A peptidomimetic degrader, composition and its use

Abstract

The present invention relates to a peptidomimetic derivative STAT degrader, a preparation method thereof, a pharmaceutical composition containing the degrader, and their applications in medicine. The present invention discloses a peptidomimetic derivative represented by the general formula (I), or its stereoisomer, or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, a preparation method thereof, and their use as a STAT degrader.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a peptidomimetic derivative, a pharmaceutical composition containing the derivative, and their use as therapeutic agents, especially as small molecule proteolysis drugs for degrading the transcription factor STAT. Background Art

[0002] STAT (Signal Transducer and Activator of Transcription), as an important transcription factor in the JAK-STAT signaling pathway, is closely related to the occurrence and development of tumors. Among them, STAT3 participates in the regulation of multiple tumor-related genes, including cMyc, survivin, BCL-XL, VEGF, HIF, and NF-kB, etc. In many tumor cells, the JAK-STAT pathway is often overactivated. The overactivated STAT3 pathway promotes the proliferation and survival of tumor cells, leads to abnormal blood vessel hyperplasia, promotes the invasion and migration of tumor cells, and at the same time helps tumor cells escape immune surveillance.

[0003] With the in-depth research, more and more evidence shows that there is overactivation of STAT1 in multiple tumors and it promotes tumor growth through multiple mechanisms. Therefore, simultaneous inhibition of STAT1 and STAT3 is expected to play a synergistic role and enhance the anti-tumor drug efficacy.

[0004] In recent years, some progress has been made in the targeted protein degradation technology. The targeted protein degradation technology mainly realizes the degradation of the target protein by inducing the ubiquitination of the target protein. The event-driven targeted protein degradation technology has advantages such as high selectivity and high efficiency. Therefore, developing targeted degradation molecules against STAT1 and STAT3 has multiple advantages. It can not only block the proliferation and survival signals of tumor cells, but also enhance the immune response and promote the immune clearance of tumor cells. Therefore, developing drugs that dual-target the STAT1 and STAT3 transcription factors has potential and prospects. Summary of the Invention

[0005] The object of the present invention is to provide a novel STAT degradation molecule with high STAT degradation activity that has not been reported in the literature, its stereoisomers, or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof.

[0006] The object of the present invention is also to provide a compound as described above, or its stereoisomers, or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof.

[0007] The present invention also provides the use of the above compound, or its stereoisomers, or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof in the preparation of drugs for treating diseases, disorders or conditions that benefit from STAT degradation.

[0008] The first aspect of the present invention is to provide a structure as shown in (I):

[0009]

[0010] or its stereoisomers, or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof;

[0011] Wherein:

[0012] X1 is selected from: -O-, -CH2-, -CF2-, -CO- (i.e., C=O carbonyl);

[0013] X2 is selected from: S, O, NRd;

[0014] Rd is selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl;

[0015] R1 is selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, wherein the alkyl, alkenyl, cycloalkyl are optionally further substituted by one or more substituents selected from H, halogen, nitro, cyano, hydroxy, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-10 membered heterocyclic group, 6-10 membered aryl, 5-10 membered heteroaryl;

[0016] R2 is selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, wherein the alkyl, alkenyl, cycloalkyl are optionally further substituted by one or more substituents selected from H, halogen, nitro, cyano, hydroxy, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-10 membered heterocyclic group, 6-10 membered aryl, 5-10 membered heteroaryl;

[0017] X3 is selected from: CR5, N;

[0018] R5 is selected from: H, halogen, nitro, cyano, hydroxy, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-10 membered heterocyclic group, 6-10 membered aryl, 5-10 membered heteroaryl;

[0019] L1 is selected from: absent, -(CH2) p -, any one of the methylene groups -(CH2)- in “-(CH2) p -” can be replaced by the following groups: -COO-, -CONH-, -OCONH-, -NHCONH-, -O-, -NRa-, -S-, -CO-, -CRa=CRb-, -C≡C-, -SO-, -SO2-, C3-C 10Subcycloalkyl, 3- to 10-membered hetero-subcycloalkyl, phenylene, 5- to 6-membered heteroaryl, -CRaRb-;

[0020] L2 is selected from: -(CH2) S -, any one of the methylenes -(CH2)- in “-(CH2) S -” can be replaced by the following groups: -COO-, -CONH-, -OCONH-, -NHCONH-, -O-, -NRe-, -S-, -CO-, -CRe═CRf-, -C≡C-, -SO-, -SO2-, C3-C 10 Subcycloalkyl, 3- to 10-membered hetero-subcycloalkyl, phenylene, 5- to 6-membered heteroaryl, -CReRf-;

[0021] Cyc1 is selected from: absent, C3-C 10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally further substituted by one or more selected from H, halogen, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -OR g , -SR 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(CH3)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)2NR x R y , -N(R x )S(O)2R g , -S(O)R g , -S(O)2R g , -S(O)2NR x R y or -P(O)R xR y is substituted by a substituent of;

[0022] Ra, Rb, Re, and Rf are each independently selected from: H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3- to 10-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, -CN, -NHRc, -ORc, and the alkyl, alkoxy, cycloalkyl heterocyclic group, phenyl, and heteroaryl are optionally further substituted by one or more substituents selected from H, halogen, nitro, cyano, hydroxy, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0023] Rc is selected from: H, C1-C6 alkyl, C1-C6 halogenated alkyl, C3-C6 cycloalkyl, 3- to 10-membered heterocyclic group, phenyl, and 5- to 6-membered heteroaryl;

[0024] R g 、R x 、R y are each independently selected from H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, C1-C8 alkoxy, C1-C8 halogenated alkyl, hydroxy-C1-C8 alkyl, amino-C1-C8 alkyl, C1-C8 alkylamino, C1-C8 alkylcarbonyl, C1-C8 alkoxycarbonyl, halogenated hydroxy-C1-C8 alkyl, C1-C8 halogenated alkylamino, C3-C 12 cycloalkyl, 3- to 12-membered heterocyclic group, carboxyl, amide, C6-C 10 aryl or 5- to 12-membered heteroaryl;

[0025] p is selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8;

[0026] s is selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8;

[0027] E3 is selected from:

[0028]

[0029] R4 is selected from: H, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl.

[0030] In the present invention, the term "optionally" means "may". For example, when it is mentioned in the text that a certain group may optionally be further substituted by a certain substituent, it means that this group may be substituted by the certain substituent or may not be so substituted.

[0031] Preferably, the compound of the present invention has the structure of general formula (II):

[0032]

[0033] or its stereoisomers, or a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof.

[0034] Preferably, in general formula (I) or general formula II:

[0035] R1 is selected from: H, C1-C3 alkyl, C2-C3 alkenyl, C3-C6 cycloalkyl;

[0036] R2 is selected from: H, C1-C3 alkyl, C2-C3 alkenyl, C3-C6 cycloalkyl;

[0037] X1 is selected from: -O-, -CH2-, -CF2-, -CO-;

[0038] X2 is selected from: NH, S, O;

[0039] X3 is selected from: CH, N;

[0040] L1 is selected from: absent, -(CH2) p -, any methylene (-CH2-) in "-(CH2) p -" can be replaced by the following groups: -COO-, -CONH-, -OCONH-, -NHCONH-, -O-, -NRa-, -S-, -CO-, -CRa=CRb-, -C≡C-, -SO-, -SO2-, C4-C6 cycloalkylene, 4-6 membered heteroalkylene, phenylene, 5-6 membered heteroarylene, -CH2-;

[0041] L2 is selected from: -(CH2) S -, any methylene (-CH2-) in "-(CH2) S -" can be replaced by the following groups: -COO-, -CONH-, -OCONH-, -NHCONH-, -O-, -NRe-, -S-, -CO-, -CRe=CRf-, -C≡C-, -SO-, -SO2-, C4-C6 cycloalkylene, 4-6 membered heteroalkylene, phenylene, 5-6 membered heteroarylene, -CH2-;

[0042] Cyc1 is selected from: absent, C4-C6 cycloalkyl, 4-9 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, wherein the cycloalkyl, heterocyclic group, aryl group, heteroaryl group are optionally further substituted by one or more selected from H, halogen, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-10 membered heterocyclic group, 6-10 membered aryl group, 5-10 membered heteroaryl group, -OR g 、-SR 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(CH3)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)2NR x R y , -N(R x )S(O)2R g , -S(O)R g , -S(O)2R g , -S(O)2NR x R y or -P(O)R x R y is substituted by a substituent;

[0043] Ra, Rb, Rc, Re, Rf, R g , R x , R y , p, s, and E3 are defined as in formula (I).

[0044] Preferably, the compounds of the present invention have the structure of formula (IIIa) or (IIIb):

[0045]

[0046] or its stereoisomers, or a mixture of its stereoisomers, or its pharmaceutically acceptable salts; the substituents are defined as in formula (I) or formula (II).

