WO2025036269A1 - Compound, composition comprising same, and use thereof - Google Patents

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

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority of 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

The present application relates to the field of medicine, and in particular to a compound, a composition comprising the compound, and applications thereof.

Background Art

Androgen receptors (AR) are a type of steroid receptor in the nuclear receptor superfamily. Wild-type AR consists of four domains: N-terminal transcriptional activation domain (NTD), DNA binding domain (DBD), hinge region, and ligand binding domain (LBD). After AR combines with its ligand androgen in vivo, it forms an AR dimer, which is then phosphorylated and transferred from the cytoplasm to the nucleus. It then mediates the transcription and activation of downstream genes in the nucleus, thereby regulating a series of physiological and pathological functions. In normal adult prostates, AR regulates the dynamic balance between proliferation and apoptosis of prostate epithelial cells. This dynamic balance is broken in prostate cancer (PC) tissues, promoting the proliferation and survival of tumor cells, which is the main cause of prostate cancer. In addition, abnormalities in the androgen receptor signaling pathway play an important role in the occurrence and development of breast cancer, bladder cancer, etc. Therefore, inhibiting or degrading androgen receptors 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, darolutamide and other drugs on the market, and 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 acquired drug resistance during treatment due to increased AR expression or new AR mutations or E3 mutations.

Heat shock proteins (such as HSP90) are one of the main proteins that play a role in maintaining cell homeostasis. HSP90 is involved in the correct folding of newly formed proteins and the repair process 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.

Summary of the invention

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

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, and the structure of the compound is shown in Formula 0:

The formula 0 is selected from any one of the following formulas I to VII:

In Formula I or Formula I', A ¹ is a 5-10 membered heteroarylene group, 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 and halogen;

R ¹ is a substituent at any position of the indolyl group, and R ¹ is 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;

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 at least two of L ¹ , L ² , L ³ , L ⁴ and L ⁵ satisfy the following conditions: one is a 4-10 membered heterocycloalkylene group and the other is a C1-C6 alkylene group;

^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 by halogen or C1-C6 alkyl;

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

^C2 is selected from 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene, and the 4-10 membered cycloalkylene and the 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;

^R2 is selected from halogen and C1-C6 haloalkyl;

X is C or N;

In formula II or formula II', ^A1 is a 5-10 membered heteroarylene group, 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, =S, halogen, R ^A1 and R ^A2 are each independently H or C1-C6 alkyl;

^A2 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 are each 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( ^RB1 ) ^RB2- , ^RB1 is H, a C1-C6 alkyl group, ^RB2 is a C0-C6 alkylene group, and at least two of L ¹ , L ² , L ³ and L ⁴ satisfy the following conditions: one is a 4-10 membered heterocycloalkylene group, and the other is a C1-C6 alkylene group;

^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 by halogen or C1-C6 alkyl;

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

^C2 is selected from 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene, and the 4-10 membered cycloalkylene and the 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;

^R2 is selected from halogen and haloalkyl;

X is C or N;

In formula III or formula III', ^A2 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 are each independently selected from a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, carbonyl, 4-10 membered heterocycloalkylene, -O-, -N( ^RB1 ) ^RB2- , ^RB1 is H, C1-C6 alkyl, ^RB2 is C0-C6 alkylene, -N( ^RB1 ) ^RB2- wherein the N atom is connected to A ² , and when L ¹ is C1-C6 alkylene, one of L ² and L ³ is a single bond and the other is a 4-10 membered heterocycloalkylene;

^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 by halogen or C1-C6 alkyl;

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

^C2 is selected from 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene, and the 4-10 membered cycloalkylene and the 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;

^R2 is selected from halogen and haloalkyl;

X is C or N;

In formula IV or formula IV', ^A1 is a 5-10 membered heteroarylene group, and the 5-10 membered heteroarylene group is optionally selected from the following groups: Any one or more of the group consisting of: C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S and halogen;

^A2 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 are each independently selected from a single bond, a C1-C6 alkylene group, a carbonyl group, a 4-10 membered heterocycloalkyl group, and at least one is not a single bond;

^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 by halogen or C1-C6 alkyl;

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

^C2 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 of the following groups: 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', ^A1 is a 5-10 membered heteroarylene group, wherein the heteroatoms are preferably N atoms and/or O atoms, and the number of heteroatoms is preferably 1-3, and the 5-10 membered heteroarylene group is optionally selected from any one of the following groups: or multiple substitutions: C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S, halogen, R ^A1 and R ^A2 are each independently H or C1-C6 alkyl;

^A2 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 are each independently selected from a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, carbonyl, 4-10 membered heterocycloalkylene, -O-, -C(O)-NH-, *-N( ^RB1 ) ^RB2- , ^RB1 is H, C1-C6 alkyl, ^RB2 is C0-C6 alkylene;

^C1 is selected from 5-10 membered heteroarylene, and the 5-10 membered heteroarylene is optionally substituted by any one or more selected from the group consisting of C1-C6 alkyl and halogen; ^L6 is selected from -R ^C1 -NH-, -R ^C1 -NH-C(O)- or a single bond, and R ^C1 is C0-C6 alkylene;

^C2 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-;

^R2 is selected from halogen and haloalkyl;

X is C or N;

In Formula VI or Formula VI', A ¹ is selected from 5-10 membered heteroarylene, and the 5-10 membered heteroarylene of A ¹ 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 are each independently H or C1-C6 alkyl;

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

L ¹ , L ² , L ³ , L ⁴ and L ⁵ are each independently selected from a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, carbonyl, 4-10 membered heterocycloalkylene, C3-C10 cycloalkylene, C6-C10 arylene, -O-, *-N( ^RB1 ) ^RB2- , phenylene, ^RB1 is H, C1-C6 alkyl, ^RB2 is C0-C6 alkylene, or for

^C1 is selected from a single bond, a C6-C10 arylene group or a 5-10-membered heteroarylene group, and the C6-C10 arylene group or the 5-10-membered heteroarylene group as ^C1 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;

^R2 is selected from halogen and haloalkyl;

X is C or N;

In formula VII, A ¹ is selected from 5-10 membered heteroarylene, and the 5-10 membered heteroarylene of A ¹ 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 are each independently H or C1-C6 alkyl;

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

L ¹ , L ² , L ³ , L ⁴ and L ⁵ are each independently selected from a single bond, C1-C6 alkylene, carbonyl, 4-10 membered heterocycloalkylene, -O-, *-N( ^RB1 ) ^RB2- , ^RB1 is H, C1-C6 alkyl, ^RB2 is C0-C6 alkylene;

The ^C1 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, NH ₂ , CN, nitro, carboxyl, C3-C6 cycloalkyl,

R ³ and R ⁴ are each independently selected from H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and R ³ and R ⁴ are connected to form a ring with the carbon atom shared by both;

^R2 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl.

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.

In some embodiments of the present application, in Formula I or Formula I', the heteroatom of ^A1 being a 5-10 membered heteroarylene group is a N atom, and the number of heteroatoms is preferably 1-3; preferably, ^A1 being a 5-10 membered heteroarylene group is a triazolyl group, and the 5-10 membered heteroarylene group is The heteroaryl group may be optionally substituted by any one or more of the group consisting of C1-C6 alkyl, =O, =S.

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, a methylene group, an ethylene group, and a propylene group;

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 the heteroatom of the 4-10 membered heterocycloalkylene of L ² is N, S or P; preferably L ² is azetidinylene, piperidinylene or piperazinylene;

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, a methylene group, an ethylene group, and a propylene group;

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 the heteroatom of the 4-10 membered heterocycloalkylene of L ⁴ is N, S or P; preferably L ⁴ is azetidinylene, piperidinylene or piperazinylene;

In some embodiments of the present application, in Formula I or Formula I', L ⁵ is selected from a single bond, a C1-C6 alkylene group, or a carbonyl group.

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':

In formula I1 or formula I1', ^C1 is selected from 5-10 membered heteroarylene groups, preferably ^C1 is imidazolylene, pyrazolylene, thiazolylene, pyrrolylene, pyridylene, pyrimidylene, pyridazinylene, pyrazinylene, preferably ^C1 is pyrazolylene, pyridylene, pyrimidylene, pyridazinylene, and the 5-10 membered heteroarylene groups are optionally substituted with halogen (e.g., F, Cl or Br), C1-C6 alkyl (e.g., methyl, ethyl, propyl or butyl);

^C2 is selected from 4-10 membered cycloalkylene, preferably 4-10 membered cycloalkylene as ^C2 is cyclobutylene, cyclopentylene, cyclohexylene or cycloheptylene, and 4-10 membered cycloalkylene as ^C2 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);

^L7 is selected from -O-, -NH-,

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

X is C or N.

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, The end is connected to C1, The end is connected to the indole group;

In some embodiments of the present application, in Formula I1' Any one selected from the following groups:

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

In formula I2, ^C1 is selected from C6-C10 aryl or 5-10 membered heteroaryl, the C6-C10 aryl as ^C1 is preferably phenylene, and the 5-10 membered heteroaryl as ^C1 is preferably pyridylene or pyridazinylene; and the C6-C10 aryl or 5-10 membered heteroaryl as ^C1 is optionally substituted by halogen (such as F, Cl or Br), C1-C6 alkyl (such as methyl, ethyl or propyl); ^R2 is selected from halogenated alkyl, preferably trifluoromethyl; X is C or N.

In some embodiments of the present application, in Formula I2 Any one selected from the following groups: in, Connect the end to ^C1 , The end is connected to the indole group.

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

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

In some embodiments of the present application, in Formula II or Formula II', the heteroatom of the 5-10 membered heteroarylene group of ^A1 is preferably N atom and/or O atom, and the number of heteroatoms is preferably 1-3, and the 5-10 membered heteroarylene group of ^A1 is substituted by any one or more of the following groups: R ^A1 and R ^A2 are each independently H or C1-C6 alkyl, preferably R ^A1 and R ^A2 are each independently H, methyl, ethyl, n-propyl or isopropyl; preferably, the 5-10 membered heteroaryl group as A ¹ is triazolylene, isoxazolylene or pyrazolylene.

In some embodiments of the present application, in Formula II or Formula II', ^A2 is a C6-C10 arylene group or a 5-10 membered heteroarylene group, preferably the C6-C10 aryl group or the 5-10 membered heteroaryl group of ^A2 is a phenylene group, a pyridylene group, a pyridazinylene group, a pyrimidinylene group, or an indolylene group, and further preferably the C6-C10 aryl group or the 5-10 membered heteroaryl group of ^A2 is a phenyl group or a pyridyl group, wherein the C6-C10 arylene group and the 5-10 membered heteroaryl group are optionally substituted by halogen or C1-C6 alkyl group.

In some embodiments of the present application, in Formula II or Formula II', L ¹ is selected from C1-C6 alkylene, -O-, -N( ^RB1 ) ^RB2- , ^RB1 is H, C1-C6 alkyl, and ^RB2 is C0-C6 alkylene.

In some embodiments of the present application, in Formula II or Formula II', ^L2 is selected from a 4-10 membered heterocycloalkylene group, a single bond, and preferably, the heteroatom in the 4-10 membered heterocycloalkylene group as ^L2 is N, S or P; preferably, the 4-10 membered heterocycloalkylene group as ^L2 is an azetidinylene group, an azacyclopentylene group, a piperidinylene group or a piperazinylene group.

In some embodiments of the present application, in Formula II or Formula II', L ³ is selected from a single bond, a C1-C6 alkylene group.

In some embodiments of the present application, in Formula II or Formula II', ^L4 is selected from a single bond, a 4-10 membered heterocycloalkylene group, -O-, and the heteroatom in the 4-10 membered heterocycloalkylene group as ^L4 is preferably N, S or P; the 4-10 membered heterocycloalkylene group as ^L4 is preferably an azetidinylene group, an azacyclopentylene group, a piperidinylene group or a piperazinylene group; and ^L2 and ^L4 are not single bonds at the same time.

In some embodiments of the present application, in Formula II or Formula II', ^C1 is selected from a C6-C10 arylene group or a 5-10-membered heteroarylene group; preferably, the C6-C10 aryl group or the 5-10-membered heteroaryl group as ^C1 is a phenylene group, a pyridylene group, a pyridazinylene group, a pyrimidinylene group, or an indolylene group; further preferably, the C6-C10 aryl group or the 5-10-membered heteroaryl group as ^C1 is a phenylene group or a pyridylene group, and the C6-C10 arylene group or the 5-10-membered heteroaryl group is optionally substituted with halogen or a C1-C3 alkyl group.

In some embodiments of the present application, in Formula II or Formula II', L ⁶ is 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 of the following groups: C1-C6 alkyl and halogen.

In some embodiments of the present application, in Formula II or Formula II', L ⁷ is selected from -O-, -NH-.

In some embodiments of the present application, in Formula II or Formula II', R ² is selected from halogen and -CF ₃ .

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

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':

In formula III or III', the heteroatom of the 5-10 membered heteroarylene group as ^A1 is preferably N atom and/or O atom, and the number of heteroatoms is preferably 1, 2 or 3, and the 5-10 membered heteroarylene group as ^A1 is substituted by any one or more of the following groups: R ^A1 and R ^A2 are each independently H, methyl or ethyl;

^L1 is selected from C1-C6 alkylene, -O-, -N( ^RB1 ) ^RB2- , ^RB1 is H, methyl, ethyl or n-propyl, ^RB2 is a single bond, methylene, ethylene, propylene or butylene;

L ² is selected from 4-6 membered heterocycloalkylene, single bond, preferably 4-6 membered heterocycloalkylene as L ² 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 the 4-16 membered heterocycloalkylene group as L ⁴ is an azetidinylene group, an azocyclopentylene group, a piperidinylene group or a piperazinylene group; and L ² and L ⁴ are not single bonds at the same time;

^C1 is preferably selected from C6-C10 arylene or 5-10 membered heteroarylene, preferably C1 is phenyl, preferably ^C1 is pyridylene, pyrimidylene, pyridazinylene, pyrazinylene, more preferably pyridazinylene, and ^C6 -C10 arylene or 5-10 membered heteroarylene is optionally substituted by halogen (e.g., F, Cl or Br), C1-C3 alkyl (e.g., methyl, ethyl or propyl);

^C2 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 (such as methyl, ethyl or propyl) and halogen (such as F, Cl or Br).

In some embodiments of the present application, in Formula III or Formula III' Any one selected from the following groups: More preferably in, Connect the end to ^C1 , The end is connected to a phenyl group;

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

Preferably

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

In some embodiments of the present application, in Formula III or Formula III', ^A2 is a phenylene group, a 5-membered heteroarylene group, or a 6-membered heteroarylene group, preferably ^A2 is a phenylene group, a pyridylene group, a pyridazinylene group, or a pyrimidylene group; the phenylene group, the 5-membered heteroarylene group, or the 6-membered heteroarylene group is optionally substituted by a halogen or a C1-C6 alkyl group.

In some embodiments of the present application, in Formula III or Formula III', L ¹ is selected from C1-C6 alkylene, -O-, -N( ^RB1 ) ^RB2- , ^RB1 is H, C1-C6 alkyl, and ^RB2 is C0-C6 alkylene.

In some embodiments of the present application, in Formula III or Formula III', ^L2 is selected from 4-10 membered heterocycloalkyl, the heteroatom is N, S or P; preferably azetidinylene, piperidinylene or piperazinylene.

In some embodiments of the present application, in Formula III or Formula III', ^L3 is selected from a single bond, a C1-C6 alkylene, a carbonyl group, a C1-C6 alkylene-carbonyl group; and when ^L1 is a C1-C6 alkylene group, one of ^L2 and ^L3 is a single bond and the other is a 4-10 membered heterocycloalkyl group.

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

In some embodiments of the present application, in Formula III or Formula III', ^C1 is selected from a C6-C10 arylene group or a 5-10-membered heteroarylene group; preferably, the C6-C10 aryl group or the 5-10-membered heteroaryl group as ^C1 is a phenylene group, a pyridylene group, a pyridazinylene group, a pyrimidinylene group, or an indolylene group; further preferably, the C6-C10 aryl group or the 5-10-membered heteroaryl group as ^C1 is a phenylene group or a pyridylene group, and the C6-C10 arylene group or the 5-10-membered heteroaryl group is optionally substituted with halogen or a C1-C3 alkyl group.

In some embodiments of the present application, in formula III or formula III', L ⁶ is 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 of the following groups: C1-C6 alkyl and halogen.

In some embodiments of the present application, in Formula III or Formula III', L ⁷ is selected from -O-, -NH-.

In some embodiments of the present application, in Formula III or Formula III', R ² is selected from halogen and -CF ₃ .

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

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':

In formula III1 or III1', ^A2 is phenylene, 5-membered heteroarylene, 6-membered heteroarylene, preferably ^A2 is phenylene, pyridylene, pyridazinylene, pyrimidylene;

^L1 is selected from C1-C6 alkylene, -O-, -N( ^RB1 ) ^RB2- , ^RB1 is H, methyl, ethyl or propyl, ^RB2 is a single bond, methylene, ethylene, propylene or butylene, preferably ^L1 is selected from methylene, ethylene, -O-, -N( ^RB1 ) ^RB2- , ^RB1 is H, methyl or ethyl, ^RB2 is a single bond, methylene or ethylene;

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

^L3 is selected from a single bond, methylene, ethylene, propylene, carbonyl, methylene-carbonyl, ethylenecarbonyl; and when ^L1 is a methylene group, ^{one of} L2 and ^L3 is a single bond and the other is a 4-10 membered heterocycloalkyl group;

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

^C1 is preferably selected from C6-C10 arylene or 5-10 membered heteroarylene, preferably C1 is phenyl, preferably ^C1 is pyridylene, pyrimidylene, pyridazinylene, pyrazinylene, more preferably pyridazinylene, and ^C6 -C10 arylene or 5-10 membered heteroarylene is optionally substituted by halogen (e.g., F, Cl or Br), C1-C3 alkyl (e.g., methyl, ethyl or propyl);

^C2 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 (such as methyl, ethyl or propyl) and halogen (such as F, Cl or Br).

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

in, The end is connected to ^C1 , The end is connected to ^A2 .

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

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

In some embodiments of the present application, in Formula IV or Formula IV', ^A1 is a 5-10 membered heteroarylene group, wherein the heteroatom is preferably a N atom, and the number of heteroatoms is preferably 1-3. Preferably, ^A1 is a 5-10 membered heteroarylene group is a triazole group, and the 5-10 membered heteroarylene group is optionally substituted by any one or more of the following groups: =O, =S.

In some embodiments of the present application, in Formula IV or Formula IV', ^A2 is a C6-C10 arylene group or a 5-10 membered heteroarylene group, preferably the C6-C10 arylene group as ^A2 is a phenylene group, preferably the 5-10 membered heteroarylene group as ^A2 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), C1-C3 alkyl group (such as methyl, ethyl, propyl or butyl).

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

In some embodiments of the present application, in Formula IV or Formula IV', ^L2 is selected from 4-10 membered heterocycloalkyl, single bond, and the heteroatom is N, S or P; preferably azetidinyl, piperidinyl or piperazinyl.

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.

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

In some embodiments of the present application, in Formula IV or Formula IV', ^C1 is selected from a 5-10 membered heteroarylene group, preferably a 5-10 membered heteroarylene group as ^C1 is imidazolylene, pyrazolylene, thiazolylene, pyrrolylene, pyridylene, pyrimidylene, pyridazinylene, pyrazinylene, preferably a 5-10 membered heteroarylene group as ^C1 is pyrazolylene, pyridylene, pyrimidylene, pyridazinylene, and the 5-10 membered heteroarylene group is optionally substituted by halogen (e.g., F, Cl or Br), C1-C6 alkyl or C1-C6 alkyl. substituted (e.g., methyl, ethyl, propyl or butyl).

In some embodiments of the present application, in Formula IV or Formula IV', L ⁶ is selected from -NH-C(O)-.

In some embodiments of the present application, in formula IV or formula IV', ^C2 is selected from 4-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, preferably the 4-10 membered cycloalkylene of ^C2 is cyclobutylene, cyclopentylene, cyclohexylene or cycloheptylene, preferably the 5-10 membered heterocycloalkylene of ^C2 is piperidinylene or piperazinylene, and the 4-10 membered cycloalkyl and 5-10 membered heterocycloalkyl of ^C2 are optionally substituted by halogen, C1-C3 alkyl.

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

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

In some embodiments of the present application, in Formula IV or Formula IV', Any one selected from the following groups:
in, The end is connected to ^C1 , The end is connected to ^A2 .

In some embodiments of the present application, in Formula V or Formula V', ^A1 is a 5-10 membered heteroarylene group, preferably the 5-10 membered heteroarylene group of ^A1 is a triazolylene group, an isoxazolylene group or a pyrazolylene group, preferably the 5-10 membered heteroarylene group of ^A1 is optionally substituted by any one or more of the following groups: a C1-C6 alkyl group, a C3-C6 cycloalkyl group, =O, or =S.

In some embodiments of the present application, in Formula V or Formula V', ^A2 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.

In some embodiments of the present application, in Formula V or Formula V', ^L1 is selected from a single bond, a C1-C3 alkylene group, a C2-C3 alkynylene group, a carbonyl group, -C(O)-NH-, -O-, *-N( ^RB1 ) ^RB2- , ^RB1 is H, a C1-C3 alkyl group, and ^RB2 is a C0-C3 alkylene group.

In some embodiments of the present application, in Formula V or Formula V', ^L2 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.

In some embodiments of the present application, in Formula V or Formula V', 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-.

In some embodiments of the present application, in Formula V or Formula V', ^L4 is selected from 4-10 membered heterocycloalkylene, single bond, heteroatom The 4-10 membered heterocycloalkylene group as L ⁴ is preferably azetidinylene, piperidinylene or piperazinylene.

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.

In some embodiments of the present application, in Formula V or Formula V', ^C1 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 ^C1 is selected from A fused heterocyclic ring, wherein wherein 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; wherein Z ¹ , Z ² , Z ³ and Z ⁴ are independently selected from C or N, and at least one of them is N; wherein Y ¹ , Y ² , Y ³ , Y ⁴ , Z ¹ , Z ² , Z ³ and Z ⁴ are independently selected from C or N, and at least one of them 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 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.

In some embodiments of the present application, in Formula V or Formula V', ^L6 is selected from -R ^C1 -NH-, -R ^C1 -NH-C(O)- or a single bond, and R ^C1 is a C0-C3 alkylene group.

In some embodiments of the present application, in Formula V or Formula V', ^C2 is selected from 4-6 membered cycloalkylene, 5-6 membered heterocycloalkylene, 5-6 membered heteroaryl, and the 4-6 membered cycloalkylene, 5-6 membered heterocycloalkylene, 5-6 membered heteroaryl as ^C2 is optionally substituted by any one or more of the group consisting of: C1-C3 alkyl and halogen.

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

In some embodiments of the present application, in Formula V or Formula V', R ² is selected from halogen and halogenated alkyl.

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

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':

In formula V1 or formula V1', ^A1 is a 5-10 membered heteroarylene group, preferably the 5-10 membered heteroarylene group as ^A1 is triazolylene, isoxazolylene or pyrazolylene, preferably the 5-10 membered heteroarylene group as ^A1 is optionally substituted by any one or more of the following groups: C1-C3 alkyl, =O, =S;

^A2 is phenylene, pyridylene, pyrimidylene, pyrazinylene, pyridazinylene, preferably phenylene or pyridylene;

^L1 is selected from a single bond, C1-C3 alkylene, C2-C3 alkynylene, carbonyl, -C(O)-NH-, -O-, *-N( ^RB1 ) ^RB2- , ^RB1 is H, C1-C3 alkyl, ^RB2 is C0-C3 alkylene;

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 L ² is azetidinylene, piperidinylene or piperazinylene;

^L3 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, a single bond, and the heteroatom is N, S or P; preferably, the 4-10 membered heterocycloalkylene as L ⁴ is azetidinylene, piperidinylene or piperazinylene;

^L5 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-;

^C1 is selected from 5-8 membered heteroarylene, and the 5-8 membered heteroarylene is optionally substituted by any one or more selected from the group consisting of: C1-C3 alkyl and halogen; preferably ^C1 is selected from A fused heterocyclic ring, wherein wherein 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; wherein Z ¹ , Z ² , Z ³ and Z ⁴ are independently selected from C or N, and at least one of them is N; wherein Y ¹ , Y ² , Y ³ , Y ⁴ , Z ¹ , Z ² , Z ³ and Z ⁴ are independently selected from C or N, and at least one of them 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; it is further preferred that 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; it is more preferred that ^C1 is an imidazolyl group, a pyrazolyl group, a thiazolyl group, a pyrrolyl group, or a triazolyl group, and it is further preferred that the pyrrolyl group, the pyrazolyl group, the triazolyl group, the pyridazinyl group, the pyridinyl group, the benzopyrrolyl group, or the pyrimidopyrrolyl group; ^L6 is 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, and it is further preferred that the methyl group or the ethyl group;

Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ are each independently selected from C or N, and at least one of them is N, preferably imidazolylene, pyrazolylene, thiazolylene, pyrrolylene, triazolylene, and more preferably pyrazolylene;

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

X is C or N.

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, Connect the end to ^C1 , The end is connected to ^A2 .

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

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

In some embodiments of the present application,

In formula V2 or formula V2', ^A1 is a 5-10 membered heteroarylene group, preferably the 5-10 membered heteroarylene group as ^A1 is triazolylene, isoxazolylene or pyrazolylene, preferably the 5-10 membered heteroarylene group as ^A1 is optionally substituted by any one or more of the following groups: C1-C3 alkyl, =O, =S;

^A2 is phenylene, pyridylene, pyrimidylene, pyrazinylene, pyridazinylene, preferably phenylene or pyridylene;

L ¹ is selected from a single bond, a C1-C3 alkylene group;

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 L ² 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, a single bond, and the heteroatom is N, S or P; preferably, the 4-10 membered heterocycloalkylene as L ⁴ 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 are each independently selected from C or N, and at least one of them is N, preferably is imidazolylene, pyrazolylene, thiazolylene, pyrrolylene, triazolylene, more preferably pyrrolylene, pyrazolylene, triazolylene;

^C2 is selected from 4-6 membered cycloalkylene, preferably butylene or hexyl, and the 4-6 membered cycloalkylene as ^C2 is optionally Any one or more substitutions selected from the group consisting of methyl, ethyl, F, and Cl;

L ⁷ is selected from -O-, -NH-;

^R2 is selected from halogen (e.g. F, Cl or Br) and haloalkyl (e.g. trifluoromethyl);

X is C or N.

