WO2022148459A1

WO2022148459A1 - Class of novel smad3 protein degraders and application thereof

Info

Publication number: WO2022148459A1
Application number: PCT/CN2022/071013
Authority: WO
Inventors: 马欣; 陈永峰; 赵存良; 王兆伏; 张玉华
Original assignee: 和径医药科技（上海）有限公司
Priority date: 2021-01-11
Filing date: 2022-01-10
Publication date: 2022-07-14
Also published as: CN116368131B; CN116368131A

Abstract

The present invention relates to a compound represented by formula (X), or a tautomer, a stereoisomer, a prodrug, a crystalline form, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and a pharmaceutical composition comprising the compound, and a use thereof.

Description

A Novel Smad3 Protein Degrader and Its Application

Related applications

This application claims the priority of Chinese patent application CN202110031709.8 filed on January 11, 2021 and Chinese patent application CN202111371038.6 filed on November 18, 2021, the contents of which are incorporated herein by reference.

technical field

The invention belongs to the field of medicinal chemistry. Specifically, it relates to a new type of PROTAC molecule targeting Smad3 protein, a preparation method thereof, and a pharmaceutical composition comprising the compound.

Background technique

The ubiquitin-proteasome pathway is a common way of degrading endogenous proteins. The proteins that need to be degraded are first modified by ubiquitination, and then decomposed by the proteasome into smaller polypeptides, amino acids, and reusable ubiquitins. PROTAC ( pro teolysis targeting c himeras), namely protein degradation targeting chimeras, is a hot research field emerging in recent years ^[1] . PROTAC molecules can generally be divided into three parts, one end is a small molecule fragment (warhead) that binds to a specific target protein, the other end is an E3 ligase ligand with ubiquitination function (E3 ligase ligand), and the two Linkers that are connected together. PROTAC molecules utilize the cellular protein ubiquitination degradation pathway to selectively degrade target proteins. Specifically, since the two ends of the PROTAC molecule are the ligand fragments of the target protein and the E3 ligase, the PROTAC molecule can bind to the target protein and the E3 ligase at the same time, which promotes the ubiquitination of the target protein, which is further processed by the proteasome. Identify and degrade. Traditional small molecule inhibitors not only need to have high binding force to the target protein, but also need to reduce the functional activity of the target protein after binding to the target protein. Different from traditional small molecule inhibitors, the small molecule fragments in PROTAC molecules that bind to the target protein do not necessarily need to have an effect on the activity of the target protein, as long as they have good binding force. This feature enables PROTAC molecules to target some traditionally "undruggable" targets, such as transcription factors, backbone proteins, etc. ^[2] . Such proteins often lack obvious active sites, making it difficult to use traditional small molecule inhibitors to exert their pharmacological effects. Therefore, PROTAC has a very broad application prospect. The reported PROTAC molecules are not only applied to some common kinase targets in the tumor field, such as EGFR ^[3] , ALK ^[4] , CDK ^[5] , etc., but also to BRD4 in the epigenetic field ^[2,6 ] ^] , HDAC ^[7] , and nuclear receptors AR ^[8] , ER ^[9] and so on.

The proteins of the Smad family can be divided into three subgroups: R-Smad (receptor-regulated Smad), Co-Smad (common-mediated Smad) and I-Smad (inhibitory Smad) according to their molecular structure and different biological functions. They act as transporters in the transforming growth factor beta (TGF-β) signaling pathway, and participate in mediating extracellular TGF-β signaling to the nucleus to regulate the expression of related target genes. After TGF-β binds to the type II receptor on the cell membrane, it recruits and activates the type I receptor (ALK5), and then phosphorylates R-Smad in the cell; the phosphorylated R-Smad forms with Co-Smad and other transcription factors The complex enters the nucleus to regulate the transcription of downstream genes ^[10] . Smad3, a member of R-Smad, mediates a series of biological responses involved in the TGF-β signaling pathway, including the promotion of epithelial-mesenchymal transition, tissue fibrosis, angiogenesis, and tumor immune escape ^{[11] ]} .

It is currently known that TGF-β is a key factor in promoting renal fibrosis. The transcription factor complex formed after Smad3 is activated by TGF-β can directly bind to a series of collagen formation gene promoter regions to promote the formation of matrix layer. ^[12] . Knockout of Smad3 gene in mice can inhibit fibrosis in various kidney diseases ^[13-16] . Overexpression of Smad7 in mouse models of kidney disease to inhibit Smad3 activity can also effectively delay the process of kidney injury ^[17] . A specific small molecule inhibitor of Smad3, SIS3, can effectively inhibit the progression of renal fibrosis in mouse models of diabetic nephropathy and obstructive nephropathy ^[18,19] . In addition, several studies have suggested that Smad3 plays an important role in the progression of various tumors ^[20] . In LLC lung cancer and B16F10 melanoma cell CDX mouse models, Smad3 gene knockout and pharmacological inhibition have significant effects on cancer growth, invasion and tumor growth. Metastasis produced a significant inhibitory effect ^[21] . These results suggest that Smad3 is a promising drug target for tissue fibrosis and tumor therapy.

Wang Xin et al. from the First Affiliated Hospital of Sun Yat-sen University reported a PROTAC molecule targeting Smad3 protein, and its degradation was achieved by recruiting Von Hippel-Lindau (VHL) E3 ligase ^[22] . In this patent application, a series of Smad3 PROTAC molecules recruiting cereblon E3 ligase were designed and synthesized, and their degradation effect on Smad3 protein was better than that of literature compounds.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a PROTAC molecule capable of degrading Smad3 protein. Specifically, in one aspect, the present invention provides compounds of formula (I), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof Object:

in,

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

L is NR";

wherein R" is independently selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

X ₁ is CR _X1 or N; X ₂ is CR _X2 or N; X ₃ is CR _X3 or N; X ₄ is CR _X4 or N; X ₅ is CR _X5 or N;

wherein R _X1 , R _X2 , R _X3 , R _X4 and R _X5 are independently selected from H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

Y ₁ is CR _Y1 or N;

_Y2 is O, S or NR _Y2 ;

wherein R _Y1 is independently selected from H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

R _{Y2 is} selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₁ and R ₂ are independently selected from H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

Or _R1 and _R2 are connected, and together with the atoms to which they are connected form

Wherein Z ₁ is CR _Z1 or N; Z ₂ is CR _Z2 or N; Z ₃ is CR _Z3 or N; Z ₄ is CR _Z4 or N;

wherein R _Z1 , R _Z2 , R _Z3 and R _Z4 are independently selected from H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

L ₁ is CR ₁ R ₁ ';

L ₂ is O, S, NR ₂ "or CR ₂ R ₂ '; L ₃ is O, S, NR ₃ " or CR ₃ R ₃ '; L ₄ is O, S, NR ₄ "or CR ₄ R ₄ '; L ₅ is O, S, NR ₅ "or CR ₅ R ₅ ';

L ₆ is O, S, NR ₆ ″ or CR ₆ R ₆ ′; L ₇ is O, S, NR ₇ ″ or CR ₇ R ₇ ′;

or L ₁ , L ₅ and L ₆ are each independently absent;

Or -L ₆ -L ₇ - combines to form -CH=CH- or -C≡C-;

Or the substituents of L ₂ and L ₅ are connected, and together with L ₂ , L ₃ , L ₄ and L ₅ form C _5-7 cycloalkylene, 5-7 membered heterocyclylene, C _6-10 arylene base or 5-7 membered heteroarylene;

Or the substituents of L ₂ and L ₄ are connected, and together with L ₂ , L ₃ and L ₄ form C _5-7 cycloalkylene, 5-7 membered heterocyclylene, C _6-10 arylene or 5 -7-membered heteroarylene;

Or the substituents of L ₃ and L ₅ are connected and together with L ₃ , L ₄ and L ₅ form C _5-7 cycloalkylene, 5-7 membered heterocyclylene, C _6-10 arylene or 5 -7-membered heteroarylene;

Or -L ₂ -L ₃ -L ₄ - represents a C _5-7 cycloalkylene group, a 5-7 membered heterocyclylene group, a C _6-10 arylene group or a 5-7 membered heteroarylene group;

Or -L ₃ -L ₄ -L ₅ -represents a C _5-7 cycloalkylene group, a 5-7-membered heterocyclylene group, a C _6-10 -membered arylene group or a 5-7-membered heteroarylene group;

wherein R ₁ , R ₁ ′, R ₂ , R ₂ ′, R ₃ , R ₃ ′, R ₄ , R ₄ ′, R ₅ , R ₅ ′, R ₆ , R ₆ ′, R ₇ , and R ₇ ′ are independently is selected from H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

Or R ₂ and R ₂ ', R ₃ and R ₃ ', R ₄ and R ₄ ', R ₅ and R ₅ ', R ₆ and R ₆ ', R ₇ and R ₇ ' combine to form =0;

R ₂ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₃ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₄ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₅ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₆ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₇ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

The condition is that two adjacent atoms cannot be heteroatoms at the same time.

In another aspect, the present invention provides methods for the preparation of compounds of the present invention.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient. In specific embodiments, the compounds of the present invention are provided in a therapeutically effective amount. In specific embodiments, the compounds of the present invention are provided in a prophylactically effective amount.

In another aspect, the present invention provides use of a compound of the present invention or a pharmaceutical composition of the present invention in the manufacture of a medicament for the treatment and/or prevention of Smad3 protein-mediated diseases.

In another aspect, the present invention provides a method of treating and/or preventing a Smad3 protein-mediated disease in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutical composition thereof.

In another aspect, the present invention provides a compound of the present invention or a pharmaceutical composition thereof for use in the treatment and/or prevention of Smad3 protein-mediated diseases.

In another aspect, the disease mediated by the Smad3 protein mentioned above is selected from autoimmune diseases and inflammation, tissue fibrosis and tumors, and the like.

Other objects and advantages of the present invention will be apparent to those skilled in the art from the ensuing detailed description, examples and claims.

Description of drawings

Figure 1 is a Western blot of the degradation of Smad3 protein by representative compounds of the present invention.

Detailed description of the invention

definition

Definitions of specific functional groups and chemical terms are described in more detail below.

When numerical ranges are listed, each value and subranges within the range are intended to be included. For example, "C _1-6 alkyl" includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _{1 -2} , _C2-6 , _C2-5 , _C2-4 , _C2-3 , _C3-6 , _C3-5 , _C3-4 , _C4-6 , _C4-5 , and _{C5 -6} alkyl.

"C _1-6 alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as "lower alkyl". In some embodiments, C _1-4 alkyl groups are particularly preferred. Examples of such alkyl groups include, but are not limited to: methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), tertiary Butyl (C ₄ ), sec-butyl (C ₄ ), isobutyl (C ₄ ), n-pentyl (C ₅ ), 3-pentyl (C ₅ ), pentyl (C ₅ ), neopentyl (C ₅ ), 3-methyl-2-butyl (C ₅ ), tert-amyl (C ₅ ) and n-hexyl (C ₆ ). Whether or not the alkyl group is modified with "substituted" or not, each of the alkyl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, suitable substituents are as follows definition.

"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). In some embodiments, the halogen group is F, Cl, or Br. In some embodiments, the halogen group is F or Cl. In some embodiments, the halogen group is F.

Thus, "C _1-6 haloalkyl" refers to the aforementioned "C _1-6 alkyl" substituted with one or more halogen groups. In some embodiments, C _1-4 haloalkyl is particularly preferred, more preferably C _1-2 haloalkyl. Exemplary such _haloalkyl groups include, but are not limited to _: _-CF3 , _-CH2F , _-CHF2 , _-CHFCH2F , _-CH2CHF2 , _-CF2CF3 , _-CCl3 , _-CH2Cl , -CHCl ₂ , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.

"C _5-7 cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 5 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, _C5-6 cycloalkyl and _C6 cycloalkyl are preferred. Cycloalkyl also includes ring systems in which the aforementioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to indicate The number of carbons in a cycloalkyl system. Exemplary such cycloalkyl groups include, but are not limited to: cyclopentyl (C ₅ ), cyclopentenyl (C ₅ ), bicyclo[1.1.1]pent-1-yl (C ₅ ), cyclohexyl (C 5 ) ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), cycloheptyl (C ₇ ), cycloheptenyl (C 7 ), cycloheptadienyl (C ₇ ), cycloheptyl (C ₇ ) Heptatrienyl (C ₇ ), and the like. Whether or not the cycloalkyl group is modified with "substituted" or not, each of the cycloalkyl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate The basis is defined as follows.

"5-7 membered heterocyclyl" alternatively refers to a 5- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 5- to 6-membered heterocyclyl groups are preferred , which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems in which the aforementioned heterocyclyl ring is fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases, the ring The number of members continues to indicate the number of ring members in a heterocyclyl ring system. Whether or not the heterocyclyl group is modified with "substituted" or not, each of the heterocyclyl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate The basis is defined as follows.

Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-diketone. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolane, oxasulfuranyl, disulfuranyl, and oxa oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiahexyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclyl groups) fused to a _C6 aryl ring include, but are not limited to: indoline, isoindolyl , dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary ₆ -membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclyl groups) fused to a C aryl ring include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and many more.

"C _6-10 aryl" refers to a monocyclic or polycyclic (eg, bicyclic or tricyclic) 4n+2 aromatic ring system (eg, having 6-10 ring carbon atoms and zero heteroatoms) 6 or 10 pi electrons shared by a cyclic arrangement). In some embodiments, an aryl group has six ring carbon atoms (" _C6 aryl"; eg, phenyl). In some embodiments, aryl groups have ten ring carbon atoms (" _C10 aryl"; eg, naphthyl, eg, 1-naphthyl and 2-naphthyl). In some embodiments, _C6 aryl groups are preferred. Aryl also includes ring systems in which the aforementioned aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on said aryl ring, in which case the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system. Whether or not the aryl group is modified with "substituted" or not, each of the aryl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, suitable substituents are as follows definition.

"5-7 membered heteroaryl" refers to a 5- to 7-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (eg, having shared in a cyclic arrangement 6 or 10 pi electrons) wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as valence allows. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the carbon atom is The numbers continue to indicate the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5- to 6-membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Whether or not the heteroaryl group is modified with "substituted" or not, each of the heteroaryl groups is independently optionally substituted, eg, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate The basis is defined as follows.

Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacyclotrienyl, oxeptrienyl, and thiacyclotrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Indanyl and purine groups. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pteridyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl .

"C _5-7 -membered cycloalkylene", "5-7-membered heterocyclylene", "C _6-10 -membered arylene" or "5-7-membered heteroarylene" represents the above-mentioned "C _5-7 ring"Alkyl","5-7 membered heterocyclyl", "C _6-10 aryl" or "5-7 membered heteroaryl" is a divalent group formed by removing another hydrogen atom.

Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, _-NO2 , _-N3 , _-SO2H , _-SO3H , -OH, ^-ORaa , -ON( ^Rbb ) ₂ , -N(R ^bb ) ₂ , -N(R ^bb ) ₃ ⁺ X ^- , -N(OR ^cc )R ^bb , -SH, -SR ^aa , -SSR ^cc , -C(=O)R ^aa , -CO ₂ H, -CHO, -C(OR ^cc ) ₂ , -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -OC(=O)N(R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -C (=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -OC(=NR ^bb )N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , -OS(=O)R ^aa , - Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ , -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=S)SR ^aa , -SC(= S)SR ^aa , -SC(=O)SR ^aa , -OC(=O)SR ^aa , -SC(=O)OR ^aa , -SC(=O)R ^aa , -P(=O) ₂ R ^aa , -OP(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -OP(=O)(R ^aa ) ₂ , -OP(=O)(OR ^cc ) ₂ , -P( =O) ₂ N(R ^bb ) ₂ , -OP(=O) ₂ N(R ^bb ) ₂ , -P(=O)(NR ^bb ) ₂ , -OP(=O)(NR ^bb ) ₂ , - NR ^bb P(=O)(OR ^cc ) ₂ , -NR ^bb P(=O)(NR ^bb ) ₂ , -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -OP(R ^cc ) ₂ , -OP(R ^cc ) ₃ , -B(R ^aa ) ₂ , -B(OR ^cc ) ₂ , -BR ^aa (OR ^cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heterocyclyl Aryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups ;

Or two geminal hydrogens on a carbon atom are surrounded by groups =O, =S, =NN( ^Rbb ) ₂ , = ^NNRbbC (=O) ^Raa , = ^NNRbbC (=O) ^ORaa , = NNR ^bb S(=O) ₂ R ^aa , =NR ^bb or =NOR ^cc substitution;

Each of R ^aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R ^aa groups are combined to form a heterocyclyl or Heteroaryl rings in which each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R ^dd groups group replacement;

Each of R ^bb is independently selected from: hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O ) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O)(NR ^cc ) ₂ , alkyl, haloalkyl, alkene radical, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R ^bb groups combined to form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkyne radyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;

Each of ^Rcc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two ^Rcc groups are combined to form a heterocycle yl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R ^dd group substitution;

Each of ^Rdd is independently selected from: halogen, -CN, _-NO2 , _-N3 , -SO2H, _-SO3H , -OH, ^-ORee , -ON( ^Rff ₎₂ _, -N (R ^ff ) ₂ , -N(R ^ff ) ₃ ⁺ X ^- , -N(OR ^ee )R ^ff , -SH, -SR ^ee , -SSR ^ee , -C(=O)R ^ee , -CO ₂ H, -CO ₂ ^Ree , -OC(=O) ^Ree , -OCO ₂ ^Ree , -C(=O)N(R ^ff ) ₂ , -OC(=O)N(R ^ff ) ₂ , - ^NRff C(=O) ^{Ree,-NRffCO2Ree} ^, ^-NRffC (=O)N( ^Rff ) ₂ , _-C (= ^NRff ) ^ORee , ^-OC(=NRff ⁾ ^Ree , -OC(=NR ^ff )OR ^ee , -C(=NR ^ff )N(R ^ff ) ₂ , -OC(=NR ^ff )N(R ^ff ) ₂ , -NR ^ff C(=NR ^ff ) N(R ^ff ) ₂ , -NR ^ff SO ₂ ^Ree , -SO ₂ N(R ^ff ) ₂ , -SO ₂ ^Ree , -SO ₂ OR ^ee , -OSO ₂ ^Ree , -S(=O)R ^ee , -Si(R ^ee ) ₃ , -OSi(R ^ee ) ₃ , -C(=S)N(R ^ff ) ₂ , -C(=O)SR ^ee , -C(=S)SR ^ee , - SC(=S)SR ^ee , -P(=O) ₂ Re ^ee , -P(=O)(R ^ee ) ₂ , -OP(=O)(R ^ee ) ₂ , -OP(=O)(OR ^ee ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocycle aryl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups, or two gem R ^dd substituents may combine to form =O or =S;

Each of R ^ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbon cyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups;

Each of ^Rff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two ^Rff groups are combined to form a heterocyclyl group or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently separated by 0, 1, 2, 3, 4, or 5 R ^gg group substitution;

Each of Rgg is independently: halogen, -CN, _-NO2 , _-N3 , ^-SO2H , _-SO3H , _-OH , _-OC1-6 alkyl, -ON( _C1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₃ ⁺ X ^- , -NH(C _1-6 alkyl) ₂ ⁺ X ^- , -NH ₂ (C _1-6 alkyl) ⁺ X ^- , -NH ₃ ⁺ X ^- , -N(OC _1-6 alkyl)(C _1-6 alkyl), -N(OH)(C _1-6 alkyl ), -NH(OH), -SH, -SC _1-6 alkyl, -SS(C _1-6 alkyl), -C(=O)(C _1-6 alkyl), -CO ₂ H, -CO ₂ (C _1-6 alkyl), -OC(=O)(C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C(=O)NH ₂ , -C (=O)N(C _1-6 alkyl) ₂ , -OC(=O)NH(C _1-6 alkyl), -NHC(=O)(C _1-6 alkyl), -N(C _1-6 alkyl) C(=O)(C _1-6 alkyl), -NHCO ₂ (C _1-6 alkyl), -NHC(=O)N(C _1-6 alkyl) ₂ , - NHC(=O)NH(C _1-6 alkyl), -NHC(=O)NH ₂ , -C(=NH)O(C _1-6 alkyl), -OC(=NH)(C _1- ₆ alkyl), -OC(=NH)OC _1-6 alkyl, -C(=NH)N(C _1-6 alkyl) ₂ , -C(=NH)NH(C _1-6 alkyl) , -C(=NH)NH ₂ , -OC(=NH)N(C _1-6 alkyl) ₂ , -OC(NH)NH(C _1-6 alkyl), -OC(NH)NH ₂ , -NHC(NH)N(C _1-6 alkyl) ₂ , -NHC(=NH)NH ₂ , -NHSO ₂ (C _1-6 alkyl), -SO ₂ N(C _1-6 alkyl) ₂ , -SO ₂ NH(C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ OC _1-6 alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si(C _1-6 alkyl) ₃ , -OSi(C _1-6 alkyl) ₃ , -C(=S)N(C _1-6 alkyl) ₂ , C (=S)NH(C _1-6 alkyl), C(=S)NH ₂ , -C(=O)S(C _1-6 alkyl), -C(=S)SC _1-6 alkyl , -SC(=S)SC _1-6 alkyl, -P(=O) ₂ (C _1-6 alkyl), -P(=O)(C _1-6 alkyl _{) 2} _, -OP(= O)(C _1-6 alkyl) ₂ , -OP (=O)(OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₇ carbon Cyclic, C ₆ -C ₁₀ aryl, C ₃ -C ₇ heterocyclyl, C ₅ -C ₁₀ heteroaryl; or two geminal R ^gg substituents may combine to form =O or =S; wherein X ^- for the counter ion.

Exemplary substituents on nitrogen include, but are not limited to: hydrogen, -OH, ^-ORaa , -N( ^Rcc ) ₂ , -CN, -C(=O) ^Raa , -C(=O)N (R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^bb )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O )( ^NRcc ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two ^Rcc groups attached to a nitrogen atom combine to form a heterocycle yl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently replaced by 0, 1, 2, 3, 4, or 5 R The ^dd group is substituted and wherein R ^aa , R ^bb , R ^cc and R ^dd are as described above.

The term "pharmaceutically acceptable salt" means, within the scope of sound medical judgment, suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergy, etc., and with reasonable benefit/risk those salts in commensurate proportions. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by Berge et al. in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or salts formed with organic acids such as acetic, oxalic, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Also included are salts formed using methods conventional in the art, eg, ion exchange methods. Other pharmaceutically acceptable salts include: adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphor acid salt, camphorsulfonate, citrate, cypionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerin Phosphate, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobate, Lactate, Laurate, Lauryl Sulfate , malate, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoic acid Salt, Pectin Acetate, Persulfate, 3-Phenylpropionate, Phosphate, Picrate, Pivalate, Propionate, Stearate, Succinate, Sulfate, Tartrate, Thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations with counter ions such as halides, hydroxides, carboxylates, sulfates, phosphates, Nitrates, lower alkyl sulfonates and aryl sulfonates.

"Subjects" for administration include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and/or non-human animals, eg, mammals, eg, primates (eg, cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep , goats, rodents, cats and/or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.

"Disease," "disorder," and "condition" are used interchangeably herein.

Unless otherwise specified, the term "treatment" as used herein includes the effect that occurs when a subject has a particular disease, disorder or condition, which reduces the severity of, or delays or slows down, the disease, disorder or condition or development of a disorder ("therapeutic treatment"), and also includes effects that occur before a subject begins to suffer from a particular disease, disorder or condition ("prophylactic treatment").

"Combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention. For example, a compound of the present invention may be administered concurrently or sequentially with another therapeutic agent in separate unit dosage forms, or concurrently with another therapeutic agent in a single unit dosage form.

Detailed ways

compound

As used herein, "compounds of the present invention" refers to compounds of formula (X) and formula (I) to (V) below (including subsets of each formula), or tautomers, stereoisomers, Prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates.

In one embodiment, the present invention relates to a compound of formula (X), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

in,

W is CRR' or C=O;

L is NR";

wherein R" is independently selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

Y ₁ is CR _Y1 or N; Y ₂ is O, S or NR _Y2 ;

R _{Y2 is} selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

L ₁ is CR ₁ R ₁ '; L ₂ is O, S, NR ₂ "or CR ₂ R ₂ '; L ₃ is O, S, NR ₃ " or CR ₃ R ₃ '; L ₄ is O, S, NR ₄ "or CR ₄ R ₄ '; L ₅ is O, S, NR ₅ " or CR ₅ R ₅ '; L ₆ is O, S, NR ₆ " or CR ₆ R ₆ '; L ₇ is O, S , NR ₇ "or CR ₇ R ₇ ';

or L ₁ , L ₅ and L ₆ are each independently absent;

Or -L ₆ -L ₇ - combines to form -CH=CH- or -C≡C-;

R ₂ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₃ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₄ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₅ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₆ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₇ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

The condition is that two adjacent atoms cannot be heteroatoms at the same time;

Ra is selected from D, halogen, C _1-6 alkyl or C _1-6 haloalkyl; n is 0, 1, 2, 3 or 4.

n is preferably 0 or 1, and Ra is preferably fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -CH ₂ CH ₂ F, - _CH2CHF2 , _-CH2CF3 , monobromo _- substituted ethyl or dibromo _- substituted ethyl.

In one embodiment, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

in,

W is CRR' or C=O;

L is NR";

wherein R" is independently selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

Y ₁ is CR _Y1 or N; Y ₂ is O, S or NR _Y2 ;

R _{Y2 is} selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

L ₁ is CR ₁ R ₁ ';

L ₂ is O, S, NR ₂ "or CR ₂ R ₂ '; L ₃ is O, S, NR ₃ " or CR ₃ R ₃ '; L ₄ is O, S, NR ₄ "or CR ₄ R ₄ '; L ₅ is O, S, NR ₅ "or CR ₅ R ₅ '; L ₆ is O, S, NR ₆ " or CR ₆ R ₆ '; L ₇ is O, S, NR ₇ "or CR ₇ R ₇ ';

or L ₁ , L ₅ and L ₆ are each independently absent;

Or -L ₆ -L ₇ - combines to form -CH=CH- or -C≡C-;

R ₂ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₃ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₄ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₅ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₆ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₇ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

W

In one embodiment, W is CRR'; in another embodiment, W is _CH2 ; in another embodiment, W is C=O.

In a more specific embodiment, R and R' are independently selected from H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl; in another specific embodiment, R and R' are independently is selected from H, D, halogen and C _1-6 alkyl; in another specific embodiment, R and R' are independently selected from H, D and halogen; in another specific embodiment, R and R' are independently is selected from H and D.

L

In one embodiment, L is NR"; in another embodiment, L is NH.

In a more specific embodiment, R" is independently selected from H, C _1-6 alkyl or C _1-6 haloalkyl; in another specific embodiment, R " is C _1-6 alkyl or C _{1 -6} haloalkyl; in another specific embodiment, R" is C _1-6 alkyl; in another specific embodiment, R" is C _1-6 haloalkyl.

X ₁ , X ₂ , X ₃ , X ₄ and X ₅

In _one embodiment, X1 is CR _X1 ; in another embodiment, X1 is CH _; in another embodiment, X1 is N _;

In one embodiment, X2 is CR _X2 ; in another embodiment, X2 is _CH _; in another embodiment, X2 is N _;

In one embodiment, _X3 is CR _X3 ; in another embodiment, _X3 is CH; in another embodiment, _X3 is N;

In one embodiment, _X4 is CR _X4 ; in another embodiment, _X4 is CH; in another embodiment, _X4 is N;

_In one embodiment, X5 is CR _X5 ; in another embodiment, X5 is CH _; in another embodiment, _X5 is N.

In a more specific embodiment, R _X1 , R _X2 , R _X3 , R _X4 and R _X5 are independently selected from H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl; in another particular In an embodiment, R _X1 , R _X2 , R _X3 , R _X4 and R _X5 are independently selected from H, D, halogen or C _1-6 alkyl; in another specific embodiment, R _X1 , R _X2 , R _X3 , R _X4 and R _X5 are independently selected from H or D; in another specific embodiment, R _X1 , R _X2 , R _X3 , R _X4 and R _X5 are independently C _1-6 alkyl; in another In specific embodiments, R _X1 , R _X2 , R _X3 , R _X4 and R _X5 are independently C _1-6 haloalkyl.

_Y1 and _Y2

In one embodiment, _Y1 is CR _Y1 ; in another embodiment, _Y1 is CH; in another embodiment, _Y1 is N.

In one embodiment, _Y2 is O; in another embodiment, _Y2 is S; in another embodiment, _Y2 is NR _Y2 ; in another embodiment, _Y2 is NMe; In one embodiment, _Y2 is NH.

In a more specific embodiment, R _Y1 is independently selected from H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl; in another specific embodiment, R _Y1 is independently selected from H, D, halogen or C _1-6 alkyl; in another specific embodiment, R _Y1 is independently selected from H or D; in another specific embodiment, R _Y1 is C _1-6 alkyl; in another specific embodiment, R Y1 is C 1-6 alkyl; In a specific embodiment, R _Y1 is C _1-6 haloalkyl.

In a more specific embodiment, R _Y2 is selected from H, C _1-6 alkyl or C _1-6 haloalkyl; in another specific embodiment, R _Y2 is selected from H or C _1-6 alkyl; in In another specific embodiment, R _Y2 is selected from H; in another specific embodiment, R _Y2 is C _1-6 alkyl; in another specific embodiment, R _Y2 is C _1-6 haloalkyl.

_R1 and _R2

_In _one embodiment, R1 and R2 are H _; in another embodiment, R1 and R2 are D _; in another embodiment, R1 and _R2 are halogen _; in another embodiment , R ₁ and R ₂ are C _1-6 alkyl; in another embodiment, R ₁ and R ₂ are C _1-6 haloalkyl.

In another embodiment, R ₁ and R ₂ are linked, and together with the atoms to which they are linked form

In _a more specific embodiment, Z1 is CR _Z1 ; in another specific embodiment, Z1 is CH _; in another specific embodiment, Z1 is N _;

In a more specific embodiment, Z2 is CR _Z2 ; in another specific embodiment, Z2 is _CH _; in another specific embodiment, Z2 is N _;

_In a more specific embodiment, Z3 is CR _Z3 ; in another specific embodiment, Z3 is CH _; in another specific embodiment, Z3 is N _;

In a more specific embodiment, _Z4 is CR _Z4 ; in another specific embodiment, _Z4 is CH; in another specific embodiment, _Z4 is N.

In a more specific embodiment, R _Z1 , R _Z2 , R _Z3 and R _Z4 are independently selected from H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl; in another specific embodiment , R _Z1 , R _Z2 , R _Z3 and R _Z4 are independently selected from H, D, halogen or C _1-6 alkyl; in another specific embodiment, R _Z1 , R _Z2 , R _Z3 and R _Z4 are independently is selected from H, D or halogen; in another specific embodiment, R _Z1 , R _Z2 , R _Z3 and R _Z4 are independently selected from H or D.

