Aryl phosphoric acid STAT3 degradation agent, composition and application

Abstract

The invention discloses an aryl phosphoric acid STAT3 degradation agent, a preparation method of the aryl phosphoric acid STAT3 degradation agent, a pharmaceutical composition containing the aryl phosphoric acid STAT3 degradation agent and application of the aryl phosphoric acid STAT3 degradation agent in medicine. The aryl phosphoric acid STAT3 degradation agent is an aryl phosphoric acid derivative represented by a general formula (I), or a stereoisomer, a tautomer and a pharmaceutically acceptable salt thereof. The compound disclosed by the invention has the capability of degrading STAT3. The compound disclosed by the invention has an obvious proliferation inhibition capability on MOLM16 cells. The compound disclosed by the invention has an obvious degradation capability on STAT3 of an SW1990 cell. The compound provided by the invention has obvious growth inhibition ability in an SW1990 pancreatic cancer transplantation tumor in-vivo pharmacodynamic model. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis and design, and specifically relates to an aryl phosphate STAT3 degrading agent, and a composition containing the derivative, and the preparation and use thereof as a STAT3 degrading agent. Background Art

[0002] The JAK-STAT signaling pathway is an important tumor-related signaling pathway. When the cytokine receptors, hormone receptors or growth factor receptors on the cell surface bind to the corresponding ligands, the intracellular JAK kinase is activated, thereby inducing the phosphorylation of the downstream transcription factor STAT and forming a homodimer, which then enters the cell nucleus and activates or inhibits the transcription of a series of tumor-related genes.

[0003] Transcription factor STAT regulates a variety of tumor-related genes, such as cMyc, Survivin, BCL-XL, VEGF, HIF, NF-kB, etc. In tumor cells, STAT gain-of-function mutations are often accompanied, leading to overactivation of the pathway. Overactivation of the STAT pathway can lead to: tumor cell proliferation, increased survival, abnormal proliferation of invading blood vessels, tumor cell invasion and migration, tumor immune escape, and maintenance of tumor stem cell-like.

[0004] In addition, recent studies have found that STAT3 has a close relationship with the inhibitory immune microenvironment of tumor tissue. Excessive activation of STAT in DC cells leads to a decrease in the expression of MHC II molecules and co-stimulatory factors, thereby reducing their antigen presentation and T cell activation capabilities. Expression in neutrophils, NK cells, and effector T cells reduces their ability to recognize, activate, and kill tumor cells. At the same time, it can promote the M2 polarization of tumor-associated macrophages, the maturation and expansion of myeloid suppressor cells, induce T cells to differentiate into regulatory T cells, and induce an increase in the expression of PD-L1 in tumor cells and the above-mentioned immunosuppressive cells, thereby forming an inhibitory immune microenvironment and promoting tumor immune escape.

[0005] In summary, the JAK-STAT signaling pathway can promote tumor proliferation through multiple pathways and is therefore a potential target for anti-tumor drug development.

[0006] Although several small molecule STAT3 inhibitors have been reported in recent years, none of them have been approved for marketing due to their poor efficacy. Therefore, it is urgent to develop a new generation of STAT3 inhibitory molecules with stronger efficacy.

[0007] In recent years, significant progress has been made in the targeted protein degradation technology (PROTAC), which achieves the degradation of target proteins by inducing the ubiquitination of target proteins. Drugs using this technology can achieve target degradation at catalytic concentrations without continuously occupying the target protein. Therefore, developing targeted degradation molecules against STAT3 is expected to solve the defect of insufficient efficacy of current small molecule STAT3 inhibitors. Summary of the Invention

[0008] In view of the above technical problems, the present invention provides an aryl phosphate STAT3 degrader capable of degrading STAT3, which is a compound represented by the general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt:

[0009]

[0010] Wherein:

[0011] X 1 is selected from: -CH 2 -, -O-, -CO- or -CF 2 -;

[0012] X 2 is selected from: NH, S, O or NR 1 ;

[0013] X 3 is selected from: -(CH 2 ) n -, -(SO 2 )-, N(R 2 )- or -(CH 2 ) m -NR 2 -(CH 2 ) o -;

[0014] X 5 is selected from: absent, -CH 2 - or -O-;

[0015] L is selected from:

[0016] Cyc1 is selected from: 3- to 12-membered heterocyclic group, C 6 -C 10 aryl or 5- to 12-membered heteroaryl, and the above heterocyclic group, aryl, heteroaryl are optionally further substituted by one or more substituents, and the substituents are selected from: halogen, halo C 1 -C 8 alkyl, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C2 -C 8 Alkynyl, C 3 -C 12 Cycloalkyl, 3 - 12 - membered heterocyclic group, C 6 -C 10 Aryl, 5 - 12 - membered heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d 、-NR b SO 2 R c 、-SO(=NR b )R c or - POR b R c ;

[0017] L 1 、L 2 、L 3 Each independently selected from: -(CH 2 ) r -, r CH 2 One or more CH 2 May be further substituted by one or more selected from -COO-, -CONH-, -OCONH-, -NHCONH-, -O-, -NR b -, -S-, -CO-, -CR b =CR c -, -CRb = N-, -C≡C-, -SO-, -SO 2 -, -POR b -, -S(=NR b )O-, C 3 -C 12 - cycloalkyl, 3-10 membered heteroalkyl, 6-10 membered arylene, 5-6 membered heteroarylene or -CR b R c - group substitution, the above cycloalkyl, heteroalkyl, arylene, heteroarylene optionally further substituted by one or more substituents selected from: halogen, halo C 1 -C 8 alkyl, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 cycloalkyl, 3-12 membered heterocyclic, C 6 -C 10 aryl, 5-12 membered heteroaryl, oxo, -CN, -NO 2 , -OR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -COOR b , -CONR b R c , -C(=NR b )NR c R d , -NR b R c , -NR b COR c , -NR b CONR c R d , -NR b CO 2 R c , -NR b SONR c R d , -NR b SO 2 NR c R d , -NR b SO 2 R c, -SO(=NR b )R c or -POR b R c ;

[0018] R 1 is selected from: C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl or 3-10 membered heterocyclic group, the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group is optionally further substituted by one or more substituents selected from: halogen, halo C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, amino, oxo, C 1 -C 6 alkylamino, carboxyl, nitro or cyano;

[0019] R 2 is selected from: R 3 is selected from: H or C 1 -C 6 alkyl;

[0020] Y is selected from: -(CH 2 ) s -, s CH 2 in which may be further substituted by one or more groups selected from -CO-, -O-, -NR b -, -S-, -CR b =CR c -, -C≡C-, -CR b =N-, -SO-, -SO 2 -, -POR b -, -S(=NR b )O-, -CR b R c - ;

[0021] R 2a is selected from: absent, C 3 -C 12Subcycloalkyl, 3- to 12-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 12-membered heteroaryl, and the above-mentioned subcycloalkyl, heterocycloalkyl, aryl, and heteroaryl can be further substituted by one or more substituents selected from: halogen, halo-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 6- to 10-membered aryl, 6- to 10-membered heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d 、-NR b SO 2 R c 、-SO(=NR b )R c or -POR b R c ;

[0022] R 2b is selected from: H, halogen, halo-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 3- to 6-membered heterocyclic group, 6- to 10-membered aryl group or 5- to 10-membered heteroaryl group, and the above cycloalkyl, heterocyclic group, aryl group, heteroaryl group may be further substituted by one or more substituents selected from: halogen, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, hydroxy, amino, oxo, C 1 -C 6 Alkylamino, carboxyl, nitro or cyano;

[0023] X 4 Selected from: absent,

[0024] When X 4 Is selected from absent and R 3 Is selected from H, then R 2a Is selected from: C 8 -C 12 Cycloalkyl, 8- to 12-membered heterocyclic group, 6- to 10-membered aryl group or 6- to 10-membered heteroaryl group, and the above cycloalkyl, heterocyclic group, aryl group, heteroaryl group are optionally further substituted by one or more substituents selected from: halogen, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, 3- to 6-membered heterocyclic group, C 6 -C 10 Aryl, 6- to 10-membered heteroaryl group, oxo, -CN, -NO 2 , -OR b , -SO 2 R b , -SO 2 , -SO b NR c , -COR b , -COOR b , -CONR b R c , -C(=NR b )NR c R d , -NRb R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d 、-NR b SO 2 R c 、-SO(=NR b )R c Or-POR b R c ;

[0025] Ra, Ra' are each independently selected from: H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl or 3-6 membered heterocyclic group, the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group may be further substituted by one or more substituents, the substituents are selected from: halogen, halogenated C 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, hydroxy, amino, oxo, C 1 -C 6 Alkylamino, carboxyl, nitro or cyano;

[0026] Or Ra, Ra' and the atoms to which they are connected (provided that the valence theory is satisfied) together form a 3-8 membered ring, wherein the 3-8 membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S, P, and the 3-8 membered ring is optionally further substituted with one or more heteroatoms selected from halogen, halogenated C 1 -C 8 Alkyl, C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C 3 -C 12Cycloalkyl, 3- to 12-membered heterocyclic group, C 1 -C 8 Alkoxy, C 1 -C 8 Alkylamino, hydroxy, amino, oxo, alkylamino(C 1 -C 8 Alkylamino), carboxyl, nitro or cyano;

[0027] R b 、R c 、R d Independently selected from: H, halogen, C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 3 -C 10 Cycloalkyl or 3- to 10-membered heterocyclic group, and the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group are optionally further substituted by one or more substituents, and the substituents are selected from: halogen, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, hydroxy, amino, oxo, C 1 -C 6 Alkylamino, carboxyl, nitro or cyano;

[0028] E3 is selected from: small molecule ligands that can bind to the E3 ubiquitin ligase, including ligands of CRBN, VHL, MDM2, cIAP proteins;

[0029] n is selected from: 0, 1 or 2; m and o are each independently selected from: 0, 1 or 2; r is selected from: an integer from 0 to 20;

[0030] s is selected from: 0, 1, 2, 3, 4 or 5.

[0031] In a preferred embodiment of the present invention, a compound of general formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof,

[0032]

[0033] Wherein:

[0034] R e Is selected from: H, halogen, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 2-C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclic group, C 6 -C 10 aryl, 6- to 10-membered heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d 、-NR b SO 2 R c 、-SO(=NR b )R c or -POR b R c ;

[0035] p is selected from: 0, 1, 2, 3 or 4.

[0036] R 2a 、R 2b 、R 3 、Y, X 1 、X 2 、X 4 、L 1 、L 2 、L 3 、E3 is defined as in general formula (I).

[0037] A preferred embodiment of the present invention is a compound of the general formula III or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0038]

[0039] Wherein:

[0040] When X 4 is absent and R 3 is selected from H, R 2a is selected from: C 8 -C 12 cycloalkyl, 8-12 membered heterocyclic group, 7-10 membered aryl group or 7-10 membered heteroaryl group, and the above cycloalkyl, heterocyclic group, aryl group, heteroaryl group are optionally further substituted by one or more substituents, and the substituents are selected from: halogen, halo C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclic group, C 6 -C 10 aryl, 6-10 membered heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c Rd 、-NR b SO 2 R c 、-SO(=NR b )R c Or-POR b R c .

[0041] R 2a , R 2b , R 3 , Y, X 1 , X 2 , X 4 , L 2 , L 3 , E3 are defined as described in the general formula (I).

[0042] In a preferred embodiment of the present invention, the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0043] Ra is selected from: H, C 1 -C 3 Alkyl, C 3 -C 6 Cycloalkyl; Ra' is selected from: H, C 1 -C 3 Alkyl, C 3 -C 6 Cycloalkyl; or Ra, Ra' together with the N atom to which they are attached form a 3-6 membered ring;

[0044] Re is selected from: H, halogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxy, amino, cyano or nitro;

[0045] Selected from: C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 3 -C 6 Cycloalkyl,

[0046]

[0047] In a preferred embodiment of the present invention, the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein Y is selected from: -CO-, -CH 2 -, -C(O)-O-, -C(O)-NH- or -C(O)-CH 2 -.

[0048] In a preferred embodiment of the present invention, the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein selected from:

[0049]

[0050] In a preferred embodiment of the present invention, the is preferably selected from more preferably from:

[0051]

[0052] In a preferred embodiment of the present invention, the X 4 is selected from: absent,

[0053]

[0054] In a preferred embodiment of the present invention, r is preferably selected from: 0, 1, 2, 3, 4, 5.

