Cyclobutane derivative and application thereof in medicine

Abstract

The invention relates to a cyclobutane derivative and application thereof in medicine, in particular to a compound shown in a general formula (I) or a stereoisomer, a tautomer, a racemate, pharmaceutically acceptable salt and an intermediate thereof, and application of the compound in inhibiting or degrading AR related diseases such as cancers. And B-L-K (I).

Description

TECHNICAL FIELD

[0001] The present application relates to a compound of general formula (I) or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and intermediates and preparation methods thereof, and uses thereof in AR-related diseases such as cancer. BACKGROUND

[0002] Prostate cancer is a cancer that is often found in the early stage, and the causes of the disease are often related to genetic factors, high-fat diet and endocrine. Generally speaking, the incidence of prostate cancer in developed countries is higher than that in developing countries. For early prostate cancer patients, radical treatment methods can be used, and the survival time is longer, while the late patients with cancer cell metastasis use castration combined with anti-androgen drug therapy, and the disease will develop into castration-resistant prostate cancer. Clinical studies have shown that most patients with castration-resistant prostate cancer have overexpression of androgen receptor (AR) in their bodies, and inhibition of androgen receptor (AR) signaling has a significant effect on hormone-refractory prostate patients, so inhibition of androgen receptor (AR) is an effective means of directly blocking the pathway.

[0003] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. Such compounds can be recognized by the proteasome of the cell, causing degradation of the target protein, and can effectively reduce the content of the target protein in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, it is possible to apply PROTAC technology to the treatment of various diseases, and this technology has received widespread attention in recent years.

[0004] Therefore, it is necessary to develop new PROTAC drugs targeting androgen receptor (AR) for the treatment of androgen receptor-related tumor diseases. SUMMARY

[0005] The purpose of the present application is to provide a compound with a novel structure, good drug efficacy, high bioavailability, safety, and the ability to inhibit or degrade AR, for the treatment of AR-related diseases such as cancer, preferably prostate cancer.

[0006] The present application provides a compound or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the compounds represented by general formula (I),

[0007] B-L-K (I);

[0008] In some embodiments, the compound of general formula (I) is selected from the group consisting of compounds of general formulae (la), (lb), (lc),

[0009]

[0010] In some embodiments, L is selected from a bond or -C 1-50 hydrocarbyl-, said hydrocarbyl having 1 to 20 methylene units optionally replaced by -Ak-, -Cy-;

[0011] In some embodiments, L is selected from a bond or -C 1-20 hydrocarbyl-, said hydrocarbyl having 1 to 10 methylene units optionally replaced by -Ak-, -Cy-;

[0012] In some embodiments, each -Ak- is independently selected from -(CH2) q -, -(CH2) q -O-, -O-(CH2) q -, -(CH2) q -S-, -S-(CH2) q -, -(CH2) q -NR L -, -NR L -(CH2) q -, -(CH2) q -NR L C(=O)-, -NR L (CH2) q C(=O)-, -(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -, -(C≡C) q -, -CH=CH-, -Si(R L )2-, -Si(OH)(R L )-, -Si(OH)2-, -P(=O)(OR L )-, -P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond, said CH, -CH2- being optionally substituted with 1 to 2 substituents selected from deuterium, halogen, =O, OH, CN, C 1-4 alkyl or C 3-6 cycloalkyl;

[0013] In some implementations, q is independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0014] In some implementation schemes, R L Selected from H, C 1-4 Alkyl, C 3-7 Carbocyclic groups, 4- to 10-membered heterocyclic groups;

[0015] In some implementations, each -Cy- is independently selected from the key or optionally selected by 1 to 4 Rs. L2 The substituted group is one of the following: 4-8 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged group, C 3-7 Monocycloalkyl, C 4-7 Monocyclic alkenyl, C 4-12 cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl;

[0016] In some implementations, Ak is selected from Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, or Ak9;

[0017] In some implementations, Ak is selected from Ak1, Ak2, Ak3, Ak4, or Ak5;

[0018] In some implementations, -Cy- is selected from Cy1, Cy2, Cy3, Cy4, or Cy5;

[0019] In some implementations, -Cy- is selected from Cy1, Cy2, Cy3, or Cy4;

[0020] In some implementations, L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak 5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak 3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1 -Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-A k3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy 3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4- Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1- Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, - Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3 -Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2 -Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy 4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy 3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-,-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-、-Ak1-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-;、

[0021] In some embodiments, L is selected from a bond, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5--Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy 2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;,

[0022] In some implementations, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0023] In some implementations, L is selected from -Cy1-, -Cy1-Ak2-, -Cy1-CH2-, -Ak1-Cy1-, -Cy1-Cy2-, -Cy1-CH2-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH2-Cy2-Cy3-, -Cy1-Cy2-CH2-Cy3-;

[0024] In some implementations, L is selected from -Cy1-CH2-, -Cy1-Cy2-, and -Cy1-CH2-Cy2-.

[0025] In some implementations, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 are each independently selected from -(CH2). q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-、-S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q - or bond, wherein the -CH2- is optionally selected from one or two elements selected from deuterium, halogen, =O, OH, CN, C 1-4 Alkyl or C 3-6 Substituents of cycloalkyl groups;

[0026] In some implementations, q is selected from 0, 1, 2, or 3;

[0027] In some implementations, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 are each independently selected from the following: -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH(CH3)-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH-, or -NHC(=O)-;

[0028] In some implementations, Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -C≡C-, -C(CH3)2-, or -CH2-;

[0029] In some implementation schemes, R L Selected from H or C 1-4 alkyl;

[0030] In some implementation schemes, R L Selected from H, methyl, or ethyl;

[0031] In some implementations, Cy1, Cy2, Cy3, Cy4, or Cy5 are each independently selected from or optionally selected by one to four R keys. L2 The substituted group is one of the following: 4-7 member nitrogen-containing heterocyclic group, 4-12 member nitrogen-containing heterocyclic group, 5-13 member nitrogen-containing heterospirocyclic group, 7-12 member nitrogen-containing heterobridged cyclic group, C 3-7 Monocycloalkyl, C 4-7 Monocyclic alkenyl, C 4-12 cycloalkyl, C 5-13 Spirocycloalkyl, C 7-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl;

[0032] In some implementations, Cy5 is defined the same as Cy1;

[0033] In some implementations, Cy1, Cy2, Cy3, and Cy4 are each independently selected from or arbitrarily selected by one to four R keys. L2 The substituted group is one of the following: phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl. s1, s3, and s5 are each independently selected from 0, 1, or 2; s2 and s4 are each independently selected from 0 or 1; s6 is selected from 0, 1, 2, or 3; and s7 is selected from 1, 2, or 3.

[0034] In some embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from one of the following groups, either bonded or optionally substituted: When substituted, it is replaced by 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, and cyclopropyl.

[0035] In some embodiments, Cy1, Cy2, and Cy3 are each independently selected from one of the following optionally substituted groups: When substituted, it is replaced by 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, and cyclopropyl.

[0036] In some embodiments, Cy1 and Cy2 are each independently selected from one of the following optionally substituted groups: When substituted, it is replaced by 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, and cyclopropyl.

[0037] In some implementations, L is selected from the structural segments shown in Table L-1:

[0038] Table L-1

[0039]

[0040]

[0041] In some implementations, B is selected from ligands that bind to the target;

[0042] In some implementations, B is selected from ligands that bind to a target, which is selected from protein kinases, nuclear receptors, bromodomain proteins, transcription factors, protein-coupled receptors, proto-oncogenes, membrane-integrated proteins, and ion channels, including but not limited to the following targets: AKT1, ALK, AXL, ABL, c-ABL, BCR-ABL, ABL1, ABL2, AKT2, API, AP2, ASH1L, ATAD2, aurorakinase, androgen receptor, androgen splice receptor, ATF2, BMX, bromodomain-containing protein, Bcl-2, Bcl-XL, BCL6, Bcl11A, BAZ2A, BAZ2B, BRD4, BRD9, BRPF1, BMX, CSF1R, CECR2, CBP, CREBBP, CNNTB1, cathepsin, cyclin-dependent kinase, DDR1, DOT1L, dihydrofolate. reductase,ERBB2,ERBB3,ERBB4,EPHA2,EPHA3,EPHA4,EPHA7,EPHB4,EZH2,EED,EHMT1,EHMT2,ERKl,ERK2,estrogen receptor,FGFRl,FGFR2,FGFR3,FGFR4,FLT3,FES,FYN,FKBP,fatty acid binding protein,factor Xa,FLAP,GSG2,HIV integrase,HIVreverse transcriptase,HIV protease,HCV protease,HDAC6,HDAC7,HDM2,HBV,HCK,histone deacetylase,histone acetyltransferase,heat shock protein,HDAC,Her3,IGF IR,INSR,IDOl,IDH1,ITK,KDM4,KDM5,KDM6,KMT5A,KIT,KSRl,kringledomain V,4BW,kallikrein 7,KSR receptor,LRRK2,lactoyl-glutathione lyase,LSDl,L3MBTL3,lysine-specific histone demethylase,lysine methyltransferase,LCK,LYN,mPGES-1,MERTK,MEKl,MDM2,MDM4,MENl,MTHl,MCL-I,MER,MET,mast / stem cell growth factorreceptor,MST1R,NTRK,NTRKl,NTRK2,NTRK3,PDZ,phospholipase A2 domain,PB1,PCAF,PHIP,protein S100-A7,PAKl,PAK4,PPAR-gamma,PDGFR receptor,PNET,PI3Ka receptor,PIK3CA,ROSl receptor,RCC receptor,RAML receptor,RET,SETD2,SETD7,SETD8,SETDB1,SMYD2,SMYD3,SUV4-20H1,saposin-B,Sec7,SH2 domain,Src-AS 1,Src AS2,SEGAreceptor,TNIK,TRIM24,TAF1,TAF1L,mTORCl,mTORC2,TANKl,TRKB,tie 2receptor,TEC,SF6D,U09-CX-5279,VEGF receptor,WDR5,TINFRlm,TNFR2,NADPH oxidase,Bel-Bax,C5areceptor,HMG-CoA reductase,PDE V,phosphodiesterase type,PDE IVphosphodiesterase type 4,PDE I,PDE II,PDE III,squalene cyclase inhibitor,CXCRl,CXCR2,nitric oxide(NO)synthase,cyclo-oxygenase 1,cyclo-oxygenase 2,5-HTreceptors,dopamine receptors,G Proteins,i.e.,Gq,histamine receptors,5-lipoxygenase,tryptase serine protease,thymidylate synthase,purine nucleosidephosphorylase,GAPDH trypanosomal,glycogen phosphorylase,Carbonic anhydrase,chemokine receptors,JAW STAT,HIV 1protease,HIV 1 integrase,influenza,neuramimidase,hepatitis B reverse transcriptase,sodium channel,multi drugresistance(MDR),protein P-glycoprotein(and MRP),tyrosine kinases,CD23,CD124,tyrosine kinase p56 lck,CD4,CD5,IL-2 receptor,IL-I receptor,TNF-alphaR,ICAM1,Cat+channels,Ca, 2+channels,VC AM,VLA-4integrin,selectins,CD40 / CD40L,inosinemonophosphate dehydrogenase,p38 MAP Kinase,RAS-RAF-MEK-ERK pathway,interleukin-1 converting enzyme,caspase,HCV,NS3 protease,HCV NS3 RNAhelicase,glycinamide ribonucleotide formyl transferase,rhinovirus 3Cprotease,herpes simplex virus-1(HSV-I)protease,cytomegalovirus(CMV)protease,poly(ADP-ribose)polymerase,cyclin dependent kinases,vascular endothelialgrowth factor,oxytocin receptor,microsomal transfer protein inhibitor,bileacid transport inhibitor,5alpha reductase inhibitors,angiotensin 11,glycinereceptor,noradrenaline reuptake receptor,endothelin receptors,adenosinereceptors,adenosine kinase and AMP deaminase,purinergic receptors(P2Y1,P2Y2,P2Y4,P2Y6,P2X1-7),farnesyl transferases,geranylgeranyl transferase,TrkA areceptor for NGF,beta-amyloid,tyrosine kinase Flk-IIKDR,vitronectin receptor,integrin receptor,Her-2 / neu,telomerase inhibition,cytosolic phospholipaseA2and EGF receptor tyrosine kinase,ecdysone 20-monooxygenase,GABA门控氯离子通道的离子通道、乙酰胆碱酯酶、电压敏感钠通道蛋白、钙释放通道、氯离子通道、乙酰辅酶A羧化酶、腺苷琥珀酸合成酶、原卟啉原氧化酶、L-1受体相关激酶-3、烯醇丙酮酸莽草酸磷酸合酶、新底物、信号转导和转录激活因子3(STAT3)、信号转导和转录激活因子5(STAT5)、信号转导和转录激活因子6(STAT6)、SWI / SNF相关、基质相关、肌动蛋白依赖的染色质调节因子A2(SMARCA2)、SWI / SNF相关、基质相关、肌动蛋白依赖的染色质调节因子A4(SMARCA4)、溴结构域蛋白2(BRD2)、CREB结合蛋白 / p300、多溴联苯1(PBRM1)、MER酪氨酸激酶(MERTK)、丝裂原活化蛋白激酶激活的蛋白激酶2(MK2)、布鲁顿酪氨酸激酶(BTK)、白细胞介素-1受体相关激酶1(IRAK1)、白细胞介素-1受体相关激酶2(IRAK2)、白细胞介素-1受体相关激酶3(IRAK3)、白细胞介素-1受体相关激酶4(IRAK4)、 Kirsten大鼠肉瘤病毒癌基因同源物(KRAS)、KRAS G12C、KRAS G12D、KRAS G12V、Janus激酶1(JAK1)、Janus激酶2(JAK2)、Janus激酶3(JAK3)、酪氨酸激酶2(TYK2)、表皮生长因子受体(EGFR)、人表皮生长因子受体2(HER2)、原癌基因Myc、造血祖细胞激酶1(HPK1)、α-突触核蛋白、微管相关蛋白Tau、突变型亨廷顿蛋白(mHTT)、G1 / S特异性周期蛋白依赖性激酶1(GSPT1)、细胞周期蛋白依赖性激酶1α(Ck1α)、锌指蛋白SALL4、IKAROS家族锌指蛋白1(IKZF1)、IKAROS家族锌指蛋白2(IKZF2)、IKAROS家族锌指蛋白3(IKZF3)、蛋白酪氨酸磷酸酶非受体型11(PTPN11)、ELL相关蛋白(ENL)、痘苗病毒蛋白V1(VV1)、粘着斑激酶(FAK)、KLHDC2蛋白、BET家族受体、蛋白酪氨酸磷酸酶非受体型1(PTPN1)、蛋白酪氨酸磷酸酶非受体型2(PTPN2)、粘膜相关淋巴组织淋巴瘤易位蛋白1(MALT1)、泛素特异性蛋白酶1(USP1)、细胞周期蛋白依赖性激酶2(CDK2)、细胞周期蛋白依赖性激酶4(CDK4)、细胞周期蛋白依赖性激酶5(CDK5)、细胞周期蛋白依赖性激酶6(CDK6)、细胞周期蛋白依赖性激酶7(CDK7)、细胞周期蛋白依赖性激酶8(CDK8)、细胞周期蛋白依赖性激酶9(CDK9)、细胞周期蛋白依赖性激酶12(CDK12)、细胞周期蛋白依赖性激酶19(CDK19)、磷脂酰肌醇-3激酶(PI3K)、聚(ADP-核糖)聚合酶(PARP)、TEA结构域家族成员(TEAD)、细胞外信号调节激酶5(ERK5)、TATA结合蛋白相关因子1(TAF1)、NMPT、谷胱甘肽过氧化物酶4(GPX4)、含Src同源2结构域蛋白酪氨酸磷酸酶2(SHP2)、丝氨酸 / 苏氨酸蛋白激酶1(PLK1)、间变性淋巴瘤激酶(ALK)、泛素特异性蛋白酶7(USP7)、泛素特异性蛋白酶30(USP30)、Ras蛋白、 Kelch样环氧氯丙烷相关蛋白1(Keap1)、七号染色体开放阅读框122(SOS1)、核因子κB(NF-Kb)、孕烷X受体(PXR)、磷脂酰肌醇-4-激酶(PIP4K)、甲基转移酶样3(METTL3)、组蛋白去乙酰化酶(HDAC)、烟酰胺磷酸核糖转移酶(NAMPT)、RAD51重组酶、G蛋白偶联受体78(GPR78)、细胞毒性T淋巴细胞相关蛋白4(CTLA4)、帕金森病相关蛋白31(PACMA31)、共济失调毛细血管扩张症突变蛋白(ATM)、人核糖体蛋白N3(hRPN3)、酪氨酸激酶受体(TRK)、S100钙结合蛋白A4(S100A4)、核糖体蛋白N13(RPN13)、乙肝病毒衣壳蛋白、溶质载体转运蛋白(SLC转运蛋白)、G蛋白偶联受体激酶2(GRK2)、DNA聚合酶、真核延伸因子1A2(eEF1A2)、SMAD家族成员3(SMAD3)、磷脂酰肌醇-4-激酶2(P1P4K2)、蛋白激酶Cβ1(pKCβ1)、受体相互作用丝氨酸 / 苏氨酸蛋白激酶1(RIPK1)、哺乳动物雷帕霉素靶蛋白(mTOR)、NOD样受体蛋白3(NLRP3)、细胞外信号调节激酶1(ERK1)、细胞外信号调节激酶2(ERK2)、混合谱系激酶样蛋白(MLKL)、LZK、干扰素基因刺激蛋白(sting)、腺苷酸活化蛋白激酶(AMPK)、丝氨酸 / 苏氨酸蛋白激酶NEK2、二氢叶酸还原酶(DHFR)、DBB1、增强子结合蛋白EZH2、DOT1样蛋白(DOT1L)、3C样蛋白酶(3CL)、去唾液酸糖蛋白受体(ASGPR)、G蛋白偶联雌激素受体(GPER)、单酰甘油脂肪酶(MAGL)、3-羟基-3-甲基戊二酰辅酶A还原酶(HMGCR)、蛋白质精氨酸甲基转移酶5(PRMT5)、Wee1蛋白激酶、甲硫氨酸氨肽酶2(MetAP-2)、干细胞因子受体(KIT)、AXL受体酪氨酸激酶、GS3α,β,FoxM1,Hsp90,HADC3,TNF,CDC20;,

