Amino-substituted aromatic compound and application thereof

Abstract

The invention provides an amino-substituted aromatic compound as shown in a formula A and application thereof. The compound disclosed by the invention can be combined with YES1 protein to inhibit the activity of the YES1 protein, inhibit transcription of related genes and inhibit cell growth, so that the compound is used for treating diseases related to the YES1 protein. In addition, the compound also has good oral bioavailability. A

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical technology, specifically relating to an amino-substituted aromatic compound and its applications. Background Technology

[0002] Protein kinases are important enzymes that catalyze the phosphorylation of proteins. They regulate protein activity through phosphorylation and amplify signals through stepwise phosphorylation, triggering cellular responses. Protein kinases play a crucial regulatory role in life processes, and abnormalities often lead to malignant diseases such as cancer. Dysregulation of protein kinase function, such as through gain-of-function mutations, gene amplification, autonomous activation, and activation via chromosomal rearrangements, is closely related to cancer development and progression, participating in cancer cell transformation, growth, proliferation, and survival.

[0003] Currently, protein kinases are considered important targets for developing molecularly targeted therapies. Src family kinases (SFKs) are a class of non-receptor protein tyrosine kinases. These SFKs are membrane-bound proteins comprising approximately nine members: Src, Fyn, YES1, Lck, Lyn, Hck, Fgr, and Blk. Src proteins are non-receptor tyrosine kinases that can be activated by multiple signal transduction pathways. Activated Src kinases then activate their corresponding target proteins by phosphorylating tyrosine residues, thereby activating the corresponding signaling pathways, including MAPK, STAT, PI3K / AKT, and EGFR. Abnormally activated Src proteins are associated with many tumors, and their activity is closely related to tumor development. Inhibiting the activity of Src family kinase members in tumor tissue may be an effective means of cancer treatment. Currently reported Src kinase family inhibitors include dasatinib and bosutinib, but due to their poor selectivity, they have not shown sufficient efficacy in clinical practice as Src family kinase inhibitors. Therefore, there is a need in clinical practice for more selective and effective Src family kinase inhibitors. Summary of the Invention

[0004] This invention provides compounds represented by formula A, including their enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs, isotope derivatives, or solvates:

[0005] A Where R1 is selected from any of the C that is substituted. 1-12 Alkyl groups, optionally substituted C 2-12 alkenyl, optionally substituted C 2-12 alkynyl group, optionally substituted C 3-20Cycloalkyl, optionally substituted 5-20 membered heterocyclic, optionally substituted 5-20 membered cycloalkenyl, optionally substituted 5-20 membered heteroaryl, or optionally substituted C 6-20 Aryl; X1, X2, X3, and X4 may be the same or different, and are independently selected from CR8 or N, provided that X1, X2, X3, and X4 are not simultaneously CR8; R2 is selected from H, halogen, cyano group, optionally substituted amino group, and optionally substituted C group. 1-12 Alkyl, or optionally substituted C 1-12 Alkoxy; n is 1, 2, 3 or 4; R3 is selected from -NR6-COO-R7; R4, R5, and R6 may be the same or different, and are independently selected from H, or arbitrarily substituted C. 1-12 alkyl; R7 is selected from any C that is arbitrarily replaced. 1-12 Alkyl groups, optionally substituted C 2-12 alkenyl, optionally substituted C 2-12 alkynyl group, optionally substituted C 3-20 Cycloalkyl, optionally substituted 5-20 membered heterocyclic, optionally substituted 5-20 membered cycloalkenyl, optionally substituted 5-20 membered heteroaryl, or optionally substituted C 6-20 Aryl; R8 is selected from hydrogen, halogen, cyano, optionally substituted amino, and optionally substituted C. 1-12 Alkyl group, optionally substituted C 1-12 Alkyl group.

[0006] In embodiments of the present invention, unless otherwise specified, the terms "optionally substituted" or "optionally substituted" shall be interpreted in accordance with the definition of "optionally substituted" in the "Terminology Definitions and Explanations" section of the specification.

[0007] In some embodiments of the invention, R1 is selected from unsubstituted or optionally substituted groups of one, two or more Ra, such as: C 1-12 Alkyl, C 3-20 Cycloalkyl, 5-20 membered heterocyclic, 5-20 membered cycloalkenyl, 5-20 membered heteroaryl or C 6-20 Aryl; Ra is selected from oxygen (=O), C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, deuterated C 1-12 Alkyl groups, unsubstituted, or optionally substituted with one, two, or more Rb groups, including the following groups: C 3-20 Cycloalkyl, 5-20 membered heterocyclic groups, -COC1-12 alkyl; Rb is selected from C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, deuterated C 1-12 Alkyl, NHC 1-12 Alkyl, N(C) 1-12 Alkyl)2; X1, X2, X3, and X4 may be the same or different, and are independently selected from CR8 or N, provided that X1, X2, X3, and X4 are not simultaneously CR8; R2 is selected from H, halogen, cyano, optionally substituted amino group, C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl or deuterated C 1-12 alkyl; n is 1, 2, 3 or 4; R3 is selected from -NR6-COO-R7; R4, R5, and R6 may be the same or different, and are independently selected from H and C. 1-12 Alkyl or deuterated C 1-12 alkyl; R7 is selected from C 1-12 Alkyl, Halogenated C 1-12 Alkyl or deuterated C 1-12 alkyl; R8 is selected from hydrogen, halogen, cyano, optionally substituted amino, and optionally substituted C. 1-12 Alkyl group, optionally substituted C 1-12 Alkyl group.

[0008] In some embodiments of the present invention, X1, X2, X3 and X4 may be the same or different, and are independently selected from CH or N.

[0009] In some embodiments of the present invention, X1, X2, X3 and X4 are selected from N.

[0010] In some embodiments of the invention, R1 is selected from unsubstituted or optionally substituted groups of one, two or more Ra, such as: C 1-6 Alkyl, C 3-12 Cycloalkyl, 5-12 membered heterocyclic, 5-12 membered cycloalkenyl, 5-14 membered heteroaryl or C 6-14 Aryl; Ra is selected from oxygen (=O), C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl groups, unsubstituted, or optionally substituted with one, two, or more Rb groups, including the following groups: C 3-12Cycloalkyl, 5-12 membered heterocyclic groups, -COC 1-6 alkyl; Rb is selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2; R2 is selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl; R3 is selected from -NR6-COO-R7; R4, R5, and R6 are H; R7 is selected from C 1-6 Alkyl, Halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl.

[0011] In some specific embodiments of the present invention, R1 is selected from -C 3-12 cycloalkyl-5-12-membered heterocyclic-C 1-6 Alkyl, -5-14-membered heteroaryl-C 1-6 Alkyl, =O and C 1-6 Alkyl-substituted 5-12-membered cycloalkenyl, -5-12-membered heterocyclic -COC 1-6 Alkyl-N(C) 1-6 Alkyl)2, C 3-12 Cycloalkyl, 5-12-membered heterocyclic, -5-14-membered heteroaryl-halogenated C 1-6 Alkyl, -5-14-membered heteroaryl-C 1-6 Alkyl, -5-14-membered heteroaryl-deuterated C 1-6 Alkyl, -5-14-membered heteroaryl-C 3-12 Cycloalkyl, =O and halogenated C 1-6 Alkyl-substituted 5-12 membered cycloalkenyl groups, =O and deuterated C 1-6 Alkyl-substituted 5-12-membered cycloalkenyl, =O-substituted 5-12-membered cycloalkenyl, 5-14-membered heteroaryl or -5-12-membered heterocyclic -5-12-membered heterocyclic -C 1-6 alkyl.

[0012] In some more specific embodiments of the invention, the terms =O and C 1-6 When the 5-12-membered cycloalkenyl group in the alkyl-substituted 5-12-membered cycloalkenyl group contains a heteroatom N, the C 1-6 Alkyl groups preferentially substitute on the heteroatom N.