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

in, End and connect, The end is connected to ^A2 .

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

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

In some embodiments of the present application, in Formula VI or Formula VI', ^A1 is selected from 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. The 5-10 membered heteroarylene group as ^A1 is preferably a triazolyl group, an isoxazolyl group or a pyrazolyl group; the 5-10 membered heteroarylene group as ^A1 is optionally substituted by any one or more of the following groups: C1-C6 alkyl, =O, =S, ^RA1 and ^RA2 are each independently H or C1-C3 alkyl.

In some embodiments of the present application, in Formula VI or Formula VI', ^A2 is selected from C6-C10 arylene or 5-10 membered heteroarylene, preferably phenylene, pyridylene or indolylene, wherein the C6-C10 arylene and 5-10 membered heteroarylene as ^A2 are optionally substituted by halogen or C1-C3 alkyl.

In some embodiments of the present application, in Formula VI or Formula VI', ^L1 is selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkynylene group, *-N( ^RB1 ) ^RB2- , ^RB1 is H, a C1-C6 alkyl group, ^RB2 is a C0-C6 alkylene group, preferably a methylene group, an ethylene group, an ethynylene group, *-N( ^RB1 ) ^RB2- , ^RB1 is H, a methyl group or an ethyl group, and ^RB2 is a single bond or a methylene group.

In some embodiments of the present application, in Formula VI or Formula VI', ^L2 is selected from 4-10 membered heterocycloalkyl, C3-C10 cycloalkylene, C6-C10 arylene, single bond, and the heteroatom is N, S or P; preferably, the 4-10 membered heterocycloalkyl as ^L2 is azetidinyl, piperidinyl or piperazinyl.

In some embodiments of the present application, in Formula VI or Formula VI', ^L3 is selected from a single bond, a C1-C6 alkylene group, -O-, *-N( ^RB1 ) ^RB2- , ^RB1 is H, a C1-C6 alkyl group, and ^RB2 is a C0-C6 alkylene group; preferably ^{, L3} is a methylene group, an ethylene group, an ethynylene group, *-N( ^RB1 ) ^RB2- , ^RB1 is H, a methyl group or an ethyl group, and ^RB2 is a single bond or a methylene group.

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

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.

In some embodiments of the present application, in Formula VI or Formula VI', ^C1 is selected from a single bond, a C6-C10 arylene group or a 5-10 The heteroarylene group is preferably a single bond, a pyrazolyl group, an imidazolyl group, a triazolyl group, in, The end is connected to ^L5 , The end is connected to ^L6 .

In some embodiments of the present application, in Formula VI or Formula VI', ^L6 is a C1-C3 alkyl group, and the C1-C3 alkyl group is optionally substituted by OH, preferably L6 is

In some embodiments of the present application, in Formula VI or Formula VI', R ² is selected from halogen and halogenated alkyl, preferably Cl or -CF ₃ .

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

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':

In formula VI1 or formula VI1', ^A1 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. The 5-10 membered heteroarylene group as ^A1 is preferably triazolylene, isoxazolylene or pyrazolylene; the 5-10 membered heteroarylene group as ^A1 is optionally substituted by any one or more of the following groups: =O, R ^A1 and R ^A2 are each independently H, methyl or ethyl;

A ² is selected from C6-C10 arylene or 5-10 membered heteroarylene, preferably phenylene, pyridylene or indolylene, wherein the C6-C10 arylene and 5-10 membered heteroarylene as A ² 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 or an ethynylene group;

^L2 is selected from 4-10 membered heterocycloalkyl, single bond, C3-C6 cycloalkylene, C6-C8 arylene, and the heteroatom is N, S or P; preferably, the 4-10 membered heterocycloalkyl as ^L2 is azetidinyl, piperidinyl or piperazinyl, preferably as The C3-C6 cycloalkylene group of L ² is hexylene, and the C6-C8 arylene group of L ² is preferably phenylene;

^L3 is selected from a single bond, C1-C3 alkylene, -O-, *-N( ^RB1 ) ^RB2- , ^RB1 is H, C1-C3 alkyl, ^RB2 is C0-C3 alkylene; preferably ^L3 is methylene, ethylene, ethynylene, *-N( ^RB1 ) ^RB2- , -O-, ^RB1 is H, methyl or ethyl, ^RB2 is a single bond or methylene;

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

^L5 is selected from C1-C3 alkenylene, C1-C3 alkynylene, carbonyl or phenylene;

n is 0, 1, 2 or 3;

R ^C3 and R ^C4 are each independently H, methyl, ethyl or hydroxyl;

R ² is selected from halogen and haloalkyl, preferably Cl or -CF ₃ ;

X is C or N.

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

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

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

In some embodiments of the present application,

In formula VI2 or formula VI2', ^A1 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. The 5-10 membered heteroarylene group as ^A1 is preferably triazolylene, isoxazolylene or pyrazolylene; the 5-10 membered heteroarylene group as ^A1 is optionally substituted by any one or more of the following groups: =O, R ^A1 and R ^A2 are each independently H, methyl or ethyl;

A ² is selected from C6-C10 arylene or 5-10 membered heteroarylene, preferably phenylene, pyridylene or indolylene, wherein the C6-C10 arylene and 5-10 membered heteroarylene as A ² are optionally substituted by F, C, methyl or ethyl;

^L1 is selected from a single bond, a C1-C6 alkylene group, *-N( ^RB1 ) ^RB2- , ^RB1 is H, a C1-C6 alkyl group, ^RB2 is a C0-C6 alkylene group, preferably a methylene group, an ethylene group or *-N( ^RB1 ) ^RB2- ,

^RB1 is H, methyl or ethyl, ^RB2 is a single bond or methylene;

L ² is selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably, 4-10 membered heterocycloalkyl as L ² 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, 4-10 membered heterocycloalkyl as L ⁴ 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 are each independently H, methyl, ethyl or hydroxyl, preferably R ^C3 and R ^C4 are each independently methyl or hydroxyl;

R ² is selected from halogen and haloalkyl, preferably Cl or -CF ₃ ;

X is C or N.

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

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

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

In some embodiments of the present application, in Formula VII, ^A1 is selected from a 5-10 membered heteroaryl group, wherein the heteroatom is preferably a N atom and/or an O atom, and the number of heteroatoms is preferably 1-3. The 5-10 membered heteroaryl group as ^A1 is preferably a triazole group, an isoxazole group or a pyrazolyl group, and is further preferably a triazole group; preferably, the 5-10 membered heteroaryl group as ^A1 is optionally substituted by any one or more of the following groups: =O, =S.

In some embodiments of the present application, in formula VII, ^A2 is selected from a C6-C10 arylene group or a 5-10 membered heteroarylene group, preferably a phenylene group, an indolylene group or a pyridylene group, wherein the C6-C10 arylene group and the 5-10 membered heteroarylene group as ^A2 are optionally substituted by F, Cl, methyl or ethyl.

In some embodiments of the present application, in Formula VII, 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, -O-, -N( ^RB1 ) ^RB2- , ^RB1 is H, a C1-C6 alkyl group, and ^RB2 is a C0-C6 alkylene group.

In some embodiments of the present application, in Formula VII, L ¹ is selected from a single bond, a C1-C6 alkylene, -N( ^RB1 ) ^RB2- , ^RB1 is H, a C1-C6 alkylene, ^RB2 is a C0-C6 alkylene, preferably L ¹ is selected from a single bond, a methylene, an ethylene, a propylene, -N( ^RB1 ) ^RB2- , ^RB1 is H, a methyl or an ethyl, and ^RB2 is a single bond, a methylene or an ethylene.

In some embodiments of the present application, in Formula VII, ^L2 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.

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

In some embodiments of the present application, in Formula VII, ^L4 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.

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

In some embodiments of the present application, in Formula VII, the ^C1 ring is selected from phenylene, pyridylene, pyrimidylene, pyridazinylene, preferably phenylene or pyridylene.

In some embodiments of the present application, in Formula VII, R ⁵ is selected from H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, OH, NH ₂ , CN, nitro, carboxyl, preferably halogen is F or Cl, preferably R ⁵ is selected from H, F or Cl.

In some embodiments of the present application, in formula VII, R ³ and R ⁴ are each independently selected from H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, and R ³ and R ⁴ are connected to form a 4-6 membered cycloalkyl group with a carbon atom shared by both, preferably R ³ and R ⁴ are connected to form a cyclobutyl or cyclohexyl group with a carbon atom shared by both.

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.

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

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

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

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

The second aspect of the present application provides a pharmaceutical composition, which comprises any one of the compounds of the first aspect above, 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 and one or more pharmaceutically acceptable excipients or carriers.

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.

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.

The fifth aspect of the present application provides 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 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, 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.

The sixth aspect of the present application provides the use of any one of the compounds of the first aspect above, 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 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.

The seventh aspect of the present application provides the use of any one of the compounds of the first aspect above, 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.

In some embodiments of the present application, 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, 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, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, non-melanoma skin cancer, melanocarcinoma), cervical cancer, uterine carcinoma, uterine carcinoma, cervical cancer ... 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, dysregulated 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).

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, which are used to treat diseases related to abnormal activity or expression of mammalian androgen receptor (AR) or AR splicing mutants.

In some embodiments, preferred diseases are cancer, tumor diseases, metabolic disorders, benign prostatic hyperplasia and prostatic hypertrophy, acne (acne vulgaris), seborrheic disease, hirsutism, male pattern baldness and male pattern hair loss, precocious puberty, polycystic ovary syndrome, paraphilia 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 Cancer, acanthopanax, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, non-melanoma-like skin cancer, Merkel cell skin cancer, mast cell tumor), 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 the catabolic side effects of glucocorticoids, dysregulated fat metabolism, long-term critically ill catabolic states, age-related testosterone reduction in men, male menopause, hypogonadism, male hormone replacement therapy, male and female sexual dysfunction (e.g., erectile dysfunction, decreased sexual drive, decreased sexual satisfaction, decreased libido).

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Definition and Description

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 special definition, but should be understood according to the ordinary meaning.

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

When the R ¹ substituent on the indole has no fixed structure, it means that R ¹ can be attached to any position on the indole ring, and R ¹ can be 1, 2, 3, 4 or 5.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are 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.

The term "pharmaceutically acceptable salt" refers to salts of compounds of the present application, prepared from compounds with specific substituents discovered in the present application and relatively non-toxic acids or bases. When the compounds of the present application 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 a pure 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 a 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, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; 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, etc.; also include 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 any base or acid addition salt.

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, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

The stereoisomers of the compounds of the present application may exist in any form of tautomerism, 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 mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may exist in substituents such as alkyl. All of these isomers may be present in the form of tautomers. The structures and mixtures thereof are all included in the scope of protection claimed in this application.

The application also includes all suitable isotope-labeled compounds of the compounds of the present invention. In this case, the isotope-labeled compounds of the compounds of the present invention are understood to be such compounds, wherein at least one atom in the compounds of the present invention is replaced by another atom with the same atomic number but atomic mass being different from the atomic mass common in nature or mainly existing. The isotope examples that can be introduced into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine and iodine, such as ² 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. Specific isotopic labels of the compounds of the present application (such as those in which one or more radioactive isotopes are introduced in particular) can be used, for example, to study the mechanism of action or distribution of the active substance in vivo; because they can be relatively easily prepared and detected, compounds labeled with ³ H- or ¹⁴ C-isotopes are particularly suitable for this. In addition, the introduction of isotopes (such as deuterium) can produce certain therapeutic advantages due to the higher metabolic stability of the compound, such as an increase in the half-life in vivo or a reduction in the effective dose required; the modifications of the compounds of the present application can therefore optionally also represent preferred embodiments of the present invention. Isotopic labels of the compounds of the present application can be prepared by methods known to those skilled in the art, such as by the specifications given in the following methods and embodiments, using the corresponding isotopic modifications of the respective reagents and/or starting compounds.

The compounds of the present application may contain non-natural ratios of atomic isotopes on one or more atoms constituting the compound. For example, compounds may be labeled with radioactive isotopes, such as tritium (3H), iodine-125 (125I) or C-14 (14C). For another example, deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. 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 the present application. "Optional" or "optionally" refers to the possibility that the event or situation described subsequently may but does not necessarily occur, and the description includes the situation in which the event or situation occurs and the situation in which the event or situation does not occur.

In the present application, "polymorph" refers to a crystalline form of a compound (or its salt, hydrate or solvate) in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystal forms usually 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 crystal form being dominant.

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

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

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.

In the present application, "prodrug" refers to a compound obtained by chemically modifying a drug, which is inactive or less active in vitro and releases active drugs through enzymatic or non-enzymatic conversion in vivo to exert its efficacy.

The term "substituted" or "substituted by..." means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. The term "optionally substituted" or "optionally substituted by..." means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be any on the basis of chemical practicability.

When any variable (e.g., R ¹ ) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1, 2, 3, 4, or 5 R ¹ s, then the group may be optionally substituted with 1, 2, 3, 4, or 5 R ^{1 s} , and each occurrence of R ¹ has independent options. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.

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

When the substituent is listed without indicating the atom through which it is connected to the substituted group, the substituent can be bonded through any atom thereof. For example, a pyridyl substituent can be bonded to the substituted group through any carbon atom on the pyridine ring.

When the listed linking group does not specify its connection direction, its connection direction is arbitrary. For example, the linking group L ⁶ is -NH-C(O)-, in this case -NH-C(O)- can be connected in the same direction as the reading order from left to right, or in the opposite direction to the reading order from right to left. The combination of the linking group, substituent and/or its variant is allowed only when such combination will produce a stable compound.

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

Unless otherwise specified, the term "C1-C6 alkylene" is used to represent a straight or branched divalent saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C1-C6 alkylene includes C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C4, C6, C5, C4, C3, C2C1 alkylene, etc. C1-C6 alkyl is also understood in the above manner; except that the alkyl is monovalent (such as CH ₃ ) and the alkylene is divalent (such as -CH ₂ -).

Unless otherwise specified, the term "C2-C6 alkenylene" is used to represent a straight or branched divalent unsaturated hydrocarbon group consisting of 2 to 6 carbon atoms. The C2-C6 alkenylene includes C2-C5, C2-C4, C2-C3, C2-C6, C6, C5, C4, C3 and C2 alkenyl, etc. C2-C6 alkenyl is also understood in the above manner; except that alkenyl is monovalent (such as _CH2 =CH-) and alkenylene is divalent (such as -CH=CH-).

Unless otherwise specified, the term "C2-C6 alkynylene" is used to represent a straight or branched divalent unsaturated hydrocarbon group consisting of 2 to 6 carbon atoms. The C2-C6 alkynylene includes C2-C5, C2-C4, C2-C3, C2-C6, C6, C5, C4, C3 and C2 alkynylene, etc. C2-C6 alkynyl is also understood in the above manner; except that alkynyl is monovalent (such as CH≡C-) and alkynylene is divalent (such as -C≡C-).

Unless otherwise specified, the term "C1-C6 alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule by an oxygen atom. The C1-C6 alkoxy includes C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C4, C6, C5, C4, C3, C2 and C1 alkoxy, etc. Examples of C1-C6 alkoxy 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, isopentyl and neopentyl), hexyl, etc.

The term "cycloalkyl" by itself or in combination with other terms represents a cyclic form of an alkyl, alkenyl or alkynyl group or a mixture thereof. In addition, the cycloalkyl group may contain fused rings, but does not include fused aryl and heteroaryl groups, unless otherwise specified as unsubstituted, otherwise the cycloalkyl group may be substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cyclohexynyl, cyclohexynyl, cyclohexadienyl, cyclopentadienyl, cyclopentenyl, cycloheptyl, norbornyl, etc. If the size of the ring is not specified, the cycloalkyl group described herein contains 3-10 ring members, 3-8 ring members, or 3-6 ring members. Cycloalkylene is also understood in the above manner, except that the cycloalkyl group is a monovalent ring and the cycloalkylene group is a divalent ring.

The term "heterocycle" or "heterocycloalkyl" or "heterocyclyl" by itself or in combination with other terms represents 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 be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. In multiple embodiments, the ring heteroatoms are selected from N, O and S. If not otherwise specified, the heterocyclic group described herein contains 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; usually containing no more than 3 of these heteroatoms in the heterocyclic group, and usually containing no more than 2 of these heteroatoms in a single ring of the heterocyclic group. The heterocyclic group may be fused with other carbocyclic, heterocyclic or aryl rings. The heterocyclic group may be connected to the rest of the molecule on the ring carbon or ring heteroatom, and the heterocyclic group may be substituted as described for the alkyl group. In addition, the heterocycle may contain fused rings, but does not include fused systems containing heteroaryl as part of the 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, dihydroindole (indoline), tetrahydrofuran-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, 1-piperazinyl, 2-piperazinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophene (including , tetrahydrothiophene-2-yl and tetrahydrothiophene-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 above manner, except that the heterocyclyl group is a monovalent ring and the heterocycloalkylene is a divalent ring.

In addition, if Similar to the heteroaryl shown, the double bond is not limited between ^Y1 and ^Y2 , between ^Y3 and the C atom, and is shifted to a chemically acceptable position depending on the valence state of the selected heteroatom.

Unless otherwise indicated, the term "aryl" refers to an aromatic hydrocarbon group, which can be a single ring or multiple rings (e.g., 1-3 rings) with rings fused together. An aryl group may contain fused rings, wherein one or more rings are optionally cycloalkyl, but do 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 above manner, except that aryl groups are monovalent rings and arylene groups are divalent rings.

The term "heteroaryl" as used herein refers to a group containing a monocyclic or two or three fused rings, wherein at least one ring is an aromatic ring containing 1-4 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. The heteroaryl group can be connected to the rest of the molecule through a ring carbon or a ring heteroatom, and if the group is a bicyclic or tricyclic ring, it can be connected through any ring of the heteroaryl group. The heteroaryl group can 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 aryl and heteroaryl ring systems are selected from the following acceptable substituents. Heteroarylene is also understood in the above manner, except that heteroaryl is a monovalent ring and heteroarylene is a divalent ring. Non-limiting examples of heteroarylene are pyrrolylene, pyrazolylene, imidazolylene, triazolyl ... oxazolyl, pyridazinyl, pyrazinyl, oxazolyl, phenyl-4-oxazolyl, isoxazolyl, thiazolyl, furanyl, thienyl, pyridinyl, 3-pyridyl, pyrimidinyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinolyl.

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-).

Unless otherwise indicated, the term "halo" or "halogen" itself or as part of other substituents refers to fluorine, chlorine, bromine or iodine atoms. In addition, terms such as "haloalkyl" should include monohaloalkyl and perhaloalkyl. For example, the term "halo (C ₁ -C ₄ ) 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 -CCl ₃ , -CF ₃ , -CCl ₂ CF ₃ , 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 -CF ₃ and -CF ₂ CF _3. Non-limiting examples of perchloroalkyl include -CCl ₃ and -CCl ₂ CCl ₃ .

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 only 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.

As used herein, "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 a disease or its symptoms; and/or may be therapeutic, capable of partially or completely curing a disease and/or side effects associated with the disease. The therapeutically effective amount of the compound of the present application generally includes any amount sufficient to inhibit AR activity that can be detected by any experiment described herein, by other AR activity assays known to those skilled in the art, or by detecting inhibition or relief of cancer symptoms.

The term "pharmaceutically acceptable carrier" and its congeners as used herein refer to adjuvants, binders, diluents, etc. known to the skilled person, 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 suitable for the intended route of administration (e.g., oral, parenteral) of a particular dosage form. The suitability 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 comprises at least one carrier or excipient other than water.

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.

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, by oral, parenteral, pulmonary, intranasal, sublingual, lingual, buccal, rectal, transdermal, transconjunctival or otic routes, or as implants or stents.

Suitable for oral administration are dosage forms which act according to the prior art, release the compound according to the invention quickly and/or in a modified manner and contain the compound according to the invention in crystalline and/or amorphisized and/or dissolved form, such as tablets (uncoated or coated tablets, for example with an enteric coating or with a coating that 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/lyophilized The invention can be in the form of a tablet, capsule (eg, hard capsule or soft capsule), dragee, granules, pellets, powder, emulsion, suspension, aerosol or solution.

Parenteral administration can be performed by bypassing an absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or including absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal). Suitable dosage forms for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

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), emulsions (milks), pastes, foams, dusting powders, implants or stents.

The term "treatment" as used herein refers to the administration of one or more drug 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. The term "prevention" as used herein refers to the administration of one or more drug substances, particularly compounds described herein and/or pharmaceutically acceptable salts thereof, to an individual with a constitution susceptible to the disease, in order to prevent the individual from suffering from 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 come directly from the combination of the two reagents initially added, that is, there may be one or more intermediates generated in the mixture, which ultimately lead to the formation of the indicated and/or desired product.

The compounds defined in the present invention or their pharmaceutically acceptable salts, or pharmaceutically acceptable compositions containing them, are effective modulators of androgen receptors. It is expected that the compounds of the present invention are potentially useful agents in treating diseases or medical conditions mediated solely or in part by androgen receptors. The compounds of the present invention may cause downregulation of androgen receptors and/or are selective agonists, partial agonists, antagonists or partial antagonists of androgen receptors.

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

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 diseases: breast cancer and breast tumors (breast cancer including ductal and lobular forms, as well as breast cancer in situ), skin tumors (basal cell carcinoma, acanthoma, 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).

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

In one embodiment, androgen receptor-associated conditions include prostate cancer, benign prostatic hyperplasia and 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 invention may also be used to improve ovulation in farmed animals.

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.

The 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 name.

Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

DETAILED DESCRIPTION

The following embodiments further describe the implementation of the present application in detail. The detailed description of the following embodiments is used to illustrate the principle of the present application, but cannot be used to limit the scope of the present application, that is, the present application is not limited to the described embodiments.

Example 1

Preparation of intermediate HSP90-1

first step:

Dissolve NaH (193 mg, 4.86 mmol) in 2 mL of anhydrous DMF, slowly add 5-nitroindole (436 mg, 2.70 mmol) in anhydrous DMF at 0°C, stirring while adding. After the addition is complete, continue stirring at 0°C. Stir for 10 min, then warm to room temperature and continue stirring for 1 h. Slowly drop the anhydrous DMF solution of the raw material HSP90-1-1 (1 g, 2.70 mmol) at 0°C, stirring while dropping. After the addition is complete, continue stirring at 0°C for 10 min, then warm to room temperature and continue stirring for 12 h. After the reaction is completed, add water and ethyl acetate to extract, add anhydrous magnesium sulfate to dry the organic phase, evaporate the solvent and column chromatography (PE: EA = 1/1) to obtain 644 mg of HSP90-1-2 as a light yellow solid, with a yield of 66.42%. UPLC-MS calculated for C ₁₉ H ₂₅ N ₃ O ₄ [M+H] ⁺ :360.19, found:360.31.

Step 2:

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

Step 3:

HSP90-1-4 (1.0 g, 6.57 mmol) and potassium ethyl xanthate (1.37 g, 8.54 mmol) were dissolved in 5 mL of anhydrous DMF and reacted at 100°C overnight. After the reaction was completed, 10 mL of ice water was added, 1N HCl was used to adjust the pH to 1-2, and a large amount of water was added. The mixture was stirred at 0°C for 1 h. Solids precipitated from the solution. The mixture was filtered and dried in vacuo to obtain HSP90-1-5, a yellow-brown solid of 1.448 g, with a yield of 96.66%. UPLC-MS calculated for C ₁₀ H ₁₂ O ₂ S ₂ [MH] ⁺ :227.02, found:227.11.

Step 4:

HSP90-1-5 (623 mg, 1.89 mmol) and NaHCO ₃ (638 mg, 7.59 mmol) were dissolved in 5 mL of anhydrous DMF. Chloroacetic acid (179 mg, 1.89 mmol) in anhydrous DMF was slowly added dropwise at 0°C under Ar protection, stirring was continued at 0°C for 5 min after the addition was completed, and then the temperature was raised to room temperature and stirring was continued for 90 min. 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 completed, the temperature was raised to 80°C and reacted for 3 h. After the reaction was completed, water and ethyl acetate were added for extraction. Anhydrous magnesium sulfate was added to dry the organic phase. The solvent was evaporated and then column chromatography (PE:EA=2/1) was performed to obtain HSP90-1-6 as a yellow solid (690 mg) with a yield of 69.71%. UPLC-MS calculated for C ₂₉ H ₃₇ N ₃ O ₄ S[M+H] ⁺ :524.26,found:524.48.

Step 5:

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, and the reaction was stirred at room temperature for 3 h. After the reaction was completed, water and ethyl acetate were added for extraction, anhydrous magnesium sulfate was added to the organic phase for drying, and the solvent was evaporated to obtain 827.1 mg of crude HSP90-1-7, which was used directly without post-treatment.

Step 6:

The crude product of 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 overnight at room temperature. When the reaction was completed, the solvent was evaporated and column chromatography (DCM/MeOH=20/1) was performed to obtain HSP90-1-8 as a yellow solid (688 mg). The yield was 83.75%. UPLC-MS calculated for C ₃₀ H ₃₇ N ₅ O ₅ [M+H] ⁺ :548.28, found:548.31.