[0047] Preferably, in formula (I), formula (II), formula (IIIa) or formula (IIIb):

[0048] R1 is selected from: H, methyl, ethyl, propyl;

[0049] R2 is selected from: H, methyl, ethyl, propyl;

[0050] Cyc1 is selected from:

[0051]

[0052] L1 is selected from: absent, methyl, ethyl, propyl;

[0053] L2 is selected from: methyl, ethyl, propyl,

[0054] n is selected from: 0, 1, 2, 3, 4.

[0055] Preferably, wherein:

[0056] is selected from:

[0057] E3 is selected from:

[0058] Preferably, the specific structures of the compounds represented by the general formula (I) of the present invention include, but are not limited to:

[0059]

[0060]

[0061]

[0062] The names are respectively:

[0063] 001: {[2-({[(5S,8S,10aR)-8-[(3S)-3-(2-carbamoylethyl)-6-{4-[methyl(methylimino)(oxo)-λ 6 -sulfanyl]phenyl}-1,4-dioxo-2,5-diazaperhydro-1-yl]-3-[(4-{2-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxobenzimidazol-5-yl]ethyl}piperidin-1-yl)carbonyl]-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-5-yl]amino}carbonyl)-1H-indol-5-yl]carbonyl}phosphonic acid

[0064] 002: {[2-({[(5S,8S,10aR)-8-[(3S)-3-(2-carbamoylethyl)-6-{4-[methyl(methylimino)(oxo)-λ 6-thiol]phenyl}-1,4-dioxo-2,5-diazahex-1-yl]-3-[(4-{2-[1-(2,6-dioxohexahydropyridin-3-yl)-3-methyl-2-oxobenzimidazo[1,2-d]imidazol-5-yl]ethyl}cyclohexyl)carbonyl]-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-5-yl]amino}carbonyl)-1H-indol-5-yl]carbonyl}phosphonic acid

[0065] 003: {[2-({[(5S,8S,10aR)-8-[(3S)-3-(2-carbamoylethyl)-6-{4-[methyl(methylimino)(oxo)-λ 6 -thiol]phenyl}-1,4-dioxo-2,5-diazahex-1-yl]-3-[2-(4-{[1-(2,6-dioxohexahydropyridin-3-yl)-3-methyl-2-oxobenzimidazo[1,2-d]imidazol-5-yl]methyl}cyclohexyl)acetyl]-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-5-yl]amino}carbonyl)-1H-indol-5-yl]carbonyl}phosphonic acid

[0066] 004: {[2-({[(5S,8S,10aR)-8-[(3S)-3-(2-carbamoylethyl)-6-{4-[methyl(methylimino)(oxo)-λ 6 -thiol]phenyl}-1,4-dioxo-2,5-diazahex-1-yl]-3-[(3-{2-[1-(2,6-dioxohexahydropyridin-3-yl)-3-methyl-2-oxobenzimidazo[1,2-d]imidazol-5-yl]ethyl}azetidin-1-yl)carbonyl]-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-5-yl]amino}carbonyl)-1H-indol-5-yl]carbonyl}phosphonic acid

[0067] 005: {[2-({[(5S,8S,10aR)-8-[(3S)-3-(2--carbamoylethyl)-6-{4-[methyl(methylimino)(oxo)-λ 6 -thiol]phenyl}-1,4-dioxo-2,5-diazahex-1-yl]-3-{7-[1-(2,6-dioxohexahydropyridin-3-yl)-3-methyl-2-oxobenzimidazo[1,2-d]imidazol-5-yl]-1-oxoheptyl}-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-5-yl]amino}carbonyl)-1H-indol-5-yl]carbonyl}phosphonic acid

[0068] 006: {[2-({[(5S,8S,10aR)-8-[(3S)-3-(2-carbamoylethyl)-6-{4-[methyl(methylimino)(oxo)-λ6 -thio]phenyl}-1,4-dioxo-2,5-diazahex-1-yl]-3-{7-[1-(2,6-dioxohexahydropyridin-3-yl)-3-methyl-2-oxobenz[d]imidazol-4-yl]-1-oxoheptyl}-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-5-yl]amino}carbonyl)-1H-indol-5-yl]carbonyl}phosphonic acid

[0069] 007: {[2-({[(5S,8S,10aR)-8-[(3S)-3-(2-carbamoylethyl)-6-{4-[methyl(methylimino)(oxo)-λ 6 -thio]phenyl}-1,4-dioxo-2,5-diazahex-1-yl]-3-{1-[2-(2,6-dioxohexahydropyridin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-10-oxodec-1-yn-10-yl}-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-5-yl]amino}carbonyl)-1H-indol-5-yl]carbonyl}phosphonic acid

[0070] 008: {[2-({[(5S,8S,10aR)-8-[(3S)-3-(2-carbamoylethyl)-6-{4-[methyl(methylimino)(oxo)-λ 6 -thio]phenyl}-1,4-dioxo-2,5-diazahex-1-yl]-3-{1-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-10-oxodec-1-yn-10-yl}-6-oxo decahydropyrrolo[1,2-a][1,5]diazocine-5-yl]amino}carbonyl)-1H-indol-5-yl]carbonyl}phosphonic acid 009: {Difluoro[2-({[(5S,8S,10aR)-8-[(3S)-3-(2-carbamoylethyl)-6-{4-[methyl(methylimino)(oxo)-λ 6 -thio]phenyl}-1,4-dioxo-2,5-diazahex-1-yl]-3-[2-(4-{[1-(2,6-dioxohexahydropyridin-3-yl)-3-methyl-2-oxobenz[d]imidazol-5-yl]methyl}cyclohexyl)acetyl]-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-5-yl]amino}carbonyl)benzo[b]thiophen-5-yl]methyl}phosphonic acid

[0071] 010: {Difluoro[2-({[(5S,8S,10aR)-8-[(3S)-3-(2-carbamoylethyl)-6-{4-[methyl(methylimino)(oxo)-λ 6-thiol]phenyl}-1,4-dioxo-2,5-diazahexan-1-yl]-3-[2-(3-{[1-(2,6-dioxohexahydropyridin-3-yl)-3-methyl-2-oxobenzimidazol-5-yl]methyl}cyclopentyl)acetyl]-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-5-yl]amino}carbonyl)benzo[b]thiophen-5-yl]methyl}phosphonic acid

[0072] 011: {Difluoro[2-({[(5S,8S,10aR)-8-[(3S)-3-(2-carbamoylethyl)-6-{4-[methyl(methylimino)(oxo)-λ 6 -thiol]phenyl}-1,4-dioxo-2,5-diazahexan-1-yl]-3-[(3-{2-[1-(2,6-dioxohexahydropyridin-3-yl)-3-methyl-2-oxobenzimidazol-5-yl]ethyl}cyclobutyl)carbonyl]-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-5-yl]amino}carbonyl)benzo[b]thiophen-5-yl]methyl}phosphonic acid

[0073] 012: {Difluoro[2-({[(5S,8S,10aR)-8-[(3S)-3-(2-carbamoylethyl)-6-{4-[methyl(methylimino)(oxo)-λ 6 -thiol]phenyl}-1,4-dioxo-2,5-diazahexan-1-yl]-3-[(4-{2-[1-(2,6-dioxohexahydropyridin-3-yl)-3-methyl-2-oxobenzimidazol-5-yl]ethyl}piperidin-1-yl)carbonyl]-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-5-yl]amino}carbonyl)benzo[b]thiophen-5-yl]methyl}phosphonic acid

[0074] or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0075] 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.

[0076] Furthermore, the present invention provides a pharmaceutical composition, said pharmaceutical composition comprising an effective dose of a compound of formula (I), (II), (IIIa) or (IIIb) or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0077] The present invention provides the use of a compound of formula (I), (II), (IIIa) or (IIIb) disclosed herein, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating a STAT-mediated related disease, wherein the medicament is preferably a STAT degrader. In some embodiments, further, the STAT degrader is preferably a STAT1 and STAT3 modulator.

[0078] The present invention provides the use of a compound of formula (I), (II), (IIIa) or (IIIb) disclosed herein, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating a STAT-mediated related disease, wherein the STAT-mediated disease is preferably a hematological malignancy, a solid tumor, an autoimmune disease.

[0079] The present invention provides the use of a compound of formula (I), (II), (IIIa) or (IIIb) disclosed herein, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating a STAT-mediated related disease, wherein the applications are preferably leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome, myelofibrosis. Solid tumors include: digestive system malignancies, respiratory system malignancies, central nervous system tumors, urinary system malignancies, gynecological malignancies, sarcomas, melanomas, bone cancers. Autoimmune diseases include: rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, multiple sclerosis, ulcerative colitis, Crohn's disease, insulin-dependent diabetes (type I) and myasthenia gravis.

