Compound, composition comprising same, and use thereof

Abstract

Provided are a compound, or a stereoisomer, or pharmaceutically acceptable salt, or deuterated compound, or tautomer, or polymorphic substance, or solvate, or N-oxide, or isotope labeled compound, or metabolite, or prodrug thereof, and a use thereof. The structure of the compound is as shown in formula 0, and the compound serves as an AR regulator and has better castration-resistant prostate cancer cell proliferation inhibition activity, better AR protein degradation activity, and better oral bioavailability.

Description

A compound, a composition comprising the same and its application

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent application No. 202311008521.7 filed on August 11, 2023, entitled “A compound, a composition comprising the same, and its application”, and Chinese patent application No. 202410503322.1 filed on April 25, 2024, entitled “A compound, a composition comprising the same, and its application”, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to the field of medicine, and in particular to a compound, a composition comprising the compound, and applications thereof. Background Art

[0004] Androgen receptors (AR) are steroid receptors belonging to the nuclear receptor superfamily. Wild-type AR consists of four domains: the N-terminal transcriptional activation domain (NTD), the DNA binding domain (DBD), the hinge domain, and the ligand binding domain (LBD). After binding to the ligand androgen in vivo, AR forms an AR dimer, which is then phosphorylated and translocated from the cytoplasm to the nucleus. There, AR mediates the transcription and activation of downstream genes, thereby regulating a range of physiological and pathological functions. In the normal adult prostate, AR regulates the dynamic balance between prostate epithelial cell proliferation and apoptosis. This dynamic balance is disrupted in prostate cancer (PC) tissue, promoting tumor cell proliferation and survival, which is the main cause of prostate cancer. Furthermore, abnormalities in the androgen receptor signaling pathway play a significant role in the occurrence and development of breast cancer, bladder cancer, and other cancers. Therefore, inhibiting or degrading the androgen receptor is an effective method for treating cancers with abnormal androgen receptor expression, such as prostate cancer. Currently, there are many androgen receptor inhibitors such as bicalutamide, enzalutamide, and darolutamide on the market. AR PROTAC degraders based on traditional E3 ubiquitin ligases (such as CRBN), such as ARV-110 (NCT03888612) and CC-94676 (NCT04958291), are also in clinical development. However, some patients still have primary drug resistance or acquire drug resistance during treatment due to increased AR expression or the generation of new AR mutations or E3 mutations.

[0005] Heat shock proteins (such as HSP90) are one of the main proteins that play a role in maintaining cellular homeostasis. HSP90 is involved in the correct folding of newly formed proteins and the repair of damaged proteins. It plays an important role in maintaining AR stability and plays an indispensable role in tumor progression. At the same time, HSP90 is highly expressed on the surface of tumor cells. HSP90 ligand-directed therapeutic conjugates can selectively target tumor cells, overcome drug resistance, and reduce systemic toxicity, which is expected to improve the therapeutic index of traditional chemotherapy drugs.

[0006] Summary of the Invention

[0007] The present application provides a compound, a composition comprising the same, and its application to improve the activity of inhibiting the proliferation of prostate cancer cells.

[0008] In the first aspect of the present application, a compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof is provided, wherein the structure of the compound is shown in Formula 0:

[0009] The formula O is selected from any one of the following formulas I to VII:

[0010] In Formula I or Formula I', A 1 is a 5-10 membered heteroarylene group, wherein the 5-10 membered heteroarylene group is optionally substituted by any one or more selected from the group consisting of a C1-C6 alkyl group, a C3-C6 cycloalkyl group, ═O, ═S and a halogen group;

[0011] R 1 is a substituent at any position of the indolyl group, and R 1 Any one or more selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, ═O, ═S and halogen;

[0012] L 1 , L 2 , L 3 , L 4 and L 5 are each independently selected from a single bond, a C1-C6 alkylene group, a carbonyl group, a 4-10 membered heterocycloalkylene group, and L 1 , L 2 , L 3 , L 4 and L 5 At least two of them meet the following conditions: one is a 4-10 membered heterocycloalkylene group and the other is a C1-C6 alkylene group;

[0013] C1 is selected from C6-C10 arylene or 5-10 membered heteroarylene, and the C6-C10 arylene or 5-10 membered heteroarylene is optionally substituted with halogen or C1-C6 alkyl;

[0014] L 6 is selected from -NH-C(O)-, a single bond;

[0015] C 2 is selected from 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene, and the 4-10 membered cycloalkylene and 5-10 membered heterocycloalkylene are optionally substituted by any one or more of the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S and halogen;

[0016] L 7 is selected from -O-, -NH-, a single bond;

[0017] R 2 is selected from halogen and C1-C6 haloalkyl;

[0018] X is C or N;

[0019] In Formula II or Formula II', A 1 is a 5-10 membered heteroarylene group, wherein the 5-10 membered heteroarylene group is optionally substituted by any one or more of the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, =S, halogen, R A1 and R A2 Each is independently H or C1-C6 alkyl;

[0020] A 2 is a C6-C10 arylene group or a 5-10 membered heteroarylene group, wherein the C6-C10 arylene group and the 5-10 membered heteroarylene group are optionally substituted with halogen or C1-C6 alkyl;

[0021] L 1 , L 2 , L 3 and L 4 Each is independently selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a carbonyl group, -O-, a 4-10 membered heterocycloalkylene group, -N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group, and L 1 , L 2 , L 3 and L 4At least two of them meet the following conditions: one is a 4-10 membered heterocycloalkylene group and the other is a C1-C6 alkylene group;

[0022] C 1 is selected from C6-C10 arylene or 5-10 membered heteroarylene, and the C6-C10 arylene or 5-10 membered heteroarylene is optionally substituted with halogen or C1-C6 alkyl;

[0023] L 6 is selected from -NH-C(O)-, a single bond;

[0024] C 2 is selected from 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene, and the 4-10 membered cycloalkylene and 5-10 membered heterocycloalkylene are optionally substituted by any one or more of the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S and halogen;

[0025] L 7 is selected from -O-, -NH-, a single bond;

[0026] R 2 is selected from halogen and haloalkyl;

[0027] X is C or N;

[0028] In formula III or formula III', A 2 is a C6-C10 arylene group or a 5-10 membered heteroarylene group, wherein the C6-C10 aryl group and the 5-10 membered heteroaryl group are optionally substituted by halogen or C1-C6 alkyl;

[0029] L 1 , L 2 , L 3 and L 4 Each is independently selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a carbonyl group, a 4-10 membered heterocycloalkylene group, -O-, -N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group, -N(R B1 )R B2 -N atom and A 2 Connect, and L 1 When L is a C1-C6 alkylene group 2 and L 3 One is a single bond and the other is a 4-10 membered heterocycloalkylene group;

[0030] C1 is selected from C6-C10 arylene or 5-10 membered heteroarylene, and the C6-C10 arylene or 5-10 membered heteroarylene is optionally substituted with halogen or C1-C6 alkyl;

[0031] L 6 is selected from -NH-C(O)-, a single bond;

[0032] C 2 is selected from 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene, and the 4-10 membered cycloalkylene and 5-10 membered heterocycloalkylene are optionally substituted by any one or more of the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S and halogen;

[0033] L 7 is selected from -O-, -NH-, a single bond;

[0034] R 2 is selected from halogen and haloalkyl;

[0035] X is C or N;

[0036] In Formula IV or Formula IV', A 1 is a 5-10 membered heteroarylene group, wherein the 5-10 membered heteroarylene group is optionally substituted by any one or more selected from the group consisting of a C1-C6 alkyl group, a C3-C6 cycloalkyl group, ═O, ═S and a halogen group;

[0037] A 2 is a C6-C10 arylene group or a 5-10 membered heteroarylene group, wherein the C6-C10 arylene group and the 5-10 membered heteroarylene group are optionally substituted with halogen or C1-C6 alkyl;

[0038] L 1 , L 2 , L 3 and L 4 Each is independently selected from a single bond, a C1-C6 alkylene group, a carbonyl group, and a 4-10 membered heterocycloalkyl group, and at least one is not a single bond;

[0039] C 1 is selected from C6-C10 arylene or 5-10 membered heteroarylene, and the C6-C10 arylene or 5-10 membered heteroarylene is optionally substituted with halogen or C1-C6 alkyl;

[0040] L 6 is selected from -NH-C(O)-, a single bond;

[0041] C 24-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, and 4-10 membered cycloalkyl, 5-10 membered heterocycloalkyl are optionally substituted by any one or more of the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S and halogen;

[0042] L 7 Selected from -O-, -NH-, single bond; R 2 is selected from halogen and haloalkyl;

[0043] X is C or N; and the compound of formula IV does not include the following compounds:

[0044] In Formula V or Formula V', A 1 It is a 5-10 membered heteroarylene group, wherein the heteroatom is preferably a N atom and / or an O atom, and the number of heteroatoms is preferably 1-3, and the 5-10 membered heteroarylene group is optionally substituted by any one or more of the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S, halogen, R A1 and R A2 Each is independently H or C1-C6 alkyl;

[0045] A 2 is a C6-C10 arylene group or a 5-10 membered heteroarylene group, wherein the C6-C10 arylene group and the 5-10 membered heteroarylene group are optionally substituted with halogen or C1-C6 alkyl;

[0046] L 1 , L 2 , L 3 , L 4 and L 5 Each is independently selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a carbonyl group, a 4-10 membered heterocycloalkylene group, -O-, -C(O)-NH-, *-N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group;

[0047] C 1 is selected from 5-10 membered heteroarylene, and the 5-10 membered heteroarylene is optionally substituted by any one or more of the following groups: C1-C6 alkyl and halogen; L 6 Selected from -R C1 -NH-, -RC1 -NH-C(O)- or single bond, R C1 is a C0-C6 alkylene group;

[0048] C 2 is selected from 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene, 5-10 membered heteroarylene, and the 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene, 5-10 membered heteroarylene are optionally substituted by any one or more of the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S and halogen;

[0049] L 7 is selected from a single bond, -O-, -NH-;

[0050] R 2 is selected from halogen and haloalkyl;

[0051] X is C or N;

[0052] In Formula VI or Formula VI', A 1 A is selected from a 5-10 membered heteroarylene group, 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more of the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S, halogen, R A1 and R A2 Each is independently H or C1-C6 alkyl;

[0053] A 2 is selected from C6-C10 arylene or 5-10 membered heteroarylene, wherein, as A 2 The C6-C10 arylene and 5-10 membered heteroarylene are optionally substituted by halogen or C1-C6 alkyl;

[0054] L 1 , L 2 , L 3 , L 4 and L 5 Each is independently selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a carbonyl group, a 4-10 membered heterocycloalkylene group, a C3-C10 cycloalkylene group, a C6-C10 arylene group, -O-, *-N(R B1 )R B2 -, phenylene, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group, or for

[0055] C1 is selected from a single bond, a C6-C10 arylene group or a 5-10 membered heteroarylene group, and as C 1 The C6-C10 arylene or 5-10 membered heteroarylene is optionally substituted with halogen or C1-C6 alkyl;

[0056] L 6 is a C1-C6 alkyl group, the C1-C6 alkyl group is optionally substituted by OH, and the C1-C6 alkyl group is preferably a branched alkyl group;

[0057] R 2 is selected from halogen and haloalkyl;

[0058] X is C or N;

[0059] In Formula VII, A 1 A is selected from a 5-10 membered heteroarylene group, 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more of the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S, halogen, R A1 and R A2 Each is independently H or C1-C6 alkyl;

[0060] A 2 is selected from C6-C10 arylene or 5-10 membered heteroarylene, wherein, as A 2 The C6-C10 arylene and 5-10 membered heteroarylene are optionally substituted by halogen or C1-C6 alkyl;

[0061] L 1 , L 2 , L 3 , L 4 and L 5 Each is independently selected from a single bond, a C1-C6 alkylene group, a carbonyl group, a 4-10 membered heterocycloalkylene group, -O-, *-N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group;

[0062] C 1 The ring is selected from C6-C10 aryl, 5-10 membered heteroaryl;

[0063] R 5 is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, OH, NH2, CN, nitro, carboxyl, C3-C6 cycloalkyl,

[0064] R3 、R 4 are each independently selected from H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and R 3 and R 4 Connected to form a ring with the carbon atom shared by the two;

[0065] R 2 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl.

[0066] As AR regulators, the above compounds have better castration-resistant prostate cancer cell proliferation inhibition activity, better AR protein degradation activity, and better oral bioavailability.

[0067] In some embodiments of the present application, in Formula I or Formula I', as A 1 The heteroatom of the 5-10 membered heteroarylene group is a N atom, and the number of heteroatoms is preferably 1-3; preferably A 1 The 5-10 membered heteroarylene group is triazolyl, and the 5-10 membered heteroarylene group is optionally substituted by any one or more of the group consisting of C1-C6 alkyl, ═O, and ═S.

[0068] In some embodiments of the present application, in Formula I or Formula I', L 1 is selected from a single bond, a C1-C6 alkylene group, and more preferably L 1 is selected from a single bond, methylene, ethylene, and propylene;

[0069] In some embodiments of the present application, in Formula I or Formula I', L 2 is selected from 4-10 membered heterocycloalkylene, single bond, preferably as said L 2 The heteroatom of the 4-10 membered heterocycloalkyl is N, S or P; preferably L 2 is azetidinylene, piperidinylene or piperazinylene;

[0070] In some embodiments of the present application, in Formula I or Formula I', L 3 is selected from a single bond, a C1-C6 alkylene group, and more preferably L 3 is selected from a single bond, methylene, ethylene, and propylene;

[0071] In some embodiments of the present application, in Formula I or Formula I', L 4 is selected from 4-10 membered heterocycloalkylene, single bond, preferably as said L 4 The heteroatom of the 4-10 membered heterocycloalkyl is N, S or P; preferably L 4 is azetidinylene, piperidinylene or piperazinylene;

[0072] In some embodiments of the present application, in Formula I or Formula I', L5 Selected from a single bond, a C1-C6 alkylene group, or a carbonyl group.

[0073] In some embodiments of the present application, the compound of formula I or the compound of formula I' is selected from any one of formula I1, formula I2 or formula I1':

[0074] In formula I1 or formula I1', C 1 Selected from 5-10 membered heteroarylene, preferably as C 1 The 5-10 membered heteroaryl group is imidazolyl, pyrazolyl, thiazolyl, pyrrolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, preferably C 1 The 5-10 membered heteroarylene group is pyrazolylene, pyridylene, pyrimidylene, or pyridazinylene, and the 5-10 membered heteroarylene group is optionally substituted by halogen (e.g., F, Cl, or Br), or C1-C6 alkyl (e.g., methyl, ethyl, propyl, or butyl);

[0075] C 2 Selected from 4-10 membered cycloalkylene, preferably as C 2 The 4-10 membered cycloalkylene group is cyclobutylene, cyclopentylene, cyclohexylene or cycloheptylene, and as C 2 The 4-10 membered cycloalkylene is optionally substituted by any one or more selected from the group consisting of: C1-C6 alkyl (e.g., methyl, ethyl, propyl or butyl) and halogen (e.g., F, Cl or Br);

[0076] L 7 Selected from -O-, -NH-,

[0077] R 2 is selected from halogen, preferably F, Cl or Br, more preferably Cl;

[0078] X is C or N.

[0079] In some embodiments of the present application, in Formula I1 or Formula I1' Any one selected from the following groups: More preferably, I1 or I1' for in, Connect the terminal to C1. The end is connected to the indole group;

[0080] In some embodiments of the present application, in Formula II' Any one selected from the following groups:

[0081] In some embodiments of the present application, in Formula I1 or Formula I1' for

[0082] In formula I2, C 1 Selected from C6-C10 aryl or 5-10 membered heteroaryl, as C 1 The C6-C10 aryl group is preferably a phenylene group, as C 1 The 5-10 membered heteroaryl is preferably pyridylene or pyridazinylene; and as C 1 The C6-C10 aryl or 5-10 membered heteroaryl is optionally substituted by halogen (eg, F, Cl or Br), C1-C6 alkyl (eg, methyl, ethyl or propyl); R 2 is selected from haloalkyl, preferably trifluoromethyl; X is C or N.

[0083] In some embodiments of the present application, in Formula I2 Any one selected from the following groups: in, End and C 1 connect, The end is connected to the indole group.

[0084] In some embodiments of the present application, in Formula I2 Any one selected from the following groups:

[0085] In some embodiments of the present application, in Formula I2 for

[0086] In some embodiments of the present application, in Formula II or Formula II', as A 1 The heteroatoms of the 5-10 membered heteroarylene group are preferably N atoms and / or O atoms, and the number of heteroatoms is preferably 1-3. 1 The 5-10 membered heteroarylene group is substituted by any one or more selected from the group consisting of: R A1 and R A2 Each is independently H or C1-C6 alkyl, preferably R A1 and R A2 Each independently is H, methyl, ethyl, n-propyl or isopropyl; preferably as A 1 The 5-10 membered heteroaryl is triazolylene, isoxazolylene or pyrazolylene.

[0087] In some embodiments of the present application, in Formula II or Formula II', A 2 is a C6-C10 arylene group or a 5-10 membered heteroarylene group, preferably as A 2 The C6-C10 aryl or 5-10 membered heteroaryl is phenylene, pyridylene, pyridazinylene, pyrimidylene, indolylene, and more preferably A 2 The C6-C10 aryl or 5-10 membered heteroaryl is phenyl or pyridyl, wherein the C6-C10 arylene and 5-10 membered heteroarylene are optionally substituted by halogen or C1-C6 alkyl.

[0088] In some embodiments of the present application, in Formula II or Formula II', L 1 selected from C1-C6 alkylene, -O-, -N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 It is a C0-C6 alkylene group.

[0089] In some embodiments of the present application, in Formula II or Formula II', L 2 is selected from 4-10 membered heterocycloalkylene, single bond, preferably as said L 2 The heteroatom in the 4-10 membered heterocycloalkylene is N, S or P; preferably, L 2 The 4- to 10-membered heterocycloalkylene group is azetidinylene, azacyclopentylene, piperidinylene or piperazinylene.

[0090] In some embodiments of the present application, in Formula II or Formula II', L 3 Selected from single bonds, C1-C6 alkylene groups.

[0091] In some embodiments of the present application, in Formula II or Formula II', L 4 is selected from a single bond, a 4-10 membered heterocycloalkylene, -O-, preferably as the L 4 The heteroatom in the 4-10 membered heterocycloalkylene is N, S or P; preferably, L 4 The 4-10 membered heterocycloalkylene group is azetidinyl, azacyclopentylene, piperidinylene or piperazinylene; and L 2 and L 4 Not single bond at the same time.

[0092] In some embodiments of the present application, in Formula II or Formula II', C 1 Selected from C6-C10 arylene or 5-10 membered heteroarylene; preferably C 1The C6-C10 aryl or 5-10 membered heteroaryl is phenylene, pyridylene, pyridazinylene, pyrimidylene, indolylene, and more preferably C 1 The C6-C10 aryl group or 5-10 membered heteroaryl group is phenylene or pyridylene, and the C6-C10 arylene group or 5-10 membered heteroarylene group is optionally substituted by halogen or C1-C3 alkyl.

[0093] In some embodiments of the present application, in Formula II or Formula II', L 6 Selected from -NH-C(O)-; C 2 The 4- to 10-membered cycloalkylene group is optionally substituted by any one or more of the following groups: C1-C6 alkyl and halogen.

[0094] In some embodiments of the present application, in Formula II or Formula II', L 7 Selected from -O-, -NH-.

[0095] In some embodiments of the present application, in Formula II or Formula II', R 2 Selected from halogen, -CF3.

[0096] In some embodiments of the present application, in Formula II or Formula II', X is C or N.

[0097] In some embodiments of the present application, the compound of formula II or the compound of formula II' is selected from any one of formula III or formula III':

[0098] In formula III or III', as A 1 The heteroatoms of the 5-10 membered heteroarylene group are preferably N atoms and / or O atoms, and the number of heteroatoms is preferably 1, 2 or 3. 1 The 5-10 membered heteroarylene group is substituted by any one or more selected from the group consisting of: R A1 and R A2 Each is independently H, methyl or ethyl;

[0099] L 1 selected from C1-C6 alkylene, -O-, -N(R B1 )R B2 -, R B1 is H, methyl, ethyl or n-propyl, R B2 is a single bond, methylene, ethylene, propylene or butylene;

[0100] L 2 is selected from 4-6 membered heterocycloalkylene, single bond, preferably as the L 2The 4-6 membered heterocycloalkylene group is azetidinylene, azacyclopentylene, piperidinylene or piperazinylene;

[0101] L 3 selected from a single bond, a C1-C3 alkylene group;

[0102] L 4 is selected from a single bond, a 4-6 membered heterocycloalkylene, -O-, preferably as the L 4 The 4-16 membered heterocycloalkylene group is azetidinyl, azacyclopentyl, piperidinyl or piperazinyl; and L 2 and L 4 Not all are single bonds at the same time;

[0103] C 1 An arylene group selected from C6-C10 or a 5-10 membered heteroarylene group is preferred, preferably as C 1 The C6-C10 arylene group is phenyl, preferably C 1 The 5-10 membered heteroarylene group is pyridylene, pyrimidylene, pyridazinylene, or pyrazinylene, more preferably pyridazinylene, and the C6-C10 arylene group or the 5-10 membered heteroarylene group is optionally substituted with halogen (e.g., F, Cl, or Br), or C1-C3 alkyl (e.g., methyl, ethyl, or propyl);

[0104] C 2 The 4-6 membered cycloalkylene group is selected from cyclobutylene, cyclopentylene and cyclohexylene, and the 4-6 membered cycloalkylene group is optionally substituted by any one or more of the following groups: C1-C6 alkyl (such as methyl, ethyl or propyl) and halogen (such as F, Cl or Br).

[0105] In some embodiments of the present application, in Formula III or Formula III' Any one selected from the following groups: More preferably in, End and C 1 connect, The end is connected to a phenyl group;

[0106] In some embodiments of the present application, in Formula III ' Any one selected from the following groups:

[0107] Preferably

[0108] In some embodiments of the present application, in Formula III or Formula III' Any one selected from the following groups: Preferably

[0109] In some embodiments of the present application, in Formula III or Formula III', A 2 is phenylene, 5-membered heteroarylene, 6-membered heteroarylene, preferably A 2 is phenylene, pyridylene, pyridazinylene, pyrimidylene; phenylene, 5-membered heteroarylene, 6-membered heteroarylene are optionally substituted by halogen or C1-C6 alkyl.

[0110] In some embodiments of the present application, in Formula III or Formula III', L 1 selected from C1-C6 alkylene, -O-, -N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 It is a C0-C6 alkylene group.

[0111] In some embodiments of the present application, in Formula III or Formula III', L 2 It is selected from 4-10 membered heterocycloalkyl, wherein the heteroatom is N, S or P; preferably azetidinylene, piperidinylene or piperazinylene.

[0112] In some embodiments of the present application, in Formula III or Formula III', L 3 is selected from a single bond, a C1-C6 alkylene group, a carbonyl group, a C1-C6 alkylene-carbonyl group; and L 1 When L is a C1-C6 alkylene group, 2 and L 3 One is a single bond and the other is a 4-10 membered heterocycloalkyl.

[0113] In some embodiments of the present application, in Formula III or Formula III', L 4 It is selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably azetidinyl, piperidinyl or piperazinyl.

[0114] In some embodiments of the present application, in Formula III or Formula III', C 1 Selected from C6-C10 arylene or 5-10 membered heteroarylene; preferably C 1 The C6-C10 aryl or 5-10 membered heteroaryl is phenylene, pyridylene, pyridazinylene, pyrimidylene, indolylene, and more preferably C 1The C6-C10 aryl group or 5-10 membered heteroaryl group is phenylene or pyridylene, and the C6-C10 arylene group or 5-10 membered heteroarylene group is optionally substituted by halogen or C1-C3 alkyl.

[0115] In some embodiments of the present application, in Formula III or Formula III', L 6 Selected from -NH-C(O)-; C 2 The 4- to 10-membered cycloalkylene group is optionally substituted by any one or more of the following groups: C1-C6 alkyl and halogen.

[0116] In some embodiments of the present application, in Formula III or Formula III', L 7 Selected from -O-, -NH-.

[0117] In some embodiments of the present application, in Formula III or Formula III', R 2 Selected from halogen, -CF3.

[0118] In some embodiments of the present application, in Formula III or Formula III', X is C or N.

[0119] In some embodiments of the present application, the compound of formula III or the compound of formula III' is selected from any one of formula III1 or formula III1':

[0120] In formula III1 or formula III1', A 2 is phenylene, 5-membered heteroarylene, 6-membered heteroarylene, preferably A 2 is phenylene, pyridylene, pyridazinylene, or pyrimidinylene;

[0121] L 1 selected from C1-C6 alkylene, -O-, -N(R B1 )R B2 -, R B1 is H, methyl, ethyl or propyl, R B2 is a single bond, methylene, ethylene, propylene or butylene, preferably L 1 Selected from methylene, ethylene, -O-, -N(R B1 )R B2 -, R B1 is H, methyl or ethyl, R B2 is a single bond, methylene or ethylene;

[0122] L 2 Selected from 4-10 membered heterocycloalkyl, the heteroatom is N, S or P; preferably azetidinyl, piperidinyl or piperazinyl;

[0123] L3 is selected from a single bond, methylene, ethylene, propylene, carbonyl, methylene-carbonyl, ethylenecarbonyl; and L 1 When L is methylene, 2 and L 3 One is a single bond and the other is a 4-10 membered heterocycloalkyl;

[0124] L 4 Selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably azetidinyl, piperidinyl or piperazinyl;

[0125] C 1 An arylene group selected from C6-C10 or a 5-10 membered heteroarylene group is preferred, preferably as C 1 The C6-C10 arylene group is phenyl, preferably C 1 The 5-10 membered heteroarylene group is pyridylene, pyrimidylene, pyridazinylene, or pyrazinylene, more preferably pyridazinylene, and the C6-C10 arylene group or the 5-10 membered heteroarylene group is optionally substituted with halogen (e.g., F, Cl, or Br), or C1-C3 alkyl (e.g., methyl, ethyl, or propyl);

[0126] C 2 The 4-6 membered cycloalkylene group is selected from cyclobutylene, cyclopentylene and cyclohexylene, and the 4-6 membered cycloalkylene group is optionally substituted by any one or more of the following groups: C1-C6 alkyl (such as methyl, ethyl or propyl) and halogen (such as F, Cl or Br).

[0127] In some embodiments of the present application, in Formula III1 or Formula III1' Any one selected from the following groups:

[0128] in, End and C 1 connect, End and A 2 connect.

[0129] In some embodiments of the present application, in formula III1' Any one selected from the following groups:

[0130] In some embodiments of the present application, in Formula III1 or Formula III1' Any one selected from the following groups:

[0131] In some embodiments of the present application, in Formula IV or Formula IV', A 1is a 5-10 membered heteroarylene group, wherein the heteroatom is preferably a N atom, the number of heteroatoms is preferably 1-3, and is preferably used as A 1 The 5- to 10-membered heteroarylene group is a triazole group, and the 5- to 10-membered heteroarylene group is optionally substituted by any one or more of the group consisting of: ═O, ═S.

[0132] In some embodiments of the present application, in Formula IV or Formula IV', A 2 is a C6-C10 arylene group or a 5-10 membered heteroarylene group, preferably as A 2 The C6-C10 arylene group is a phenylene group, preferably 2 The 5-10 membered heteroarylene group is a pyrimidinyl group or a pyridinyl group, wherein the C6-C10 arylene group and the 5-10 membered heteroarylene group are optionally substituted by halogen (such as F, Cl or Br) or C1-C3 alkyl (such as methyl, ethyl, propyl or butyl).

[0133] In some embodiments of the present application, in Formula IV or Formula IV', L 1 Selected from single bond, C1-C6 alkylene, carbonyl, preferably L 1 is selected from a single bond, methylene, ethylene or carbonyl.

[0134] In some embodiments of the present application, in Formula IV or Formula IV', L 2 It is selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably azetidinyl, piperidinyl or piperazinyl.

[0135] In some embodiments of the present application, in Formula IV or Formula IV', L 3 is selected from a single bond or a methylene group.

[0136] In some embodiments of the present application, in Formula IV or Formula IV', L 4 It is selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably azetidinyl, piperidinyl or piperazinyl.

[0137] In some embodiments of the present application, in Formula IV or Formula IV', C 1 Selected from 5-10 membered heteroarylene, preferably as C 1 The 5-10 membered heteroaryl group is imidazolyl, pyrazolyl, thiazolyl, pyrrolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, preferably C 1 The 5-10 membered heteroarylene group is pyrazolylene, pyridylene, pyrimidylene, or pyridazinylene, and the 5-10 membered heteroarylene group is optionally substituted by halogen (e.g., F, Cl, or Br), or C1-C6 alkyl (e.g., methyl, ethyl, propyl, or butyl).

[0138] In some embodiments of the present application, in Formula IV or Formula IV', L 6 Selected from -NH-C(O)-.

[0139] In some embodiments of the present application, in Formula IV or Formula IV', C 2 Selected from 4-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, preferably as C 2 The 4-10 membered cycloalkylene group is cyclobutylene, cyclopentylene, cyclohexylene or cycloheptylene, preferably C 2 The 5-10 membered heterocycloalkyl group is a piperidinylene or a piperazinylene group, and as C 2 The 4-10 membered cycloalkyl and 5-10 membered heterocycloalkyl are optionally substituted by halogen or C1-C3 alkyl.

[0140] In some embodiments of the present application, in Formula IV or Formula IV', L 7 Selected from -O-, -NH-, and a single bond.

[0141] In some embodiments of the present application, in Formula IV or Formula IV', R 2 is selected from halogen and haloalkyl, preferably Cl or trifluoromethyl.

[0142] In some embodiments of the present application, in Formula IV or Formula IV', Any one selected from the following groups: in, End and C 1 connect, End and A 2 connect.

[0143] In some embodiments of the present application, in Formula V or Formula V', A 1 is a 5-10 membered heteroarylene group, preferably as A 1 The 5-10 membered heteroarylene group is triazole-, isoxazole- or pyrazolyl-, preferably as A 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, ═O, and ═S.

[0144] In some embodiments of the present application, in Formula V or Formula V', A 2 is a phenylene group or a 6-membered heteroarylene group, wherein the phenylene group and the 6-membered heteroarylene group are optionally substituted by halogen or C1-C3 alkyl.

[0145] In some embodiments of the present application, in Formula V or Formula V', L 1Selected from single bond, C1-C3 alkylene, C2-C3 alkynylene, carbonyl, -C(O)-NH-, -O-, *-N(R B1 )R B2 -, R B1 is H, C1-C3 alkyl, R B2 It is a C0-C3 alkylene group.

[0146] In some embodiments of the present application, in Formula V or Formula V', L 2 is selected from 4-10 membered heterocycloalkylene, single bond, heteroatom is N, S or P; preferably as L 2 The 4- to 10-membered heterocycloalkylene group is azetidinylene, piperidinylene or piperazinylene.

[0147] In some embodiments of the present application, in Formula V or Formula V', L 3 Selected from a single bond, a C1-C3 alkylene group, a C2-C3 alkynylene group, a carbonyl group, and -C(O)-NH-.

[0148] In some embodiments of the present application, in Formula V or Formula V', L 4 is selected from 4-10 membered heterocycloalkylene, single bond, heteroatom is N, S or P; preferably as L 4 The 4- to 10-membered heterocycloalkylene group is azetidinylene, piperidinylene or piperazinylene.

[0149] In some embodiments of the present application, in Formula V or Formula V', L 5 is selected from a single bond, a C1-C3 alkylene group, a C2-C3 alkenylene group, a C2-C3 alkynylene group, -C(O)-NH-, or a carbonyl group.

[0150] In some embodiments of the present application, in Formula V or Formula V', C 1 is selected from 5-8 membered heteroarylene, and the 5-8 membered heteroarylene is optionally substituted by any one or more of the following groups: C1-C3 alkyl and halogen; preferably C 1 Selected from A fused heterocyclic ring, wherein Middle Y 1 、Y 2 、Y 3 and Y 4 are each independently selected from C or N, and at least one is N; Middle Z 1 、Z 2 、Z 3 and Z 4 are independently selected from C or N, and at least one is N; Y in the fused heterocycle 1 、Y 2 、Y 3 、Y4 、Z 1 、Z 2 、Z 3 and Z 4 Each is independently selected from C or N, and at least one is N; further preferably is an imidazole ring, a pyrazole ring, a thiazole ring, a pyrrole ring, or a triazole ring; further preferably is a benzene ring, a pyrimidine ring, a pyridazine ring, or a pyrazine ring; and further preferably, the fused heterocyclic ring is a fused heterocyclic ring of any one of a benzene ring, a pyrimidine ring, a pyridazine ring, or a pyrazine ring and a pyrrole ring.

[0151] In some embodiments of the present application, in Formula V or Formula V', L 6 Selected from -R C1 -NH-, -R C1 -NH-C(O)- or single bond, R C1 It is a C0-C3 alkylene group.

[0152] In some embodiments of the present application, in Formula V or Formula V', C 2 is selected from 4-6 membered cycloalkylene, 5-6 membered heterocycloalkylene, 5-6 membered heteroaryl, and as C 2 The 4-6 membered cycloalkylene, 5-6 membered heterocycloalkylene, and 5-6 membered heteroaryl are optionally substituted by any one or more selected from the group consisting of C1-C3 alkyl and halogen.

[0153] In some embodiments of the present application, in Formula V or Formula V', L 7 Selected from a single bond, -O-, and -NH-.

[0154] In some embodiments of the present application, in Formula V or Formula V', R 2 is selected from halogen and haloalkyl.

[0155] In some embodiments of the present application, in Formula V or Formula V', X is C or N.

[0156] In some embodiments of the present application, the compound of formula V or the compound of formula V' is selected from any one of formula V1, formula V2, formula V1' or formula V2':

[0157] In Formula V1 or Formula V1', A 1 is a 5-10 membered heteroarylene group, preferably as A 1 The 5-10 membered heteroarylene group is triazole-, isoxazole- or pyrazolyl-, preferably as A 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more selected from the group consisting of: C1-C3 alkyl, ═O, ═S;

[0158] A 2 is phenylene, pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene, preferably phenylene or pyridinylene;

[0159] L 1 Selected from single bond, C1-C3 alkylene, C2-C3 alkynylene, carbonyl, -C(O)-NH-, -O-, *-N(R B1 )R B2 -, R B1 is H, C1-C3 alkyl, R B2 is a C0-C3 alkylene group;

[0160] L 2 is selected from 4-10 membered heterocycloalkylene, single bond, heteroatom is N, S or P; preferably as L 2 The 4-10 membered heterocycloalkylene group is azetidinylene, piperidinylene or piperazinylene;

[0161] L 3 Selected from a single bond, a C1-C3 alkylene group, a C2-C3 alkynylene group, a carbonyl group, and -C(O)-NH-;

[0162] L 4 is selected from 4-10 membered heterocycloalkylene, single bond, heteroatom is N, S or P; preferably as L 4 The 4-10 membered heterocycloalkylene group is azetidinylene, piperidinylene or piperazinylene;

[0163] L 5 is selected from a single bond, a C1-C3 alkylene group, a C2-C3 alkenylene group, a C2-C3 alkynylene group or -C(O)-NH-;

[0164] C 1 is selected from 5-8 membered heteroarylene, and the 5-8 membered heteroarylene is optionally substituted by any one or more of the following groups: C1-C3 alkyl and halogen; preferably C 1 Selected from A fused heterocyclic ring, wherein Middle Y 1 、Y 2 、Y 3 and Y 4 are each independently selected from C or N, and at least one is N; Middle Z 1 、Z 2 、Z 3 and Z 4 are independently selected from C or N, and at least one is N; Y in the fused heterocycle 1 、Y 2 、Y 3 、Y4 、Z 1 、Z 2 、Z 3 and Z 4 Each is independently selected from C or N, and at least one is N; further preferably is an imidazole ring, a pyrazole ring, a thiazole ring, a pyrrole ring, or a triazole ring; further preferably is a benzene ring, a pyrimidine ring, a pyridazine ring, or a pyrazine ring; more preferably, the fused heterocycle is a fused heterocycle of any one of a benzene ring, a pyrimidine ring, a pyridazine ring, or a pyrazine ring and a pyrrole ring; more preferably, C 1 is imidazolylene, pyrazolylene, thiazolylene, pyrrolylene, or triazolylene, and is more preferably pyrrolylene, pyrazolylene, triazolylene, pyridazinylene, pyridinylene, benzopyrrolylene, or pyrimidopyrrolylene; L 6 Selected from -R C1 -NH-, -R C1 -NH-C(O), R C1 is a C0-C3 alkylene group, preferably R C1 is a C1-C3 alkyl group, more preferably a methyl group or an ethyl group;

[0165] Y 5 、Y 6 、Y 7 and Y 8 Each is independently selected from C or N, and at least one is N, preferably imidazolylene, pyrazolylene, thiazolylene, pyrrolylene, triazolylene, more preferably pyrazolylene;

[0166] R 2 is selected from halogen, preferably F or Cl;

[0167] X is C or N.

[0168] In some embodiments of the present application, in Formula V1 or Formula V1' Any one selected from the following groups: Methylene, Ethynylene, space, -NH-, in, End and C 1 connect, End and A 2 connect.

[0169] In some embodiments of the present application, in formula V1' Any one selected from the following groups:

[0170] In some embodiments of the present application, in Formula V1 or Formula V1' Any one selected from the following groups:

[0171] In some embodiments of the present application,

[0172] In formula V2 or formula V2', A 1 is a 5-10 membered heteroarylene group, preferably as A 1 The 5-10 membered heteroarylene group is triazole-, isoxazole- or pyrazolyl-, preferably as A 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more selected from the group consisting of: C1-C3 alkyl, ═O, ═S;

[0173] A 2 is phenylene, pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene, preferably phenylene or pyridinylene;

[0174] L 1 selected from a single bond, a C1-C3 alkylene group;

[0175] L 2 is selected from 4-10 membered heterocycloalkylene, single bond, heteroatom is N, S or P; preferably as L 2 The 4-10 membered heterocycloalkylene group is azetidinylene, piperidinylene or piperazinylene;

[0176] L 3 selected from a single bond, a C1-C3 alkylene group;

[0177] L 4 is selected from 4-10 membered heterocycloalkylene, single bond, heteroatom is N, S or P; preferably as L 4 The 4-10 membered heterocycloalkylene group is azetidinylene, piperidinylene or piperazinylene;

[0178] L 5 is selected from a single bond, a C1-C3 alkylene group, and a carbonyl group;

[0179] Y 1 、Y 2 、Y 3 and Y 4 Each independently selected from C or N, and at least one is N, preferably is imidazolylene, pyrazolylene, thiazolylene, pyrrolylene, or triazolylene, more preferably pyrrolylene, pyrazolylene, or triazolylene;

[0180] C 2 is selected from 4-6 membered cycloalkylene, preferably butylene or hexyl, and as C 2The 4-6 membered cycloalkylene group is optionally substituted by any one or more selected from the group consisting of methyl, ethyl, F, and Cl;

[0181] L 7 Selected from -O-, -NH-;

[0182] R 2 is selected from halogen (e.g. F, Cl or Br) and haloalkyl (e.g. trifluoromethyl);

[0183] X is C or N.

[0184] In some embodiments of the present application, in Formula V2 or Formula V2' Any one selected from the following groups:

[0185] in, End and connect, End and A 2 connect.

[0186] In some embodiments of the present application, in formula V2' Any one selected from the following groups:

[0187] In some embodiments of the present application, in Formula V2 or Formula V2' Any one selected from the following groups:

[0188] In some embodiments of the present application, in Formula VI or Formula VI', A 1 is selected from 5-10 membered heteroarylene groups, wherein the heteroatoms are preferably N atoms and / or O atoms, and the number of heteroatoms is preferably 1-3, preferably as A 1 The 5-10 membered heteroarylene group is triazole-, isoxazole- or pyrazolyl-; 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more of the following groups: C1-C6 alkyl, =O, =S, R A1 and R A2 Each is independently H or C1-C3 alkyl.

[0189] In some embodiments of the present application, in Formula VI or Formula VI', A 2 is selected from C6-C10 arylene or 5-10 membered heteroarylene, preferably phenylene, pyridylene or indoleylene, wherein A 2 The C6-C10 arylene group and the 5-10 membered heteroarylene group are optionally substituted by halogen or C1-C3 alkyl.

[0190] In some embodiments of the present application, in Formula VI or Formula VI', L 1 Selected from single bond, C1-C6 alkylene, C2-C6 alkynylene, *-N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group, preferably a methylene group, an ethylene group, an ethynyl group, a *-N(R B1 )R B2 -, R B1 is H, methyl or ethyl, R B2 is a single bond or a methylene group.

[0191] In some embodiments of the present application, in Formula VI or Formula VI', L 2 is selected from 4-10 membered heterocycloalkyl, C3-C10 cycloalkylene, C6-C10 arylene, single bond, heteroatom is N, S or P; preferably L 2 The 4- to 10-membered heterocycloalkyl group is azetidinyl, piperidinyl or piperazinyl.

[0192] In some embodiments of the present application, in Formula VI or Formula VI', L 3 Selected from single bond, C1-C6 alkylene, -O-, *-N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group; preferably L 3 For methylene, ethylene, ethynylene, *-N(R B1 )R B2 -, R B1 is H, methyl or ethyl, R B2 is a single bond or a methylene group.

[0193] In some embodiments of the present application, in Formula VI or Formula VI', L 4 is selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably as L 4 The 4- to 10-membered heterocycloalkyl group is azetidinylene, piperidinylene or piperazinylene.

[0194] In some embodiments of the present application, in Formula VI or Formula VI', L 5 is selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, or a carbonyl group.

[0195] In some embodiments of the present application, in Formula VI or Formula VI', C 1is selected from a single bond, a C6-C10 arylene group or a 5-10 membered heteroarylene group, preferably a single bond, a pyrazolyl group, an imidazolyl group, a triazolyl group, in, End and L 5 connect, End and L 6 connect.

[0196] In some embodiments of the present application, in Formula VI or Formula VI', L 6 is a C1-C3 alkyl group, wherein the C1-C3 alkyl group is optionally substituted by OH, and preferably L6 is

[0197] In some embodiments of the present application, in Formula VI or Formula VI', R 2 Selected from halogen and haloalkyl, preferably Cl or -CF3.