Step 7:

HSP90-1-8 was dissolved in 10 mL DCM, and 2.5 mL 4M 1,4-dioxane-hydrogen chloride solution was added, and stirred at room temperature overnight. After the reaction was completed, the solvent was evaporated to obtain HSP90-1, a light yellow solid of 530 mg, with a yield of 94.30%. UPLC-MS calculated for C ₂₅ H ₂₉ N ₅ O ₃ [M+H] ⁺ :448.23, found:448.31.

Example 2

Preparation of intermediate HSP90-2

first step:

Place p-nitrobenzyl alcohol (500 mg, 3.3 mmol), p-toluenesulfonic acid pyridinium salt (82 mg, 0.3 mmol), and 2,3-dihydropyran (330 mg, 4.0 mmol) in dichloromethane (20 mL) and react at room temperature for 1 h. The reaction solution was washed with saturated sodium bicarbonate solution (50 mL) and saturated sodium chloride solution (50 mL) in turn, and the organic phase solvent was evaporated to dryness to obtain 760 mg of colorless oil, with a yield of 98%. UPLC-MS calculated for C ₁₂ H ₁₅ NO ₄ [M+H] ⁺ :237.10, found:238.33.

Step 2:

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 replaced with hydrogen three times and reacted at room temperature for 6 h. The reaction solution was filtered, the filtrate was dried by spin drying, and separated by column chromatography (PE:EA=9:1) to obtain 540 mg of colorless oil, with a yield of 81%. UPLC-MS calculated for C ₁₂ H ₁₇ NO ₂ [M+H] ⁺ :207.13, found:208.34.

Step 3:

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 solution. The reaction was carried out at 0°C for 3 h. The reaction solution 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. Column chromatography (PE:EA＝5:1) was used to separate the product, and 850 mg of a yellow oil was obtained, with a yield of 98%. UPLC-MS calculated for C ₁₉ H ₂₁ NO ₄ [M+H] ⁺ :327.15, found:328.30.

Step 4:

HSP90-2-4 (850 mg, 2.6 mmol) and hydrazine hydrate (80%, 972 mg, 19.4 mmol) were dissolved in dioxane (20 mL) and heated 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 N ₃ O ₃ [M+H] ⁺ :265.14, found:266.34.

Step 5:

At 0℃, POCl ₃ (1.53mL, 16.43mmol) was slowly added dropwise to DMF (1.53mL). (1.0g, 6.57mmol) of raw material HSP90-2-6 was dissolved in DMF (2.5mL) and slowly added dropwise to the mixture. The mixture was moved to room temperature for reaction for 1h, heated to 50℃ for reaction for 1h, cooled to room temperature, and 14% NaOH/water (3g/18mL) solution was added. The mixture was stirred and heated to 75℃ for reaction for 15min. The mixture was cooled to room temperature, and the solution was acidified to pH=2-3 with dilute hydrochloric acid. The mixture was stirred for about 1h, 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 O ₃ [M+H] ⁺ :180.20, found:180.32.

Step 6:

The intermediate HSP90-2-7 was dissolved in acetonitrile (15 mL), K ₂ CO ₃ (7.26 g, 52.56 mmol) and benzyl bromide (1.95 mL, 16.43 mmol) were added, and the mixture was refluxed for 1.5 h, cooled to room temperature, the solvent was evaporated, and separated by column chromatography (PE:EA=20/1) to obtain 1.5 g of a light yellow solid, with a two-step yield of 63.34%. UPLC-MS calculated for C ₂₄ H ₂₄ O ₃ [M+H] ⁺ :360.45, found:360.62.

Step 7:

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 step.

Step 8:

Sodium hydroxide (263 mg, 6.5 mmol) and potassium ferrocyanide (1.3 g, 3.9 mmol) were added to the reaction solution of the previous step, and the temperature was raised to 80°C for reaction 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 brown oil, with a two-step yield of 88%. UPLC-MS calculated for C ₃₇ H ₃₉ N ₃ O ₅ [M+H] ⁺ :605.29, found:605.51.

Step 9:

HSP90-2-10 (710 mg, 1.2 mmol) was dissolved in tetrahydrofuran (20 mL), and hydrochloric acid solution (6 M, 10 mL) was added, and 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, and the mixture was extracted with ethyl acetate (20 mL*2). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and the organic phase was spin-dried to obtain 590 mg of a yellow solid with a yield of 96%. UPLC-MS calculated for C ₃₂ H ₃₁ N ₃ O ₄ [M+H] ⁺ :521.23, found:522.61.

Step 10:

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, and the mixture was reacted at room temperature for 3 h. The reaction solution was filtered, and the filtrate was spin-dried and separated by column chromatography (DCM: MeOH = 20: 1) to obtain 510 mg of brown solid with a yield of 86%. UPLC-MS calculated for C ₃₂ H ₂₉ N ₃ O ₄ [M+H] ⁺ :519.22, found:520.50.

Step 11:

HSP90-2-12 (510 mg, 0.9 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0 °C before reaction. Boron trichloride solution (1M in Tol, 2.5mL) was added dropwise to the solution and reacted at 0°C for 3h. Saturated sodium bicarbonate solution (50mL) was added to the reaction solution, and extracted with a dichloromethane-methanol mixed solution (10:1) (20mL*3). The organic phase was dried over anhydrous sodium sulfate, spin-dried and separated by column chromatography (DCM:MeOH=20:1) to obtain 150mg of brown solid with a yield of 45%. UPLC-MS calculated for C ₁₈ H ₁₇ N ₃ O ₄ [M+H] ⁺ :339.12, found:340.33.

Example 3

Preparation of intermediate HSP90-3

The synthesis steps refer to the synthesis of HSP90-1. UPLC-MS calculated for C ₂₃ H ₃₁ N ₆ O ₃ [M+H] ⁺ :439.24, found:439.53.

Example 4

Preparation of intermediate HSP90-4

first step:

The raw material HSP90-4-1 (5 g, 32.8 mmol) was added to a 100 mL reaction bottle, and boron trifluoride etherate (28 g, 197.1 mmol) and acetic acid (3.9 g, 65.7 mmol) were added. The argon gas was replaced three times, and the mixture was stirred at 90°C overnight. 10% NaOAc was added to neutralize the mixture to pH = 7 under ice bath, and the mixture was stirred for 10 min. The mixture was extracted with ethyl acetate (200 mL*2), and the organic phase was washed with saturated brine (100 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 6 g of crude product. 5.4 g of light yellow solid was obtained by column chromatography (PE:EA=20:1-10:1), and the yield was 84.6%. UPLC-MS calculated for C ₁₁ H ₁₄ O ₃ [M+H] ⁺ :195.09, found:195.11.

Step 2:

HSP90-4-2 (5.4 g, 27.8 mmol), K ₂ CO ₃ (11.5 g, 83.5 mmol) and DMF (200 mL) were added to a 500 mL reaction bottle, and benzyl bromide (10.5 g, 61.2 mmol) was added dropwise. The argon atmosphere was replaced three times, and the temperature was raised to 110°C and stirred overnight. The reaction solution was poured into 1.5 L of ice water, stirred for 30 min, and the precipitated solid was filtered and washed with 300 mL of water, and dried to obtain 11 g of crude product. Recrystallization was performed with MeOH/DCM to obtain 9.1 g of white solid, with a yield of 87.4%. UPLC-MS calculated for C ₂₅ H ₂₆ O ₃ [M+H] ⁺ :375.19, found:375.23.

Step 3:

HSP90-4-3 (6.5 g, 17.4 mmol) was added to an ethanol (100 mL) solution of EtONa (2.4 g, 34.7 mmol), replaced with argon three times, stirred for 10 min, and diethyl oxalate (3.9 g, 26.1 mmol) was added dropwise, and the temperature was raised to reflux and stirred for 4 h. After cooling to room temperature, the solution was neutralized with 1 M HCl to pH = 7, and the precipitated solid was filtered, and the filter cake was washed with cold methanol (20 mL) and dried to obtain 7 g of yellow solid, with a yield of 84.9%. UPLC-MS calculated for C ₂₉ H ₃₀ O ₆ [M+H] ⁺ :475.20, found:475.23.

Step 4:

HSP90-4-4 (7 g, 14.8 mmol), hydroxylamine hydrochloride (1.2 g, 17.7 mmol) and ethanol (80 mL) were added to the reaction bottle, replaced with argon three times, heated to reflux and stirred for 3 h, cooled in an ice bath, stirred for 30 min, filtered, the filter cake was washed with cold ethanol (20 mL), and dried to obtain 5 g of white solid, with a yield of 71.4%. UPLC-MS calculated for C ₂₉ H ₂₉ NO ₅ [M+H] ⁺ :472.20, found: 472.23.

Step 5:

5 (5.3 g, 11.2 mmol), NBS (2 g, 11.2 mmol) and acetonitrile (70 mL) were added to a reaction flask, and ammonium cerium nitrate (0.06 g, 0.1 mmol) was added. The argon gas was replaced three times, and the temperature was raised to reflux and stirred overnight. The reaction solution was cooled to room temperature and concentrated to obtain a crude product. Column chromatography (PE: EA = 95%: 5%) gave 5.6 g of a white solid, with a yield of 90.4%.

UPLC-MS calculated for C ₂₉ H ₂₈ BrNO ₅ [M+H] ⁺ :550.12, 552.11, found: 550.14, 552.15.

Step 6:

(2.2 g, 4.0 mmol) and 25 mL of methanol were added to a reaction flask, argon was replaced three times, ethylamine (12 mL, 24 mmol, 2M THF solution) was added, and the temperature was raised to reflux and stirred overnight. The reaction solution was concentrated and pumped dry to obtain 2.3 g of a light yellow solid, with a yield of 100%. UPLC-MS calculated for C ₂₉ H ₂₉ BrN ₂ O ₄ [M+H] ⁺ :549.13, 551.13, found:549.21, 551.20.

Step 7:

(6 g, 10.9 mmol), 4-formylphenylboronic acid (2.45 g, 16.3 mmol), K ₂ CO ₃ (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)Cl ₂ (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 a 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 N ₂ O ₅ [M+H] ⁺ :575.25, found: 575.31.

Step 8:

(480 mg, 0.83 mmol) and 25 mL DCM were added to a reaction bottle, argon was replaced three times, BCl ₃ (5 mL, 1 M toluene solution) was added dropwise under ice bath, stirred for 2 h, quenched with saturated NaHCO ₃ solution, extracted with DCM (50 mL*2), the organic phase was washed with saturated brine 50 mL, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. Purification by column chromatography (5 g silica gel, DCM: MeOH = 100: 5) gave 300 mg brown solid, yield 87%. UPLC-MS calculated for C ₂₂ H ₂₂ N ₂ O ₅ [M+H] ⁺ :395.15, found:395.17.

Example 5

Preparation of intermediate HSP90-5

first step:

HSP90-4-7 (1 g, 1.82 mmol), 4-hydroxymethylphenylboronic acid (415 mg, 2.73 mmol), K ₃ PO ₄ (1.2 g, 5.46 mmol) and 1,4-dioxane (20 mL) were added to a reaction flask, replaced with argon three times, added with Pd(dtbpf)Cl ₂ (120 mg, 0.182 mmol), replaced with argon three times again, and stirred at 95°C overnight. The reaction solution was cooled to room temperature, 100 mL of water was added, extracted with ethyl acetate (100 mL*2), the organic phase was washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain a crude product. Purified by column chromatography (DCM:EA=8:2) to obtain 460 mg of a brown solid with a yield of 44%. UPLC-MS calculated for C ₃₆ H ₃₆ N ₂ O ₅ [M+H] ⁺ :577.26, found: 577.25.

Step 2:

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, and NBS (220 mg, 1.2 mmol) was added. The argon gas was replaced three times, and the mixture was stirred overnight at room temperature. 20 mL of saturated Na ₂ S ₂ O ₃ solution was added to quench the reaction, and DCM (50 mL*2) and 50 mL of saturated brine were washed, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a 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 BrN ₂ O ₄ [M+H] ⁺ :639.18, 641.18, found:639.25, 641.24.

Step 3:

HSP90-5-2 (480 mg, 0.75 mmol) and dichloromethane (10 mL) were added to a reaction flask, replaced with argon three times, and BCl ₃ (5 mL, 5 mmol, 1 M toluene solution) was added dropwise under an ice-water bath, and stirred for 2 h under an ice-water bath. Water (50 mL) was added under an ice-water bath to quench, and dichloromethane (50 mL*2) was used for extraction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain 350 mg of a light brown solid, with a yield of 100%. UPLC-MS calculated for C ₂₂ H ₂₃ BrN ₂ O ₄ [M+H] ⁺ :459.08, 461.08, found:459.13, 459.14.

Example 6

Preparation of intermediate HSP90-6

first step:

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, replaced with argon three times, stirred overnight at 85°C, cooled to room temperature, poured into 500 mL of water, stirred for 30 min, filtered, and the filter cake was washed with cold ethanol (20 mL) and dried to obtain 2.6 g of white solid, with a yield of 97%. UPLC-MS calculated for C ₂₉ H ₃₀ N ₂ O ₄ [M+H] ⁺ :471.22, found:471.25.

Step 2:

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, and ammonium cerium nitrate (0.3 g, 0.55 mmol) was added. The argon gas was replaced three times, and the temperature was raised to reflux and stirred overnight. The reaction solution was cooled to room temperature and concentrated to obtain a crude product. Column chromatography (PE:EA=95%:5%) was performed to obtain 2.6 g of a light yellow solid, with a yield of 85%. UPLC-MS calculated for C ₂₉ H ₂₉ BrN ₂ O ₄ [M+H] ⁺ :549.13, 551.13, found:549.14, 551.15.

Step 3:

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

Step 4:

HSP90-6-3 (500 mg, 0.95 mmol) and DCM (10 mL) were added to a reaction flask, argon was replaced three times, SOCl ₂ (150 mg, 1.15 mmol) and 1 drop of DMF were added, 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, the acid chloride was added dropwise, and stirred overnight under argon atmosphere. 50 mL of water was added to the reaction solution, extracted with ethyl acetate (50 mL*2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain 700 mg of brown solid, with a yield of 87%. UPLC-MS calculated for C ₂₉ H ₃₀ BrN ₃ O ₃ [M+H] ⁺ :548.15, 550.15, found:548.14, 550.15.

Step 5:

HSP90-6-4 (600 mg, 1.09 mmol), 4-formylphenylboronic acid (240 mg, 1.6 mmol), K ₃ PO ₄ (300 mg, 3.3 mmol) and 1,4-dioxane (10 mL) were added to a reaction flask, replaced with argon three times, added with Pd(dtbpf)Cl ₂ (84 mg, 0.11 mmol), replaced with argon three times again, and stirred at 95°C overnight. The reaction solution was cooled to room temperature, 100 mL of water was added, extracted with ethyl acetate (100 mL*2), the organic phase was washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain a crude product. 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 N ₃ O ₄ [M+H] ⁺ :574.27, found: 574.25.

Step 6:

HSP90-6-5 (240 mg) and acetic acid (5 mL) were added to a reaction bottle, and 10% Pd/C (24 mg) was added. The mixture was stirred overnight under a hydrogen atmosphere, filtered and 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 N ₃ O ₄ [M+H] ⁺ :394.17, found:394.29.

Example 7

Preparation of intermediate HSP90-7:

The synthesis steps refer to the synthesis of HSP90-1. UPLC-MS calculated for C ₂₄ H ₃₃ N ₆ O ₃ [M+H] ⁺ :453.25, found:453.56.

Example 8

Preparation of intermediate HSP90-8:

first step:

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, extracted with water (100 mL × 3), and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After removing the solvent, it 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 N ₃ O ₄ [M+H] ⁺ :321.38, found:321.92.

Step 2:

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 sodium bicarbonate solution (20 mL) was added and stirred vigorously for 1 hour. The solid was removed by filtration, extracted with ethyl acetate and water, and the organic phase was dried over anhydrous magnesium sulfate and concentrated to obtain 1.09 g of yellow solid, with a yield of 80.15%. UPLC-MS calculated for C ₁₆ H ₂₅ N ₃ O ₂ [M+H] ⁺ :291.40, found:291.93.

Step 3:

Dissolve phenyl chloroformate (0.47mL, 3.74mmol) in dichloromethane, slowly add dichloromethane solution of intermediate HSP90-8-3 (1.09g, 3.74mmol) to the solution at 0℃, stirring while adding, and continue to react at 0℃ for 30min after the addition is complete. Slowly add dichloromethane solution of triethylamine (0.62mL, 4.49mmol), react overnight, add water and dichloromethane to extract, add anhydrous magnesium sulfate to dry the organic phase, evaporate the solvent and column chromatography (PE:EA＝1/1) to obtain 900mg of white solid, with a yield of 58.48%. UPLC-MS calculated for C ₂₃ H ₂₉ N ₃ O ₄ [M+H] ⁺ :411.50,found:412.06.

Step 4:

The intermediate HSP90-8-4 (230 mg, 0.59 mmol) was dissolved in 1,4-dioxane (10 mL), hydrazine hydrate (2.95 mmol) was added, and 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 solid was precipitated upon cooling to obtain the crude intermediate HSP-8-5.

Step 5:

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

Step 6:

The intermediate HSP90-8-6 (290 mg, 0.42 mmol) was added to ethanol (5 mL) to form a suspension, K ₃ Fe(CN) ₆ (414 mg, 1.26 mmol) and NaOH (84 mg, 2.1 mmol) were added, and the mixture was refluxed at 100°C for 8 h. TLC showed that the reaction of the raw material was complete, and the inorganic residue was filtered out. After the solvent was evaporated, column chromatography (DCM: MeOH = 35/1) was used for purification to obtain 284 mg of the intermediate with a yield of 98.02%. UPLC-MS calculated for C ₄₁ H ₄₇ N ₅ O ₅ [M+H] ⁺ :689.86, found:690.11.

Step 7:

The intermediate HSP90-8-7 (280 mg, 0.45 mmol) was dissolved in dichloromethane (20 mL), and 4M hydrochloric acid/dioxane solution (1.5 mL) was added, and the mixture was stirred at room temperature for 2 h. After TLC detected that the reaction of the raw material was complete, the solvent was evaporated, 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 the organic phase was evaporated to obtain the crude intermediate HSP90-8-8.

Step 8:

The intermediate HSP90-8-8 from the previous step was dissolved in methanol (20 mL), an appropriate amount of Pd/C was added, and the mixture was stirred at room temperature under _H2 environment. The reaction was continued for 5 h. After TLC showed that the reaction of the raw material was complete, the product was filtered and the solvent was evaporated to obtain 130 mg of a yellow solid with a two-step yield of 75.59%. UPLC-MS calculated for C ₂₂ H ₂₇ N ₅ O ₃ [M+H] ⁺ :409.49, found:410.13.

Example 9

Preparation of intermediate HSP90-9:

The synthesis from the first step to the fourth step refers to the synthesis route of HSP90-8.

Step 5:

HSP90-9-5 (500 mg, 0.97 mmol) was dissolved in 10 mL DCM, replaced with argon three times, BCl ₃ (5 mL, 1 M toluene solution) was added dropwise in an ice-water bath, stirred for 2 h in an ice-water bath, and NaHCO ₃ was added to neutralize to pH=7, and water and ethyl acetate were added to extract, and anhydrous magnesium sulfate was added to dry the organic phase, and the solvent was evaporated and then column chromatography (DCM:MeOH=50/1) was performed to obtain 162 mg of HSP90-9-5 as a light yellow solid, with a yield of 50%. UPLC-MS calculated for C ₁₉ H ₁₇ N ₃ O ₃ [M+H] ⁺ :336.13, found:336.08.

Step 6:

HSP90-9-6 (162 mg, 0.49 mmol), CuI (18 mg, 0.098 mmol), (PPh ₃ ) ₂ Pd Cl ₂ (34 mg, 0.049 mmol) and triethylamine (148 mg, 1.47 mmol) were dissolved in anhydrous DMF, replaced with argon three times, reacted at room temperature for 3 h, extracted with water and ethyl acetate, dried over anhydrous magnesium sulfate, evaporated the solvent and column chromatographed (DCM:MeOH=50/1) 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 N ₅ O ₅ [M+H] ⁺ :460.16, found:460.12.

Step 7:

HSP90-9-7 (202 mg, 0.44 mmol) was dissolved in 10 mL of methanol solution, and then 5 mL of LiOH (74 mg, 1.76 mmol) aqueous solution was added dropwise at room temperature and stirred overnight. The prepared 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 N ₅ O ₅ [M+H] ⁺ :446.14, found:446.08.

Example 10

Preparation of intermediate HSP90-10:

The synthetic route and method refer to HSP90-1. UPLC-MS calculated for C ₂₄ H ₂₇ N ₅ O ₃ [M+H] ⁺ :434.22, found:434.29.

Embodiment 11

Preparation of intermediate HSP90-11:

The synthetic route and method refer to HSP90-1. UPLC-MS calculated for C ₂₆ H ₃₁ N ₅ O ₃ [M+H] ⁺ :462.25,found:462.39.

Example 12

Preparation of intermediate HSP90-12:

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

Step 3:

HSP90-12-3 (430.92 mg, 1.89 mmol) was dissolved in DMF (5 mL), NaHCO ₃ (577.31 mg, 6.87 mmol) was added, chloroacetic acid (162.37 mg, 1.17 mmol) was added under argon protection at 0°C, 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, aqueous ammonium chloride solution was added, extracted with ethyl acetate, the organic phase solvent was evaporated, and separated by column chromatography (PE:EA=1/1) to obtain 400 mg of yellow solid, with a yield of 48%. UPLC-MS calculated for C ₂₆ H ₃₅ N ₃ O ₄ S[M+H] ⁺ :485.23, found:486.62.

Step 4:

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

Step 5:

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 protection and stirred overnight. The solvent was evaporated and 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 N ₅ O ₆ [M+H] ⁺ :565.29, found:566.52.

Step 6:

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 obtain 80 mg of a yellow solid. UPLC-MS calculated for C ₂₅ H ₃₂ N ₆ O ₃ [M+H] ⁺ :464.25, found:465.26.

Example 13

Preparation of intermediate HSP90-13:

The synthetic route and method refer to HSP90-12, UPLC-MS calculated for C ₂₄ H ₃₀ N ₆ O ₄ [M+H] ⁺ :465.24, found:466.52.

Embodiment 14

Preparation of intermediate HSP90-14:

first step:

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 DMF, heated to 130°C under argon atmosphere, and reacted for 2 h. LC-MS detection, after the reaction was completed, water and ethyl acetate were added for extraction, anhydrous magnesium sulfate was added to the organic phase for drying, the solvent was evaporated and column chromatography (PE:EA＝1/1) was performed to obtain 1.20 g of HSP90-14-2 as a light yellow solid, with a yield of 86.16%. UPLC-MS calculated for C ₁₈ H ₂₄ N ₂ O ₄ [M+H] ⁺ :332.40, found:332.68.

Step 2:

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

Step 3:

HSP90-1-5 (750 mg, 3.29 mmol) and NaHCO ₃ (829 mg, 9.87 mmol) were dissolved in 10 mL of anhydrous DMF. Chloroacetic acid (311 mg, 3.29 mmol) in anhydrous DMF was slowly added dropwise at 0°C under Ar protection, stirring was continued at 0°C for 5 min after the addition was completed, and then the temperature was raised to room temperature and stirring was continued for 90 min. 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 completed, the temperature was raised to 80°C for reaction for 3 h. After the reaction was completed, water and ethyl acetate were added for extraction. The organic phase was dried by adding anhydrous magnesium sulfate. The solvent was evaporated and then column chromatography (PE:EA=2/1) was performed to obtain HSP90-14-4 as a yellow solid of 1200 mg with a yield of 73.14%. UPLC-MS calculated for C ₂₈ H ₃₈ N ₂ O ₄ S[M+H] ⁺ :499.26,found:499.17.

Step 4:

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. The mixture was stirred at room temperature for 3 h. After the reaction was completed, water and ethyl acetate were added for extraction. Anhydrous magnesium sulfate was added to the organic phase for drying. The solvent was evaporated to obtain 940.86 mg of crude HSP90-14-5, which was used directly without post-treatment.

Step 5:

The crude product of HSP90-14-5 (940.86 mg, 1.81 mmol) was dissolved in 10 mL of anhydrous ethanol and hydrated at room temperature. Hydrazine (224 mg, 2.08 mmol) was added and stirred overnight at room temperature. When the reaction was completed, the solvent was evaporated and then column chromatography (DCM: MeOH = 20/1) was performed to obtain HSP90-14-6 as a yellow solid (610 mg) with a yield of 64.53%. UPLC-MS calculated for C ₂₉ H ₃₈ N ₄ O ₅ [M+H] ⁺ :523.29, found:523.20.

Step 6:

HSP90-14-6 (610 mg, 1.17 mmol) was dissolved in 10 mL DCM, 2.5 mL 4M 1,4-dioxane-hydrogen chloride solution was added, and stirred at room temperature overnight. After the reaction was completed, the solvent was evaporated to obtain HSP90-14, 484 mg of light yellow solid, with a yield of 98%. UPLC-MS calculated for C ₂₄ H ₃₀ N ₄ O ₃ [M+H] ⁺ :423.24, found:423.10.

Embodiment 15

Preparation of intermediate HSP90-15:

The synthetic route was referenced to HSP90-14. UPLC-MS calculated for C ₂₃ H ₂₈ N ₄ O ₄ [M+H] ⁺ :425.21, found:425.18.

Example 16

Preparation of intermediate HSP90-16:

The synthetic route was referenced to HSP90-14. UPLC-MS calculated for C ₂₃ H ₂₉ N ₅ O ₃ [M+H] ⁺ :424.23, found:424.20.

Embodiment 17

Preparation of intermediate HSP90-17:

The synthetic route was referenced to HSP90-14. UPLC-MS calculated for C ₂₄ H ₃₁ N ₅ O ₃ [M+H] ⁺ :438.25, found:438.24.

Embodiment 18

Preparation of intermediate HSP90-18:

The synthetic route and method refer to HSP90-1, UPLC-MS calculated for C ₂₇ H ₃₃ N ₅ O ₃ [M+H] ⁺ :476.27, found:476.35.

