H). MS(ESI)m / z[M+H] + : 381.19.

[0743] Example 160: (S)-2-((3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-5-methyl-6a,7,9,10-tetrahydro-[1,4]oxazin[3,4-h]pterin-6(5H)-one

[0744]

[0745] The synthesis of the compound in Example 160 was carried out by steps similar to those described in Examples 1 and 6, except that in step 2 of Example 1, methyl morpholine-3-carboxylate hydrochloride was used instead of ethyl phenylglycine, and in step 8 of Example 1, 3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholineaniline. The remaining steps were the same as in Examples 1 and 6. 1H NMR(500MHz,DMSO-d6)δ9.06(s,1H),7.84(s,1H),7.74(d,J=2.5Hz,1H),7.49(dd,J=8.6,2.4Hz,1H), 7.14(d,J=8.5Hz,1H),4.34(dd,J=13.3,2.4Hz,1H),4.25(dd,J=10.6,3.8Hz,1H),4.18(dd,J=11.3,3 .8Hz,1H),3.95(ddd,J=16.0,11.4,3.8Hz,3H),3.57-3.47(m,2H),3.42(td,J=11.6,2.1Hz,2H),3.34 (s,2H),3.22(s,3H),3.12-3.04(m,1H),2.98(td,J=12.8,3.7Hz,1H),2.16(s,6H),1.71-1.54(m,4H). MS(ESI)m / z[M+H] + : 453.25.

[0746] Example 161: (S)-5,6-dimethyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-6a,7,8,9-tetrahydropyrrolo[2,1-h]pterin-6(5H)-one

[0747]

[0748] The synthesis of the compound in Example 161 was carried out in a manner similar to that described in Example 1, except that in step 2 of Example 1, L-proline methyl ester was used instead of phenylglycine ethyl ester, and in step 8 of Example 1, 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ8.93(s,1H),7.79(s,1H),7.54(d,J=2.1Hz,1H),7.45(dd,J=8.3,2.2Hz,1H),6.94(d,J=8.3Hz,1H),3.75- 3.59(m,2H),3.46(s,2H),3.23(s,3H),2.73(t,J=5.9Hz,2H),2.60(t,J=5.9Hz,2H),2.35(s,3H),2.22-1.97(m,3H),1.18(s,3H). MS(ESI)m / z[M+H] + : 379.21.

[0749] Example 162: (S)-2-((4-(4-fluoropiperidin-1-yl)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)amino)-5,6-dimethyl-6a,7,8,9-tetrahydropyrrolo[2,1-h]pterin-6(5H)-one

[0750]

[0751] The synthesis of the compound in Example 162 was carried out by steps similar to those described in Examples 1 and 40, except that in step 2 of Example 1, L-proline methyl ester was used instead of phenylglycine ethyl ester, in step 1 of Example 40, 4-fluoropiperidine was used instead of 1-methylpiperazine, and in step 8 of Example 1, 4-(4-fluoropiperidine-1-yl)-3-(1-methyl-1H-pyrazol-5-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline. The remaining steps were the same as in Examples 1 and 40. 1 HNMR(500MHz,DMSO-d6)δ9.09(s,1H),7.79(s,1H),7.77(dd,J=8.8,2.7Hz,1H ),7.72(d,J=2.6Hz,1H),7.47(d,J=1.8Hz,1H),7.07(d,J=8.9Hz,1H),4.80-4 .58(m,1H),3.78-3.59(m,5H),3.22(s,3H),2.85(t,J=9.5Hz,2H),2.68-2.64 (m,2H),2.21-1.94(m,4H),1.83-1.66(m,2H),1.64-1.56(m,2H),1.18(s,3H). MS(ESI)m / z[M+H] + : 491.26.

[0752] Example 163: (6aS,6bR,7aS)-5,7,7-trimethyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-6b,7,7a,8-tetrahydro-5H-cyclopropyl[3,4]pyrrolo[2,1-h]pterin-6(6aH)-one

[0753]

[0754] The synthesis of compound 163 in Example 1 was carried out by a procedure similar to that described in Example 1, except that in step 2 of Example 1, methyl (1S,5R)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid hydrochloride was replaced with ethyl phenylglycine, and in step 8 of Example 1, 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine. The remaining steps were the same as in Example 1. 1 H NMR(500MHz,DMSO-d6)δ8.98(s,1H),7.81(s,1H),7.52(d,J=2.2Hz,1H),7.43(d d,J=8.3,2.2Hz,1H),6.93(d,J=8.3Hz,1H),3.93-3.83(m,2H),3.44-3.39(m,3H) ,3.23(s,3H),2.72(t,J=5.9Hz,2H),2.57(t,J=5.9Hz,2H),2.33(s,3H),2.11(dd ,J=8.2,2.0Hz,1H),1.65(ddd,J=8.3,6.6,1.7Hz,1H),1.13(s,3H),0.99(s,3H). MS(ESI)m / z[M+H] + : 405.23.

[0755] Example 164: (6aS,6bR,7aS)-2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5,7,7-trimethyl-6b,7,7a,8-tetrahydro-5H-cyclopropyl[3,4]pyrrolo[2,1-h]pterin-6(6aH)-one

[0756]

[0757] The synthesis of compound 164 in Example 1 was carried out by a procedure similar to that described in Example 1, except that in step 2 of Example 1, methyl (1S,5R)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid hydrochloride was used instead of ethyl phenylglycine. The remaining steps were the same as in Example 1. MS (ESI) m / z [M+H] + : 478.28.

[0758] Example 165: 8-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one

[0759]

[0760] The synthesis of the compound in Example 165 was carried out by a procedure similar to that described in Example 1, except that in step 1 of Example 1, aniline was replaced with 6-amino-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid tert-butyl ester, and the remaining steps were the same as in Example 1. 1 H NMR (500MHz, DMSO-d6) δ8.87(s,1H),7.86(s,1H),7.51(d,J=8.7Hz,1H),7.44(s,1H),6.86(s,1H),6.72(d,J=8.4Hz,1H),6.60(d,J=2.5Hz,1H),6.5 0(dd,J=8.4,2.4Hz,1H),5.93(s,1H),4.37(s,2H),4.23-4.14(m,2H),3.7 7-3.65(m,5H),3.33(s,3H),3.27(s,3H),2.87-2.75(m,4H),2.16(s,6H). MS(ESI)m / z[M+H] + : 531.27.

[0761] Example 166: 8-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7,8-dihydropterin-6(5H)-one

[0762]

[0763] The synthesis of compound 166 in Example 1 was carried out by a procedure similar to that described in Example 1, except that in step 1 of Example 1, aniline was replaced with 6-amino-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid tert-butyl ester, and in step 8 of Example 1, 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Example 1. 1H NMR(500MHz,DMSO-d6)δ8.89(s,1H),7.86(s,1H),7.52(dd,J=8.7,2.4Hz,1H) ,7.42(s,1H),6.87(d,J=8.2Hz,1H),6.72(d,J=8.4Hz,1H),6.60(d,J=2.5Hz,1 H),6.50(dd,J=8.4,2.5Hz,1H),5.93(s,1H),4.37(s,2H),4.24-4.13(m,2H), 3.41(s,2H),3.27(s,4H),2.84(s,4H),2.54(s,2H),2.29(s,3H),2.23(s,6H). MS(ESI)m / z[M+H] + : 544.30.

[0764] Example 167: (S)-2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5,8-dimethyl-7-phenyl-7,8-dihydropterin-6(5H)-one

[0765]

[0766] Step 1: Methyl (S)-2-((2-chloro-5-nitropyrimidin-4-yl)amino)-2-phenylacetate (A36): Methyl (S)-2-amino-2-phenylacetate (2 g, 12.1 mmol, 1.0 eq), 2,4-dichloro-5-nitropyrimidin (3.52 g, 18.2 mmol, 1.5 eq), and potassium carbonate (3.34 g, 24.2 mmol, 2.0 eq) were added to a round-bottom flask and dissolved in acetone (30 mL). The reaction mixture was stirred at 0 °C for 6 hours. After the reaction was complete, the solvent was removed from the mixture under reduced pressure. The residue was purified by pressurized silica gel column chromatography to give compound A36 (2.89 g, 74% yield). MS (ESI) M / Z [M+H] + 323.04.

[0767] Step 2: (S)-2-chloro-7-phenyl-7,8-dihydropterin-6(5H)-one (A37): Methyl (S)-2-((2-chloro-5-nitropyrimidin-4-yl)amino)-2-phenylacetate (5 g, 15.5 mmol, 1.0 eq) dissolved in glacial acetic acid (60 mL) was added to a round-bottom flask, followed by the addition of iron powder (8.68 g, 155 mmol, 10.0 eq) with stirring. The reaction mixture was stirred at 60 °C for 40 min. After the reaction was complete, the solvent was evaporated under reduced pressure, and the product was neutralized to alkaline with saturated sodium bicarbonate solution. Extraction with ethyl acetate was performed, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. The organic phase was filtered, evaporated under reduced pressure to obtain a crude product, and washed with diethyl ether to give compound A37 (2.46 g, 61% yield). MS(ESI)M / Z[M+H] + : 261.04.

[0768] Step 3: (S)-2-chloro-5,8-dimethyl-7-phenyl-7,8-dihydropterin-6(5H)-one (A38): In a round-bottom flask, (S)-2-chloro-7-phenyl-7,8-dihydropterin-6(5H)-one (500 mg, 1.9 mmol, 1.0 eq) and N,N-dimethylformamide (10 mL) were added. Iodimethane (593 mg, 4.2 mmol, 2.2 eq) was added under ice bath conditions, followed by sodium hydride (152 mg, 3.8 mmol, 2.0 eq). The reaction mixture was stirred under ice bath conditions for 5 minutes. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. The organic phase was filtered, evaporated under reduced pressure to obtain a crude product, and washed with diethyl ether to obtain compound A38 (365 mg, 66% yield). MS(ESI)M / Z[M+H] + : 289.07.

[0769] Step 4: (S)-2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-5,8-dimethyl-7-phenyl-7,8-dihydropterin-6(5H)-one: In a sealed tube, add (S)-2-chloro-5,8-dimethyl-7-phenyl-7,8-dihydropterin-6(5H)-one (100 mg, 0.35 mmol, 1.0 eq), 3-((dimethylamino)methyl)-4-morpholinoaniline (75 mg, 0.32 mmol, 0.9 eq), p-toluenesulfonic acid (180 mg, 1.05 mmol, 3.0 eq), and sec-butanol (5 mL). The reaction mixture was stirred overnight at 120 °C. After the reaction was complete, the mixture was quenched with water, adjusted to alkalinity with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered, concentrated, and purified by thin-layer chromatography to obtain compound 167 (37 mg, yield 24%).