[0198] In some embodiments of the present application, in Formula VI or Formula VI', X is C or N.

[0199] In some embodiments of the present application, the compound of formula VI or the compound of formula VI' is selected from any one of formula VI1, formula VI2, formula VI1', and formula VI2':

[0200] In Formula VI1 or Formula VI1', A 1 is selected from 5-10 membered heteroarylene groups, wherein the heteroatoms are preferably N atoms and / or O atoms, and the number of heteroatoms is preferably 1-3, preferably as A 1 The 5-10 membered heteroarylene group is triazole-, isoxazole- or pyrazolyl-; 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more of the following groups: =O, R A1 and R A2 Each is independently H, methyl or ethyl;

[0201] A 2 is selected from C6-C10 arylene or 5-10 membered heteroarylene, preferably phenylene, pyridylene or indoleylene, wherein A 2 The C6-C10 arylene and 5-10 membered heteroarylene are optionally substituted by F, C, methyl, or ethyl;

[0202] L 1 is selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkynylene group, preferably a single bond, a methylene group, an ethylene group or an ethynylene group;

[0203] L 2is selected from 4-10 membered heterocycloalkyl, single bond, C3-C6 cycloalkylene, C6-C8 arylene, wherein the heteroatom is N, S or P; preferably L 2 The 4-10 membered heterocycloalkyl group is azetidinyl, piperidinyl or piperazinyl, preferably as L 2 The C3-C6 cycloalkylene group is hexylene, preferably L 2 The C6-C8 arylene group is a phenylene group;

[0204] L 3 Selected from single bond, C1-C3 alkylene, -O-, *-N(R B1 )R B2 -, R B1 is H, C1-C3 alkyl, R B2 is a C0-C3 alkylene group; preferably L 3 For methylene, ethylene, ethynylene, *-N(R B1 )R B2 -、-O-,R B1 is H, methyl or ethyl, R B2 is a single bond or a methylene group;

[0205] L 4 is selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably as L 4 The 4-10 membered heterocycloalkyl group is azetidinyl, piperidinyl or piperazinyl;

[0206] L 5 is selected from C1-C3 alkenylene, C1-C3 alkynylene, carbonyl or phenylene;

[0207] n is 0, 1, 2, or 3;

[0208] R C3 and R C4 Each is independently H, methyl, ethyl or hydroxy;

[0209] R 2 Selected from halogen and haloalkyl, preferably Cl or -CF3;

[0210] X is C or N.

[0211] In some embodiments of the present application, in Formula VI1 or Formula VI1' Any one selected from the following groups:

[0212] In some embodiments of the present application, in Formula VI1' Any one selected from the following groups:

[0213] In some embodiments of the present application, in Formula VI1 or Formula VI1' Any one selected from the following groups:

[0214] In some embodiments of the present application,

[0215] In Formula VI2 or Formula VI2', A 1 is selected from 5-10 membered heteroarylene groups, wherein the heteroatoms are preferably N atoms and / or O atoms, and the number of heteroatoms is preferably 1-3, preferably as A 1 The 5-10 membered heteroarylene group is triazole-, isoxazole- or pyrazolyl-; 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more of the following groups: =O, R A1 and R A2 Each is independently H, methyl or ethyl;

[0216] A 2 is selected from C6-C10 arylene or 5-10 membered heteroarylene, preferably phenylene, pyridylene or indoleylene, wherein A 2 The C6-C10 arylene and 5-10 membered heteroarylene are optionally substituted by F, C, methyl, or ethyl;

[0217] L 1 Selected from single bond, C1-C6 alkylene, *-N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group, preferably a methylene group, an ethylene group or a *-N(R B1 )R B2 -,

[0218] R B1 is H, methyl or ethyl, R B2 is a single bond or a methylene group;

[0219] L 2 is selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably as L 2 The 4-10 membered heterocycloalkyl group is azetidinyl, piperidinyl or piperazinyl;

[0220] L 3 A single bond, a C1-C6 alkylene group, preferably a single bond, a methylene group or an ethylene group;

[0221] L 4is selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably as L 4 The 4-10 membered heterocycloalkyl group is azetidinyl, piperidinyl or piperazinyl;

[0222] L 5 A single bond, a C1-C6 alkylene group, preferably a single bond, a methylene group or an ethylene group;

[0223] n is 0, 1, 2 or 3, preferably 0;

[0224] R C3 and R C4 Each independently represents H, methyl, ethyl or hydroxyl, preferably R C3 and R C4 are each independently methyl or hydroxy;

[0225] R 2 Selected from halogen and haloalkyl, preferably Cl or -CF3;

[0226] X is C or N.

[0227] In some embodiments of the present application, in Formula VI2 or Formula VI2' Any one selected from the following groups:

[0228] In some embodiments of the present application, in Formula VI2' Any one selected from the following groups:

[0229] In some embodiments of the present application, in Formula VI2 or Formula VI2' Any one selected from the following groups:

[0230] In some embodiments of the present application, in Formula VII, A 1 is selected from 5-10 membered heteroarylene groups, wherein the heteroatoms are preferably N atoms and / or O atoms, and the number of heteroatoms is preferably 1-3, as A 1 The 5-10 membered heteroaryl is preferably triazole-ene, isoxazole-ene or pyrazolyl-ene, and more preferably triazole-ene; preferably as A 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more selected from the group consisting of ═O, ═S.

[0231] In some embodiments of the present application, in Formula VII, A 2 is selected from C6-C10 arylene or 5-10 membered heteroarylene, preferably phenylene, indolylene or pyridylene, wherein A 2The C6-C10 arylene and 5-10 membered heteroarylene are optionally substituted by F, Cl, methyl or ethyl.

[0232] In some embodiments of the present application, in Formula VII, L 1 , L 2 , L 3 , L 4 and L 5 Each independently selected from a single bond, a C1-C6 alkylene group, a carbonyl group, a 4-10 membered heterocycloalkylene group, -O-, -N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 It is a C0-C6 alkylene group.

[0233] In some embodiments of the present application, in Formula VII, L 1 Selected from single bond, C1-C6 alkylene, -N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group, preferably L 1 Selected from single bond, methylene, ethylene, propylene, -N(R B1 )R B2 -, R B1 is H, methyl or ethyl, R B2 is a single bond, methylene or ethylene.

[0234] In some embodiments of the present application, in Formula VII, L 2 It is selected from 4-10 membered heterocycloalkylene, a single bond, and the heteroatom is N, S or P; preferably, the 4-10 membered heterocycloalkylene as L2 is azetidinylene, piperidinylene or piperazinylene.

[0235] In some embodiments of the present application, in Formula VII, L 3 It is selected from a single bond, a C1-C6 alkylene group, and is preferably a single bond, a methylene group or an ethylene group.

[0236] In some embodiments of the present application, in Formula VII, L 4 It is selected from 4-10 membered heterocycloalkylene, a single bond, and the heteroatom is N, S or P; preferably, the 4-10 membered heterocycloalkylene as L4 is azetidinylene, piperidinylene or piperazinylene.

[0237] In some embodiments of the present application, in Formula VII, L 5 is selected from a single bond or a carbonyl group.

[0238] In some embodiments of the present application, in Formula VII, C 1The ring is selected from phenylene, pyridinylene, pyrimidinylene, pyridazinylene, preferably phenylene or pyridinylene.

[0239] In some embodiments of the present application, in Formula VII, R 5 is selected from H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, OH, NH2, CN, nitro, carboxyl, preferably halogen is F or Cl, preferably R 5 is selected from H, F or Cl.

[0240] In some embodiments of the present application, in Formula VII, R 3 、R 4 are each independently selected from H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, and R 3 and R 4 Connected to the carbon atom shared by the two 4-6 membered cycloalkyl, preferably R 3 and R 4 Connected to the carbon atom common to both cyclobutyl or cyclohexyl.

[0241] In some embodiments of the present application, in Formula VII, R 2 is halogen, C1-C3 alkyl, C1-C3 haloalkyl, preferably F, Cl or trifluoromethyl.

[0242] In some embodiments of the present application, in Formula VII Any one selected from the following groups:

[0243] In some embodiments of the present application, in Formula VII Any one selected from the following groups:

[0244] In some embodiments of the present application, in Formula VII Any one selected from the following groups:

[0245] In some embodiments of the present application, the compound is selected from any one of the following compounds:

[0246] The second aspect of the present application provides a pharmaceutical composition comprising any one of the compounds of the first aspect above, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof and one or more pharmaceutically acceptable excipients or carriers.

[0247] The third aspect of the present application provides a drug kit product comprising: a) a container; b) at least one compound provided by the first aspect, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof, located in the container; and c) optional packaging and / or instructions.

[0248] The fourth aspect of the present application provides a drug conjugate comprising any one of the compounds provided in the first aspect, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof.

[0249] The fifth aspect of the present application provides a method for preventing and / or treating diseases or conditions associated with abnormal activity or expression of the androgen receptor (AR) or AR splicing mutant in mammals, comprising administering to the receptor a therapeutically effective amount of any one of the compounds provided in the first aspect, or its stereoisomers, or its pharmaceutically acceptable salts, or its deuterated compounds, or its tautomers, or its polymorphs, or its solvates, or its N-oxides, or its isotope-labeled compounds, or its metabolites, or its prodrugs, any one of the pharmaceutical compositions provided in the second aspect, any one of the drug kit products provided in the third aspect, or any one of the drug conjugates provided in the fourth aspect.

[0250] The sixth aspect of the present application provides the use of any one of the compounds of the first aspect above, or its stereoisomers, or its pharmaceutically acceptable salts, or its deuterated compounds, or its tautomers, or its polymorphs, or its solvates, or its N-oxides, or its isotope-labeled compounds, or its metabolites, or its prodrugs, any one of the pharmaceutical compositions provided in the second aspect above, or any one of the drug conjugates provided in the fourth aspect in the preparation of androgen receptor or androgen receptor splicing mutant regulators.

[0251] The seventh aspect of the present application provides the use of any one of the compounds of the first aspect, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, the pharmaceutical composition provided in the second aspect, or any one of the drug conjugates provided in the fourth aspect in the preparation of a drug for treating a disease associated with abnormal activity or expression of androgen receptor or androgen receptor splicing mutants.

[0252] In some embodiments of the present application, the disease is cancer, tumor disease, metabolic disorder, benign prostatic hyperplasia and benign prostatic hyperplasia, acne (acne vulgaris), seborrheic disease, hirsutism, male pattern baldness and male pattern baldness, precocious puberty, polycystic ovary syndrome, sexual perversion and virilization; preferably, the cancer or tumor disease includes breast cancer and breast tumors (breast cancer including ductal and lobular forms, AR positive breast cancer, breast cancer in situ), skin tumors (basal cell carcinoma, acanthocytic cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, non-melanoma skin cancer, melanoma Kerr cell skin cancer, mast cell tumors), tumors of the reproductive organs (endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer and uterine cancer in women and prostate cancer and testicular cancer in men); preferred metabolic disorders include catabolic side effects of glucocorticoids, dysregulation of fat metabolism, long-term critically ill catabolic states, age-related decreases in testosterone levels in men, andropause, hypogonadism, male hormone replacement therapy, male and female sexual dysfunction (e.g., erectile dysfunction, decreased sexual drive, decreased sexual satisfaction, decreased libido).

[0253] The eighth aspect of the present application provides any one of the compounds provided in the first aspect, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, any one of the pharmaceutical compositions provided in the second aspect, any one of the drug kit products provided in the third aspect, or any one of the drug conjugates provided in the fourth aspect, for use in treating diseases associated with abnormal activity or expression of mammalian androgen receptor (AR) or AR splicing mutants.

[0254] In some embodiments, preferred diseases are cancer, tumor diseases, metabolic disorders, benign prostatic hyperplasia and benign prostatic hyperplasia, acne (acne vulgaris), seborrheic dermatitis, hirsutism, male pattern baldness and male pattern baldness, precocious puberty, polycystic ovary syndrome, sexual perversion and virilization; preferred cancer or tumor diseases include breast cancer and breast tumors (breast cancer including ductal and lobular forms, AR positive breast cancer, breast cancer in situ), skin tumors (basal cell carcinoma, acanthocytic cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, non-melanoma skin cancer, Meckstrom's disease, sarcoma, ... sarcoma, non-melanoma skin cancer, Meckstrom's disease, sarcoma, Preferred metabolic disorders include catabolic side effects of glucocorticoids, dysregulation of fat metabolism, long-term critically ill catabolic states, age-related decreases in testosterone levels in men, andropause, hypogonadism, male hormone replacement therapy, male and female sexual dysfunction (e.g., erectile dysfunction, decreased sexual drive, decreased sexual satisfaction, decreased libido).

[0255] .

[0256] Definition and Description

[0257] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear without a specific definition, but should be understood according to its ordinary meaning.

[0258] A dash ("-") that is not between two letters or symbols indicates the attachment point of a substituent, and the order of attachment is arbitrary. However, when the attachment point of a substituent is obvious to those skilled in the art, for example, a halogen substituent, the "-" may be omitted.

[0259] When the R 1 When the substituent has no fixed structure, it means R 1 Can be connected to any position on the indole ring, and R 1 It can be 1, 2, 3, 4 or 5.

[0260] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0261] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, and salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present application contain basic and acidic functional groups and can be converted into either base or acid addition salts.

[0262] The pharmaceutically acceptable salts of the present application can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, the compounds in the form of free acid or base are reacted with a stoichiometric amount of a suitable base or acid to prepare.

[0263] The stereoisomers of the compounds of the present invention may exist in any form of tautomers, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present invention.

[0264] The present application also includes all suitable isotope-labeled compounds of the compounds of the present application. In this case, an isotope-labeled compound of the compound of the present application is understood to be a compound in which at least one atom in the compound of the present application is replaced by another atom having the same atomic number but an atomic mass different from the atomic mass commonly or predominantly found in nature. Examples of isotopes that can be introduced into the compounds of the present application are isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine and iodine, such as2 H (deuterium), 3 H (tritium), 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 129 I and 131 I. Certain isotopically labeled compounds of the present invention (such as, in particular, those into which one or more radioactive isotopes are incorporated) can be used, for example, to study the mechanism of action or distribution of the active substance in vivo; since they can be prepared and detected relatively easily, 3 H- or 14 Compounds labeled with C-isotopes are particularly suitable for this. In addition, the introduction of isotopes (e.g., deuterium) can produce certain therapeutic advantages due to the greater metabolic stability of the compound, such as an increase in half-life in vivo or a reduction in the effective dose required; the modifications of the compounds of the present application may therefore optionally also represent preferred embodiments of the present invention. Isotopically labeled compounds of the present application can be prepared by methods known to those skilled in the art, such as by the methods and specifications given in the embodiments below, using corresponding isotopic modifications of the individual reagents and / or starting compounds.

[0265] The compounds of the present application may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound. For example, compounds can be labeled with radioactive isotopes, such as tritium (3H), iodine-125 (125I) or C-14 (14C). For another example, heavy hydrogen can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of this application. "Optional" or "optionally" means that the event or situation described subsequently may but does not necessarily occur, and the description includes the situation where the event or situation occurs and the situation where the event or situation does not occur.

[0266] In this application, "polymorph" refers to a crystalline form of a compound (or its salt, hydrate or solvate) that is arranged in a specific crystal packing. All polymorphs have the same elemental composition. Different polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures and other factors may lead to one polymorph being dominant.

[0267] In the present application, "solvate" refers to a mixture produced by dissolving a compound in a solvent.

[0268] In this application, "N-oxide" is also called amine oxide, which is a class of compounds with the general formula R 3 N+-O-(also written as R 3 N=O or R 3 N→O) organic compounds.

[0269] In this application, "metabolites" refer to substances generated by chemical structural transformation of drug molecules under the action of the body after the drug molecules are absorbed by the body.

[0270] In this application, "prodrug" refers to a compound that is obtained by chemically modifying a drug, is inactive or has low activity in vitro, and releases active drugs through enzymatic or non-enzymatic conversion in vivo to exert its pharmacological effect.

[0271] The term "substituted" or "substituted with" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. The term "optionally substituted" or "optionally substituted with" means that the atom may or may not be substituted. Unless otherwise specified, the type and number of substituents may be any based on chemical practicability.

[0272] When any variable (such as R 1 ) occurs more than once in the composition or structure of a compound, its definition is independent on each occurrence. Thus, for example, if a group is replaced by 1, 2, 3, 4 or 5 R 1 substituted, the group may optionally have 1, 2, 3, 4 or 5 R 1 is replaced, and in each case R 1 Also, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0273] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected.

[0274] When the substituents listed do not specify through which atom they are connected to the substituted group, such substituents can be bonded through any atom thereof. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0275] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary. For example, the linking group L 6 In the case of -NH-C(O)-, -NH-C(O)- can be connected in the same direction as the reading order from left to right, or in the opposite direction as the reading order from right to left. Combinations of the linking groups, substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0276] Unless otherwise specified, the number of atoms in a ring is generally defined as the ring member number, for example, a "3-6 membered ring" refers to a "ring" having 3-6 atoms arranged around it.

[0277] Unless otherwise specified, the term "C1-C6 alkylene" is used to refer to a linear or branched divalent saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C1-C6 alkylene group includes C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C4, C6, C5, C4, C3, and C2C1 alkylene groups. C1-C6 alkyl groups are also understood in the same manner as above, except that alkyl groups are monovalent (e.g., CH3) and alkylene groups are divalent (e.g., -CH2-).

[0278] Unless otherwise specified, the term "C2-C6 alkenylene" is used to refer to a straight or branched, divalent, unsaturated hydrocarbon group consisting of 2 to 6 carbon atoms. The C2-C6 alkenylene group includes C2-C5, C2-C4, C2-C3, C2-C6, C6, C5, C4, C3, and C2 alkenyl groups. C2-C6 alkenyl groups are also understood in the same manner as above, except that alkenyl groups are monovalent (e.g., CH2=CH-) and alkenylene groups are divalent (e.g., -CH=CH-).

[0279] Unless otherwise specified, the term "C2-C6 alkynylene" refers to a linear or branched, divalent, unsaturated hydrocarbon group consisting of 2 to 6 carbon atoms. Examples of C2-C6 alkynylene groups include C2-C5, C2-C4, C2-C3, C2-C6, C6, C5, C4, C3, and C2 alkynylene groups. C2-C6 alkynyl groups are also understood in the same manner as above, except that alkynyl groups are monovalent (e.g., CH≡C-) while alkynylene groups are divalent (e.g., -C≡C-).

[0280] Unless otherwise specified, the term "C1-C6 alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms that is connected to the rest of the molecule via an oxygen atom. The C1-C6 alkoxy group includes C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C4, C6, C5, C4, C3, C2, and C1 alkoxy groups. Examples of C1-C6 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy, and t-butoxy), pentoxy (including n-pentoxy, isopentoxy, and neopentoxy), hexoxy, and the like.

[0281] The term "cycloalkyl" by itself or in combination with other terms represents a cyclic form of an alkyl, alkenyl, or alkynyl group, or mixtures thereof. Additionally, cycloalkyl groups may include fused rings, but exclude fused aryl and heteroaryl groups, and unless specifically designated as unsubstituted, cycloalkyl groups may be substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cyclohexynyl, cyclohexadienyl, cyclopentadienyl, cyclopentenyl, cycloheptyl, norbornyl, and the like. Unless the ring size is specified, cycloalkyl groups herein are defined as containing 3-10 ring members, 3-8 ring members, or 3-6 ring members. Cycloalkylene groups are also understood in the same manner, except that cycloalkyl groups are monovalent rings and cycloalkylene groups are divalent rings.

[0282] The term "heterocycle" or "heterocycloalkyl" or "heterocyclyl" by itself or in combination with other terms refers to a cycloalkyl group containing at least one ring carbon atom and at least one ring heteroatom selected from O, N, P, Si and S, preferably selected from N, O and S, wherein the ring is non-aromatic but may contain unsaturation. The nitrogen and sulfur atoms in the heterocyclic group may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. In various embodiments, the ring heteroatoms are selected from N, O and S. Unless otherwise specified, the heterocyclic groups described herein contain 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-5, 4-6, 4-7, 4-8, 5-10, 5-8 ring members, and at least one ring member is a heteroatom selected from N, O and S; typically, there are no more than 3 of these heteroatoms in the heterocyclic group, and typically no more than 2 of these heteroatoms in a single ring of the heterocyclic group. The heterocyclic group may be fused to other carbocyclic, heterocyclic or aryl rings. Heterocyclic groups can be connected to the rest of the molecule on a ring carbon or a ring heteroatom, and heterocyclic groups can be substituted as described for alkyl. In addition, heterocycles can include fused rings, but do not include fused systems containing heteroaryl as a part of a fused ring system. Examples of heterocyclic groups include but are not limited to 1-(1,2,5,6-tetrahydropyridyl), 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, 1,2,3,4-tetrahydropyridyl, indoline (indoline), tetrahydrofuran-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, 1-piperazinyl, 2-piperazinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophene (including The term "heterocycloalkylene" refers to any of the following: tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc. Heterocycloalkylene is also understood in the same manner as above, except that the heterocyclyl group is a monovalent ring and the heterocycloalkylene group is a divalent ring.

[0283] In addition, if The double bond is not limited to Y 1 and Y 2 Between, Y 3 and C atoms, which are switched to chemically acceptable positions depending on the valence state of the selected heteroatom.

[0284] Unless otherwise indicated, the term "aryl" refers to an aromatic hydrocarbon radical, which can be a single ring or multiple rings (e.g., 1-3 rings) with rings fused together. An aryl group can contain fused rings, wherein one or more rings are optionally cycloalkyl, but does not include heterocyclic or heteroaromatic rings; a fused system containing at least one heteroaromatic ring is referred to as a heteroaryl group, and a phenyl ring fused to a heterocyclic ring is referred to herein as a heterocyclic group. Aryl groups include fused ring systems in which a phenyl ring is fused to a cycloalkyl ring. Examples of aryl groups include, but are not limited to, phenyl, 1-naphthyl, tetralin, dihydro-1H-indene, 2-naphthyl, tetralinyl, and the like. Arylene groups are also understood in the same manner as above, except that aryl groups are monovalent rings and arylene groups are divalent rings.

[0285] As used herein, the term "heteroaryl" refers to a group containing a monocyclic ring or two or three fused rings, wherein at least one ring is an aromatic ring containing 1 to 4 heteroatoms selected from N, O and S as ring members (i.e., it contains at least one heteroaromatic ring), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl group may be attached to the rest of the molecule via a ring carbon or a ring heteroatom, and if the group is bicyclic or tricyclic, it may be attached via any ring of the heteroaryl group. A heteroaryl group may contain fused rings, wherein one or more rings are optionally cycloalkyl or heterocycloalkyl or aryl, provided that at least one ring is a heteroaromatic ring. Non-limiting examples of heteroaryl groups are 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, triazole, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above-mentioned aryl and heteroaryl ring systems are selected from the group consisting of the acceptable substituents described below. Heteroarylene is also understood in the same manner as above, except that heteroaryl is a monovalent ring and heteroarylene is a divalent ring. Non-limiting examples of heteroarylene are pyrrolylene, pyrazolylene, imidazolylene, triazole-containing rings, pyridazinylene, pyrazinylene, oxazolylene, phenyl-4-oxazolylene, isoxazolylene, thiazolylene, furanylene, thienylene, pyridinylene, 3-pyridinylene, pyrimidinylene, benzothiazolylene, purinylene, benzimidazolylene, indolylene, isoquinolinylene, and quinolinylene.

[0286] Aryl and / or heteroaryl groups typically contain up to 4 substituents per ring (0-4), sometimes 0-3 or 0-2 substituents. The terms "aryloxy" and "heteroaryloxy" refer to aryl and heteroaryl groups, respectively, attached to the rest of the molecule through an oxygen linker (-O-).

[0287] Unless otherwise stated, the term "halo" or "halogen" itself or as a part of other substituents refers to fluorine, chlorine, bromine or iodine atoms. In addition, the term "haloalkyl" should include monohaloalkyl and perhaloalkyl. For example, the term "halo (C1-C4) alkyl" should include but is not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc. The prefix "perhalo" refers to each group in which all available valence bonds are replaced by halogen. For example, "perhaloalkyl" includes -CCl3, -CF3, -CCl2CF3, etc. The terms "perfluoroalkyl" and "perchloroalkyl" are subgroups of perhaloalkyl, in which all available valence bonds are replaced by fluorine and chlorine, respectively. Non-limiting examples of perfluoroalkyl include -CF3 and -CF2CF3. Non-limiting examples of perchloroalkyl include -CCl3 and -CCl2CCl3.

[0288] The pharmaceutical composition of the present invention contains at least one compound according to any embodiment disclosed herein (including pharmaceutically acceptable salts of these compounds) mixed with at least one pharmaceutically acceptable excipient, carrier or diluent. Preferably, the pharmaceutical composition is a sterile composition, or a composition consisting mainly of or solely of the above-mentioned compound and one or more pharmaceutically acceptable excipients, carriers and / or diluents. In some embodiments, the pharmaceutical composition comprises at least two pharmaceutically acceptable carriers and / or excipients described herein.

[0289] As used herein, a "therapeutically effective amount" refers to an amount capable of producing the desired pharmacological and / or physiological effect. The effect may be preventive, capable of completely or partially preventing the disease or its symptoms; and / or may be therapeutic, capable of partially or completely curing the disease and / or side effects associated with the disease. A therapeutically effective amount of a compound of the present application generally includes any amount sufficient to inhibit AR activity that can be detected by any assay described herein, by other AR activity assays known to those skilled in the art, or by detecting inhibition or relief of cancer symptoms.

[0290] As used herein, the term "pharmaceutically acceptable carrier" and its congeners refer to adjuvants, binders, diluents, etc. known to those skilled in the art, which are suitable for administration to an individual (e.g., a mammal or a non-mammal). Combinations of two or more carriers are also encompassed in the present invention. The pharmaceutically acceptable carrier and any other ingredients described herein can be adapted for use in the intended route of administration (e.g., oral, parenteral) of a particular dosage form. Such adaptability is readily recognized by the skilled person, particularly in light of the teachings provided herein. The pharmaceutical compositions described herein comprise at least one pharmaceutically acceptable carrier or excipient; preferably, the composition comprises at least one carrier or excipient other than water or at least one carrier or excipient in addition to water.

[0291] Pharmaceutical excipients can be pharmaceutically acceptable carriers, adjuvants, or vehicles, which, as used in the present invention, include any solvents, diluents, or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., suitable for the specific target dosage form.

[0292] The compounds of the present application may have systemic and / or local effects. For this purpose, they may be administered in a suitable manner, for example, orally, parenterally, pulmonary, intranasally, sublingually, lingually, buccally, rectally, transdermally, transconjunctivally or otically, or as an implant or stent.

[0293] Suitable for oral administration are dosage forms which act according to the prior art, release the compound according to the invention quickly and / or with modification and contain the compound according to the invention in crystalline and / or amorphisized and / or dissolved form, such as tablets (uncoated or coated, for example with an enteric coating or with a coating which delays dissolution or an insoluble coating which controls the release of the compound according to the invention), tablets which disintegrate rapidly in the mouth, or films / wafers, films / lyophilisates, capsules (for example hard or soft capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

[0294] Parenteral administration can be performed by bypassing an absorption step (e.g., intravenously, intraarterially, intracardially, intraspinally, or intralumbarly) or including absorption (e.g., intramuscularly, subcutaneously, intradermally, transdermally, or intraperitoneally). Suitable dosage forms for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates, or sterile powders.

[0295] Dosage forms suitable for other routes of administration are, for example, inhalation forms (including powder inhalers, nebulizers), nasal drops, solutions and sprays; tablets, films / wafers or capsules for lingual, sublingual or buccal administration; suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milks, pastes, foams, dusting powders, implants or stents.

[0296] As used herein, the term "treatment" refers to the administration of one or more pharmaceutical substances, particularly compounds described herein and / or pharmaceutically acceptable salts thereof, to an individual suffering from a disease or symptoms of the disease, in order to cure, alleviate, mitigate, alter, cure, improve, ameliorate or affect the disease or symptoms of the disease. As used herein, the term "prevention" refers to the administration of one or more pharmaceutical substances, particularly compounds described herein and / or pharmaceutically acceptable salts thereof, to an individual with a predisposition to the disease, in order to prevent the individual from developing the disease. When referring to a chemical reaction, the terms "treating," "contacting," and "reacting" refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and / or desired product. It should be understood that the reaction that produces the indicated and / or desired product may not necessarily result directly from the combination of the two reagents initially added, that is, there may be one or more intermediates generated in the mixture that ultimately lead to the formation of the indicated and / or desired product.

[0297] The compounds defined in the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions containing the same, are effective modulators of the androgen receptor. The compounds of the present invention are expected to be potentially useful agents in treating diseases or medical conditions mediated solely or in part by the androgen receptor. The compounds of the present invention may cause downregulation of the androgen receptor and / or be selective agonists, partial agonists, antagonists or partial antagonists of the androgen receptor.

[0298] The compounds according to the invention are preferably suitable for the treatment and / or prevention of androgen receptor-dependent diseases.

[0299] Diseases that can be treated with the compounds of the invention include, in particular, cancer and tumor diseases. In the context of the present invention, these diseases include, in particular, but are not limited to, the following: breast cancer and breast tumors (breast cancer includes ductal and lobular forms, as well as breast cancer in situ), skin tumors (basal cell carcinoma, acanthocytic cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, non-melanoma-like skin cancer, Merkel cell skin cancer, mast cell tumors), tumors of the reproductive organs (endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer and uterine cancer in women and prostate cancer and testicular cancer in men).

[0300] In some embodiments, the compounds of the present invention can be administered to animals (e.g., humans) for the treatment of various conditions and disorders, including, but not limited to, the treatment of the catabolic side effects of glucocorticoids; the treatment of fat metabolism disorders (e.g., in patients receiving HIV or AIDS treatments such as protease inhibitors); the treatment of long-term, critically ill catabolic states; age-related testosterone decline in men, male menopause, hypogonadism, male hormone replacement therapy, male and female sexual dysfunction (e.g., erectile dysfunction, decreased sex drive, decreased sexual satisfaction, loss of libido).

[0301] In one embodiment, conditions associated with the androgen receptor include prostate cancer, benign prostatic hyperplasia and benign prostatic hypertrophy, acne (acne vulgaris), seborrheic dermatitis, hirsutism, male pattern baldness and male pattern hair loss, precocious puberty, polycystic ovary syndrome, paraphilia, virilization, etc. The compounds of the present invention may also be used to improve ovulation in farmed animals.

[0302] The compounds of the present application can be used alone or, if necessary, in combination with one or more other pharmacologically effective substances, provided that the combination does not cause undesirable and unacceptable side effects.

[0303] Compounds were named according to conventional nomenclature in the art or using software, and commercially available compounds were named according to the supplier's catalog.

[0304] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0305] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0306] The following embodiments of the present invention are further described in detail with reference to the following examples. The detailed description of the following examples is used to illustrate the principles of the present invention, but is not intended to limit the scope of the present invention, that is, the present invention is not limited to the described examples.

[0307] Example 1

[0308] Preparation of intermediate HSP90-1

[0309] first step:

[0310] NaH (193 mg, 4.86 mmol) was dissolved in 2 mL of anhydrous DMF. A solution of 5-nitroindole (436 mg, 2.70 mmol) in anhydrous DMF was slowly added dropwise at 0°C with stirring. After the addition was complete, stirring was continued at 0°C for 10 minutes, then the mixture was warmed to room temperature and stirred for 1 hour. A solution of HSP90-1-1 (1 g, 2.70 mmol) in anhydrous DMF was slowly added dropwise at 0°C with stirring. After the addition was complete, stirring was continued at 0°C for 10 minutes, then the mixture was warmed to room temperature and stirred for 12 hours. After the reaction was complete, water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous magnesium sulfate, the solvent was evaporated, and column chromatography (PE:EA = 1 / 1) was performed to obtain 644 mg of HSP90-1-2 as a pale yellow solid, with a yield of 66.42%. UPLC-MS calculated for C 19 H 25 N3O4[M+H] + :360.19,found:360.31.

[0311] Step 2:

[0312] HSP90-1-2 (644 mg, 1.79 mmol) was dissolved in 10 mL of anhydrous methanol, and 10% palladium on carbon (64.4 mg) was added. H2 was replaced three times and the mixture was allowed to stand at room temperature overnight. After the reaction was complete, the palladium on carbon was filtered through celite, the solvent was evaporated, and column chromatography (PE:EA = 1 / 1) was performed to obtain HSP90-1-3 as a light yellow solid (577 mg, 98% yield). UPLC-MS calculated for C 19 H 27 N3O2[M+H] + :330.22,found:330.82.

[0313] Step 3:

[0314] HSP90-1-4 (1.0 g, 6.57 mmol) and potassium ethylxanthate (1.37 g, 8.54 mmol) were dissolved in 5 mL of anhydrous DMF and reacted at 100°C overnight. After the reaction was complete, 10 mL of ice water was added and the pH was adjusted to 1-2 with 1N HCl. A large amount of water was then added and stirred at 0°C for 1 h. Solid precipitated from the solution, which was filtered and dried under vacuum to obtain HSP90-1-5 as a yellow-brown solid (1.448 g, yield 96.66%). UPLC-MS calculated for C 10 H 12 O2S2[MH] + :227.02,found:227.11.

[0315] Step 4:

[0316] HSP90-1-5 (623 mg, 1.89 mmol) and NaHCO3 (638 mg, 7.59 mmol) were dissolved in 5 mL of anhydrous DMF. A solution of chloroacetic acid (179 mg, 1.89 mmol) in anhydrous DMF was slowly added dropwise at 0°C under Ar gas with stirring. After the addition was complete, stirring was continued at 0°C for 5 minutes, then the mixture was warmed to room temperature and stirred for 90 minutes. A solution of HSP90-1-3 (577 mg, 1.75 mmol) in anhydrous DMF was slowly added dropwise to the above solution at room temperature. After the addition was complete, the mixture was heated to 80°C and reacted for 3 hours. After completion of the reaction, water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous magnesium sulfate, the solvent was evaporated, and column chromatography (PE:EA = 2 / 1) was performed to obtain HSP90-1-6 as a yellow solid (690 mg, yield 69.71%). UPLC-MS calculated for C 29 H 37 N3O4S[M+H] + :524.26,found:524.48.

[0317] Step 5:

[0318] HSP90-1-6 (690 mg, 1.32 mmol) was dissolved in 10 mL of anhydrous THF. CDI (428 mg, 2.64 mmol) was added at 0°C under Ar protection. The mixture was stirred at room temperature for 3 h. After the reaction was completed, water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was evaporated to give 827.1 mg of crude HSP90-1-7, which was used directly without post-treatment.

[0319] Step 6:

[0320] The crude product HSP90-1-7 (827.1 mg, 1.50 mmol) was dissolved in 10 mL of anhydrous ethanol, and hydrazine hydrate (150 mg, 3.00 mmol) was added at room temperature. The mixture was stirred at room temperature overnight. When the reaction was complete, the solvent was evaporated and column chromatography (DCM / MeOH = 20 / 1) was performed to obtain HSP90-1-8 as a yellow solid (688 mg, yield 83.75%). UPLC-MS calculated for C 30 H 37 N5O5[M+H] + :548.28,found:548.31.

[0321] Step 7:

[0322] HSP90-1-8 was dissolved in 10 mL of DCM, and 2.5 mL of a 4 M 1,4-dioxane-hydrochloride solution was added. The mixture was stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated to dryness to obtain HSP90-1 as a light yellow solid (530 mg). The yield was 94.30%. UPLC-MS calculated for C 25 H 29 N5O3[M+H] + :448.23,found:448.31.

[0323] Example 2

[0324] Preparation of intermediate HSP90-2

[0325] first step:

[0326] p-Nitrobenzyl alcohol (500 mg, 3.3 mmol), pyridinium p-toluenesulfonate (82 mg, 0.3 mmol), and 2,3-dihydropyran (330 mg, 4.0 mmol) were placed in dichloromethane (20 mL) and reacted at room temperature for 1 h. The reaction solution was washed with saturated sodium bicarbonate solution (50 mL) and then saturated sodium chloride solution (50 mL). The organic phase solvent was evaporated to dryness to obtain 760 mg of a colorless oil, with a yield of 98%. UPLC-MS calculated for C 12 H 15 NO4[M+H] + :237.10,found:238.33.

[0327] Step 2:

[0328] HSP90-2-2 (760 mg, 3.2 mmol) was dissolved in methanol (20 mL), and 10% palladium on carbon (100 mg) was added. The reaction system was purged with hydrogen three times and allowed to react at room temperature for 6 h. The reaction solution was filtered, the filtrate was dried, and then separated by column chromatography (PE:EA = 9:1) to obtain 540 mg of a colorless oil, with a yield of 81%. UPLC-MS calculated for C 12 H 17 NO2[M+H] + :207.13,found:208.34.

[0329] Step 3:

[0330] HSP90-2-3 (540 mg, 2.6 mmol) and triethylamine (773 mg, 7.6 mg) were dissolved in dichloromethane (20 mL). After cooling to 0°C, phenyl chloroformate (980 mg, 6.3 mmol) was added dropwise to the reaction mixture. The mixture was allowed to react at 0°C for 3 h. The reaction mixture was washed with water (50 mL) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and the organic phase solvent was evaporated to dryness. The product was separated by column chromatography (PE:EA = 5:1) to obtain 850 mg of a yellow oil, with a yield of 98%. UPLC-MS calculated for C 19 H 21 NO4[M+H] + :327.15,found:328.30.

[0331] Step 4:

[0332] HSP90-2-4 (850 mg, 2.6 mmol) and hydrazine hydrate (80%, 972 mg, 19.4 mmol) were dissolved in dioxane (20 mL) and the temperature was raised to 80°C for 3 h. After cooling to room temperature, the organic phase solvent was evaporated and separated by column chromatography (DCM:MeOH = 20:1) to obtain 350 mg of a white solid, with a yield of 51%. UPLC-MS calculated for C 13 H 19 N3O3[M+H] + :265.14,found:266.34.

[0333] Step 5:

[0334] POCl3 (1.53 mL, 16.43 mmol) was slowly added dropwise to DMF (1.53 mL) at 0°C. HSP90-2-6 (1.0 g, 6.57 mmol) was dissolved in DMF (2.5 mL) and slowly added dropwise to the mixture. The mixture was allowed to react at room temperature for 1 hour, then raised to 50°C for 1 hour. The mixture was cooled to room temperature, and a 14% NaOH / water solution (3 g / 18 mL) was added. The mixture was stirred and raised to 75°C for 15 minutes. The mixture was cooled to room temperature and acidified to pH 2-3 with dilute hydrochloric acid. The mixture was stirred for about 1 hour, extracted with ethyl acetate, and the organic phase was dried to obtain a reddish-brown viscous liquid. UPLC-MS calculated for C 10 H 12 O3[M+H] + :180.20,found:180.32.

[0335] Step 6:

[0336] The intermediate HSP90-2-7 was dissolved in acetonitrile (15 mL), and K2CO3 (7.26 g, 52.56 mmol) and benzyl bromide (1.95 mL, 16.43 mmol) were added. The mixture was refluxed for 1.5 h, cooled to room temperature, and the solvent was evaporated. The mixture was separated by column chromatography (PE:EA=20 / 1) to obtain 1.5 g of a light yellow solid. The yield for the two steps was 63.34%. UPLC-MS calculated for C 24 H 24 O3[M+H] + :360.45,found:360.62.

[0337] Step 7:

[0338] HSP90-2-5 (350 mg, 1.3 mmol) and HSP90-2-8 (475 mg, 1.3 mmol) were dissolved in anhydrous ethanol (40 mL), heated to 80°C for 2 h, and then cooled to room temperature and used directly in the next reaction.

[0339] Step 8:

[0340] Sodium hydroxide (263 mg, 6.5 mmol) and potassium ferricyanide (1.3 g, 3.9 mmol) were added to the reaction mixture from the previous step and the temperature was raised to 80°C for 18 h. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated to dryness and separated by column chromatography (DCM:MeOH = 20:1) to obtain 710 mg of a brown oil, with a two-step yield of 88%. UPLC-MS calculated for C 37 H 39 N3O5[M+H] + :605.29,found:605.51.

[0341] Step 9:

[0342] HSP90-2-10 (710 mg, 1.2 mmol) was dissolved in tetrahydrofuran (20 mL), and hydrochloric acid solution (6 M, 10 mL) was added. The mixture was reacted at room temperature for 3 h. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 8. The mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and dried to obtain 590 mg of a yellow solid (96% yield). UPLC-MS calculated for C 32 H 31 N3O4[M+H] + :521.23,found:522.61.

[0343] Step 10:

[0344] HSP90-2-11 (590 mg, 1.1 mmol) was dissolved in chloroform (50 mL), and active manganese dioxide (1.5 g, 17.2 mmol) was added. The mixture was allowed to react at room temperature for 3 h. The reaction solution was filtered, the filtrate was dried, and then separated by column chromatography (DCM:MeOH = 20:1) to obtain 510 mg of a brown solid, with a yield of 86%. UPLC-MS calculated for C 32 H 29 N3O4[M+H] + :519.22,found:520.50.

[0345] Step 11:

[0346] HSP90-2-12 (510 mg, 0.9 mmol) was dissolved in dichloromethane (50 mL). After cooling to 0°C, boron trichloride solution (1 M in Tol, 2.5 mL) was added dropwise to the reaction mixture and allowed to react at 0°C for 3 h. Saturated sodium bicarbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted with a dichloromethane-methanol mixture (10:1) (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, dried, and separated by column chromatography (DCM:MeOH = 20:1) to obtain 150 mg of a brown solid, with a yield of 45%. UPLC-MS calculated for C 18 H 17 N3O4[M+H] + :339.12,found:340.33.

[0347] Example 3

[0348] Preparation of intermediate HSP90-3

[0349] The synthesis steps were similar to those of HSP90-1. UPLC-MS calculated for C 23 H 31 N6O3[M+H] + :439.24,found:439.53.

[0350] Example 4

[0351] Preparation of intermediate HSP90-4

[0352] first step:

[0353] The raw material HSP90-4-1 (5 g, 32.8 mmol) was added to a 100 mL reaction flask, followed by boron trifluoride etherate (28 g, 197.1 mmol) and acetic acid (3.9 g, 65.7 mmol). The atmosphere was replaced with argon three times and stirred at 90°C overnight. 10% NaOAc was added to neutralize the mixture to pH 7 under ice-cooling. The mixture was stirred for 10 min and extracted with ethyl acetate (200 mL x 2). The organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 6 g of crude product. Purification by column chromatography (PE:EA = 20:1 to 10:1) afforded 5.4 g of a light yellow solid with a yield of 84.6%. UPLC-MS calculated for C 11 H 14 O3[M+H] + :195.09,found:195.11.