Embodiment 19

Preparation of intermediate HSP90-19:

The synthetic route and method refer to HSP90-1, UPLC-MS calculated for C ₂₃ H ₂₅ N ₅ O ₃ [M+H] ⁺ :420.20, found:420.28.

Embodiment 20

Preparation of intermediate HSP90-20:

The synthetic route and method refer to HSP90-8, UPLC-MS calculated for C ₂₂ H ₂₆ FN ₅ O ₃ [M+H] ⁺ :447.20found:428.02.

Embodiment 21

Preparation of intermediate HSP90-21:

first step:

HSP90-21-1 (800 mg, 5.06 mmol) was dissolved in DCE (10 mL), STAB (2.23 g, 10.52 mmol) was added, and the mixture was stirred at room temperature overnight. After 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 C ₆ H ₆ N ₂ O ₃ [M+H] ⁺ :154.04, found:155.12.

Step 2:

HSP90-21-3 (600 mg, 3.89 mmol) was dissolved in DCM (10 mL), and PBr ₃ (703.89 mg, 2.59mmol), stirred at room temperature for 4h. After the reaction, NaHCO ₃ dichloromethane was added for extraction, and the concentrated organic phase was subjected to column chromatography (PE:EA＝1/1) to obtain 600mg of yellow solid with a yield of 71.3%. UPLC-MS calculated for C ₆ H ₅ BrN ₂ O ₂ [M+H] ⁺ :215.95, found:217.13.

The synthetic route and method of steps 3 to 10 refer to the key intermediate HSP90-8, UPLC-MS calculated for C ₂₁ H ₂₆ N ₆ O ₃ [M+H] ⁺ :410.21, found:411.38.

Embodiment 22

Preparation of intermediate HSP90-22:

The synthetic route and method refer to HSP90-1, UPLC-MS calculated for C ₂₂ H ₂₇ N ₄ O ₄ [M+H] ⁺ :411.20, found:411.47.

Embodiment 23

Preparation of intermediate HSP90-23:

The synthetic route and method refer to HSP90-1, UPLC-MS calculated for C ₂₂ H ₂₈ N ₅ O ₃ [M+H] ⁺ :410.21, found:411.49.

Embodiment 24

Preparation of intermediate HSP90-24:

The synthetic route and method refer to HSP90-8, UPLC-MS calculated for C ₂₁ H ₂₇ N ₆ O ₃ [M+H] ⁺ :411.21, found:411.48.

Embodiment 25

Preparation of intermediate HSP90-25:

The synthetic route and method refer to HSP90-8, UPLC-MS calculated for C ₂₀ H ₂₆ N ₇ O ₃ [M+H] ⁺ :412.20, found:412.47.

Embodiment 26

Preparation of intermediate HSP90-26:

The synthetic route and method refer to HSP90-8, UPLC-MS calculated for C ₂₀ H ₂₆ N ₇ O ₃ [M+H] ⁺ :412.20, found:412.48.

Embodiment 27

Preparation of intermediate HSP90-27:

The synthetic route and method refer to HSP90-3, UPLC-MS calculated for C ₂₂ H ₂₉ N ₆ O ₃ [M+H] ⁺ :425.22, found:425.51.

Embodiment 28

Preparation of intermediate HSP90-28:

The synthetic route and method refer to HSP90-3, UPLC-MS calculated for C ₂₁ H ₂₇ N ₆ O ₃ [M+H] ⁺ :411.21, found:411.48.

Embodiment 29

Preparation of intermediate AR-1:

first step:

At 0°C, NaH (60%) (50 mg, 1.23 mmol) was added to a DMF (20 mL) solution containing trans-4-BOC-aminocyclohexanol (222 mg, 1.03 mmol) and stirred for 20 min. Raw material AR-1-1 (161 mg, 1.03 mmol) was added to the reaction system and the mixture was heated to room temperature for 4 h. TLC detected that the reaction of the raw material was complete. The mixture was extracted with ethyl acetate and water. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was dried by spin drying and then column chromatography (PE:EA=5/1) was performed to obtain 280 mg of a white solid with a yield of 77.48%. UPLC-MS calculated for C ₁₈ H ₂₃ ClN ₂ O ₃ [M+H] ⁺ :350.84, found:350.82.

Step 2:

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

Step 3:

Dissolve 6-chloropyridazine-3-carbonyl chloride (50 mg, 0.17 mmol) and DIPEA (0.09 mL, 0.52 mmol) in anhydrous dichloromethane (20 mL), stir at room temperature for 20 min, add to AR-1-3 (36 mg, 0.21 mmol), stir at room temperature under argon protection overnight, evaporate the solvent and perform column chromatography (PE:EA=5/1) to obtain 67 mg of light yellow solid, with a yield of 99.84%. UPLC-MS calculated for C ₁₈ H ₁₆ Cl ₂ N ₄ O ₂ [M+H] ⁺ :391.25, found:390.79.

Embodiment 30

Preparation of intermediate AR-2:

first step:

AR-1-1 (300 mg, 1.93 mmol) was dissolved in dimethylformamide (20 mL), cesium carbonate (1.3 g, 10 mmol) and trans-(4-aminocyclohexyl)carbamic acid tert-butyl ester (455.6 mg, 2.12 mmol) were added, and the temperature was raised to 100°C for 18 h. After cooling to room temperature, 100 mL of water was added for dilution, and ethyl acetate (30 mL*3) was used for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried 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 ClN ₃ O ₂ [M+H] ⁺ :349.16, found:350.22.

Step 2:

AR-2-1 (250 mg, 0.716 mmol) was dissolved in 10 mL of 4 M hydrogen chloride dioxane solution and stirred at room temperature for 1 h. After spin drying, 180 mg of a white solid crude product was obtained. Yield: 100%. UPLC-MS calculated for C ₁₃ H ₁₆ ClN ₃ [M+H] ⁺ :249.10, found:250.33.

Step 3:

AR-2-2 (270 mg, 1.08 mmol) was dissolved in 10 mL of tetrahydrofuran and DIEA (420 mg, 3.25 mmol). The reaction solution was cooled to 0°C, and a tetrahydrofuran solution (10 mL) of 6-chloropyridazine-3-carbonyl chloride (222 mg, 1.26 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to room temperature and the reaction was continued for 18 h. 40 mL of saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL*2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by column chromatography (DCM:MeOH=15/1) to obtain 320 mg of a yellow solid with a yield of 76.19%. UPLC-MS calculated for C ₁₈ H ₁₇ Cl ₂ N ₅ O[M+H] ⁺ :389.08, found:390.11.

Embodiment 31

Preparation of intermediate AR-3:

first step:

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), and 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, and the reaction 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 light yellow solid, with a yield of 55.56%. UPLC-MS calculated for C ₁₂ H ₁₄ FNO ₄ [M+H] ⁺ :255.09, found:256.79.

Step 2:

AR-3-2 (3 g, 11.7 mmol) was dissolved in anhydrous MeOH (50 mL) and added (1.27 g, 11.7 mmol), refluxed at 80°C overnight, extracted with ethyl acetate and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was spin-dried and column chromatographed (PE:EA＝3/1) to obtain 1.7 g of off-white solid, with a yield of 54.8%. UPLC-MS calculated for C ₁₃ H ₁₆ FNO ₄ [M+H] ⁺ :269.11, found:27.82.

Step 3:

AR-3-3 (1.7 g, 6.3 mmol) was dissolved in anhydrous THF (20 mL) under argon protection, and 3-(trifluoromethyl)pyridine-2-cyano (1.5 g, 6.63 mmol) was added at 0°C, and 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 obtain 1.7 g of a yellow solid with a yield of 58.6%. UPLC-MS calculated for C ₂₁ H ₁₅ F ₄ N ₃ O ₃ S[M+H] ⁺ :465.08, found:466.12.

Step 4:

Intermediate AR-3-4 (1.7 g, 3.6 mmol), anhydrous THF (6 mL) and MeOH (6 mL) were added to anhydrous H ₂ O with LiOH (584 mg, 14.6 mmol) and stirred at room temperature for 4 hours. HCl was used to adjust the pH and water and ethyl acetate were added for extraction. The organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine in sequence, dried over anhydrous magnesium sulfate, and column chromatography (DCM: MeOH = 15/1) to obtain 1 g of solid, with a yield of 62%. UPLC-MS calculated for C ₂₀ H ₁₃ F ₄ N ₃ O ₃ S[MH] ^- :450.06, found:450.28.

Embodiment 32

Preparation of intermediate AR-4:

The synthetic route and method refer to AR-1, UPLC-MS calculated for C ₁₈ H ₁₆ Cl ₂ N ₄ O ₂ [M+H] ⁺ :391.25, found:390.79.

Embodiment 33

Preparation of intermediate AR-5:

first step:

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 successively. The temperature was raised to 80°C for 18 h. After cooling to room temperature, water (200 mL) was added to the reaction solution, and ethyl acetate was extracted (30 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain 920 mg of a golden solid crude product. UPLC-MS calculated for C ₁₃ H ₁₉ N ₃ O ₄ [M+H] ⁺ :281.14, found:282.30.

Step 2:

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

Step 3:

AR-5-2 (200 mg, 0.79 mmol) was dissolved in methanol (30 mL), cyclobutanone (75 mg, 1.07 mmol) and zinc iodide (15 mg, 0.05 mmol) were added, and TMSCN (120 mg, 1.2 mmol) was added after reacting at room temperature for 30 min, and the temperature was raised to 50°C 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 brown oil with a yield of 79.86%. UPLC-MS calculated for C ₁₄ H ₂₆ N ₄ O ₂ [M+H] ⁺ :330.21, found:331.58.

Step 4:

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 temperature was raised to 60°C for 4 h. After cooling to room temperature, water (200 mL) was added to the reaction solution, and ethyl acetate was extracted (30 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried and purified by column chromatography (PE:EA=1:2) to obtain 430 mg of brown oil with a yield of 94.37%. UPLC-MS calculated for C ₂₆ H ₂₈ F ₃ N ₇ O ₂ S[M+H] ⁺ :559.20,found:560.16.

Step 5:

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

Embodiment 34

Preparation of intermediate AR-6:

The synthetic route and method refer to AR-3, UPLC-MS calculated for C ₂₀ H ₁₂ F ₄ N ₄ O ₃ S[MH] ^- :463.06, found:463.39.

Embodiment 35

Preparation of intermediate AR-7:

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

Embodiment 36

Preparation of intermediate AR-8:

The synthetic route and method refer to AR-8, UPLC-MS calculated for C ₁₁ H ₁₀ BrClN ₂ O ₂ [MH] ^- :316.57, found:315.96.

Embodiment 37

Preparation of intermediate AR-9:

first step:

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

Step 2:

The intermediate AR-9-3 (1.2 g, 3.48 mmol) was dissolved in MeOH (10 mL), HCl-dioxane (2 ml) was added dropwise to the system 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 H ₆ ClN ₃ [M+H] ⁺ :203.03, found:204.31.

Step 3:

The raw material AR-9-4 (1g, 4.92mmol), (S)-(1-hydroxypropyl-2-yl)carbamic acid tert-butyl ester (858mg, 4.92mmol), and PPh ₃ (1.5g, 1.3mmol) were dissolved in THF (20mL), and DBAD (1.7g, 7.38mmol) was added under argon protection and stirred, and the reaction was stirred at room temperature overnight. Water and ethyl acetate were added for extraction, and the organic phase was washed with saturated ammonium chloride and saturated brine in turn, dried over anhydrous magnesium sulfate, and column chromatography (PE:EA=1/1) to obtain 500mg of solid, with a yield of 45%. UPLC-MS calculated for C ₁₅ H ₁₄ ClN ₃ O[M+H] ⁺ :360.14, found:361.15.

Step 4:

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, spin dry to obtain 500 mg of solid, yield 45%. UPLC-MS calculated for C ₁₅ H ₁₄ ClN ₃ O[M+H]+:260.14, found:261.15.

Embodiment 38

Preparation of intermediate AR-10:

first step:

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 solution. React at 0°C for 3 h. Add saturated sodium chloride solution (100 mL) to the reaction solution, extract with dichloromethane (30 mL*3), dry the organic phase with 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 BrF ₃ N ₂ O[M+H] ⁺ :333.99, found:335.21.

Step 2:

AR-10-2 (2.5 g, 7.4 mmol), 3-iodo-pyrazole (1.75 g, 8.9 mmol), cesium carbonate (3.6 g, 11.1 mmol) were placed in acetonitrile (40 mL), heated to 50 ° C and reacted for 3 h. After the reaction solution was cooled to room temperature, water (100 mL) was added thereto, and ethyl acetate was extracted (30 mL*3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the organic phase solvent was evaporated to dryness. Column chromatography (PE: EA = 9: 1) was used for separation to obtain 1.7 g of yellow oil, with a yield of 52%. UPLC-MS calculated for C ₁₅ H ₁₂ F ₃ IN ₄ O[M+H] ⁺ :448.00, found:449.22.

Embodiment 39

Preparation of intermediate AR-11:

first step:

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. The mixture was reacted at room temperature for 2 h. Saturated ammonium chloride solution (200 mL) was added. The mixture was extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography (DCM: MeOH = 10:1) after being dried by rotation to obtain 850 mg of a white solid with a yield of 88.26%. UPLC-MS calculated for C ₁₇ H ₁₇ ClN ₄ O ₂ [M+H] ⁺ :344.10, found:345.18.

Step 2:

Dissolve AR-11-1 (360 mg, 1.05 mmol) in dimethylformamide (10 mL), add potassium carbonate (290 mg, 2.10 mg), potassium iodide (35 mg, 0.21 mol), 2-bromo-1,1-dimethoxyethane (263 mg, 1.56 mmol), heat to 100 ° C and react for 48 hours. After cooling to room temperature, add water (100 mL) to the reaction solution and extract with ethyl acetate. (20mL*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 400mg of white solid with a yield of 88.49%. UPLC-MS calculated for C ₂₁ H ₂₅ ClN ₄ O ₄ [M+H] ⁺ :432.16, found:433.28.

Step 3:

AR-11-2 (400 mg, 0.292 mmol) was dissolved in tetrahydrofuran (50 mL), and 6 M hydrochloric acid solution (20 mL) was added, and the mixture was reacted at room temperature for 3 h. Saturated sodium bicarbonate was added to the reaction solution until the pH was 8, and the mixture was extracted with ethyl acetate (30 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain 320 mg of a yellow solid crude product with a yield of 89%. UPLC-MS calculated for C ₁₉ H ₁₉ ClN ₄ O ₃ [M+H] ⁺ :386.11, found:387.33. Example 40

Preparation of compound I-1:

first step:

AR-1 (670 mg, 1.70 mmol) was dissolved in dichloromethane (40 mL) together with 4-hydroxymethylpiperidine (230 mg, 2.10 mmol) and DIPEA (0.6 mL, 3.4 mmol) and stirred at room temperature overnight. TLC detected that the raw material was completely reacted. After evaporating the solvent, column chromatography (DCM: MeOH = 25/1) was performed to obtain 750 mg of intermediate I-1-1, a light yellow viscous liquid, with a yield of 93.87%. UPLC-MS calculated for C ₂₄ H ₂₉ ClN ₅ O ₃ [M+H] ⁺ :470.20, found:470.22.

Step 2:

I-1-1 (750 mg, 1.50 mmol) was dissolved in dichloromethane (40 mL), DMP (1.26 g, 3.00 mmol) was slowly added to the reaction bottle, and the reaction was stirred at room temperature for 4 h. TLC detected that the raw material reaction was complete, and the organic phase was washed with saturated sodium bicarbonate and saturated brine in turn, dried over anhydrous sodium sulfate, and the solvent was evaporated and column chromatography (DCM: MeOH = 50/1) was performed to obtain 580 mg of intermediate I-1-2 as a white solid with a yield of 82.63%. UPLC-MS calculated for C ₂₄ H ₂₇ ClN ₅ O ₃ [M+H] ⁺ :468.18, found:468.20.

Step 3:

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, 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 phase, as a white powdery solid (30 mg), with a yield of 30.36%. UPLC-MS calculated for C ₄₉ H ₅₆ ClN ₁₀ O ₅ [M+H] ⁺ :899.41, found:899.53. ¹ H NMR (500 MHz, DMSO-d ₆ )δ11.90(s,1H),9.58(d,J＝28.4Hz,2H),8.58(dd,J＝8.3,2.5Hz,1H),7.83(ddd,J＝23.0,9.2,2.3Hz,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).

Embodiment 41

Preparation of compound I-2:

Synthesis was performed with reference to I-1. I-2 was obtained by preparing liquid phase, 25 mg of white powdery solid, with a yield of 13.44%. UPLC-MS calculated for C ₄₈ H ₅₄ ClN ₁₀ O ₅ [M+H] ⁺ :885.40, found:885.45. ¹ H NMR (500MHz, DMSO-d ₆ )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＝3.1H z,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),2.16–1.94(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).

Embodiment 42

Preparation of compound I-3:

Synthesis was performed with reference to I-1. I-3 was obtained by preparing liquid phase, 36 mg of white powdery solid, with a yield of 31.05%. UPLC-MS calculated for C ₄₈ H ₅₄ ClN ₁₀ O ₅ [M+H] ⁺ :885.40, found:885.45. ¹ H NMR (500MHz, DMSO-d ₆ )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＝3.1H z,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),2.16–1.94(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).

Embodiment 43

Preparation of compound I-4:

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 the reaction was completed, I-4 was obtained by preparing a liquid phase, a white powder solid of 40 mg, with a yield of 23.52%. UPLC-MS calculated for C ₄₁ H ₄₀ ClN ₉ O ₅ [M+H] ⁺ :774.28, found:774.10. ¹ H NMR (400 MHz, DMSO-d ₆ )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＝3.1Hz,1H),6.2 4(s,1H),4.53(t,J＝6.1Hz,3H),4.14(t,J＝8.3Hz,2H),3.95(dd,J＝8.8,5.3Hz,2H),3.90–3.77(m,1H),3.47(t,J＝5.3Hz,2H),2.89(p,J＝6.9H z,1H),2.16–2.03(m,2H),1.94–1.82(m,2H),1.72–1.56(m,2H),1.51( td,J＝13.8,13.3,7.0Hz,2H),1.31–1.19(m,1H),0.80(d,J＝6.9Hz,6H).

Embodiment 44

Preparation of compound I-5:

Synthesis was performed by referring to I-2, and I-5 was obtained by preparing liquid phase, 36 mg of white powdery solid, with a yield of 14.09%. UPLC-MS calculated for C ₄₆ H ₄₉ ClN ₁₀ O ₅ [M+H] ⁺ :857.41, found:857.12. ¹ H NMR (500MHz, DMSO-d ₆ )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＝3.1H z,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),2.16–1.94(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).

Embodiment 45

Preparation of compound I-6:

Synthesis was performed with reference to I-4. I-6 was obtained by preparing liquid phase, 33 mg of white powdery solid, with a yield of 24.56%. UPLC-MS calculated for C ₄₅ H ₄₈ ClN ₉ O ₅ [M+H] ⁺ :830.39, found:830.21. ¹ H NMR (400MHz, DMSO-d ₆ )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(dd,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).

Embodiment 46

Preparation of compound I-7:

Synthesis was performed by referring to I-1, and I-7 was obtained by preparing liquid phase, 40 mg of white powdery solid, with a yield of 35.56%. UPLC-MS calculated for C ₅₁ H ₅₉ ClN ₁₀ O ₅ [M+H] ⁺ :927.55, found:927.10. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.42(s,1H),8.02(d,J＝7.5Hz,1H),7.83(t,J＝2.0Hz,1H),7.78(d,J＝8.9H z,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,1H),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),3.3 7–3.25(m,1H),2.96–2.87(m,2H),2.62–2.53(m,1H),2.53–2.46(m,2H),2.4 2(dt,J＝12.3,8.3Hz,1H),2.11–1.98(m,4H),1.98–1.87(m,8H),1.86–1.80( m,2H),1.80–1.69(m,7H),1.58(td,J＝8.2,5.9Hz,2H),1.30(d,J＝6.8Hz,6H).

Embodiment 47

Preparation of compound I-8:

The synthetic route was referred to I-7, and I-8 was obtained by preparing liquid phase, 35 mg of white powder solid, with a yield of 29.56%. UPLC-MS calculated for C ₄₉ H ₅₅ ClN ₁₀ O ₅ [M+H] ⁺ :899.49, found:899.40. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.84(s,1H),7.89(d,J＝7.5Hz,1H),7.73(t,J＝1.9Hz,1H),7.66(d,J＝8 .9Hz,1H),7.57–7.52(m,3H),7.42(d,J＝0.7Hz,1H),7.38–7.33(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,2H),3.25 –3.13(m,1H),2.65(ddd,J＝12.3,6.9,4.2Hz,2H),2.54–2.41(m,3H),2.3 0(dt,J＝12.2,8.2Hz,1H),2.06–1.97(m,2H),1.97–1.65(m,14H),1.61(d p, J＝6.2, 5.4Hz, 1H), 1.46 (td, J＝8.3, 6.0Hz, 2H), 1.20 (d, J＝6.8Hz, 6H).

Embodiment 48

Preparation of compound I-9:

Synthesis was performed by referring to I-1, and I-9 was obtained by preparing liquid phase, 50 mg of white powdery solid, with a yield of 39.10%. UPLC-MS calculated for C ₅₀ H ₅₇ ClN ₁₀ O ₅ [M+H] ⁺ :913.52, found:913.20. ¹ H NMR (500MHz, DMSO-d ₆ )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＝8.6,2.0Hz,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,2H),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,3H) ,1.21(d,J＝25.6Hz,5H),1.12–1.01(m,2H),0.78(dd,J＝6.9,2.1Hz,7H).

Embodiment 49

Preparation of compound I-10:

Synthesis was performed with reference to I-2. I-10 was obtained by preparative liquid phase, 23 mg of white powdery solid, yield 20.05%. UPLC-MS calculated for C ₅₀ H ₅₇ ClN ₁₀ O ₅ [M+H] ⁺ :913.52, found:913.20. ¹ H NMR (400MHz, DMSO-d ₆ )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,1H),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).

Embodiment 50

Preparation of compound I-11:

Synthesis was performed with reference to I-1. I-11 was obtained by preparative liquid phase, in the form of white powder, 35 mg solid, with a yield of 35.62%. UPLC-MS calculated for C ₅₀ H ₅₈ ClN ₁₁ O ₄ , [M+H] ⁺ : 913.52, found: 913.26. ¹ H NMR (400 MHz, DMSO-d ₆ )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＝6.9H z,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).

Embodiment 51

Preparation of compound I-12:

Synthesis was performed by referring to I-1, and I-12 was obtained by preparing liquid phase, in the form of white powder, 40 mg solid, with a yield of 40.13%. UPLC-MS calculated for C ₅₁ H ₆₀ ClN ₁₁ O ₄ [M+H] ⁺ :927.54, found:927.24. ¹ H NMR (400MHz, DMSO-d ₆ )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＝6.9Hz,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).

Embodiment 52

Preparation of compound I-13:

Synthesis reference I-4, I-13 was obtained by preparing liquid phase, 43 mg of white powder solid. UPLC-MS calculated for C ₄₄ H ₄₆ ClN ₉ O ₅ [M+H] ⁺ :817.34found:817.11. ¹ H NMR (400MHz, DMSO-d ₆ )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＝3.1Hz,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).

Embodiment 53

Preparation of compound I-14:

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, 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 phase, as a white powdery solid (70.15 mg), with a yield of 43.12%. UPLC-MS calculated for C ₄₅ H ₅₀ ClN ₉ O ₅ [M+H] ⁺ :823.38, found:823.24. ¹ H NMR (400 MHz, DMSO-d ₆ )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).

Embodiment 54

Preparation of compound I-15:

Synthesis reference I-14, I-15 was obtained by preparative liquid phase, white powder solid 50 mg, yield 36.91%. UPLC-MS calculated for C ₄₂ H ₄₄ ClN ₉ O ₅ [M+H] ⁺ :791.03, found:791.10. ¹ H NMR (400MHz, DMSO-d ₆ )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＝8.7,2.4 Hz,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＝10.2,5.2H z,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＝6.8 Hz,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).

Embodiment 55

Preparation of compound I-16:

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, 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 phase, as a white powdery solid (45.82 mg), with a yield of 40.31%. UPLC-MS calculated for C ₅₀ H ₅₂ F ₃ N ₁₁ O ₄ S[M+H] ⁺ :961.07, found:961.10. ¹ H NMR (400 MHz, DMSO-d ₆ )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).

Embodiment 56

Preparation of compound I-17:

The synthetic route was referred to I-16, and I-17 was obtained by preparing the liquid phase, with a solid content of 30 mg and a yield of 43.68%. UPLC-MS calculated for C ₄₉ H ₅₀ F ₃ N ₁₁ O ₄ S[M+H] ⁺ :947.02,found:947.08. ¹ H NMR (500MHz, DMSO-d ₆ )δ11.93(s,1H),10.61(s,1H),9.66(s,1H),9.41(s,1H),8.51(dd,J＝9.2,2.0Hz,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,5H),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).

Embodiment 57

Preparation of compound I-18:

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 DMF and stirred at room temperature for 12 h. I-18 was obtained by preparative liquid phase, solid 20 mg, yield 21.74%. UPLC-MS calculated for C ₄₇ H ₄₃ F ₄ N ₉ O ₅ S [M + H] ⁺ : 921.97, found: 924.30. ¹ H NMR (400 MHz, DMSO-d ₆ )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).

Embodiment 58

Preparation of compound I-19:

The synthetic route was referred to I-18, and I-19 was obtained by preparing the liquid phase, with a solid of 18 mg and a yield of 19.23%. UPLC-MS calculated for C ₄₇ H ₄₄ F ₄ N ₈ O ₅ S[M+H] ⁺ :908.97,found:908.18. ¹ H NMR (400MHz, DMSO-d ₆ δ8.14 (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=4.9 Hz, 1H), 6.31 (dd, J=7.2, 1.8 Hz, 1H), 5.85 (dd, J=5.1, 2.0 Hz, 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).