[0770] The synthesis of the compound in Example 167 was completed using the steps described above. MS (ESI) m / z [M+H] + : 474.58.

[0771] Example 168: (S)-2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,8-dimethyl-7-phenyl-7,8-dihydropterin-6(5H)-one

[0772]

[0773] The synthesis of the compound in Example 168 was carried out through a procedure similar to that described in Example 167, except that in step 4 of Example 167, 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline; the remaining steps were the same as in Example 167. MS (ESI) m / z [M+H] + : 501.30.

[0774] Example 169: (S)-2-((3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-5,8-dimethyl-7-phenyl-7,8-dihydropterin-6(5H)-one

[0775]

[0776] The synthesis of the compound in Example 169 was carried out by steps similar to those described in Examples 167 and 6, except that in step 4 of Example 167, 3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Examples 167 and 6. 1 H NMR (500MHz, DMSO-d6) δ9.04 (s, 1H), 7.85 (s, 1H), 7.75 (d, J = 2.4Hz, 1H), 7.54 (dd, J = 8. 5,2.4Hz,1H),7.40-7.30(m,3H),7.24-7.18(m,2H),7.13(d,J=8.5Hz,1H),5.34(s,1H) ,3.93(dd,J=10.5,4.4Hz,2H),3.41(td,J=11.6,2.1Hz,2H),3.33(s,2H),3.26(s,3H), 3.12-3.03(m,1H),2.99(s,3H),2.14(s,6H),1.71-1.61(m,2H),1.57(d,J=12.7Hz,2H). MS(ESI)m / z[M+H] + : 487.27.

[0777] Example 170: (S)-5,8-dimethyl-2-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-7-phenyl-7,8-dihydropterin-6(5H)-one

[0778]

[0779] The synthesis of the compound in Example 170 was carried out by a procedure similar to that described in Example 167, except that in step 4 of Example 167, 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine, and the remaining steps were the same as in Example 167. 1 H NMR(500MHz, DMSO-d6)δ9.01(s,1H),7.86(s,1H),7.52(d,J=2.2Hz,1H),7.43(dd,J=8.3,2.3Hz,1H),7.39-7.29(m,3H),7.23-7.17(m, 2H), 6.95 (d, J = 8.3Hz, 1H), 5.34 (s, 1H), 3.42 (s, 2H), 3.25 (s, 3H), 2.96 (s, 3H), 2.75-2.69 (m, 2H), 2.56 (t, J = 5.9Hz, 2H), 2.32 (s, 3H). MS(ESI)m / z[M+H]+ :415.21.

[0780] Example 171: (S)-2-((4-(4-acetylpiperazin-1-yl)-3-((dimethylamino)methyl)phenyl)amino)-5,8-dimethyl-7-phenyl-7,8-dihydropterin-6(5H)-one

[0781]

[0782] The synthesis of the compound in Example 171 was carried out by a procedure similar to that described in Example 167, except that in step 4 of Example 167, 3-((dimethylamino)methyl)-4-morpholinaniline was replaced with 1-(4-(4-amino-2-((dimethylamino)methyl)phenyl)piperazin-1-yl)ethane-1-one, and the remaining steps were the same as in Example 167. 1 H NMR(500MHz,DMSO-d6)δ9.04(s,1H),7.89(d,J=2.7Hz,1H),7.84(s,1H),7.5 6-7.51(m,1H),7.40-7.30(m,3H),7.21(dt,J=6.0,1.6Hz,2H),6.99(d,J=8.6 Hz,1H),5.34(s,1H),3.55(d,J=5.3Hz,4H),3.43(s,2H),3.25(s,3H),2.98(s ,3H),2.84(t,J=4.9Hz,2H),2.77(t,J=5.1Hz,2H),2.19(s,6H),2.03(s,3H). MS(ESI)m / z[M+H] + 529.29.

[0783] Example 172: (S)-2-((3-((dimethylamino)methyl)-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)amino)-5,8-dimethyl-7-phenyl-7,8-dihydropterin-6(5H)-one

[0784]

[0785] The synthesis of the compound in Example 172 was carried out by a procedure similar to that described in Example 167, except that in step 4 of Example 167, 3-((dimethylamino)methyl)-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Example 167. 1HNMR(500MHz,DMSO-d6)δ9.01(s,1H),7.87(d,J=2.7Hz,1H),7.84(s,1H),7.48( dd,J=8.7,2.7Hz,1H),7.40-7.29(m,3H),7.23-7.17(m,2H),7.03(d,J=8.7Hz,1 H),5.33(s,1H),3.41(s,2H),3.25(s,3H),3.12(s,2H),2.98(s,3H),2.89(d,J= 10.4Hz, 2H), 2.64 (d, J = 8.9Hz, 2H), 2.23 (s, 3H), 2.14 (s, 6H), 2.00-1.87 (m, 4H). MS(ESI)m / z[M+H] + : 527.31.

[0786] Example 173: (S)-2-((3-((dimethylamino)methyl)-4-((R)-3-(dimethylamine)pyrrolidine-1-yl)phenyl)amino)-5,8-dimethyl-7-phenyl-7,8-dihydropterin-6(5H)-one

[0787]

[0788] The synthesis of the compound in Example 173 was carried out by a procedure similar to that described in Example 167, except that in step 4 of Example 167, 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with (R)-1-(4-amino-2-((dimethylamino)methyl)phenyl)-N,N-dimethylpyrrolidine-3-amine; the remaining steps were the same as in Example 167. MS (ESI) m / z [M+H] + : 515.31.

[0789] Example 174: (S)-2-((3-((dimethylamino)methyl)-4-(4-(methanesulfonyl)piperazin-1-yl)phenyl)amino)-5,8-dimethyl-7-phenyl-7,8-dihydropterin-6(5H)-one

[0790]

[0791] The synthesis of the compound in Example 174 was carried out by a procedure similar to that described in Example 167, except that in step 4 of Example 167, 3-((dimethylamino)methyl)-4-(4-(methanesulfonyl)piperazin-1-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Example 167. 1H NMR(500MHz,DMSO-d6)δ9.14(s,1H),7.90(d,J=2.6Hz,1H),7.85(s,1H),7.61(s,1H),7.41-7.30(m,3H),7.26-7 .18(m,2H),7.13(s,1H),5.35(s,1H),3.26(s,6H),2.99(s,3H),2.95(s,3H),2.92(t,J=4.8Hz,4H),2.29(s,6H). MS(ESI)m / z[M+H] + : 565.26.

[0792] Example 175: (S)-2-((3-((dimethylamino)methyl)-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5,8-dimethyl-7-phenyl-7,8-dihydropterin-6(5H)-one

[0793]

[0794] The synthesis of the compound in Example 175 was carried out by a procedure similar to that described in Example 167, except that in step 4 of Example 167, 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 2-(4-(4-amino-2-((dimethylamino)methyl)phenyl)piperazin-1-yl)ethane-1-ol, and the remaining steps were the same as in Example 167. 1 H NMR(500MHz,DMSO-d6)δ9.10(s,1H),7.87(d,J=2.7Hz,1H),7.84(s,1H),7.58(s,1H),7.36(tt,J=6.9,5.9Hz,3H),7.26-7.17(m, 2H),7.08(s,1H),5.35(s,1H),4.53(s,1H),3.57(s,3H),3.26(s,4H),2.98(s,3H),2.87(s,4H),2.79-2.56(m,5H),2.33(s,6H). MS(ESI)m / z[M+H] + : 531.31.

[0795] Example 176: (S)-2-((3-((dimethylamino)methyl)-4-(4-methylpiperidin-1-yl)phenyl)amino)-5,8-dimethyl-7-phenyl-7,8-dihydropterin-6(5H)-one

[0796]

[0797] The synthesis of the compound in Example 176 was carried out through a procedure similar to that described in Example 167, except that in step 4 of Example 167, 3-((dimethylamino)methyl)-4-(4-methylpiperidin-1-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline; the remaining steps were the same as in Example 167. MS (ESI) m / z [M+H] + : 500.30.

[0798] Example 177: (S)-2-((3-((dimethylamino)methyl)-4-(1-methylpiperidin-4-yl)phenyl)amino)-5,8-dimethyl-7-phenyl-7,8-dihydropterin-6(5H)-one

[0799]

[0800] The synthesis of the compound in Example 177 was carried out by steps similar to those described in Examples 167 and 6, except that in step 4 of Example 167, 3-((dimethylamino)methyl)-4-(1-methylpiperidin-4-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Examples 167 and 6. 1 H NMR(500MHz,DMSO-d6)δ8.99(s,1H),7.86(d,J=2.7Hz,1H),7.84(s,1H),7.53-7 .48(m,1H),7.40-7.29(m,3H),7.23-7.17(m,2H),6.99(d,J=8.7Hz,1H),5.33(s ,1H),3.42(s,1H),3.25(s,3H),2.98(s,5H),2.56(t,J=11.4Hz,2H),2.19(s,6H ), 1.67 (d, J = 13.9Hz, 2H), 1.46 (s, 1H), 1.35-1.22 (m, 3H), 0.96 (d, J = 6.5Hz, 3H). MS(ESI)m / z[M+H] + : 500.30.

[0801] Example 178: (S)-5,8-dimethyl-2-((4-(4-methylpiperazin-1-yl)-3-(1H-pyrazol-5-yl)phenyl)amino)-7-phenyl-7,8-dihydropterin-6(5H)-one

[0802]

[0803] The synthesis of compound 178 in Example 1 was carried out by a method similar to that described in Examples 167 and 40, except that in step 4 of Example 167, 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 4-(4-methylpiperazin-1-yl)-3-(1H-pyrazol-5-yl)aniline; the remaining steps were the same as in Examples 167 and 40. MS (ESI) m / z [M+H] + : 510.26.

