TW202523315A - Cyanoaromatic ring derivatives and their applications in medicine - Google Patents

Abstract

A cyano aromatic ring derivative and the pharmaceutical use thereof. Specifically, the present invention relates to a compound of general formula (I) or a stereoisomer, a tautomer, a deuterated substance, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or cocrystal thereof, an intermediate thereof, and the use thereof in diseases associated with the inhibition or degradation of AR, such as cancers. B-L-K (I).

Description

Cyanoaromatic ring derivatives and their applications in medicine

The present invention relates to a compound of general formula (I) or its stereoisomers, tautomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods thereof, as well as uses thereof in AR-related diseases such as cancer.

Prostate cancer is a type of cancer that is often found in the early stages. Its causes are often related to genetic factors, high-fat diet and endocrine. Generally speaking, the incidence of prostate cancer in developed countries is higher than in developing countries. In 2016, there were 120,000 new prostate cancer patients in China. By 2030, it is expected that the number of new patients will reach 237,000, and the market share will reach US$4.8 billion. Radical treatment can be used for early prostate cancer patients, and the survival time is longer. For advanced patients with cancer cell metastasis, castration combined with anti-androgen drug therapy is used, and the disease will develop into castration-resistant prostate cancer. Clinical studies have shown that the androgen receptor (AR) is overexpressed in most patients with resistant prostate cancer. Inhibiting the androgen receptor (AR) signal has a significant therapeutic effect on patients with hormone-refractory prostate cancer. Therefore, inhibiting the androgen receptor (AR) is an effective means to directly block this pathway.

PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can bind to target proteins and E3 ubiquitin ligases at the same time. Such compounds can be recognized by the proteasome of cells, causing the degradation of target proteins, and can effectively reduce the content of target proteins in cells. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology can be applied to the treatment of various diseases. This technology has also received widespread attention in recent years.

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

The purpose of the present invention is to provide a novel structure, good efficacy, high bioavailability, safer compound capable of inhibiting or degrading AR, for the treatment of AR-related diseases such as cancer.

The compound of the present invention has good prostate cancer cell (such as VCaP cell) proliferation inhibitory activity, has good degradation effect on AR protein, shows good oral performance in in vivo pharmacokinetics, has no obvious inhibitory effect on hERG potassium channel current, has good liver microsomal stability, has no obvious inhibitory activity on human liver microsomal cytochrome P450, and has no significant inhibitory effect on CD34+ hematopoietic stem cell proliferation.

The present invention provides a compound or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the compound represented by the general formula (I), B-L-K (I);

In some embodiments, L is selected from a bond or -C _1-50 alkyl-, wherein 1 to 20 methylene units in the alkyl are optionally replaced by -Ak-, -Cy-;

In some embodiments, L is selected from a bond or -C _1-20 alkyl-, wherein 1 to 10 methylene units in the alkyl are optionally replaced by -Ak-, -Cy-;

In some embodiments, each -Ak- is independently selected from -( _CH2 ) _q- , -(CH2) _q -O-, -O-( _CH2 ) _q- , -( _CH2 ) _q -S-, -S-( _CH2 ) _q- , -( _CH2 ) _q -NR ^L- , -NR ^L- ( _CH2 )q-, -( _CH2 ) _q -NR ^L C(=O)-, -NR ^L ( _CH2 ) _qC (=O)-, -( _{CH2 ) q} -C(=O)NR ^L -, _-C (=O)-, -C(=O)-( _CH2 ) _q -NR ^L -, -(C≡C) _q- , -CH=CH-, -Si( ^RL ) _2- , -Si(OH)( ^RL )-, -Si(OH) ₂ -, -P(=O)(OR ^L )-, -P(=O)(R ^L )-, -S-, -S(=O)-, -S(=O) ₂ - or a bond, wherein the CH, -CH ₂ - is optionally substituted with 1 to 2 substituents selected from deuterium, halogen, =O, OH, CN, C _1-4 alkyl or C _3-6 cycloalkyl;

In some embodiments, q is independently selected from 0, 1, 2, 3, 4, 5 or 6;

In some embodiments, ^RL is selected from H, _C1-4 alkyl, _C3-7 carbocyclyl, 4 to 10 membered heterocyclyl;

In some embodiments, each -Cy- is independently selected from a bond or one of the following groups optionally substituted with 1 to 4 ^RL2 : a 4-8 membered heteromonocyclic group, a 4-12 membered heterocycloalkyl group, a 5-13 membered heterospirocyclic group, a 7-12 membered heterobridged cycloalkyl group, a _C3-7 monocycloalkyl group, a _C4-7 monocycloalkenyl group, a _C4-12 cycloalkyl group, a _C5-13 spirocycloalkyl group, a _C5-12 bridged cycloalkyl group, a 5-10 membered heteroaryl group, or a _C6-10 aryl group;

In some embodiments, Ak is selected from Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8 or Ak9;

In some embodiments, Ak is selected from Ak1, Ak2, Ak3, Ak4 or Ak5;

In some embodiments, -Cy- is selected from Cy1, Cy2, Cy3, Cy4 or Cy5;

In some embodiments, -Cy- is selected from Cy1, Cy2, Cy3 or Cy4;

In some embodiments, L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, k1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4 -, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3 -Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3 -Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2 -Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1 -Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-A k5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-A k3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-A k4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-C y1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -A k1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5 -Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2 -Cy3-Ak5-Cy4-, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-A k6-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-;

In some embodiments, L is selected from a bond, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak 2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, - Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2 -Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-A k3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak 1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3- , -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3 -, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1 -Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy 2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy 4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-A k2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2 -, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy 2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak 5-, -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;

In some embodiments, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

In some embodiments, L is selected from -Cy1-, -Cy1-Ak2-, -Cy1-CH ₂ -, -Ak1-Cy1-, -Cy1-Cy2-, -Cy1-CH ₂ -Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH ₂ -Cy2-Cy3-, -Cy1-Cy2-CH ₂ -Cy3-;

In some embodiments, L is selected from -Cy1-Ak2-Cy2-, -Cy1-O-Cy2-;

In some embodiments, L is selected from -Cy1-, -Cy1-Ak2-, -Cy1-CH ₂ -, -Cy1-C(CH ₃ ) ₂ -, -Ak1-Cy1-, -C≡C-Cy1-;

In some embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 are each independently selected from -( _CH2 ) _q- , -( _CH2 ) _q -O-, -O-(CH2) _q- , -( _CH2 ) _q -S-, -S-( _CH2 )q-, -( _CH2 ) _q - _NR ^L -, _-NR ^L -( _CH2 ) _q- , -( _CH2 ) _q -NR ^L C(=O)-, -( _CH2 ) _q -C(=O)NR ^L -, -C(=O)-, -C(=O)-( _CH2 ) _q -NR ^L -, -(C≡C) _q- , or a bond, wherein the _-CH2 - optionally substituted with 1 to 2 substituents selected from deuterium, halogen, =0, OH, CN, C _1-4 alkyl or C _3-6 cycloalkyl;

In some embodiments, q is selected from 0, 1, 2 or 3;

In some embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6 _, Ak7, Ak8, and Ak9 are each independently selected from a bond, _-O- , -S-, _-OCH2- , -CH2O-, _-OCH2CH2- , -CH2CH2O- _{, -C≡C- ,} -C( _CH3 ) _2- , -CH( _CH3 )-, _-CH2- , -CH2CH2-, _-CH2CH2CH2- , -N _{( CH3 )} -, -NH-, -CH2N _{( CH3 )} -, _{-CH2NH- ,} -NHCH2-, _-CH2CH2N ( _CH3 ) _- , _-CH2CH2NH- , _-NHCH2CH2- , _-C (=O) _- , -C(=O)CH ₂ NH-, -CH ₂ C(=O)NH-, -C(=O)NH- or -NHC(=O)-;

In some embodiments, Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -C≡C-, -C(CH ₃ ) ₂ -, or -CH ₂ -;

In some embodiments, ^RL is selected from H or _C1-4 alkyl;

In some embodiments, ^RL is selected from H, methyl or ethyl;

In some embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 is independently selected from a bond or one of the following groups optionally substituted by 1 to 4 ^RL2 : a 4-7 membered nitrogen-containing heteromonocyclic group, a 4-12 membered nitrogen-containing heterocycloalkyl group, a 5-13 membered nitrogen-containing heterospirocyclic group, a 7-12 membered nitrogen-containing heterobridged cyclic group, a _C3-7 monocyclic alkyl group, a _C4-7 monocyclic alkenyl group, a _C4-12 cycloalkyl group, a _C5-13 spirocyclic alkyl group, a _C7-12 bridged cycloalkyl group, a 5-10 membered heteroaryl group or a _C6-10 aryl group;

In some embodiments, Cy5 is defined the same as Cy1;

In some embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following groups optionally substituted with 1 to 4 R ^L2 : phenyl, pyridyl, pyrimidinyl, pyrazinyl, oxazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , s1, s3, s5 are each independently selected from 0, 1 or 2, s2, s4 are each independently selected from 0 or 1, s6 is selected from 0, 1, 2 or 3, s7 is selected from 1, 2 or 3;

In some embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from one of the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , when substituted, by 1 to 4 substituents selected from deuterium, F, CF ₃ , OH, =O, COOH, CN, NH ₂ , hydroxymethyl, methyl, methoxy, cyclopropyl;

In some embodiments, Cy1, Cy2, and Cy3 are each independently selected from one of the following optionally substituted groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , when substituted, by 1 to 4 substituents selected from deuterium, F, CF ₃ , OH, =O, COOH, CN, NH ₂ , hydroxymethyl, methyl, methoxy, cyclopropyl;

In some embodiments, L is selected from one of the structural fragments shown in Table L-1:

Table L-1 ;

In some embodiments, B is selected from ;

In some embodiments, B is selected from , , , In some embodiments, B is selected from ;

In some embodiments, B is selected from , , , , , , , , , , , , , , , , , , , ;

In some embodiments, B is selected from , , , , , In some embodiments, B is selected from , , , ; In some embodiments, Y ₁ and Y ₂ are each independently selected from -CR ^y1 R ^y2 -, -(CR ^y1 R ^y2 ) ₂ -, -(CR ^y1 R ^y2 ) ₃ -;

In some embodiments, Y ₁ and Y ₂ are each independently selected from -CR ^y1 R ^y2 -, -(CR ^y1 R ^y2 ) ₂ -;

In some embodiments, Y ₁ and Y ₂ are each independently selected from -CH ₂ -, -CH ₂ CH ₂ -, -C(CH ₃ ) ₂ -;

In some embodiments, _X1 is selected from N or ^CRx1 ; _X2 is selected from N or ^CRx2 ; _X3 is selected from N or ^CRx3 ; _X4 is selected from N or ^CRx4 ; _X5 is selected from N or ^CRx5 ; at most 2 of _X1 , _X2 , _X3 , _X4 , and _X5 are selected from N; in some embodiments, _X3 is selected from ^CRx3 ; in some embodiments, 1 of _X1 , _X2 , _X3 , _X4 , and _X5 is selected from N; in some embodiments, _X1 is selected from ^CRx1 , _X2 is selected from CRx2, _X3 is selected ^{from CRx3} , _X4 is selected from ^CRx4 , and _X5 is selected from ^CRx5 ;

In some embodiments, X ₆ is selected from N or CH; in some embodiments, X ₇ is selected from NH or O; in some embodiments, X ₇ is selected from O;

In some embodiments, _Z1 is selected from N or ^CRz1 ; _Z2 is selected from N or ^CRz2 ; _Z3 is selected from N or ^CRz3 ; _Z4 is selected from N or ^CRz4 ; at most 3 of _Z1 , _Z2 , _Z3 , and _Z4 are selected from N; in some embodiments, at most 2 of _Z1 , _Z2 , _Z3 , and _Z4 are selected from N; in some embodiments, 1 of _Z1 , _Z2 , _Z3 , and _Z4 is selected from N; in some embodiments, 2 of _Z1 , _Z2 , _Z3 , and _Z4 are selected from N; in some embodiments, _Z1 is selected from ^CRz1 , _Z2 is selected from ^CRz2 , _Z3 is selected from ^CRz3 , and _Z4 is selected from ^CRz4 ;

In some embodiments, ^Rx1 , ^Rx2 , ^Rx3 , Rx4, ^Rx5 , Rz1, ^Rz2 , ^Rz3 , and ^Rz4 are each independently selected from H, deuterium, halogen, OH, NH2, CN, _NO2 , COOH, _CONH2 , _NHC1-4 alkyl, N( _C1-4 alkyl) ₂ , ^{C1-4 alkyl} , C2-4 alkenyl, _C2-4 alkynyl, -OC1-4 alkyl, -SC1-4 alkyl, -C0-4 alkylene-C3-6 carbocyclyl, -C0-4 alkylene-4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, _-OC1-4 alkyl, _-SC1-4 alkyl, _-C0-4 alkylene-C3-6 carbocyclyl, -C0-4 alkylene-4 to _{6 membered} heterocyclyl, 5 to ₆ membered heteroaryl, -OC1-4 alkyl, -SC1-4 alkyl, _-C0-4 alkylene- _C3-6 carbocyclyl, _-C0-4 alkylene-4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, -OC1-4 alkyl, -SC1-4 alkyl, -C0-4 alkylene-C3-6 carbocyclyl, _3-6- membered carbocyclic group, -0-4 to 6-membered heterocyclic group, wherein the alkylene group, alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocyclic group and heteroaryl group are optionally substituted by 1 to 4 R ^s ;

In some embodiments, ^Rx1 , ^Rx2 , ^Rx3 , Rx4, ^Rx5 , Rz1, ^Rz2 , ^Rz3 , and ^Rz4 are each independently selected from H, deuterium, halogen, OH, NH2, CN, _NO2 , COOH, CONH2, _NHC1-4 alkyl, N( _C1-4 alkyl) ₂ , ^{C1-4 alkyl} , ^C2-4 alkenyl, _C2-4 alkynyl, -OC1-4 alkyl, -SC1-4 alkyl, -C0-2 alkylene-C3-6 cycloalkyl, -C0-2 alkylene- ₄ to 6 membered heterocyclic group, 5 to 6 membered heteroaryl, _-OC1-4 alkyl, _-SC1-4 alkyl, _-C0-2 alkylene-C3-6 cycloalkyl, -C0-2 alkylene-4 to 6 membered heterocyclic group, ₅ to 6 membered heteroaryl, -OC1-4 alkyl, _-SC1-4 alkyl, _-C0-2 alkylene- _C3-6 cycloalkyl, _-C0-2 alkylene-4 to 6 membered heterocyclic group, 5 to 6 membered heteroaryl, -OC1-4 alkyl, -SC1-4 alkyl, -C0-2 alkylene-C3-6 cycloalkyl, _3-6- membered cycloalkyl, -0-4 to 6-membered heterocyclic group, wherein the alkylene group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, heteroaryl group are optionally substituted by 1 to 4 ^Rs ;

In some embodiments, ^Rx1 , ^Rx2 , ^Rx3 , Rx4, ^Rx5 , ^Rz1 , ^Rz2 , ^{Rz3 , Rz4} are each independently selected from H, deuterium, F, Cl, Br, I, OH, _NH2 , CN, _NO2 , COOH, _CONH2 , N( _CH3 ) ₂ , _NHCH3 , or one of the following groups optionally substituted with 1 to 4 ^Rs : methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, _-CH2 -cyclopropyl, _-CH2 -cyclobutyl, -O-cyclopropyl, pyrazolyl;

In some embodiments, R ^x1 , R ^x2 , R ^x3 , and R ^x4 are each independently selected from -S(=O) ₂ NH ₂ , -S(=O) ₂ C _1-4 alkyl;

In some embodiments, R ^x1 , R ^x2 , R ^x3 , and R ^x4 are each independently selected from -S(=O) ₂ NH ₂ , -S(=O) ₂ methyl, and -S(=O) ₂ ethyl;

In some embodiments, R ^x2 , R ^x3 , R ^x4 are each independently selected from H, deuterium, F, Cl, Br, I, OH, NH ₂ , CN, NO ₂ , COOH, CONH ₂ , N(CH ₃ ) ₂ , NHCH ₃ , CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , OCH ₂ F, OCD ₃ , CH ₂ OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, -CH ₂ -cyclopropyl, -O-cyclopropyl;

In some embodiments, R ^x3 and R ^x4 are each independently selected from H, deuterium, F, Cl, Br, I, OH, NH ₂ , CN, NO ₂ , COOH, CONH ₂ , N(CH ₃ ) ₂ , NHCH ₃ , CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , OCH ₂ F, CH ₂ OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, -CH ₂ -cyclopropyl, -O-cyclopropyl;

In some embodiments, R ^x2 and R ^x4 are each independently selected from -S(=O) ₂ CH ₃ , -O-CH ₂ -propynyl, -O-CH ₂ -cyclopropyl, -O-CH ₂ CH ₂ -OCH ₃ , -O-CH ₂ CH ₂ -O-cyclopropyl, , , , ;

In some embodiments, R ² , R ³ , R ^y1 , and R ^y2 are each independently selected from H, deuterium, halogen, OH, NH ₂ , CN, NO ₂ , COOH, CONH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -OC _1-4 alkyl, -SC _1-4 alkyl, and the alkyl, alkenyl, and alkynyl are optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH ₂ , CN, C _1-4 alkyl, and C _1-4 alkoxy;

In some embodiments, R ² , R ³ , R ^y1 , and R ^y2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, NH ₂ , CN, NO ₂ , COOH, CONH ₂ , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, and methylthio, and the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, and methylthio are substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH ₂ , CN, C _1-4 alkyl, and C _1-4 alkoxy;

In some embodiments, R ² and R ³ are each independently selected from H, deuterium, F, Cl, and Br;

In some embodiments, R ^y1 and R ^y2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, NH ₂ , CN, NO ₂ , COOH, CONH ₂ , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, and the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio are substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH ₂ , CN, methyl, ethyl, methoxy;

In some embodiments, R ¹ is selected from H, deuterium, C _1-4 alkyl or C _3-6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH ₂ , CN, C _1-4 alkyl, C _1-4 alkoxy;

In some embodiments, R ¹ is selected from H, deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH ₂ , CN, C _1-4 alkyl, C _1-4 alkoxy;

In some embodiments, R ¹ is selected from H, deuterium, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ OH, methyl, ethyl, isopropyl, cyclopropyl;

In some embodiments, R ^x1 and R ^x2 , R ^x2 and R ^x3 , R ^x3 and R ^x4 , R ^x4 and R ^x5 , R ¹ and R ^z3 , R ¹ and R ^z1 are directly linked to form a C _4-6 carbocyclic group or a 4-7 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R ^s ;

In some embodiments, R ^x1 and R ^x2 , R ^x2 and R ^x3 , R ^x3 and R ^x4 , R ^x4 and R ^x5 are directly linked to form a C _4-6 carbocyclic group, a 5-6-membered heteroaryl group or a 5-7-membered heterocyclic group, wherein the carbocyclic group, heteroaryl group or heterocyclic group is optionally substituted by 1 to 4 R ^s ;

In some embodiments, ^R1 and ^Rz3 , ^R1 and ^Rz1 are directly linked to form a 5- to 7-membered heterocyclic group, and the heterocyclic group is optionally substituted by 1 to 4 ^Rs ;

In some embodiments, R ^x1 and R ^x2 , R ^x2 and R ^x3 , R ^x3 and R ^x4 , R ^x4 and R ^x5 are directly linked to form one of the following groups optionally substituted with 1 to 3 R ^s : piperidinyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, oxazinyl, pyrazinyl; in some embodiments, R ^x1 and R ^x2 , R ^x2 and R ^x3 , R ^x3 and R ^x4 , R ^x4 and R ^x5 are directly linked to form one of the following groups optionally substituted with 1 to 3 R ^s : pyrrolidinyl, oxacyclopentyl, oxacyclohexyl, 1,3-dioxolane;

In some embodiments, ^R1 and ^Rz3 , ^R1 and ^Rz1 are directly linked to form the following structure which is optionally substituted by 1 to 4 ^Rs : , ;

In some embodiments, K is selected from ; The ring where the representative is located is an aromatic ring or a non-aromatic ring;

In some embodiments, K is selected from , , ;

In some embodiments, K is selected from , , , , , , ;

In some embodiments, K is selected from , ;

In some embodiments, K is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

In some embodiments, K is selected from , , , , , , , , , , , , , ;

In some embodiments, F ₁ is selected from N, NH, CH, CH ₂ , CHR ^k1 , NR ^k1 , CR ^k1 , C(═O), C(R ^k1 ) ₂ ;

In some embodiments, _F2 is selected from a bond, O, N, NH, CH, _CH2 , ^CHRk1 , ^NRk1 , ^CRk1 or C( ^Rk1 ) ₂ ;

In some implementations, When the ring where the representative is located is a non-aromatic ring, _F1 is selected from NH, _CH2 , ^CHRk1 , ^NRk1 , C(=O), C( ^Rk1 ) ₂ , and _F2 is selected from a bond, O, NH, _CH2 , ^CHRk1 , ^NRk1 or C( ^Rk1 ) ₂ ;

In some implementations, represents that the ring is an aromatic ring, _F1 is selected from N, CH, CR ^k1 , and _F2 is selected from a bond, O, N, CH, CR ^k1 ;

In some embodiments, F ₆ , F ₇ , and F ₈ are each independently selected from N, C, CH, or CR ^k1 , and F ₆ , F ₇ , and F ₈ contain at most 2 Ns; in some embodiments, one of F ₆ , F ₇ , and F ₈ is selected from N, and the other two are selected from CH or CR ^k1 ;

In some embodiments, G is selected from CH or N;

In some embodiments, _E1 is selected from N or CH, preferably N;

In some embodiments, _E2 is selected from C, N or CH, preferably N;

In some embodiments, Q is each independently selected from a bond, -O-, -S-, -CH2-, _-NRq- , ^-CO- , -NRqCO-, ^{-CONRq- ;}

In some embodiments, each Q is independently selected from a bond, CH ₂ , NH, N(CH ₃ ), O, S, C(═O), NHC(═O), C(═O)NH, N(CH ₃ )C(═O), C(═O)N(CH ₃ );

In some embodiments, each Q is independently selected from a bond, NH, N(CH ₃ ), O, S, NHC(═O), C(═O)NH, N(CH ₃ )C(═O), C(═O)N(CH ₃ );

In some embodiments, Q is independently selected from a bond, NH, C(=O)NH;

In some embodiments, Q and G cannot directly form a nitrogen-nitrogen bond or a nitrogen-oxygen bond;

In some implementations, Selected from , , , ;

In some embodiments, ^Rq is each independently selected from H or _C1-4 alkyl;

In some embodiments, ^Rq is each independently selected from H, methyl, ethyl or isopropyl;

In some embodiments, ^Rq is selected from H or methyl;

In some embodiments, R ^k1 is independently selected from deuterium, halogen, OH, NH ₂ , CN, COOH, CONH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 4 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 4 R ^s ;

In some embodiments, R ^k1 is each independently selected from deuterium, halogen, OH, NH ₂ , CN, COOH, CONH ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 4 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, CF ₃ , CN, NH ₂ , C _1-4 alkyl;

In some embodiments, R ^k1 is independently selected from deuterium, F, Cl, Br, I, OH, NH ₂ , CN, COOH, CONH ₂ , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH ₂ ;

In some embodiments, each ^Rk1 is independently selected from deuterium, F, Cl, Br, I, _OH , NH2, CN, COOH, CONH2, _CF3 , _CHF2 , _CH2F , _OCF3 , _OCH2F , _CH2OH , methyl, ethyl, _isopropyl , methoxy, ethoxy, isopropoxy, cyclopropyl;

In some embodiments, ^RL2 and ^Rs are each independently selected from deuterium, halogen, OH, CN, =O, _CF3 , _SF5 , _NO2 , _NH2 , _NHC1-4 alkyl, N( _C1-4 alkyl) ₂ , COOH, _CONH2 , _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C1-4 alkoxy, _-SC1-4 alkyl, _-C0-4 alkylene- _C3-6 cycloalkyl, _-C0-4 alkylene-4 to 6 membered heterocyclic group, and the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, _C1-4 alkyl, _C1-4 alkoxy;

In some embodiments, ^RL2 and ^Rs are each independently selected from deuterium, halogen, OH, CN, =O, _CF3 , _SF5 , _NO2 , _NH2 , _NHC1-4 alkyl, N( _C1-4 alkyl) ₂ , COOH, _CONH2 , _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, C1-4 alkoxy, _-SC1-4 alkyl, _-C0-2 alkylene- _C3-6 cycloalkyl, _-C0-2 alkylene-4 to 6 membered heterocyclic group, and the alkyl, alkylene, alkoxy, _alkenyl , alkynyl, cycloalkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, _C1-4 alkyl, _C1-4 alkoxy;

In some embodiments, R ^L2 and R ^s are each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF ₃ , SF ₅ , CN, NH ₂ , NO ₂ , COOH, CONH ₂ , N(CH ₃ ) ₂ , NHCH ₃ , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally replaced by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C Substituted by a _{C 1-4} alkyl or C _1-4 alkoxy substituent;

In some embodiments, ^RL2 and ^Rs are each independently selected from deuterium, F, Cl, Br, I, OH, =O, _CF3 , _SF5 , CN, _NH2 , _NO2 , COOH, _CONH2 , N( _CH3 ) ₂ , NHCH3, _CHF2 , _CH2F , _OCF3 , _OCH2F , _{OCHF2, CH2OH, OCH2OH , methyl} , ethyl, _vinyl , ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, _-CH2 -cyclopropyl, _-CH2 -cyclobutyl, _-CH2 -cyclopentyl, _-CH2 -cyclohexyl;

In some embodiments, ^Rs are each independently selected from -OC _3-6 cycloalkyl;

In some embodiments, ^Rs are each independently selected from propynyl, -O-cyclopropyl;

In some embodiments, p1 is independently selected from 0, 1 or 2;

In some embodiments, p1 is independently selected from 0 and 1.

As a first embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

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

Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -( _CH2 ) _q- , -( _CH2 ) _q -O-, -O-( _CH2 ) _q- , -( _CH2 ) _q -S-, -S-( _CH2 ) _q- , -( _CH2 ) _q -NR ^L -, -NR ^L -(CH2) _q- , -( _CH2 ) _q -NR ^L C(= _O )-, -( _CH2 ) _q -C(=O)NR ^L -, -C(=O)-, -C(=O)-( _CH2 ) _q -NR ^L -, -(C≡C) _q- , or a bond, wherein the _-CH2- is optionally replaced by 1 to 2 groups selected from deuterium, halogen, =O, OH, CN, _C1-4 alkyl or C substituted by a _3-6 -cycloalkyl substituent;

q is selected from 0, 1, 2 or 3;

R ^L are each independently selected from H or C _1-4 alkyl;

Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or one of the following groups optionally substituted by 1 to 4 ^RL2 : a 4-7 membered heteromonocyclic group, a 4-12 membered heterocycloalkyl group, a 5-13 membered heterospirocyclic group, a 7-12 membered heterobridged group, a _C3-7 monocyclic alkyl group, a _C4-7 monocyclic alkenyl group, a _C4-12 cycloalkyl group, a _C5-13 spirocyclic alkyl group, a _C5-12 bridged cycloalkyl group, a 5-10 membered heteroaryl group or a _C6-10 aryl group;

B Selected from ;

_X1 is selected from N or CR ^x1 ; _X2 is selected from N or CR ^x2 ; _X3 is selected from N or CR ^x3 ; _X4 is selected from N or CR ^x4 ; _X5 is selected from N or CR ^x5 ;

At most 2 of X ₁ , X ₂ , X ₃ , X ₄ , and X ₅ are selected from N;

_Z1 is selected from N or CR ^z1 ; _Z2 is selected from N or CR ^z2 ; _Z3 is selected from N or CR ^z3 ; _Z4 is selected from N or CR ^z4 ;

At most 3 of Z ₁ , Z ₂ , Z ₃ , and Z ₄ are selected from N;

Y ₁ and Y ₂ are each independently selected from -CR ^y1 R ^y2 -, -(CR ^y1 R ^y2 ) ₂ -, -(CR ^y1 R ^y2 ) ₃ -;

R ¹ is selected from H, deuterium, C _1-4 alkyl or C _3-6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH ₂ , CN, C _1-4 alkyl, C _1-4 alkoxy;

^Rx1 , ^Rx2 , ^Rx3 , Rx4, ^Rx5 , ^Rz1 , ^Rz2 , ^Rz3 , and ^Rz4 are each independently selected from H, ^deuterium , halogen, OH, _NH2 , CN, _NO2 , COOH, CONH2, _NHC1-4 alkyl, N( _C1-4 alkyl) _{2 ,} C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, _-OC1-4 alkyl, -SC1-4 alkyl, _-C0-4 alkylene-C3-6 carbocyclic group, _-C0-4 alkylene-4 to 6 membered heterocyclic group, 5 to ₆ membered heteroaryl, -OC1-4 alkyl, -SC1-4 alkyl, _-C0-4 alkylene- _C3-6 carbocyclic group, _-C0-4 alkylene-4 to 6 membered heterocyclic group, 5 to 6 membered heteroaryl, -OC1-4 alkyl, _{-SC1-4 alkyl, -C0-4 alkylene-C3-6} carbocyclic group, _3-6- membered carbocyclic group, -0-4 to 6-membered heterocyclic group, wherein the alkylene group, alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocyclic group and heteroaryl group are optionally substituted by 1 to 4 R ^s ;

or R ^x1 , R ^x2 , R ^x3 , and R ^x4 are each independently selected from -S(=O) ₂ NH ₂ , -S(=O) ₂ C _1-4 alkyl;

Alternatively, R ^x1 and R ^x2 , R ^x2 and R ^x3 , R ^x3 and R ^x4 , R ^x4 and R ^x5 , R ¹ and R ^z3 , R ¹ and R ^z1 are directly linked to form a C _4-6 carbocyclic group or a 4-7 membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R ^s ;

R ² , R ³ , R ^y1 , and R ^y2 are each independently selected from H, deuterium, halogen, OH, NH ₂ , CN, NO ₂ , COOH, CONH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -OC _1-4 alkyl, and -SC _1-4 alkyl, wherein the alkyl, alkenyl, and alkynyl are optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH ₂ , CN, C _1-4 alkyl, and C _1-4 alkoxy;

K Selected from ;

The ring where the representative is located is an aromatic ring or a non-aromatic ring;

_F1 is selected from N, NH, CH, _CH2 , ^CHRk1 , ^NRk1 , ^CRk1 , C(=O), C( ^Rk1 ) ₂ ;

_F2 is selected from a bond, O, N, NH, CH, _CH2 , ^CHRk1 , ^NRk1 , ^CRk1 or C( ^Rk1 ) ₂ ;

F ₆ , F ₇ , and F ₈ are each independently selected from N, C, CH, or CR ^k1 , and F ₆ , F ₇ , and F ₈ contain at most 2 N;

G is selected from CH or N;

E ₁ is selected from N or CH;

_E2 is selected from C, N or CH;

Q is each independently selected from a bond, -O-, -S-, -CH2-, _-NRq- , ^-C (=O)-, ^-NRqC (=O)-, -C(=O) ^NRq- ;

Q and G cannot directly form nitrogen-nitrogen bonds or nitrogen-oxygen bonds;

^Rq are each independently selected from H or _C1-4 alkyl;

R ^k1 are each independently selected from deuterium, halogen, OH, NH ₂ , CN, COOH, CONH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 4 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted with 1 to 4 R ^s ;

R ^L2 and R ^s are each independently selected from deuterium, halogen, OH, CN, =O, CF ₃ , SF ₅ , NO ₂ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , COOH, CONH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -C _1-4 alkyl, -C _0-4 alkylene-C _3-6 cycloalkyl, -C _0-4 alkylene-4 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl and cycloalkyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, C _1-4 alkyl and C _1-4 alkoxy;

p1 is independently selected from 0, 1 or 2;

Or ^Rs are each independently selected from -OC _3-6 cycloalkyl.

As a second embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

^Rx1 , ^Rx2 , ^Rx3 , Rx4, ^Rx5 , ^Rz1 , ^Rz2 , ^Rz3 , and ^Rz4 are each independently selected from H, ^deuterium , halogen, OH, _NH2 , CN, _NO2 , COOH, CONH2, _NHC1-4 alkyl, N( _C1-4 alkyl) ₂ , C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -OC1-4 alkyl, -SC1-4 alkyl, _-C0-2 alkylene-C3-6 cycloalkyl, -C0-2 alkylene- _{4 to} 6 membered heterocyclic group, 5 to 6 membered heteroaryl, -OC1-4 alkyl, _-SC1-4 alkyl, -C0-2 alkylene-C3-6 cycloalkyl, -C0-2 alkylene- ₄ to 6 membered heterocyclic group, 5 to 6 membered heteroaryl, _-OC1-4 alkyl, _-SC1-4 alkyl, _-C0-2 alkylene- _C3-6 cycloalkyl, _-C0-2 alkylene-4 to 6 membered heterocyclic group, 5 to 6 membered heteroaryl, -OC1-4 alkyl, -SC1-4 alkyl, -C0-2 alkylene-C3-6 cycloalkyl, _3-6- membered cycloalkyl, -0-4 to 6-membered heterocyclic group, wherein the alkylene group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, heteroaryl group are optionally substituted by 1 to 4 ^Rs ;

or R ^x1 , R ^x2 , R ^x3 , and R ^x4 are each independently selected from -S(=O) ₂ NH ₂ , -S(=O) ₂ C _1-4 alkyl;

Alternatively, R ^x1 and R ^x2 , R ^x2 and R ^x3 , R ^x3 and R ^x4 , R ^x4 and R ^x5 are directly linked to form a C _4-6 carbocyclic group, a 5-6-membered heteroaryl group or a 5-7-membered heterocyclic group, and the carbocyclic group, heteroaryl group or heterocyclic group is optionally substituted by 1 to 4 R ^s ;

Alternatively, ^R1 and ^Rz3 , ^R1 and ^Rz1 are directly linked to form a 5- to 7-membered heterocyclic group, and the heterocyclic group is optionally substituted by 1 to 4 ^Rs ;

^RL is selected from H, methyl or ethyl;

^Rq are each independently selected from H, methyl, ethyl or isopropyl;

Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following groups optionally substituted by 1 to 4 R ^L2 : phenyl, pyridyl, pyrimidinyl, pyrazinyl, oxazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;

s1, s3, s5 are independently selected from 0, 1 or 2;

s2 and s4 are independently selected from 0 or 1;

s6 is selected from 0, 1, 2 or 3;

s7Choose from 1, 2 or 3;

R ^L2 and R ^s are each independently selected from deuterium, halogen, OH, CN, =O, CF ₃ , SF ₅ , NO ₂ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , COOH, CONH ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -C _1-4 alkyl, -C _0-2 alkylene-C _3-6 cycloalkyl, -C _0-2 alkylene-4 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl and cycloalkyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, C _1-4 alkyl and C _1-4 alkoxy;

or ^Rs are each independently selected from -OC _3-6 cycloalkyl;

The remaining group definitions are the same as those in the first embodiment of the present invention.