Embodiment 59

Preparation of compound II-1:

first step:

N-BOC-L-prolinol (108 mg, 0.53 mmol) and THF (5 mL) were added to a reaction flask, argon was replaced three times, NaH (41 mg, 1.02 mmol, 60%) was added under an ice-water bath, stirred for 2 h, AR-1 (200 mg, 0.51 mmol) was added, the mixture was returned to room temperature and stirred overnight, saturated NH ₄ Cl solution was added to quench, ethyl acetate (50 mL*2) was used for extraction, the organic phase was washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain a crude product, and 180 mg of a colorless oil was obtained by column chromatography (DCM/MeOH=100:1), with a yield of 63%. UPLC-MS calculated for C ₂₈ H ₃₄ ClN ₅ O ₅ [M+H] ⁺ :556.22, found:556.20.

Step 2:

Add Ⅱ-1-1 (180 mg, 0.32 mmol) to the reaction flask, add HCl (1 mL, 4 mmol, 4M 1,4-dioxane solution) dropwise at room temperature, and stir for 1 h. Add 5 mL of methanol, filter, concentrate, and pump dry to obtain 120 mg of white solid. The yield is 75%. UPLC-MS calculated for C ₂₃ H ₂₆ ClN ₅ O ₃ [M+H] ⁺ :456.17, found:456.19.

Step 3:

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 the reaction flask, replaced with argon three times, stirred at 85°C overnight, concentrated to obtain a crude product, and purified by reverse phase preparative HPLC to obtain 15 mg of a white solid with a yield of 14%. UPLC-MS calculated for C ₄₅ H ₄₈ ClN ₇ O ₇ [M+H] ⁺ :834.33, found:834.35. ¹ H NMR (400 MHz, DMSO-d ₆ )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),2.96(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).

Embodiment 60

Preparation of compound II-2:

Synthesis was carried out according to II-1. 18 mg of white solid was obtained by preparing liquid phase, with a yield of 10%. UPLC-MS calculated for C ₄₅ H ₄₈ ClN ₇ O ₇ [M+H] ⁺ :834.33, found:834.35. ¹ H NMR (400 MHz, DMSO-d ₆ )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),3.97–3.7 5(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).

Embodiment 61

Preparation of compound II-3:

Step 3:

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), stirred at room temperature for 5 h, and NaBH ₃ CN (30 mg, 0.44 mmol) was added, stirred for 1 h, the reaction solution was concentrated, acetonitrile was added to dissolve, filtered and concentrated to obtain a 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 ClN ₇ O ₄ [M+H] ⁺ :638.31, found: 638.42.

Step 4:

II-3-1 (140 mg, 0.21 mmol) was added to the reaction flask, HCl (0.5 mL, 2.1 mmol, 4M 1,4-dioxane solution) was added dropwise at room temperature, and stirred for 1 h. 2 mL of methanol was added, filtered, concentrated, and pumped dry to obtain 120 mg of white solid, with a yield of 95%. UPLC-MS calculated for C ₂₈ H ₃₆ ClN ₇ O ₂ [M+H] ⁺ :538.26, found:538.18.

Step 5:

The hydrochloride of II-3-2 (120 mg, 0.21 mmol) and MeOH (3 mL) were added to a reaction flask, triethylamine (27 mg, 0.26 mmol) was added, and the mixture was stirred at room temperature for 30 min. HSP90-4 (69 mg, 0.21 mmol) and acetic acid (37 mg, 0.61 mmol) were added in sequence, and the mixture was stirred at room temperature for 5 h. NaBH ₃ CN (22 mg, 0.35 mmol) was added, and the mixture was stirred for 1 h. The reaction solution was concentrated, acetonitrile was added to dissolve, and the crude product was filtered and concentrated to obtain a 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 ClN ₉ O ₆ [M+H] ⁺ :916.42, found:916.51. ¹ H NMR (400 MHz, DMSO-d ₆ )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,1 H),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＝9.0Hz,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).

Embodiment 62

Preparation of compound II-4:

first step:

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, and NaBH(OAc) ₃ (93 mg, 0.44 mmol) was added. The mixture was stirred for 1 h. The reaction solution was concentrated, acetonitrile was added to dissolve the mixture, and the crude product was filtered and concentrated to obtain a crude product. The crude 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 ClN ₇ O ₄ [M+H] ⁺ :624.30, found:624.33.

Step 2:

Add Ⅱ-4-1 (70 mg) to the reaction bottle, add HCl (1 mL, 4M 1,4-dioxane solution) dropwise at room temperature, and stir for 1 h. Add 2 mL of methanol, filter, concentrate, and dry with an oil pump to obtain 70 mg of a white solid. UPLC-MS calculated for C ₂₇ H ₃₄ ClN ₇ O ₂ [M+H] ⁺ :524.25, found: 524.19.

Step 3:

The synthesis method was referred to Example II-3. 30 mg of white solid was obtained by reverse phase preparation and purification, with a yield of 25%. UPLC-MS calculated for C ₄₉ H ₅₆ ClN ₉ O ₆ [M+H] ⁺ :902.40, found:902.26. ¹ H NMR (400MHz, DMSO-d ₆ )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＝14.6Hz,4 H),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).

Embodiment 63

Preparation of compound II-5:

first step:

AR-1 (950 mg, 2.43 mmol), mono-Boc piperazine (540 mg, 2.91 mmol), DIEA (1 g, 7.28 mmol) and 20 mL 1,4-dioxane were added to the reaction flask, replaced with argon three times, heated to 110 ° C and stirred for 3 h. Added to 50 mL of water, extracted with ethyl acetate (50 mL*2), the organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. Purified by column chromatography (DCM: MeOH = 100: 2) to obtain 500 mg of white solid, yield 65%. UPLC-MS calculated for C ₂₇ H ₃₃ ClN ₆ O ₄ [M+H] ⁺ :541.23, found:541.35.

Step 2:

II-5-1 (500 mg, 0.93 mmol) was added to the reaction flask, HCl (2.5 mL, 10 mmol, 4M 1,4-dioxane solution) was added dropwise at room temperature, and stirred for 1 h. 5 mL of methanol was added, filtered, concentrated, and pumped dry to obtain 330 mg of white solid. The yield was 74%. UPLC-MS calculated for C ₂₂ H ₂₅ ClN ₆ O ₂ [M+H] ⁺ :441.17, found:441.19.

Step 3:

The synthesis method is as in Example II-3. 40 mg of white solid was obtained by reverse phase preparation and purification, with a yield of 40%. UPLC-MS calculated for C ₄₄ H ₄₇ ClN ₈ O ₆ [M+H] ⁺ :819.33, found:819.38. ¹ H NMR (500 MHz, DMSO-d ₆ )δ9.75(s, 2H),8.82(t, J＝5.7 Hz, 1H),8.60(d, J＝8.2 Hz, 1H),7.84(dd, J＝11.1,9.1 Hz, 2H),7.41–7.31(m, 2H),7.27(d, J＝7.9 Hz, 2H),7.21(d, J＝8.0 Hz, 2H),7.13(dd, J＝8.8,2.4 Hz, 1H ),6.72(s,1H),6.45(s,1H),4.53(tt,J＝10.1,4.3Hz,1H),3.86(dtd,J＝11.5,7.8,4.2Hz,1 H),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).

Embodiment 64

Preparation of compound II-6:

first step:

The hydrochloride of II-5-2 (240 mg, 0.44 mmol) and MeOH (5 mL) were added to a reaction flask, triethylamine (67 mg, 0.66 mmol) was added, and the mixture was stirred 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 added in sequence, and the mixture was stirred at room temperature for 5 h. NaBH ₃ CN (30 mg, 0.5 mmol) was added, and the mixture was stirred for 1 h. The reaction solution was concentrated, acetonitrile was added to dissolve, and the crude product was filtered and concentrated to obtain a crude product. Column chromatography purification (DCM: MeOH = 100: 2) gave 300 mg of a white solid with a yield of 98%. UPLC-MS calculated for C ₃₃ H ₄₄ ClN ₇ O ₄ [M+H] ⁺ :638.31, found:638.35.

Step 2:

II-6-1 (200 mg, 0.29 mmol) was added to the reaction flask, HCl (1 mL, 4 mmol, 4M 1,4-dioxane solution) was added dropwise at room temperature, and stirred for 1 h. 5 mL of methanol was added, 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 ClN ₆ O ₂ [M+H] ⁺ :538.26, found:538.26.

Step 3:

The synthesis method was as described in Example II-3. 58 mg of white solid was obtained by reverse phase preparation and purification, with a yield of 20%. UPLC-MS calculated for C ₅₀ H ₅₈ ClN ₉ O ₆ [M+H] ⁺ :916.42, found:916.48. ¹ H NMR (400 MHz, DMSO-d ₆ )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＝8.1,4.3Hz,2 H),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).

Embodiment 65

Preparation of compound II-7:

The synthesis method was referred to Example II-6. 58 mg of white solid was purified by reverse phase preparation, with a yield of 20%. UPLC-MS calculated for C ₄₈ H ₅₄ ClN ₉ O ₆ [M+H] ⁺ :888.39, found:888.41. ¹ H NMR (400 MHz, DMSO-d ₆ )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,2H),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),1.8 4(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).

Embodiment 66

Preparation of compound II-8:

The synthesis method was similar to that of Example II-3, and 17 mg of a white solid was obtained by reverse phase preparation and purification, with a yield of 20%. UPLC-MS calculated for C ₅₀ H ₅₉ ClN ₁₀ O ₅ [M+H] ⁺ :914.44, found:914.46. ¹ H NMR (400 MHz, DMSO-d ₆ )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),7.3 2(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).

Embodiment 67

Preparation of compound II-9:

The synthesis method was similar to that of Example II-3, and 15 mg of a white solid was obtained by reverse phase preparation and purification, with a yield of 19%. UPLC-MS calculated for C ₅₀ H ₅₉ ClN ₁₀ O ₅ [M+H] ⁺ :914.44, found:914.45. ¹ H NMR (420 MHz, DMSO-d ₆ )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),7.44(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).

Embodiment 68

Preparation of compound II-10:

The synthesis method was similar to that of Example II-5, and 48 mg of a white solid was obtained by reverse phase preparation and purification, with a yield of 45%. UPLC-MS calculated for C ₄₄ H ₄₇ ClN ₈ O ₆ [M+H] ⁺ :832.35, found:832.39. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.75(s,2H),8.87(t,J＝5.7Hz,1H),8.62(d,J＝8.2Hz,1H),7.86(d,J＝8.7 Hz,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),6.8 0(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,2H),3.00 (p,J＝6.9Hz,1H),2.79(dt,J＝9.7,5.8Hz,1H),2.11(dd,J＝12.8,4.3Hz,2H) ,2.00–1.84(m,4H),1.72–1.58(m,2H),1.58–1.44(m,2H),1.33(q,J＝10.6H z, 2H), 1.24 (d, J = 3.3Hz, 1H), 1.09 (t, J = 7.2Hz, 3H), 0.97 (d, J = 6.9Hz, 6H).

Embodiment 69

Preparation of compound II-11:

first step:

AR-1 (300 mg, 0.77 mmol), methyl (piperidin-4-yl) carbamic acid tert-butyl ester hydrochloride (246 mg, 1.15 mmol), Na ₂ CO ₃ (320 mg, 2.3 mmol) and 6 mL DMF were added to a reaction flask, argon was replaced three times, the temperature was raised to 85°C and stirred for 4 h. 50 mL of water was added, ethyl acetate (50 mL*2) was used for extraction, the organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. 380 mg of white solid was obtained by column chromatography purification (DCM: MeOH = 100: 2), and the yield was 87%. UPLC-MS calculated for C ₂₉ H ₃₇ ClN ₆ O ₄ [M+H] ⁺ :569.26, found:569.35.

Step 2:

II-11-1 (380 mg, 0.67 mmol) was added to the 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, 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 ClN ₆ O ₂ [M+H] ⁺ :469.20, found:469.22.

Step 3:

The third step was the same as in Example II-1, and 38 mg of a white solid was obtained by reverse phase preparation and purification, with a yield of 34%. UPLC-MS calculated for C ₄₆ H ₅₁ ClN ₈ O ₆ [M+H] ⁺ :847.36, found:847.20. ¹ H NMR (400MHz, DMSO-d ₆ )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),3.93–3.7 7(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＝12.8,6.5H z,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).

Embodiment 70

Preparation of compound II-12:

first step:

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 obtain 160 mg of a white solid. UPLC-MS calculated for C ₃₀ H ₄₀ N ₆ O ₅ [M+H] ⁺ :564.31, found:565.69.

Step 2:

Dissolve the intermediate II-12-1 (160 mg, 0.28 mmol) in MeOH (4 mL) and add HCl-dixoane (1 mL). Stir overnight at room temperature and evaporate the solvent to obtain 80 mg of a yellow solid. UPLC-MS calculated for C ₂₅ H ₃₂ N ₆ O ₃ [M+H] ⁺ :464.25, found:465.26.

Step 3:

Ⅱ-12-2 (55 mg, 0.11 mmol) was dissolved in DMF (6 mL), TEA (21.6 mg, 0.21 mmol) was added, and the mixture was stirred at room temperature for 20 min. Intermediate I-1-2 (52 mg, 0.11 mmol) was added 2 hours later, and NaBH(OAc) ₃ (46 mg, 0.22 mmol) was added, and the mixture was stirred at room temperature overnight. 35 mg of Ⅱ-12 was obtained as a white powder solid by preparing the liquid phase. UPLC-MS calculated for C ₄₉ H ₅₈ ClN ₁₁ O ₅ [M+H] ⁺ :915.43, found:916.53. ¹ H NMR (400 MHz, DMSO-d ₆ )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).

Embodiment 71

Preparation of compound II-13:

The synthesis method was similar to that of Example Ⅰ-1, and 30 mg of white powdery solid II-13 was obtained by preparing the liquid phase. UPLC-MS calculated for C ₄₉ H ₅₇ ClN ₁₀ O ₆ [M+H] ⁺ :916.42, found: 917.51. ¹ H NMR (400MHz, DMSO-d ₆ )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＝23.6,9.1Hz,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).

Embodiment 72

Preparation of compound II-14:

The synthesis method was similar to that of Example I-1, and 30 mg of white powdery solid II-14 was obtained by preparing the liquid phase. UPLC-MS calculated for C ₄₉ H ₅₇ ClN ₁₀ O ₆ [M+H] ⁺ :916.42, found:917.51. ¹ H NMR (400MHz, DMSO-d ₆ )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).

Embodiment 73

Preparation of compound II-15:

The synthesis method was similar to that of Example I-1, and 40 mg of white powdery solid II-15 was obtained by preparing the liquid phase. UPLC-MS calculated for C ₄₉ H ₅₇ ClN ₁₀ O ₆ [M+H] ⁺ :916.42, found:917.51. ¹ H NMR (400MHz, DMSO-d ₆ )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＝8.7Hz,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).

Embodiment 74

Preparation of compound II-16:

The synthesis method was similar to that of Example I-1, and 20 mg of white powder solid II-16 was obtained by preparing the liquid phase. UPLC-MS calculated for C ₅₀ H ₆₀ ClN ₁ 1O ₅ [M+H] ⁺ :929.45, found:930.55. ¹ H NMR (400MHz, DMSO-d ₆ )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),4.6 2–4.36(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).

Embodiment 75

Preparation of compound II-17:

The synthesis method was similar to that of Example I-1, and 46 mg of white powder solid II-17 was obtained by preparing the liquid phase. UPLC-MS calculated for C ₅₀ H ₅₉ ClN ₁₀ O ₆ [M+H] ⁺ :930.43, found:931.54. ¹ H NMR (400MHz, DMSO-d ₆ )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,1H),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),1.98–1.8 0(m,4H),1.74(d,J＝12.7Hz,2H),1.60(h,J＝10.0Hz,5H),1.53–1.34(m,4H),1.20–1.07(m,2H),1.00(t,J＝7.2Hz,3H),0.79(d,J＝6.9Hz,6H).

Embodiment 76

Preparation of compound II-18:

first step:

The intermediate HSP90-12 (400 mg, 0.7 mmol) was dissolved in THF (3 mL) and EtOH (3 mL), and LiOH (220.8 mg, 2.8 mmol) was dissolved in anhydrous H ₂ O (1 mL) and added dropwise to the system, and stirred at room temperature for 4 h. The pH was adjusted with 1M-HCl, extracted with EA, and the organic phase was concentrated. Column chromatography (PE/EA=2/1) was performed to obtain 200 mg of solid, with a yield of 40%. UPLC-MS calculated for C ₂₇ H ₃₅ N ₅ O ₄ [M+H] ⁺ :493.27, found:494.31.

Step 2:

The intermediate II-18-1 (200 mg, 0.4 mmol) was dissolved in MeOH (8 mL), HCl-dioxane (2 mL) was added dropwise to the system at 0°C, and 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 N ₅ O ₂ [M+H] ⁺ :393.22, found:394.31.

Step 3:

The synthesis method was similar to that of Example II-12, and 20 mg of white powder solid II-18 was obtained by preparing the liquid phase. UPLC-MS calculated for C ₄₆ H ₅₃ ClN ₁₀ O ₄ [M+H] ⁺ :844.39, found:845.86. ¹ H NMR (500MHz, DMSO-d ₆ )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,1 H),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).

Embodiment 77

Preparation of compound III-1:

Synthesis was performed by referring to I-4, and III-1 was obtained by preparing liquid phase, 20 mg of white powdery solid, yield: 23.14%. UPLC-MS calculated for C ₄₂ H ₄₅ ClN ₈ O ₅ [M+H] ⁺ :778.33 found:778.24. ¹ H NMR (400MHz, DMSO-d ₆ )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).

Embodiment 78

Preparation of compound III-2:

The synthetic route was referred to I-4, and III-2 was obtained by preparing liquid phase, 29 mg of white powder solid, yield: 26.31%. UPLC-MS calculated for C ₄₁ H ₄₃ ClN ₈ O ₆ [M+H] ⁺ :780.30found:780.24. ¹ H NMR (400MHz, DMSO-d ₆ )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＝11.7,5.1Hz ,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,2H),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).

Embodiment 79

Preparation of compound III-3:

The synthetic route was referred to I-4, and III-3 was obtained by preparing liquid phase, 33 mg of white powder solid, yield: 25.56%. UPLC-MS calculated for C ₄₁ H ₄₄ ClN ₉ O ₅ [M+H] ⁺ :779.12found:779.26. ¹ H NMR (400MHz, DMSO-d ₆ )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＝8.9,2.3 Hz,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),3.2 0–3.06(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).

Embodiment 80

Preparation of compound III-4:

The synthetic route was referred to I-4, and III-4 was obtained by preparing liquid phase, 20.56 mg of white powder solid, yield: 21.18%. UPLC-MS calculated for C ₄₂ H ₄₆ ClN ₉ O ₅ [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),6.71(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).

Embodiment 81

Preparation of compound III-5:

The synthetic route was referred to I-4, and III-5 was obtained by preparing liquid phase, 30 mg of white powder solid. UPLC-MS calculated for C ₄₀ H ₄₁ ClN ₈ O ₆ [M+H] ⁺ :764.28, found:765.46. ¹ H NMR (400MHz, DMSO-d ₆ )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),7.1 4–7.04(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),3.8 9–3.74(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).

Embodiment 82

Preparation of compound III-6:

The synthetic route was referred to I-4, and III-6 was obtained by preparing liquid phase, 20 mg of white powder solid. UPLC-MS calculated for C ₄₀ H ₄₂ ClN ₉ O ₅ [M+H] ⁺ :763.30, found:764.37. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.62(s,1H),9.54(s,1H),8.56(d,J＝8.2Hz,1H),7.80(dd,J＝12.0,9.1Hz,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).

Embodiment 83

Preparation of compound III-7:

The synthetic route was referred to I-4, and III-7 was obtained by preparing liquid phase, 20 mg of white powder solid. UPLC-MS calculated for C ₄₀ H ₄₂ ClN ₉ O ₅ [M+H] ⁺ :763.30, found:764.28. ¹ H NMR (400MHz, DMSO-d ₆ )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＝1.8H z,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).

Embodiment 84

Preparation of compound III-8:

The synthetic route was referred to I-4, and III-8 was obtained by preparing liquid phase, 18 mg of white powder solid. UPLC-MS calculated for C ₃₉ H ₄₂ ClN ₁₀ O ₅ [M+H] ⁺ :765.30, found:765.27. ¹ H NMR (400MHz, DMSO-d ₆ )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＝9.2,7.0Hz,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),2.99(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).

Embodiment 85

Preparation of compound III-9:

The synthetic route was referred to I-4, and III-9 was obtained by preparing liquid phase, 25 mg of white powder solid. UPLC-MS calculated for C ₃₈ H ₄₁ ClN ₁₁ O ₅ [M+H] ⁺ :766.29, found:766.31. ¹ H NMR (400MHz, DMSO-d ₆ )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＝10.1,5.0Hz,1H),3.8 9–3.81(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).

Embodiment 86

Preparation of compound III-10:

The synthetic route was referred to I-4, and III-10 was obtained by preparing liquid phase, and the white powder solid was 10 mg. UPLC-MS calculated for C ₃₈ H ₄₁ ClN ₁₁ O ₅ [M+H] ⁺ :766.29, found:766.31. ¹ H NMR (400MHz, DMSO-d ₆ )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,2H),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).

Embodiment 87

Preparation of compound III-11:

The synthetic route was referred to I-4, and III-11 was obtained by preparing liquid phase, and the white powder solid was 13 mg. UPLC-MS calculated for C ₄₁ H ₄₆ ClN ₁₀ O ₅ [M+H] ⁺ :793.33, found:793.34. ¹ H NMR (400MHz, DMSO-d ₆ )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)

Embodiment 88

Preparation of compound III-12:

The synthetic route was referred to I-4, and III-12 was obtained by preparing liquid phase, and the white powder solid was 13 mg. UPLC-MS calculated for C ₄₂ H ₄₈ ClN ₁₀ O ₅ [M+H] ⁺ :807.35, found:807.32. ¹ H NMR (400MHz, DMSO-d ₆ )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,3H),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(dd,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)

Embodiment 89

Preparation of compound III-13:

first step:

The intermediate HSP90-27 (70 mg, 0.15 mmol) and the raw 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 reaction 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 obtain 80 mg of solid with a yield of 83.99%. UPLC-MS calculated for C ₃₃ H ₄₆ N ₇ O ₆ [M+H] ⁺ :636.34 found:636.76.

Step 2:

Dissolve the intermediate III-13-1 (80 mg, 0.12 mmol) in anhydrous methanol (1.5 mL), add dioxane hydrochloride (1.5 mL), and react at room temperature overnight. Evaporate the solvent to obtain 70 mg of a light yellow oil with a yield of 100%. UPLC-MS calculated for C ₂₈ H ₃₈ N ₇ O ₄ [M+H] ⁺ :536.29, found:536.65.

Step 3:

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. III-13 was obtained by preparative liquid phase, as a white powdery solid (27 mg). UPLC-MS calculated for C ₄₆ H ₅₃ ClN ₁₁ O ₆ [M+H] ⁺ :890.38, found:890.44.

Embodiment 90

Preparation of compound III-14:

The synthetic route was referred to III-13, and III-14 was obtained by preparing liquid phase, 22 mg of white powder solid. UPLC-MS calculated for C ₄₆ H ₅₄ ClN ₁₂ O ₆ [M+H] ⁺ :905.39, found:905.46. ¹ H NMR (500MHz, DMSO-d ₆ )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,2 H),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),3.25–3.1 4(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).

Embodiment 91

Preparation of compound III-15:

The synthetic route was referred to I-1, and III-15 was obtained by preparing liquid phase, 22 mg of white powder solid. UPLC-MS calculated for C ₄₇ H ₅₇ ClN ₁₁ O ₅ [M+H] ⁺ :890.42,found:890.48. ¹ H NMR (400MHz, DMSO-d ₆ )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,2 H),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).

Embodiment 92

Preparation of compound III-16:

The synthetic route was referred to I-1, and III-16 was obtained by preparing liquid phase, 28 mg of white powder solid. UPLC-MS calculated for C ₄₈ H ₅₉ ClN ₁₁ O ₅ [M+H] ⁺ :904.43,found:904.51. ¹ H NMR (400MHz, DMSO-d ₆ )δ11.83(s,1H),8.56(d,J＝8.2Hz,1H),7.84–7.73(m,3H),7.35(d,J＝2.4Hz,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),4.5 6–4.37(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).

Embodiment 93

Preparation of compound IV-1:

first step:

Intermediate Ⅰ-1-2 (100 mg, 0.27 mmol), methyl 4-piperidincarboxylate (43.5 mg, 0.40 mmol) and K ₂ CO ₃ (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, and the organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine in sequence, dried over anhydrous magnesium sulfate, and column chromatography (DCM/MeOH=15/1) to obtain 100 mg of solid, with a yield of 75%. UPLC-MS calculated for C ₂₅ H ₂₉ ClN ₅ O ₄ [M+H] ⁺ :498.13, found:498.98.

Step 2:

Intermediate IV-1-1 (100 mg, 0.27 mmol), anhydrous THF 6 mL and MeOH 6 mL were added to anhydrous H ₂ O with LiOH (43.5 mg, 0.40 mmol) and stirred at RT for 4 hours. HCl was used to adjust the pH.

Water and ethyl acetate were added for extraction, and the organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine in sequence, dried over anhydrous magnesium sulfate, and column chromatography (DCM/MeOH=15/1) was performed to obtain 46 mg of solid, with a yield of 35%. UPLC-MS calculated for C ₂₄ H ₂₅ ClN ₅ O ₄ [MH] ^- :482.17, found:482.95.