[0013] In some more specific embodiments of the invention, the term =O and deuterated C 1-6 When the 5-12-membered cycloalkenyl group in the alkyl-substituted 5-12-membered cycloalkenyl group contains a heteroatom N, the deuterated C 1-6 Alkyl groups preferentially substitute on the heteroatom N.

[0014] In some more specific embodiments of the present invention, the -5-12 membered heterocyclic group -5-12 membered heterocyclic group -C 1-6 The linking sites in alkyl groups are preferentially located on heteroatoms such as N.

[0015] In some more specific embodiments of the present invention, R1 is selected from -C 3-6 cycloalkyl-5-6-membered heterocyclic-C 1-3 Alkyl, -5-6-membered heteroaryl-C 1-3 Alkyl, =O and C 1-3 Alkyl-substituted 5-6 membered cycloalkenyl, -5-6 membered heterocyclic -COC 1-3 Alkyl-N(C) 1-3 Alkyl)2, C 3-6 Cycloalkyl, 5-6 membered heterocyclic, -5-6 membered heteroaryl-halogenated C 1-3 Alkyl, -5-6-membered heteroaryl-C 1-3 Alkyl, -5-6-membered heteroaryl-deuterated C 1-3 Alkyl, -5-6-membered heteroaryl-C 3-6 Cycloalkyl, =O and halogenated C 1-4 Alkyl-substituted 5-6 membered cycloalkenyl groups, with =O and deuterated C 1-3 Alkyl-substituted 5-6 membered cycloalkenyl, =O-substituted 5-6 membered cycloalkenyl, 5-6 membered heteroaryl or -5-6 membered heterocyclic -5-6 membered heterocyclic -C 1-3 alkyl; Among the above groups, C 3-6 The cycloalkyl groups may be the same or different, and are independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; The 5-6 membered heterocyclic group is, for example, a 5- or 6-membered heterocyclic group containing N or O, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolealkyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazineyl; The 5-6 membered cycloalkenyl group is, for example, cyclopentenyl, cyclohexenyl, or... ; The 5-6 membered heteroaryl group is selected, for example, from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or thia-4H-pyrazolyl; The C 1-3 Alkyl groups are selected, for example, from methyl, ethyl, or propyl; The deuterated C 1-3 Alkyl groups are selected, for example, from trideuterated methyl or pentadeuterated ethyl; The halogenated C 1-3 Alkyl groups are selected, for example, from groups substituted with one, two, or more F or Cl: methyl, ethyl, or propyl; for example, the halogenated C. 1-3 The alkyl group is selected from monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoropropyl, Or trifluoroethyl; The -N(C 1-3 Alkyl)2, for example, is -N(methyl)2, -N(ethyl)2 or -N(propyl)2.

[0016] As an example, R1 is selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , or .

[0017] In some specific embodiments of the present invention, R2 is selected from C. 1-3 Alkyl or C 1-3 Alkoxy groups, such as methyl, ethyl, propyl, methoxy, ethoxy, or propoxy.

[0018] In some specific embodiments of the present invention, when R2 is selected from C 1-3 Alkyl or C 1-3 When alkoxy is present, it is located at the ortho or meta position of R3.

[0019] In some more specific embodiments of the present invention, R3 is selected from -NH-COO-R7, and R7 is selected from C. 1-4 Alkyl groups, such as methyl, ethyl, propyl, n-butyl, isobutyl, or tert-butyl.

[0020] In some embodiments of the present invention, the compound represented by Formula A further has a structure as shown in Formula B: (B) The definitions of R1, R2, and R3 are as described in any of the previous schemes.

[0021] As an example, the compound represented by formula A is selected from any of the compounds shown in Table 1: Table 1. Compounds

[0022]

[0023]

[0024]

[0025]

[0027] The present invention also provides a method for preparing the compound shown in Formula A, comprising the following steps: , Compound A1 reacts with compound A2 to give the compound shown in formula A; Wherein, X is selected from halogens; preferably, X is selected from Br or I; X1, X2, X3, X4, R1, R2, R3, R4, R5 and n are defined as described in any of the preceding schemes.

[0028] The present invention also provides a pharmaceutical composition comprising at least one of the following as an active ingredient: a compound of formula A or formula B, or an enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug, isotope derivative, or solvate thereof.

[0029] According to embodiments of the present invention, the pharmaceutical composition further includes a pharmaceutically acceptable carrier.

[0030] According to embodiments of the present invention, the pharmaceutically acceptable carrier includes: fillers, excipients, disintegrants, binders, and wetting agents.

[0031] Depending on the route of administration, the composition of this application may contain 10% to 90% by weight of the active ingredient, such as 20% to 80%, 30% to 70%, or 40% to 60% by weight of the active ingredient.

[0032] The pharmaceutical composition of this application is in the form of an oral formulation or an injection. The oral formulation may be a capsule, tablet, etc., and the injection may be administered intravenously, intramuscularly, or subcutaneously.

[0033] The present invention also provides the use of at least one of the compounds of Formula A or Formula B as described above, their enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs, isotope derivatives, solvates, or the pharmaceutical compositions described above in the preparation of medicaments for the prevention or treatment of diseases related to YES1 amplification or YES1 overexpression.

[0034] According to embodiments of the present invention, the purpose of preventing or treating diseases related to YES1 amplification or YES1 overexpression can be achieved by administering a therapeutically effective amount and / or a preventively effective amount of the compound represented by Formula A or Formula B or the above-described pharmaceutical composition to the patient.

[0035] According to an embodiment of the present invention, the disease associated with YES1 amplification or YES1 overexpression is selected from cancer; the cancer includes at least one of the following: acute myeloid leukemia, chloroma, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, B-cell lymphoma, multiple myeloma, Waldenström macroglobulinemia, myelodysplastic syndrome, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, reproductive tract cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, uterine cancer, gestational trophoblastic disease, gastric cancer, bile duct cancer, gallbladder cancer, small bowel cancer, esophageal cancer, oropharyngeal cancer, hypopharyngeal cancer, eye cancer, neurogenic cancer, head and neck cancer, melanoma, plasmacytoma, endocrine gland tumors, neuroendocrine carcinoma, brain tumors, bone cancer, and sarcoma.

[0036] Beneficial effects The compounds of this invention can inhibit YES1 protein activity, suppress transcription of related genes, and inhibit cell growth by binding to the YES1 protein, thereby enabling the treatment of YES1 protein-related diseases. Furthermore, the compounds also exhibit good oral bioavailability.

[0037] Terminology Definitions and Explanations Unless otherwise defined, all technical terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains.

[0038] "More than three" means three or more.

[0039] This application partially substitutes the base " The "" indicates the connection point. The term "halogenated" means that the halogenated product is replaced by one, two or more of the following groups: F, Cl, Br or I.

[0040] Term "C" 1-12 "alkyl" should be understood to refer to a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 12 carbon atoms. In one embodiment, the alkyl group is C1-C2. 12 C1-C10 C1-C8, C1-C6, or C2-C3. For example, "C 1-6 "Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0041] Term "C" 1-12 "Alkoxy" should be understood as -OC 1-12 Alkyl, wherein C 1-12 Alkyl groups have the above definition.

[0042] The term "halogenated C" 1-12 "alkyl" indicates C 1-12 One, two, or more H atoms in the alkyl group are substituted by at least one of the following groups: F, Cl, Br, or I. The C 1-12 Alkyl groups have the above definition.

[0043] The term "deuterated C" 1-12 "alkyl" should be understood as C 1-12 At least one H in the alkyl group is substituted with deuterium. The C... 1-12 Alkyl groups have the above definition.