As a third embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

X ₃ selected from CR ^x3 ;

Y ₁ and Y ₂ are each independently selected from -CR ^y1 R ^y2 -, -(CR ^y1 R ^y2 ) ₂ -;

R ¹ is selected from H, deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH ₂ , CN, C _1-4 alkyl, C _1-4 alkoxy;

^Rx1 , ^Rx2 , ^Rx3 , Rx4, ^Rx5 , ^Rz1 , ^Rz2 , ^Rz3 , ^Rz4 are each independently selected from H ^, deuterium, F, Cl, Br, I, OH, _NH2 , CN, _NO2 , COOH, _CONH2 , N( _CH3 ) ₂ , _NHCH3 , or one of the following groups optionally substituted with 1 to 4 ^Rs : methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, _-CH2 -cyclopropyl, _-CH2 -cyclobutyl, -O-cyclopropyl, pyrazolyl;

or R ^x1 , R ^x2 , R ^x3 , and R ^x4 are each independently selected from -S(=O) ₂ NH ₂ , -S(=O) ₂ methyl, and -S(=O) ₂ ethyl;

Alternatively, R ^x1 and R ^x2 , R ^x2 and R ^x3 , R ^x3 and R ^x4 , R ^x4 and R ^x5 are directly linked to form one of the following groups optionally substituted with 1 to 3 R ^s : piperidinyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, oxazinyl, pyrazinyl;

Alternatively, R ^x1 and R ^x2 , R ^x2 and R ^x3 , R ^x3 and R ^x4 , R ^x4 and R ^x5 are directly linked to form one of the following groups optionally substituted with 1 to 3 R ^s : pyrrolidinyl, oxacyclopentyl, oxacyclohexyl, 1,3-dioxolane;

Alternatively, ^R1 and ^Rz3 , ^R1 and ^Rz1 are directly connected to form the following structure which is optionally substituted by 1 to 4 ^Rs : , ;

R ² , R ³ , R ^y1 , and R ^y2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, NH ₂ , CN, NO ₂ , COOH, CONH ₂ , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, and methylthio, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, and methylthio are substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH ₂ , CN, C _1-4 alkyl, and C _1-4 alkoxy;

Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from the group consisting of bonds, -O-, -S-, -OCH ₂ -, -CH ₂ O-, -OCH ₂ CH ₂ -, -CH ₂ CH ₂ O-, -C≡C-, -CH(CH ₃ )-, -CH ₂ -, -C(CH ₃ ) ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -N(CH ₃ )-, -NH-, -CH ₂ N(CH ₃ )-, -CH ₂ NH-, -NHCH ₂ -, -CH ₂ CH ₂ N(CH ₃ )-, -CH ₂ CH ₂ NH-, -NHCH ₂ CH ₂ -, -C(=O)-, -C(=O)CH ₂ NH-, -CH ₂ C(=O)NH-, -C(=O)NH- or -NHC(=O)-;

K Selected from , , ;

Q is independently selected from a bond, CH ₂ , NH, N(CH ₃ ), O, S, C(═O), NHC(═O), C(═O)NH, N(CH ₃ )C(═O), C(═O)N(CH ₃ );

R ^k1 are each independently selected from deuterium, F, Cl, Br, I, OH, NH ₂ , CN, COOH, CONH ₂ , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, and cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, and cyclopropyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, and NH ₂ ;

R ^L2 and R ^s are each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF ₃ , SF ₅ , CN, NH ₂ , NO ₂ , COOH, CONH ₂ , N(CH ₃ ) ₂ , NHCH ₃ , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH _{2 -cyclopentyl, -CH 2 -cyclohexyl} , wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally replaced by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C _1-4 alkyl ... substituted by _1-4 alkoxy substituents;

or ^Rs are each independently selected from propynyl, -O-cyclopropyl;

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

As a fourth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein

B Selected from , , , ;

Or B is selected from ;

X ₆ is selected from N or CH;

X ₇ is selected from NH or O;

At most 2 of Z ₁ , Z ₂ , Z ₃ , and Z ₄ are selected from N;

R ² and R ³ are each independently selected from H, deuterium, F, Cl, and Br;

R ^y1 and R ^y2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, NH ₂ , CN, NO ₂ , COOH, CONH ₂ , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH ₂ , CN, methyl, ethyl, methoxy;

Cy1, Cy2, Cy3, and Cy4 are each independently selected from one of the following groups which are optionally substituted: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , when substituted, by 1 to 4 substituents selected from deuterium, F, CF ₃ , OH, =O, COOH, CN, NH ₂ , hydroxymethyl, methyl, methoxy, cyclopropyl;

K Selected from , , , , , , ;

Or K is selected from , ;

The remaining group definitions are the same as those of the first, second or third embodiment of the present invention.

As a fifth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

B Selected from , , , , , , , , , , , , , , , , , , , ;

Or B is selected from , , , ;

R ^x2 , R ^x3 , R ^x4 are each independently selected from H, deuterium, F, Cl, Br, I, OH, NH ₂ , CN, NO ₂ , COOH, CONH ₂ , N(CH ₃ ) ₂ , NHCH ₃ , CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , OCH ₂ F, OCD ₃ , CH ₂ OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, -CH ₂ -cyclopropyl, -O-cyclopropyl;

or R ^x2 and R ^x4 are each independently selected from -S(=O) ₂ CH ₃ , -O-CH ₂ -propynyl, -O-CH ₂ -cyclopropyl, -O-CH ₂ CH ₂ -OCH ₃ , -O-CH ₂ CH ₂ -O-cyclopropyl, , , , ;

Q is independently selected from a bond, NH, N(CH ₃ ), O, S, NHC(═O), C(═O)NH, N(CH ₃ )C(═O), C(═O)N(CH ₃ );

L is selected from -Cy1-, -Cy1-Ak2-, -Cy1-CH ₂ -, -Ak1-Cy1-, -Cy1-Cy2-, -Cy1-CH ₂ -Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH ₂ -Cy2-Cy3-, -Cy1-Cy2-CH ₂ -Cy3-;

Or L is selected from -Cy1-Ak2-Cy2-, -Cy1-O-Cy2-;

Cy1, Cy2, and Cy3 are each independently selected from one of the following substituted groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , when substituted, by 1 to 4 substituents selected from deuterium, F, CF ₃ , OH, =O, COOH, CN, NH ₂ , hydroxymethyl, methyl, methoxy, cyclopropyl;

The remaining group definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

As a sixth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

K Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

Or K is selected from , , , , , , , , , , , , , ;

Q is independently selected from bonds, NH, C(=O)NH;

R ^k1 are each independently selected from deuterium, F, Cl, Br, I, OH, NH ₂ , CN, COOH, CONH ₂ , CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , OCH ₂ F, CH ₂ OH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl;

L is selected from one of the structural fragments shown in Table L-1;

The remaining group definitions are the same as those of the first, second, third, fourth or fifth embodiment of the present invention.

As a seventh embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

B Selected from , ; Z ₃ is selected from N or CR ^z3 ; Z ₄ is selected from N or CR ^z4 ; preferably, B is selected from , , , , , , , ;

L is selected from -Cy1-, -Cy1-Ak2-, -Cy1-Ak2-Cy2-; preferably, L is selected from -Cy1-, -Cy1-CH ₂ -, -Cy1-C(CH ₃ ) ₂ -, -Cy1-O-Cy2; more preferably, L is selected from ;

Cy1 and Cy2 are each independently selected from one of the following substituted groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , when substituted, is substituted by 1 to 4 substituents selected from deuterium, F, CF ₃ , OH, =O, COOH, CN, NH ₂ , hydroxymethyl, methyl, methoxy, cyclopropyl; preferably, Cy1 and Cy2 are each independently selected from one of the following optional substituents: , , , , , , , , , , , , , , when substituted, by 1 to 4 substituents selected from deuterium, F, CF ₃ , OH, =O, COOH, CN, NH ₂ , hydroxymethyl, methyl, methoxy, cyclopropyl;

Ak2 is selected from -C(CH ₃ ) ₂ - or -CH ₂ -;

K Selected from ; Preferably, K is selected from , ;

Selected from , , ;

The definitions of the remaining groups are consistent with those described in any embodiment of the present invention.

The present invention relates to the following compound or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table E below:

Table E .

The present invention relates to a pharmaceutical composition, comprising the above-mentioned compound of the present invention or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and a pharmaceutically acceptable carrier.

The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in the preparation of drugs for treating diseases related to AR activity or expression.

The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of a drug for treating and inhibiting or degrading AR-related diseases. In some embodiments, the AR-related disease is cancer, preferably prostate cancer.

The present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal and pharmaceutically acceptable excipient. The pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").

The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or pharmaceutical composition. In some embodiments, the mammal of the present invention includes a human.

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

In some embodiments, the pharmaceutical composition includes but is not limited to 1-1500 mg, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 1 25 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg, 1000 mg of a compound of the present invention or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, preferably 1-1500 mg, wherein the disease is preferably cancer, further preferably prostate cancer.

A method for treating a disease in a mammal, the method comprising administering a drug compound of the present invention or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof to a subject at a daily dose of 1-1500 mg/day, the daily dose may be a single dose or a divided dose. In some embodiments, the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, 2 In some embodiments, the daily dose includes but is not limited to 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day, 200 mg/day, 300 mg/day, 320 mg/day, 400 mg/day, 480 mg/day, 600 mg/day, 640 mg/day, 800 mg/day, 1000 mg/day, 1500 mg/day.

The present invention relates to a kit which may include a composition in a single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof is the same as that in the above-mentioned pharmaceutical composition.

The amount of the compound of the present invention or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as a free base.

Unless otherwise defined, the terms used in the specification and claims have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds of the present invention include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds of the present invention are arbitrarily further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include ¹¹ C, ¹² C, ¹³ C and ¹⁴ C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called superdeuterium), oxygen isotopes include ¹⁵ O, ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S, ³⁵ S and ³⁶ S, nitrogen isotopes include ¹³ N, ¹⁴ N and ¹⁵ N, isotopes of fluorine include ¹⁷ F, ¹⁸ F and ¹⁹ F, isotopes of chlorine include ³⁵ Cl, ³⁶ Cl and ³⁷ Cl, isotopes of bromine include ⁷⁹ Br and ⁸¹ Br, isotopes of iodine include ¹²³ I and ¹²⁵ I, and isotopes of phosphorus include ³¹ P and ³² P.

"CN" refers to cyano.

"Halogen" refers to F, Cl, Br or I.

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

"Alkylene" refers to a substituted or unsubstituted straight or branched divalent saturated hydrocarbon group, including -(CH ₂ ) _v -(v is an integer from 1 to 10). Examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

"Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 12 carbon atoms, and the cycloalkyl group can be a monocyclic, paracyclic, bridged, and spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutylparacyclobutyl, cyclobutylspirocyclobutyl, adamantane, etc. The cycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

"Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of the heterocycloalkyl group can be oxidized to various oxidation states. The heterocycloalkyl group can be a monocyclic, cyclic, bridged and spirocyclic ring. The heterocycloalkyl group may be attached to a heteroatom or a carbon atom, and non-limiting examples include oxirane, cyclopropyl, cyclobutyl, cyclobutyl, tetrahydrofuranyl, tetrahydro- 2H -pyranyl, dioxolanyl, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinanyl, oxolinyl, hexahydropyrimidinyl, piperazinyl, , , , , , , , The heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

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

"Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated alkyl groups having at least one, typically one, two or three carbon-carbon triple bonds, with the main chain comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the main chain, 2 to 4 carbon atoms in the main chain, examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13-pentynyl, 14-pentynyl, 15-pentynyl, 16-pentynyl, 17-pentynyl, 18-pentynyl, 19-pentynyl, 20-pentynyl, 21-pentynyl, 22-pentynyl, 23-pentynyl, 24-pentynyl, 25-pentynyl, 26-pentynyl, 27-pentynyl, 28-pentynyl, 29-pentynyl, 30-pentynyl, 31-pentynyl, 32-pentynyl, 33-pentynyl, 34-pentynyl, 35-pentynyl, 36-pentynyl, 37-pentynyl, 38-pentynyl, 39-pentynyl, 40-pentynyl, 41-pentynyl, 42-pentynyl, 43-pentynyl, 44-pentynyl, 45-pentynyl, 46-pentynyl, 47-pentynyl, 48 alkynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; alkynyl can be monovalent, divalent, trivalent, or tetravalent.

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

"Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which may be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered tetracyclic ring. The carbocyclyl may be attached to the aromatic ring or the non-aromatic ring, and the ring may be a monocyclic ring, a cyclic ring, a bridged ring, or a spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthyl ring, , , or "Carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent or tetravalent.

"Heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which may be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, or a 10-15 membered tricyclic ring, or a 12-18 membered quaternary system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se selectively substituted in the ring of the heterocyclic group may be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group can be optionally a monocyclic ring, a bridged ring, a cyclic ring or a spirocyclic ring. Non-limiting examples include ethylene oxide, azidopropyl, oxycyclobutyl, azidobutyl, 1,3-dioxolane, 1,4-dioxolane, ‒dioxolanyl, 1,3-dioxane, azacycloheptyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, oxazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantanyl, oxaspiro[3.3]heptanyl, , , , , , , , , , , , , , , , , , , , , , "Heterocyclic group" or "heterocyclic ring" may be monovalent, divalent, trivalent or tetravalent.

"Spiro" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted rings share one atom (called spiro atom), and the number of ring atoms in the spirocyclic system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 heteroatoms selected from N, O or S (=O) _n (n is 0, 1 or 2). Non-limiting examples include: "Spiro" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

"Cyclic" or "Cyclic group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and may be substituted or unsubstituted, and each ring in the cyclic system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to selected from N, S(=O) _n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include: "Cyclo" or "cycloalkyl" may be monovalent, divalent, trivalent or tetravalent.

"Bridged ring" or "bridged cyclic group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, which may contain 0 or more double bonds, and any ring in the bridged ring system may contain 0 to 5 groups selected from heteroatoms or heteroatoms (including but not limited to N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12 or 5 to 10. Non-limiting examples include: Cubane, diamond. "Bridging ring" or "bridged ring group" can be monovalent, divalent, trivalent or tetravalent.

"Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" whose ring system consists of only carbon atoms.

"Carbocyclic", "cyclic carbocyclic group", "cyclic carbocyclic group" or "cyclic carbocyclic group" refers to a "cyclic group" whose ring system consists of only carbon atoms.

"Carbobridged ring", "bridged ring carbocyclic group", "bridged carbocyclic group" or "carbobridged cyclic group" refers to a "bridged ring" whose ring system consists of only carbon atoms.

"Heteromonocyclic", "monocyclic heterocyclic group" or "heteromonocyclic group" refers to a "heterocyclic group" or "heterocyclic group" of a monocyclic ring system.

"Heterocyclic", "heterocyclic group", "cyclic heterocyclic group" or "heterocyclic group" refers to a "cyclic group" containing a hetero atom.

"Heterospirocycle", "heterospirocycloyl", "spiroheterocycloyl" or "spiroheterocycloyl" refers to a "spirocycle" containing a hetero atom.

“Hetero-bridged ring”, “hetero-bridged cyclic group”, “bridged-cyclic heterocyclic group” or “bridged heterocyclic group” refers to a “bridged ring” containing a hetero atom.

"Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include a benzene ring, a naphthalene ring, "Aryl" or "aryl ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

“Heteroaryl” or “heteroaryl ring” refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or a group containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, where n is 0, 1 or 2). The number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. The atoms C, N, and S on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, n is 1 or 2). Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furanyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, oxazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridone, etc. The heteroaryl ring may be fused to a saturated or unsaturated carbon ring or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include: , , The heteroaryl groups mentioned herein have the same definition as in this definition. The heteroaryl groups may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment point is located on the aromatic ring.

“Substituted” or “substituted” means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, alkyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridging, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, ‒(CH ₂ ) _m ‒C(=O)‒R ^a , ‒O‒(CH ₂ ) _m ‒C(=O)‒R ^a , ‒(CH ₂ ) _m ‒C(=O)‒NR ^b R ^c , ‒(CH ₂ ) _m S(=O) _nRa , ^‒ ( _CH2 ) _m ‒alkenyl‒ ^Ra , ^ORd or ‒( _CH2 ) _m ‒alkynyl‒ ^Ra (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or ^‒NRbRc , wherein ^{Rb and Rc} are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and ^Rb and ^Rc can form a five- or six-membered cycloalkyl or heterocyclic group, ^Ra ... ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic, carbonyl, ester, bridged, spiro, or bicyclic groups.

"Replaced by 1 to X substituents selected from..." means substituted by 1, 2, 3 ....X substituents selected from...", X is any integer selected from 1 to 10. For example, "replaced by 1 to 4 R ^k " means substituted by 1, 2, 3 or 4 R ^k . For example, "replaced by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4 or 5 substituents selected from..." For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

X-Y membered rings (X and Y are integers, and 3≤X＜Y, X＜Y≤20 are any integers selected from 4 to 20) include X, X+1, X+2, X+3, X+4….Y membered rings. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heteroparacyclic rings, heterospirocyclic rings or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to 4-, 5-, 6- or 7-membered heteromonocyclic rings, and "5-10 membered heteroparacyclic rings" refers to 5-, 6-, 7-, 8-, 9- or 10-membered heteroparacyclic rings.

_Cxy carbocycle (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, biscyclic carbocycle or bridged carbocycle) includes _Cx , Cx ₊₁ , Cx ₊₂ , Cx ₊₃ , Cx ₊₄ ... _Cy -membered ring (x is an integer, and 3≤x＜y, y is any integer selected from 4 _to 20), for example. For example, " _{C3-6 cycloalkyl} " refers to _C3 , _C4 , _C5 or _C6 cycloalkyl.

When a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection is non-positional and there are hydrogen atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected to become a group of corresponding valence. For example Indicates that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if an H atom is drawn on -N-, Also included .For example Indicates that the R group on the piperidine group can be located on C, can be located on N, and at least includes For example, the general formula fragment is , when X is selected from CH ₂ or NH, it means that the R group on the general fragment can be located on C or X. When X is selected from CH ₂ , the general fragment can be , When X is selected from NH, the general formula fragment can be .

When the listed linking groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in reading order, for example, A-L-B, when L is selected from -M-W-, includes A-M-W-B and A-W-M-B.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with F" means that alkyl may but need not be substituted with F, and the description includes instances where alkyl is substituted with F and instances where alkyl is not substituted with F.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is reacted with a non-toxic inorganic base or organic base, and the free base is reacted with a non-toxic inorganic acid or organic acid to obtain a salt.

"Drug composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.

"Preparation specification" refers to the weight of the active drug contained in each vial, tablet or other unit of preparation.

"Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

"Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through metabolism in the body. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

"Cocrystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, where the API and CCF are solid in their pure state at room temperature and there is a fixed stoichiometric ratio between the components. Cocrystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

"Animal" is intended to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

"Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

"Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imide alcohol isomers.

Synthesis method 1:

The compound of the general formula (Z-1) reacts with the compound of the general formula (Z-2) to generate the compound of the general formula (Z-3) through nucleophilic substitution or coupling reaction;

The compound of the general formula (Z-3) undergoes a deprotection reaction to obtain the compound of the general formula (Z-4);

The compound of the general formula (Z-4) and the compound of the general formula (Z-5) are subjected to a condensation reaction to obtain the compound of the general formula (Z-6);

The compound of the general formula (Z-6) is subjected to an oxidation reaction to obtain the compound of the general formula (Z-7);

The general formula compound (Z-7) and the general formula compound (Z-8) undergo a reductive amination reaction to obtain the general formula compound (Z-9).

R ^x1 is selected from F, Cl, Br, I, OTf or borate;

R ^x2 is selected from protecting groups such as Boc, Cbz, Fmoc, SEM, etc.

The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include: Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) NMR spectrometers, with deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));

HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

The thin layer chromatography silica plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica plate. The silica plate used in thin layer chromatography (TLC) uses a specification of 0.15 mm-0.20 mm, and the specification used for thin layer chromatography separation and purification products is 0.4 mm - 0.5 mm;

Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh as the carrier.

Synthesis reagent abbreviation:

DMAP: CAS No.: 1122-58-3; NBS: CAS No.: 128-08-5; HATU: CAS No.: 148893-10-1;

Synthesis of intermediate 1:

Step 1: Preparation of 1-B

1-A (2.8 g, 13.58 mmol) (synthesis method, see Bioorganic & Medicinal Chemistry Letters , 2016 , 26 , 5877-5882) was dissolved in dichloromethane (50 mL), and _Boc2O (5.93 g, 27.17 mmol) and DMAP (3.32 g, 27.18 mmol) were added. The reaction was allowed to react at room temperature for 16 h. The reaction system was washed with 0.5 mol/L hydrochloric acid (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) = 0:1-1:9) to obtain the racemate of 1-B (3.4 g, yield: 82%).

The racemate of 1-B is subjected to chiral separation. The chiral separation method is as follows:

1. Instrument: SFC Prep 150 AP; Chromatographic column: Celluloid IC-H (19 mm × 250 mm).

2. Dissolve the sample in methanol and filter it with a 0.45 μm filter to prepare a sample solution.

3. Preparation of chromatographic conditions: a. The mobile phase consists of A and B systems: mobile phase A: CO ₂ ; mobile phase B: methanol/isopropanol (v/v) = 1:1; b. Isocratic extraction, mobile phase B content is 20%; c. Flow rate is 40 mL/min.

Peak time: chiral isomer 1 (compound 1-B): 5.7 min, chiral isomer 2 (compound 2-A): 6.47 min.

According to the MicroED structure determination of compound 2-B, compound 1-B is in R configuration and compound 2-A is in S configuration.

LCMS m/z = 307.3 [M+1] ⁺ .

Step 2: Preparation of 1-C

Dissolve 1-B (1.8 g, 5.88 mmol) in acetonitrile (50 mL), add NBS (1.05 g, 5.90 mmol), and react at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) = 0:1-1:9) to obtain 1-C (1.6 g, yield: 71%).

LCMS m/z = 385.3 [M+1] ⁺ .

Step 3: Preparation of 1-D

1-C (0.77 g, 2.0 mmol), 1-C′ (1.67 g, 4.0 mmol) (synthesis method see WO2022235945), Pd(dppf)Cl ₂ ·DCM (0.16 g, 0.20 mmol) and cesium carbonate (1.30 g, 4.0 mmol) were added to a reaction bottle, and 1,4-dioxane (30 mL) and water (3 mL) were added, and the reaction was carried out at 100°C for 20 h under nitrogen atmosphere. The reaction system was cooled to room temperature, 50 mL of water and 50 mL of ethyl acetate were added, the aqueous phase was extracted with 50 mL of ethyl acetate, the organic phase was washed with 30 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-9:1) to obtain 1-D (0.70 g, yield: 59%).

Step 4: Preparation of 1-E

1-D (0.70 g, 1.18 mmol) was dissolved in THF (20 mL), 10% palladium on carbon (0.63 g) was added, and the mixture was reacted at 45°C under a hydrogen balloon atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel chromatography (MeOH:DCM (v/v) = 0:1-5:95) to obtain 1-E (0.25 g, yield: 51%).

LCMS m/z = 418.1 [M+1] ⁺ .

Step 5: Preparation of Intermediate 1

Dissolve 1-E (250 mg, 0.6 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (2 mL), and react at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and the system was concentrated under reduced pressure to obtain a crude intermediate 1 (190 mg).

LCMS m/z = 318.3 [M+1] ⁺ .

Synthesis of intermediate 2:

Step 1: Preparation of 2-B

Dissolve 2-A (1.4 g, 4.57 mmol) in acetonitrile (50 mL), add NBS (0.81 g, 4.55 mmol), and react at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) = 0:1-1:9) to obtain 2-B (1.6 g, yield: 92%).

LCMS m/z = 385.3 [M+1] ⁺ .

The compound 2-B was determined to be in S configuration by MicroED structure analysis.

Step 2: Preparation of 2-C

2-B (1.6 g, 4.16 mmol), 2-B′ (3.46 g, 8.29 mmol), Pd(dppf)Cl ₂ ·DCM (0.34 g, 0.42 mmol) and cesium carbonate (2.70 g, 8.3 mmol) were added to a reaction bottle, and 1,4-dioxane (50 mL) and water (5 mL) were added. The mixture was reacted at 100°C for 20 h under nitrogen atmosphere. The reaction system was cooled to room temperature, 50 mL of water and 50 mL of ethyl acetate were added, the aqueous phase was extracted with ethyl acetate (50 mL), the organic phase was washed with 30 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-9:1) to obtain 2-C (1.4 g, yield: 56%).

Step 3: 2-D Preparation

Dissolve 2-C (1.4 g, 2.35 mmol) in THF (50 mL), add 10% palladium on carbon (1.25 g), and react at 45°C under a hydrogen balloon atmosphere for 20 h. Cool the reaction system to room temperature, filter, and concentrate the filtrate under reduced pressure. The crude product is separated and purified by silica gel chromatography (MeOH:DCM (v/v) = 0:1-5:95) to obtain 2-D (0.85 g, yield: 87%).

LCMS m/z = 418.1 [M+1] ⁺ .

Step 4: Preparation of Intermediate 2

Dissolve 2-D (620 mg, 1.49 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (3 mL), and react at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and the system was concentrated under reduced pressure to obtain a crude intermediate 2 (460 mg).

LCMS m/z = 318.3 [M+1] ⁺ .

Preparation of intermediate 3:

Step 1: Preparation of 3-A

In a nitrogen atmosphere, 1-C (7.00 g, 18.17 mmol) and 70 mL of tetrahydrofuran were added to the reaction flask, and 2.5 mol/L n-butyl lithium n-hexane solution (14.50 mL, 36.25 mmol) was slowly added dropwise at -78°C. After stirring for 1.5 h at -78°C, the carbon dioxide was replaced three times, and the system temperature was controlled below -40°C under a carbon dioxide balloon atmosphere for 0.5 h. The reaction system was returned to room temperature, 20 mL of ethyl acetate was added, the pH was adjusted to 2 with 1 mol/L hydrochloric acid, and extracted with ethyl acetate (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column (petroleum ether/ethyl acetate (v/v) = 10:1-2:1) to obtain 3-A (2.4 g, yield: 38%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.42 (d, 1H), 6.64 (d, 1H), 4.00 – 3.82 (m, 3H), 3.23 – 3.09 (m, 1H), 3.08 – 2.90 (m, 1H), 2.90 – 2.77 (m, 1H), 2.76 – 2.60 (m, 3H), 2.05 – 1.90 (m, 1H), 1.65 – 1.50 (m, 1H), 1.49 – 1.35 (m, 9H).

Step 2: Preparation of Intermediate 3

3-A (2.4 g, 6.85 mmol), HATU (3.13 g, 8.23 mmol), diisopropylethylamine (2.66 g, 20.58 mmol) and 10 mL DMF were added to the reaction flask, stirred at room temperature for 10 min, and then 3-amino-2,6-piperidindione hydrochloride (1.35 g, 8.20 mmol) was added. The reaction was allowed to react at room temperature for 30 min. The reaction solution was poured into 100 mL of water, filtered, and the filter cake was washed with 50 mL of water. The filter cake was dried under reduced pressure to obtain intermediate 3 (2.0 g, yield: 63%).

LCMS m/z = 461.2 [M+1] ⁺

Preparation of intermediate 4:

Intermediate 4 is prepared by using compound 2-B as a raw material by referring to the synthesis method of intermediate 3.

LCMS m/z = 461.2 [M+1] ⁺

Preparation of intermediate 5:

Step 1: Preparation of 5-B

Dissolve 5-A (10 g, 42.02 mmol) in 80 mL DMSO, add 5-A′ (7.41 g, 46.25 mmol) and DIPEA (16.29 g, 126.03 mmol), and react at 50°C for 3 h. Cool the reaction system to room temperature, add 300 mL of water and 400 mL of ethyl acetate, wash the organic phase with 300 mL of saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude 5-B (6.2 g).

Step 2: Preparation of 5-C

The crude product 5-B (6.2 g) was added to 150 mL of methanol and 30 mL of water, and iron powder (9.15 g, 163.4 mmol) and ammonium chloride (8.77 g, 163.96 mmol) were added, and the mixture was reacted at 70°C for 20 h. The reaction system was cooled to room temperature, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, 300 mL of water and 400 mL of ethyl acetate were added to the residue, the organic phase was washed with 300 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (methanol: dichloromethane (v/v) = 0:1-1:9) to obtain 5-C (1.9 g, two-step yield based on compound 5-A: 13%).

Step 3: Preparation of 5-D

Dissolve 5-C (1.9 g, 5.46 mmol) and TEA (1.66 g, 16.40 mmol) in 20 mL of dichloromethane, add chloroacetyl chloride (0.99 g, 8.77 mmol) dropwise, and react at room temperature for 20 h. Add 50 mL of water to the reaction solution, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude 5-D (2.1 g).

Step 4: Preparation of 5-E

The crude product 5-D (0.95 g) was added to 15 mL of acetic acid and reacted at 50°C for 20 h. The reaction system was cooled to 0°C, the pH was adjusted to 8 with 25% aqueous ammonia, and extracted with 150 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (methanol: dichloromethane (v/v) = 0:1-1:9) to obtain 5-E (0.85 g, two-step yield based on compound 5-C: 85%).

Step 5: Preparation of 5-F

Dissolve 5-E (7.3 g, 17.95 mmol) in 80 mL THF, add 20 mL 1 mol/L potassium tert-butoxide in tetrahydrofuran solution, and react at room temperature for 19 h. Add 30 mL water and 50 mL ethyl acetate to the reaction system, wash the organic phase with 300 mL saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the crude product by silica gel column chromatography (methanol: dichloromethane (v/v) = 0:1-1:9) to obtain 5-F (3.6 g, yield: 54%).

Step 6: Preparation of 5-G

5-F (2.0 g, 5.4 mmol), 2,6-bis(benzyloxy)pyridine-3-boronic acid pinacol ester (3.4 g, 8.15 mmol), Pd(dppf)Cl ₂ ·DCM (0.44 g, 0.54 mmol) and cesium carbonate (3.5 g, 10.74 mmol) were added to the reaction bottle in sequence, and 1,4-dioxane (100 mL) and water (10 mL) were added. The mixture was reacted at 100°C for 20 h under nitrogen atmosphere. The reaction system was cooled to room temperature, 300 mL of water and 300 mL of ethyl acetate were added, the organic phase was washed with 100 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-9:1) to obtain 5-G (2.6 g, yield: 83%).

LCMS m/z = 581.4 [M+1] ⁺ .

Step 7: Preparation of 5-H

Dissolve 5-G (2.6 g, 4.48 mmol) in THF (10 mL) and methanol (30 mL), add 10% palladium on carbon (2.5 g), and react at 40°C for 20 h under a hydrogen balloon atmosphere. Cool the reaction system to room temperature, filter, and concentrate the filtrate under reduced pressure to obtain crude 5-H (0.98 g).

LCMS m/z = 403.3 [M+1] ⁺ .

Step 8: Preparation of Intermediate 5

The crude product 5-H (100 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the reaction was carried out at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of methanol was added, 150 mg of solid sodium bicarbonate was added, and the mixture was stirred for 10 min, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude intermediate 5 (80 mg).

Example 1: Preparation of trifluoroacetic acid salt of compound 1

Dissolve 1a (0.23 g, 0.47 mmol) (synthesis method, see WO2021127443) in 1,2-dichloroethane (10 mL), add the above crude intermediate 2 (0.15 g), add 1 mL of acetic acid, stir at room temperature for 1 h, add sodium triacetoxyborohydride (0.30 g, 1.42 mmol), and react at room temperature for 16 h. 20 mL of saturated sodium bicarbonate aqueous solution was slowly added to the reaction solution, and the mixture was extracted with 50 mL of dichloromethane. The organic phase was washed with 50 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol (v/v) = 10:1). The crude product was prepared by HPLC (preparation method: the DMSO solution of the crude product was filtered with a 0.45 μm filter membrane to prepare a sample solution. The mobile phase system was water (containing 0.1% TFA)/acetonitrile. Gradient extraction method: acetonitrile was gradiently extracted from 10% to 50% (extraction time 15 min)), and the trifluoroacetic acid salt of compound 1 (10 mg) was obtained by freeze-drying.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.80 – 7.72 (m, 2H), 7.52 (d, 1H), 7.08 – 7.00 (m, 2H), 6.91 (d, 1H), 6.71 (d, 1H), 6.64 – 6.60 (m, 1H), 6.55 (dd, 1H), 4.26 (s, 1H), 4.18 – 4.03 (m, 2H), 4.02 – 3.83 (m, 6H), 3.80 – 3.60 (m, 2H), 3.43 – 3.30 (m, 1H), 3.28 – 3.06 (m, 4H), 3.04 – 2.57 (m, 7H), 2.33 – 2.02 (m, 4H), 2.01 – 1.70 (m, 3H), 1.56 – 1.40 (m, 2H), 1.36 – 1.19 (m, 12H).

LCMS m/z = 791.4 [M+1] ⁺

The crude product of the reaction solution obtained in this step can also be prepared by neutral HPLC (preparation method: the DMSO solution of the crude product is filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: 10 mmol/L ammonium bicarbonate aqueous solution/acetonitrile. Gradient extraction method: acetonitrile gradient extraction from 47% to 87% (extraction time 28 min)), and freeze-dried to obtain compound 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.73 – 7.64 (m, 2H), 7.45 (d, 1H), 6.95 – 6.87 (m, 2H), 6.72 (d, 1H), 6.53 – 6.44 (m, 2H), 6.40 (dd, 1H), 6.10 (d, 1H), 4.18 – 4.11 (m, 1H), 4.04 (s, 1H), 3.91 (s, 3H), 3.89 – 3.72 (m, 3H), 3.65 – 3.54 (m, 1H), 3.14 – 3.00 (m, 1H), 2.97 – 2.72 (m, 7H), 2.70 – 2.57 (m, 2H), 2.32 – 2.11 (m, 5H), 1.99 – 1.82 (m, 4H), 1.81 – 1.65 (m, 2H), 1.40 – 1.19 (m, 14H).

Compound 1 was chirally resolved to obtain chiral isomer 1 and chiral isomer 2, respectively.

First chiral separation purification conditions:

1. Instrument: SHIMADZU LC-20AP; Chromatographic column: Chiral Whelk column.

2. Dissolve the sample in acetonitrile and filter with a 0.45 μm filter to prepare a sample solution.

3. Preparation of chromatographic conditions: a. The mobile phase consists of A and B systems: mobile phase A: n-hexane; mobile phase B: a mixed solvent of ethanol/acetonitrile containing 0.1% ammonia water; b. Isocratic elution, the content of mobile phase B is 70%; c. The flow rate is 100 mL/min.

Second chiral separation purification conditions:

1. Instrument: Waters 150 Prep-SFC; Chromatographic column: Chiral AD column.

2. Dissolve the sample in acetonitrile and filter with a 0.45 μm filter to prepare a sample solution.

3. Preparation of chromatographic conditions: a. The mobile phase consists of A and B systems: mobile phase A: CO ₂ ; mobile phase B: a mixed solvent of isopropanol/acetonitrile containing 0.1% ammonia water; b. Isocratic elution, mobile phase B content is 70%; c. Flow rate is 100 mL/min.