Step 3:

Dissolve the intermediate IV-1-2 (50 mg, 0.1 mmol), DIEA (40 mg, 0.3 mmol), and HATU (43 mg, 0.1 mmol) in anhydrous DMF, stir and react for 10 min under argon protection, add the DMF solution of the intermediate HSP90-8 (47 mg, 0.1 mmol), stir and react at room temperature overnight. Add water and ethyl acetate to extract, wash the organic phase with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine in turn, dry with anhydrous magnesium sulfate, and prepare the liquid phase to obtain IV-1 white 30 mg of colorless powdery solid, yield 33.3%. UPLC-MS calculated for C ₄₆ H ₅₂ ClN ₁₀ O ₆ [M+H] ⁺ :875.37,found:875.43. ¹ H NMR (400MHz,DMSO-d ₆ )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＝11.6,8.0,3.8H z,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,2 H),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).

Embodiment 94

Preparation of compound IV-2:

The synthetic route was referred to I-1, and IV-2 was obtained by preparing the liquid phase, 36 mg of white powdery solid. UPLC-MS calculated for C ₄₇ H ₅₆ ClN ₁₀ O ₅ [M+H] ⁺ :875.40, found:875.47. ¹ H NMR (400MHz, DMSO-d ₆ )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,2 H), 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).

Embodiment 95

Preparation of compound IV-3:

The synthetic route was referred to I-1, and IV-3 was obtained by preparing the liquid phase, 31 mg of white powdery solid. UPLC-MS calculated for C ₄₅ H ₅₂ ClN ₁₀ O ₅ [M+H] ⁺ :847.37, found:847.42. ¹ H NMR (400MHz, DMSO-d ₆ )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).

Embodiment 96

Preparation of compound IV-4:

The synthetic route was referred to I-1, and IV-4 was obtained by preparing liquid phase, 40 mg of white powder solid. UPLC-MS calculated for C ₅₂ H ₆₅ ClN ₁₁ O ₅ [M+H] ⁺ :958.48,found:958.61. ¹ H NMR (400MHz, DMSO-d ₆ )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,1H),4.56–4.71(s,1H),4.89(s,1H),4.10(s,1H),4.64(s,1H),4.90(s,1H),4.80(s,1H),4.69(s,1H),4.91(s,1H),4.84(s,1H),4.90(s,1H),4.62(s,1H),4.91(s,1H),4.60(s,1H),4.91(s,1H),4.69(s,1H),4.90(s,1H),4.91(s,1H),4.91(s,1H),4.91(s,1H),4.91(s,1H .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).

Embodiment 97

Preparation of compound IV-5:

The synthetic route was referred to I-1, and IV-5 was obtained by preparing liquid phase, 40 mg of white powder solid. UPLC-MS calculated for C ₄₆ H ₅₅ ClN ₁₁ O ₄ [M+H] ⁺ :860.40, found:860.44. ¹ H NMR (400MHz, DMSO-d ₆ )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),3.83–3.70(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).

Embodiment 98

Preparation of compound IV-6:

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 O ₅ [M+H] ⁺ :879.38, found:879.44. ¹ H NMR (400MHz, DMSO-d ₆ )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).

Embodiment 99

Preparation of compound IV-7:

The synthetic route was referred to I-1, and IV-7 was obtained by preparing the liquid phase, 12 mg of white powdery solid. UPLC-MS calculated for C ₄₇ H ₅₅ ClFN ₁₀ O ₅ [M+H] ⁺ :893.40, found:893.46. ¹ H NMR (400MHz, DMSO-d ₆ )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),3.8 5–3.78(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),1.6 4–1.58(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).

Embodiment 100

Preparation of compound IV-8:

The synthetic route was referred to I-1, and IV-8 was obtained by preparing liquid phase, 26 mg of white powder solid. UPLC-MS calculated for C ₄₅ H ₅₃ ClN ₁₁ O ₅ [M+H] ⁺ :862.38,found:862.43. ¹ H NMR (400MHz, DMSO-d ₆ )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,1H),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).

Embodiment 101

Preparation of compound IV-9:

The synthetic route was referred to I-1, and IV-9 was obtained by preparing the liquid phase, 25 mg of white powdery solid. UPLC-MS calculated for C ₄₆ H ₅₅ ClN ₁₁ O ₅ [M+H] ⁺ :876.40, found:876.46. ¹ H NMR (400MHz, DMSO-d ₆ )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),4.6 1–4.37(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).

Embodiment 102

Preparation of compound IV-10:

first step:

2-Chloro-5-nitropyridine (500 mg, 3.16 mmol) was dissolved in 10 mL dimethylformamide, and DIEA (816 mg, 3.56 mmol) and 4-(((tert-butyldimethylsilyl)oxy)methyl)piperidine (873 mg, 3.80 mmol) were added successively. The temperature was raised to 100°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=5:1) to obtain 820 mg of a yellow solid with a yield of 73.80%. UPLC-MS calculated for C ₁₇ H ₃₀ N ₃ O ₃ Si[M+H] ⁺ :352.20, found:352.26.

Step 2:

IV-10-1 (600 mg, 1.70 mmol) was dissolved in 20 mL of methanol, 10% palladium carbon (60 mg) was added, hydrogen was replaced three times, and the reaction was carried out at room temperature under hydrogen atmosphere for 6 h. The reaction solution was filtered, and the filtrate was directly used in the next reaction after being dried by rotation to obtain 550 mg of brown oil with a yield of 100%. UPLC-MS calculated for C ₁₇ H ₃₂ N ₃ OSi[M+H] ⁺ :322.22, found:322.30.

Step 3:

Dissolve IV-10-2 (550 mg, 1.71 mmol) in 20 ml tetrahydrofuran, add pyridine (148 mg, 1.87 mmol) and phenyl chloroformate (294 mg, 1.87 mmol) in an ice bath, and react at room temperature for 3 h. Add water (50 mL) to the reaction solution, extract with ethyl acetate (20 mL*2), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, and purify the filtrate by column chromatography (PE:EA=4:1) after drying to obtain 600 mg of pink solid, with a yield of 79.57%. UPLC-MS calculated for C ₂₄ H ₃₆ N ₃ O ₃ Si[M+H] ⁺ :442.24, found:442.37.

Step 4:

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

Step 5:

IV-10-5 (770 mg, 2.16 mmol) was dissolved in 30 mL of 4 M hydrogen chloride dioxane solution and stirred at room temperature for 2 h. After spin drying, 550 mg of a white solid crude product was obtained. Yield: 100%. UPLC-MS calculated for C ₁₂ H ₁₃ F ₃ N ₃ [M+H] ⁺ :256.10, found:256.21.

Step 6:

IV-10-3 (600 mg, 1.36 mmol) was dissolved in acetonitrile (30 mL), DIEA (526 mg, 4.07 mmol) and IV-10-6 (550 mg, 2.15 mmol) were added successively, and the temperature was raised to 90°C for 2 h. After cooling to room temperature, the solvent was removed by rotary evaporation, and the product was purified by column chromatography (DCM: MeOH = 15:1) to obtain 750 mg of a blue solid with a yield of 91.46%. UPLC-MS calculated for: C ₃₀ H ₄₂ F ₃ N ₆ O ₂ Si[M+H] ⁺ :603.30, found:603.44.

Step 7:

IV-10-7 (750 mg, 1.24 mmol) was dissolved in tetrahydrofuran (20 mL), TBAF (1 M in THF, 1.5 mL) was added, and the mixture was reacted at room temperature for 3 h. The solvent was removed by rotary evaporation, and the mixture was purified by column chromatography (DCM: MeOH = 15: 1) to obtain 500 mg of a brown solid with a yield of 82.37%. UPLC-MS calculated for: C ₂₄ H ₂₈ F ₃ N ₆ O ₂ [M+H] ⁺ :489.21, found:489.36.

Step 8:

IV-10-8 (200 mg, 0.40 mmol) was dissolved in 20 mL of dichloromethane, and DMP (200 mg, 0.47 mmol) was added. The mixture was reacted at room temperature for 3 h. 50 mL of saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL*2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by column chromatography (DCM: MeOH = 15: 1) to obtain 120 mg of brown solid with a yield of 60.30%. UPLC-MS calculated for C ₂₄ H ₂₆ F ₃ N ₆ O ₂ [M+H] ⁺ :487.20, found:487.23.

Step 9:

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), and triethylamine was added dropwise to adjust the pH to about 8. The reaction was stirred at room temperature for 30 min, and then added under ice bath. Sodium cyanoborohydride (8.1 mg, 0.12 mmol) was added and the reaction was stirred at room temperature overnight. 38 mg of white powdery solid was obtained by preparative liquid phase analysis, with a yield of 42.23%. UPLC-MS calculated for C ₄₆ H ₅₃ F ₃ N ₁₁ O ₄ [M+H] ⁺ :880.42, found:880.99. ¹ H NMR (400 MHz, DMSO-d ₆ )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(d d,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).

Embodiment 103

Preparation of compound V-1:

first step:

AR-9 (312 mg, 1.2 mmol), DIEA (464.4 mg, 3.6 mmol), HATU (501.6 mg, 1.32 mmol) were dissolved in anhydrous DMF, stirred and reacted for 10 min under argon protection, and a DMF solution of p-pyrrole carboxylic acid (147.84 mg, 1.32 mmol) was added, and the reaction was stirred at room temperature overnight. Water and ethyl acetate were added for extraction, and the organic phase was washed with saturated ammonium chloride and saturated brine in turn, dried over anhydrous magnesium sulfate, and column chromatography (DCM/MeOH=15/1) to obtain 250 mg of solid, with a yield of 59%. UPLC-MS calculated for C ₁₇ H ₁₆ ClN ₆ O[M+H] ⁺ :355.10, found:355.80.

Step 2:

Dissolve V-1-1 (250 mg, 0.70 mmol), 2-bromo-1,1-dimethoxyethane (134.3 mg, 0.79 mmol), K ₂ CO ₃ (150.4 mg, 1.1 mmol) and KI (3.6 mg, 0.07 mmol) in anhydrous DMF and stir at 80°C for 4 h. Add water and ethyl acetate for extraction, wash the organic phase with saturated ammonium chloride and saturated brine in turn, dry over anhydrous magnesium sulfate, and column chromatography (DCM/MeOH=15/1) to obtain 200 mg of solid, with a yield of 65%. UPLC-MS calculated for C ₂₁ H ₂₄ ClN ₆ O ₃ [M+H] ⁺ :443.15, found:443.90.

Step 3:

Dissolve the intermediate V-1-2 (200 mg, 0.45 mmol) in anhydrous THF (5 mL), drip (1 mL) 4M-HCl into the system, and stir at 50°C for 4 h. Cool to a warm state, add 20 mL of distilled water, and freeze-dry directly to obtain 200 mg of solid. UPLC-MS calculated for C ₁₉ H ₁₈ ClN ₆ O ₂ [M+H] ⁺ :397.11, found:397.84.

The remaining synthesis steps were referred to I-1, and V-1 was obtained by preparing the liquid phase, and the white powder solid was 25 mg. UPLC-MS calculated for C ₄₇ H ₅₆ ClN ₁₂ O ₄ [M+H] ⁺ :887.42,found:887.48. ¹ H NMR (400MHz, DMSO-d ₆ )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).

Embodiment 104

Preparation of compound V-2:

The synthesis steps were referred to I-1, and V-2 was obtained by preparing the liquid phase, and the white powder solid was 25 mg. UPLC-MS calculated for C ₃₆ H ₃₄ ClN ₈ O ₄ [M+H] ⁺ :677.23,found:677.16. ¹ H NMR (400MHz, DMSO-d ₆ )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).

Embodiment 105

Preparation of compound V-3:

The synthesis steps were referred to I-1, and V-3 was obtained by preparing the liquid phase, and the white powder solid was 10 mg. UPLC-MS calculated for C ₃₃ H ₃₁ ClN ₁₁ O ₄ [M+H] ⁺ :680.22, found:680.13. ¹ H NMR (400MHz, DMSO-d ₆ )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＝7.5,1.5Hz,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).

Embodiment 106

Preparation of compound V-4:

The synthesis steps were referred to V-3, and V-4 was obtained by preparing the liquid phase, and the white powder solid was 15 mg. UPLC-MS calculated for C ₃₄ H ₃₁ ClN ₁₁ O ₅ [M+H] ⁺ :708.21,found:708.14. ¹ H NMR (400MHz, DMSO-d ₆ )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,2 H),7.48(d,J＝0.6Hz,1H),6.63(d,J＝7.5Hz,1H),6.42(s,1H),4.22–4.12(m,1H),4.1 2–3.97(m,2H),3.20–3.13(m,1H),1.24(dd,J＝6.6,4.0Hz,6H),1.20(d,J＝6.7Hz,3H).

Embodiment 107

Preparation of compound V-5:

The synthesis steps were referred to V-3, and V-5 was obtained by preparing the liquid phase, and the white powder solid was 10 mg. UPLC-MS calculated for C ₃₆ H ₃₁ ClN ₉ O ₄ [M+H] ⁺ :688.21,found:688.15. ¹ H NMR (400MHz, DMSO-d ₆ )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),7.56–7.45(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,2 H), 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).

Embodiment 108

Preparation of compound V-6:

The synthesis steps were referred to V-3, and V-6 was obtained by preparing the liquid phase, 31 mg of white powder solid. UPLC-MS calculated for C ₃₄ H ₃₁ ClN ₉ O ₄ [M+H] ⁺ :664.21, found:664.49. ¹ H NMR (500MHz, Chloroform-d) δ8.85 (s, 1H), 7.91 (dd, J＝7.5, 2.2 Hz, 1H), 7.82 (d, J＝2.3 Hz, 1H), 7.79–7.71 (m, 3H), 7.58 (d, J＝9.3 Hz, 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).

Embodiment 109

Preparation of compound V-7:

The synthesis steps were similar to those of V-3, and V-7 was obtained by preparing the liquid phase, 8 mg of a white powdery solid. UPLC-MS calculated for C ₃₄ H ₃₃ ClN ₁₁ O ₄ [M+H] ⁺ :694.23, found:694.15. ¹ H NMR (400 MHz, DMSO-d ₆ )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),7.8 7(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＝0.6H z,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).

Embodiment 110

Preparation of compound V-8:

first step:

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), stirred at room temperature for 30 min, sodium cyanoborohydride (29 mg, 0.46 mmol) was added under ice bath, stirred at room temperature for overnight. The solvent was removed by rotary evaporation and purified by column chromatography (DCM: MeOH = 15: 1) to obtain 120 mg of brown oil with a yield of 58%. UPLC-MS calculated for C ₂₇ H ₃₇ ClN ₅ O ₄ [M+H] ⁺ :530.25, found:530.50.

Step 2:

Dissolve V-8-1 (120 mg, 0.23 mmol) in tetrahydrofuran (10 mL), add 6 M hydrochloric acid solution (5 mL), react at room temperature for 3 h. Saturated sodium bicarbonate was added to the reaction solution until the pH was 8, extracted with ethyl acetate (10 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain 95 mg of a yellow solid crude product with a yield of 86%. UPLC-MS calculated for C ₂₅ H ₃₁ ClN ₅ O ₃ [M+H] ⁺ :484.20, found:484.40.

Step 3:

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), and triethylamine was added dropwise to adjust the pH to about 8. The mixture was stirred at room temperature for 30 min, and sodium cyanoborohydride (10 mg, 0.26 mmol) was added under ice bath. The mixture was stirred at room temperature overnight. 41 mg of white powdery solid was obtained by preparative liquid phase analysis, with a yield of 24%. UPLC-MS calculated for C ₄₇ H ₅₇ ClN ₁₀ O ₅ [M+H] ⁺ :877.42, found:877.62. ¹ H NMR (400 MHz, Methanol-d ₄ )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),2.20(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).

Embodiment 111

Preparation of compound V-9:

The synthesis steps were referred to V-8, and V-9 was obtained by preparing the liquid phase, 36 mg of white powder solid. UPLC-MS calculated for C ₄₁ H ₄₇ ClN ₉ O ₅ [M+H] ⁺ :780.33, found:780.34. ¹ H NMR (400MHz, DMSO-d ₆ )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,1 H),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).

Embodiment 112

Preparation of compound V-10:

The synthesis steps were similar to those of AR-11 and V-8, and V-10 was obtained by preparative liquid phase, 39 mg of white powdery solid. UPLC-MS calculated for C ₄₇ H ₅₉ ClN ₁₁ O ₄ [M+H] ⁺ :876.44, found:876.50. ¹ H NMR (400 MHz, DMSO-d ₆ )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＝8.1Hz,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,2 H),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＝11.8Hz ,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).

Embodiment 113

Preparation of compound V-11:

The synthesis steps were similar to those of V-10, and V-11 was obtained by preparing the liquid phase, and the white powder solid was 21 mg. UPLC-MS calculated for C ₄₆ H ₅₅ ClN ₁₁ O ₆ [M+H] ⁺ :892.39, found:892.46. ¹ H NMR (400MHz, DMSO-d ₆ )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),5.13(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),3.22–3.1 1(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).

Embodiment 114

Preparation of compound V-12:

The synthesis steps were similar to those of V-10, and V-12 was obtained by preparing the liquid phase, with 22 mg of white powdery solid. UPLC-MS calculated for C ₄₇ H ₅₈ ClN ₁₀ O ₅ [M+H] ⁺ :877.42, found:877.49. ¹ H NMR (500 MHz, DMSO-d ₆ )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,2 H),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).

Embodiment 115

Preparation of compound V-13:

The synthesis steps were similar to those of V-10, and V-13 was obtained by preparing a liquid phase, and the white powder solid (22 mg) was obtained. UPLC-MS calculated for C ₄₇ H ₅₈ ClN ₁₀ O ₅ [M+H] ⁺ :877.42, found:877.51. ¹ H NMR (400MHz, DMSO-d ₆ )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),7.1 7(d,J＝1.5Hz,1H),6.99(dd,J＝7.5,1.5Hz,1H),6.76(d,J＝7.5Hz,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).

Embodiment 116

Preparation of compound V-14:

The synthesis steps were similar to those of V-10, and V-14 was obtained by preparing the liquid phase, 35 mg of a white powdery solid. UPLC-MS calculated for C ₄₃ H ₅₁ ClN ₉ O ₅ [M+H] ⁺ :808.36, found:808.38. ¹ H NMR (400 MHz, DMSO-d ₆ )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＝8.8,2.5Hz,1H),6.7 5(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).

Embodiment 117

Preparation of compound V-15:

The synthesis steps were referred to V-10, and V-15 was obtained by preparing liquid phase, 21 mg of white powder solid. UPLC-MS calculated for C ₄₉ H ₆₂ ClN ₁₀ O ₅ [M+H] ⁺ :905.45,found:905.54. ¹ H NMR (400MHz, DMSO-d ₆ )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).

Embodiment 118

Preparation of compound VI-1:

first step:

(4-Bromophenylethynyl)trimethylsilane (400mg, 1.58mmol) and 4-(dimethoxymethyl)-piperidine (480mg, 3.01mmol) were dissolved in tetrahydrofuran (20mL), Pd ₂ (dba) ₃ (55mg, 0.06mmol) and Davephos (24mg, 0.06mol) were added, and the argon atmosphere was replaced three times. LiHMDS solution (3.2ml, 3.2mmol, 1M in THF) was added dropwise under argon atmosphere, and the temperature was raised to reflux for reaction for 3h. After cooling to room temperature, water (50mL) was added to the reaction solution, and ethyl acetate was extracted (20mL*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 450mg of brown solid, with a yield of 86.04%. UPLC-MS calculated for C ₁₉ H ₂₉ NO ₂ Si[M+H] ⁺ :331.52,found:332.45.

Step 2:

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 yellow solid, with a yield of 76.70%. UPLC-MS calculated for C ₁₆ H ₂₂ NO ₂ [M+H] ⁺ :260.34, found:360.41.

Step 3:

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

Step 4:

Dissolve VI-1-3 (130 mg, 0.41 mmol) and VI-1-4 (130 mg, 0.50 mmol) in tert-butyl alcohol (20 mL), add CuSO ₄ (6 mg, 0.03 mmol) and NaAsc (6 mg, 0.03 mmol) in water (5 mL), and react at room temperature for 8 h. Remove the solvent by rotary evaporation, add water (50 mL), extract with ethyl acetate (20 mL*2), and add saturated The product was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography (PE:EA=1:10) after being spin-dried to obtain 160 mg of a yellow solid with a yield of 67.51%. UPLC-MS calculated for C ₂₈ H ₃₁ F ₃ N ₆ O ₄ [M+H] ⁺ :572.24, found:574.58.

Step 5:

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*3), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, and spin dry the filtrate to obtain 130 mg of yellow solid crude product, with a yield of 88.43%. UPLC-MS calculated for C ₂₆ H ₂₆ F ₃ N ₆ O ₃ [M+H] ⁺ :527.19, found:527.33.

Step 6:

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), and triethylamine was added dropwise to adjust the pH to about 8. The mixture was stirred at room temperature for 30 min, and sodium cyanoborohydride (10 mg, 0.26 mmol) was added under ice bath. The mixture was stirred at room temperature overnight. 54 mg of white powdery solid was obtained by preparative liquid phase analysis, with a yield of 31.03%. UPLC-MS calculated for C ₄₈ H ₅₃ F ₃ N ₁₁ O ₅ [M+H] ⁺ :920.41, found:920.42. ¹ H NMR (400 MHz, DMSO-d ₆ )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＝6.9Hz,2 H), 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).

Embodiment 119

Preparation of compound VI-2:

first step:

Dissolve AR-5 (300 mg, 0.86 mmol) and methyl pyrazole-4-carboxylate (162 mg, 1.29 mmol) in tetrahydrofuran (20 mL), add NaH (60% in mineral oil, 205 mg, 5.16 mmol) under ice bath. React at room temperature for 18 h. Add water (100 mL) to the reaction solution, adjust the pH to neutral with 1M hydrochloric acid solution, extract with ethyl acetate (30 mL*2), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, and purify the filtrate by column chromatography after spin drying. (PE:EA＝1:10), 270 mg of white oil was obtained, with a yield of 72.58%. UPLC-MS calculated for C ₁₇ H ₁₆ F ₃ N ₄ O ₄ [M+H] ⁺ :397.10, found:397.22.

Step 2:

Dissolve VI-2-1 (270 mg, 0.68 mmol) in tetrahydrofuran (10 mL) and water (2 mL), add lithium hydroxide (25 mg, 1.04 mmol), and react at room temperature for 18 h. Add water (30 mL) to the reaction solution, adjust the pH to about 4 with 1M hydrochloric acid solution, extract with ethyl acetate (10 mL*2), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, and spin dry the filtrate to obtain 250 mg of white oil, with a yield of 96.15%. UPLC-MS calculated for C ₁₆ H ₁₄ F ₃ N ₄ O ₄ [M+H] ⁺ :383.09, found:383.21.

Step 3:

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. After reacting at room temperature for 30 min, 4-(dimethoxymethyl)-piperidine (46 mg, 0.29 mmol) was added and reacted at room temperature for 18 h. Water (200 mL) was added to the reaction solution, and ethyl acetate was extracted (30 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried and purified by column chromatography (DCM: MeOH = 15: 1) to obtain 110 mg of colorless oil with a yield of 80.88%. UPLC-MS calculated for C ₂₄ H ₂₉ F ₃ N ₅ O ₅ [M+H] ⁺ :524.20, found:524.19.

The subsequent synthesis of VI-1 was referred to to obtain 46 mg of white powdery solid with a yield of 42.54%. UPLC-MS calculated for C ₄₄ H ₅₀ F ₃ N ₁₀ O ₆ [M+H] ⁺ :871.38, found:871.44. ¹ H NMR (400MHz, DMSO-d ₆ )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,1H),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).

Embodiment 120

Preparation of compound VI-3:

The synthesis steps were referred to VI-2, and 25 mg of white powdery solid was obtained. UPLC-MS calculated for C ₄₃ H ₄₉ F ₃ N ₁₁ O ₆ [M+H] ⁺ :872.37,found:872.61. ¹ H NMR (500MHz, DMSO-d ₆ )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).

Embodiment 121

Preparation of compound VI-4:

Step 1 & Step 2:

Dissolve indoline-6-carboxylic acid (1g, 5.64mmol) in methanol (30mL), add potassium hydroxide (640mg, 11.28mmol) in water (10mL), and heat to 50℃ for 18h. After cooling to room temperature, add 1M hydrochloric acid solution to the reaction solution to adjust the pH to about 2, remove the solvent by rotary evaporation, dissolve the residue in dimethylformamide (50mL), filter to remove insoluble matter, add diisopropylethylamine (2.6g, 20.15mmol), HATU (2.5g, 6.57mmol) and 4-(dimethoxymethyl)-piperidine (1.5g, 9.42mmol) to the filtrate, and react at room temperature for 18h. Water (500 mL) 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, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried and purified by column chromatography (DCM:MeOH=15:1) to obtain 1.38 g of brown oil with a two-step yield of 80.70%. UPLC-MS calculated for C ₁₇ H ₂₅ N ₂ O ₃ [M+H] ⁺ :305.18, found:305.20.

Step 3:

Dissolve VI-4-3 (173 mg, 0.57 mmol) in tetrahydrofuran (10 mL), cool to -78 °C, add LDA solution (2M in THF, 0.9 ml, 1.8 mmol), react for 30 min, add AR-7 (200 mg, 0.57 mmol) in tetrahydrofuran (5 mL) at -78 °C, slowly warm to room temperature and react for 18 h. Add saturated ammonium chloride solution (50 mL) to the reaction solution, extract with ethyl acetate (20 mL*3), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, and purify the filtrate by column chromatography (PE:EA=1:10) after drying to obtain 180 mg of brown oil with a yield of 55.04%. UPLC-MS calculated for C ₂₉ H ₃₄ F ₃ N ₄ O ₅ [M+H] ⁺ :575.24, found:575.33.