[0055] L2 is preferably selected from: -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -.

[0056] L3 is preferably selected from: absent, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 2 -NH-C(O)-, -(CH 2 ) 3 -O-.

[0057] In a preferred embodiment of the present invention, the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L is selected from:

[0058]

[0059] In a preferred embodiment of the present invention, the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein E3 is selected from:

[0060]

[0061] wherein,

[0062] q, u or s are each independently selected from: 0, 1 or 2;

[0063] Y 1Independently selected from: CO, methylene, vinyl or ethyl;

[0064] Y 2 Independently selected from: CH or N;

[0065] Y 3 Independently selected from: absent, CH 2 , NH, NMe or O;

[0066] Y 4 Independently selected from: CH or N;

[0067] Y 5 Independently selected from: CH or N;

[0068] R 4 、R 5 、R 6 、R 7 、R 8 、R 9 Each independently selected from: H, halogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, 5-12 membered heterocyclic group, 6-10 membered aryl group, 6-10 membered heteroaryl group, oxo, -CN, -NO 2 、-OR b 、-SO 2 R a 、-SO 2 NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2NR c R d 、 -NR b SO 2 R c , -SO(=NR b )R c 、 -POR b R c , The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may be further substituted by one or more substituents selected from: halogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, 5 - 12 - membered heterocyclic, 6 - 10 - membered aryl, 6 - 10 - membered heteroaryl, oxo, -CN, -NO 2 、 -OR b 、 -SO 2 R b 、 -SO 2 NR b R c 、 -COR b 、 -COOR b 、 -CONR b R c 、 -C(=NR b )NR c R d 、 -NR b R c 、 -NR b COR c 、 -NR b CONR c R d 、 -NR b CO 2 R c 、 -NR b SONR c R d 、 -NR b SO 2 NR c R d 、 -NR b SO 2 R c , -SO(=NR b )R c or -POR b R c ;

[0069] Cy3 Selected from:

[0070]

[0071] Cy 4 Selected from:

[0072]

[0073] Cy 5 Selected from:

[0074]

[0075] In a preferred embodiment of the present invention, the compound or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein E3 is selected from:

[0076]

[0077]

[0078]

[0079]

[0080] In a preferred embodiment of the present invention, the compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, is selected from:

[0081]

[0082]

[0083]

[0084]

[0085] Note: If there is a difference between the drawn structure and the name given for that structure, the drawn structure will be given greater weight.

[0086] It should be noted that when referring to specific compounds in the present invention, the numbers corresponding to the compounds below (for example, 40 in the above table corresponds to the corresponding compound; when the compound number is mentioned in the rest of this article, it refers to this compound, for example, "compound 40" corresponds to the compound structure corresponding to number 40.

[0087] It should be noted that in this text, when there are different substituents (N-level substituents) and further substitution occurs, if the same letter appears when representing the further substituents (N + 1-level substituents), the same letter in different substituents (N-level substituents) can be selected from the same substituents or different substituents, and the same letter has no restrictive effect on the corresponding substituent structure. For example, in this text, "Rb" appears in the substituents of Y, R2a, L1-L3, Cyc1, and R2a. However, in the specific compound structure, the "Rb" in Y, R2a, L1-L3, Cyc1, and R2a can be the same or different. The above explanation also applies to other similar cases.

[0088] The present invention provides a pharmaceutical composition, which contains a therapeutically effective dose of a compound as described in any one of general formulas (I), (II), or (III), or its stereoisomer, tautomer, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, excipient, or a combination thereof.

[0089] The present invention provides an application of a compound as described in general formula (I), (II), or (III), or its stereoisomer, tautomer, or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for degrading STAT3 protein.

[0090] The present invention provides an application of a compound as described in general formula (I), (II), or (III), or its stereoisomer, tautomer, or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for preventing and / or treating diseases related to the activity or expression level of STAT3 protein, wherein the diseases include solid tumors, hematological tumor diseases, or autoimmune diseases.

[0091] The present invention provides the use of a compound of general formula (I) or (II) or (III), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing and / or treating a disease related to the activity or expression level of STAT3 protein, wherein the solid tumors include, but are not limited to, digestive system malignancies, respiratory system malignancies, central nervous system tumors, urinary system malignancies, gynecological malignancies, sarcomas, melanomas, bone cancers, and more preferably selected from: lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, breast ductal carcinoma, head and neck cancer, endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvic cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, in situ cancer, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testis, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, colorectal villous adenoma, melanoma, cell tumor and sarcoma, one or more of which. The autoimmune diseases include, but are not limited to: ulcerative colitis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis syndrome, insulin-dependent diabetes (type I), ulcerative colitis, chronic active hepatitis, psoriasis, inflammatory bowel disease, ankylosing spondylitis, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Still's disease, Graves' disease, Sjogren's syndrome, asthma, multiple sclerosis, Addison's disease, opsoclonus-myoclonus syndrome, Crohn's disease, polymyositis, dermatomyositis, vasculitis, antiphospholipid antibody syndrome, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, immune thrombocytopenia, autoimmune cholangitis, autoimmune nephritis, autoimmune myocarditis, autoimmune encephalitis, optic neuritis, Takayasu arteritis, temporal arteritis, autoimmune hepatitis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, infectious neuronitis, acute disseminated encephalomyelitis, endometriosis, interstitial cystitis, Reiter's syndrome, immune hemolytic anemia, aplastic anemia, Wegener's granulomatosis, alopecia universalis, Behcet's disease, chronic fatigue, familial dysautonomia, neuromyotonia congenita, scleroderma, vulvodynia, graft-versus-host disease, transplantation, blood transfusion, allergic reaction, allergy, type I hypersensitivity reaction, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, one or more of which. The hematological malignancies include, but are not limited to, leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome, myelofibrosis, and more preferably acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, myelofibrosis, myelodysplastic syndrome, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinemia, multiple myeloma, T-cell lymphoma, one or more of which.

[0092] The pharmaceutical carrier provided by the present invention may be one or more solid or liquid fillers or gel substances suitable for human use. The pharmaceutical carrier may be any conventional carrier and / or diluent in the field of pharmaceutical preparations, preferably having sufficient purity and sufficiently low toxicity, and being compatible with the active ingredient of the present invention and not significantly reducing the efficacy of the active ingredient. For example, the pharmaceutical carrier may be a filler, binder, disintegrant, lubricant, aqueous solvent or non-aqueous solvent, etc.

[0093] The pharmaceutical preparation provided by the present invention can be made into any pharmaceutically acceptable dosage form and administered to patients or subjects in need of such treatment by any suitable administration method, such as oral, parenteral, rectal or pulmonary administration, etc. When used for oral administration, it can be made into solid dosage forms, such as capsules, tablets, pills, lozenges, dragees, granules, powders, soft pastes, emulsions, drops, etc.; it can also be made into liquid dosage forms, such as elixirs, syrups, emulsions, dispersions, suspensions, solutions, sprays, etc. When used for parenteral administration, it can be made into injections, sterile powders for injection, etc.

[0094] Term Explanation

[0095] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0096] "Bond" means that the indicated substituent does not exist, and the two ends of the substituent are directly connected to form a bond.

[0097] "Alkyl", when regarded as a group or part of a group, refers to an aliphatic hydrocarbon group including C 1 -C 20 a straight-chain or branched-chain aliphatic hydrocarbon group. Preferably C 1 -C 10 alkyl, more preferably C 1 -C 8 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl may be substituted or unsubstituted.

[0098] "Alkylene" refers to a divalent alkyl group, where the alkyl group is defined as above. The alkylene preferably has an alkylene group with 1 to 12 carbon atoms (i.e., C1-12 (alkylene), more preferably alkylene having 1 to 6 carbon atoms (i.e., C 1-6 alkylene), still more preferably alkylene having 1 to 4 carbon atoms (i.e., C 1-4 alkylene). Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 ))-, 1,2-ethylene (-CH 2 CH 2 ))-, 1,1-propylene (-CH(CH 2 CH 3 ))-, 1,2-propylene (-CH 2 CH(CH 3 ))-, 1,3-propylene (-CH 2 CH 2 CH 2 -), and 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc. The alkylene may be substituted or unsubstituted. When substituted, it may be substituted at any available attachment point, and the substituents may be selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclic group, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo group.

[0099] "Alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond, which may be straight-chain or branched. Preferably it is C 2 -C 10 alkenyl, more preferably C 2 -C 8 alkenyl. Representative examples include, but are not limited to, vinyl,

[0100]

[0101] , etc. The alkenyl may be substituted or unsubstituted.

[0102] "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight-chain or branched. Preferably it is C 2 -C 10 alkynyl, more preferably C 2 -C 8 alkynyl, most preferably C 2 -C 4 alkynyl. Examples of the alkynyl group include, but are not limited to, ethynyl,

[0103] etc. The alkynyl group can be substituted or unsubstituted.

[0104] "Alkenylene" refers to a divalent straight-chain or branched-chain aliphatic hydrocarbon group containing one or more carbon-carbon double bonds, which contains a specified number of carbon atoms, such as 2 to 8 carbon atoms, such as -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, etc. The alkenylene group can be optionally substituted by one or more (such as 1 to 3) identical or different substituents.

[0105] "Alkynylene" refers to a divalent straight-chain or branched-chain hydrocarbon group having one or more carbon-carbon triple bonds, which contains a specified number of carbon atoms, such as 2 to 8 carbon atoms, including but not limited to, etc. The alkynylene group can be optionally substituted by one or more (such as 1 to 3) identical or different substituents.

[0106] "Cycloalkyl" refers to saturated or partially saturated monocyclic, fused-ring, bridged-ring, and spiro carbon rings. Preferably C 3 -C 12 cycloalkyl, more preferably C 3 -C 8 cycloalkyl, most preferably C 3 -C 6 cycloalkyl. Examples of monocyclic cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl, cyclohexenyl. The cycloalkyl group can be substituted or unsubstituted.

[0107] "Subcycloalkyl" refers to a divalent saturated or partially saturated monocyclic, fused-ring, bridged-ring, and spiro carbon ring, and is connected to one group through a single bond and to other groups through another single bond, such as C 3-10 subcycloalkyl containing 3-10 carbon atoms, C 3-6 subcycloalkyl containing 3-6 carbon atoms; common subcycloalkyl groups include (but are not limited to) cyclopropane-1,1-ylidene, cyclopropane-1,2-ylidene, cyclobutane-1,1-ylidene, cyclobutane-1,2-ylidene, cyclobutane-1,3-ylidene, etc.

[0108] "Spiroalkyl" refers to a polycyclic group having 5 to 18 members, two or more cyclic structures, and a polycyclic group in which each single ring shares one carbon atom (referred to as a spiro atom) with each other. One or more double bonds may be contained in the ring, but none of the rings has aromaticity. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spiroalkyl group is classified into monospiro, dispiro or polyspiroalkyl groups according to the number of spiro atoms shared between the rings, preferably monospiro and dispiroalkyl groups, preferably 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered. Examples of "spiroalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0109] "Fused cycloalkyl" refers to a fully carbon polycyclic group having 5 to 18 members, containing two or more cyclic structures sharing a pair of carbon atoms with each other. One or more rings may contain one or more double bonds, but none of the rings has aromaticity. It is preferably 6 to 12 members, more preferably 7 to 10 members. It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl or tetradecahydrophenanthryl.

[0110] "Bridged cycloalkyl" refers to a fully carbon polycyclic group having 5 to 18 members, containing two or more cyclic structures, and sharing two non-directly connected carbon atoms with each other. One or more rings may contain one or more double bonds, but none of the rings has aromaticity. It is preferably 6 to 14 members, more preferably 7 to 10 members. It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl.