[0044] Term "C" 2-12 "Alkenyl" should be understood as a straight-chain or branched monovalent hydrocarbon group having at least one carbon-carbon double bond and comprising 2 to 12 carbon atoms, and including groups having "cis" and "trans" orientations or "E" and "Z" orientations. In one embodiment, the alkenyl group is C2-C. 12 C2-C 10 C2-C8, C2-C6, or C2-C3. For example, "C 2-6"Alkenyl" refers to straight-chain and branched alkenyl groups having 2, 3, 4, 5, or 6 carbon atoms. Examples include, but are not limited to, ethenyl or vinyl (-CH=CH2), propenyl (-CH=CHCH3), propenyl (-CH2CH=CH2), 2-methylpropenyl, butenyl, butenyl, butenyl, butenyl, butenyl, butenyl, 2-methylbutenyl, hexenyl, hexenyl, hexenyl, hexenyl, hexenyl, hexenyl, hexenyl, hexenyl, hexenyl, hexenyl, hexenyl, and hexenyl.

[0045] Term "C" 2-12 "Alynyl" should be understood as a straight-chain or branched monovalent hydrocarbon group having at least one carbon-carbon triple bond and comprising 2 to 12 carbon atoms. In some embodiments, the alkynyl group is C2-C. 12 C2-C 10 C2-C8, C2-C6, or C2-C3. For example, "C 2-6 "Alynyl" refers to a straight-chain or branched alkynyl group having 2, 3, 4, 5, or 6 carbon atoms. Examples include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH3), propynyl (propynyl, -CH2C≡CH), butynyl, butynyl, and butynyl-3.

[0046] Term "C" 6-20 "Aryl" should be understood to represent an aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably "C". 6-14 "Aromatic". The term "C" 6-14 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14 Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl groups, such as anthracene groups, or rings with 16 carbon atoms (“C”). 16 Aryl), such as pyrene. When the C 6-22 When the base is substituted, it can be a single substitution or multiple substitutions. Furthermore, there are no restrictions on the substitution site; for example, it can be an ortho, para, or meta substitution.

[0047] The term "5-20-membered heteroaryl" should be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms, and containing 1 to 5 heteroatoms independently selected from N, O, and S, for example, "5-14-membered heteroaryl". The term "5-14-membered heteroaryl" should be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5, 6, 9, or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S, and, in each case, may be benzo-fused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazoleyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or acrylinyl, inazinyl, purinyl, and their benzo[derivatives]; or terpenolyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphridinyl, pteridinyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, phenothiazinyl, etc.

[0048] Term "C" 3-20 "Cycloalkyl" should be understood to represent a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, preferably "C". 3-12 "Cycloalkyl". 3-12 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or bicyclic hydrocarbon groups such as decahydronaphthalene ring.

[0049] The term "3-20 membered heterocyclic group" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3, heteroatoms selected from N, O, and S, and having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms, preferably "3-12 membered heterocyclic group". The heterocyclic group can be connected to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). Specifically, the heterocyclic group may include, but is not limited to: 4-membered rings, such as azirrobutyl and oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group may be benzofused. The heterocyclic group may be bicyclic, for example, but not limited to, 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrolo-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl rings. The nitrogen-containing ring can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrole, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. According to the invention, the heterocyclic group is non-aromatic.

[0050] The term "5-20 membered cycloalkenyl" refers to an unsaturated monocyclic or bicyclic hydrocarbon ring containing 1-5 double bonds and having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms. The ring atoms may also be 1-3 heteroatoms selected from N, O, and S, preferably "5-12 membered cycloalkenyl". The "5-12 membered cycloalkenyl" can be a 5- or 6-membered cycloalkenyl, such as cyclopentenyl, cyclohexenyl, or... .

[0051] The term "alkylene" refers to a divalent group derived from "alkyl," and is used merely as an example. 1-12 Examples of "alkylene" include, but are not limited to, -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -CH(CH2CH3)-, -C(CH3)2-, -CH(CH3)CH2-, -C(CH3)2-CH2CH2CH2-, -C(CH3)2-CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH(CH3)CH2-.

[0052] Unless otherwise indicated, the term "optionally substituted" means that the group may be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range thereof) of the substituents listed for the group, wherein said substituents may be the same or different. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 substituents. In another embodiment, the optionally substituted group has 3 substituents. In another embodiment, the optionally substituted group has 4 substituents. In another embodiment, the optionally substituted group has 5 substituents. The optionally substituted group may be selected from the following groups: deuterium; halogen; OH; NH2; CN; NO2; oxo group; C 1-12 Alkyl; C 2-12 alkenyl; C 2-12 alkynyl group; C 3-20 Cycloalkyl; 3-20 membered heterocyclic group; C 6-20 Aryl; 5-20 heteroaryl; C 2-12 alkenyl-C 1-12 Alkylene-; C 2-12 alkynyl-C 1-12 Alkylene-; C 6-20 Aryl-C 1-12 alkylene-; 5-20-membered heteroaryl-C 1-12 Alkylene - -OR' -C(O)R' -CO2R' -OC(O)R' -S(O)R' -S(O)2R' -NR''R''' -CONR''R''' -OC(O)NR'' R''' -NR'' C(O)R'; -S(O)NR''R'''; -S(O)2NR''R'''; -NR''S(O)R'; -NR''S(O)2R'; -NR'C(O)NR''R'''; -NR'S(O)NR''R'''; -NR'S(O)2NR''R'''; -(CH2) 1-6 -R';-(CH2) 1-6 -OR';-(CH2) 1-6 -NR''R''';-(CH2) 1-6 -SR';-(CH2) 1-6 -SiR'R''R''';-(CH2) 1-6 -OC(O)R';-(CH2) 1-6 -C(O)R';-(CH2) 1-6 -CO2R'; or -(CH2) 1-6 CONR''R'''; Each R', R'', and R''' independently signifies the following group: hydrogen; C 1-12 Alkyl; C 2-12alkenyl; C 2-12 alkynyl group; C 3-20 Cycloalkyl; 3-20 membered heterocyclic group; C 6-20 Aryl; 5-20 heteroaryl; C 2-12 alkenyl-C 1-12 Alkylene-; C 2-12 alkynyl-C 1-12 Alkylene-; C 6-20 Aryl-C 1-12 alkylene-; 5-20-membered heteroaryl-C 1-12 Alkylene-; C 1-12 Alkyl acyl; C 2-12 alkenyl acyl; C 2-12 Entyl acyl group; C 3-20 Cycloalkyl acyl; 3-20 membered heterocyclic acyl; C 6-20 Aryl acyl; 5-20 membered heteroaryl acyl; C 1-12 alkylsulfonyl; C 2-12 alkenylsulfonyl; C 2-12 alkynylsulfonyl; C 3-20 Cycloalkylsulfonyl; 3-20 membered heterocyclic sulfonyl; C 6-20 arylsulfonyl; 5-20 membered heteroarylsulfonyl; C 1-12 alkylsulfinyl; C 2-12 alkenylsulfinyl; C 2-12 alkynyl sulfinyl; C 3-20 Cycloalkyl sulfinyl; 3-20 membered heterocyclic sulfinyl; C 6-20 Arylsulfinyl group; 5-20 membered heteroarylsulfinyl group; when R'' and R''' are attached to the same nitrogen atom, it can combine with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring, wherein the ring atom is optionally substituted with N, O, or S and the ring is optionally substituted with halogen, OH, CN, or C. 1-12 Alkyl, C 1-12 Alkoxy or oxo substitution. Detailed Implementation

[0053] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0054] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0055] Preparation Examples

[0056] Example 1:

[0057] Step 1: Dissolve 1.0 g of 3-iodo-1H-pyrazolo[3,4-d]pyrimidine-4-amine in 20 mL of DMF and cool to 0 °C. Add NaH (192 mg) in portions. Stir the mixture at 0 °C for 30 minutes, then add 715 mg of 3-bromocyclobutanone. After the addition is complete, heat the mixture to 100 °C and continue stirring overnight until the reaction is complete. After the reaction is complete, cool to 0 °C and quench the reaction with ice water. Extract the resulting mixture three times with ethyl acetate and combine the organic phases. Wash the organic phase with water and saturated brine, dry with anhydrous sodium sulfate, and remove the solvent. Purify the residue by column chromatography to give the target compound (500 mg).