Chiral analysis method:

1. Instrument: SHIMAZU LC-20AD; Chromatographic column: Chiral Whelk column.

2. Analytical chromatographic conditions: a. The mobile phase consists of A and B systems: mobile phase A: n-hexane; mobile phase B: ethanol and acetonitrile solution containing 0.1% isopropylamine; b. Isocratic extraction, mobile phase B content is 60%; c. Flow rate is 1 mL/min.

Peak time: chiral isomer 1: 2.594 min, chiral isomer 2: 5.557 min.

Example 3: Preparation of trifluoroacetic acid salt of compound 3

Add 2 mL of dichloromethane and 1 mL of trifluoroacetic acid to intermediate 4 (160 mg, 0.35 mmol) and react at room temperature for 2 h. Reduce the pressure and concentrate the reaction system, add 5 mL of dichloromethane and 1 mL of triethylamine, and reduce the pressure and concentrate to obtain crude product 1 (120 mg). Dissolve 1a (0.160 g, 0.33 mmol) in 1,2-dichloroethane (10 mL), add the above crude product 1 (0.120 g), add 1 mL of acetic acid, stir at room temperature for 1 h, add sodium triacetoxyborohydride (0.21 g, 0.99 mmol), and react at room temperature for 16 h. 20 mL of saturated sodium bicarbonate aqueous solution was slowly added to the reaction solution, and the mixture was extracted with 50 mL of dichloromethane. The organic phase was washed with 50 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol (v/v) = 10:1). The crude product was prepared by HPLC (preparation method: the DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. The mobile phase system was water (containing 0.1% TFA)/acetonitrile. Gradient extraction method: acetonitrile was gradiently extracted from 10% to 50% (extraction time 15 min)), and the trifluoroacetic acid salt of compound 3 (45 mg) was obtained by freeze-drying.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.80 – 7.72 (m, 2H), 7.60 – 7.48 (m, 2H), 7.10 – 7.00 (m, 2H), 6.76 (d, 1H), 6.65 – 6.60 (m, 1H), 6.55 (dd, 1H), 4.85 – 4.72 (m, 1H), 4.30 – 4.10 (m, 3H), 4.02 – 3.88 (m, 5H), 3.82 – 3.63 (m, 2H), 3.60 – 3.43 (m, 1H), 3.33 – 3.10 (m, 4H), 3.07 – 2.62 (m, 7H), 2.37 – 2.06 (m, 4H), 2.02 – 1.88 (m, 2H), 1.85 – 1.72 (m, 1H), 1.57 – 1.42 (m, 2H), 1.35 – 1.17 (m, 12H).

LCMS m/z = 834.6 [M+1] ⁺

Example 5: Preparation of trifluoroacetic acid salt of compound 5

Step 1: Preparation of 5A trifluoroacetate

Dissolve 3-A (650 mg, 1.86 mmol) in 2 mL of dichloromethane, add 2 mL of trifluoroacetic acid, and react at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of crude 5A (700 mg).

Step 2: Preparation of 5b trifluoroacetic acid salt

Dissolve 5a (3.00 g, 11.75 mmol) in 5 mL of dichloromethane, add 5 mL of trifluoroacetic acid, and react at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of crude 5b (3.2 g).

Step 3: Preparation of 5c

The trifluoroacetic acid salt of the crude product 5b (3.2 g), ethyl 4-fluorobenzoate (1.85 g, 11.00 mmol), potassium carbonate (3.04 g, 22.0 mmol) and 15 mL of dimethyl sulfoxide were added to the reaction flask and reacted at 100°C for 16 h. The reaction system was cooled to room temperature, 100 mL of water and 100 mL of ethyl acetate were added to the reaction solution, the liquid was separated, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-1:1) to obtain 5c (2.40 g, yield: 72%).

Step 4: 5d preparation

5c (2.40 g, 7.91 mmol), potassium hydroxide (1.78 g, 31.79 mmol), 10 mL ethanol, 10 mL tetrahydrofuran and 10 mL water were added to the reaction bottle and stirred at room temperature for 16 h. The reaction system was concentrated under reduced pressure, the pH was adjusted to 2 with 2 mol/L hydrochloric acid, filtered, the filter cake was collected, and the filter cake was dried under reduced pressure to obtain crude product 5d (1.50 g).

LCMS m/z = 276.3 [M+1] ⁺

Step 5: Preparation of 5e

The crude product 5d (0.6 g), HATU (0.99 g, 2.60 mmol), diisopropylethylamine (1.41 g, 10.91 mmol) and 10 mL DMF were added to the reaction flask respectively. After stirring at room temperature for 0.5 h, trans-4-(3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-methoxybenzonitrile hydrochloride (0.66 g, 2.12 mmol) (synthesis method see CN115175901) was added and stirred at room temperature for 2 h. 100 mL of water and 100 mL of ethyl acetate were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-0:1) to obtain 5e (1.10 g, yield: 98%).

LCMS m/z = 532.6 [M+1] ⁺

Step 6: Preparation of 5f

5e (1.10 g, 2.07 mmol), Dess-Martin oxidant (1.05 g, 2.48 mmol) and 10 mL of dichloromethane were added to the reaction bottle and reacted at room temperature for 4 h. The reaction system was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v) = 0:1-1:9) to obtain 5f (0.52 g, yield: 47%).

LCMS m/z = 530.2 [M+1] ⁺

Step 7: Preparation of 5g

5f (0.25 g, 0.47 mmol), the trifluoroacetic acid salt of the crude product 5A (0.18 g), 0.2 mL of glacial acetic acid and 3 mL of DMAc were added to the reaction flask respectively. After reacting at room temperature for 1 h, sodium triacetoxyborohydride (0.30 g, 1.42 mmol) was added and the reaction was continued at room temperature for 16 h. Add 20 mL of water and 20 mL of ethyl acetate to the reaction solution, separate the layers, extract the aqueous phase with ethyl acetate (20 mL×3), combine the organic phases, wash the organic phases with 50 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Separate and purify the crude product by silica gel column chromatography (methanol/dichloromethane (v/v) = 0:1-1:9) to obtain 5 g (0.20 g, yield: 56%).

Step 8: Preparation of trifluoroacetic acid salt of compound 5

5 g (0.10 g, 0.13 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (0.043 g, 0.26 mmol), EDCI (0.037 g, 0.19 mmol), HOBt (0.026 g, 0.19 mmol), N-methylmorpholine (0.065 g, 0.64 mmol) and 4 mL DMF were added to the reaction bottle and reacted at room temperature for 16 h. The reaction solution was subjected to Pre-HPLC (instrument and preparation column: Waters 2767 was used for preparation of liquid phase, the preparation column model was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA)/acetonitrile. Gradient extraction method: acetonitrile was gradiently extracted from 10% to 50% (extraction time 15 min), and the trifluoroacetic acid salt of compound 5 (20 mg) was obtained by freeze-drying.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.74 (d, 2H), 7.57 – 7.48 (m, 2H), 7.02 (d, 2H), 6.75 (d, 1H), 6.62 (d, 1H), 6.55 (dd, 1H), 4.82 – 4.74 (m, 1H), 4.30 – 4.23 (m, 1H), 4.23 – 4.17 (m, 1H), 4.13 (s, 1H), 3.93 (s, 3H), 3.68 – 3.49 (m, 2H), 3.48 – 3.30 (m, 5H), 3.28 – 3.08 (m, 4H), 3.02 – 2.90 (m, 1H), 2.88 – 2.65 (m, 5H), 2.35 – 2.05 (m, 5H), 1.89 – 1.82 (m, 2H), 1.82 – 1.65 (m, 5H), 1.26 (d, 12H).

LCMS m/z = 874.4 [M+1] ⁺

Example 7: Preparation of trifluoroacetic acid salt of compound 7

The trifluoroacetic acid salt of compound 7 is prepared using compound 4-A as a raw material according to the synthesis method of Example 5.

¹ H NMR (400 MHz, CD3OD) δ 7.81 – 7.71 (m, 2H), 7.57 – 7.48 (m, 2H), 7.13 – 7.01 (m, 2H), 6.75 (d, 1H), 6.62 (d, 1H), 6.55 (dd, 1H), 4.80 – 4.74 (m, 1H), 4.26 (s, 1H), 4.24 – 4.16 (m, 1H), 4.13 (s, 1H), 3.93 (s, 3H), 3.67 – 3.50 (m, 2H), 3.50 – 3.15 (m, 9H), 3.01 – 2.91 (m, 1H), 2.91 – 2.63 (m, 5H), 2.35 – 2.07 (m, 5H), 1.94 – 1.84 (m, 2H), 1.84 – 1.67 (m, 5H), 1.26 (d, 12H).

LCMS m/z = 437.8 [M/2 +1] ⁺

The following compounds were obtained by referring to other examples of synthesis: Example No. Structure raw material LCMS / ^1H NMR Example 2 (Trifluoroacetic acid salt of compound 2) Intermediate 1+1a (see Example 1 for synthesis method) ¹ H NMR (400 MHz, CD ₃ OD) δ 7.79 – 7.73 (m, 2H), 7.52 (d, 1H), 7.08 – 6.99 (m, 2H), 6.91 (d, 1H), 6.71 (d, 1H), 6.62 (d, 1H), 6.55 (dd, 1H), 4.29 – 4.23 (m, 1H), 4.18 – 4.03 (m, 2H), 4.00 – 3.91 (m, 5H), 3.91 – 3.83 (m, 1H), 3.79 – 3.60 (m, 2H), 3.41 – 3.33 (m, 1H), 3.26 – 3.08 (m, 4H), 3.01 – 2.88 (m, 3H), 2.87 – 2.60 (m, 4H), 2.30 – 2.15 (m, 2H), 2.15 – 2.03 (m, 2H), 2.00 – 1.88 (m, 2H), 1.85 – 1.71 (m, 1H), 1.56 – 1.42 (m, 2H), 1.26 (d, 12H). LCMS m/z = 791.4 [M+1] ⁺ Example 2 (Compound 2) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.75 (s, 1H), 7.73 (d, 2H), 7.64 (d, 1H), 7.46 (d, 1H), 6.95 (d, 2H), 6.79 (d, 1H), 6.69 – 6.56 (m, 2H), 6.54 (dd, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.91 (s, 3H), 3.90 – 3.76 (m, 3H), 3.76 – 3.66 (m, 1H), 3.05 – 2.84 (m, 3H), 2.84 – 2.64 (m, 5H), 2.64 – 2.55 (m, 1H), 2.54 – 2.45 (m, 1H), 2.26 – 2.13 (m, 2H), 2.13 – 2.00 (m, 2H), 1.99 – 1.70 (m, 6H), 1.68 – 1.50 (m, 1H), 1.29 – 1.08 (m, 14H). Example 4 (Trifluoroacetic acid salt of compound 4) Intermediate 3+1a (see Example 3 for the synthesis method) ¹ H NMR (400 MHz, CD ₃ OD) δ 7.81 – 7.72 (m, 2H), 7.60 – 7.47 (m, 2H), 7.07 – 6.96 (m, 2H), 6.76 (d, 1H), 6.65 – 6.60 (m, 1H), 6.55 (dd, 1H), 4.87 – 4.72 (m, 1H), 4.31 – 4.10 (m, 3H), 4.02 – 3.88 (m, 5H), 3.83 – 3.63 (m, 2H), 3.60 – 3.42 (m, 1H), 3.34 – 3.10 (m, 4H), 3.07 – 2.62 (m, 7H), 2.35 – 2.06 (m, 4H), 2.02 – 1.88 (m, 2H), 1.85 – 1.72 (m, 1H), 1.57 – 1.40 (m, 2H), 1.35 – 1.15 (m, 12H). LCMS m/z = 834.4 [M+1] ⁺ Example 6 (Trifluoroacetic acid salt of compound 6) 5g+ (R)-3-aminopiperidine-2,6-dione hydrochloride (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, CD ₃ OD) δ 7.74 (d, 2H), 7.57 – 7.45 (m, 2H), 7.02 (d, 2H), 6.75 (d, 1H), 6.62 (d, 1H), 6.55 (dd, 1H), 4.80 – 4.73 (m, 1H), 4.32 – 4.23 (m, 1H), 4.23 – 4.16 (m, 1H), 4.13 (s, 1H), 3.93 (s, 3H), 3.69 – 3.49 (m, 2H), 3.48 – 3.30 (m, 5H), 3.28 – 3.05 (m, 4H), 3.02 – 2.89 (m, 1H), 2.88 – 2.65 (m, 5H), 2.35 – 2.05 (m, 5H), 1.89 – 1.82 (m, 2H), 1.82 – 1.65 (m, 5H), 1.26 (d, 12H). LCMS m/z = 437.8 [M/2 +1] ⁺ Example 8 (Trifluoroacetic acid salt of compound 8) 7a+ (R)-3-aminopiperidine-2,6-dione hydrochloride (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, CD ₃ OD) δ 7.79 – 7.71 (m, 2H), 7.57 – 7.48 (m, 2H), 7.10 – 6.99 (m, 2H), 6.75 (d, 1H), 6.62 (d, 1H), 6.55 (dd, 1H), 4.79 – 4.74 (m, 1H), 4.30 – 4.23 (m, 1H), 4.23 – 4.15 (m, 1H), 4.13 (s, 1H), 3.93 (s, 3H), 3.68 – 3.48 (m, 2H), 3.48 – 3.30 (m, 5H), 3.28 – 3.07 (m, 4H), 3.02 – 2.90 (m, 1H), 2.88 – 2.65 (m, 5H), 2.35 – 2.05 (m, 5H), 1.89 – 1.82 (m, 2H), 1.82 – 1.65 (m, 5H), 1.26 (d, 12H). LCMS m/z = 874.4 [M+1] ⁺ Example 9 (Trifluoroacetic acid salt of compound 9) 5f+Intermediate 1 (see Example 1 for the synthesis method) ¹ H NMR (400 MHz, CD ₃ OD) δ 7.80 – 7.69 (m, 2H), 7.52 (d, 1H), 7.10 – 6.99 (m, 2H), 6.90 (d, 1H), 6.70 (d, 1H), 6.63 (d, 1H), 6.56 (dd, 1H), 4.26 (s, 1H), 4.16 – 4.05 (m, 2H), 3.93 (s, 3H), 3.91 – 3.83 (m, 1H), 3.65 – 3.49 (m, 2H), 3.41 – 3.33 (m, 2H), 3.32 – 3.23 (m, 5H), 3.23 – 3.12 (m, 1H), 3.12 – 3.00 (m, 1H), 2.99 – 2.89 (m, 1H), 2.89 – 2.63 (m, 5H), 2.31 – 2.16 (m, 3H), 2.15 – 1.99 (m, 2H), 1.91 – 1.83 (m, 2H), 1.83 – 1.65 (m, 5H), 1.28 (s, 6H), 1.24 (s, 6H). LCMS m/z = 831.8 [M+1] ⁺ Example 10 (Trifluoroacetic acid salt of compound 10) 5f+Intermediate 2 (see Example 1 for synthesis method) ¹ H NMR (400 MHz, CD ₃ OD) δ 7.82 – 7.69 (m, 2H), 7.52 (d, 1H), 7.10 – 6.96 (m, 2H), 6.90 (d, 1H), 6.70 (d, 1H), 6.63 (d, 1H), 6.56 (dd, 1H), 4.26 (s, 1H), 4.16 – 4.03 (m, 2H), 3.93 (s, 3H), 3.91 – 3.82 (m, 1H), 3.65 – 3.49 (m, 2H), 3.41 – 3.33 (m, 2H), 3.33 – 3.23 (m, 5H), 3.23 – 3.12 (m, 1H), 3.12 – 3.00 (m, 1H), 2.99 – 2.89 (m, 1H), 2.89 – 2.63 (m, 5H), 2.34 – 2.16 (m, 3H), 2.15 – 1.97 (m, 2H), 1.92 – 1.83 (m, 2H), 1.83 – 1.65 (m, 5H), 1.28 (s, 6H), 1.24 (s, 6H). LCMS m/z = 831.6 [M+1] ⁺ Example 12 (Compound 12) 11a+ (R)-3-aminopiperidine-2,6-dione hydrochloride (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 (s, 1H), 7.94 (t, 1H), 7.74 (d, 2H), 7.64 (d, 1H), 7.47 (d, 1H), 7.36 (d, 1H), 6.95 (d, 2H), 6.74 – 6.61 (m, 2H), 6.54 (dd, 1H), 4.82 – 4.60 (m, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.95 – 3.79 (m, 6H), 3.17 – 3.04 (m, 1H), 2.97 – 2.87 (m, 2H), 2.87 – 2.62 LCMS m/z = 418.0 [M/2 +1] ⁺ Example 14 (Compound 14) 13a+(R)-3-aminopiperidine-2,6-dione hydrochloride (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 (s, 1H), 7.94 (t, 1H), 7.74 (d, 2H), 7.64 (d, 1H), 7.47 (d, 1H), 7.36 (d, 1H), 6.95 (d, 2H), 6.74 – 6.60 (m, 2H), 6.54 (dd, 1H), 4.83 – 4.59 (m, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.97 – 3.79 (m, 6H), 3.16 – 3.04 (m, 1H), 2.98 – 2.87 (m, 2H), 2.87 – 2.62 LCMS m/z = 418.0 [M/2 +1] ⁺

Example 11: Preparation of Compound 11

Compound 11 was prepared from trifluoroacetic acid salts of compounds 1a and 5A by the synthesis method of Example 5 and then freeze-dried in a neutral solution (aqueous solution of ammonium acetate (5 mmol/L)/acetonitrile).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 (s, 1H), 7.94 (t, 1H), 7.78 – 7.69 (m, 2H), 7.64 (d, 1H), 7.47 (d, 1H), 7.36 (d, 1H), 7.00 – 6.90 (m, 2H), 6.73 – 6.61 (m, 2H), 6.54 (dd, 1H), 4.78 – 4.65 (m, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.95 – 3.79 (m, 6H), 3.16 – 3.06 (m, 1H), 2.97 – 2.61 (m, 8H), 2.57 – 2.50 (m, 1H), 2.26 – 2.14 (m, 2H), 2.13 – 1.88 (m, 4H), 1.87 – 1.72 (m, 4H), 1.66 – 1.52 (m, 1H), 1.28 – 1.09 (m, 14H).

LCMS m/z = 418.0 [M/2 +1] ⁺

Example 13: Preparation of Compound 13

Compound 13 was prepared from compounds 1a and 7A by the synthesis method of Example 11, and then freeze-dried using a neutral preparation (aqueous solution of ammonium acetate (5 mmol/L)/acetonitrile).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 (s, 1H), 7.94 (t, 1H), 7.74 (d, 2H), 7.64 (d, 1H), 7.47 (d, 1H), 7.36 (d, 1H), 6.95 (d, 2H), 6.74 – 6.61 (m, 2H), 6.54 (dd, 1H), 4.82 – 4.60 (m, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.95 – 3.79 (m, 6H), 3.17 – 3.04 (m, 1H), 2.97 – 2.87 (m, 2H), 2.87 – 2.62 (m, 6H), 2.57 – 2.52 (m, 1H), 2.25 – 1.88 (m, 6H), 1.88 – 1.70 (m, 4H), 1.67 – 1.51 (m, 1H), 1.29 – 1.08 (m, 14H).

LCMS m/z = 418.0 [M/2 +1] ⁺

Example 15: Preparation of Compound 15

Step 1: Preparation of 15b

15a (1.28 g, 3.48 mmol) (synthesis method see Bioorg. Med. Chem. Lett. 2016 , 26 , 5877-5882), cesium carbonate (2.27 g, 6.97 mmol), sodium acetate (0.16 g, 0.71 mmol), XantPhos (0.20 g, 0.35 mmol) and 15A (0.89 g, 4.91 mmol) were added to 1,4-dioxane solution (40 mL) and reacted at 105°C for 3 h under nitrogen atmosphere. The reaction system was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (80 mL×3). The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-7:3) to obtain 15b (1.30 g, yield: 80%).

LCMS m/z = 468.4 [M+1] ⁺

Step 2: Preparation of 15c

15b (1.30 g, 2.78 mmol) was added to methanol (10 mL), and 10% palladium on carbon (1.33 g) and ammonium acetate (1.32 g, 17.13 mmol) were added, and the mixture was reacted at room temperature for 12 h under a hydrogen balloon atmosphere. The reaction system was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-1:1) to obtain 15c (0.76 g, yield: 90%).

LCMS m/z = 304.4 [M+1] ⁺

Step 3: 15d preparation

15c (0.76 g, 2.55 mmol), 15B (0.75 g, 7.49 mmol) and DIPEA (0.97 g, 7.50 mmol) were added to ethanol (50 mL) in sequence and reacted at 100°C for 48 h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column (methanol/dichloromethane (v/v) = 0:1-6:94) to obtain 15d (0.70 g, yield: 68%).

LCMS m/z = 404.2 [M+1] ⁺

Step 4: Preparation of 15e

15d (700 mg, 1.74 mmol) and DIPEA (671 mg, 5.19 mmol) were added to THF (20 mL), triphosgene (565 mg, 1.90 mmol) was slowly added, and the reaction was carried out at room temperature for 1 h. Aqueous ammonia (5 mL) was added to the reaction system, and the reaction was carried out at 50°C for 2 h. The reaction system was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×2). The organic phase was concentrated under reduced pressure, and the crude product was separated and purified by silica gel chromatography (methanol/dichloromethane (v/v) = 0:1-1:9) to obtain 15e (700 mg, yield: 90%).

Step 5: Preparation of 15f

15e (0.70 g, 1.57 mmol) was added to acetonitrile (30 mL), and 40% benzyltrimethylammonium hydroxide methanol solution (2 mL) was added, and the reaction was carried out at 60°C for 2 h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column (methanol/dichloromethane (v/v) = 0:1-8:92) to obtain 15f (530 mg, yield: 84%).

LCMS m/z = 401.4 [M+1] ⁺

Step 6: Preparation of compound 15

15f (0.15 g, 0.37 mmol), 2 mL of trifluoroacetic acid and 3 mL of dichloromethane were added to the reaction bottle and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, triethylamine was added to adjust the pH to 7, the solution was concentrated under reduced pressure, the residue was dissolved with 5 mL of DMA, 1a (0.23 g, 0.47 mmol), 0.5 mL of acetic acid and sodium triacetoxyborohydride (0.24 g, 1.13 mmol) were added in sequence and reacted at room temperature for 16 h. Add 10 mL of methanol to the reaction solution, reduce the pressure and concentrate, and pass the reaction solution through Pre-HPLC (Instrument and preparative column: Waters 2767 preparative liquid phase, preparative column model is SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product is filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: aqueous solution of ammonium acetate (5 mmol/L)/acetonitrile. Gradient extraction method: Acetonitrile is gradiently extracted from 10% to 70% (extraction time 12 min), and freeze-dried to obtain compound 15 (0.20 g, yield: 70%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.21 (s, 1H), 7.74 (d, 2H), 7.64 (d, 1H), 7.47 (d, 1H), 6.99 – 6.91 (m, 3H), 6.91 – 6.85 (m, 1H), 6.85 – 6.77 (m, 1H), 6.64 (d, 1H), 6.54 (dd, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.97 – 3.81 (m, 5H), 3.80 – 3.72 (m, 1H), 3.70 – 3.61 (m, 2H), 2.99 – 2.73 (m, 6H), 2.73 – 2.57 (m, 4H), 2.24 – 2.13 (m, 2H), 2.13 – 2.02 (m, 1H), 1.93 – 1.72 (m, 5H), 1.69 – 1.54 (m, 1H), 1.29 – 1.10 (m, 14H).

LCMS m/z = 774.6 [M+1] ⁺ .

Example 16: Preparation of trifluoroacetic acid salt of compound 16

Step 1: Preparation of 16b trifluoroacetate

Dissolve 16a (2.77 g, 11.48 mmol) in 5 mL of dichloromethane, add 5 mL of trifluoroacetic acid, and react at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of crude 16b (3.0 g).

Step 2: Preparation of 16c

The trifluoroacetic acid salt of the crude product 16b (3.0 g), ethyl 4-fluorobenzoate (1.85 g, 11.00 mmol), potassium carbonate (3.04 g, 22.00 mmol) and 15 mL of dimethyl sulfoxide were added to the reaction flask and reacted at 100°C for 16 h. The reaction system was cooled to room temperature, 100 mL of water and 100 mL of ethyl acetate were added to the reaction solution, the liquid was separated, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-1:1) to obtain 16c (2.5 g, yield: 79%).

Step 3: Preparation of 16d

16c (2.4 g, 8.29 mmol), potassium hydroxide (1.86 g, 33.21 mmol), 10 mL ethanol, 10 mL tetrahydrofuran and 10 mL water were added to the reaction bottle and reacted at room temperature for 16 h. The reaction system was concentrated under reduced pressure, the pH was adjusted to 2 with 2 mol/L hydrochloric acid, filtered, the filter cake was collected, and the filter cake was dried under reduced pressure to obtain crude product 16d (1.80 g).

LCMS m/z = 262.1 [M+1] ⁺

Step 4: Preparation of 16e

The crude product 16d (0.68 g), HATU (0.99 g, 2.60 mmol), diisopropylethylamine (1.41 g, 10.91 mmol) and 10 mL DMF were added to a reaction flask, stirred at room temperature for 0.5 h, and then trans-4-(3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-methoxybenzonitrile hydrochloride (0.57 g, 1.83 mmol) (synthesis method see CN115175901) was added and reacted at room temperature for 2 h. 100 mL of water and 100 mL of ethyl acetate were added to the reaction solution, and the liquids were separated. The aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-0:1) to obtain 16e (1.10 g, two-step yield based on compound 16c: 68%).

LCMS m/z = 518.5 [M+1] ⁺

Step 5: Preparation of 16f

16e (1.10 g, 2.13 mmol), Dess-Martin oxidant (1.08 g, 2.55 mmol) and 10 mL of dichloromethane were added to the reaction flask and reacted at room temperature for 4 h. The reaction system was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (methanol/dichloromethane (v/v) = 0:1-1:9) to obtain 16f (0.9 g, yield: 82%).

LCMS m/z = 516.2 [M+1] ⁺

Step 6: Preparation of 16g

16f (0.25 g, 0.485 mmol), the trifluoroacetate of the crude product 5A (0.18 g), 0.2 mL of glacial acetic acid and 3 mL of DMAc were added to the reaction flask respectively. After reacting at room temperature for 1 h, sodium triacetoxyborohydride (0.30 g, 1.42 mmol) was added and the reaction was continued at room temperature for 16 h. Add 20 mL of water and 20 mL of ethyl acetate to the reaction solution, separate the layers, extract the aqueous phase with ethyl acetate (20 mL×3), combine the organic phases, wash the organic phases with 50 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Separate and purify the crude product by silica gel column chromatography (methanol/dichloromethane (v/v) = 0:1-1:9) to obtain 16 g (0.25 g, yield: 69%).

LCMS m/z = 750.4 [M+1] ⁺

Step 7: Preparation of trifluoroacetic acid salt of compound 16

16 g (0.2 g, 0.27 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (0.069 g, 0.42 mmol), EDCI (0.13 g, 0.68 mmol), HOBt (0.073 g, 0.54 mmol), N-methylmorpholine (0.17 g, 1.68 mmol) and 4 mL DMF were added to the reaction bottle and reacted at room temperature for 16 h. The reaction solution was subjected to Pre-HPLC (instrument and preparation column: Waters 2767 was used for preparation of liquid phase, the preparation column model was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA)/acetonitrile. Gradient extraction method: acetonitrile was gradiently extracted from 10% to 50% (extraction time 15 min), and the trifluoroacetic acid salt of compound 16 (50 mg) was obtained by freeze-drying.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.79 – 7.69 (m, 2H), 7.59 – 7.47 (m, 2H), 7.07 – 6.98 (m, 2H), 6.76 (d, 1H), 6.62 (d, 1H), 6.55 (dd, 1H), 4.79 – 4.74 (m, 1H), 4.29 – 4.18 (m, 2H), 4.13 (s, 1H), 3.93 (s, 3H), 3.86 – 3.72 (m, 1H), 3.67 – 3.54 (m, 2H), 3.51 – 3.40 (m, 1H), 3.40 – 3.30 (m, 4H), 3.26 – 3.15 (m, 1H), 3.08 – 2.94 (m, 1H), 2.89 – 2.74 (m, 4H), 2.74 – 2.65 (m, 1H), 2.47 – 2.37 (m, 2H), 2.35 – 2.25 (m, 1H), 2.21 – 2.05 (m, 4H), 1.87 – 1.70 (m, 5H), 1.26 (d, 12H).

LCMS m/z = 431.0 [M/2 +1] ⁺

The following compounds were obtained by referring to other examples of synthesis: Example No. Structure raw material LCMS / ^1H NMR Example 17 (Trifluoroacetic acid salt of compound 17) 16g+(R)-3-aminopiperidine-2,6-dione hydrochloride (see Example 16 for the synthesis method) ¹ H NMR (400 MHz, CD ₃ OD) δ 7.78 – 7.69 (m, 2H), 7.59 – 7.47 (m, 2H), 7.06 – 6.98 (m, 2H), 6.76 (d, 1H), 6.64 – 6.60 (m, 1H), 6.55 (dd, 1H), 4.79 – 4.73 (m, 1H), 4.29 – 4.16 (m, 2H), 4.13 (s, 1H), 3.93 (s, 3H), 3.87 – 3.72 (m, 1H), 3.68 – 3.54 (m, 2H), 3.51 – 3.40 (m, 1H), 3.40 – 3.30 (m, 4H), 3.25 – 3.15 (m, 1H), 3.08 – 2.94 (m, 1H), 2.89 – 2.74 (m, 4H), 2.74 – 2.65 (m, 1H), 2.46 – 2.37 (m, 2H), 2.35 – 2.25 (m, 1H), 2.22 – 2.05 (m, 4H), 1.87 – 1.70 (m, 5H), 1.26 (d, 12H). LCMS m/z = 431.0 [M/2 +1] ⁺ Example 19 (Trifluoroacetic acid salt of compound 19) 18a+ (R)-3-aminopiperidine-2,6-dione hydrochloride (see Example 16 for the synthesis method) ¹ H NMR (400 MHz, CD ₃ OD) δ 7.78 – 7.69 (m, 2H), 7.59 – 7.47 (m, 2H), 7.07 – 6.98 (m, 2H), 6.76 (d, 1H), 6.62 (d, 1H), 6.55 (dd, 1H), 4.79 – 4.73 (m, 1H), 4.31 – 4.18 (m, 2H), 4.13 (s, 1H), 3.93 (s, 3H), 3.86 – 3.71 (m, 1H), 3.67 – 3.54 (m, 2H), 3.52 – 3.40 (m, 1H), 3.40 – 3.30 (m, 4H), 3.26 – 3.15 (m, 1H), 3.08 – 2.94 (m, 1H), 2.89 – 2.74 (m, 4H), 2.74 – 2.65 (m, 1H), 2.48 – 2.36 (m, 2H), 2.35 – 2.24 (m, 1H), 2.21 – 2.05 (m, 4H), 1.88 – 1.70 (m, 5H), 1.26 (d, 12H). LCMS m/z = 430.9 [M/2 +1] ⁺

Example 18: Preparation of trifluoroacetic acid salt of compound 18

The trifluoroacetic acid salt of compound 18 was prepared using compounds 16f and 7A as raw materials according to the synthesis method of Example 16.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.77 – 7.69 (m, 2H), 7.59 – 7.47 (m, 2H), 7.05 – 6.98 (m, 2H), 6.76 (d, 1H), 6.66 – 6.60 (m, 1H), 6.55 (dd, 1H), 4.79 – 4.74 (m, 1H), 4.28 – 4.18 (m, 2H), 4.13 (s, 1H), 3.93 (s, 3H), 3.86 – 3.72 (m, 1H), 3.67 – 3.54 (m, 2H), 3.51 – 3.40 (m, 1H), 3.40 – 3.31 (m, 4H), 3.27 – 3.15 (m, 1H), 3.10 – 2.94 (m, 1H), 2.89 – 2.74 (m, 4H), 2.74 – 2.63 (m, 1H), 2.48 – 2.37 (m, 2H), 2.36 – 2.25 (m, 1H), 2.21 – 2.05 (m, 4H), 1.88 – 1.70 (m, 5H), 1.26 (d, 12H).

LCMS m/z = 860.4 [M+1] ⁺

Example 20: Preparation of Trifluoroacetic Acid Salt of Compound 20

Step 1: Preparation of 20b

Trans-4-(3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-methoxybenzonitrile hydrochloride (3.93 g, 12.64 mmol) (synthesis method see CN115175901) was dissolved in 30 mL DMF, and DIPEA (5.84 g, 45.18 mmol), HATU (5.16 g, 13.57 mmol) and 20a (2.0 g, 9.04 mmol) were added. The reaction was carried out at room temperature under nitrogen atmosphere for 16 h. 50 mL of ethyl acetate and 50 mL of purified water were added to the reaction solution, the aqueous phase was extracted with ethyl acetate (25 mL×2), the organic phases were combined, washed with 25 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (v/v) = 1:2) to obtain 20b (4.0 g, yield: 93%).

LCMS m/z = 478.3 [M+1] ⁺

Step 2: Preparation of 20c

20b (4.0 g, 8.38 mmol) was dissolved in 80 mL of dichloromethane, and Desmartin oxidant (4.27 g, 10.07 mmol) was added and refluxed for 3 h. The reaction system was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (v/v) = 1:2) to obtain 20c (2.5 g, yield: 63%).

LCMS m/z = 476.2 [M+1] ⁺

Step 3: Preparation of trifluoroacetate salt of compound 20

1-E (0.3 g, 0.72 mmol), 1 mL trifluoroacetic acid and 3 mL dichloromethane were added to the reaction bottle and reacted at room temperature for 3 h. The reaction solution was concentrated under reduced pressure, triethylamine was added to adjust the pH to 7, the solution was concentrated under reduced pressure, 5 mL N,N-dimethylacetamide was added to the residue, and 20c (0.34 g, 0.72 mmol), 0.3 mL acetic acid and sodium triacetoxyborohydride (0.31 g, 1.46 mmol) were added in sequence and reacted at room temperature for 16 h. Add 15 mL of dichloromethane and 15 mL of saturated sodium bicarbonate aqueous solution to the reaction solution, extract the aqueous phase with dichloromethane (15 mL×3), combine the organic phases, wash the organic phases with 15 mL of saturated salt water, dry over anhydrous sodium sulfate, concentrate under reduced pressure, separate and purify the crude product with a silica gel column (dichloromethane: methanol (v/v) = 10:1), and pass the obtained crude product through Pre-HPLC (Instrument and preparation column: Waters 2767 preparation liquid phase, preparation column model is SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm×250 mm). Preparation method: The DMSO solution of the crude product is filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA)/acetonitrile. Gradient extraction method: acetonitrile was gradiently extracted from 10% to 50% (extraction time 15 min), and the trifluoroacetic acid salt of compound 20 (50 mg) was obtained by freeze-drying.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.75 (s, 1H), 7.74 (d, 2H), 7.64 (d, 1H), 7.48 (d, 1H), 6.97 (d, 2H), 6.78 (d, 1H), 6.66 – 6.57 (m, 2H), 6.54 (dd, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.97 – 3.85 (m, 5H), 3.81 (dd, 1H), 3.77 – 3.68 (m, 1H), 3.02 – 2.86 (m, 3H), 2.86 – 2.75 (m, 2H), 2.75 – 2.55 (m, 4H), 2.50 – 2.39 (m, 2H), 2.35 – 2.22 (m, 1H), 2.18 – 2.04 (m, 1H), 2.03 – 1.80 (m, 5H), 1.67 – 1.43 (m, 3H), 1.19 (d, 12H).