[0354] Step 2:

[0355] HSP90-4-2 (5.4 g, 27.8 mmol), K2CO3 (11.5 g, 83.5 mmol), and DMF (200 mL) were added dropwise to a 500 mL reaction flask. Benzyl bromide (10.5 g, 61.2 mmol) was added dropwise. The atmosphere was replaced with argon three times, and the temperature was raised to 110°C and stirred overnight. The reaction mixture was poured into 1.5 L of ice water and stirred for 30 min. The precipitated solid was filtered, washed with 300 mL of water, and dried to obtain 11 g of crude product. Recrystallization from MeOH / DCM afforded 9.1 g of a white solid (87.4% yield). UPLC-MS calculated for C 25 H 26 O3[M+H] + :375.19,found:375.23.

[0356] Step 3:

[0357] HSP90-4-3 (6.5 g, 17.4 mmol) was added to a solution of EtONa (2.4 g, 34.7 mmol) in ethanol (100 mL). The atmosphere was replaced with argon three times and stirred for 10 min. Diethyl oxalate (3.9 g, 26.1 mmol) was then added dropwise. The mixture was heated to reflux and stirred for 4 h. After cooling to room temperature, the solution was neutralized with 1 M HCl to pH 7. The precipitated solid was filtered, and the filter cake was washed with cold methanol (20 mL) and dried to obtain 7 g of a yellow solid, with a yield of 84.9%. UPLC-MS calculated for C 29 H 30 O6[M+H] + :475.20,found:475.23.

[0358] Step 4:

[0359] HSP90-4-4 (7 g, 14.8 mmol), hydroxylamine hydrochloride (1.2 g, 17.7 mmol) and ethanol (80 mL) were added to a reaction flask. The atmosphere was replaced with argon three times. The mixture was heated to reflux with stirring for 3 h, cooled in an ice bath, stirred for 30 min, and filtered. The filter cake was washed with cold ethanol (20 mL) and dried to obtain 5 g of a white solid with a yield of 71.4%. UPLC-MS calculated for C 29 H 29 NO5[M+H] + :472.20,found:472.23.

[0360] Step 5:

[0361] 5 (5.3 g, 11.2 mmol), NBS (2 g, 11.2 mmol), and acetonitrile (70 mL) were added to a reaction flask. Cerium ammonium nitrate (0.06 g, 0.1 mmol) was added, and the atmosphere was replaced with argon three times. The mixture was heated and refluxed with stirring overnight. The reaction mixture was cooled to room temperature and concentrated to obtain the crude product. Column chromatography (PE:EA = 95%:5%) afforded 5.6 g of a white solid, yielding 90.4%.

[0362] UPLC-MS calculated for C 29 H 28 BrNO5[M+H] + :550.12, 552.11, found:550.14, 552.15.

[0363] Step 6:

[0364] Add 2.2 g (4.0 mmol) and 25 mL of methanol to a reaction flask, replace the atmosphere with argon three times, add ethylamine (12 mL, 24 mmol, 2 M THF solution), and stir under reflux overnight. Concentrate the reaction mixture and pump dry to obtain 2.3 g of a light yellow solid, with a yield of 100%. UPLC-MS calculated for C 29 H 29 BrN2O4[M+H] + :549.13, 551.13,found:549.21, 551.20.

[0365] Step 7:

[0366] (6 g, 10.9 mmol), 4-formylphenylboronic acid (2.45 g, 16.3 mmol), K2CO3 (4.5 g, 32.7 mmol), 1,4-dioxane (90 mL) and water (10 mL) were added to a reaction flask, the atmosphere was replaced with argon three times, Pd(dppf)Cl2 (0.8 g, 1.09 mmol) was added, the atmosphere was replaced with argon three times again, the temperature was raised to 85°C and stirred overnight, 200 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL*2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, which was purified by column chromatography (DCM:EA=80:20) to obtain 4.2 g of a light brown solid with a yield of 80%. UPLC-MS calculated for C 36 H 34 N2O5[M+H] + :575.25,found:575.31.

[0367] Step 8:

[0368] (480 mg, 0.83 mmol) and 25 mL of DCM were added to a reaction flask. The atmosphere was replaced with argon three times. BCl₃ (5 mL, 1 M in toluene) was added dropwise under an ice bath and stirred for 2 h. The mixture was quenched with saturated NaHCO₃ solution and extracted with DCM (50 mL x 2). The organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Column chromatography (5 g silica gel, DCM:MeOH = 100:5) afforded 300 mg of a brown solid, with a yield of 87%. UPLC-MS calculated for C 22 H 22 N2O5[M+H] + :395.15,found:395.17.

[0369] Example 5

[0370] Preparation of intermediate HSP90-5

[0371] first step:

[0372] HSP90-4-7 (1 g, 1.82 mmol), 4-hydroxymethylphenylboronic acid (415 mg, 2.73 mmol), K3PO4 (1.2 g, 5.46 mmol), and 1,4-dioxane (20 mL) were added to a reaction flask. The atmosphere was purged with argon three times, and Pd(dtbpf)Cl2 (120 mg, 0.182 mmol) was added. The atmosphere was purged with argon three times again, and the mixture was stirred at 95°C overnight. The reaction mixture was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous Na2SO4, and filtered and concentrated to obtain the crude product. Purification by column chromatography (DCM:EA = 8:2) gave 460 mg of a brown solid, with a yield of 44%. UPLC-MS calculated for C 36 H 36 N2O5[M+H] + :577.26,found:577.25.

[0373] Step 2:

[0374] HSP90-5-1 (460 mg, 0.80 mmol), N,N′-dimethylthiourea (42 mg, 0.4 mmol), and DCM (20 mL) were added to a reaction flask. NBS (220 mg, 1.2 mmol) was added, and the atmosphere was replaced with argon three times. The reaction was stirred at room temperature overnight and quenched by adding 20 mL of saturated Na2S2O3 solution. The product was washed with DCM (50 mL x 2) and 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered and concentrated to obtain the crude product. Purification by column chromatography (100% DCM) gave 480 g of a brown solid with a yield of 90%. UPLC-MS calculated for C 36 H 35 BrN2O4[M+H] + :639.18, 641.18,found:639.25, 641.24.

[0375] Step 3:

[0376] HSP90-5-2 (480 mg, 0.75 mmol) and dichloromethane (10 mL) were added to a reaction flask. The atmosphere was replaced with argon three times, and BCl (5 mL, 5 mmol, 1 M solution in toluene) was added dropwise under ice-water bath. The mixture was stirred under ice-water bath for 2 h. Water (50 mL) was added to quench the mixture under ice-water bath, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous NaSO, and filtered and concentrated to yield 350 mg of a light brown solid (100% yield). UPLC-MS calculated for C 22 H 23BrN2O4[M+H] + :459.08, 461.08,found:459.13, 459.14.

[0377] Example 6

[0378] Preparation of intermediate HSP90-6

[0379] first step:

[0380] HSP90-4-4 (2.7 g, 5.7 mmol), hydrazine hydrate (0.43 g, 6.8 mmol, 80%), and acetic acid (30 mL) were added to a reaction flask. The atmosphere was replaced with argon three times and stirred at 85°C overnight. After cooling to room temperature, the reaction solution was poured into 500 mL of water and stirred for 30 min. The mixture was filtered and the filter cake was washed with cold ethanol (20 mL). The mixture was dried to obtain 2.6 g of a white solid with a yield of 97%. UPLC-MS calculated for C 29 H 30 N2O4[M+H] + :471.22,found:471.25.

[0381] Step 2:

[0382] HSP90-6-1 (2.6 g, 5.5 mmol), NBS (1 g, 5.6 mmol), and acetonitrile (40 mL) were added to a reaction flask. Cerium ammonium nitrate (0.3 g, 0.55 mmol) was added, and the atmosphere was replaced with argon three times. The mixture was heated and refluxed with stirring overnight. The reaction mixture was cooled to room temperature and concentrated to obtain the crude product. Column chromatography (PE:EA = 95%:5%) afforded 2.6 g of a light yellow solid, yielding 85%. UPLC-MS calculated for C 29 H 29 BrN2O4[M+H] + :549.13, 551.13,found:549.14, 551.15.

[0383] Step 3:

[0384] HSP90-6-2 (2.6 g, 4.7 mmol) and 1,4-dioxane were added to a reaction flask, followed by a 20% aqueous solution of NaOH (303 mg, 7.6 mmol). The mixture was stirred at room temperature overnight, and 50 mL of water was added. The mixture was neutralized with 1 M HCl to pH 5, and extracted with ethyl acetate (100 mL x 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous Na2SO4, and filtered and concentrated to obtain 2.7 g of a light yellow solid. UPLC-MS calculated for C 27H 25 BrN2O4[MH] - :519.10, 521.10, found:519.13, 521.14.

[0385] Step 4:

[0386] HSP90-6-3 (500 mg, 0.95 mmol) and DCM (10 mL) were added to a reaction flask. The atmosphere was replaced with argon three times, and SOCl2 (150 mg, 1.15 mmol) and 1 drop of DMF were added. The mixture was stirred at room temperature for 2 h and concentrated to obtain the acid chloride. Ethylamine hydrochloride (800 mg, 9.5 mmol), triethylamine (1 g, 1.9 mmol), and DCM (10 mL) were added to the reaction flask, and the acid chloride was added dropwise. The mixture was stirred under argon overnight. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered and concentrated to obtain 700 mg of a brown solid with a yield of 87%. UPLC-MS calculated for C 29 H 30 BrN3O3[M+H] + :548.15, 550.15,found:548.14, 550.15.

[0387] Step 5:

[0388] HSP90-6-4 (600 mg, 1.09 mmol), 4-formylphenylboronic acid (240 mg, 1.6 mmol), K3PO4 (300 mg, 3.3 mmol), and 1,4-dioxane (10 mL) were added to a reaction flask. The atmosphere was purged with argon three times, and Pd(dtbpf)Cl2 (84 mg, 0.11 mmol) was added. The atmosphere was purged with argon three times again, and the mixture was stirred at 95°C overnight. The reaction mixture was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous Na2SO4, and filtered and concentrated to obtain the crude product. The product was purified by column chromatography (DCM:EA = 8:2) to obtain 300 mg of a brown solid with a yield of 47%. UPLC-MS calculated for C 36 H 35 N3O4[M+H] + :574.27,found:574.25.

[0389] Step 6:

[0390] HSP90-6-5 (240 mg) and acetic acid (5 mL) were added to a reaction flask, followed by 10% Pd / C (24 mg). The mixture was stirred overnight under a hydrogen atmosphere, filtered, concentrated, and purified by column chromatography (5 g silica gel, DCM:MeOH = 100:5) to obtain 70 mg of a light yellow solid, with a yield of 42%. UPLC-MS calculated for C 22 H 23 N3O4[M+H] + :394.17,found:394.29.

[0391] Example 7

[0392] Preparation of intermediate HSP90-7:

[0393] The synthesis steps were similar to those of HSP90-1. UPLC-MS calculated for C 24 H 33 N6O3[M+H] + :453.25,found:453.56.

[0394] Example 8

[0395] Preparation of intermediate HSP90-8:

[0396] first step:

[0397] The raw material HSP90-8-1 (2.0 g, 9.26 mmol) was dissolved in dichloromethane (60 mL), and tert-butyl piperazine-1-carboxylate (1.75 g, 9.4 mmol) and triethylamine (2 mL, 14.0 mmol) were added. The reaction mixture was stirred at room temperature for 6 h and extracted with water (100 mL x 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After removing the solvent, the product was recrystallized from ethanol to obtain 2.4 g of a light yellow solid with a yield of 80.60%. UPLC-MS calculated for C 16 H 23 N3O4[M+H] + :321.38,found:321.92.

[0398] Step 2:

[0399] The raw material HSP90-8-2 (1.5 g, 4.67 mmol) and stannous chloride dihydrate (5.27 g, 23.33 mmol) were placed in ethyl acetate (50 mL) and stirred at room temperature overnight. Saturated aqueous sodium bicarbonate (20 mL) was added and stirred vigorously for 1 hour. The solid was removed by filtration, and the mixture was extracted with ethyl acetate and water. The organic phase was dried over anhydrous magnesium sulfate and concentrated to give 1.09 g of a yellow solid, with a yield of 80.15%. UPLC-MS calculated for C 16 H 25 N3O2[M+H] + :291.40,found:291.93.

[0400] Step 3:

[0401] Dissolve phenyl chloroformate (0.47 mL, 3.74 mmol) in dichloromethane. Slowly add a dichloromethane solution of the intermediate HSP90-8-3 (1.09 g, 3.74 mmol) dropwise at 0°C with stirring. After the addition is complete, maintain the reaction at 0°C for 30 minutes. Slowly add a dichloromethane solution of triethylamine (0.62 mL, 4.49 mmol). Allow to react overnight, extract with water and dichloromethane, and dry the organic phase over anhydrous magnesium sulfate. Evaporate the solvent and perform column chromatography (PE:EA = 1 / 1) to obtain 900 mg of a white solid, with a yield of 58.48%. UPLC-MS calculated for C 23 H 29 N3O4[M+H] + :411.50,found:412.06.

[0402] Step 4:

[0403] The intermediate HSP90-8-4 (230 mg, 0.59 mmol) was dissolved in 1,4-dioxane (10 mL), and hydrazine hydrate (2.95 mmol) was added. The reaction was carried out at 100°C for 4 h. TLC showed that the reaction of the raw material was complete. The solvent was removed and the solid precipitated after cooling to obtain the crude intermediate HSP-8-5.

[0404] Step 5:

[0405] Intermediate HSP90-2-8 (201 mg, 0.59 mmol) was dissolved in ethanol (5 mL), and glacial acetic acid (0.04 mL) was added. Intermediate HSP-8-5 (195 mg, 0.59 mmol) was slowly added to the solution with stirring at room temperature. The reaction was moved to 80°C for 1 h. After completion of the reaction, column chromatography (DCM:MeOH = 35 / 1) afforded 290 mg of a white solid, with a yield of 71.04%. UPLC-MS calculated for C 41 H 49 N5O5[M+H] + :691.87,found:692.10.

[0406] Step 6:

[0407] The intermediate HSP90-8-6 (290 mg, 0.42 mmol) was added to ethanol (5 mL) to form a suspension. K3Fe(CN)6 (414 mg, 1.26 mmol) and NaOH (84 mg, 2.1 mmol) were added and refluxed at 100°C for 8 h. TLC confirmed the complete reaction of the starting material. The inorganic residue was filtered off, the solvent was evaporated, and the product was purified by column chromatography (DCM:MeOH = 35 / 1) to obtain 284 mg of the intermediate with a yield of 98.02%. UPLC-MS calculated for C 41 H 47 N5O5[M+H] + :689.86,found:690.11.

[0408] Step 7:

[0409] Intermediate HSP90-8-7 (280 mg, 0.45 mmol) was dissolved in dichloromethane (20 mL), and a 4M hydrochloric acid / dioxane solution (1.5 mL) was added. The mixture was stirred at room temperature for 2 h. After TLC analysis, the solvent was evaporated to dryness, and the mixture was extracted with ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude intermediate HSP90-8-8.

[0410] Step 8:

[0411] The intermediate HSP90-8-8 from the previous step was dissolved in methanol (20 mL), and an appropriate amount of Pd / C was added. The reaction was stirred at room temperature under a H2 atmosphere for 5 h. After TLC analysis of the reaction, the reaction mixture was filtered and the solvent was evaporated to dryness to obtain 130 mg of a yellow solid. The yield for the two steps was 75.59%. UPLC-MS calculated for C 22 H 27 N5O3[M+H] +:409.49,found:410.13.

[0412] Example 9

[0413] Preparation of intermediate HSP90-9:

[0414] The synthesis of the first to fourth steps refers to the synthesis route of HSP90-8.

[0415] Step 5:

[0416] HSP90-9-5 (500 mg, 0.97 mmol) was dissolved in 10 mL of DCM and replaced with argon three times. BCl3 (5 mL, 1 M toluene solution) was added dropwise in an ice-water bath and stirred for 2 h. NaHCO3 was added to neutralize the mixture to pH 7. Water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous magnesium sulfate, the solvent was evaporated, and column chromatography (DCM:MeOH = 50 / 1) was performed to obtain 162 mg of HSP90-9-5 as a pale yellow solid, with a yield of 50%. UPLC-MS calculated for C 19 H 17 N3O3[M+H] + :336.13,found:336.08.

[0417] Step 6:

[0418] HSP90-9-6 (162 mg, 0.49 mmol), CuI (18 mg, 0.098 mmol), (PPh3)2PdCl2 (34 mg, 0.049 mmol), and triethylamine (148 mg, 1.47 mmol) were dissolved in anhydrous DMF. The atmosphere was replaced with argon three times and the mixture was reacted at room temperature for 3 h. Water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous magnesium sulfate, the solvent was evaporated, and column chromatography (DCM:MeOH = 50 / 1) was performed to obtain 202 mg of HSP90-9-6 as a pale yellow solid, with a yield of 90%. UPLC-MS calculated for C 24 H 21 N5O5[M+H] + :460.16,found:460.12.

[0419] Step 7:

[0420] HSP90-9-7 (202 mg, 0.44 mmol) was dissolved in 10 mL of methanol. 5 mL of LiOH (74 mg, 1.76 mmol) was added dropwise at room temperature and stirred overnight. The preparative liquid phase gave 186 mg of HSP90-9 as a white solid, with a yield of 95%. UPLC-MS calculated for C 23 H 19 N5O5[M+H] + :446.14,found:446.08.

[0421] Example 10

[0422] Preparation of intermediate HSP90-10:

[0423] The synthetic route and method refer to HSP90-1. UPLC-MS calculated for C 24 H 27 N5O3[M+H] + :434.22,found:434.29.

[0424] Example 11

[0425] Preparation of intermediate HSP90-11:

[0426] The synthetic route and method refer to HSP90-1. UPLC-MS calculated for C 26 H 31 N5O3[M+H] + :462.25,found:462.39.

[0427] Example 12

[0428] Preparation of intermediate HSP90-12:

[0429] The first and second steps of the synthesis route refer to HSP90-8.

[0430] Step 3:

[0431] HSP90-12-3 (430.92 mg, 1.89 mmol) was dissolved in DMF (5 mL), and NaHCO3 (577.31 mg, 6.87 mmol) was added. Under argon protection, chloroacetic acid (162.37 mg, 1.17 mmol) was added at 0°C and the mixture was returned to room temperature and stirred for 2 h. Intermediate 3 (500 mg, 1.71 mmol) was dissolved in DMF and added to the system. The reaction was continued at 80°C overnight, cooled to room temperature, and aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate, and the organic phase solvent was evaporated to dryness. The product was separated by column chromatography (PE:EA = 1 / 1) to obtain 400 mg of a yellow solid, with a yield of 48%. UPLC-MS calculated for C 26 H 35 N3O4S[M+H] + :485.23,found:486.62.

[0432] Step 4:

[0433] HSP90-12-4 (400 mg, 0.82 mmol) was dissolved in 1,4-dioxane (15 mL), and NH-NH (206.18 mg, 4.13 mmol) was added under argon protection. The mixture was reacted at 80°C for 5 h, cooled to room temperature, and the solvent was evaporated to dryness to obtain 400 mg of a yellow oil. UPLC-MS calculated for C 26 H 37 N5O4[M+H] + :483.28,found:484.62.

[0434] Step 5:

[0435] The intermediate HSP90-12-5 (400 mg, 0.83 mmol) was dissolved in EtOH (10 mL), and two drops of AcOH were added. Diethyl oxalate (181.36 mg, 1.24 mmol) was dissolved in ethanol and added dropwise to the above system at 0°C. The mixture was returned to room temperature under argon and stirred overnight. The solvent was evaporated and the mixture was separated by column chromatography (PE:EA=2 / 1) to obtain 80 mg of a white solid, with a yield of 34%. UPLC-MS calculated for C 30 H 39 N5O6[M+H] + :565.29,found:566.52.

[0436] Step 6:

[0437] HSP90-12-6 (160 mg, 0.28 mmol) was dissolved in MeOH (4 mL) and HCl-dixoane (1 mL) was added. The mixture was stirred at room temperature overnight and the solvent was evaporated to dryness to obtain 80 mg of a yellow solid. UPLC-MS calculated for C 25 H 32 N6O3[M+H] + :464.25,found:465.26.

[0438] Example 13

[0439] Preparation of intermediate HSP90-13:

[0440] The synthetic route and method refer to HSP90-12, UPLC-MS calculated for C 24 H 30 N6O4[M+H] + :465.24,found:466.52.

[0441] Example 14

[0442] Preparation of intermediate HSP90-14:

[0443] first step:

[0444] HSP90-14-1 (917 mg, 4.19 mmol), trans-dichloro(tri-O-toluenephosphine)palladium (102 mg, 0.13 mmol), triethylamine (2116 mg, 20.95 mmol), and N-Boc-4-vinylpiperidine (884 mg, 4.19 mmol) were dissolved in 10 mL of DMF and heated to 130°C under an argon atmosphere for 2 h. LC-MS analysis was performed. After completion of the reaction, the mixture was extracted with water and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, the solvent evaporated, and column chromatography (PE:EA = 1 / 1) was performed to obtain 1.20 g of HSP90-14-2 as a pale yellow solid, with a yield of 86.16%. UPLC-MS calculated for C 18 H 24 N2O4[M+H] + :332.40,found:332.68.

[0445] Step 2:

[0446] HSP90-14-2 (1.20 g, 3.61 mmol) was dissolved in 40 mL of methanol, and 10% Pd / C (120 mg) was added. H2 was purged three times and the reaction was allowed to react at room temperature overnight. After completion of the reaction, the palladium-carbon mixture was filtered through Celite, the solvent was evaporated, and column chromatography (DCM:MeOH = 100 / 1) was performed to obtain HSP90-14-3 as a light yellow solid (1.152 g, 96% yield). UPLC-MS calculated for C 18 H 28 N2O2[M+H] + :304.43,found:304.56.

[0447] Step 3:

[0448] HSP90-1-5 (750 mg, 3.29 mmol) and NaHCO3 (829 mg, 9.87 mmol) were dissolved in 10 mL of anhydrous DMF. A solution of chloroacetic acid (311 mg, 3.29 mmol) in anhydrous DMF was slowly added dropwise at 0°C under Ar gas with stirring. After the addition was complete, stirring was continued at 0°C for 5 minutes, then the mixture was warmed to room temperature and stirred for 90 minutes. A solution of HSP90-14-3 (1000 mg, 3.29 mmol) in 5 mL of anhydrous DMF was slowly added dropwise to the above solution at room temperature. After the addition was complete, the mixture was heated to 80°C and reacted for 3 hours. After completion of the reaction, water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous magnesium sulfate, the solvent was evaporated, and column chromatography (PE:EA = 2 / 1) was performed to obtain HSP90-14-4 as a yellow solid (1200 mg, yield 73.14%). UPLC-MS calculated for C 28 H 38 N2O4S[M+H] + :499.26,found:499.17.

[0449] Step 4:

[0450] HSP90-14-4 (1200 mg, 2.41 mmol) was dissolved in 20 mL of anhydrous THF. CDI (780 mg, 4.82 mmol) was added at 0°C under Ar protection and the reaction was stirred at room temperature for 3 h. After the reaction was completed, water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated to give 940.86 mg of crude HSP90-14-5, which was used directly without post-treatment.

[0451] Step 5:

[0452] The crude product HSP90-14-5 (940.86 mg, 1.81 mmol) was dissolved in 10 mL of anhydrous ethanol, and hydrazine hydrate (224 mg, 2.08 mmol) was added at room temperature. The mixture was stirred at room temperature overnight. When the reaction was complete, the solvent was evaporated and the mixture was purified by column chromatography (DCM:MeOH=20 / 1) to obtain HSP90-14-6 as a yellow solid (610 mg). The yield was 64.53%. UPLC-MS calculated for C 29 H 38 N4O5[M+H] + :523.29,found:523.20.

[0453] Step 6:

[0454] HSP90-14-6 (610 mg, 1.17 mmol) was dissolved in 10 mL of DCM, and 2.5 mL of a 4 M 1,4-dioxane-hydrochloride solution was added. The mixture was stirred at room temperature overnight. After the reaction was complete, the solvent was evaporated to dryness to obtain HSP90-14 as a light yellow solid (484 mg, 98% yield). UPLC-MS calculated for C 24 H 30 N4O3[M+H] + :423.24,found:423.10.

[0455] Example 15

[0456] Preparation of intermediate HSP90-15:

[0457] The synthetic route was referenced to HSP90-14, and UPLC-MS calculated for C 23 H 28 N4O4[M+H] + :425.21,found:425.18.

[0458] Example 16

[0459] Preparation of intermediate HSP90-16:

[0460] The synthetic route was referenced to HSP90-14, and UPLC-MS calculated for C 23 H 29 N5O3[M+H] + :424.23,found:424.20.

[0461] Example 17

[0462] Preparation of intermediate HSP90-17:

[0463] The synthetic route was referenced to HSP90-14, and UPLC-MS calculated for C 24 H 31 N5O3[M+H] + :438.25,found:438.24.

[0464] Example 18

[0465] Preparation of intermediate HSP90-18:

[0466] The synthetic route and method refer to HSP90-1, UPLC-MS calculated for C 27 H 33 N5O3[M+H] + :476.27,found:476.35.

[0467] Example 19

[0468] Preparation of intermediate HSP90-19:

[0469] The synthetic route and method refer to HSP90-1, UPLC-MS calculated for C 23 H 25 N5O3[M+H] + :420.20,found:420.28.

[0470] Example 20

[0471] Preparation of intermediate HSP90-20:

[0472] The synthetic route and method refer to HSP90-8, UPLC-MS calculated for C 22 H 26 FN5O3[M+H] + :447.20found:428.02.

[0473] Example 21

[0474] Preparation of intermediate HSP90-21:

[0475] first step:

[0476] HSP90-21-1 (800 mg, 5.06 mmol) was dissolved in DCE (10 mL), and STAB (2.23 g, 10.52 mmol) was added. The mixture was stirred at room temperature overnight. After completion of the reaction, column chromatography (PE:EA = 1 / 1) was performed to obtain 600 mg of a white solid, with a yield of 74.07%. UPLC-MS calculated for C6H6N2O3[M+H] + :154.04,found:155.12.

[0477] Step 2:

[0478] HSP90-21-3 (600 mg, 3.89 mmol) was dissolved in DCM (10 mL). PBr (703.89 mg, 2.59 mmol) was added at 0°C and stirred at room temperature for 4 h. After the reaction, NaHCO was added and extracted with dichloromethane. The concentrated organic phase was purified by column chromatography (PE:EA = 1 / 1) to obtain 600 mg of a yellow solid in a 71.3% yield. UPLC-MS calculated for C6H5BrN2O2 [M+H] + :215.95,found:217.13.

[0479] The synthetic routes and methods of steps 3 to 10 refer to the key intermediate HSP90-8, and UPLC-MS calculated for C 21 H 26 N6O3[M+H] + :410.21,found:411.38.

[0480] Example 22

[0481] Preparation of intermediate HSP90-22:

[0482] The synthetic route and method refer to HSP90-1, UPLC-MS calculated for C 22 H 27 N4O4[M+H] + :411.20,found:411.47.

[0483] Example 23

[0484] Preparation of intermediate HSP90-23:

[0485] The synthetic route and method refer to HSP90-1, UPLC-MS calculated for C 22 H 28N5O3[M+H] + :410.21,found:411.49.

[0486] Example 24

[0487] Preparation of intermediate HSP90-24:

[0488] The synthetic route and method refer to HSP90-8, UPLC-MS calculated for C 21 H 27 N6O3[M+H] + :411.21,found:411.48.

[0489] Example 25

[0490] Preparation of intermediate HSP90-25:

[0491] The synthetic route and method refer to HSP90-8, UPLC-MS calculated for C 20 H 26 N7O3[M+H] + :412.20,found:412.47.

[0492] Example 26

[0493] Preparation of intermediate HSP90-26:

[0494] The synthetic route and method refer to HSP90-8, UPLC-MS calculated for C 20 H 26 N7O3[M+H] + :412.20,found:412.48.

[0495] Example 27

[0496] Preparation of intermediate HSP90-27:

[0497] The synthetic route and method refer to HSP90-3, UPLC-MS calculated for C 22 H 29 N6O3[M+H] + :425.22,found:425.51.

[0498] Example 28

[0499] Preparation of intermediate HSP90-28:

[0500] The synthetic route and method refer to HSP90-3, UPLC-MS calculated for C 21 H 27 N6O3[M+H] + :411.21,found:411.48.

[0501] Example 29

[0502] Preparation of intermediate AR-1:

[0503] first step:

[0504] NaH (60%) (50 mg, 1.23 mmol) was added to a solution of trans-4-BOC-aminocyclohexanol (222 mg, 1.03 mmol) in DMF (20 mL) at 0°C and stirred for 20 minutes. Raw material AR-1-1 (161 mg, 1.03 mmol) was added to the reaction system and the mixture was allowed to react at room temperature for 4 hours. TLC confirmed the complete reaction. The mixture was extracted with ethyl acetate and water, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was then dried and purified by column chromatography (PE:EA = 5 / 1) to afford 280 mg of a white solid, with a yield of 77.48%. UPLC-MS calculated for C 18 H 23 ClN2O3[M+H] + :350.84,found:350.82.

[0505] Step 2:

[0506] AR-1-2 (280 mg, 0.80 mmol) was dissolved in dichloromethane (20 mL), and 4 M hydrochloric acid / dioxane solution (2.0 mL) was added. The mixture was stirred at room temperature for 4 h. TLC confirmed that the reaction was complete, and the solvent was evaporated to obtain a yellow solid. UPLC-MS calculated for C 13 H 15 ClN2O[M+H] + :250.73,found:250.75.

[0507] Step 3:

[0508] 6-Chloropyridazine-3-carbonyl chloride (50 mg, 0.17 mmol) and DIPEA (0.09 mL, 0.52 mmol) were dissolved in anhydrous dichloromethane (20 mL) and stirred at room temperature for 20 min. The mixture was then added to AR-1-3 (36 mg, 0.21 mmol) and stirred at room temperature under argon protection overnight. The solvent was evaporated and column chromatography (PE:EA = 5 / 1) was performed to obtain 67 mg of a light yellow solid, with a yield of 99.84%. UPLC-MS calculated for C 18 H 16 Cl2N4O2[M+H] + :391.25,found:390.79.

[0509] Example 30

[0510] Preparation of intermediate AR-2:

[0511] first step:

[0512] AR-1-1 (300 mg, 1.93 mmol) was dissolved in dimethylformamide (20 mL), and cesium carbonate (1.3 g, 10 mmol) and tert-butyl trans-(4-aminocyclohexyl)carbamate (455.6 mg, 2.12 mmol) were added. The temperature was raised to 100°C and the reaction was allowed to react for 18 h. After cooling to room temperature, the mixture was diluted with 100 mL of water and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then purified by column chromatography (PE:EA = 1:1) to obtain 250 mg of a white solid with a yield of 37.03%. UPLC-MS calculated for C 18 H 24 ClN3O2[M+H] + :349.16,found:350.22.

[0513] Step 2:

[0514] AR-2-1 (250 mg, 0.716 mmol) was dissolved in 10 mL of 4 M hydrogen chloride in dioxane and stirred at room temperature for 1 h. After spin drying, 180 mg of crude white solid was obtained. Yield: 100%. UPLC-MS calculated for C 13 H 16 ClN3[M+H] + :249.10,found:250.33.

[0515] Step 3:

[0516] AR-2-2 (270 mg, 1.08 mmol) was dissolved in 10 mL of tetrahydrofuran, and DIEA (420 mg, 3.25 mmol) was added. The reaction mixture was cooled to 0°C, and a solution of 6-chloropyridazine-3-carbonyl chloride (222 mg, 1.26 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise. After the addition was complete, the mixture was warmed to room temperature and allowed to react for 18 h. 40 mL of saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then dried and purified by column chromatography (DCM:MeOH = 15 / 1) to obtain 320 mg of a yellow solid in a yield of 76.19%. UPLC-MS calculated for C 18 H 17 Cl2N5O[M+H] + :389.08,found:390.11.

[0517] Example 31

[0518] Preparation of intermediate AR-3:

[0519] first step:

[0520] AR-3-1 (5 g, 21.5 mmol) and 2-amino-2-methylpropionic acid (2.7 g, 25.86 mmol) were dissolved in anhydrous DMSO (100 mL). CuI (821 mg, 4.3 mmol) and DBU (7.9 g, 51.7 mmol) were added under argon protection. The reaction was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate to remove impurities. The aqueous phase was adjusted to pH ~2 and the filter cake was filtered to obtain 3 g of the product as a light yellow solid with a yield of 55.56%. UPLC-MS calculated for C 12 H 14 FNO4[M+H] + :255.09,found:256.79.

[0521] Step 2:

[0522] AR-3-2 (3 g, 11.7 mmol) was dissolved in anhydrous MeOH (50 mL) and then added (1.27 g, 11.7 mmol). The mixture was refluxed at 80°C overnight, extracted with ethyl acetate and water, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was then spin-dried and subjected to column chromatography (PE:EA=3 / 1) to obtain 1.7 g of an off-white solid with a yield of 54.8%. UPLC-MS calculated for C 13 H 16 FNO4[M+H] +:269.11,found:27.82.

[0523] Step 3:

[0524] AR-3-3 (1.7 g, 6.3 mmol) was dissolved in anhydrous THF (20 mL) under argon protection. 3-(trifluoromethyl)pyridine-2-cyanoisothiocyanato (1.5 g, 6.63 mmol) was added at 0°C. The mixture was stirred in an ice bath under argon protection for one hour. The pH was adjusted to 5-6 and the mixture was extracted with ethyl acetate and dried to give 1.7 g of a yellow solid with a yield of 58.6%. UPLC-MS calculated for C 21 H 15 F4N3O3S[M+H] + :465.08,found:466.12.

[0525] Step 4:

[0526] Intermediate AR-3-4 (1.7 g, 3.6 mmol), anhydrous THF (6 mL), and MeOH (6 mL) were added to a solution of LiOH (584 mg, 14.6 mmol) in anhydrous H₂O and stirred at room temperature for 4 hours. The pH was adjusted with HCl, and water and ethyl acetate were added for extraction. The organic phase was washed sequentially with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography (DCM:MeOH = 15 / 1) to afford 1 g of a solid in a 62% yield. UPLC-MS calculated for C 20 H 13 F4N3O3S[MH] - :450.06,found:450.28.

[0527] Example 32

[0528] Preparation of intermediate AR-4:

[0529] The synthetic route and method refer to AR-1, UPLC-MS calculated for C 18 H 16 Cl2N4O2[M+H] + :391.25,found:390.79.

[0530] Example 33

[0531] Preparation of intermediate AR-5:

[0532] first step:

[0533] HSP90-3-1 (500 mg, 3.16 mmol) was dissolved in 20 mL of dimethylformamide, and potassium carbonate (524 mg, 3.79 mmol) and 4-(dimethoxymethyl)-piperidine (553 mg, 3.47 mmol) were added sequentially. The temperature was raised to 80°C and the reaction mixture was allowed to react for 18 h. After cooling to room temperature, water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then dried to give 920 mg of a crude golden solid. UPLC-MS calculated for C 13 H 19 N3O4[M+H] + :281.14,found:282.30.

[0534] Step 2:

[0535] AR-5-1 was dissolved in 30 mL of methanol, and 10% palladium on carbon (15 mg) was added. The hydrogen atmosphere was replaced three times, and the reaction was allowed to proceed at room temperature for 6 h. The reaction solution was filtered, dried, and purified by column chromatography (PE:EA = 1:3) to obtain 590 mg of a red oil, with a two-step yield of 74.30%. UPLC-MS calculated for C 27 H 37 N5O3[M+H] + :251.16,found:252.30.

[0536] Step 3:

[0537] AR-5-2 (200 mg, 0.79 mmol) was dissolved in methanol (30 mL), and cyclobutanone (75 mg, 1.07 mmol) and zinc iodide (15 mg, 0.05 mmol) were added. The mixture was reacted at room temperature for 30 min, followed by the addition of TMSCN (120 mg, 1.2 mmol). The temperature was raised to 50°C and the reaction was continued for 18 h. After cooling to room temperature, the solvent was removed by rotary evaporation and the product was purified by column chromatography (PE:EA = 1:2) to obtain 210 mg of a brown oil with a yield of 79.86%. UPLC-MS calculated for C 14 H 26 N4O2[M+H] + :330.21,found:331.58.

[0538] Step 4:

[0539] AR-5-3 (210 mg, 0.63 mmol) and 5-isothiocyanato-2-cyano-3-trifluoromethylpyridine (220 mg, 0.96 mmol) were dissolved in dimethylacetamide (20 mL) and the reaction mixture was heated to 60°C for 4 h. After cooling to room temperature, water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then purified by column chromatography (PE:EA = 1:2) to obtain 430 mg of a brown oil with a yield of 94.37%. UPLC-MS calculated for C 26 H 28 F3N7O2S[M+H] + :559.20,found:560.16.

[0540] Step 5:

[0541] AR-5-4 (430 mg, 0.77 mmol) was dissolved in tetrahydrofuran (20 mL), and 6 M hydrochloric acid solution (10 mL) was added. The reaction mixture was heated to 40°C and reacted for 18 h. After cooling to room temperature, water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then purified by column chromatography (PE:EA = 3:2) to obtain 240 mg of a brown oil with a yield of 60.75%. UPLC-MS calculated for C 24 H 21 F3N6O2S[M+H] + :514.14,found:515.33.

[0542] Example 34

[0543] Preparation of intermediate AR-6:

[0544] The synthetic route and method refer to AR-3, UPLC-MS calculated for C 20 H 12 F4N4O3S[MH] - :463.06,found:463.39.

[0545] Example 35

[0546] Preparation of intermediate AR-7:

[0547] AR-7-1 (1 g, 5.49 mmol) was dissolved in tetrahydrofuran (30 mL). Thionyl chloride (900 mg, 7.63 mmol) was added dropwise in an ice bath and allowed to react at 0°C for 3 h. Triethylamine (670 mg, 6.63 mmol) was slowly added dropwise to the reaction mixture at 0°C. After 10 min of reaction, a solution of 4-amino-2-trifluoromethylbenzonitrile (820 mg, 4.40 mmol) in tetrahydrofuran (10 mL) was added dropwise. The temperature was raised to 50°C and the reaction was allowed to react for 18 h. After cooling to room temperature, saturated ammonium chloride solution (100 mL) was added to the reaction mixture and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified by column chromatography (PE:EA = 1:1) to obtain 1.8 g of a brown solid, with a two-step yield of 93%. UPLC-MS calculated for C 12 H 10 BrF3N2O2[MH] - :349.99,found:349.01.

[0548] Example 36

[0549] Preparation of intermediate AR-8:

[0550] The synthetic route and method refer to AR-8, UPLC-MS calculated for C 11 H 10 BrClN2O2[MH] - :316.57, found:315.96.

[0551] Example 37

[0552] Preparation of intermediate AR-9:

[0553] first step:

[0554] The raw materials AR-9-1 (3 g, 13.8 mmol), AR-9-2 (5.8 g, 20.8 mmol), Pd(dtbpf)Cl2 (1 g, 1.3 mmol), and K2CO3 (6.0 g, 41.6 mmol) were dissolved in dioxane (50 mL) and H2O (5 mL). The mixture was stirred at 85°C overnight under argon. Water and ethyl acetate were added for extraction. The organic phase was washed sequentially with saturated ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography (PE:EA = 1 / 1) to obtain 3.0 g of a solid, with a yield of 75%. UPLC-MS calculated for C 15 H 14 ClN3O[M+H] +:287.08,found:288.15.

[0555] Step 2:

[0556] Intermediate AR-9-3 (1.2 g, 3.48 mmol) was dissolved in MeOH (10 mL). HCl-dioxane (2 ml) was added dropwise at 0°C and stirred at room temperature for 4 h. The organic phase was concentrated to obtain 1 g of solid. UPLC-MS calculated for C 10 H6ClN3[M+H] + :203.03,found:204.31.

[0557] Step 3:

[0558] The raw materials AR-9-4 (1 g, 4.92 mmol), tert-butyl (S)-(1-hydroxypropyl-2-yl)carbamate (858 mg, 4.92 mmol), and PPh3 (1.5 g, 1.3 mmol) were dissolved in THF (20 mL). DBAD (1.7 g, 7.38 mmol) was added with stirring under argon. The mixture was stirred at room temperature overnight. Water and ethyl acetate were added for extraction. The organic phase was washed sequentially with saturated ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography (PE:EA = 1 / 1) to obtain 500 mg of a solid, with a yield of 45%. UPLC-MS calculated for C 15 H 14 ClN3O[M+H] + :360.14,found:361.15.

[0559] Step 4:

[0560] Add the raw material AR-9-5 (500 mg, 1.38 mmol) to the hydrochloric acid-1,4-dioxane solution, stir at room temperature and react overnight. After spin drying, 500 mg of solid was obtained, with a yield of 45%. UPLC-MS calculated for C 15 H 14 ClN3O[M+H]+:260.14,found:261.15.

[0561] Example 38

[0562] Preparation of intermediate AR-10:

[0563] first step:

[0564] Dissolve 3-trifluoromethyl-4-cyano-aniline (1.0 g, 5.3 mmol) and triethylamine (1.4 g, 10.6 mmol) in dichloromethane (30 mL). After cooling to 0°C, add 2-bromo-2-methyl-propionyl bromide (1.3 g, 5.6 mmol) dropwise to the reaction mixture. Allow to react at 0°C for 3 h. Add saturated sodium chloride solution (100 mL) to the reaction mixture, extract with dichloromethane (30 mL x 3), dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain 1.8 g of solid, with a yield of 99%. UPLC-MS calculated for C 12 H 10 BrF3N2O[M+H] + :333.99,found:335.21.