The subsequent synthesis method was referred to VI-2, and VI-4 was obtained as a white powder solid (64 mg) by preparing the liquid phase. UPLC-MS calculated for C ₅₅ H ₆₆ F ₃ N ₁₀ O ₆ [M+H] ⁺ :1019.50, found:1019.52. ¹ H NMR (400MHz, DMSO-d ₆ )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(dd,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).

Embodiment 122

Preparation of compound VI-5:

The synthesis method was referred to HSP90-27, and 21 mg of white powder solid VI-5 was obtained by preparative liquid phase. UPLC-MS calculated for C ₃₅ H ₃₈ F ₃ N ₇ O ₅ [M+H] ⁺ :694.29, found:694.73. ¹ H NMR (400MHz, DMSO-d ₆ )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,1 H),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),3.02–2.92(m,3 H), 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).

Embodiment 123

Preparation of compound VI-6:

The synthesis method was similar to that of VI-5, and 22 mg of VI-6 was obtained as a white powdery solid by preparing the liquid phase. UPLC-MS calculated for C ₃₆ H ₄₁ F ₃ N ₇ O ₅ [M+H] ⁺ :708.30, found:708.76. ¹ H NMR (400MHz, DMSO-d ₆ )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,1 H),5.05(s,1H),3.62(t,J＝0.9Hz,2H),3.22–3.10(m,1H),3.06(d,J＝12.5Hz,1H),3.02–2. 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).

Embodiment 124

Preparation of compound VI-7:

The synthesis method was similar to that of VI-5, and 19 mg of VI-7 was obtained as a white powdery solid by preparing the liquid phase. UPLC-MS calculated for C ₃₄ H ₃₇ F ₃ N ₇ O ₅ [M+H] ⁺ :680.27, found:680.70. ¹ H NMR (400MHz, DMSO-d ₆ )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).

Embodiment 125

Preparation of compound VI-8:

The synthesis method was similar to that of VI-4, and 29 mg of VI-8 was obtained by preparative liquid phase analysis. UPLC-MS calculated for C ₄₀ H ₄₈ F ₃ N ₈ O ₅ [M+H] ⁺ :777.36, found:777.86. ¹ H NMR (400MHz, DMSO-d ₆ )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).

Embodiment 126

Preparation of compound VI-9:

The synthesis method was referred to VI-4, and 41 mg of VI-9 was obtained as a white powder solid by preparative liquid phase. UPLC-MS calculated for C ₃₉ H ₄₈ ClN ₈ O ₅ [M+H] ⁺ :743.34,found:743.31. ¹ H NMR (400MHz, DMSO-d ₆ )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＝12.4,6.9Hz,1 H), 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).

Embodiment 127

Preparation of compound VI-10:

The synthesis method was similar to that of VI-4, and 41 mg of white powdery solid VI-10 was obtained by preparative liquid phase. UPLC-MS calculated for C ₄₄ H ₅₁ F ₃ N ₇ O ₅ [M+H] ⁺ :814.38, found:814.92. ¹ H NMR (400MHz, DMSO-d ₆ )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).

Embodiment 128

Preparation of compound VI-11:

The synthesis method was referred to VI-4, and 41 mg of VI-11 was obtained as a white powder solid by preparing the liquid phase. UPLC-MS calculated for C ₃₈ H ₄₂ F ₃ N ₆ O ₆ [M+H] ⁺ :735.30,found:735.78. ¹ H NMR (400MHz, DMSO-d ₆ )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＝7.7,1.0Hz,2H),6.5 2(s,1H),5.04(s,1H),3.66–3.53(m,2H),3.50–3.27(m,2H),3.20(dtd,J＝13.5,6.7,0.6Hz,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).

Embodiment 129

Preparation of compound VI-12:

The synthesis method was similar to that of VI-4, and 18 mg of VI-12 was obtained as a white powdery solid by preparing the liquid phase. UPLC-MS calculated for C ₄₄ H ₅₃ F ₃ N ₇ O ₆ [M+H] ⁺ :832.39, found:832.94. ¹ H NMR (400MHz, DMSO-d ₆ )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),3.2 5–3.12(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).

Embodiment 130

Preparation of compound VI-13:

The synthesis method was similar to that of VI-4, and 8 mg of VI-13 was obtained as a white powdery solid by preparing the liquid phase. UPLC-MS calculated for C ₅₀ H ₆₄ F ₃ N ₈ O ₆ [M+H] ⁺ :929.48, found:929.10. ¹ H NMR (400MHz, DMSO-d ₆ )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,2H),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).

Embodiment 131

Preparation of compound VI-14:

first step:

AR-10 (900 mg, 2.0 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (216 mg, 0.2 mmol), cuprous iodide (36 mg, 0.2 mmol), triethylamine (610 mg, 6.0 mmol), tert-butyl 3-ethynyl-1-azetidinecarboxylate (540 mg, 3.0 mmol) were dissolved in dichloromethane (30 mL), replaced 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 separated by column chromatography (PE:EA=2:1) after being spin-dried to obtain 570 mg of brown solid with a yield of 57%. UPLC-MS calculated for C ₂₅ H ₂₇ F ₃ N ₅ O ₃ [M+H] ⁺ :502.20, found:502.41.

Step 2:

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 dried, and dichloromethane (20 mL) and sodium hydroxide solution (4M, 20 mL) were added. The reaction was stirred at room temperature for 30 min, and the organic phase was separated and dried over anhydrous sodium sulfate. The brown-black solid after drying was 420 mg, and the yield was 92%. UPLC-MS calculated for C ₂₀ H ₁₉ F ₃ N ₅ O[M+H] ⁺ :402.15, found:402.33.

Step 3:

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), and 1 drop of acetic acid was added. The mixture was reacted at room temperature for 2 h. After cooling to 0°C, sodium cyanoborohydride (19 mg, 0.3 mmol) was added and the mixture was reacted at 0°C for 2 h. The solvent was dried and then purified by reverse preparative liquid phase to obtain 54 mg of a white solid with a yield of 30%. UPLC-MS calculated for C ₃₈ H ₃₆ F ₃ N ₈ O ₄ [M+H] ⁺ :725.27, found:725.47. ¹ H NMR (400MHz, DMSO-d ₆ )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).

Embodiment 132

Preparation of compound VI-15:

first step:

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), extract with ethyl acetate (50 mL*3), wash the organic phase with saturated brine (150 mL), dry over anhydrous sodium sulfate, filter and concentrate to obtain a crude product, and obtain 350 mg of light yellow solid by column chromatography (PE:EA＝2:1), with a yield of 60%. UPLC-MS calculated for C ₂₆ H ₂₂ F ₃ N ₆ O ₃ [M+H] ⁺ :523.16,found:523.31.

Step 2:

Dissolve VI-15-1 (350 mg, 0.67 mmol) in methanol (20 mL), add hydrosulfite (630 mg, 3.6 mmol) and sodium carbonate (385 mg, 3.6 mmol) in water (20 mL), and react at room temperature for 2 h. Remove methanol by rotary evaporation, add saturated ammonium chloride solution (20 mL), extract with ethyl acetate (20 mL*3), wash the organic phase with saturated brine (60 mL), dry over anhydrous sodium sulfate, filter and concentrate to obtain 330 mg of light yellow solid. UPLC-MS calculated for C ₂₆ H ₂₄ F ₃ N ₆ O[M+H] ⁺ :493.19, found:493.33.

Step 3:

HSP90-1-5 (153 mg, 0.67 mmol), sodium carbonate (170 mg, 2.0 mmol), chloroacetic acid (63 mg, 0.67 mmol) were dissolved in anhydrous dimethylformamide (20 mL), reacted at room temperature for 2 h, added dimethylformamide solution (20 mL) of crude VI-15-2 (330 mg), heated to 80 ° C and reacted for 1 h. After cooling to room temperature, water (400 mL) was added, and ethyl acetate was extracted (50 mL*3). The organic phase was washed with saturated brine (150 mL) and dried over anhydrous sodium sulfate. The residue was dried, filtered and concentrated to obtain a crude product, which was purified by column chromatography (PE:EA=1:1) to obtain 230 mg of a brown solid, with a two-step yield of 50%. UPLC-MS calculated for C ₃₆ H ₃₄ F ₃ N ₆ O ₃ S[M+H] ⁺ :687.23, found:687.60.

Step 4:

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 F ₃ N ₆ O ₄ S[M+H] ⁺ :713.21, found:713.26.

Step 5:

300 mg of crude VI-15-4 was dissolved in ethanol (20 mL), and hydrazine hydrate (80%, 33 mg, 0.84 mmol) was added, and the mixture was reacted at room temperature for 2 h. After concentration, the mixture was purified by reverse phase preparative method to obtain 51 mg of a white solid, with a two-step yield of 21%. UPLC-MS calculated for C ₃₇ H ₃₄ F ₃ N ₈ O ₄ [M+H] ⁺ :711.26, found:711.36. ¹ H NMR (400 MHz, DMSO-d ₆ )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).

Embodiment 133

Preparation of compound VI-16:

The synthesis steps were referred to VI-14, and 22 mg of white powder solid was obtained. UPLC-MS calculated for C ₄₀ H ₄₀ F ₃ N ₈ O ₄ [M+H] ⁺ :753.30, found:753.33. ¹ H NMR (400MHz, DMSO-d ₆ )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).

Embodiment 134

Preparation of compound VI-17:

The synthesis steps were referred to VI-15, and 22 mg of white powdery solid was obtained. UPLC-MS calculated for C ₃₉ H ₃₈ F ₃ N ₈ O ₄ [M+H] ⁺ :739.29, found:739.35. ¹ H NMR (400MHz, DMSO-d ₆ )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,1 H),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,2 H), 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).

Embodiment 135

Preparation of compound VI-18:

first step:

1-Triphenylmethyl-4-bromo-pyrazole (2.5 g, 6.4 mmol), 4-(dimethoxymethyl)-piperidine (2.0 g, 12.5 mmol), Pd ₂ (dba) ₃ (300 mg, 0.32 mmol), tBuDavephos (220 mg, 0.64 mmol), sodium tert-butoxide (1.9 g, 19.2 mmol) were placed in a round-bottom flask, toluene (50 mL) was added, argon was replaced three times, and the temperature was raised to 90°C under argon atmosphere for 18 h. After cooling to room temperature, toluene was removed by rotary evaporation, water (100 mL) was added, and ethyl acetate was extracted (30 mL*3). The organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and column chromatography (PE:EA=5:1) was performed to obtain 1.4 g of brown solid, with a yield of 46%. UPLC-MS calculated for C ₃₀ H ₃₄ N ₃ O ₂ [M+H] ⁺ : 468.26,found:468.52.

Step 2:

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

The subsequent synthesis steps refer to VI-1, and 27 mg of white powder solid is obtained by preparing liquid phase. UPLC-MS calculated for C ₄₃ H ₅₀ F ₃ N ₁₀ O ₄ [M+H] ⁺ :827.39,found:827.66. ¹ H NMR (400MHz, DMSO-d ₆ )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).

Embodiment 136

Preparation of compound VI-19:

The synthesis steps were referred to VI-18, and 22 mg of white powder solid was obtained by preparing the liquid phase. UPLC-MS calculated for C ₃₇ H ₃₉ F ₃ N ₉ O ₄ [M+H] ⁺ :730.30, found:730.77. ¹ H NMR (400MHz, DMSO-d ₆ )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,2H) z,1H),7.41–7.29(m,4H),6.42(s,1H),3.60(t,J＝1.0Hz,2H),3.31(dt,J＝12.5,7.1H z,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).

Embodiment 137

Preparation of compound VI-20:

The synthesis steps were referred to VI-18, and 31 mg of white powder solid was obtained by preparing the liquid phase. UPLC-MS calculated for C ₄₀ H ₄₈ F ₃ N ₈ O ₄ [M+H] ⁺ :761.37, found:761.86. ¹ H NMR (400MHz, DMSO-d ₆ )δ11.36(s,1H),10.72(s,1H),9.47(s,1H),8.96(s,1H),8.32(d,J＝1.5Hz,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,1 0H),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).

Embodiment 138

Preparation of compound VI-21:

The synthesis steps were similar to those of VI-18, and 18 mg of white powdery solid was obtained by preparing the liquid phase. UPLC-MS calculated for C ₃₆ H ₃₇ F ₃ N ₇ O ₄ [M+H] ⁺ :664.28, found:664.30. ¹ H NMR (400MHz, DMSO-d ₆ )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).

Embodiment 139

Preparation of compound VI-22:

The synthesis steps were similar to those of VI-18, and 18 mg of white powdery solid was obtained by preparing the liquid phase. UPLC-MS calculated for C ₃₈ H ₄₂ F ₃ N ₆ O ₅ [M+H] ⁺ :719.31,found:719.78. ¹ H NMR(400MHz,DMSO-d ₆ )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,1 H),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).

Embodiment 140

Preparation of compound VII-1:

first step:

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, stirred and reacted for 10 min under argon protection, and a DMF solution of AR-6 (60 mg, 0.13 mmol) was added, and stirred and reacted at room temperature overnight. Water and ethyl acetate were added for extraction, and the organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine in turn, dried over anhydrous magnesium sulfate, and column chromatography (PE:EA=5:1) was performed to obtain 47 mg of solid VII-1-1, with a yield of 65%. UPLC-MS calculated for C ₂₈ H ₂₈ F ₄ N ₅ O ₄ S[M+H] ⁺ :606.17, found:606.61.

Subsequent experimental operations were performed with reference to VI-1, and 33 mg of white powdery solid was obtained by preparing the liquid phase. UPLC-MS calculated for C ₄₈ H ₄₉ F ₇ N ₁₀ O ₅ S[M+H] ⁺ :953.35, found:953.43. ¹ H NMR (400MHz, DMSO-d ₆ )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,1 H),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).

Embodiment 141

Preparation of compound VII-2:

The synthesis method was similar to that of Example VII-1, and VII-2 was obtained as a white powdery solid (20 mg) by preparing the liquid phase. UPLC-MS calculated for C ₄₂ H ₃₉ F ₄ N ₈ O ₅ S[M+H] ⁺ :843.26, found:843.87. ¹ H NMR (400 MHz, DMSO-d ₆ )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).

Embodiment 142

Preparation of compound VII-3:

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 preparing a liquid phase. UPLC-MS calculated for C ₄₁ H ₃₈ F ₄ N ₉ O ₅ S[M+H] ⁺ :844.26, found:844.86. ¹ H NMR (400 MHz, DMSO-d ₆ )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),3.92–3.7 8(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).

Embodiment 143

Preparation of compound VII-4:

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 preparing a liquid phase. UPLC-MS calculated for C ₄₁ H ₃₆ F ₄ N ₉ O ₅ S[M+H] ⁺ :857.25, found:857.86. ¹ H NMR (400 MHz, DMSO-d ₆ )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,2 H),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).

Embodiment 144

Preparation of compound VII-5:

The synthesis method was similar to that of Example VII-1, and 20 mg of VII-5 white powder solid was obtained by preparing the liquid phase. UPLC-MS calculated for C ₄₂ H ₃₈ F ₅ N ₈ O ₅ S[M+H] ⁺ :861.25, found:861.86. ¹ H NMR (400 MHz, DMSO-d ₆ )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).

Embodiment 145

Preparation of compound VII-6:

The synthesis method was similar to that of Example VII-1, and 41 mg of VII-6 white powder solid was obtained by preparing the liquid phase. UPLC-MS calculated for C ₄₈ H ₅₀ F ₄ N ₉ O ₅ S[M+H] ⁺ :940.35,found:940.03. ¹ H NMR (400MHz, DMSO-d ₆ )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).

Embodiment 146

Preparation of compound VII-7:

The synthesis method was similar to that of Example VII-1, and 41 mg of white powdery solid VII-7 was obtained by preparing the liquid phase. UPLC-MS calculated for C ₄₆ H ₄₉ F ₃ N ₁₁ O ₄ S[M+H] ⁺ :908.36, found:908.66. ¹ H NMR (400MHz, DMSO-d ₆ )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,2 H), 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).

The beneficial effects of the present application will be further illustrated below in combination with examples and comparative examples, but the scope of the present invention is not limited to these examples.

Test Example 1: Prostate tumor cell proliferation inhibitory activity

Prostate tumor cells LNCaP, VCaP and 22Rv1 were purchased from Wuhan Punosai Life Science Technology Co., Ltd. The cell culture medium of LNCaP and 22Rv1 was RPMI 1640 + 10% FBS, and the cell culture medium of VCaP was DMEM + 10% FBS. All experimental cells were cultured at 37 ° C, 5% CO ₂ incubator. Cells in the exponential growth phase were collected on the day of the experiment. LNCaP cells were adjusted to the corresponding cell concentration for plating with RPMI 1640 culture medium containing 5% carbon adsorbed serum (CSS), and the number of cells was 6000/well. VCaP cells were adjusted to the corresponding cell concentration for plating with DMEM culture medium containing 5% CSS, and the number of cells was 20000/well. 22Rv1 cells were adjusted to the corresponding cell concentration for plating with RPMI 1640 culture medium containing 10% FBS, and the number of cells 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, and different concentrations of compounds were added to the culture medium after 22Rv1 cells were cultured overnight. The three cells were placed in an incubator and continued to be cultured for 5 days. After the culture was completed, the culture medium was removed, and 100μL of the corresponding culture medium containing 10% CCK-8 was added to each well according to the operating instructions of the CCK-8 kit (Biosharp, BS350B), and the cells were placed in an incubator for incubation for 1 to 4 hours, and the absorbance value at 450nM was measured using an enzyme marker. The results were processed according to formula (1), and the inhibition rate of each concentration of the compound was calculated, and the _IC50 value of the compound inhibition rate of 50% was calculated using Prism 8 software.

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

The results of prostate tumor cell proliferation inhibition are shown in Table 1. The example compounds showed a certain degree of castration-resistant prostate cancer cell proliferation inhibition activity (ND stands for not measured).

Table 1 Inhibitory effect of some compounds of the present invention on tumor cell growth

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

Prostate tumor cells LNCaP and 22Rv1 were purchased from Wuhan Punosai Life Science Technology Co., Ltd., and the cell culture medium was RPMI 1640 + 10% FBS. All experimental cells were cultured in a 37 ° C, 5% CO ₂ incubator. On the day of the experiment, LNCaP and 22Rv1 cells in the exponential growth phase were collected and plated with the culture medium to adjust the corresponding cell concentration, and the number of cells was 200000/well. After the cells were cultured overnight, the example compounds were added to the culture medium, and the final concentrations of the compounds were adjusted to 10, 30, 100, 300 and 1000nM, respectively, and 1‰ DMSO was used as a negative control. After the cells were cultured in the incubator for 24 hours, the culture 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. After lysis and centrifugation, the total protein extract was obtained, and the protein was quantified by the BCA method; the protein sample was electrophoresed by SDS-PAGE, and then electrophoresed at 200mA constant current for 90min, and the protein was transferred to a PVDF (Millipore Sigma IPVH00010) membrane; the PVDF membrane was blocked in 5% skim milk at 4°C overnight; anti-Androgen Receptor antibody (Santa, sc-7305) and anti-AR-V7 Speccific antibody (RevMAb Biosciences, 31-1109-00) were used for immune reaction respectively; the secondary antibody dilution was contacted with the membrane and incubated at room temperature for 1-2h; after washing the membrane, ECL luminescent liquid was added dropwise and exposed. Image J software was used to analyze the grayscale of the bands. The internal reference band was detected for each sample at the same time. The protein degradation rate of AR-FL or AR-V7 relative to the negative control group at different drug concentrations was calculated according to formula (2) and formula (3), and the DC ₅₀ value of the compound protein degradation rate of 50% was calculated using Prism 8 software.

Among them, AR-FL _Compound is the grayscale value of the AR-FL in the drug-treated group, and AR-FL _DMSO is the grayscale value of the AR-FL in the negative control group. AR-V7 _Compound is the grayscale value of the AR-V7 in the drug-treated group, and AR-V7 _DMSO is the grayscale value of the AR-V7 in the negative control group.

AR-FL degradation rate = (1-AR-FL _Compound /AR-FL _DMSO ) × 100% formula (2);

AR-V7 degradation rate = (1-AR-V7 _Compound /AR-V7 _DMSO ) x 100% Formula (3).

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 ≥1000nM=/; ND=not measured).

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

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

Six male ICR mice (20±2g) were randomly divided into two groups. The Example compounds were dissolved in the corresponding solvents and then administered by oral gavage (po) and tail vein injection (iv). The intravenous injection group was administered at 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h after administration; the oral gavage group was administered at 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h after administration. About 50μL of blood was collected from the orbital venous plexus, placed in 1.5mL EP containing EDTA-2K, and allowed to stand for 15min in a wet ice environment. The blood was centrifuged at 6000r/min for 3min, and the plasma was separated and stored at -80℃ for testing. Plasma sample analysis The concentration of the Example compounds in the plasma samples at each time point was determined by LC-MS/MS, and the pharmacokinetic parameters were calculated using WinNolin software. Including T _max (peak time), C _max (peak concentration), t _1/2 (elimination half-life), AUC (area under the blood concentration-time curve) and other parameter values. Absolute bioavailability is calculated according to formula (3), where Dose _iv is the dose of the tail vein injection group, Dose _po is the dose of the oral gavage group; AUC _{iv (0-∞)} is the area under the blood concentration-time curve of the tail vein injection group, and AUC _{oral (0-∞)} is the area under the blood concentration-time curve of the oral gavage group.

F(%)=(Dose _iv ×AUC _po(0-∞) )/(Dose _po ×AUC _iv(0-∞) )×100%.

The animal pharmacokinetic data of some of the example compounds 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).

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

It should be noted that the present application is not limited to the above-mentioned embodiments. The above-mentioned embodiments are only examples, and the embodiments having the same structure as the technical idea and exerting the same effect within the scope of the technical solution of the present application are all included in the technical scope of the present application. In addition, without departing from the scope of the main purpose of the present application, various modifications that can be thought of by those skilled in the art to the embodiments and other methods of combining some of the constituent elements in the embodiments are also included in the scope of the present application.