[0111] "Heterocyclic group", "heterocycle" or "heterocyclic" can be used interchangeably in this application, and all refer to a non-aromatic heterocyclic group, in which one or more ring-forming atoms are heteroatoms, such as N, O, S, P, Se, and the rest are carbon atoms, where the carbon atoms are optionally oxo-substituted (i.e., forming C=O), the nitrogen atoms are optionally quaternized, and nitrogen, sulfur, phosphorus can be optionally oxidized (i.e., NO, S(O) n , n is selected from 1 or 2, P(O) m, m is selected from 1, 2 or 3), the ring includes a monocyclic ring, a fused ring, a bridged ring and a spiro ring, and the ring may contain one or more double bonds. It preferably has 3 to 12 ring atoms, more preferably a 4- to 7-membered monocyclic ring or a 7- to 10-membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from N, O, S(O) n (where n is selected from 0, 1 or 2), P(O) m (where m is selected from 0 or 1), Se atoms. Examples of "heterocyclic group" include but are not limited to morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl or 3,6-dihydro-2H-pyranyl. The heterocyclic group may be substituted or unsubstituted.

[0112] "Heterocyclylene" refers to a divalent non-aromatic heterocyclic group in which one or more ring-forming atoms are heteroatoms such as N, O, S, P, Se, including monocyclic rings, fused rings, bridged rings and spiro rings, and the ring may contain one or more double bonds, and is connected to a group through a single bond and to other groups (or ring systems) through another single bond. For example, a 3- to 10-membered heterocyclylene, a 3- to 7-membered heterocyclylene or a 4- to 10-membered heterocyclylene; common heterocyclylenes include (but are not limited to) oxirane-2,2-ylidene, oxirane-2,3-ylidene, azetidine-2,2-ylidene, azetidine-2,3-ylidene, azetidine-2,4-ylidene, tetrahydrofuran-2,5-ylidene, tetrahydro-2H-pyran-2,3-ylidene, tetrahydro-2H-pyran-2,4-ylidene, tetrahydro-2H-pyran-2,5-ylidene, tetrahydro-2H-pyran-2,6-ylidene, pyrrolidine-1,2-ylidene, pyrrolidine-1,3-ylidene, pyrrolidine-2,3-ylidene, pyrrolidine-2,4-ylidene, pyrrolidine-2,5-ylidene, piperidine-1,2-ylidene, piperidine-1,3-ylidene, piperidine-1,4-ylidene, piperidine-2,3-ylidene, piperidine-2,4-ylidene, piperidine-2,5-ylidene, piperidine-2,6-ylidene, etc.

[0113] "Spiroheterocyclic group" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one atom with each other. The ring may contain one or more double bonds, but none of the rings has aromaticity, and one or more ring atoms are selected from one or more ring atoms are selected from N, O, S(O) n (where n is selected from 0, 1 or 2), P(O) m(where m is selected from 0 or 1), a heteroatom of Se, and the remaining ring atoms are carbon. It is preferably 6 to 14-membered, more preferably 7 to 10-membered. The spiroheterocyclic group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspiroheterocyclic group according to the number of spiro atoms shared between rings, preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclic group. Examples of the "spiroheterocyclic group" include but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl and 5-oxaspiro[2.4]heptyl.

[0114] "Fused heterocyclic group" refers to a fully carbon polycyclic group containing two or more ring structures sharing a pair of atoms with each other, and one or more rings may contain one or more double bonds, but none of the rings is aromatic, and one or more ring atoms are selected from N, O, S(O) n (where n is selected from 0, 1 or 2), P(O) m (where m is selected from 0 or 1), a heteroatom of Se, and the remaining ring atoms are carbon. It is preferably 6 to 14-membered, more preferably 7 to 10-membered. It can be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group according to the number of constituent rings, preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of the "fused heterocyclic group" include but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxine.

[0115] "Bridged heterocyclic group" refers to a 5 to 18-membered polycyclic group containing two or more ring structures sharing two non-directly connected atoms with each other, and one or more rings may contain one or more double bonds, but none of the rings is aromatic, and one or more ring atoms are selected from N, O, S(O) n (where n is selected from 0, 1 or 2), P(O) m (where m is selected from 0 or 1), a heteroatom of Se, and the remaining ring atoms are carbon. It is preferably 6 to 14-membered, more preferably 7 to 10-membered. It can be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group according to the number of constituent rings, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Examples of the "bridged heterocyclic group" include but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3.3.2]decyl.

[0116] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be connected together in a fused manner. "Aryl" includes monocyclic or bicyclic aryl, such as aromatic groups of phenyl, naphthyl, tetrahydronaphthyl. Preferably, aryl is C6 -C 10 An aryl group, more preferably the aryl group is a phenyl group and a naphthyl group, and most preferably a phenyl group. The aryl group may be substituted or unsubstituted.

[0117] "Arylene" refers to an aryl group as defined herein, which has two monovalent group centers obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent aryl group. Typical arylenes include, but are not limited to, phenylene and naphthylene.

[0118] "Heteroaryl" and "heteroaromatic ring" are used interchangeably in this application, and both refer to a monocyclic or polycyclic aromatic ring group containing 5 to 14 ring atoms, which may contain 1 to 4 atoms selected from N, O, S, Se. Preferably, it contains 5 to 12 ring atoms, more preferably a 5- to 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl. Common heteroaryls are as follows:

[0119]

[0120]

[0121] The heteroaryl group may be substituted or unsubstituted.

[0122] "Heteroarylene" refers to a heteroaryl group as described above, which has two monovalent group centers obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent heteroaryl group or by removing one hydrogen atom from a carbon atom and one hydrogen atom from a nitrogen atom.

[0123] "Fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms with each other. One or more rings may contain one or more double bonds, but at least one ring is not aromatic, and at least one ring is aromatic, where 0, 1, or more of the ring atoms are selected from N, O, S(O) n (where n is selected from 0, 1, or 2), P(O) m(where m is selected from 0 or 1), a heteroatom of Se, and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, and the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. It is preferably 7 to 14 members, more preferably 9 to 10 members. Examples of the "fused ring" include, but are not limited to:

[0124]

[0125] The fused ring can be substituted or unsubstituted.

[0126] "Alkoxy" refers to a group of (alkyl - O-). Among them, the alkyl group is as defined herein. C 1 -C 8 alkoxy is preferred. Examples thereof include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc. The alkoxy can be substituted or unsubstituted.

[0127] "Alkenyloxy" refers to a group of (alkenyl - O-). Among them, the alkenyl group is as defined herein. C 2 -C 8 alkenyloxy is preferred. The alkenyloxy can be substituted or unsubstituted.

[0128] "Hydroxyalkyl" is a group of (-alkyl - OH). Among them, the alkyl group is as defined herein. C 1 -C 8 hydroxyalkyl is preferred. Examples thereof include, but are not limited to: hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, etc. The hydroxyalkyl can be substituted or unsubstituted.

[0129] "Alkylamino" refers to a group of (alkyl - NH-). Among them, the alkyl group is as defined herein. C 1 -C 8 alkylamino is preferred. Examples thereof include, but are not limited to: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutoxy, tert-butoxy, etc. The alkylamino can be substituted or unsubstituted, and the substituent can be on the alkyl group or on the N, such as examples: dimethylamino, diethylamino.

[0130] "Aminoalkyl" refers to a group of (-alkyl - NH 2 ). Among them, the alkyl group is as defined herein. Examples thereof include, but are not limited to: aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, aminopentyl, etc. The aminoalkyl can be substituted or unsubstituted, and the substituent can be on the alkyl group or on the N, such as examples: dimethylaminoalkyl.

[0131] "Alkylcarbonyl" refers to the group of (alkyl-C(O)-). Among them, the definition of alkyl can be found in this article. Its examples include, but are not limited to: methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, etc. Alkylcarbonyl can be substituted or unsubstituted.

[0132] "Alkoxycarbonyl" refers to the group of (alkyl-O-C(O)-). Among them, the definition of alkyl can be found in this article. Its examples include, but are not limited to: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, etc. Alkoxycarbonyl can be substituted or unsubstituted.

[0133] "Haloalkyl" refers to an alkyl group substituted by a halogen. Among them, the definitions of halogen and alkyl can be found in this article. "Haloalkoxy" refers to an alkoxy group substituted by a halogen. Among them, the definitions of halogen and alkoxy can be found in this article. "Halo-hydroxyalkyl" refers to a hydroxyalkyl group substituted by a halogen. Among them, the definitions of halogen and hydroxyalkyl can be found in this article. "Haloalkylamino" refers to an alkylamino group substituted by a halogen. Among them, the definitions of halogen and alkylamino can be found in this article. "Cycloalkoxy" refers to the group of (cycloalkyl-O-). Among them, the definition of cycloalkyl can be found in this article. "Heteroepoxy" refers to the group of (heterocyclic-O-). Among them, the definition of heterocyclic can be found in this article. "Hydroxy" refers to the -OH group. "Halogen" refers to fluorine, chlorine, bromine and iodine. "Amino" refers to -NH 2 . "Cyano" refers to -CN. "Nitro" refers to -NO 2 . "Carboxyl" refers to -C(O)OH. "Amide" refers to -C(O)NH 2 .

[0134] "Substituted" means that one or more hydrogen atoms in the group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) the possible or impossible substitutions without much effort. For example, an amino or hydroxy group with a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (such as olefinic) bond.

[0135] As used in this specification, "substituted" or "substitution", unless otherwise specified, means that the group can be substituted by one or more groups selected from the following: H, deuterium, halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkenyloxy, C3 -C 12 cycloalkyl, C 3 -C 8 cycloalkoxy, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclic oxy group, sulfamoyl, C 6 -C 10 aryl, 5- to 12-membered heteroaryl, cyano, amino, nitro, hydroxy, oxo, carboxy, amide, hydroxyalkyl, aminoalkyl, alkanoyl, alkoxycarbonyl, C 1 -C 8 alkylamino, C 1 -C 8 haloalkylamino, -OR g 、-SR g 、-C 1 -C 8 alkylene-R g 、-OC(O)R g 、-C(O)R g 、-C(O)OR g 、-C(O)N(R x )R y 、-NR x R y 、-N(CH 3 )R g 、-N(R x )C(O)R y 、-N(R x )C(O)NR x R y 、-N(R x )C(O)OR g 、-N(R x )S(O)NR x R y 、-N(R x )S(O) 2 NR x R y 、-N(R x )S(O) 2 R g 、-S(O)R g 、-S(O) 2 R g 、-S(O) 2 NR x R y 、-P(O)R x R y ; the alkyl, alkylene, alkoxy, alkenyl, alkynyl, alkenyloxy, cycloalkyl, cycloalkoxy, heterocyclic group, heterocyclic oxy group, aryl, heteroaryl, 3- to 12-membered ring, amino, hydroxy or amide is optionally further substituted by one or more Ro Substitute;

[0136] When two Rs o are substituted on the same atom, the two Rs o together with the atom to which they are attached form a 3- to 6-membered ring, or when two Rs o are substituted on adjacent atoms, the two Rs o together with the atoms to which they are attached form a 3- to 12-membered ring;

[0137] R g , R x , R y , R o each independently selected from H, deuterium, halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkenyloxy, C 3 -C 12 cycloalkyl, C 3 -C 8 cycloalkoxy, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclic oxy group, aminosulfonyl, C 6 -C 10 aryl, 5- to 12-membered heteroaryl, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide, hydroxyalkyl, aminoalkyl, alkcarbonyl, alkoxycarbonyl, C 1 -C 8 alkylamino, C 1 -C 8 haloalkylamino, -OR s , -SR s , -C 1 -C 8 alkylene-R s , -OC(O)R s , -C(O)R s , -C(O)OR s , -C(O)N(R s )R t , -NR s R t , -N(CH 3 )R s , -N(R s )C(O)R t , -N(R s )C(O)NR s R t, -N(R s )C(O)OR t , -N(R s )S(O)NR s R t , -N(R s )S(O) 2 NR s R t , -N(R s )S(O) 2 R t , -S(O)R s , -S(O) 2 R s , -S(O) 2 NR s R t or -P(O)R s R t , wherein the alkyl, alkylene, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally further substituted by one or more R r substituents;

[0138] When two R r substitute on the same atom, the two R r and the atom to which they are attached together form a 3 - 6 - membered ring, or when two R r substitute on adjacent atoms, the two R r and the atoms to which they are attached together form a 3 - 12 - membered ring;

[0139] R r , R s , R t are each independently selected from H, deuterium, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, C 1 -C 8 alkoxy, C 1 -C 8 haloalkyl, hydroxyalkyl, aminoalkyl, C 1 -C 8 alkylamino, alkylcarbonyl, alkoxycarbonyl, halo - hydroxyalkyl, C 1 -C 8 haloalkylamino, C 3 -C 12 cycloalkyl, 3 - 12 - membered heterocyclic group, carboxyl, amide, C 6 -C 10 aryl or 5 - 12 - membered heteroaryl.