L ₁ , L ₂ , L ₃ , L ₄ , L ₅ , L ₆ and L ₇

In _one embodiment, L1 is _CR1R1 _' ; in another embodiment, L1 is _CH2 _; in another embodiment, L1 is absent _;

In one embodiment, L ₂ is O; in another embodiment, L ₂ is S; in another embodiment, L ₂ is NR ₂ "; in another embodiment, L ₂ is NH; _In another embodiment, L2 is NMe _; in another embodiment, L2 is _CR2R2 '_; in another embodiment, L2 is _CH2 _; in another embodiment, _L2 is C=O;

_In one embodiment, L3 is O; in another embodiment, L3 is _S ; in another embodiment, L3 is _NR3 "_; in another embodiment, L3 is NH _; _In another embodiment, L3 is NMe; in another embodiment, L3 is _CR3R3 '_; in another embodiment, _L3 is _CH2 _; in another embodiment, _L3 is C=O;

_In one embodiment, L4 is O; in another embodiment, _L4 is S; in another embodiment, _L4 is _NR4 "; in another embodiment, L4 is NH _; _In another embodiment, L4 is NMe; _In another embodiment, L4 is _CR4R4 '; _In another embodiment, L4 is _CH2 ; _In another embodiment, _L4 is C=O;

_In one embodiment, L5 is O; in another embodiment, _L5 is S; in another embodiment, _L5 is _NR5 "; in another embodiment, L5 is NH _; _In another embodiment, L5 is NMe; in another embodiment, L5 is _CR5R5 '_; in another embodiment, _L5 is _CH2 _; in another embodiment, _L5 is C=O; in another embodiment, L is absent _;

In one embodiment, L6 is O _; in another embodiment, L6 is S _; in another embodiment, L6 is _NR6 "_; in another embodiment, L6 is NH _; In another embodiment, L6 is NMe _; in another embodiment, L6 is _CR6R6 '_; in another embodiment, _L6 is _CH2 _; in another embodiment, _L6 is C=O; in another embodiment, L is absent _;

In one embodiment, _L7 is O; in another embodiment, _L7 is S; in another embodiment, _L7 is NH; in another embodiment, _L7 is _CH2 ; In one embodiment, L ₇ is C=O;

In another embodiment, -L6 _- _L7- combines to form -CH=CH-; in another embodiment, -L6 _- _L7- combines to form -C≡C-.

In another embodiment, the substituents of L ₂ and L ₅ are linked and together with L ₂ , L ₃ , L ₄ and L ₅ form C _5-7 cycloalkylene, 5-7 membered heterocyclylene, C _6-10 arylene or 5-7 membered heteroarylene; in another embodiment, the substituents of L ₂ and L ₅ are linked and together with L ₂ , L ₃ , L ₄ and L ₅ form C _5-7 cycloalkylene; in another embodiment, the substituents of L ₂ and L ₅ are connected, and together with L ₂ , L ₃ , L ₄ and L ₅ form a 5-7 membered heterocyclylene; in In another embodiment, the substituents of L ₂ and L ₅ are linked and together with L ₂ , L ₃ , L ₄ and L ₅ form a C _6-10 arylene; in another embodiment, L ₂ and L The substituents of ₅ are attached and together with L ₂ , L ₃ , L ₄ and L ₅ form a 5-7 membered heteroarylene; in another embodiment, the substituents of L ₂ and L ₅ are attached and are attached to L ₂ , L ₃ , L ₄ and L ₅ together form 1,4-phenylene; in another embodiment, the substituents of L ₂ and L ₅ are attached and are linked to L ₂ , L ₃ , L ₄ and L ₅ taken together to form 2,5-pyridylene; in another embodiment, the substituents of L ₂ and L ₅ are attached and together with L ₂ , L ₃ , L ₄ and L ₅ form 2,5-pyrimidinylene; In another embodiment, the substituents of L ₂ and L ₅ are attached and together with L ₂ , L ₃ , L ₄ and L ₅ form 2,5-pyrazinylidene; in another embodiment, L ₂ is attached to the substituent of L ₅ and forms together with L ₂ , L ₃ , L ₄ and L ₅

In another embodiment, the substituents of L ₂ and L ₅ are linked and form together with L ₂ , L ₃ , L ₄ and L ₅

In another embodiment, the substituents of L ₂ and L ₅ are attached and together with L ₂ , L ₃ , L ₄ and L ₅ form 1,4-pyrazolylidene; in another embodiment, L ₂ is attached to the substituents of L ₅ and together with L ₂ , L ₃ , L ₄ and L ₅ form a 1,3-pyrazolylidene; in another embodiment, the substituents of L ₂ and L ₅ are attached, and together with L ₂ , L ₃ , L ₄ and L ₅ to form a 1,3-pyrrolidene group; in another embodiment, the substituents of L ₂ and L ₅ are attached, and together with L ₂ , L ₃ , L ₄ and L ₅ together form 1,4-triazolylidene; in another embodiment, the substituents of L ₂ and L ₅ are linked and together with L ₂ , L ₃ , L ₄ and L ₅ form 2,5- thiadiazolylidene _; in another embodiment, the substituents _of L2 and _L5 are linked and together with L2, _L3 , _L4 and _L5 form tetrazolylylene.

In another embodiment, the substituents of L ₂ and L ₄ are linked and together with L ₂ , L ₃ and L ₄ form C _5-7 cycloalkylene, 5-7 membered heterocyclylene, C _{6- 10} arylene or 5-7 membered heteroarylene; in another embodiment, the substituents of L ₂ and L ₄ are connected and together with L ₂ , L ₃ and L ₄ form a C _5-7 cycloalkane In another embodiment, the substituents of L ₂ and L ₄ are connected and together with L ₂ , L ₃ and L ₄ form a 5-7 membered heterocyclylene group; in another embodiment, L ₂ and The substituents of L ₄ are connected and together with L ₂ , L ₃ and L ₄ form a C _6-10 arylene; in another embodiment, the substituents of L ₂ and L ₄ are connected and together with L ₂ , L ₃ and L ₄ together form a 5-7 membered heteroarylene; in another embodiment, the substituents of L ₂ and L ₄ are linked and together with L ₂ , L ₃ and L ₄ form 1,3-phenylene In another embodiment, the substituents of L ₂ and L ₄ are linked and together with L ₂ , L ₃ and L ₄ form 2,6-pyridylene; in another embodiment, L ₂ and L The substituents of ₄ are connected and together with L ₂ , L ₃ and L ₄ form 2,4-pyridylene; in another embodiment, the substituents of L ₂ and L ₄ are connected and are connected with L ₂ , L ₃ together with L ₄ to form 3,5-pyridylene; in another embodiment, the substituents of L ₂ and L ₄ are linked, and together with L ₂ , L ₃ and L ₄ form 2,4-pyrimidinylene; In another embodiment, the substituents of L ₂ and L ₄ are linked and together with L ₂ , L ₃ and L ₄ form 4,6-pyrimidinylene; in another embodiment, the substituents of L ₂ and L ₄ The substituents are attached and together with L ₂ , L ₃ and L ₄ form 2,6-pyrazinylidene; in another embodiment, the substituents of L ₂ and L ₄ are attached and together with L ₂ , L ₃ and L ₄ together form 1,4-triazolylidene; in another embodiment, the substituents of L ₂ and L ₄ are linked and together with L ₂ , L ₃ and L ₄ form 2,5-triazolylylene .

In another embodiment, the substituents of L ₃ and L ₅ are linked and together with L ₃ , L ₄ and L ₅ form C _5-7 cycloalkylene, 5-7 membered heterocyclylene, C _{6- 10} arylene or 5-7 membered heteroarylene; in another embodiment, the substituents of L ₃ and L ₅ are connected and together with L ₃ , L ₄ and L ₅ form C _5-7 cycloalkane In another embodiment, the substituents of L ₃ and L ₅ are connected and together with L ₃ , L ₄ and L ₅ form a 5-7 membered heterocyclylene group; in another embodiment, L ₃ and The substituents of L ₅ are connected and together with L ₃ , L ₄ and L ₅ form a C _6-10 arylene; in another embodiment, the substituents of L ₃ and L ₅ are connected and together with L ₃ , L ₄ and L ₅ together form a 5-7 membered heteroarylene; in another embodiment, the substituents of L ₃ and L ₅ are connected and together with L ₃ , L ₄ and L ₅ form 1,3-phenylene In another embodiment, the substituents of L ₃ and L ₅ are connected and together with L ₃ , L ₄ and L ₅ form a 2,6-pyridylene group; in another embodiment, L ₃ and L The substituents of ₅ are connected and together with L ₃ , L ₄ and L ₅ form 2,4-pyridylene; in another embodiment, the substituents of L ₃ and L ₅ are connected and are connected with L ₃ , L ₄ together with L ₅ form 3,5-pyridylene; in another embodiment, the substituents of L and L ₅ are linked and together with L ₃ , L ₄ and L ₅ form 2,4-pyrimidinylene _; In another embodiment, the substituents of L ₃ and L ₅ are linked and together with L ₃ , L ₄ and L ₅ form 4,6-pyrimidinylene; in another embodiment, the substituents of L ₃ and L ₅ The substituents are attached and together with L ₃ , L ₄ and L ₅ form 2,6-pyrazinylidene; in another embodiment, the substituents of L ₃ and L ₅ are attached and together with L ₃ , L ₄ and L ₅ is taken together to form 1,4-triazolylylene; in another embodiment, the substituents of L ₃ and L ₅ are linked and together with L ₃ , L ₄ and L ₅ form 2,5-triazolylylene .

In another embodiment, -L ₂ -L ₃ -L ₄ - represents C _5-7 cycloalkylene, 5-7 membered heterocyclylene, C _6-10 arylene or 5-7 membered heterocyclylene Aryl; in another embodiment, -L ₂ -L ₃ -L ₄ - represents C _5-7 cycloalkylene; in another embodiment, -L ₂ -L ₃ -L ₄ - represents 5- 7-membered heterocyclylene; in another embodiment, -L ₂ -L ₃ -L ₄ - represents a C _6-10 arylene; in another embodiment, -L ₂ -L ₃ -L ₄ - represents a 5-7 membered heteroarylene; in another embodiment, -L ₂ -L ₃ -L ₄ - represents 1,4-phenylene; in another embodiment, -L ₂ -L ₃ - L ₄ - represents 2,5-pyridylene; in another embodiment, -L ₂ -L ₃ -L ₄ - represents 2,5-pyrimidinylene; in another embodiment, -L ₂ -L ₃ -L ₄ - represents 2,5-pyrazinylene; in another embodiment, -L ₂ -L ₃ -L ₄ - represents

In another embodiment, -L ₂ -L ₃ -L ₄ - represents

In another embodiment, -L ₂ -L ₃ -L ₄ - represents 1,3-phenylene; in another embodiment, -L ₂ -L ₃ -L ₄ - represents 2,6-pyridine In another embodiment, -L ₂ -L ₃ -L ₄ - represents 2,4-pyridylene; in another embodiment, -L ₂ -L ₃ -L ₄ - represents 3,5- Pyridylene; in another embodiment, -L ₂ -L ₃ -L ₄ - represents 2,4-pyrimidinylene; in another embodiment, -L ₂ -L ₃ -L ₄ - represents 4, 6-pyrimidylene; in another embodiment, -L ₂ -L ₃ -L ₄ - represents 2,6-pyrazinylene; in another embodiment, -L ₂ -L ₃ -L ₄ - represents 1,4-triazolylylene; in another embodiment, -L ₂ -L ₃ -L ₄ - represents 2,5-triazolylylene.

In another embodiment, -L ₃ -L ₄ -L ₅ - represents C _5-7 cycloalkylene, 5-7 membered heterocyclylene, C _6-10 arylene or 5-7 membered heterocyclylene Aryl; in another embodiment, -L ₃ -L ₄ -L ₅ - represents C _5-7 cycloalkylene; in another embodiment, -L ₃ -L ₄ -L ₅ - represents 5- 7-membered heterocyclylene; in another embodiment, -L ₃ -L ₄ -L ₅ - represents a C _6-10 arylene; in another embodiment, -L ₃ -L ₄ -L ₅ - represents a 5-7 membered heteroarylene; in another embodiment, -L ₃ -L ₄ -L ₅ - represents 1,4-phenylene; in another embodiment, -L ₃ -L ₄ - L ₅ -represents 2,5-pyridylene; in another embodiment, -L ₃ -L ₄ -L ₅ -represents 2,5-pyrimidinylene; in another embodiment, -L ₃ -L ₄ -L ₅ - represents 2,5-pyrazinylene; in another embodiment, -L ₃ -L ₄ -L ₅ - represents

In another embodiment, -L ₃ -L ₄ -L ₅ - represents

In another embodiment, -L ₃ -L ₄ -L ₅ - represents 1,3-phenylene; in another embodiment, -L ₃ -L ₄ -L ₅ - represents 2,6-pyridine In another embodiment, -L ₃ -L ₄ -L ₅ - represents 2,4-pyridylene; in another embodiment, -L ₃ -L ₄ -L ₅ - represents 3,5- Pyridylene; in another embodiment, -L ₃ -L ₄ -L ₅ - represents 2,4-pyrimidinylene; in another embodiment, -L ₃ -L ₄ -L ₅ - represents 4, 6-pyrimidylene; in another embodiment, -L ₃ -L ₄ -L ₅ - represents 2,6-pyrazinylene; in another embodiment, -L ₃ -L ₄ -L ₅ - represents 1,4-triazolylylene; in another embodiment, -L ₃ -L ₄ -L ₅ - represents 2,5-triazolylylene.

R ₁ , R ₁ ′, R ₂ , R ₂ ′, R ₃ , R ₃ ′, R ₄ , R ₄ ′, R ₅ , R ₅ ′, R ₆ , R ₆ ′, R ₇ , and R ₇ ′

In one embodiment, R ₁ , R ₁ ′, R ₂ , R ₂ ′, R ₃ , R ₃ ′, R ₄ , R ₄ ′, R ₅ , R ₅ ′, R ₆ , R ₆ ′, R ₇ and R ₇ ′ are independently selected from H, D, halogen, C _1-6 alkyl, or C _1-6 haloalkyl; in another embodiment, R ₁ , R ₁ ′, R ₂ , R ₂ ′, R ₃ , R ₃ ', R ₄ , R ₄ ', R ₅ , R ₅ ', R ₆ , R ₆ ', R ₇ and R ₇ ' are independently selected from H, D, halogen or C _1-6 alkyl; _In another embodiment, R1, R1 _' , R2, _R2 _' , _R3 , _R3 ', _R4 , _R4 ', _R5 , _R5 ', _R6 , _R6 ', R ₇ and _R7 ' are independently selected from H, D or halogen; in another embodiment, R1, R1 _' , _R2 , _R2 _' , _R3 , _R3 ', _R4 , _R4 ', R ₅ , R ₅ ′, R ₆ , R ₆ ′, R ₇ and R ₇ ′ are independently selected from H or D.

In another embodiment, R ₂ and R ₂ ' combine to form =O; in another embodiment, R ₃ and R ₃ ' combine to form =O; in another embodiment, R ₄ and R ₄ ' combine In another embodiment, R ₅ and R ₅ ' combine to form =O; in another embodiment, R ₆ and R ₆ ' combine to form =O; in another embodiment, R ₇ and R ₇ ' combines to form =O.

_R2 ", _R3 ", _R4 ', _R5 ", _R6 " and _R7 "

In one embodiment, R ₂ " is H; in another embodiment, R ₂ " is C _1-6 alkyl; in another embodiment, R ₂ " is C _1-6 haloalkyl;

In one embodiment, R ₃ " is H; in another embodiment, R ₃ " is C _1-6 alkyl; in another embodiment, R ₃ " is C _1-6 haloalkyl;

In one embodiment, R ₄ " is H; in another embodiment, R ₄ " is C _1-6 alkyl; in another embodiment, R ₄ " is C _1-6 haloalkyl;

In one embodiment, R ₅ " is H; in another embodiment, R ₅ " is C _1-6 alkyl; in another embodiment, R ₅ " is C _1-6 haloalkyl;

In one embodiment, R ₆ " is H; in another embodiment, R ₆ " is C _1-6 alkyl; in another embodiment, R ₆ " is C _1-6 haloalkyl;

In one embodiment, R ₇ " is H; in another embodiment, R ₇ " is C _1-6 alkyl; in another embodiment, R ₇ " is C _1-6 haloalkyl.

Any technical solution in any of the above specific embodiments or any combination thereof may be combined with any technical solution in other specific embodiments or any combination thereof. For example, any technical solution of W or any combination thereof can be carried out with any technical solution of L, X ₁ -X ₅ , Y ₁ -Y ₂ , R ₁ -R ₂ and L ₁ -L ₇ or any combination thereof. combination. The present invention is intended to include all the combinations of these technical solutions, and is not listed one by one due to space limitations.

In a more specific embodiment, wherein W is C=O.

In a more specific embodiment, wherein L is NH.

In a more specific embodiment, wherein X ₂ is N.