[0565] Step 2:

[0566] AR-10-2 (2.5 g, 7.4 mmol), 3-iodo-pyrazole (1.75 g, 8.9 mmol), and cesium carbonate (3.6 g, 11.1 mmol) were placed in acetonitrile (40 mL) and heated to 50°C for 3 h. After the reaction solution cooled to room temperature, water (100 mL) was added and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The organic phase solvent was evaporated to dryness and separated by column chromatography (PE:EA = 9:1) to obtain 1.7 g of a yellow oil, with a yield of 52%. UPLC-MS calculated for C 15 H 12 F3IN4O[M+H] + :448.00,found:449.22.

[0567] Example 39

[0568] Preparation of intermediate AR-11:

[0569] first step:

[0570] AR-1-3 (700 mg, 2.80 mmol) was dissolved in dimethylformamide (20 mL), and diisopropylethylamine (1.1 g, 8.52 mmol), HATU (1.3 g, 3.42 mmol), and methyl pyrazole-4-carboxylate (345 mg, 2.80 mmol) were added. The mixture was reacted at room temperature for 18 h. 1 M sodium hydroxide solution (10 mL) was added to the reaction solution, and the reaction was continued at room temperature for 2 h. Saturated ammonium chloride solution (200 mL) was added, and the mixture was extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then purified by column chromatography (DCM:MeOH=10:1) to obtain 850 mg of a white solid with a yield of 88.26%. UPLC-MS calculated for C 17 H 17 ClN4O2[M+H] + :344.10,found:345.18.

[0571] Step 2:

[0572] AR-11-1 (360 mg, 1.05 mmol) was dissolved in dimethylformamide (10 mL), and potassium carbonate (290 mg, 2.10 mg), potassium iodide (35 mg, 0.21 mol), and 2-bromo-1,1-dimethoxyethane (263 mg, 1.56 mmol) were added. The reaction mixture was heated to 100°C and reacted for 48 h. After cooling to room temperature, water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then purified by column chromatography (PE:EA = 1:10) to obtain 400 mg of a white solid with a yield of 88.49%. UPLC-MS calculated for C 21 H 25 ClN4O4[M+H] + :432.16,found:433.28.

[0573] Step 3:

[0574] AR-11-2 (400 mg, 0.292 mmol) was dissolved in tetrahydrofuran (50 mL), and 6 M hydrochloric acid solution (20 mL) was added. The mixture was reacted at room temperature for 3 h. Saturated sodium bicarbonate was added to the reaction solution until the pH reached 8. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was dried to give 320 mg of a crude yellow solid, with a yield of 89%. UPLC-MS calculated for C 19 H 19 ClN4O3[M+H] +:386.11, found:387.33. Example 40

[0575] Preparation of compound I-1:

[0576] first step:

[0577] AR-1 (670 mg, 1.70 mmol) was dissolved in dichloromethane (40 mL) along with 4-hydroxymethylpiperidine (230 mg, 2.10 mmol) and DIPEA (0.6 mL, 3.4 mmol). The mixture was stirred at room temperature overnight. TLC confirmed the complete reaction. The solvent was evaporated and column chromatography (DCM:MeOH = 25 / 1) was performed to obtain 750 mg of intermediate I-1-1 as a light yellow viscous liquid in a 93.87% yield. UPLC-MS calculated for C 24 H 29 ClN5O3[M+H] + :470.20,found:470.22.

[0578] Step 2:

[0579] I-1-1 (750 mg, 1.50 mmol) was dissolved in dichloromethane (40 mL), and DMP (1.26 g, 3.00 mmol) was slowly added to the reaction flask. The reaction was stirred at room temperature for 4 h. TLC confirmed the complete reaction of the starting material. The organic phase was washed sequentially with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Column chromatography (DCM:MeOH = 50 / 1) was performed to obtain 580 mg of intermediate I-1-2 as a white solid. The yield was 82.63%. UPLC-MS was calculated for C 24 H 27 ClN5O3[M+H] + :468.18,found:468.20.

[0580] Step 3:

[0581] I-1-2 (51 mg, 0.11 mmol) and HSP90-1 (50 mg, 0.11 mmol) were dissolved in DMF (6 mL). Two drops of glacial acetic acid were added dropwise and the mixture was stirred at room temperature for 20 min. NaBH(OAc)3 (47 mg, 0.22 mmol) was added and the mixture was stirred at room temperature overnight. I-1 was obtained by preparative liquid chromatography as a white powdery solid (30 mg, yield 30.36%). UPLC-MS calculated for C 49 H 56 C1N 10 O5[M+H] +:899.41,found:899.53. 1 H NMR (500MHz, DMSO-d6) δ11.90(s,1H),9.58(d,J=28.4Hz,2H),8.58(dd,J=8.3,2.5Hz,1H),7.83(ddd,J=23.0,9.2,2.3 Hz,2H),7.54(d,J=8.7Hz,1H),7.43(dd,J=6.7,2.6Hz,2H),7.40–7.30(m,2H),7.13(dd,J=8.8,2.4Hz,1H),6.96(dd,J= 8.7,2.1Hz,1H),6.68(d,J=2.6Hz,1H),6.45(d,J=2.9Hz,1H),6.27(s,1H),4.61–4.41(m,3H),4.13(d,J=6.7Hz,2H),3 .85(d,J=8.8Hz,1H),3.01(t,J=12.6Hz,3H),2.93–2.79(m,2H),2.15–1.94(m,4H),1.86(dd,J=30.7,12.3Hz,5H),1.68 –1.45(m,9H),1.32–1.04(m,4H),0.78(dd,J=6.9,2.5Hz,6H).

[0582] Example 41

[0583] Preparation of compound I-2:

[0584] Synthesis was performed with reference to I-1. I-2 was obtained by preparative liquid phase chromatography, 25 mg of a white powdery solid, with a yield of 13.44%. UPLC-MS calculated for C 48 H 54 C1N 10 O5[M+H] + :885.40,found:885.45. 1H NMR (500MHz, DMSO-d6) δ11.90(s,1H),8.57(d,J=8.2Hz,1H),7.85(d,J=8.7Hz,1H),7.79(d,J=9.5Hz,1H),7.52(d,J=8 .7Hz,1H),7.46–7.33(m,4H),7.32(s,1H),7.12(dd,J=8.8,2.4Hz,1H),6.94(dd,J=8.7,2.1Hz,1H),6.62(s,1H),6.42 (d,J=3.1Hz,1H),6.25(s,1H),4.63–4.43(m,3H),4.06(d,J=7.1Hz,2H),2.85(td,J=12.8,11.7,6.5Hz,4H),2.16–1.9 4(m,5H),1.88(d,J=12.3Hz,3H),1.68–1.58(m,3H),1.48–1.33(m,6H),1.21(d,J=13.7Hz,4H),0.72(d,J=6.9Hz,6H).

[0585] Example 42

[0586] Preparation of compound I-3:

[0587] The synthesis was carried out according to I-1. I-3 was obtained by preparative liquid phase chromatography, with a white powdery solid (36 mg) and a yield of 31.05%. UPLC-MS calculated for C 48 H 54 C1N 10 O5[M+H] + :885.40,found:885.45. 1H NMR (500MHz, DMSO-d6) δ11.90(s,1H),8.57(d,J=8.2Hz,1H),7.85(d,J=8.7Hz,1H),7.79(d,J=9.5Hz,1H),7.52(d,J=8 .7Hz,1H),7.46–7.33(m,4H),7.32(s,1H),7.12(dd,J=8.8,2.4Hz,1H),6.94(dd,J=8.7,2.1Hz,1H),6.62(s,1H),6.42 (d,J=3.1Hz,1H),6.25(s,1H),4.63–4.43(m,3H),4.06(d,J=7.1Hz,2H),2.85(td,J=12.8,11.7,6.5Hz,4H),2.16–1.9 4(m,5H),1.88(d,J=12.3Hz,3H),1.68–1.58(m,3H),1.48–1.33(m,6H),1.21(d,J=13.7Hz,4H),0.72(d,J=6.9Hz,6H).

[0588] Example 43

[0589] Preparation of compound I-4:

[0590] AR-1 (100 mg, 0.22 mmol), HSP90-19 (95 mg, 0.24 mmol), and DIEA (171 mg, 1.32 mmol) were added to DMF and heated at 80°C for 12 h. After completion of the reaction, I-4 was obtained by preparative liquid chromatography as a white powdery solid (40 mg, yield 23.52%). UPLC-MS calculated for C 41 H 40 ClN9O5[M+H] + :774.28,found:774.10. 1H NMR (400MHz, DMSO-d6) δ9.59(d,J=34.2Hz,1H),8.58(d,J=8.2Hz,1H),7.84(t,J=9.0Hz,2H),7.61(d,J=8.8Hz,1H),7.56(d,J=3.1Hz,1H),7.44(d ,J=2.0Hz,1H),7.38(d,J=2.4Hz,1H),7.13(dd,J=8.8,2.5Hz,1H),6.97( dd,J=8.7,2.0Hz,1H),6.87(d,J=9.3Hz,1H),6.70(s,1H),6.46(d,J=3.1H z,1H),6.24(s,1H),4.53(t,J=6.1Hz,3H),4.14(t,J=8.3Hz,2H),3.95(d d,J=8.8,5.3Hz,2H),3.90–3.77(m,1H),3.47(t,J=5.3Hz,2H),2.89(p,J= 6.9Hz,1H),2.16–2.03(m,2H),1.94–1.82(m,2H),1.72–1.56(m,2H),1.5 1(td,J=13.8,13.3,7.0Hz,2H),1.31–1.19(m,1H),0.80(d,J=6.9Hz,6H).

[0591] Example 44

[0592] Preparation of compound I-5:

[0593] Synthesis was performed with reference to I-2. I-5 was obtained by preparative liquid phase chromatography, 36 mg of a white powdery solid, with a yield of 14.09%. UPLC-MS calculated for C 46 H 49 C1N 10 O5[M+H] + :857.41,found:857.12. 1H NMR (500MHz, DMSO-d6) δ11.90(s,1H),8.57(d,J=8.2Hz,1H),7.85(d,J=8.7Hz,1H),7.79(d,J=9.5Hz,1H),7.52(d,J=8 .7Hz,1H),7.46–7.33(m,4H),7.32(s,1H),7.12(dd,J=8.8,2.4Hz,1H),6.94(dd,J=8.7,2.1Hz,1H),6.62(s,1H),6.42 (d,J=3.1Hz,1H),6.25(s,1H),4.63–4.43(m,3H),4.06(d,J=7.1Hz,2H),2.85(td,J=12.8,11.7,6.5Hz,4H),2.16–1.9 4(m,5H),1.88(d,J=12.3Hz,3H),1.68–1.58(m,3H),1.48–1.33(m,6H),1.21(d,J=13.7Hz,4H),0.72(d,J=6.9Hz,8H).

[0594] Example 45

[0595] Preparation of compound I-6:

[0596] The synthesis was based on I-4. I-6 was obtained by preparative liquid phase chromatography, 33 mg of a white powdery solid, with a yield of 24.56%. UPLC-MS calculated for C 45 H 48 ClN9O5[M+H] + :830.39,found:830.21. 1H NMR (400MHz, DMSO-d6) δ11.90(s,1H),9.60(d,J=29.0Hz,2H),8.58(d,J=8.2Hz,1H),7.85(d,J=8.8Hz,1H),7.78(d,J=9.6Hz,1H),7.52– 7.41(m,3H),7.38(d,J=2.4Hz,1H),7.30(d,J=9.7Hz,1H),7.13(dd,J=8.8,2.5Hz,1H),6.94(dd,J=8.7,2.0Hz,1H),6.66(s,1H),6.42(d d,J=3.1,0.7Hz,1H),6.24(s,1H),4.59–4.33(m,3H),4.17(t,J=6.8Hz,2H),3.94–3.77(m,1H),3.02–2.79(m,3H),2.20–2.02(m,2H),1. 88(dd,J=12.7,3.9Hz,2H),1.82–1.66(m,4H),1.66–1.55(m,3H),1.32–1.10(m,4H),1.05(qd,J=12.6,3.9Hz,2H),0.75(d,J=6.9Hz,6H).

[0597] Example 46

[0598] Preparation of compound I-7:

[0599] Synthesis was performed by referring to I-1, and I-7 was obtained by preparative liquid phase, 40 mg of white powdery solid, with a yield of 35.56%. UPLC-MS calculated for C 51 H 59 C1N 10 O5[M+H] + :927.55,found:927.10. 1H NMR (400MHz, DMSO-d6) δ8.42(s,1H),8.02(d,J=7.5Hz,1H),7.83(t,J=2.0Hz,1 H),7.78(d,J=8.9Hz,1H),7.69–7.63(m,2H),7.60(d,J=7.8Hz,1H),7.41(d,J= 5.1Hz,1H),7.36–7.31(m,2H),7.16(d,J=2.3Hz,1H),7.03(dd,J=8.9,2.3Hz,1 H),6.91(d,J=0.6Hz,1H),6.67(dd,J=5.1,1.9Hz,1H),4.20–4.11(m,1H),4.09– 3.95(m,4H),3.91(dtt,J=9.4,6.2,3.2Hz,1H),3.68(ddd,J=12.3,8.4,6.3Hz, 2H),3.37–3.25(m,1H),2.96–2.87(m,2H),2.62–2.53(m,1H),2.53–2.46(m,2H) ,2.42(dt,J=12.3,8.3Hz,1H),2.11–1.98(m,4H),1.98–1.87(m,8H),1.86–1.8 0(m,2H),1.80–1.69(m,7H),1.58(td,J=8.2,5.9Hz,2H),1.30(d,J=6.8Hz,6H).

[0600] Example 47

[0601] Preparation of compound I-8:

[0602] The synthetic route was similar to that of I-7. I-8 was obtained by preparative liquid phase chromatography, with a white powdery solid (35 mg) and a yield of 29.56%. UPLC-MS calculated for C 49 H 55 C1N 10 O5[M+H] + :899.49,found:899.40. 1H NMR (400MHz, DMSO-d6) δ8.84(s,1H),7.89(d,J=7.5Hz,1H),7.73(t,J=1.9H z,1H),7.66(d,J=8.9Hz,1H),7.57–7.52(m,3H),7.42(d,J=0.7Hz,1H),7.3 8–7.33(m,1H),7.20(s,1H),7.04(d,J=1.9Hz,1H),6.91(dd,J=8.8,2.0Hz, 1H),6.57(dd,J=5.2,1.9Hz,1H),6.34(s,1H),4.29–4.23(m,1H),3.96–3.83 (m,3H),3.79(dtt,J=9.3,5.9,3.6Hz,1H),3.55(ddd,J=12.3,8.4,6.3Hz,2 H),3.25–3.13(m,1H),2.65(ddd,J=12.3,6.9,4.2Hz,2H),2.54–2.41(m,3H ),2.30(dt,J=12.2,8.2Hz,1H),2.06–1.97(m,2H),1.97–1.65(m,14H),1.6 1(dp,J=6.2,5.4Hz,1H),1.46(td,J=8.3,6.0Hz,2H),1.20(d,J=6.8Hz,6H).

[0603] Example 48

[0604] Preparation of compound I-9:

[0605] Synthesis was performed by preparative liquid phase with reference to I-1, yielding I-9 as a white powdery solid (50 mg, 39.10%). UPLC-MS calculated for C 50 H 57 C1N 10 O5[M+H] + :913.52,found:913.20. 1H NMR(500MHz,DMSO-d6)δ11.89(s,1H),8.57(dd,J=8.2,2.3Hz,1H),7.85(dd ,J=8.8,2.5Hz,1H),7.82–7.72(m,1H),7.52–7.40(m,3H),7.40–7.32(m,2H ),7.30(d,J=2.7Hz,1H),7.13(dt,J=8.8,2.4Hz,1H),6.95(dd,J=8.6,2.0H z,1H),6.67(d,J=2.2Hz,1H),6.43(d,J=3.0Hz,1H),6.25(s,1H),4.53(dt, J=10.5,5.9Hz,1H),4.20(t,J=7.3Hz,2H),3.86(dtd,J=11.1,7.4,3.9Hz,2 H),2.89(h,J=6.9Hz,2H),2.81(d,J=10.6Hz,2H),2.10(dd,J=13.1,5.2Hz, 5H),1.90(d,J=14.2Hz,3H),1.65(dt,J=24.8,10.4Hz,8H),1.57–1.41(m,3 H),1.21(d,J=25.6Hz,5H),1.12–1.01(m,2H),0.78(dd,J=6.9,2.1Hz,7H).

[0606] Example 49

[0607] Preparation of compound I-10:

[0608] The synthesis was based on I-2. I-10 was obtained by preparative liquid phase chromatography, with a white powdery solid of 23 mg and a yield of 20.05%. UPLC-MS calculated for C 50 H 57 C1N 10 O5[M+H] + :913.52,found:913.20. 1H NMR (400MHz, DMSO-d6) δ8.92(s,1H),8.73(s,2H),7.78(t,J=2.0Hz,1H),7.73(d,J=8.9Hz,1H),7.60(dd,J=7.7,2.2Hz,1H),7.55(d,J=7.8Hz, 1H),7.50(d,J=0.6Hz,1H),7.41–7.32(m,2H),7.11(d,J=1.9Hz,1H),6.98(dd,J=8.8,2.0Hz,1H),6.62(dd,J=5.1,2.0Hz,1H),6.41(s,1H),4. 12–4.04(m,1H),4.04–3.96(m,2H),3.83–3.72(m,3H),3.32–3.20(m,1 H),3.10(ddd,J=12.5,8.8,6.1Hz,2H),2.99–2.90(m,2H),2.84–2.74(m ,2H),2.51(p,J=5.3Hz,1H),2.06–1.62(m,20H),1.46(dtd,J=12.6,8.2 ,5.6Hz,1H),1.34(dtd,J=12.8,8.1,5.5Hz,1H),1.27(d,J=6.8Hz,6H).

[0609] Example 50

[0610] Preparation of compound I-11:

[0611] The synthesis was based on I-1. I-11 was obtained by preparative liquid phase chromatography as a white powder, 35 mg solid, with a yield of 35.62%. UPLC-MS calculated for C 50 H 58 C1N 11 O4, [M+H] + :913.52,found:913.26. 1H NMR (400MHz, DMSO-d6) δ11.91(s,1H),8.56(d,J=8.4Hz,1H),7.79(d,J=9.6Hz,1H),7.55–7.39(m,5H),7.31(d,J=9.8Hz, 1H),6.99–6.89(m,2H),6.76(d,J=2.2Hz,1H),6.67(s,1H),6.61(dd,J=8.8,2.2Hz,1H),6.42(d,J=3.1Hz,1H),6.24(s,1H ),4.45(d,J=13.0Hz,2H),4.20(t,J=7.2Hz,2H),3.87–3.72(m,2H),2.98(t,J=12.3Hz,3H),2.91–2.73(m,3H),2.12(d,J= 6.9Hz,2H),2.05–1.90(m,3H),1.81(dt,J=27.5,8.1Hz,8H),1.73–1.47(m,7H),1.37–1.23(m,3H),0.78(d,J=6.9Hz,7H).

[0612] Example 51

[0613] Preparation of compound I-12:

[0614] The synthesis was based on I-1. I-12 was obtained by preparative liquid phase chromatography as a white powder, 40 mg solid, with a yield of 40.13%. UPLC-MS calculated for C 51 H 60 C1N 11 O4[M+H] + :927.54,found:927.24. 1H NMR (400MHz, DMSO-d6) δ11.92(s,1H),8.56(d,J=8.3Hz,1H),8.25(s,1H),7.78(d,J=9.5Hz,1H),7.53–7.39(m,4H),7.30( d,J=9.7Hz,1H),6.94(dd,J=8.6,2.0Hz,2H),6.76(d,J=2.2Hz,1H),6.66(s,1H),6.61(dd,J=8.8,2.2Hz,1H),6.42(d,J=3. 0Hz,1H),6.25(s,1H),4.44(d,J=13.2Hz,2H),4.15(t,J=6.9Hz,2H),3.37–3.23(m,2H),3.04–2.71(m,6H),2.11(d,J=6.9H z,2H),1.98(d,J=11.4Hz,3H),1.92–1.62(m,11H),1.57(dt,J=12.8,5.9Hz,5H),1.39–1.19(m,4H),0.77(d,J=6.9Hz,7H).

[0615] Example 52

[0616] Preparation of compound I-13:

[0617] Synthesis was performed with reference to I-4. I-13 was obtained by preparative liquid phase chromatography, as a white powdery solid (43 mg). UPLC-MS calculated for C 44 H 46 ClN9O5[M+H] + :817.34found:817.11. 1H NMR (400MHz, DMSO-d6) δ11.89(s,1H),9.55(d,J=25.1Hz,2H),8.60(d,J=8.2Hz,1H),7.82(dd,J=24.4,9.2Hz ,2H),7.52–7.29(m,5H),7.12(dd,J=8.8,2.4Hz,1H),6.93(dd,J=8.7,2.0Hz,1H),6.68(s,1H),6.43(d,J=3.1 Hz,1H),6.23(s,1H),4.61–4.40(m,3H),4.24(t,J=7.2Hz,2H),3.85(ddt,J=15.2,11.1,5.8Hz,1H),3.00–2. 81(m,3H),2.20–2.04(m,2H),1.93–1.75(m,4H),1.74–1.40(m,8H),1.37(d,J=3.0Hz,1H),1.30–1.09(m,6H).

[0618] Example 53

[0619] Preparation of compound I-14:

[0620] AR-11 (77.8 mg, 0.2 mmol) and HSP90-11 (100 mg, 0.20 mmol) were dissolved in DMF (6 mL). Two drops of glacial acetic acid were added dropwise and the mixture was stirred at room temperature for 20 min. NaBH(OAc)3 (50.85 mg, 0.24 mmol) was added and the mixture was stirred at room temperature overnight. I-14 was obtained by preparative liquid chromatography as a white powdery solid (70.15 mg, 43.12% yield). UPLC-MS calculated for C 45 H 50 ClN9O5[M+H] + :823.38,found:823.24. 1H NMR(400MHz,DMSO-d6)δ11.90(s,1H),8.13(s,1H),7.89–7.80(m,3H),7.49–7.38(m,3H),7.38(d, J=2.5Hz,1H),7.13(dd,J=8.8,2.4Hz,1H),6.93(dd,J=8.7,2.0Hz,1H),6.66(s,1H),6.41 (d,J=3.0Hz,1H),6.23(s,1H),4.59–4.32(m,1H),4.18(t,J=6.7Hz,4H),3.75(d,J=11.4H z,2H),2.95–2.75(m,3H),2.64(t,J=6.5Hz,2H),2.17–2.00(m,2H),1.88(q,J=9.3,7.2Hz ,4H),1.64(q,J=7.0,6.6Hz,4H),1.55–1.34(m,4H),1.31–1.03(m,4H),0.86–0.67(m,6H).

[0621] Example 54

[0622] Preparation of compound I-15:

[0623] Synthesis was performed with reference to I-14. I-15 was obtained by preparative liquid phase chromatography, 50 mg of a white powdery solid, with a yield of 36.91%. UPLC-MS calculated for C 42 H 44 ClN9O5[M+H] + :791.03,found:791.10. 1H NMR(400MHz,DMSO-d6)δ11.90(s,1H),9.56(s,1H),8.12(s,1H),7.89–7.77(m,3H),7.54–7.30(m,4H),7.13 (dd,J=8.7,2.4Hz,1H),6.93(d,J=8.6Hz,1H),6.66(s,1H),6.40(d,J=3.0Hz,1H),6.22(s,1H),4.52(dt,J= 10.2,5.2Hz,1H),4.30(d,J=7.1Hz,2H),4.02(t,J=6.0Hz,2H),3.73(s,3H),3.14(t,J=7.0Hz,3H),2.86(q, J=6.8Hz,4H),2.75(dt,J=16.4,6.4Hz,3H),2.08(d,J=6.4Hz,2H),1.94–1.75(m,2H),0.77(d,J=6.8Hz,7H).

[0624] Example 55

[0625] Preparation of compound I-16:

[0626] AR-5 (51 mg, 0.10 mmol) and HSP90-11 (50 mg, 0.10 mmol) were dissolved in DMF (3 mL). Two drops of glacial acetic acid were added dropwise and the mixture was stirred at room temperature for 20 min. NaBH(OAc)3 (25.43 mg, 0.12 mmol) was added and the mixture was stirred at room temperature overnight. I-16 was obtained by preparative liquid chromatography as a white powdery solid (45.82 mg, 40.31% yield). UPLC-MS calculated for C 50 H 52 F3N 11 O4S[M+H] + :961.07,found:961.10. 1H NMR (400MHz, DMSO-d6) δ11.87(s,1H),9.17(d,J=2.0Hz,1H),8.72(d,J=2.1Hz,1H),8.19(s,1H),8.03(d,J=2.6Hz ,1H),7.50–7.36(m,4H),6.98–6.86(m,2H),6.64(s,1H),6.39(d,J=3.0Hz,1H),6.21(s,1H),4.33(d,J=12.5Hz,2H ),4.17(t,J=7.2Hz,2H),2.83(tt,J=12.7,7.3Hz,6H),2.56(d,J=10.7Hz,2H),2.11(d,J=6.6Hz,2H),1.93(q,J=9 .5Hz,1H),1.87–1.69(m,6H),1.70–1.49(m,5H),1.25–1.10(m,4H),1.05(d,J=12.2Hz,2H),0.75(d,J=6.9Hz,6H).

[0627] Example 56

[0628] Preparation of compound I-17:

[0629] The synthetic route was similar to that of I-16, and I-17 was obtained by preparative liquid phase chromatography, with a solid content of 30 mg and a yield of 43.68%. UPLC-MS calculated for C 49 H 50 F3N 11 O4S[M+H] + :947.02,found:947.08. 1 H NMR(500MHz,DMSO-d6)δ11.93(s,1H),10.61(s,1H),9.66(s,1H),9.41(s,1H),8.51(dd,J=9.2,2.0H z,1H),8.31–8.20(m,1H),8.20–8.02(m,3H),7.33(s,2H),7.15(d,J=7.9Hz,2H),6.77(s,1H),6.31(s ,1H),1.80(d,J=13.0Hz,4H),1.76–1.58(m,6H),1.55–1.40(m,5H),1.35(s,6H),1.22(d,J=12.3Hz,5 H), 1.19 (d, J = 7.3Hz, 6H), 0.94 (d, J = 6.8Hz, 7H), 0.84 (d, J = 7.2Hz, 1H), 0.71 (dd, J = 12.6, 6.8Hz, 3H).

[0630] Example 57

[0631] Preparation of compound I-18:

[0632] AR-6 (39.50 mg, 0.10 mmol), HSP90-18 (50.00 mg, 0.10 mmol), HATU (38.50 mg, 0.10 mmol), and DIEA (33 mg, 0.25 mmol) were dissolved in 2 mL of DMF and stirred at room temperature for 12 h. I-18 was obtained by preparative liquid chromatography as a solid (20 mg, yield 21.74%). UPLC-MS calculated for C 47 H 43 F4N9O5S[M+H] + :921.97,found:924.30. 1 H NMR (400MHz, DMSO-d6) δ9.03(s,1H),8.11(d,J=7.3Hz,1H),7.90(t,J=2.0Hz,1H),7.79(d,J=7.3Hz,1H),7.74–7.64(m,3H),7.61 (d,J=0.6Hz,1H),7.57(dd,J=8.0,1.9Hz,1H),7.46(d,J=4.9Hz,1H),7.21(dd,J=7.1,2.0Hz,1H),6.74(dd,J=5.1,2.0Hz,1H),6. 53(s,1H),4.24–4.09(m,2H),4.05(ddd,J=12.4,8.1,6.1Hz,2H),3.45–3.32(m,3H),2.47(dt,J=12.4,7.4Hz,2H),2.34(dt,J=12 .4,7.3Hz,2H),2.02–1.78(m,9H),1.60(dtd,J=12.8,8.1,5.6Hz,1H),1.46(dtd,J=12.6,8.1,5.5Hz,1H),1.39(d,J=6.8Hz,6H).

[0633] Example 58

[0634] Preparation of compound I-19:

[0635] The synthetic route was similar to that of I-18, and I-19 was obtained by preparative liquid phase chromatography, with a solid content of 18 mg and a yield of 19.23%. UPLC-MS calculated for C 47 H 44F4N8O5S[M+H] + :908.97,found:908.18. 1 H NMR (400MHz, DMSO-d6δ8.14(s,1H),7.38–7.32(m,2H),7.03–6.96(m,2H),6.85–6.75(m,3H),6.74–6. 68(m,2H),6.57(d,J=4.9Hz,1H),6.31(dd,J=7.2,1.8Hz,1H),5.85(dd,J=5.1,2.0Hz,1H),5.64(s,1H ),3.35–3.20(m,2H),3.16(ddd,J=12.4,8.1,6.0Hz,2H),2.56–2.43(m,3H),1.11–0.87(m,7H),0.82( s,6H),0.71(dtd,J=12.8,8.1,5.6Hz,1H),0.57(dtd,J=12.6,8.1,5.5Hz,1H),0.50(d,J=6.8Hz,6H).

[0636] Example 59

[0637] Preparation of compound II-1:

[0638] first step:

[0639] N-BOC-L-prolinol (108 mg, 0.53 mmol) and THF (5 mL) were added to a reaction flask, and the atmosphere was replaced with argon three times. NaH (41 mg, 1.02 mmol, 60%) was added under an ice-water bath and stirred for 2 h. AR-1 (200 mg, 0.51 mmol) was added, and the mixture was returned to room temperature and stirred overnight. Saturated NH4Cl solution was added to quench the mixture, and the mixture was extracted with ethyl acetate (50 mL*2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. Column chromatography (DCM / MeOH = 100:1) gave 180 mg of a colorless oil, with a yield of 63%. UPLC-MS calculated for C 28 H 34 ClN5O5[M+H] + :556.22,found:556.20.

[0640] Step 2:

[0641] Add II-1-1 (180 mg, 0.32 mmol) to a reaction flask and add HCl (1 mL, 4 mmol, 4 M 1,4-dioxane solution) dropwise at room temperature. Stir for 1 h. Add 5 mL of methanol, filter, concentrate, and pump dry to obtain 120 mg of a white solid. Yield: 75%. UPLC-MS calculated for C 23 H 26 ClN5O3[M+H] + :456.17,found:456.19.

[0642] Step 3:

[0643] The hydrochloride of II-1-2 (80 mg, 0.17 mmol), HSP90-5 (80 mg, 0.17 mmol), DIEA (113 mg, 0.88 mmol) and DMF (2 mL) were added to a reaction flask, replaced with argon three times, stirred at 85°C overnight, and concentrated to obtain a crude product. The crude product was purified by reverse phase preparative purification to obtain 15 mg of a white solid with a yield of 14%. UPLC-MS calculated for C 45 H 48 ClN7O7[M+H] + :834.33,found:834.35. 1 H NMR(400MHz, DMSO-d6)δ9.78(s,1H),9.66(s,1H),8.92–8.80(m,2H),8.07(d,J=9.1Hz,1H),7.86( d,J=8.7Hz,1H),7.40(d,J=2.4Hz,1H),7.35(d,J=9.2Hz,1H),7.22(s,2H),7.19–7.10(m,3H),6.73 (s,1H),6.44(s,1H),4.64–4.38(m,3H),4.12(s,1H),3.95–3.80(m,1H),3.21(p,J=7.0Hz,2H),2.9 6(p,J=6.9Hz,2H),2.16–2.05(m,3H),2.04–1.93(m,1H),1.93–1.82(m,3H),1.66(dd,J=25.5,12.1 Hz,5H),1.51(td,J=13.5,6.8Hz,2H),1.23(s,1H),1.06(t,J=7.2Hz,3H),0.90(d,J=6.9Hz,6H).

[0644] Example 60

[0645] Preparation of compound II-2:

[0646] Synthesis was performed according to II-1. 18 mg of white solid was obtained by preparative liquid phase analysis with a yield of 10%. UPLC-MS calculated for C 45 H 48 ClN7O7[M+H] + :834.33,found:834.35. 1 H NMR (400MHz, DMSO-d6) δ9.80 (s, 1H), δ9.69 (s, 1H), 8.85 (q, J = 6.9Hz, 2H), 8.06 (d, J = 9.1Hz, 1H), 7.86 (d, J = 8.7Hz, 1H) ,7.47–7.28(m,2H),7.17(dt,J=16.4,8.2Hz,5H),6.72(s,1H),6.43(s,1H),4.69–4.30(m,3H),4.10(d,J=13.3Hz,1H) ,3.97–3.75(m,1H),3.24–3.15(m,2H),3.10–2.89(m,2H),2.80(s,1H),2.21(q,J=8.3Hz,1H),2.09(t,J=8.9Hz,2H),2 .05–1.76(m,4H),1.73–1.61(m,4H),1.50(q,J=12.1Hz,2H),1.23(s,1H),1.06(t,J=7.2Hz,3H),0.89(d,J=6.9Hz,6H).

[0647] Example 61

[0648] Preparation of compound II-3:

[0649] Step 3:

[0650] I-1-2 (100 mg, 0.21 mmol) and MeOH (3 mL) were added to a reaction flask, followed by mono-Boc piperazine (44 mg, 0.235 mmol) and acetic acid (26 mg, 0.43 mmol). The mixture was stirred at room temperature for 5 h. NaBH3CN (30 mg, 0.44 mmol) was added and stirred for 1 h. The reaction solution was concentrated, dissolved in acetonitrile, and filtered and concentrated to obtain the crude product. Purification by column chromatography (DCM / MeOH = 100:2) gave 140 mg of a white solid with a yield of 82%. UPLC-MS calculated for C 33 H 44 ClN7O4[M+H] + :638.31,found:638.42.

[0651] Step 4:

[0652] II-3-1 (140 mg, 0.21 mmol) was added to a reaction flask, and HCl (0.5 mL, 2.1 mmol, 4 M 1,4-dioxane solution) was added dropwise at room temperature. The mixture was stirred for 1 h. 2 mL of methanol was added, the mixture was filtered, concentrated, and pumped dry to obtain 120 mg of a white solid, with a yield of 95%. UPLC-MS calculated for C 28 H 36 ClN7O2[M+H] + :538.26,found:538.18.

[0653] Step 5:

[0654] The hydrochloride of II-3-2 (120 mg, 0.21 mmol) and MeOH (3 mL) were added to a reaction flask, followed by triethylamine (27 mg, 0.26 mmol) and stirring at room temperature for 30 min. HSP90-4 (69 mg, 0.21 mmol) and acetic acid (37 mg, 0.61 mmol) were then added in sequence and stirred at room temperature for 5 h. NaBH3CN (22 mg, 0.35 mmol) was added and stirred for 1 h. The reaction solution was concentrated, dissolved in acetonitrile, and filtered and concentrated to obtain the crude product. 40 mg of a white solid was obtained by reverse phase preparative purification with a yield of 25%. UPLC-MS calculated for C 50 H 58 ClN9O6[M+H] + :916.42,found:916.51. 1H NMR (400MHz, DMSO-d6) δ9.71(s,2H),8.82(t,J=5.7Hz,1H),8.59(d,J=8.2Hz,1H),7.84(d,J=8.7Hz,1H),7.78(d,J=9.6Hz,1H),7.38 (d,J=2.4Hz,1H),7.30(d,J=9.7Hz,1H),7.19(q,J=8.3Hz,4H),7.12(dd,J=8.8,2.4Hz,1H),6.70(s,1H),6.44(s,1H),4.52(dp,J=9. 6,4.1Hz,1H),4.44(d,J=13.0Hz,2H),3.90–3.79(m,1H),3.21(qd,J=7.2,5.6Hz,3H),3.03–2.89(m,3H),2.34(s,7H),2.10(t,J=9.0 Hz,4H),1.88(d,J=12.1Hz,3H),1.77(d,J=13.5Hz,2H),1.68–1.41(m,4H),1.22(s,1H),1.06(t,J=7.2Hz,5H),0.88(d,J=6.9Hz,6H).

[0655] Example 62

[0656] Preparation of compound II-4:

[0657] first step:

[0658] I-2-2 (100 mg, 0.22 mmol) and DCE (3 mL) were added to a reaction flask, followed by mono-Boc piperazine (45 mg, 0.25 mmol) and 1 drop of acetic acid. The mixture was stirred at room temperature for 5 h. NaBH(OAc)3 (93 mg, 0.44 mmol) was added and stirred for 1 h. The reaction solution was concentrated, dissolved in acetonitrile, and filtered and concentrated to obtain the crude product. The product was purified by column chromatography (DCM / MeOH = 100:2) to obtain 70 mg of a white solid with a yield of 51%. UPLC-MS calculated for C 32 H 42 ClN7O4[M+H] + :624.30,found:624.33.

[0659] Step 2:

[0660] Add Ⅱ-4-1 (70 mg) to the reaction flask, add HCl (1 mL, 4M 1,4-dioxane solution) dropwise at room temperature, and stir for 1 hour. Add 2 mL of methanol, filter, concentrate, and pump dry to obtain 70 mg of a white solid. UPLC-MS calculated for C 27 H 34 ClN7O2[M+H] + :524.25,found:524.19.

[0661] Step 3:

[0662] The synthesis method was similar to that of Example II-3. 30 mg of a white solid was obtained by reverse phase preparative purification with a yield of 25%. UPLC-MS calculated for C 49 H 56 ClN9O6[M+H] + :902.40,found:902.26. 1 H NMR (400MHz, DMSO-d6) δ9.86(d,J=94.0Hz,2H),8.85(q,J=5.5Hz,1H),8.62(d,J=8.2Hz,1H),7.86(d,J=8.8Hz,1H),7.80(d, J=9.5Hz,1H),7.39(d,J=2.4Hz,1H),7.35(d,J=9.7Hz,1H),7.25–7.10(m,6H),6.72(s,1H),6.44(s,1H),4.48(d,J=14.1Hz, 3H),3.97–3.73(m,1H),3.22(qd,J=7.2,5.6Hz,3H),3.07–2.90(m,4H),2.35(s,3H),2.10(d,J=11.3Hz,2H),1.87(t,J=14.6 Hz,4H),1.72–1.32(m,7H),1.24(d,J=3.2Hz,2H),1.07(t,J=7.2Hz,4H),0.99(dd,J=6.9,4.6Hz,1H),0.90(d,J=6.9Hz,6H).

[0663] Example 63

[0664] Preparation of compound II-5:

[0665] first step:

[0666] AR-1 (950 mg, 2.43 mmol), mono-Boc piperazine (540 mg, 2.91 mmol), DIEA (1 g, 7.28 mmol), and 20 mL of 1,4-dioxane were added to a reaction flask. The atmosphere was replaced with argon three times, and the temperature was raised to 110°C and stirred for 3 h. The mixture was added to 50 mL of water and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purification by column chromatography (DCM:MeOH = 100:2) afforded 500 mg of a white solid, with a yield of 65%. UPLC-MS calculated for C 27 H 33 ClN6O4[M+H] + :541.23,found:541.35.

[0667] Step 2:

[0668] II-5-1 (500 mg, 0.93 mmol) was added to a reaction flask. HCl (2.5 mL, 10 mmol, 4 M 1,4-dioxane solution) was added dropwise at room temperature and stirred for 1 h. 5 mL of methanol was added, the mixture was filtered, concentrated, and pumped dry to obtain 330 mg of a white solid. The yield was 74%. UPLC-MS calculated for C 22 H 25 ClN6O2[M+H] + :441.17,found:441.19.

[0669] Step 3:

[0670] The synthesis method was similar to that of Example II-3. 40 mg of a white solid was obtained by reverse phase preparative purification with a yield of 40%. UPLC-MS calculated for C 44 H 47 ClN8O6[M+H] + :819.33,found:819.38. 1H NMR(500MHz,DMSO-d6)δ9.75(s,2H),8.82(t,J=5.7Hz,1H),8.60(d,J=8.2Hz,1H),7.84(dd,J=1 1.1,9.1Hz,2H),7.41–7.31(m,2H),7.27(d,J=7.9Hz,2H),7.21(d,J=8.0Hz,2H),7.13(dd,J=8.8 ,2.4Hz,1H),6.72(s,1H),6.45(s,1H),4.53(tt,J=10.1,4.3Hz,1H),3.86(dtd,J=11.5,7.8,4.2 Hz,1H),3.69(t,J=5.0Hz,4H),3.51(s,3H),3.27–3.18(m,3H),2.96(h,J=6.8Hz,1H),2.16–2.05 (m,2H),1.95–1.84(m,2H),1.70–1.58(m,2H),1.57–1.43(m,2H),1.23(s,2H),1.08(t,J=7.2Hz,3H),0.90(d,J=6.9Hz,6H).

[0671] Example 64

[0672] Preparation of compound II-6:

[0673] first step:

[0674] The hydrochloride of II-5-2 (240 mg, 0.44 mmol) and MeOH (5 mL) were added to a reaction flask, followed by triethylamine (67 mg, 0.66 mmol) and stirring at room temperature for 30 min. N-Boc-piperidine-4-carboxaldehyde (103 mg, 0.48 mmol) and acetic acid (100 mg, 1.54 mmol) were then added in sequence and stirred at room temperature for 5 h. NaBH3CN (30 mg, 0.5 mmol) was added and stirred for 1 h. The reaction solution was concentrated, dissolved in acetonitrile, and filtered and concentrated to obtain the crude product. Purification by column chromatography (DCM:MeOH=100:2) gave 300 mg of a white solid with a yield of 98%. UPLC-MS calculated for C 33 H 44 ClN7O4[M+H] + :638.31,found:638.35.

[0675] Step 2:

[0676] II-6-1 (200 mg, 0.29 mmol) was added to a reaction flask. HCl (1 mL, 4 mmol, 4 M 1,4-dioxane solution) was added dropwise at room temperature and stirred for 1 h. 5 mL of methanol was added, the mixture was filtered, concentrated, and pumped dry to obtain 200 mg of a white solid. The yield was 100%. UPLC-MS calculated for C 22 H 25 ClN6O2[M+H] + :538.26,found:538.26.