[0140] The compounds of the present invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0141] Unless otherwise indicated, the structures described in the present invention also include all isomers of such structures (e.g., diastereomeric, enantiomeric, atropisomeric, and geometric (conformational) isomeric forms; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Thus, individual stereoisomers of the compounds of the present invention, as well as mixtures of enantiomers, mixtures of diastereomers, and mixtures of geometric (conformational) isomers are within the scope of the present invention.

[0142] As used herein, the C, H, O, S, N, F, Cl, Br, I, etc. involved in the groups and compounds of the present invention include their isotopic forms. At the same time, the C, H, O, S, N, F, Cl, Br, I involved in the groups and compounds of the present invention may optionally be substituted by one or more of their corresponding isotopes, including but not limited to isotopes of carbon 12 C, 13 C, 14 C, the isotopes of hydrogen, protium (H), deuterium (D), tritium (T), and the isotopes of oxygen 16 O, 17 O, 18 O, and the isotopes of sulfur 32 S, 33 S, 34 S, 36 S, and the isotopes of nitrogen 14 N, 15 N, and the isotopes of fluorine 17 F, 19 F, and the isotopes of chlorine 35 Cl, 37 Cl, and the isotopes of bromine 79 Br, 81 Br, etc.

[0143] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any claims. It should be noted that in the specification and the appended claims, unless otherwise stated, the singular forms such as "a", "an", "the" include plural referents. It should also be noted that, unless otherwise indicated, "or" means "and / or". In addition, terms such as "comprising", "including", etc. are not restrictive.

[0144] "Pharmaceutically acceptable salts" refer to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds represented by formula (I) can be metal salts, salts formed with suitable acids, or salts formed with suitable bases. A preferred class of salts is the salts formed by the compounds of the present invention with acids. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, etc.; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, lycium acid, isonicotinic acid, salicylic acid, ascorbic acid, gentisic acid, gluconic acid, pyruvic acid, naphthalenesulfonic acid, stearic acid, phenylacetic acid, p-aminobenzenesulfonic acid, 2-hydroxyethanesulfonic acid, pamoic acid, tannic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid. A preferred class of salts is the salts formed by the compounds of the present invention with bases. Bases suitable for forming salts include, but are not limited to: inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, etc.; organic bases such as ammonia water, triethylamine, diethylamine, piperazine, guanidine, diethanolamine, etc.

[0145] "Effective amount" or "therapeutically effective amount" refers to the amount of an active ingredient (such as a compound) that, when administered to a subject to treat a disease or at least one clinical symptom of a disease or disorder, is sufficient to affect such treatment of the disease, disorder, or symptom. The "therapeutically effective amount" can vary with: the compound, the disease, the disorder, and / or the symptom of the disease or disorder, the severity of the disease, disorder, and / or the symptom of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. In any given instance, the appropriate amount will be apparent to those skilled in the art or can be determined by routine experimentation. In some embodiments, the "therapeutically effective amount" is the amount of at least one compound and / or at least one of its stereoisomers and / or at least one of its pharmaceutically acceptable salts disclosed herein that is effective in "treating" (as defined above) a disease or disorder of a subject. In the case of combination therapy, the "therapeutically effective amount" refers to the total amount of the combination agents effective for treating a disease, disorder, or condition.

[0146] "Pharmaceutical preparation" refers to any pharmaceutically acceptable dosage form, administered by any suitable route of administration, such as locally, orally, transdermally, rectally, vaginally, parenterally, intranasally, intralungally, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracutaneously, intraperitoneally, subcutaneously, subcuticularly or by inhalation, etc., to a patient or subject in need of such treatment. The pharmaceutical composition containing the active ingredient can be in a form suitable for oral administration, such as tablets, troches, lozenges, liquid preparations such as aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft gelatin capsules, or syrups or elixirs or solutions or suspensions. Tablets contain the active ingredient and a non-toxic pharmaceutically acceptable carrier suitable for mixing for the preparation of tablets. For parenteral administration, the pharmaceutical composition can be a solution, aqueous solution, oily suspension concentrate, lyophilized powder, etc. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays or injections, more preferably tablets or capsules. The pharmaceutical composition can be a single unit dosage with an accurate dose. In addition, the pharmaceutical composition can also contain other active ingredients. The dosage forms for local or transdermal administration can include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound can be mixed with a pharmaceutically acceptable carrier under sterile conditions, and it can be mixed with any preservatives, buffers or propellants that may be required.

[0147] The inventors of the present invention have confirmed through experiments that the compounds of the present invention have the ability to degrade STAT3.

[0148] The inventors of the present invention have confirmed through experiments that the compounds of the present invention have an obvious ability to inhibit the proliferation of MOLM16 cells.

[0149] The inventors of the present invention have confirmed through experiments that the compounds of the present invention have an obvious ability to degrade STAT3 in SW1990 cells.

[0150] The inventors of the present invention have confirmed through experiments that the compounds of the present invention have an obvious ability to inhibit growth in the in vivo pharmacodynamic model of SW1990 pancreatic cancer xenografts. Detailed implementation manners

[0151] Chemical substances represented by some abbreviations in the embodiments of the present invention:

[0152] DCM: Dichloromethane; HCL: Hydrochloric acid; DMF: N,N-Dimethylformamide; HATU: 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; STAB: Sodium triacetoxyborohydride; Pd / C: Palladium on carbon; DCC: Dicyclohexylcarbodiimide; BSTFA: N,O-Bis(trimethylsilyl)trifluoroacetamide; TMSI: Trimethylsilyl iodide; DMAP: 4-Dimethylaminopyridine; THF: Tetrahydrofuran; LHMDS: Lithium bis(trimethylsilyl)amide; NBS: N-Bromosuccinimide; Boc 2 O: Di-tert-butyl dicarbonate. NFSB: N-Fluorobenzenesulfonimide; BSTFA: N,O-Bis(trimethylsilyl)trifluoroacetamide.

[0153] Synthesis of Intermediate A1 in Example 1

[0154]

[0155] Synthesis Step 1: Synthesis of A1-1

[0156] Dissolve tert-butyl (S)-(1-(4-fluorophenyl)ethyl)carbamate (1.9 g, 7.95 mmol) in dichloromethane (20 mL). Add trifluoroacetic acid (6.8 g, 60.2 mmol) to the system and react at room temperature for 4 h. After the reaction is completed, concentrate to remove the solvent to obtain A1-1, which is directly used in the next step. LC-MS (ESI-MS): m / z = 140.1 [M+H] + 。

[0157] Synthesis Step 2: Synthesis of A1-2

[0158] Dissolve A1-1 (1.3 g, 7.40 mmol) in dichloromethane (20 mL). Sequentially add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.2 g, 22.20 mmol), N-hydroxy-7-azabenzotriazole (1.5 g, 11.10 mmol), triethylamine (2.2 g, 22.20 mmol), and (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (3.1 g, 8.88 mmol) to the system. React at room temperature for 6 h. After the reaction is completed, quench with water, extract with DCM, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain 2.5 g of A1-2 by column chromatography, yield: 73%. LC-MS (ESI-MS): m / z = 466.3 [M+H] + 。

[0159] Synthesis Step 3: Synthesis of A1

[0160] Dissolve A1-2 (1.5 g, 3.23 mmol) in 1,4-dioxane (15 mL). Add a dioxane hydrochloride solution (15 mL) to the system and react at room temperature for 1 h. After the reaction is completed, remove 1,4-dioxane by concentration under reduced pressure to obtain 1.2 g of A1 with a yield of 92%. LC-MS (ESI-MS): m / z = 366.2 [M+H] + 。

[0161] With reference to the synthetic route and method of intermediate A1, the following intermediates were synthesized:

[0162]

[0163] Synthesis of Intermediate A6 in Example 2

[0164]

[0165] Synthesis Step 1: Synthesis of A6-1

[0166] Dissolve methyl 2-(3-methylisoxazol-5-yl)acetate (2 g, 12.90 mmol) in tetrahydrofuran (20 mL). Add potassium tert-butoxide (2.4 g, 19.35 mmol) to the system and add 1-iodopropane (1.6 mL, 13.69 mmol) under ice bath. React at room temperature for 16 h. After the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, remove ethyl acetate by concentration under reduced pressure, and purify by column chromatography to obtain 1.6 g of A6-1 with a yield of 62%. LC-MS (ESI-MS): m / z = 198.1 [M+H] + 。

[0167] Synthesis Step 2: Synthesis of A6-2

[0168] Dissolve A6-1 (1.5 g, 7.61 mmol) in tetrahydrofuran (15 mL). Add water (15 mL), methanol (15 mL), and lithium hydroxide (1.8 g, 76.10 mmol) to the system and react at room temperature for 4 h. After the reaction is completed, adjust the pH to 7, remove tetrahydrofuran and methanol by concentration under reduced pressure, add ethyl acetate for extraction, remove ethyl acetate from the organic phase by concentration under reduced pressure, and purify by column chromatography to obtain 1.2 g of A6-2 with a yield of 86%. LC-MS (ESI-MS): m / z = 184.1 [M+H] + 。

[0169] Synthesis Step 3: Synthesis of A6-3

[0170] Dissolve A6-2 (10 g, 50.73 mmol) in ethyl acetate (50 mL), add cinchonine (13.2 g, 45.15 mmol) to the system, and react at room temperature for 6 h. After the reaction is completed, filter. The solid is extracted with saturated aqueous citric acid solution and ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 4.3 g of A6-3 is obtained, yield: 43%.

[0171] Synthesis step 4: Synthesis of A6

[0172] Dissolve A6-3 (3.6 g, 10.94 mmol) in dichloromethane (30 mL), then successively add (2S,4R)-N-(4-ethynyl-2-hydroxybenzyl)-4-hydroxypyrrolidine-2-carboxamide (2 g, 10.94 mmol), HATU (4.6 g, 12.03 mmol), and diisopropylethylamine (3.1 g, 24.06 mmol), and react at room temperature for 3 h. After the reaction is completed, add ethyl acetate and water for extraction and liquid separation. The organic phase is dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 2.7 g of A6, yield 51%. LC-MS (ESI-MS): m / z = 426.2 [M+H] + 。

[0173] With reference to the synthetic route and method of intermediate A6, the following intermediates were synthesized:

[0174]

[0175] Synthesis of intermediate A8 in Example 3

[0176]

[0177] Synthesis step 1: Synthesis of A8-1

[0178] Dissolve (S)-3-(4-bromophenyl)-3-((tert-butoxycarbonyl)amino)propanoic acid (10 g, 29.15 mmol) in DMF, successively add potassium carbonate (8 g, 58.30 mmol) and methyl iodide (6.2 g, 43.73 mmol) to the system, and react at room temperature for 12 h. After the reaction is completed, quench with water, extract with ethyl acetate after adding water, and concentrate the organic phase to remove ethyl acetate and then purify by column chromatography to obtain 8.5 g of A8-1, yield 81%. LC-MS (ESI-MS): m / z = 358.1 [M+H] + 。

[0179] Synthesis step 2: Synthesis of A8-2

[0180] A8-1 (8.2 g, 22.97 mmol) was dissolved in 1,4-dioxane (80 mL). Water (16 mL), 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (6.2 g, 27.56 mmol), sodium carbonate (7.3 g, 68.89 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (1.7 g, 2.30 mmol) were successively added thereto, and the mixture was reacted at 100 °C for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. After the organic phase was concentrated under reduced pressure to remove ethyl acetate, it was purified by column chromatography to obtain 5.8 g of A8-2, with a yield of 67%. LC-MS (ESI-MS): m / z = 377.2 [M+H] + 。

[0181] Synthesis step 3: Synthesis of A8-3

[0182] A8-2 (5.5 g, 14.62 mmol) was dissolved in 1,4-dioxane (55 mL). A hydrochloric acid dioxane solution (55 mL) was added to the system, and the mixture was reacted at room temperature for 1 h. After the reaction was completed, 1,4-dioxane was removed by concentration under reduced pressure to obtain 5.2 g of A8-3, with a yield of 97%. LC-MS (ESI-MS): m / z = 277.1 [M+H] + 。