In a more specific embodiment, wherein Y ₁ is CR _Y1 , preferably CH.

In a more specific embodiment, wherein Y ₂ is O or S, preferably O.

_In _a more specific embodiment, wherein R1 and R2 are connected, and together with the atoms to which they are connected form

Preferably, Z ₁ , Z ₂ , Z ₃ and Z ₄ are respectively CR _Z1 , CR _Z2 , CR _Z3 and CR _Z4 , preferably all CH; preferably, Z ₁ , Z ₂ , Z ₃ and Z ₄ are respectively CH, CH, CH, and N.

_In a more specific embodiment, wherein L2 is O, _S or _CR2R2 '; L3 is O, _S or _CR3R3 '_; L4 is O, _S or _CR4R4 '_; _L5 is O, S or CR ₅ R ₅ ′; L ₆ is O, S or CR ₆ R ₆ ′.

In a more specific embodiment, wherein L ₇ is O, S, NH or CH ₂ ; or -L ₆ -L ₇ - combines to form -CH=CH- or -C≡C-.

In a more specific embodiment, wherein the substituents of L ₂ and L ₅ are linked and together with L ₂ , L ₃ , L ₄ and L ₅ form a C _6-10 aryl ring or a 5-7 membered heteroarylene , preferably 1,4-phenylene.

In a more specific embodiment, wherein the substituents of L ₂ and L ₄ are connected and together with L ₂ , L ₃ and L ₄ form a C _6-10 arylene or 5-7 membered heteroarylene, preferably 1 , 3-phenylene.

In a more specific embodiment, wherein -L ₂ -L ₃ -L ₄ - represents C _5-7 cycloalkylene,

or C _6-10 arylene, preferably

In a more specific embodiment, the present invention relates to the above-mentioned compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which are Compound of formula:

wherein each group is as defined above.

In a more specific embodiment, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which are of formula (II) or (II-a) compound:

in,

W is CRR' or C=O;

L is NR";

wherein R" is independently selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

X ₁ is CR _X1 or N; X ₂ is CR _X2 or N; preferably N; X ₃ is CR _X3 or N; X ₄ is CR _X4 or N; X ₅ is CR _X5 ;

Y ₁ is CR _Y1 or N;

_Y2 is O, S or NR _Y2 ;

R _{Y2 is} selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

Z ₁ is CR _Z1 or N; Z ₂ is CR _Z2 or N; Z ₃ is CR _Z3 or N; Z ₄ is CR _Z4 or N;

L ₂ is O, S, NR ₂ "or CR ₂ R ₂ '; L ₃ is O, S, NR ₃ " or CR ₃ R ₃ '; L ₄ is O, S, NR ₄ "or CR ₄ R ₄ ';

L ₅ is O, S, NR ₅ "or CR ₅ R ₅ '; L ₁ and L ₆ are CR ₁ R ₁ ' and CR ₆ R ₆ ', respectively;

or L ₁ , L ₅ and L ₆ are each independently absent;

wherein R ₁ , R ₁ ′, R ₂ , R ₂ ′, R ₃ , R ₃ ′, R ₄ , R ₄ ′, R ₅ , R ₅ ′, R ₆ and R ₆ ′ are independently selected from H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

Or R ₂ and R ₂ ', R ₃ and R ₃ ', R ₄ and R ₄ ', R ₅ and R ₅ ', R ₆ and R ₆ ' combine to form =0;

R ₂ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₃ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₄ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₅ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

In a more specific embodiment, the present invention relates to a compound of formula (II) above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a tautomer, stereoisomer, prodrug, crystalline form thereof ,in:

W is CRR' or C=O;

wherein R and R' are independently selected from H or D;

L is NH;

X1 is CR _X1 or N _;

X2 is CR _X2 or N _; preferably N;

_X3 is CR _X3 or N;

_X4 is CR _X4 or N;

_X5 is CR _X5 ;

wherein R _X1 , R _X2 , R _X3 , R _X4 and R _X5 are independently selected from H or D;

Y ₁ is CR _Y1 or N;

_Y2 is O, S or NR _Y2 ;

wherein R _Y1 is independently selected from H or D;

R _{Y2 is} selected from H or C _1-6 alkyl;

Z1 is CR _Z1 or N _;

Z2 is CR _Z2 or N _;

Z ₃ is CR _Z3 or N;

Z ₄ is CR _Z4 or N;

wherein R _Z1 , R _Z2 , R _Z3 and R _Z4 are independently selected from H or D;

L ₂ is O, NR ₂ "or CR ₂ R ₂ ';

L ₃ is O, NR ₃ "or CR ₃ R ₃ ';

L ₄ is O, NR ₄ "or CR ₄ R ₄ ';

L ₁ , L ₅ and L ₆ are CR ₁ R ₁ ', CR ₅ R ₅ ' and CR ₆ R ₆ ', respectively;

or L ₁ , L ₅ and L ₆ are each independently absent;

Or the substituents of L ₂ and L ₅ are connected, and together with L ₂ , L ₃ , L ₄ and L ₅ form 1,4-phenylene or

Or the substituents of L ₂ and L ₄ are connected, and together with L ₂ , L ₃ and L ₄ form 1,3-phenylene;

Or the substituents of L ₃ and L ₅ are connected, and together with L ₃ , L ₄ and L ₅ form 1,3-phenylene or 2,6-pyridylene;

Or -L ₂ -L ₃ -L ₄ - represents 1,4-phenylene,

Or -L ₃ -L ₄ -L ₅ - represents 1,4-phenylene;

wherein R ₁ , R ₁ ′, R ₂ , R ₂ ′, R ₃ , R ₃ ′, R ₄ , R ₄ ′, R ₅ , R ₅ ′, R ₆ and R ₆ ′ are independently selected from H or D;

R ₂ " is selected from H or C _1-6 alkyl;

R ₃ " is selected from H or C _1-6 alkyl;

R ₄ " is selected from H or C _1-6 alkyl;

In a more specific embodiment, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which are of formula (II-1) or (II-1-a) compound:

in,

W is CRR' or C=O;

X1 is CR _X1 or N _;

X2 is CR _X2 or N _; preferably N;

_X3 is CR _X3 or N;

_X4 is CR _X4 or N;

_X5 is CR _X5 ;

_Y1 is CR _Y1 ;

_Y2 is O, S or NR _Y2 ;

R _{Y2 is} selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

Z ₄ is CR _Z4 or N;

wherein R _Z4 is selected from H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

L ₂ is O, S, NR ₂ ″ or CR ₂ R ₂ ′;

L ₃ is O, S or CR ₃ R ₃ ';

L ₄ is O, S or CR ₄ R ₄ ';

L ₁ , L ₅ and L ₆ are CR ₁ R ₁ ′, CR ₅ R ₅ ′ and CR ₆ R ₆ ′, respectively; or L ₅ is absent;

Or the substituents of L ₂ and L ₅ are connected, and together with L ₂ , L ₃ , L ₄ and L ₅ form C _5-7 cycloalkylene, 5-7 membered heterocyclylene or C _6-10 arylene base;

Or the substituents of L ₂ and L ₄ are connected, and together with L ₂ , L ₃ and L ₄ form a C _5-7 cycloalkylene group, a 5-7 membered heterocyclylene group or a C _6-10 arylene group _;

Or -L ₂ -L ₃ -L ₄ - represents C _5-7 cycloalkylene, C _6-10 arylene or

R ₂ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

The condition is that when Y ₂ is O, L ₁ , L ₂ , L ₃ , L ₄ , L ₅ and L ₆ cannot be CH ₂ at the same time;

In a more specific embodiment, the present invention relates to a compound of formula (II-1) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:

W is CRR' or C=O;

wherein R and R' are independently selected from H or D;

X1 is CR _X1 or N _;

X2 is CR _X2 or N _; preferably N;

_X3 is CR _X3 or N;

_X4 is CR _X4 or N;

_X5 is CR _X5 ;

_Y1 is CR _Y1 ;

_Y2 is O, S or NR _Y2 ;

wherein R _Y1 is independently selected from H or D;

R _{Y2 is} selected from H or C _1-6 alkyl;

Z ₄ is CR _Z4 or N;

wherein R _Z4 is selected from H or D;

L ₂ is O, NR ₂ "or CR ₂ R ₂ ';

L ₃ is O or CR ₃ R ₃ ';

L ₄ is O or CR ₄ R ₄ ';

L ₁ , L ₅ and L ₆ are CR ₁ R ₁ ', CR ₅ R ₅ ' and CR ₆ R ₆ ', respectively; or L ₅ is absent;

or -L ₂ -L ₃ -L ₄ - represents 1,4-phenylene or

R ₂ " is selected from H or C _1-6 alkyl;

In a more specific embodiment, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which are of formula (II-2) or (II-2-a) compound:

in,

W is CRR' or C=O;

_Y1 is CR _Y1 ;

_Y2 is O, S or NR _Y2 ;

R _{Y2 is} selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

Z ₄ is CR _Z4 or N;

wherein R _Z4 is selected from H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

L ₂ is O, S, NR ₂ ″ or CR ₂ R ₂ ′;

L ₃ is O, S or CR ₃ R ₃ ';

L ₁ , L ₄ , L ₅ and L ₆ are CR ₁ R ₁ ', CR ₄ R ₄ ', CR ₅ R ₅ ' and CR ₆ R ₆ ', respectively;

Or -L ₂ -L ₃ -L ₄ - represents C _5-7 cycloalkylene, C _6-10 arylene or

R ₂ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

In a more specific embodiment, the present invention relates to a compound of formula (II-2) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof. compounds, including:

W is CRR' or C=O;

wherein R and R' are independently selected from H or D;

_Y1 is CR _Y1 ;

_Y2 is O, S or NR _Y2 ;

wherein R _Y1 is independently selected from H or D;

R _{Y2 is} selected from H or C _1-6 alkyl;

Z ₄ is CR _Z4 or N;

wherein R _Z4 is selected from H or D;

L ₂ is O, NR ₂ "or CR ₂ R ₂ ';

L ₃ is O or CR ₃ R ₃ ';

Or the substituents of L ₂ and L ₅ are connected, and together with L ₂ , L ₃ , L ₄ and L ₅ form 1,4-phenylene;

or -L ₂ -L ₃ -L ₄ - represents 1,4-phenylene or

R ₂ " is selected from H or C _1-6 alkyl;

In a more specific embodiment, the present invention relates to a compound of formula (II-2) above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:

W is CRR' or C=O;

_Y1 is CR _Y1 ;

Y ₂ is O or S;

Z ₄ is CR _Z4 or N;

wherein R _Z4 is selected from H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

L ₁ , L ₂ , L ₃ , L ₄ , L ₅ and L ₆ are CR ₁ R ₁ ′, CR ₂ R ₂ ′, CR ₃ R ₃ ′, CR ₄ R ₄ ′, CR ₅ R ₅ ′ and CR, respectively _6R6 '_;

Or -L ₂ -L ₃ -L ₄ - represents a C _5-7 cycloalkylene group, a 5-7 membered heterocyclic group or a C _6-10 arylene group;

The condition is that when Y ₂ is O, L ₁ , L ₂ , L ₃ , L ₄ , L ₅ and L ₆ cannot be CH ₂ at the same time.

W is CRR' or C=O;

wherein R and R' are independently selected from H or D;

_Y1 is CR _Y1 ;

wherein R _Y1 is independently selected from H or D;

Y ₂ is O or S;

Z ₄ is CR _Z4 or N;

wherein R _Z4 is selected from H or D;

Or -L ₂ -L ₃ -L ₄ - represents 1,4-phenylene;

In a more specific embodiment, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which are of formula (III-3) or (III-a) compound:

in,

W is CRR' or C=O;

L ₂ is O, S, NR ₂ ″ or CR ₂ R ₂ ′;

L ₃ is O, S, NR ₃ "or CR ₃ R ₃ ';

L ₄ is O, S, NR ₄ "or CR ₄ R ₄ ';

L ₅ is O, S, NR ₅ "or CR ₅ R ₅ ';

L ₁ and L ₆ are CR ₁ R ₁ ' and CR ₆ R ₆ ', respectively;

R ₂ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₃ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₄ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₅ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

In a more specific embodiment, the present invention relates to a compound of formula (III-3) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:

W is C=O;

L ₂ is O or CR ₂ R ₂ ';

L ₃ is O, NR ₃ "or CR ₃ R ₃ ';

R ₃ " is selected from H or C _1-6 alkyl;

W is CRR' or C=O;

L ₃ is O, S or CR ₃ R ₃ ';

L ₁ , L ₂ , L ₄ , L ₅ and L ₆ are CR ₁ R ₁ ′, CR ₂ R ₂ ′, CR ₄ R ₄ ′, CR ₅ R ₅ ′ and CR ₆ R ₆ ′, respectively;

wherein R ₁ , R ₁ ', R ₂ , R ₂ ', R ₄ , R ₄ ', R ₅ , R ₅ ', R ₆ and R ₆ ' are independently selected from H, D, halogen, C _1-6 alkanes group or C _1-6 haloalkyl;

Or R ₂ and R ₂ ', R ₃ and R ₃ ', R ₄ and R ₄ ', R ₅ and R ₅ ', R ₆ and R ₆ ' combine to form =O.

W is C=O;

L ₃ is O or CR ₃ R ₃ ';

wherein R ₁ , R ₁ ′, R ₂ , R ₂ ′, R ₃ , R ₃ ′, R ₄ , R ₄ ′, R ₅ , R ₅ ′, R ₆ and R ₆ ′ are independently selected from H or D.

W is CRR' or C=O;

L ₃ is O or S;

W is C=O;

L ₃ is O;

wherein R ₁ , R ₁ ′, R ₂ , R ₂ ′, R ₄ , R ₄ ′, R ₅ , R ₅ ′, R ₆ and R ₆ ′ are independently selected from H or D.

In a more specific embodiment, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which are of formula (IV-3) or (IV-3-a) compound:

W is CRR' or C=O;

L ₂ is O, S, NR ₂ ″ or CR ₂ R ₂ ′;

L ₃ is O, S, NR ₃ "or CR ₃ R ₃ ';

L ₄ is O, S, NR ₄ "or CR ₄ R ₄ ';

L ₅ is O, S, NR ₅ "or CR ₅ R ₅ ';

L ₁ and L ₆ are CR ₁ R ₁ ' and CR ₆ R ₆ ', respectively;

R ₂ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₃ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₄ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₅ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

In a more specific embodiment, the present invention relates to a compound of formula (IV-3) above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:

W is C=O;

L ₂ is O or CR ₂ R ₂ ';

L ₃ is O or CR ₃ R ₃ ';

L ₄ is O or CR ₄ R ₄ ';

The condition is that two adjacent atoms cannot be O at the same time.

W is CRR' or C=O;

L ₂ is O, S or CR ₂ R ₂ ';

L ₃ is O, S or CR ₃ R ₃ ';

W is C=O;

L ₂ is O or CR ₂ R ₂ ';

L ₃ is O or CR ₃ R ₃ ';

Or the substituents of L ₂ and L ₅ are connected, and together with L ₂ , L ₃ , L ₄ and L ₅ form 1,4-phenylene, 2,5-pyridylene, 1,4-pyrazolyl , 1,3-pyrazolylidene, 1,3-pyrrolidene, 1,4-triazolylidene, 2,5-thiadiazolylidene or tetrazolylidene;

The condition is that two adjacent atoms cannot be O at the same time.

W is CRR' or C=O;

L ₃ is O, S or CR ₃ R ₃ ';

W is C=O;

L ₃ is O or CR ₃ R ₃ ';

In a more specific embodiment, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which are of formula (V-2) or (V-2-a) compound:

in,

W is CRR' or C=O;

_Y1 is CR _Y1 ;

_Y2 is O, S or NR _Y2 ;

R _{Y2 is} selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

L ₁ is CR ₁ R ₁ ';

L ₅ is CR ₅ R ₅ ';

L ₆ is CR ₆ R ₆ ' or absent;

L ₇ is O, S, NR ₇ "or CR ₇ R ₇ ';

The substituents of L ₂ and L ₅ are connected and together with L ₂ , L ₃ , L ₄ and L ₅ form C _6-10 arylene, 5-7 membered heteroarylene or

Preferably C _6-10 arylene or 5-7 membered heteroarylene;

Or the substituents of L ₂ and L ₄ are connected, and together with L ₂ , L ₃ and L ₄ form a C _6-10 arylene group or a 5-7 membered heteroarylene group;

Or -L ₂ -L ₃ -L ₄ - represents C _6-10 arylene, 5-7 membered heteroarylene or

wherein R ₁ , R ₁ ', R ₅ , R ₅ ', R ₆ , R ₆ ', R ₇ and R ₇ ' are independently selected from H, D, halogen, C _1-6 alkyl or C _1-6 haloalkane base;

R ₇ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl.