[0043] In some implementation schemes, B is selected from

[0044] In some implementation schemes, B is selected from

[0045] In some implementation schemes, B is selected from

[0046] In some implementation schemes, R w Each is independently selected from methyl or CD3;

[0047] In some implementations, W is selected from O or S;

[0048] In some implementations, L A or L B Selected from key or NR 1 ;

[0049] In some implementations, L A or L B Selected from bond or NH;

[0050] In some implementations, ring A is selected from 4-12 membered heterocyclic groups or C 3-12 A carbocyclic group, wherein ring A is optionally divided by 1 to 4 R groups. a replace;

[0051] In some implementations, ring A is selected from 5-12 membered heterocyclic groups or C 6-12 A carbocyclic group, wherein ring A is optionally divided by 1 to 4 R groups. a replace;

[0052] In some embodiments, ring A is selected from phenyl, 5-6-membered heteroaryl, benzo[a]C 4-6 Carbocyclic, benzo5-6 membered heterocyclic, pyridoC 4-6 Carbocyclic, pyrido5-6 membered heterocyclic, pyrimidoC 4-6 Carbocyclic group, pyrimidine 5-6 membered heterocyclic group, pyrrolocyclic C 4-6 Carbocyclic, pyrrolo 5-6 membered heterocyclic, thiophene C 4-6 Carbocyclic, thiophene 5-6 membered heterocyclic group, wherein ring A is optionally surrounded by 1 to 4 R groups. a replace;

[0053] In some embodiments, ring A is selected from phenyl, naphthyl, benzocyclobutenyl, benzocyclopentenyl, benzocyclohexenyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazinyl, benzopyrrolyl, benzopyrazolyl, benzoimidazolyl, benzothiophenyl, benzothiazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, pyridopyrrolyl, pyridopyrazolyl, pyridoimidazolyl, pyridothiophenyl, pyridothiazolyl, pyridopyridyl, pyridopyrimidinyl, pyridopyrazinyl, and the ring A is optionally surrounded by 1 to 4 R a replace;

[0054] In some embodiments, ring A is selected from phenyl, pyridyl, thiophene, benzothiophene, benzocyclopentenyl, and naphthyl, and ring A is optionally surrounded by 1 to 4 R groups. a replace;

[0055] In some implementation schemes, Y1 and Y2 are each independently selected from -CR y1 R y2 -、-(CR y1 R y2 )2-、-(CR y1 R y2 )3-;

[0056] In some implementation schemes, Y1 and Y2 are each independently selected from -CR y1 R y2 -、-(CR y1 R y2 )2-;

[0057] In some implementation schemes, Y1 and Y2 are each independently selected from -CH2-, -CH2CH2-, and -C(CH3)2-;

[0058] In some implementations, X1 is selected from N or CR x1 X2 is selected from N or CR x2 X3 is selected from N or CR x3 X4 is selected from N or CR x4 X5 is selected from N or CR x5 At most two of X1, X2, X3, X4, and X5 are selected from N; in some implementations, X3 is selected from CR. x3 In some implementations, one of X1, X2, X3, X4, and X5 is selected from N; in some implementations, X1 is selected from CR. x1 X2 is selected from CR x2 X3 is selected from CR x3 X4 is selected from CR x4 X5 is selected from CR x5 ;

[0059] In some implementation schemes, R x1 R x2 R x3 R x4 R x5 R a Each is independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 carbonyl group, -C 0-4 alkylene-4 to 6-membered heterocyclic groups, 5 to 6-membered heteroaryl groups, -OC 3-6 Carbocyclic, -O-4 to 6-membered heterocyclic groups, wherein the alkylene, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, or heteroaryl groups are optionally surrounded by 1 to 4 R groups. s Replaced;

[0060] In some implementation schemes, R x1 R x2 R x3 R x4 R x5 R a Each is independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 alkylene-4 to 6-membered heterocyclic groups, 5 to 6-membered heteroaryl groups, -OC 3-6 Cycloalkyl, -O-4 to 6-membered heterocyclic groups, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, or heteroaryl groups are optionally surrounded by 1 to 4 R groups. s Replaced;

[0061] In some implementation schemes, R x1 R x2 R x3 R x4 R x5R a Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3, or arbitrarily selected by 1 to 4 R. s The substituted group is one of the following: methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, pyrazolyl;

[0062] In some implementation schemes, R x1 R x2 R x3 R x4 Each is independently selected from -S(=O)2NH2 and -S(=O)2C 1-4 alkyl;

[0063] In some implementation schemes, R x1 R x2 R x3 R x4 Each is independently selected from -S(=O)2NH2, -S(=O)2methyl, and -S(=O)2ethyl;

[0064] In some implementation schemes, R x2 R x3 R x4 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3, CF3, CHF2, CH2F, OCF3, OCH2F, OCD3, CH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, -CH2-cyclopropyl, -O-cyclopropyl;

[0065] In some implementation schemes, R x3 R x4 or R a Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3, CF3, CHF2, CH2F, OCF3, OCH2F, OCD3, CH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, -CH2-cyclopropyl, -O-cyclopropyl;

[0066] In some implementation schemes, R x2 R x4Each is independently selected from -S(=O)2CH3, -O-CH2-propynyl, -O-CH2-cyclopropyl, -O-CH2CH2-OCH3, -O-CH2CH2-O-cyclopropyl,

[0067] In some implementation schemes, R 2 R 3 R y1 R y2 Each is independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl groups, wherein the alkyl, alkenyl, or alkynyl groups are optionally composed of 1 to 4 groups selected from deuterium, halogen, OH, NH2, CN, C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0068] In some implementation schemes, R 2 R 3 R y1 R y2 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, and methylthio, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, and methylthio groups are selected from 1 to 4 of the following groups: deuterium, F, Cl, Br, I, OH, NH2, CN, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0069] In some implementation schemes, R 2 R 3 Each is independently selected from H, deuterium, F, Cl, and Br;

[0070] In some implementation schemes, R y1 R y2 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, and methylthio, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, and methylthio groups are substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, methyl, ethyl, and methoxy.

[0071] In some implementation schemes, R 1 Selected from H, deuterium, and C1-4 Alkyl or C 3-6 Cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally composed of 1 to 4 elements selected from deuterium, halogen, OH, NH2, CN, C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0072] In some implementation schemes, R 1 The group is selected from H, deuterium, methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl groups are optionally replaced by 1 to 4 groups selected from deuterium, F, Cl, Br, I, OH, NH2, CN, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0073] In some implementation schemes, R 1 Selected from H, deuterium, CF3, CHF2, CH2F, CH2OH, methyl, ethyl, isopropyl, and cyclopropyl;

[0074] In some implementation schemes, R x1 With R x2 R x2 With R x3 R x3 With R x4 R x4 With R x5 R 1 With R a Two Rs a Direct connection forms C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0075] In some implementation schemes, R x1 With R x2 R x2 With R x3 R x3 With R x4 R x4 With R x5 R 1 With R a Two Rs a Direct connection forms C 4-6 A carbocyclic group, a 5-6 membered heteroaryl group, or a 5-7 membered heterocyclic group, wherein the carbocyclic group, heteroaryl group, or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0076] In some implementation schemes, R x1 With R x2 R x2 With Rx3 R x3 With R x4 R x4 With R x5 Direct connection forms an optional 1 to 3 R s The substituted group is one of the following: piperidinyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl; in some embodiments, R x1 With R x2 R x2 With R x3 R x3 With R x4 R x4 With R x5 Direct connection forms an optional 1 to 3 R s The substituted group is one of the following: pyrrolidinyl, oxetyl, oxetylhexyl, 1,3-dioxolane;

[0077] In some implementations, B is selected from the structural segments shown in Table B-1;

[0078] Table B-1

[0079]

[0080] In some implementation schemes, K is selected from This indicates whether the ring in question is aromatic or non-aromatic.

[0081] In some implementation schemes, K is selected from

[0082] In some implementation schemes, K is selected from

[0083] In some implementations, F1 is selected from N, NH, CH, CH2, CHR. k1 NR k1 CR k1 C(=O), C(R) k1 )2;

[0084] In some implementations, F2 is selected from bonds, O, N, NH, CH, CH2, CHR. k1 NR k1 CR k1 or C(R) k1 )2;

[0085] In some implementation schemes, When the ring containing the symbol is a non-aromatic ring, F1 is selected from NH, CH2, and CHR. k1 NRk1 C(=O), C(R) k1 )2, F2 is selected from bond, O, NH, CH2, CHR k1 NR k1 or C(R) k1 )2;

[0086] In some implementation schemes, The ring in question is an aromatic ring, and F1 is selected from N, CH, and CR. k1 F2 is selected from bonds O, N, CH, and CR. k1 ;

[0087] In some implementations, F6, F7, and F8 are each independently selected from N, C, CH, or CR. k1 Furthermore, F6, F7, and F8 contain at most two N atoms; in some implementations, one of F6, F7, and F8 is selected from N, and the other two are selected from CH or CR. k1 ;

[0088] In some implementations, G is selected from CH or N;

[0089] In some implementations, E1 is selected from N or CH, with N being preferred;

[0090] In some implementations, E2 is selected from C, N, or CH, with N being preferred;

[0091] In some implementations, Q1 is independently selected from -C(=O)- and -NR. q C(=S)-、-C(=S)NR q -、-NR q CR s 2-、-CR s 2NR q -、

[0092] In some implementations, Q1 is independently selected from C(=O), NHC(=S), C(=S)NH, -NHCF2-, -CF2NH-, -NHCH(CF3)-, -CH(CF3)NH-,

[0093] In some implementations, Q2 is independently selected from -C(=O)- and -NR-. q C(=S)-、-C(=S)NR q -、-NR q C(=O)-、-C(=O)NR q -、-S(=O)NR q -、-NR q S(=O)-、-S(=O)2NRq -、-NR q S(=O)2-, -C(=O)CH2-, -C(=O)CD2-, -C(=O)CF2-, -NR q C(=S)NR q -、-NR q C(=O)NR q -、 -NR q CR s 2-、-CR s 2NR q -;

[0094] In some implementations, Q2 is independently selected from -C(=O)-, -NHC(=S)-, -C(=S)NH-, -NHC(=O)-, -C(=O)NH-, -S(=O)NH-, -NHS(=O)-, -S(=O)2NH-, -NHS(=O)2-, -C(=O)CH2-, -C(=O)CD2-, -C(=O)CF2-, -NHC(=S)NH-, -NHC(=O)NH-, -NHCF2-, -CF2NH-, -NHCH(CF3)-, -CH(CF3)NH-;

[0095] In some implementations, Q2 is independently selected from -C(=O)-, -NHC(=S)-, -C(=S)NH-, -NHC(=O)-, -S(=O)NH-, -NHS(=O)-, -S(=O)2NH-, -NHS(=O)2-, -C(=O)CH2-, -C(=O)CD2-, -C(=O)CF2-, -NHC(=S)NH-, -NHC(=O)NH-, -NHCF2-, -CF2NH-, -NHCH(CF3)-, -CH(CF3)NH-;

[0096] In some implementations, Q1 or Q2 cannot directly form nitrogen-nitrogen bonds or nitrogen-oxygen bonds with G;

[0097] In some implementation schemes, R q Each is independently selected from H or C 1-4 alkyl;

[0098] In some implementation schemes, R q Each is independently selected from H, methyl, ethyl, or isopropyl;

[0099] In some implementation schemes, R q Selected from H or methyl;

[0100] In some implementation schemes, Rk1 Each is independently selected from deuterium, halogen, OH, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl is optionally surrounded by 1 to 4 R... s Replaced;

[0101] In some implementation schemes, R k1 Each is independently selected from deuterium, halogen, OH, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl group is optionally selected from 1 to 4 elements selected from deuterium, halogen, OH, CF3, CN, NH2, C 1-4 Substituents of alkyl groups;

[0102] In some implementation schemes, R k1 Each of the following groups is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl groups are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, and NH2;

[0103] In some implementation schemes, R k1 Each is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, CF3, CHF2, CH2F, OCF3, OCH2F, OCHF2, OCD3, CH2OH, CD3, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl;

[0104] In some implementation schemes, R L2 R s Each is independently selected from deuterium, halogens, OH, CN, ⁻, CF₃, SF₅, NO₂, NH₂, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl group 2, COOH, CONH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 Alkylene-4 to 6-membered heterocyclic group, wherein the alkylene, alkylene, alkoxy, alkenyl, alkynyl, or cycloalkyl group is optionally selected from one to four of deuterium, F, Cl, Br, I, OH, CN, C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0105] In some implementation schemes, R L2 R s Each is independently selected from deuterium, halogens, OH, CN, ⁻, CF₃, SF₅, NO₂, NH₂, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl group 2, COOH, CONH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkylene-4 to 6-membered heterocyclic group, wherein the alkylene, alkylene, alkoxy, alkenyl, alkynyl, or cycloalkyl group is optionally selected from one to four of deuterium, F, Cl, Br, I, OH, CN, C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0106] In some implementation schemes, R L2 R s Each of the following is independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0107] In some implementation schemes, R L2 R sEach is independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, CHF2, CH2F, OCF3, OCH2F, OCHF2, CH2OH, OCH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, hydroxymethyl;

[0108] In some implementation schemes, R L2 Selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, and cyclopropyl;

[0109] In some implementation schemes, R s Each independently selected from -OC 3-6 cycloalkyl;

[0110] In some implementation schemes, R s Each is independently selected from propynyl and -O-cyclopropyl;

[0111] In some implementations, p1 is independently selected from 0, 1, or 2;

[0112] In some implementations, p1 is independently selected from 0 and 1;

[0113] In some implementations, K is selected from the structural segments shown in Table K-1;

[0114] Table K-1

[0115]

[0116]

[0117] Optionally, when Q2 is selected from -C(=O)NH,

[0118] 1) At least one of Cy1, Cy2, Cy3, or Cy4 is selected from 1 to 4 R values. L2 The following groups are substituted: 8-12 membered heterocyclic cyclogroups, 8-13 membered heterospirocyclic cyclogroups, 8-12 membered heterobridged cyclogroups, C 8-12 cycloalkyl, C 8-13 Spirocycloalkyl, C 8-12 Bridged cycloalkyl;

[0119] or 2)L A Selected from key;

[0120] Or 3)L B Selected from NH;

[0121] Or 4) W is selected from S.