[0677] Step 3:

[0678] The synthesis method was similar to that of Example II-3. 58 mg of a white solid was obtained by reverse phase preparative purification with a yield of 20%. UPLC-MS calculated for C 50 H 58 ClN9O6[M+H] + :916.42,found:916.48. 1 H NMR (400MHz, DMSO-d6) δ9.68(s,2H),8.84(t,J=5.7Hz,1H),8.62(d,J=8.2Hz,1H),7.83(dd,J=11.5,9.1Hz,2H),7.38(d,J=2.3Hz,1H),7.33(d,J=9.6Hz ,1H),7.28–7.06(m,5H),6.72(s,1H),6.44(s,1H),4.59–4.46(m,1H),3.85( tdt,J=11.6,8.3,4.1Hz,1H),3.67(t,J=5.1Hz,4H),3.47(s,2H),3.26–3.18 (m,2H),2.95(h,J=6.9Hz,1H),2.82(d,J=10.7Hz,2H),2.44(t,J=5.0Hz,3H) ,2.16(d,J=7.1Hz,2H),2.13–2.04(m,2H),1.95(s,2H),1.87(tt,J=8.1,4.3 Hz,2H),1.73–1.63(m,3H),1.63–1.57(m,1H),1.57–1.45(m,3H),1.23(d,J= 4.0Hz,1H),1.19–1.10(m,2H),1.07(t,J=7.2Hz,3H),0.90(d,J=6.9Hz,6H).

[0679] Example 65

[0680] Preparation of compound II-7:

[0681] The synthesis method was similar to that of Example II-6. 58 mg of white solid was purified by reverse phase preparative method with a yield of 20%. UPLC-MS calculated for C 48 H 54 ClN9O6[M+H] + :888.39,found:888.41. 1 H NMR (400MHz, DMSO-d6) δ9.78(s,1H),9.64(s,1H),8.84(t,J=5.7Hz,1H),8.57(d,J=8.2Hz,1H),7.80(d,J=8.6Hz,2H),7.37(d,J=7.8Hz,2 H),7.35–7.29(m,2H),7.25(d,J=7.8Hz,2H),7.08(dd,J=8.8,2.5Hz,1H),6.72(s,1H),6.40(s,1H),4.47(dq,J=10.0,5.0,4.2Hz,1H),4. 27(s,2H),4.01(s,2H),3.85–3.71(m,4H),3.65(s,3H),3.20–3.16(m,2H),3.03(d,J=7.5Hz,1H),2.94(p,J=6.8Hz,2H),2.08–2.00(m,2H ),1.84(d,J=12.1Hz,2H),1.58(q,J=11.7,8.1Hz,2H),1.50–1.41(m,2H),1.24–1.10(m,5H),1.03(t,J=7.2Hz,3H),0.90(d,J=6.9Hz,6H).

[0682] Example 66

[0683] Preparation of compound II-8:

[0684] The synthesis method was similar to that of Example II-3, and 17 mg of a white solid was obtained by reverse phase preparative purification with a yield of 20%. UPLC-MS calculated for C 50 H 59 C1N 10 O5[M+H] + :914.44,found:914.46. 1H NMR (400MHz, DMSO-d6) δ9.46(s,2H),8.62(d,J=8.2Hz,1H),7.86(d,J=8.7Hz,1H),7.79(d,J=9.4Hz,1H),7.39(d,J =2.4Hz,1H),7.32(d,J=9.6Hz,1H),7.14(q,J=5.0,4.0Hz,5H),6.49(s,1H),6.41(s,1H),4.60–4.40(m,3H),3.97–3 .73(m,2H),3.17(q,J=6.9Hz,2H),2.99(t,J=12.3Hz,2H),2.88(q,J=6.9Hz,1H),2.37(s,7H),2.20–2.04(m,5H),1 .94–1.73(m,5H),1.63(q,J=12.1Hz,2H),1.57–1.40(m,2H),1.23(s,2H),1.13–0.98(m,6H),0.78(d,J=6.8Hz,6H).

[0685] Example 67

[0686] Preparation of compound II-9:

[0687] The synthesis method was similar to that of Example II-3, and 15 mg of a white solid was obtained by reverse phase purification with a yield of 19%. UPLC-MS calculated for C 50 H 59 C1N 10 O5[M+H] + :914.44,found:914.45. 1H NMR(420MHz, DMSO-d6)δ9.08(s,1H),8.02(t,J=4.5Hz,1H),7.93–7.83(m,2H),7.71(d,J=8.8Hz,1H),7.60–7.48(m,4H),7.4 4(d,J=0.6Hz,1H),7.21–7.14(m,2H),6.95(dd,J=8.8,1.9Hz,1H),6.47(s,1H),3.93(tt,J=6.2,3.6Hz,1H),3.77(m,J=9.3,5 .6,3.6Hz,1H),3.66–3.53(m,4H),3.52(t,J=1.0Hz,2H),3.33(m,J=6.3,4.6Hz,2H),3.28–3.13(m,1H),2.80–2.56(m,7H),2 .35–2.24(m,2H),1.96(m,J=11.8,8.4,5.9,3.4Hz,2H),1.87–1.61(m,11H),1.22(t,J=6.3Hz,3H),1.20(s,3H),1.18(s,3H).

[0688] Example 68

[0689] Preparation of compound II-10:

[0690] The synthesis method was similar to that of Example II-5, and 48 mg of a white solid was obtained by reverse phase purification with a yield of 45%. UPLC-MS calculated for C 44 H 47 ClN8O6[M+H] + :832.35,found:832.39. 1H NMR (400MHz, DMSO-d6) δ9.75 (s, 2H), 8.87 (t, J = 5.7Hz, 1H), 8.62 (d, J = 8.2Hz, 1H),7.86(d,J=8.7Hz,1H),7.81(d,J=9.6Hz,1H),7.40(d,J=2.4Hz,1H),7.35 (d,J=9.7Hz,1H),7.30(d,J=8.2Hz,2H),7.24–7.17(m,2H),7.14(dd,J=8.8,2 .5Hz,1H),6.80(s,1H),6.44(s,1H),4.54(tt,J=9.7,4.1Hz,1H),4.34(d,J=12 .8Hz,2H),3.91–3.83(m,1H),3.78(s,2H),3.26–3.21(m,2H),3.18–3.08(m,2 H),3.00(p,J=6.9Hz,1H),2.79(dt,J=9.7,5.8Hz,1H),2.11(dd,J=12.8,4.3H z,2H),2.00–1.84(m,4H),1.72–1.58(m,2H),1.58–1.44(m,2H),1.33(q,J=10 .6Hz, 2H), 1.24 (d, J = 3.3Hz, 1H), 1.09 (t, J = 7.2Hz, 3H), 0.97 (d, J = 6.9Hz, 6H).

[0691] Example 69

[0692] Preparation of compound II-11:

[0693] first step:

[0694] AR-1 (300 mg, 0.77 mmol), methyl(piperidin-4-yl)carbamic acid tert-butyl ester hydrochloride (246 mg, 1.15 mmol), Na2CO3 (320 mg, 2.3 mmol), and 6 mL of DMF were added to a reaction flask. The atmosphere was replaced with argon three times, and the temperature was raised to 85°C and stirred for 4 h. The mixture was added to 50 mL of water and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purification by column chromatography (DCM:MeOH = 100:2) gave 380 mg of a white solid, with a yield of 87%. UPLC-MS calculated for C 29 H 37 ClN6O4[M+H] + :569.26,found:569.35.

[0695] Step 2:

[0696] II-11-1 (380 mg, 0.67 mmol) was added to a reaction flask. HCl (2 mL, 8 mmol, 4M 1,4-dioxane solution) was added dropwise at room temperature and stirred for 1 h. 5 mL of methanol was added, the mixture was filtered, concentrated, and pumped dry to obtain 370 mg of a white solid. The yield was 100%. UPLC-MS calculated for C 24 H 29 ClN6O2[M+H] + :469.20,found:469.22.

[0697] Step 3:

[0698] The third step was the same as in Example II-1, and 38 mg of a white solid was obtained by reverse phase preparative purification with a yield of 34%. UPLC-MS calculated for C 46 H 51 ClN8O6[M+H] + :847.36,found:847.20. 1 H NMR (400MHz, DMSO-d6) δ9.86(d,J=84.7Hz,2H),8.84(t,J=5.7Hz,1H),8.62(d,J=8.2Hz,1H),7.83(dd,J=20 .1,9.2Hz,2H),7.47–7.31(m,2H),7.25–7.12(m,5H),6.73(s,1H),6.43(s,1H),4.52(dd,J=11.8,7.4Hz,3H) ,3.93–3.77(m,1H),3.24–3.18(m,2H),3.01–2.93(m,3H),2.81–2.70(m,1H),2.07(s,6H),1.88(dd,J=12.8, 6.5Hz, 4H), 1.70–1.57 (m, 2H), 1.55–1.45 (m, 4H), 1.22 (s, 1H), 1.06 (t, J = 7.2Hz, 3H), 0.91 (d, J = 6.9Hz, 6H).

[0699] Example 70

[0700] Preparation of compound II-12:

[0701] first step:

[0702] The intermediate HSP90-12-6 (160 mg, 0.28 mmol) was dissolved in MeOH (3 mL) and diethylamine (3 mL) was added. The mixture was stirred at 70°C overnight and the solvent was evaporated to dryness to obtain 160 mg of a white solid. UPLC-MS calculated for C 30 H 40 N6O5[M+H] + :564.31,found:565.69.

[0703] Step 2:

[0704] Intermediate II-12-1 (160 mg, 0.28 mmol) was dissolved in MeOH (4 mL) and HCl-dixoane (1 mL) was added. The mixture was stirred at room temperature overnight and the solvent was evaporated to give 80 mg of a yellow solid. UPLC-MS calculated for C 25 H 32 N6O3[M+H] + :464.25,found:465.26.

[0705] Step 3:

[0706] Dissolve II-12-2 (55 mg, 0.11 mmol) in DMF (6 mL), add TEA (21.6 mg, 0.21 mmol), and stir at room temperature for 20 min. Add intermediate I-1-2 (52 mg, 0.11 mmol) and 2 hours later add NaBH(OAc)3 (46 mg, 0.22 mmol), and stir at room temperature overnight. 35 mg of II-12 was obtained by preparative liquid chromatography as a white powdery solid. UPLC-MS calculated for C 49 H 58 C1N 11 O5[M+H] + :915.43,found:916.53. 1H NMR (400MHz, DMSO-d6) δ10.58(s,1H),9.78(s,1H),8.94(t,J=5.9Hz,1H),8.57(d,J=8.2Hz,1H),7.79(dd,J= 25.1,9.2Hz,2H),7.36–7.32(m,3H),7.30–7.24(m,3H),7.10(dd,J=8.8,2.5Hz,1H),6.54(s,1H),6.31(s,1H ),4.55–4.38(m,3H),3.90–3.71(m,1H),3.17–3.08(m,3H),2.96(t,J=12.3Hz,2H),2.86(q,J=6.9Hz,1H),2. 36(s,7H),2.13–2.04(m,4H),1.89–1.71(m,6H),1.67–1.44(m,4H),1.12–0.96(m,6H),0.77(d,J=6.9Hz,6H).

[0707] Example 71

[0708] Preparation of compound II-13:

[0709] The synthesis method was similar to that of Example I-1, and 30 mg of white powdery solid II-13 was obtained by preparative liquid phase. UPLC-MS calculated for C 49 H 57 C1N 10 O6[M+H] + :916.42,found:917.51. 1H NMR (400MHz, DMSO-d6) δ10.71(s,1H),9.81(s,1H),8.92(t,J=5.9Hz,1H),8.57(d,J=8.2Hz,1H),7.79(dd,J=2 3.6,9.1Hz,2H),7.39–7.20(m,4H),7.10(dd,J=8.8,2.4Hz,1H),7.04–6.95(m,2H),6.53(s,1H),6.32(s,1H), 4.53–4.40(m,3H),3.89–3.79(m,1H),3.20–3.08(m,2H),3.02–2.83(m,3H),2.64(s,2H),2.26–2.01(m,6H),1 .98–1.71(m,7H),1.68–1.40(m,6H),1.20(d,J=3.2Hz,1H),1.01(q,J=7.7,7.2Hz,5H),0.79(d,J=6.9Hz,6H).

[0710] Example 72

[0711] Preparation of compound II-14:

[0712] The synthesis method was similar to that of Example I-1, and 30 mg of white powdery solid II-14 was obtained by preparative liquid phase. UPLC-MS calculated for C 49 H 57 C1N 10 O6[M+H] + :916.42,found:917.51. 1H NMR (400MHz, DMSO-d6) δ10.51(s,1H),9.79(s,1H),8.56(d,J=8.2Hz,1H),7.79(dd,J=24.4,9.1Hz,2H),7.35(d ,J=2.1Hz,5H),7.28(d,J=9.6Hz,1H),7.10(dd,J=8.8,2.5Hz,1H),6.58(s,1H),6.31(s,1H),4.51–4.36(m,3H), 4.14(q,J=7.1Hz,2H),3.92–3.73(m,1H),3.05–2.69(m,4H),2.36(s,7H),2.08(dd,J=14.5,7.9Hz,5H),1.91–1 .68(m,6H),1.65–1.56(m,2H),1.47(dt,J=13.8,10.4Hz,2H),1.05(q,J=5.7,4.3Hz,5H),0.78(d,J=6.9Hz,6H).

[0713] Example 73

[0714] Preparation of compound II-15:

[0715] The synthesis method was similar to that of Example I-1, and 40 mg of II-15 as a white powdery solid was obtained by preparative liquid phase. UPLC-MS calculated for C 49 H 57 C1N 10 O6[M+H] + :916.42,found:917.51. 1H NMR (400MHz, DMSO-d6) δ10.78(s,1H)8.92(t,J=5.9Hz,1H),8.70(s,2H),8.18(s,1H),8.08(d,J=7.4Hz,1H),7.82(d,J=8.7 Hz,1H),7.35(d,J=2.3Hz,1H),7.26–7.19(m,2H),7.10(dd,J=8.8,2.4Hz,1H),7.01–6.95(m,2H),6.53(s,1H),6.32(s,1H), 4.68(d,J=12.8Hz,2H),4.61–4.30(m,2H),3.13(dt,J=14.2,7.0Hz,3H),2.90(ddd,J=13.6,8.9,4.7Hz,3H),2.64(s,2H),2 .29–1.98(m,7H),1.97–1.72(m,8H),1.61(d,J=9.3Hz,2H),1.55–1.38(m,4H),1.01(d,J=7.2Hz,3H),0.79(d,J=6.8Hz,6H).

[0716] Example 74

[0717] Preparation of compound II-16:

[0718] The synthesis method was similar to that of Example I-1, and 20 mg of white powdery solid II-16 was obtained by preparative liquid phase. UPLC-MS calculated for C 50 H 60 ClN11O5[M+H] + :929.45,found:930.55. 1H NMR (400MHz, DMSO-d6) δ10.77(s,1H),9.84(s,1H),8.77(s,1H),8.59(d,J=8.2Hz,1H),7.88–7.78(m,2H),7.45(d ,J=8.4Hz,2H),7.38(dd,J=5.4,2.9Hz,3H),7.31(d,J=9.7Hz,1H),7.12(dd,J=8.8,2.4Hz,1H),6.66(s,1H),6.37( s,1H),4.62–4.36(m,4H),3.84(dtd,J=11.1,7.4,4.0Hz,2H),3.51(s,3H),3.08–2.87(m,4H),2.39(s,8H),2.20– 2.03(m,5H)II,1.93–1.73(m,6H),1.69–1.56(m,2H),1.55–1.44(m,2H),1.25–1.03(m,3H),0.81(d,J=6.9Hz,6H).

[0719] Example 75

[0720] Preparation of compound II-17:

[0721] The synthesis method was similar to that of Example I-1, and 46 mg of II-17 as a white powdery solid was obtained by preparative liquid phase. UPLC-MS calculated for C 50 H 59 C1N 10 O6[M+H] + :930.43,found:931.54. 1H NMR (400MHz, DMSO-d6) δ10.71(s,1H),9.78(s,1H),8.91(t,J=5.9Hz,1H),8.56(d,J=8.2Hz,1H),7.79(dd,J=24.4,9.1Hz,2H),7.35(d,J=2.4Hz,1 H),7.29(d,J=9.7Hz,1H),7.26–7.19(m,2H),7.10(dd,J=8.8,2.4Hz,1H) ,7.02–6.92(m,2H),6.53(s,1H),6.31(s,1H),4.55–4.38(m,4H),3.86–3 .79(m,1H),3.16–3.11(m,2H),3.00–2.84(m,3H),2.68(d,J=6.4Hz,2H), 2.34(t,J=7.4Hz,2H),2.22(t,J=9.7Hz,2H),2.06(d,J=11.4Hz,2H),1.9 8–1.80(m,4H),1.74(d,J=12.7Hz,2H),1.60(h,J=10.0Hz,5H),1.53–1.3 4(m,4H),1.20–1.07(m,2H),1.00(t,J=7.2Hz,3H),0.79(d,J=6.9Hz,6H).

[0722] Example 76

[0723] Preparation of compound II-18:

[0724] first step:

[0725] Intermediate HSP90-12 (400 mg, 0.7 mmol) was dissolved in THF (3 mL) and EtOH (3 mL). LiOH (220.8 mg, 2.8 mmol) was dissolved in anhydrous H2O (1 mL) and added dropwise to the system. Stir at room temperature for 4 h. The pH was adjusted with 1M HCl, and the mixture was extracted with EA. The organic phase was concentrated and purified by column chromatography (PE / EA = 2 / 1) to obtain 200 mg of a solid, with a yield of 40%. UPLC-MS calculated for C 27 H 35 N5O4[M+H] + :493.27,found:494.31.

[0726] Step 2:

[0727] Intermediate II-18-1 (200 mg, 0.4 mmol) was dissolved in MeOH (8 mL), and HCl-dioxane (2 mL) was added dropwise to the system at 0°C. The mixture was stirred at room temperature for 4 h. The organic phase was concentrated to obtain 200 mg of solid, with a yield of 40%. UPLC-MS calculated for C 22 H 27 N5O2[M+H] + :393.22,found:394.31.

[0728] Step 3:

[0729] The synthesis method was similar to that of Example II-12, and 20 mg of II-18 white powder solid was obtained by preparative liquid phase. UPLC-MS calculated for C 46 H 53 C1N 10 O4[M+H] + :844.39,found:845.86. 1 H NMR (500MHz, DMSO-d6) δ10.77(s,1H),9.78(s,1H),8.75(d,J=1.9Hz,1H),8.56(dd,J=8.2,2.3Hz,1H),7.84(dd,J=8.7,1.9Hz,1H ),7.78(dd,J=9.6,1.7Hz,1H),7.47–7.41(m,2H),7.40–7.35(m,3H),7.30(d,J=9.6Hz,1H),7.11(dd,J=8.8,2.3Hz,1H),6.65(d, J=1.8Hz,1H),6.37(d,J=1.6Hz,1H),4.53–4.34(m,3H),3.92–3.77(m,1H),3.04–2.86(m,4H),2.37(d,J=24.4Hz,8H),2.10(dd,J =21.9,8.9Hz,4H),1.91–1.73(m,5H),1.62(q,J=12.4Hz,2H),1.54–1.44(m,2H),1.23–1.00(m,3H),0.81(dd,J=6.8,1.8Hz,6H).

[0730] Example 77

[0731] Preparation of compound III-1:

[0732] Synthesis was performed by referring to I-4. Ⅲ-1 was obtained by preparative liquid phase, 20 mg of white powdery solid, yield: 23.14%. UPLC-MS calculated for C 42 H 45 ClN8O5[M+H] + :778.33found:778.24. 1 H NMR (400MHz, DMSO-d6) δ8.58(d,J=8.2Hz,1H),7.85(d,J=8.8Hz,1H),7.79(dd,J=9.6,3.1Hz,1H),7.38 (d,J=2.4Hz,1H),7.31(dd,J=11.8,9.7Hz,1H),7.26–7.17(m,2H),7.16–7.04(m,3H),6.72(s,1H), 6.26(s,1H),4.61–4.42(m,3H),3.85(qt,J=7.5,5.0,4.0Hz,1H),3.01–2.87(m,3H),2.62(t,J=7.8 Hz,1H),2.17–2.03(m,2H),1.95–1.85(m,2H),1.81(d,J=12.5Hz,2H),1.70–1.57(m,3H),1.57–1.4 3(m,4H),1.30–1.17(m,4H),1.17–1.05(m,2H),0.92(d,J=6.8Hz,4H),0.85(dd,J=7.0,5.4Hz,2H).

[0733] Example 78

[0734] Preparation of compound III-2:

[0735] The synthetic route was referred to I-4, and III-2 was obtained by preparative liquid phase, 29 mg of white powdery solid, yield: 26.31%. UPLC-MS calculated for C 41 H 43 ClN8O6[M+H] + :780.30found:780.24. 1H NMR (400MHz, DMSO-d6) δ9.20(s,1H),8.25(d,J=7.5Hz,1H),8.02(d,J=8.9Hz,1H),7.90(d,J=9.7Hz,1H ),7.78(d,J=0.6Hz,1H),7.63–7.54(m,3H),7.40(s,1H),7.30–7.21(m,3H),6.70(s,1H),4.36(dd,J=1 1.7,5.1Hz,1H),4.32–4.19(m,4H),4.14(dtt,J=9.4,5.9,3.6Hz,1H),3.94(ddd,J=12.3,8.5,6.2Hz,2 H),3.61–3.49(m,1H),2.55–2.45(m,1H),2.36–2.22(m,6H),2.20–2.01(m,6H),1.56(d,J=6.8Hz,6H).

[0736] Example 79

[0737] Preparation of compound III-3:

[0738] The synthetic route was similar to that of I-4. III-3 was obtained by preparative liquid phase chromatography. The product was a white powdery solid (33 mg). The yield was 25.56%. UPLC-MS calculated for C 41 H 44 ClN9O5[M+H] + :779.12found:779.26. 1 H NMR (400MHz, DMSO-d6) δ8.17(s,1H),7.22(d,J=7.5Hz,1H),6.98(d,J=8.9Hz,1H),6.87(d,J=9.7Hz, 1H),6.75(d,J=0.6Hz,1H),6.73–6.67(m,2H),6.53(d,J=7.5Hz,1H),6.36(d,J=2.3Hz,1H),6.23(dd, J=8.9,2.3Hz,1H),5.95–5.90(m,2H),5.66(s,1H),4.48(t,J=5.8Hz,1H),3.24(tt,J=6.2,3.6Hz,1H) ,3.20–3.06(m,3H),2.96–2.87(m,2H),2.57–2.45(m,3H),1.31–0.97(m,13H),0.52(d,J=6.8Hz,6H).

[0739] Example 80

[0740] Preparation of compound III-4:

[0741] The synthetic route was similar to that of I-4. III-4 was obtained by preparative liquid phase chromatography. The product was a white powdery solid (20.56 mg) with a yield of 21.18%. UPLC-MS calculated for C 42 H 46 ClN9O5[M+H] + :793.34found:793.18. 1 H NMR(500MHz,Chloroform-d)δ8.00(s,1H),7.06(d,J=7.5Hz,1H),6.82(d,J=8.9Hz,1H),6.7 1(d,J=9.7Hz,1H),6.59(d,J=0.7Hz,1H),6.54–6.48(m,2H),6.37(d,J=7.5Hz,1H),6.20(d, J=2.3Hz,1H),6.10–6.02(m,3H),5.50(s,1H),3.15–3.05(m,3H),3.05–2.90(m,3H),2.53–2 .46(m,4H),2.41–2.29(m,2H),1.14–1.01(m,7H),1.00–0.81(m,6H),0.36(d,J=6.8Hz,6H).

[0742] Example 81

[0743] Preparation of compound III-5:

[0744] The synthetic route was referred to I-4, and III-5 was obtained by preparative liquid phase, 30 mg of white powdery solid. UPLC-MS calculated for C 40 H 41 ClN8O6[M+H] + :764.28,found:765.46. 1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),9.43(s,1H),8.57(d,J=8.2Hz,1H),7.81(dd,J=9.2,7.9Hz,2H),7.44– 7.26(m,2H),7.14–7.04(m,3H),7.01–6.87(m,2H),6.74(s,1H),6.24(s,1H),4.70–4.45(m,2H),4.09–3.99( m,2H),3.89–3.74(m,1H),3.54(ddd,J=12.7,8.5,3.3Hz,2H),2.96(h,J=6.9Hz,1H),2.10–1.95(m,4H),1.86 (dd,J=13.4,3.9Hz,2H),1.60(tdd,J=12.7,10.1,8.7,5.4Hz,4H),1.53–1.42(m,2H),0.93(d,J=6.9Hz,6H).

[0745] Example 82

[0746] Preparation of compound III-6:

[0747] The synthetic route was referred to I-4, and III-6 was obtained by preparative liquid phase, 20 mg of white powdery solid. UPLC-MS calculated for C 40 H 42 ClN9O5[M+H] + :763.30,found:764.37. 1 H NMR (400MHz, DMSO-d6) δ9.62(s,1H),9.54(s,1H),8.56(d,J=8.2Hz,1H),7.80(dd,J=12.0,9.1H z,2H),7.43–7.29(m,2H),7.10(dd,J=8.8,2.4Hz,1H),6.98–6.82(m,2H),6.71(s,1H),6.65–6. 45(m,2H),6.25(s,1H),5.76(d,J=8.1Hz,1H),4.53–4.23(m,3H),3.82(ddp,J=11.4,8.1,4.0Hz ,1H),3.60–3.41(m,2H),2.97–2.89(m,1H),2.10–2.02(m,2H),2.00–1.81(m,4H),1.66–1.53(m, 2H),1.54–1.19(m,4H),0.89(d,J=6.9Hz,6H).

[0748] Example 83

[0749] Preparation of compound III-7:

[0750] The synthetic route was referred to I-4, and III-7 was obtained by preparative liquid phase, 20 mg of white powdery solid. UPLC-MS calculated for C 40 H 42 ClN9O5[M+H] + :763.30,found:764.28. 1 H NMR (400MHz, DMSO-d6) δ11.91(s,1H),9.64(s,1H),9.42(s,1H),8.58(d,J=8.2Hz,1H),7.80(dd,J=9.1,7.3Hz,2H),7.34(d,J=2.4Hz, 1H),7.30(dd,J=8.9,2.6Hz,3H),7.13(d,J=1.6Hz,1H),7.13–7.05(m,2H),6.73(s,1H),6.24(d,J=2.0Hz,1H),4.49(dq,J=10.3,5.7,5 .0Hz,1H),3.82(dtt,J=11.2,7.6,4.1Hz,1H),3.66(t,J=4.8Hz,4H),3.48(s,2H),2.91(h,J=6.9Hz,1H),2.53–2.48(m,0H),2.47(d,J =1.8Hz,4H),2.29(p,J=2.0Hz,0H),2.10–2.02(m,2H),1.89–1.81(m,2H),1.66–1.53(m,2H),1.53–1.39(m,2H),0.90(d,J=6.9Hz,6H).

[0751] Example 84

[0752] Preparation of compound III-8:

[0753] The synthetic route was referred to I-4, and III-8 was obtained by preparative liquid phase, 18 mg of white powdery solid. UPLC-MS calculated for C 39 H 42 C1N 10 O5[M+H] + :765.30,found:765.27. 1H NMR (400MHz, DMSO-d6) δ8.60(d,J=8.2Hz,1H),8.31(d,J=2.2Hz,1H),7.91(dd,J=8.2,2.3Hz,1H),7.84(dd,J=9.2,7.0 Hz,2H),7.47(d,J=8.1Hz,1H),7.38(d,J=2.4Hz,1H),7.35(d,J=9.6Hz,1H),7.13(dd,J=8.8,2.5Hz,1H),6.81(s,1H), 6.25(s,1H),4.53(tt,J=10.1,4.4Hz,1H),3.85(dtt,J=11.6,8.3,4.0Hz,2H),3.71(t,J=5.1Hz,5H),3.58(s,4H),2.9 9(p,J=6.9Hz,1H),2.13–2.07(m,2H),1.93–1.86(m,2H),1.70–1.43(m,5H),1.26–1.22(m,1H),0.99(d,J=6.9Hz,6H).

[0754] Example 85

[0755] Preparation of compound III-9:

[0756] The synthetic route was referred to I-4, and III-9 was obtained by preparative liquid phase, 25 mg of white powdery solid. UPLC-MS calculated for C 38 H 41 C1N 11 O5[M+H] + :766.29,found:766.31. 1H NMR (400MHz, DMSO-d6) δ9.48(d,J=142.0Hz,1H),8.62(d,J=8.2Hz,1H),7.93(d,J=8.9Hz,1H),7.88–7.82(m,3H),7.39 (d,J=2.4Hz,1H),7.36(d,J=9.6Hz,1H),7.13(dd,J=8.8,2.5Hz,1H),7.06(s,1H),6.18(s,1H),4.54(td,J=10.1,5.0H z,1H),3.89–3.81(m,3H),3.72(d,J=5.5Hz,4H),3.05(p,J=6.9Hz,1H),2.56(q,J=4.4,3.9Hz,4H),2.13–2.07(m,2H), 1.93–1.86(m,2H),1.70–1.58(m,2H),1.50(dt,J=13.5,9.8Hz,2H),1.22(dd,J=8.0,5.4Hz,1H),1.10(d,J=6.9Hz,6H).

[0757] Example 86

[0758] Preparation of compound III-10:

[0759] The synthetic route was referred to I-4, and III-10 was obtained by preparative liquid phase, 10 mg of white powdery solid. UPLC-MS calculated for C 38 H 41 C1N 11 O5[M+H] + :766.29,found:766.31. 1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.77(s,1H),9.47(s,1H),8.41(s,2H),8.12–8.05(m,2H),8.03(s,1H),7 .77(d,J=7.5Hz,1H),7.53–7.45(m,2H),7.19(d,J=1.4Hz,1H),7.00(dd,J=7.4,1.4Hz,1H),6.41(s,1H),4.20–4 .09(m,1H),3.92(s,2H),3.79–3.67(m,1H),3.57(t,J=7.1Hz,4H),3.22–3.09(m,1H),2.83(dt,J=12.3,7.1Hz,2 H),2.73(dt,J=12.5,7.1Hz,2H),1.98–1.87(m,2H),1.87–1.75(m,4H),1.69–1.56(m,2H),1.22(d,J=6.8Hz,6H).

[0760] Example 87

[0761] Preparation of compound III-11:

[0762] The synthetic route was referred to I-4, and III-11 was obtained by preparative liquid phase, with a white powder solid of 13 mg. UPLC-MS calculated for C 41 H 46 C1N 10 O5[M+H] + :793.33,found:793.34. 1 H NMR (400MHz, DMSO-d6) δ11.81(s,1H),9.57(d,J=77.3Hz,2H),8.59(s,1H),7.91–7.74(m,3H),7.31(dd,J=26.3,15.3Hz,3H),7.11 (s,1H),6.83(s,1H),6.59(s,1H),6.25(s,1H),4.48(s,4H),3.83(s,1H),2.95(d,J=21.8Hz,7H),2.13–1.45(m,13H),0.98(s,6H)

[0763] Example 88

[0764] Preparation of compound III-12:

[0765] The synthetic route was referred to I-4, and III-12 was obtained by preparative liquid phase, 13 mg of white powdery solid. UPLC-MS calculated for C 42 H 48 C1N 10 O5[M+H] + :807.35,found:807.32. 1 H NMR (400MHz, DMSO-d6) δ11.86(s,1H),9.66(s,1H),9.47(s,1H),8.60(d,J=8.3Hz,1H),7.88–7.77(m,3H),7.42–7.27(m,3 H),7.13(dd,J=8.8,2.4Hz,1H),6.86(s,1H),6.56(d,J=9.1Hz,1H),6.27(s,1H),4.58–4.41(m,3H),3.85(td,J=11.0,9.3, 5.5Hz,1H),3.54(t,J=7.6Hz,2H),3.02–2.90(m,6H),2.16–2.05(m,2H),1.93–1.85(m,2H),1.81(d,J=12.7Hz,2H),1.65(d d,J=13.8,10.7Hz,2H),1.52(td,J=11.5,10.4,3.2Hz,2H),1.44(q,J=6.9Hz,2H),1.27–1.10(m,3H),0.99(d,J=6.8Hz,6H)

[0766] Example 89

[0767] Preparation of compound III-13:

[0768] first step:

[0769] Intermediate HSP90-27 (70 mg, 0.15 mmol) and starting material 1-Boc-4-piperidinic acid (37 mg, 0.15 mmol) were dissolved in DMF (1.5 mL). DIEA (58 mg, 0.46 mmol), EDCI (29 mg, 0.15 mmol), and HOBT (20.5 mg, 0.15 mmol) were added, and the mixture was stirred at room temperature overnight. The mixture was extracted with water and ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated to dryness to obtain 80 mg of a solid with a yield of 83.99%. UPLC-MS calculated for C 33 H 46 N7O6[M+H] + :636.34found:636.76.

[0770] Step 2:

[0771] Intermediate III-13-1 (80 mg, 0.12 mmol) was dissolved in anhydrous methanol (1.5 mL), and dioxane hydrochloride (1.5 mL) was added. The mixture was allowed to react overnight at room temperature. The solvent was evaporated to dryness to obtain 70 mg of a light yellow oil with a yield of 100%. UPLC-MS calculated for C 28 H 38 N7O4[M+H] + :536.29,found:536.65.

[0772] Step 3:

[0773] Intermediate III-13-2 (70 mg, 0.12 mmol) and AR-1 (62.4 mg, 0.16 mmol) were dissolved in DMF (2 mL), DIEA (62 mg, 0.48 mmol) was added, and the mixture was stirred at 80°C overnight. 27 mg of III-13 was obtained as a white powdery solid by preparative liquid chromatography. UPLC-MS calculated for C 46 H 53 C1N 11 O6[M+H] + :890.38,found:890.44.

[0774] Example 90

[0775] Preparation of compound III-14:

[0776] The synthetic route was referred to III-13, and III-14 was obtained by preparative liquid phase, 22 mg of white powdery solid. UPLC-MS calculated for C 46 H 54 C1N 12 O6[M+H] + :905.39,found:905.46. 1H NMR(500MHz,DMSO-d6)δ9.65(s,1H),8.28(d,J=2.3Hz,1H),7.90(d,J=7.5Hz,1H),7.86(d,J=9.7Hz,1H),7.71(d,J=8.8Hz,1H),7.53–7.47(m,2H), 7.21–7.14(m,2H),6.95(dd,J=8.8,2.2Hz,1H),6.75(d,J=7.6Hz,1H),6. 36(s,1H),4.01(dtdd,J=7.9,6.4,4.9,1.5Hz,1H),3.93(tt,J=6.2,3.5Hz ,1H),3.77(dtt,J=12.7,6.2,3.2Hz,1H),3.67(ddd,J=12.4,8.1,5.4Hz, 2H),3.60(dd,J=5.8,5.1Hz,4H),3.41(ddd,J=12.5,8.2,5.5Hz,2H),3.25 –3.14(m,2H),3.12(d,J=13.0Hz,1H),3.08(s,3H),2.71(ddd,J=7.3,5.8 ,5.1Hz,4H),2.01–1.76(m,8H),1.73–1.59(m,4H),1.20(d,J=6.9Hz,6H).

[0777] Example 91

[0778] Preparation of compound III-15:

[0779] The synthetic route was referred to I-1, and III-15 was obtained by preparative liquid phase, 22 mg of white powdery solid. UPLC-MS calculated for C 47 H 57 C1N 11 O5[M+H] + :890.42,found:890.48. 1H NMR (400MHz, DMSO-d6) δ11.87(s,1H),9.60(s,1H),9.43(s,1H),9.20(d,J=2.1Hz,1H),8.74(d,J=2.1Hz ,1H),7.90–7.71(m,2H),7.46(dd,J=10.2,1.9Hz,1H),7.40–7.30(m,2H),6.86(s,1H),6.65(d,J=9.1Hz ,1H),6.25(s,1H),4.19–4.08(m,2H),3.95–3.75(m,4H),2.99(d,J=6.8Hz,5H),2.62(dq,J=8.6,4.9,3. 7Hz,2H),2.04–1.89(m,1H),1.57(dq,J=10.2,5.6,4.4Hz,1H),1.32–1.07(m,2H),1.00(d,J=6.9Hz,6H).

[0780] Example 92

[0781] Preparation of compound III-16:

[0782] The synthetic route was referred to I-1, and III-16 was obtained by preparative liquid phase, 28 mg of white powdery solid. UPLC-MS calculated for C 48 H 59 C1N 11 O5[M+H] + :904.43,found:904.51. 1 H NMR (400MHz, DMSO-d6) δ11.83(s,1H),8.56(d,J=8.2Hz,1H),7.84–7.73(m,3H),7.35(d,J=2.4H z,1H),7.33–7.22(m,2H),7.09(dd,J=8.8,2.4Hz,1H),6.82(s,1H),6.51(d,J=9.1Hz,1H),6.24( s,1H),4.56–4.37(m,3H),3.82(dt,J=8.2,5.4Hz,1H),3.44(s,1H),3.01–2.88(m,6H),2.76(d, J=10.7Hz,2H),2.13–1.68(m,11H),1.68–1.31(m,8H),1.25–1.01(m,6H),0.97(d,J=6.9Hz,6H).

[0783] Example 93

[0784] Preparation of compound IV-1:

[0785] first step:

[0786] Intermediate I-1-2 (100 mg, 0.27 mmol), methyl 4-piperidincarboxylate (43.5 mg, 0.40 mmol), and K2CO3 (57 mg, 0.41 mmol) were dissolved in anhydrous DMF and stirred at 80°C for 4 hours. Water and ethyl acetate were added for extraction. The organic phase was washed sequentially with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography (DCM / MeOH = 15 / 1) to obtain 100 mg of a solid, with a yield of 75%. UPLC-MS calculated for C 25 H 29 ClN5O4[M+H] + :498.13,found:498.98.

[0787] Step 2:

[0788] Intermediate IV-1-1 (100 mg, 0.27 mmol), anhydrous THF 6 mL and MeOH 6 mL were added to anhydrous H2O with LiOH (43.5 mg, 0.40 mmol) and stirred at RT for 4 hours. HCl was used to adjust the pH.

[0789] Water and ethyl acetate were added for extraction. The organic phase was washed sequentially with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography (DCM / MeOH = 15 / 1) to obtain 46 mg of a solid, with a yield of 35%. UPLC-MS calculated for C 24 H 25 ClN5O4[MH] - :482.17,found:482.95.

[0790] Step 3:

[0791] Intermediate IV-1-2 (50 mg, 0.1 mmol), DIEA (40 mg, 0.3 mmol), and HATU (43 mg, 0.1 mmol) were dissolved in anhydrous DMF and stirred under argon for 10 minutes. A DMF solution of intermediate HSP90-8 (47 mg, 0.1 mmol) was added and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added for extraction. The organic phase was washed sequentially with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. A preparative liquid chromatography system was used to obtain 30 mg of IV-1 as a white powdery solid, with a yield of 33.3%. UPLC-MS calculated for C 46 H 52C1N 10 O6[M+H] + :875.37,found:875.43. 1 H NMR (400MHz, DMSO-d6) δ11.91(s,1H),9.56(s,1H),8.56(d,J=8.2Hz,1H),8.17(s,1H),7.78(dd,J=25.9,9.1Hz ,2H),7.39–7.18(m,4H),7.09(dd,J=8.6,3.1Hz,3H),6.72(s,1H),6.23(s,1H),4.43(s,2H),3.80(ddt,J=11.6 ,8.0,3.8Hz,2H),3.39(s,4H),2.94(d,J=13.3Hz,2H),2.43–2.20(m,6),2.13–2.00(m,2H),1.85(dd,J=9.1,4. 4Hz,2H),1.78–1.66(m,2H),1.66–1.39(m,5H),1.33(d,J=7.4Hz,2H),1.15–1.01(m,2H),0.90(d,J=6.9Hz,6H).

[0792] Example 94

[0793] Preparation of compound IV-2:

[0794] The synthetic route was similar to that of I-1. IV-2 was obtained by preparative liquid phase, and 36 mg of white powdery solid was obtained. UPLC-MS calculated for C 47 H 56 C1N 10 O5[M+H] + :875.40,found:875.47. 1H NMR (400MHz, DMSO-d6) δ11.91(s,1H),9.56(s,1H),8.56(d,J=8.2Hz,1H),8.17(s,1H),7.78(dd,J=25.9,9.1Hz ,2H),7.39–7.18(m,4H),7.09(dd,J=8.6,3.1Hz,3H),6.72(s,1H),6.23(s,1H),4.43(s,2H),3.80(ddt,J=11.6, 8.0,3.8Hz,2H),3.39(s,4H),2.94(d,J=13.3Hz,2H),2.43–2.20(m,9H),2.13–2.00(m,2H),1.85(dd,J=9.1,4. 4Hz, 2H), 1.78–1.66 (m, 2H), 1.66–1.39 (m, 5H), 1.33 (d, J = 7.4Hz, 2H), 1.15–1.01 (m, 2H), 0.90 (d, J = 6.9Hz, 6H).

[0795] Example 95

[0796] Preparation of compound IV-3:

[0797] The synthetic route was referred to I-1, and IV-3 was obtained by preparative liquid phase, 31 mg of white powdery solid. UPLC-MS calculated for C 45 H 52 C1N 10 O5[M+H] + :847.37,found:847.42. 1H NMR (400MHz, DMSO-d6) δ11.95(s,1H),9.51(d,J=92.2Hz,1H),8.56(d,J=8.2Hz,1H),8.17(s,1H)7.82(d,J=8.8Hz,1H),7.75( d,J=9.5Hz,1H),7.35(d,J=2.5Hz,1H),7.29(dd,J=16.6,9.0Hz,2H),7.09(dd,J=8.8,2.4Hz,1H),7.02(dd,J=10.8,2.0Hz,1H ),6.93(dd,J=8.2,2.0Hz,1H),6.82(s,1H),6.23(s,1H),4.65–4.24(m,3H),3.81(dd,J=9.5,5.4Hz,2H),3.11–2.86(m,4H),2 .33(s,7H),2.07(t,J=8.3Hz,5H),1.92–1.64(m,4H),1.70–1.36(m,4H),1.05(dd,J=17.9,7.9Hz,2H),0.96(d,J=6.9Hz,6H).

[0798] Example 96

[0799] Preparation of compound IV-4:

[0800] The synthetic route was referred to I-1, and IV-4 was obtained by preparative liquid phase, 40 mg of white powdery solid. UPLC-MS calculated for C 52 H 65 C1N 11 O5[M+H] + :958.48,found:958.61. 1H NMR (400MHz, DMSO-d6) δ11.91(s,1H),9.60(s,1H),9.40(s,1H),8.59(d,J=8.1Hz,1H),7.79(dd,J=29.2,9. 1Hz,2H),7.36(d,J=2.4Hz,1H),7.26(dd,J=17.0,8.8Hz,3H),7.09(t,J=8.3Hz,3H),6.73(s,1H),6.22(s,1 H),4.56–4.35(m,3H),3.81(d,J=9.8Hz,1H),3.38(s,4H),3.02–2.69(m,5H),2.39–2.18(m,6H),2.06(t,J= 7.2Hz, 6H), 1.79 (dt, J = 35.1, 13.5Hz, 7H), 1.66–1.35 (m, 7H), 1.02 (q, J = 12.1Hz, 4H), 0.90 (d, J = 6.8Hz, 6H).