[0058] Step 2: At room temperature, the product obtained in Step 1 (139 mg) and 4-methylpiperazine (45 mg) were dissolved in dichloromethane (5 mL), and acetic acid (30 mg) and sodium triacetoxyborohydride (267 mg) were added. The mixture was stirred at room temperature for 16 hours until the reaction was complete. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate aqueous solution, and the pH of the mixture was adjusted to 8-9. The resulting mixture was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by column chromatography to give the target compound (130 mg).

[0059] Step 3: At room temperature, the product obtained in Step 2 (130 mg) was dissolved in a mixed solution of 1,4-dioxane and water (2.5 mL, v / v = 4 / 1), and Pd(PPh3)4 (70 mg), potassium carbonate (138 mg), and tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)carbamate (158 mg) were added. The mixture was thoroughly purged with nitrogen and heated to 100 °C with stirring for 2 hours until the reaction was complete. After the reaction was complete, the reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate to remove the solvent, and the residue was purified by column chromatography to give the title compound (11 mg). LCMS (ES, m / z): 509.3 [M+H] + .

[0060] Example 2:

[0061] Step 1: At room temperature, 3-hydroxycyclobutanone (500 mg) and 4-methylpiperazine (580 mg) were dissolved in dichloromethane (15 mL), and acetic acid (350 mg) and sodium triacetoxyborohydride (2.5 g) were added. The mixture was stirred at room temperature for 16 hours until the reaction was complete. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate aqueous solution, and the pH of the mixture was adjusted to 8-9. The resulting mixture was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by column chromatography to give the target compound (680 mg).

[0062] Step 2: At room temperature, the product obtained in Step 1 (660 mg) was dissolved in dichloromethane (10 mL), and triethylamine (400 mg) was added. After cooling the mixture to 0°C, methanesulfonic anhydride (675 mg) was added dropwise. The mixture was stirred at room temperature for 30 minutes, then slowly raised to room temperature and stirred until the reaction was complete. After the reaction was complete, ice water was added to quench the reaction. The mixture was separated, the organic phase was washed with saturated brine, and dried with anhydrous sodium sulfate. The organic phase was removed, and the remaining aqueous phase was dried under vacuum to obtain the crude product (730 mg), which was used directly in the next reaction.

[0063] Step 3: At room temperature, the product obtained in Step 2 (360 mg) was dissolved in DMF (5 mL), and 3-iodo-1H-pyrazolo[3,4-d]pyrimidine-4-amine (380 mg) and potassium carbonate (400 mg) were added. The mixture was stirred at room temperature for 3 hours, then heated to 60°C and stirred overnight. After the reaction was complete, water and ethyl acetate were added to the reaction solution, and the mixture was stirred thoroughly and then separated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by column chromatography to give the target compound (220 mg).

[0064] Step 4: At room temperature, the product obtained in Step 3 (180 mg) was dissolved in a mixed solution of 1,4-dioxane and water (3 mL, v / v = 4 / 1), and tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)carbamate (180 mg), Pd(PPh3)4 (50 mg), and potassium carbonate (150 mg) were added. The mixture was thoroughly purged with nitrogen and heated to 100 °C with stirring for 2 hours until the reaction was complete. After the reaction was complete, the reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate to remove the solvent, and the residue was purified by column chromatography to give the title compound (11 mg). LCMS (ES, m / z): 509.3 [M+H]+ .

[0065] Example 3:

[0066] Step 1: At room temperature, anhydrous copper acetate (554 mg) was added to a mixed solution (11 mL, v / v = 10 / 1) of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (800 mg) and (1-methyl-2-oxo-1,2-dihydropyridin-4-yl)boronic acid (703 mg) in DMF and pyridine. The mixture was then heated to 40 °C and stirred overnight. After the reaction was complete, ethyl acetate was added to the mixture, and the mixture was stirred thoroughly and filtered. The filtrate was washed with ammonium chloride aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by column chromatography to give the target compound (360 mg). LCMS (ES, m / z): 368.7 [M+H] + .

[0067] Step 1: At room temperature, the product obtained in Step 1 (360 mg) and (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)carbamate tert-butyl ester (410 mg) were dissolved in a mixed solution of 1,4-dioxane and water (5 mL, v / v = 4 / 1), and potassium carbonate (405 mg) and Pd(PPh3)4 (113 mg) were added. The mixture was thoroughly purged with nitrogen and heated to 100°C, stirred overnight until the reaction was complete. After the reaction was complete, the mixture was separated, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (31 mg). LCMS (ES, m / z): 464.2 [M+H] + .

[0068] 1 H NMR (400 MHz, DMSO- d 6) δ (ppm): 8.43 (s, 1H), 8.09 (s, 1H), 7.99(d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 4.0 Hz, 1H), 7.34 -7.29 (m, 3H), 3.91 (s, 3H), 3.46 (s, 3H), 1.49 (s, 9H).

[0069] Example 4:

[0070] The synthetic method was similar to that of Example 3, except that the intermediate 1-methyl-2-oxo-1,2-dihydropyridin-4-yl)boronic acid was replaced with 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxanthracene-2-yl)-1H-pyrazole to obtain the title compound. LCMS (ES, m / z): 437.2 [M+H] + .

[0071] Example 5:

[0072] Step 1: At room temperature, anhydrous copper acetate (400 mg) was added to a mixed solution (11 mL, v / v = 10 / 1) of 3-bromo-4-methoxy-1H-pyrazolo[3,4-d]pyrimidine (500 mg) and (1-methyl-1H-pyrazol-4-yl)boronic acid (556 mg) in DMF and pyridine. The mixture was thoroughly purged of oxygen and heated to 40 °C with continuous stirring overnight. After the reaction was complete, ethyl acetate was added to the mixture, and the mixture was stirred thoroughly and filtered. The filtrate was washed with ammonium chloride aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by column chromatography to give the target compound (200 mg). LCMS (ES, m / z): 308.7 [M+H] + .

[0073] Step 2: At room temperature, the product obtained in Step 1 (200 mg) and (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)carbamate tert-butyl ester (453 mg) were dissolved in a mixed solution of 1,4-dioxane and water (5 mL, v / v = 4 / 1), and potassium carbonate (269 mg) and Pd(PPh3)4 (188 mg) were added. The mixture was thoroughly purged with nitrogen and heated to 100°C, stirred overnight until the reaction was complete. After the reaction was complete, the mixture was separated, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (100 mg). LCMS (ES, m / z): 451.9 [M+H] + .

[0074] Step 3: At room temperature, ammonia (3 mL, 30%) was added to a 3 mL isopropanol solution of the product (100 mg) obtained in Step 2. The mixture was heated to 95°C and stirred overnight until the reaction was complete. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound (57 mg). LCMS (ES, m / z): 437.2 [M+H] + .

[0075] 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 8.36 (s, 1H), 8.34 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 4.0 Hz, 1H), 7.28 -7.26 (m, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 1.49 (s, 9H).

[0076] Example 6:

[0077] Step 1: At room temperature, N,N-dimethylglycine (1.8 g) was dissolved in anhydrous acetonitrile (510 mL), and triethylamine (3.5 g) was added. After thorough stirring, CDI (3.3 g) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes, and (S)-3-pyrrolidone (1.5 g) was added. The mixture was stirred at room temperature for 3 hours until the reaction was complete. After the reaction was complete, the solvent was removed, and the residue was purified by column chromatography to obtain the target compound (4 g).

[0078] Step 2: At room temperature, the product obtained in Step 1 (1.1 g) was dissolved in dichloromethane (25 mL), and triethylamine (1.2 g) was added. After cooling the mixture to 0°C, methanesulfonic anhydride (1.1 g) was added dropwise. The mixture was then slowly heated to room temperature and stirred for 2 hours until the reaction was complete. After the reaction was complete, the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed to obtain 1.2 g of crude target compound.