[0122] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein...

[0123] L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0124] Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -(CH2). q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-、-S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q - or bond, wherein the -CH2- is optionally selected from one or two elements selected from deuterium, halogen, =O, OH, CN, C 1-4 Alkyl or C 3-6 Substituents of cycloalkyl groups;

[0125] q is selected from 0, 1, 2, or 3;

[0126] R L Each independently selected from H or C 1-4 alkyl;

[0127] Cy1, Cy2, Cy3, or Cy4 are each independently selected from the key or arbitrarily selected by 1 to 4 Rs. L2 The substituted group is one of the following: 4-7 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged cyclic group, C 3-7 Monocycloalkyl, C 4-7 Monocyclic alkenyl, C 4-12 cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl;

[0128] B is selected from ligands that bind to the target;

[0129] K is selected from

[0130] This indicates whether the ring in question is aromatic or non-aromatic.

[0131] F1 is selected from N, NH, CH, CH2, CHR k1 NR k1 CR k1 C(=O), C(R) k1 )2;

[0132] F2 is selected from bonds, O, N, NH, CH, CH2, CHR. k1 NR k1 CR k1 or C(R) k1 )2;

[0133] F6, F7, and F8 are each independently selected from N, C, CH, or CR. k1 Furthermore, F6, F7, and F8 contain at most two N's;

[0134] G is selected from CH or N;

[0135] E1 is selected from N or CH;

[0136] E2 is selected from C, N, or CH;

[0137] Q1 is independently selected from -C(=O)- and -NR. q C(=S)-、-C(=S)NR q -、-NR q CR s 2-、-CR s 2NR q -、

[0138] Q2 is independently selected from -C(=O)- and -NR. q C(=S)-、-C(=S)NR q -、-NR q C(=O)-、-C(=O)NR q -、-S(=O)NR q -、-NR q S(=O)-、-S(=O)2NR q -、-NR q S(=O)2-, -C(=O)CH2-, -C(=O)CD2-, -C(=O)CF2-, -NR q C(=S)NR q-、-NR q C(=O)NR q -、 -NR q CR s 2-、-CR s 2NR q -;

[0139] Q1 or Q2 cannot directly form nitrogen-nitrogen bonds or nitrogen-oxygen bonds with G;

[0140] R q Each is independently selected from H or C 1-4 alkyl;

[0141] R k1 Each is independently selected from deuterium, halogen, OH, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl is optionally surrounded by 1 to 4 R... s Replaced;

[0142] R L2 R s Each is independently selected from deuterium, halogens, OH, CN, ⁻, CF₃, SF₅, NO₂, NH₂, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl group 2, COOH, CONH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 Alkylene-4 to 6-membered heterocyclic group, wherein the alkylene, alkylene, alkoxy, alkenyl, alkynyl, or cycloalkyl group is optionally selected from one to four of deuterium, F, Cl, Br, I, OH, CN, C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0143] p1 is selected independently from 0, 1, or 2;

[0144] Or R s Each independently selected from -OC 3-6 Cycloalkyl.

[0145] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein...

[0146] B is selected from

[0147] L A or L B Selected from key or NR 1 ;

[0148] W is selected from O or S;

[0149] Ring A is selected from 4-12 membered heterocyclic groups or C 3-12 A carbocyclic group, wherein ring A is optionally divided by 1 to 4 R groups. a replace;

[0150] X1 is selected from N or CR x1 X2 is selected from N or CR x2 X3 is selected from N or CR x3 X4 is selected from N or CR x4 X5 is selected from N or CR x5 ;

[0151] At most two of X1, X2, X3, X4, and X5 are selected from N;

[0152] Y1 and Y2 are each independently selected from -CR y1 R y2 -、-(CR y1 R y2 )2-、-(CR y1 R y2 )3-;

[0153] R 1 Selected from H, deuterium, and C 1-4 Alkyl or C 3-6 Cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally composed of 1 to 4 elements selected from deuterium, halogen, OH, NH2, CN, C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0154] R x1 R x2 R x3 R x4 R x5 R a Each is independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 carbonyl group, -C 0-4 alkylene-4 to 6-membered heterocyclic groups, 5 to 6-membered heteroaryl groups, -OC 3-6 Carbocyclic, -O-4 to 6-membered heterocyclic groups, wherein the alkylene, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, or heteroaryl groups are optionally surrounded by 1 to 4 R groups. s Replaced;

[0155] Or R x1 R x2 R x3 R x4 Each is independently selected from -S(=O)2NH2 and -S(=O)2C 1-4 alkyl;

[0156] Or, R x1 With R x2 R x2 With R x3 R x3 With R x4 R x4 With R x5 R 1 With R a Two Rs a Direct connection forms C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0157] R 2 R 3 R y1 R y2 Each is independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl groups, wherein the alkyl, alkenyl, or alkynyl groups are optionally composed of 1 to 4 groups selected from deuterium, halogen, OH, NH2, CN, C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0158] The condition is that Q2 is selected from -C(=O)NH.

[0159] 1) At least one of Cy1, Cy2, Cy3, or Cy4 is selected from 1 to 4 R values.L2 The following groups are substituted: 8-12 membered heterocyclic cyclogroups, 8-13 membered heterospirocyclic cyclogroups, 8-12 membered heterobridged cyclogroups, C 8-12 cycloalkyl, C 8-13 Spirocycloalkyl, C 8-12 Bridged cycloalkyl;

[0160] or 2)L A Selected from key;

[0161] Or 3)L B Selected from NH;

[0162] Or 4) W is selected from S;

[0163] The remaining definitions are the same as those in the first embodiment of the present invention.

[0164] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein...

[0165] Ring A is selected from 5-12 membered heterocyclic groups or C 6-12 A carbocyclic group, wherein ring A is optionally divided by 1 to 4 R groups. a replace;

[0166] R x1 R x2 R x3 R x4 R x5 R a Each is independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 alkylene-4 to 6-membered heterocyclic groups, 5 to 6-membered heteroaryl groups, -OC 3-6 Cycloalkyl, -O-4 to 6-membered heterocyclic groups, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, or heteroaryl groups are optionally surrounded by 1 to 4 R groups. s Replaced;

[0167] Or R x1 R x2 R x3 R x4 Each is independently selected from -S(=O)2NH2 and -S(=O)2C1-4 alkyl;

[0168] Or, R x1 With R x2 R x2 With R x3 R x3 With R x4 R x4 With R x5 R 1 With R a Two Rs a Direct connection forms C 4-6 A carbocyclic group, a 5-6 membered heteroaryl group, or a 5-7 membered heterocyclic group, wherein the carbocyclic group, heteroaryl group, or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced;

[0169] R L Selected from H, methyl, or ethyl;

[0170] R q Each is independently selected from H, methyl, ethyl, or isopropyl;

[0171] Cy1, Cy2, Cy3, and Cy4 are each independently selected from key or arbitrarily assigned to one to four R values. L2 The substituted group is one of the following: phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl.

[0172]

[0173] s1, s3, and s5 are each independently selected from 0, 1, or 2;

[0174] s2 and s4 are each independently selected from 0 or 1;

[0175] s6 is selected from 0, 1, 2, or 3;

[0176] s7 is selected from 1, 2, or 3;

[0177] R L2 R s Each is independently selected from deuterium, halogens, OH, CN, ⁻, CF₃, SF₅, NO₂, NH₂, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl group 2, COOH, CONH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-2 Alkylene-C3-6 cycloalkyl, -C 0-2 Alkylene-4 to 6-membered heterocyclic group, wherein the alkylene, alkylene, alkoxy, alkenyl, alkynyl, or cycloalkyl group is optionally selected from one to four of deuterium, F, Cl, Br, I, OH, CN, C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0178] Or R s Each independently selected from -OC 3-6 cycloalkyl;

[0179] The remaining definitions are the same as those in the first or second embodiment of the present invention.

[0180] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein...

[0181] Ring A is selected from phenyl, 5-6 membered heteroaryl, benzo[C] 4-6 Carbocyclic, benzo5-6 membered heterocyclic, pyridoC 4-6 Carbocyclic, pyrido5-6 membered heterocyclic, pyrimidoC 4-6 Carbocyclic group, pyrimidine 5-6 membered heterocyclic group, pyrrolocyclic C 4-6 Carbocyclic, pyrrolo 5-6 membered heterocyclic, thiophene C 4-6 Carbocyclic, thiophene 5-6 membered heterocyclic group, wherein ring A is optionally surrounded by 1 to 4 R groups. a replace;

[0182] X3 is selected from CR x3 ;

[0183] Y1 and Y2 are each independently selected from -CR y1 R y2 -、-(CR y1 R y2 )2-;

[0184] R 1 The group is selected from H, deuterium, methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl groups are optionally replaced by 1 to 4 groups selected from deuterium, F, Cl, Br, I, OH, NH2, CN, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0185] R x1 R x2 R x3 R x4 R x5 R aEach is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3, or arbitrarily selected by 1 to 4 R. s The substituted group is one of the following: methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, pyrazolyl;

[0186] Or R x1 R x2 R x3 R x4 Each is independently selected from -S(=O)2NH2, -S(=O)2methyl, and -S(=O)2ethyl;

[0187] Or, R x1 With R x2 R x2 With R x3 R x3 With R x4 R x4 With R x5 Direct connection forms an optional 1 to 3 R s The substituted group is one of the following: piperidinyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl.

[0188] Or, R x1 With R x2 R x2 With R x3 R x3 With R x4 R x4 With R x5 Direct connection forms an optional 1 to 3 R s The substituted group is one of the following: pyrrolidinyl, oxetyl, oxetylhexyl, 1,3-dioxolane;

[0189] R 2 R 3 R y1 R y2 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, and methylthio, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, and methylthio groups are selected from 1 to 4 of the following groups: deuterium, F, Cl, Br, I, OH, NH2, CN, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0190] Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from the following: -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -CH(CH3)-, -CH2-, -C(CH3)2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH-, or -NHC(=O)-;

[0191] K is selected from

[0192] Q1 is independently selected from C(=O), NHC(=S), C(=S)NH, -NHCF2-, -CF2NH-, -NHCH(CF3)-, -CH(CF3)NH-,

[0193] Q2 is independently selected from -C(=O)-, -NHC(=S)-, -C(=S)NH-, -NHC(=O)-, -C(=O)NH-, -S(=O)NH-, -NHS(=O)-, -S(=O)2NH-, -NHS(=O)2-, -C(=O)CH2-, -C(=O)CD2-, -C(=O)CF2-, -NHC(=S)NH-, -NHC(=O)NH-,

[0194] -NHCF2-, -CF2NH-, -NHCH(CF3)-, -CH(CF3)NH-;

[0195] R k1 Each of the following groups is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl groups are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, and NH2;

[0196] R L2 R sEach of the following is independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0197] Or R s Each is independently selected from propynyl and -O-cyclopropyl;

[0198] The remaining definitions are the same as those in the first, second, or third embodiments of the present invention.

[0199] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein...

[0200] Ring A is selected from phenyl, naphthyl, benzocyclobutenyl, benzocyclopentenyl, benzocyclohexenyl, pyrrolyl, pyrazolyl, imidazoleyl, furanyl, thiophenyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazinyl, benzopyrrolyl, benzopyrazolyl, benzoimidazolyl, benzothiophenyl, benzothiazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, pyridopyrrolyl, pyridopyrazolyl, pyridoimidazolyl, pyridothiophenyl, pyridothiazolyl, pyridopyridyl, pyridopyrimidinyl, pyridopyrazinyl, wherein ring A is optionally surrounded by 1 to 4 R a replace;

[0201] R y1 R y2 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, and methylthio, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, and methylthio groups are substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, methyl, ethyl, and methoxy.

[0202] Cy1, Cy2, Cy3, and Cy4 are each independently selected from one of the following groups, either bonded or optionally substituted:

[0203]

[0204] When substituted, it is replaced by 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, and cyclopropyl.

[0205] K is selected from

[0206] R k1 Each is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, CF3, CHF2, CH2F, OCF3, OCH2F, OCHF2, OCD3, CH2OH, CD3, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl;

[0207] The remaining definitions are the same as those in the first, second, third, or fourth embodiments of this invention.

[0208] As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein...

[0209] B is selected from

[0210] L A or L B Selected from bond or NH;

[0211] W is selected from O or S;

[0212] Ring A is selected from phenyl, pyridyl, thienyl, benzothienyl, benzocyclopentenyl, and naphthyl, wherein ring A is optionally surrounded by 1 to 4 R groups. a replace;

[0213] R x3 R x4 or R a Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3, CF3, CHF2, CH2F, OCF3, OCH2F, OCD3, CH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, -CH2-cyclopropyl, -O-cyclopropyl;

[0214] L is selected from -Cy1-, -Cy1-Ak2-, -Cy1-CH2-, -Ak1-Cy1-, -Cy1-Cy2-, -Cy1-CH2-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH2-Cy2-Cy3-, -Cy1-Cy2-CH2-Cy3-;

[0215] Cy1, Cy2, and Cy3 are each independently selected from one of the following groups that can be substituted: When substituted, it is replaced by 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, and cyclopropyl.

[0216] The remaining definitions are the same as those in the first, second, third, fourth, or fifth embodiments of this invention.

[0217] As a seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein...

[0218] B is selected from the structural segments shown in Table B-1;

[0219] L is selected from the structural segments shown in Table L-1;

[0220] K is selected from the structural segment shown in K-1.

[0221] As an eighth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein the compound represented by general formula (I) is selected from the compounds represented by general formulas (Ia), (Ib), and (Ic).

[0222]

[0223] Cy1 and Cy2 are each independently selected from one of the following groups that can be substituted:

[0224] When substituted, it is replaced by 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, and cyclopropyl.

[0225] R k1Each is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, CF3, CHF2, CH2F, OCF3, OCH2F, OCHF2, OCD3, CH2OH, CD3, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl;

[0226] R w Each is independently selected from methyl or CD3;

[0227] p1 is selected from 0, 1, or 2.

[0228] This invention relates to a compound or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts thereof, wherein the compound is selected from the structures shown in Table E, and preferably, the compound is selected from the structures shown in Table E-1.

[0229] This invention relates to a pharmaceutical composition comprising the above-described compound or its stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, and pharmaceutically acceptable carriers.

[0230] This invention relates to the use of the above-described compound or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts in the preparation of medicaments for treating diseases related to AR activity or expression levels.

[0231] This invention relates to the use of the above-described compound or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts in the preparation of medicaments for treating and inhibiting or degrading AR-related diseases, wherein the inhibition or degradation of AR-related diseases is cancer, preferably prostate cancer.

[0232] This invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of the compound of the invention or its stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, and pharmaceutical excipients. The pharmaceutical composition may be in unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as a "dosage strength").

[0233] The present invention also provides a method for treating diseases in mammals, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, or pharmaceutical compositions. In some embodiments, the mammals described in the present invention include humans.

[0234] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition (e.g., cancer) being treated. In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3... -500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg , 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400 mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300- 400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 9 0-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40 -200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1500mg, 80-1000mg, 80-800mg;.

[0235] In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500 mg, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 1 The compounds of the present invention, or their stereoisomers, tautomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, in doses of 25 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg, or 1000 mg.

[0236] A method for treating a disease in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, preferably 1-1500 mg, wherein the disease is preferably cancer, and more particularly prostate cancer.

[0237] A method for treating a disease in mammals, the method comprising administering a drug, a compound of the present invention or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts thereof, to a subject at a daily dose of 1-1500 mg / day, said daily dose being a single dose or multiple doses. In some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, and 25-400 mg / day. The daily dose may be 50-400 mg / day, 100-400 mg / day, or 200-400 mg / day. In some embodiments, the daily dose may include, but is not limited to, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day, or 1500 mg / day.

[0238] This invention relates to a kit that may include a single-dose or multi-dose composition comprising a compound of the present invention or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts thereof, wherein the amount of the compound of the present invention or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts is the same as the amount in the aforementioned pharmaceutical composition.

[0239] In this invention, the amount of the compound of the invention or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts is converted in each case as a free base.

[0240] The compounds of the present invention also include their deuterated derivatives, solvates, prodrugs, metabolites, and cocrystals.