In a more specific embodiment, the present invention relates to a compound of formula (V-2) above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof compounds, including:

W is CRR' or C=O;

wherein R and R' are independently selected from H or D;

_Y1 is CR _Y1 ;

Y ₂ is O or S;

wherein R _Y1 is independently selected from H or D;

L ₁ is CR ₁ R ₁ ';

L ₅ is CR ₅ R ₅ ';

L ₆ is CR ₆ R ₆ ' or absent;

L ₇ is O, S, NR ₇ "or CR ₇ R ₇ ';

The substituents of L ₂ and L ₅ are connected, and together with L ₂ , L ₃ , L ₄ and L ₅ form 1,4-phenylene, 1,4-triazolylylene or

1,4-phenylene or 1,4-triazolylylene is preferred;

or -L ₂ -L ₃ -L ₄ - represents 1,4-phenylene or

wherein R ₁ , R ₁ ′, R ₅ , R ₅ ′, R ₆ , R ₆ ′, R ₇ and R ₇ ′ are independently selected from H or D;

R ₇ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl.

W is CRR' or C=O;

_Y1 is CR _Y1 ;

_Y2 is O, S or NR _Y2 ;

R _{Y2 is} selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

L ₁ is CR ₁ R ₁ ';

L ₅ is CR ₅ R ₅ ';

L ₆ is CR ₆ R ₆ ′;

L ₇ is S or NR ₇ ";

The substituents of L ₂ and L ₅ are connected, and together with L ₂ , L ₃ , L ₄ and L ₅ form a C _6-10 arylene group or a 5-7 membered heteroarylene group;

Or -L ₂ -L ₃ -L ₄ - represents a C _6-10 arylene group or a 5-7 membered heteroarylene group;

wherein R ₁ , R ₁ ', R ₅ , R ₅ ', R ₆ and R ₆ ' are independently selected from H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl;

R ₇ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl.

W is CRR' or C=O;

wherein R and R' are independently selected from H or D;

_Y1 is CR _Y1 ;

Y ₂ is O or S;

wherein R _Y1 is independently selected from H or D;

L ₁ is CR ₁ R ₁ ';

L ₅ is CR ₅ R ₅ ';

L ₆ is CR ₆ R ₆ ′;

L ₇ is S or NH;

The substituents of L ₂ and L ₅ are connected, and together with L ₂ , L ₃ , L ₄ and L ₅ form 1,4-phenylene or 1,4-triazolylylene;

Or -L ₂ -L ₃ -L ₄ - represents 1,4-phenylene;

wherein R ₁ , R ₁ ′, R ₅ , R ₅ ′, R ₆ and R ₆ ′ are independently selected from H or D.

In a more specific embodiment, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which are of formula (V-3) or (V-3-a) compound:

in,

W is CRR' or C=O;

L ₂ is O, S, NR ₂ ″ or CR ₂ R ₂ ′;

L ₃ is O, S, NR ₃ "or CR ₃ R ₃ ';

L ₄ is O, S, NR ₄ "or CR ₄ R ₄ ';

L ₅ is O, S, NR ₅ "or CR ₅ R ₅ ';

L ₆ is O, S, NR ₆ "or CR ₆ R ₆ ';

L ₁ and L ₇ are CR ₁ R ₁ ' and CR ₇ R ₇ ', respectively;

Or -L ₆ -L ₇ - combines to form -CH=CH- or -C≡C-;

R ₂ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₃ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₄ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₅ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

R ₆ " is selected from H, C _1-6 alkyl or C _1-6 haloalkyl;

In a more specific embodiment, the present invention relates to a compound of formula (V-3) above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent thereof, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof. compounds, including:

W is C=O;

L ₂ is O or CR ₂ R ₂ ';

L ₃ is O or CR ₃ R ₃ ';

L ₄ is O or CR ₄ R ₄ ';

L ₁ , L ₅ , L ₆ and L ₇ are CR ₁ R ₁ ', CR ₅ R ₅ ', CR ₆ R ₆ ' and CR ₇ R ₇ ', respectively;

Or -L ₆ -L ₇ - combines to form -C≡C-;

wherein R ₁ , R ₁ ′, R ₂ , R ₂ ′, R ₃ , R ₃ ′, R ₄ , R ₄ ′, R ₅ , R ₅ ′, R ₆ , R ₆ ′, R ₇ , and R ₇ ′ are independently is selected from H or D;

The condition is that two adjacent atoms cannot be O at the same time.

W is CRR' or C=O;

L ₂ is O or S;

L ₁ , L ₃ , L ₄ and L ₅ are CR ₁ R ₁ ', CR ₃ R ₃ ', CR ₄ R ₄ ' and CR ₅ R ₅ ', respectively;

-L ₆ -L ₇ - combines to form -CH=CH- or -C≡C-;

wherein R ₁ , R ₁ ', R ₃ , R ₃ ', R ₄ , R ₄ ', R ₅ and R ₅ ' are independently selected from H, D, halogen, C _1-6 alkyl or C _1-6 haloalkane base;

Or R ₃ and R ₃ ′, R ₄ and R ₄ ′, R ₅ and R ₅ ′ combine to form =O.

W is C=O;

L ₂ is O;

-L ₆ -L ₇ - combines to form -C≡C-;

wherein R ₁ , R ₁ ′, R ₃ , R ₃ ′, R ₄ , R ₄ ′, R ₅ and R ₅ ′ are independently selected from H or D.

W is CRR' or C=O;

L ₂ is O, S or CR ₂ R ₂ ';

L ₃ is O, S or CR ₃ R ₃ ';

L ₁ , L ₄ , L ₅ , L ₆ and L ₇ are CR ₁ R ₁ ′, CR ₄ R ₄ ′, CR ₅ R ₅ ′, CR ₆ R ₆ ′ and CR ₇ R ₇ ′, respectively;

W is C=O;

L ₂ is O or CR ₂ R ₂ ';

L ₃ is O or CR ₃ R ₃ ';

L ₁ , L ₄ , L ₅ , L ₆ and L ₇ are CR ₁ R ₁ ', CR ₄ R ₄ ', CR ₅ R ₅ ', CR ₆ R ₆ ' and CR ₇ R ₇ ', respectively;

The condition is that two adjacent atoms cannot be O at the same time.

In another more specific embodiment, the present invention relates to the following compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof:

Furthermore, the present invention is also intended to exclude specific compounds disclosed in conflicting applications of the present invention.

The compounds of the present invention may contain one or more asymmetric centers, and thus may exist in various stereoisomeric, eg, enantiomeric and/or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (eg, cis and trans isomers), or may be in the form of a mixture of stereoisomers, Include racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and chiral salt formation and crystallization; or preferred isomers can be separated by prepared by asymmetric synthesis.

"Tautomer" means that one functional group in some compounds changes its structure into another functional group isomer, and can rapidly convert into each other, becoming two isomers in dynamic equilibrium, and the two isomers are in dynamic equilibrium. isomers are called tautomers.

Those skilled in the art will appreciate that organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are called "solvates". When the solvent is water, the complex is called a "hydrate". The present invention encompasses all solvates of the compounds of the present invention.

The term "solvate" refers to a solvent-bound compound or salt form thereof usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, eg, in crystalline forms, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.

The term "hydrate" refers to a compound that is combined with water. Typically, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, a hydrate of a compound can be represented, for example, by the general formula R _· xH2O, where R is the compound and x is a number greater than zero. A given compound can form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R 0.5 H _{2 )} O)) and polyhydrates (x is a number greater than 1, eg, dihydrate (R _· 2H2O) and hexahydrate (R _· 6H2O)).

The compounds of the present invention may be in amorphous or crystalline form (crystalline or polymorphic). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the present invention. The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) of a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature and other factors can cause one crystalline form to dominate. Various polymorphs of the compounds can be prepared by crystallization under different conditions.

The present invention also includes isotopically-labeled compounds that are equivalent to those described in formula (I), but with one or more atoms replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that may be introduced into the compounds of the present invention include isotopes of ^hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, ^3H , ^13C , ^11C , ^14C , ^15N , ¹⁸ , respectively O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs containing the above isotopes and/or other isotopes of other atoms are within the scope of the present invention. Certain isotopically-labeled compounds of the invention, such as those into which radioactive isotopes (eg, ^3H ^and14C ) have been incorporated, are useful in drug and/or substrate tissue distribution assays. Tritium, ie ³ H, and carbon-14, ie ¹⁴ C isotopes are particularly preferred because of their ease of preparation and detection. Furthermore, substitution with heavier isotopes, such as deuterium, ie, 2H, may be preferred in some circumstances because greater metabolic stability may provide therapeutic benefits, such as increased in vivo half ^- life or reduced dosage requirements. Isotopically labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents in carrying out the processes disclosed in the following Schemes and/or Examples and Preparations labeled reagents.

Furthermore, prodrugs are also included within the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo to its active form having a medical effect by, for example, hydrolysis in blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra, "Improved oral drug delivery: solution limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each cited This article is for reference.

A prodrug is any covalently bonded compound of the invention which, when administered to a patient, releases the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in a manner such that the modification can be cleaved, either by routine manipulation or in vivo, to yield the parent compound. Prodrugs include, for example, compounds of the present invention wherein a hydroxyl, amino or sulfhydryl group is bonded to any group that, when administered to a patient, can be cleaved to form a hydroxyl, amino or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide and benzoate/amide derivatives of the hydroxy, sulfhydryl and amino functional groups of compounds of formula (I). Additionally, in the case of carboxylic acids (-COOH), esters such as methyl esters, ethyl esters, and the like can be used. The esters themselves may be active and/or hydrolyzable under human in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups which are readily cleaved in humans to release the parent acid or salt thereof.

Pharmaceutical compositions, formulations and kits

In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

A pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin. ), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block segment polymers, polyethylene glycol, and lanolin.

The present invention also includes kits (eg, pharmaceutical packages). Provided kits can include a compound of the present invention, other therapeutic agents, and first and second containers (eg, vials, ampoules, bottles, syringes, and/or dispersible packs or other) containing the compounds of the present invention, other therapeutic agents. suitable container). In some embodiments, provided kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the present invention and/or other therapeutic agent. In some embodiments, a compound of the present invention and other therapeutic agent provided in a first container and a second container are combined to form one unit dosage form.

The pharmaceutical compositions provided by the present invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration Drugs, administration via implants, or other modes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , intrameningeal administration, intralesional administration, and intracranial injection or infusion techniques.

Typically, an effective amount of a compound provided herein is administered. The amount of compound actually administered can be determined by the physician depending on the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .

When used to prevent the disorders of the present invention, the compounds provided herein are administered to subjects at risk of developing the disorders, typically on the advice and supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular disorder typically include subjects with a family history of the disorder, or those identified by genetic testing or screening as being particularly susceptible to developing the disorder.

The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to administration of a compound or a pharmaceutical composition thereof over an extended period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely, For example, the rest of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over an extended period of time, eg, within a therapeutic window.

Various methods of administration can be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus injection, eg, in order to rapidly increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient, eg, intramuscular or subcutaneous bolus doses provide slow release of the active ingredient, whereas boluses delivered directly into the vein (eg, by IV infusion) can be more effective. It is delivered rapidly, resulting in a rapid increase in the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, eg, by IV infusion, to provide a steady state concentration of the active ingredient in the body of the subject. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.

Oral compositions can take the form of bulk liquid solutions or suspensions or bulk powders. More generally, however, the compositions are presented in unit dosage form for ease of precise dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable for producing the desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, and the like. In such compositions, the compound will generally be the minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various components useful in forming the desired administration form. carriers or excipients and processing aids.

For oral doses, a typical regimen is one to five oral doses, especially two to four oral doses, typically three oral doses per day. Using these dosing patterns, each dose provides about 0.01 to about 20 mg/kg of a compound of the invention, with preferred doses each providing about 0.1 to about 10 mg/kg, especially about 1 to about 5 mg/kg.

In order to provide blood levels similar to, or lower than, the use of injectable doses, transdermal doses are typically selected in amounts of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

From about 1 to about 120 hours, especially 24 to 96 hours, injection dose levels are in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. To achieve adequate steady state levels, a preloaded bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be administered. For human patients of 40 to 80 kg, the maximum total dose cannot exceed approximately 2 g/day.

Liquid forms suitable for oral administration can include suitable aqueous or non-aqueous carriers as well as buffering agents, suspending and dispersing agents, coloring agents, flavoring agents, and the like. Solid forms may include, for example, any of the following components, or compounds of similar properties: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or cornstarch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, peppermint, water Methyl cylate or orange flavoring.

Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. In such compositions, as previously mentioned, the active compound is typically the minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope of the present invention.

The compounds of the present invention may also be administered by transdermal devices. Thus, transdermal administration can be accomplished using reservoir or porous membrane types, or patches of various solid matrices.

The above-described components of compositions for oral administration, injection or topical administration are only representative. Additional materials and processing techniques, etc. are described in Section 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

The compounds of the present invention can also be administered in sustained release form, or from a sustained release drug delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively, which optionally include a or more substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, eg, a sulfobutyl ether beta-cyclodextrin, also known as Captisol. See, eg, U.S. 5,376,645. In some embodiments, the formulation includes hexapropyl-beta-cyclodextrin (eg, in water, 10-50%).

drug combination

The compounds of the present invention may be used in combination with one or more other active ingredients in pharmaceutical compositions or methods for the treatment of the diseases and disorders described herein. Other additional active ingredients include other therapeutic agents or agents that moderate the adverse effects of the therapeutic agent against the intended disease target. The combination can be used to increase efficacy, ameliorate symptoms of other diseases, reduce one or more adverse effects, or reduce the required dose of a compound of the present invention. The additional active ingredients may be formulated in separate pharmaceutical compositions from the compounds of the present invention or may be included with the compounds of the present invention in a single pharmaceutical composition. The additional active ingredient may be administered concurrently with, prior to or subsequent to administration of the compounds of the present invention.

Detailed ways

The present invention will be further described below with reference to specific embodiments, but the present invention is not limited to these embodiments.

Example

Preparation of compounds of formula I

The present invention also provides the preparation method of formula I compound and its intermediate, and described scheme comprises:

Option One:

The raw material amine 1 (or its salt) and the acid 2 are condensed into the target product I under the action of a condensing agent (such as HATU) and a base (such as N,N-diisopropylethylamine (DIPEA)).

Option II:

The raw material amine 3 (or its salt) and compound 4 undergo a nucleophilic substitution reaction under the action of a base (such as triethylamine, N,N-diisopropylethylamine, etc.) to obtain the target product II.

All raw materials in Scheme 1 or Scheme 2 can be purchased from reagent companies or prepared according to published literature.

Compound Preparation Examples

The meanings of the abbreviations used hereinafter are as follows:

The raw materials in the following synthetic steps, for the non-commercial reagents, the synthetic steps have been provided. The batches corresponding to the raw materials in each step are not necessarily the same as those described in the synthesis method.