[0183] Synthesis step 4: Synthesis of A8-4

[0184] A8-3 (5 g, 16.03 mmol) was dissolved in dichloromethane (50 mL). N,N-Diisopropylethylamine (9.3 g, 72.44 mmol), (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (9.3 g, 27.16 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (10.3 g, 27.16 mmol) were successively added to the system, and the mixture was reacted at room temperature for 4 h. After the reaction was completed, water was added, and the mixture was extracted with dichloromethane. After the organic phase was concentrated under reduced pressure to remove dichloromethane, it was purified by column chromatography to obtain 6.9 g of A8-4, with a yield of 72%. LC-MS (ESI-MS): m / z = 603.3 [M+H] + 。

[0185] Synthesis step 5: Synthesis of A8-5

[0186] A8-4 (6.5 g, 10.79 mmol) was dissolved in 1,4-dioxane (65 mL). Hydrochloric acid dioxane solution (65 mL) was added to the system, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, 1,4-dioxane was removed by concentration under reduced pressure to obtain 6 g of A8-5, with a yield of 95%. LC-MS (ESI-MS): m / z = 503.2 [M+H] + 。

[0187] Synthesis step 6: Synthesis of A8-6

[0188] A8-5 (5.5 g, 10.19 mmol) was dissolved in 50 mL of dichloromethane. N,N-Diisopropylethylamine (5.2 g, 40.76 mmol), 1-fluorocyclopropane-1-carboxylic acid (1.6 g, 15.29 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.8 g, 15.29 mmol) were successively added to the system, and the reaction was carried out at room temperature for 4 h. After the reaction was completed, water was added and the mixture was extracted with dichloromethane. The organic phase was concentrated under reduced pressure to remove dichloromethane and then purified by column chromatography to obtain 4.2 g of A8-6, with a yield of 70%. LC-MS (ESI-MS): m / z = 589.2 [M+H] + 。

[0189] Synthesis step 7: Synthesis of A8

[0190] A8-6 (4 g, 6.80 mmol) was dissolved in tetrahydrofuran (40 ml). Water (40 ml), methanol (40 ml), and lithium hydroxide (1.6 g, 68.00 mmol) were added to the system, and the reaction was carried out at room temperature for 4 h. After the reaction was completed, the pH was adjusted to 7, and tetrahydrofuran and methanol were removed by concentration under reduced pressure. Ethyl acetate was added for extraction, and the organic phase was concentrated under reduced pressure to remove ethyl acetate and then purified by column chromatography to obtain 3.1 g of A8, with a yield of 78%. LC-MS (ESI-MS): m / z = 575.2 [M+H] + 。

[0191] With reference to the synthetic route and method of intermediate A8, the following intermediates were synthesized:

[0192]

[0193] Synthesis of intermediate B1 in Example 4

[0194]

[0195] Synthesis step 1: Synthesis of B1-1

[0196] Dissolve 2-chloro-3-hydroxybenzaldehyde (10 g, 64.10 mmol) in tetrahydrofuran (100 mL). Sequentially add N,N-diisopropylethylamine (12 g, 96.15 mmol) and benzyl bromide (16 g, 96.15 mmol) to the system, and react at room temperature for 16 h. After the reaction is completed, concentrate under reduced pressure, add water and extract with ethyl acetate. After the organic phase is concentrated under reduced pressure to remove ethyl acetate, it is purified by column chromatography to obtain 15 g of B1-1, with a yield of 95%. LC-MS (ESI-MS): m / z = 247.0 [M+H] + 。

[0197] Synthesis step 2: Synthesis of B1-2

[0198] Dissolve B1-1 (13 g, 52.85 mmol) in methanol (130 mL), add water (4 ml), add sodium borohydride (2 g, 52.85 mmol) under ice bath, and react at room temperature for 1 h. After the reaction is completed, add water (300 ml) and stir for 10 min, add water and extract with ethyl acetate. Combine the organic phases, dry with anhydrous sodium sulfate, and concentrate the organic phase under reduced pressure to remove ethyl acetate to obtain 12 g of B1-2, with a yield of 78%. LC-MS (ESI-MS): m / z = 249.1 [M+H] + 。

[0199] Synthesis step 3: Synthesis of B1-3

[0200] Dissolve B1-2 (10 g, 40.32 mmol) in tetrahydrofuran (200 mL), cool down to -20 °C, slowly add phosphorus tribromide (2.3 ml, 14.52 mmol) to the system, and react at room temperature for 1 h. After the reaction is completed, add water to quench, concentrate to remove tetrahydrofuran and then add dichloromethane for extraction. After the organic phase is concentrated under reduced pressure, it is purified by column chromatography to obtain 9 g of B1-3, with a yield of 71%. LC-MS (ESI-MS): m / z = 311.0 [M+H] + 。

[0201] Synthesis step 4: Synthesis of B1-4

[0202] Dissolve B1-3 (9 g, 28.89 mmol) in dimethyl sulfoxide (50 mL), add methoxyamine hydrochloride (3.6 g, 43.34 mmol) to the system, and react at room temperature for 1 h. After the reaction is completed, add water to quench and then add ethyl acetate for extraction. After the organic phase is concentrated under reduced pressure, it is purified by column chromatography to obtain 6.7 g of B1-4, with a yield of 83%. LC-MS (ESI-MS): m / z = 278.1 [M+H] + 。

[0203] Synthesis step 5: Synthesis of B1-5

[0204] Dissolve B1-4 (8 g, 25.89 mmol) in tetrahydrofuran (80 mL). Sequentially add N,N-diisopropylethylamine (5 g, 38.83 mmol) and benzyl 2-bromoacetate (7.5 g, 38.83 mmol) to the system, and react at 70 °C for 12 h. After the reaction is completed, concentrate under reduced pressure, add water, extract with ethyl acetate, and concentrate the organic phase under reduced pressure to remove ethyl acetate, then purify by column chromatography to obtain 6.8 g of B1-5, with a yield of 59%. LC-MS (ESI-MS): m / z = 426.1 [M+H] + 。

[0205] Synthesis step 6: Synthesis of B1-6

[0206] Dissolve B1-5 (6.5 g, 14.81 mmol) in methanol (70 ml). Add Pd / BaSO 4 (650 mg, 10% Wt) to the system, and react at room temperature under a H 2 atmosphere for 16 h. After the reaction is completed, filter through diatomaceous earth, and purify the mother liquor by column chromatography to obtain 3.3 g of B1-6, with a yield of 86%. LC-MS (ESI-MS): m / z = 246.1 [M+H] + 。

[0207] Synthesis step 7: Synthesis of B1-7

[0208] Dissolve B1-6 (3.2 g, 12.35 mmol) in dichloromethane (30 mL). Add tert-butyl trichloroacetimidate (4 g, 18.52 mmol) to the system, and react at room temperature for 12 h. After the reaction is completed, add dichloromethane for extraction, concentrate the organic phase under reduced pressure to remove dichloromethane, and then purify by column chromatography to obtain 2.6 g of B1-7, with a yield of 67%. LC-MS (ESI-MS): m / z = 302.1 [M+H] + 。

[0209] Synthesis step 8: Synthesis of B1-8

[0210] Dissolve B1-7 (1 g, 3.32 mmol) in tetrahydrofuran (10 mL). Sequentially add (S)-(5-amino-1-hydroxy-5-oxopentan-2-yl)carbamic acid tert-butyl ester (925 mg, 3.99 mmol), triphenylphosphine (1.7 g, 6.64 mmol) to the system, and dropwise add diisopropyl azodicarboxylate (1.3 g, 3.99 mmol) under an ice bath. React at room temperature for 15 min. After the reaction is completed, quench with water, extract with EA. After the organic phase is concentrated under reduced pressure to remove EA, purify by column chromatography to obtain 610 mg of B1-8, with a yield of 34%. LC-MS (ESI-MS): m / z = 516.2 [M+H] + 。

[0211] Synthesis step 9: Synthesis of B1-9

[0212] Dissolve B1-8 (500 mg, 0.97 mmol) in DCM (5 mL). Add trifluoroacetic acid (5 ml, 10V) to the system and react at room temperature for 4 h. After the reaction is completed, concentrate under reduced pressure to remove dichloromethane and trifluoroacetic acid to obtain 310 mg of B1-9, with a yield of 88%. LC-MS (ESI-MS): m / z = 360.1 [M+H] + 。

[0213] Synthesis step 10: Synthesis of B1

[0214] Dissolve B1-9 (290 mg, 0.81 mmol) in DCM (3 mL). Sequentially add triethylamine (408 mg, 4.04 mmol), di-tert-butyl dicarbonate (353 mmol, 1.62 mmol) to the system and react at room temperature for 2 h. After the reaction is completed, extract with dichloromethane. After the organic phase is concentrated under reduced pressure to remove dichloromethane, purify by column chromatography to obtain 300 mg of B1, with a yield of 67%. LC-MS (ESI-MS): m / z = 460.2 [M+H] + 。

[0215] Refer to the synthetic route and method of intermediate B1 to synthesize the following intermediates:

[0216]

[0217]

[0218] Synthesis of intermediate B15 in Example 5

[0219]

[0220] Synthesis step 1: Synthesis of B15-1

[0221] Dissolve 1-bromo-3,3-dimethoxybutane (5 g, 27.53 mmol) in THF (50 mL), add 2N HCl (50 mL) to the system, and reflux for 16 h. After the reaction is completed, concentrate under reduced pressure, add water and extract with EA. After the organic phase is concentrated under reduced pressure to remove EA, it is purified by column chromatography to obtain 2.6 g of B15-1, with a yield of 70%. LC-MS (ESI-MS): m / z = 137.0 [M+H] + 。

[0222] Synthesis step 2: Synthesis of B15-2

[0223] Dissolve B15-1 (2.5 g, 18.38 mmol) in DCM (50 mL), add B1-4 (5 g, 18.38 mmol) to the system, and react at room temperature for 30 min. Then add STAB (5.8 g, 27.57 mmol) and react at room temperature for 12 h. After the reaction is completed, add water for extraction. After the organic phase is concentrated under reduced pressure to remove DCM, it is purified by column chromatography to obtain 4.0 g of B15-2, with a yield of 54%. LC-MS (ESI-MS): m / z = 398.0 [M+H] + 。

[0224] Synthesis steps 3-4: Synthesis of B15

[0225] The synthesis operation and route of B15 refer to Synthesis steps 6 and 8 of intermediate B1

[0226] Synthesis of intermediate B16 in Example 6

[0227]

[0228] Synthesis step 1: Synthesis of B16-1

[0229] The synthesis operation and route of B16-1 refer to Synthesis step 2 of intermediate B15

[0230] Synthesis steps 2-3: Synthesis of B16-3

[0231] The synthesis operation and route of B16-3 refer to Synthesis steps 6 and 8 of intermediate B1

[0232] Synthesis step 4: Synthesis of B16

[0233] Dissolve B16-3 (2 g, 3.0 mmol) in DCM (20 mL), add DBU (685 mg, 4.5 mmol), stir at room temperature for 12 h. After the reaction is completed, add water for extraction. After the organic phase is concentrated under reduced pressure to remove DCM, it is purified by column chromatography to obtain 1.1 g of B16, with a yield of 82%. LC-MS (ESI-MS): m / z = 445.2 [M+H] + 。

[0234] Synthesis of Intermediate B18 in Example 7

[0235]

[0236] Synthesis Step 1: Synthesis of B18-1

[0237] With reference to the first-step synthesis operation and method of Intermediate B1, B18-1 was synthesized. LC-MS (ESI-MS): m / z = 247.0 [M+H] + .

[0238] Synthesis Step 2: Synthesis of B18-2

[0239] 2-(Ethoxycarbonyl)ethyltriphenylphosphonium bromide (10.3 g, 23.23 mmol) was dissolved in 100 ml of tetrahydrofuran. Sodium hydride (1.1 g, 27.89 mmol) with a mass fraction of 60% and B18-1 (5.7 g, 23.23 mmol) were successively added to the system, and the reaction was carried out at room temperature for 15 h. After the reaction was completed, water was added to quench the reaction, and ethyl acetate was added for extraction. After the organic phase was concentrated under reduced pressure to remove ethyl acetate, it was purified by column chromatography to obtain 6.1 g of B18-2 with a yield of 80%. LC-MS (ESI-MS): m / z = 331.0 [M+H] + .