[0801] Example 97

[0802] Preparation of compound IV-5:

[0803] The synthetic route was referred to I-1, and IV-5 was obtained by preparative liquid phase, 40 mg of white powdery solid. UPLC-MS calculated for C 46 H 55 C1N 11 O4[M+H] + :860.40,found:860.44. 1 H NMR (400MHz, DMSO-d6) δ11.90(s,1H),9.56(s,1H),8.53(d,J=8.3Hz,1H),7.76(s,1H),7.47(d,J=8.7Hz,1H), 7.31–7.21(m,3H),7.08(s,2H),6.92(s,1H),6.73(s,2H),6.58(d,J=8.8Hz,1H),6.23(s,1H),4.40(s,2H),3.8 3–3.70(m,1H),3.37–3.19(m,5H),2.94(dd,J=18.4,8.9Hz,3H),2.32(s,6H),2.08(s,2H),1.94(d,J=10.8Hz, 2H),1.83(d,J=9.3Hz,5H),1.61–1.47(m,2H),1.32–1.17(m,3H),1.03(d,J=9.6Hz,2H),0.90(d,J=6.8Hz,6H).

[0804] Example 98

[0805] Preparation of compound IV-6:

[0806] The synthetic route was referred to I-1, and IV-6 was obtained by preparative liquid phase, 30 mg of white powdery solid. UPLC-MS calculated for C 46 H 53 ClFN 10 O5[M+H] + :879.38,found:879.44. 1 H NMR (400MHz, DMSO-d6) δ11.95(s,1H),9.51(d,J=92.2Hz,1H),8.56(d,J=8.2Hz,1H),8.17(s,1H)7.82(d,J=8.8Hz,1H),7.75( d,J=9.5Hz,1H),7.35(d,J=2.5Hz,1H),7.29(dd,J=16.6,9.0Hz,2H),7.09(dd,J=8.8,2.4Hz,1H),7.02(dd,J=10.8,2.0Hz,1H ),6.93(dd,J=8.2,2.0Hz,1H),6.82(s,1H),6.23(s,1H),4.65–4.24(m,3H),3.81(dd,J=9.5,5.4Hz,2H),3.11–2.86(m,4H),2 .33(s,7H),2.07(t,J=8.3Hz,5H),1.92–1.64(m,5H),1.70–1.36(m,4H),1.05(dd,J=17.9,7.9Hz,2H),0.96(d,J=6.9Hz,6H).

[0807] Example 99

[0808] Preparation of compound IV-7:

[0809] The synthetic route was referred to I-1, and IV-7 was obtained by preparative liquid phase, 12 mg of white powdery solid. UPLC-MS calculated for C 47 H 55 ClFN 10 O5[M+H] + :893.40,found:893.46. 1H NMR (400MHz, DMSO-d6) δ11.96(s,1H),9.50(d,J=113.6Hz,2H),8.55(d,J=8.1Hz,1H),8.16(s,1H),7.80(dd,J=32.2,9.1Hz,2H),7 .38–7.28(m,3H),7.11(dd,J=8.8,2.4Hz,1H),7.03(d,J=10.7Hz,1H),6.94(d,J=8.1Hz,1H),6.84(s,1H),6.25(s,1H),4.56–4.38( m,4H),3.85–3.78(m,1H),3.03–2.88(m,5H),2.39–2.26(m,9H),2.08(dd,J=13.0,4.6Hz,2H),1.90–1.84(m,2H),1.77–1.71(m,2H) ,1.64–1.58(m,3H),1.50(td,J=11.6,10.2,3.5Hz,2H),1.34(q,J=7.1Hz,2H),1.11(tt,J=11.8,6.0Hz,2H),0.98(d,J=6.9Hz,6H).

[0810] Example 100

[0811] Preparation of compound IV-8:

[0812] The synthetic route was referred to I-1, and IV-8 was obtained by preparative liquid phase, 26 mg of white powdery solid. UPLC-MS calculated for C 45 H 53 C1N 11 O5[M+H] + :862.38,found:862.43. 1H NMR (400MHz, DMSO-d6) δ12.03(s,1H),9.56(s,1H),8.60(d,J=8.2Hz,1H),8.23(t,J=4.0Hz,2H),7. 82(dd,J=25.6,9.1Hz,2H),7.59(dd,J=8.2,2.5Hz,1H),7.47–7.24(m,3H),7.13(dd,J=8.9,2.4Hz,1 H),6.92(s,1H),6.24(s,1H),4.56–4.39(m,3H),3.90–3.81(m,2H),3.08–2.87(m,4H),2.39(s,6H) ,2.15–2.06(m,5H),1.96–1.73(m,6H),1.68–1.58(m,2H),1.55–1.45(m,2H),1.03(d,J=6.8Hz,8H).

[0813] Example 101

[0814] Preparation of compound IV-9:

[0815] The synthetic route was referred to I-1, and IV-9 was obtained by preparative liquid phase, 25 mg of white powdery solid. UPLC-MS calculated for C 46 H 55 C1N 11 O5[M+H] + :876.40,found:876.46. 1 H NMR (400MHz, DMSO-d6) δ11.99(s,1H),9.52(d,J=96.1Hz,2H),8.57(d,J=8.2Hz,1H),8.18(d,J=2.3Hz,1H),7.79(dd ,J=27.4,9.1Hz,2H),7.55(dd,J=8.3,2.4Hz,1H),7.43–7.22(m,3H),7.10(dd,J=8.7,2.3Hz,1H),6.90(s,1H),6.20( s,1H),4.61–4.37(m,3H),3.82(d,J=9.1Hz,1H),3.06–2.88(m,4H),2.45–2.22(m,9H),2.12–1.95(m,2H),1.78(dd, J=53.7,12.5Hz,5H),1.53(dq,J=52.5,12.5Hz,6H),1.33(q,J=7.2Hz,2H),1.21–1.06(m,2H),1.00(d,J=6.9Hz,6H).

[0816] Example 102

[0817] Preparation of compound IV-10:

[0818] first step:

[0819] 2-Chloro-5-nitropyridine (500 mg, 3.16 mmol) was dissolved in 10 mL of dimethylformamide. DIEA (816 mg, 3.56 mmol) and 4-(((tert-butyldimethylsilyl)oxy)methyl)piperidine (873 mg, 3.80 mmol) were added sequentially. The temperature was raised to 100°C and the reaction mixture was allowed to react for 18 hours. After cooling to room temperature, the solvent was removed by rotary evaporation and the product was purified by column chromatography (PE:EA = 5:1) to obtain 820 mg of a yellow solid in a yield of 73.80%. UPLC-MS calculated for C 17 H 30 N3O3Si[M+H] + :352.20,found:352.26.

[0820] Step 2:

[0821] IV-10-1 (600 mg, 1.70 mmol) was dissolved in 20 mL of methanol, and 10% palladium on carbon (60 mg) was added. The hydrogen atmosphere was replaced three times, and the mixture was allowed to react at room temperature for 6 h under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was directly used in the next reaction after being dried. 550 mg of a brown oil was obtained, with a yield of 100%. UPLC-MS calculated for C 17 H 32 N3OSi[M+H] + :322.22,found:322.30.

[0822] Step 3:

[0823] IV-10-2 (550 mg, 1.71 mmol) was dissolved in 20 ml of tetrahydrofuran. Pyridine (148 mg, 1.87 mmol) and phenyl chloroformate (294 mg, 1.87 mmol) were added sequentially under an ice bath and allowed to react at room temperature for 3 h. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then purified by column chromatography (PE:EA = 4:1) to obtain 600 mg of a pink solid in a yield of 79.57%. UPLC-MS calculated for C 24 H 36 N3O3Si[M+H] + :442.24,found:442.37.

[0824] Step 4:

[0825] 4-Fluoro-2-(trifluoromethyl)benzonitrile (500 mg, 2.64 mmol) and 1-Boc-piperazine (800 mg, 4.29 mmol) were dissolved in dimethylformamide (20 mL) and heated to 80°C for 3 h. After cooling to room temperature, water (200 mL) was added to the reaction solution, and extraction was performed with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then purified by column chromatography (PE:EA = 5:1) to obtain 770 mg of a white solid, with a yield of 82.00%. UPLC-MS calculated for C 17 H 21 F3N3O2[M+H] + :356.15,found:356.30.

[0826] Step 5:

[0827] Dissolve IV-10-5 (770 mg, 2.16 mmol) in 30 mL of 4 M hydrogen chloride in dioxane and stir at room temperature for 2 h. After spin drying, 550 mg of crude white solid was obtained. Yield: 100%. UPLC-MS calculated for C 12 H 13 F3N3[M+H] + :256.10,found:256.21.

[0828] Step 6:

[0829] Dissolve IV-10-3 (600 mg, 1.36 mmol) in acetonitrile (30 mL), add DIEA (526 mg, 4.07 mmol) and IV-10-6 (550 mg, 2.15 mmol), and heat to 90°C for 2 h. After cooling to room temperature, remove the solvent by rotary evaporation and purify by column chromatography (DCM:MeOH = 15:1) to obtain 750 mg of a blue solid in a yield of 91.46%. UPLC-MS calculated for: C 30 H 42 F3N6O2Si[M+H] + :603.30,found:603.44.

[0830] Step 7:

[0831] Dissolve IV-10-7 (750 mg, 1.24 mmol) in tetrahydrofuran (20 mL) and add TBAF (1 M in THF, 1.5 mL). React at room temperature for 3 h. Remove the solvent by rotary evaporation and purify by column chromatography (DCM:MeOH = 15:1) to obtain 500 mg of a brown solid in a yield of 82.37%. UPLC-MS calculated for: C 24 H 28 F3N6O2[M+H] + :489.21,found:489.36.

[0832] Step 8:

[0833] Dissolve IV-10-8 (200 mg, 0.40 mmol) in 20 mL of dichloromethane, add DMP (200 mg, 0.47 mmol), and react at room temperature for 3 h. Add 50 mL of saturated sodium bicarbonate solution to the reaction solution, extract with dichloromethane (10 mL x 2). Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and filter. The filtrate is then dried and purified by column chromatography (DCM:MeOH = 15:1) to obtain 120 mg of a brown solid, with a yield of 60.30%. UPLC-MS calculated for C 24 H 26 F3N6O2[M+H] + :487.20,found:487.23.

[0834] Step 9:

[0835] IV-10-9 (50 mg, 0.10 mmol) and HSP90-8 (48 mg, 0.12 mmol) were dissolved in dichloroethane (4 mL) and methanol (1 mL). Triethylamine was added dropwise to adjust the pH to approximately 8. The mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (8.1 mg, 0.12 mmol) was added under ice-cooling and the mixture was stirred at room temperature overnight. A preparative liquid chromatography system was used to obtain 38 mg of a white powdery solid in a yield of 42.23%. UPLC-MS was calculated for C 46 H 53 F3N 11 O4[M+H] + :880.42,found:880.99. 1H NMR (400MHz, DMSO-d6) δ11.94(s,1H),9.53(d,J=62.3Hz,1H),8.43(s,1H),8.19(s,1H),8.11(s,1H),7.87(d,J=8. 8Hz,1H),7.57(dd,J=9.1,2.7Hz,1H),7.34(d,J=2.2Hz,1H),7.31–7.23(m,3H),7.13(d,J=8.4Hz,2H),6.79–6.71(m ,2H),6.27(s,1H),4.15(d,J=12.8Hz,2H),3.56(dd,J=17.7,6.3Hz,10H),3.43(s,3H),2.97(p,J=6.9Hz,1H),2.67 (d, J=12.1Hz, 2H), 2.36 (s, 6H), 2.11 (s, 2H), 1.73 (d, J= 12.6Hz, 3H), 1.06 (d, J= 10.9Hz, 2H), 0.94 (d, J= 6.9Hz, 6H).

[0836] Example 103

[0837] Preparation of compound V-1:

[0838] first step:

[0839] AR-9 (312 mg, 1.2 mmol), DIEA (464.4 mg, 3.6 mmol), and HATU (501.6 mg, 1.32 mmol) were dissolved in anhydrous DMF and stirred under argon for 10 minutes. A DMF solution of p-pyrrolecarboxylic acid (147.84 mg, 1.32 mmol) was added and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added for extraction. The organic phase was washed sequentially with saturated ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography (DCM / MeOH = 15 / 1) to obtain 250 mg of a solid, with a yield of 59%. UPLC-MS calculated for C 17 H 16 ClN6O[M+H] + :355.10,found:355.80.

[0840] Step 2:

[0841] V-1-1 (250 mg, 0.70 mmol), 2-bromo-1,1-dimethoxyethane (134.3 mg, 0.79 mmol), K2CO3 (150.4 mg, 1.1 mmol), and KI (3.6 mg, 0.07 mmol) were dissolved in anhydrous DMF and stirred at 80°C for 4 h. Water and ethyl acetate were added for extraction. The organic phase was washed sequentially with saturated ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography (DCM / MeOH = 15 / 1) to obtain 200 mg of a solid, with a yield of 65%. UPLC-MS calculated for C 21 H 24 ClN6O3[M+H] + :443.15,found:443.90.

[0842] Step 3:

[0843] Intermediate V-1-2 (200 mg, 0.45 mmol) was dissolved in anhydrous THF (5 mL). 1 mL of 4M HCl was added dropwise to the mixture and stirred at 50°C for 4 h. After cooling to a relatively warm state, 20 mL of distilled water was added and the mixture was lyophilized to obtain 200 mg of a solid. UPLC-MS calculated for C 19 H 18 ClN6O2[M+H] + :397.11,found:397.84.

[0844] The remaining synthetic steps were followed by reference to I-1, and V-1 was obtained by preparative liquid phase, 25 mg of a white powdery solid. UPLC-MS calculated for C 47 H 56 C1N 12 O4[M+H] + :887.42,found:887.48. 1H NMR(400MHz,DMSO-d6)δ11.93(s,1H),9.74(s,1H),9.41(s,1H),8.30–8.25(m,2H),8.12 –8.09(m,1H),7.87(s,1H),7.81–7.71(m,3H),7.12(d,J=7.8Hz,2H),6.83(d,J=2.3Hz,1H ),6.75(s,1H),6.60(d,J=2.2Hz,1H),6.35(s,1H),4.64–4.16(m,6H),2.93(q,J=6.9Hz, 3H), 2.44 (s, 8H), 1.82 (s, 3H), 1.43 (s, 2H), 1.07 (d, J = 6.4Hz, 3H), 0.92 (d, J = 6.8Hz, 6H).

[0845] Example 104

[0846] Preparation of compound V-2:

[0847] The synthesis steps were similar to those of I-1. V-2 was obtained by preparative liquid phase, and 25 mg of white powdery solid was obtained. UPLC-MS calculated for C 36 H 34 ClN8O4[M+H] + :677.23,found:677.16. 1 H NMR(400MHz,DMSO-d6)δ11.93(s,1H),9.74(s,1H),9.41(s,1H),8.30–8.25(m,2H),8.12 –8.09(m,1H),7.87(s,1H),7.81–7.71(m,3H),7.12(d,J=7.8Hz,2H),6.83(d,J=2.3Hz,1H ),6.75(s,1H),6.60(d,J=2.2Hz,1H),6.35(s,1H),4.64–4.16(m,6H),2.93(q,J=6.9Hz, 3H), 2.44 (s, 8H), 1.82 (s, 3H), 1.43 (s, 2H), 1.07 (d, J = 6.4Hz, 3H), 0.92 (d, J = 6.8Hz, 6H).

[0848] Example 105

[0849] Preparation of compound V-3:

[0850] The synthesis steps were similar to those of I-1. V-3 was obtained by preparative liquid phase, and 10 mg of a white powdery solid was obtained. UPLC-MS calculated for C 33 H 31 C1N 11 O4[M+H] + :680.22,found:680.13. 1 H NMR(400MHz,DMSO-d6)δ12.65(s,1H),11.39(s,1H),10.72(s,1H),9.47(s,1H),9.38(s,1H),8.33–8.26(m,1H ),8.07(d,J=1.5Hz,1H),7.87(d,J=1.3Hz,1H),7.84–7.74(m,2H),7.71(d,J=7.3Hz,1H),7.62(dd,J=7.5,1.5 Hz,1H),7.48(d,J=0.6Hz,1H),7.23(s,1H),6.70(d,J=7.5Hz,1H),6.63(d,J=7.5Hz,1H),6.42(s,1H),4.22–4 .11(m,1H),4.10–3.94(m,2H),3.16(pd,J=6.8,0.6Hz,1H),1.24(dd,J=6.7,2.9Hz,6H),1.20(d,J=6.7Hz,3H).

[0851] Example 106

[0852] Preparation of compound V-4:

[0853] The synthesis steps were similar to those of V-3. V-4 was obtained by preparative liquid phase, and 15 mg of white powdery solid was obtained. UPLC-MS calculated for C 34 H 31 C1N 11 O5[M+H] + :708.21,found:708.14. 1H NMR(400MHz,DMSO-d6)δ11.36(s,1H),10.72(s,1H),10.64(s,1H),9.47(s,1H),8.39–8.30 (m,1H),8.14(d,J=1.5Hz,1H),7.87(d,J=1.4Hz,1H),7.84–7.72(m,3H),7.71(s,1H),7.61 –7.54(m,2H),7.48(d,J=0.6Hz,1H),6.63(d,J=7.5Hz,1H),6.42(s,1H),4.22–4.12(m,1H) ,4.12–3.97(m,2H),3.20–3.13(m,1H),1.24(dd,J=6.6,4.0Hz,6H),1.20(d,J=6.7Hz,3H).

[0854] Example 107

[0855] Preparation of compound V-5:

[0856] The synthesis steps were similar to those of V-3. V-5 was obtained by preparative liquid phase, and 10 mg of white powdery solid was obtained. UPLC-MS calculated for C 36 H 31 ClN9O4[M+H] + :688.21,found:688.15. 1 H NMR (400MHz, DMSO-d6) δ11.39(s,1H),10.72(s,1H),9.47(s,1H),8.36–8.29(m,1H),7. 83(d,J=1.5Hz,1H),7.70(dd,J=13.4,7.5Hz,2H),7.62(dd,J=7.5,1.5Hz,1H),7.56–7.4 5(m,5H),7.11(s,1H),6.65(d,J=7.5Hz,1H),6.42(s,1H),4.21–4.12(m,1H),4.10–3.92 (m, 2H), 3.16 (pd, J = 6.8, 0.6Hz, 1H), 1.24 (dd, J = 6.7, 4.0Hz, 6H), 1.20 (d, J = 6.7Hz, 3H).

[0857] Example 108

[0858] Preparation of compound V-6:

[0859] The synthesis steps were similar to those of V-3. V-6 was obtained by preparative liquid phase chromatography, and 31 mg of white powdery solid was obtained. UPLC-MS calculated for C 34 H 31 ClN9O4[M+H] + :664.21,found:664.49. 1 H NMR (500MHz, Chloroform-d) δ8.85 (s, 1H), 7.91 (dd, J = 7.5, 2.2Hz, 1H), 7.82 (d, J = 2. 3Hz,1H),7.79–7.71(m,3H),7.58(d,J=9.3Hz,1H),7.47–7.41(m,4H),7.14(s,1H),6 .68(d,J=3.8Hz,1H),6.35(s,1H),4.40–4.30(m,1H),4.20–4.09(m,2H),3.20(pd,J= 6.9, 0.7Hz, 1H), 1.28 (d, J = 6.2Hz, 3H), 1.24 (d, J = 6.9Hz, 3H), 1.19 (d, J = 6.9Hz, 3H).

[0860] Example 109

[0861] Preparation of compound V-7:

[0862] The synthesis steps were similar to those of V-3. V-7 was obtained by preparative liquid phase chromatography, and the product was 8 mg of white powdery solid. UPLC-MS calculated for C 34 H 33 C1N 11 O4[M+H] + :694.23,found:694.15. 1H NMR (400MHz, DMSO-d6) δ12.82(s,1H),11.39(s,1H),10.72(s,1H),9.47(s,1H),8.33–8.26(m,1H),8.11(d,J= 1.5Hz,1H),7.87(d,J=1.4Hz,1H),7.84–7.74(m,2H),7.71(d,J=7.3Hz,1H),7.57(dd,J=7.5,1.5Hz,1H),7.48 (d,J=0.6Hz,1H),6.88(d,J=7.5Hz,1H),6.63(d,J=7.5Hz,1H),6.46(s,1H),6.42(s,1H),4.22–4.12(m,1H),4 .10–3.94(m,2H),3.81(s,3H),3.16(pd,J=6.8,0.6Hz,1H),1.25(dd,J=6.7,1.6Hz,6H),1.20(d,J=6.7Hz,3H).

[0863] Example 110

[0864] Preparation of compound V-8:

[0865] first step:

[0866] AR-11 (150 mg, 0.39 mmol) and 4-(dimethoxymethyl)-piperidine (74 mg, 0.46 mmol) were dissolved in dichloroethane (20 mL) and methanol (5 mL) and stirred at room temperature for 30 min. Sodium cyanoborohydride (29 mg, 0.46 mmol) was added under ice-cooling and stirred at room temperature overnight. The solvent was removed by rotary evaporation and then purified by column chromatography (DCM:MeOH = 15:1) to obtain 120 mg of a brown oil, with a yield of 58%. UPLC-MS calculated for C 27 H 37 ClN5O4[M+H] + :530.25,found:530.50.

[0867] Step 2:

[0868] Dissolve V-8-1 (120 mg, 0.23 mmol) in tetrahydrofuran (10 mL), add 6 M hydrochloric acid solution (5 mL), and react at room temperature for 3 h. Add saturated sodium bicarbonate to the reaction solution until the pH reaches 8, extract with ethyl acetate (10 mL x 3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and filter. The filtrate is then dried to give 95 mg of a crude yellow solid (86% yield). UPLC-MS calculated for C25 H 31 ClN5O3[M+H] + :484.20,found:484.40.

[0869] Step 3:

[0870] V-8-2 (95 mg, 0.19 mmol) and HSP90-8 (82 mg, 0.19 mmol) were dissolved in dichloroethane (4 mL) and methanol (1 mL). Triethylamine was added dropwise to adjust the pH to approximately 8. The mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (10 mg, 0.26 mmol) was added under ice-cooling and the mixture was stirred at room temperature overnight. 41 mg of a white powdery solid was obtained by preparative liquid chromatography (HPLC), with a yield of 24%. UPLC-MS was calculated for C 47 H 57 C1N 10 O5[M+H] + :877.42,found:877.62. 1 H NMR(400MHz, Methanol-d4)δ8.33(s,1H),8.14(s,1H),7.95(s,1H),7.69(d,J=8.7Hz,1H),7.50–7.45(m,2H),7.32–7.26(m,2H),7 .19(d,J=2.4Hz,1H),7.03(dd,J=8.8,2.4Hz,1H),6.76(s,1H),6.26(s,1H),4.44(dt,J=19.7,5.9Hz,3H),3.90(dt,J=10.7,5.6Hz, 1H),3.77(s,2H),3.20–3.08(m,4H),3.03(p,J=6.9Hz,1H),2.91(s,3H),2.78(s,3H),2.63(d,J=6.5Hz,2H),2.52–2.40(m,2H),2.2 0(d,J=9.6Hz,2H),2.05(d,J=9.8Hz,2H),1.86(d,J=13.2Hz,3H),1.58(q,J=11.7Hz,4H),1.38–1.27(m,3H),0.93(d,J=6.8Hz,6H).

[0871] Example 111

[0872] Preparation of compound V-9:

[0873] The synthesis steps were similar to those of V-8. V-9 was obtained by preparative liquid phase chromatography, and 36 mg of white powdery solid was obtained. UPLC-MS calculated for C 41 H 47 ClN9O5[M+H] + :780.33,found:780.34. 1 H NMR(400MHz,DMSO-d6)δ11.95(s,1H),9.64(s,1H),9.42(s,1H),8.18(s,1H),7.90–7.84(m,3H ),7.39(d,J=2.3Hz,1H),7.33(d,J=7.9Hz,2H),7.14(d,J=6.7Hz,3H),6.77(s,1H),6.28(s,1H) ,4.54(s,1H),4.23(s,2H),3.77(s,1H),3.53(s,3H),2.97(p,J=6.9Hz,1H),2.76(s,2H),2.54 (s,3H),2.09(s,2H),1.88(s,2H),1.56–1.37(m,5H),1.26–1.10(m,1H),0.94(d,J=6.8Hz,6H).

[0874] Example 112

[0875] Preparation of compound V-10:

[0876] The synthesis steps were similar to those of AR-11 and V-8. V-10 was obtained by preparative liquid phase chromatography, and the product was a white powdery solid (39 mg). UPLC-MS calculated for C 47 H 59 C1N 11 O4[M+H] + :876.44,found:876.50. 1H NMR (400MHz, DMSO-d6) δ11.93(s,1H),9.52(d,J=78.2Hz,1H),8.14(d,J=5.4Hz,2H),7.86(d,J=5.7Hz,2H),7.50(d,J=8.7Hz,1H),7.28(d,J=8.1 Hz,2H),7.12(d,J=8.0Hz,2H),6.93(d,J=7.7Hz,1H),6.77(d,J=3.1Hz,2H),6.62(dd,J=8.8,2.2Hz,1H),6.26(s,1H),4.20(t,J=6.6Hz,2H),3.76 –3.63(m,2H),3.32(s,1H),2.96(p,J=6.9Hz,1H),2.83(d,J=10.6Hz,2H ),2.68(t,J=6.6Hz,2H),2.35(s,6H),2.11(d,J=7.0Hz,2H),1.97(d,J=1 1.8Hz,4H),1.89–1.81(m,2H),1.66–1.57(m,2H),1.42(q,J=12.2Hz,3H) ,1.32–1.20(m,3H),1.03(q,J=12.8,11.5Hz,2H),0.93(d,J=6.9Hz,6H).

[0877] Example 113

[0878] Preparation of compound V-11:

[0879] The synthesis steps were similar to those of V-10. V-11 was obtained by preparative liquid phase chromatography, and the product was a white powdery solid (21 mg). UPLC-MS calculated for C 46 H 55 C1N 11 O6[M+H] + :892.39,found:892.46. 1H NMR (400MHz, DMSO-d6) δ11.36(s,1H),10.72(s,1H),9.47(s,1H),8.50(s,1H),8.16(d,J=12.3Hz,1H),7.77(d,J=7 .4Hz,1H),7.48(d,J=0.6Hz,1H),7.38(s,4H),7.17(d,J=1.5Hz,1H),7.00(dd,J=7.5,1.5Hz,1H),6.42(s,1H),5.1 3(s,2H),4.20–4.11(m,1H),3.72(dt,J=12.4,7.0Hz,3H),3.57(d,J=0.9Hz,2H),3.45(dt,J=12.4,7.0Hz,2H),3.2 2–3.11(m,1H),2.63–2.52(m,8H),2.52–2.43(m,2H),1.94–1.75(m,11H),1.62–1.49(m,2H),1.22(d,J=6.8Hz,6H).

[0880] Example 114

[0881] Preparation of compound V-12:

[0882] The synthesis steps were similar to those of V-10. V-12 was obtained by preparative liquid phase chromatography, and 22 mg of white powdery solid was obtained. UPLC-MS calculated for C 47 H 58 C1N 10 O5[M+H] + :877.42,found:877.49. 1H NMR(500MHz, DMSO-d6)δ8.85(s,1H),7.67(d,J=8.9Hz,1H),7.53(t,J=1.7Hz,1H),7.47–7.41(m,2H),7.34–7.23(m,4H),7.08 –7.03(m,2H),6.92(dd,J=8.9,2.3Hz,1H),6.79(dd,J=4.9,1.6Hz,1H),6.35(s,1H),4.00(t,J=3.8Hz,2H),3.97–3.90(m,1H), 3.71(dtt,J=9.3,6.2,3.3Hz,1H),3.59(t,J=1.0Hz,2H),3.26–3.14(m,1H),2.86(ddd,J=12.3,8.1,6.3Hz,2H),2.73(t,J=3. 8Hz,2H),2.66(ddd,J=12.4,8.0,6.4Hz,2H),2.61–2.54(m,3H),2.54–2.44(m,7H),2.00–1.60(m,13H),1.21(d,J=6.8Hz,6H).

[0883] Example 115

[0884] Preparation of compound V-13:

[0885] The synthesis steps were similar to those of V-10. V-13 was obtained by preparative liquid phase chromatography, and 22 mg of white powdery solid was obtained. UPLC-MS calculated for C 47 H 58 C1N 10 O5[M+H] + :877.42,found:877.51. 1H NMR (400MHz, DMSO-d6) δ11.36(s,1H),10.72(s,1H),9.47(s,1H),8.03(d,J=12.3Hz,1H),7.77(dd,J=7.5,1.8Hz,2H),7.48(d,J=0.6Hz,1H),7.38( s,4H),7.17(d,J=1.5Hz,1H),6.99(dd,J=7.5,1.5Hz,1H),6.76(d,J=7.5 Hz,1H),6.42(s,1H),4.31(t,J=7.1Hz,2H),4.20–4.09(m,1H),3.79–3.65 (m,1H),3.57(d,J=0.9Hz,2H),3.24–3.09(m,1H),2.98–2.82(m,6H),2.65–2.43(m,1 0H), 1.97–1.72 (m, 7H), 1.72–1.62 (m, 4H), 1.61–1.47 (m, 2H), 1.22 (d, J = 6.8Hz, 6H).

[0886] Example 116

[0887] Preparation of compound V-14:

[0888] The synthesis steps were similar to those of V-10. V-14 was obtained by preparative liquid phase chromatography, and 35 mg of white powdery solid was obtained. UPLC-MS calculated for C 43 H 51 ClN9O5[M+H] + :808.36,found:808.38. 1H NMR (400MHz, DMSO-d6) δ11.90(s,1H),9.46(d,J=17.0Hz,1H),8.27(s,1H),7.93(s,1H),7.90(d,J=8.8Hz,1H), 7.33(d,J=9.4Hz,1H),7.28(d,J=8.5Hz,2H),7.21(d,J=2.5Hz,1H),7.12(d,J=8.4Hz,2H),7.00(dd,J=8.8,2.5H z,1H),6.75(s,1H),6.26(s,1H),4.29(s,1H),4.22(t,J=6.5Hz,2H),4.04(d,J=9.3Hz,1H),3.41(s,3H),2.96( p,J=6.9Hz,1H),2.70(t,J=6.5Hz,2H),2.37(d,J=25.2Hz,7H),1.20(s,6H),1.09(s,6H),0.92(d,J=6.9Hz,6H).

[0889] Example 117

[0890] Preparation of compound V-15:

[0891] The synthesis steps were similar to those of V-10. V-15 was obtained by preparative liquid phase chromatography, and the product was a white powdery solid (21 mg). UPLC-MS calculated for C 49 H 62 C1N 10 O5[M+H] + :905.45,found:905.54. 1H NMR (400MHz, DMSO-d6) δ11.93(s,1H),9.53(d,J=76.7Hz,1H),8.22(d,J=29.4Hz,2H),7.99–7.83 (m,2H),7.28(td,J=28.7,23.4,11.6Hz,5H),7.12(d,J=7.8Hz,2H),7.00(dd,J=8.9,2.6Hz,1H), 6.76(s,1H),6.26(s,1H),4.29(s,1H),4.22(d,J=7.2Hz,2H),4.04(d,J=8.9Hz,1H),2.95(t,J=6 .9Hz,2H),2.85–2.79(m,2H),2.67(t,J=6.6Hz,3H),2.36(s,6H),2.07(s,2H),1.95(d,J=10.1Hz, 2H), 1.60 (s, 2H), 1.43 (s, 2H), 1.20 (s, 6H), 1.09 (s, 6H), 0.93 (d, J = 6.9Hz, 6H).

[0892] Example 118

[0893] Preparation of compound VI-1:

[0894] first step:

[0895] (4-Bromophenylethynyl)trimethylsilane (400 mg, 1.58 mmol) and 4-(dimethoxymethyl)-piperidine (480 mg, 3.01 mmol) were dissolved in tetrahydrofuran (20 mL). Pd2(dba)3 (55 mg, 0.06 mmol) and Davephos (24 mg, 0.06 mol) were added. The atmosphere was replaced with argon three times. LiHMDS solution (3.2 ml, 3.2 mmol, 1 M in THF) was added dropwise under an argon atmosphere. The mixture was heated to reflux for 3 h. After cooling to room temperature, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified by column chromatography (PE:EA = 3:1) to obtain 450 mg of a brown solid with a yield of 86.04%. UPLC-MS calculated for C 19 H 29 NO2Si[M+H] + :331.52,found:332.45.

[0896] Step 2:

[0897] Dissolve VI-1-2 (450 mg, 1.34 mmol) in methanol (10 mL), add potassium carbonate (270 mg, 2.01 mmol), and react at room temperature for 4 h. Remove the solvent by rotary evaporation and purify by column chromatography (PE:EA=10:1) to obtain 270 mg of a yellow solid, with a yield of 76.70%. UPLC-MS calculated for C 16 H 22 NO2[M+H] + :260.34,found:360.41.

[0898] Step 3:

[0899] AR-5 (100 mg, 0.28 mmol) was dissolved in dimethyl sulfoxide (10 mL), and TMSN3 (40 mg, 0.34 mmol) and TBAF (1 drop, 1 M in THF) were added. The temperature was raised to 80°C and the reaction mixture was allowed to react for 48 h. After cooling to room temperature, water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then purified by column chromatography (PE:EA = 3:2) to obtain 58 mg of a colorless oil with a yield of 70.73%. UPLC-MS calculated for C 12 H 11 F3N5O2[M+H] + :314.08,found:314.28.

[0900] Step 4:

[0901] VI-1-3 (130 mg, 0.41 mmol) and VI-1-4 (130 mg, 0.50 mmol) were dissolved in tert-butanol (20 mL). A solution of CuSO4 (6 mg, 0.03 mmol) and NaAsc (6 mg, 0.03 mmol) in water (5 mL) was added and the mixture was allowed to react at room temperature for 8 h. The solvent was removed by rotary evaporation, and water (50 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then purified by column chromatography (PE:EA = 1:10) to obtain 160 mg of a yellow solid in a yield of 67.51%. UPLC-MS calculated for C 28 H 31 F3N6O4[M+H] + :572.24,found:574.58.

[0902] Step 5:

[0903] Dissolve VI-1-5 (160 mg, 0.28 mmol) in tetrahydrofuran (20 mL), add 6 M hydrochloric acid solution (10 mL), and heat to 40°C for 18 h. After cooling to room temperature, add water (100 mL) to the reaction solution, extract with ethyl acetate (30 mL x 3), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and filter. The filtrate is then dried to give 130 mg of a crude yellow solid, with a yield of 88.43%. UPLC-MS calculated for C 26 H 26 F3N6O3[M+H] + :527.19,found:527.33.

[0904] Step 6:

[0905] VI-1-6 (100 mg, 0.19 mmol) and HSP90-8 (100 mg, 0.24 mmol) were dissolved in dichloroethane (4 mL) and methanol (1 mL). Triethylamine was added dropwise to adjust the pH to approximately 8. The mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (10 mg, 0.26 mmol) was added under ice-cooling and the mixture was stirred at room temperature overnight. A preparative liquid chromatography system was used to obtain 54 mg of a white powdery solid in a 31.03% yield. UPLC-MS calculated for C 48 H 53 F3N 11 O5[M+H] + :920.41,found:920.42. 1 H NMR (400MHz, DMSO-d6) δ11.92(s,1H),10.47(s,1H),9.50(d,J=92.8Hz,2H),8.45(d,J=2.1Hz,1H),8.23(dd,J=8.6,2.1Hz, 1H),8.19(s,1H),8.17(s,1H),8.09(d,J=8.5Hz,1H),7.60(d,J=8.8Hz,2H),7.31–7.27(m,2H),7.15–7.11(m,2H),6.98–6. 92(m,2H),6.76(s,1H),6.27(s,1H),4.72(d,J=14.0Hz,1H),4.55(d,J=14.0Hz,1H),3.71(d,J=12.1Hz,2H),2.96(p,J=6.9 Hz, 2H), 2.70–2.61 (m, 2H), 2.37 (s, 6H), 2.15 (d, J = 7.1Hz, 2H), 1.76 (d, J = 12.4Hz, 2H), 1.42 (s, 3H), 0.94 (d, J = 6.9Hz, 6H).

[0906] Example 119

[0907] Preparation of compound VI-2:

[0908] first step:

[0909] AR-5 (300 mg, 0.86 mmol) and methyl pyrazole-4-carboxylate (162 mg, 1.29 mmol) were dissolved in tetrahydrofuran (20 mL). NaH (60% in mineral oil, 205 mg, 5.16 mmol) was added under ice-cooling. The reaction was allowed to react at room temperature for 18 h. Water (100 mL) was added to the reaction solution, and the pH was adjusted to neutral with 1 M hydrochloric acid solution. The mixture was extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then purified by column chromatography (PE:EA = 1:10) to obtain 270 mg of a white oil with a yield of 72.58%. UPLC-MS calculated for C 17 H 16 F3N4O4[M+H] + :397.10,found:397.22.

[0910] Step 2:

[0911] VI-2-1 (270 mg, 0.68 mmol) was dissolved in tetrahydrofuran (10 mL) and water (2 mL). Lithium hydroxide (25 mg, 1.04 mmol) was added and allowed to react at room temperature for 18 h. Water (30 mL) was added to the reaction solution, and the pH was adjusted to approximately 4 with 1 M hydrochloric acid. The solution was extracted with ethyl acetate (10 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then dried to give 250 mg of a white oil (96.15% yield). UPLC-MS calculated for C 16 H 14 F3N4O4[M+H] + :383.09,found:383.21.

[0912] Step 3:

[0913] VI-2-2 (100 mg, 0.26 mmol) was dissolved in dimethylformamide (20 mL), and EDCI (60 mg, 0.31 mmol), HOBt (43 mg, 0.31 mmol), and DIEA (68 mg, 0.52 mmol) were added. The mixture was allowed to react at room temperature for 30 min, followed by the addition of 4-(dimethoxymethyl)-piperidine (46 mg, 0.29 mmol) and the reaction was continued at room temperature for 18 h. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then purified by column chromatography (DCM:MeOH = 15:1) to obtain 110 mg of a colorless oil with a yield of 80.88%. UPLC-MS calculated for C 24 H 29 F3N5O5[M+H] + :524.20,found:524.19.

[0914] The subsequent synthesis was performed by referring to the synthesis of VI-1 to obtain 46 mg of white powdery solid with a yield of 42.54%. UPLC-MS calculated for C 44 H 50 F3N 10 O6[M+H] + :871.38,found:871.44. 1 H NMR(400MHz,DMSO-d6)δ11.94(s,1H),10.41(s,1H),9.48(s,1H),8.47(s,1H),8.27–8.15(m,2H),8.09(d,J =8.6Hz,1H),7.88(s,1H),7.55(s,1H),7.28(d,J=8.0Hz,2H),7.12(d,J=7.9Hz,2H),6.76(s,1H),6.27(s,1 H),4.47(d,J=13.9Hz,1H),4.30(d,J=14.0Hz,1H),3.95(s,2H),3.43(s,4H),2.96(d,J=13.8Hz,2H),2.43– 2.26(m,6H),2.09(d,J=7.2Hz,3H),1.68(d,J=41.2Hz,3H),1.37(s,3H),1.23(s,1H),0.93(d,J=7.0Hz,6H).

[0915] Example 120

[0916] Preparation of compound VI-3:

[0917] The synthesis steps were similar to those in VI-2, and 25 mg of white powdery solid was obtained. UPLC-MS calculated for C 43 H 49 F3N 11 O6[M+H] + :872.37,found:872.61. 1 H NMR(500MHz,DMSO-d6)δ11.92(s,1H),10.66(s,1H),9.54(d,J=111.2Hz,2H),9.31(s,1H),8.81(s,1H),8.21(s,1H),7.90(s,1H),7.55(s,1H),7.28 (s,2H),7.13(d,J=7.9Hz,2H),6.75(s,1H),6.27(s,1H),4.46(s,1H),4.31(d,J=14.0Hz,1H),3.95(s,2H),3.43(s,3H),3.34(s,2 H),3.01–2.91(m,2H),2.35(s,6H),2.09(d,J=6.9Hz,2H),1.70(d,J=46.6Hz,3H),1.39(s,3H),1.23(s,1H),0.93(d,J=6.8Hz,6H).

[0918] Example 121

[0919] Preparation of compound VI-4:

[0920] Step 1 & Step 2:

[0921] Dissolve indoline-6-carboxylic acid (1 g, 5.64 mmol) in methanol (30 mL), add potassium hydroxide (640 mg, 11.28 mmol) in water (10 mL), and heat to 50°C for 18 h. After cooling to room temperature, add 1 M hydrochloric acid solution to adjust the pH to approximately 2. The solvent is removed by rotary evaporation, and the residue is dissolved in dimethylformamide (50 mL). The insoluble material is removed by filtration. To the filtrate, diisopropylethylamine (2.6 g, 20.15 mmol), HATU (2.5 g, 6.57 mmol), and 4-(dimethoxymethyl)-piperidine (1.5 g, 9.42 mmol) are added and the reaction is continued at room temperature for 18 h. Water (500 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then spin-dried and purified by column chromatography (DCM:MeOH = 15:1) to obtain 1.38 g of a brown oil, with a two-step yield of 80.70%. UPLC-MS calculated for C 17H 25 N2O3[M+H] + :305.18,found:305.20.

[0922] Step 3:

[0923] VI-4-3 (173 mg, 0.57 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to -78°C, and LDA solution (2M in THF, 0.9 ml, 1.8 mmol) was added dropwise. After reacting for 30 min, a tetrahydrofuran solution (5 mL) of AR-7 (200 mg, 0.57 mmol) was added dropwise at -78°C. The temperature was slowly raised to room temperature and the reaction was continued for 18 h. Saturated ammonium chloride solution (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified by column chromatography (PE:EA = 1:10) to obtain 180 mg of a brown oil with a yield of 55.04%. UPLC-MS calculated for C 29 H 34 F3N4O5[M+H] + :575.24,found:575.33.