LCMS m/z = 389.4 [M/2+1] ⁺

Example 21: Preparation of trifluoroacetic acid salt of compound 21

The trifluoroacetic acid salt of compound 21 was obtained using compound 20c and 2-D as raw materials according to the synthetic method of Example 20.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.76 (s, 1H), 7.79 – 7.70 (m, 2H), 7.64 (d, 1H), 7.48 (d, 1H), 7.01 – 6.91 (m, 2H), 6.78 (d, 1H), 6.67 – 6.49 (m, 3H), 4.27 (s, 1H), 4.05 (d, 1H), 3.97 – 3.85 (m, 5H), 3.81 (dd, 1H), 3.78 – 3.68 (m, 1H), 3.01 – 2.86 (m, 3H), 2.86 – 2.75 (m, 2H), 2.75 – 2.54 (m, 4H), 2.50 – 2.39 (m, 2H), 2.36 – 2.22 (m, 1H), 2.18 – 2.04 (m, 1H), 2.03 – 1.80 (m, 5H), 1.67 – 1.43 (m, 3H), 1.19 (d, 12H).

LCMS m/z = 777.4 [M+1] ⁺

Example 22: Preparation of trifluoroacetic acid salt of compound 22

Step 1: Preparation of 22a

3-A (0.5 g, 1.43 mmol), 2 mL of trifluoroacetic acid and 6 mL of dichloromethane were added to the reaction bottle and reacted at room temperature for 3 h. The reaction solution was concentrated under reduced pressure, and 5 mL of N,N-dimethylacetamide was added to the residue, followed by 20c (0.68 g, 1.43 mmol), 0.3 mL of acetic acid and sodium triacetoxyborohydride (0.61 g, 2.88 mmol) and reacted at room temperature for 16 h. 15 mL of dichloromethane and 15 mL of saturated sodium bicarbonate aqueous solution were added to the reaction solution, the aqueous phase was extracted with dichloromethane (15 mL×3), the organic phases were combined, washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel chromatography (dichloromethane: methanol (v/v) = 10:1) to obtain 22a (0.4 g, yield: 39%).

LCMS m/z = 710.3 [M+1] ⁺

Step 2: Preparation of trifluoroacetate salt of compound 22

To the reaction flask were added 22a (0.2 g, 0.28 mmol), EDCI (0.11 g, 0.57 mmol), HOBt (0.038 g, 0.28 mmol) and N-methylmorpholine (0.14 g, 1.38 mmol), and (S)-3-aminopiperidine-2,6-dione hydrochloride (0.092 g, 0.56 mmol) was added under nitrogen protection. The reaction was carried out at room temperature for 16 h under nitrogen atmosphere. Add 15 mL of dichloromethane and 15 mL of purified water to the reaction solution, extract the aqueous phase with dichloromethane (15 mL×3), combine the organic phases, dry the organic phases with anhydrous sodium sulfate, reduce the pressure and concentrate, and pass the crude product through Pre-HPLC (Instrument and preparation column: Waters 2767 preparation liquid phase, preparation column model is SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product is filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA)/acetonitrile. Gradient extraction method: acetonitrile was gradiently extracted from 10% to 50% (extraction time 15 min), and the product was lyophilized to obtain the trifluoroacetate salt of compound 22 (50 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 (s, 1H), 7.93 (t, 1H), 7.74 (d, 2H), 7.64 (d, 1H), 7.48 (d, 1H), 7.35 (d, 1H), 6.97 (d, 2H), 6.71 – 6.62 (m, 2H), 6.54 (dd, 1H), 4.78 – 4.61 (m, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.98 – 3.78 (m, 6H), 3.13 – 3.02 (m, 1H), 3.02 – 2.91 (m, 2H), 2.87 – 2.62 (m, 6H), 2.57 – 2.41 (m, 2H), 2.36 – 2.21 (m, 1H), 2.17 – 1.80 (m, 6H), 1.66 – 1.44 (m, 3H), 1.19 (d, 12H).

LCMS m/z = 820.4 [M+1] ⁺

The following compounds were obtained by referring to other examples of synthesis: Example No. Structure raw material LCMS / ^1H NMR Example 23 (Trifluoroacetic acid salt of compound 23) 22a+ (R)-3-aminopiperidine-2,6-dione hydrochloride (see Example 22 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 (s, 1H), 7.98 – 7.89 (m, 1H), 7.78 – 7.70 (m, 2H), 7.68 – 7.61 (m, 1H), 7.49 (d, 1H), 7.35 (d, 1H), 6.97 (d, 2H), 6.72 – 6.61 (m, 2H), 6.54 (dd, 1H), 4.79 – 4.61 (m, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.98 – 3.80 (m, 6H), 3.14 – 3.02 (m, 1H), 3.02 – 2.90 (m, 2H), 2.87 – 2.61 (m, 6H), 2.57 – 2.42 (m, 2H), 2.36 – 2.21 (m, 1H), 2.17 – 1.81 (m, 6H), 1.66 – 1.44 (m, 3H), 1.19 (d, 12H). LCMS m/z = 820.4 [M+1] ⁺ Example 25 (Trifluoroacetic acid salt of compound 25) 24a+(R)-3-aminopiperidine-2,6-dione hydrochloride (see Example 22 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 (s, 1H), 7.98 – 7.86 (m, 1H), 7.77 – 7.70 (m, 2H), 7.69 – 7.61 (m, 1H), 7.49 (d, 1H), 7.35 (d, 1H), 6.97 (d, 2H), 6.73 – 6.61 (m, 2H), 6.54 (dd, 1H), 4.79 – 4.61 (m, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.98 – 3.80 (m, 6H), 3.14 – 3.03 (m, 1H), 3.02 – 2.91 (m, 2H), 2.87 – 2.61 (m, 6H), 2.58 – 2.42 (m, 2H), 2.36 – 2.21 (m, 1H), 2.17 – 1.81 (m, 6H), 1.66 – 1.43 (m, 3H), 1.19 (d, 12H). LCMS m/z = 820.4 [M+1] ⁺

Example 24: Preparation of trifluoroacetic acid salt of compound 24

The trifluoroacetic acid salt of compound 24 was prepared from compound 20c and 4-A according to the synthesis method of Example 22.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 (s, 1H), 7.98 – 7.88 (m, 1H), 7.78 – 7.70 (m, 2H), 7.68 – 7.61 (m, 1H), 7.49 (d, 1H), 7.35 (d, 1H), 6.97 (d, 2H), 6.73 – 6.61 (m, 2H), 6.54 (dd, 1H), 4.79 – 4.61 (m, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.98 – 3.81 (m, 6H), 3.14 – 3.03 (m, 1H), 3.02 – 2.90 (m, 2H), 2.87 – 2.61 (m, 6H), 2.58 – 2.42 (m, 2H), 2.36 – 2.22 (m, 1H), 2.17 – 1.81 (m, 6H), 1.66 – 1.43 (m, 3H), 1.19 (d, 12H).

LCMS m/z = 820.4 [M+1] ⁺

Example 26: Preparation of Compound 26

Step 1: Preparation of 26b

The hydrochloride of 26a (5.0 g, 29.48 mmol), ethyl 4-fluorobenzoate (4.96 g, 29.50 mmol), potassium carbonate (10.19 g, 73.7 mmol) and 50 mL of dimethyl sulfoxide were added to the reaction bottle and reacted at 100 °C for 16 h. The reaction system was cooled to room temperature, 100 mL of water and 100 mL of ethyl acetate were added to the reaction solution, the liquid was separated, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-1:1) to obtain 26b (5.0 g, yield: 60%).

Step 2: Preparation of 26c

26b (5.0 g, 17.77 mmol), potassium hydroxide (4 g, 71.43 mmol), 50 mL ethanol, 50 mL tetrahydrofuran and 50 mL water were added to the reaction bottle and reacted at room temperature for 16 h. The reaction system was concentrated under reduced pressure, the pH was adjusted to 2 with 2 mol/L hydrochloric acid, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with 50 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 26c (3.0 g).

LCMS m/z = 254.1 [M+1] ⁺

Step 3: Preparation of 26d

The crude product 26c (0.82 g), HATU (2.46 g, 6.47 mmol), diisopropylethylamine (2.09 g, 16.17 mmol) and 10 mL DMF were added to a reaction flask, stirred at room temperature for 0.5 h, and then trans-4-(3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-methoxybenzonitrile hydrochloride (1.0 g, 3.22 mmol) (synthesis method see CN115175901) was added and reacted at room temperature for 2 h. 100 mL of water and 100 mL of ethyl acetate were added to the reaction solution, and the liquids were separated. The aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-0:1) to obtain 26d (1.5 g, yield: 91%).

LCMS m/z = 510.3 [M+1] ⁺

Step 4: Preparation of 26e

26d (0.9 g, 1.77 mmol), Dess-Martin oxidant (0.9 g, 2.12 mmol) and 10 mL of dichloromethane were added to the reaction bottle and reacted at room temperature for 4 h. The reaction solution was washed with 10 mL of saturated sodium bicarbonate aqueous solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 26e (0.9 g).

Step 5: Preparation of compound 26

The crude product 26e (0.25 g), the crude intermediate 1 (0.2 g), 0.2 mL of glacial acetic acid and 3 mL of DMAc were added to the reaction bottle, and the reaction was carried out at room temperature for 1 h. Then, sodium triacetoxyborohydride (0.31 g, 1.46 mmol) was added and the reaction was carried out at room temperature for 16 h. The reaction solution was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid phase was used, and the preparative column model was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 10 mmol/L ammonium bicarbonate)/acetonitrile. Gradient extraction method: acetonitrile was gradiently extracted from 10% to 50% (extraction time 15 min), and the product was freeze-dried to obtain compound 26 (91 mg, two-step yield based on compound 26d: 23%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.75 (s, 1H), 7.75 (d, 2H), 7.64 (d, 1H), 7.48 (d, 1H), 7.00 (d, 2H), 6.79 (d, 1H), 6.67 – 6.58 (m, 2H), 6.54 (dd, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.91 (s, 3H), 3.85 – 3.77 (m, 1H), 3.75 – 3.59 (m, 3H), 3.19 – 3.07 (m, 2H), 3.04 – 2.89 (m, 3H), 2.80 – 2.64 (m, 3H), 2.63 – 2.52 (m, 4H), 2.31 – 2.21 (m, 1H), 2.18 – 2.05 (m, 1H), 2.04 – 1.88 (m, 4H), 1.88 – 1.68 (m, 3H), 1.64 – 1.51 (m, 1H), 1.18 (d, 12H).

LCMS m/z = 809.4 [M+1] ⁺

Example 28: Preparation of Compound 28

Compound 28 was prepared from compounds 1-C and 15A by the synthesis method of Example 15 and then freeze-dried in a neutral solution (aqueous solution of ammonium bicarbonate (10 mmol/L)/acetonitrile).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.33 (s, 1H), 7.74 (d, 2H), 7.64 (d, 1H), 7.47 (d, 1H), 7.00 – 6.90 (m, 3H), 6.72 (d, 1H), 6.64 (d, 1H), 6.54 (dd, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.91 (s, 3H), 3.89 – 3.81 (m, 2H), 3.79 – 3.71 (m, 1H), 3.60 (t, 2H), 3.04 – 2.95 (m, 1H), 2.94 – 2.85 (m, 2H), 2.84 – 2.57 (m, 7H), 2.19 (d, 2H), 2.11 – 2.00 (m, 1H), 1.94 – 1.85 (m, 1H), 1.85 – 1.71 (m, 4H), 1.67 – 1.54 (m, 1H), 1.28 – 1.10 (m, 14H).

LCMS m/z = 792.6 [M+1] ⁺

Example 29: Preparation of Compound 29

Compound 29 was prepared from compounds 2-B and 15A by the synthesis method of Example 15 and then freeze-dried in a neutral solution (aqueous solution of ammonium bicarbonate (10 mmol/L)/acetonitrile).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.33 (s, 1H), 7.77 – 7.70 (m, 2H), 7.64 (d, 1H), 7.47 (d, 1H), 7.00 – 6.91 (m, 3H), 6.76 – 6.68 (m, 1H), 6.64 (d, 1H), 6.54 (dd, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.91 (s, 3H), 3.91 – 3.81 (m, 2H), 3.79 – 3.71 (m, 1H), 3.60 (t, 2H), 3.06 – 2.94 (m, 1H), 2.94 – 2.85 (m, 2H), 2.84 – 2.55 (m, 7H), 2.19 (d, 2H), 2.11 – 2.00 (m, 1H), 1.94 – 1.85 (m, 1H), 1.85 – 1.71 (m, 4H), 1.67 – 1.53 (m, 1H), 1.29 – 1.11 (m, 14H).

Example 30: Preparation of Compound 30

Step 1: Preparation of 30b trifluoroacetate

Dissolve 30a (2.00 g, 5.06 mmol) (synthesis method, see US2023135173) in 20 mL of dichloromethane, add 10 mL of trifluoroacetic acid, and react at room temperature for 3 h. The reaction system was reduced pressure and concentrated to obtain the trifluoroacetic acid salt of crude 30b (3.00 g).

LCMS m/z = 296.2 [M+1] ⁺

Step 2: Preparation of 30c

30A (1.43 g, 6.07 mmol) (synthesis method, see CN115974840), HATU (2.87 g, 7.56 mmol), diisopropylethylamine (1.96 g, 15.18 mmol) and 10 mL DMF were added to the reaction flask, stirred at room temperature for 0.5 h, and then the trifluoroacetic acid salt (3.00 g) of the crude product 30b was added and stirred at room temperature for 2 h. 100 mL of water was added to the reaction solution, filtered, and the filter cake was collected and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-0:1) to obtain 30c (1.50 g, yield: 58%).

LCMS m/z = 513.2 [M+1] ⁺

Step 3: 30d preparation

30c (1.50 g, 2.93 mmol), Dess-Martin oxidant (2.49 g, 5.86 mmol) and 20 mL of dichloromethane were added to the reaction bottle and reacted at room temperature for 30 min. The reaction system was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to obtain crude product 30d (2.00 g).

LCMS m/z = 511.3 [M+1] ⁺

Step 4: Preparation of compound 30

The crude product 30d (0.20 g), the crude intermediate 1 (0.15 g), 0.2 mL of glacial acetic acid and 5 mL of DMAc were added to the reaction flask, and the reaction was carried out at room temperature for 1 h. Then, sodium triacetoxyborohydride (0.25 g, 1.17 mmol) was added and the reaction was carried out at room temperature for 16 h. The reaction solution was subjected to Pre-HPLC (instrument and preparation column: SHIMADZU LC-20AP was used for preparation of liquid phase, the preparation column model was C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMF solution of the crude product was filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 10 mmol/L ammonium bicarbonate)/acetonitrile. Gradient extraction method: acetonitrile was gradiently extracted from 52% to 82% (extraction time 15 min), and the product was freeze-dried to obtain compound 30 (16.2 mg, two-step yield based on compound 30c: 7%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.76 (s, 1H), 9.13 – 9.08 (m, 1H), 8.74 (dd, 1H), 8.30 (d, 1H), 7.80 – 7.69 (m, 3H), 7.52 (d, 1H), 6.96 (d, 3H), 6.79 (d, 1H), 6.62 (d, 1H), 4.49 (s, 1H), 4.15 (d, 1H), 3.90 – 3.76 (m, 3H), 3.76 – 3.66 (m, 1H), 3.00 – 2.84 (m, 3H), 2.84 – 2.64 (m, 5H), 2.64 – 2.54 (m, 1H), 2.54 – 2.45 (m, 1H), 2.25 – 1.99 (m, 4H), 1.99 – 1.68 (m, 6H), 1.66 – 1.51 (m, 1H), 1.35 – 1.11 (m, 14H).

LCMS m/z = 812.4 [M+1] ⁺

The following compounds were obtained by referring to other examples of synthesis: Example No. Structure raw material LCMS / ^1H NMR Example 27 (Compound 27) 26e+Intermediate 2 (see Example 26 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.75 (s, 1H), 7.79 – 7.71 (m, 2H), 7.64 (d, 1H), 7.48 (d, 1H), 7.05 – 6.95 (m, 2H), 6.79 (d, 1H), 6.67 – 6.58 (m, 2H), 6.54 (dd, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.91 (s, 3H), 3.85 – 3.77 (m, 1H), 3.75 – 3.58 (m, 3H), 3.19 – 3.06 (m, 2H), 3.04 – 2.88 (m, 3H), 2.80 – 2.64 (m, 3H), 2.63 – 2.51 (m, 4H), 2.31 – 2.21 (m, 1H), 2.18 – 2.05 (m, 1H), 2.04 – 1.88 (m, 4H), 1.88 – 1.68 (m, 3H), 1.64 – 1.50 (m, 1H), 1.18 (d, 12H). LCMS m/z = 809.4 [M+1] ⁺ Example 31 (Compound 31) 30d + intermediate 2 (see Example 30 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.75 (s, 1H), 9.10 (dd, 1H), 8.74 (dd, 1H), 8.30 (d, 1H), 7.80 – 7.70 (m, 3H), 7.52 (d, 1H), 6.96 (d, 3H), 6.79 (d, 1H), 6.62 (d, 1H), 4.49 (s, 1H), 4.16 (d, 1H), 3.90 – 3.76 (m, 3H), 3.76 – 3.66 (m, 1H), 3.02 – 2.84 (m, 3H), 2.84 – 2.65 (m, 5H), 2.64 – 2.54 LCMS m/z = 812.4 [M+1] ⁺ Example 32 (Compound 32) 30d+28f (see Example 28 for synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.33 (s, 1H), 9.10 (dd, 1H), 8.74 (dd, 1H), 8.30 (d, 1H), 7.81 – 7.70 (m, 3H), 7.53 (d, 1H), 7.02 – 6.88 (m, 4H), 6.72 (d, 1H), 4.49 (s, 1H), 4.16 (d, 1H), 3.92 – 3.82 (m, 2H), 3.80 – 3.71 (m, 1H), 3.60 (t, 2H), 3.04 – 2.95 (m, 1H), 2.95 – 2.86 (m, 2H), 2.85 – 2.56 (m, 7H), 2.26 – 2.13 (m, 2H), 2.11 – 2.00 (m, 1H), 1.94 – 1.86 (m, 1H), 1.85 – 1.72 (m, 4H), 1.67 – 1.54 (m, 1H), 1.32 – 1.16 (m, 14H). LCMS m/z = 813.3 [M+1] ⁺ Example 33 (Trifluoroacetic acid salt of compound 33) 30d+29f (see Example 28 for synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.37 (s, 1H), 9.15 – 9.04 (m, 1H), 8.80 – 8.70 (m, 1H), 8.30 (d, 1H), 7.83 – 7.70 (m, 3H), 7.55 (d, 1H), 7.06 – 6.85 (m, 5H), 4.50 (s, 1H), 4.19 – 4.09 (m, 2H), 3.95 – 3.87 (m, 2H), 3.69 – 3.57 (m, 4H), 3.43 – 3.32 (m, 1H), 3.17 – 3.00 (m, 4H), 2.93 – 2.79 LCMS m/z = 813.3 [M+1] ⁺ Example 34 (Compound 34) 30d+5A (see Example 5 for synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 (s, 1H), 9.10 (dd, 1H), 8.74 (dd, 1H), 8.30 (d, 1H), 7.93 (t, 1H), 7.80 – 7.66 (m, 3H), 7.52 (d, 1H), 7.36 (d, 1H), 7.02 – 6.88 (m, 3H), 6.68 (d, 1H), 4.78 – 4.65 (m, 1H), 4.49 (s, 1H), 4.16 (d, 1H), 3.94 – 3.76 (m, 3H), 3.19 – 3.04 (m, 1H), 2.96 – 2.87 (m, 2H), 2.87 – 2.61 (m, 6H), 2.57 – 2.48 (m, 1H), 2.23 – 2.13 (m, 2H), 2.13 – 1.97 (m, 3H), 1.97 – 1.88 (m, 1H), 1.88 – 1.70 (m, 4H), 1.67 – 1.52 (m, 1H), 1.41 – 1.08 (m, 14H). LCMS m/z = 855.4 [M+1] ⁺ Example 35 (Compound 35) 30d+7A (see Example 5 for synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.80 (s, 1H), 9.10 (dd, 1H), 8.74 (dd, 1H), 8.29 (d, 1H), 7.93 (t, 1H), 7.82 – 7.67 (m, 3H), 7.52 (d, 1H), 7.36 (d, 1H), 7.04 – 6.88 (m, 3H), 6.68 (d, 1H), 4.78 – 4.65 (m, 1H), 4.49 (s, 1H), 4.15 (d, 1H), 3.95 – 3.76 (m, 3H), 3.17 – 3.03 (m, 1H), 2.96 – 2.87 (m, 2H), 2.87 – 2.60 (m, 6H), 2.58 – 2.48 (m, 1H), 2.24 – 2.13 (m, 2H), 2.13 – 1.97 (m, 3H), 1.97 – 1.88 (m, 1H), 1.88 – 1.69 (m, 4H), 1.67 – 1.52 (m, 1H), 1.42 – 1.05 (m, 14H). LCMS m/z = 855.4 [M+1] ⁺

Example 36: Preparation of Compound 36

Step 1: Preparation of 36b

36a (10.00 g, 52.32 mmol) was dissolved in 100 mL DMF, potassium carbonate (14.46 g, 104.64 mmol) and deuterated iodomethane (9.10 g, 62.78 mmol) were added, and the reaction was carried out at room temperature for 19 h. The reaction solution was poured into 200 mL water and extracted with 100 mL ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) = 10:1-2:1) to obtain crude product 36b (11.5 g).

Step 2: Preparation of 36c

The crude product 36b (11.5 g) was dissolved in 100 mL NMP, and cuprous cyanide (11.30 g, 126.17 mmol) was added, and the mixture was reacted at 180°C for 19 h. The reaction solution was cooled to room temperature, 10 mL of concentrated aqueous ammonia and 200 mL of water were added, and the mixture was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) = 10:1-2:1) to obtain 36c (7.5 g, two-step yield based on compound 36a: 93%).

Step 3: Preparation of 36d

36h (8.37 g, 34.38 mmol) was dissolved in 50 mL THF, 60% sodium hydroxide (1.65 g) was added at 0°C, and the reaction was continued at 0°C for 30 min. Then, 36c (5.30 g, 34.38 mmol) was added and the reaction was continued at room temperature for 19 h. The reaction solution was poured into 100 mL water and extracted with 100 mL ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) = 10:1-2:1) to obtain 36d (2.5 g, yield: 19%).

LCMS m/z = 378.3 [M+1] ⁺

Step 4: Preparation of 36e hydrochloride

Dissolve 36d (2.5 g, 6.62 mmol) in 5 mL of ethyl acetate, add 10 mL of 4 mol/L hydrochloric acid ethyl acetate solution, and react at room temperature for 5 h. Filter the reaction system, collect the filter cake, and dry the filter cake under reduced pressure to obtain the hydrochloride salt of crude 36e (3.5 g).

LCMS m/z = 278.2 [M+1] ⁺

Step 5: Preparation of 36f

30A (1.35 g, 5.74 mmol) (synthesis method, see CN115974840), HATU (2.73 g, 7.17 mmol), diisopropylethylamine (1.85 g, 14.34 mmol) and 10 mL DMF were added to the reaction flask, stirred at room temperature for 0.5 h, and then the above crude product 36e hydrochloride (2.5 g) was added and stirred at room temperature for 2 h. 100 mL of water was added to the reaction solution, filtered, and the filter cake was collected and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-0:1) to obtain 36f (1.6 g, two-step yield based on compound 36d: 68%).

LCMS m/z = 495.3 [M+1] ⁺

Step 6: Preparation of 36g

Add 36f (99 mg, 0.20 mmol), Dess-Martin oxidant (0.17 g, 0.40 mmol) and 3 mL of dichloromethane to the reaction bottle and react at room temperature for 30 min. Add 10 mL of saturated sodium bicarbonate aqueous solution to the reaction system, extract with 30 mL of dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product 36g (110 mg).

Step 7: Preparation of compound 36

36 g (0.11 g) of the crude product, crude intermediate 1 (0.12 g), 0.1 mL of glacial acetic acid and 5 mL of DMAc were added to the reaction flask, and the reaction was carried out at room temperature for 1 h. Then, sodium triacetoxyborohydride (0.13 g, 0.6 mmol) was added and the reaction was carried out at room temperature for 16 h. The reaction solution was subjected to Pre-HPLC (instrument and preparation column: SHIMADZU LC-20AP was used for preparation of liquid phase, and the preparation column model was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 10 mmol/L NH ₄ HCO ₃ )/acetonitrile. Gradient extraction method: acetonitrile was gradiently extracted from 53% to 83% (extraction time 15 min), and the product was freeze-dried to obtain compound 36 (46 mg, two-step yield based on compound 36f: 29%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (s, 1H), 7.68 (d, 2H), 7.45 (d, 1H), 6.91 (d, 2H), 6.78 – 6.65 (m, 1H), 6.54 – 6.43 (m, 2H), 6.40 (dd, 1H), 6.10 (d, 1H), 4.15 (d, 1H), 4.04 (s, 1H), 3.93 – 3.71 (m, 3H), 3.68 – 3.50 (m, 1H), 3.16 – 2.99 (m, 1H), 2.99 – 2.71 (m, 7H), 2.71 – 2.55 (m, 2H), 2.35 – 2.07 (m, 5H), 2.02 – 1.61 (m, 6H), 1.39 – 1.17 (m, 14H).

LCMS m/z = 794.7 [M+1] ⁺

The following compounds were obtained by referring to other examples of synthesis: Example No. Structure raw material LCMS / ^1H NMR Example 37 (Compound 37) 36g + intermediate 2 (see Example 36 for synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.76 (s, 1H), 7.73 (d, 2H), 7.64 (d, 1H), 7.47 (d, 1H), 6.95 (d, 2H), 6.79 (d, 1H), 6.67 – 6.57 (m, 2H), 6.54 (dd, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.91 – 3.76 (m, 3H), 3.76 – 3.66 (m, 1H), 3.00 – 2.85 (m, 3H), 2.84 – 2.64 (m, 5H), 2.64 – 2.54 (m, 1H), 2.54 LCMS m/z = 794.7 [M+1] ⁺ Example 38 (Compound 38) 36g+28f (see Example 15 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.33 (s, 1H), 7.73 (d, 2H), 7.64 (d, 1H), 7.47 (d, 1H), 7.00 – 6.88 (m, 3H), 6.72 (d, 1H), 6.65 – 6.61 (m, 1H), 6.53 (dd, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.91 – 3.80 (m, 2H), 3.80 – 3.69 (m, 1H), 3.59 (t, 2H), 3.04 – 2.95 (m, 1H), 2.94 – 2.85 (m, 2H), 2.84 – 2.64 (m, 6H), 2.64 – 2.56 (m, 1H), 2.23 – 2.13 (m, 2H), 2.10 – 1.99 (m, 1H), 1.94 – 1.71 (m, 5H), 1.67 – 1.53 (m, 1H), 1.28 – 1.09 (m, 14H). LCMS m/z = 795.7 [M+1] ⁺ Example 39 (Compound 39) 36g+29f (see Example 15 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.33 (s, 1H), 7.78 – 7.69 (m, 2H), 7.64 (d, 1H), 7.47 (d, 1H), 7.00 – 6.88 (m, 3H), 6.72 (d, 1H), 6.66 – 6.60 (m, 1H), 6.54 (dd, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.91 – 3.80 (m, 2H), 3.79 – 3.70 (m, 1H), 3.59 (t, 2H), 3.04 – 2.95 (m, 1H), 2.94 – 2.85 (m, 2H), 2.84 – 2.56 (m, 7H), 2.24 – 2.12 (m, 2H), 2.10 – 1.98 (m, 1H), 1.94 – 1.85 (m, 1H), 1.85 – 1.70 (m, 4H), 1.67 – 1.52 (m, 1H), 1.29 – 1.10 (m, 14H). LCMS m/z = 795.7 [M+1] ⁺ Example 41 (Compound 41) 36g+7A (see Example 11 for synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 (s, 1H), 7.94 (t, 1H), 7.79 – 7.69 (m, 2H), 7.64 (d, 1H), 7.47 (d, 1H), 7.36 (d, 1H), 7.02 – 6.91 (m, 2H), 6.73 – 6.59 (m, 2H), 6.54 (dd, 1H), 4.79 – 4.65 (m, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.93 – 3.78 (m, 3H), 3.16 – 3.05 (m, 1H), 2.98 – 2.61 (m, 8H), 2.58 – 2.44 (m, 1H), 2.25 – 1.88 (m, 6H), 1.87 – 1.70 (m, 4H), 1.67 – 1.52 (m, 1H), 1.28 – 1.10 (m, 14H). LCMS m/z = 419.3 [M/2 +1] ⁺

Example 40: Preparation of Compound 40

Compound 40 was obtained using compound 36g and 5A trifluoroacetate as raw materials according to the synthetic method of Example 11.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 (s, 1H), 7.94 (t, 1H), 7.78 – 7.68 (m, 2H), 7.64 (d, 1H), 7.47 (d, 1H), 7.36 (d, 1H), 6.95 (d, 2H), 6.74 – 6.59 (m, 2H), 6.54 (dd, 1H), 4.79 – 4.65 (m, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.93 – 3.76 (m, 3H), 3.17 – 3.05 (m, 1H), 3.00 – 2.61 (m, 8H), 2.58 – 2.44 (m, 1H), 2.25 – 1.88 (m, 6H), 1.87 – 1.70 (m, 4H), 1.67 – 1.51 (m, 1H), 1.28 – 1.11 (m, 14H).

LCMS m/z = 419.3 [M/2 +1] ⁺

Example 42: Preparation of Compound 42

Compound 42 was obtained using the hydrochloride of compound 36e and 5d as raw materials according to the synthetic method of Example 36.

1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.72 (d, 2H), 7.64 (d, 1H), 7.47 (d, 1H), 6.95 (d, 2H), 6.78 (d, 1H), 6.65 – 6.57 (m, 2H), 6.56 – 6.50 (m, 1H), 4.26 (s, 1H), 4.04 (d, 1H), 3.81 (dd, 1H), 3.74 – 3.62 (m, 1H), 3.29 – 3.22 (m, 2H), 3.21 – 3.12 (m, 2H), 2.99 – 2.78 (m, 3H), 2.75 – 2.54 (m, 4H), 2.54 – 2.45 (m, 2H), 2.43 – 2.34 (m, 2H), 2.17 – 1.90 (m, 5H), 1.89 – 1.72 (m, 2H), 1.71 – 1.63 (m, 2H), 1.63 – 1.50 (m, 3H), 1.50 – 1.39 (m, 2H), 1.18 (d, 12H).

LCMS m/z = 834.7 [M+1] ⁺

The following compounds were obtained by referring to other examples of synthesis: Example No. Structure raw material LCMS / ^1H NMR Example 43 (Compound 43) 42b + intermediate 2 (see Example 36 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.75 (s, 1H), 7.72 (d, 2H), 7.64 (d, 1H), 7.47 (d, 1H), 6.95 (d, 2H), 6.78 (d, 1H), 6.66 – 6.56 (m, 2H), 6.56 – 6.50 (m, 1H), 4.26 (s, 1H), 4.04 (d, 1H), 3.85 – 3.75 (m, 1H), 3.74 – 3.62 (m, 1H), 3.30 – 3.21 (m, 2H), 3.21 – 3.11 (m, 2H), 2.99 – 2.76 (m, 3H), 2.75 – 2.54 (m, 4H), 2.54 – 2.45 (m, 2H), 2.44 – 2.34 (m, 2H), 2.18 – 1.90 (m, 5H), 1.89 – 1.72 (m, 2H), 1.71 – 1.63 (m, 2H), 1.63 – 1.50 (m, 3H), 1.50 – 1.39 (m, 2H), 1.18 (d, 12H). LCMS m/z = 834.7 [M+1] ⁺ Example 44 (Trifluoroacetic acid salt of compound 44) 42b+28f (see Example 15 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.36 (s, 1H), 7.79 – 7.69 (m, 2H), 7.64 (d, 1H), 7.52 – 7.44 (m, 1H), 7.05 – 6.93 (m, 3H), 6.88 (d, 1H), 6.63 (d, 1H), 6.53 (dd, 1H), 4.27 (s, 1H), 4.15 – 4.08 (m, 1H), 4.07 – 4.03 (m, 1H), 3.60 (t, 2H), 3.56 – 3.44 (m, 2H), 3.35 – 3.15 (m, 7H), 3.14 – 3.00 (m, 2H), 2.91 – 2.81 (m, 1H), 2.80 – 2.61 (m, 5H), 2.14 – 1.95 (m, 3H), 1.76 – 1.52 (m, 7H), 1.18 (d, 12H). LCMS m/z = 835.7 [M+1] ⁺ Example 45 (Trifluoroacetic acid salt of compound 45) 42b+29f (see Example 15 for the synthesis method) ¹ H NMR (400 MHz, CD ₃ OD) δ 7.72 (d, 2H), 7.52 (d, 1H), 7.41 (d, 1H), 7.06 – 6.95 (m, 3H), 6.79 (d, 1H), 6.62 (d, 1H), 6.55 (dd, 1H), 4.26 (s, 1H), 4.16 – 4.03 (m, 2H), 3.72 (t, 2H), 3.66 – 3.57 (m, 1H), 3.56 – 3.49 (m, 1H), 3.38 – 3.21 (m, 7H), 3.19 – 3.08 (m, 2H), 2.98 – 2.87 (m, 1H), 2.87 – 2.72 (m, 5H), 2.26 – 2.16 (m, 2H), 2.12 – 1.99 (m, 1H), 1.88 – 1.64 (m, 7H), 1.26 (d, 12H). LCMS m/z = 835.7 [M+1] ⁺ Example 46 (Compound 46) 42b+5A trifluoroacetate (see Example 40 for synthesis) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.80 (s, 1H), 7.92 (t, 1H), 7.73 (d, 2H), 7.64 (d, 1H), 7.46 (d, 1H), 7.35 (d, 1H), 6.95 (d, 2H), 6.71 – 6.60 (m, 2H), 6.53 (dd, 1H), 4.77 – 4.65 (m, 1H), 4.27 (s, 1H), 4.04 (d, 1H), 3.88 – 3.77 (m, 1H), 3.32 – 3.22 (m, 2H), 3.22 – 3.13 (m, 2H), 3.13 – 3.02 (m, 1H), 2.90 – 2.64 (m, 6H), 2.56 – 2.45 (m, 2H), 2.43 – 2.36 (m, 2H), 2.17 – 1.86 (m, 6H), 1.83 – 1.73 (m, 1H), 1.71 – 1.63 (m, 2H), 1.63 – 1.50 (m, 3H), 1.50 – 1.41 (m, 2H), 1.18 (d, 12H). LCMS m/z = 877.7 [M+1] ⁺ Example 47 (Compound 47) 42b+7A (see Example 40 for synthesis) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.80 (s, 1H), 7.92 (t, 1H), 7.73 (d, 2H), 7.64 (d, 1H), 7.46 (d, 1H), 7.35 (d, 1H), 6.95 (d, 2H), 6.70 – 6.60 (m, 2H), 6.53 (dd, 1H), 4.77 – 4.65 (m, 1H), 4.27 (s, 1H), 4.04 (d, 1H), 3.89 – 3.77 (m, 1H), 3.33 – 3.22 (m, 2H), 3.22 – 3.13 (m, 2H), 3.13 – 3.00 (m, 1H), 2.91 – 2.64 (m, 6H), 2.55 – 2.44 (m, 2H), 2.44 – 2.36 (m, 2H), 2.17 – 1.85 (m, 6H), 1.83 – 1.73 (m, 1H), 1.71 – 1.63 (m, 2H), 1.63 – 1.50 (m, 3H), 1.50 – 1.41 (m, 2H), 1.18 (d, 12H). LCMS m/z = 877.6 [M+1] ⁺

Example 48: Preparation of Compound 48

Compound 48 was obtained using compound 48a (synthesis method, see WO2021231927) and intermediate 1 as raw materials, with reference to the synthesis method of Example 36.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.75 (s, 1H), 7.90 (d, 1H), 7.73 (d, 2H), 7.45 (d, 1H), 7.23 – 7.17 (m, 1H), 7.03 – 6.97 (m, 1H), 6.95 (d, 2H), 6.79 (d, 1H), 6.62 (d, 1H), 4.32 (s, 1H), 4.05 (d, 1H), 3.90 – 3.77 (m, 3H), 3.76 – 3.67 (m, 1H), 2.99 – 2.85 (m, 3H), 2.83 – 2.55 (m, 6H), 2.54 – 2.45 (m, 1H), 2.21 – 2.14 (m, 2H), 2.14 – 2.02 (m, 2H), 1.98 – 1.73 (m, 6H), 1.65 – 1.53 (m, 1H), 1.26 – 1.08 (m, 14H).