[0241] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0242] The carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention include their isotopic forms. That is, the carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention may be optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 11 C 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 15 O、 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S, 35 S and 36 S, nitrogen isotopes include 13 N、 14 N and 15 N, isotopes of fluorine include 17 F, 18 F and 19 F, isotopes of chlorine include 35 Cl、 36 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br, an isotope of iodine, includes 123 I, 125 I, phosphorus isotopes include 31 P, 32 P.

[0243] “CN” refers to cyano.

[0244] "Halogen" refers to F, Cl, Br or I.

[0245] "Halogen-substituted" refers to substitution with F, Cl, Br, or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br, or I, 1 to 6 substituents selected from F, Cl, Br, or I, and 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen-substituted" is abbreviated as "halogenated".

[0246] "alkyl" refers to a substituted or unsubstituted straight-chain or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups with 1 to 20 carbon atoms, alkyl groups with 1 to 8 carbon atoms, alkyl groups with 1 to 6 carbon atoms, and alkyl groups with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched isomers; the alkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0247] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2). v - (v is an integer from 1 to 10), alkylene examples include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0248] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirobutyl, adamantane, etc. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0249] "Heterocyclic alkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms or 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, S, or Se. The C, N, and S atoms on the ring of the heterocyclic alkyl group can be oxidized to various oxidation states. Heterocyclic alkyl groups can be monocyclic, fused, bridged, or spirocyclic. Heterocyclic alkyl groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxopentyl, dioxohexyl, pyrrolylalkyl, piperidinyl, imidazoalkyl, oxazolidinyl, oxazinylalkyl, morpholinyl, hexahydropyrimidinyl, piperazineyl, etc. Heterocyclic alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0250] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon double bonds. The main chain has, but is not limited to, 2 to 10, 2 to 6, or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2... -Methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent, or tetravalent.

[0251] "Alynyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon triple bonds. The main chain comprises 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms on the main chain, or 2 to 4 carbon atoms on the main chain. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, and 4-pentynyl. The alkynyl group can be monovalent, divalent, trivalent, or tetravalent.

[0252] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

[0253] "Carbocyclic group" or "carbocyclic ring" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system. The carbocyclic group can be attached to an aromatic or non-aromatic ring, and the ring can be optionally a monocyclic, fused, bridged, or spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, etc. "Carbocyclic group" or "carbon ring" can be monovalent, divalent, trivalent or tetravalent.

[0254] "Heterocyclic group" or "heterocyclic" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se selectively substituted in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused, or spirocyclic ring. Non-limiting examples include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexane, aziridineheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithioyl, dihydrofuranyl, dihydropyranyl, dithiapentylcycloyl. Tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophene, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl, "Heterocyclic group" or "heterocyclic" can be monovalent, divalent, trivalent or tetravalent.

[0255] A "spirocyclic" or "spirocyclic group" refers to a polycyclic group in which substituted or unsubstituted rings share a single atom (called a spiro atom). The number of ring atoms in a spirocyclic system includes, but is not limited to, 5 to 20, 6 to 14, 6 to 12, or 6 to 10. One or more rings may contain zero or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally, may contain 0 to 5 double bonds selected from N, O, or S (=O). n Heteroatoms (n is 0, 1, or 2). Non-limiting embodiments include:

[0256]

[0257] "Spirocyclic" or "spirocyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0258] "Circular fused" or "circular fused group" refers to a polycyclic group in which each ring in a system shares a pair of adjacent atoms with other rings in the system. One or more rings may contain zero or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted. Each ring in a circular fused system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to those selected from N, S (=O)). n Or O, where n is 0, 1, or 2). The number of ring atoms in a cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:

[0259] "Cyclone" or "cyclone base" can be monovalent, divalent, trivalent, or tetravalent.

[0260] A “bridged ring” or “bridged ring group” refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in a bridged ring system may contain 0 to 5 groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S(=O)n, or O, where n is 0, 1, or 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include:

[0261]

[0262] Cubicane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0263] "Carbon spirocyclic", "spirocyclic carbon cyclic", "spirocarbon cyclic", or "carbon spirocyclic" refers to a spirocyclic system composed only of carbon atoms.

[0264] "Carbon fused ring", "fused cyclic carbon cyclic group", "fused carbon cyclic group" or "carbon fused cyclic group" refers to a ring system composed only of carbon atoms.

[0265] "Carbon bridged ring", "bridged ring carbon cyclo group", "bridged carbon cyclo group" or "carbon bridged ring group" refers to a ring system composed only of carbon atoms.

[0266] "Hybrid monocyclic", "monocyclic heterocyclic group" or "hybrid monocyclic group" refers to the "heterocyclic group" or "heterocyclic" in a monocyclic system.

[0267] "Hydrocyclic ring", "hydrocyclic cyclic group", "fused cyclic heterocyclic group" or "fused heterocyclic group" refers to a "fused ring" containing heteroatoms.

[0268] "Heterospirocyclic", "heterospirocyclic group", "spirocyclic heterocyclic group" or "spiroheterocyclic group" refers to a "spirocycle" containing heteroatoms.

[0269] "Hybrid-bridged ring", "hybrid-bridged ring group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing heteroatoms.

[0270] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring. Non-limiting embodiments include benzene rings, naphthalene rings, etc. The "aryl" or "aryl ring" can be monovalent, divalent, trivalent, or tetravalent. When it is divalent, trivalent, or tetravalent, the linking site is located on the aryl ring.

[0271] "Heteroaryl" or "heteroary ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or a group containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, where n is 0, 1, or 2). The number of ring atoms in the heteroaryl ring includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. The atoms C, N, and S on the ring may be optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1 or 2). Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furanyl, thiophenyl, selenyl, pyridyl, pyranyl, N-alkylpyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazoleyl, benzopyrazolyl, benzimidazoleyl, benzopyridyl, pyrrolopyridyl, pyridinoneyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbon ring or heterocycle, wherein the ring connected to the parent structure is an aryl ring. Non-limiting embodiments include: The heteroaryl groups mentioned in this article are defined in accordance with this definition. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the linkage site is located on an aromatic ring.

[0272] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4, or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged cyclic, spirocyclic, fused cyclic, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, and -(CH2). m -C(=O)-R a *O-(CH2) m *C(=O)*R a 、*(CH2) m *C(=O)*NR b R c 、*(CH2) m S(=O) n R a -(CH2) m *Alkenyl*R a OR d Or -(CH2) m -alkynyl-R a (where m and n are 0, 1, or 2), arylthio, thiocarbonyl, silyl, or -NR b R c Groups, wherein R b With R c Independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, R b With R c It can form five- or six-membered cycloalkyl or heterocyclic groups, R a With R d Each group is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic, carbonyl, ester, bridged cyclic, spirocyclic, or fused cyclic groups.

[0273] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is any integer between 1 and 10. For example, "1 to 4 R..." k "Replace" refers to being replaced by 1, 2, 3, or 4 Rs. k Substitution. For example, "1 to 5 substituents selected from ..." means that the ring is substituted by 1, 2, 3, 4 or 5 substituents selected from .... For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0274] XY-membered rings (where X and Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, selected from any integer between 4 and 20) include rings of the X, X+1, X+2, X+3, X+4…Y-membered types. These rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterofused rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7-membered heteromonocyclic rings" refers to heteromonocyclic rings of 4, 5, 6, or 7 members, and "5-10-membered heterofused rings" refers to heterofused rings of 5, 6, 7, 8, 9, or 10 members.

[0275] C x-y Carbocyclic rings (including aryl, cycloalkyl, monocyclic, spirocyclic, fused, or bridged carbocyclic rings) include C x C x+1 C x+2 C x+3 C x+4 …C y A ring of elements (x is an integer, and 3 ≤ x < y, where y is any integer between 4 and 20), for example, C. 3-6 "Cycloalkyl" refers to C3, C4, C5, or C6 cycloalkyl groups.

[0276] When a functional group has one or more connectable sites, any one or more of these sites can be linked to other functional groups via chemical bonds. When the chemical bond connection is non-directional and a hydrogen atom is present at the connectable site, the number of hydrogen atoms at that site decreases accordingly with the number of bonds being formed, resulting in a functional group with a corresponding valence. For example... This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... These four connection methods, even if an H atom is drawn on -N-, This also includes For example This indicates that the R group on the piperidinyl group can be located on C or N, and at least includes [missing information]. For example, the general formula segment is: When X is selected from CH2 or NH, it means that the R group on the general formula fragment can be located on C or X. When X is selected from CH2, the general formula fragment can be... When X is selected from NH, the general formula fragment can be:

[0277] When the listed linking groups do not specify their linking direction, the linking direction includes the direction of the reading order from left to right and from right to left. For example, when ALB is selected from -MW-, it includes AMWB and AWMB.

[0278] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or possibility that the event or environment may or may not occur. For example, "optionally substituted F alkyl" means that the alkyl group may but does not have to be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

[0279] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0280] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, or stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0281] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0282] "Carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0283] "Prodrug" refers to a compound of the present invention that can be metabolized in vivo and converted into a biologically active compound. The prodrug of the present invention is prepared by modifying the amino or carboxyl groups in the compound of the present invention. This modification can be performed through conventional procedures or removed in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free amino or carboxyl groups.

[0284] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and a fixed stoichiometric ratio exists between the components. Co-crystal is a multi-component crystal, encompassing both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0285] "Animals" refers to mammals, such as humans, companion animals, zoo animals, and livestock, with humans, horses, or dogs being preferred.

[0286] "Stereoisomers" refer to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0287] "Tautomers" refer to functional group isomers that are produced by the rapid movement of an atom in two positions within a molecule, such as keto-enol isomers and amide-imine alcohol isomers.

[0288] IC 50 "It refers to the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of that process, such as an enzyme, receptor, or cell) by half."

[0289] Synthesis Scheme 1:

[0290]

[0291] Compound of general formula (Z-1) and compound of general formula (Z-2) react by condensation to form compound of general formula (Z-3);

[0292] Compound of general formula (Z-3) and compound of general formula (Z-4) react via nucleophilic substitution or coupling to generate compound of general formula (Z-5);

[0293] The general formula compound (Z-5) undergoes a deprotection reaction to give the general formula compound (Z-6);

[0294] Compounds of general formula (Z-6) and (Z-7) are reacted via nucleophilic substitution or reductive amination to yield compound of general formula (Ia);

[0295] R m1 Selected from groups such as F, Br, I, and OTf;

[0296] R m2 Selected from protecting groups such as Boc, Cbz, Ac, and Bn;

[0297] R m3 Selected from structures such as CHO, CH2I, CH2Br, CH2OMs, CH2OTs, and CH2OTf

[0298] The definitions of the remaining groups are the same as those of compounds of general formula (I). Detailed Implementation

[0299] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0300] The compounds used in the reactions described herein were prepared according to organic synthesis techniques known to those skilled in the art, and were derived from commercially available chemicals and / or compounds described in chemical literature. “Commercially available chemicals” are obtained from legitimate commercial sources, and suppliers include: Titan Technology, Energetic Chemicals, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, among others.

[0301] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0302] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0303] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0304] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.20mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4mm-0.5mm in diameter.

[0305] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0306] Example 1: Preparation of chiral isomers 1 and 2 of compound 1

[0307]

[0308] Step 1: Preparation of 1b

[0309] Add 1A hydrochloride (5.81 g, 35.3 mmol), triethylamine (9.52 g, 94.08 mmol), and 100 mL of dichloromethane to the reaction flask. Under nitrogen protection, add 1a (5.00 g, 23.55 mmol) at 0 °C and allow the mixture to return to room temperature for 6 h. Add 100 mL of water to the reaction mixture, separate the layers, and extract the aqueous phase with dichloromethane (50 mL × 3). Combine the organic phases, wash with 50 mL of saturated brine, concentrate under reduced pressure, add 40 mL of petroleum ether and 40 mL of ethyl acetate to the residue, stir at room temperature for 0.5 h, filter, and dry the filter cake under reduced pressure to obtain crude product 1b (3.7 g).

[0310] LCMSm / z = 305.0 [M+1] +

[0311] Step 2: Preparation of 1c

[0312] Add the above crude product 1b (1.00 g), N-Boc-piperazine (0.61 g, 3.28 mmol), DIPEA (1.28 g, 9.90 mmol), and 20 mL DMSO to the reaction flask, and heat to 100 °C and stir for 4 h. Cool the reaction system to room temperature, add 50 mL of water and 50 mL of ethyl acetate to the reaction solution, separate the layers, extract the aqueous phase with ethyl acetate (20 mL × 3), combine the organic phases, wash the organic phase with 50 mL of saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:1) to obtain 1c (0.51 g, yield: 33%).

[0313] Step 3: Preparation of chiral isomer 1 and chiral isomer 2 of compound 1

[0314] Add 1c (0.30 g, 0.64 mmol), 3 mL of trifluoroacetic acid, and 10 mL of dichloromethane to the reaction flask, and react at room temperature for 3 h. Concentrate the reaction solution under reduced pressure, dissolve the residue in 10 mL of dichloromethane, add triethylamine to adjust the pH to 7, concentrate under reduced pressure, dissolve the residue in 10 mL of tetrahydrofuran, add 1B (0.31 g, 0.63 mmol) (synthetic method see WO2021127443) and 0.5 mL of glacial acetic acid, react at room temperature for 1 h, then add sodium triacetoxyborohydride (0.27 g, 1.27 mmol), and react at room temperature for 16 h. Add 20 mL of water and 20 mL of ethyl acetate to the reaction solution, separate the layers, extract the aqueous phase with ethyl acetate (20 mL × 3), combine the organic phases, wash the organic phase with 50 mL of saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-1:9) to give the racemic mixture of compound 1 (50 mg, yield: 9%).

[0315] LCMSm / z = 844.3 [M+1] +

[0316] The racemic mixture of compound 1 was separated by chiral SFC to obtain chiral isomer 1 and chiral isomer 2 of compound 1.

[0317] The preparation conditions for chiral resolution are as follows:

[0318] 1. Instrument: SHIMADZU LC-20AP; Column: Chiral IC column.

[0319] 2. Dissolve the sample in acetonitrile and filter it through a 0.45μm filter to prepare the sample solution.

[0320] 3. Preparative chromatographic conditions: a. The mobile phase consists of system A and system B: Mobile phase A: n-hexane; Mobile phase B: isopropanol and acetonitrile; b. Isocratic elution, with mobile phase B having a content of 70%; c. Flow rate of 90 mL / min.

[0321] The conditions for chiral analysis are as follows:

[0322] 1. Instrument: SHIMADZU LC-20AD; Column: Chiralcel IC column.

[0323] 2. Analytical chromatographic conditions: a. The mobile phase consists of system A and system B: Mobile phase A: n-hexane; Mobile phase B: isopropanol and acetonitrile (containing 0.1% isopropylamine); b. Isocratic elution, with mobile phase B containing 70%; c. Flow rate is 1 mL / min.

[0324] Peak elution times: chiral isomer 1: 2.183 min, chiral isomer 2: 2.897 min.

[0325] Chiral isomers 1 and 2 of compound 1 are compound 1-P1 and compound 1-P2, respectively.

[0326] Characterization data of chiral isomer 1 of compound 1:

[0327] 1 H NMR(400MHz,DMSO-d6)δ10.73(s,1H),7.91(d,1H),7.78–7.70(m,2H),7.64(d,1H) ,7.55(t,1H),7.46(d,1H),7.00–6.72(m,4H),6.66–6.61(m,1H),6.54(dd,1H),4. 27(s,1H),4.20–4.00(m,2H),3.95–3.76(m,5H),3.38–3.28(m,4H),2.86–2.59(m, 3H),2.55–2.39(m,5H),2.28–2.15(m,2H),1.95–1.70(m,5H),1.28–1.10(m,14H).

[0328] LCMSm / z = 844.3 [M+1] +

[0329] Characterization data of chiral isomer 2 of compound 1:

[0330] 1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),7.98–7.84(m,1H),7.78–7.70(m,2H),7.64(d ,1H),7.55(t,1H),7.46(d,1H),7.00–6.72(m,4H),6.66–6.60(m,1H),6.54(dd,1H) ,4.27(s,1H),4.20–4.00(m,2H),3.95–3.79(m,5H),3.40–3.28(m,4H),2.86–2.59( m,3H),2.55–2.39(m,5H),2.27–2.15(m,2H),1.95–1.70(m,5H),1.30–1.10(m,14H).