[0924] The subsequent synthesis method was similar to that of VI-2, and 64 mg of VI-4 was obtained as a white powdery solid by preparative liquid phase. UPLC-MS calculated for C 55 H 66 F3N 10 O6[M+H] + :1019.50,found:1019.52. 1 H NMR (400MHz, DMSO-d6) δ11.93(s,1H),10.52(s,1H),9.62(s,1H),9.40(s,1H),8.49(d,J=2.0Hz,1H),8.28(d d,J=8.5,2.1Hz,1H),8.07(d,J=8.6Hz,1H),7.34(s,2H),7.16(d,J=7.9Hz,2H),6.98(d,J=7.2Hz,1H),6.79(s ,1H),6.50–6.45(m,2H),6.29(s,1H),6.07(s,1H),3.68–3.54(m,3H),3.49(d,J=14.3Hz,2H),3.43–3.37(m, 3H), 3.15 (d, J = 14.3Hz, 2H), 2.96 (h, J = 6.8Hz, 2H), 2.88 (t, J = 8.6Hz, 3H), 1.42 (s, 3H), 0.95 (d, J = 6.9Hz, 6H).

[0925] Example 122

[0926] Preparation of compound VI-5:

[0927] The synthesis method was based on HSP90-27. 21 mg of VI-5 was obtained as a white powdery solid by preparative liquid phase. UPLC-MS calculated for C 35 H 38 F3N7O5[M+H] + :694.29,found:694.73. 1 H NMR (400MHz, DMSO-d6) δ11.39(s,1H),10.72(s,1H),9.47(s,1H),9.28(s,1H),8.38(d,J=1.5Hz,1H),8.17(dd,J =7.5,1.5Hz,1H),8.04(d,J=7.5Hz,1H),7.48(d,J=0.7Hz,1H),7.43–7.36(m,2H),6.96–6.88(m,2H),6.42(s,1H) ,5.05(s,1H),3.39(pq,J=6.9,1.5Hz,1H),3.16(dtd,J=13.6,6.8,0.7Hz,1H),3.06(d,J=12.5Hz,1H),3.02–2.9 2(m,3H),2.92–2.86(m,3H),2.55(dt,J=12.5,7.1Hz,2H),1.97–1.76(m,4H),1.48(s,3H),1.22(d,J=6.8Hz,6H).

[0928] Example 123

[0929] Preparation of compound VI-6:

[0930] The synthesis method was similar to that of VI-5. 22 mg of VI-6 was obtained as a white powdery solid by preparative liquid phase. UPLC-MS calculated for C 36 H 41 F3N7O5[M+H] + :708.30,found:708.76. 1H NMR (400MHz, DMSO-d6) δ11.36(s,1H),10.72(s,1H),9.47(s,1H),9.28(s,1H),8.38(d,J=1.5Hz, 1H),8.17(dd,J=7.5,1.5Hz,1H),8.03(d,J=7.4Hz,1H),7.48(d,J=0.6Hz,1H),7.40–7.30(m,4H) ,6.42(s,1H),5.05(s,1H),3.62(t,J=0.9Hz,2H),3.22–3.10(m,1H),3.06(d,J=12.5Hz,1H),3.0 2–2.91(m,3H),2.71(pq,J=6.9,1.5Hz,1H),2.51(dt,J=12.5,7.1Hz,2H),2.30(d,J=1.5Hz,3H), 1.85–1.65(m,4H),1.48(s,3H),1.22(d,J=6.8Hz,6H).

[0931] Example 124

[0932] Preparation of compound VI-7:

[0933] The synthesis method was similar to that of VI-5. 19 mg of VI-7 was obtained as a white powdery solid by preparative liquid phase. UPLC-MS calculated for C 34 H 37 F3N7O5[M+H] + :680.27,found:680.70. 1 H NMR (400MHz, DMSO-d6) δ11.39(s,1H),10.72(s,1H),9.47(s,1H),9.06(s,1H),8.04(d,J=1.5Hz ,1H),7.72(dd,J=7.5,1.5Hz,1H),7.65(d,J=7.4Hz,1H),7.48(d,J=0.7Hz,1H),7.41–7.32(m,4H ),6.42(s,1H),5.05(s,1H),3.64–3.51(m,2H),3.16(dtd,J=13.7,6.8,0.7Hz,1H),3.04(d,J=12 .5Hz,1H),2.98(d,J=12.5Hz,1H),2.61–2.50(m,8H),1.47(s,3H),1.22(dd,J=20.0,6.7Hz,6H).

[0934] Example 125

[0935] Preparation of compound VI-8:

[0936] The synthesis method was similar to that of VI-4. 29 mg of VI-8 was obtained as a white powdery solid by preparative liquid phase. UPLC-MS calculated for C 40 H 48 F3N8O5[M+H] + :777.36,found:777.86. 1 H NMR (400MHz, DMSO-d6) δ11.36(s,1H),10.72(s,1H),9.47(s,1H),9.07(s,1H),8.03(d,J=1.5Hz,1H),7.72(dd, J=7.5,1.4Hz,1H),7.65(d,J=7.5Hz,1H),7.48(d,J=0.6Hz,1H),7.40–7.29(m,4H),6.42(s,1H),5.05(s,1H),3. 57(t,J=0.9Hz,2H),3.22–3.11(m,1H),3.05(d,J=12.3Hz,1H),3.01–2.95(m,2H),2.95–2.86(m,3H),2.69(dd,J =12.4,6.9Hz,1H),2.63–2.43(m,9H),1.89–1.76(m,1H),1.76–1.64(m,4H),1.48(s,3H),1.22(d,J=6.8Hz,6H).

[0937] Example 126

[0938] Preparation of compound VI-9:

[0939] The synthesis method was similar to that of VI-4. 41 mg of VI-9 was obtained as a white powdery solid by preparative liquid phase. UPLC-MS calculated for C 39 H 48 ClN8O5[M+H] + :743.34,found:743.31. 1H NMR (400MHz, DMSO-d6) δ11.36(s,1H),10.72(s,1H),9.47(s,1H),9.01(s,1H),7.76(d,J=1.5Hz,1H) ,7.71(dd,J=7.5,1.5Hz,1H),7.54(d,J=7.4Hz,1H),7.48(d,J=0.6Hz,1H),7.40–7.29(m,4H),6.42(s ,1H),5.05(s,1H),3.57(t,J=0.9Hz,2H),3.22–3.11(m,1H),3.09–2.86(m,6H),2.69(dd,J=12.4,6.9 Hz,1H),2.63–2.43(m,9H),1.89–1.76(m,1H),1.76–1.64(m,4H),1.48(s,3H),1.22(d,J=6.8Hz,6H).

[0940] Example 127

[0941] Preparation of compound VI-10:

[0942] The synthesis method was similar to that of VI-4. 41 mg of VI-10 was obtained as a white powdery solid by preparative liquid phase. UPLC-MS calculated for C 44 H 51 F3N7O5[M+H] + :814.38,found:814.92. 1H NMR (400MHz, DMSO-d6) δ11.73(s,1H),11.54(s,1H),9.41(s,1H),9.30(s,1H),8.38(d,J=1.6Hz,1H),8.17(dd,J=7.5,1.5Hz,1H),8.04(d ,J=7.5Hz,1H),7.48(dd,J=7.1,1.9Hz,1H),7.39(d,J=1.0Hz,1H),7.28–7.16(m,3H),6.80(d,J=7.4Hz,1H),6.48(s,1H),5.55(s,1H),5. 05(s,1H),3.96(dd,J=12.4,6.9Hz,1H),3.79(dd,J=12.4,6.9Hz,1H),3.16(heptd,J=6.8,1.0Hz,1H),3.08–2.82(m,10H),2.68(dd,J=12 .4,6.9Hz,1H),2.51(dd,J=12.4,6.9Hz,1H),1.94–1.79(m,2H),1.72(dq,J=13.9,7.0Hz,8H),1.48(s,3H),1.22(dd,J=20.0,6.8Hz,6H).

[0943] Example 128

[0944] Preparation of compound VI-11:

[0945] The synthesis method was similar to that of VI-4. 41 mg of VI-11 was obtained as a white powdery solid by preparative liquid phase. UPLC-MS calculated for C 38 H 42 F3N6O6[M+H] + :735.30,found:735.78. 1H NMR (400MHz, DMSO-d6) δ10.78(s,1H),9.28(s,1H),9.06(s,1H),8.38(d,J=1.6Hz,1H),8.17(dd,J= 7.5,1.5Hz,1H),8.08(dd,J=15.4,7.7Hz,1H),8.03(s,1H),7.64–7.57(m,3H),7.53(dt,J=7.7,1.0H z,2H),6.52(s,1H),5.04(s,1H),3.66–3.53(m,2H),3.50–3.27(m,2H),3.20(dtd,J=13.5,6.7,0.6H z,1H),3.08–2.94(m,2H),2.62–2.50(m,8H),1.50(s,3H),1.24(d,J=6.8Hz,3H),1.21–1.13(m,6H).

[0946] Example 129

[0947] Preparation of compound VI-12:

[0948] The synthesis method was similar to that of VI-4. 18 mg of VI-12 was obtained as a white powdery solid by preparative liquid phase. UPLC-MS calculated for C 44 H 53 F3N7O6[M+H] + :832.39,found:832.94. 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),9.28(s,1H),9.06(s,1H),8.38(d,J=1.6Hz,1H),8.17(dd,J=7.5,1.4Hz,1H),8.11– 8.01(m,2H),7.64–7.56(m,3H),7.53(dt,J=7.6,1.0Hz,2H),6.52(s,1H),5.04(s,1H),3.52(t,J=1.0Hz,2H),3.50–3.25( m,2H),3.25–3.12(m,1H),3.08–2.94(m,2H),2.81(dt,J=12.4,7.0Hz,2H),2.69(dd,J=12.4,6.8Hz,1H),2.63–2.55(m,4H ),2.55–2.49(m,4H),2.35(dt,J=12.4,7.0Hz,2H),1.88–1.77(m,1H),1.77–1.65(m,4H),1.49(s,3H),1.25–1.17(m,9H).

[0949] Example 130

[0950] Preparation of compound VI-13:

[0951] The synthesis method was similar to that of VI-4. 8 mg of VI-13 was obtained as a white powdery solid by preparative liquid phase. UPLC-MS calculated for C 50 H 64 F3N8O6[M+H] + :929.48,found:929.10. 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),9.28(s,1H),9.06(s,1H),8.38(d,J=1.6Hz,1H),8.17(dd,J=7.4,1.5Hz,1H),8.11 –8.02(m,2H),7.62(d,J=0.8Hz,1H),7.58–7.51(m,4H),6.52(s,1H),5.04(s,1H),3.52(t,J=0.9Hz,2H),3.50–3.25(m,2 H),3.25–3.14(m,1H),3.08–2.94(m,2H),2.87–2.74(m,4H),2.67(dd,J=12.4,6.9Hz,1H),2.63–2.47(m,11H),2.33(dt, J=12.4,7.0Hz,2H),2.11(dt,J=12.4,7.0Hz,2H),1.93–1.75(m,2H),1.75–1.63(m,8H),1.49(s,3H),1.25–1.17(m,9H).

[0952] Example 131

[0953] Preparation of compound VI-14:

[0954] first step:

[0955] AR-10 (900 mg, 2.0 mmol), Pd(PPh3)2Cl2 (216 mg, 0.2 mmol), cuprous iodide (36 mg, 0.2 mmol), triethylamine (610 mg, 6.0 mmol), and tert-butyl 3-ethynyl-1-azetidinecarboxylate (540 mg, 3.0 mmol) were dissolved in dichloromethane (30 mL), purged with nitrogen three times, and reacted at room temperature for 8 h. The reaction solution was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and then separated by column chromatography (PE:EA = 2:1) to obtain 570 mg of a brown solid, with a yield of 57%. UPLC-MS calculated for C 25 H 27 F3N5O3[M+H] + :502.20,found:502.41.

[0956] Step 2:

[0957] Dissolve VI-14-1 (570 mg, 1.1 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (10 mL), and react at room temperature for 2 h. The solvent was evaporated, and dichloromethane (20 mL) and sodium hydroxide solution (4 M, 20 mL) were added. Stir and react at room temperature for 30 min. The organic phase was separated and dried over anhydrous sodium sulfate. The resulting brown-black solid was 420 mg, with a yield of 92%. UPLC-MS calculated for C 20 H 19 F3N5O[M+H] + :402.15,found:402.33.

[0958] Step 3:

[0959] VI-14-2 (100 mg, 0.25 mmol) and HSP90-2 (85 mg, 0.25 mmol) were dissolved in dichloroethane (4 mL) and methanol (1 mL). One drop of acetic acid was added and the mixture was allowed to react at room temperature for 2 h. After cooling to 0°C, sodium cyanoborohydride (19 mg, 0.3 mmol) was added and the mixture was allowed to react at 0°C for 2 h. The solvent was evaporated and the mixture was purified by reverse preparative liquid chromatography to obtain 54 mg of a white solid (30% yield). UPLC-MS calculated for C 38 H 36 F3N8O4[M+H] + :725.27,found:725.47. 1H NMR (400MHz, DMSO-d6) δ10.08(s,1H),8.26(d,J=4.5Hz,2H),8.23(s,1H),8.16–8.11(m,1H),8.08(d,J=8.6Hz,1H),7.62(s,1H),7.26(d,J =8.0Hz,2H),7.11(d,J=7.9Hz,2H),6.78(s,1H),6.26(s,1H),3.54(d,J=6.6Hz,5H),3.00–2.93(m,1H),1.79(s,6H),0.96(d,J=6.9Hz,6H).

[0960] Example 132

[0961] Preparation of compound VI-15:

[0962] first step:

[0963] Dissolve VI-14-2 (450 mg, 1.1 mmol) and p-fluoronitrobenzene (160 mg, 1.1 mmol) in dimethylformamide (20 mL). Add anhydrous potassium carbonate (320 mg, 2.2 mmol) and heat to 100°C for 3 h. After cooling to room temperature, add water (200 mL) and extract with ethyl acetate (50 mL*3). The organic phase is washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Column chromatography (PE:EA = 2:1) afforded 350 mg of a light yellow solid, with a yield of 60%. UPLC-MS calculated for C 26 H 22 F3N6O3[M+H] + :523.16,found:523.31.

[0964] Step 2:

[0965] Dissolve VI-15-1 (350 mg, 0.67 mmol) in methanol (20 mL), add hydrosulfite (630 mg, 3.6 mmol) and a solution of sodium carbonate (385 mg, 3.6 mmol) in water (20 mL), and react at room temperature for 2 h. Remove the methanol by rotary evaporation, add saturated ammonium chloride solution (20 mL), and extract with ethyl acetate (20 mL*3). The organic phase is washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 330 mg of a light yellow solid. UPLC-MS calculated for C 26 H 24 F3N6O[M+H] + :493.19,found:493.33.

[0966] Step 3:

[0967] HSP90-1-5 (153 mg, 0.67 mmol), sodium carbonate (170 mg, 2.0 mmol), and chloroacetic acid (63 mg, 0.67 mmol) were dissolved in anhydrous dimethylformamide (20 mL) and reacted at room temperature for 2 h. A solution of crude VI-15-2 (330 mg) in dimethylformamide (20 mL) was added, and the temperature was raised to 80°C for 1 h. After cooling to room temperature, water (400 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Column chromatography (PE:EA = 1:1) afforded 230 mg of a brown solid, with a two-step yield of 50%. UPLC-MS calculated for C 36 H 34 F3N6O3S[M+H] + :687.23,found:687.60.

[0968] Step 4:

[0969] VI-15-3 (230 mg, 0.33 mmol) and CDI (65 mg, 0.4 mmol) were dissolved in tetrahydrofuran (20 mL) and reacted at room temperature for 2 h. The solvent was dried to obtain 300 mg of crude product. UPLC-MS calculated for C 37 H 32 F3N6O4S[M+H] + :713.21,found:713.26.

[0970] Step 5:

[0971] Dissolve 300 mg of crude VI-15-4 in ethanol (20 mL) and add hydrazine hydrate (80%, 33 mg, 0.84 mmol). React at room temperature for 2 h. After concentration, the product was purified by reverse phase preparative purification to obtain 51 mg of a white solid, with a two-step yield of 21%. UPLC-MS calculated for C 37 H 34 F3N8O4[M+H] + :711.26,found:711.36. 1H NMR(400MHz,DMSO-d6)δ11.80(s,1H),10.06(s,1H),9.63(s,1H),9.46(s,1H),8.22(d, J=4.3Hz,2H),8.10(d,J=8.9Hz,1H),8.04(d,J=8.6Hz,1H),7.61(s,1H),6.70(s,1H),6 .41(d,J=8.3Hz,2H),6.24(s,1H),4.13(t,J=7.0Hz,2H),3.69(q,J=6.2,5.3Hz,2H),2. 93(p,J=6.9Hz,1H),2.03(s,1H),1.75(s,6H),1.22–1.17(m,2H),0.91(d,J=6.9Hz,6H).

[0972] Example 133

[0973] Preparation of compound VI-16:

[0974] The synthesis steps were similar to those of VI-14, and 22 mg of white powdery solid was obtained. UPLC-MS calculated for C 40 H 40 F3N8O4[M+H] + :753.30,found:753.33. 1 H NMR (400MHz, DMSO-d6) δ11.93(s,1H),10.05(s,1H),8.30(s,1H),8.25(d,J=2.0Hz,1H),8.19(s, 1H),8.14(dd,J=8.6,2.1Hz,1H),8.08(d,J=8.6Hz,1H),7.60(s,1H),7.33–7.26(m,2H),7.16–7. 09(m,2H),6.75(s,1H),6.28(s,1H),2.96(p,J=6.9Hz,1H),2.69–2.61(m,2H),2.58(s,1H),2.10 (d, J = 21.0Hz, 2H), 1.78 (s, 6H), 1.56 (dd, J = 9.5, 3.8Hz, 2H), 1.24 (s, 1H), 0.93 (d, J = 6.9Hz, 6H).

[0975] Example 134

[0976] Preparation of compound VI-17:

[0977] The synthesis steps were similar to those of VI-15, and 22 mg of white powdery solid was obtained. UPLC-MS calculated for C 39 H 38 F3N8O4[M+H] + :739.29,found:739.35. 1 H NMR(400MHz,DMSO-d6)δ11.80(s,1H),9.98(s,1H),9.58(s,1H),9.44(s,1H),8.20(s,1H),8.16( s,1H),8.11–8.01(m,2H),7.57(s,1H),6.98(d,J=8.4Hz,2H),6.89(d,J=8.6Hz,2H),6.72(s,1H) ,6.24(s,1H),3.46(dt,J=10.6,4.4Hz,2H),3.02–2.88(m,3H),2.77(tt,J=8.3,3.8Hz,1H),2.50 (s,2H),1.91–1.82(m,2H),1.74(s,6H),1.61(qd,J=9.5,8.9,4.7Hz,2H),0.91(d,J=6.9Hz,6H).

[0978] Example 135

[0979] Preparation of compound VI-18:

[0980] first step:

[0981] 1-Triphenylmethyl-4-bromo-pyrazole (2.5 g, 6.4 mmol), 4-(dimethoxymethyl)-piperidine (2.0 g, 12.5 mmol), Pd2(dba)3 (300 mg, 0.32 mmol), tBuDavephos (220 mg, 0.64 mmol), and sodium tert-butoxide (1.9 g, 19.2 mmol) were placed in a round-bottom flask. Toluene (50 mL) was added, and the atmosphere was replaced with argon three times. The temperature was raised to 90°C under an argon atmosphere and the reaction was allowed to proceed for 18 h. After cooling to room temperature, the toluene was removed by rotary evaporation, and water (100 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:EA = 5:1) to obtain 1.4 g of a brown solid, with a yield of 46%. UPLC-MS calculated for C 30 H 34 N3O2[M+H] + : 468.26,found:468.52.

[0982] Step 2:

[0983] Dissolve VI-19-2 (1.4 g, 2.9 mmol) in dioxane (50 mL), add a 4 M solution of hydrochloric acid in dioxane (10 mL), and react at room temperature for 10 min. Filter, dissolve the residue in dichloromethane (30 mL) and methanol (3 mL), and wash with saturated sodium bicarbonate solution (30 mL). The organic phase is washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 15:1) to obtain 320 mg of a brown solid, with a yield of 47%. UPLC-MS calculated for C 11 H 20 N3O2[M+H] + :226.15,found:226.32.

[0984] The subsequent synthesis steps were referred to VI-1, and 27 mg of white powdery solid was obtained by preparative liquid phase. UPLC-MS calculated for C 43 H 50 F3N 10 O4[M+H] + :827.39,found:827.66. 1 H NMR (400MHz, DMSO-d6) δ11.93(s,1H),10.01(s,1H),8.29(d,J=2.1Hz,1H),8.15(dd,J=8.6,2. 1Hz,1H),8.07(d,J=8.7Hz,1H),7.44(s,1H),7.30–7.24(m,3H),7.12(d,J=8.2Hz,2H),6.76(s ,1H),6.26(s,1H),3.45-3.56(m,4H),3.37–3.28(m,4H),2.95(h,J=6.9Hz,1H),2.45–2.26(m, 9H), 2.13 (d, J = 7.2Hz, 2H), 1.72 (s, 6H), 1.55 (s, 1H), 1.28–1.10 (m, 3H), 0.93 (d, J = 6.9Hz, 6H).

[0985] Example 136

[0986] Preparation of compound VI-19:

[0987] The synthesis steps were similar to those of VI-18. 22 mg of white powdery solid was obtained by preparative liquid phase. UPLC-MS calculated for C 37 H 39 F3N9O4[M+H]+ :730.30,found:730.77. 1 H NMR (400MHz, DMSO-d6) δ11.36(s,1H),10.72(s,1H),9.59(s,1H),9.47(s,1H),8.33(d,J= 1.5Hz,1H),8.12(dd,J=7.5,1.5Hz,1H),8.04(d,J=7.5Hz,1H),7.79(t,J=1.1Hz,2H),7.48 (d,J=0.7Hz,1H),7.41–7.29(m,4H),6.42(s,1H),3.60(t,J=1.0Hz,2H),3.31(dt,J=12.5 ,7.1Hz,2H),3.25–3.11(m,3H),2.61(t,J=7.1Hz,4H),1.95(s,6H),1.22(d,J=6.8Hz,6H).

[0988] Example 137

[0989] Preparation of compound VI-20:

[0990] The synthesis steps were similar to those of VI-18. 31 mg of white powdery solid was obtained by preparative liquid phase. UPLC-MS calculated for C 40 H 48 F3N8O4[M+H] + :761.37,found:761.86. 1 H NMR (400MHz, DMSO-d6) δ11.36(s,1H),10.72(s,1H),9.47(s,1H),8.96(s,1H),8.32(d,J=1.5 Hz,1H),8.12(dd,J=7.5,1.5Hz,1H),8.04(d,J=7.5Hz,1H),7.48(d,J=0.6Hz,1H),7.40–7.29 (m,4H),6.42(s,1H),3.57(t,J=0.9Hz,2H),3.22–3.11(m,1H),2.93–2.74(m,4H),2.65–2.43 (m,10H),1.87–1.76(m,1H),1.72(td,J=7.1,6.0Hz,4H),1.40(s,6H),1.22(d,J=6.8Hz,6H).

[0991] Example 138

[0992] Preparation of compound VI-21:

[0993] The synthesis steps were similar to those of VI-18. 18 mg of white powdery solid was obtained by preparative liquid phase. UPLC-MS calculated for C 36 H 37 F3N7O4[M+H] + :664.28,found:664.30. 1 H NMR(400MHz,DMSO-d6)δ11.39(s,1H),10.72(s,1H),9.47(s,1H),8.75(s,1H),8.04( d,J=1.4Hz,1H),7.70(dd,J=7.5,1.4Hz,1H),7.65(d,J=7.5Hz,1H),7.48(d,J=0.7Hz ,1H),7.41–7.30(m,4H),6.42(s,1H),3.58(t,J=1.0Hz,2H),3.16(dtd,J=13.6,6.8, 0.7Hz, 1H), 2.90–2.72 (m, 4H), 2.66–2.57 (m, 4H), 1.39 (s, 6H), 1.22 (d, J = 6.8Hz, 6H).

[0994] Example 139

[0995] Preparation of compound VI-22:

[0996] The synthesis steps were similar to those of VI-18. 18 mg of white powdery solid was obtained by preparative liquid phase. UPLC-MS calculated for C 38 H 42 F3N6O5[M+H] + :719.31,found:719.78. 1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),9.06(s,1H),8.92(s,1H),8.32(d,J=1.5Hz,1H), 8.15–8.05(m,2H),8.03(d,J=7.5Hz,1H),7.64–7.57(m,3H),7.53(dt,J=7.5,1.0Hz,2H) ,6.52(s,1H),3.62(t,J=1.0Hz,2H),3.37(p,J=8.0Hz,2H),3.27–3.14(m,1H),2.91–2. 73(m,4H),2.67–2.58(m,4H),1.39(s,6H),1.22(d,J=6.8Hz,6H),1.17(t,J=8.0Hz,3H).

[0997] Example 140

[0998] Preparation of compound VII-1:

[0999] first step:

[1000] 4-(Dimethoxymethyl)piperidine (20 mg, 0.12 mmol), DIEA (47.3 mg, 0.37 mmol), and HATU (209 mg, 0.55 mmol) were dissolved in anhydrous DMF and stirred under argon for 10 minutes. A DMF solution of p-AR-6 (60 mg, 0.13 mmol) was added and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added for extraction. The organic phase was washed sequentially with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography (PE:EA = 5:1) to afford 47 mg of VII-1-1 as a solid, in a 65% yield. UPLC-MS calculated for C 28 H 28 F4N5O4S[M+H] + :606.17,found:606.61.

[1001] Subsequent experimental procedures were performed with reference to VI-1, and 33 mg of white powdery solid was obtained by preparative liquid phase analysis. UPLC-MS calculated for C 48 H 49 F7N 10 O5S[M+H] + :953.35,found:953.43. 1H NMR (400MHz, DMSO-d6) δ11.89(s,1H),9.56(s,1H),9.36(s,1H),9.17(d,J=2.1Hz,1H),8.71(d,J=2.1Hz,1H),7.60 (t,J=7.8Hz,1H),7.45–7.32(m,2H),7.26(d,J=8.2Hz,2H),7.14–7.04(m,2H),6.73(s,1H),6.22(s,1H),4.47(d,J =12.8Hz,1H),3.44(d,J=25.6Hz,4H),3.07(t,J=12.8Hz,2H),2.97–2.74(m,3H),2.60(q,J=7.4,5.1Hz,3H),2.50( d,J=9.9Hz,2H),2.23(s,6H),2.06–1.91(m,1H),1.87–1.52(m,4H),1.11(d,J=66.0Hz,2H),0.90(d,J=6.9Hz,6H).

[1002] Example 141

[1003] Preparation of compound VII-2:

[1004] The synthesis method was similar to that of Example VII-1, and 20 mg of VII-2 was obtained as a white powdery solid by preparative liquid phase. UPLC-MS calculated for C 42 H 39 F4N8O5S[M+H] + :843.26,found:843.87. 1 H NMR (400MHz, DMSO-d6) δ11.90(s,1H),9.57(s,1H),9.36(s,1H),8.37(d,J=8.3Hz,1H),8.26(d,J=1 .9Hz,1H),8.05(dd,J=8.2,2.0Hz,1H),7.57(t,J=7.8Hz,1H),7.40(dd,J=9.9,1.9Hz,1H),7.29(dt ,J=8.8,2.3Hz,3H),7.11(d,J=7.9Hz,2H),6.74(s,1H),6.22(s,1H),3.55(d,J=61.5Hz,3H),3.24( s,2H),3.00–2.89(m,1H),2.40–2.30(m,3H),1.51(s,6H),1.29–1.09(m,1H),0.90(d,J=6.9Hz,6H).

[1005] Example 142

[1006] Preparation of compound VII-3:

[1007] The synthesis method was similar to that of Example VII-1, and 25 mg of VII-3 as a white powdery solid was obtained by preparative liquid phase. UPLC-MS calculated for C 41 H 38 F4N9O5S[M+H] + :844.26,found:844.86. 1 H NMR (400MHz, DMSO-d6) δ11.90(s,1H),9.53(d,J=67.5Hz,2H),8.41(d,J=8.3Hz,1H),8.29(d ,J=1.9Hz,1H),8.08(dd,J=8.2,1.9Hz,1H),7.84(d,J=2.6Hz,1H),7.72(t,J=7.9Hz,1H),7. 46–7.31(m,3H),6.89(s,1H),6.72(d,J=9.3Hz,1H),6.26(s,1H),4.12(t,J=9.0Hz,2H),3.9 2–3.78(m,4H),3.07–2.94(m,5H),1.53(s,6H),1.24(d,J=3.2Hz,1H),1.01(d,J=6.9Hz,6H).

[1008] Example 143

[1009] Preparation of compound VII-4:

[1010] The synthesis method was similar to that of Example VII-1, and 22 mg of VII-4 as a white powdery solid was obtained by preparative liquid phase. UPLC-MS calculated for C 41 H 36 F4N9O5S[M+H] + :857.25,found:857.86. 1H NMR (400MHz, DMSO-d6) δ11.87(s,1H),9.60(s,1H),9.43(s,1H),9.20(d,J=2.1Hz,1H),8.74(d,J=2.1Hz ,1H),7.90–7.71(m,2H),7.46(dd,J=10.2,1.9Hz,1H),7.40–7.30(m,2H),6.86(s,1H),6.65(d,J=9.1Hz ,1H),6.25(s,1H),4.19–4.08(m,2H),3.95–3.75(m,4H),2.99(d,J=6.8Hz,5H),2.62(dq,J=8.6,4.9,3. 7Hz,2H),2.04–1.89(m,1H),1.57(dq,J=10.2,5.6,4.4Hz,1H),1.32–1.07(m,2H),1.00(d,J=6.9Hz,6H).

[1011] Example 144

[1012] Preparation of compound VII-5:

[1013] The synthesis method was similar to that of Example VII-1, and 20 mg of VII-5 as a white powdery solid was obtained by preparative liquid phase. UPLC-MS calculated for C 42 H 38 F5N8O5S[M+H] + :861.25,found:861.86. 1 H NMR (400MHz, DMSO-d6) δ11.95(s,1H),9.59(s,1H),9.35(s,1H),8.37(d,J=8.3Hz,1H),8 .26(d,J=1.9Hz,1H),8.15–7.93(m,1H),7.62–7.52(m,1H),7.41–7.27(m,3H),7.05–6.90 (m,2H),6.81–6.67(m,1H),6.22(s,1H),3.57(d,J=41.9Hz,4H),3.23(t,J=4.9Hz,2H),2 .99–2.93(m,1H),2.42(s,2H),2.35(t,J=5.0Hz,2H),1.51(s,6H),0.96(d,J=6.9Hz,6H).

[1014] Example 145

[1015] Preparation of compound VII-6:

[1016] The synthesis method was similar to that of Example VII-1, and 41 mg of VII-6 was obtained as a white powdery solid by preparative liquid phase. UPLC-MS calculated for C 48 H 50 F4N9O5S[M+H] + :940.35,found:940.03. 1 H NMR (400MHz, DMSO-d6) δ11.36(s,1H),10.72(s,1H),9.47(s,1H),8.01(d,J=1.4Hz,1H),7.97 (d,J=7.5Hz,1H),7.71(dd,J=7.5,5.0Hz,1H),7.65(dd,J=7.4,1.4Hz,1H),7.51–7.44(m,2H), 7.38(s,4H),6.96(dd,J=7.5,1.5Hz,1H),6.42(s,1H),3.71–3.63(m,2H),3.60–3.49(m,4H), 3.22–3.11(m,1H),2.63–2.43(m,10H),1.92–1.77(m,5H),1.47(s,6H),1.22(d,J=6.8Hz,6H).

[1017] Example 146

[1018] Preparation of compound VII-7:

[1019] The synthesis method was similar to that of Example VII-1, and 41 mg of VII-7 was obtained as a white powdery solid by preparative liquid phase. UPLC-MS calculated for C 46 H 49 F3N 11 O4S[M+H] + :908.36,found:908.66. 1H NMR(400MHz, DMSO-d6)δ11.94(s,1H),9.55(d,J=81.9Hz,1H),9.21(s,1H),8.75(s,1H),8.19(s,1H),8.07(s,1H),7.48(s,1H),7. 29(d,J=7.8Hz,2H),7.13(d,J=7.8Hz,2H),6.98(d,J=9.2Hz,1H),6.79(s,1H),6.29(s,1H),4.35(s,2H),3.52(s,2H), 2.97(q,J=6.7Hz,1H),2.87(t,J=12.0Hz,2H),2.60(t,J=10.0Hz,2H),2.40(dd,J=25.5,13.0Hz,9H),2.16(d,J=5.9Hz ,2H),1.97(q,J=9.3Hz,1H),1.80(d,J=11.3Hz,3H),1.65–1.54(m,1H),1.09(d,J=11.2Hz,3H),0.94(d,J=6.8Hz,6H).

[1020] The following examples and comparative examples will further illustrate the beneficial effects of the present application, but the scope of the present invention is not limited to these examples.

[1021] Test Example 1: Prostate tumor cell proliferation inhibitory activity

[1022] Prostate tumor cells LNCaP, VCaP, and 22Rv1 were purchased from Wuhan Punosai Life Science Technology Co., Ltd. The cell culture medium for LNCaP and 22Rv1 was RPMI 1640 + 10% FBS, and the cell culture medium for VCaP was DMEM + 10% FBS. All experimental cells were cultured at 37°C in a 5% CO2 incubator. On the day of the experiment, cells in the exponential growth phase were collected. LNCaP cells were adjusted to the corresponding cell concentration for plating with RPMI 1640 medium containing 5% carbon-sorbed serum (CSS), and the cell number was 6000 / well. VCaP cells were adjusted to the corresponding cell concentration for plating with DMEM medium containing 5% CSS, and the cell number was 20,000 / well. 22Rv1 cells were adjusted to the corresponding cell concentration for plating with RPMI 1640 medium containing 10% FBS, and the cell number was 6000 / well. Among them, after LNCaP and VCaP cells were cultured for 48 hours, different concentrations of compounds were added to the corresponding culture medium containing 0.1nM R1881. After culturing 22Rv1 cells overnight, different concentrations of compounds were added to the culture medium. The three cell types were placed in an incubator and cultured for 5 days. After the culture was completed, the culture medium was removed, and according to the operating instructions of the CCK-8 kit (Biosharp, BS350B), 100μL of the corresponding culture medium containing 10% CCK-8 was added to each well, and the cells were placed in an incubator and incubated for 1 to 4 hours. The absorbance value at 450nM was measured using a microplate reader. The results were processed according to formula (1) to calculate the inhibition rate of each concentration of the compound, and the IC value of the compound inhibition rate of 50% was calculated using Prism 8 software. 50 value.

[1023] Inhibition rate (%) = (1-absorbance value of test group / absorbance value of control group) × 100% Formula (1)

[1024] The results of prostate tumor cell proliferation inhibition are shown in Table 1. The example compounds showed certain activity in inhibiting the proliferation of castration-resistant prostate cancer cells (ND stands for not determined).

[1025] Table 1 Inhibitory effects of some compounds of the present invention on tumor cell growth

[1026] Experimental Example 2: Degradation of full-length AR (AR-FL) and AR splice variant (AR-V7) in prostate tumor cells

[1027] Prostate tumor cells, LNCaP and 22Rv1, were purchased from Wuhan Pronocell Life Science Co., Ltd. Cell culture medium was RPMI 1640 + 10% FBS. All experimental cells were cultured at 37°C in a 5% CO2 incubator. On the day of the experiment, LNCaP and 22Rv1 cells were harvested from the exponential growth phase and plated at the appropriate cell density using culture medium. The number of cells per well was 200,000. After overnight cell culture, the example compounds were added to the culture medium to adjust the final concentrations of the compounds to 10, 30, 100, 300, and 1000 nM, respectively. 1‰ DMSO was used as a negative control. After the cells were cultured in an incubator for 24 h, the medium was removed, the cells were washed with PBS, and RIPA lysis buffer (Beijing Pulilai Gene Technology Co., Ltd., C1053) containing 1% Protease Inhibitor Cocktail (Sigma, 04693116001) was added. Total protein extracts were obtained after lysis and centrifugation, and protein quantification was performed by BCA assay. Protein samples were subjected to SDS-PAGE electrophoresis, followed by constant current electrophoresis at 200 mA for 90 min, and proteins were transferred to PVDF (Millipore Sigma IPVH00010) membranes. The PVDF membranes were blocked in 5% skim milk overnight at 4°C. Immunoreactivity was performed using anti-Androgen Receptor antibodies (Santa, sc-7305) and anti-AR-V7 Speccific antibodies (RevMAb Biosciences, 31-1109-00), respectively. The membranes were incubated with secondary antibody dilutions at room temperature for 1-2 h. After washing, ECL luminescence solution was added dropwise and exposed to light. Grayscale analysis of the bands was performed using Image J software. The internal reference band was also detected for each sample. The protein degradation rates of AR-FL or AR-V7 relative to the negative control group at different drug concentrations were calculated according to formulas (2) and (3), and the DC required for the compound protein degradation rate to be 50% was calculated using Prism 8 software. 50 value.

[1028] Among them, AR-FL Compound is the grayscale value of AR-FL in the drug-treated group, DMSO is the grayscale value of the AR-FL band in the negative control group. Compound is the grayscale value of AR-V7 in the drug-treated group, AR-V7 DMSO is the grayscale value of the AR-V7 band in the negative control group.

[1029] AR-FL degradation rate = (1-AR-FL Compound / AR-FL DMSO )×100%Formula (2);

[1030] AR-V7 degradation rate = (1-AR-V7 Compound / AR-V7 DMSO )×100%Formula (3).

[1031] The results of protein degradation in LNCaP and 22Rv1 cells are shown in Table 2. Some of the compounds in the examples showed certain AR and AR-V7 protein degradation effects. (DC 50 ≤10nM=+++;DC 50 ≤100nM=++;DC 50 ≤1000nM=+;DC 50 ≥1000 nM = / ; ND = not determined).

[1032] Table 2 Degradation effect of some compounds of the present invention on tumor cell AR or AR-V7

[1033] Experimental Example 3: Pharmacokinetic study of the example compounds in mice.

[1034] Six male ICR mice (20±2 g) were randomly divided into two groups. The example compounds were dissolved in the corresponding solvents and then administered orally (po) and intravenously (iv). The intravenous injection group received blood at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration; the oral gavage group received blood at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. Approximately 50 μL of blood was collected from the orbital venous plexus and placed in 1.5 mL of EP containing EDTA-2K. The blood was placed on wet ice for 15 min, centrifuged at 6000 rpm for 3 min, and the plasma was separated and stored at -80°C for testing. Plasma sample analysis: LC-MS / MS was used to determine the concentration of the example compounds in the plasma samples at each time point, and WinNolin software was used to calculate the pharmacokinetic parameters, including T max (peak time), C max (peak concentration), t 1 / 2 (elimination half-life), AUC (area under the plasma concentration-time curve) and other parameter values. Absolute bioavailability is calculated according to formula (3), where Dose i.v. Dose is the dosage of the tail vein injection group. p.o. is the dosage of the oral administration group; AUC iv(0-∞) AUC is the area under the blood drug concentration-time curve of the tail vein injection group oral(0-∞) It is the area under the blood drug concentration-time curve of the oral administration group.

[1035] F(%)=(Dose i.v. ×AUCp.o.(0-∞) ) / (Dose p.o. ×AUC i.v.(0-∞) )×100%.

[1036] The in vivo pharmacokinetic data of some of the compounds in the examples are shown in Table 3. Vehicle: 5% DMSO + 10% Solutol + 85% (10% HP-β-CD in saline) or 10% PEG300 + 5% Cremophor EL + 85% (10% HP-β-CD in saline).

[1037] Table 3 Pharmacokinetic parameters of some compounds of the present invention in mouse plasma

[1038] It should be noted that the present application is not limited to the above-mentioned embodiments. The above-mentioned embodiments are merely examples, and within the scope of the technical solution of the present application, embodiments having substantially the same structure as the technical concept and exerting the same effects are all included in the technical scope of the present application. In addition, within the scope of the subject matter of the present application, various modifications that can be conceived by those skilled in the art to the embodiments, and other methods constructed by combining some of the constituent elements in the embodiments are also included in the scope of the present application.