Claims (21)

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 as 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, 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 and halogen; R ¹ is a substituent at any position of the indolyl group, and R ¹ is 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; 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 at least two of L ¹ , L ² , L ³ , L ⁴ and L ⁵ satisfy the following conditions: one is a 4-10 membered heterocycloalkylene group and the other is a C1-C6 alkylene group; ^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 by halogen or C1-C6 alkyl; L ⁶ is selected from -NH-C(O)-, a single bond; ^C2 is selected from 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene, and the 4-10 membered cycloalkylene and the 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; ^R2 is selected from halogen and C1-C6 haloalkyl; X is C or N;
In formula II or formula II', ^A1 is a 5-10 membered heteroarylene group, 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, =S, halogen, R ^A1 and R ^A2 are each independently H or C1-C6 alkyl; ^A2 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 are each 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( ^RB1 ) ^RB2- , ^RB1 is H, a C1-C6 alkyl group, ^RB2 is a C0-C6 alkylene group, and at least two of L ¹ , L ² , L ³ and L ⁴ satisfy the following conditions: one is a 4-10 membered heterocycloalkylene group, and the other is a C1-C6 alkylene group; ^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 by halogen or C1-C6 alkyl; L ⁶ is selected from -NH-C(O)-, a single bond; ^C2 is selected from 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene, and the 4-10 membered cycloalkylene and the 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; ^R2 is selected from halogen and haloalkyl; X is C or N;
In formula III or formula III', ^A2 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 are each independently selected from a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, carbonyl, 4-10 membered heterocycloalkylene, -O-, -N( ^RB1 ) ^RB2- , ^RB1 is H, C1-C6 alkyl, ^RB2 is C0-C6 alkylene, -N( ^RB1 ) ^RB2- wherein the N atom is connected to A ² , and when L ¹ is C1-C6 alkylene, one of L ² and L ³ is a single bond and the other is a 4-10 membered heterocycloalkylene; ^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 by halogen or C1-C6 alkyl; L ⁶ is selected from -NH-C(O)-, a single bond; ^C2 is selected from 4-10 membered cycloalkylene, 5-10 membered heterocycloalkylene, and the 4-10 membered cycloalkylene and the 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; ^R2 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, 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 and halogen; ^A2 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 are each independently selected from a single bond, a C1-C6 alkylene group, a carbonyl group, a 4-10 membered heterocycloalkyl group, and at least one is not a single bond; ^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 by halogen or C1-C6 alkyl; L ⁶ is selected from -NH-C(O)-, a single bond; ^C2 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 of the following groups: 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', ^A1 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 are each independently H or C1-C6 alkyl; ^A2 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 are each independently selected from a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, carbonyl, 4-10 membered heterocycloalkylene, -O-, -C(O)-NH-, *-N( ^RB1 ) ^RB2- , ^RB1 is H, C1-C6 alkyl, ^RB2 is C0-C6 alkylene; ^C1 is selected from 5-10 membered heteroarylene, and the 5-10 membered heteroarylene is optionally substituted by any one or more selected from the group consisting of C1-C6 alkyl and halogen; ^L6 is selected from -R ^C1 -NH-, -R ^C1 -NH-C(O)- or a single bond, and R ^C1 is a C0-C6 alkylene group; ^C2 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-; ^R2 is selected from halogen and haloalkyl; X is C or N;
In Formula VI or Formula VI', A ¹ is selected from 5-10 membered heteroarylene, and the 5-10 membered heteroarylene of A ¹ 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 are each independently H or C1-C6 alkyl; A ² is selected from C6-C10 arylene or 5-10 membered heteroarylene, wherein the C6-C10 arylene and 5-10 membered heteroarylene as A ² are optionally substituted by halogen or C1-C6 alkyl; L ¹ , L ² , L ³ , L ⁴ and L ⁵ are each independently selected from a single bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, carbonyl, 4-10 membered heterocycloalkylene, C3-C10 cycloalkylene, C6-C10 arylene, -O-, *-N( ^RB1 ) ^RB2- , phenylene, ^RB1 is H, C1-C6 alkyl, ^RB2 is C0-C6 alkylene, or for ^C1 is selected from a single bond, a C6-C10 arylene group or a 5-10-membered heteroarylene group, and the C6-C10 arylene group or the 5-10-membered heteroarylene group as ^C1 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; ^R2 is selected from halogen and haloalkyl; X is C or N;
In formula VII, ^A1 is selected from 5-10 membered heteroarylene, and the 5-10 membered heteroarylene of ^A1 is optionally substituted by any one or more of the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S, halogen white, R ^A1 and R ^A2 are each independently H or C1-C6 alkyl; A ² is selected from C6-C10 arylene or 5-10 membered heteroarylene, wherein the C6-C10 arylene and 5-10 membered heteroarylene as A ² are optionally substituted by halogen or C1-C6 alkyl; L ¹ , L ² , L ³ , L ⁴ and L ⁵ are each independently selected from a single bond, C1-C6 alkylene, carbonyl, 4-10 membered heterocycloalkylene, -O-, *-N( ^RB1 ) ^RB2- , ^RB1 is H, C1-C6 alkyl, ^RB2 is C0-C6 alkylene; The ^C1 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, NH ₂ , CN, nitro, carboxyl, C3-C6 cycloalkyl, R ³ and R ⁴ are each independently selected from H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and R ³ and R ⁴ are connected to form a ring with the carbon atom shared by the two; ^R2 is H, halogen, C1-C6 alkyl, C1-C6 halogenated alkyl. 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: The heteroatom of ^A1 being a 5-10 membered heteroarylene group is a N atom, and the number of heteroatoms is preferably 1-3; preferably, ^A1 being a 5-10 membered heteroarylene group is a triazolyl group, 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, a methylene group, an ethylene group, and a propylene group; L ² is selected from 4-10 membered heterocycloalkylene, single bond, preferably the heteroatom of the 4-10 membered heterocycloalkylene as L ² 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, a methylene group, an ethylene group, and a propylene group; L ⁴ is selected from 4-10 membered heterocycloalkylene, single bond, preferably the hetero atom of the 4-10 membered heterocycloalkylene of L ⁴ is N, S or P; preferably L ⁴ is azetidinylene, piperidinylene or piperazinylene; L ⁵ is selected from a single bond, a C1-C6 alkylene group, or a carbonyl group. 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', ^C1 is selected from 5-10 membered heteroarylene groups, preferably ^C1 is imidazolylene, pyrazolylene, thiazolylene, pyrrolylene, pyridylene, pyrimidylene, pyridazinylene, pyrazinylene, preferably ^C1 is pyrazolylene, pyridylene, pyrimidylene, pyridazinylene, and the 5-10 membered heteroarylene groups are optionally substituted with halogen (e.g., F, Cl or Br), C1-C6 alkyl (e.g., methyl, ethyl, propyl or butyl); ^C2 is selected from 4-10 membered cycloalkylene, preferably 4-10 membered cycloalkylene as ^C2 is cyclobutylene, cyclopentylene, cyclohexylene or cycloheptylene, and 4-10 membered cycloalkylene as ^C2 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); ^L7 is 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, ^C1 is selected from C6-C10 aryl or 5-10 membered heteroaryl, the C6-C10 aryl as ^C1 is preferably phenylene, the 5-10 membered heteroaryl as ^C1 is preferably pyridylene or pyridazinylene; and the C6-C10 aryl or 5-10 membered heteroaryl as ^C1 is optionally substituted by halogen (e.g., F, Cl or Br), C1-C6 alkyl (e.g., methyl, ethyl or propyl); ^R2 is selected from halogenated alkyl, preferably trifluoromethyl; X is C or N; Preferably, in formula I2 Any one selected from the following groups:
in, Connect the end to ^C1 , The end is connected to the indole group; Preferably, in formula I2 Any one selected from the following groups:
Preferably, in formula I2 for 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', the heteroatom of the 5-10 membered heteroarylene group as ^A1 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 as ^A1 is substituted by any one or more of the following groups: R ^A1 and R ^A2 are each independently H or C1-C6 alkyl, preferably R ^A1 and R ^A2 are each independently H, methyl, ethyl, n-propyl or isopropyl; preferably, the 5-10 membered heteroaryl group as A ¹ is triazolyl, isoxazolyl or pyrazolyl; ^A2 is a C6-C10 arylene group or a 5-10 membered heteroarylene group, preferably a ^C6 -C10 aryl group or a 5-10 membered heteroarylene group is a phenylene group, a pyridylene group, a pyridazinylene group, a pyrimidylene group, or an indolylene group, and more preferably a ^C6 -C10 aryl group or a 5-10 membered heteroaryl group is a phenylene group or a pyridylene group, wherein the C6-C10 arylene group and the 5-10 membered heteroarylene group are optionally substituted with halogen or a C1-C6 alkyl group; ^L1 is selected from C1-C6 alkylene, -O-, -N( ^RB1 ) ^RB2- , ^RB1 is H, C1-C6 alkyl, ^RB2 is C0-C6 alkylene; L ² is selected from 4-10 membered heterocycloalkylene, single bond, preferably the hetero atom in the 4-10 membered heterocycloalkylene as L ² is N, S or P; preferably the 4-10 membered heterocycloalkylene as L ² is azetidinylene, azacyclopentylene, piperidinylene or piperazinylene; L ³ is selected from a single bond, a C1-C6 alkylene group; L ⁴ is selected from a single bond, a 4-10 membered heterocycloalkylene group, and -O-, wherein the heteroatom in the 4-10 membered heterocycloalkylene group as L ⁴ is preferably N, S or P; wherein the 4-10 membered heterocycloalkylene group as L ⁴ is preferably azetidinylene, azacyclopentylene, piperidinylene or piperazinylene; and L ² and L ⁴ are not simultaneously single bonds; ^C1 is selected from C6-C10 arylene or 5-10 membered heteroarylene; preferably, C1 is phenylene, pyridylene, pyridazinylene, pyrimidylene, indolylene; more preferably, ^C1 is phenylene, pyridylene, and C6-C10 aryl or 5-10 membered heteroaryl, and ^C1 is phenylene or pyridylene, and C6-C10 arylene or 5-10 membered heteroarylene is optionally substituted by halogen or C1-C3 alkyl; L ⁶ is 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 is selected from halogen, -CF ₃ ; X is C or N. 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 III or III', the heteroatom of the 5-10 membered heteroarylene group as ^A1 is preferably N atom and/or O atom, and the number of heteroatoms is preferably 1, 2 or 3, and the 5-10 membered heteroarylene group as ^A1 is substituted by any one or more of the following groups: R ^A1 and R ^A2 are each independently H, methyl or ethyl; ^L1 is selected from C1-C6 alkylene, -O-, -N( ^RB1 ) ^RB2- , ^RB1 is H, methyl, ethyl or n-propyl, ^RB2 is a single bond, methylene, ethylene, propylene or butylene; L ² is selected from 4-6 membered heterocycloalkylene, single bond, preferably 4-6 membered heterocycloalkylene as L ² 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, -O-, preferably the 4-16 membered heterocycloalkylene as L ⁴ is azetidinylene, azacyclopentylene, piperidinylene or piperazinylene; and L ² and L ⁴ are not single bonds at the same time; C ¹ is selected from a C6-C10 arylene or a 5-10 membered heteroarylene, preferably a ^C6 -C10 arylene is phenyl, preferably a ^C1 5-10 membered heteroarylene is pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene, further preferably pyridazinylene, and the C6-C10 arylene or 5-10 membered heteroarylene is optionally substituted with halogen (e.g., F, Cl or Br), C1-C3 alkyl (e.g., methyl, ethyl or propyl); ^C2 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 III or III' Any one selected from the following groups: More preferably in, Connect the end to ^C1 , 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 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', ^A2 is phenylene, 5-membered heteroarylene, 6-membered heteroarylene, preferably ^A2 is phenylene, pyridylene, pyridazinylene, pyrimidylene; phenylene, 5-membered heteroarylene, 6-membered heteroarylene are optionally substituted by halogen or C1-C6 alkyl; ^L1 is selected from C1-C6 alkylene, -O-, -N( ^RB1 ) ^RB2- , ^RB1 is H, C1-C6 alkyl, ^RB2 is C0-C6 alkylene; L ² is selected from 4-10 membered heterocycloalkyl, the heteroatom is N, S or P; preferably azetidinyl, piperidinyl or piperazinyl; ^L3 is selected from a single bond, a C1-C6 alkylene group, a carbonyl group, and a C1-C6 alkylene-carbonyl group; and when ^L1 is a C1-C6 alkylene group, one of ^L2 and ^L3 is a single bond and the other is a 4-10 membered heterocycloalkyl group; L ⁴ is selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably azetidinyl, piperidinyl or piperazinyl; ^C1 is selected from C6-C10 arylene or 5-10 membered heteroarylene; preferably, C1 is phenylene, pyridylene, pyridazinylene, pyrimidylene, indolylene; more preferably, ^C1 is phenylene, pyridylene, and C6-C10 aryl or 5-10 membered heteroaryl, and ^C1 is phenylene or pyridylene, and C6-C10 arylene or 5-10 membered heteroarylene is optionally substituted by halogen or C1-C3 alkyl; L ⁶ is 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 is selected from halogen, -CF ₃ ; X is C or N. 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', ^A2 is a phenylene group, a 5-membered heteroarylene group, or a 6-membered heteroarylene group, preferably ^A2 is a phenylene group, a pyridylene group, a pyridazinylene group, or a pyrimidylene group; ^L1 is selected from C1-C6 alkylene, -O-, -N( ^RB1 ) ^RB2- , ^RB1 is H, methyl, ethyl or propyl, ^RB2 is a single bond, methylene, ethylene, propylene or butylene, preferably ^L1 is selected from methylene, ethylene, -O-, -N( ^RB1 ) ^RB2- , ^RB1 is H, methyl or ethyl, ^RB2 is a single bond, methylene or ethylene; L ² is selected from 4-10 membered heterocycloalkyl, the heteroatom is N, S or P; preferably azetidinyl, piperidinyl or piperazinyl; ^L3 is selected from a single bond, methylene, ethylene, propylene, carbonyl, methylene-carbonyl, ethylenecarbonyl; and when ^L1 is a methylene group, ^{one of} L2 and ^L3 is a single bond and the other is a 4-10 membered heterocycloalkyl group; L ⁴ is selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably azetidinyl, piperidinyl or piperazinyl; ^C1 is preferably selected from C6-C10 arylene or 5-10 membered heteroarylene, preferably C1 is phenyl, preferably ^C1 is pyridylene, pyrimidylene, pyridazinylene, pyrazinylene, more preferably pyridazinylene, and ^C6 -C10 arylene or 5-10 membered heteroarylene is optionally substituted by halogen (e.g., F, Cl or Br), C1-C3 alkyl (e.g., methyl, ethyl or propyl); ^C2 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, Connect the end to ^C1 , The end is connected to A ² ; 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:
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. Preferably, A ¹ is a 5-10 membered heteroarylene group is a triazole group, and 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 the C6-C10 arylene group as A ² is a phenyl group, preferably the 5-10 membered heteroarylene group as A ² 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 (e.g., F, Cl or Br), C1-C3 alkyl group (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 is 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 is selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably azetidinyl, piperidinyl or piperazinyl; ^C1 is selected from 5-10 membered heteroarylene, preferably ^C1 is imidazolylene, pyrazolylene, thiazolylene, pyrrolylene, pyridylene, pyrimidylene, pyridazinylene, pyrazinylene, preferably ^C1 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); ^L6 is selected from -NH-C(O)-; ^C2 is selected from 4-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, preferably 4-10 membered cycloalkylene as ^C2 is cyclobutylene, cyclopentylene, cyclohexylene or cycloheptylene, preferably 5-10 membered heterocycloalkylene as ^C2 is piperidinylene or piperazinylene, and 4-10 membered cycloalkyl, 5-10 membered heterocycloalkylene as ^C2 is optionally substituted by halogen, C1-C3 alkyl; L ⁷ is selected from -O-, -NH-, a single bond; ^R2 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, The end is connected to ^C1 , The end is connected to ^A2 . 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', ^A1 is a 5-10 membered heteroarylene group, preferably the 5-10 membered heteroarylene group as ^A1 is triazolylene, isoxazolylene or pyrazolylene, preferably the 5-10 membered heteroarylene group as ^A1 is optionally substituted by any one or more of the following groups: C1-C6 alkyl, C3-C6 cycloalkyl, =O, =S; ^A2 is phenylene or 6-membered heteroarylene, wherein the phenylene and 6-membered heteroarylene are optionally substituted by halogen or C1-C3 alkyl; ^L1 is selected from a single bond, C1-C3 alkylene, C2-C3 alkynylene, carbonyl, -C(O)-NH-, -O-, *-N( ^RB1 ) ^RB2- , ^RB1 is H, C1-C3 alkyl, ^RB2 is C0-C3 alkylene; 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 L ² is azetidinylene, piperidinylene or piperazinylene; ^L3 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, a single bond, and the heteroatom is N, S or P; preferably, the 4-10 membered heterocycloalkylene as L ⁴ 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; ^C1 is selected from 5-8 membered heteroarylene, and the 5-8 membered heteroarylene is optionally substituted by any one or more selected from the group consisting of: C1-C3 alkyl and halogen; preferably ^C1 is selected from A fused heterocyclic ring, wherein wherein 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; wherein Z ¹ , Z ² , Z ³ and Z ⁴ are independently selected from C or N, and at least one of them is N; wherein Y ¹ , Y ² , Y ³ , Y ⁴ , Z ¹ , Z ² , Z ³ and Z ⁴ are independently selected from C or N, and at least one of them 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; 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; ^L6 is selected from -R ^C1 -NH-, -R ^C1 -NH-C(O)- or a single bond, and R ^C1 is a C0-C3 alkylene group; ^C2 is selected from 4-6 membered cycloalkylene, 5-6 membered heterocycloalkylene, 5-6 membered heteroaryl, and the 4-6 membered cycloalkylene, 5-6 membered heterocycloalkylene, 5-6 membered heteroaryl as ^C2 is 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-; ^R2 is selected from halogen and haloalkyl; X is C or N. The compound according to claim 1 or 9, or its stereoisomer, or its pharmaceutically acceptable salt, or A deuterated compound, 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 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', ^A1 is a 5-10 membered heteroarylene group, preferably the 5-10 membered heteroarylene group as ^A1 is triazolylene, isoxazolylene or pyrazolylene, preferably the 5-10 membered heteroarylene group as ^A1 is optionally substituted by any one or more of the following groups: C1-C3 alkyl, =O, =S; ^A2 is phenylene, pyridylene, pyrimidylene, pyrazinylene, pyridazinylene, preferably phenylene or pyridylene; ^L1 is selected from a single bond, C1-C3 alkylene, C2-C3 alkynylene, carbonyl, -C(O)-NH-, -O-, *-N( ^RB1 ) ^RB2- , ^RB1 is H, C1-C3 alkyl, ^RB2 is C0-C3 alkylene; 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 L ² is azetidinylene, piperidinylene or piperazinylene; ^L3 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, a single bond, and the heteroatom is N, S or P; preferably, the 4-10 membered heterocycloalkylene as L ⁴ is azetidinylene, piperidinylene or piperazinylene; ^L5 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-; ^C1 is selected from 5-8 membered heteroarylene, and the 5-8 membered heteroarylene is optionally substituted by any one or more selected from the group consisting of: C1-C3 alkyl and halogen; preferably ^C1 is selected from A fused heterocyclic ring, wherein wherein 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; wherein Z ¹ , Z ² , Z ³ and Z ⁴ are independently selected from C or N, and at least one of them is N; wherein Y ¹ , Y ² , Y ³ , Y ⁴ , Z ¹ , Z ² , Z ³ and Z ⁴ are independently selected from C or N, and at least one of them 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; it is further preferred that 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; it is more preferred that ^C1 is an imidazolyl group, a pyrazolyl group, a thiazolyl group, a pyrrolyl group, or a triazolyl group, and it is further preferred that the pyrrolyl group, the pyrazolyl group, the triazolyl group, the pyridazinyl group, the pyridinyl group, the benzopyrrolyl group, or the pyrimidopyrrolyl group; ^L6 is 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, and it is further preferred that the methyl group or the ethyl group; Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ are each independently selected from C or N, and at least one of them is N, preferably imidazolylene, pyrazolylene, thiazolylene, pyrrolylene, triazolylene, and more preferably pyrazolylene; 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, Connect the end to ^C1 , The end is connected to A ² ; 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', ^A1 is a 5-10 membered heteroarylene group, preferably the 5-10 membered heteroarylene group as ^A1 is triazolylene, isoxazolylene or pyrazolylene, preferably the 5-10 membered heteroarylene group as ^A1 is optionally substituted by any one or more of the following groups: C1-C3 alkyl, =O, =S; ^A2 is phenylene, pyridylene, pyrimidylene, pyrazinylene, pyridazinylene, preferably phenylene or pyridylene; L ¹ is selected from a single bond, a C1-C3 alkylene group; 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 L ² 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, a single bond, and the heteroatom is N, S or P; preferably, the 4-10 membered heterocycloalkylene as L ⁴ 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 are each independently selected from C or N, and at least one of them is N, preferably is imidazolylene, pyrazolylene, thiazolylene, pyrrolylene, triazolylene, more preferably pyrrolylene, pyrazolylene, triazolylene; ^C2 is selected from 4-6 membered cycloalkylene, preferably butylene or hexyl, and the 4-6 membered cycloalkylene as ^C2 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-; ^R2 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, The end is connected to A ² ; 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:
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', ^A1 is selected from 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. The 5-10 membered heteroarylene group as ^A1 is preferably a triazolyl group, an isoxazolyl group or a pyrazolyl group; the 5-10 membered heteroarylene group as ^A1 is optionally substituted by any one or more of the following groups: a C1-C6 alkyl group, =O, =S, R ^A1 and R ^A2 are each 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 the C6-C10 arylene and 5-10 membered heteroarylene as A ² are optionally substituted by halogen or C1-C3 alkyl; ^L1 is selected from a single bond, C1-C6 alkylene, C2-C6 alkynylene, *-N( ^RB1 ) ^RB2- , ^RB1 is H, C1-C6 alkyl, ^RB2 is C0-C6 alkylene; preferably ^L1 is methylene, ethylene, ethynylene, *-N( ^RB1 ) ^RB2- , ^RB1 is H, methyl or ethyl, ^RB2 is a single bond or methylene; L ² is selected from 4-10 membered heterocycloalkyl, C3-C10 cycloalkylene, C6-C10 arylene, single bond, heteroatom is N, S or P; preferably, 4-10 membered heterocycloalkyl as L ² is azetidinyl, piperidinyl or piperazinyl; ^L3 is selected from a single bond, C1-C6 alkylene, -O-, *-N( ^RB1 ) ^RB2- , ^RB1 is H, C1-C6 alkyl, ^RB2 is C0-C6 alkylene; preferably ^L3 is methylene, ethylene, ethynylene, *-N( ^RB1 ) ^RB2- , ^RB1 is H, methyl or ethyl, ^RB2 is a single bond or methylene; Preferably, L ⁴ is selected from 4-10 membered heterocycloalkyl, a single bond, and the heteroatom is N, S or P; preferably, the 4-10 membered heterocycloalkyl as L ⁴ 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; ^C1 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, The end is connected to ^L5 , The end is connected to ^L6 ; L ⁶ is C1-C3 alkyl, C1-C3 alkyl is optionally substituted by OH, preferably L ⁶ is R ² is selected from halogen and haloalkyl, preferably Cl or -CF ₃ ; X is C or N. 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', ^A1 is selected from 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. The 5-10 membered heteroarylene group as ^A1 is preferably a triazolyl group, an isoxazolyl group or a pyrazolyl group; the 5-10 membered heteroarylene group as ^A1 is optionally substituted by any one or more of the following groups: =O, R ^A1 and R ^A2 are each independently H, methyl or ethyl; A ² is selected from C6-C10 arylene or 5-10 membered heteroarylene, preferably phenylene, pyridylene or indolylene, wherein the C6-C10 arylene and 5-10 membered heteroarylene as A ² 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, and the heteroatom is N, S or P; preferably, the 4-10 membered heterocycloalkyl as L ² is azetidinylene, piperidinylene or piperazinylene, preferably, the C3-C6 cycloalkylene as L ² is hexylene, and preferably, the C6-C8 arylene as L ² is phenylene; ^L3 is selected from a single bond, C1-C3 alkylene, -O-, *-N( ^RB1 ) ^RB2- , ^RB1 is H, C1-C3 alkyl, ^RB2 is C0-C3 alkylene; preferably ^L3 is methylene, ethylene, ethynylene, *-N( ^RB1 ) ^RB2- , -O-, ^RB1 is H, methyl or ethyl, ^RB2 is a single bond or methylene; L ⁴ is selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably, 4-10 membered heterocycloalkyl as L ⁴ is azetidinyl, piperidinyl or piperazinyl; ^L5 is selected from C1-C3 alkenylene, C1-C3 alkynylene, carbonyl or phenylene; n is 0, 1, 2 or 3; R ^C3 and R ^C4 are each independently H, methyl, ethyl or hydroxyl; R ² is selected from halogen and haloalkyl, preferably Cl or -CF ₃ ; 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', ^A1 is selected from 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. The 5-10 membered heteroarylene group as ^A1 is preferably a triazolyl group, an isoxazolyl group or a pyrazolyl group; the 5-10 membered heteroarylene group as ^A1 is optionally substituted by any one or more of the following groups: =O, R ^A1 and R ^A2 are each independently H, methyl or ethyl; A ² is selected from C6-C10 arylene or 5-10 membered heteroarylene, preferably phenylene, pyridylene or indolylene, wherein the C6-C10 arylene and 5-10 membered heteroarylene as A ² are optionally substituted by F, C, methyl or ethyl; ^L1 is selected from a single bond, a C1-C6 alkylene group, *-N( ^RB1 ) ^RB2- , ^RB1 is H, a C1-C6 alkyl group, ^RB2 is a C0-C6 alkylene group, preferably a methylene group, an ethylene group or *-N( ^RB1 ) ^RB2- , ^RB1 is H, methyl or ethyl, ^RB2 is a single bond or methylene; L ² is selected from 4-10 membered heterocycloalkyl, single bond, heteroatom is N, S or P; preferably, 4-10 membered heterocycloalkyl as L ² 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, 4-10 membered heterocycloalkyl as L ⁴ 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 are each independently H, methyl, ethyl or hydroxyl, preferably R ^C3 and R ^C4 are each independently methyl or hydroxyl; R ² is selected from halogen and haloalkyl, preferably Cl or -CF ₃ ; 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:
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 homologue The isotope-labeled compound, or its metabolite, or its prodrug, is characterized in that the formula VII satisfies any one or more of the following conditions: In formula VII, A ¹ is selected from a 5-10 membered heteroaryl group, wherein the heteroatom is preferably a N atom and/or an O atom, and the number of heteroatoms is preferably 1-3. The 5-10 membered heteroaryl group as A ¹ is preferably a triazolyl group, an isoxazolyl group or a pyrazolyl group, and is further preferably a triazolyl group; preferably, the 5-10 membered heteroaryl group as A ¹ is optionally substituted by any one or more of the following groups: =O, =S; A ² is selected from C6-C10 arylene or 5-10 membered heteroarylene, preferably phenylene, indolylene or pyridylene, wherein the C6-C10 arylene and 5-10 membered heteroarylene as A ² are optionally substituted by F, Cl, methyl or ethyl; L ¹ , L ² , L ³ , L ⁴ and L ⁵ are each independently selected from a single bond, C1-C6 alkylene, carbonyl, 4-10 membered heterocycloalkylene, -O-, -N(R ^B1 )R ^B2 -, R ^B1 is H, C1-C6 alkyl, and R ^B2 is C0-C6 alkylene; ^L1 is selected from a single bond, a C1-C6 alkylene group, -N( ^RB1 ) ^RB2- , ^RB1 is H, a C1-C6 alkyl group, ^RB2 is a C0-C6 alkylene group, preferably ^L1 is selected from a single bond, a methylene group, an ethylene group, a propylene group, -N( ^RB1 ) ^RB2- , ^RB1 is H, a methyl group or an ethyl group, ^RB2 is a single bond, a methylene group or an ethylene group; ^L2 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; ^L4 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; The ^C1 ring is selected from phenylene, pyridylene, pyrimidylene, pyridazinylene, preferably phenylene or pyridylene; R ⁵ is selected from H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, OH, NH ₂ , CN, nitro, carboxyl, preferably halogen is F or Cl, preferably R ⁵ is selected from H, F or Cl R ³ and R ⁴ are each independently selected from H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, and R ³ and R ⁴ are connected to form a 4-6 membered cycloalkyl group with a carbon atom shared by both, preferably R ³ and R ⁴ are connected to form a cyclobutyl or cyclohexyl group with a carbon atom shared by both; ^R2 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:
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:












A pharmaceutical composition comprising 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, and one or more pharmaceutically acceptable excipients or carriers. A pharmaceutical 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. 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. 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. 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, or the pharmaceutical composition according to claim 15 Or use of the drug conjugate according to claim 17 in the preparation of an androgen receptor or androgen receptor splicing mutant regulator. 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 a mammalian androgen receptor (AR) or AR splicing mutant, 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 breast Adenocarcinoma 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, dysregulation of fat metabolism, long-term critically ill catabolic state, age-related decrease in testosterone levels in men, male menopause, hypogonadism, male hormone replacement therapy, male and female sexual dysfunction (e.g., erectile dysfunction, decreased sexual drive, decreased sexual satisfaction, decreased libido). 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, the drug kit product according to claim 16, or the drug conjugate according to claim 17, which is used to treat diseases related to abnormal activity or expression of mammalian androgen receptor (AR) or AR splicing mutants, 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).