[0079] Step 3: At room temperature, the product obtained in Step 2 (1.2 g) was dissolved in DMF (30 mL), and cesium carbonate (5.7 g) and 3-iodo-1H-pyrazolo[3,4-d]pyrimidine-4-amine (1.5 g) were added. The mixture was stirred overnight at room temperature until the reaction was complete. After the reaction was complete, water and ethyl acetate were added to the mixture, and the mixture was stirred thoroughly and separated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by column chromatography to give the target compound (150 mg).

[0080] Step 4: At room temperature, the product obtained in Step 3 (150 mg) and (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)carbamate tert-butyl ester (164 mg) were dissolved in a mixed solution of 1,4-dioxane and water (4 mL, v / v = 4 / 1), and potassium carbonate (100 mg) and Pd(PPh3)4 (83 mg) were added. The mixture was thoroughly purged with nitrogen and stirred overnight at 100 °C until the reaction was complete. After the reaction was complete, the mixture was separated, and the organic phase was concentrated. The residue was purified by column chromatography to give the title compound (45 mg). LCMS (ES, m / z): 511.3 [M+H] + .

[0081] 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 8.26 (d, J = 2.8 Hz, 1H), 8.03 (s,1H), 7.90 (dd, J = 8.4, 2.8 Hz, 1H), 7.28 - 7.15 (m, 2H), 5.51-5.40 (m, 1H), 4.08 - 3.90 (m, 1H), 3.88 (s, 3H), 3.84 - 3.42 (m, 3H), 3.13 - 2.95 (m, 2H), 2.40 (s, 3H), 2.21 (s, 3H), 2.15 (s, 3H), 1.48 (s, 9H).

[0082] Example 7:

[0083] The synthetic method was similar to that of Example 6, except that the intermediate (S)-3-pyrrolanol was replaced with (R)-3-pyrrolanol to obtain the title compound. LCMS (ES, m / z): 511.3 [M+H] + .

[0084] 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 8.26 (d, J = 2.8 Hz, 1H), 8.03 (s,1H), 7.90 (dd, J= 8.0, 2.8 Hz, 1H), 7.27 - 7.15 (m, 2H), 5.51 - 5.40 (m, 1H), 4.07 - 3.91 (m, 1H), 3.88 (s, 3H), 3.84 - 3.42 (m, 3H), 3.09 - 2.99 (m, 2H), 2.40 (s, 3H), 2.21 (s, 3H), 2.15 (s, 3H), 1.48 (s, 9H).

[0085] Example 8:

[0086] The synthesis method was similar to that of Example 3, except that the intermediate 1-methyl-2-oxo-1,2-dihydropyridin-4-yl)boronic acid was replaced with cyclopropylboronic acid to obtain the title compound. LCMS (ES, m / z): 397.2 [M+H] + .

[0087] Example 9:

[0088] Step 1: At room temperature, 3-iodo-1H-pyrazolo[3,4-d]pyrimidine-4-amine (525 mg) was dissolved in tetrahydrofuran (10 mL), and (R)-(-)-3-hydroxytetrahydrofuran (170 mg), triphenylphosphine (520 mg), and triethylamine (210 mg) were added. After cooling the mixture to 0°C, diethyl azodicarbonate (360 mg) was added dropwise. After the addition was complete, the mixture was slowly brought to room temperature and stirred for 3 hours until the reaction was complete. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give the target compound (380 mg).

[0089] Step 2: At room temperature, the product obtained in Step 1 (190 mg) and (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)carbamate tert-butyl ester (220 mg) were dissolved in a mixed solution of 1,4-dioxane and water (3 mL, v / v = 4 / 1), and potassium carbonate (198 mg) and Pd(PPh3)4 (66 mg) were added. The mixture was thoroughly purged with nitrogen and stirred overnight at 100 °C until the reaction was complete. After the reaction was complete, the mixture was separated, and the organic phase was concentrated. The residue was purified by column chromatography to give the title compound (42 mg). LCMS (ES, m / z): 427.2 [M+H] + .

[0090] Example 10:

[0091] The synthetic method was similar to that of Example 9, except that the intermediate (R)-(-)-3-hydroxytetrahydrofuran was replaced with (S)-(-)-3-hydroxytetrahydrofuran to obtain the title compound. LCMS (ES, m / z): 427.2 [M+H] + .

[0092] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.00 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 6.0Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.13 - 7.11 (m, 1H),7.05 (d, J = 5.2 Hz, 1H), 6.04 (s, 2H), 4.18 - 4.12 (m, 1H), 3.97 - 3.81 (m,7H), 2.42 - 2.20 (m, 2H).

[0093] Example 11:

[0094] The synthetic method was similar to that of Example 9, except that the intermediate (R)-(-)-3-hydroxytetrahydrofuran was replaced with (R)-tetrahydro-2H-pyran-3-ol to obtain the title compound. LCMS (ES, m / z): 441.2 [M+H] + .

[0095] Example 12:

[0096] The synthesis method was similar to that of Example 4, except that the intermediate (1-methyl-1H-pyrazol-4-yl)boronic acid was replaced with 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazol, yielding the title compound. LCMS (ES, m / z): 473.2 [M+H] + .

[0097] Example 13:

[0098] The synthesis method was similar to that of Example 4, except that the intermediate (1-methyl-1H-pyrazol-4-yl)boronic acid was replaced with 1-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-1H-pyrazol, yielding the title compound. LCMS (ES, m / z): 451.2 [M+H] + .

[0099] 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 8.39 (s, 1H), 8.34 (s, 1H), 8.06(s, 1H), 8.02 (d, J = 4.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.32 - 7.25 (m,2H), 4.23 (q, J = 7.2 Hz, 3H), 3.90 (d, J = 4.0 Hz, 3H), 1.48 (d, J = 2.8 Hz, 9H), 1.43 (t, J = 7.2 Hz, 3H).

[0100] Example 14:

[0101] The synthesis method was similar to that of Example 4, except that the intermediate (1-methyl-1H-pyrazol-4-yl)boronic acid was replaced with 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazol, yielding the title compound. LCMS (ES, m / z): 473.2 [M+H] + .

[0102] 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 8.87 (s, 1H), 8.44 (s, 1H), 8.39 (s, 1H), 8.08 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.92 (t, J = 58.8 Hz, 1H), 7.33(s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 3.91 (s, 3H), 1.50 (s, 9H).

[0103] Example 15:

[0104] The synthesis method was similar to that of Example 4, except that the intermediate (1-methyl-1H-pyrazol-4-yl)boronic acid was replaced with 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-1H-pyrazol, yielding the title compound. LCMS (ES, m / z): 451.2 [M+H] + .

[0105] 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 8.38 (s, 1H), 8.34 (s, 1H), 8.07 -7.93 (m, 3H), 7.32 - 7.25 (m, 2H), 4.26-4.20 (m, 2H), 3.90 (d, J = 4.0 Hz,3H), 2.07 (s, 1H), 1.48 (d, J = 2.8 Hz, 9H), 1.43 (t, J = 7.2 Hz, 3H).

[0106] Example 16:

[0107] The synthesis method was similar to that of Example 4, except that the intermediate (1-methyl-1H-pyrazol-4-yl)boronic acid was replaced with 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazol, yielding the title compound. LCMS (ES, m / z): 440.2 [M+H] + .

[0108] 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 8.37 (d, J = 0.8 Hz, 1H), 8.34 (s,1H), 8.06 (s, 1H), 8.00 (d, J = 0.8 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.30 -7.25 (m, 2H), 3.90 (s, 3H), 1.49 (s, 9H).

[0109] Example 19:

[0110] The synthesis method was similar to that of Example 4, except that the intermediate (1-methyl-1H-pyrazol-4-yl)boronic acid was replaced with 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol, yielding the title compound. LCMS (ES, m / z): 463.2 [M+H] + .