[0240] Synthesis Step 3: Synthesis of B18-3

[0241] B18-2 (5.0 g, 15.11 mmol) was dissolved in methanol (70 mL). Pd / BaSO 4 (500 mg, 10% Wt) was added to the system, and the reaction was carried out at room temperature for 16 h under a H 2 atmosphere. After the reaction was completed, it was filtered through diatomaceous earth, and the mother liquor was purified by column chromatography to obtain 3.1 g of B18-3 with a yield of 85%. LC-MS (ESI-MS): m / z = 243.1 [M+H] + .

[0242] Synthesis Step 4: Synthesis of B18-4

[0243] With reference to the synthesis method of the eighth step of Intermediate B1, B18-4 was synthesized. LC-MS (ESI-MS): m / z = 457.2 [M+H] + .

[0244] Synthesis Step 5: Synthesis of B18

[0245] Dissolve B18-4 (950 mg, 2.14 mmol) in 20 mL / 20 mL water / tetrahydrofuran. Add lithium hydroxide (515 mg, 21.4 mmol) to the system and react at room temperature for 6 h. After the reaction, adjust the pH to 4 - 5 with 2N hydrochloric acid, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 825 mg of B18 is obtained by column chromatography, yield: 90%. LC-MS (ESI-MS): m / z = 429.1 [M + H] + 。

[0246] Synthesis of Intermediate C1 in Example 8

[0247]

[0248] Synthesis Step 1: Synthesis of C1-1

[0249] Dissolve methyl (5S, 8S, 10aR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (1.0 g, 2.93 mmol) in dichloromethane (20 mL). Sequentially add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1 g, 5.86 mmol), N-hydroxy-7-azabenzotriazole (477 mg, 3.51 mmol), triethylamine (889 mg, 8.79 mmol), and cyclopropylcarboxylic acid (301 mg, 3.51 mmol) to the system. React at room temperature for 6 h. After the reaction, quench with water, extract with DCM, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 990 mg of C1-1 is obtained by column chromatography. LC-MS (ESI-MS): m / z = 410.2 [M + H] + 。

[0250] Synthesis Step 2: Synthesis of C1

[0251] Dissolve C1-1 (950 mg, 2.32 mmol) in 1:1 water / tetrahydrofuran (40 mL). Add lithium hydroxide (557 mg, 23.2 mmol) to the system and react at room temperature for 6 h. After the reaction, adjust the pH to 4 - 5 with 2N hydrochloric acid, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 825 mg of C1 is obtained by column chromatography, yield: 90%. LC-MS (ESI-MS): m / z = 396.2 [M + H] + 。

[0252] With reference to the synthetic route and method of Intermediate C-1, the following intermediates are synthesized:

[0253]

[0254]

[0255] Synthesis of Intermediate C13 in Example 9

[0256]

[0257] Synthesis Step 1: Synthesis of C13-1

[0258] Dissolve methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate-8-carboxylate (1 g, 2.93 mmol) in dichloromethane (10 mL). Add triethylamine (1.8 g, 17.58 mmol) to the system successively. Add triphosgene (2.6 g, 8.79 mmol) under ice bath. React at room temperature for 4 h. Then add methylamine in tetrahydrofuran solution (5.3 ml, 10.55 mmol) and react at 40 °C for 12 h. After the reaction, add water and extract with dichloromethane. The organic phase is concentrated under reduced pressure to remove dichloromethane and then purified by column chromatography to obtain 780 mg of C13-1, with a yield of 64%. LC-MS (ESI-MS): m / z = 399.2 [M+H] + 。

[0259] Synthesis Step 2: Synthesis of C13

[0260] Refer to the second-step synthesis route and method of Intermediate C1 to synthesize the target compound C13. LC-MS (ESI-MS): m / z = 385.2 [M+H] + 。

[0261] Refer to the synthesis route and method of Intermediate C13 to synthesize the following intermediates:

[0262]

[0263]

[0264] Synthesis of Intermediate C17 in Example 10

[0265]

[0266] Synthesis Step 1: Synthesis of C17-1

[0267] Imidazo[1,2-a]pyridin-7-ylmethanol (1.0 g, 6.75 mmol) was dissolved in N,N-dimethylformamide (20 mL). The temperature was lowered to 0 °C, and sodium hydride (540 mg, 13.5 mmol, 60% content) was added to the system. After reacting for 5 min, p-toluenesulfonyl chloride (1.5 g, 8.1 mmol) was added to the system, and the reaction was carried out at room temperature for 6 h. After the reaction was completed, the reaction was quenched with water, extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 1.2 g of C17-1 was obtained by column chromatography, yield: 60%. LC-MS (ESI-MS): m / z = 303.1 [M+H] + 。

[0268] Synthesis step 2: Synthesis of C-17-2

[0269] C17-1 (1.0 g, 2.93 mmol) was dissolved in N,N-dimethylformamide (20 mL). Potassium carbonate (1.2 g, 8.79 mmol) and methyl (5S,8S,10aR)-5-({[(2-methylpropan-2-yl)oxy]carbonyl}amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (1.1 g, 3.51 mmol) were successively added to the system, and the reaction was carried out at room temperature for 6 h. After the reaction was completed, the reaction was quenched with water, extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 1.2 g of C17-2 was obtained by column chromatography, yield: 91%. LC-MS (ESI-MS): m / z = 472.2 [M+H] + 。

[0270] Synthesis step 3: Synthesis of C17

[0271] Referring to the second synthesis route and method of intermediate C1, the target compound C17 was synthesized. LC-MS (ESI-MS): m / z = 458.2 [M+H] + 。

[0272] Referring to the synthesis route and method of intermediate C-17, the following intermediates were synthesized:

[0273]

[0274]

[0275] Synthesis of intermediate D1 in Example 11

[0276]

[0277] Synthesis step 1: Synthesis of D1-2

[0278] D1-1 (5.00 g, 24.60 mmol) and Boc 2 O (6.44 g, 29.57 mmol) were added to DMF (60 mL). DMAP (0.30 g, 2.46 mmol) was added to the mixture. The reaction solution was stirred at 25 °C for 2 h and then the reaction was completed. Water (100 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (300 mL × 2). The layers were separated, and the organic phases were combined. The organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7.20 g of crude D1-2 with a yield of 96.5%. LC-MS (ESI-MS): m / z = 304.2 [M+H] + 。

[0279] Synthesis step 2: Synthesis of D1-3

[0280] D1-2 (0.23 g, 0.95 mmol) was added to carbon tetrachloride (150 mL). NBS (4.27 g, 23.73 mmol) was added to the mixture in portions. The reaction solution was heated to 80 °C and stirred for 12 h until the reaction was completed. The reaction solution was cooled to 25 °C. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (SiO 2 , PE / EA = 10 / 1) to obtain 6.50 g of D1-3 with a yield of 71.6%. LC-MS (ESI-MS): m / z = 382.1 [M+H] + 。

[0281] Synthesis step 3: Synthesis of D1-4

[0282] Triethyl phosphite (3.39 g, 20.40 mmol) was added to D1-3 (3.39 g, 20.40 mmol). The reaction solution was heated to 100 °C and stirred for 12 h, and then the reaction solution was cooled to 25 °C. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (SiO 2 , PE / EA = 3 / 1) to obtain 7.00 g of D1-4 with a yield of 93.7%. LC-MS (ESI-MS): m / z = 440.2 [M+H] + 。

[0283] Synthesis step 4: Synthesis of D1-5

[0284] D1-4 (6.80 g, 15.47 mmol) and titanium(IV) isopropoxide (1.10 g, 3.87 mmol) were added to benzyl alcohol (35 L). The reaction mixture was heated to 100 °C and stirred for 12 h until the reaction was completed. The reaction mixture was cooled to 35 °C, quenched with 1 N hydrochloric acid (50 mL), extracted twice with ethyl acetate (200 mL × 2), separated, and the organic layers were combined. The organic layer was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (SiO 2 , PE / EA = 2 / 1) to give 3.80 g of D1-5 in 85.5% yield. LC-MS (ESI-MS): m / z = 402.1 [M+H] + .

[0285] Synthesis step 5: Synthesis of D1-6

[0286] D1-5 (3.30 g, 8.22 mmol) and Boc 2 O (2.15 g, 9.87 mmol) were added to DMF (30 mL). DMAP (0.10 g, 0.82 mmol) was added to the mixture. The reaction mixture was stirred at 25 °C for 2 h until the reaction was completed. Water (100 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (300 mL × 2), separated, and the organic layers were combined. The organic layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give D1-6 in 89.3% yield. LC-MS (ESI-MS): m / z = 502.2 [M+H] + .

[0287] Synthesis step 6: Synthesis of D1-7

[0288] D1-6 (4.74 g, 9.45 mmol) and NFSB (8.89 g, 28.35 mmol) were added to dry THF (200 mL). Under nitrogen protection, the mixture was cooled to -78 °C, and LHMDS (1.0 M) (28.4 mL, 28.35 mmol) was added dropwise to the mixture. The reaction mixture was stirred at -78 °C for 2 h, then slowly warmed to 25 °C until the reaction was completed. Saturated ammonium chloride (100 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (300 mL × 2), separated, and the organic layers were combined. The organic layer was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (SiO2, PE / EA = 5 / 1) to give 4.05 g of D1-7 in 72.5% yield. LC-MS (ESI-MS): m / z = 538.2 [M+H] + .

[0289] Synthesis step 7: Synthesis of D1-8

[0290] Dissolve D1-7 (4.00 g, 7.44 mmol) in THF (240 mL). Add 10% Pd / C (2.00 g) to the mixture. Under a hydrogen atmosphere, the mixture was stirred at 25 °C for 3 hours until the reaction was completed. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to obtain 2.50 g of D1-8, with a yield of 69.1%. LC-MS (ESI-MS): m / z = 448.1 [M+H] + 。

[0291] Synthesis step 8: Synthesis of D1-9

[0292] Take a 50 mL round-bottom flask, dissolve D1-8 (896 mg, 2.00 mmol) and 4-nitrophenol (306 mg, 2.20 mmol) in DCM (10 mL), and add DCC (539 mg, 2.60 mmol) and DMAP (25 mg, 0.20 mmol) at 0 °C. The reaction solution was stirred at 25 °C for 1 hour until the reaction was completed. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography to obtain D1-9 (492 mg, 0.94 mmol, yield: 47.2%). The product was an off-white solid. LC-MS (ESI-MS): m / z = 569.1 [M+H] + 。

[0293] Synthesis step 9: Synthesis of D1

[0294] Take a 50 mL round-bottom flask, dissolve D1-8 (492 mg, 0.94 mmol) in DCM (10 mL), and add BSTFA (1.46 g, 5.64 mmol) and TMSI (1.13 g, 5.64 mmol) at 0 °C. The reaction solution was stirred at 0 °C for 1 hour until the reaction was completed. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography to obtain 292 mg of D1, with a yield of 75.5%. LC-MS (ESI-MS): m / z = 413.1 [M+H] + 。

[0295] Synthesis of intermediate D2 in Example 12

[0296]

[0297] Synthesis step 1: Synthesis of D2-1

[0298] A mixture of 5-bromo-1H-indole-2-carboxylic acid (4.5 g, 18.80 mmol) in toluene (90 mL) was heated at 120 °C under a nitrogen atmosphere. (Dimethylamino){bis[(2-methylpropan-2-yl)oxy]}methane (6.7 g, 37.50 mmol) was added dropwise to the above mixture at 120 °C over 1 hour. The resulting mixture was stirred at 120 °C overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2.7 g of D2-1, with a yield of 49%. LC-MS (ESI-MS): m / z = 296.0 [M+H] + 。

[0299] Synthesis step 2: Synthesis of D2-2

[0300] D2-1 (2.0 g, 6.75 mmol) was dissolved in 20 mL of toluene, and tris(dibenzylideneacetone)dipalladium-chloroform adduct (350 mg, 0.34 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (196 mg, 0.34 mmol), and triethylamine (684 mg, 6.75 mmol) were added successively. The reaction system was degassed under vacuum and purged with carbon monoxide several times, and then stirred under a carbon monoxide balloon (1 atm) at 25 °C for 10 minutes. Then diethyl phosphonate (932 mg, 6.95 mmol) was added to the above mixture, and the resulting mixture was stirred under a carbon monoxide atmosphere at 90 °C for 4 hours. After completion, the reaction mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure and purified by reverse-phase flash chromatography to obtain 580 mg of D2-2, with a yield of 67%. LC-MS (ESI-MS): m / z = 382.1 [M+H] + 。