Preparation of intermediates

Intermediate 1: Synthesis of Compound Int-1

Step 1: 4-Alkynyl-1-pentanol 1-1 (5.00 g, 59.44 mmol) and tetrabutylammonium bromide (6.32 g, 19.62 mmol) were added to toluene (170 mL) at 0°C, then Sodium hydroxide (61.2 g, 535.45 mmol) and tert-butyl bromoacetate (34.78 g, 178.32 mmol) were sequentially added, then slowly warmed to room temperature and stirred at room temperature for 5 hours. After the reaction, the reaction mixture was diluted with water (50 mL), then extracted with ethyl acetate (2×50 mL), the organic layers were combined, washed with saturated sodium chloride solution (2×40 mL), and dried by adding anhydrous sodium sulfate, Filter to obtain crude product. Normal-phase silica gel column separation and purification (petroleum ether:ethyl acetate (V/V)=100:1-10:1) to obtain compound 1-2 (16 g, crude product) as a yellow transparent oily liquid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.97 (s, 2H), 3.62 (t, J=6.2 Hz, 2H), 2.33 (td, J=7.1, 2.7 Hz, 2H), 1.95 (t, J= 2.7Hz, 1H), 1.89–1.81 (m, 2H), 1.49 (s, 9H).

Step 2: Compound 1-2 (1 g, 5.04 mmol) and 4-bromo-1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-isoindoline 1-3 (850.22mg, 2.52mmol) was added to N,N-dimethylformamide (8mL), followed by triethylamine (4.59g, 45.40mmol), cuprous iodide (48.03mg, 252.2μmol) and bis(triphenylphosphine)palladium(II) dichloride (178 mg, 252.2 μmol), and the reaction system was microwaved at 80° C. for 1 hour. After the reaction was completed, water (100 mL) and ethyl acetate (100 mL) were added, and the mixture was extracted and separated. The obtained organic phase was washed 5 times with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. . The obtained crude product was separated and purified with a normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=100:1-1:1) to obtain compound 1-4, (0.966 g, yield 84.3%) as a brown solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.79 (dd, J=7.2, 1.3 Hz, 1H), 7.74-7.69 (m, 1H), 7.67 (d, J=7.3 Hz, 1H), 4.98(dd, J＝12.3, 5.3Hz, 1H), 4.01(s, 2H), 3.74(t, J＝6.1Hz, 2H), 2.97–2.72(m, 3H), 2.67(t, J = 7.0Hz, 2H), 2.18–2.10 (m, 1H), 1.98 (p, J = 6.6Hz, 2H), 1.49 (s, 9H).

Step 3: At room temperature, the above compound 1-4 (0.97 g, 2.1 mmol) was dissolved in dichloromethane (4 mL), and then trifluoroacetic acid (1.54 g, 13.51 mmol) was slowly added dropwise, and stirred at room temperature for 1 hour . After the reaction was completed, under reduced pressure, dichloromethane and trifluoroacetic acid were removed by concentration to obtain the crude compound Int-1 (0.58 g, yield 69%).

Intermediate 2: Preparation of Compound Int-2

Step 1: Under argon protection, wet palladium/carbon (300 mg, 10% Pd/C) was added to a solution of compound 1-4 (0.3 g, 0.66 mmol) in tetrahydrofuran (10 mL), after three hydrogen replacements, 50 psi Under hydrogen, it was stirred at 40°C for 12 hours. After the reaction was completed, filtered, the filter cake was washed three times with ethyl acetate (3×15 mL), the filtrates were combined and concentrated under reduced pressure to obtain crude compound 2-1 (0.3 g, yield 99.6%) as a colorless oil. used directly in the next reaction. LCMS[M-tBu+H] ⁺ 401.0.

Step 2: Compound 2-1 (0.3 g, 657.2 μmol) was dissolved in dichloromethane (6 mL) at room temperature, then trifluoroacetic acid (3.09 g, 27.13 mmol, 2 mL) was added and stirred for 2 hours. The reaction mixture was concentrated to give crude compound Int-2 (0.26 g) as a colorless oil. used directly in the next reaction. LCMS[M+H] ⁺ 401.1.

Intermediate 3: Preparation of Compound Int-3

Step 1: At room temperature, to a solution of 3-alkynyl-1-butanol 3-1 (5 g, 71.34 mmol, 5.40 mL) in tetrahydrofuran (80 mL) was added potassium tert-butoxide (400.24 mg, 3.57 mmol), followed by tert-Butyl acrylate (11.89 g, 92.74 mmol, 13.46 mL) was added dropwise, followed by stirring at room temperature for 12 hours. TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified with a normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-1:1) to obtain compound 3-2 (11 g, yield 77.7%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.70 (t, J=6.5 Hz, 2H), 3.57 (t, J=7.0 Hz, 2H), 2.49 (t, J=6.5 Hz, 2H), 2.44 (td , J=7.0, 2.7Hz, 2H), 1.96 (t, J=2.7Hz, 1H), 1.44 (s, 9H).

Step 2: At room temperature, compound 3-2 (1.18 g, 5.93 mmol), 4-bromo-1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-iso Indoline 1-3 (1 g, 2.97 mmol), bis(triphenylphosphine)palladium(II) dichloride (208.20 mg, 296.63 μmol), cuprous iodide (56.49 mg, 296.63 μmol) and triethyl The amine (5.40 g, 53.39 mmol, 7.43 mL) was dissolved in N,N-dimethylformamide (10 mL), and the reaction was carried out at 80° C. for 1 hour with a microwave after nitrogen substitution. TLC detected that the reaction was complete, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (2×20 mL), the organic layers were combined and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=15:1-1:1) to obtain compound 3-3 (1 g, yield 37.0%) as a brown solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (s, 1H), 7.77 (dd, J=7.2, 1.2 Hz, 1H), 7.70 (dd, J=7.9, 1.2 Hz, 1H), 7.66 (d, J＝7.4Hz, 1H), 4.97(dd, J＝12.4, 5.3Hz, 1H), 3.75(t, J＝6.6Hz, 2H), 3.70(t, J＝7.0Hz, 2H), 2.93–2.71( m, 3H), 2.78 (t, J=7.0Hz, 2H), 2.51 (t, J=6.5Hz, 2H), 2.19–2.07 (m, 1H), 1.43 (s, 9H).

Step 3: Compound 3-3 (0.3 g, 660.1 μmol) was dissolved in tetrahydrofuran (10 mL), and under argon protection, wet palladium/carbon (500 mg, 10% Pd/C) was added, and after hydrogen replacement three times, the mixture was heated at 40 °C, stirring at 50 psi for 12 hours. After the reaction was completed, filtered, the filter cake was washed three times with ethyl acetate (3×15 mL), the filtrates were combined and concentrated under reduced pressure to obtain compound 3-4 (0.3 g, yield 99.1%) as a brown oil.

Step 4: Compound 3-4 (0.3 g, 654.3 μmol) was dissolved in dichloromethane (6 mL) at room temperature, then trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL) was added and stirred for 3 hours. The reaction mixture was concentrated to give crude compound Int-3 (0.26 g). used directly in the next reaction. LCMS[M+H] ⁺ 403.1.

Intermediate 4: Preparation of Compound Int-4

Compound 3-3 (0.3 g, 660.1 μmol) was dissolved in dichloromethane (10 mL) at room temperature, then trifluoroacetic acid (3.08 g, 27.01 mmol) was added, and the mixture was stirred for 2 hours. The reaction mixture was concentrated to give crude compound Int-4 (0.3 g). used directly in the next reaction.

LCMS[M+H] ⁺ 399.1.

Intermediate 5: Preparation of Compound Int-5

Step 1: To compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline 5-1 (500 mg, 1.82 mmol) and 7 - To a solution of tert-butyl bromoheptanoate (580 mg, 2.2 mmol) in NMP (10 mL), N,N-diisopropylethylamine (306 mg, 2.4 mmol) was added, and the mixture was heated and stirred at 40° C. for 5 hours. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was extracted twice. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated and purified by normal phase silica gel column (petroleum ether/ethyl acetate, ethyl acetate 10%-50%) to obtain compound 5-2 (530 mg, yield 63.4%). LCMS[M+H] ⁺ 459.2.

Step 2: Compound 5-2 (100 mg, 0.22 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.8 mL) was added, and the mixture was stirred at room temperature for 3 hours. The solvent was spin-dried to obtain compound Int-5 (80 mg), which was directly used in the next step. LCMS[M+H] ⁺ 403.2.

Intermediate 6: Preparation of Compound Int-6

Step 1: Sodium hydride (2.88 g, 72.1 mmol, 60% purity) was added portionwise to 3-bromopropyne (5.45 g, 36.6 mmol, 3.95 mL, 80% purity) in anhydrous tetrahydrofuran ( 50 mL) solution, then the reaction was stirred at 0 °C for 1 hour. 1,4-Butanediol 6-1 (10.0 g, 110.9 mmol, 9.80 mL) was added, and the reaction was stirred at room temperature for 12 hours. After completion of the reaction, the reaction was quenched with water (20 mL), then extracted with ethyl acetate (3×50 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-0:1) to obtain compound 6-2 (3.78 g, yield 26.5%) as a yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.37 (s, 1H), 4.09 (d, J=2.4 Hz, 2H), 3.45-3.36 (m, 5H), 1.57-1.39 (m, 4H).

Step 2: To a solution of compound 6-2 (1.50 g, 11.7 mmol) in 1,2-dichloroethane (10 mL) was added 2,2,6,6-tetramethylpiperidine oxide ( TEMPO) (184.0 mg, 1.17 mmol), potassium chloride (87.2 mg, 1.17 mmol) and ferric nitrate nonahydrate (472.8 mg, 1.17 mmol), then the reaction was stirred at room temperature for 5 h under O ₂ protection. The reaction mixture was filtered through celite and concentrated to give crude compound 6-3 (1.50 g, yield 90.1%) as a yellow oil. used directly in the next reaction.

¹ H NMR (400MHz, DMSO-d ₆ )δ12.05(s, 1H), 4.09(s, 2H), 3.42(t, J=5.9Hz, 2H), 3.38(s, 1H), 2.24(t, J=7.0Hz, 2H), 1.72 (t, J=6.5Hz, 2H).

Step 3: To compound 6-3 (500 mg, 3.52 mmol), benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 (788.7 mg, 3.52 mmol) in N,N- To the dimethylformamide (5 mL) solution, HATU (1.47 g, 3.87 mmol) and N,N-diisopropylethylamine (1.36 g, 10.5 mmol, 1.84 mL) were added, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (2 x 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and filtered to give crude product. The crude product was separated and purified with a normal phase column (petroleum ether:ethyl acetate (V/V)=10:1-0:1) to obtain compound Int-6 (1.00 g, yield 81.6%) as a yellow oil. LCMS[M+H] ⁺ 349.1.

Intermediate 7: Preparation of Compound Int-7

At room temperature, 7-aminoheptanoic acid 7-1 (6.31 g, 43.44 mmol) and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoro Isoindoline 7-2 (10 g, 36.20 mmol) was dissolved in N,N-dimethylformamide (100 mL), and N,N-diisopropylethylamine (18.92 mL, 114.4 mmol) was slowly added dropwise ), then slowly raised to 90°C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to give crude product. The crude product was separated and purified by reverse phase column to obtain compound Int-7 (1.51 g, yield 10.4%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 7.58 (dd, J=8.6, 7.1 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 7.02 (d, J=7.0Hz, 1H), 6.53 (t, J=6.0Hz, 1H), 5.05 (dd, J=12.9, 5.4Hz, 1H), 3.30–3.25 (m, 2H), 2.94–2.82 (m, 1H) ), 2.63–2.45 (m, 2H), 2.20 (t, J=7.3Hz, 2H), 2.08–1.99 (m, 1H), 1.62–1.45 (m, 4H), 1.40–1.27 (m, 4H).

Intermediate 8: Preparation of Compound Int-8

Step 1: At 0°C, add tert-butyl acrylate (30.32 g, 236.55 mmol) and 1,3-propanediol 8-1 (20 g, 262.83 mmol) into the reaction flask, and slowly add sodium hydroxide solid (315.37 mmol) mg, 7.88 mmol), then slowly warmed to room temperature and stirred for 24 hours. The resulting reaction mixture was diluted with water (50 mL), then extracted with ethyl acetate (2×50 mL), the organic layers were combined, washed with saturated sodium chloride solution (2×10 mL), dried over anhydrous sodium sulfate, filtered, Concentration under reduced pressure gave crude product. The crude product was separated and purified with a normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-5:1) to obtain compound 8-2 (26.03 g, yield 48.5%) as pale yellow transparent oily liquid .

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.70 (t, J=5.7 Hz, 2H), 3.64 (t, J=6.2 Hz, 2H), 3.59 (t, J=5.8 Hz, 2H), 2.44 (t , J=6.2Hz, 2H), 2.44 (s, 1H), 1.77 (p, J=5.7Hz, 2H), 1.42 (s, 9H).

Step 2: At room temperature, compound 8-2 (10 g, 48.96 mmol) was dissolved in anhydrous dichloromethane (200 mL), and p-toluenesulfonyl chloride (14.00 g, 73.43 mmol), 4-dimethylaminopyridine ( 299.04 mg, 2.45 mmol) and triethylamine (14.86 g, 146.87 mmol), and then the reaction was stirred at room temperature for 18 hours. After the reaction was completed, water (150 mL) was added to dilute, shake, extract and separate, and the organic phase was washed with saturated sodium chloride solution (2×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-10:1) to obtain compound 8-3 (11.98 g, yield 68.3%) as pale yellow liquid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.79-7.75 (m, 2H), 7.51-7.43 (m, 2H), 4.04 (t, J=6.4 Hz, 2H), 3.44 (t, J=6.2 Hz, 2H), 3.33(t, J＝6.1Hz, 2H), 2.42(s, 3H), 2.32(t, J＝6.2Hz, 2H), 1.77(p, J＝6.3Hz, 2H), 1.36( s, 9H).

Step 3: At room temperature, sodium azide (108.82 mg, 1.67 mmol) was added to a solution of compound 8-3 (0.5 g, 1.39 mmol) in N,N-dimethylformamide (5 mL), at 60° C. Stir for 12 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic layers were combined and concentrated under reduced pressure to obtain crude compound 8-4 (0.31 g, yield 96.9%).

Step 4: Under argon protection, wet palladium/carbon (310 mg, 10% Pd/C) was added to a solution of compound 8-4 (0.31 g, 1.35 mmol) in methanol (5 mL), after three hydrogen replacements, 50 psi Under hydrogen, it was stirred at room temperature for 12 hours. After the completion of the reaction, filter, and the filter cake was washed with ethyl acetate three times (3×15 mL), the filtrates were combined and concentrated under reduced pressure to obtain compound 8-5 (0.32 g) as a colorless oil. used directly in the next reaction.

Step 5: At room temperature, compound 8-5 (242.86 mg, 1.19 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (205.88 mg, 1.59 mmol) was added. , 277.46 μL), and stirred at 90 °C for 0.5 h. Then compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7-2 (0.22 g, 796.47 μmol) was added, followed by Stir at 90°C for 12 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (2×15 mL). The organic layers were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase preparative HPLC (formic acid system) to give compound 8-6 (0.12 g, yield 32.8%) as a green oil.

LCMS[M+H] ⁺ 460.2.

Step 6: Compound 8-6 (0.12 g, 261.16 μmol) was dissolved in dichloromethane (6 mL), then trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain crude compound Int-8 (0.105 g, yield 99.7%). used directly in the next reaction. LCMS[M+H] ⁺ 404.1.

Intermediate 9: Preparation of Compound Int-9

Step 1: At room temperature, compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline 5-1 (0.2 g, 729.32 μmol) was dissolved in N,N-dimethylformamide (5 mL), and then compound 8-3 (313.71 mg, 875.18 μmol), potassium bicarbonate (109.52 mg, 1.09 mmol), and sodium iodide (12.11 mg) were added in sequence. , 80.77 μmol), and the resulting reaction solution was stirred at 80° C. for 16 hours. After the reaction, water (10 mL) was added to dilute the reaction solution, extracted with ethyl acetate (2×10 mL), the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried. The crude compound 9-1 (0.463 g) was obtained. LCMS[M+Na] ⁺ 483.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 7.81 (dd, J=8.5, 7.2 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.45 (d, J＝7.2Hz, 1H), 5.08(dd, J＝12.8, 5.4Hz, 1H), 4.24(t, J＝6.2Hz, 2H), 3.58(t, J＝6.0Hz, 4H), 2.93–2.83( m, 1H), 2.64–2.48 (m, 2H), 2.41 (t, J=6.1 Hz, 2H), 2.07–1.93 (m, 3H), 1.35 (s, 9H).