[0111] 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 8.39 (d, J = 0.8 Hz, 1H), 8.34 (s,1H), 8.09 (s, 1H), 8.00 (d, J = 0.8 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.30 -7.25 (m, 2H), 3.90 (s, 3H), 3.88 - 3.83 (m, 2H), 1.48 (s, 9H), 1.14 - 1.12 (m, 2H), 1.02 - 0.99 (m, 2H). Example 27:

[0112] The synthesis method was similar to that of Example 5, except that the intermediate (1-methyl-1H-pyrazol-4-yl)boronic acid was replaced with pyridine-3-boronic acid to obtain the title compound. LCMS (ES, m / z): 434.2 [M+H] + .

[0113] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 9.45 (d, J = 2.4 Hz, 1H), 8.63-8.54(m, 2H), 8.40 (s, 1H), 8.09 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.65-7.60 (m,1H), 7.37 (d, J = 1.6 Hz, 1H), 7.33 (dd, J = 84, 1.6 Hz, 1H), 3.92 (s, 3H), 1.49 (s, 9H). Example 28:

[0114] The synthesis method was similar to that of Example 5, except that the intermediate (1-methyl-1H-pyrazol-4-yl)boronic acid was replaced with (6-methylpyridin-3-yl)boronic acid to obtain the title compound. LCMS (ES, m / z): 448.2 [M+H] + .

[0115] 1 H NMR (400 MHz, DMSO-d6) δ(ppm): 9.27 (d, J = 2.4 Hz, 1H), 8.48-8.43(m, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.46 (d, J =8.4 Hz, 1H), 7.37-7.34 (m, 1H), 7.33-7.29 (m, 1H), 3.91 (s, 3H), 2.55 (s,3H), 1.49 (s, 9H). Example 29:

[0116] Step 1: At room temperature, 1-(azacyclobutane-3-yl)-3-iodo-1H-pyrazole[3,4-D]pyrimidine-4-amine hydrochloride (352 mg) and 4-methylpiperazine (100 mg) were dissolved in dichloromethane (5 mL), and sodium acetate (200 mg) and sodium triacetoxyborohydride (414 mg) were added. The mixture was stirred at room temperature for 16 hours until the reaction was complete. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate aqueous solution, and the pH of the mixture was adjusted to 8-9. The resulting mixture was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by column chromatography to give the target compound (302 mg).

[0117] Step 2: At room temperature, the product obtained in Step 1 (160 mg) was dissolved in a mixed solution of 1,4-dioxane and water (3 mL, v / v = 4 / 1), and tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)carbamate (130 mg), Pd(PPh3)4 (46 mg), and potassium carbonate (120 mg) were added. The mixture was thoroughly purged with nitrogen and heated to 100 °C with stirring for 2 hours until the reaction was complete. After the reaction was complete, the reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate to remove the solvent, and the residue was purified by column chromatography to give the title compound (11 mg). LCMS (ES, m / z): 537.3 [M+H] + .

[0118] 1 H NMR (400 MHz, DMSO- d 6 ) δ (ppm): 8.24 (s, 1H), 8.04 (s. 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.25 - 7.19 (m, 2H), 5.40 - 5.33 (m, 1H), 3.89 (s, 3H), 3.77 - 3.72 (m, 2H), 3.54 - 3.47 (m, 2H), 2.79 - 2.71 (m, 3H), 2.20 - 2.14(m, 3H), 1.74 - 1.66 (m, 2H), 1.49 (s, 9H), 1.26 - 1.16 (m, 2H), 0.97 (d, J =6.4 Hz, 6H).

[0119] Example 30:

[0120] Step 1: At room temperature, 3-bromo-4-methoxy-1H-pyrazolo[3,4-d]pyrimidine (450 mg) was dissolved in tetrahydrofuran (10 mL), and oxetane-3-ol (219 mg) and triphenylphosphine (623 mg) were added. After cooling the mixture to 0°C, diethyl azodicarbonate (478 mg) was added dropwise. After the addition was complete, the mixture was slowly brought to room temperature and stirred for 3 hours until the reaction was complete. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give the target compound (400 mg).

[0121] Step 2: At room temperature, the product obtained in Step 1 (400 mg) and (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)carbamate tert-butyl ester (737 mg) were dissolved in a mixed solution of 1,4-dioxane and water (5 mL, v / v = 4 / 1), and potassium carbonate (663 mg) and Pd(PPh3)4 (218 mg) were added. The mixture was thoroughly purged with nitrogen and stirred overnight at 100 °C until the reaction was complete. After the reaction was complete, the mixture was separated, and the organic phase was concentrated. The residue was purified by column chromatography to obtain the target compound (500 mg).

[0122] Step 3: At room temperature, ammonia (3 mL, 30%) was added to a 5 mL isopropanol solution of the product (500 mg) obtained in Step 2. The mixture was heated to 95°C and stirred overnight until the reaction was complete. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound (48 mg). LCMS (ES, m / z): 413.2 [M+H] + .

[0123] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.25 (s, 1H), 8.05 (s, 1H), 7.94 (d, J = 8.0, 1H), 7.29 -7.25 (m, 2H), 6.03-5.99 (m, 1H), 5.11 (t, J = 8.0 Hz, 2H), 4.99 (t, J = 8.0 Hz, 2H), 3.90 (s, 3H), 1.49 (s, 9H). Example 31:

[0124] The synthetic method was similar to that of Example 6, except that the intermediate (S)-3-pyrrolanol was replaced with (R)-piperidin-3-ol to obtain the title compound. LCMS (ES, m / z): 525.3 [M+H] + .

[0125] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.24 (d, J = 8.0, 1H), 8.03 (s, 1H), 7.91 (d, J = 8.0, 1H), 7.24 -7.20 (m, 2H), 4.83-4.46 (m, 1H), 4.22-4.16 (m,1H), 4.04 (d, J = 12.0, 1H),3.87 (s, 3H), 3.20-2.93 (m, 5H), 2.20 (s, 3H),2.12 (s, 3H), 1.91-1.88 (m, 1H), 1.70-1.64 (m, 1H), 1.48 (s, 9H). Example 32:

[0126]

[0127] The synthesis method was similar to that of Example 5, except that the intermediate (1-methyl-1H-pyrazol-4-yl)boronic acid was replaced with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2(1H)-one to obtain the title compound. LCMS (ES, m / z): 464.2 [M+H] + .

[0128] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.19 (s, 1H), 8.05 (s, 1H), 7.95 (dd, J = 7.6, 2.4 Hz, 2H), 7.76 (dd, J = 7.2, 2.0 Hz, 1H), 7.29-7.22 (m, 2H), 6.39 (t, J = 6.8 Hz, 1H), 3.89 (s, 3H), 3.54 (s, 3H), 1.48 (s, 9H). III. Performance Testing Test Example 1: YES1 Enzyme Inhibitory Activity 1.1 Compound preparation is shown in Table 2. Table 2

[0129] 1) Prepare 2 using kinase reaction buffer. ATP / substrate solution and 2 Kinase solution.

[0130] 2) Transfer 50 nL of the compound dilution buffer to a 384 detection plate using an Echo 655; after centrifugation, add 2.5 μL of 2 Transfer the kinase solution to a 384 detection plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 10 min; 3) Add 2.5 μL of 2 The substrate and ATP solution were added to the 384 detection plate, centrifuged at 1000 rpm for 1 min, and incubated at 25°C for 30 min.

[0131] 4) Prepare 2 using detection buffer solution XL 665 and antibody detection reagents.

[0132] 5) Add 5 μL of kinase detection reagent to the detection plate and incubate at 25 °C. Centrifuge at 1000 rpm for 1 min and incubate at 25 °C for 1 h.

[0133] 6) Use the BMG high-throughput drug screening multi-electrode reader to read the fluorescence signals at 620 nm (Cryptate) and 665 nm (XL665).

[0134] 1.2 Data Analysis The negative control (1% DMSO well) was set to 0% inhibition rate, and the positive control (well with the highest concentration of the control compound) was set to 100% inhibition rate. After calculating the inhibition rate, the IC50 values ​​of the control compound and the test compound were obtained using a nonlinear fitting formula from the software. 50 Value (half-maximal inhibitory concentration);

[0135] : The average value of the positive control wells; : The average value of the negative control wells.