[0301] Synthesis step 3: Synthesis of D2-3

[0302] D2-2 (550 mg, 1.44 mmol) was dissolved in dichloromethane (11 mL), trifluoroacetic acid (5 mL) was added dropwise at room temperature, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After completion, the resulting mixture was concentrated under reduced pressure. The residue was triturated with ethyl acetate (10 mL) to obtain 460 mg of D2-3, with a yield of 98%. LC-MS (ESI-MS): m / z = 326.1 [M+H] + 。

[0303] Synthesis step 4: Synthesis of D2-4

[0304] Dissolve D2-3 (450 mg, 1.39 mmol) in dichloromethane (15 mL), add p-nitrophenol (289 mg, 2.08 mmol), and add DCC (428 mg, 2.08 mmol) under a nitrogen atmosphere. Stir the resulting mixture at room temperature under a nitrogen atmosphere for 3 hours. Concentrate the resulting mixture under reduced pressure. Purify by reverse-phase flash chromatography to obtain 270 mg of D2-4, with a yield of 44%. LC-MS (ESI-MS): m / z = 447.1 [M+H] + 。

[0305] Synthesis step 5: Synthesis of D2

[0306] Dissolve D2-4 (270 mg, 0.60 mmol) in dichloromethane (10.0 mL), and dropwise add iodotrimethylsilane (364 mg, 1.82 mmol) under nitrogen. Stir the resulting mixture at room temperature under a nitrogen atmosphere for 2 hours. Concentrate the resulting mixture under reduced pressure. Purify the crude product by reverse-phase flash chromatography to obtain 135 mg of D2, with a yield of 57%. LC-MS (ESI-MS): m / z = 391.0 [M+H] + 。

[0307] Synthesis of intermediate D3 in Example 13

[0308]

[0309] Synthesis step 1: Synthesis of D3-1

[0310] Add 5-bromo-1-benzothiophene-2-carboxylic acid (6.00 g, 23.3 mmol) to dichloromethane (200 mL), and add oxalyl chloride (4.44 g, 35 mmol) and DMF (2 mL, 25.91 mmol) at 0 °C under a nitrogen atmosphere. Stir the reaction solution at 25 °C for 2 hours until the reaction is complete. After completion, concentrate the resulting mixture under reduced pressure to obtain 5 g of D3-1, with a yield of 78%. LC-MS (ESI-MS): m / z = 274.9 [M+H] + 。

[0311] Synthesis step 2: Synthesis of D3-2

[0312] D3-1 (5.00 g, 18.1 mmol) was added to dichloromethane (50 mL). After cooling to 0 °C, benzyl alcohol (3.9 g, 36.2 mmol) and triethylamine (5.5 g, 54.3 mmol) were added successively. The reaction mixture was stirred at 25 °C for 2 hours and then the reaction was completed. Water (100 ml) was added to the reaction mixture, and it was extracted twice with ethyl acetate (300 mL × 2). After liquid separation, the organic phases were combined. The organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6.0 g of D3-2, with a yield of 96.5%. LC-MS (ESI-MS): m / z = 347.0 [M+H] + 。

[0313] Synthesis step 3: Synthesis of D3-3

[0314] D3-2 (6.00 g, 17.4 mmol), CuI (330 mg, 1.74 mmol), NaI (5.2 g, 34.8 mmol), and methyl[2-(methylamino)ethyl]amine (1 mL, 0.348 mmol) were added to dioxane (150 mL). A 400 mL sealed bottle equipped with a magnetic stir bar was filled with argon and stirred at 110 °C for 16 hours. 100 ml of water was added to the reaction mixture, and it was extracted twice with ethyl acetate (300 mL × 2). After liquid separation, the organic phases were combined. The organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5.4 g of D3-3, with a yield of 79%. LC-MS (ESI-MS): m / z = 395.0 [M+H] + 。

[0315] Synthesis step 4: Synthesis of D3-4

[0316] A 250 ml three-necked flask was taken, and zinc powder (3.4 g, 48.7 mmol) was evenly dispersed in anhydrous tetrahydrofuran. Dibromoethane (457 mg, 2.4 mmol) was added at room temperature. It was heated to 50 °C under nitrogen protection and maintained for 15 minutes. After cooling to room temperature, trimethylchlorosilane (317 mg, 2.9 mmol) was added and stirred at room temperature for 15 minutes. Diethyl bromodifluoromethylphosphonate (13.0 g, 48.7 mmol) was slowly added dropwise to the above reaction solution. After dropping, it was heated to 50 °C and stirred for 1 hour. After cooling to room temperature, cuprous bromide (3.5 g, 24.4 mmol) was quickly added to the above reaction and stirred at room temperature for 30 minutes. D3-3 (6.4 g, 16.2 mmol) was dissolved in tetrahydrofuran (60 mL) and added dropwise to the above reaction solution at room temperature. After dropping, it was heated to 45 °C and stirred overnight. After cooling to room temperature, it was filtered, and the filtrate was rotary evaporated. The residue was subjected to column chromatography to obtain 2.3 g of D3-5 with a yield of 31%. LC-MS (ESI-MS): m / z = 455.1 [M+H]+ .

[0317] Synthesis Step 5: Synthesis of D3

[0318] Referring to the operations and methods of Steps 7, 8, and 9 in the synthesis of D1, D3 was synthesized. LC-MS (ESI-MS): m / z = 430.0 [M+H] + .

[0319] Synthesis of Compound 001 in Example 14

[0320]

[0321] Synthesis Step 1: Synthesis of 001-1

[0322] Dissolve intermediate A4 (300 mg, 0.68 mmol) in dichloromethane (5 mL). To the system, add N,N-diisopropylethylamine (262 mg, 2.02 mmol), intermediate B2 (352 mg, 0.74 mmol), and 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (385 mg, 1.01 mmol) in sequence, and react at room temperature for 4 h. After the reaction is completed, add water and extract with dichloromethane. After the organic phase is concentrated under reduced pressure to remove dichloromethane, it is purified by column chromatography to obtain 324 mg of intermediate 001-1, with a yield of 53%. LC-MS (ESI-MS): m / z = 900.4 [M+H] + .

[0323] Synthesis Step 2: Synthesis of 001-2

[0324] Dissolve intermediate 001-1 (300 mg, 0.33 mmol) in 1,4-dioxane (3 mL). Add hydrochloric acid dioxane solution (3 mL) to the system and react at room temperature for 1 h. After the reaction is completed, concentrate under reduced pressure to remove 1,4-dioxane to obtain intermediate 001-2, with a yield of 95%. LC-MS (ESI-MS): m / z = 800.4 [M+H] + .

[0325] Synthesis Step 3: Synthesis of 001-3

[0326] Dissolve 001-2 (250 mg, 0.30 mmol) in 5 mL of dichloromethane. Sequentially add N,N-diisopropylethylamine (116 mg, 0.90 mmol), intermediate C10 (122 mg, 0.33 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (171 mg, 0.45 mmol) to the system, and react at room temperature for 4 h. After the reaction is completed, add water and extract with dichloromethane. After concentrating under reduced pressure to remove dichloromethane, purify by column chromatography to obtain 248 mg of intermediate 001-3 with a yield of 72%. LC-MS (ESI-MS): m / z = 1151.5 [M+H] + 。

[0327] Synthesis step 4: Synthesis of 001-4

[0328] Dissolve intermediate 001-3 (230 mg, 0.20 mmol) in 1,4-dioxane (3 mL). Add 1,4-dioxane hydrochloride solution (3 mL, 10V) to the system and react at room temperature for 1 h. After the reaction is completed, concentrate under reduced pressure to remove 1,4-dioxane to obtain 206 mg of intermediate 001-4 with a yield of 95%. LC-MS (ESI-MS): m / z = 1051.5 [M+H] + 。

[0329] Synthesis step 5: Synthesis of 001

[0330] Dissolve 001-4 (200 mg, 0.18 mmol) in N,N-dimethylformamide (4 mL). Sequentially add intermediate D1 (103 mg, 0.28 mmol), N-hydroxy-7-azabenzotriazole (37 mg, 0.28 mmol), and N,N-diisopropylethylamine (71 mg, 0.55 mmol) to the system, and react at room temperature for 6 h. After the reaction is completed, purify by semi-preparation to obtain 52 mg of the target compound 001 with a yield of 22%. LC-MS (ESI-MS): m / z = 1302.5 [M+H] + 。

[0331] Referring to the synthesis route and method of Reference Example 001, the following compounds were synthesized:

[0332]

[0333]

[0334]

[0335]

[0336] Synthesis of Compound 030 in Example 15

[0337]

[0338] Step 1: Synthesis of 030-1

[0339] Dissolve intermediate B15 (1 g, 1.92 mmol) in N,N-dimethylformamide (10 mL). Subsequently, add intermediate A7 (1.1 g, 2.30 mmol), sodium carbonate (610 mg, 5.76 mmol), and tetrabutylammonium bromide (62 mg, 0.19 mmol) to the system, and react at 80 °C for 1 h. After the reaction is completed, add ethyl acetate for extraction. After the organic phase is concentrated under reduced pressure to remove ethyl acetate, it is purified by column chromatography to obtain 324 mg of intermediate 030-1 with a yield of 18%. LC-MS (ESI-MS): m / z = 940.4 [M+H] + 。

[0340] Refer to the synthesis steps 2, 3, 4, and 5 and methods of Example 001 to synthesize 030. LC-MS (ESI-MS): m / z = 1342.5 [M+H] + 。

[0341] Refer to the synthesis route and method of Example 030 to synthesize the following compounds:

[0342]

[0343] Synthesis of Compound 028 in Example 14

[0344]

[0345] Synthesis Step 1: Synthesis of 028-1

[0346] Dissolve intermediate A8 (300 mg, 0.68 mmol) in dichloromethane (5 ml). Subsequently, add N,N-diisopropylethylamine (262 mg, 2.02 mmol), intermediate B16 (333 mg, 0.74 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (385 mg, 1.01 mmol) to the system, and react at room temperature for 4 h. After the reaction is completed, add water and extract with dichloromethane. After the organic phase is concentrated under reduced pressure to remove dichloromethane, it is purified by column chromatography to obtain 389 mg of intermediate 028-1 with a yield of 57%. LC-MS (ESI-MS): m / z = 1001.4 [M+H] + 。

[0347] Synthesis Steps 2-5: Synthesis of Compound 028

[0348] Referring to the second, third, fourth, and fifth synthetic operations and methods of Example 001, 028 was synthesized. LC-MS (ESI-MS): m / z = 1403.5 [M+H] + 。

[0349] Referring to the synthetic route and method of Example 028, the following compound was synthesized:

[0350]

[0351]

[0352] Biological evaluation

[0353] Example 29. STAT3 degradation activity

[0354] Hela-STAT3-HiBiT cells were collected and resuspended in EMEM (30-2003, ATCC) cell culture medium containing 10% FBS (#76294-180, Avantar). The cell density was determined using a cell counter. An appropriate volume of the resuspended cells was taken from the centrifuge tube and 40 μL of the resuspended Hela-STAT3-HiBiT cells were dispensed per well at 1000 cells / well in a 384-well plate (#3764, Corning). The test compounds were added to the wells using an Echo 650 acoustic pipetting system (Echo 650, Beckman Coulter). Incubate in a 37 °C, 5% CO 2 cell incubator (CLM-240B-8-TC, ESCO) for 24 hours. Equilibrate the cell culture plate at room temperature for 10 minutes. The HiBiT Lytic Detection System (N3040, Promega) LgBiT protein was diluted 1:100 and HiBiT lysis substrate was diluted 1:50 to an appropriate volume in a new tube at room temperature HiBiT lysis buffer, inverted and mixed. Add 40 μL HiBiT lysis reagent to the plate, protect from light, shake on a plate shaker at 300 rpm for 3 minutes, and incubate at room temperature for 15 minutes. Read the signal using a microplate reader (PHERAstar FSX, BMG) in Luminescence mode. Data analysis, curve fitting, and reporting were completed using IDBS XLfit.