[0080] Term Explanation

[0081] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0082] "Alkyl", when taken as a group or part of a group, means including C1-C 20A straight-chain or branched aliphatic hydrocarbon group. Preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group. 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 group can be substituted or unsubstituted.

[0083] "Alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond, which can be straight-chain or branched. Preferably a C2-C 10 alkenyl, more preferably a C2-C8 alkenyl. Representative examples include, but are not limited to, vinyl,

[0084]

[0085] etc. The alkenyl group can be substituted or unsubstituted.

[0086] "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which can be straight-chain or branched. Preferably a C2-C 10 alkynyl, more preferably a C2-C8 alkynyl, most preferably a C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl,

[0087] etc. The alkynyl group can be substituted or unsubstituted.

[0088] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused-ring, bridged-ring and spiro carbon ring. Preferably a C3-C 12 cycloalkyl, more preferably a C3-C8 cycloalkyl, most preferably a C3-C6 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.

[0089] "Spiroalkyl" refers to a polycyclic group with 5 to 18 members, having two or more cyclic structures, and with a single carbon atom (referred to as a spiro atom) shared between the single rings. One or more double bonds may be contained within the rings, but none of the rings is aromatic. It is preferably 6 to 14 members, more preferably 7 to 10 members. Spirolalkyls are classified into monospiro, dispiro or polyspiroalkyls according to the number of spiro atoms shared between the rings, preferably monospiro and dispiroalkyls, 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.

[0090] "Fused cycloalkyl" refers to a fully carbonaceous polycyclic group with 5 to 18 members, having two or more cyclic structures sharing a pair of carbon atoms with each other. One or more of the rings may contain one or more double bonds, but none of the rings is aromatic. It is preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyls, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyls. 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.

[0091] "Bridged cycloalkyl" refers to a fully carbonaceous polycyclic group with 5 to 18 members, having two or more cyclic structures, and sharing two non-directly connected carbon atoms with each other. One or more of the rings may contain one or more double bonds, but none of the rings is aromatic. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, 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.

[0092] "Heterocyclic group", "heterocycle" or "heterocyclic" are used interchangeably in this application, and all refer to non-aromatic heterocyclic groups, where one or more of the ring-forming atoms are heteroatoms such as N, O, S, P, Se, including monocyclic, fused-ring, bridged-ring and spiro rings. One or more double bonds may be contained within the rings. It preferably has 3 to 12 ring atoms, more preferably a 4 to 7-membered monocyclic or 7 to 10-membered bi- or tricyclic ring, which may contain 1, 2 or 3 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), atoms of Se. 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 can be substituted or unsubstituted.

[0093] "Spiroheterocyclic group" refers to a polycyclic group having 5 to 18 members, two or more ring structures, and sharing one atom between single rings, and one or more double bonds may be contained in the rings, 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), heteroatoms of Se, and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spiroheterocyclic group is classified into monospiroheterocyclic group, dispiroheterocyclic group or polyspiroheterocyclic group according to the number of spiro atoms shared between rings, and preferably monospiroheterocyclic group and dispiroheterocyclic group. More preferably 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member or 5-member / 6-member monospiroheterocyclic group. Examples of "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.

[0094] "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 has aromaticity, 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), heteroatoms of Se, and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-member / 5-member or 5-member / 6-member bicyclic fused heterocyclic groups. Non-limiting examples of "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.

[0095] "Bridged heterocyclic group" refers to a polycyclic group having 5 to 18 members, containing two or more ring structures, sharing two non-directly connected atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has aromaticity, and one 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), heteroatoms of Se, and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Examples of "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.

[0096] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be connected in a fused manner. "Aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, aromatic groups of tetrahydronaphthyl. Preferably the aryl is C6-C 10 aryl, more preferably the aryl is phenyl and naphthyl, and most preferably phenyl. The aryl may be substituted or unsubstituted.

[0097] "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 or an 8- to 10-membered bicyclic heteroaryl. 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,

[0098]

[0099] The heteroaryl may be substituted or unsubstituted.

[0100] "Fused ring" refers to a polycyclic group in which two or more ring 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 does not have aromaticity, and at the same time at least one ring has aromaticity, and 0, 1 or more of the ring atoms among 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 membered, more preferably 9 to 10 membered. Examples of the "fused ring" include but are not limited to:

[0101]

[0102] The fused ring can be substituted or unsubstituted.

[0103] "Alkoxy" refers to a group of (-O-alkyl). Among them, alkyl is as defined herein. C1-C8 alkoxy is preferred. Examples include but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc. The alkoxy can be substituted or unsubstituted.

[0104] "Alkoxycarbonyl" refers to a group of (-C(O)-O-alkyl). Among them, alkyl is as defined herein. Examples include, but are not limited to: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, etc. The alkoxycarbonyl can be substituted or unsubstituted.

[0105] "Haloalkyl" refers to an alkyl group substituted by a halogen. Among them, halogen and alkyl are as defined herein.

[0106] "Haloalkoxy" refers to an alkoxy group substituted by a halogen. Among them, halogen and alkoxy are as defined herein.

[0107] "Cycloalkoxy" refers to a group of (-O-cycloalkyl). Among them, cycloalkyl is as defined herein.

[0108] "Heteroepoxy" refers to a group of (-O-heterocyclic group). Among them, heterocyclic group is as defined herein.

[0109] "Halogen" refers to fluorine, chlorine, bromine and iodine. "Hydroxy" refers to -OH. "Amino" refers to -NH2. "Cyano" refers to -CN. "Nitro" refers to -NO2. "Carboxyl" refers to -C(O)OH. "Amide" refers to -C(O)NH2. "DMSO" refers to dimethyl sulfoxide. "BOC" refers to tert-butoxycarbonyl. "Ts" refers to p-toluenesulfonyl.

[0110] "Substituted" means that one or more, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms in a group are independently replaced by the corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (by experiment or theory) what substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (such as an olefinic) bond.

[0111] As used in this specification, "substituted" or "substitution", unless otherwise specified, means that a group can be substituted by one or more groups selected from the following: H, deuterium, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkenyloxy, C3-C 12 cycloalkyl, C3-C8 cycloalkoxy, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclic oxy group, aminosulfonyl, C6-C 10 aryl, 5- to 12-membered heteroaryl, cyano, amino, nitro, hydroxyl, oxo, carboxyl, amide, hydroxyalkyl, aminoalkyl, alkcarbonyl, alkoxycarbonyl, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR g -SR g -C1-C8 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(CH3)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)2NR x R y -N(R x )S(O)2R g -S(O)R g -S(O)2R g -S(O)2NR x R y -P(O)R xR y or two Rs n or two Rs n ’ together with the atoms to which they are attached form a 3- to 12-membered ring, and the 3- to 12-membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S, P; the alkyl, alkylene, alkoxy, alkenyl, alkynyl, alkenyloxy, cycloalkyl, cycloalkoxy, heterocyclic group, heterocyclic oxy group, aryl, heteroaryl, 3- to 12-membered ring, amino, hydroxyl or amide are optionally further substituted by one or more Rs o substituted;

[0112] 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;

[0113] R g 、R x 、R y 、R o are each independently selected from H, deuterium, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkenyloxy, C3-C 12 cycloalkyl, C3-C8 cycloalkoxy, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclic oxy group, aminosulfonyl, C6-C 10 aryl, 5- to 12-membered heteroaryl, cyano, amino, nitro, hydroxyl, oxo, carboxyl, amide, hydroxyalkyl, aminoalkyl, alkcarbonyl, alkoxycarbonyl, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR s 、-SR s 、-C1-C8 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(CH3)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)NRs R t ,-N(R s )S(O)2NR s R t ,-N(R s )S(O)2R t ,-S(O)R s ,-S(O)2R s ,-S(O)2NR 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;

[0114] When two R r substitute on the same atom, the two R r together with the atom to which they are attached form a 3- to 6-membered ring, or when two R r substitute on adjacent atoms, the two R r together with the atoms to which they are attached form a 3- to 12-membered ring;

[0115] R r 、R s 、R t are each independently selected from H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyalkyl, aminoalkyl, C1-C8 alkylamino, alkylcarbonyl, alkoxycarbonyl, halo-hydroxyalkyl, C1-C8 haloalkylamino, C3-C 12 cycloalkyl, 3- to 12-membered heterocyclic group, carboxyl, amide, C6-C 10 aryl or 5- to 12-membered heteroaryl.

[0116] The compounds of the present invention may contain asymmetric centers 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 diastereoisomers, enantiomers and atropisomers and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0117] Unless otherwise indicated, the structures described in this invention also include all isomers of such structures (e.g., diastereoisomers, enantiomers, atropisomers, and geometric (conformational) isomer forms; for example, the R and S configurations of each asymmetric center, the (Z) and (E) double bond isomers, and the (Z) and (E) conformational isomers). Thus, the individual stereoisomers of the compounds of this invention, as well as mixtures of enantiomers, mixtures of diastereoisomers, and mixtures of geometric (conformational) isomers are within the scope of this invention.