[0136] Data analysis was performed using Graphpad 7.0 software, and the IC of the compound was obtained using the following nonlinear fitting formula. 50 (Half-maximal inhibitory concentration): Y=Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X) *HillSlope)) X: Compound concentration log value; Y: Compound inhibition rate (% inh); Z' factor calculation equation: Z' = 1 - 3(SD min +SD max ) / (AVE max -AVE min ) Among them: SD min The standard error of the Data value for the positive control DMSO is SD. max The standard error of the Data values ​​for the negative control DMSO is given by AVE. min The difference between the mean and mean values ​​of the data for the positive control DMSO is represented by AVE. max The average Data value is for the negative control DMSO. Test results are shown in Table 3.

[0137] Table 3. IC50 of the compounds in the examples inhibiting the enzyme activity of YES1 50 value

[0138] The reagents used in the experiment are shown in Table 4: Table 4. Information on reagents used in the experiment

[0139] Experimental conclusion: Testing revealed that the compound of this invention exhibits good YES1 inhibitory activity, showing an inhibition level of approximately 0.1-1000 nM (IC50) in the inhibition test. 50 The biological activity of the compounds of this invention. In some embodiments, the IC50 of the compounds of this invention is... 50 IC50 values ​​less than about 500 nM, preferred compounds 50 IC50 values ​​less than approximately 100 nM, for further optimized compounds 50 The IC50 value is less than about 50 nM, and the IC50 of the further preferred compounds is... 50 Values ​​less than approximately 10 nM, more preferably ICs such as those in Examples 2, 6, 7, 8, 9, 10, 11, 13, 19, 28, 30, and 31. 50 The value is less than 1 nM.

[0140] Test Example 2: Pharmacokinetic Test in Rats 1.1. Instruments: High-performance liquid chromatography (HPLC): SHIMADZU LC-30AD; Mass spectrometry: AB SCIEX TripleQuad 5500. All data were calculated and processed using Microsoft Excel, and relevant pharmacokinetic parameters were calculated using WinNonlin software. The main kinetic parameter obtained was T... max , T 1 / 2, C max AUC 0-24h AUC inf Chromatographic column: XSelect Hss T3 2.5 µm (2.1 x 50 mm) Column XP, column temperature 40 °C. oC. Mobile phase A is water (0.1% formic acid), mobile phase B is acetonitrile, flow rate is 0.60 mL / min, gradient elution is used, elution gradient is 0.30 min: 5% B; 1.00 min: 98% B; 1.48 min: 98% B; 1.51 min: 5% B; 2.00 min: stop. Injection volume: 1 μL.

[0141] 1.2. Animals: Three male SD rats, weighing between 180g and 300g, were purchased and housed in the experimental animal center for two days before use. They were fasted for 12 hours before and 4 hours after administration, but had free access to water during the experiment. Blood samples were collected from the rats at predetermined time points after gavage.

[0142] 1.3. Solvent: DMSO / PEG400 / H2O (volume ratio 1 / 3 / 6). Preparation of the oral administration solution: Accurately weigh the compound, add the solvent, and sonicate at room temperature for 5 minutes to completely dissolve the drug, preparing a solution of 0.5 mg / mL.

[0143] Blood samples were collected at 0.083 h, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 7.0 h, and 24 h after gavage administration. The blood collection method was as follows: 0.2 mL of blood was collected from the jugular vein. EDTA-K2 was used as the anticoagulant. The collected blood samples were transferred to microcentrifuge tubes containing the anticoagulant and centrifuged at 4°C and 4000 g for 5 min to separate the plasma. All collected plasma samples were stored at -75±15 °C until analysis.

[0144] Compounds were accurately weighed to prepare standard curve working solutions and quality control working solutions of different concentrations. Blank plasma was added to prepare plasma standard curves and quality control samples. After pretreatment using protein precipitation, LC / MS / MS analysis was performed to determine the concentration of the aforementioned plasma compounds. All measurement data were acquired and processed using relevant software, and pharmacokinetic parameters were calculated using Winnonlin software. The kinetic parameters of some representative compounds are shown in Table 5.

[0145] Table 5. Pharmacokinetic parameters of the compounds in the examples in rats.

[0146] According to the pharmacokinetic data obtained in rats in Table 5, the amino-substituted aromatic compounds of this application are absorbed rapidly in the gastrointestinal tract and have good oral bioavailability.

[0147] Test Example 3: Pharmacokinetic Study in Mice 1.1 Instruments: High-performance liquid chromatograph: SHIMADZU LC-30AD; Mass spectrometer: AB SCIEX TripleQuad 5500. Column: HALO 90A AQ-C18, 2µm 3×30mm; Mobile phase A: 5% acetonitrile-water (containing 0.1% formic acid); Mobile phase B: 95% acetonitrile-water (containing 0.1% formic acid); Flow rate: 0.60 mL / min; Gradient elution: 0.20 min: 20% B; 1.10 min: 100% B; 1.50 min: 100% B; 1.51 min: 20% B; 1.80 min: stop. Injection volume: 10 μL.

[0148] 1.2 Animals: Three male Balbc mice, weighing between 22g and 26g, were purchased and housed in the experimental animal center for two days before use. They were fasted for 12 hours before and 2 hours after administration, but had free access to water during the experiment. Blood samples were collected from the mice at predetermined time points after gavage administration.

[0149] 1.3 Solvent: DMSO / PEG400 / H2O (volume ratio 1 / 3 / 6). Preparation of oral administration solution: Accurately weigh the compound, add the solvent, vortex and sonicate to dissolve the drug, and prepare a 1 mg / mL dosage form.

[0150] Blood samples were collected at 0.083 h, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, and 24 h after oral administration. Blood was collected via dorsal pedis vein, using EDTA-K2 as the anticoagulant. The collected blood samples were transferred to microcentrifuge tubes containing the anticoagulant and centrifuged at 4000 g for 5 min at 4°C to separate the plasma. All collected plasma samples were stored at -75±15 °C until analysis.

[0151] Compounds were accurately weighed to prepare standard curve working solutions and quality control working solutions of different concentrations. Blank plasma was added to prepare plasma standard curves and quality control samples. After pretreatment using protein precipitation, LC / MS / MS analysis was performed to determine the concentration of the plasma compounds. All data were acquired and processed using relevant software. Winnonlin software was used to calculate pharmacokinetic parameters, with the main kinetic parameter T being obtained. 1 / 2 , T max C max AUC 0-24h AUC inf .

[0152] Table 6. Pharmacokinetic parameters of the compounds in the examples in mice.

[0153] According to the pharmacokinetic data obtained in mice in Table 6, the amino-substituted aromatic compounds of this application are absorbed rapidly in the gastrointestinal tract and have good oral bioavailability.

[0154] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the principles of the present invention should be included within the protection scope of the present invention.

Claims

1. The compound represented by formula A, its enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs, isotopic derivatives, or solvates: A in, R1 is selected from any C that is arbitrarily replaced. 1-12 Alkyl groups, optionally substituted C 2-12 alkenyl, optionally substituted C 2-12 alkynyl group, optionally substituted C 3-20 Cycloalkyl, optionally substituted 5-20 membered heterocyclic, optionally substituted 5-20 membered cycloalkenyl, optionally substituted 5-20 membered heteroaryl, or optionally substituted C 6-20 Aryl; X1, X2, X3, and X4 may be the same or different, and are independently selected from CR8 or N, provided that X1, X2, X3, and X4 are not simultaneously CR8; R2 is selected from H, halogen, cyano group, optionally substituted amino group, and optionally substituted C group. 1-12 Alkyl, or optionally substituted C 1-12 Alkoxy; n is 1, 2, 3 or 4; R3 is selected from -NR6-COO-R7; R4, R5, and R6 may be the same or different, and are independently selected from H, or arbitrarily substituted C. 1-12 alkyl; R7 is selected from any C that is arbitrarily replaced. 1-12 Alkyl groups, optionally substituted C 2-12 alkenyl, optionally substituted C 2-12 alkynyl group, optionally substituted C 3-20 Cycloalkyl, optionally substituted 5-20 membered heterocyclic, optionally substituted 5-20 membered cycloalkenyl, optionally substituted 5-20 membered heteroaryl, or optionally substituted C 6-20 Aryl; R8 is selected from hydrogen, halogen, cyano, optionally substituted amino, and optionally substituted C. 1-12 Alkyl group, optionally substituted C 1-12 Alkyl group.