[0804] Example 179: (S)-2-((4-(4-(cyclopropanecarbonyl)piperazin-1-yl)-3-(1-methyl-1H-pyrazole-5-yl)phenyl)amino)-5,8-dimethyl-7-phenyl-7,8-dihydropterin-6(5H)-one

[0805]

[0806] The synthesis of the compound in Example 179 was carried out by steps similar to those described in Examples 167 and 40, except that in step 4 of Example 167, 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with (4-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenyl)piperazin-1-yl)(cyclopropyl)methyl ketone, and the remaining steps were the same as in Examples 167 and 40. 1 H NMR(500MHz,DMSO-d6)δ9.19(s,1H),7.86(s,1H),7.76-7.73(m,2H),7.46(d ,J=1.8Hz,1H),7.38-7.31(m,3H),7.21-7.19(m,2H),7.07(d,J=8.5Hz,1H), 6.27(d,J=1.8Hz,1H),5.34(s,1H),3.70(s,3H),3.54(s,2H),3.37(s,4H),3 .25(s,3H),2.94(s,3H),2.70(s,4H),1.95-1.92(m,1H),0.71-0.66(m,4H). MS(ESI)m / z[M+H] + : 578.29.

[0807] Example 180: (S)-2-((2-(3-hydroxypropyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-5,8-dimethyl-7-phenyl-7,8-dihydropterin-6(5H)-one

[0808]

[0809] The synthesis of the compound in Example 180 was carried out by steps similar to those described in Examples 167 and 28, except that in step 1 of Example 28, 2-iodopropane was replaced with 3-bromopropane-1-ol, and in step 4 of Example 167, 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 2-(7-amino-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-ol. The remaining steps were the same as in Examples 167 and 28. 1 H NMR (500MHz, DMSO-d6) δ9.01(s,1H),7.86(s,1H),7.52(d,J=2.2Hz,1H),7.43(dd,J=8.3,2.2Hz,1H),7.38-7.33(m,3H),7.22-7.20(m,2H),6. 94(d,J=8.3Hz,1H),5.34(s,1H),3.48-3.45(m,5H),3.25(s,3H),2.96( s, 3H), 2.71 (t, J = 5.8Hz, 2H), 2.62 (t, J = 5.8Hz, 2H), 1.69-1.63 (m, 2H). MS(ESI)m / z[M+H] + : 459.24.

[0810] Example 181: (S)-2-((3-((cyclopropyl(methyl)amino)methyl)-4-morpholinylphenyl)amino)-5,8-dimethyl-7-phenyl-7,8-dihydropterin-6(5H)-one

[0811]

[0812] The synthesis of the compound in Example 181 was carried out by a procedure similar to that described in Example 167, except that in step 4 of Example 167, 3-((dimethylamino)methyl)-4-morpholinaniline was replaced with 3-((cyclopropyl(methyl)amino)methyl)-4-morpholinaniline, and the remaining steps were the same as in Example 167. 1H NMR (500MHz, DMSO-d6) δ9.01 (s, 1H), 7.83 (s, 1H), 7.82 (d, J = 2.6Hz, 1H), 7.50 (dd ,J=8.7,2.7Hz,1H),7.38-7.31(m,3H),7.21-7.19(m,2H),7.02(d,J=8.7Hz,1H),5 .34(s,1H),3.70(t,J=4.5Hz,4H),3.66(s,2H),3.25(s,3H),2.97(s,3H),2.78-2. 77(m,4H),2.14(s,3H),1.76-1.73(m,1H),0.43(d,J=6.4,2H),0.28-0.26(m,2H). MS(ESI)m / z[M+H] + : 514.28.

[0813] Example 182: (S)-7-(2-chlorophenyl)-2-((3-((dimethylamino)methyl)-4-morpholinylphenyl)amino)-5,8-dimethyl-7,8-dihydropterin-6(5H)-one

[0814]

[0815] The synthesis of the compound in Example 182 was carried out by a procedure similar to that described in Example 167, except that in step 1 of Example 167, (S)-2-amino-2-phenylacetic acid methyl ester was replaced with (S)-2-chlorophenylglycine methyl ester, and the remaining steps were the same as in Example 167. 1 H NMR(500MHz,DMSO-d6)δ8.99(s,1H),7.86-7.85(m,2H),7.53-7.50(m,2H),7.41-7.32(m,3H),7.00(d,J=8.7Hz,1 H), 5.73 (s, 1H), 3.70 (t, J = 4.5Hz, 4H), 3.41 (s, 2H), 3.27 (s, 3H), 2.87 (s, 3H), 2.82 (t, J = 4.6Hz, 4H), 2.16 (s, 6H). MS(ESI)m / z[M+H] + : 522.23.

[0816] Example 183: (S)-7-(2-chlorophenyl)-2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,8-dimethyl-7,8-dihydropterin-6(5H)-one

[0817]

[0818] The synthesis of the compound in Example 183 was carried out by a method similar to that described in Example 167, except that in step 1 of Example 167, (S)-2-chlorophenylglycine methyl ester was used instead of (S)-2-amino-2-phenylacetic acid methyl ester, and in step 4 of Example 167, 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Example 167. 1 H NMR(500MHz,DMSO-d6)δ8.95(s,1H),7.85-7.84(m,2H),7.50(ddd,J=10.2,8.1,2.2Hz,2H),7.41-7.32(m,3H),6.97(d, J=8.7Hz,1H),5.73(s,1H),3.36(s,2H),3.27(s,3H),2.87(s,3H),2.82(s,4H),2.44(s,4H),2.22(s,3H),2.14(s,6H). MS(ESI)m / z[M+H] + : 535.26.

[0819] Example 184: (S)-7-(2-chlorophenyl)-2-((3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-5,8-dimethyl-7,8-dihydropterin-6(5H)-one

[0820]

[0821] The synthesis of the compound in Example 184 was carried out by steps similar to those described in Examples 167 and 6, except that in step 1 of Example 167, (S)-2-amino-2-phenylacetic acid methyl ester was replaced with (S)-2-chlorophenylglycine methyl ester, and in step 4 of Example 167, 3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Examples 167 and 6. 1H NMR (500MHz, DMSO-d6) δ8.99(s,1H),7.85(s,1H),7.72(d,J=2.5Hz,1H),7.54-7.50(m,2H),7.41-7.32(m,3H),7.12(d,J=8.5Hz,1H),5.73(s, 1H),3.92(dd,J=10.7,4.0Hz,2H),3.40(td,J=11.5,2.1Hz,2H),3.27( s,3H),3.09-3.05(m,1H),2.87(s,3H),2.12(s,6H),1.68-1.55(m,4H). MS(ESI)m / z[M+H] + : 521.23.

[0822] Example 185: (S)-7-(3-chlorophenyl)-2-((3-((dimethylamino)methyl)-4-morpholinylphenyl)amino)-5,8-dimethyl-7,8-dihydropterin-6(5H)-one

[0823]

[0824] The synthesis of the compound in Example 185 was carried out by a procedure similar to that described in Example 167, except that in step 1 of Example 167, (S)-2-amino-2-phenylacetic acid methyl ester was replaced with (S)-3-chlorophenylglycine methyl ester, and the remaining steps were the same as in Example 167. 1 H NMR (500MHz, DMSO-d6) δ9.10 (s, 1H), 7.88-7.86 (m, 2H), 7.58 (d, J = 8.6Hz, 1H), 7.43-7.39 (m, 2H), 7.31 (s, 1H), 7.13 (dt, J = 6. 5,2.0Hz,1H),7.06(s,1H),5.42(s,1H),3.72(t,J=4.4Hz,4H),3.26(s,3H),2.99(s,3H),2.83(t,J=4.5Hz,4H),2.25(s,6H). MS(ESI)m / z[M+H] + : 522.23.

[0825] Example 186: (S)-7-(3-chlorophenyl)-2-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,8-dimethyl-7,8-dihydropterin-6(5H)-one

[0826]

[0827] The synthesis of the compound in Example 186 was carried out by a method similar to that described in Example 167, except that in step 1 of Example 167, (S)-2-amino-2-phenylacetic acid methyl ester was replaced with (S)-3-chlorophenylglycine methyl ester, and in step 4 of Example 167, 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-morpholinoaniline, and the remaining steps were the same as in Example 167. 1 H NMR(500MHz,DMSO-d6)δ9.09(s,1H),7.87(s,1H),7.76(s,1H),7.55(d,J=8.4Hz,1H),7.43-7.39(m,2H),7.31(s,1H),7.15-7.12(m,2H ),5.42(s,1H),3.95-3.92(m,2H),3.41(t,J=11.3Hz,2H),3.26(s,3H),3.13-3.03(m,1H),3.00(s,3H),2.15(s,6H),1.69-1.56(m,5H). MS(ESI)m / z[M+H] + : 535.26.

[0828] Example 187: (S)-2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-7-(3-fluorophenyl)-5,8-dimethyl-7,8-dihydropterin-6(5H)-one

[0829]

[0830] The synthesis of the compound in Example 187 was carried out by a procedure similar to that described in Example 167, except that in step 1 of Example 167, (S)-2-amino-2-phenylacetic acid methyl ester was replaced with (S)-3-fluorophenylglycine methyl ester, and the remaining steps were the same as in Example 167. 1H NMR(500MHz,DMSO-d6)δ9.06(s,1H),7.87(s,1H),7.75(d,J=2.4Hz,1H),7.54(dd,J=8.5,2.4Hz,1 H),7.42(td,J=8.0,6.0Hz,1H),7.19(td,J=8.6,2.6Hz,1H),7.13(d,J=8.5Hz,1H),7.08-6.99(m,2 H),5.41(s,1H),3.93(dd,J=10.8,4.0Hz,2H),3.41(td,J=11.6,2.1Hz,2H),3.33(s,2H),3.26(s, 3H), 3.11-3.08 (m, 1H), 3.00 (s, 3H), 2.14 (s, 6H), 1.65 (qd, J = 12.3, 4.2Hz, 2H), 1.58-1.55 (m, 2H). MS(ESI)m / z[M+H] + 506.26.

[0831] Example 188: 2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-7-(2-fluoro-6-methylphenyl)-5,8-dimethyl-7,8-dihydropterin-6(5H)-one

[0832]

[0833] The synthesis of compound 188 in Example 1 was carried out through a procedure similar to that described in Example 167, except that in step 1 of Example 167, methyl (S)-2-amino-2-phenylacetate was replaced with methyl 2-amino-2-(2-fluoro-6-methylphenyl)acetate; the remaining steps were the same as in Example 167. MS (ESI) m / z [M+H] + : 520.27.