[0118] The C, H, O, S, N, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention include their isotopic situations. At the same time, the C, H, O, S, N, F, Cl, Br, I involved in the groups and compounds described in this invention may optionally be substituted by one or more of their corresponding isotopes, including but not limited to the isotopes of carbon 12 C, 13 C, 14 C, the isotopes of hydrogen, protium (H), deuterium (D), tritium (T), the isotopes of oxygen 16 O, 17 O, 18 O, the isotopes of sulfur 32 S, 33 S, 34 S, 36 S, the isotopes of nitrogen 14 N, 15 N, the isotopes of fluorine 17 F, 19 F, the isotopes of chlorine 35 Cl, 37 Cl, the isotopes of bromine 79 Br, 81 Br, etc.

[0119] It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory and are not restrictive of any claims. It should be noted that in the specification and the appended claims, unless otherwise stated in the text, the singular forms such as "a", "an", "the" include plural referents. It should also be noted that unless otherwise stated, "or" means "and / or". In addition, terms such as "comprising", "including", etc. are not restrictive.

[0120] "Pharmaceutically acceptable salts" refer to certain salts of the above-mentioned compounds that can maintain their original biological activities and are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds represented by formula (I), (II), (IIIa), (IIIb), and formulas 001 to 0012 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. The 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. The 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.

[0121] The second object of the present invention is to provide a pharmaceutical composition comprising one or more of the compounds described in any one of the above technical solutions. The pharmaceutical composition of the present invention can be composed of one or more of the compounds described in any one of the above technical solutions and other compounds, or composed of one or more of the compounds described in any one of the above technical solutions.

[0122] The present invention provides a pharmaceutical preparation comprising at least one active ingredient, and the active ingredient is one or more of the compounds described in any one of the above technical solutions. The pharmaceutical preparation comprises at least one active ingredient and one or more pharmaceutically acceptable carriers or excipients, and the active ingredient can be any one or any combination of the STAT degrading agent compounds of the present invention, stereoisomers of the compounds, pharmaceutically acceptable salts of the compounds or their stereoisomers, and solvates of the compounds or their stereoisomers.

[0123] The carriers include conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field. When necessary, flavoring agents, sweetening agents, etc. can also be added.

[0124] The drugs of the present invention can be made into various forms such as tablets, powders, granules, capsules, oral liquids, and injectable drugs, and the drugs of the above various dosage forms can be prepared according to the conventional methods in the pharmaceutical field.

[0125] On the other hand, the present invention provides diseases, disorders or conditions that benefit from the degradation of STAT using the compounds of general formula (I) to general formula IIIa, IIIb, formula 001 to 0012 disclosed herein, their optical isomers, or their pharmaceutically acceptable salts or solvates.

[0126] In a further preferred embodiment, the present invention provides a method for degrading STAT in a subject in need thereof by administering to the subject a composition comprising a therapeutically effective amount of at least one compound, wherein the structural formula of the compound is general formula I to general formula IIIa, IIIb, formula 001 to 0012. In some embodiments, the subject in need has cancer.

[0127] In a further embodiment, the subject in need has cancer, which includes but is not limited to:

[0128] Hematological malignancies, including lymphoma, leukemia, multiple myeloma, myelodysplastic syndromes, myelofibrosis, such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia ( macroglobulinemia), splenic marginal zone lymphoma, plasmacytic myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma, AML, CML, multiple myeloma or lymphomatoid granulomatosis.

[0129] Autoimmune diseases or conditions, including single-organ or single-cell type autoimmune conditions, such as Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy, those involving systemic autoimmune conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis dermatomyositis, psoriasis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid), and other O cell (humoral) type or T cell type autoimmune diseases (including Cogan syndrome), ankylosing spondylitis, Wegener's granulomatosis, alopecia areata, type I diabetes or juvenile-onset diabetes, Crohn's disease or thyroiditis;

[0130] Solid tumors include: digestive system malignancies, respiratory system malignancies, central nervous system tumors, urinary system malignancies, gynecological malignancies, sarcomas, melanomas, bone cancers. Preferably, they are digestive tract / gastrointestinal cancers, colorectal cancers, liver cancers, skin cancers (including mast cell tumors and squamous cell carcinomas), breast and breast cancers, ovarian cancers, prostate cancers, kidney cancers, lung cancers, myosarcomas, bone cancers, bladder cancers, brain cancers, melanomas (including oral and metastatic melanomas), Kaposi's sarcoma, thyroid cancers, retinoblastomas, rhabdomyosarcomas, urinary system tumors, central nervous system tumors, nasopharyngeal cancers, pancreatic cancers, head and neck cancers;

[0131] The inventors of the present invention have confirmed through experiments that the compounds of the present invention can simultaneously degrade the transcription factors STAT3 and STAT1.

[0132] The inventors of the present invention have confirmed through experiments that the compounds of the present invention have a significant inhibitory effect on the proliferation of Karpas299 tumor cells. Detailed implementation manners

[0133] Chemical substances represented by some abbreviations in the present invention:

[0134] DMAP: 4-dimethylaminopyridine

[0135] The feasibility of the present invention will be illustrated below through examples. Those skilled in the art should understand that, according to the teachings of the prior art, modifying or replacing the corresponding technical features still falls within the scope of protection required by the present invention.

[0136] Synthesis of Intermediate A1

[0137]

[0138] Synthesis step 1:

[0139] Dissolve 6-heptynoic acid (427 mg, 3.38 mmol) in N,N-dimethylformamide (10 mL). To the system, sequentially add 3-(5-iodo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1.0 g, 2.59 mmol), bis(triphenylphosphine)palladium(II) dichloride (183 mg, 0.26 mmol), copper(I) iodide (100 mg, 0.52 mmol), and triethylamine (1.3 g, 12.95 mmol). The reaction is stirred at 80 °C for 3 hours. After the reaction is completed as detected by LCMS, the reaction mixture is cooled to room temperature, water (50 mL) is added, and the mixture is extracted with ethyl acetate three times. The organic phases are combined, dried, and concentrated under reduced pressure. The crude product is purified by column chromatography to obtain 700 mg of 7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)hept-6-ynoic acid (A1-1) as a brown oil, with a yield of 70%.

[0140] Synthesis step 2:

[0141] Dissolve A1-1 (600 mg, 1.56 mmol) in tetrahydrofuran (10 mL), add Raney nickel (previously dehydrated with tetrahydrofuran) (1.0 g), and replace the gas with hydrogen three times. The reaction solution is hydrogenated at 40 °C under atmospheric pressure for 16 hours. After the reaction is completed as detected by LCMS, it is filtered, and the filtrate is concentrated under reduced pressure to obtain 520 mg of A1, with a yield of 85%, MS(ESI)[M+1] + = 388.2.

[0142] The following intermediates A2 - A3, A7 - A8 are obtained by referring to the synthesis method of intermediate A1.

[0143]

[0144] Synthesis of intermediate A4

[0145] Synthesis step 1:

[0146] Dissolve 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1.0 g, 2.59 mmol), tert-butyl 2-(4-methylenecyclohexyl)acetate (655 mg, 3.12 mmol), N,N-diisopropylethylamine (645 mg, 5 mmol), tri-tert-butylphosphine (105 mg, 0.52 mmol), tridibenzylideneacetone dipalladium (238 mg, 0.26 mmol), and triethylamine (1.3 g, 12.95 mmol) in dioxane solvent (10 mL) and react at 80 °C for 16 h. The reaction was completed by LCMS detection. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, dried and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain tert-butyl 2-(4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetate A4-1, MS (ESI) [M+1] + =470.3.

[0147] Synthesis step 2:

[0148] The intermediate A4-1 (470 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran solution (5 mL), palladium carbon (2 g) was added, and the reaction solution was hydrogenated at 40°C under normal pressure for 16 hours. LCMS detected the completion of the reaction, filtered, and the filtrate was concentrated under reduced pressure to obtain A4. MS (ESI) [M+1] + =414.2.

[0149] The following intermediates A5-A6 were obtained by referring to the synthesis method of intermediate A4.

[0150]

[0151]

[0152] Synthesis of intermediate A9

[0153]

[0154] Synthesis step 1:

[0155] In a 50 mL three-necked flask, methyl 2-methyl-3-bromobenzoate (5.0 g, 21.90 mmol) was dissolved in carbon tetrachloride (20 mL). After displacing nitrogen, N-bromosuccinimide (4.3 g, 24.10 mmol) and azobisisobutyronitrile (359 mg, 2.19 mmol) were added portionwise at 0 °C, and the mixture was stirred at 0 °C for 10 minutes. Then it was heated to 80 °C and stirred for 8 hours. After the reaction was completed, it was slowly poured into ice water, extracted with dichloromethane, dried and concentrated. The residue was purified by column chromatography to obtain 6.1 g of methyl 3-bromo-2-bromomethylbenzoate (A9-1) as a white oil, with a yield of 90%. 1H NMR: (400 MHz, CDCl3) δ 7.92 (dd, J = 8.0, 1.2 Hz, 1H), 7.80 (dd, J = 8.0, 1.2 Hz, 1H), 7.29–7.24 (m, 1H), 5.16 (s, 2H), 3.99 (s, 3H).