[0331] LCMSm / z = 844.3 [M+1] +

[0332] Example 3: Preparation of Compound 3

[0333]

[0334] Step 1: Preparation of 3b

[0335] 3a (20.0 g, 126.50 mmol) was dissolved in 800 mL of toluene, and phosphorus pentasulfide (7.31 g, 32.21 mmol) was added. The reaction mixture was reacted at 110 °C for 16 h. The reaction system was cooled to room temperature and washed with 5% hydrochloric acid aqueous solution (200 mL × 3) and 250 mL of saturated brine, respectively, to separate the organic phase. 500 mL of 5% sodium hydroxide aqueous solution was added to the organic phase, and the mixture was stirred at room temperature for 10 min. The aqueous phase was then separated, and the pH of the aqueous phase was adjusted to 4 with 6 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate (200 mL × 3), and the organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (8.5 g). The crude product (8.5 g) was dissolved in 150 mL of water and 50 mL of tetrahydrofuran. Sodium bicarbonate (3.75 g, 44.64 mmol) and chloroacetic acid (5.07 g, 53.65 mmol) were added, and the reaction was carried out at room temperature for 16 h. The reaction system was extracted with ethyl acetate (100 mL × 3), the organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was dissolved in 100 mL of DMF to obtain solution 3B-1. 3-Amino-2,6-piperidinidone hydrochloride (5.51 g, 33.48 mmol) was dissolved in 50 mL of DMF, and sodium bicarbonate (3.75 g, 44.64 mmol) was added. Under nitrogen protection, solution 3B-1 (50 mL) was added to the reaction solution, and the reaction was carried out at 70 °C for 8 h. The reaction system was cooled to room temperature and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 1:1) to give 3b (0.25 g, yield: 3%).

[0336] LCMSm / z = 285.0 [M+1] +

[0337] Step 2: Preparation of 3C

[0338] 3b (0.25 g, 0.88 mmol) was dissolved in 10 mL of dimethyl sulfoxide. Under nitrogen protection, N-Boc-piperazine (0.20 g, 1.07 mmol) and DIPEA (0.34 g, 2.63 mmol) were added, and the reaction was carried out at 100 °C for 20 h. The reaction solution was cooled to room temperature, and 20 mL of ethyl acetate and 20 mL of purified water were added. The aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with 50 mL of saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to give 3c (0.12 g, yield: 30%).

[0339] LCMSm / z = 451.1[M+1] +

[0340] Step 3: Preparation of Compound 3

[0341] Add 3c (0.12 g, 0.267 mmol), 1 mL trifluoroacetic acid, and 5 mL dichloromethane to the reaction flask, and react at room temperature for 2 h. Concentrate the reaction solution under reduced pressure, dissolve the residue in 5 mL dichloromethane, add triethylamine to adjust the pH to 7, concentrate under reduced pressure, dissolve the residue in 5 mL N,N-dimethylacetamide, add 1B (0.12 g, 0.25 mmol) and 0.3 mL glacial acetic acid, react at room temperature for 1 h, then add sodium triacetoxyborohydride (0.11 g, 0.52 mmol), and react at room temperature for 2 h. Add 15 mL of water and 15 mL of ethyl acetate to the reaction solution, separate the liquid and extract the aqueous phase with ethyl acetate (10 mL × 3), combine the organic phases, wash the organic phase with 30 mL of saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-1:15) to give compound 3 (50 mg, yield: 24%).

[0342] LCMSm / z = 824.5 [M+1] +

[0343] Compound 3 was chirally separated to obtain chiral isomer 1 and chiral isomer 2.

[0344] The preparation conditions for chiral resolution are as follows:

[0345] 1. Instrument: SHIMADZU LC-20AP; Column: Chiral IC column.

[0346] 2. Dissolve the sample in acetonitrile and filter it through a 0.45μm filter to prepare the sample solution.

[0347] 3. Preparative chromatographic conditions: a. The mobile phase consists of system A and system B: Mobile phase A: n-hexane; Mobile phase B: isopropanol and acetonitrile; b. Isocratic elution, with mobile phase B having a content of 65%; c. Flow rate of 100 mL / min.

[0348] The conditions for chiral analysis are as follows:

[0349] 1. Instrument: SHIMADZU LC-20AD; Column: Chiral IC column.

[0350] 2. Analytical chromatographic conditions: a. The mobile phase consists of system A and system B: Mobile phase A: n-hexane; Mobile phase B: isopropanol and acetonitrile (containing 0.1% isopropylamine); b. Isocratic elution, with mobile phase B containing 70%; c. Flow rate is 1 mL / min.

[0351] Peak elution times: chiral isomer 1: 2.123 min, chiral isomer 2: 4.296 min.

[0352] The obtained chiral isomers 1 and 2 were subjected to acidic preparation and lyophilization to obtain trifluoroacetate salts of chiral isomer 1 and chiral isomer 2 of compound 3. The acidic preparation conditions are as follows:

[0353] 1. Instrument: SHIMADZU LC-20AP; Column: C18 column.

[0354] 2. Dissolve the sample in acetonitrile and filter it through a 0.45μm filter to prepare the sample solution.

[0355] 3. Preparative chromatographic conditions: a. The mobile phase consists of system A and system B: mobile phase A: water (containing 0.1% TFA); mobile phase B: acetonitrile; b. The content of mobile phase B is 20-50%; c. The flow rate is 75 mL / min.

[0356] Characterization data of trifluoroacetate of chiral isomer 1 of compound 3:

[0357] 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),10.18–9.91(m,1H),7.81–7.71(m,2H),7.69–7.62(m,2H),7.51 –7.43(m,1H),7.01–6.92(m,2H),6.87–6.69(m,2H),6.68–6.61(m,1H),6.54(dd,1H),5.62–5.46(m,1 H),4.27(s,1H),4.05(d,1H),3.94–3.81(m,5H),3.32–3.22(m,4H),2.86–2.72(m,3H),2.60–2.54(m, 1H),2.52–2.40(m,4H),2.27–2.15(m,3H),2.06–1.97(m,1H),1.85–1.73(m,3H),1.31–1.05(m,14H).

[0358] LCMSm / z = 824.7 [M+1] +

[0359] Characterization data of trifluoroacetate of chiral isomer 2 of compound 3:

[0360] 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),10.08–9.96(m,1H),7.74(d,2H),7.70–7.61(m,2H),7.51–7. 43(m,1H),6.96(d,2H),6.84–6.69(m,2H),6.65–6.61(m,1H),6.57–6.50(m,1H),5.60–5.50(m,1H), 4.27(s,1H),4.05(d,1H),3.93–3.79(m,5H),3.33–3.21(m,4H),2.83–2.70(m,3H),2.60–2.51(m,1 H),2.51–2.42(m,4H),2.27–2.13(m,3H),2.07–1.97(m,1H),1.87–1.70(m,3H),1.27–1.10(m,14H).

[0361] LCMSm / z = 824.3 [M+1] +

[0362] Example 4: Preparation of Compound 4

[0363]

[0364] Step 1: Preparation of 4b

[0365] Under a nitrogen atmosphere, 4a (7.00 g, 18.17 mmol) (synthetic method see WO2023232133) and 70 mL of tetrahydrofuran were added to a reaction flask. A 2.5 mol / L n-butyllithium solution in n-hexane (14.50 mL, 36.25 mmol) was slowly added dropwise at -78 °C. The mixture was stirred at -78 °C for 1.5 h, then the carbon dioxide was replaced three times. The reaction was carried out under a carbon dioxide balloon atmosphere, maintaining the system temperature below -40 °C for 0.5 h. The reaction system was brought back to room temperature, 20 mL of ethyl acetate was added, and the pH was adjusted to 2 with 1 mol / L hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1-2:1) to obtain 4b (2.4 g, yield: 38%).

[0366] 1H NMR(400MHz,DMSO-d6)δ7.42(d,1H),6.64(d,1H),4.00–3.82(m,3H),3.23–3.09(m,1H),3.08–2.90(m ,1H),2.90–2.77(m,1H),2.76–2.60(m,3H),2.05–1.90(m,1H),1.65–1.50(m,1H),1.49–1.35(m,9H).

[0367] Step 2: Preparation of 4C

[0368] 4b (1.0 g, 2.85 mmol) was dissolved in 20 mL of DMF, and EDCI (1.1 g, 5.74 mmol), HOBt (0.39 g, 2.89 mmol), and DIPEA (1.11 g, 8.59 mmol) were added. 4A hydrochloride (0.87 g, 3.43 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 3 h. 50 mL of ethyl acetate and 150 mL of water were added to the reaction mixture. The mixture was separated, and the aqueous phase was extracted twice with 50 mL of ethyl acetate. The organic phase was washed with 100 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1-4:1) to give 4c (1.1 g, yield: 70%).

[0369] LCMSm / z = 550.3 [M+1] +

[0370] Step 3: 4D preparation

[0371] 4c (1.1 g, 2.0 mmol) was dissolved in 30 mL of dry toluene, and Lawesson's reagent (0.49 g, 1.21 mmol) was added at room temperature. The reaction mixture was reacted at 100 °C for 5 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 10:1-4:1) to give 4d (0.8 g, yield: 71%).

[0372] LCMSm / z = 566.5 [M+1] +

[0373] Step 4: Preparation of 4e

[0374] Under nitrogen protection, 4d (0.8 g, 1.41 mmol) was dissolved in 8 mL of tetrahydrofuran, and 3 mL of an aqueous solution of sodium hydroxide (0.062 g, 1.55 mmol) was added. The reaction was carried out at room temperature for 4 h. 20 mL of dichloromethane was added to the reaction solution, and the pH was adjusted to 4 with 1 mol / L sulfuric acid aqueous solution. The aqueous phase was extracted with dichloromethane (20 mL × 3). The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 100:1-20:1) to give 4e (0.7 g, yield: 90%).

[0375] LCMSm / z = 552.4 [M+1] +

[0376] Step 5: Preparation of 4f

[0377] Under nitrogen protection, 4e (0.7 g, 1.27 mmol) was dissolved in 20 mL of 1,4-dioxane, and Boc₂O (0.44 g, 2.02 mmol) was added dropwise. The temperature was controlled at 5 °C, and pyridine (0.20 g, 2.53 mmol) was added dropwise. After reacting at room temperature for 2 h, ammonium bicarbonate (0.30 g, 3.79 mmol) was added to the reaction solution at 5 °C, and the reaction was carried out at room temperature for 3 h. 30 mL of ethyl acetate and 30 mL of saturated potassium dihydrogen phosphate aqueous solution were added to the reaction solution. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with 50 mL of saturated sodium chloride aqueous solution, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 20:1-1:2) to give 4f (0.67 g, yield: 96%).

[0378] LCMSm / z = 551.5[M+1] +

[0379] Step 6: Preparation of 4g

[0380] Under nitrogen protection, 4f (0.37 g, 0.67 mmol) was dissolved in 10 mL of acetonitrile, and dextrorotatory camphor sulfonic acid (0.47 g, 2.02 mmol) was added. The reaction mixture was reacted at 80 °C for 16 h. The reaction system was cooled to room temperature, and 15 mL of dichloromethane was added. The pH was adjusted to 9 with saturated sodium bicarbonate aqueous solution. The mixture was separated, and the aqueous phase was extracted with dichloromethane (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4 g (0.22 g) of crude product.

[0381] LCMSm / z = 377.3 [M+1] +

[0382] Step 7: Preparation of Compound 4

[0383] Under nitrogen protection, 4 g (0.22 g) of the above crude product was dissolved in 5 mL of N,N-dimethylacetamide, 1B (0.31 g, 0.633 mmol) and 0.5 mL of glacial acetic acid were added, and the reaction was carried out at room temperature for 0.5 h. Then, sodium triacetoxyborohydride (0.25 g, 1.18 mmol) was added, and the reaction was carried out at room temperature for 2 h. 15 mL of water and 15 mL of dichloromethane were added to the reaction solution, and the mixture was separated. The aqueous phase was extracted with dichloromethane (10 mL × 3), and the organic phase was washed with 30 mL of saturated brine. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-1:15). The obtained crude product was subjected to chiral preparation to give compound 4 (0.15 g, yield: 28%).

[0384] LCMSm / z = 850.4 [M+1] +

[0385] Example 5: Preparation of Compound 5

[0386]

[0387] Compound 5 was obtained from compound 5a (synthesis method see WO2023232133) as a raw material, following the synthesis method of Example 4.

[0388] Example 6: Preparation of trifluoroacetate of compound 6

[0389]

[0390] The trifluoroacetate of compound 6 was prepared by acidic treatment using compound 6A as the starting material, following the synthesis method in Example 4.

[0391] The preparation method is as follows:

[0392] 1. Instrument: SHIMADZU LC-20AP; Column: C18 column.

[0393] 2. Dissolve the sample in acetonitrile and filter it through a 0.45μm filter to prepare the sample solution.

[0394] 3. Preparative chromatographic conditions: a. The mobile phase consists of system A and system B: mobile phase A: water (containing 0.1% TFA); mobile phase B: acetonitrile; b. The content of mobile phase B is 35-55%; c. The flow rate is 30 mL / min.

[0395] Chiral isomers 1 and 2 of compound 6 were prepared chirally from compound 6A according to the synthesis method in Example 4.

[0396] The preparation conditions for chiral resolution are as follows:

[0397] 1. Instrument: SHIMADZU LC-20AP; Column: Chiral IC column.

[0398] 2. Dissolve the sample in acetonitrile and filter it through a 0.45μm filter to prepare the sample solution.

[0399] 3. Preparative chromatographic conditions: a. The mobile phase consists of system A and system B: Mobile phase A: n-hexane; Mobile phase B: isopropanol and acetonitrile; b. Isocratic elution, with mobile phase B having a content of 70%; c. Flow rate of 100 mL / min.

[0400] The conditions for chiral analysis are as follows:

[0401] 1. Instrument: SHIMADZU LC-20AD; Column: Chiral IC column.

[0402] 2. Analytical chromatographic conditions: a. The mobile phase consists of system A and system B: Mobile phase A: n-hexane; Mobile phase B: isopropanol and acetonitrile (containing 0.1% isopropylamine); b. Isocratic elution, with mobile phase B containing 70%; c. Flow rate is 1 mL / min.

[0403] Peak elution times: chiral isomer 1: 2.666 min, chiral isomer 2: 6.958 min.

[0404] Characterization data of chiral isomer 1 of compound 6:

[0405] 1 H NMR (400MHz, CDCl3) δ8.83–8.71(m,1H),8.14–7.99(m,2H),7.75–7.61(m,2H),7.45(d,1H), 6.91(d,2H),6.51–6.44(m,1H),6.42–6.30(m,2H),6.12(d,1H),5.52–5.39(m,1H),4.15(d,1 H),4.04(s,1H),3.91(s,3H),3.88–3.80(m,2H),3.75–3.66(m,1H),3.34–3.21(m,1H),3.16 –3.04(m,2H),2.89–2.71(m,6H),2.40–2.16(m,3H),2.07–1.57(m,11H),1.27–1.21(m,12H).

[0406] LCMSm / z = 850.3 [M+1] +

[0407] Characterization data of chiral isomer 2 of compound 6:

[0408] 1 H NMR (400MHz, CDCl) 3- d)δ8.89–8.70(m,1H),8.13–7.98(m,2H),7.68(d,2H),7.45(d,1H),6.91(d,2H),6.49 –6.44(m,1H),6.42–6.31(m,2H),6.11(d,1H),5.50–5.39(m,1H),4.15(d,1H),4.04(s, 1H),3.91(s,3H),3.88–3.82(m,2H),3.76–3.65(m,1H),3.35–3.22(m,1H),3.15–3.05 (m,2H),2.89–2.76(m,6H),2.43–2.16(m,3H),2.02–1.47(m,11H),1.29–1.18(m,12H).

[0409] LCMSm / z = 850.3 [M+1] +

[0410] Example 7: Preparation of trifluoroacetate of compound 7

[0411]

[0412] The trifluoroacetate of compound 7 was prepared by acidic treatment using compound 6A as the starting material, following the synthesis method of Example 5.

[0413] The preparation method is as follows:

[0414] 1. Instrument: SHIMADZU LC-20AP; Column: C18 column.

[0415] 2. Dissolve the sample in acetonitrile and filter it through a 0.45μm filter to prepare the sample solution.

[0416] 3. Preparative chromatographic conditions: a. The mobile phase consists of system A and system B: mobile phase A: water (containing 0.1% TFA); mobile phase B: acetonitrile; b. The content of mobile phase B is 35-55%; c. The flow rate is 25 mL / min.