[0834] Example 189: 2-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-7-(2,6-dimethylphenyl)-5,8-dimethyl-7,8-dihydropterin-6(5H)-one

[0835]

[0836] The synthesis of the compound in Example 189 was carried out by a procedure similar to that described in Example 167, except that in step 1 of Example 167, methyl 2-amino-2-(2,6-dimethylphenyl)acetate was used instead of methyl (S)-2-amino-2-phenylacetate, and the remaining steps were the same as in Example 167. 1H NMR(500MHz,DMSO-d6)δ9.17(s,1H),7.88(d,J=2.6Hz,1H),7.79(s,1H),7.71(dd,J=8.8,2.5Hz,1H),7.26(d,J=8.8Hz,1H),7.16-7.12(m,2H), 7.02(d,J=7.0Hz,1H),5.96(s,1H),4.21(s,2H),3.76-3.74(dd,J=5.8, 3.2Hz,4H),3.26(s,3H),2.81-2.74(m,13H),2.47(s,3H),2.01(s,3H). MS(ESI)m / z[M+H] + : 516.30.

[0837] Example 190: 7-(2,6-difluorophenyl)-2-((3-((dimethylamino)methyl)-4-morpholinylphenyl)amino)-5,8-dimethyl-7,8-dihydropterin-6(5H)-one

[0838]

[0839] The synthesis of the compound in Example 190 was carried out by a procedure similar to that described in Example 167, except that in step 1 of Example 167, methyl 2-amino-2-(2,6-difluorophenyl)acetate was used instead of methyl (S)-2-amino-2-phenylacetate, and the remaining steps were the same as in Example 167. 1 H NMR (500MHz, DMSO-d6) δ9.18 (s, 1H), 7.86-7.85 (m, 2H), 7.67 (d, J = 8.6Hz, 1H), 7.54-7.48 (m, 1H), 7.25-7.16 (m, 3H), 5.84 (s, 1H), 4.14 (s, 2H), 3.75-3.73 (m, 4H), 3.29 (s, 3H), 2.91 (s, 3H), 2.80 (t, J = 4.5Hz, 4H), 2.69 (s, 6H). MS(ESI)m / z[M+H] + 524.25.

[0840] Example 191: 7-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-methyl-3-phenyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0841]

[0842] Step 1: N-((2,4-dichloropyrimidin-5-yl)methyl)aniline (A39): 2,4-dichloro-5-(chloromethyl)pyrimidine (2 g, 10.1 mmol, 1.0 eq), aniline (846 mg, 9.1 mmol, 0.9 eq), sodium iodide (1.82 g, 12.1 mmol, 1.2 eq), and potassium carbonate (2.10 g, 15.2 mmol, 1.5 eq) were added to a round-bottom flask and dissolved in acetone (20 mL). The reaction mixture was reacted overnight at 50 °C. After the reaction was complete, the solvent was removed from the mixture under reduced pressure, and the residue was purified by pressurized silica gel column chromatography to give compound A39 (1.72 g, 67% yield). MS (ESI) M / Z [M+H] + : 254.01.

[0843] Step 2: 2-Chloro-N-methyl-5-((phenylamino)methyl)pyrimidin-4-amine (A40): In a round-bottom flask, N-((2,4-dichloropyrimidin-5-yl)methyl)aniline (2.5 g, 9.8 mmol, 1.0 eq), methylamine (30% aqueous solution, 8 mL), and N,N-diisopropylethylamine (3.81 g, 29.4 mmol, 3.0 eq) were added and dissolved in 1,4-dioxane (20 mL). The reaction system was stirred at 60 °C for 1 hour. After the reaction was complete, the mixture was quenched with water, extracted with dichloromethane, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. The organic phase was filtered, concentrated, and the residue was purified by pressurized silica gel column chromatography to give compound A39 (1.61 g, 66% yield). MS (ESI) M / Z [M+H] + : 249.08.

[0844] Step 3: 7-Chloro-1-methyl-3-phenyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one (A41): 2-chloro-N-methyl-5-((phenylamino)methyl)pyrimidin-4-amine (1 g, 4.0 mmol, 1.0 eq), triphosgene (596 mg, 2.0 mmol, 0.5 eq), and N,N-diisopropylethylamine (1.03 g, 8.0 mmol, 2.0 eq) were added to a round-bottom flask and dissolved in tetrahydrofuran (50 mL). The reaction system was stirred overnight at reflux. After the reaction was complete, the mixture was quenched with water, extracted with dichloromethane, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. The organic phase was filtered, evaporated under reduced pressure, and the crude product was obtained. The crude product was washed with diethyl ether to obtain compound A41 (585 mg, 53% yield). MS(ESI)M / Z[M+H] + 275.06.

[0845] Step 4: 7-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-methyl-3-phenyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one: 7-chloro-1-methyl-3-phenyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one (100 mg, 0.36 mmol, 1.0 eq), 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline (79 mg, 0.32 mmol, 0.9 eq), p-toluenesulfonic acid (189 mg, 1.1 mmol, 3.0 eq), and sec-butanol (5 mL) were added to a sealed tube. The reaction mixture was stirred overnight at 120 °C. After the reaction was completed, the mixture was quenched with water, adjusted to a weakly alkaline state with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, respectively, and dried with anhydrous sodium sulfate. The organic phase was filtered, concentrated, and purified by thin-layer chromatography to give compound 191 (35 mg, yield 23%).

[0846] The synthesis of the compound in Example 191 was accomplished using the steps described above. 1 H NMR(500MHz,DMSO-d6)δ9.39(s,1H),8.11(s,1H),7.88(d,J=2.6Hz,1H),7.53(dd,J=8.7,2.7Hz,1H),7.44-7.36(m,4H), 7.30-7.24(m,1H),7.03(d,J=8.6Hz,1H),4.71(s,2H),3.36(s,3H),2.85(s,4H),2.46(s,4H),2.23(s,3H),2.19(s,6H). MS(ESI)m / z[M+H] + : 487.28.

[0847] Example 192: 7-((3-((dimethylamino)methyl)-4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1-methyl-3-phenyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0848]

[0849] The synthesis of the compound in Example 192 was carried out by a method similar to that described in Example 191, except that in step 4 of Example 191, 3-((dimethylamino)methyl)-4-(4-isopropylpiperazin-1-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline, and the remaining steps were the same as in Example 191. 1H NMR(500MHz,DMSO-d6)δ9.39(s,1H),8.11(s,1H),7.90(s,1H),7.52(dd,J=8.6,2.7Hz,1H),7.44-7.36(m,4H),7.29-7.24(m,1H),7.03(d, J=8.7Hz,1H),4.71(s,2H),3.42(s,2H),3.36(s,3H),2.84(s,4H),2.69-2.67(m,1H),2.58(s,4H),2.20(s,6H),1.02(s,3H),1.01(s,3H). MS(ESI)m / z[M+H] + : 515.31.

[0850] Example 193: 7-((3-((dimethylamino)methyl)-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-methyl-3-phenyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0851]

[0852] The synthesis of the compound in Example 193 was carried out by a procedure similar to that described in Example 191, except that in step 4 of Example 191, 3-((dimethylamino)methyl)-5-fluoro-4-(4-methylpiperazin-1-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline, and the remaining steps were the same as in Example 191. 1 HNMR(500MHz,DMSO-d6)δ9.64(s,1H),8.16(s,1H),7.63-7.55(m,2H),7.44-7.37(m,4H),7.29-7.26 (m,1H),4.73(s,2H),3.46(s,2H),3.36(s,3H),2.97(s,4H),2.39(s,4H),2.22(s,3H),2.18(s,6H). MS(ESI)m / z[M+H] + : 505.27.

[0853] Example 194: 7-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-1-methyl-3-phenyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0854]

[0855] The synthesis of the compound in Example 194 was carried out through steps similar to those described in Example 191, except that in step 4 of Example 191, 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline; the remaining steps were the same as in Example 191. MS (ESI) m / z [M+H] + : 474.25.

[0856] Example 195: 7-((3-((cyclopropyl(methyl)amino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-methyl-3-phenyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0857]

[0858] The synthesis of the compound in Example 195 was carried out by a procedure similar to that described in Example 191, except that in step 4 of Example 191, 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was replaced with 3-((cyclopropyl(methyl)amino)methyl)-4-(4-methylpiperazin-1-yl)aniline, and the remaining steps were the same as in Example 191. 1 HNMR(500MHz,DMSO-d6)δ9.38(s,1H),8.10(s,1H),7.82(d,J=2.7Hz,1H),7.50( dd,J=8.7,2.7Hz,1H),7.43-7.37(m,4H),7.28-7.25(m,1H),7.04(d,J=8.7Hz,1H ),4.71(s,2H),3.67(s,2H),3.34(s,3H),2.81(t,J=4.7Hz,4H),2.47(s,4H),2. 24(s,3H),2.16(s,3H),1.80-1.76(m,1H),0.49-0.46(m,2H),0.36-0.33(m,2H). MS(ESI)m / z[M+H] + : 513.30.

[0859] Example 196: 7-((3-((dimethylamino)methyl)-4-(4-ethylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)amino)-1-methyl-3-phenyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0860]

[0861] The synthesis of the compound in Example 196 was carried out through steps similar to those described in Example 191, except that in step 4 of Example 191, 3-((dimethylamino)methyl)-4-(4-ethylpiperazin-1-yl)-5-(trifluoromethyl)aniline was used instead of 3-(dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline; the remaining steps were the same as in Example 191. MS (ESI) m / z [M+H] + : 569.28.

[0862] Example 197: 1-Methyl-7-((4-(4-methylpiperazin-1-yl)-3-(1H-pyrazol-5-yl)phenyl)amino)-3-phenyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0863]

[0864] The synthesis of the compound in Example 197 was carried out by steps similar to those described in Examples 191 and 40, except that in step 2 of Example 40, 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole was replaced with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole, and in step 4 of Example 191, 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was replaced with 4-(4-methylpiperazin-1-yl)aniline. The remaining steps were the same as in Examples 191 and 40. MS (ESI) m / z [M+H] + : 496.24.

[0865] Example 198: 1-Methyl-7-((3-(1-methyl-1H-pyrazol-5-yl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-3-phenyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0866]

[0867] The synthesis of the compound in Example 198 was carried out by a method similar to that described in Examples 191 and 40, except that in step 4 of Example 191, 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was replaced with 3-(1-methyl-1H-pyrazol-5-yl)-4-(4-methylpiperazin-1-yl)aniline, and the remaining steps were the same as in Examples 191 and 40. 1H NMR (500MHz, DMSO-d6) δ9.54(s,1H),8.12(d,J=1.1Hz,1H),7.79(dt,J=8.9,2.1Hz,1H),7.66(t,J=2.1Hz,1H),7.47-7.36(m,6H),7.27(td,J=7.2 ,1.6Hz,1H),7.10(d,J=8.8Hz,1H),6.27(d,J=1.8Hz,1H),4.71(s,2H),3 .69(s,3H),3.32(s,3H),2.72(s,4H),2.23(s,4H),2.14(d,J=1.5Hz,3H). MS(ESI)m / z[M+H] + : 510.27.