[0156] Synthesis step 2:

[0157] A9-1 (6.1 g, 19.93 mmol) was dissolved in acetonitrile (61 mL). To the system were successively added 3-aminopiperidine-2,6-dione hydrochloride (3.3 g, 19.93 mmol) and N,N-diisopropylethylamine (10.3 g, 79.72 mmol). After displacing argon, the mixture was heated to 90 °C and stirred for 16 hours. The reaction solution was filtered, washed with dichloromethane, and concentrated to obtain 5.5 g of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (A9-2) as a purple-gray solid, with a yield of 85%. 1H NMR: (400 MHz, CDCl3): δ 7.98 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.48-7.44 (m, 1H), 5.31–5.26 (m, 1H), 4.48 (d, J = 16.4 Hz, 1H), 4.33 (d, J = 16.4 Hz, 1H), 3.05–2.88 (m, 2H), 2.48-2.45 (m, 1H), 2.42–2.29 (m, 1H).

[0158] Synthesis step 3:

[0159] A9-2 (985 mg, 3.1 mmol) was dissolved in dimethyl sulfoxide (8 mL). Tetrakis(triphenylphosphine)palladium (358 mg, 0.31 mmol), copper(I) iodide (118 mg, 0.62 mmol), triethylamine (1.56 g, 15.5 mmol), and dec-9-enoic acid (1.2 g, 5.1 mmol) were successively added to the system. After purging with nitrogen, the mixture was stirred at 80 °C for 4 hours. The reaction solution was cooled to room temperature, quenched with water, extracted three times with ethyl acetate, the organic phases were combined, dried and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 673 mg of 10-[2-(2,6-dioxohexahydropyridin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]dec-9-ynoic acid, yield: 53%. MS: (ESI) [M - 100] + = 411.2

[0160] Synthesis of Intermediate A10

[0161]

[0162] Referring to the method of Step 5 for the synthesis of Intermediate A9, 4-bromo-2-(2,6-dioxopiperidin-3-yl)-isoindole-1,3-dione was used instead of A9-2 to obtain Intermediate A10. MS: (ESI) [M - 100] + = 425.2

[0163] Synthesis of Intermediate B1

[0164]

[0165] Synthesis Step 1:

[0166] Ethyl 5-methyl-1H-indole-2-carboxylate (5.0 g, 24.60 mmol) was dissolved in N,N-dimethylformamide (60 mL). Di-tert-butyl dicarbonate (6.4 g, 29.57 mmol) and 4-dimethylaminopyridine (0.3 g, 2.46 mmol) were added to the system. The reaction solution was stirred at 25 °C for 2 hours. After the reaction was completed, it was quenched with water, extracted twice with ethyl acetate, the organic phases were combined, dried and concentrated under reduced pressure to obtain 7.2 g of crude 1-tert-butyl 2-ethyl 5-methyl-1H-indole-1,2-dicarboxylate (B1-1), yield 96%. MS: (ESI) [M + 1] + = 304.1

[0167] Synthesis Step 2:

[0168] B1-1 (7.2 g, 23.73 mmol.) and benzoyl peroxide (0.2 g, 0.95 mmol) were dissolved in carbon tetrachloride (150 mL). N-Bromosuccinimide (4.3 g, 23.73 mmol) was added to the system in portions, and the reaction was carried out at 80 °C for 12 hours. After the reaction was completed, it was cooled to 25 °C. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 6.5 g of 1-tert-butyl 2-ethyl 5-(bromomethyl)-1H-indole-1,2-dicarboxylate (B1-2) with a yield of 71%. MS: (ESI) [M-56+1] + = 326.0.

[0169] Synthesis step 3:

[0170] B1-2 (6.5 g, 17.00 mmol) was dissolved in triethyl phosphite (3.4 g, 20.40 mmol). The reaction solution was heated to 100 °C and stirred for 12 hours. After the reaction was completed, it was cooled to 25 °C. The reaction solution was concentrated under reduced pressure, and the residue was obtained by column chromatography to obtain 7.0 g of 1-tert-butyl 2-ethyl 5-((diethoxyphosphoryl)methyl)-1H-indole-1,2-dicarboxylate (B1-3) with a yield of 93%. MS: (ESI) [M+1] + = 440.0.

[0171] Synthesis step 4:

[0172] B1-3 (6.8 g, 15.47 mmol) and titanium(IV) isopropoxide (1.1 g, 3.87 mmol) were dissolved in benzyl alcohol (35 L). The reaction solution was heated to 100 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to 35 °C, quenched with 1N hydrochloric acid (50 mL), extracted twice with ethyl acetate, the organic phases were combined, dried and concentrated, and the residue was obtained by column chromatography to obtain 3.8 g of benzyl 5-((diethoxyphosphoryl)methyl)-1H-indole-2-carboxylate (B1-4) with a yield of 85%. MS: (ESI) [M+1] + = 401.8.

[0173] Synthesis step 5:

[0174] B1-4 (3.3 g, 8.22 mmol) and di-tert-butyl dicarbonate (2.2 g, 9.87 mmol) were dissolved in N,N-dimethylformamide (30 mL). 4-Dimethylaminopyridine (0.10 g, 0.82 mmol) was added to the system, and the mixture was stirred at 25 °C for 2 hours. After the reaction was completed, it was quenched with water, extracted twice with ethyl acetate, the organic phases were combined, dried and concentrated, and the residue was obtained by column chromatography to obtain 4.0 g of 2-benzyl 1-tert-butyl 5-((diethoxyphosphoryl)methyl)-1H-indole-1,2-dicarboxylate (B1-5) with a yield of 89%. MS: (ESI) [M+1]+ = 502.2.

[0175] Synthesis step 6:

[0176] Dissolve B1-5 (4.7 g, 9.45 mmol) and N-fluorobenzenesulfonimide (8.9 g, 28.35 mmol) in dry tetrahydrofuran (200 mL), cool to -78 °C under a nitrogen atmosphere, add lithium bis(trimethylsilyl)amide (1.0 M, 28.4 mL, 28.35 mmol) dropwise, then stir at -78 °C for 2 hours and slowly warm to 25 °C. After the reaction is completed, add saturated ammonium chloride aqueous solution, extract twice with ethyl acetate, combine the organic phases, dry and concentrate. The residue is purified by column chromatography to obtain 4.0 g of 2-benzyl 1-tert-butyl 5-((diethoxyphosphoryl)difluoromethyl)-1H-indole-1,2-dicarboxylate (B1-6) with a yield of 72%. MS: (ESI) [M+1]+ = 538.1.

[0177] Synthesis step 7:

[0178] Dissolve B1-6 (4.00 g, 7.44 mmol) in tetrahydrofuran (240 mL), add palladium on carbon (2.0 g, 0.5 m / m) to the system, and stir the mixture at 25 °C for 3 hours under a hydrogen atmosphere. After the reaction is completed, concentrate the reaction solution under reduced pressure. The residue is purified by column chromatography to obtain 2.5 g of 1-tert-butoxycarbonyl-5-((diethoxyphosphoryl)difluoromethyl)-1H-indole-2-carboxylic acid (B1-7) with a yield of 69%. MS: (ESI) [M-100+1] + = 348.0.

[0179] Synthesis step 8:

[0180] Dissolve B1-7 (500 mg, 1.18 mmol) in dichloromethane (6 mL), and sequentially add p-nitrophenol (213 mg, 1.53 mmol), 1,3-dicyclohexylcarbodiimide (316 mg, 1.53 mmol), and 4-dimethylaminopyridine (14 mg, 0.12 mmol) to the system under an ice bath, and react at room temperature for 2 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry and concentrate under reduced pressure. Purification by column chromatography gives 300 mg of 1-(tert-butyl) 2-(4-nitrophenyl) 5-((diethoxyphosphoryl)difluoromethyl)-1H-indole-1,2-dicarboxylate (B1-8) with a yield of 47%.

[0181] Synthesis step 9:

[0182] Dissolve B1-8 (300 mg, 0.52 mmol) in dichloromethane (5 mL). Under an ice bath, successively add bis(trimethylsilyl)trifluoroacetamide (1.3 g, 5.20 mmol) and trimethylsilyl iodide (1.5 g, 7.81 mmol) to the system, and react for 2 h under the ice bath. After the reaction is completed, quench with water, combine the organic phases, dry and concentrate under reduced pressure. (1-(tert-Butoxycarbonyl)-2-((4-nitrophenoxy)carbonyl)-1H-indol-5-yl)difluoromethyl)phosphonic acid (B1-9) (200 mg) is obtained by column chromatography with a yield of 73%.