[0417] Chiral isomers 1 and 2 of compound 7 were prepared chirally from compound 6A according to the synthesis method in Example 5.

[0418] The preparation conditions for chiral resolution are as follows:

[0419] 1. Instrument: SHIMADZU LC-20AP; Column: Chiral IC column.

[0420] 2. Dissolve the sample in acetonitrile and filter it through a 0.45μm filter to prepare the sample solution.

[0421] 3. Preparative chromatographic conditions: a. The mobile phase consists of system A and system B: Mobile phase A: n-hexane; Mobile phase B: isopropanol and acetonitrile; b. Isocratic elution, with mobile phase B having a content of 70%; c. Flow rate of 100 mL / min.

[0422] The conditions for chiral analysis are as follows:

[0423] 1. Instrument: SHIMADZU LC-20AD; Column: Chiral IC column.

[0424] 2. Analytical chromatographic conditions: a. The mobile phase consists of system A and system B: Mobile phase A: n-hexane; Mobile phase B: isopropanol and acetonitrile (containing 0.1% isopropylamine); b. Isocratic elution, with mobile phase B having a content of 80%; c. Flow rate of 1 mL / min.

[0425] Peak elution times: chiral isomer 1: 2.108 min, chiral isomer 2: 5.081 min.

[0426] Characterization data of chiral isomer 1 of compound 7:

[0427] H NMR (400MHz, DMSO-d6) δ10.97–10.87(m,1H),10.10–9.84(m,1H),7.79–7.69(m,2H),7.64(d,1H),7.50 –7.35(m,2H),7.03–6.91(m,2H),6.71–6.59(m,2H),6.57–6.51(m,1H),5.61–5.46(m,1H),4.27(s,1H) ,4.05(d,1H),3.97–3.77(m,6H),3.18–3.00(m,2H),2.94–2.64(m,8H),2.60–2.52(m,1H),2.26–2.11( m,3H),2.10–1.99(m,2H),1.97–1.89(m,1H),1.88–1.71(m,3H),1.69–1.54(m,1H),1.26–1.11(m,14H).

[0428] LCMSm / z = 850.0 [M+1] +

[0429] Characterization data of chiral isomer 2 of compound 7:

[0430] 1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),9.96–9.82(m,1H),7.79–7.69(m,2H),7.64(d,1H),7.49–7.35(m, 2H),6.95(d,2H),6.69–6.59(m,2H),6.58–6.49(m,1H),5.60–5.47(m,1H),4.27(s,1H),4.05(d,1H),3. 96–3.76(m,6H),3.16–3.04(m,1H),2.95–2.86(m,2H),2.86–2.61(m,6H),2.59–2.52(m,1H),2.24–2.13 (m,3H),2.10–1.99(m,2H),1.98–1.90(m,1H),1.85–1.72(m,4H),1.64–1.53(m,1H),1.31–1.00(m,14H).

[0431] LCMSm / z = 850.1 [M+1] +

[0432] Example 8: Preparation of Compound 8

[0433]

[0434] Step 1: Preparation of 8b

[0435] Dissolve 8a (10.00 g, 52.36 mmol) in 100 mL of DMF, add potassium carbonate (14.46 g, 104.63 mmol) and deuterated iodomethane (9.10 g, 62.78 mmol), and react at room temperature for 19 h. Pour the reaction solution into 200 mL of water, extract with 100 mL of ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1-2:1) to obtain crude product 8b (11.5 g).

[0436] Step 2: Preparation of 8c

[0437] The crude product 8b (11.5 g) was dissolved in 100 mL of NMP, and cuprous cyanide (11.30 g, 126.17 mmol) was added. The mixture was reacted at 180 °C for 19 h. The reaction solution was cooled to room temperature, and 10 mL of concentrated ammonia and 200 mL of water were added. The mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1-2:1) to give 8c (7.5 g, two-step yield from compound 8a: 93%).

[0438] Step 3: Preparation of 8 days

[0439] Dissolve 8A (8.37 g, 34.39 mmol) in 50 mL THF, add 60% sodium hydride (1.65 g) at 0 °C, react for 30 min at 0 °C, then add 8c (5.30 g, 34.34 mmol), and react at room temperature for 19 h. Pour the reaction solution into 100 mL of water, extract with 100 mL of ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1-2:1) to give 8d (2.5 g, yield: 19%).

[0440] LCMSm / z = 378.3 [M+1] +

[0441] Step 4: Preparation of 8e hydrochloride

[0442] Dissolve 2.5 g (6.63 mmol) of 8e in 5 mL of ethyl acetate, add 10 mL of 4 mol / L ethyl hydrochloride solution, and react at room temperature for 5 h. Filter the reaction mixture, collect the filter cake, and dry the filter cake under reduced pressure to obtain crude 8e hydrochloride (3.5 g).

[0443] LCMSm / z = 278.2[M+1] +

[0444] Step 5: Preparation of 8f

[0445] Add 8B (1.35 g, 5.74 mmol) (synthetic method referred to CN115974840), HATU (2.73 g, 7.18 mmol), diisopropylethylamine (1.85 g, 14.31 mmol), and 10 mL of DMF to the reaction flask. After stirring at room temperature for 0.5 h, add the hydrochloride salt of the above crude product 8e (2.5 g) and stir at room temperature for 2 h. Add 100 mL of water to the reaction solution, filter, collect the filter cake, and purify the filter cake by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-0:1) to obtain 8f (1.6 g, two-step yield from compound 8d: 68%).

[0446] LCMSm / z = 495.3 [M+1] +

[0447] Step 6: Preparation of 8g

[0448] Add 8g (99mg, 0.20mmol), Dess-Martin oxidant (0.17g, 0.40mmol), and 3mL of dichloromethane to the reaction flask, and react at room temperature for 30min. Add 10mL of saturated sodium bicarbonate aqueous solution to the reaction system, extract with 30mL of dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 8g (110mg) of crude product.

[0449] Compound 8 was obtained from compounds 3c and 8g using the synthesis method described in Example 3.

[0450] LCMSm / z = 827.6 [M+1] +

[0451] Compound 8 was chiralized to obtain chiral isomers 1 and 2.

[0452] Characterization data of chiral isomer 1 of compound 8:

[0453] 1 H NMR(400MHz, CDCl3)δ8.86–8.71(m,1H),8.38–8.27(m,1H),7.99(s,1H),7.72–7.63(m,2H),7 .45(d,1H),6.96–6.83(m,2H),6.73–6.64(m,1H),6.51–6.43(m,2H),6.42–6.36(m,1H),6.11( d,1H),5.48–5.37(m,1H),4.14(d,1H),4.04(s,1H),3.91–3.79(m,2H),3.65–3.36(m,4H),3.1 8–3.05(m,1H),3.04–2.33(m,10H),2.00–1.79(m,4H),1.48–1.34(m,2H),1.28–1.20(m,12H).

[0454] LCMSm / z = 827.6 [M+1] +

[0455] Characterization data of chiral isomer 2 of compound 8:

[0456] 1H NMR (400MHz, CDCl3) δ8.87–8.73(m,1H),8.39–8.25(m,1H),7.96(s,1H),7.73–7.63(m,2H),7 .45(d,1H),6.97–6.87(m,2H),6.73–6.63(m,1H),6.52–6.43(m,2H),6.42–6.37(m,1H),6.11( d,1H),5.49–5.40(m,1H),4.15(d,1H),4.04(s,1H),3.90–3.78(m,2H),3.59–3.23(m,4H),3.1 8–3.06(m,1H),2.92–2.19(m,10H),1.98–1.77(m,4H),1.44–1.32(m,2H),1.27–1.20(m,12H).

[0457] LCMSm / z = 827.6 [M+1] +

[0458] Biological test cases

[0459] 1. Detection of AR degradation in VCap cells

[0460] VCap is a human prostate cancer cell line purchased from ATCC. Culture conditions: DMEM + 10% FBS + 1% antibiotics, cultured at 37°C in a 5% CO2 incubator. Cells were seeded into 6-well plates at 5 × 10⁶ cells / well. 5 Cells / well. After plating, different concentrations of compounds were added, and the cells were incubated at 37°C and 5% CO2 for 24 hours. After the culture, the cells were collected, and RIPA lysis buffer (beyotime, Cat. P0013B) was added and lysed on ice for 15 minutes. After centrifugation at 12000 rpm and 4°C for 10 minutes, the supernatant protein sample was collected. After protein quantification using the BCA kit (Beyotime, Cat. P0009), the protein was diluted to 0.25 mg / mL, and the expression of AR (CST, Cat. 5153S) and internal control β-actin (CST, Cat. 3700S) was detected using a fully automated Western blot quantitative analyzer (Proteinsimple). The relative peak area of ​​AR when the internal control area was 10000 was calculated using the "Compass for SW" software. The proportion of AR relative to the solvent control group at different drug concentrations was calculated according to Equation (1), where AR treat AR represents the relative peak area of ​​the treatment group. solvent The relative peak area is the solvent control group. The data processed according to equation (1) were analyzed using GraphPadPrism 8.3.0 software, and a four-parameter nonlinear regression model was employed to calculate DC. 50 value;

[0461] AR% = AR treat / AR solvent ×100% Formula 1

[0462] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good AR degradation activity.

[0463] 2. Rat pharmacokinetic assay

[0464] Experimental objective: This experiment aimed to evaluate the pharmacokinetic characteristics of the test substance in rats by administering a single dose of the test substance intravenously and by gavage to SD rats, measuring the concentration of the test substance in rat plasma, and administering it intravenously and by gavage.

[0465] Experimental animals: Male SD rats, 200-220g, 6 rats / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0466] Experimental method: On the day of the experiment, 6 SD rats were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0467] Table 1. Dosage information for rat pharmacokinetic tests

[0468]

[0469] *Dosage is calculated based on free base.

[0470] Sampling: Before and after administration of isoflurane anesthesia, 0.15 mL of blood was collected via the orbital cavity and placed in an EDTAK2 centrifuge tube. The plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min.

[0471] Plasma collection time points for IV&PO groups: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 24, 48 h.

[0472] All samples were stored at -60℃ before analysis and testing. Quantitative analysis of the samples was performed using LC-MS / MS.

[0473] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in rats.

[0474] 3. Experiment on inhibiting VCaP cell proliferation

[0475] Prostate cancer cells (VCaP) were purchased from ATCC. The cell culture medium was RPMI 1640 + 10% FBS, and the cells were cultured in a 37°C, 5% CO2 incubator. Before the experiment, the cells cultured in normal medium were passaged into phenol red-free RPMI 1640 containing 10% activated charcoal-adsorbed FBS and cultured for 3 days. On day 4, cells were digested with phenol red-free digestion solution (Trypsin LE trypsin). Digestion was stopped with phenol red-free RPMI 1640 medium containing 1% activated charcoal-adsorbed FBS, 0.5% PS, and 0.1 nM R1881. Cells were centrifuged and resuspended, and viable cell counts were performed using a Vi-Cell XR cell counter. The cell suspension was adjusted to an appropriate concentration with phenol red-free RPMI 1640 medium containing 1% activated charcoal-adsorbed FBS, 0.5% PS, and 0.1 nM R1881. 180 μl of cell suspension was added to each well of a 96-well cell culture plate to achieve a cell density of 7500 cells / well. T0 wells were also seeded simultaneously. The next day, R1881 at a final concentration of 0.1 nM and different concentrations of the compound were added, and the plates were incubated for another 7 days. The T0 plates were detected using the CellTiter-Glo (CTG) (Promega, product number: G7572) kit, and the results were recorded as RLU0. After culture, 75 μl of pre-melted and equilibrated CellTiter-Glo solution was added to each well, mixed with a microplate shaker for 2 minutes, and incubated at room temperature for 10 minutes before measuring the fluorescence signal using an Envision 2104 plate reader. Results were processed according to equation (2), and the cell growth rate at each compound concentration was calculated in Excel. GraphPad software was used to calculate the GI concentration of the compound at a proliferation rate of 50%. 50 Values. Among them, RLU... compound For the drug treatment group, RLU readings control This represents the average value of the solvent control group.

[0476] Growth % = (RLU) compound -RLU0) / (RLU control - RLU0)×100% Equation (2)

[0477] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against VCaP cell proliferation.

[0478] 4. Caco2 permeability test

[0479] The experiment used monolayers of Caco-2 cells, incubated in triple parallel in 96-well Transwell plates. A transport buffer solution (HBSS, 10 mM HEPES, pH 7.4±0.05) containing either the compound of the present invention (2 μM) or the control compounds digoxin (10 μM), naldolol (2 μM), and metoprolol (2 μM) was added to the dosing well on the apical or basal side. A transport buffer solution containing DMSO was added to the corresponding receiving well. After incubation at 37±1 °C for 2 hours, the cell plate was removed, and appropriate amounts of sample were transferred from both the apical and basal sides to new 96-well plates. Acetonitrile containing an internal standard was then added to precipitate the protein. The samples were analyzed using LC MS / MS to determine the concentrations of the compound of the present invention and the control compounds. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to the basal side of the monolayer cells, and from the basal side to the apical side, thereby calculating the efflux rate. Leakage of fluorescein was used to evaluate the integrity of the monolayer cells after 2 hours of incubation.

[0480] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good CaCO2 permeability.

[0481] 5. Mouse pharmacokinetic assay

[0482] Experimental objective: This experiment aimed to evaluate the pharmacokinetic characteristics of the test substance in mice by administering a single dose of the test substance intravenously and by gavage to ICR mice, measuring the concentration of the test substance in mouse plasma, and administering it intravenously and by gavage.

[0483] Experimental animals: 6 male ICR mice per compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0484] Experimental method: On the day of the experiment, 6 SD mice were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0485] Table 2. Dosage information for mouse pharmacokinetic tests

[0486]

[0487] *Dosage is calculated based on free base.

[0488] Sampling: Before and after administration of isoflurane anesthesia, 0.15 mL of blood was collected via the orbital cavity and placed in an EDTAK2 centrifuge tube. The plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min.

[0489] Plasma collection time points for the PO group: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, 24, 48 h.

[0490] Plasma collection time points for Group IV: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, 24, 48 h.

[0491] All samples were stored at -60℃ before analysis and testing. Quantitative analysis of the samples was performed using LC-MS / MS.

[0492] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in mice.

[0493] 6. Pharmacokinetics of Beagle Dogs

[0494] Experimental animals: Male beagles, weighing approximately 8-10 kg, 6 per compound, purchased from Beijing Mars Biotechnology Co., Ltd.

[0495] Experimental method: On the day of the experiment, 6 beagle dogs were randomly divided into groups according to their weight. They were fasted for 14-18 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0496] Table 3. Dosing information for beagle pharmacokinetic studies

[0497]

[0498] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline;

[0499] Oral (oral) administration solvent: 5% DMSO + 5% Solutol + 90% (20% SBE-CD);

[0500] *Dosage is calculated based on free base.

[0501] Blood samples (1 ml) were collected via jugular or limb veins before and after drug administration and placed in EDTAK2 centrifuge tubes. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min. Blood collection time points for both the intravenous and gavage groups were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h. All samples were stored at -60°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0502] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in dogs.

[0503] 7. Pharmacokinetics in monkeys

[0504] Experimental animals: Male cynomolgus monkeys, 3–5 kg, 3–6 years old, 4 animals / compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0505] Experimental method: On the day of the experiment, four monkeys were randomly divided into groups according to their body weight. They were fasted for 14-18 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0506] Table 4. Dosing information for pharmacokinetic studies in monkeys.

[0507]

[0508] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline;

[0509] Oral (oral) administration solvent: 5% DMSO + 5% Solutol + 90% (20% SBE-CD);

[0510] *Dosage is calculated based on free base.

[0511] Blood samples of 1.0 mL were collected via the jugular vein before and after drug administration and placed in EDTAK2 centrifuge tubes. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min. Blood collection time points for both the intravenous and gavage groups were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h. All samples were stored at -60°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0512] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in monkeys.