2. The compound according to claim 1, wherein the enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug, isotope derivative, or solvate is an enantiomer, a pharmaceutically acceptable salt, a prodrug, an isotope derivative, or a solvate, wherein, R1 is selected from unsubstituted groups, or optionally substituted by one, two or more Ra groups, of the following groups: C 1-12 Alkyl, C 3-20 Cycloalkyl, 5-20 membered heterocyclic, 5-20 membered cycloalkenyl, 5-20 membered heteroaryl or C 6-20 Aryl; Ra is selected from oxygen (=O), C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, deuterated C 1-12 Alkyl groups, unsubstituted, or optionally substituted with one, two, or more Rb groups, including the following groups: C 3-20 Cycloalkyl, 5-20 membered heterocyclic groups, -COC 1-12 alkyl; Rb is selected from C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl, deuterated C 1-12 Alkyl, NHC 1-12 Alkyl, N(C) 1-12 Alkyl)2; X1, X2, X3, and X4 may be the same or different, and are independently selected from CR8 or N, provided that X1, X2, X3, and X4 are not simultaneously CR8; R2 is selected from H, halogen, cyano, optionally substituted amino group, C 1-12 Alkyl, C 1-12 Alkoxy, halogenated C 1-12 Alkyl or deuterated C 1-12 alkyl; n is 1, 2, 3 or 4; R3 is selected from -NR6-COO-R7; R4, R5, and R6 may be the same or different, and are independently selected from H and C. 1-12 Alkyl or deuterated C 1-12 alkyl; R7 is selected from C 1-12 Alkyl, Halogenated C 1-12 Alkyl or deuterated C 1-12 alkyl; R8 is selected from hydrogen, halogen, cyano, optionally substituted amino, and optionally substituted C. 1-12 Alkyl group, optionally substituted C 1-12 Alkyl group.

3. The compound according to claim 1 or 2, wherein its enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs, isotope derivatives, or solvates, are wherein, X1, X2, X3, and X4 may be the same or different, and are independently selected from CH or N; Preferably, X1, X2, X3 and X4 are selected from N.

4. The compound according to any one of claims 1-3, wherein the enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug, isotope derivative, or solvate is... R1 is selected from unsubstituted groups, or optionally substituted by one, two or more Ra groups, of the following groups: C 1-6 Alkyl, C 3-12 Cycloalkyl, 5-12 membered heterocyclic, 5-12 membered cycloalkenyl, 5-14 membered heteroaryl or C 6-14 Aryl; Ra is selected from oxygen (=O), C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl groups, unsubstituted, or optionally substituted with one, two, or more Rb groups, including the following groups: C 3-12 Cycloalkyl, 5-12 membered heterocyclic groups, -COC 1-6 alkyl; Rb is selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2; R2 is selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl; R3 is selected from -NR6-COO-R7; R4, R5, and R6 are H; R7 is selected from C 1-6 Alkyl, Halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl; Preferably, R1 is selected from -C 3-12 cycloalkyl-5-12-membered heterocyclic-C 1-6 Alkyl, -5-14-membered heteroaryl-C 1-6 Alkyl, =O and C 1-6 Alkyl-substituted 5-12-membered cycloalkenyl, -5-12-membered heterocyclic -COC 1-6 Alkyl-N(C) 1-6 Alkyl)2, C 3-12 Cycloalkyl, 5-12-membered heterocyclic, -5-14-membered heteroaryl-halogenated C 1-6 Alkyl, -5-14-membered heteroaryl-C 1-6 Alkyl, -5-14-membered heteroaryl-deuterated C 1-6 Alkyl, -5-14-membered heteroaryl-C 3-12 Cycloalkyl, =O and halogenated C 1-6 Alkyl-substituted 5-12 membered cycloalkenyl groups, =O and deuterated C 1-6 Alkyl-substituted 5-12-membered cycloalkenyl, =O-substituted 5-12-membered cycloalkenyl, 5-14-membered heteroaryl or -5-12-membered heterocyclic -5-12-membered heterocyclic -C 1-6 alkyl; Preferably, R1 is selected from -C 3-6 cycloalkyl-5-6-membered heterocyclic-C 1-3 Alkyl, -5-6-membered heteroaryl-C 1-3 Alkyl, =O and C 1-3 Alkyl-substituted 5-6 membered cycloalkenyl, -5-6 membered heterocyclic -COC 1-3 Alkyl-N(C) 1-3 Alkyl)2, C 3-6 Cycloalkyl, 5-6 membered heterocyclic, -5-6 membered heteroaryl-halogenated C 1-3 Alkyl, -5-6-membered heteroaryl-C 1-3 Alkyl, -5-6-membered heteroaryl-deuterated C 1-3 Alkyl, -5-6-membered heteroaryl-C 3-6 Cycloalkyl, =O and halogenated C 1-4 Alkyl-substituted 5-6 membered cycloalkenyl groups, with =O and deuterated C 1-3 Alkyl-substituted 5-6 membered cycloalkenyl, =O-substituted 5-6 membered cycloalkenyl, 5-6 membered heteroaryl or -5-6 membered heterocyclic -5-6 membered heterocyclic -C 1-3 alkyl.

5. The compound according to any one of claims 1-4, wherein the enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug, isotope derivative, or solvate is... R1 is selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , or ; Preferably, R2 is selected from C 1-3 Alkyl or C 1-3 Alkoxy groups, such as methyl, ethyl, propyl, methoxy, ethoxy, or propoxy; Preferably, R3 is selected from -NH-COO-R7, and R7 is selected from C. 1-4 alkyl.

6. The compound according to any one of claims 1-5, wherein the enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug, isotope derivative, or solvate is an enantiomer, a pharmaceutically acceptable salt, a prodrug, an isotope derivative, or a solvate, wherein, The compound represented by formula A is selected from any one of the following compounds: 。 7. A pharmaceutical composition comprising, as an active ingredient, at least one of the compounds of formula A as claimed in any one of claims 1-6, or an enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug, isotope derivative, or solvate thereof.

8. The pharmaceutical composition according to claim 7, wherein, The pharmaceutical composition also includes a pharmaceutically acceptable carrier; Preferably, the pharmaceutically acceptable carrier includes fillers, excipients, disintegrants, binders, and wetting agents.

9. Use of the compound of Formula A according to any one of claims 1-6, or at least one of its enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs, isotope derivatives, solvates, or the pharmaceutical composition according to claim 7 or 8 in the preparation of a medicament for the prevention or treatment of diseases related to YES1 amplification or YES1 overexpression.

10. The use according to claim 9, wherein, The diseases associated with YES1 amplification or YES1 overexpression are selected from cancer. Preferably, the cancer includes at least one of the following: acute myeloid leukemia, chloroma, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, B-cell lymphoma, multiple myeloma, Waldenström macroglobulinemia, myelodysplastic syndrome, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, reproductive tract cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, uterine cancer, gestational trophoblastic disease, gastric cancer, bile duct cancer, gallbladder cancer, small intestine cancer, esophageal cancer, oropharyngeal cancer, hypopharyngeal cancer, eye cancer, neurocarcinoma, head and neck cancer, melanoma, plasmacytoma, endocrine gland tumors, neuroendocrine carcinoma, brain tumors, bone cancer, and sarcoma.

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