[0183] Synthesis step 10:

[0184] Dissolve B1-9 (200 mg, 0.39 mmol) in acetonitrile (5 mL). Add trifluoroacetic acid (1 mL) and water (2 mL) to the system, and react at 60 °C for 6 h. After the reaction is completed, concentrate under reduced pressure, and (2-((4-nitrophenoxy)carbonyl)-1H-indole-5-carbonyl)phosphonic acid B1 (120 mg) is obtained by column chromatography with a yield of 76%. MS: (ESI)[M+Na] + = 391.2.

[0185] Synthesis of intermediate B2

[0186]

[0187] Synthesis step 1:

[0188] Dissolve 5-bromobenzo[b]thiophene-2-carboxylic acid (10 g, 39 mmol) in dichloromethane (200 mL). Slowly add oxalyl chloride (15 g, 117 mmol) and N,N-dimethylformamide (1 mL) under an ice bath, displace with nitrogen, and stir at room temperature for 2 h. After the reaction is completed, concentrate under reduced pressure to obtain 5-bromobenzo[b]thiophene-2-carbonyl chloride (B2-1) (11 g), which is directly used in the next step.

[0189] Synthesis step 2:

[0190] Dissolve B2-1 (11 g, 39 mmol) in dichloromethane (200 mL). Slowly add benzyl alcohol (51 g, 46.8 mmol) and triethylamine (118 g, 117 mmol) under an ice bath, displace with nitrogen, and stir at room temperature for 1 h. After the reaction is completed, cool to room temperature, quench with water, extract three times with ethyl acetate, combine the organic phases, dry and concentrate. The residue is subjected to column chromatography to obtain benzyl 5-bromobenzo[b]thiophene-2-carboxylate (B2-2) (9 g) with a yield of 67%. 11H NMR: (400 MHz, DMSO): δ 8.30 (d, J = 2.0 Hz, 1H), 8.24 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 8.0, 2.0 Hz, 1H), 7.51 (d, J = 6.8 Hz, 2H), 7.47–7.40 (m, 3H), 5.42 (s, 2H).

[0191] Synthesis step 3:

[0192] Dissolve B2-2 (4.8 g, 13.8 mmol) in 1,4-dioxane (48 mL). To the system, add N1,N2-dimethylethane-1,2-diamine (244 mg, 2.8 mmol) and copper(I) iodide (263 mg, 1.4 mmol) successively. Seal the tube and heat to 110 °C and react for 16 h. After the reaction is completed, cool to room temperature, filter, concentrate the filtrate, and obtain benzyl 5-iodobenzo[b]thiophene-2-carboxylate (B2-3) by column chromatography. MS: (ESI) [M+Na] + = 417.2. 1 1H NMR: (400 MHz, DMSO): δ 8.47 (d, J = 1.6 Hz, 1H), 8.22 - 8.19 (m, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.82 (dd, J = 8.4, 1.6 Hz, 1H), 7.53 - 7.48 (m, 2H), 7.46 - 7.38 (m, 3H), 5.41 (s, 2H).

[0193] Synthesis step 4:

[0194] Disperse zinc powder (3.4 g, 48.7 mmol) evenly in anhydrous tetrahydrofuran. Add 1,2-dibromoethane (457 mg, 2.4 mmol) at room temperature, heat to 50 °C under a nitrogen atmosphere and maintain for 15 minutes. Cool to room temperature, add trimethylchlorosilane (317 mg, 2.9 mmol), and stir at room temperature for 15 minutes. Slowly dropwise add diethyl bromodifluoromethylphosphonate (13.0 g, 48.7 mmol) to the system, heat to 50 °C and stir for 1 hour. Cool to room temperature, quickly add copper(I) bromide (3.5 g, 24.4 mmol) to the above system, and stir at room temperature for 30 minutes. Then, at room temperature, dropwise add a tetrahydrofuran solution of B2-3 (6.4 g, 16.2 mmol / 60 mL) to the system, and then heat to 45 °C and stir overnight. After the reaction is completed, cool to room temperature, filter, concentrate the filtrate, and obtain 2.3 g of benzyl 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (B2-4) by column chromatography. Yield: 31%. 11H NMR: (400 MHz, CDCl3): δ 8.19 (s, 2H), 7.99 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.53 - 7.51 (m, 2H), 7.48–7.39 (m, 3H), 5.45 (s, 2H), 4.34 - 4.20 (m, 4H), 1.46 - 1.30 (m, 6H).

[0195] Synthesis step 5:

[0196] Dissolve B2-4 (5.8 g, 12.81 mmol) in methanol (58 mL). Add palladium on carbon (5.8 g) to the system and stir at room temperature for 12 h under a hydrogen atmosphere. After the reaction is completed, filter, concentrate the filtrate, and obtain 1.6 g of intermediate B2 by column chromatography with a yield of 35%. MS: (ESI) [M + H]+ = 365.0. 1H NMR: (400 MHz, DMSO): δ 8.30 - 8.24 (m, 3H), 7.66 (d, J = 8.0 Hz, 1H), 4.21–4.10 (m, 4H), 1.26 - 1.23 (m, 6H).

[0197] Synthesis of intermediate C1

[0198]

[0199] Synthesis step 1:

[0200] Dissolve Boc-L-pyroglutamic acid methyl ester (10.0 g, 41.11 mmol) in methanol (100 mL). Add sodium borohydride (2.2 g, 57.55 mmol) portionwise at -10 °C, and then stir at -10 °C for 1 hour. After the reaction is completed, slowly add water (80 mL) to the system at 0 °C. After stirring for about half an hour, extract with ethyl acetate, dry, and concentrate to obtain 8.9 g of 1-(tert-butyl) 2-methyl (2S)-5-hydroxypyrrolidine-1,2-dicarboxylate (C1-1) with a yield of 88%. The crude product is directly used for the next step of the reaction. LC-MS: (ESI) [M + H] + = 246.1

[0201] Synthesis step 2:

[0202] Dissolve C1-1 (25.6 g, 104.38 mmol) in anhydrous methanol (250 mL). Add p-toluenesulfonic acid (3.6 g, 20.88 mmol) at room temperature and stir at room temperature for 18 hours. After the reaction is completed, concentrate and obtain 24.7 g of 1-(tert-butyl) 2-methyl (2S)-5-methoxypyrrolidine-1,2-dicarboxylate (C1-2) by column chromatography with a yield of 91%. The crude product is directly used for the next step of the reaction. MS: (ESI) [M + H]+ = 260.1.1 1H NMR: (400 MHz, CDCl3): δ 5.36–5.16 (m, 1H), 4.42–4.25 (m, 1H), 3.81–3.73 (m, 3H), 3.53–3.37 (m, 3H), 2.53–2.29 (m, 1H), 2.23–1.80 (m, 3H), 1.54–1.43 (m, 9H).

[0203] Synthesis Step 3:

[0204] Dissolve C1-2 (10.0 g, 38.56 mmol) and allyltrimethylsilane (13.2 g, 115.70 mmol) in dichloromethane (200 mL). Under a nitrogen atmosphere, add boron trifluoride diethyl etherate (5.5 g, 38.56 mmol) dropwise at -72 °C, and then stir at -72 °C for 1 hour. After the reaction is completed, add water (100 mL) dropwise to the reaction solution at -72 °C, warm to room temperature, extract with dichloromethane, combine the organic phases, dry and concentrate, and obtain 5.3 g of 1-(tert-butyl) 2-methyl (2S)-5-allylpyrrolidine-1,2-dicarboxylate (C1-3) by column chromatography, yield: 51%. MS: (ESI) [M+H]+ = 270.2. 1 1H NMR: (400 MHz, CDCl3): δ 5.86–5.72 (m, 1H), 5.11–5.02 (m, 2H), 4.37–4.19 (m, 1H), 4.00–3.81 (m, 1H), 3.74–3.71 (m, 3H), 2.76–2.53 (m, 1H), 2.26–2.14 (m, 2H), 2.01–1.89 (m, 2H), 1.81–1.71 (m, 1H), 1.47–1.40 (m, 9H).

[0205] Synthesis Step 4:

[0206] Dissolve C1-3 (4.6 g, 17.08 mmol) in dichloromethane (40 mL), add a 1,4-dioxane solution of hydrogen chloride (21 mL, 168 mmol) to the system, and stir the reaction solution at room temperature for 3 hours. After the reaction is completed, concentrate the reaction solution, dry to obtain (2S)-5-allylpyrrolidine-2-carboxylate hydrochloride C1-4, and directly use it in the next step of the reaction.