[0513] 8. hERG potassium ion channel function test

[0514] Experimental platform: Electrophysiological manual patch-clamp system

[0515] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channels

[0516] Experimental Methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch-clamp technique. Glass microelectrodes were fabricated from glass electrode blanks (BF150-86-10, Sutter) using a stretching device. The tip resistance after perfusion with electrode fluid was approximately 2-5 MΩ. The glass microelectrodes were inserted into the amplifier probe to connect to the patch-clamp amplifier. Clamp voltage and data recording were controlled and recorded using pClamp 10 software via computer, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -80 mV to induce hERG potassium current (Ig). hERG The step voltage was applied from -80 mV to +20 mV for 2 seconds, then repolarized to -50 mV for 1 second before returning to -80 mV. This voltage stimulation was applied every 10 seconds, and the drug administration process began after the hERG potassium current stabilized (at least 1 minute). Each test concentration of the compound was administered for at least 1 minute, and at least 2 cells (n≥2) were tested for each concentration.

[0517] Data processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The degree of inhibition of hERG potassium current (the peak hERG tail current induced at -50mV) by different compound concentrations was calculated using the following formula:

[0518] Inhibition%=[1–(I / Io)]×100%

[0519] Where Inhibition% represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current before and after drug administration, respectively.

[0520] Compound IC 50 The following equations were fitted and calculated using GraphPad Prism 5 software:

[0521] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0522] Where X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0523] Conclusion: The compounds of the present invention, such as the compounds in the examples, do not have a significant inhibitory effect on the hERG potassium channel current.

[0524] 9. Liver microsomal stability test

[0525] This experiment used liver microsomes from five genera—human, canine, rat, and mouse—as in vitro models to evaluate the metabolic stability of the test substance.

[0526] At 37°C, 1 μM of the test substance was co-incubated with microsomal protein and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard after certain time intervals (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. T was calculated using the ln value of the drug residue in the incubation system and the incubation time. 1 / 2 Furthermore, the intrinsic clearance rate (CL) of liver microsomes was calculated. int(mic) and hepatic intrinsic clearance rate CL int(Liver) .

[0527] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good liver microsomal stability.

[0528] 10. CYP450 enzyme inhibition test

[0529] The aim of this study was to evaluate the effects of test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro assay system. Specific probe substrates for CYP450 isoenzymes were co-incubated with human liver microsomes and different concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) after sample processing, and the changes in CYP enzyme activity were measured. The IC50 values ​​were calculated. 50 The value is used to evaluate the inhibitory potential of the test substance against each CYP enzyme subtype.

[0530] Conclusion: The compounds of the present invention, such as the compounds in the examples, do not have a significant inhibitory effect on the five isoenzymes of CYP.

[0531] 11. Human CD34+ hematopoietic stem cell proliferation inhibition experiment

[0532] Human CD34+ Hematopoietic stem cells (TPCS, Cat.hmPB34-P-2CW) are CD34-positive stem cells obtained from human PBMCs through immunomagnetic bead sorting. The culture conditions were: DPBS (Gibco, Cat.14190-144) + StemSpan SFEMII (STEMCELL, Cat.9655) + 1X StemSpan CD34+Expansion Supplement (STEMCELL, Cat.2691). First, 40 nL of DMSO, the positive control Talazoparib, or the test compound were added to each well of a 384-well plate (Corning, Cat.3764). Then, cell suspension was added at a concentration of 400 cells / 40 μL / well, resulting in a final concentration of 0.1% DMSO, 3 μM Talazoparib, or different concentrations of the compound per well. The plates were centrifuged at 1000 rpm for 1 minute at room temperature and then cultured at 37°C in a 5% CO2 incubator for 7 days. After culture, 20 μL of CellTiter-Glo Reagent (Promega, Cat. G7573) was added directly to each well, centrifuged at 1000 rpm for 1 minute at room temperature, and then incubated in the dark for 20 minutes. After incubation, the chemiluminescent signal (CFU) was read and recorded using an Envision multi-mode microplate reader (PerkinElmer, Cat. 2104). The cell proliferation inhibition rate of different concentrations of the compound was calculated according to equation (3), and the CFU was recorded. high control The average signal value of the DMSO group, CFUlow control The average signal value of the Talazoparib group, CFU compound The average signal value of the compound group is given. The data processed according to equation (3) were subjected to curve fitting using XLfit or GraphPad Prism software with four parameters to calculate the IC50 concentration of the compound when the inhibition rate was 50%. 50 value.

[0533] Inhibiton% = (CFU) high control -CFU compound ) / (CFU high control -CFU low control ) ×100% (Equation 3)

[0534] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on the proliferation of CD34+ hematopoietic stem cells.

[0535] 12. Study on AR degradation activity in MDA-PCA-2B cells

[0536] Human prostate cancer cells MDA-PCA-2B were cultured in a complete medium consisting of F-12K + 20% FBS + 25 ng / ml cholera toxin + 10 ng / ml mouse epidermal growth factor + 0.005 mM phosphoethanolamine + 100 pg / ml hydrocortisone + 45 nM sodium selenite + 0.005 mg / ml linsulin at 37°C in a 5% CO2 incubator. Cells in the exponential growth phase were collected and the cell suspension was adjusted to the appropriate concentration using hormone-deprived medium (containing 10% carbon-adsorbed serum) for plating. Cells were seeded in 12-well plates at 5 × 10⁶ cells / well. 5Cells / well. After plating, incubate in an incubator for 72 hours, then replace with experimental medium (containing 1% carbon-adsorbed serum), add different concentrations of compounds, and incubate at 37°C in a 5% CO2 incubator for 24 hours. After culture, cells were washed with pre-chilled PBS and then lysed on ice for 15 minutes with complete cell lysis buffer containing a Protease / Phosphatase Inhibitor Cocktail (cell lysis buffer information: CST, Cat. 9803, diluted to 1X before use; Protease / Phosphatase Inhibitor Cocktail (100X) information: Cat. 5872. The Cocktail was then diluted 100-fold with the 1X cell lysis buffer to obtain the complete cell lysis buffer). Cells were scraped into new pre-chilled EP tubes and centrifuged at 13500 rpm, 4°C for 20 minutes. The supernatant protein sample was collected, and protein quantification was performed using a BCA kit (Thermofisher, Cat. 23225). The protein concentration was then diluted to 2 mg / mL. The prepared sample was loaded into a 4-12% precast gel at a loading volume of 5 μL (10 μg), and Androgen Receptor (D6F11) was detected using a conventional Western blot method. The expression levels of Rabbit mAb (CST, Cat. 5153S) and the internal control β-Actin (CST, Cat. 3700S) were measured. Secondary antibodies were HRP-labeled Anti-rabbit IgG Antibody (CST, Cat. 7074V) and Anti-mouse IgG Antibody (CST, Cat. 7076V). The expression levels of AR and the internal control were calculated using the protein expression quantification software "Image Studio". The degradation rate (%Degradation) of the compounds at different concentrations was calculated according to equation (4), where R... compound AVE_R represents the relative expression level of AR in different concentration groups. DMSO The value represents the average relative expression level of AR in the DMSO control group. Then, inhibition curves and DC values ​​were calculated using GraphPad Prism software. 50 .

[0537] % Degradation = (AVE_R DMSO -R compound ) / AVE_R DMSO × 100% Equation (4)

[0538] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good degradation activity against AR proteins in MDA-PCA-2B cells.

[0539] 13. Experiment on inhibiting the proliferation of MDA-PCA-2B cells

[0540] Human prostate cancer cells MDA-PCA-2B were purchased from ATCC. The complete culture medium consisted of F-12K + 20% FBS + 25 ng / ml cholera toxin + 10 ng / ml mouse epidermal growth factor + 0.005 mM phosphoethanolamine + 100 pg / ml hydrocortisone + 45 nM sodium selenite + 0.005 mg / ml human recombinant insulin + 1% PS. Cells were cultured at 37°C in a 5% CO2 incubator. At the start of the experiment, cells were digested with 0.25% trypsin-EDTA (1x), phenolred, and the digestion was terminated with the complete culture medium, followed by centrifugation. The cells were resuspended in experimental medium (DMEM / F-12, phenol red-free + 1% carbon-adsorbed FBS + 0.5% PS + 25 ng / ml cholera toxin + 10 ng / ml mouse epidermal growth factor + 0.005 mM phosphoethanolamine + 100 pg / ml hydrocortisone + 45 nM sodium selenite + 0.005 mg / ml human recombinant insulin), and viable cells were counted using a cell counter. The cell suspension was adjusted to an appropriate concentration, and 100 μl was seeded into each well of a 96-well cell culture plate at a cell density of 30,000 cells / well. The cells were incubated overnight. The following day, 100 μL of diluted 2x working solution (containing different concentrations of test samples and exogenous androgen R1881, totaling 200 μL, with a final R1881 concentration of 0.2 nM) was added, bringing the total volume to 200 μL. The mixture was then incubated for 7 days. Simultaneously, T0 wells were set up, and Day 0 cell viability was measured using a CellCounting-lite 2.0 (Vazyme, DD1101-03) kit, denoted as RLU0. After incubation, 100 μL of supernatant was discarded from each well, and 60 μL of pre-melted and equilibrated CellCounting-lite 2.0 solution was added. The mixture was shaken for 2 minutes and incubated at room temperature for 30 minutes before measuring the luminescence signal using a BMG multi-plate reader.

[0541] The results were processed according to equation (5). The inhibition rate of each concentration of the compound was calculated in Excel, and the concentration GI of the compound when the inhibition rate was 50% was calculated using GraphPad software. 50 Values. Where RLU compound represents the readings of the drug-treated group, and RLU control represents the average value of the solvent-controlled group.

[0542] Inhibition % =1-(RLU compound-RLU0) / (RLU control- RLU0)×100% Formula (5)

[0543] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against the proliferation of MDA-PCA-2B cells.

[0544] 14. Inhibition of LNCaP AR F877L Cell proliferation experiment

[0545] LNCaP AR prostate cancer cells F877L The cells were constructed using WuXi AppTec, with RPMI 1640 culture medium containing 10% FBS, and cultured in a 37℃, 5% CO2 incubator. Before the experiment, cells cultured in normal medium were passaged into phenol red-free RPMI 1640 culture medium containing 10% activated carbon-adsorbed FBS and cultured for 3 days. On day 4, cells were digested with phenol red-free digestion solution (Trypsin LE trypsin). Digestion was stopped with phenol red-free RPMI 1640 medium containing 1% activated charcoal-adsorbed FBS, 0.5% PS, and 0.1 nM R1881. Cells were centrifuged and resuspended, and viable cell counts were performed using a Vi-Cell XR cell counter. The cell suspension was adjusted to an appropriate concentration with phenol red-free RPMI 1640 medium containing 1% activated charcoal-adsorbed FBS, 0.5% PS, and 0.1 nM R1881. 180 μl of cell suspension was added to each well of a 96-well cell culture plate to achieve a cell density of 2500 cells / well. T0 wells were also seeded simultaneously. The next day, R1881 at a final concentration of 0.1 nM and different concentrations of the compound were added, and the plates were incubated for another 7 days. The T0 plates were detected using the CellTiter-Glo (CTG) (Promega, product number: G7572) kit and recorded as RLU0. After incubation, 75 μl of pre-melted and equilibrated CellTiter-Glo solution was added to each well, mixed with a microplate shaker for 2 minutes, and incubated at room temperature for 10 minutes before measuring the fluorescence signal value (RLU) using an Envision 2104 plate reader. The results were processed according to equation (6), and the inhibition rate (Inhibition%) of each compound concentration was calculated in Excel. The concentration (GI) of the compound at an inhibition rate of 50% was calculated using GraphPad software. 50Values. Among them, RLU... compound For the drug treatment group, RLU readings control This represents the average value of the solvent control group.

[0546] Inhibition% = 1 - (RLU) compound -RLU0) / (RLU control -RLU0)×100% Equation (6)

[0547] Conclusion: The compounds of the present invention, such as the compounds in the examples, are effective against LNCaP AR. F877L It exhibits good inhibitory activity against cell proliferation.

[0548] 15. LNCaP AR F877L Study on AR degradation activity in cells

[0549] LNCaP AR prostate cancer cells F877L The assay was constructed using WuXi AppTec, with complete cell culture medium consisting of RPMI 1640 + 10% FBS + 1% PS, and cultured at 37°C in a 5% CO2 incubator. Before the experiment, cells cultured in normal medium were passaged into phenol red-free RPMI 1640 culture medium containing 10% activated charcoal-adsorbed FBS and cultured for 3 days. On day 4, cells were digested with phenol red-free digestion solution (Trypsin LE trypsin), and the cell suspension was adjusted to the appropriate concentration using hormone-deprived medium (containing 1% carbon-adsorbed serum) for plating. Cells were plated in 24-well plates at 50,000 cells / well. After plating, cells were incubated for 24 hours, and then different concentrations of the compound were added, followed by another 24 hours of incubation at 37°C in a 5% CO2 incubator. After culture, cells were digested with phenol red-free trypsin LE, and digestion was stopped with phenol red-free RPMI 1640 medium containing 1% activated charcoal-adsorbed FBS + 0.5% PS. Cells were collected in 1.5 mL centrifuge tubes, centrifuged and resuspended, and washed twice with PBS. 20 μL of pre-chilled, ice-cold complete cell lysis buffer containing a Protease / Phosphatase Inhibitor Cocktail was added to each tube (RIPA information for cell lysis buffer: Sigma, Cat. R0278; complete). TM Mini protease inhibitor mixture information: Roche, Cat. 04693124001; Mix RIPA and cOmplete according to the instructions. TMThe Mini protease inhibitor mixture (prepared as a complete cell lysis buffer) was lysed on ice for 30 minutes, followed by centrifugation at 12000×g, 4°C for 10 minutes. The supernatant protein sample was collected, and SDS-PAGE protein loading buffer (5X) was added. The sample was heated at 100°C for 10 minutes. The prepared sample was loaded in 15 μL volumes into a 4-12% precast gel, and Androgen Receptor (D6F11) was detected using a conventional Western blot method. Rabbit mAb (CST, Cat. 5153S) and internal control β-Actin (CST, Cat. 3700S) expression were used as the secondary antibody. Anti-rabbit IgG (H+L) (DyLight) was used as the secondary antibody. TM 800 4X PEG Conjugate)(CST,Cat.5151), Anti-mouse IgG(H+L)(DyLight TM 680 Conjugate)(CST, Cat. 5470). The expression levels of AR and internal control were calculated using the protein expression quantification software "Image Studio". The degradation rate (%Degradation) of the compound at different concentrations was calculated according to Equation (7), where R compound AVE_R represents the relative expression level of AR in different concentration groups. DMSO The value represents the average relative expression level of AR in the DMSO control group. Then, inhibition curves and DC values ​​were calculated using GraphPad Prism software. 50 .

[0550] %Degradation=(AVE_R DMSO -R compound ) / AVE_R DMSO ×100% formula (7)

[0551] Conclusion: The compounds of the present invention, such as the compounds in the examples, are effective against LNCaP AR. F877L AR proteins in cells exhibit good degradation activity.

[0552] 16. Study on AR degradation activity in VCAP cells

[0553] Human prostate cancer cells VCAP (AR WT amplified morphology) were cultured in complete medium of DMEM + 10% FBS + 1% penicillin-drug antibiotics at 37°C in a 5% CO2 incubator. Cells in the exponential growth phase were collected and the cell suspension was adjusted to the appropriate concentration using experimental medium (phenol red-free RPMI 1640 + 1% carbon-adsorbed fetal bovine serum + 0.5% PS). Cells were seeded into 12-well plates at 3 × 10⁶ cells / well. 5Cells / well. After plating, the compound diluted with experimental culture medium was added, and the cells were incubated in a CO2 incubator for 24 hours. After incubation, cells were collected, and RIPA lysis buffer (cocktail (Beyotime, Cat. P1010), RIPA (Beyotime, Cat. P0013B, RIPA lysis buffer is prepared by mixing cocktail and RIPA at a ratio of 1:100) was added. The cells were lysed on ice for 15 minutes, centrifuged at 12000 rpm and 4°C for 10 minutes, and the supernatant protein sample was collected. Protein quantification was performed using a BCA kit (Beyotime, Cat. P0009). The protein was then diluted to 0.2 mg / mL, and the expression of AR (Abcam, Cat. ab133273) and the internal control β-Actin Mouse mAb (CST, Cat. 3700S) was detected using a fully automated Western blot quantitative analyzer (Proteinsimple). The expression level of AR relative to the internal reference was calculated using the fully automated protein expression quantification software "Compass for SW". The data processed according to Equation (8) were used to calculate DC using GraphPad Prism 8.0 software with a four-parameter nonlinear regression model. 50 and DC 90 Value, where Protein 给药 The relative expression levels of AR in different dose groups, Protein 溶媒 The relative expression level of AR in the solvent control group is shown.