Step 2: Compound 9-1 (0.4 g, 868.67 μmol) was dissolved in dichloromethane (4 mL) at room temperature, trifluoroacetic acid (4.11 g, 36.02 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain the crude compound Int-9 (0.426 g).

LCMS[M+H] ⁺ 405.0.

Intermediate 10: Preparation of Compound Int-10

Step 1: Compound 2-(benzyloxy)ethanol (5.00 g, 32.85 mmol) was added to tert-butanol (50 mL) at room temperature, followed by potassium tert-butoxide (4.42 g, 39.42 mmol) and compound 4- tert-Butyl bromobutyrate 10-1 (7.33 g, 32.85 mmol), and the reaction was stirred for 2 hours. The reaction mixture was diluted with water (100 mL), then extracted with ethyl acetate (2 x 80 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-1:1) to obtain compound 10-2 (0.68 g, yield 7.0%). used directly in the next reaction.

¹ H NMR (400MHz, CDCl ₃ ) δ 7.38-7.24 (m, 5H), 4.57 (s, 2H), 3.65-3.57 (m, 4H), 3.49 (t, J=6.4Hz, 2H), 2.31 ( t, J=7.4Hz, 2H), 1.87 (tt, J=7.4, 6.4Hz, 2H), 1.44 (s, 9H).

Step 2: Compound 10-2 (0.68 g, 2.31 mmol) was dissolved in methanol (10 mL), under argon protection, wet palladium/carbon (300 mg, 10% Pd/C) was added, and after hydrogen replacement three times, 15 psi hydrogen Stir at room temperature for 12 hours. After the reaction was completed, filtered, the filter cake was washed three times with ethyl acetate (3×15 mL), the filtrates were combined and concentrated under reduced pressure to obtain compound 10-3 (0.47 g, yield 99.6%) as a colorless oil. used directly in the next reaction.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.76-3.67 (m, 2H), 3.56-3.46 (m, 4H), 2.31 (t, J=7.2 Hz, 2H), 2.19 (t, J=6.0 Hz, 1H), 1.88 (tt, J=7.3, 6.2 Hz, 2H), 1.44 (s, 9H).

Step 3: Compound 10-3 (0.47 g, 2.30 mmol) was dissolved in anhydrous dichloromethane (10 mL), 4-dimethylaminopyridine (14.06 mg, 115.05 μmol), triethylamine (698.49 mg, 6.90 mmol) and p-toluenesulfonyl chloride (658.01 mg, 3.45 mmol), and the reaction was stirred at room temperature for 12 hours. The reaction mixture was concentrated to give crude product. The crude product was separated and purified by reversed-phase medium pressure column (formic acid system) to obtain compound 10-4 (0.60 g, yield 72.8%). used directly in the next reaction. LCMS[M+Na] ⁺ 381.1.

Step 4: Compound 10-4 (520 mg, 1.45 mmol) was added to N,N-dimethylformamide (10 mL), then sodium azide (113.17 mg, 1.74 mmol) was added, and the mixture was stirred at 60°C 12 hours. The reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (2×20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain crude compound 10-5 (330 mg, yield 99.2%). used directly in the next reaction.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.55 (dd, J=5.6, 4.2 Hz, 2H), 3.42 (t, J=6.3 Hz, 2H), 3.37 (dd, J=5.5, 4.2 Hz, 2H), 2.25 (t, J=7.4Hz, 2H), 1.77–1.67 (m, 2H), 1.39 (s, 9H).

Step 5: Under argon protection, wet palladium/carbon (300 mg, 10% Pd) was added to a solution of compound 10-5 (330 mg, 1.44 mmol) in methanol (5 mL), and after hydrogen replacement three times, at room temperature under 50 psi Stir for 12 hours. Filtration, the filter cake was washed with methanol (2×10 mL), the organic layers were combined and spun dry to obtain crude compound 10-6 (200 mg, yield 68.4%) as colorless oil. used directly in the next reaction.

Step 6: 1,3-Dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7-2 (113.24 mg, 409.95 μmol) was added to N , N-dimethylformamide (5 mL), then N,N-diisopropylethylamine (105.97 mg, 819.90 μmol) was added, and the mixture was stirred at 90° C. for 0.5 h, and then compound 10-6 (100 mg, 491.94umol), the reaction was stirred at 90°C for 12 hours. The reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (3 x 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and filtered to give crude product. The crude product was separated and purified by reverse phase column (formic acid system) to obtain compound 10-7 (60 mg, yield 31.8%) as a yellow solid. LCMS[M+Na] ⁺ 482.3.

Step 7: Compound 10-7 (60 mg, 130.58 μmol) was added to anhydrous dichloromethane (6 mL), trifluoroacetic acid (3.08 g, 27.01 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude compound Int-10 (52 mg, yield 98.7%) as a yellow solid. used directly in the next reaction.

Intermediate 11: Preparation of Compound Int-11

Step 1: Compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline 5-1 (382.52 mg, 1.39 mmol) was added N,N-dimethylformamide (5 mL), then compound 10-4 (0.60 g, 1.67 mmol), KHCO ₃ (209.48 mg, 2.09 mmol) and NaI (23.21 mg, 154.83 umol) were added, and the mixture was placed in Stir at 80°C for 16 hours. The reaction mixture was diluted with water (10 mL), then extracted with ethyl acetate (2×10 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain crude compound 11-1 (0.64 g, yield 99.6%). used directly in the next reaction. LCMS[M+ _NH4 ] ⁺ 478.2.

Step 2: Compound 11-1 (0.64 mg, 1.39 mmol) was dissolved in anhydrous dichloromethane (9 mL), trifluoroacetic acid (4.62 g, 40.52 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude compound Int-11 (0.56 g, 99.6% yield). used directly in the next reaction. LCMS[M+H] ⁺ 405.0.

Intermediate 12: Preparation of Compound Int-12

Step 1: At room temperature, compound 4-(benzyloxy)-1-butanol 12-1 (5.00 g, 27.74 mmol), tert-butyl bromoacetate (10.82 g, 55.48 mmol), 37% aqueous sodium hydroxide solution (29.99 g, 277.40 mmol) and tetrabutylammonium bromide (894.25 mg, 2.77 mmol) were added to dichloromethane (100 mL) and stirred for 12 hours. The reaction mixture was diluted with water (200 mL), then extracted with dichloromethane (2 x 100 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and filtered to give the crude product. The crude product was separated and purified with a normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-1:1) to obtain compound 12-2 (3.70 g, yield 43.9%). used directly in the next reaction.

¹ H NMR (400MHz, CDCl ₃ )δ7.39-7.22(m,5H), 4.50(s,2H), 3.94(s,2H), 3.58-3.45(m,4H), 1.74-1.68(m,4H) ), 1.47(s, 9H). LCMS[M+Na] ⁺ 316.9.

Step 2: Compound 12-2 (0.5 g, 1.65 mmol) was dissolved in methanol (8 mL), under argon protection, wet palladium/carbon (300 mg, 10% Pd/C) was added, and after hydrogen replacement three times, at 15 psi Under hydrogen, it was stirred at room temperature for 12 hours. After the reaction was completed, filtered, the filter cake was washed three times with ethyl acetate (3×15 mL), the filtrates were combined and concentrated under reduced pressure to obtain compound 12-3 (0.336 g, yield 99.9%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.95 (s, 2H), 3.67 (t, J=5.9 Hz, 2H), 3.56 (t, J=5.8 Hz, 2H), 1.78-1.64 (m, 4H) , 1.47(s, 9H).

Step 3: Compound 12-3 (330.40 mg, 1.62 mmol) was dissolved in anhydrous dichloromethane (10 mL), then 4-dimethylaminopyridine (9.87 mg, 80.78 μmol), triethylamine (490.43 mg) were added , 4.85 mmol) and p-toluenesulfonyl chloride (462.00 mg, 2.42 mmol), and the reaction was stirred at room temperature for 12 hours. The reaction mixture was concentrated to give crude product. The crude product was purified by reverse-phase medium pressure preparative column (formic acid system) to obtain compound 12-4 (0.50 g, yield 86.3%). used directly in the next reaction. LCMS[M+ _NH4 ] ⁺ 376.1.

Step 4: Compound 12-4 (1.00 g, 2.79 mmol) was added to N,N-dimethylformamide (10 mL), then sodium azide (217.64 mg, 3.35 mmol) was added, and the mixture was heated at 60 °C Stir for 12 hours. The reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (2×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to give crude compound 12-5 (0.64 g) as a yellow oil. used directly in the next reaction.

Step 5: Under argon protection, wet palladium/carbon (400 mg, 10% Pd/C) was added to a solution of crude compound 12-5 (640 mg, 2.79 mmol) in methanol (10 mL), and after hydrogen replacement three times, Stir at 50 psi for 12 hours at room temperature. The reaction mixture was filtered, then the filter cake was rinsed with ethyl acetate (3×50 mL), and the organic layers were combined to give crude compound 12-6 (430 mg, 75.8% yield) as a yellow oil. used directly in the next reaction.

Step 6: 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7-2 (380 mg, 1.87 mmol) was added to N, N-dimethylformamide (10 mL), then N,N-diisopropylethylamine (322.14 mg, 2.49 mmol) was added, and the mixture was stirred at 90° C. for 0.5 hour, and then compound 12-6 (344.2 mg, 1.25 mmol), and the reaction was stirred at 90°C for 12 hours. The reaction mixture was diluted with water (30 mL), then extracted with ethyl acetate (2 x 30 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and filtered to give crude product. The crude product was separated and purified by reverse phase column (formic acid system) to obtain compound 12-7 (140 mg, yield 24.4%) as a yellow oil. LCMS[M+H] ⁺ 460.2.

Step 7: Compound 12-7 (0.18 g, 391.74 μmol) was added to anhydrous dichloromethane (9 mL), then trifluoroacetic acid (4.62 g, 40.52 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude compound Int-12 (0.16 g). used directly in the next reaction.

Intermediate 13: Preparation of Compound Int-13

step 1:

Compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline 5-1 (318.77 mg, 1.16 mmol) was added to N,N - dimethylformamide (5 mL), then compound 12-4 (0.50 g, 1.39 mmol), KHCO ₃ (174.56 mg, 1.74 mmol) and NaI (19.34 mg, 129.03 μmol) were added, and the mixture was heated at 80° C. Stir for 16 hours. The reaction mixture was diluted with water (10 mL), then extracted with ethyl acetate (2×10 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain crude compound 13-1 (0.53 g, yield 99.0%), used directly in the next reaction. LCMS[M+ _NH4 ] ⁺ 478.2.

Step 2: Compound 13-1 (0.53 g, 1.15 mmol) was added to anhydrous dichloromethane (9 mL), then trifluoroacetic acid (4.62 g, 40.52 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain crude compound Int-13 (0.46 g, yield 98.8%). used directly in the next reaction.

Intermediate 14: Preparation of Compound Int-14

Step 1: To tert-butyl (3-(methylamino)propyl)carbamate 14-1 (2.00 g, 10.6 mmol) and ethyl 3-bromopropionate (2.31 g, 12.7 mmol, 1.63 mmol) at room temperature mL) in N,N-dimethylformamide (30 mL), was added N,N-diisopropylethylamine (4.12 g, 31.8 mmol, 5.55 mL), and the reaction was stirred at 85° C. for 12 hours. The reaction solution was diluted with water (50 mL), and then extracted with ethyl acetate (2×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-0:1) to obtain compound 14-2 (2.18 g, yield 71.1%) as a yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.72 (t, J=5.1 Hz, 1H), 4.04 (q, J=7.1 Hz, 2H), 2.96-2.84 (m, 2H), 2.54 (t, J=7.0Hz, 2H), 2.43–2.35(m, 2H), 2.26(t, J=7.1Hz, 2H), 2.10(s, 3H), 1.47(p, J=7.0Hz, 2H), 1.37( s, 9H), 1.17 (t, J=7.1 Hz, 3H).

Step 2: To a solution of compound 14-2 (1.00 g, 3.47 mmol) in ethanol (5 mL) was added lithium hydroxide monohydrate (727.5 mg, 17.3 mmol) at room temperature, and the reaction was stirred at room temperature for 12 hours. The reaction solution was concentrated, adjusted to pH about 3 with 1M hydrochloric acid, extracted with ethyl acetate (2×20 mL), and concentrated to give compound 14-3 (900 mg, yield 99.7%) as a white solid. used directly in the next reaction.

Step 3: To compound 14-3 (250 mg, 960.3 μmol), benzofuran-2-yl(pyridin-3-yl)methanamine (6-4 (215.3 mg, 960.3 μmol) in N,N at room temperature - In dimethylformamide (5 mL) solution, HATU (401.6 mg, 1.06 mmol) and N,N-diisopropylethylamine (372.3 mg, 2.88 mmol, 501.8 μL) were added. Stirred at room temperature for 12 hours. The mixture was diluted with water (20 mL), then extracted with ethyl acetate (2×20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and filtered to obtain the crude product. The crude product was purified by reverse phase column (formic acid system) to obtain compound 14- 4 (250 mg, 55.8% yield), white solid. LCMS [M+H] ⁺ 467.3.

Step 4: Compound 14-4 (150 mg, 321.4 μmol) was added to dichloromethane (6 mL) at room temperature, followed by trifluoroacetic acid (3.08 g, 27.0 mmol, 2 mL), and stirred for 0.5 hour. The reaction mixture was concentrated to give crude compound Int-14 (120 mg). used directly in the next reaction. LCMS[M+H] ⁺ 367.1.

Intermediate 15: Preparation of Compound Int-15

Step 1: Compound benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 dihydrochloride (435 mg, 1.46 mmol) was dissolved in DMF (5 mL), potassium carbonate (300 mg, 2.17 mmol) was added and ethyl bromoacetate (290 mg, 1.75 mmol), heated and stirred at 55°C for 16 hours. Ethyl acetate and water were added, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether/ethyl acetate, ethyl acetate%: 50%-100%) to obtain compound 15-1 (120 mg, yield 26%) as a brown oil. LCMS[M+H] ⁺ 311.4.

Step 2: Compound 15-1 (120 mg, 0.38 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2.4 mL), methanol (0.8 mL) and water (0.8 mL), and lithium hydroxide monohydrate (80 mg, 1.94 mmol) was added , and stirred at room temperature for 16 hours. Adjust pH=3 with 2M hydrochloric acid aqueous solution, extract with ethyl acetate, concentrate the organic phase and purify by reverse-phase preparative HPLC to obtain compound Int-15 (42 mg, yield 38%) as a colorless oil. LCMS[M+H] ⁺ 283.1.

Intermediate 16: Preparation of Compound Int-16

Step 1: Compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7-2 (353 mg, 1.28 mmol) was dissolved in In DMF (8 mL), N-tert-butoxycarbonyl-1,4-butanediamine (350 mg, 1.86 mmol) and N,N-diisopropylethylamine (0.46 mL, 2.8 mmol) were added successively, 100°C Heat and stir for 18 hours. The reaction was cooled to room temperature and quenched by the addition of water. Extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether/ethyl acetate, ethyl acetate%: 20%-50%) to obtain compound 16-1 (275 mg, yield 61%) as a yellow solid. LCMS[M-Boc+H] ⁺ 345.4.

Step 2: Compound 16-1 (100 mg, 0.22 mmol) was dissolved in 4M HCl/dioxane (5 mL, 20 mmol) and stirred at room temperature for 3 hours. The solvent was spin-dried to obtain compound Int-16 (95 mg) as a yellow oil. LCMS[M+H] ⁺ 345.5.

Intermediate 17: Preparation of compound Int-17

Step 1: Compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline 5-1 (300 mg, 1.09 mmol) was dissolved in In DMF (6 mL), tert-butyl N-(4-bromobutyl)carbamate (330 mg, 1.3 mmol), sodium bicarbonate (460 mg, 5.45 mmol) and potassium iodide (50 mg, 0.3 mmol) were sequentially added, and heated at 55°C Stir for 16 hours. The reaction was cooled to room temperature, water and ethyl acetate were added, and extraction was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether/ethyl acetate, ethyl acetate%: 20%-80%) to obtain compound 17-1 (120 mg, yield 25%) as colorless oil. LCMS[M+H] ⁺ 446.5.