LCMS m/z = 795.3 [M+1] ⁺

The following compounds were obtained by referring to other examples of synthesis: Example No. Structure raw material LCMS / ^1H NMR Example 49 (Compound 49) 48a+Intermediate 2 (see Example 36 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.75 (s, 1H), 7.90 (d, 1H), 7.73 (d, 2H), 7.45 (d, 1H), 7.24 – 7.16 (m, 1H), 7.03 – 6.96 (m, 1H), 6.95 (d, 2H), 6.79 (d, 1H), 6.62 (d, 1H), 4.32 (s, 1H), 4.05 (d, 1H), 3.90 – 3.76 (m, 3H), 3.76 – 3.66(m, 1H), 2.99 – 2.85 (m, 3H), 2.84 – 2.54 (m, 6H), 2.54 LCMS m/z = 795.3 [M+1] ⁺ Example 50 (Compound 50) 48a+28f (see Example 15 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.31 (s, 1H), 7.90 (d, 1H), 7.77 – 7.68 (m, 2H), 7.45 (d, 1H), 7.25 – 7.15 (m, 1H), 7.05 – 6.89 (m, 4H), 6.72 (d, 1H), 4.32 (s, 1H), 4.05 (d, 1H), 3.90 – 3.80 (m, 2H), 3.79 – 3.68 (m, 1H), 3.59 (t, 2H), 3.05 – 2.94 (m, 1H), 2.94 – 2.84 (m, 2H), 2.84 – 2.64 (m, 6H), 2.64 – 2.53 (m, 1H), 2.23 – 2.13 (m, 2H), 2.10 – 2.01 (m, 1H), 1.93 – 1.72 (m, 5H), 1.66 – 1.52 (m, 1H), 1.25 – 1.11 (m, 14H). LCMS m/z = 796.3 [M+1] ⁺ Example 51 (Compound 51) 48a+29f (see Example 15 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.31 (s, 1H), 7.90 (d, 1H), 7.77 – 7.68 (m, 2H), 7.45 (d, 1H), 7.22 – 7.17 (m, 1H), 7.03 – 6.97 (m, 1H), 6.97 – 6.89 (m, 3H), 6.72 (d, 1H), 4.32 (s, 1H), 4.05 (d, 1H), 3.90 – 3.80 (m, 2H), 3.79 – 3.68 (m, 1H), 3.59 (t, 2H), 3.04 – 2.95 (m, 1H), 2.94 – 2.84 (m, 2H), 2.84 – 2.64 (m, 6H), 2.64 – 2.56 (m, 1H), 2.23 – 2.13 (m, 2H), 2.10 – 2.00 (m, 1H), 1.93 – 1.73 (m, 5H), 1.66 – 1.52 (m, 1H), 1.24 – 1.11 (m, 14H). LCMS m/z = 796.3 [M+1] ⁺ Example 52 (Compound 52) 48a+5A trifluoroacetate (see Example 40 for synthesis) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 (s, 1H), 7.97 – 7.86 (m, 2H), 7.73 (d, 2H), 7.45 (d, 1H), 7.36 (d, 1H), 7.20 (d, 1H), 7.04 – 6.91 (m, 3H), 6.68 (d, 1H), 4.78 – 4.66 (m, 1H), 4.32 (s, 1H), 4.05 (d, 1H), 3.93 – 3.77 (m, 3H), 3.17 – 3.05 (m, 1H), 2.97 – 2.86 (m, 2H), 2.86 – 2.61 (m, 6H), 2.57 – 2.47 (m, 1H), 2.25 – 2.14 (m, 2H), 2.14 – 1.87 (m, 4H), 1.86 – 1.71 (m, 4H), 1.66 – 1.53 (m, 1H), 1.27 – 1.08 (m, 14H). LCMS m/z = 838.5 [M+1] ⁺ Example 53 (Compound 53) 48a+7A (see Example 40 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 (s, 1H), 7.97 – 7.86 (m, 2H), 7.73 (d, 2H), 7.45 (d, 1H), 7.36 (d, 1H), 7.20 (d, 1H), 7.05 – 6.90 (m, 3H), 6.68 (d, 1H), 4.78 – 4.65 (m, 1H), 4.32 (s, 1H), 4.05 (d, 1H), 3.94 – 3.75 (m, 3H), 3.17 – 3.05 (m, 1H), 2.98 –2.61 (m, 8H), 2.57 – 2.47 (m, 1H), 2.26 – 2.14 (m, 2H), 2.14 – 1.86 (m, 4H), 1.86 – 1.70 (m, 4H), 1.67 – 1.52 (m, 1H), 1.27 – 1.07 (m, 14H). LCMS m/z = 838.6 [M+1] ⁺

Example 54: Preparation of Compound 54

Compound 54 was obtained using compound 54a hydrochloride (synthesis method, see WO2021231927) and 5d as raw materials, with reference to the synthesis method of Example 42.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.74 (s, 1H), 7.90 (d, 1H), 7.72 (d, 2H), 7.45 (d, 1H), 7.20 (d, 1H), 7.04 – 6.90 (m, 3H), 6.78 (d, 1H), 6.60 (d, 1H), 4.32 (s, 1H), 4.04 (d, 1H), 3.81 (dd, 1H), 3.74 – 3.62 (m, 1H), 3.28 – 3.23 (m, 2H), 3.20 – 3.15 (m, 2H), 2.97 – 2.79 (m, 3H), 2.74 – 2.56 (m, 4H), 2.55 – 2.51 (m, 2H), 2.42 – 2.36 (m, 2H), 2.14 – 2.03 (m, 2H), 2.00 – 1.90 (m, 3H), 1.89 – 1.81 (m, 1H), 1.81 – 1.73 (m, 1H), 1.71 – 1.63 (m, 2H), 1.62 – 1.50 (m, 3H), 1.50 – 1.40 (m, 2H), 1.17 (d, 12H).

LCMS m/z = 835.4 [M+1] ⁺

The following compounds were obtained by referring to other examples of synthesis: Example No. Structure raw material LCMS / ^1H NMR Example 55 (Compound 55) 54c + intermediate 2 (see Example 54 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.74 (s, 1H), 7.90 (d, 1H), 7.76 – 7.67 (m, 2H), 7.45 (d, 1H), 7.20 (d, 1H), 7.04 – 6.91 (m, 3H), 6.78 (d, 1H), 6.60 (d, 1H), 4.32 (s, 1H), 4.04 (d, 1H), 3.81 (dd, 1H), 3.74 – 3.61 (m, 1H), 3.29 – 3.23 (m, 2H), 3.21 – 3.15 (m, 2H), 2.97 – 2.79 (m, 3H), 2.74 – 2.55 (m, 4H), 2.55 – 2.50 (m, 2H), 2.42 – 2.36 (m, 2H), 2.14 – 2.02 (m, 2H), 2.00 – 1.90 (m, 3H), 1.89 – 1.81 (m, 1H), 1.81 – 1.72 (m, 1H), 1.71 – 1.62 (m, 2H), 1.62 – 1.50 (m, 3H), 1.50 – 1.40 (m, 2H), 1.17 (d, 12H). LCMS m/z = 418.1 [M/2 +1] ⁺ Example 56 (Compound 56) 54c+28f (see Example 15 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.32 (s, 1H), 7.90 (d, 1H), 7.77 – 7.67 (m, 2H), 7.46 (d, 1H), 7.23 – 7.16 (m, 1H), 7.04 – 6.87 (m, 4H), 6.70 (d, 1H), 4.31 (s, 1H), 4.04 (d, 1H), 3.79 – 3.65 (m, 1H), 3.59 (t, 2H), 3.29 – 3.23 (m, 2H), 3.21 – 3.13 (m, 2H), 3.01 – 2.90 (m, 1H), 2.90 – 2.79 (m, 2H), 2.79 – 2.51 (m, 6H), 2.43 – 2.35 (m, 2H), 2.10 – 1.72 (m, 5H), 1.72 – 1.39 (m, 7H), 1.17 (d, 12H). LCMS m/z = 836.4 [M+1] ⁺ Example 57 (Compound 57) 54c+29f (see Example 15 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.32 (s, 1H), 7.90 (d, 1H), 7.78 – 7.65 (m, 2H), 7.46 (d, 1H), 7.25 – 7.13 (m, 1H), 7.05 – 6.86 (m, 4H), 6.70 (d, 1H), 4.31 (s, 1H), 4.04 (d, 1H), 3.79 – 3.63 (m, 1H), 3.59 (t, 2H), 3.29 – 3.22 (m, 2H), 3.21 – 3.13 (m, 2H), 3.02 – 2.90 (m, 1H), 2.90 – 2.79 (m, 2H), 2.79 – 2.51 (m, 6H), 2.45 – 2.33 (m, 2H), 2.12 – 1.72 (m, 5H), 1.72 – 1.37 (m, 7H), 1.17 (d, 12H). LCMS m/z = 836.3 [M+1] ⁺ Example 58 (Compound 58) 54c+5A trifluoroacetate (see Example 40 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 (s, 1H), 7.98 – 7.87 (m, 2H), 7.76 – 7.68 (m, 2H), 7.46 (d, 1H), 7.35 (d, 1H), 7.20 (d, 1H), 7.04 – 6.90 (m, 3H), 6.67 (d, 1H), 4.78 – 4.66 (m, 1H), 4.32 (s, 1H), 4.05 (d, 1H), 3.91 – 3.75 (m, 1H), 3.28 – 3.23 (m, 2H), 3.22 – 3.14 (m, 2H), 3.12 – 3.04 (m, 1H), 2.90 – 2.61 (m, 6H), 2.58 – 2.52 (m, 2H), 2.44 – 2.35 (m, 2H), 2.17 – 1.85 (m, 6H), 1.83 – 1.73 (m, 1H), 1.72 – 1.63 (m, 2H), 1.63 – 1.50 (m, 3H), 1.50 – 1.40 (m, 2H), 1.17 (d, 12H). LCMS m/z = 439.8 [M/2 +1] ⁺ Example 59 (Compound 59) 54c+7A (see Example 40 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 (s, 1H), 7.98 – 7.86 (m, 2H), 7.72 (d, 2H), 7.46 (d, 1H), 7.35 (d, 1H), 7.24 – 7.16 (m, 1H), 7.04 – 6.88 (m, 3H), 6.67 (d, 1H), 4.77 – 4.63 (m, 1H), 4.32 (s, 1H), 4.05 (d, 1H), 3.88 – 3.76 (m, 1H), 3.33 – 3.22 (m, 2H), 3.22 – 3.14 (m, 2H), 3.13 – 3.03 (m, 1H), 2.92 – 2.61 (m, 6H), 2.57 – 2.46 (m, 2H), 2.44 – 2.37 (m, 2H), 2.18 – 1.84 (m, 6H), 1.84 – 1.73 (m, 1H), 1.72 – 1.63 (m, 2H), 1.63 – 1.50 (m, 3H), 1.50 – 1.40 (m, 2H), 1.17 (d, 12H). LCMS m/z = 439.8 [M/2 +1] ⁺

Example 60: Preparation of Compound 60 Trifluoroacetic Acid

Step 1: Preparation of 60b

Compound 60a (0.51 g, 2.15 mmol) (synthesis method see WO2023066350) was dissolved in 15 mL DMF. Under nitrogen protection, trans-4-(3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-methoxybenzonitrile hydrochloride (1.00 g, 3.22 mmol) (synthesis method see CN115175901), N,N-diisopropylethylamine (1.39 g, 10.75 mmol) and HATU (0.98 g, 2.58 mmol) were added respectively, and the reaction was carried out at room temperature for 16 h. 30 mL of ethyl acetate and 30 mL of water were added to the reaction solution, and the liquids were separated. The aqueous phase was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (v/v) = 1:2) to obtain 60b (0.8 g, yield: 75%).

LCMS m/z = 494.2 [M+1] ⁺

Step 2: Preparation of 60c

60b (0.8 g, 1.62 mmol) was dissolved in 15 mL of dichloromethane, and Dess-Martin periodinane (0.82 g, 1.94 mmol) was added and reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (v/v) = 1:2) to obtain 60c (0.6 g, yield: 75%).

LCMS m/z = 492.4 [M+1] ⁺

Step 3: Preparation of trifluoroacetate salt of compound 60

Compound 60 trifluoroacetate was obtained using compound 60c and intermediate 1 as raw materials according to the synthesis method of Example 1.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.78 (s, 1H), 8.23 (d, 1H), 7.86 (d, 1H), 7.64 (d, 1H), 7.42 (d, 1H), 6.88 (d, 1H), 6.80 (d, 1H), 6.67 (d, 1H), 6.57 (dd, 1H), 4.60 – 4.48 (m, 2H), 4.40 (s, 1H), 4.14 – 4.05 (m, 1H), 4.04 – 3.98 (m, 1H), 3.92 (s, 3H), 3.89 – 3.82 (m, 1H), 3.70 – 3.57 (m, 2H), 3.39 – 3.30 (m, 1H), 3.19 – 2.98 (m, 6H), 2.93 – 2.82 (m, 1H), 2.81 – 2.62 (m, 3H), 2.56 – 2.52 (m, 1H), 2.31 – 2.21 (m, 1H), 2.20 – 2.06 (m, 1H), 2.06 – 1.79 (m, 4H), 1.70 – 1.56 (m, 1H), 1.34 – 1.14 (m, 14H).

LCMS m/z = 793.8 [M+1] ⁺

Example 62: Preparation of Compound 62 Trifluoroacetic Acid

The trifluoroacetic acid salt of compound 62 was prepared from compounds 60c and 28f by lyophilization in acidic preparation (water (containing 0.1% TFA)/acetonitrile) according to the synthesis method of Example 15.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.36 (s, 1H), 8.23 (d, 1H), 7.86 (d, 1H), 7.64 (d, 1H), 7.42 (d, 1H), 7.03 (d, 1H), 6.96 – 6.86 (m, 1H), 6.67 (d, 1H), 6.57 (dd, 1H), 4.61 – 4.47 (m, 2H), 4.40 (s, 1H), 4.14 – 4.08 (m, 1H), 4.04 – 3.98 (m, 1H), 3.91 (s, 3H), 3.68 – 3.58 (m, 4H), 3.43 – 3.33 (m, 1H), 3.19 – 3.00 (m, 6H), 2.95 – 2.82 (m, 1H), 2.81 – 2.61 (m, 4H), 2.31 – 2.17 (m, 1H), 2.08 – 1.97 (m, 1H), 1.95 – 1.80 (m, 2H), 1.72 – 1.57 (m, 1H), 1.32 – 1.12 (m, 14H).

LCMS m/z = 794.6 [M +1]+

Example 64: Preparation of Compound 64 with trifluoroacetic acid

Step 1: Preparation of 64b

Compound 64a (1.12 g, 4.74 mmol) (synthesis method see WO2021249534A1) was dissolved in 30 mL DMF. Under nitrogen protection, trans-4-(3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-methoxybenzonitrile hydrochloride (2.21 g, 7.11 mmol) (synthesis method see CN115175901), N,N-diisopropylethylamine (3.06 g, 23.70 mmol) and HATU (2.16 g, 5.69 mmol) were added respectively, and the reaction was carried out at room temperature for 16 h. 50 mL of ethyl acetate and 50 mL of water were added to the reaction solution, and the liquids were separated. The aqueous phase was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (v/v) = 1:2) to obtain 64b (1.5 g, yield: 64%).

LCMS m/z = 493.2 [M+1] ⁺

Step 2: Preparation of 64c

Compound 64b (1.5 g, 3.04 mmol) was dissolved in 30 mL of dichloromethane, and Dess-Martin periodinane (1.55 g, 3.65 mmol) was added. The reaction mixture was reacted at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (v/v) = 1:2) to obtain compound 64c (1.4 g, yield: 93%).

LCMS m/z = 491.2 [M+1] ⁺

Step 3: Preparation of trifluoroacetate salt of compound 64

The trifluoroacetic acid salt of compound 64 was obtained using compound 64c and intermediate 1 as raw materials according to the synthesis method of Example 1.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.78 (s, 1H), 8.63 (d, 1H), 8.00 (dd, 1H), 7.68 – 7.58 (m, 2H), 6.97 – 6.91 (m, 1H), 6.88 (d, 1H), 6.80 (d, 1H), 6.64 (d, 1H), 6.54 (dd, 1H), 4.48 – 4.37 (m, 2H), 4.26 (s, 1H), 4.13 – 4.02 (m, 2H), 3.91 (s, 3H), 3.89 – 3.82 (m, 1H), 3.68 – 3.57 (m, 2H), 3.40 – 3.30 (m, 1H), 3.19 – 2.81 (m, 7H), 2.81 – 2.58 (m, 3H), 2.57 – 2.45 (m, 1H), 2.27 – 2.07 (m, 2H), 2.05 – 1.79 (m, 4H), 1.70 – 1.57 (m, 1H), 1.27 – 1.10 (m, 14H).

LCMS m/z = 396.8 [M/2 +1] ⁺

The following compounds were obtained by referring to other examples of synthesis methods: Example No. Structure raw material LCMS / ^1H NMR Example 61 (Trifluoroacetic acid salt of compound 61) 60c + intermediate 2 (see Example 1 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 – 10.74 (m, 1H), 8.23 (d, 1H), 7.86 (d, 1H), 7.64 (d, 1H), 7.42 (d, 1H), 6.88 (d, 1H), 6.80 (d, 1H), 6.67 (d, 1H), 6.57 (dd, 1H), 4.61 – 4.48 (m, 2H), 4.40 (s, 1H), 4.16 – 3.96 (m, 2H), 3.95 – 3.80 (m, 4H), 3.71 – 3.57 (m, 2H), 3.41 – 3.29 (m, 1H), 3.19 – 2.99 (m, 6H), 2.87 (d, 1H), 2.81 – 2.60 (m, 3H), 2.58 – 2.51 (m, 1H), 2.31 – 2.06 (m, 2H), 2.06 – 1.78 (m, 4H), 1.70 – 1.56 (m, 1H), 1.32 – 1.14 (m, 14H). LCMS m/z = 793.8 [M +1] ⁺ Example 63 (Trifluoroacetic acid salt of compound 63) 60c+29f (see Example 15 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.36 (s, 1H), 8.23 (d, 1H), 7.86 (d, 1H), 7.64 (d, 1H), 7.42 (d, 1H), 7.03 (d, 1H), 6.95 – 6.85 (m, 1H), 6.67 (d, 1H), 6.57 (dd, 1H), 4.61 – 4.48 (m, 2H), 4.40 (s, 1H), 4.16 – 4.07 (m, 1H), 4.04 – 3.98 (m, 1H), 3.91 (s, 3H), 3.71 – 3.55 (m, 4H), 3.45 – 3.32 (m, 1H), 3.22 – 2.97 (m, 6H), 2.95 – 2.82 (m, 1H), 2.81 – 2.60 (m, 4H), 2.32 – 2.18 (m, 1H), 2.08 – 1.98 (m, 1H), 1.96 – 1.81 (m, 2H), 1.72 – 1.55 (m, 1H), 1.32 – 1.14 (m, 14H). LCMS m/z = 794.6 [M +1]+ Example 65 (Trifluoroacetic acid salt of compound 65) 64c + intermediate 2 (see Example 1 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.78 (s, 1H), 8.63 (d, 1H), 8.00 (dd, 1H), 7.68 – 7.57 (m, 2H), 6.99 – 6.90 (m, 1H), 6.88 (d, 1H), 6.80 (d, 1H), 6.64 (d, 1H), 6.54 (dd, 1H), 4.50 – 4.36 (m, 2H), 4.26 (s, 1H), 4.15 – 4.01 (m, 2H), 3.91 (s, 3H), 3.89 – 3.80 (m, 1H), 3.69 – 3.56 (m, 2H), 3.42 – 3.30 (m, 1H), 3.21 – 2.81 (m, 7H), 2.81 – 2.57 (m, 3H), 2.57 – 2.43 (m, 1H), 2.27 – 2.06 (m, 2H), 2.05 – 1.78 (m, 4H), 1.70 – 1.56 (m, 1H), 1.27 – 1.10 (m, 14H). LCMS m/z = 396.8 [M/2 +1] ⁺ Example 66 (Trifluoroacetic acid salt of compound 66) 64c+28f (see Example 15 for the synthesis method) ¹ H NMR (400 MHz, CD ₃ OD) δ 8.54 (d, 1H), 8.12 (dd, 1H), 7.52 (d, 1H), 7.10 (d, 1H), 7.04 (d, 1H), 6.85 – 6.77 (m, 1H), 6.63 (d, 1H), 6.55 (dd, 1H), 4.52 – 4.41 (m, 2H), 4.26 (s, 1H), 4.19 – 4.04 (m, 2H), 3.93 (s, 3H), 3.81 – 3.61 (m, 4H), 3.46 – 3.35 (m, 1H), 3.27 – 3.09 (m, 6H), 3.06 – 2.92 (m, 1H), 2.91 – 2.70 (m, 4H), 2.41 – 2.25 (m, 1H), 2.15 – 2.05 (m, 1H), 2.05 – 1.91 (m, 2H), 1.85 – 1.71 (m, 1H), 1.51 – 1.36 (m, 2H), 1.26 (d, 12H). LCMS m/z = 397.3 [M/2+1] ⁺ Example 67 (Trifluoroacetic acid salt of compound 67) 64c+29f (see Example 15 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.36 (s, 1H), 8.63 (d, 1H), 7.99 (dd, 1H), 7.68 – 7.56 (m, 2H), 7.02 (d, 1H), 6.97 – 6.84 (m, 2H), 6.64 (d, 1H), 6.54 (dd, 1H), 4.52 – 4.35 (m, 2H), 4.26 (s, 1H), 4.17 – 4.02 (m, 2H), 3.91 (s, 3H), 3.71 – 3.51 (m, 4H), 3.47 – 3.30 (m, 1H), 3.18 – 3.03 (m, 4H), 3.03 – 2.92 (m, 2H), 2.92 – 2.81 (m, 1H), 2.81 – 2.60 (m, 4H), 2.31 – 2.10 (m, 1H), 2.09 – 1.96 (m, 1H), 1.94 – 1.73 (m, 2H), 1.72 – 1.56 (m, 1H), 1.29 – 1.08 (m, 14H). LCMS m/z = 397.3 [M/2+1] ⁺ Example 68 (Trifluoroacetic acid salt of compound 68) 64c+5A trifluoroacetate (see Example 5 for synthesis) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.83 (s, 1H), 8.63 (d, 1H), 8.09 – 7.95 (m, 2H), 7.69 – 7.58 (m, 2H), 7.43 (d, 1H), 6.94 (d, 1H), 6.86 (d, 1H), 6.64 (d, 1H), 6.54 (dd, 1H), 4.78 – 4.67 (m, 1H), 4.50 – 4.39 (m, 2H), 4.26 (s, 1H), 4.24 – 4.14 (m, 1H), 4.10 – 4.03 (m, 1H), 3.91 (s, 3H), 3.71 – 3.58 (m, 2H), 3.55 – 3.45 (m, 1H), 3.26 – 3.15 (m, 1H), 3.15 – 3.03 (m, 3H), 3.02 – 2.85 (m, 3H), 2.83 – 2.70 (m, 3H), 2.58 – 2.49 (m, 1H), 2.25 – 1.95 (m, 4H), 1.94 – 1.76 (m, 2H), 1.71 – 1.57 (m, 1H), 1.32 – 1.07 (m, 14H). LCMS m/z = 835.8 [M+1] ⁺ Example 69 (Trifluoroacetic acid salt of compound 69) 64c+7A (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.83 (s, 1H), 8.68 – 8.53 (m, 1H), 8.09 – 7.92 (m, 2H), 7.69 – 7.53 (m, 2H), 7.43 (d, 1H), 6.99 – 6.79 (m, 2H), 6.69 – 6.59 (m, 1H), 6.54 (dd, 1H), 4.80 – 4.67 (m, 1H), 4.50 – 4.36 (m, 2H), 4.30 – 4.11 (m, 2H), 4.10 – 4.00 (m, 1H), 3.91 (s, 3H), 3.71 – 3.55 (m, 2H), 3.55 – 3.39 (m, 1H), 3.26 – 3.15 (m, 1H), 3.15 – 3.03 (m, 3H), 3.02 – 2.85 (m, 3H), 2.83 – 2.70 (m, 3H), 2.58 – 2.49 (m, 1H), 2.28 – 1.95 (m, 4H), 1.94 – 1.73 (m, 2H), 1.71 – 1.57 (m, 1H), 1.32 – 1.07 (m, 14H). LCMS m/z = 835.5 [M+1] ⁺ Example 70 (Trifluoroacetic acid salt of compound 70) 60c+5A trifluoroacetate (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.83 (s, 1H), 8.24 (d, 1H), 8.09 – 8.00 (m, 1H), 7.86 (d, 1H), 7.64 (d, 1H), 7.48 – 7.37 (m, 2H), 6.87 (d, 1H), 6.67 (d, 1H), 6.57 (dd, 1H), 4.80 – 4.67 (m, 1H), 4.61 – 4.47 (m, 2H), 4.40 (s, 1H), 4.25 – 4.15 (m, 1H), 4.01 (d, 1H), 3.92 (s, 3H), 3.76 – 3.41 (m, 3H), 3.26 – 3.16 (m, 1H), 3.16 – 3.01 (m, 5H), 2.95 – 2.84 (m, 1H), 2.83 – 2.67 (m, 3H), 2.59 – 2.51 (m, 1H), 2.33 – 2.19 (m, 1H), 2.18 – 1.96 (m, 3H), 1.96 – 1.81 (m, 2H), 1.72 – 1.58 (m, 1H), 1.33 – 1.12 (m, 14H). LCMS m/z = 836.6 [M+1] ⁺ Example 71 (Trifluoroacetic acid salt of compound 71) 60c+7A (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 (s, 1H), 8.23 (d, 1H), 8.09 – 7.98 (m, 1H), 7.86 (d, 1H), 7.64 (d, 1H), 7.50 – 7.36 (m, 2H), 6.86 (d, 1H), 6.67 (d, 1H), 6.57 (dd, 1H), 4.79 – 4.67 (m, 1H), 4.61 – 4.47 (m, 2H), 4.40 (s, 1H), 4.27 – 4.15 (m, 1H), 4.01 (d, 1H), 3.92 (s, 3H), 3.76 – 3.41 (m, 3H), 3.26 – 3.16 (m, 1H), 3.16 – 3.00 (m, 5H), 2.97 – 2.84 (m, 1H), 2.83 – 2.67 (m, 3H), 2.59 – 2.51 (m, 1H), 2.33 – 2.19 (m, 1H), 2.18 – 1.96 (m, 3H), 1.96 – 1.80 (m, 2H), 1.72 – 1.56 (m, 1H), 1.34 – 1.12 (m, 14H). LCMS m/z = 836.6 [M+1] ⁺

Example 72: Preparation of Compound 72

Step 1: Preparation of 72a

5d (1.00 g, 3.63 mmol), HATU (2.07 g, 5.45 mmol), diisopropylethylamine (1.41 g, 10.89 mmol) and 8 mL DMF were added to the reaction flask, stirred at room temperature for 0.5 h, and then the crude product 30b trifluoroacetate (1.0 g) was added and stirred at room temperature for 2 h. 100 mL of water was added to the reaction solution, filtered, and the filter cake was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-0:1) to obtain 72a (0.97 g, yield: 48%).

LCMS m/z = 553.4 [M+1] ⁺

Step 2: Preparation of 72b

72a (0.97 g, 1.76 mmol), Dess-Martin oxidant (1.49 g, 3.52 mmol) and 20 mL of dichloromethane were added to the reaction bottle and reacted at room temperature for 30 min. The reaction system was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to obtain crude product 72b (1.50 g).

LCMS m/z = 551.3 [M+1] ⁺

Step 3: Preparation of Compound 72

The crude product 72b (0.10 g), the crude intermediate 1 (0.15 g), 0.2 mL of glacial acetic acid and 5 mL of DMAc were added to the reaction bottle, respectively. After reacting at room temperature for 1 h, sodium triacetoxyborohydride (0.25 g, 1.17 mmol) was added. The reaction was carried out at room temperature for 16 h. The reaction solution was subjected to Pre-HPLC (Instrument and preparation column: SHIMADZU LC-20AP was used for preparation of liquid phase. The preparation column model was SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 10 mmol/L NH ₄ HCO ₃ )/acetonitrile. Gradient extraction method: acetonitrile was gradiently extracted from 53% to 83% (extraction time 15 min), and the product was freeze-dried to obtain compound 72 (27.0 mg, two-step yield based on compound 72a: 27%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.76 (s, 1H), 9.10 (dd, 1H), 8.74 (dd, 1H), 8.30 (d, 1H), 7.80 – 7.68 (m, 3H), 7.54 (d, 1H), 7.01 – 6.90 (m, 3H), 6.78 (d, 1H), 6.61 (d, 1H), 4.49 (s, 1H), 4.15 (d, 1H), 3.81 (dd, 1H), 3.74 – 3.63 (m, 1H), 3.30 – 3.24 (m, 4H), 3.22 – 3.14 (m, 2H), 2.98 – 2.78 (m, 3H), 2.78 – 2.46 (m, 5H), 2.44 – 2.35 (m, 2H), 2.19 – 1.72 (m, 7H), 1.72 – 1.63 (m, 2H), 1.63 – 1.51 (m, 2H), 1.50 – 1.41 (m, 2H), 1.26 (d, 12H).

LCMS m/z = 426.8 [M/2 +1] ⁺

Example 78: Preparation of Compound 78

Compound 78 was prepared by freeze-drying from compound 78a (synthesis method, see WO2021127443) and intermediate 2 according to the synthesis method of Example 1, and neutral preparation (aqueous solution of ammonium bicarbonate (10 mmol/L)/acetonitrile).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.75 (s, 1H), 7.73 (d, 2H), 7.44 (d, 1H), 6.95 (d, 2H), 6.79 (d, 1H), 6.73 (s, 2H), 6.62 (d, 1H), 4.22 (s, 1H), 4.03 (d, 1H), 3.90 – 3.76 (m, 3H), 3.76 – 3.67 (m, 1H), 3.00 – 2.85 (m, 3H), 2.84 – 2.64 (m, 5H), 2.64 – 2.54 (m, 1H), 2.54 – 2.46 (m, 1H), 2.43 (s, 6H), 2.25 – 2.00 (m, 4H), 1.99 – 1.70 (m, 6H), 1.67 – 1.52 (m, 1H), 1.26 – 1.07 (m, 14H).