Claims

1. A compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof, characterized in that: The structure of the compound is shown in Formula 0: The formula 0 is selected from any one of the following formulas I-VII, I'-VI': In Formula I or Formula I', A 1 is a 5-10 membered heteroarylene group, wherein the 5-10 membered heteroarylene group is optionally substituted by any one or more selected from the group consisting of a C1-C6 alkyl group, a C3-C6 cycloalkyl group, =O, =S and a halogen; R 1 is a substituent at any position of the indolyl group, and R 1 Any one or more selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S and halogen; L 1 , L 2 , L 3 , L 4 and L 5 are each independently selected from a single bond, a C1-C6 alkylene group, a carbonyl group, a 4-10 membered heterocycloalkylene group, and L 1 , L 2 , L 3 , L 4 and L 5 At least two of them satisfy the following conditions: one is a 4-10 membered heterocycloalkylene group and the other is a C1-C6 alkylene group; C 1 is selected from C6-C10 arylene or 5-10 membered heteroarylene, and the C6-C10 arylene or 5-10 membered heteroarylene is optionally substituted by halogen or C1-C6 alkyl; L 6 is selected from -NH-C(O)-, a single bond; C 2 is selected from 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene, and the 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene are optionally substituted by any one or more selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S and halogen; L 7 is selected from -O-, -NH-, a single bond; R 2 is selected from halogen and C1-C6 haloalkyl; X is C or N; In Formula II or Formula II', A 1 is a 5-10 membered heteroarylene group, wherein the 5-10 membered heteroarylene group is optionally substituted by any one or more of the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, =S, halogen, R A1 and R A2 Each is independently H or C1-C6 alkyl; A 2 is a C6-C10 arylene group or a 5-10 membered heteroarylene group, wherein the C6-C10 arylene group and the 5-10 membered heteroarylene group are optionally substituted by halogen or C1-C6 alkyl; L 1 , L 2 , L 3 and L 4 Each is independently selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a carbonyl group, -O-, a 4-10 membered heterocycloalkylene group, -N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group, and L 1 , L 2 , L 3 and L 4 At least two of them satisfy the following conditions: one is a 4-10 membered heterocycloalkylene group and the other is a C1-C6 alkylene group; C 1 is selected from C6-C10 arylene or 5-10 membered heteroarylene, and the C6-C10 arylene or 5-10 membered heteroarylene is optionally substituted by halogen or C1-C6 alkyl; L 6 is selected from -NH-C(O)-, a single bond; C 2 is selected from 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene, and the 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene are optionally substituted by any one or more selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S and halogen; L 7 is selected from -O-, -NH-, a single bond; R 2 is selected from halogen and haloalkyl; X is C or N; In Formula III or Formula III', A 2 is a C6-C10 arylene group or a 5-10 membered heteroarylene group, wherein the C6-C10 aryl group and the 5-10 membered heteroaryl group are optionally substituted by halogen or C1-C6 alkyl; L 1 , L 2 , L 3 and L 4 Each is independently selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a carbonyl group, a 4-10 membered heterocycloalkylene group, -O-, -N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group, -N(R B1 )R B2 -N atom and A 2 Connect, and L 1 When L is a C1-C6 alkylene group 2 and L 3 One is a single bond and the other is a 4-10 membered heterocycloalkylene group; C 1 is selected from C6-C10 arylene or 5-10 membered heteroarylene, and the C6-C10 arylene or 5-10 membered heteroarylene is optionally substituted by halogen or C1-C6 alkyl; L 6 is selected from -NH-C(O)-, a single bond; C 2 is selected from 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene, and the 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene are optionally substituted by any one or more selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S and halogen; L 7 is selected from -O-, -NH-, a single bond; R 2 is selected from halogen and haloalkyl; X is C or N; In Formula IV or Formula IV', A 1 is a 5-10 membered heteroarylene group, wherein the 5-10 membered heteroarylene group is optionally substituted by any one or more selected from the group consisting of a C1-C6 alkyl group, a C3-C6 cycloalkyl group, =O, =S and a halogen; A 2 is a C6-C10 arylene group or a 5-10 membered heteroarylene group, wherein the C6-C10 arylene group and the 5-10 membered heteroarylene group are optionally substituted by halogen or C1-C6 alkyl group; L 1 , L 2 , L 3 and L 4 Each is independently selected from a single bond, a C1-C6 alkylene group, a carbonyl group, and a 4-10 membered heterocycloalkyl group, and at least one is not a single bond; C 1 is selected from C6-C10 arylene or 5-10 membered heteroarylene, and the C6-C10 arylene or 5-10 membered heteroarylene is optionally substituted by halogen or C1-C6 alkyl; L 6 is selected from -NH-C(O)-, a single bond; C 2 is selected from 4-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, and the 4-10 membered cycloalkyl, 5-10 membered heterocycloalkyl is optionally substituted by any one or more selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S and halogen; L 7 is selected from -O-, -NH-, a single bond; R 2 is selected from halogen and haloalkyl; X is C or N; and the compound of formula IV does not include the following compounds: In Formula V or Formula V', A 1 is a 5-10 membered heteroarylene group, wherein the heteroatom is preferably a N atom and / or an O atom, and the number of heteroatoms is preferably 1-3, and the 5-10 membered heteroarylene group is optionally substituted by any one or more of the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S, halogen, R A1 and R A2 Each is independently H or C1-C6 alkyl; A 2 is a C6-C10 arylene group or a 5-10 membered heteroarylene group, wherein the C6-C10 arylene group and the 5-10 membered heteroarylene group are optionally substituted by halogen or C1-C6 alkyl; L 1 , L 2 , L 3 , L 4 and L 5 Each is independently selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a carbonyl group, a 4-10 membered heterocycloalkylene group, -O-, -C(O)-NH-, *-N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group; C 1 is selected from 5-10 membered heteroarylene, and the 5-10 membered heteroarylene is optionally substituted by any one or more of the following groups: C1-C6 alkyl and halogen; L 6 Selected from -R C1 -NH-, -R C1 -NH-C(O)- or single bond, R C1 is a C0-C6 alkylene group; C 2 is selected from 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene, 5-10 membered heteroarylene, and the 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene, 5-10 membered heteroarylene are optionally substituted by any one or more selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S and halogen; L 7 is selected from a single bond, -O-, -NH-; R 2 is selected from halogen and haloalkyl; X is C or N; In Formula VI or Formula VI', A 1 is selected from a 5- to 10-membered heteroarylene group, as A 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S, halogen, R A1 and R A2 Each is independently H or C1-C6 alkyl; A 2 is selected from C6-C10 arylene or 5-10 membered heteroarylene, wherein A 2 The C6-C10 arylene and 5-10 membered heteroarylene are optionally substituted by halogen or C1-C6 alkyl; L 1 , L 2 , L 3 , L 4 and L 5 Each is independently selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a carbonyl group, a 4-10 membered heterocycloalkylene group, a C3-C10 cycloalkylene group, a C6-C10 arylene group, -O-, *-N(R B1 )R B2 -, phenylene, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group, or for C 1 is selected from a single bond, a C6-C10 arylene group or a 5-10 membered heteroarylene group, and as C 1 The C6-C10 arylene or 5-10 membered heteroarylene is optionally substituted by halogen or C1-C6 alkyl; L 6 is a C1-C6 alkyl group, the C1-C6 alkyl group is optionally substituted by OH, and the C1-C6 alkyl group is preferably a branched alkyl group; R 2 is selected from halogen and haloalkyl; X is C or N; In Formula VII, A 1 is selected from a 5- to 10-membered heteroarylene group, as A 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more selected from the group consisting of: C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S, halogen white, R A1 and R A2 Each is independently H or C1-C6 alkyl; A 2 is selected from C6-C10 arylene or 5-10 membered heteroarylene, wherein A 2 The C6-C10 arylene and 5-10 membered heteroarylene are optionally substituted by halogen or C1-C6 alkyl; L 1 , L 2 , L 3 , L 4 and L 5 Each is independently selected from a single bond, a C1-C6 alkylene group, a carbonyl group, a 4-10 membered heterocycloalkylene group, -O-, *-N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group; C 1 The ring is selected from C6-C10 aryl, 5-10 membered heteroaryl; R 5 is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, OH, NH2, CN, nitro, carboxyl, C3-C6 cycloalkyl, R 3 , R 4 are each independently selected from H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and R 3 and R 4 Connected to form a ring with the carbon atom shared by both; R 2 It is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl.

2. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The formula I or the formula I' satisfies any one or more of the following conditions: As A 1 The heteroatom of the 5-10 membered heteroarylene group is a N atom, and the number of heteroatoms is preferably 1-3; preferably A 1 The 5-10 membered heteroarylene group is triazolylene, and the 5-10 membered heteroarylene group is optionally substituted by any one or more of the following groups: C1-C6 alkyl, =O, =S; L 1 is selected from a single bond, a C1-C6 alkylene group, and more preferably L 1 is selected from a single bond, methylene, ethylene, propylene; L 2 is selected from 4-10 membered heterocycloalkylene, single bond, preferably as said L 2 The heteroatom of the 4-10 membered heterocycloalkyl is N, S or P; preferably L 2 is azetidinylene, piperidinylene or piperazinylene; L 3 is selected from a single bond, a C1-C6 alkylene group, and more preferably L 3 is selected from a single bond, methylene, ethylene, propylene; L 4 is selected from 4-10 membered heterocycloalkylene, single bond, preferably as said L 4 The heteroatom of the 4-10 membered heterocycloalkyl is N, S or P; preferably L 4 is azetidinylene, piperidinylene or piperazinylene; L 5 Selected from a single bond, a C1-C6 alkylene group, or a carbonyl group.

3. The compound according to claim 1 or 2, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The compound of formula I or the compound of formula I' is selected from any one of formula I1, formula I2 or formula I1': In Formula I1 or Formula I1', C 1 is selected from 5-10 membered heteroarylene groups, preferably as C 1 The 5-10 membered heteroarylene group is imidazolylene, pyrazolylene, thiazolylene, pyrrolylene, pyridylene, pyrimidylene, pyridazinylene, pyrazinylene, preferably C 1 The 5-10 membered heteroarylene is pyrazolylene, pyridylene, pyrimidylene, pyridazinylene, and the 5-10 membered heteroarylene is optionally substituted by halogen (e.g., F, Cl or Br), C1-C6 alkyl (e.g., methyl, ethyl, propyl or butyl); C 2 is selected from 4-10 membered cycloalkylene groups, preferably as C 2 The 4-10 membered cycloalkylene group is cyclobutylene, cyclopentylene, cyclohexylene or cycloheptylene, and as C 2 The 4-10 membered cycloalkylene is optionally substituted by any one or more selected from the group consisting of: C1-C6 alkyl (e.g., methyl, ethyl, propyl or butyl) and halogen (e.g., F, Cl or Br); L 7 Selected from -O-, -NH-, R 2 is selected from halogen, preferably F, Cl or Br, more preferably Cl; X is C or N; Preferably, in formula I1 or formula I1' Any one selected from the following groups: More preferably, I1 or I1' for in, The end is connected to C1, The end is connected to the indole group; Preferably, in formula I1′ Any one selected from the following groups: Preferably, in formula I1 or formula I1' for In formula I2, C 1 is selected from a C6-C10 aryl group or a 5-10 membered heteroaryl group, as C 1 The C6-C10 aryl group is preferably a phenylene group, as C 1 The 5-10 membered heteroaryl is preferably pyridylene or pyridazinylene; and as C 1 The C6-C10 aryl or 5-10 membered heteroaryl is optionally substituted by halogen (eg, F, Cl or Br), C1-C6 alkyl (eg, methyl, ethyl or propyl); R 2 is selected from haloalkyl, preferably trifluoromethyl; X is C or N; Preferably, in formula I2 Any one selected from the following groups: in, End and C 1 connect, The end is connected to the indole group; Preferably, in formula I2 Any one selected from the following groups: Preferably, in formula I2 for 4. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The formula II or the formula II' satisfies any one or more of the following conditions: In Formula II or Formula II', as A 1 The heteroatoms of the 5-10 membered heteroarylene group are preferably N atoms and / or O atoms, and the number of heteroatoms is preferably 1-3. 1 The 5-10 membered heteroarylene group is substituted by any one or more selected from the group consisting of: R A1 and R A2 Each independently is H or a C1-C6 alkyl group, preferably A1 and R A2 Each independently is H, methyl, ethyl, n-propyl or isopropyl; preferably as the A 1 The 5-10 membered heteroaryl is triazolyl, isoxazolyl or pyrazolyl; A 2 is a C6-C10 arylene group or a 5-10 membered heteroarylene group, preferably 2 The C6-C10 aryl or 5-10 membered heteroaryl is phenylene, pyridylene, pyridazinylene, pyrimidylene, indolylene, and more preferably A 2 The C6-C10 aryl or 5-10 membered heteroaryl is phenylene or pyridylene, wherein the C6-C10 arylene and 5-10 membered heteroarylene are optionally substituted by halogen or C1-C6 alkyl; L 1 is selected from C1-C6 alkylene, -O-, -N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group; L 2 is selected from 4-10 membered heterocycloalkylene, single bond, preferably as said L 2 The heteroatom in the 4-10 membered heterocycloalkylene is N, S or P; preferably, L 2 The 4-10 membered heterocycloalkylene group is azetidinylene, azacyclopentylene, piperidinylene or piperazinylene; L 3 A single bond, a C1-C6 alkylene group; L 4 is selected from a single bond, a 4-10 membered heterocycloalkylene group, -O-, preferably as the L 4 The heteroatom in the 4-10 membered heterocycloalkylene is N, S or P; preferably, L 4 The 4-10 membered heterocycloalkylene group is azetidinylene, azacyclopentylene, piperidinylene or piperazinylene; and L 2 and L 4 Not all are single bonds at the same time; C 1 is selected from C6-C10 arylene or 5-10 membered heteroarylene; preferably C 1 The C6-C10 aryl or 5-10 membered heteroaryl is phenylene, pyridylene, pyridazinylene, pyrimidylene, indolylene, and more preferably C 1 The C6-C10 aryl or 5-10 membered heteroaryl is phenylene or pyridylene, and the C6-C10 arylene or 5-10 membered heteroarylene is optionally substituted by halogen or C1-C3 alkyl; L 6 Selected from -NH-C(O)-; C 2 is selected from 4-10 membered cycloalkylene, and the 4-10 membered cycloalkyl is optionally substituted by any one or more selected from the group consisting of C1-C6 alkyl and halogen; L 7 is selected from -O-, -NH-; R 2 Selected from halogen, -CF3; X is C or N.

5. The compound according to claim 1 or 4, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The compound of formula II or formula II' is selected from any one of formula III or formula III': In Formula III1 or Formula III', as A 1 The heteroatoms of the 5-10 membered heteroarylene group are preferably N atoms and / or O atoms, and the number of heteroatoms is preferably 1, 2 or 3. 1 The 5-10 membered heteroarylene group is substituted by any one or more selected from the group consisting of: R A1 and R A2 Each is independently H, methyl or ethyl; L 1 is selected from C1-C6 alkylene, -O-, -N(R B1 )R B2 -, R B1 is H, methyl, ethyl or n-propyl, R B2 is a single bond, methylene, ethylene, propylene or butylene; L 2 is selected from 4-6 membered heterocycloalkylene, single bond, preferably as said L 2 The 4-6 membered heterocycloalkylene is azetidinylene, azacyclopentylene, piperidinylene or piperazinylene; L 3 is selected from a single bond, a C1-C3 alkylene group; L 4 is selected from a single bond, a 4-6 membered heterocycloalkylene group, -O-, preferably as the L 4 The 4-16 membered heterocycloalkylene group is azetidinylene, azacyclopentylene, piperidinylene or piperazinylene; and L 2 and L 4 Not single bond at the same time; C 1 Preferably, the arylene group is selected from C6-C10 or 5-10 membered heteroarylene group, preferably C 1 The C6-C10 arylene group is phenyl, preferably C 1 The 5-10 membered heteroarylene group is pyridylene, pyrimidylene, pyridazinylene, pyrazinylene, and more preferably pyridazinylene, and the C6-C10 arylene group or the 5-10 membered heteroarylene group is optionally substituted by halogen (e.g., F, Cl or Br), C1-C3 alkyl (e.g., methyl, ethyl or propyl); C 2 is selected from 4-6 membered cycloalkylene, preferably cyclobutylene, cyclopentylene, cyclohexylene, and the 4-6 membered cycloalkylene is optionally substituted by any one or more of the following groups: C1-C6 alkyl (e.g., methyl, ethyl or propyl) and halogen (e.g., F, Cl or Br); Preferably, in Formula III1 or Formula III' Any one selected from the following groups: More preferably in, End and C 1 connect, The end is connected to a phenyl group; Preferably, in Formula III ' Any one selected from the following groups: More preferably Preferably, in Formula III or III' Any one selected from the following groups: More preferably 6. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The formula III or formula III' satisfies any one or more of the following conditions: In the formula III or III', A 2 is phenylene, 5-membered heteroarylene, 6-membered heteroarylene, preferably A 2 is phenylene, pyridylene, pyridazinylene, pyrimidylene; phenylene, 5-membered heteroarylene, 6-membered heteroarylene are optionally substituted by halogen or C1-C6 alkyl; L 1 is selected from C1-C6 alkylene, -O-, -N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group; L 2 Selected from 4-10 membered heterocycloalkyl, the heteroatom is N, S or P; preferably azetidinyl, piperidinyl or piperazinyl; L 3 is selected from a single bond, a C1-C6 alkylene group, a carbonyl group, a C1-C6 alkylene-carbonyl group; and L 1 When L is a C1-C6 alkylene group, 2 and L 3 One is a single bond and the other is a 4-10 membered heterocycloalkyl; L 4 Selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably azetidinyl, piperidinyl or piperazinyl; C 1 is selected from C6-C10 arylene or 5-10 membered heteroarylene; preferably C 1 The C6-C10 aryl or 5-10 membered heteroaryl is phenylene, pyridylene, pyridazinylene, pyrimidylene, indolylene, and more preferably C 1 The C6-C10 aryl or 5-10 membered heteroaryl is phenylene or pyridylene, and the C6-C10 arylene or 5-10 membered heteroarylene is optionally substituted by halogen or C1-C3 alkyl; L 6 Selected from -NH-C(O)-; C 2 is selected from 4-10 membered cycloalkylene, and the 4-10 membered cycloalkyl is optionally substituted by any one or more selected from the group consisting of C1-C6 alkyl and halogen; L 7 is selected from -O-, -NH-; R 2 Selected from halogen, -CF3; X is C or N.

7. The compound according to claim 1 or 6, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The compound of formula III or formula III' is selected from any one of formula III1 or formula III1': In the formula III1 or III1', A 2 is phenylene, 5-membered heteroarylene, 6-membered heteroarylene, preferably A 2 is phenylene, pyridylene, pyridazinylene, pyrimidylene; L 1 is selected from C1-C6 alkylene, -O-, -N(R B1 )R B2 -, R B1 is H, methyl, ethyl or propyl, R B2 is a single bond, methylene, ethylene, propylene or butylene, preferably L 1 Selected from methylene, ethylene, -O-, -N(R B1 )R B2 -, R B1 is H, methyl or ethyl, R B2 is a single bond, methylene or ethylene; L 2 Selected from 4-10 membered heterocycloalkyl, the heteroatom is N, S or P; preferably azetidinyl, piperidinyl or piperazinyl; L 3 is selected from a single bond, methylene, ethylene, propylene, carbonyl, methylene-carbonyl, ethylenecarbonyl; and L 1 When L is methylene, 2 and L 3 One is a single bond and the other is a 4-10 membered heterocycloalkyl; L 4 Selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably azetidinyl, piperidinyl or piperazinyl; C 1 Preferably, the arylene group is selected from C6-C10 or 5-10 membered heteroarylene group, preferably C 1 The C6-C10 arylene group is phenyl, preferably C 1 The 5-10 membered heteroarylene group is pyridylene, pyrimidylene, pyridazinylene, pyrazinylene, and more preferably pyridazinylene, and the C6-C10 arylene group or the 5-10 membered heteroarylene group is optionally substituted by halogen (e.g., F, Cl or Br), C1-C3 alkyl (e.g., methyl, ethyl or propyl); C 2 is selected from 4-6 membered cycloalkylene, preferably cyclobutylene, cyclopentylene, cyclohexylene, and the 4-6 membered cycloalkylene is optionally substituted by any one or more of the following groups: C1-C6 alkyl (e.g., methyl, ethyl or propyl) and halogen (e.g., F, Cl or Br); Preferably, in Formula III1 or Formula III1' Any one selected from the following groups: ,in, End and C 1 connect, End and A 2 connect; Preferably, in formula III1' Any one selected from the following groups: Preferably, in Formula III1 or Formula III1' Any one selected from the following groups:

8. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The formula IV or formula IV' satisfies any one or more of the following conditions: In Formula IV or Formula IV', A 1 is a 5-10 membered heteroarylene group, wherein the heteroatom is preferably a N atom, and the number of heteroatoms is preferably 1-3, and is preferably used as A 1 The 5-10 membered heteroarylene group is a triazole group, wherein the 5-10 membered heteroarylene group is optionally substituted by any one or more of the following groups: =O, =S; A 2 is a C6-C10 arylene group or a 5-10 membered heteroarylene group, preferably 2 The C6-C10 arylene group is phenyl, preferably as A 2 The 5-10 membered heteroarylene is pyrimidinyl or pyridinyl, wherein the C6-C10 arylene and the 5-10 membered heteroarylene are optionally substituted by halogen (e.g., F, Cl or Br), C1-C3 alkyl (e.g., methyl, ethyl, propyl or butyl); L 1 is selected from a single bond, a C1-C6 alkylene group, a carbonyl group, preferably L 1 is selected from a single bond, a methylene group, an ethylene group or a carbonyl group; L 2 Selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably azetidinyl, piperidinyl or piperazinyl; L 3 is selected from a single bond or a methylene group; L 4 Selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably azetidinyl, piperidinyl or piperazinyl; C 1 is selected from 5-10 membered heteroarylene groups, preferably as C 1 The 5-10 membered heteroarylene group is imidazolylene, pyrazolylene, thiazolylene, pyrrolylene, pyridylene, pyrimidylene, pyridazinylene, pyrazinylene, preferably C 1 The 5-10 membered heteroarylene is pyrazolylene, pyridylene, pyrimidylene, pyridazinylene, and the 5-10 membered heteroarylene is optionally substituted by halogen (e.g., F, Cl or Br), C1-C6 alkyl (e.g., methyl, ethyl, propyl or butyl); L 6 Selected from -NH-C(O)-; C 2 is selected from 4-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, preferably as C 2 The 4-10 membered cycloalkylene group is cyclobutylene, cyclopentylene, cyclohexylene or cycloheptylene, preferably C 2 The 5-10 membered heterocycloalkyl group is piperidinylene or piperazinylene, and as C 2 The 4-10 membered cycloalkyl or 5-10 membered heterocycloalkyl is optionally substituted by halogen or C1-C3 alkyl; L 7 is selected from -O-, -NH-, a single bond; R 2 is selected from halogen and haloalkyl, preferably Cl or trifluoromethyl; Preferably, in Formula IV or Formula IV' Any one selected from the following groups: in, End and C 1 connect, End and A 2 connect.

9. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The formula V or formula V' satisfies any one or more of the following conditions: In Formula V or Formula V', A 1 is a 5-10 membered heteroarylene group, preferably as A 1 The 5-10 membered heteroarylene group is triazole group, isoxazole group or pyrazolyl group, preferably as A 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S; A 2 is phenylene or 6-membered heteroarylene, wherein the phenylene and 6-membered heteroarylene are optionally substituted by halogen or C1-C3 alkyl; L 1 is selected from a single bond, a C1-C3 alkylene group, a C2-C3 alkynylene group, a carbonyl group, -C(O)-NH-, -O-, *-N(R B1 )R B2 -, R B1 is H, C1-C3 alkyl, R B2 is a C0-C3 alkylene group; L 2 is selected from 4-10 membered heterocycloalkylene, single bond, heteroatom is N, S or P; preferably L 2 The 4-10 membered heterocycloalkylene group is azetidinylene, piperidinylene or piperazinylene; L 3 is selected from a single bond, a C1-C3 alkylene group, a C2-C3 alkynylene group, a carbonyl group, and -C(O)-NH-; L 4 is selected from 4-10 membered heterocycloalkylene, single bond, heteroatom is N, S or P; preferably L 4 The 4-10 membered heterocycloalkylene group is azetidinylene, piperidinylene or piperazinylene; L 5 is selected from a single bond, a C1-C3 alkylene group, a C2-C3 alkenylene group, a C2-C3 alkynylene group, -C(O)-NH- or a carbonyl group; C 1 is selected from 5-8 membered heteroarylene, and the 5-8 membered heteroarylene is optionally substituted by any one or more of the following groups: C1-C3 alkyl and halogen; preferably C 1 Selected from A fused heterocyclic ring, wherein Middle Y 1 , Y 2 , Y 3 and Y 4 Each is independently selected from C or N, and at least one is N; Middle Z 1 , Z 2 , Z 3 and Z 4 are independently selected from C or N, and at least one of them is N; Y 1 , Y 2 , Y 3 , Y 4 , Z 1 , Z 2 , Z 3 and Z 4 Each is independently selected from C or N, and at least one is N; more preferably is an imidazole ring, a pyrazole ring, a thiazole ring, a pyrrole ring, or a triazole ring; further preferably is a benzene ring, a pyrimidine ring, a pyridazine ring, or a pyrazine ring; further preferably, the fused heterocyclic ring is a fused heterocyclic ring of any one of a benzene ring, a pyrimidine ring, a pyridazine ring, or a pyrazine ring and a pyrrole ring; L 6 Selected from -R C1 -NH-, -R C1 -NH-C(O)- or single bond, R C1 is a C0-C3 alkylene group; C 2 is selected from 4-6 membered cycloalkylene, 5-6 membered heterocycloalkylene, 5-6 membered heteroaryl, and as C 2 The 4-6 membered cycloalkylene, 5-6 membered heterocycloalkylene, 5-6 membered heteroaryl are optionally substituted by any one or more selected from the group consisting of: C1-C3 alkyl and halogen; L 7 is selected from a single bond, -O-, -NH-; R 2 is selected from halogen and haloalkyl; X is C or N.

10. The compound according to claim 1 or 9, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The compound of formula V or formula V' is selected from any one of formula V1, formula V2, formula V1' or formula V2': In Formula V1 or Formula V1', A 1 is a 5-10 membered heteroarylene group, preferably as A 1 The 5-10 membered heteroarylene group is triazole group, isoxazole group or pyrazolyl group, preferably as A 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more selected from the group consisting of: C1-C3 alkyl, =O, =S; A 2 is phenylene, pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene, preferably phenylene or pyridinylene; L 1 is selected from a single bond, a C1-C3 alkylene group, a C2-C3 alkynylene group, a carbonyl group, -C(O)-NH-, -O-, *-N(R B1 )R B2 -, R B1 is H, C1-C3 alkyl, R B2 is a C0-C3 alkylene group; L 2 is selected from 4-10 membered heterocycloalkylene, single bond, heteroatom is N, S or P; preferably L 2 The 4-10 membered heterocycloalkylene group is azetidinylene, piperidinylene or piperazinylene; L 3 is selected from a single bond, a C1-C3 alkylene group, a C2-C3 alkynylene group, a carbonyl group, and -C(O)-NH-; L 4 is selected from 4-10 membered heterocycloalkylene, single bond, heteroatom is N, S or P; preferably L 4 The 4-10 membered heterocycloalkylene group is azetidinylene, piperidinylene or piperazinylene; L 5 is selected from a single bond, a C1-C3 alkylene group, a C2-C3 alkenylene group, a C2-C3 alkynylene group or -C(O)-NH-; C 1 is selected from 5-8 membered heteroarylene, and the 5-8 membered heteroarylene is optionally substituted by any one or more of the following groups: C1-C3 alkyl and halogen; preferably C 1 Selected from A fused heterocyclic ring, wherein Middle Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from C or N, and At least one of them is N; Middle Z 1 , Z 2 , Z 3 and Z 4 are independently selected from C or N, and at least one of them is N; Y 1 , Y 2 , Y 3 , Y 4 , Z 1 , Z 2 , Z 3 and Z 4 Each is independently selected from C or N, and at least one is N; more preferably is an imidazole ring, a pyrazole ring, a thiazole ring, a pyrrole ring, or a triazole ring; further preferably is a benzene ring, a pyrimidine ring, a pyridazine ring, or a pyrazine ring; more preferably, the fused heterocyclic ring is a fused heterocyclic ring of any one of a benzene ring, a pyrimidine ring, a pyridazine ring, or a pyrazine ring and a pyrrole ring; more preferably, C 1 is imidazolylene, pyrazolylene, thiazolylene, pyrrolylene, or triazolylene, and is more preferably pyrrolylene, pyrazolylene, triazolylene, pyridazinylene, pyridinylene, benzopyrrolylene, or pyrimidopyrrolylene; L 6 Selected from -R C1 -NH-, -R C1 -NH-C(O), R C1 is a C0-C3 alkylene group, preferably R C1 is a C1-C3 alkyl group, more preferably a methyl group or an ethyl group; Y 5 , Y 6 , Y 7 and Y 8 Each is independently selected from C or N, and at least one is N, preferably imidazolyl, pyrazolyl, thiazolyl, pyrrolyl, triazolyl, and more preferably pyrazolyl; R 2 is selected from halogen, preferably F or Cl; X is C or N; Preferably, in formula V1 or formula V1' Any one selected from the following groups: Methylene, Ethynylene, space, -NH-, in, End and C 1 connect, End and A 2 connect; Preferably, in formula V1' Any one selected from the following groups: Preferably, in Formula V1 or Formula V1' Any one selected from the following groups: In Formula V2 or Formula V2', A 1 is a 5-10 membered heteroarylene group, preferably as A 1 The 5-10 membered heteroarylene group is triazole group, isoxazole group or pyrazolyl group, preferably as A 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more selected from the group consisting of: C1-C3 alkyl, =O, =S; A 2 is phenylene, pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene, preferably phenylene or pyridinylene; L 1 is selected from a single bond, a C1-C3 alkylene group; L 2 is selected from 4-10 membered heterocycloalkylene, single bond, heteroatom is N, S or P; preferably L 2 The 4-10 membered heterocycloalkylene group is azetidinylene, piperidinylene or piperazinylene; L 3 is selected from a single bond, a C1-C3 alkylene group; L 4 is selected from 4-10 membered heterocycloalkylene, single bond, heteroatom is N, S or P; preferably L 4 The 4-10 membered heterocycloalkylene group is azetidinylene, piperidinylene or piperazinylene; L 5 is selected from a single bond, a C1-C3 alkylene group, and a carbonyl group; Y 1 , Y 2 , Y 3 and Y 4 Each is independently selected from C or N, and at least one is N, preferably is imidazolylene, pyrazolylene, thiazolylene, pyrrolylene, triazolylene, more preferably pyrrolylene, pyrazolylene, triazolylene; C 2 is selected from 4-6 membered cycloalkylene, preferably butylene or hexyl, and as C 2 The 4-6 membered cycloalkylene is optionally substituted by any one or more selected from the group consisting of methyl, ethyl, F, and Cl; L 7 is selected from -O-, -NH-; R 2 is selected from halogen (e.g. F, Cl or Br) and haloalkyl (e.g. trifluoromethyl); X is C or N; Preferably, in formula V2 or formula V2' Any one selected from the following groups: in, End and connect, End and A 2 connect; Preferably, in formula V2' Any one selected from the following groups: Preferably, in Formula V2 or Formula V2' Any one selected from the following groups:

11. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The formula VI or formula VI' satisfies any one or more of the following conditions: In Formula VI or Formula VI', A 1 is selected from 5-10 membered heteroarylene groups, wherein the heteroatoms are preferably N atoms and / or O atoms, and the number of heteroatoms is preferably 1-3, and is preferably used as A 1 The 5-10 membered heteroarylene group is triazolyl, isoxazolyl or pyrazolyl; 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more selected from the group consisting of: C1-C6 alkyl, =O, =S, R A1 and R A2 Each is independently H or C1-C3 alkyl; A 2 is selected from C6-C10 arylene or 5-10 membered heteroarylene, preferably phenylene, pyridylene or indolylene, wherein A 2 The C6-C10 arylene and 5-10 membered heteroarylene are optionally substituted by halogen or C1-C3 alkyl; L 1 is selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkynylene group, *-N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group; preferably L 1 Methylene, ethylene, ethynyl, *-N(R B1 ) R B2 -, R B1 is H, methyl or ethyl, R B2 is a single bond or a methylene group; L 2 is selected from 4-10 membered heterocycloalkyl, C3-C10 cycloalkylene, C6-C10 arylene, single bond, heteroatom is N, S or P; preferably L 2 The 4-10 membered heterocycloalkyl of is azetidinyl, piperidinyl or piperazinyl; L 3 is selected from a single bond, a C1-C6 alkylene group, -O-, *-N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group; preferably L 3 Methylene, ethylene, ethynyl, *-N(R B1 )R B2 -, R B1 is H, methyl or ethyl, R B2 is a single bond or a methylene group; Preferably, L 4 is selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably L 4 The 4-10 membered heterocycloalkyl of is azetidinyl, piperidinyl or piperazinyl; L 5 is selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, or a carbonyl group; C 1 is selected from a single bond, a C6-C10 arylene group or a 5-10 membered heteroarylene group, preferably a single bond, a pyrazolyl group, an imidazolyl group, a triazolyl group, in, End and L 5 connect, End and L 6 connect; L 6 is a C1-C3 alkyl group, the C1-C3 alkyl group is optionally substituted by OH, preferably L 6 for R 2 Selected from halogen and haloalkyl, preferably Cl or -CF3; X is C or N.

12. The compound according to claim 1 or 11, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The compound of formula VI or formula VI' is selected from any one of formula VI1, formula VI2, formula VI1', and formula VI2': In Formula VI1 or Formula VI1', A 1 is selected from 5-10 membered heteroarylene groups, wherein the heteroatoms are preferably N atoms and / or O atoms, and the number of heteroatoms is preferably 1-3, and is preferably used as A 1 The 5-10 membered heteroarylene group is triazolyl, isoxazolyl or pyrazolyl; 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more of the following groups: =O, R A1 and R A2 Each is independently H, methyl or ethyl; A 2 is selected from C6-C10 arylene or 5-10 membered heteroarylene, preferably phenylene, pyridylene or indolylene, wherein A 2 The C6-C10 arylene and 5-10 membered heteroarylene are optionally substituted by F, C, methyl, or ethyl; L 1 is selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkynylene group, preferably a single bond, a methylene group, an ethylene group, an ethynylene group; L 2 is selected from 4-10 membered heterocycloalkyl, single bond, C3-C6 cycloalkylene, C6-C8 arylene, the heteroatom is N, S or P; preferably L 2 The 4-10 membered heterocycloalkyl group is azetidinyl, piperidinyl or piperazinyl, preferably L 2 The C3-C6 cycloalkylene group is hexylene, preferably L 2 The C6-C8 arylene group is a phenylene group; L 3 is selected from a single bond, a C1-C3 alkylene group, -O-, *-N(R B1 )R B2 -, R B1 is H, C1-C3 alkyl, R B2 is a C0-C3 alkylene group; preferably L 3 Methylene, ethylene, ethynyl, *-N(R B1 )R B2 -、-O-,R B1 is H, methyl or ethyl, R B2 is a single bond or a methylene group; L 4 is selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably L 4 The 4-10 membered heterocycloalkyl of is azetidinyl, piperidinyl or piperazinyl; L 5 is selected from C1-C3 alkenylene, C1-C3 alkynylene, carbonyl or phenylene; n is 0, 1, 2 or 3; R C3 and R C4 Each is independently H, methyl, ethyl or hydroxyl; R 2 Selected from halogen and haloalkyl, preferably Cl or -CF3; X is C or N; Preferably, in formula VI1 or formula VI1' Any one selected from the following groups: Preferably, in Formula VI1' Any one selected from the following groups: Preferably, in Formula VI1 or Formula VI1' Any one selected from the following groups: In Formula VI2 or Formula VI2', A 1 is selected from 5-10 membered heteroarylene groups, wherein the heteroatoms are preferably N atoms and / or O atoms, and the number of heteroatoms is preferably 1-3, and is preferably used as A 1 The 5-10 membered heteroarylene group is triazolyl, isoxazolyl or pyrazolyl; 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more of the following groups: =O, R A1 and R A2 Each is independently H, methyl or ethyl; A 2 is selected from C6-C10 arylene or 5-10 membered heteroarylene, preferably phenylene, pyridylene or indolylene, wherein A 2 The C6-C10 arylene and 5-10 membered heteroarylene are optionally substituted by F, C, methyl, or ethyl; L 1 Selected from single bonds, C1-C6 alkylene, *-N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group, preferably a methylene group, an ethylene group or a *-N(R B1 )R B2 -, R B1 is H, methyl or ethyl, R B2 is a single bond or a methylene group; L 2 is selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably L 2 The 4-10 membered heterocycloalkyl of is azetidinyl, piperidinyl or piperazinyl; L 3 is selected from a single bond, a C1-C6 alkylene group, preferably a single bond, a methylene group or an ethylene group; L 4 is selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably L 4 The 4-10 membered heterocycloalkyl of is azetidinyl, piperidinyl or piperazinyl; L 5 is selected from a single bond, a C1-C6 alkylene group, preferably a single bond, a methylene group or an ethylene group; n is 0, 1, 2 or 3, preferably 0; R C3 and R C4 Each independently represents H, methyl, ethyl or hydroxyl, preferably R C3 and R C4 are each independently methyl or hydroxy; R 2 Selected from halogen and haloalkyl, preferably Cl or -CF3; X is C or N; Preferably, in formula VI2 or formula VI2' Any one selected from the following groups: Preferably, in Formula VI2' Any one selected from the following groups: Preferably, in Formula VI2 or Formula VI2' Any one selected from the following groups:

13. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The formula VII satisfies any one or more of the following conditions: In Formula VII, A 1 is selected from 5-10 membered heteroarylene groups, wherein the heteroatoms are preferably N atoms and / or O atoms, and the number of heteroatoms is preferably 1-3, as A 1 The 5-10 membered heteroaryl is preferably triazolyl, isoxazolyl or pyrazolyl, and more preferably triazolyl; preferably as A 1 The 5-10 membered heteroarylene group is optionally substituted by any one or more selected from the group consisting of: =O, =S; A 2 is selected from C6-C10 arylene or 5-10 membered heteroarylene, preferably phenylene, indolylene or pyridylene, wherein A 2 The C6-C10 arylene and 5-10 membered heteroarylene are optionally substituted by F, Cl, methyl or ethyl; L 1 , L 2 , L 3 , L 4 and L 5 Each is independently selected from a single bond, a C1-C6 alkylene group, a carbonyl group, a 4-10 membered heterocycloalkylene group, -O-, -N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group; L 1 A single bond, a C1-C6 alkylene group, -N(R B1 )R B2 -, R B1 is H, C1-C6 alkyl, R B2 is a C0-C6 alkylene group, preferably L 1 Selected from single bonds, methylene, ethylene, propylene, -N(R B1 )R B2 -, R B1 is H, methyl or ethyl, R B2 is a single bond, methylene or ethylene; L 2 is selected from 4-10 membered heterocycloalkylene, a single bond, and the heteroatom is N, S or P; preferably, the 4-10 membered heterocycloalkylene as L2 is azetidinylene, piperidinylene or piperazinylene; L 3 is selected from a single bond, a C1-C6 alkylene group, preferably a single bond, a methylene group or an ethylene group; L 4 is selected from 4-10 membered heterocycloalkylene, a single bond, and the heteroatom is N, S or P; preferably, the 4-10 membered heterocycloalkylene as L4 is azetidinylene, piperidinylene or piperazinylene; L 5 is selected from a single bond or a carbonyl group; C 1 The ring is selected from phenylene, pyridinylene, pyrimidinylene, pyridazinylene, preferably phenylene or pyridinylene; R 5 is selected from H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, OH, NH2, CN, nitro, carboxyl, preferably halogen is F or Cl, preferably R 5 Selected from H, F or Cl R 3 , R 4 are each independently selected from H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, and R 3 and R 4 Connected to the carbon atom shared by the two 4-6 membered cycloalkyl, preferably R 3 and R 4 connected to the carbon atom common to both cyclobutyl or cyclohexyl; R 2 is halogen, C1-C3 alkyl, C1-C3 haloalkyl, preferably F, Cl or trifluoromethyl; Preferably, in formula VII Any one selected from the following groups: Preferably, in Formula VII Any one selected from the following groups: Preferably, in Formula VII Any one selected from the following groups:

14. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, characterized in that: The compound is selected from any one of the following compounds:

15. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof and one or more pharmaceutically acceptable excipients or carriers.

16. A kit product comprising: a) a container; b) at least one compound according to any one of claims 1 to 14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof, located in the container; and c) optional packaging and / or instructions.

17. A drug conjugate comprising the compound according to any one of claims 1 to 14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof.

18. A method for preventing and / or treating a disease or condition associated with abnormal activity or expression of an androgen receptor (AR) or an AR splicing mutant in a mammal, comprising administering to the receptor a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof, the pharmaceutical composition according to claim 15, the kit product according to claim 16, or the drug conjugate according to claim 17.

19. Use of the compound according to any one of claims 1 to 14, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, the pharmaceutical composition according to claim 15, or the drug conjugate according to claim 17 in the preparation of an androgen receptor or androgen receptor splicing mutant modulator.

20. Use of the compound according to any one of claims 1 to 14, or its stereoisomer, or its pharmaceutically acceptable salt, or its deuterated compound, or its tautomer, or its polymorph, or its solvate, or its N-oxide, or its isotope-labeled compound, or its metabolite, or its prodrug, the pharmaceutical composition according to claim 15, or the drug conjugate according to claim 17 in the preparation of a medicament for treating a disease associated with abnormal activity or expression of mammalian androgen receptor (AR) or AR splicing mutants, wherein the disease is preferably cancer, tumor disease, metabolic disorder, benign prostatic hyperplasia and prostatic hypertrophy, acne (acne vulgaris), seborrheic dermatitis, hirsutism, male pattern baldness and male-pattern baldness, precocious puberty, polycystic ovary syndrome, sexual inversion and virilization; preferably, the cancer or tumor disease includes Including breast cancer and breast tumors (breast cancer including ductal and lobular forms, AR-positive breast cancer, breast cancer in situ), skin tumors (basal cell carcinoma, acanthoma, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, non-melanoma skin cancer, Merkel cell skin cancer, mast cell tumors), tumors of the reproductive organs (endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer and uterine cancer in women and prostate cancer and testicular cancer in men); preferably, the metabolic disorder includes the catabolic side effects of glucocorticoids, fat metabolism disorders, long-term critically ill catabolic states, age-related testosterone level decreases in men, male menopause, gonadal function decline, male hormone replacement therapy, male and female sexual dysfunction (e.g., erectile dysfunction, decreased sexual drive, decreased sexual satisfaction, decreased libido).

21. A compound according to any one of claims 1 to 14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof, a pharmaceutical composition according to claim 15, a kit product according to claim 16, or a drug conjugate according to claim 17, for treating a disease associated with abnormal activity or expression of a mammalian androgen receptor (AR) or an AR splicing mutant, Preferably, the disease is cancer, tumor disease, metabolic disorder, benign prostatic hyperplasia and prostatic hypertrophy, acne (acne vulgaris), seborrheic disease, hirsutism, male pattern baldness and male-pattern baldness, precocious puberty, polycystic ovary syndrome, sexual perversion and virilization; Preferably, the cancer or tumor disease includes breast cancer and breast tumors (breast cancer including ductal and lobular forms, AR-positive breast cancer, breast cancer in situ), skin tumors (basal cell carcinoma, acanthoma cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, non-melanoma-like skin cancer, Merkel cell skin cancer, mast cell tumors), tumors of reproductive organs (endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer and uterine cancer in women and prostate cancer and testicular cancer in men); Preferably, the metabolic disorders include the catabolic side effects of glucocorticoids, dysregulated fat metabolism, long-term critically ill catabolic states, age-related decreases in testosterone levels in males, male menopause, hypogonadism, male hormone replacement therapy, male and female sexual dysfunction (e.g., erectile dysfunction, decreased sexual drive, decreased sexual satisfaction, loss of libido).

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