[0207] Synthesis Step 5:

[0208] Dissolve C1-4 (3.5 g, 17.11 mmol) and (S)-3-((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid (5.8 g, 17.11 mmol) in N,N-dimethylformamide (40 mL). At 10 °C, sequentially add N,N-diisopropylethylamine (6.6 g, 51.34 mmol) and 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.8 g, 17.97 mmol) to the system, and stir at room temperature for 18 hours. After the reaction is completed, pour it into water (100 mL), extract with ethyl acetate, combine the organic phases, dry and concentrate, and obtain 6.5 g of methyl (2S)-5-allyl-1-((S)-3-((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)propionyl)pyrrolidine-2-carboxylate (C1-5) by column chromatography, yield: 77%. MS: (ESI) [M+H] + = 490.3.

[0209] Synthesis step 6:

[0210] Dissolve C1-5 (1.7 g, 3.51 mmol) in dichloromethane (60 mL). At -78 °C, introduce ozone into the system until the reaction solution turns light blue, then stop introducing. Then introduce air into the system to remove the excess ozone. At -78 °C, add triethylamine (7.5 g, 73.78 mmol), and raise the temperature to room temperature and stir for 1 hour. After the reaction is completed, concentrate the reaction solution, and obtain 1.3 g of methyl (2S)-1-((S)-3-((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)propionyl)-5-(2-oxoethyl)pyrrolidine-2-carboxylate (C1-6) by column chromatography for the crude product, yield: 75%.

[0211] Synthesis step 7:

[0212] Dissolve C1-6 (1.3 g, 2.64 mmol) in isopropanol (20 mL), then add palladium on carbon (130 mg, 10% wt), and stir at room temperature for 18 hours under a hydrogen atmosphere (1 atm). After the reaction is completed, filter, wash the filter cake with methanol, concentrate and dry the filtrate, then dissolve it in tetrahydrofuran (100 mL), add sodium triacetoxyborohydride (1.7 g, 7.94 mmol) at room temperature, and stir at room temperature for 18 hours. After the reaction is completed, add saturated brine (20 mL) to the reaction solution and stir for half an hour, remove tetrahydrofuran under reduced pressure, extract with chloroform / isopropanol (3:1), combine the organic phases, dry and concentrate, and obtain methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (C1-7) 270 mg by column chromatography, with a yield of 30%. MS: (ESI) [M+H]+ = 342.2. 1H NMR: (400 MHz, CDCl3): δ 5.43 (d, J = 8.0 Hz, 1H), 4.76 - 4.68 (m, 1H), 4.54 (t, J = 8.8 Hz, 1H), 4.36 - 4.29 (m, 1H), 3.77 (s, 3H), 3.25 - 3.18 (m, 2H), 2.95 - 2.85 (m, 1H), 2.74 (dd, J = 13.6, 10.8 Hz, 1H), 2.40 - 2.33 (m, 1H), 2.20 - 2.12 (m, 1H), 2.01 - 1.95 (m, 1H), 1.90 - 1.79 (m, 2H), 1.67 - 1.61 (m, 1H), 1.42 (s, 9H).

[0213] Synthesis step 8:

[0214] Dissolve C1-7 (220 mg, 0.64 mmol) in dichloromethane (5 mL), and sequentially add benzylcarbonyl succinimide (132 mg, 0.77 mmol) and triethylamine (163 mg, 1.61 mmol) to the system at low temperature, then stir at room temperature for 4 hours. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry and concentrate, and obtain 3-benzyl 8-methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxylate (C1-8) 240 mg by column chromatography, with a yield of 78%. MS: (ESI) [M+H]+ = 476.3.

[0215] Synthesis step 9:

[0216] Dissolve C1-8 (240 mg, 0.50 mmol) in tetrahydrofuran (12 mL), add an aqueous solution (4 mL) of lithium hydroxide (73 mg, 3.03 mmol) at room temperature, and stir at room temperature for 4 hours. After the reaction is completed, dilute with water (10 mL), and remove tetrahydrofuran under reduced pressure. Adjust the aqueous phase to pH = 7 with dilute hydrochloric acid (1 N), extract with chloroform / isopropanol (chloroform:isopropanol = 3:1), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain 220 mg of the intermediate (5S, 8S, 10aR)-3-((benzyloxy)carbonyl)-5-(tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepine-8-carboxylic acid, with a yield of 94%. MS: (ESI) [M+H] + = 462.2.

[0217] Synthesis of Intermediate D1

[0218]

[0219] Synthesis Step 1:

[0220] Dissolve (4-(methylthio)phenyl)methanol (2.0 g, 12.98 mmol) in tetrahydrofuran (25 mL), and successively add phthalimide (2.8 g, 19.48 mmol) and triphenylphosphine (8.5 g, 32.45 mmol) to the system. Add diisopropyl azodicarboxylate (6.5 g, 32.54 mmol) to the system at 0 °C under a nitrogen atmosphere, and react at room temperature for 2 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry and concentrate under reduced pressure. Obtain 2.3 g of 2-(4-(methylthio)benzyl)isoindoline-1,3-dione (D1-1) by column chromatography, with a yield of 88%.

[0221] Synthesis Step 2:

[0222] Dissolve D1-1 (2.0 g, 7.06 mmol) in a mixed solvent (dichloromethane / methanol = 3:1, 20 mL), and successively add iodobenzene diacetate (2.7 g, 8.5 mmol) and ammonium acetate (108 mg, 1.4 mmol) to the system. React at room temperature for 1 h under a N2 atmosphere. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry and concentrate under reduced pressure. Obtain 1.5 g of 2-(4-(S-methylsulfinyl)benzyl)isoindoline-1,3-dione (D1-2) by column chromatography, with a yield of 67%.

[0223] Synthesis Step 3:

[0224] Dissolve D1-2 (1.5 g, 4.77 mmol) in formic acid (20 mL), add formaldehyde (715 mg, 23.85 mmol) to the system, and react at 125 °C for 12 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry and concentrate under reduced pressure. 2-(4-(N,S-Dimethylsulfamoylamino)benzyl)isoindoline-1,3-dione (D1-3) (1.5 g) is obtained by column chromatography with a yield of 95%.

[0225] Synthesis step 4:

[0226] Dissolve D1-3 (1.5 g, 4.57 mmol) in ethanol (20 mL), add hydrazine hydrate (50%) to the system, and react at 60 °C for 6 h. After the reaction is completed, concentrate under reduced pressure, dissolve and dilute with dichloromethane, filter, and concentrate the filtrate to obtain (4-(Aminomethyl)phenyl)(methyl)(methylimino)-λ 6 Aminosulfone (D1-4) (800 mg) with a yield of 88%.

[0227] Synthesis step 5:

[0228] Dissolve D1-4 (800 mg, 4.04 mmol) in dichloromethane (10 mL), and successively add 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.3 g, 6.06 mmol), N2-((9H-Fluoren-9-yl)methoxycarbonyl)-N 5 -Trityl-L-glutamine (3.6 g, 6.06 mmol), and triethylamine (1.2 g, 12.12 mmol) to the system, and react at room temperature for 1 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry and concentrate under reduced pressure. Then, (9H-Fluoren-9-yl)methyl ((2S)-1-((4-(N,S-Dimethylsulfamoylamino)benzyl)amino)-1,5-dioxo-5-(tritylamino)pent-2-yl)carbamate (D1-5) (1.2 g) is obtained by column chromatography with a yield of 37%.

[0229] Synthesis step 6:

[0230] Dissolve D1-5 (1.2 g, 1.51 mmol) in dichloromethane (15 mL), add 1,8-Diazabicyclo[5.4.0]undec-7-ene (460 mg, 3.02 mmol) to the system, and react at room temperature for 1 h. After the reaction is completed, quench with water, dry and concentrate under reduced pressure. (2S)-2-Amino-N 1 -(4-(N,S-Dimethylsulfinyl)benzyl)-N 5 -Tritylpentanediamide (Intermediate D1) (1.0 g). MS: (ESI) [M+H] + = 569.5

[0231] Synthesis of 005

[0232]

[0233] Synthesis Step 1:

[0234] Dissolve D1 (2 mmol) and C1 (2.2 mmol) in N,N-dimethylformamide (20 mL). Add N,N-diisopropylethylamine (6 mmol) to the system. After stirring at room temperature for 3 minutes, add 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.2 mmol) portionwise at 10 °C, and then raise the temperature to room temperature and stir for 18 hours. After the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify the crude product by column chromatography to obtain benzyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-(2S)-((1-((4-(N,S-dimethylsulfamoylamino)benzyl)amino)-1,5-dioxo-5-(tritylamino)pentan-2-yl)carbamoyl)-6-oxooctahydropyrrolo[1,2-a][1,5]diazepine-3(4H)-carboxylate 005-1.

[0235] Synthesis Step 2:

[0236] Dissolve 005-1 (1.8 mmol) in tetrahydrofuran (5 mL), add 200 mg of Pd / C, replace with hydrogen, and reflux for 6 hours under a hydrogen atmosphere. After the reaction is completed, filter and concentrate to obtain the crude product tert-butyl ((5S,8S,10aR)-8-(((2S)-((1-((4-(N,S-dimethylsulfamoylamino)benzyl)amino)-1,5-dioxo-5-(tritylamino)pentan-2-yl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepin-5-yl)carbamate 005-2, which is directly used in the next step.