LCMS m/z = 789.4 [M+1] ⁺ Example No. Structure raw material LCMS / ^1H NMR Example 73 (Compound 73) 72b + intermediate 2 (see Example 72 for synthesis) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.76 (s, 1H), 9.10 (dd, 1H), 8.74 (dd, 1H), 8.30 (d, 1H), 7.81 – 7.66 (m, 3H), 7.54 (d, 1H), 7.03 – 6.91 (m, 3H), 6.78 (d, 1H), 6.61 (d, 1H), 4.49 (s, 1H), 4.15 (d, 1H), 3.81 (dd, 1H), 3.75 – 3.62 (m, 1H), 3.32 – 3.22 (m, 4H), 3.22 – 3.12 (m, 2H), 2.99 – 2.78 (m, 3H), 2.78 – 2.45 (m, 5H), 2.44 – 2.33 (m, 2H), 2.22 – 1.72 (m, 7H), 1.72 – 1.63 (m, 2H), 1.63 – 1.50 (m, 2H), 1.50 – 1.40 (m, 2H), 1.26 (d, 12H). LCMS m/z = 852.4 [M+1] ⁺ Example 74 (Compound 74) 72b+29f (see Example 15 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.32 (s, 1H), 9.10 (dd, 1H), 8.74 (dd, 1H), 8.30 (d, 1H), 7.80 – 7.70 (m, 3H), 7.53 (d, 1H), 7.01 – 6.86 (m, 4H), 6.71 (d, 1H), 4.49 (s, 1H), 4.15 (d, 1H), 3.78 – 3.65 (m, 1H), 3.59 (t, 2H), 3.30 – 3.23 (m, 2H), 3.22 – 3.14 (m, 2H), 3.01 – 2.91 (m, 1H), 2.90 – 2.79 (m, 2H), 2.79 – 2.55 (m, 5H), 2.55 – 2.45 (m, 1H), 2.44 – 2.34 (m, 2H), 2.11 – 1.92 (m, 3H), 1.92 – 1.83 (m, 1H), 1.83 – 1.73 (m, 1H), 1.72 – 1.64 (m, 2H), 1.64 – 1.51 (m, 3H), 1.51 – 1.41 (m, 2H), 1.26 (d, 12H). LCMS m/z = 853.4 [M+1] ⁺ Example 75 (Compound 75) 72b+28f (see Example 15 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.32 (s, 1H), 9.13 – 9.05 (m, 1H), 8.78 – 8.69 (m, 1H), 8.30 (d, 1H), 7.80 – 7.67 (m, 3H), 7.53 (d, 1H), 7.01 – 6.85 (m, 4H), 6.71 (d, 1H), 4.49 (s, 1H), 4.15 (d, 1H), 3.78 – 3.65 (m, 1H), 3.59 (t, 2H), 3.35 – 3.22 (m, 2H), 3.22 – 3.13 (m, 2H), 3.01 – 2.91 (m, 1H), 2.90 – 2.79 (m, 2H), 2.79 – 2.55 (m, 5H), 2.55 – 2.45 (m, 1H), 2.44 – 2.33 (m, 2H), 2.13 – 1.92 (m, 3H), 1.92 – 1.83 (m, 1H), 1.83 – 1.72 (m, 1H), 1.72 – 1.64 (m, 2H), 1.64 – 1.51 (m, 3H), 1.51 – 1.40 (m, 2H), 1.26 (d, 12H). LCMS m/z = 853.5 [M+1] ⁺ Example 76 (Compound 76) 72b+7A (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 (s, 1H), 9.10 (dd, 1H), 8.74 (dd, 1H), 8.30 (d, 1H), 7.93 (t, 1H), 7.80 – 7.69 (m, 3H), 7.53 (d, 1H), 7.35 (d, 1H), 7.01 – 6.91 (m, 3H), 6.67 (d, 1H), 4.77 – 4.66 (m, 1H), 4.49 (s, 1H), 4.15 (d, 1H), 3.89 – 3.77 (m, 1H), 3.32 – 3.23 (m, 2H), 3.22 – 3.15 (m, 2H), 3.13 – 3.03 (m, 1H), 2.91 – 2.64 (m, 6H), 2.57 – 2.48 (m, 2H), 2.44 – 2.36 (m, 2H), 2.17 – 1.86 (m, 6H), 1.84 – 1.73 (m, 1H), 1.71 – 1.64 (m, 2H), 1.63 – 1.51 (m, 3H), 1.51 – 1.41 (m, 2H), 1.26 (d, 12H). LCMS m/z = 895.4 [M+1] ⁺ Example 77 (Compound 77) 72b+5A trifluoroacetate (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.06 – 10.44 (m, 1H), 9.10 (dd, 1H), 8.74 (dd, 1H), 8.30 (d, 1H), 7.93 (t, 1H), 7.81 – 7.69 (m, 3H), 7.52 (d, 1H), 7.36 (d, 1H), 7.01 – 6.91 (m, 3H), 6.67 (d, 1H), 4.73 – 4.60 (m, 1H), 4.49 (s, 1H), 4.19 – 4.11 (m, 1H), 3.89 – 3.77 (m, 1H), 3.35 – 3.23 (m, 2H), 3.22 – 3.14 (m, 2H), 3.13 – 3.03 (m, 1H), 2.91 – 2.64 (m, 6H), 2.57 – 2.46 (m, 2H), 2.44 – 2.36 (m, 2H), 2.17 – 1.86 (m, 6H), 1.84 – 1.73 (m, 1H), 1.71 – 1.64 (m, 2H), 1.63 – 1.51 (m, 3H), 1.51 – 1.41 (m, 2H), 1.26 (d, 12H). LCMS m/z = 895.4 [M+1] ⁺ Example 79 (Compound 79) 16f+28f (see Example 15 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.32 (s, 1H), 7.73 (d, 2H), 7.64 (d, 1H), 7.46 (d, 1H), 7.00 – 6.88 (m, 3H), 6.71 (d, 1H), 6.64 (d, 1H), 6.54 (dd, 1H), 4.30 – 4.22 (m, 1H), 4.05 (d, 1H), 3.91 (s, 3H), 3.81 – 3.71 (m, 1H), 3.59 (t, 2H), 3.29 – 3.24 (m, 2H), 3.23 – 3.15 (m, 2H), 3.02 – 2.92 (m, 1H), 2.91 – 2.80 (m, 2H), 2.79 – 2.54 (m, 6H), 2.06 – 1.95 (m, 2H), 1.94 – 1.80 (m, 2H), 1.70 – 1.51 (m, 8H), 1.18 (d, 12H). LCMS m/z = 818.3 [M+1] ⁺ Example 80 (Compound 80) 78a+29f (see Example 15 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.32 (s, 1H), 7.78 – 7.68 (m, 2H), 7.44 (d, 1H), 6.99 – 6.88 (m, 3H), 6.76 – 6.66 (m, 3H), 4.22 (s, 1H), 4.03 (d, 1H), 3.89 – 3.80 (m, 2H), 3.79 – 3.71 (m, 1H), 3.60 (t, 2H), 3.04 – 2.95 (m, 1H), 2.94 – 2.86 (m, 2H), 2.83 – 2.55 (m, 7H), 2.43 (s, 6H), 2.24 LCMS m/z = 790.4 [M+1] ⁺ Example 81 (Compound 81) 78a+Intermediate 1 (see Example 1 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.76 (s, 1H), 7.77 – 7.70 (m, 2H), 7.45 (d, 1H), 6.99 – 6.91 (m, 2H), 6.79 (d, 1H), 6.73 (s, 2H), 6.62 (d, 1H), 4.22 (s, 1H), 4.03 (d, 1H), 3.89 – 3.77 (m, 3H), 3.77 – 3.68 (m, 1H), 3.01 – 2.85 (m, 3H), 2.84 – 2.55 (m, 6H), 2.54 – 2.51 (m, 1H), 2.43 (s, 6H), 2.22 – 2.00 (m, 4H), 1.99 – 1.71 (m, 6H), 1.66 – 1.51 (m, 1H), 1.30 – 1.07 (m, 14H). LCMS m/z = 789.6 [M+1] ⁺ Example 82 (Compound 82) 78a+28f (see Example 15 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.33 (s, 1H), 7.78 – 7.67 (m, 2H), 7.45 (d, 1H), 6.99 – 6.88 (m, 3H), 6.76 – 6.66 (m, 3H), 4.22 (s, 1H), 4.03 (d, 1H), 3.89 – 3.79 (m, 2H), 3.79 – 3.70 (m, 1H), 3.60 (t, 2H), 3.04 – 2.94 (m, 1H), 2.94 – 2.85 (m, 2H), 2.83 – 2.54 (m, 7H), 2.43 (s, 6H), 2.24 LCMS m/z = 790.5 [M+1] ⁺

Example 83: Preparation of Compound 83

Step 1: Preparation of 83b

83a (3.3 g, 8.96 mmol) (synthesis method see Tetrahedron Letters, 2018 , 59, 2030–2033) was dissolved in 20 mL of methanol, 10% palladium on carbon (2.38 g) was added, hydrogen was replaced three times, and the reaction was carried out at 45°C under hydrogen atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain crude 83b (2.55 g).

LCMS m/z = 290.2 [M+1] ⁺

Step 2: Preparation of 83c

The crude product 83b (2.55 g) was dissolved in 20 ml acetonitrile, and NBS (1.54 g, 8.64 mmol) was added and stirred at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) = 0:1-1:9) to obtain 83c (3.1 g, yield: 98%).

Step 3: Preparation of 83d

83c (1.00 g, 2.72 mmol), 2, 6-bis(benzyloxy)pyridine-3-boronic acid pinacol ester (1.70 g, 4.08 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.22 g, 0.27 mmol) and cesium carbonate (1.77 g, 5.44 mmol) were added to the reaction bottle respectively. The nitrogen atmosphere was replaced three times, 30 mL of 1,4-dioxane and 3 mL of water were added, and the reaction was carried out at 100 °C for 20 h under nitrogen atmosphere. The reaction system was cooled to room temperature, 50 mL of water and 50 mL of ethyl acetate were added, the liquids were separated, the aqueous phase was extracted with 50 mL of ethyl acetate, the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-9:1) to obtain 83d (1.10 g, yield: 70%).

LCMS m/z = 579.3 [M+1] ⁺

Step 4: Preparation of 83e

83d (1.10 g, 1.90 mmol) was dissolved in 20 mL of tetrahydrofuran, 10% palladium on carbon (1.0 g) was added, the hydrogen atmosphere was replaced three times, and the reaction was carried out at 45°C for 20 h under a hydrogen atmosphere. The reaction system was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with 30 mL of tetrahydrofuran. The filtrate was collected and the filter cake was dried under reduced pressure to obtain 83e (0.70 g, yield: 92%).

LCMS m/z = 401.2 [M+1] ⁺

Step 5: Preparation of 83f

83e (200 mg, 0.50 mmol) was dissolved in 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 3 h. The reaction system was concentrated under reduced pressure, and 5 mL of dichloromethane and 1 mL of triethylamine were added, and the system was concentrated under reduced pressure to obtain crude product 83f (150 mg).

LCMS m/z = 301.3 [M+1] ⁺

Step 6: Preparation of compound 83

Compound 83 was prepared from crude products 83f and 1a by the synthesis method of Example 1, and then freeze-dried (aqueous solution of ammonium bicarbonate (10 mmol/L)/acetonitrile).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.76 (s, 1H), 7.80 – 7.69 (m, 3H), 7.64 (d, 1H), 7.46 (d, 1H), 7.11 – 7.04 (m, 1H), 7.00 – 6.90 (m, 2H), 6.64 (d, 1H), 6.54 (dd, 1H), 4.65 – 4.49 (m, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.93 – 3.79 (m, 5H), 3.68 (dd, 1H), 3.27 – 3.17 (m, 1H), 2.99 – 2.86 (m, 2H), 2.85 – 2.56 (m, 6H), 2.56 – 2.50 (m, 1H), 2.25 – 2.08 (m, 3H), 2.02 – 1.87 (m, 3H), 1.87 – 1.70 (m, 4H), 1.66 – 1.52 (m, 1H), 1.29 – 1.08 (m, 14H).

LCMS m/z = 774.5 [M+1] ⁺

Example 85: Preparation of Compound 85

Compound 85 was prepared from compound 36e hydrochloride and compound 60a according to the synthesis method of Example 60 by neutral preparation (aqueous solution of ammonium bicarbonate (10 mmol/L)/acetonitrile) and freeze-dried.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.76 (s, 1H), 8.24 (d, 1H), 7.82 (d, 1H), 7.64 (d, 1H), 7.36 (d, 1H), 6.79 (d, 1H), 6.69 – 6.52 (m, 3H), 4.55 – 4.44 (m, 2H), 4.40 (s, 1H), 4.00 (d, 1H), 3.81 (dd, 1H), 3.76 – 3.67 (m, 1H), 3.09 – 2.84 (m, 5H), 2.79 – 2.54 (m, 4H), 2.54 – 2.44 (m, 1H), 2.24 – 2.00 (m, 4H), 1.99 – 1.70 (m, 6H), 1.66 – 1.52 (m, 1H), 1.28 – 1.05 (m, 14H).

LCMS m/z = 796.6 [M+1] ⁺

The following compounds were obtained by referring to other examples of synthesis: Example No. Structure raw material LCMS / ^1H NMR Example 84 (Trifluoroacetic acid salt of compound 84) 16f+29f (see Example 15 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.35 (s, 1H), 7.75 (d, 2H), 7.64 (d, 1H), 7.48 (d, 1H), 7.05 – 6.95 (m, 3H), 6.91 (d, 1H), 6.64 (d, 1H), 6.54 (dd, 1H), 4.28 (s, 1H), 4.22 – 4.11 (m, 1H), 4.08 – 4.01 (m, 1H), 3.91 (s, 3H), 3.85 – 3.72 (m, 1H), 3.61 (t, 2H), 3.54 – 3.43 (m, 2H), 3.35 – 3.17 (m, 5H), 3.08 – 2.97 (m, 1H), 2.96 – 2.83 (m, 1H), 2.81 – 2.60 (m, 5H), 2.30 – 2.17 (m, 2H), 2.12 – 1.99 (m, 3H), 1.74 – 1.54 (m, 5H), 1.19 (d, 12H). LCMS m/z = 818.7 [M+1] ⁺ Example 86 (Compound 86) 85b + intermediate 2 (see Example 60 for synthesis) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.75 (s, 1H), 8.23 (d, 1H), 7.82 (d, 1H), 7.63 (d, 1H), 7.35 (d, 1H), 6.79 (d, 1H), 6.69 – 6.53 (m, 3H), 4.56 – 4.44 (m, 2H), 4.40 (s, 1H), 4.00 (d, 1H), 3.81 (dd, 1H), 3.76 – 3.66 (m, 1H), 3.09 – 2.81 (m, 5H), 2.79 – 2.54 (m, 4H), 2.54 – 2.44 (m, 1H), 2.23 – 2.00 (m, 4H), 1.99 – 1.68 (m, 6H), 1.65 – 1.50 (m, 1H), 1.29 – 1.04 (m, 14H). LCMS m/z = 796.6 [M+1] ⁺ Example 87 (Compound 87) 85b+5A trifluoroacetate (see Example 11 for synthesis) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 (s, 1H), 8.24 (d, 1H), 7.94 (t, 1H), 7.82 (d, 1H), 7.64 (d, 1H), 7.42 – 7.31 (m, 2H), 6.74 – 6.64 (m, 2H), 6.57 (dd, 1H), 4.78 – 4.65 (m, 1H), 4.58 – 4.45 (m, 2H), 4.40 (s, 1H), 4.00 (d, 1H), 3.94 – 3.78 (m, 1H), 3.18 – 2.99 (m, 3H), 2.98 – 2.60 (m, 6H), 2.58 – 2.47 (m, 1H), 2.27 – 2.15 (m, 2H), 2.14 – 1.72 (m, 8H), 1.68 – 1.52 (m, 1H), 1.29 – 1.03 (m, 14H). LCMS m/z = 839.6 [M +1] ⁺ Example 88 (Compound 88) 85b+7A (see Example 11 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 (s, 1H), 8.24 (d, 1H), 7.94 (t, 1H), 7.82 (d, 1H), 7.64 (d, 1H), 7.42 – 7.29 (m, 2H), 6.74 – 6.63 (m, 2H), 6.57 (dd, 1H), 4.78 – 4.66 (m, 1H), 4.58 – 4.44 (m, 2H), 4.40 (s, 1H), 4.00 (d, 1H), 3.93 – 3.79 (m, 1H), 3.19 – 2.98 (m, 3H), 2.98 – 2.60 (m, 6H), 2.58 – 2.47 (m, 1H), 2.28 – 2.15 (m, 2H), 2.14 – 1.72 (m, 8H), 1.68 – 1.53 (m, 1H), 1.29 – 1.02 (m, 14H). LCMS m/z = 839.6 [M +1] ⁺

Example 89: Preparation of Compound 89

Compound 89 was prepared from trifluoroacetic acid salt of compound 30b and compound 60a by referring to the synthesis method of Example 60 and then freeze-dried in neutral solution (water (containing 10 mmol/L ammonium bicarbonate)/acetonitrile).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.75 (s, 1H), 9.10 (d, 1H), 8.76 (d, 1H), 8.33 – 8.24 (m, 2H), 7.83 (d, 1H), 7.79 – 7.72 (m, 1H), 7.36 (d, 1H), 7.01 (d, 1H), 6.79 (d, 1H), 6.62 (d, 1H), 4.61 (s, 1H), 4.56 – 4.44 (m, 2H), 4.12 (d, 1H), 3.85 – 3.77 (m, 1H), 3.76 – 3.69 (m, 1H), 3.10 – 2.85 (m, 5H), 2.78 – 2.64 (m, 3H), 2.64 – 2.45 (m, 2H), 2.23 – 2.15 (m, 2H), 2.14 – 2.01 (m, 2H), 1.99 – 1.72 (m, 6H), 1.67 – 1.53 (m, 1H), 1.28 (d, 12H), 1.20 – 1.07 (m, 2H).

LCMS m/z = 814.6 [M+1] ⁺

Example 93: Preparation of Compound 93

Compound 93 was prepared using compound 93a (for the synthesis method, see Tetrahedron Letters, 2018 , 59, 2030-2033) as a raw material according to the synthesis method of Example 83.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.76 (s, 1H), 7.80 – 7.67 (m, 3H), 7.64 (d, 1H), 7.46 (d, 1H), 7.11 – 7.03 (m, 1H), 6.95 (d, 2H), 6.64 (d, 1H), 6.54 (dd, 1H), 4.66 – 4.49 (m, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.93 – 3.78 (m, 5H), 3.68 (dd, 1H), 3.29 – 3.15 (m, 1H), 2.99 – 2.87 (m, 2H), 2.86 – 2.56 (m, 6H), 2.56 – 2.45 (m, 1H), 2.25 – 2.06 (m, 3H), 2.02 – 1.87 (m, 3H), 1.87 – 1.69 (m, 4H), 1.66 – 1.52 (m, 1H), 1.29 – 1.08 (m, 14H).

The following compounds were obtained by referring to other examples of synthesis: Example No. Structure raw material LCMS / ^1H NMR Example 90 (Compound 90) 89b + intermediate 2 (see Example 60 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.75 (s, 1H), 9.14 – 9.07 (m, 1H), 8.76 (d, 1H), 8.34 – 8.23 (m, 2H), 7.83 (d, 1H), 7.79 – 7.70 (m, 1H), 7.36 (d, 1H), 7.01 (d, 1H), 6.79 (d, 1H), 6.62 (d, 1H), 4.61 (s, 1H), 4.56 – 4.44 (m, 2H), 4.12 (d, 1H), 3.85 – 3.77 (m, 1H), 3.76 – 3.69 (m, 1H), 3.13 – 2.84 (m, 5H), 2.79 – 2.64 (m, 3H), 2.64 – 2.45 (m, 2H), 2.23 –2.01 (m, 4H), 1.99 – 1.71 (m, 6H), 1.67 – 1.53 (m, 1H), 1.28 (d, 12H), 1.20 – 1.05 (m, 2H). LCMS m/z = 814.6 [M+1] ⁺ Example 91 (Compound 91) 89b+5A trifluoroacetate (see Example 11 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 (s, 1H), 9.15 – 9.06 (m, 1H), 8.76 (d, 1H), 8.33 – 8.24 (m, 2H), 7.93 (t, 1H), 7.83 (d, 1H), 7.76 (dd, 1H), 7.42 – 7.31 (m, 2H), 7.01 (d, 1H), 6.68 (d, 1H), 4.78 – 4.66 (m, 1H), 4.61 (s, 1H), 4.57 – 4.42 (m, 2H), 4.12 (d, 1H), 3.91 – 3.81 (m, 1H), 3.18 – 2.99 (m, 3H), 2.98 – 2.61 (m, 6H), 2.59 – 2.47 (m, 1H), 2.27 – 2.15 (m, 2H), 2.14 – 1.72 (m, 8H), 1.67 – 1.52 (m, 1H), 1.28 (d, 12H), 1.21 – 1.07 (m, 2H). LCMS m/z = 857.4 [M +1] ⁺ Example 92 (Compound 92) 89b+7A (see Example 11 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 (s, 1H), 9.14 – 9.06 (m, 1H), 8.76 (d, 1H), 8.33 – 8.24 (m, 2H), 7.93 (t, 1H), 7.83 (d, 1H), 7.79 – 7.72 (m, 1H), 7.42 – 7.30 (m, 2H), 7.01 (d, 1H), 6.68 (d, 1H), 4.78 – 4.66 (m, 1H), 4.61 (s, 1H), 4.57 – 4.43 (m, 2H), 4.12 (d, 1H), 3.91 – 3.79 (m, 1H), 3.17 – 2.99 (m, 3H), 2.98 – 2.60 (m, 6H), 2.58 – 2.47 (m, 1H), 2.27 – 2.15 (m, 2H), 2.12 – 1.73 (m, 8H), 1.67 – 1.52 (m, 1H), 1.28 (d, 12H), 1.21 – 1.07 (m, 2H). LCMS m/z = 857.4 [M +1] ⁺ Example 94 (Compound 94) 36e hydrochloride + 16d + 28f (see Examples 15 and 16 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.32 (s, 1H), 7.73 (d, 2H), 7.64 (d, 1H), 7.47 (d, 1H), 7.01 – 6.88 (m, 3H), 6.72 (d, 1H), 6.66 – 6.61 (m, 1H), 6.53 (dd, 1H), 4.27 (s, 1H), 4.05 (d, 1H), 3.82 – 3.72 (m, 1H), 3.63 – 3.55 (m, 2H), 3.30 – 3.24 (m, 2H), 3.23 – 3.15 (m, 2H), 3.02 – 2.92 (m, 1H), 2.92 – 2.80 (m, 2H), 2.79 – 2.55 (m, 6H), 2.06 – 1.95 (m, 2H), 1.94 – 1.81 (m, 2H), 1.71 – 1.51 (m, 8H), 1.18 (d, 12H). LCMS m/z = 821.8 [M+1] ⁺ Example 95 (Compound 95) 16f+Intermediate 5 (see Example 20 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.83 (s, 1H), 7.73 (d, 2H), 7.64 (d, 1H), 7.51 – 7.44 (m, 2H), 7.38 (d, 1H), 6.96 (d, 2H), 6.64 (d, 1H), 6.54 (dd, 1H), 4.27 (s, 1H), 4.14 – 4.01 (m, 4H), 3.91 (s, 3H), 3.69 (s, 2H), 3.34 – 3.26 (m, 2H), 3.25 – 3.16 (m, 2H), 3.12 – 3.03 (m, 1H), 2.94 – 2.82 (m, 2H), 2.82 – 2.70 (m, 1H), 2.60 – 2.53 (m, 1H), 2.36 – 2.20 (m, 1H), 2.18 – 1.97 (m, 3H), 1.77 – 1.64 (m, 4H), 1.64 – 1.53 (m, 2H), 1.18 (d, 12H). LCMS m/z = 802.4 [M+1] ⁺ Example 96 (Compound 96) 1a+Intermediate 5 (see Example 1 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.83 (s, 1H), 7.73 (d, 2H), 7.64 (d, 1H), 7.50 – 7.43 (m, 2H), 7.39 (d, 1H), 6.96 (d, 2H), 6.64 (d, 1H), 6.54 (dd, 1H), 4.27 (s, 1H), 4.15 – 3.99 (m, 4H), 3.95 – 3.75 (m, 7H), 3.04 – 2.95 (m, 2H), 2.90 – 2.68 (m, 3H), 2.60 – 2.42 (m, 3H), 2.35 – 2.24 (m, 1H), 2.08 – 1.98 (m, 1H), 1.96 – 1.77 (m, 3H), 1.29 – 1.11 (m, 14H). LCMS m/z = 776.6 [M+1] ⁺

Example 97: Preparation of Compound 97 Trifluoroacetic Acid

Step 1: Preparation of 97b

97a (5.0 g, 36.47 mmol), 1-bromo-2-butyne (9.7 g, 72.94 mmol), potassium carbonate (10.08 g, 72.94 mmol), potassium iodide (0.61 g, 3.67 mmol) and 100 mL acetone were added to the reaction bottle and reacted at room temperature for 12 h. 200 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-1:1) to obtain 97b (5.0 g, yield: 72%).

The trifluoroacetic acid salt of compound 97 was prepared from compounds 97b, 36h and intermediate 2 by acidic preparation (water (containing 0.1% TFA)/acetonitrile) and lyophilization according to the synthesis method of Example 36.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.78 (s, 1H), 7.76 (d, 2H), 7.64 (d, 1H), 7.46 (d, 1H), 6.99 (d, 2H), 6.88 (d, 1H), 6.80 (d, 1H), 6.69 (d, 1H), 6.60 (dd, 1H), 5.00 – 4.92 (m, 2H), 4.25 (s, 1H), 4.10 – 4.03 (m, 2H), 3.95 – 3.78 (m, 3H), 3.68 – 3.57 (m, 2H), 3.41 – 3.28 (m, 1H), 3.21 – 2.97 (m, 4H), 2.93 – 2.77 (m, 3H), 2.77 – 2.60 (m, 3H), 2.58 – 2.48 (m, 1H), 2.20 – 2.06 (m, 2H), 2.05 – 1.91 (m, 2H), 1.91 – 1.76 (m, 5H), 1.71 – 1.56 (m, 1H), 1.38 – 1.09 (m, 14H).

LCMS m/z = 829.6 [M+1] ⁺

The following compounds were obtained by referring to other examples of synthesis: Example No. Structure raw material LCMS / ^1H NMR Example 98 (Trifluoroacetic acid salt of compound 98) 97f+Intermediate 1 (see Example 97 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.78 (s, 1H), 7.76 (d, 2H), 7.64 (d, 1H), 7.47 (d, 1H), 6.99 (d, 2H), 6.88 (d, 1H), 6.80 (d, 1H), 6.69 (d, 1H), 6.60 (dd, 1H), 5.00 – 4.93 (m, 2H), 4.26 (s, 1H), 4.12 – 4.02 (m, 2H), 3.95 – 3.82 (m, 3H), 3.69 – 3.57 (m, 2H), 3.42 – 3.27 (m, 1H), 3.21 – 2.96 (m, 4H), 2.93 – 2.77 (m, 3H), 2.77 – 2.60 (m, 3H), 2.59 – 2.48 (m, 1H), 2.21 – 2.06 (m, 2H), 2.05 – 1.91 (m, 2H), 1.91 – 1.75 (m, 5H), 1.71 – 1.56 (m, 1H), 1.38 – 1.09 (m, 14H). LCMS m/z = 829.3 [M+1] ⁺ Example 99 (Trifluoroacetic acid salt of compound 99) 97f (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.83 (s, 1H), 8.04 (t, 1H), 7.76 (d, 2H), 7.65 (d, 1H), 7.53 – 7.38 (m, 2H), 6.99 (d, 2H), 6.86 (d, 1H), 6.69 (d, 1H), 6.60 (dd, 1H), 5.04 – 4.88 (m, 2H), 4.80 – 4.66 (m, 1H), 4.30 – 4.14 (m, 2H), 4.10 – 4.02 (m, 1H), 3.96 – 3.83 (m, 2H), 3.73 – 3.56 (m, 2H), 3.56 – 3.41 (m, 1H), 3.28 – 2.97 (m, 4H), 2.96 – 2.65 (m, 6H), 2.58 – 2.51 (m, 1H), 2.20 – 1.95 (m, 4H), 1.95 – 1.76 (m, 5H), 1.72 – 1.57 (m, 1H), 1.38 – 1.08 (m, 14H). LCMS m/z = 872.6 [M+1] ⁺ Example 100 (Trifluoroacetic acid salt of compound 100) 97f+4-A (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 (s, 1H), 8.08 – 7.98 (m, 1H), 7.76 (d, 2H), 7.64 (d, 1H), 7.52 – 7.37 (m, 2H), 6.99 (d, 2H), 6.86 (d, 1H), 6.69 (d, 1H), 6.60 (dd, 1H), 4.97 (d, 2H), 4.80 – 4.67 (m, 1H), 4.31 – 4.14 (m, 2H), 4.10 – 4.04 (m, 1H), 3.94 – 3.86 (m, 2H), 3.70 – 3.58 (m, 2H), 3.54 – 3.41 (m, 1H), 3.27 – 2.98 (m, 4H), 2.97 – 2.66 (m, 6H), 2.59 – 2.47 (m, 1H), 2.21 – 1.95 (m, 4H), 1.95 – 1.75 (m, 5H), 1.72 – 1.53 (m, 1H), 1.38 – 1.07 (m, 14H). LCMS m/z = 872.6 [M+1] ⁺

Example 101: Preparation of Trifluoroacetic Acid Salt of Compound 101

Step 1: Preparation of 101b

101a (10 g, 72.93 mmol), 2-cyclopropoxyethyl 4-methylbenzenesulfonate (22.62 g, 88.25 mmol) and cesium carbonate (35.64 g, 109.38 mmol) were dissolved in 100 mL DMF and reacted at 90°C for 16 h. The reaction system was cooled to room temperature, added to 300 mL of water, extracted with ethyl acetate (200 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) = 1:0-1:1) to obtain 101b (10 g, yield: 62%).

The trifluoroacetic acid salt of compound 101 was prepared from compounds 101b, 36h and intermediate 2 by referring to the synthesis method of Example 36 and then freeze-dried in acidic solution (water (containing 0.1% TFA)/acetonitrile).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.79 (s, 1H), 7.76 (d, 2H), 7.64 (d, 1H), 7.48 (d, 1H), 6.99 (d, 2H), 6.88 (d, 1H), 6.80 (d, 1H), 6.65 (d, 1H), 6.55 (dd, 1H), 4.29 – 4.20 (m, 3H), 4.13 – 3.99 (m, 2H), 3.95 – 3.74 (m, 5H), 3.70 – 3.56 (m, 2H), 3.46 – 3.38 (m, 1H), 3.38 – 3.28 (m, 1H), 3.24 – 2.98 (m, 4H), 2.93 – 2.59 (m, 6H), 2.56 – 2.46 (m, 1H), 2.21 – 2.05 (m, 2H), 2.05 – 1.75 (m, 4H), 1.70 – 1.55 (m, 1H), 1.37 – 1.08 (m, 14H), 0.55 – 0.38 (m, 4H).

LCMS m/z = 861.6 [M+1] ⁺

Example 105: Preparation of Compound 105

Step 1: Preparation of 105b

105a (1.6 g, 11.67 mmol), 1-bromo-2-methoxyethane (3.80 g, 15.18 mmol), potassium carbonate (4.84 g, 35.02 mmol), potassium iodide (0.19 g, 1.14 mmol) and 15 mL DMF were added to the reaction flask and reacted at room temperature for 12 h. 100 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-3:1) to obtain 105b (1.1 g, yield: 48%).

LCMS m/z = 196.1 [M+1] ⁺

Compound 105 was obtained using compounds 105b and 36h as raw materials according to the synthetic method of Example 36.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.76 (s, 1H), 7.73 (d, 2H), 7.64 (d, 1H), 7.46 (d, 1H), 6.95 (d, 2H), 6.79 (d, 1H), 6.70 – 6.58 (m, 2H), 6.54 (dd, 1H), 4.30 – 4.21 (m, 3H), 4.04 (d, 1H), 3.90 – 3.77 (m, 3H), 3.76 – 3.66 (m, 3H), 3.34 (s, 3H), 3.00 – 2.85 (m, 3H), 2.83 – 2.64 (m, 5H), 2.64 – 2.54 (m, 1H), 2.54 – 2.46 (m, 1H), 2.23 – 1.99 (m, 4H), 1.99 – 1.72 (m, 6H), 1.66 – 1.52 (m, 1H), 1.27 – 1.09 (m, 14H).

LCMS m/z = 835.3 [M+1] ⁺

The following compounds were obtained by referring to other examples of synthesis: Example No. Structure raw material LCMS / ^1H NMR Example 102 (Trifluoroacetic acid salt of compound 102) 101f+Intermediate 1 (see Example 101 for synthesis) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.78 (s, 1H), 7.76 (d, 2H), 7.64 (d, 1H), 7.48 (d, 1H), 6.99 (d, 2H), 6.88 (d, 1H), 6.80 (d, 1H), 6.65 (d, 1H), 6.55 (dd, 1H), 4.31 – 4.20 (m, 3H), 4.13 – 4.01 (m, 2H), 3.95 – 3.72 (m, 5H), 3.70 – 3.56 (m, 2H), 3.46 – 3.38 (m, 1H), 3.38 – 3.27 (m, 1H), 3.24 – 2.98 (m, 4H), 2.93 – 2.59 (m, 6H), 2.57 – 2.47 (m, 1H), 2.21 – 2.05 (m, 2H), 2.05 – 1.75 (m, 4H), 1.71 – 1.55 (m, 1H), 1.39 – 1.08 (m, 14H), 0.56 – 0.41 (m, 4H). LCMS m/z = 861.3 [M+1] ⁺ Example 103 (Trifluoroacetic acid salt of compound 103) 101f (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 (s, 1H), 8.08 – 8.00 (m, 1H), 7.76 (d, 2H), 7.64 (d, 1H), 7.53 – 7.38 (m, 2H), 6.99 (d, 2H), 6.86 (d, 1H), 6.65 (d, 1H), 6.55 (dd, 1H), 4.78 – 4.67 (m, 1H), 4.30 – 4.15 (m, 4H), 4.09 – 4.02 (m, 1H), 3.95 – 3.85 (m, 2H), 3.84 – 3.76 (m, 2H), 3.72 – 3.57 (m, 2H), 3.55 – 3.45 (m, 1H), 3.45 – 3.38 (m, 1H), 3.31 – 2.96 (m, 4H), 2.96 – 2.64 (m, 6H), 2.59 – 2.52 (m, 1H), 2.20 – 1.94 (m, 4H), 1.94 – 1.76 (m, 2H), 1.72 – 1.57 (m, 1H), 1.38 – 1.08 (m, 14H), 0.57 – 0.38 (m, 4H). LCMS m/z = 904.6 [M+1] ⁺ Example 104 (Trifluoroacetic acid salt of compound 104) 101f+4-A (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 (s, 1H), 8.08 – 8.00 (m, 1H), 7.76 (d, 2H), 7.64 (d, 1H), 7.53 – 7.38 (m, 2H), 7.06 – 6.91 (m, 2H), 6.86 (d, 1H), 6.65 (d, 1H), 6.60 – 6.49 (m, 1H), 4.80 – 4.66 (m, 1H), 4.34 – 4.12 (m, 4H), 4.09 – 4.02 (m, 1H), 3.95 – 3.75 (m, 4H), 3.72 – 3.57 (m, 2H), 3.55 – 3.45 (m, 1H), 3.45 – 3.38 (m, 1H), 3.31 – 2.96 (m, 4H), 2.97 – 2.64 (m, 6H), 2.59 – 2.52 (m, 1H), 2.21 – 1.94 (m, 4H), 1.94 – 1.77 (m, 2H), 1.71 – 1.57 (m, 1H), 1.40 – 1.06 (m, 14H), 0.56 – 0.38 (m, 4H). LCMS m/z = 904.6 [M+1] ⁺ Example 106 (Compound 106) 105f+Intermediate 2 (see Example 105 for synthesis) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.76 (s, 1H), 7.73 (d, 2H), 7.64 (d, 1H), 7.46 (d, 1H), 6.95 (d, 2H), 6.79 (d, 1H), 6.71 – 6.58 (m, 2H), 6.54 (dd, 1H), 4.30 – 4.19 (m, 3H), 4.04 (d, 1H), 3.91 – 3.77 (m, 3H), 3.76 – 3.64 (m, 3H), 3.34 (s, 3H), 3.00 – 2.84 (m, 3H), 2.83 – 2.64 (m, 5H), 2.64 LCMS m/z = 835.6 [M+1] ⁺ Example 107 (Compound 107) 105f (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 (s, 1H), 7.94 (t, 1H), 7.73 (d, 2H), 7.64 (d, 1H), 7.46 (d, 1H), 7.36 (d, 1H), 6.95 (d, 2H), 6.74 – 6.61 (m, 2H), 6.54 (dd, 1H), 4.77 – 4.66 (m, 1H), 4.31 – 4.21 (m, 3H), 4.04 (d, 1H), 3.92 – 3.78 (m, 3H), 3.75 – 3.67 (m, 2H), 3.34 (s, 3H), 3.17 – 3.05 (m, 1H), 2.97 – 2.61 (m, 8H), 2.56 – 2.48 (m, 1H), 2.25 – 1.88 (m, 6H), 1.88 – 1.69 (m, 4H), 1.67 – 1.50 (m, 1H), 1.29 – 1.07 (m, 14H). LCMS m/z = 878.6 [M+1] ⁺ Example 108 (Compound 108) 105f+4-A (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 (s, 1H), 7.94 (t, 1H), 7.73 (d, 2H), 7.64 (d, 1H), 7.46 (d, 1H), 7.36 (d, 1H), 6.95 (d, 2H), 6.74 – 6.62 (m, 2H), 6.54 (dd, 1H), 4.78 – 4.67 (m, 1H), 4.32 – 4.21 (m, 3H), 4.04 (d, 1H), 3.92 – 3.77 (m, 3H), 3.76 – 3.65 (m, 2H), 3.34 (s, 3H), 3.17 – 3.04 (m, 1H), 2.98 – 2.60 (m, 8H), 2.55 – 2.48 (m, 1H), 2.25 – 1.87 (m, 6H), 1.87 – 1.69 (m, 4H), 1.68 – 1.51 (m, 1H), 1.29 – 1.07 (m, 14H). LCMS m/z = 878.6 [M+1] ⁺

Example 109 : Preparation of Compound 109

Step 1: Preparation of 109b

109a (5.0 g, 36.47 mmol), (bromomethyl)cyclopropane (6.4 g, 47.41 mmol), potassium carbonate (15.12 g, 109.41 mmol), potassium iodide (0.61 g, 3.67 mmol) and 50 mL DMF were added to the reaction flask and reacted at room temperature for 12 h. 200 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-3:1) to obtain 109b (6.2 g, yield: 89%).