[0355] Table 1 Compound STAT3 degradation activity

[0356]

[0357]

[0358] +:Degradation% @ 1 μM ≤ 50%; ++: 50% < Degradation% @ 1 μM ≤ 100%.

[0359] As can be seen from the results in Table 1, the compounds of the present invention have significant degradation activity against STAT3 protein.

[0360] Example 30: Proliferation inhibition activity on MOLM16 cells

[0361] By measuring the inhibitory effect of the test compound on the proliferation of MOLM16 cells, its anti-tumor efficacy was detected. MOLM16 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. Digest the cells and inoculate the cell suspension into a 96-well plate at a cell concentration of 80,000 cells / well, and place it in a 37 °C, 5% CO 2 cell incubator and incubate overnight. Add test compounds at different concentrations (initial concentration 1000 nM, 4-fold dilution, 8 concentrations) to the 96-well plate, and incubate at 37 °C, 5% CO 2 After incubating for 96 hours, add 20 μL MTS to each well. After incubating for 2 h, add 25 μL 10% SDS to each well to terminate the reaction. Measure the absorbance at 490 nm and 650 nm with a microplate reader. Calculate the IC 50 .

[0362] Table 2 Proliferation inhibition activity of the compounds of the present invention on MOLM16 cells

[0363] Compound Number <![CDATA[IC 50 > Compound Number <![CDATA[IC 50 > Compound Number <![CDATA[IC 50 > 001 + 016 + 031 + 002 + 017 + 032 + 003 + 018 + 033 + 004 + 019 + 034 + 005 + 020 + 035 + 006 + 021 + 036 + 007 + 022 + 037 + 008 + 023 + 038 + 009 + 024 + 039 + 010 + 025 + 040 + 011 + 026 + 041 + 012 + 027 + 042 + 013 + 028 + 043 + 014 + 029 + 044 + 015 + 030 +

[0364] +:IC 50 less than 10 nM; ++: IC 50 greater than 10 nM and less than 50 nM; +++ IC 50 greater than 50 nM.

[0365] As can be seen from Table 2, the compounds of the present invention have significant inhibitory effects on the proliferation of MOLM16 cells.

[0366] Test Example 3: STAT3 degradation activity

[0367] 1) Cell plating: Select the SW1990 cell line with good growth state, collect cells in the logarithmic growth phase and count, inoculate the cell suspension into a 24-well plate at a certain density, and place it in a 37 °C, 5% CO 2 incubator and incubate overnight.

[0368] 2) Preparation of the test compound: The test compound was serially diluted with DMSO according to the experimental requirements and added to the corresponding cell wells, and incubated at 37 °C, 5% CO2 Incubate in an incubator for 24 h.

[0369] 3) Sample preparation: After the action of the compound to be tested is completed, collect the cells in a 1.5 mL EP tube, centrifuge at 1500 rpm for 5 min. After discarding the supernatant, wash once with PBS, perform BCA protein quantification and adjust the concentration. Add the adjusted sample to 5*loading buffer, react at 100 °C for 10 min, and load the sample after returning to room temperature.

[0370] 4) Sample detection: Perform electrophoresis using 10% SDS-PAGE, and the sample loading volume is 8 μL / well. After transferring the membrane, block it with 5% BSA at room temperature for 1 h. After washing away the residual blocking solution with TBST, add STAT3 and GAPDH antibodies and incubate overnight at 4 °C. Then wash 3 times with TBST on a shaker, 10 min each time. After the washing is completed, add the secondary antibody and incubate at room temperature for 1 h, then wash 3 times with TBST on a shaker, 10 min each time. Finally, use the ECL exposure solution to develop and image the bands to detect the change of STAT3 protein.

[0371] Table 1 Degradation activity of the compound on STAT3

[0372] Compound Number <![CDATA[DC 50 > Compound Number <![CDATA[DC 50 > Compound Number <![CDATA[DC 50 > 001 + 016 + 031 + 002 + 017 + 032 + 003 + 018 + 033 + 004 + 019 + 034 + 005 + 020 + 035 + 006 + 021 + 036 + 007 + 022 + 037 + 008 + 023 + 038 + 009 + 024 + 039 + 010 + 025 + 040 + 011 + 026 + 041 + 012 + 027 + 042 + 013 + 028 + 043 + 014 + 029 + 044 + 015 + 030 +

[0373] +: DC 50 Less than 50 nM; ++: DC 50 Greater than 50 nM.

[0374] As can be seen from Table 3, the compound of the present invention has significant degradation activity on STAT3 protein in SW1990 cells.

[0375] Test Example 4: In vivo efficacy

[0376] Experimental procedure:

[0377] 1. Animal inoculation and drug administration experiment

[0378] The SW1990 cell line, 500,000 cells / mouse, was inoculated into the right axilla of NSG mice. Wait for the tumor to grow to 80 mm 3 After that, group and administer drugs. Each group of mice was given the corresponding dose of the compound to be tested, administered once a week by intravenous injection (vehicle: 100% normal saline).

[0379] 2. Measure the tumor volume twice a week and calculate the tumor growth inhibition rate (TGI).

[0380] TGI = [1 - (RTV experimental group / RTV control group)] * 100%

[0381] V = a * b * b / 2.

[0382] RTV = V / V day0 。

[0383] Where a is the major axis of the tumor and b is the minor axis of the tumor

[0384] Table 4 In vivo pharmacodynamic activities of the compounds

[0385] Cpd No. TGI 004 +++ 011 +++ 031 +++

[0386] +: TGI < 20%, ++: 20% < TGI ≤ 50%, +++: 50% < TGI ≤ 100%.

[0387] As can be seen from Table 4, the compounds of the present invention have a significant ability to inhibit growth in the in vivo pharmacodynamic model of SW1990 pancreatic cancer xenografts.

Claims

1. A compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof: in: X1 is selected from: -CH2-, -O-, -CO- or -CF2-; X2 is selected from: NH, S, O or NR1; X3 is selected from: -(CH2) n -、-(SO2) n -、-N(R2)- or -(CH2) m -NR2-(CH2) o -; X5 is selected from: absent, -CH2- or -O-; L is selected from: Cyc1 is selected from: 3-12 membered heterocyclic group, C6-C 10 The above heterocyclic group, aryl group and heteroaryl group are optionally further substituted by one or more substituents, and the substituents are selected from: halogen, halogenated C1-C8 alkyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R b 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b S02R c 、-SO(=NR b )R c Or-POR b R c ; L1, L2, L3 are each independently selected from: -(CH2) r -, one or more of the r CH2 can be further replaced by one or more selected from -COO-, -CONH-, -OCONH-, -NHCONH-, -O-, -NR b -、-S-、-CO-、-CR b =CR c -、-CR b =N-, -C≡C-, -SO-, -SO2-, -POR b -、-S(=NR b )O-、C3-C 12 Cycloalkylene, 3-10 membered heterocyclylene, 6-10 membered arylene, 5-6 membered heteroarylene or -CR b R c -, the above cycloalkylene, heterocyclylene, arylene, heteroarylene may be further substituted by one or more substituents, the substituents are selected from: halogen, halogenated C1-C8 alkyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R b 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b S02R c 、-SO(=NR b )R c Or-POR b R c ； R1 is selected from: C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl or 3-10 membered heterocyclyl, the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl optionally further substituted by one or more substituents, the substituents selected from: halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, amino, oxo, C1-C6 alkylamino, carboxyl, nitro or cyano; R2 is selected from: R3 is selected from: H or C1-C6 alkyl; Y is selected from: -(CH2) s -, one or more of the above s CH2 can be further replaced by one or more selected from -CO-, -O-, -NR b -、-S-、-CR b =CR c -、-C≡C-、-CR b =N-, -SO-, -SO2-, -POR b -、-S(=NR b )O-、-CR b R c - Group replacement; R 2a Selected from: Not present, C3-C 12 Cycloalkylene, 3-12 membered heterocyclylene, 6-10 membered arylene, 5-12 membered heteroarylene, the above cycloalkylene, heterocyclylene, arylene, heteroarylene may be further substituted by one or more substituents, the substituents are selected from: halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl, 6-10 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R b 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b S02R c 、-SO(=NR b )R c Or-POR b R c ; R 2b Selected from: H, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, the above cycloalkyl, heterocyclyl, aryl, heteroaryl may be further substituted by one or more substituents selected from: halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, amino, oxo, C1-C6 alkylamino, carboxyl, nitro or cyano; X4 is selected from: does not exist, When X4 is selected from absent and R3 is selected from H, R 2a Selected from: C8-C 12 Cycloalkyl, 8-12 membered heterocyclyl, 6-10 membered aryl or 6-10 membered heteroaryl, the above cycloalkyl, heterocyclyl, aryl, heteroaryl may be further substituted by one or more substituents, the substituents are selected from: halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C 10 Aryl, 6-10 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R b 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b S02R c 、-SO(=NR b )R c Or-POR b R c ; Ra, Ra' are each independently selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or 3-6 membered heterocyclyl, wherein the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl is optionally further substituted by one or more substituents selected from: halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, amino, oxo, C1-C6 alkylamino, carboxyl, nitro or cyano; Or Ra, Ra' and the atoms to which they are attached (provided that the valence theory is satisfied) together form a 3-8 membered ring, wherein the 3-8 membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S, and P, and the 3-8 membered ring is optionally further substituted with one or more halogen, halogenated C1-C8 alkyl, C1-C8 alkyl, C1-C8 alkoxy, C3-C 12 substituted by a cycloalkyl group, a 3-12 membered heterocyclyl group, a C1-C8 alkoxy group, a C1-C8 alkylamino group, a hydroxyl group, an amino group, an oxo group, a C1-C8 alkylamino group, a carboxyl group, a nitro group or a cyano group; R b , R c , R d Independently selected from: H, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl or 3-10 membered heterocyclyl, wherein the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, amino, oxo, C1-C6 alkylamino, carboxyl, nitro or cyano; E3 is selected from: small molecule ligands that can bind to E3 ubiquitin ligases, including ligands of CRBN, VHL, MDM2, and cIAP proteins; n is selected from: 0, 1 or 2; m and o are each independently selected from: 0, 1 or 2; r is selected from: an integer from 0 to 20; s is selected from: 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof: in: R e Selected from: H, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, C6-C 10 Aryl, 6-10 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R b 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b S02R c 、-SO(=NR b )R c Or-POR b R c ; p is selected from: 0, 1, 2, 3 or 4.

3. The compound according to claim 2, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound represented by general formula III, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: in: When X4 is selected from absent and R3 is selected from H, R 2a Selected from: C8-C 12 Cycloalkyl, 8-12 membered heterocyclyl, 7-10 membered aryl or 7-10 membered heteroaryl, the above cycloalkyl, heterocyclyl, aryl, heteroaryl may be further substituted by one or more substituents, the substituents are selected from: halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C6-C 10 Aryl, 6-10 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R b 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b S02R c 、-SO(=NR b )R c Or-POR b R c .

4. The compound according to claim 3 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: Ra is selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl; Ra' is selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl; Or Ra, Ra' together with the N atom to which they are attached form a 3-6 membered ring; Re is selected from: H, halogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxy, amino, cyano or nitro; Selected from: C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, 5. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L is selected from: E3 is selected from: in Selected from:

6. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

7. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 6 or its stereoisomer, tautomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

8. Use of the compound according to any one of claims 1 to 6 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a drug for degrading STAT3 protein.

9. Use of the compound according to any one of claims 1 to 6 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing and / or treating a disease associated with the activity or expression of STAT3 protein, wherein the disease comprises a solid tumor, a hematological tumor disease or an autoimmune system disease.

10. The use according to claim 9, characterized in that: The hematological tumor diseases include leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome, and myelofibrosis; the autoimmune system diseases include rheumatoid arthritis, juvenile arthritis, multiple sclerosis, Sjögren's syndrome, systemic lupus erythematosus, insulin-dependent diabetes mellitus (type I), Hashimoto's thyroiditis, Graves' disease, ulcerative colitis, chronic active hepatitis, psoriasis, inflammatory bowel disease, and ankylosing spondylitis; the solid tumors include digestive system malignancies, respiratory system malignancies, central nervous system tumors, urinary system malignancies, gynecological malignancies, sarcomas, melanomas, and bone cancer.

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