[0868] Example 199: 7-((3-(1-(dimethylamino)ethyl)-4-morpholinophenyl)amino)-1-methyl-3-phenyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0869]

[0870] The synthesis of the compound in Example 199 was carried out by steps similar to those described in Examples 191 and 140, except that in step 4 of Example 191, 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was replaced with 3-(1-(dimethylamino)ethyl)-4-morpholinoaniline, and the remaining steps were the same as in Examples 191 and 140. 1 H NMR (500MHz, DMSO-d6) δ9.41 (s, 1H), 8.12 (s, 1H), 7.92 (d, J = 2.6Hz, 1H), 7.52 (dd,J=8.7,2.7Hz,1H),7.44-7.37(m,4H),7.27(t,J=7.2Hz,1H),7.11(d,J=8 .7Hz,1H),4.71(s,2H),3.94(q,J=6.7Hz,1H),3.72(t,J=4.8Hz,4H),3.37(s, 3H), 2.87-2.83 (m, 2H), 2.75-2.71 (m, 2H), 2.13 (s, 6H), 1.22 (d, J = 6.7Hz, 3H). MS(ESI)m / z[M+H] + : 488.27.

[0871] Example 200: 7-((3-((dimethylamino)methyl)-5-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-methyl-3-phenyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0872]

[0873] The synthesis of the compound in Example 200 was carried out through a procedure similar to that described in Example 191, except that in step 4 of Example 191, 3-((dimethylamino)methyl)-5-methoxy-4-(4-methylpiperazin-1-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline; the remaining steps were the same as in Example 191. MS (ESI) m / z [M+H] + : 517.30.

[0874] Example 201: 7-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-3-(3-fluorophenyl)-1-methyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0875]

[0876] The synthesis of the compound in Example 201 was carried out by a method similar to that described in Example 191, except that 3-fluoroaniline was used instead of aniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-morpholinoaniline was used instead of 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191. The remaining steps were the same as in Example 191. 1 H NMR (500MHz, DMSO-d6) δ9.47(s,1H),8.13(s,1H),7.89(d,J=2.7Hz,1H),7.58(d,J=8.7Hz,1H),7.45(td,J=8.2,6.8Hz,1H),7.29(dt,J=10.8,2.3Hz ,1H),7.24(dd,J=7.7,2.0Hz,1H),7.11(td,J=8.7,2.7Hz,2H),4.74(s,2H ), 3.73 (t, J = 4.5Hz, 4H), 3.37 (s, 4H), 2.85 (t, J = 4.5Hz, 5H), 2.26 (s, 6H). MS(ESI)m / z[M+H] + : 492.24.

[0877] Example 202: 7-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-3-(3-fluorophenyl)-1-methyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0878]

[0879] The synthesis of the compound in Example 202 was carried out by a procedure similar to that described in Example 191, except that aniline was replaced with 3-fluoroaniline in step 1 of Example 191, and the remaining steps were the same as in Example 191. 1 H NMR (500MHz, DMSO-d6) δ9.42 (s, 1H), 8.12 (s, 1H), 7.88 (d, J = 2.7Hz, 1H), 7.53 (d d,J=8.6,2.7Hz,1H),7.45(td,J=8.2,6.7Hz,1H),7.33-7.25(m,1H),7.27-7.21 (m,1H),7.11(td,J=8.6,2.6Hz,1H),7.03(d,J=8.7Hz,1H),4.73(s,2H),3.42(s ,2H),3.36(s,4H),2.85(t,J=4.8Hz,4H),2.48(s,3H),2.24(s,3H),2.20(s,6H). MS(ESI)m / z[M+H] + : 505.27.

[0880] Example 203: 3-(3-fluorophenyl)-1-methyl-7-((4-(4-methylpiperazin-1-yl)-3-(1H-pyrazol-5-yl)phenyl)amino)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0881]

[0882] The synthesis of the compound in Example 203 was carried out by steps similar to those described in Examples 191 and 40, except that in step 2 of Example 40, 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole was replaced with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole; in step 1 of Example 191, aniline was replaced with 3-fluoroaniline; and in step 4 of Example 191, 3-(4-methylpiperazin-1-yl)-3-(1H-pyrazole-5-yl)aniline was replaced with 4-(4-(dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline. The remaining steps were the same as in Examples 191 and 40. MS (ESI) m / z [M+H] +: 514.24.

[0883] Example 204: 3-(3-fluorophenyl)-1-methyl-7-((3-(1-methyl-1H-pyrazol-5-yl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0884]

[0885] The synthesis of the compound in Example 204 was carried out by steps similar to those described in Examples 191 and 40, except that aniline was replaced with 3-fluoroaniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was replaced with 3-(1-methyl-1H-pyrazol-5-yl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191. The remaining steps were the same as those in Examples 191 and 40. 1 H NMR(500MHz,DMSO-d6)δ9.55(s,1H),8.13(s,1H),7.79(dd,J=8.8,2.7Hz,1H ),7.65(d,J=2.7Hz,1H),7.50-7.41(m,2H),7.29(dt,J=10.8,2.3Hz,1H),7.2 4(dd,J=7.5,2.0Hz,1H),7.14-7.07(m,2H),6.27(d,J=1.8Hz,1H),4.73(s,2H ), 3.69 (s, 3H), 3.32 (s, 4H), 2.72 (t, J = 4.8Hz, 4H), 2.24 (s, 3H), 2.15 (s, 3H). MS(ESI)m / z[M+H] + 528.25.

[0886] Example 205: 7-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-1-methyl-3-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0887]

[0888] The synthesis of the compound in Example 205 was carried out by a method similar to that described in Example 191, except that aniline was replaced with 3-trifluoromethylaniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191, with the remaining steps being the same as in Example 191. 1H NMR(500MHz,DMSO-d6)δ9.45(s,1H),8.13(s,1H),7.89(d,J=2.7Hz,1H),7.78(d,J=2.0Hz,1H),7.72-7.60(m,3H),7.59-7.53(m,1H),7 .07(d,J=8.6Hz,1H),4.79(s,2H),3.72(t,J=4.4Hz,4H),3.49(d,J=23.1Hz,2H),3.38(s,3H),2.85(t,J=4.5Hz,4H),2.29-2.14(s,6H). MS(ESI)m / z[M+H] + : 542.24.

[0889] Example 206: 7-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-methyl-3-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0890]

[0891] The synthesis of the compound in Example 206 was carried out by a procedure similar to that described in Example 191, except that aniline was replaced with 3-trifluoromethylaniline in step 1 of Example 191, and the remaining steps were the same as in Example 191. 1 H NMR (500MHz, DMSO-d6) δ9.43(s,1H),8.13(s,1H),7.88(d,J=2.8Hz,1H),7.78(d,J=2.2Hz,1H),7.74-7.58(m,4H),7.54(dd,J=8.7,2. 7Hz,1H),7.04(d,J=8.7Hz,1H),4.79(s,2H),3.43(s,2H),3.37(s,4H),2.86(t,J=4.8Hz,4H),2.50(s,2H),2.25(s,3H),2.21(s,6H). MS(ESI)m / z[M+H] + : 555.27.

[0892] Example 207: 7-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-3-(4-fluorophenyl)-1-methyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0893]

[0894] The synthesis of the compound in Example 207 was carried out by a method similar to that described in Example 191, except that 4-fluoroaniline was used instead of aniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-morpholinoaniline was used instead of 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191, with the remaining steps being the same as in Example 191. 1 H NMR(500MHz,DMSO-d6)δ9.45(s,1H),8.12(s,1H),7.89(d,J=2.1Hz,1H),7.58(d,J=5.8Hz,1H),7.42(ddd,J=10.5,5.3,2.9Hz,2H), 7.30-7.21(m,2H),7.09(s,1H),4.69(s,2H),3.81-3.66(m,4H),3.50(d,J=8.1Hz,2H),3.35(s,3H),2.94-2.79(m,4H),2.26(s,6H). MS(ESI)m / z[M+H] + : 492.24.

[0895] Example 208: 7-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-3-(4-fluorophenyl)-1-methyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0896]

[0897] The synthesis of the compound in Example 208 was carried out by a procedure similar to that described in Example 191, except that 4-fluoroaniline was used instead of aniline in step 1 of Example 191, and the remaining steps were the same as in Example 191. 1 H NMR (500MHz, DMSO-d6) δ9.43 (s, 1H), 8.11 (s, 1H), 7.88 (d, J = 2.0Hz, 1H), 7.57 (d, J = 6.9Hz, 1H), 7.46-7.39 (m, 2H), 7.29-7.2 1(m,2H),7.07(d,J=8.6Hz,1H),4.69(s,2H),3.51(s,2H),3.35(s,4H),2.88(s,4H),2.57(s,3H),2.30(s,3H),2.27(s,6H). MS(ESI)m / z[M+H] + : 505.27.

[0898] Example 209: 3-(4-fluorophenyl)-1-methyl-7-((3-(1-methyl-1H-pyrazol-5-yl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0899]

[0900] The synthesis of the compound in Example 209 was carried out by steps similar to those described in Examples 191 and 40, except that 4-fluoroaniline was used instead of aniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was used instead of 3-(1-methyl-1H-pyrazol-5-yl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191. The remaining steps were the same as those in Examples 191 and 40. 1 H NMR(500MHz,DMSO-d6)δ9.55(s,1H),8.12(s,1H),7.80(dd,J=8.8,2.6Hz,1H),7.66(d,J=2.6Hz,1H),7.47(d,J=1.8Hz,1H),7.45-7.37(m,2H), 7.29-7.21(m,2H),7.11(d,J=8.8Hz,1H),6.28(d,J=1.8Hz,1H),4.69(s ,2H),3.69(s,3H),3.69(s,4H),2.77(s,4H),2.41(s,3H),2.28(s,3H). MS(ESI)m / z[M+H] + 528.25.