LCMS m/z = 192.1 [M+1] ⁺

Compound 109 was obtained using compounds 109b and 36h as raw materials according to the synthetic method of Example 36.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.76 (s, 1H), 7.73 (d, 2H), 7.63 (d, 1H), 7.46 (d, 1H), 6.95 (d, 2H), 6.79 (d, 1H), 6.66 – 6.58 (m, 2H), 6.52 (dd, 1H), 4.25 (s, 1H), 4.04 (d, 1H), 3.98 (d, 2H), 3.89 – 3.77 (m, 3H), 3.76 – 3.67 (m, 1H), 3.01 – 2.84 (m, 3H), 2.83 – 2.64 (m, 5H), 2.64 – 2.52 (m, 2H), 2.24 – 1.98 (m, 4H), 1.98 – 1.71 (m, 6H), 1.66 – 1.51 (m, 1H), 1.32 – 1.06 (m, 15H), 0.64 – 0.57 (m, 2H), 0.40 – 0.34 (m, 2H).

LCMS m/z = 831.5 [M+1] ⁺

Example 113: Preparation of Compound 113 Trifluoroacetic Acid

Step 1: Preparation of 113b

Dissolve 113a (5 g, 24.63 mmol) in 100 mL tetrahydrofuran, cool to -78°C under nitrogen, add 1 mol/L cyclopropylmagnesium bromide tetrahydrofuran solution (24.63 mL) dropwise, slowly warm to room temperature and react for 3 h. Add 100 mL saturated aqueous ammonium chloride to the reaction solution, extract with ethyl acetate (100 mL×3), combine the organic phases, wash with 100 mL saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the crude product by silica gel chromatography (petroleum ether: ethyl acetate (v/v) = 2:1) to obtain crude 113b (3.3 g).

Step 2: Preparation of 113c

The crude product 113b (4.5 g) was dissolved in 20 mL of dichloromethane, and triethylsilane (3.20 g, 27.52 mmol) and trifluoroacetic acid (12.56 g, 110.16 mmol) were added at 0°C, and the mixture was reacted at 40°C for 2 h. The reaction solution was cooled to room temperature, and the crude product was separated and purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) = 5:1) to obtain 113c (4.0 g, two-step yield based on compound 113a: 52%).

Step 3: Preparation of 113d

Compound 113c (4.0 g, 17.46 mmol) was added to 40 mL of DMF. Zinc cyanide (3.08 g, 26.23 mmol) and tetrakistriphenylphosphine palladium (2.02 g, 1.75 mmol) were added under nitrogen protection and the reaction was carried out at 110°C for 2 h. The reaction solution was cooled to room temperature, 60 mL of water and 60 mL of ethyl acetate were added, the liquids were separated, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (v/v) = 5:1) to obtain 113d (2.2 g, yield: 72%).

LCMS m/z = 176.1 [M+1] ⁺

The trifluoroacetic acid salt of compound 113 was prepared from compounds 113d and 36h by referring to the synthesis method of Example 36 and then freeze-dried in acidic solution (water (containing 0.1% TFA)/acetonitrile).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.79 (s, 1H), 7.81 – 7.65 (m, 3H), 7.50 (d, 1H), 7.04 – 6.93 (m, 3H), 6.91 – 6.83 (m, 2H), 6.80 (d, 1H), 4.25 (s, 1H), 4.12 – 4.00 (m, 2H), 3.96 – 3.79 (m, 3H), 3.68 – 3.55 (m, 2H), 3.41 – 3.27 (m, 1H), 3.19 – 2.98 (m, 4H), 2.93 – 2.59 (m, 8H), 2.57 – 2.46 (m, 1H), 2.21 – 2.05 (m, 2H), 2.05 – 1.75 (m, 4H), 1.70 – 1.54 (m, 1H), 1.38 – 1.09 (m, 14H), 1.09 – 0.96 (m, 1H), 0.57 – 0.47 (m, 2H), 0.31 – 0.24 (m, 2H).

LCMS m/z = 408.4 [M/2+1] ⁺

The following compounds were obtained by referring to other examples of synthesis: Example No. Structure raw material LCMS / ^1H NMR Example 110 (Compound 110) 109f+Intermediate 2 (see Example 109 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.76 (s, 1H), 7.73 (d, 2H), 7.63 (d, 1H), 7.46 (d, 1H), 6.95 (d, 2H), 6.79 (d, 1H), 6.67 – 6.58 (m, 2H), 6.52 (dd, 1H), 4.25 (s, 1H), 4.04 (d, 1H), 3.98 (d, 2H), 3.89 – 3.76 (m, 3H), 3.76 – 3.65 (m, 1H), 3.00 – 2.84 (m, 3H), 2.84 – 2.64 (m, 5H), 2.64 – 2.52 (m, 2H), 2.25 – 1.98 (m, 4H), 1.98 – 1.71 (m, 6H), 1.65 – 1.51 (m, 1H), 1.32 – 1.06 (m, 15H), 0.65 – 0.57 (m, 2H), 0.40 – 0.34 (m, 2H). LCMS m/z = 831.4 [M+1] ⁺ Example 111 (Compound 111) 109f (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 (s, 1H), 7.94 (t, 1H), 7.73 (d, 2H), 7.63 (dd, 1H), 7.46 (d, 1H), 7.35 (d, 1H), 6.95 (d, 2H), 6.68 (d, 1H), 6.60 (s, 1H), 6.55 – 6.48 (m, 1H), 4.77 – 4.66 (m, 1H), 4.25 (s, 1H), 4.03 (d, 1H), 4.01 – 3.93 (m, 2H), 3.92 – 3.76 (m, 3H), 3.18 – 3.05 (m, 1H), 2.96 – 2.86 (m, 2H), 2.86 – 2.60 (m, 6H), 2.58 – 2.45 (m, 1H), 2.24 – 1.88 (m, 6H), 1.87 – 1.71 (m, 4H), 1.67 – 1.51 (m, 1H), 1.31 – 1.09 (m, 15H), 0.66 – 0.55 (m, 2H), 0.41 – 0.33 (m, 2H). LCMS m/z = 874.3 [M+1] ⁺ Example 112 (Compound 112) 109f+4-A (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 (s, 1H), 7.94 (t, 1H), 7.77 – 7.68 (m, 2H), 7.63 (dd, 1H), 7.46 (d, 1H), 7.35 (d, 1H), 6.95 (d, 2H), 6.68 (d, 1H), 6.60 (s, 1H), 6.52 (dd, 1H), 4.77 – 4.67 (m, 1H), 4.25 (s, 1H), 4.03 (d, 1H), 3.98 (d, 2H), 3.92 – 3.79 (m, 3H), 3.16 – 3.06 (m, 1H), 2.97 – 2.86 (m, 2H), 2.86 – 2.61 (m, 6H), 2.59 – 2.45 (m, 1H), 2.24 – 1.87 (m, 6H), 1.87 – 1.70 (m, 4H), 1.67 – 1.51 (m, 1H), 1.31 – 1.09 (m, 15H), 0.66 – 0.54 (m, 2H), 0.42 – 0.32 (m, 2H). LCMS m/z = 874.6 [M+1] ⁺ Example 114 (Trifluoroacetic acid salt of compound 114) 113h+Intermediate 2 (see Example 113 for synthesis) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.79 (s, 1H), 7.82 – 7.67 (m, 3H), 7.50 (d, 1H), 7.05 – 6.92 (m, 3H), 6.91 – 6.82 (m, 2H), 6.80 (d, 1H), 4.25 (s, 1H), 4.13 – 4.01 (m, 2H), 3.98 – 3.76 (m, 3H), 3.69 – 3.55 (m, 2H), 3.43 – 3.27 (m, 1H), 3.19 – 2.95 (m, 4H), 2.95 – 2.59 (m, 8H), 2.59 – 2.46 (m, 1H), 2.21 – 2.05 (m, 2H), 2.05 – 1.75 (m, 4H), 1.73 – 1.54 (m, 1H), 1.39 – 1.09 (m, 14H), 1.09 – 0.95 (m, 1H), 0.58 – 0.47 (m, 2H), 0.32 – 0.24 (m, 2H). LCMS m/z = 408.4 [M/2+1] ⁺ Example 115 (Trifluoroacetic acid salt of compound 115) 113h (see Example 5 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 (s, 1H), 8.08 – 7.99 (m, 1H), 7.77 (d, 2H), 7.71 (d, 1H), 7.49 (d, 1H), 7.43 (d, 1H), 7.04 – 6.94 (m, 3H), 6.91 – 6.81 (m, 2H), 4.77 – 4.68 (m, 1H), 4.31 – 4.14 (m, 2H), 4.10 – 4.01 (m, 1H), 3.98 – 3.83 (m, 2H), 3.71 – 3.58 (m, 2H), 3.55 – 3.41 (m, 1H), 3.28 – 2.99 (m, 4H), 2.95 – 2.64 (m, 8H), 2.59 – 2.52 (m, 1H), 2.20 – 1.94 (m, 4H), 1.94 – 1.76 (m, 2H), 1.71 – 1.58 (m, 1H), 1.39 – 1.09 (m, 14H), 1.08 – 0.97 (m, 1H), 0.56 – 0.48 (m, 2H), 0.34 – 0.24 (m, 2H). Example 116 (Trifluoroacetic acid salt of compound 116) 113h + 4-A (see Example 5 for synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.82 (s, 1H), 8.07 – 7.99 (m, 1H), 7.77 (d, 2H), 7.71 (d, 1H), 7.49 (d, 1H), 7.43 (d, 1H), 7.04 – 6.95 (m, 3H), 6.90 – 6.81 (m, 2H), 4.78 – 4.68 (m, 1H), 4.30 – 4.14 (m, 2H), 4.10 – 4.02 (m, 1H), 3.97 – 3.83 (m, 2H), 3.71 – 3.58 (m, 2H), 3.54 – 3.41 (m, 1H), 3.28 – 2.99 (m, 4H), 2.94 – 2.64 (m, 8H), 2.59 – 2.52 (m, 1H), 2.20 – 1.95 (m, 4H), 1.94 – 1.76 (m, 2H), 1.71 – 1.58 (m, 1H), 1.39 – 1.09 (m, 14H), 1.09 – 0.97 (m, 1H), 0.57 – 0.48 (m, 2H), 0.32 – 0.24 (m, 2H).

Example 117: Preparation of Compound 117

Step 1: Preparation of 117b

117a (5.00 g, 25.0 mmol), cyclopropylboronic acid (2.79 g, 32.48 mmol), sodium acetate (0.56 g, 2.49 mmol), tricyclohexylphosphine (0.76 g, 2.71 mmol), potassium phosphate (15.92 g, 75.0 mmol) and 100 mL toluene were added to the reaction flask, and the reaction was carried out at 100°C for 3 h under nitrogen protection. The reaction system was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:0-9:1) to obtain 117b (3.8 g, yield: 94%).

Compound 117 was obtained using compounds 117b and 36h as raw materials according to the synthetic method of Example 36.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.75 (s, 1H), 7.79 – 7.60 (m, 3H), 7.45 (d, 1H), 6.95 (d, 2H), 6.79 (dd, 2H), 6.62 (d, 1H), 6.45 (d, 1H), 4.24 (s, 1H), 4.03 (d, 1H), 3.93 – 3.76 (m, 3H), 3.76 – 3.64 (m, 1H), 3.00 – 2.84 (m, 3H), 2.84 –2.55 (m, 6H), 2.55 – 2.46 (m, 1H), 2.25 – 2.00 (m, 5H), 1.99 – 1.70 (m, 6H), 1.68 – 1.52 (m, 1H), 1.29 – 1.05 (m, 16H), 0.86 – 0.74 (m, 2H).

LCMS m/z = 801.4 [M+1] ⁺

Example 119: Preparation of Compound 119

Compound 119 was prepared from compound 117f by the synthesis method of Example 5, and then freeze-dried (10 mmol/L aqueous ammonium bicarbonate solution/acetonitrile).

¹ H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.94 (t, 1H), 7.79 – 7.63 (m, 3H), 7.46 (d, 1H), 7.36 (d, 1H), 6.95 (d, 2H), 6.79 (dd, 1H), 6.68 (d, 1H), 6.45 (d, 1H), 4.79 – 4.66 (m, 1H), 4.24 (s, 1H), 4.03 (d, 1H), 3.95 – 3.74 (m, 3H), 3.17 – 3.05 (m, 1H), 2.98 – 2.62 (m, 8H), 2.58 – 2.48 (m, 1H), 2.25 – 1.97 (m, 6H), 1.97 – 1.87 (m, 1H), 1.87 – 1.69 (m, 4H), 1.68 – 1.51 (m, 1H), 1.25 – 1.07 (m, 16H), 0.85 – 0.75 (m, 2H).

LCMS m/z = 844.5 [M+1]+

The following compounds were obtained by referring to other examples of synthesis: Example No. Structure raw material LCMS / ^1H NMR Example 118 (Compound 118) 117f + intermediate 2 (see Example 117 for synthesis) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.75 (s, 1H), 7.78 – 7.61 (m, 3H), 7.45 (d, 1H), 6.95 (d, 2H), 6.79 (dd, 2H), 6.62 (d, 1H), 6.45 (d, 1H), 4.24 (s, 1H), 4.03 (d, 1H), 3.91 – 3.77 (m, 3H), 3.76 – 3.66 (m, 1H), 3.00 – 2.84 (m, 3H), 2.84 – 2.64 (m, 5H), 2.64 – 2.55 (m, 1H), 2.54 – 2.46 (m, 1H), 2.24 – 2.00 (m, 5H), 1.99 – 1.71 (m, 6H), 1.66 – 1.52 (m, 1H), 1.27 – 1.05 (m, 16H), 0.84 – 0.76 (m, 2H). LCMS m/z = 801.4 [M+1] ⁺ Example 120 (Compound 120) 117f + 4-A (see Example 119 for synthesis) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.81 (s, 1H), 7.93 (t, 1H), 7.78 – 7.63 (m, 3H), 7.45 (d, 1H), 7.36 (d, 1H), 6.95 (d, 2H), 6.79 (dd, 1H), 6.68 (d, 1H), 6.45 (d, 1H), 4.79 – 4.67 (m, 1H), 4.24 (s, 1H), 4.03 (d, 1H), 3.92 – 3.72 (m, 3H), 3.17 – 3.06 (m, 1H), 2.98 – 2.61 (m, 8H), 2.58 – 2.47 (m, 1H), 2.25 – 1.97 (m, 6H), 1.97 – 1.87 (m, 1H), 1.87 – 1.68 (m, 4H), 1.68 – 1.51 (m, 1H), 1.25 – 1.07 (m, 16H), 0.85 – 0.76 (m, 2H). LCMS m/z = 844.4 [M+1] ⁺ Example 121 (Trifluoroacetic acid salt of compound 121) 16f + intermediate 2 (see Example 1 for synthesis method) ¹ H NMR (400 MHz, CD ₃ OD) δ 7.81 – 7.70 (m, 2H), 7.52 (d, 1H), 7.12 – 7.01 (m, 2H), 6.90 (d, 1H), 6.70 (d, 1H), 6.62 (d, 1H), 6.55 (dd, 1H), 4.26 (s, 1H), 4.17 – 4.05 (m, 2H), 3.93 (s, 3H), 3.87 (dd, 1H), 3.83 – 3.71 (m, 1H), 3.67 – 3.50 (m, 2H), 3.42 – 3.35 (m, 2H), 3.34 – 3.22 (m, 3H), 3.13 – 2.94 (m, 2H), 2.89 – 2.59 (m, 5H), 2.48 – 2.35 (m, 2H), 2.30 – 1.99 (m, 5H), 1.93 – 1.68 (m, 5H), 1.26 (d, 12H). LCMS m/z = 817.6 [M+1] ⁺ Example 122 (Trifluoroacetic acid salt of compound 122) 16f + intermediate 1 (see Example 1 for the synthesis method) ¹ H NMR (400 MHz, CD ₃ OD) δ 7.79 – 7.70 (m, 2H), 7.52 (d, 1H), 7.11 – 7.01 (m, 2H), 6.90 (d, 1H), 6.71 (d, 1H), 6.62 (d, 1H), 6.55 (dd, 1H), 4.26 (s, 1H), 4.17 – 4.07 (m, 2H), 3.93 (s, 3H), 3.87 (dd, 1H), 3.83 – 3.71 (m, 1H), 3.67 – 3.50 (m, 2H), 3.42 – 3.35 (m, 2H), 3.33 – 3.24 (m, 3H), 3.12 – 2.95 (m, 2H), 2.89 – 2.59 (m, 5H), 2.48 – 2.35 (m, 2H), 2.30 – 2.17 (m, 1H), 2.17 – 2.04 (m, 4H), 1.90 – 1.69 (m, 5H), 1.26 (d, 12H). LCMS m/z = 817.6 [M+1] ⁺

Example 127: Preparation of Compound 127

Step 1: Preparation of 127b

Dissolve 127a (4.98 g, 18.35 mmol) (synthesis method, see CN112912376) in 20 mL of dichloromethane, add 10 mL of trifluoroacetic acid, and react at room temperature for 3 h. Reduce the pressure and concentrate the reaction solution, add 50 mL of DMSO to dissolve, add DIPEA (11.86 g, 91.76 mmol) and tert-butyl 4-fluorobenzoate (3.6 g, 18.35 mmol) respectively, and react at 100°C for 19 h. The reaction solution was cooled to room temperature, 100 mL of water and 100 mL of ethyl acetate were added, the liquid was separated, the aqueous phase was extracted with ethyl acetate (80 mL×3), the organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (v/v) = 5:1-1:1) to obtain 127b (2.75 g, yield: 43%).

Step 2: Preparation of 127c

Dissolve 127b (0.4 g, 1.15 mmol) in 2 mL of dichloromethane, add triethylamine (0.58 g, 5.73 mmol), cool the system to -50 ^° C and slowly add trifluoromethanesulfonic anhydride (0.39 g, 1.38 mmol), return to room temperature and react for 3 h. The reaction solution was concentrated under reduced pressure to obtain crude product 127c (1.0 g).

Step 3: Preparation of 127d

The crude product 127c (1.0 g) was dissolved in 5 mL of acetonitrile, and DIPEA (0.59 g, 4.6 mmol) and the crude intermediate 1 (0.30 g) were added respectively, and the reaction was carried out at room temperature for 19 h. 10 mL of water and 20 mL of ethyl acetate were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (80 mL×3). The organic phases were combined, washed with 50 mL of saturated salt water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) = 5:1-2:1) to obtain 127d (0.45 g, two-step yield based on compound 127b: 60%).

Step 4: Preparation of 127e hydrochloride

Dissolve 127d (0.2 g, 0.31 mmol) in 2 mL of dichloromethane, add 4 mol/L hydrochloric acid ethyl acetate solution (5 mL), and react at room temperature for 5 h. The reaction solution was concentrated under reduced pressure to obtain the crude hydrochloride of 127e (0.22 g).

LCMS m/z = 591.3 [M+1] ⁺

Step 5: Preparation of compound 127

The crude product 127e hydrochloride (0.22 g) was dissolved in 5 mL DMF, and DIPEA (0.2 g, 1.55 mmol), HATU (0.18 g, 0.47 mmol) and 123A hydrochloride (96 mg, 0.31 mmol) were added respectively, and the reaction was carried out at room temperature under nitrogen atmosphere for 16 h. 50 mL of ethyl acetate and 50 mL of purified water were added to the reaction solution, the aqueous phase was extracted with ethyl acetate (25 mL×2), the organic phases were combined, washed with 25 mL of saturated saline, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (v/v) = 1:2) to obtain compound 127 (110 mg, two-step yield based on compound 127d: 42%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 (s, 1H), 7.67 (d, 2H), 7.45 (d, 1H), 6.96 – 6.86 (m, 2H), 6.72 (d, 1H), 6.53 – 6.43 (m, 2H), 6.40 (dd, 1H), 6.10 (d, 1H), 4.33 – 4.20 (m, 1H), 4.18 – 4.10 (m, 1H), 4.04 (s, 1H), 3.91 (s, 3H), 3.84 – 3.72 (m, 1H), 3.71 – 3.56 (m, 3H), 3.56 – 3.46 (m, 1H), 3.12 – 2.71 (m, 9H), 2.70 – 2.59 (m, 2H), 2.32 – 2.07 (m, 6H), 2.03 – 1.84 (m, 4H), 1.79 – 1.62 (m, 4H), 1.24 (d, 12H).

LCMS m/z = 847.4 [M+1] ⁺

The following compounds were obtained by referring to other examples of synthesis: Example No. Structure raw material LCMS / ^1H NMR Example 128 (Compound 128) 127c + intermediate 2 (see Example 127 for synthesis) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 (s, 1H), 7.68 (d, 2H), 7.45 (d, 1H), 6.97 – 6.85 (m, 2H), 6.72 (d, 1H), 6.53 – 6.42 (m, 2H), 6.40 (dd, 1H), 6.09 (d, 1H), 4.35 – 4.20 (m, 1H), 4.20 – 4.11 (m, 1H), 4.04 (s, 1H), 3.91 (s, 3H), 3.86 – 3.56 (m, 4H), 3.56 – 3.44 (m, 1H), 3.12 – 2.70 (m, 9H), 2.70 – 2.58 (m, 2H), 2.33 – 2.06 (m, 6H), 2.06 – 1.83 (m, 4H), 1.79 – 1.61 (m, 4H), 1.24 (d, 12H). LCMS m/z = 847.4 [M+1] ⁺ Example 129 (Compound 129) 127c+28f (see Examples 127 and 15 for the synthesis method) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.32 (s, 1H), 7.77 – 7.69 (m, 2H), 7.64 (d, 1H), 7.49 (d, 1H), 7.00 – 6.89 (m, 3H), 6.72 (d, 1H), 6.67 – 6.60 (m, 1H), 6.56 – 6.50 (m, 1H), 4.27 (s, 1H), 4.22 – 4.13 (m, 1H), 4.05 (d, 1H), 3.91 (s, 3H), 3.81 – 3.72 (m, 1H), 3.70 – 3.55 (m, 4H), 3.54 – 3.45 (m, 1H), 3.04 – 2.87 (m, 5H), 2.82 – 2.56 (m, 6H), 2.26 – 2.14 (m, 2H), 2.04 – 1.94 (m, 2H), 1.94 – 1.78 (m, 4H), 1.65 – 1.41 (m, 4H), 1.18 (d, 12H). LCMS m/z = 848.4 [M+1] ⁺ Example 130 (Compound 130) 127c+29f (see Examples 127 and 15 for synthesis) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.32 (s, 1H), 7.77 – 7.68 (m, 2H), 7.64 (d, 1H), 7.49 (d, 1H), 7.01 – 6.88 (m, 3H), 6.72 (d, 1H), 6.69 – 6.60 (m, 1H), 6.57 – 6.50 (m, 1H), 4.27 (s, 1H), 4.24 – 4.12 (m, 1H), 4.05 (d, 1H), 3.91 (s, 3H), 3.82 – 3.70 (m, 1H), 3.70 – 3.55 (m, 4H), 3.54 – 3.45 (m, 1H), 3.05 – 2.85 (m, 5H), 2.82 – 2.56 (m, 6H), 2.27 – 2.14 (m, 2H), 2.05 – 1.94 (m, 2H), 1.94 – 1.78 (m, 4H), 1.67 – 1.40 (m, 4H), 1.18 (d, 12H). LCMS m/z = 848.4 [M+1] ⁺ .

Biological test examples

1. Detection of AR degradation in VCap cells

VCap is a human prostate cancer cell line purchased from ATCC. The culture conditions are: DMEM + 10% FBS + 1% double antibody, cultured at 37°C, 5% CO ₂ incubator. Cells were plated in 6-well plates, 5×10 ⁵ cells/well. After plating, different concentrations of compounds were added and cultured in a 37°C, 5% CO ₂ incubator for 24 hours. After the culture, the cells were collected and lysed on ice for 15 minutes with RIPA lysis buffer (beyotime, Cat. P0013B). The cells were centrifuged at 12,000 rpm and 4°C for 10 minutes. The supernatant protein samples were collected and quantified using a BCA reagent kit (Beyotime, Cat. P0009). The protein was diluted to 0.25 mg/mL and the expression of AR (CST, Cat.5153S) and internal reference β-actin (CST, Cat. 3700S) was detected using a fully automatic protein blotting quantitative analyzer (Proteinsimple). The relative peak area of AR was calculated using the "Compass for SW" software when the internal reference area was 10,000. The percentage of AR relative to the solvent control group at different drug concentrations was calculated according to formula (1), where AR _treat is the relative peak area of the drug group and AR _solvent is the relative peak area of the solvent control group. The DC ₅₀ value was calculated using GraphPad Prism 8.3.0 software and a four-parameter nonlinear regression model based on the data processed according to formula (1); the degradation rate at a specific concentration was determined to be 100-AR; AR%=AR _treat/ AR _solvent ×100% Formula 1 The DC ₅₀ value of AR protein degradation in VCaP cells is shown in Table 1.

Table 1 DC ₅₀ values of the compounds of the present invention for degradation of AR protein in VCaP cells Serial number Compound No. DC ₅₀ (nM) Serial number Compound No. DC ₅₀ (nM) 1 Trifluoroacetate of compound 1 <100 29 Compound 37 <100 2 Chiral isomer 1 of compound 1 <100 30 Compound 38 <100 3 Chiral isomer 2 of compound 1 <100 31 Compound 39 <100 4 Trifluoroacetate of compound 2 <100 32 Compound 40 <100 5 Trifluoroacetate of compound 3 <100 33 Compound 42 <100 6 Trifluoroacetate of compound 4 <100 34 Compound 43 <100 7 Trifluoroacetate of compound 5 <100 35 Trifluoroacetate of compound 44 <100 8 Trifluoroacetate of compound 7 <100 36 Compound 48 <100 9 Trifluoroacetate of compound 9 <100 37 Compound 49 <100 10 Trifluoroacetate of compound 10 <100 38 Compound 50 <100 11 Compound 11 <100 39 Compound 51 <100 12 Compound 13 <100 40 Compound 54 <100 13 Compound 14 <100 41 Compound 55 <100 14 Compound 15 <100 42 Compound 56 <100 15 Trifluoroacetate of compound 18 <100 43 Compound 58 <100 16 Trifluoroacetate of compound 20 <100 44 Trifluoroacetate of compound 60 <100 17 Trifluoroacetate salt of compound 21 <100 45 Trifluoroacetate salt of compound 61 <100 18 Trifluoroacetate of compound 22 <100 46 Trifluoroacetate salt of compound 62 <100 19 Trifluoroacetate of compound 24 <100 47 Trifluoroacetate salt of compound 63 <100 20 Trifluoroacetate of compound 25 <100 48 Compound 72 <100 twenty one Compound 28 <100 49 Compound 73 <100 twenty two Compound 29 <100 50 Compound 78 <100 twenty three Compound 30 <100 51 Compound 79 <100 twenty four Compound 31 <100 52 Compound 80 <100 25 Compound 32 <100 53 Compound 82 <100 26 Trifluoroacetate of compound 33 <100 54 Compound 83 <100 27 Compound 34 <100 55 Trifluoroacetate salt of compound 84 <100 28 Compound 35 <100

Table 2 The degradation rate of AR protein in VCaP cells by the compounds of the present invention at a concentration of 30 nM Serial number Compound No. Degradation rate% 1 Compound 93 >70% 2 Trifluoroacetate of compound 99 >70% 4 Compound 117 >70% 5 Compound 118 >70% 6 Compound 119 >70% 7 Trifluoroacetate salt of compound 121 >70%

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

2. Pharmacokinetics test in rats

Purpose: This study administered the test substance to SD rats by intravenous and oral administration of a single dose, measured the concentration of the test substance in rat plasma, and evaluated the pharmacokinetic characteristics of the test substance in rats.

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

Experimental method: On the day of the experiment, 6 SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 h one day before drug administration and were fed 4 h after drug administration.

Table 3 Drug administration information for rat pharmacokinetic test Group quantity Medication Information male Test substance Dosage* (mg/kg) Dosage concentration (mg/mL) Dosage volume (mL/kg) Collect samples How to give medicine solvent G1 3 Compounds of the present invention 5 0.5 10 Plasma Oral (gavage) 5%DMSO+5%Solutol+90%(20%SBE-β-CD) G2 3 Compounds of the present invention 2 0.4 5 Plasma Intravenous injection 5%DMA+5%Solutol+90%Saline

*Dosage is based on free base.

Sampling: Before and after drug administration, 0.1 mL of blood was collected from the eye socket under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. The tube was centrifuged at 5000 rpm, 4 ^° C for 10 min, and the plasma was collected.

The time points for plasma collection in the IV&PO group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, 24, and 48 h.

All samples were stored at -60 ^° C before analysis. Quantitative analysis of samples was performed using LC-MS/MS.

Table 4 Pharmacokinetic parameters of the compounds of the present invention in rat plasma Test compound How to give medicine AUC _0-t (hr*ng/mL) F (%) Control compound ^### ig (5 mg/kg) 2867±338 26.9±3.2 Compound 1 ^### ig (5 mg/kg) 5494±1011 46.5±8.6 Compound 2 ^# ig (5 mg/kg) 6009±889 61.4±9.1 Compound 31 ^## ig (5 mg/kg) 5427±1362 49.1±12 Trifluoroacetate of compound 60 ^### ig (5 mg/kg) 6605±349 57.5±3.0 Trifluoroacetic acid salt of compound 61 ^### ig (5 mg/kg) 5463±1776 43.5±14 Compound 79 ^## ig (5 mg/kg) 6968±2007 -

^#Oral solvent is 5% DMSO+ 5%Solutol+30%PEG-400+60% (20%SBE-β-CD)

^## Oral solvent is 5% DMSO + 5% Solutol + 10% PEG400 + 80% (20% SBE-β-CD)

^### Oral solvent is 5%DMSO+5%Solutol+90%(20%SBE-β-CD)

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

3. Inhibition of VCaP cell proliferation experiment

Prostate cancer cells VCaP were purchased from ATCC, and the cell culture medium was 1640 + 10% FBS, and cultured in an incubator at 37 ºC, 5% CO _2. Before the experiment, cells cultured in normal culture medium were subcultured to phenol red-free RPMI1640 containing 10% activated carbon-adsorbed FBS and cultured for 3 days. On the 4th day, cells were digested with phenol red-free digestion solution (Trypsin LE trypsin), and digestion was terminated with phenol red-free RPMI1640 medium containing 1% activated carbon-absorbed FBS + 0.5% PS + 0.1nM R1881. The cells were resuspended by centrifugation and the viable cells were counted using a Vi-Cell XR cell counter. The cell suspension was adjusted to an appropriate concentration with phenol red-free RPMI1640 medium containing 1% activated carbon-absorbed FBS + 0.5% PS + 0.1nM R1881. 180 µl of the cell suspension was added to each well of a 96-well cell culture plate to make 7500 cells/well. The plate was also plated in the T0 well. The next day, a final concentration of 0.1 nM R1881 and compounds of different concentrations were placed in an incubator and incubated for 7 days. At the same time as the drug was added, the _T0 plate was detected using the CellTiter-Glo (CTG) (Promega, product number: G7572) reagent kit, which was recorded as RLU _0. After the incubation, 75 µl of CellTiter-Glo solution that had been melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes before the fluorescence signal value was measured using an Envision2104 plate reader. The results were processed according to formula (2), and the cell growth rate of each concentration of the compound was calculated in Excel, and the concentration GI ₅₀ value of the compound when the proliferation rate was 50% was calculated using GraphPad software. Where RLU _compound is the reading of the drug-treated group, and RLU _control is the average value of the solvent control group. Growth % = (RLU _compound - RLU ₀ ) / (RLU _control - RLU ₀ ) × 100% Formula (2) The GI ₅₀ value results for inhibiting VCaP cell proliferation are shown in Table 5.

Table 5 GI ₅₀ values of the compounds of the present invention for inhibiting VCaP cell proliferation Serial number Compound No. GI ₅₀ (nM) Serial number Compound No. GI ₅₀ (nM) 1 Control compound ＞2000 15 Trifluoroacetate salt of compound 65 ＜300 2 Compound 1 ＜300 16 Trifluoroacetate salt of compound 66 ＜300 3 Compound 11 ＜300 17 Trifluoroacetate salt of compound 67 ＜300 4 Trifluoroacetate of compound 33 ＜500 18 Trifluoroacetate salt of compound 68 ＜300 5 Compound 36 ＜300 19 Trifluoroacetate salt of compound 69 ＜300 6 Compound 37 ＜300 20 Trifluoroacetate salt of compound 70 ＜500 7 Compound 40 ＜300 twenty one Trifluoroacetate salt of compound 71 ＜500 8 Compound 41 ＜300 twenty two Compound 79 ＜300 9 Compound 52 ＜300 twenty three Compound 85 ＜300 10 Compound 53 ＜300 twenty four Compound 86 ＜300 11 Compound 57 ＜500 25 Compound 87 ＜500 12 Compound 59 ＜300 26 Compound 88 ＜500 13 Trifluoroacetate of compound 60 ＜300 27 Compound 94 ＜300 14 Trifluoroacetate salt of compound 61 ＜300

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

4. Caco2 permeability test

The experiment used a monolayer of Caco-2 cells and was incubated in triplicate in a 96-well Transwell plate. A transport buffer solution (HBSS, 10 mM HEPES, pH 7.4±0.05) containing the compound of the present invention (2 μM) or the control compounds digoxin (10 μM), nadolol (2 μM) and metoprolol (2 μM) was added to the drug-administering wells on the apical or basolateral side. A transport buffer solution containing DMSO was added to the corresponding receiving wells. After incubation at 37±1°C for 2 hours, the cell plate was removed and appropriate amounts of samples were taken from the top and bottom ends to a new 96-well plate. Subsequently, acetonitrile containing an internal standard was added to precipitate the protein. The samples were analyzed using LC MS/MS and the concentrations of the compound of the present invention and the control compound were determined. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to the basolateral side of the monolayer and vice versa, and thus the efflux rate. The integrity of the monolayer was assessed after 2 hours of incubation by leakage of fluorescent yellow.

Conclusion: The compounds of the present invention, such as the compounds of the examples, have good Caco2 permeability.

5. Pharmacokinetics test in mice

Purpose: This study administered the test substance to ICR mice by intravenous and oral administration of a single dose, measured the concentration of the test substance in mouse plasma, and evaluated the pharmacokinetic characteristics of the test substance in mice.