[0554] Protein% = Protein 给药 / Protein 溶媒 ×100% Formula (8) DCs that degrade AR protein in VCAP cells 90 The results are shown in Table 5.

[0555] Table 5. DCs of VCAP cells degraded by the compounds of the present invention. 90

[0556]

[0557] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good AR degradation activity.

[0558] 17. Study on AR T878A degradation activity in LNCAP cells

[0559] Human prostate cancer cells LNCAP (AR T878A mutant expression) were cultured in complete medium of RPMI 1640 + 10% FBS + 1% penicillin-drug antibiotics at 37°C in a 5% CO2 incubator. Cells in the exponential growth phase were collected and the cell suspension was adjusted to the appropriate concentration using experimental medium (phenol red-free RPMI 1640 + 1% carbon-adsorbed fetal bovine serum + 0.5% PS). Cells were seeded in 12-well plates at 1.5 × 10⁶ cells / well. 5 Cells / well. After plating, the compound diluted with experimental culture medium was added, and the cells were incubated in a CO2 incubator for 24 hours. After incubation, cells were collected, and RIPA lysis buffer (cocktail (Beyotime, Cat. P1010), RIPA (Beyotime, Cat. P0013B, RIPA lysis buffer is prepared by mixing cocktail and RIPA at a ratio of 1:100) was added. The cells were lysed on ice for 15 minutes, centrifuged at 12000 rpm and 4°C for 10 minutes, and the supernatant protein sample was collected. After protein quantification using a BCA kit (Beyotime, Cat. P0009), the protein was diluted to 0.4 mg / mL, and the expression of AR (Abcam, Cat. ab133273) and the internal control β-Actin Mouse mAb (CST, Cat. 3700S) was detected using a fully automated Western blot quantitative analyzer (Proteinsimple). The expression level of AR T878A relative to the internal reference was calculated using the fully automated protein expression quantification software "Compass for SW". The data processed according to equation (9) were then analyzed using GraphPad Prism 8.0 software, and a four-parameter nonlinear regression model was used to calculate DC. 50 Value, where Protein 给药 The relative expression levels of AR T878A in different dosage groups, Protein 溶媒 The relative expression level of ART878A in the solvent control group is shown.

[0560] Protein% = Protein 给药 / Protein 溶媒 ×100% Equation (9)

[0561] The degradation rate of AR T878A protein in LNCAP cells at a concentration of 60 nM is shown in Table 5.

[0562] Table 6. Degradation rate of the compound of the present invention at a concentration of 60 nM to LNCAP cells for AR T878A protein degradation.

[0563]

[0564] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good degradation activity against AR T878A.

Claims

1. A compound or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein, The compounds are selected from those represented by general formula (I). BLK(I); L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -(CH2). q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-、-S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q - or bond, wherein the -CH2- is optionally selected from one or two elements selected from deuterium, halogen, =O, OH, CN, C 1-4 Alkyl or C 3-6 Substituents of cycloalkyl groups; q is selected from 0, 1, 2, or 3; R L Each independently selected from H or C 1-4 alkyl; Cy1, Cy2, Cy3, or Cy4 are each independently selected from the key or arbitrarily selected by 1 to 4 Rs. L2 The substituted group is one of the following: 4-7 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged cyclic group, C 3-7 Monocycloalkyl, C 4-7 Monocyclic alkenyl, C 4-12 cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl; B is selected from ligands that bind to the target; B is preferred. L A or L B Selected from key or NR 1 ; W is selected from O or S; Ring A is selected from 4-12 membered heterocyclic groups or C 3-12 A carbocyclic group, wherein ring A is optionally divided by 1 to 4 R groups. a replace; X1 is selected from N or CR x1 X2 is selected from N or CR x2 X3 is selected from N or CR x3 X4 is selected from N or CR x4 X5 is selected from N or CR x5 ; At most two of X1, X2, X3, X4, and X5 are selected from N; Y1 and Y2 are each independently selected from -CR y1 R y2 -、-(CR y1 R y2 )2-、-(CR y1 R y2 )3-; R 1 Selected from H, deuterium, and C 1-4 Alkyl or C 3-6 Cycloalkyl groups, wherein the alkyl or cycloalkyl group is optionally composed of 1 to 4 elements selected from deuterium, halogen, OH, NH2, CN, C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; R x1 R x2 R x3 R x4 R x5 R a Each is independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 alkylene-4 to 6-membered heterocyclic groups, 5 to 6-membered heteroaryl groups, -OC 3-6 Carbocyclic, -O-4 to 6-membered heterocyclic groups, wherein the alkylene, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, or heteroaryl groups are optionally surrounded by 1 to 4 R groups. s Replaced; Or R x1 R x2 R x3 R x4 Each is independently selected from -S(=O)2NH2 and -S(=O)2C 1-4 alkyl; Or, R x1 With R x2 R x2 With R x3 R x3 With R x4 R x4 With R x5 R 1 With R a Two Rs a Direct connection forms C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally surrounded by 1 to 4 R groups. s Replaced; R 2 R 3 R y1 R y2 Each element is independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl groups, wherein the alkyl, alkenyl, or alkynyl groups are optionally composed of 1 to 4 groups selected from deuterium, halogens, OH, NH2, CN, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; K is selected from This indicates whether the ring in question is aromatic or non-aromatic. F1 is selected from N, NH, CH, CH2, CHR k1 NR k1 CR k1 C(=O), C(R) k1 )2; F2 is selected from bonds, O, N, NH, CH, CH2, CHR. k1 NR k1 CR k1 or C(R) k1 )2; F6, F7, and F8 are each independently selected from N, C, CH, or CR. k1 Furthermore, F6, F7, and F8 contain at most two N's; G is selected from CH or N; E1 is selected from N or CH; E2 is selected from C, N, or CH; Q1 is independently selected from -C(=O)- and -NR. q C(=S)-、-C(=S)NR q -、-NR q CR s 2-、-CR s 2NR q -、 Q2 is independently selected from -C(=O)- and -NR. q C(=S)-、-C(=S)NR q -、-NR q C(=O)-、-C(=O)NR q -、-S(=O)NR q -、-NR q S(=O)-、-S(=O)2NR q -、-NR q S(=O)2-, -C(=O)CH2-, -C(=O)CD2-, -C(=O)CF2-, -NR q C(=S)NR q -、-NR q C(=O)NR q -、 -NR q CR s 2-、-CR s 2NR q -; Q1 or Q2 cannot directly form nitrogen-nitrogen bonds or nitrogen-oxygen bonds with G; R q Each is independently selected from H or C 1-4 alkyl; R k1 Each is independently selected from deuterium, halogen, OH, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic alkyl, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, or heterocyclic alkyl is optionally surrounded by 1 to 4 R... s Replaced; R L2 R s Each is independently selected from deuterium, halogens, OH, CN, ⁻, CF₃, SF₅, NO₂, NH₂, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl group 2, COOH, CONH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 cycloalkyl, -C 0-4 Alkylene-4 to 6-membered heterocyclic group, wherein the alkylene, alkylene, alkoxy, alkenyl, alkynyl, or cycloalkyl group is optionally selected from one to four of deuterium, F, Cl, Br, I, OH, CN, C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; p1 is selected independently from 0, 1, or 2; Or R s Each independently selected from -OC 3-6 cycloalkyl; The condition is that Q2 is selected from -C(=O)NH. 1) At least one of Cy1, Cy2, Cy3, or Cy4 is selected from 1 to 4 R values. L2 The following groups are substituted: 8-12 membered heterocyclic cyclogroups, 8-13 membered heterospirocyclic cyclogroups, 8-12 membered heterobridged cyclogroups, C 8-12 cycloalkyl, C 8-13 Spirocycloalkyl, C 8-12 Bridged cycloalkyl; or 2)L A Selected from key; Or 3)L B Selected from NH; Or 4) W is selected from S.

2. The compound according to claim 1, or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein, Ring A is selected from 5-12 membered heterocyclic groups or C 6-12 A carbocyclic group, wherein ring A is optionally divided by 1 to 4 R groups. a replace; Preferably, ring A is selected from phenyl, 5-6-membered heteroaryl, and benzo[C]. 4-6 Carbocyclic, benzo5-6 membered heterocyclic, pyridoC 4-6 Carbocyclic, pyrido5-6 membered heterocyclic, pyrimidoC 4-6 Carbocyclic group, pyrimidine 5-6 membered heterocyclic group, pyrrolocyclic C 4-6 Carbocyclic, pyrrolo 5-6 membered heterocyclic, thiophene C 4-6 Carbocyclic, thiophene 5-6 membered heterocyclic group, wherein ring A is optionally surrounded by 1 to 4 R groups. a replace; More preferably, ring A is selected from phenyl, naphthyl, benzocyclobutenyl, benzocyclopentenyl, benzocyclohexenyl, pyrrolyl, pyrazolyl, imidazoleyl, furanyl, thiophenyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazinyl, benzopyrrolyl, benzopyrazolyl, benzoimidazolyl, benzothiophenyl, benzothiazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, pyridopyrrolyl, pyridopyrazolyl, pyridoimidazolyl, pyridothiophenyl, pyridothiazolyl, pyridopyridyl, pyridopyrimidinyl, pyridopyrazinyl, and wherein ring A is optionally divided by 1 to 4 R a replace; X3 is selected from CR x3 ; Y1 and Y2 are each independently selected from -CR y1 R y2 -、-(CR y1 R y2 )2-; R 1 The group is selected from H, deuterium, methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl groups are optionally replaced by 1 to 4 groups selected from deuterium, F, Cl, Br, I, OH, NH2, CN, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; R x1 R x2 R x3 R x4 R x5 R a Each is independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 alkylene-4 to 6-membered heterocyclic groups, 5 to 6-membered heteroaryl groups, -OC 3-6 Cycloalkyl, -O-4 to 6-membered heterocyclic groups, wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, or heteroaryl groups are optionally surrounded by 1 to 4 R groups. s Replaced; Preferably R x1 R x2 R x3 R x4 R x5 R a Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3, or arbitrarily selected by 1 to 4 R. s The substituted group is one of the following: methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, pyrazolyl; Or R x1 R x2 R x3 R x4 Each is independently selected from -S(=O)2NH2 and -S(=O)2C 1-4 Alkyl, preferably, R x1 R x2 R x3 R x4 Each is independently selected from -S(=O)2NH2, -S(=O)2methyl, and -S(=O)2ethyl; Or, R x1 With R x2 R x2 With R x3 R x3 With R x4 R x4 With R x5 R 1 With R a Two Rs a Direct connection forms C 4-6 A carbocyclic group, a 5-6 membered heteroaryl group, or a 5-7 membered heterocyclic group, wherein the carbocyclic group, heteroaryl group, or heterocyclic group is optionally surrounded by 1 to 4 R groups. s The replacement, preferably, R x1 With R x2 R x2 With R x3 R x3 With R x4 R x4 With R x5 Direct connection forms an optional 1 to 3 R s The substituted group is one of the following: piperidinyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolylyl, oxecyclopentyl, oxecyclohexyl, 1,3-dioxolane; R 2 R 3 R y1 R y2 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, and methylthio, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, and methylthio groups are selected from 1 to 4 of the following groups: deuterium, F, Cl, Br, I, OH, NH2, CN, and C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; Preferably, R y1 R y2 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, and methylthio, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, and methylthio groups are substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, methyl, ethyl, and methoxy. R L Selected from H, methyl, or ethyl; R q Each is independently selected from H, methyl, ethyl, or isopropyl; Preferably, Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from the following: -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -CH(CH3)-, -CH2-, -C(CH3)2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH-, or -NHC(=O)-; Cy1, Cy2, Cy3, and Cy4 are each independently selected from key or arbitrarily selected by 1 to 4 R values. L2 The substituted group is one of the following: phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl. s1, s3, and s5 are each independently selected from 0, 1, or 2; s2 and s4 are each independently selected from 0 or 1; s6 is selected from 0, 1, 2, or 3; s7 is selected from 1, 2, or 3; Preferably, Cy1, Cy2, Cy3, and Cy4 are each independently selected from one of the following groups, either bonded or optionally substituted: When substituted, it is replaced by 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, and cyclopropyl. K is selected from More preferably, K is selected from Q1 is independently selected from C(=O), NHC(=S), C(=S)NH, -NHCF2-, -CF2NH-, -NHCH(CF3)-, -CH(CF3)NH-, Q2 is independently selected from -C(=O)-, -NHC(=S)-, -C(=S)NH-, -NHC(=O)-, -C(=O)NH-, -S(=O)NH-, -NHS(=O)-, -S(=O)2NH-, -NHS(=O)2-, -C(=O)CH2-, -C(=O)CD2-, -C(=O)CF2-, -NHC(=S)NH-, -NHC(=O)NH-, -NHCF2-、-CF2NH-、 -NHCH(CF3)-, -CH(CF3)NH-; R k1 Each of the following groups is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl groups are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, and NH2; Preferably, R k1 Each is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, CF3, CHF2, CH2F, OCF3, OCH2F, OCHF2, OCD3, CH2OH, CD3, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl; R L2 R s Each is independently selected from deuterium, halogens, OH, CN, ⁻, CF₃, SF₅, NO₂, NH₂, and NHC. 1-4 Alkyl, N(C) 1-4 Alkyl group 2, COOH, CONH2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 cycloalkyl, -C 0-2 Alkylene-4 to 6-membered heterocyclic group, wherein the alkylene, alkylene, alkoxy, alkenyl, alkynyl, or cycloalkyl group is optionally selected from one to four of deuterium, F, Cl, Br, I, OH, CN, C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; Preferably, R L2 R s Each of the following is independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups; Or R s Each independently selected from -OC 3-6 cycloalkyl, preferably, R s Each is independently selected from propynyl and -O-cyclopropyl.

3. The compound according to claim 2, or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein, B is selected from L A or L B Selected from bond or NH; W is selected from O or S; Ring A is selected from phenyl, pyridyl, thienyl, benzothienyl, benzocyclopentenyl, and naphthyl, wherein ring A is optionally surrounded by 1 to 4 R groups. a replace; R x3 R x4 Or R a Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3, CF3, CHF2, CH2F, OCF3, OCH2F, OCD3, CH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, -CH2-cyclopropyl, -O-cyclopropyl; L is selected from -Cy1-, -Cy1-Ak2-, -Cy1-CH2-, -Ak1-Cy1-, -Cy1-Cy2-, -Cy1-CH2-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH2-Cy2-Cy3-, -Cy1-Cy2-CH2-Cy3-; Cy1, Cy2, and Cy3 are each independently selected from one of the following groups that can be substituted: When substituted, it is replaced by 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, and cyclopropyl.

4. The compound according to claim 3, or its stereoisomers, tautomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein, B is selected from the structural segments shown in Table B-1; L is selected from the structural segments shown in Table L-1; K is selected from the structural segment shown in K-1.

5. The compound according to claim 3, or its stereoisomers, tautomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein, The compounds represented by general formula (I) are selected from the compounds represented by general formulas (Ia), (Ib), and (Ic). Cy1 and Cy2 are each independently selected from one of the following groups that can be substituted: When substituted, it is replaced by 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, and cyclopropyl. R k1 Each is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, CF3, CHF2, CH2F, OCF3, OCH2F, OCHF2, OCD3, CH2OH, CD3, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl; R w Each is independently selected from methyl or CD3; p1 is selected from 0, 1, or 2.

6. The compound according to claim 1, or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein the compound is selected from the structures shown in Table E, preferably, the compound is selected from the structures shown in Table E-1. Table E-1 7. A pharmaceutical composition comprising the compound of any one of claims 1-6 or its stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, preferably, the pharmaceutical composition containing 1 to 1500 mg of the compound of any one of claims 1-6 or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts.

8. The use of the compound of any one of claims 1-6, or its stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, or the pharmaceutical composition of claim 7, in the preparation of a medicament for treating diseases related to AR activity or expression levels.

9. The use of the compound of any one of claims 1-6, or its stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, or the pharmaceutical composition of claim 7, in the preparation of a medicament for treating and inhibiting or degrading AR-related diseases.

10. The application according to claim 9, characterized in that, The disease mentioned is selected from cancers, preferably prostate cancer.

Images