[0901] Example 210: 3-(4-fluorophenyl)-1-methyl-7-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0902]

[0903] The synthesis of the compound in Example 210 was carried out by a method similar to that described in Example 191, except that 4-fluoroaniline was used instead of aniline in step 1 of Example 191, and 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine was used instead of 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191, with the remaining steps being the same as in Example 191. 1H NMR (500MHz, DMSO-d6) δ9.42(s,1H),8.12(s,1H),7.50(s,1H),7.48-7.45(m,1H),7.45-7.39(m,2H),7.25(t,J=8.8Hz,2H ), 7.01 (d, J = 8.3Hz, 1H), 4.69 (s, 2H), 3.51 (d, J = 1.8Hz, 2H), 3.33 (s, 3H), 2.77 (t, J = 5.7Hz, 2H), 2.63 (s, 2H), 2.37 (s, 3H). MS(ESI)m / z[M+H] + :419.19.

[0904] Example 211: 3-(4-fluorophenyl)-7-((2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-1-methyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0905]

[0906] The synthesis of the compound in Example 211 was carried out by steps similar to those described in Examples 191 and 28, except that 4-fluoroaniline was used instead of aniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was used instead of 2-(7-amino-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-ol in step 4 of Example 191. The remaining steps were the same as those in Examples 191 and 28. 1 H NMR(500MHz,DMSO-d6)δ9.47(s,1H),8.13(s,1H),7.55--7.48(m,2H),7.46-7.39(m,2H),7.30-7. 21(m,2H),7.05(d,J=8.2Hz,1H),4.70(s,3H),3.83(s,2H),3.67(s,2H),3.33(s,3H),2.83(s,6H). MS(ESI)m / z[M+H] + :419.19.

[0907] Example 212: 7-((3-((cyclopropyl(methyl)amino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-3-(4-fluorophenyl)-1-methyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0908]

[0909] The synthesis of the compound in Example 212 was carried out by a method similar to that described in Example 191, except that 4-fluoroaniline was used instead of aniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was used instead of 3-((cyclopropyl(methyl)amino)methyl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191. The remaining steps were the same as in Example 191. 1 H NMR (500MHz, DMSO-d6) δ9.39 (s, 1H), 8.10 (s, 1H), 7.82 (d, J = 2.7Hz, 1H), 7.50 (dd ,J=8.7,2.7Hz,1H),7.44-7.41(m,2H),7.25(t,J=8.8Hz,2H),7.05(d,J=8.7Hz,1 H),4.68(s,2H),3.67(s,2H),3.33(s,3H),2.83(t,J=4.7Hz,4H),2.54(s,4H),2. 29(s,3H),2.17(s,3H),1.79-1.77(m,1H),0.49-0.47(m,2H),0.35-0.33(m,2H). MS(ESI)m / z[M+H] + : 531.29.

[0910] Example 213: 7-((3-((dimethylamino)methyl)-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-3-(4-fluorophenyl)-1-methyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0911]

[0912] The synthesis of the compound in Example 213 was carried out by a method similar to that described in Example 191, except that 4-fluoroaniline was used instead of aniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-5-fluoro-4-(4-methylpiperazin-1-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191. The remaining steps were the same as in Example 191. 1H NMR (500MHz, DMSO-d6) δ9.64(s,1H),8.15(s,1H),7.63(d,J=2.5Hz,1H),7.56(dd,J=15.5,2.5Hz,1H),7.44-7. 41(m,2H),7.25(t,J=8.8Hz,2H),4.71(s,2H),3.46(s,2H),3.36(s,3H),2.96(s,4H),2.22(s,3H),2.18(s,6H). MS(ESI)m / z[M+H] + : 523.26.

[0913] Example 214: 7-((3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-(4-fluorophenyl)-1-methyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0914]

[0915] The synthesis of the compound in Example 214 was carried out by steps similar to those described in Examples 191 and 6, except that 4-fluoroaniline was used instead of aniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191. The remaining steps were the same as those in Examples 191 and 6. 1 H NMR(500MHz,DMSO-d6)δ9.44(s,1H),8.12(s,1H),7.76(d,J=2.4Hz,1H),7.55(dd ,J=8.5,2.4Hz,1H),7.45-7.40(m,2H),7.25(t,J=8.8Hz,2H),7.19(d,J=8.5Hz,1H ),4.69(s,2H),3.94(dd,J=11.2,3.8Hz,2H),3.42(td,J=11.6,2.1Hz,2H),3.37-3 .36(m,5H),3.14-3.08(m,1H),2.17(s,6H),1.71-1.63(m,2H),1.60-1.57(m,2H). MS(ESI)m / z[M+H] + : 491.24.

[0916] Example 215: 7-((3-((dimethylamino)methyl)-4-(1-methylpiperidin-4-yl)phenyl)amino)-3-(4-fluorophenyl)-1-methyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0917]

[0918] The synthesis of the compound in Example 215 was carried out by steps similar to those described in Examples 191 and 6, except that 4-fluoroaniline was used instead of aniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-(1-methylpiperidin-4-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191. The remaining steps were the same as those in Examples 191 and 6. 1 H NMR (500MHz, DMSO-d6) δ9.43 (s, 1H), 8.12 (s, 1H), 7.75 (d, J = 2.4Hz, 1H), 7.53 (d d,J=8.5,2.4Hz,1H),7.44-7.41(m,2H),7.25(t,J=8.8Hz,2H),7.16(d,J=8.5Hz, 1H),4.69(s,2H),3.36(s,3H),3.33(s,3H),2.87(d,J=11.0Hz,2H),2.82-2.77(m ,1H),2.20(s,3H),2.16(s,6H),1.96(td,J=11.1,3.6Hz,2H),1.67-1.62(m,4H). MS(ESI)m / z[M+H] + : 504.28.

[0919] Example 216: 7-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-3-(2-fluorophenyl)-1-methyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0920]

[0921] The synthesis of the compound in Example 216 was carried out by a method similar to that described in Example 191, except that aniline was replaced with 2-fluoroaniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-morpholinoaniline was replaced with 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191, with the remaining steps being the same as in Example 191. 1H NMR (500MHz, DMSO-d6) δ9.45 (s, 1H), 8.12 (s, 1H), 7.89 (d, J = 2.6Hz, 1H), 7.57-7.51 (m, 2H), 7.42-7.37 (m, 1H), 7.35-7.27 (m, 2H), 7.06 (d, J = 8.7Hz, 1H), 4.67 (s, 2H), 3.72 (t, J = 4.4Hz, 4H), 3.44 (s, 2H), 3.36 (s, 3H), 2.85 (t, J = 4.5Hz, 4H), 2.21 (s, 6H). MS(ESI)m / z[M+H] + : 492.24.

[0922] Example 217: 7-((3-((dimethylamino)methyl)-4-(1-methylpiperidin-4-yl)phenyl)amino)-3-(2-fluorophenyl)-1-methyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0923]

[0924] The synthesis of the compound in Example 217 was carried out by steps similar to those described in Examples 191 and 6, except that aniline was replaced with 2-fluoroaniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-(1-methylpiperidin-4-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191. The remaining steps were the same as those in Examples 191 and 6. 1 H NMR (500MHz, DMSO-d6) δ9.47(s,1H),8.13(s,1H),7.76(d,J=2.4Hz,1H),7.55-7.51(m,2H),7.42-7.38(m,1H),7.35-7.27(m,2H),7.16(d,J=8. 5Hz,1H),4.67(s,2H),3.36(s,3H),3.35(s,2H),2.97(d,J=11.0Hz,2H) ,2.88-2.82(m,1H),2.30(s,3H),2.18-2.14(m,7H),1.71-1.66(m,4H). MS(ESI)m / z[M+H] + : 504.28.

[0925] Example 218: 7-((3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-3-(2-fluorophenyl)-1-methyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0926]

[0927] The synthesis of the compound in Example 218 was carried out by steps similar to those described in Examples 191 and 6, except that aniline was replaced with 2-fluoroaniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-(tetrahydro-2H-pyran-4-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191. The remaining steps were the same as those in Examples 191 and 6. 1 H NMR (500MHz, DMSO-d6) δ9.47 (s, 1H), 8.13 (s, 1H), 7.77 (d, J = 2.4Hz, 1H), 7.56-7. 51(m,2H),7.42-7.38(m,1H),7.35-7.27(m,2H),7.19(d,J=8.5Hz,1H),4.67(s,2 H),3.94(dd,J=10.7,4.0Hz,2H),3.42(td,J=11.5,2.1Hz,2H),3.37-3.36(m,5H) ,3.13-3.08(m,1H),2.17(s,6H),1.67(qd,J=12.3,4.2Hz,2H),1.60-1.57(m,2H). MS(ESI)m / z[M+H] + : 491.24.

[0928] Example 219: 7-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-methyl-3-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0929]

[0930] The synthesis of the compound in Example 219 was carried out by a procedure similar to that described in Example 191, except that aniline was replaced with 4-trifluoromethylaniline in step 1 of Example 191, and the remaining steps were the same as in Example 191. 1H NMR (500MHz, DMSO-d6) δ9.45(s,1H),8.14(s,1H),7.91-7.86(m,1H),7.78(d,J=8.4Hz,2H),7.61(d,J=8.3Hz,2H),7.54(dd,J=8.7,2. 6Hz, 1H), 7.04 (d, J = 8.7Hz, 1H), 4.79 (s, 2H), 3.43 (s, 2H), 3.38 (s, 3H), 2.85 (t, J = 4.8Hz, 4H), 2.48 (s, 2H), 2.24 (s, 3H), 2.20 (s, 6H). MS(ESI)m / z[M+H] + : 555.28.

[0931] Example 220: 7-((3-((dimethylamino)methyl)-4-(1-methylpiperidin-4-yl)phenyl)amino)-1-methyl-3-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0932]

[0933] The synthesis of the compound in Example 220 was carried out through steps similar to those described in Examples 191 and 6, except that aniline was replaced with 4-trifluoromethylaniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-(1-methylpiperidin-4-yl)aniline was replaced with 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191. The remaining steps were the same as in Examples 191 and 6. MS (ESI) m / z [M+H] + : 554.28.

[0934] Example 221: 1-Methyl-7-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-3-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0935]

[0936] The synthesis of the compound in Example 221 was carried out by a method similar to that described in Example 191, except that 4-trifluoromethylaniline was used instead of aniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was used instead of 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine in step 4 of Example 191, with the remaining steps being the same as in Example 191. 1H NMR (500MHz, DMSO-d6) δ9.46(s,1H),8.15(s,1H),7.78(d,J=8.5Hz,2H),7.61(d,J=8.4Hz,2H),7.51-7.42(m,2H),7. 01(d,J=8.3Hz,1H),4.79(s,2H),3.45(s,2H),3.36(s,3H),2.75(t,J=5.9Hz,2H),2.58(t,J=5.9Hz,2H),2.34(s,3H). MS(ESI)m / z[M+H] + : 469.18.