Experimental animals: Male ICR mice, 6 mice/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

Experimental method: On the day of the experiment, 6 SD mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 h one day before drug administration, and were fed 4 h after drug administration.

Table 6 Drug administration information for mouse pharmacokinetic test Group quantity Medication Information male Test substance Dosage* (mg/kg) Dosage concentration (mg/mL) Dosage volume (mL/kg) Collect samples How to give medicine solvent G1 3 Compounds of the present invention 5 0.5 10 Plasma Oral (gavage) Solvent 1: 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE-CD) Solvent 2: 5% DMSO+5% Solutol+10% PEG400+80% (20% SBE-CD) Solvent 3: 5%DMSO+5%Solutol+90%(20%SBE-β-CD) G2 3 Compounds of the present invention 2 0.4 5 Plasma Intravenous injection 5%DMA+5%HS+90%NS

*Dosage is based on free base.

Sampling: Before and after drug administration, 0.15 mL of blood was collected through the eye socket under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. The tube was centrifuged at 5000 rpm, 4 ^° C for 10 min, and the plasma was collected.

The time points for plasma collection in the PO group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, 24, and 48 h.

The time points for plasma collection in group IV were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, 24, and 48 h.

All samples were stored at -60 ^° C before analysis. Quantitative analysis of samples was performed using LC-MS/MS.

Table 7 Pharmacokinetic parameters of the compounds of the present invention in mouse plasma Test compound How to give medicine solvent AUC _0-t (hr*ng/mL) F (%) Control compound ig (5 mg/kg) solvent 1 20727±1076 63.4±3.3% Compound 13 ig (5 mg/kg) solvent 1 33521±1683 - Compound 30 ig (5 mg/kg) Solvent 3 33000±9331 - Compound 32 ig (5 mg/kg) Solvent 3 30874±6079 - Trifluoroacetate of compound 60 ig (5 mg/kg) Solvent 3 41602±4140 84.2±8.4% Trifluoroacetate salt of compound 61 ig (5 mg/kg) Solvent 3 28537±3461 98.8±12% Trifluoroacetate salt of compound 66 ig (5 mg/kg) Solvent 3 30449±9308 -

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

6. Beagle dog pharmacokinetic test

Experimental animals: Male beagle dogs, about 8-10 kg, 6 per compound, purchased from Beijing Mars Biotechnology Co., Ltd.

Test method: On the day of the test, 6 beagles were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours before drug administration, and were fed 4 hours after drug administration.

Table 8. Dosage information for beagle dog pharmacokinetic test Group quantity Medication Information male Test compound Dosage (mg/kg) Dosage concentration (mg/mL) Dosage volume (mL/kg) Collect samples How to give medicine G1 3 Compounds of the present invention 0.5 0.5 1 Plasma Venous G2 3 Compounds of the present invention 2 0.4 5 Plasma Oral (gavage)

Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% NS;

Oral (gavage) administration solvent: 5% DMSO + 5% Solutol + 10% PEG400 + 80% (20% SBE-CD);

*Dosage is based on free base.

Before and after drug administration, 1 ml of blood was collected from the cervical vein or limb vein and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4°C for 10 min, and the plasma was collected. The blood sampling time points for the intravenous group and the gavage group were: 0, 5, 15, 30min, 1, 2, 4, 6, 8, 10, 12, 24, 48 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

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

7. Pharmacokinetics in Monkeys

Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

Experimental method: On the day of the experiment, 4 monkeys were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours one day before drug administration, and were fed 4 hours after drug administration.

Table 9. Dosage information for monkey pharmacokinetic test Group quantity Medication Information male Test compound Dosage (mg/kg) Dosage concentration (mg/mL) Dosage volume (mL/kg) Collect samples How to give medicine G1 2 Compounds of the present invention 0.5 0.5 1 Plasma Venous G2 2 Compounds of the present invention 2 0.4 5 Plasma Oral (gavage)

Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% NS;

Oral (gavage) administration solvent: 5% DMSO + 5% Solutol + 10% PEG400 + 80% (20% SBE-CD);

*Dosage is based on free base.

Before and after drug administration, 1.0 mL of blood was collected from the cervical vein and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4 ^° C for 10 min, and the plasma was collected. The blood sampling time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48 h. Before analysis and detection, all samples were stored at -60 ^° C and quantitatively analyzed by LC-MS/MS.

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

8. hERG potassium channel function test

Experimental platform: Electrophysiology manual patch clamp system

Cell line: Chinese hamster ovary (CHO) cell line that stably expresses the hERG potassium channel

Experimental methods: CHO (Chinese Hamster Ovary) cells that stably express hERG potassium channels were used to record hERG potassium channel currents at room temperature using the whole-cell patch clamp technique. The glass microelectrode was pulled from a glass electrode blank (BF150-86-10, Sutter) using a puller. The tip resistance after perfusion of the electrode liquid was about 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2kHz. After obtaining whole-cell recordings, cells were clamped at -80 mV, and the step voltage to induce hERG potassium current ( I _hERG ) was given from -80 mV to +20 mV for 2 s, then repolarized to -50 mV, and returned to -80 mV after 1 s. This voltage stimulation was given every 10 s, and the drug administration process was started after confirming that the hERG potassium current was stable (at least 1 minute). The compound was given for at least 1 minute at each tested concentration, and at least 2 cells (n ≥ 2) were tested at each concentration.

Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5 and Excel software. The degree of inhibition of hERG potassium current (peak value of hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula: Inhibition % = [1 – ( I / I o)] × 100%

Wherein, Inhibition % represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current before and after drug addition, respectively.

The _IC50 of the compound was calculated using GraphPad Prism 5 software by fitting the following equation: Y=Bottom + (Top-Bottom)/(1+10^(( _LogIC50 -X)*HillSlope))

Among them, X is the Log value of the test concentration of the test product, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

Conclusion: The compounds of the present invention, such as the example compounds, have no obvious inhibitory effect on the hERG potassium channel current. Specifically, the trifluoroacetic acid salt of compound 1, the trifluoroacetic acid salt of 2, the trifluoroacetic acid salt of 3, the trifluoroacetic acid salt of 4, compounds 11, 28, 30, 31, 34, 35, 73, 79, and 118 have inhibitory activity _IC50 values on the hERG potassium channel current that are all greater than 40µM.

9. Liver microsome stability test

This experiment uses liver microsomes from five species, including humans, dogs, rats, and mice, as in vitro models to evaluate the metabolic stability of the test substances.

At 37°C, 1 µM of the test substance was incubated with microsomal proteins and coenzyme NADPH. After a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing the internal standard was added to terminate the reaction. The concentration of the test substance in the sample was detected by LC-MS/MS. T _1/2 was calculated using the ln value of the drug residue rate in the incubation system and the incubation time. The hepatic microsomal intrinsic clearance CL _int(mic) and the hepatic intrinsic clearance CL _int(Liver) were further calculated.

Conclusion: The compounds of the present invention, such as the compounds in the examples, have good liver microsome stability.

10. CYP450 enzyme inhibition test

The purpose of this study was to evaluate the effects of the test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system. Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the samples were treated and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS), the changes in CYP enzyme activity were measured, and the IC ₅₀ values were calculated to evaluate the inhibitory potential of the test substances on each CYP enzyme subtype.

Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on the five isozymes of CYP.

11. Human CD34+ hematopoietic stem cell proliferation inhibition experiment

Human CD34+ Hematopoietic stem cells (TPCS, Cat.hmPB34-P-2CW) are CD34-positive stem cells obtained from human PBMC by immunomagnetic sorting. The culture conditions are: DPBS (Gibco, Cat.14190-144) + StemSpan SFEM II (STEMCELL, Cat.9655) + 1X StemSpan CD34+ Expansion Supplement (STEMCELL, Cat.2691). First, 40 nL of DMSO, positive reference Talazoparib or test compound were added to a 384-well plate (Corning, Cat.3764), and then the cell suspension was added, 400 cells/40 μL/well, so that the final concentration of each well was 0.1% DMSO, 3 μM Talazoparib or different concentrations of compounds, centrifuged at 1000 rpm for 1 minute at room temperature, and then cultured in a 37°C, 5% CO ₂ incubator for 7 days. After the incubation, 20 μL of CellTiter-Glo Reagent (Promega, Cat.G7573) was directly added to each well, centrifuged at 1000 rpm for 1 minute at room temperature, and then incubated in the dark for 20 minutes. After the incubation, the Envision multi-mode microplate reader (PerkinElmer, Cat.2104) was used to read and record the chemiluminescent signal CFU. The cell proliferation inhibition rate of compounds at different concentrations was calculated according to formula (3), where CFU _{high control} was the average signal value of the DMSO group, CFU _{low control} was the average signal value of the Talazoparib group, and CFU _compound was the average signal value of the compound group. The data processed according to formula (3) were used to fit the curve using XLfit or GraphPad Prism software using four parameters to calculate the concentration _IC50 value of the compound when the inhibition rate was 50%. Inhibiton% = (CFU _{high control} -CFU _compound )/(CFU _{high control} -CFU _{low control} ) ×100% (Formula 3)

Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on the proliferation of CD34+ hematopoietic stem cells. Specifically, the _IC50 values of the trifluoroacetic acid salt of compound 7, compound 11, and compound 31 on the proliferation inhibition activity of CD34+ hematopoietic stem cells are all greater than 10000 nM.

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

Human prostate cancer cells MDA-PCA-2B were cultured in complete cell culture medium of F-12K+20%FBS+25 ng/ml cholera toxin+10 ng/ml mouse Epidermal Growth Factor+0.005 mM phosphoethanolamine+100 pg/ml hydrocortisone+45 nM sodium selenite+0.005 mg/ml insulin at 37°C, 5% CO ₂ incubator. Cells in exponential growth phase were collected, and the cell suspension was adjusted to the corresponding concentration with hormone-depleted culture medium (containing 10% carbon-absorbed serum) and plated in 12-well plates at 5×10 ⁵ cells/well. After plating, the cells were cultured in an incubator for 72 hours, then the medium was replaced with experimental medium (containing 1% carbon-adsorbed serum), and different concentrations of compounds were added. The cells were cultured in an incubator at 37°C and ₅ % CO2 for 24 hours. After the incubation, the cells were washed with pre-cooled PBS and then added with complete cell lysis buffer containing Protease/Phosphatase Inhibitor Cocktail (Cell lysis buffer information: CST, Cat. 9803, diluted to 1X before use, Protease/Phosphatase Inhibitor Cocktail (100X) information: Cat.5872. The Cocktail was then diluted 100 times with 1X cell lysis buffer to obtain complete cell lysis buffer). After lysing on ice for 15 minutes, the cells were scraped with a cell scraper and placed in a new pre-cooled EP tube. The cells were centrifuged at 13500 rpm and 4 ℃ for 20 minutes, and the supernatant protein samples were collected. After protein quantification using a BCA reagent kit (Thermofisher, Cat. 23225), the protein was diluted to 2 mg/mL. The prepared samples were loaded into 4-12% precast gel at a volume of 5 μL (10 μg). The expression of Androgen Receptor (D6F11) XP® Rabbit mAb (CST, Cat. 5153S) and internal reference β-Actin (CST, Cat. 3700S) were detected by traditional Western blot. The secondary antibodies used were HRP-labeled Anti-rabbit IgG Antibody (CST, Cat. 7074V) and Anti-mouse IgG Antibody (CST, Cat. 7076V). The protein expression quantitative analysis software "Image Studio" was used to calculate the expression of AR and internal reference, and the degradation rate (% Degradation) of the compound at different concentrations was calculated according to formula (4), where R _compound is the relative expression of AR in the drug administration groups at different concentrations, and AVE_R _DMSO is the average relative expression of AR in the DMSO control group. Then, GraphPad Prism software was used to draw the inhibition curve and calculate DC _50. % Degradation = (AVE_R _DMSO -R _compound ) / AVE_R _DMSO × 100% Formula (4)

Conclusion: The compounds of the present invention, such as the compounds in the examples, have good degradation activity on AR protein in MDA-PCA-2B cells.

13. Inhibition of MDA-PCA-2B cell proliferation experiment

Human prostate cancer cells MDA-PCA-2B were purchased from ATCC. The complete medium was F-12K+20% FBS+25 ng/ml cholera toxin+10 ng/ml mouse Epidermal Growth Factor+0.005 mM phosphoethanolamine+100 pg/ml hydrocortisone+45 nM sodium selenite+0.005 mg/ml human recombinant insulin+1% PS. The cells were cultured at 37°C, 5% CO ₂ in an incubator. At the beginning of the experiment, the cells were digested with 0.25% Trypsin-EDTA (1x), phenol red, terminated with complete medium, and centrifuged. Resuspend the cells with experimental culture medium (DMEM/F-12 without phenol red + 1% carbon-adsorbed FBS + 0.5% PS + 25 ng/ml cholera toxin + 10 ng/ml mouse Epidermal Growth Factor + 0.005 mM phosphoethanolamine + 100 pg/ml hydrocortisone + 45 nM sodium selenite + 0.005 mg/ml human recombinant insulin), count the live cells using a cell counter, adjust the cell suspension to an appropriate concentration, seed 100 µl per well in a 96-well cell culture plate at a cell density of 30,000 cells/well, and incubate overnight. The next day, add the diluted 2x working solution (containing different concentrations of test samples and exogenous androgen R1881, a total of 100 μL, so that the total system is 200 μL, and the final concentration of R1881 is 0.2 nM. Incubate in the incubator for 7 days. At the same time, set the T0 well to detect the cell activity reading on Day 0 using the CellCounting-lite 2.0 (Vazyme, DD1101-03) kit on the day of compound treatment, recorded as RLU0. After the incubation, discard 100 μL of the supernatant from each well and add 60 μl of CellCounting-lite 2.0 (Vazyme, DD1101-03) pre-melted and equilibrated to room temperature. 2.0 solution, mix well with a microplate shaker for 2 minutes, and place at room temperature for 30 minutes before measuring the luminescence signal value with a BMG multifunctional enzyme labeler.

The results were processed according to formula (5), and the inhibition rate of each concentration of the compound was calculated in Excel, and the concentration GI ₅₀ value of the compound when the inhibition rate was 50% was calculated using GraphPad software. RLU compound is the reading of the drug-treated group, and RLU control is the average value of the solvent control group. Inhibition % = 1- (RLU compound-RLU0) / (RLU control- RLU0) × 100% Formula (5)

Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity on MDA-PCA-2B cell proliferation.

14. Inhibition of LNCaP AR ^F877L cell proliferation experiment

Prostate cancer cells LNCaP AR ^F877L were constructed in WuXi AppTec, and the cell culture medium was RPMI1640 + 10% FBS, and cultured in an incubator at 37 ℃, 5% CO _2. Before the experiment, cells cultured in normal culture medium were subcultured to phenol red-free RPMI1640 containing 10% activated carbon-adsorbed FBS for 3 days. On the 4th day, cells were digested with phenol red-free digestion solution (Trypsin LE trypsin), and digestion was terminated with phenol red-free RPMI1640 medium containing 1% activated carbon-absorbed FBS + 0.5% PS + 0.1 nM R1881. The cells were resuspended by centrifugation and the living cells were counted using a Vi-Cell XR cell counter. The cell suspension was adjusted to an appropriate concentration with phenol red-free RPMI1640 medium containing 1% activated carbon-absorbed FBS + 0.5% PS + 0.1 nM R1881. 180 µl of the cell suspension was added to each well of a 96-well cell culture plate to make 2500 cells/well. The plate was also plated in the T0 well. The next day, a final concentration of 0.1 nM R1881 and compounds of different concentrations were placed in an incubator and incubated for 7 days. At the same time as the drug was added, the _T0 plate was detected using the CellTiter-Glo (CTG) (Promega, product number: G7572) reagent kit, which was recorded as RLU _0. After the incubation, 75 µl of CellTiter-Glo solution that had been melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes before using the Envision2104 plate reader to measure the fluorescence signal value RLU. The results were processed according to formula (6), and the inhibition rate (Inhibition %) of each concentration of the compound was calculated in Excel, and the concentration GI ₅₀ value of the compound when the inhibition rate was 50% was calculated using GraphPad software. Where RLU _compound is the reading of the drug-treated group, and RLU _control is the average value of the solvent control group. Inhibition % = 1- (RLU _compound - RLU ₀ ) / (RLU _control - RLU ₀ ) × 100% Formula (6)

Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against LNCaP AR ^F877L cell proliferation.

15. Study on AR degradation activity in LNCaP AR ^F877L cells

Prostate cancer cells LNCaP AR ^F877L were constructed in WuXi AppTec, and the complete cell culture medium was RPMI1640+10% FBS+1% PS, and cultured in a 37°C, 5% CO ₂ incubator. Before the experiment, cells cultured in normal culture medium were subcultured to phenol red-free RPMI1640 containing 10% activated carbon-adsorbed FBS for 3 days. On the 4th day, cells were digested with phenol red-free digestion solution (Trypsin LE trypsin), and the cell suspension was adjusted to the corresponding concentration with hormone-stripped culture medium (containing 1% carbon-adsorbed serum) for plating. Cells were plated in 24-well plates at 50,000 cells/well. After plating, the cells were cultured in an incubator for 24 hours, and then different concentrations of compounds were added. The cells were then cultured in an incubator at 37°C and 5% CO ₂ for another 24 hours. After the incubation, cells were digested with phenol red-free digestion buffer (Trypsin LE trypsin), and digestion was terminated with phenol red-free RPMI1640 medium containing 1% activated carbon-absorbed FBS + 0.5% PS. The cells were collected into 1.5 mL centrifuge tubes, resuspended by centrifugation, and washed twice with PBS. 20 μL of ice-cold complete cell lysis buffer containing Protease/Phosphatase Inhibitor Cocktail (Cell Lysis Buffer RIPA information: Sigma, Cat. R0278; Complete™ Mini Protease Inhibitor Cocktail information: Roche, Cat. 04693124001; RIPA and cOmplete™ Mini Protease Inhibitor Cocktail were prepared into complete cell lysis buffer according to the instructions) were added to each tube, and the cells were lysed on ice for 30 minutes, and then centrifuged at 12000×g for 4 ℃ for 10 minutes, collect the supernatant protein sample, add SDS-PAGE protein loading buffer (5X), and heat the sample at 100 ℃ for 10 minutes. Load the prepared sample with a sample volume of 15 μL on a 4-12% precast gel, and use traditional protein immunoblotting method (Western blot) to detect the expression of Androgen Receptor (D6F11) XP® Rabbit mAb (CST, Cat. 5153S) and internal reference β-Actin (CST, Cat. 3700S). The secondary antibody used was Anti-rabbit IgG (H+L) (DyLight™ 800 4X PEG Conjugate) (CST, Cat. 5151) and Anti-mouse IgG (H+L) (DyLight™ 680 Conjugate) (CST, Cat. 5470). The protein expression quantitative analysis software "Image Studio" was used to calculate the expression of AR and internal reference, and the degradation rate (% Degradation) of the compound at different concentrations was calculated according to formula (7), where R _compound is the relative expression of AR in the drug administration groups at different concentrations, and AVE_R _DMSO is the average relative expression of AR in the DMSO control group. Then, GraphPad Prism software was used to draw the inhibition curve and calculate DC _50. % Degradation = (AVE_R _DMSO -R _compound ) / AVE_R _DMSO × 100% Formula (7)

Conclusion: The compounds of the present invention, such as the compounds in the examples, have good degradation activity on AR protein in LNCaP AR ^F877L cells.

Structure of reference compound:

without

without

without

Claims (12)

A compound or a stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compound represented by the general formula (I), BLK (I); L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH ₂ ) _q -, -(CH ₂ ) _q -O-, -O-(CH ₂ ) _q -, -(CH ₂ ) _q -S-, -S-(CH ₂ ) _q -, -(CH ₂ ) _q -NR ^L -, -NR ^L -(CH ₂ ) _q -, -(CH ₂ ) _q -NR ^L C(=O)-, -(CH ₂ ) _q -C(=O)NR ^L -, -C(=O)-, -C(=O)-(CH ₂ ) _q -NR ^L -, -(C≡C) _q - or a bond, wherein -CH ₂ - is optionally substituted with 1 to 2 substituents selected from deuterium, halogen, =O, OH, CN, C _1-4 alkyl or C _3-6 cycloalkyl; q is selected from 0, 1, 2 or 3; ^RL is independently selected from H or C _1-4 alkyl; Cy1, Cy2, Cy3 or Cy4 are independently selected from a bond or optionally substituted with 1 to 4 R ^L2 is substituted by one of the following groups: 4-7 membered heteromonocyclic group, 4-12 membered heterocycloalkyl group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged group, _C3-7 monocyclic alkyl group, _C4-7 monocyclic alkenyl group, _C4-12 cycloalkyl group, _C5-13 spirocyclic alkyl group, _C5-12 bridged cycloalkyl group, 5-10 membered heteroaryl group or _C6-10 aryl group; B is selected from ； _X1 is selected from N or ^CRx1 ; _X2 is selected from N or ^CRx2 ; _X3 is selected from N or ^CRx3 ; _X4 is selected from N or ^CRx4 ; _X5 is selected from N or ^CRx5 ; at most 2 of _X1 , _X2 , _X3 , _X4 , and _X5 are selected from N; _Z1 is selected from N or ^CRz1 ; _Z2 is selected from N or ^CRz2 ; _Z3 is selected from N or ^CRz3 ; _Z4 is selected from N or ^CRz4 ; at most 3 of _Z1 , _Z2 , _Z3 , and _Z4 are selected ^from N; _Y1 and _Y2 are each independently selected ^{from -CRy1Ry2-} , -( ^CRy1Ry2 ) _2- , and -( ^CRy1Ry2 ) _3- ; ^R1 is selected ^from H, deuterium, C _wherein the alkyl or cycloalkyl is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH ₂ , CN, C _1-4 alkyl, and C _1-4 alkoxy; R ^x1 , R ^x2 , R ^x3 , R _x4 , R ^x5 , R ^z1 , R ^z2 , R ^z3 , and R ^z4 are each independently selected from H, deuterium, halogen, OH, NH ₂ , CN, NO ₂ , COOH, CONH ₂ , NHC _1-4 alkyl, N ⁽ C _1-4 alkyl) ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -OC _1-4 alkyl, -SC _1-4 alkyl, -C _0-4 alkylene-C _3-6 carbocyclyl, -C _0-4 alkylene-4 to 6 membered heterocyclic group, 5 to 6 membered heteroaryl group, -OC _3-6 carbocyclic group, -O-4 to 6 membered heterocyclic group, wherein the alkylene, alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group, heteroaryl group are optionally substituted by 1 to 4 R ^s ; or R ^x1 , R ^x2 , R ^x3 , R ^x4 are each independently selected from -S(=O) ₂ NH ₂ , -S(=O) ₂ C _1-4 alkyl; or, R ^x1 and R ^x2 , R ^x2 and R ^x3 , R ^x3 and R ^x4 , R ^x4 and R ^x5 , R ¹ and R ^z3 , R ¹ and R ^z1 are directly connected to form C _4-6 membered carbocyclic group or 4-7 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 ^Rs ; ^R2 , ^R3 , ^Ry1 , ^Ry2 are each independently selected from H, deuterium, halogen, OH, _NH2 , CN, _NO2 , COOH, _CONH2 , _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _-OC1-4 alkyl, _-SC1-4 alkyl, wherein the alkyl, alkenyl, alkynyl are optionally substituted by 1 to 4 substituents selected from deuterium, halogen, OH, _NH2 , CN, _C1-4 alkyl, _C1-4 alkoxy; K is selected from ; represents that the ring in which it is located is an aromatic ring or a non-aromatic ring; _F1 is selected from N, NH, CH, _CH2 , ^CHRk1 , ^NRk1 , ^CRk1 , C(=O), C( ^Rk1 ) ₂ ; _F2 is selected from a bond, O, N, NH, CH, _CH2 , ^CHRk1 , ^NRk1 , ^CRk1 or C( ^Rk1 ) ₂ ; _F6 , _F7 , _F8 are each independently selected from N, C, CH or ^CRk1 , and _F6 , _F7 , _F8 contain at most 2 N; G is selected from CH or N; _E1 is selected from N or CH; _E2 is selected from C, N or CH; Q is each independently selected from a bond, _-O- , -S-, -CH2-, ^-NRq- , -C(=O)-, ^-NRq C(=O)-, -C(=O) ^NRq- ; Q and G cannot directly form a nitrogen-nitrogen bond or a nitrogen-oxygen bond; ^Rq is independently selected from H or _C1-4 alkyl; ^Rk1 is independently selected from deuterium, halogen, OH, _NH2 , CN, COOH, _CONH2 , _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C1-4 alkoxy, _C3-6 cycloalkyl, 4 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 ^Rs ; ^RL2 and ^Rs are independently selected from deuterium, halogen, OH, CN, =O, _CF3 , _SF5 , _NO2 , _NH2 , _NHC1-4 alkyl, N(C _wherein the alkyl, alkylene, alkoxy, _alkenyl , alkynyl _, cycloalkyl is _optionally substituted with ₁ to ₄ substituents selected from deuterium, _F , Cl, Br, _{I ,} OH, CN, C _1-4 alkyl, C _1-4 alkoxy; p1 is independently selected from 0 _, 1 or 2; or R ^s is independently selected from -OC _3-6 cycloalkyl _. The compound as claimed in claim 1 or its stereoisomer, tautomer, deuterated isomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein R ^x1 , R x2 , ^{R x3 , R x4 , R x5 , R z1 , R z2 , R z3 , R z4 are each independently} selected from H, deuterium, halogen, OH, NH ₂ , CN, NO ₂ , COOH, CONH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ² _, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -OC _1-4 alkyl, -SC _1-4 alkyl, -C _0-2 alkylene-C _3-6 cycloalkyl, -C _0-2 alkylene-4 to 6 membered heterocyclic group, 5 to 6 membered heteroaryl group, -OC _3-6 cycloalkyl group, -O-4 to 6 membered heterocyclic group, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, heteroaryl group are optionally substituted by 1 to 4 R ^s ; or R ^x1 , R ^x2 , R ^x3 , R ^x4 are each independently selected from -S(=O) ₂ NH ₂ , -S(=O) ₂ C _1-4 alkyl; or, R ^x1 and R ^x2 , R ^x2 and R ^x3 , R ^x3 and R ^x4 , R ^x4 and R ^x5 are directly connected to form C _4-6 carbocyclic group, 5-6 membered heteroaryl group or 5-7 membered heterocyclic group, the carbocyclic group, heteroaryl group or heterocyclic group is optionally substituted by 1 to 4 ^Rs ; or, ^R1 and ^Rz3 , ^R1 and ^Rz1 are directly connected to form a 5-7 membered heterocyclic group, the heterocyclic group is optionally substituted by 1 to 4 ^Rs ; ^RL is selected from H, methyl or ethyl; ^Rq is independently selected from H, methyl, ethyl or isopropyl; Cy1, Cy2, Cy3, Cy4 are independently selected from a bond or one of the following groups optionally substituted by 1 to 4 ^RL2 : phenyl, pyridyl, pyrimidinyl, pyrazinyl, oxazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; s1, s3, s5 are each independently selected from 0, 1 or 2; s2, s4 are each independently selected from 0 or 1; s6 are selected from 0, 1, 2 or 3; s7 are selected from 1, 2 or ₃ ; ^RL2 , ^Rs are each independently selected from deuterium, halogen, OH, CN, =O, _CF3 , _SF5 , _NO2 , _NH2 , _NHC1-4alkyl , N( _C1-4alkyl ) ₂ , COOH, _CONH2 , _C1-4alkyl , _C2-4alkenyl , _C2-4alkynyl , _C1-4alkoxy , _-SC1-4alkyl , -C0-2alkylene- _{C3-6cycloalkyl} , -C _0-2- alkylene-4 to 6-membered heterocyclic group, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, C _1-4 alkyl, C _1-4 alkoxy; or R ^s are each independently selected from -OC _3-6 cycloalkyl. The compound as claimed in claim 2 or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein _X3 is selected ^{from CRx3} ; _Y1 and _Y2 are each independently selected from ^-CRy1Ry2- , -( ^CRy1Ry2 ) _2- ; ^R1 is selected from H, deuterium, methyl, ethyl, isopropyl, cyclopropyl, ^cyclobutyl , and the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, _NH2 , CN, _C1-4 alkyl, _C1-4 alkoxy; ^Rx1 , ^Rx2 , ^Rx3 , ^Rx4 , ^Rx5 , ^Rz1 R , R ^z2 , R ^z3 , R ^z4 are each independently selected from H, deuterium, F, Cl, Br, I, OH, NH ₂ , CN, NO ₂ , COOH, CONH ₂ , N(CH ₃ ) ₂ , NHCH ₃ or one of the following groups optionally substituted with 1 to 4 R ^s : methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -O-cyclopropyl, pyrazolyl; or R ^x1 , R ^x2 , R ^x3 , R ^x4 are each independently selected from -S(=O) ₂ NH ₂ , -S(=O) ₂ methyl, -S(=O) ₂ ethyl; or R ^x1 and R ^x2 , R ^x2 and R ^x3 , R ^{R x3} and R ^x4 , R ^x4 and R ^x5 are directly linked to form one of the following groups optionally substituted with 1 to 3 R ^s : piperidinyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, oxazinyl, pyrazinyl; or, R ^x1 and R ^x2 , R ^x2 and R ^x3 , R ^x3 and R ^x4 , R ^x4 and R ^x5 are directly linked to form one of the following groups optionally substituted with 1 to 3 R ^s : pyrrolidinyl, oxacyclopentyl, oxacyclohexyl, 1,3-dioxolane; or, R ¹ and R ^z3 , R ¹ and R ^z1 are directly linked to form the following structure optionally substituted with 1 to 4 R ^s : , ^R2 , ^R3 , ^Ry1 , ^Ry2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, _NH2 , CN, _NO2 , COOH, _CONH2 , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, _NH2 , CN _{, C1-4} alkyl, _C1-4 alkoxy; Ak1, Ak2, Ak3, Ak4, Ak5 are each independently _{selected from a} bond, _-O- , -S-, _-OCH2- , -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -CH(CH3 ₎ -, _-CH2 -, -C(CH ₃ ) ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -N(CH ₃ )-, -NH-, -CH ₂ N(CH ₃ )-, -CH ₂ NH-, -NHCH ₂ -, -CH ₂ CH ₂ N(CH ₃ )-, -CH ₂ CH ₂ NH-, -NHCH ₂ CH ₂ -, -C(=O)-, -C(=O)CH ₂ NH-, -CH ₂ C(=O)NH-, -C(=O)NH- or -NHC(=O)-; K is selected from , , ; Q is each independently selected from a bond, CH ₂ , NH, N(CH ₃ ), O, S, C(═O), NHC(═O), C(═O)NH, N(CH ₃ )C(═O), C(═O)N(CH ₃ ); R ^k1 is each independently selected from deuterium, F, Cl, Br, I, OH, NH ₂ , CN, COOH, CONH ₂ , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH ₂ ; ^RL2 and R ^s are each independently selected from deuterium, F, Cl, Br, I, OH, ═O, CF ₃ , SF ₅ , CN, NH ₂ , NO ₂ , COOH, CONH ₂ , N(CH ₃ ) ₂ , NHCH ₃ , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, C _1-4 alkyl, C _1-4 alkoxy; or R ^s are each independently selected from propynyl, -O-cyclopropyl. The compound as claimed in claim 3 or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein B is selected from , , , ; or B is selected from ; _X6 is selected from N or CH; _X7 is selected from NH or O; at most 2 of _Z1 , _Z2 , _Z3 and _Z4 are selected from N; ^R2 and ^R3 are each independently selected from H, deuterium, F, Cl, Br; ^Ry1 and ^Ry2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, _NH2 , CN, _NO2 , COOH, _CONH2 , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy and methylthio, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy and methylthio are substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, _NH2 , CN, methyl, ethyl and methoxy; Cy1, Cy2, Cy3 and Cy4 are each independently selected from a bond or one of the following optionally substituted groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , when substituted, is substituted with 1 to 4 substituents selected from deuterium, F, CF ₃ , OH, =O, COOH, CN, NH ₂ , hydroxymethyl, methyl, methoxy, cyclopropyl; K is selected from , , , , , , ; or K is selected from , . The compound as claimed in claim 4 or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein B is selected from , , , , , , , , , , , , , , , , , , , ; or B is selected from , , , ; R ^x2 , R ^x3 , and R ^x4 are each independently selected from H, deuterium, F, Cl, Br, I, OH, NH ₂ , CN, NO ₂ , COOH, CONH ₂ , N(CH ₃ ) ₂ , NHCH ₃ , CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , OCH ₂ F, OCD ₃ , CH ₂ OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, -CH ₂ -cyclopropyl, -O-cyclopropyl; or R ^x2 , R ^x4 are each independently selected from -S(═O) ₂ CH ₃ , -O-CH ₂ -propynyl, -O-CH ₂ -cyclopropyl, -O-CH ₂ CH ₂ -OCH ₃ , -O-CH ₂ CH ₂ -O-cyclopropyl, , , , ; Q is each independently selected from a bond, NH, N(CH ₃ ), O, S, NHC(═O), C(═O)NH, N(CH ₃ )C(═O), C(═O)N(CH ₃ ); L is selected from -Cy1-, -Cy1-Ak2-, -Cy1-CH ₂ -, -Ak1-Cy1-, -Cy1-Cy2-, -Cy1-CH ₂ -Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH ₂ -Cy2-Cy3-, -Cy1-Cy2-CH ₂ -Cy3-; or L is selected from -Cy1-Ak2-Cy2-, -Cy1-O-Cy2-; Cy1, Cy2, Cy3 are each independently selected from one of the following optionally substituted groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , when substituted, by 1 to 4 substituents selected from deuterium, F, CF ₃ , OH, =0, COOH, CN, NH ₂ , hydroxymethyl, methyl, methoxy, cyclopropyl. The compound as claimed in claim 5 or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein K is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; or K is selected from , , , , , , , , , , , , , ; Q is independently selected from a bond, NH, C(=O)NH; R ^k1 is independently selected from deuterium, F, Cl, Br, I, OH, NH ₂ , CN, COOH, CONH ₂ , CF ₃ , CHF ₂ , CH ₂ F, OCF ₃ , OCH ₂ F, CH ₂ OH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl; L is selected from one of the structural fragments shown in Table L-1. The compound as claimed in claim 1 or its stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in Table E. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 7 or a stereoisomer, tautomer, deuterated isomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1 to 1500 mg of the compound as described in any one of claims 1 to 7 or a stereoisomer, tautomer, deuterated isomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof. Use of a compound as described in any one of claims 1 to 7 or its stereoisomers, tautomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, or the drug composition as described in claim 8 in the preparation of a drug for treating a disease associated with AR activity or expression. Use of a compound as described in any one of claims 1 to 7 or its stereoisomers, tautomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, or the drug composition as described in claim 8 in the preparation of drugs for treating, inhibiting or degrading AR-related diseases. The use as described in claim 10 is characterized in that the disease is selected from cancer, preferably prostate cancer. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound as described in any one of claims 1 to 7 or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or the pharmaceutical composition as described in claim 8, the therapeutically effective amount being preferably 1-1500 mg, and the disease being preferably cancer, preferably prostate cancer.