[0237] Synthesis Step 3:

[0238] Dissolve 005-2 (1 mmol) and intermediate A1 (1 mmol) in N,N-dimethylformamide (15 mL), then add N,N-diisopropylethylamine (2 mmol) and 1-propylphosphonic anhydride (1.05 mmol), and stir at room temperature for 15 hours. After the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and obtain tert-butyl ((5S,8S,10aR)-8-(((2S)-1-((4-(N,S-dimethylsulfimido)benzyl)amino)-1,5-dioxo-5-(tritylamino)pent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate 005-3 by column chromatography of the crude product.

[0239] Synthesis step 4:

[0240] Dissolve 005-3 (0.5 mmol) in dichloromethane (1 mL), add a 1,4-dioxane solution of hydrogen chloride (3.3 mL, 13.3 mmol) to the system, stir at room temperature for 3 hours, concentrate and dry, then dissolve in N,N-dimethylformamide (5 mL), and then add B1 (0.5 mmol), N,N-diisopropylethylamine (1 mmol) and 1-propylphosphonic anhydride (0.6 mmol), and stir at room temperature for 15 hours. After the reaction is completed, obtain {[2-({[(5S,8S,10aR)-8-[(3S)-3-(2-carbamoylethyl)-6-{4-[methyl(methylimino)(oxo)-λ 6 -sulfanyl]phenyl}-1,4-dioxo-2,5-diazahex-1-yl]-3-{7-[1-(2,6-dioxohexahydropyridin-3-yl)-3-methyl-2-oxobenz[d]imidazol-5-yl]-1-oxoheptyl}-6-oxo-decahydropyrrolo[1,2-a][1,5]diazocine-5-yl]amino}carbonyl)-1H-indol-5-yl]carbonyl}phosphonic acid 005 by column chromatography after concentration. MS: (ESI) [M+H] + = 1156.4.

[0241] Referring to the synthesis method of reference compound 005, the following compounds were synthesized:

[0242]

[0243]

[0244]

[0245] Synthesis of Compound 010

[0246]

[0247] Referring to the first three steps of the synthesis of Reference 005, the corresponding intermediate tert-butyl ((5S,8S,10aR)-8-(((2S)-1-((4-(N,S-dimethylsulfonimidoyl)benzyl)amino)-1,5-dioxo-5-(tritylamino)pentan-2-yl)carbamoyl)-3-(2-(3-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclopentyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepin-5-yl)carbamate (010-3) was obtained.

[0248] Synthesis Step 4:

[0249] Dissolve 010-3 (498 mg, 0.40 mmol) in dichloromethane (1 mL). Add a 1,4-dioxane solution of hydrogen chloride (3.3 mL, 13.3 mmol) to the system and stir at room temperature for 3 hours. After concentration and drying, dissolve it in N,N-dimethylformamide (5 mL). Add 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (186 mg, 0.51 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (166 mg, 0.45 mmol), and N,N-diisopropylethylamine (511 mg, 3.95 mmol) to the system in sequence and stir at 25 °C for 1 hour. After the reaction is completed, quench with water, extract three times with ethyl acetate, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and obtain 340 mg of diethyl ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-((4-(N,S-dimethylsulfonimidoyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2-(3-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclopentyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonate (010-4) with a yield of 67%. MS: (ESI) [M+H] + = 1264.9.

[0250] Synthesis Step 5:

[0251] (010-4) (340 mg, 0.27 mmol) was dissolved in a mixed solution of dichloromethane (5 mL) and trifluoroacetic acid (1 mL), and stirred at 0 °C for 1 hour. After the reaction was completed, it was concentrated under reduced pressure and purified by column chromatography to obtain {difluoro[2-({[(5S,8S,10aR)-8-[(3S)-3-(2-carbamoylethyl)-6-{4-[methyl(methylimino)(oxo)-λ 6 -sulfanyl]phenyl}-1,4-dioxo-2,5-diazahex-1-yl]-3-[2-(3-{[1-(2,6-dioxohexahydropyridin-3-yl)-3-methyl-2-oxobenz[d]imidazol-5-yl]methyl}cyclopentyl)acetyl]-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl]amino}carbonyl)benzo[b]thiophen-5-yl]methyl}phosphonic acid 010, 50 mg. MS: (ESI) [M+H] + = 1207.4

[0252] Other compounds were obtained by the synthesis methods of compound 005 and compound 010

[0253]

[0254] STAT1 / 3 Degradation Activity Test HiBiT assay in Hela-STAT3-HiBiT Cells

[0255] 1) Cell Seeding and Recovery Resuscitate MOLM16 cells, select a cell line with good growth state, collect cells in the logarithmic growth phase and count them. Inoculate the cell suspension into 12- or 24-well plates at a density of 500,000 - 1,000,000 cells / well, and place them in a 37 °C, 5% CO2 incubator overnight.

[0256] 2) Preparation of Compounds

[0257] The compounds were serially diluted with DMSO according to the experimental requirements and added to the cell wells, and incubated in a 37 °C, 5% CO2 incubator for 24 h.

[0258] 3) Sample Preparation

[0259] After the compounds had their effects, collect the cells in 1.5 mL EP tubes, centrifuge at 1500 rpm for 5 min, discard the supernatant, wash once with PBS, perform BCA protein quantification and adjust the concentration. Add the adjusted samples to 5*loading buffer, boil at 100 °C for 10 min, and load the samples after returning to room temperature.

[0260] 4) Sample Detection

[0261] Electrophoresis was performed using 10% SDS-PAGE with a sample loading volume of 8 μL / well. After transferring the membrane, it was blocked with 5% BSA at room temperature for 1 h. After washing away the residual blocking solution with TBST, STAT1, STAT3, and GAPDH antibodies were added and incubated overnight at 4 °C. Then, it was washed 3 times with TBST on a shaker, 10 min each time. After the washing was completed, the secondary antibody was added and incubated at room temperature for 1 h, followed by washing 3 times with TBST on a shaker, 10 min each time. Finally, the ECL exposure solution was used to develop and image the bands to detect the changes in STAT1 and STAT3 proteins.

[0262] Table 1 Degradation activities of the compounds of the present invention against STAT3 and STAT1

[0263] Compound number <![CDATA[STAT3 DC 50 > <![CDATA[STAT1 DC 50 > 001 A A 002 A A 003 A A 004 A A 005 A A 006 A A 007 A A 008 A A 009 A A 010 A A 011 A A 012 A A Compound a A B

[0264] A: DC 50 <300 nM. B: 300 nM < DC 50 <1000 nM C: 1000 nM < DC 50

[0265] Table 1 shows that the compounds of the present invention have obvious degradation activities against STAT1 and STAT3.

[0266] The structure of compound a is:

[0267] Biological evaluation 2: Inhibitory activity of tumor cell proliferation

[0268] Karpas299 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. The cells were seeded in a 96-well plate at a cell concentration of 4000 Karpas299 cells / well and incubated overnight at 37 °C and 5% CO2. Different concentrations (1000 nM, 4-fold dilution, 8 points) of the test compounds were added to the 96-well plate and incubated at 37 °C and 5% CO2 for 96 h. Then, 10 μL of CCK8 was added to each well. After incubation for 2 h, the absorbance at 450 nm was measured using a microplate reader. The IC 50 .

[0269] Table 2 Proliferation inhibitory activities of the compounds of the present invention against Karpas299 cells

[0270] Compound number <![CDATA[IC 50 > Compound number <![CDATA[IC 50 > 001 A 007 A 002 A 008 A 003 A 009 A 004 A 010 A 005 A 011 A 006 A 012 A

[0271] A: IC 50 <50 nM; B: 50 nM < IC 50 <200 nM; C: 200 nM < IC 50

[0272] Table 2 shows that the compounds of the present invention have significant inhibitory activity against Karpas 299 tumor cells.

Claims

1. A compound, characterized in that Select from the following structures: or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition, characterized in that Comprising the compound described in claim 1.

3. A use of the compound as claimed in claim 1 in the preparation of a drug for treating a disease that benefits from the degradation of STAT3 and STAT1, either alone or in combination with other drugs; the disease is selected from hematological malignancies, solid tumors, and autoimmune diseases; the hematological malignancies are selected from one or more of leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome, and myelofibrosis; the solid tumors are selected from one or more of digestive system malignancies, respiratory system malignancies, central nervous system tumors, urinary system malignancies, gynecological malignancies, sarcomas, melanomas, and bone cancer; the autoimmune system diseases are selected from one or more of rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, multiple sclerosis, ulcerative colitis, Crohn's disease, insulin-dependent diabetes mellitus (type I), and myasthenia gravis.

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