[0937] Example 222: 7-((2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-1-methyl-3-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0938]

[0939] The synthesis of the compound in Example 222 was carried out by steps similar to those described in Examples 191 and 28, except that aniline was replaced with 4-trifluoromethylaniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was replaced with 2-(7-amino-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-ol in step 4 of Example 191. The remaining steps were the same as those in Examples 191 and 28. 1 H NMR (500MHz, DMSO-d6) δ9.46(s,1H),8.15(s,1H),7.78(d,J=8.3Hz,2H),7.62(d,J=8.3Hz,2H),7.50-7.44(m,2H),7.00(d,J=8.1 Hz,1H),4.79(s,2H),4.47(s,1H),3.59(dd,J=11.8,6.0Hz,4H),3.36(s,3H),2.72(dd,J=16.5,5.5Hz,4H),2.56(t,J=6.2Hz,2H). MS(ESI)m / z[M+H] + : 499.19.

[0940] Example 223: 7-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-3-(4-methoxyphenyl)-1-methyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0941]

[0942] The synthesis of the compound in Example 223 was carried out by a method similar to that described in Example 191, except that 4-methoxyaniline was used instead of aniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-morpholinoaniline was used instead of 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191, with the remaining steps being the same as in Example 191. 1 H NMR (500MHz, DMSO-d6) δ9.39(s,1H),8.09(d,J=5.2Hz,1H),7.89(d,J=2.6Hz,1H),7.55(dd,J=8.7,2.6Hz,1H),7.29(d,J=8.9Hz,2H),7.04(d,J= 8.7Hz,1H),6.96(d,J=9.0Hz,2H),4.65(s,2H),3.77(s,3H),3.72(t,J=4 .4Hz, 4H), 3.43 (s, 2H), 3.35 (s, 3H), 2.85 (t, J = 4.5Hz, 4H), 2.19 (s, 6H). MS(ESI)m / z[M+H] + 504.26.

[0943] Example 224: 7-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-3-(4-methoxyphenyl)-1-methyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0944]

[0945] The synthesis of the compound in Example 224 was carried out by a procedure similar to that described in Example 191, except that 4-methoxyaniline was used instead of aniline in step 1 of Example 191, and the remaining steps were the same as in Example 191. 1 HNMR(500MHz,DMSO-d6)δ9.37(s,1H),8.09(s,1H),7.88(d,J=2.6Hz,1H),7.53(dd,J=8.7,2.6Hz,1H),7.29(d,J=8.9Hz,2H),7.02(d,J=8.7Hz ,1H),6.96(d,J=8.9Hz,2H),4.65(s,2H),3.77(s,3H),3.40(s,2H),3.3 4(s,3H),2.85(t,J=4.8Hz,4H),2.46(s,4H),2.23(s,3H),2.19(s,6H). MS(ESI)m / z[M+H] + : 517.29.

[0946] Example 225: 7-((3-((cyclopropyl(methyl)amino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-3-(4-methoxyphenyl)-1-methyl-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0947]

[0948] The synthesis of the compound in Example 225 was carried out by a method similar to that described in Example 191, except that 4-methoxyaniline was used instead of aniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was used instead of 3-((cyclopropyl(methyl)amino)methyl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191. The remaining steps were the same as in Example 191. 1 H NMR (500MHz, DMSO-d6) δ9.36 (s, 1H), 8.09 (s, 1H), 7.82 (d, J = 2.7Hz, 1H), 7.50 (dd, J = 8. 6,2.7Hz,1H),7.29(d,J=8.9Hz,2H),7.04(d,J=8.6Hz,1H),6.96(d,J=8.9Hz,2H),4.64( s,2H),3.77(s,3H),3.66(s,2H),3.32(s,3H),2.81(t,J=4.7Hz,4H),2.48(s,4H),2.25 (s,3H),2.16(s,3H),1.77(dt,J=6.5,3.1Hz,1H),0.49-0.46(m,2H),0.36-0.34(m,2H). MS(ESI)m / z[M+H] + : 543.31.

[0949] Example 226: 7-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino)-1-methyl-3-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0950]

[0951] The synthesis of the compound in Example 226 was carried out by a method similar to that described in Example 191, except that 4-trifluoromethoxyaniline was used instead of aniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-morpholinoaniline was used instead of 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191, with the remaining steps being the same as in Example 191. 1H NMR(500MHz,DMSO-d6)δ9.44(s,1H),8.11(s,1H),7.90(d,J=2.6Hz,1H),7.58-7.48(m,3H),7.46-7.39(m,2H),7.05 (d,J=8.7Hz,1H),4.73(s,2H),3.72(t,J=4.4Hz,4H),3.44(s,2H),3.37(s,3H),2.85(t,J=4.5Hz,4H),2.20(s,6H). MS(ESI)m / z[M+H] + : 558.23.

[0952] Example 227: 7-((3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-1-methyl-3-(4-(trifluoromethoxy)benzene)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0953]

[0954] The synthesis of the compound in Example 227 was carried out by a procedure similar to that described in Example 191, except that aniline was replaced with 4-trifluoromethoxyaniline in step 1 of Example 191, and the remaining steps were the same as in Example 191. 1 H NMR(500MHz,DMSO-d6)δ9.44(s,1H),8.11(s,1H),7.91-7.86(m,1H),7.57-7.48(m,3H),7.42(d,J=8.5Hz,2H),7.04( d,J=8.7Hz,1H),4.73(s,2H),3.43(s,2H),3.36(s,3H),2.85(t,J=4.8Hz,4H),2.43(s,2H),2.25(s,3H),2.21(s,6H). MS(ESI)m / z[M+H] + 571.26.

[0955] Example 228: 7-((3-((dimethylamino)methyl)-4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1-methyl-3-(4-(trifluoromethoxy)benzene)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0956]

[0957] The synthesis of the compound in Example 228 was carried out by a method similar to that described in Example 191, except that 4-trifluoromethoxyaniline was used instead of aniline in step 1 of Example 191, and 3-((dimethylamino)methyl)-4-(4-isopropylpiperazin-1-yl)aniline was used instead of 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline in step 4 of Example 191, with the remaining steps being the same as in Example 191. 1 H NMR (500MHz, DMSO-d6) δ9.42(s,1H),8.11(s,1H),7.90(d,J=2.8Hz,1H),7.55-7.48(m,3H),7.42(d,J=8.5Hz,2H),7.03(d,J=8.7Hz,1 H), 4.73 (s, 2H), 3.42 (s, 2H), 3.37 (s, 3H), 2.84 (t, J = 4.6Hz, 4H), 2.73-2.65 (m, 1H), 2.58 (s, 4H), 2.20 (s, 6H), 1.02 (d, J = 6.5Hz, 6H). MS(ESI)m / z[M+H] + : 599.29.

[0958] Example 229: 1-Methyl-7-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-3-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0959]

[0960] The synthesis of the compound in Example 229 was carried out through steps similar to those described in Example 191, except that in step 1 of Example 191, aniline was replaced with 4-trifluoromethoxyaniline, and in step 4 of Example 191, 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was replaced with 2-methyl-1,2,3,4-tetrahydroisoquinoline-7-amine. The remaining steps were the same as in Example 191. MS (ESI) m / z [M+H] + :485.19.

[0961] Example 230: 1-Methyl-7-((2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-3-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrimidino[4,5-d]pyrimidin-2(1H)-one

[0962]

[0963] The synthesis of the compound in Example 230 was carried out through steps similar to those described in Examples 191 and 28, except that in step 1 of Example 191, aniline was replaced with 4-trifluoromethoxyaniline, and in step 4 of Example 191, 3-((dimethylamino)methyl)-4-(4-methylpiperazin-1-yl)aniline was replaced with 2-(7-amino-3,4-dihydroisoquinoline-2(1H)-yl)ethane-1-ol. The remaining steps were the same as in Examples 191 and 28. MS (ESI) m / z [M+H] + : 515.20.

[0964] Example 231: 3-(benzo[d][1,3]dihydroxy-5-yl)-7-((3-((dimethylamino)methyl)-4-morpholinophenyl)amino...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof, in, X, Y, and Z are each -NR 5 -、-(C=O)- and -CR 6a R 6b -, provided that X is not -(C=O)- and Z is not -NR. 5 -; R 1 Selected from hydrogen, C 3-6 Cycloalkenyl, unsubstituted, or with one or two independent R 7 Substituted heterocyclic groups, and unsubstituted or substituted groups, or those with one or two independent R groups 7 Substituted heteroaryl groups; R 2 and R 3 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Alkylamino C 1-3 Alkyl, C 1-6 Alkylaminoyl, (C 1-3 Alkyl)(C 3-6 Cycloalkyl)aminoC 1-3 Alkyl, unsubstituted, or with one or two independent R 7 Substituted heterocyclic groups, and unsubstituted or substituted groups, or those with one or two independent R groups 7 Substituted heteroaryl groups; Or R 1 With adjacent R 2 Or R 3 Together they form a heteroalkylene group containing one heteroatom selected from N and O and 2-4 carbon atoms, wherein when the heteroatom is an N atom, the N atom is not substituted or is replaced by R. 7 replace; The condition is R 1 R 2 and R 3 They are not both hydrogen; R 4 Selected from C 1-6 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl; R 5 Selected from C 1-6 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl; R 6a and R 6b Each is independently selected from hydrogen and C. 1-6 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl, or R 6a R 6b Together with the carbon atoms bonded to them, they form C 3-6 cycloalkyl; Or R 4 With adjacent R 6a Or R 6b Together they form C 3-5 Alkylene, or a heteroalkylene containing one heteroatom selected from N and O and 2-4 carbon atoms, wherein the C 3-5 Alkylenes are optionally further divided by one or two independent C 1-3 Alkyl substitution, and the C 3-5 Two non-adjacent carbon atoms on an alkylene group are optionally connected to form a bridging bond; R 7 Each is independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkoxyalkyl, C 2-6 Alkyl group, C 3-6 Cycloalkylformyl, C 1-6 Alkylamino, C 1-6 alkylsulfonyl, C 1-3 Alkylaminoacyl C 1-3 Alkyl and C 3-6 Cycloalkylaminoacyl C 1-3 Alkyl group, or two adjacent R groups 7 Connect to form C 2-4 Alkylene; R 8 Each is independently selected from amino, halogen, and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Alkylamino, or two adjacent R 8 They are linked to form a heteroalkylene group containing two independent heteroatoms selected from N and O and 1-3 carbon atoms; Wherein, the heterocyclic group is a 5-7 member monocyclic heterocyclic group containing one or two heteroatoms independently selected from N and O, or a 7-10 member bridged bicyclic heterocyclic group containing one or two heteroatoms independently selected from N and O; The heteroaryl group is a 5-6 membered monocyclic heteroaryl group containing one or two heteroatoms independently selected from N and O.

2. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof, wherein... R 1 Selected from hydrogen, C 5-6 Cycloalkenyl, unsubstituted, or with one or two independent R 7 Substituted heterocyclic groups, and unsubstituted or substituted groups, or those with one or two independent R groups 7 Substituted heteroaryl groups; R 2 and R 3 Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-4 Alkylamino C 1-2 Alkyl, C 1-2 Alkylaminoyl, (C 1-2 Alkyl)(C 3-4 Cycloalkyl)aminoC 1-2 Alkyl, unsubstituted, or with one or two independent R 7 Substituted heterocyclic groups, and unsubstituted or substituted groups, or those with one or two independent R groups 7 Substituted heteroaryl groups; Or R 1 With adjacent R 2 Or R 3 Together they form a heteroalkylene group containing one heteroatom selected from N and O and three carbon atoms, wherein when the heteroatom is an N atom, the N atom is not substituted or is replaced by R. 7 replace; R 7 Each is independently selected from hydroxyl, halogen, C 1-3 Alkyl, C 3-6 cycloalkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy C 1-3 Alkyl, C 2-4 Alkyl group, C 3-4 Cycloalkylformyl, C 1-4 Alkylamino, C 1-3 alkylsulfonyl, C 1-2 Alkylaminoacyl C 1-2 Alkyl and C 3-4 Cycloalkylaminoacyl C 1-2 Alkyl group, or two adjacent R groups 7 They connect to form propylidene; in, Each of the heterocyclic groups is independently selected from morpholino, piperazino, homopiperazino, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and 8-9 membered bridged bicyclic heterocyclic groups containing 2 N atoms; Each of the heteroaryl groups is independently selected from pyrazolyl, pyridyl, and pyrroleyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof, wherein... R 1 Selected from unsubstituted or with one selected from hydroxyl, halogen, C 1-3 Alkyl, C 3-5 cycloalkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 2-3 Alkyl group, C 3-4 Cycloalkylformyl, C 2-4 Alkylamino and C 1-2 alkylsulfonyl groups substituted with heterocyclic groups, and unsubstituted or substituted groups with 1 carbon atom. 1-3 Alkyl-substituted pyrazolyl group; R 2 and R 3 Each is independently selected from hydrogen, halogen, and C. 1-2 Alkylamino C 1-2 Alkyl groups, and unsubstituted or substituted with one carbon atom 1-3 Alkyl-substituted heteroaryl groups; Or R 1 With adjacent R 2 Or R 3 Together they form a heteroalkylene group containing one heteroatom selected from N and O and three carbon atoms, wherein when the heteroatom is an N atom, the N atom is not substituted or is selected from C. 1-3 Alkyl, C 1-2 Alkoxy C 1-2 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 2-3 Alkyl group, C 1-2 Alkylaminoacyl C 1-2 Alkyl and C 3-4 Cycloalkylaminoacyl C 1-2 Alkyl group substitution; in, The heterocyclic group is selected from morpholino, piperazino, homopiperazino, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and... The heteroaryl group is selected from pyrazolyl, pyridyl, and pyrroleyl.

4. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof, wherein... R 4 Selected from C 1-3 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl; R 5 Selected from C 1-3 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl; R 6a and R 6b Each is independently selected from hydrogen and C. 1-3 Alkyl groups, and unsubstituted or those with one or two independent R groups 8 Substituted phenyl, or R 6a R 6b Together with the carbon atoms bonded to them, they form C 3-6 cycloalkyl; Or R 4 With adjacent R 6a Or R 6b Together they form C 3-4 Alkylene, or heteroalkylene containing one oxygen atom and three carbon atoms, wherein the C 3-4 The alkylene group is optionally further substituted with two methyl groups, and the C 3-4 Two non-adjacent carbon atoms on an alkylene group are optionally connected to form a bridging bond; R 8 Each is independently selected from amino, halogen, and C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups and C 1-3 Alkylamino, or two adjacent R 8 They are linked to form a heteroalkylene group containing two heteroatoms independently selected from N and O and one to two carbon atoms.

5. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof, wherein... R 4 Selected from C 1-3 Alkyl groups, and unsubstituted or with one or two independently selected from amino, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Phenyl groups substituted with alkylamino groups; R 5 Selected from C 1-3 Alkyl groups, and unsubstituted or with one or two independently selected from halogens, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 Phenyl groups substituted with halogenated alkoxy groups; R 6a and R 6b Each is independently selected from hydrogen, and unsubstituted or by one or two independently selected from halogens and C. 1-3 Alkyl groups substituted with phenyl groups, or R 6a R 6b Together with the carbon atoms bonded to them, they form C 3-6 cycloalkyl; Or R 4 With adjacent R 6a Or R 6b They connect together to form butylene.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof, wherein the compound has the structure of formula (II):

7. The compound of claim 6 or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof, wherein... R 1 Selected from hydrogen, unsubstituted or selected by one or two independently selected hydroxyl groups, halogens, C 1-3 Alkyl, C 3-5 cycloalkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 2-3 Alkyl group, C 3-4 Cycloalkylformyl, C 2-4 Alkylamino and C 1-2 alkylsulfonyl groups substituted with heterocyclic groups, and unsubstituted or substituted groups with 1 carbon atom. 1-3 Alkyl-substituted pyrazolyl group; wherein, The heterocyclic group is selected from morpholino, piperazino, homopiperazino, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and... R 2 and R 3 Each is independently selected from hydrogen, halogen, and C. 1-2 Alkylamino C 1-2 Alkyl groups, and unsubstituted or substituted with one carbon atom 1-3 Alkyl-substituted heteroaryl; wherein the heteroaryl group is selected from pyrazolyl, pyridyl, and pyrrolithyl; Or R 1 With adjacent R 2 Or R 3 Together they form a heteroalkylene group containing one heteroatom selected from N and O and three carbon atoms, wherein when the heteroatom is an N atom, the N atom is not substituted or is selected from C. 1-3 Alkyl, C 1-2 Alkoxy C 1-2 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 2-3 Alkyl group, C 1-2 Alkylaminoacyl C 1-2 Alkyl and C 3-4 Cycloalkylaminoacyl C 1-2 Alkyl group substitution; R 4 Selected from unsubstituted or by one or two independently selected amino, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and C 1-3 Phenyl groups substituted with alkylamino groups; R 5 Selected from C 1-3 alkyl; R 6a and R 6b Each is independently selected from hydrogen, and unsubstituted or halogenated phenyl groups, or R 6a R 6b Together with the carbon atoms bonded to them, they form C 3-6 cycloalkyl; Or R 4 With adjacent R 6a Or R 6b They connect together to form butylene.

8. The compound of claim 6 or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof, wherein... R 1 Selected from unsubstituted or by one or two independently selected halogens, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 2-3 alkyl acyl and C 2-4 Alkylamino groups substituted with heterocyclic groups, and unsubstituted or substituted groups with one carbon atom. 1-3 Alkyl-substituted pyrazolyl group; wherein, The heterocyclic group is selected from morpholino, piperazino, homopiperazino, pyrrolidinyl, piperidinyl, tetrahydropyranyl, and... R 2 and R 3 Each is independently selected from hydrogen, halogens, and C. 1-2 Alkylamino C 1-2 alkyl; Or R 1 With adjacent R 2 Or R 3 Together they form a heteroalkylene group containing 1 nitrogen atom and 3 carbon atoms, wherein the nitrogen atom is not substituted or is replaced by a carbon atom. 1-3 Alkyl or C 1-2 Alkoxy C 1-2 Alkyl substitution; R 4 Selected from unsubstituted or one selected from halogen and C 1-3 Phenyl groups substituted with alkyl groups; R 5 It is methyl; R 6a and R 6b Each is independently selected from hydrogen and phenyl, or R 6a R 6b Together with the carbon atoms bonded to them, they form C 3-6 cycloalkyl; Or R 4 With adjacent R 6a Or R 6b They connect together to form butylene.

9. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof, wherein the compound has the structure of formula (III):

10. The compound of claim 9 or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof, wherein... R 1 Selected from unsubstituted or by 1 C 1-3 Alkyl-substituted heterocyclic groups; wherein, The heterocyclic group is selected from morpholino, piperazino, piperidino, and tetrahydropyrano; R 2 and R 3 Each is independently selected from hydrogen and C. 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-2 Alkylamino C 1-2 Alkyl, (C 1-2 Alkyl)(C 3-4 Cycloalkyl)aminoC 1-2 Alkyl groups, and unsubstituted or substituted with one carbon atom 1-3 Alkyl-substituted pyrazolyl group; Or R 1 With adjacent R 2 Or R 3 Together they form a heteroalkylene group containing one nitrogen atom and three carbon atoms, wherein the nitrogen atom is unsubstituted or selected from C. 1-3 Alkyl and C 1-3 Hydroxyl alkyl group substitution; R 4 Selected from C 1-3 alkyl; R 5 Selected from unsubstituted or one selected from halogen, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 Phenyl groups substituted with halogenated alkoxy groups; R 6a and R 6b Each is hydrogen.

11. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof, wherein the compound is selected from:

12. A pharmaceutical composition comprising a compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

13. Use of the compound of any one of claims 1-11, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, acid, ester, metabolite, or prodrug thereof, in the preparation of a medicament for the treatment and / or prevention of diseases mediated by HPK1 activity.

14. The use as described in claim 13, wherein the disease is selected from: Parkinson's disease, Alzheimer's disease, stroke and related memory loss, arthritis, allergies, asthma, diabetes, symptoms characterized by inflammation, hepatic ischemia, reperfusion injury, hearing loss or deafness, neural tube defects, obesity, oxidative damage to organs, heart disease, and transplant rejection.

15. The use as described in claim 13, wherein the disease is a hyperproliferative disease selected from: melanoma, thyroid cancer, adenocarcinoma, breast cancer, central nervous system cancer, colorectal cancer, squamous cell carcinoma, small cell and non-small cell lung cancer, ovarian cancer, endometrial cancer, pancreatic cancer, prostate cancer, sarcoma, and skin cancer.

16. The use as described in claim 13, wherein the disease is a hematologic cancer selected from: leukemia, acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, megakaryoblastic leukemia, and multiple myeloma.

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