Step 2: Compound 17-1 (120 mg, 0.27 mmol) was dissolved in 4M HCl/dioxane (5 mL, 20 mmol) and stirred at room temperature for 3 hours. The solvent was spin-dried to obtain compound Int-17 (82 mg) as a white solid. LCMS[M+H] ⁺ 346.2.

Intermediate 18: Preparation of Compound Int-18

Step 1: Compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-bromoisoindoline 1-3 (675 mg, 2 mmol) and N- tert-Butoxycarbonyl-4-pentyn-1-amine (730 mg, 4 mmol) was dissolved in DMF (8 mL), followed by triethylamine (2.0 g, 20 mmol), cuprous iodide (76 mg, 0.4 mmol) and Bis(triphenylphosphine)palladium(II) dichloride (280 mg, 0.4 mmol) was heated to 80°C under nitrogen protection and stirred for 3 hours. It was cooled to room temperature, ethyl acetate and water were added, and extraction was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether/ethyl acetate, ethyl acetate%: 20%-80%) to obtain compound 18-1 (280 mg, yield 32%) as colorless oil. LCMS[M+H] ⁺ 440.4.

Step 2: At room temperature, 10% palladium/carbon (110 mg) was added to a suspension of compound 18-1 (220 mg, 0.5 mmol) in 95% ethanol (20 mL), the temperature was raised to 40 °C, and the reaction was carried out under 1 atmosphere of hydrogen. 16 hours. The reaction solution was filtered, and the filtrate was spin-dried to obtain the product 18-2 (200 mg, yield 95%) as a colorless oil. LCMS[M+H] ⁺ 444.6.

Step 3: Compound 18-2 (200 mg, 0.45 mmol) was dissolved in 4M HCl/dioxane (5 mL, 20 mmol) and stirred at room temperature for 3 hours. The solvent was spin-dried to obtain compound Int-18 (155 mg, yield 90%) as a colorless oil. LCMS[M+H] ⁺ 344.7.

Intermediate 19: Preparation of Compound Int-19

Step 1: Compound benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 dihydrochloride (100 mg, 336 μmol) was dissolved in acetonitrile (2 mL) and water (2 mL) at room temperature, followed by Add tert-butyl 3-bromopropionate (106 mg, 505 μmol), potassium carbonate (186 mg, 1.35 mmol), heat at 90° C. and stir for 16 hours. After the reaction was detected by LCMS, it was filtered, purified by reverse-phase C18 medium pressure preparative column, concentrated and lyophilized to obtain compound 19-1 as a pale yellow solid. LCMS[M+H] ⁺ 353.6.

Step 2: The compound 19-1 obtained above was dissolved in DCM (5 mL), then trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was detected by LCMS, the solvent was replaced with acetonitrile three times, concentrated to dryness, and water was added for lyophilization to obtain the trifluoroacetic acid salt of compound Int-19 (35.0 mg, yield 21.1%) as a pale yellow solid. LCMS[M+H] ⁺ 297.5.

Intermediate 20: Preparation of Compound Int-20

Step 1: Compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7-2 (100 mg, 362 μmol) at room temperature Dissolved in DMF (5 mL), N-tert-butoxycarbonyl-1,3-propanediamine (126 mg, 724 μmol) and potassium carbonate (200 mg, 1.45 mmol) were added successively, heated at 90° C. and stirred for 16 hours. After the reaction was detected by LCMS, the mixture was filtered, purified by reverse-phase C18 medium pressure preparative column, concentrated and lyophilized to obtain compound 20-1 as a pale yellow solid.

Step 2: The obtained compound 20-1 was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was detected by LCMS, the solvent was replaced with acetonitrile three times, concentrated to dryness, and water was added for lyophilization to obtain the trifluoroacetic acid salt of compound Int-20 (28.5 mg, yield 18.4%) as a yellow solid. LCMS[M+H] ⁺ 331.5.

Intermediate 21: Preparation of Compound Int-21

Step 1: At room temperature, compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline 5-1 (200 mg, 729 μmol) Dissolved in DMF (5 mL), N-tert-butoxycarbonyl-3-bromo-1-propylamine (226 mg, 948 μmol), sodium bicarbonate (123 mg, 1.46 mmol) and potassium iodide (10.9 mg, 72.9 μmol) were added successively , heated at 60°C and stirred for 16 hours. After the reaction was detected by LCMS, it was filtered, purified by reverse-phase C18 medium pressure preparative column, concentrated and lyophilized to obtain compound 21-1 as a pale yellow solid.

Step 2: The obtained compound 21-1 was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was detected by LCMS, the solvent was replaced with acetonitrile three times, concentrated to dryness, and water was added for lyophilization to obtain the trifluoroacetic acid salt of compound Int-21 (148.5 mg, yield 47.4%) as a yellow solid. LCMS[M+H] ⁺ 332.6.

Intermediate 22: Preparation of Compound Int-22

Step 1: To compound benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 dihydrochloride (270 mg, 0.91 mmol) and tert-butyl 2-bromoethylcarbamate (245 mg, 1.1 mmol) ) in N-methylpyrrolidone solution (5 mL), cesium carbonate (700 mg, 2.15 mmol) was added, and the reaction mixture was heated and stirred at 90° C. for 16 hours. The reactant was cooled to room temperature, ethyl acetate and water were added, extracted, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried to obtain the crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether/ethyl acetate, ethyl acetate%: 50%-100%) to obtain compound 22-1 (60 mg, yield 18%) as a brown oil. LCMS[M+H] ⁺ 368.7.

Step 2: Compound 22-1 (60 mg, 0.16 mmol) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL, 1.94 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Spin-dried under reduced pressure to obtain compound Int-22 (78 mg) as a yellow oil, which was directly used in the next reaction. LCMS[M+H] ⁺ 268.4.

Intermediate 23: Preparation of Compound Int-23

Step 1: Compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7-2 (275 mg, 1.0 mmol) was dissolved in To N-methylpyrrolidone (4 mL), tert-butyl 4-aminobutyrate (206 mg, 1.3 mmol) and N,N-diisopropylethylamine (0.4 mL, 2.4 mmol) were added in sequence, and the reaction mixture was heated at 100°C Stir for 18 hours. The reaction was cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried to obtain the crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether/ethyl acetate, ethyl acetate%: 50%-100%) to obtain compound 23-1 (200 mg, yield 43%) as a yellow oil. LCMS[M+H] ⁺ 416.6.

Step 2: Compound 23-1 (100 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.65 mL) was added, and the mixture was stirred at room temperature for 3 hours. The solvent was spin-dried to obtain compound Int-23 (85 mg) as a yellow oil, which was directly used in the next step. LCMS[M+H] ⁺ 360.5.

Intermediate 24: Preparation of Compound Int-24

Step 1: Dissolve 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline 5-1 (200 mg, 0.73 mmol) in N , N-dimethylformamide (4 mL), tert-butyl 4-bromobutyrate (195 mg, 0.87 mmol), sodium bicarbonate (307 mg, 3.65 mmol) and potassium iodide (30 mg, 0.18 mmol) were added successively, and the reaction The mixture was stirred with heating at 55°C for 16 hours. The reaction was cooled to room temperature and quenched by the addition of water. Extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether/ethyl acetate, ethyl acetate%: 50%-80%) to obtain compound 24-1 (120 mg, yield 36%) as a white solid. LCMS[MH] ^- 415.4.

Step 2: Compound 24-1 (120 mg, 0.29 mmol) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL, 1.94 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Spin-dried under reduced pressure to obtain compound Int-24 (78 mg) as a yellow oil, which was directly used in the next reaction.

Intermediate 25: Preparation of Compound Int-25

Step 1: Compound benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 dihydrochloride (297 mg, 1 mmol) and tert-butyl 3-bromopropylcarbamate (357 mg, 1.5 mmol) , dissolved in N-methylpyrrolidone (5 mL), cesium carbonate (815 mg, 2.5 mmol) and potassium iodide (50 mg, 0.3 mmol) were added, and the mixture was heated to 90° C. and stirred for 18 hours. After the reaction was completed, it was cooled to room temperature and filtered. Ethyl acetate and water were added, shaken, and allowed to stand to separate the layers. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether/ethyl acetate, ethyl acetate%: 50%-100%) to obtain compound 25-1 (260 mg, yield 68%) as colorless oil. LCMS[M+H] ⁺ 382.7.

Step 2: Compound 25-1 (260 mg, 0.62 mmol) was dissolved in dichloromethane (1.0 mL), 4M HCl in 1,4-dioxane solution (3 mL, 12 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Spin-dried under reduced pressure to obtain crude compound Int-25 (118 mg) as a yellow oil. used directly in the next reaction. LCMS[M+H] ⁺ 282.5.

Intermediate 26: Preparation of Compound Int-26

In a similar manner to intermediate 23, by using tert-butyl 3-aminopropionate as starting material, compound Int-26 was obtained as a yellow oil. used directly in the next reaction. LCMS[M+H] ⁺ 346.4.

Intermediate 27: Preparation of Compound Int-27

In a similar manner to Intermediate 24, by using tert-butyl 3-bromopropionate as starting material, compound Int-27 was obtained as a yellow oil. used directly in the next reaction. LCMS[M+H] ⁺ 347.4.

Intermediate 28: Preparation of Compound Int-28

Using a procedure similar to Intermediate 23 by using tert-butyl 4-(aminomethyl)piperidine-1-carboxylate as starting material, compound Int-28 was obtained as a colorless oil. used directly in the next reaction. LCMS[M+H] ⁺ 371.6.

Intermediate 29: Preparation of Compound Int-29

Step 1-2: In a similar manner to Intermediate 28, by using tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate as starting material, compound 29-2 was obtained as a colorless oil. used directly in the next reaction. LCMS[M+H] ⁺ 385.7.

Step 3: Compound 29-2 (50 mg, 0.10 mmol) was dissolved in N-methylpyrrolidone (4 mL), followed by adding tert-butyl bromoacetate (0.18 mL, 0.12 mmol), and sodium iodide (15 mg, 0.1 mmol) , potassium carbonate (35 mg, 0.25 mmol), and the mixture was heated to 55°C and stirred for 3 hours. The reaction was cooled to room temperature and filtered, and the filtrate was purified by reverse-phase preparative HPLC to give compound 29-3 (25 mg, yield 50%) as a yellow oil. LCMS[M+H] ⁺ 499.7.

Step 4: Compound 29-3 (25 mg, 0.05 mmol) was dissolved in dichloromethane (1.5 mL), trifluoroacetic acid (0.5 mL, 6.7 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Spin to dryness under reduced pressure to obtain the crude compound Int-29 (20 mg, yield 74.1%) as a yellow oil, which is directly used in the next reaction. LCMS[M+H] ⁺ 443.5.

Intermediate 30: Preparation of Compound Int-30

Step 1: Compound 1-tert-butoxycarbonyl-4-piperidineacetic acid (124 mg, 0.42 mmol), benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 dihydrochloride (137 mg, 0.56 mmol) and N,N-diisopropylethylamine (0.4 mL, 2.4 mmol) were dissolved in N,N-dimethylformamide (4 mL), HATU (242 mg, 0.64 mmol) was added, and the mixture was stirred at room temperature for 18 hours post-filtering. Ethyl acetate and water were added, and the mixture was left to stand for separation after extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried. The obtained crude product was separated and purified by normal phase silica gel column (petroleum ether/ethyl acetate, ethyl acetate%: 40%-100%) to obtain compound 30-1 (178 mg, yield 94.3%) as colorless oil. LCMS[M+H] ⁺ 450.8.

Step 2: Compound 30-1 (175 mg, 0.39 mmol) was dissolved in dichloromethane (3.0 mL), trifluoroacetic acid (1 mL, 13.1 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Spin to dryness under reduced pressure to obtain the crude compound 30-2 trifluoroacetate (180 mg) as a colorless oil, which was directly used in the next reaction. LCMS[M+H] ⁺ 350.8.

Step 3: Compound 30-2 (80 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (4 mL), followed by adding tert-butyl 2-bromoethylcarbamate (58 mg, 0.26 mmol), potassium carbonate (50 mg, 0.37 mmol) and potassium iodide (10 mg, 0.06 mmol), the mixture was heated to 55°C and stirred for 3 hours. The reaction was cooled to room temperature, ethyl acetate and water were added, and extraction was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The obtained crude product was separated and purified by normal phase silica gel column (ethyl acetate/methanol, methanol %: 0%-5%) to obtain compound 30-3 (40 mg, yield 45.4%) as a colorless oil. LCMS[M+H] ⁺ 493.8.

Step 4: Compound 30-3 (36 mg, 0.073 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL, 13.1 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Spin to dryness under reduced pressure to obtain crude compound Int-30 (22 mg) as a yellow oil. used directly in the next reaction. LCMS[M+H] ⁺ 393.5.

Intermediate 31: Preparation of Compound Int-31

Using a procedure similar to Intermediate 29 by using tert-butyl 4-(aminoethyl)piperazine-1-carboxylate as starting material, compound Int-31 was obtained as a yellow oil. used directly in the next reaction. LCMS[M+H] ⁺ 444.4.

Intermediate 32: Preparation of Compound Int-32

Step 1: Dissolve benzofuran (5.0 g, 42.33 mmol) in anhydrous tetrahydrofuran (100 mL) at -78 °C, slowly add n-butyllithium (2.5 M, 17.78 mL, 44.44 mmol) dropwise, and then slowly warm up to room temperature and stirred for 0.5 hour. The temperature of the system was lowered to -78°C again, isonicotinaldehyde 32-1 (4.53 g, 42.33 mmol) was added dropwise, the temperature was slowly raised to room temperature after dropping, and the mixture was stirred for 3 hours. The reaction mixture was quenched with saturated aqueous _NH4Cl (20 mL), diluted with water (200 mL), and then extracted with ethyl acetate (2 x 200 mL). The organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude compound 32-2 (9.0 g, yield 94.4%). used directly in the next reaction. LCMS[M+H] ⁺ 226.1.

Step 2: Compound 32-2 (9.0 g, 39.96 mmol) was added to thionyl chloride (50 mL) at room temperature and stirred for 3 hours. TLC detected new substances, and the reaction solution was directly spin-dried to obtain a crude compound 32-3 (10.6 g), which was directly used in the next reaction.

Step 3: At room temperature, the crude compound 32-3 (9.74 g, 39.97 mmol) was added to a mixed solution of tetrahydrofuran (10 mL) and ammonia water (50 mL), and stirred for 3 hours. The reaction mixture was diluted with water (200 mL), then extracted with ethyl acetate (2 x 200 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude compound 32-4 (1.92 g, 19.4% yield). used directly in the next reaction. LCMS[M+H] ⁺ 225.1.

Step 4: At room temperature, 7-((tert-butoxycarbonyl)amino)heptanoic acid (1.64 g, 6.69 mmol) was dissolved in N,N-dimethylformamide (35 mL), and then compound 32-4 was added sequentially (1.5 g, 6.69 mmol), HATU (2.80 g, 7.36 mmol) and N,N-diisopropylethylamine (3.5 mL, 20.07 mmol) and stirred for 2 hours. The reaction mixture was diluted with water (50 mL), then extracted with ethyl acetate (3 x 50 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was purified by reverse phase preparation (formic acid system) to give compound 32-5 (1.74 g, yield 57.5%). LCMS[M+H] ⁺ 452.3.

Step 5: Compound 32-5 (1.6 g, 3.54 mmol) was dissolved in dichloromethane (32 mL) at room temperature, then trifluoroacetic acid (8 mL, 108.05 mmol) was added, and the mixture was stirred for 2 hours. The reaction solution was spun dry to obtain the crude compound Int-32 (3.33 g). used directly in the next reaction. LCMS[M+H] ⁺ 352.1.

Intermediate 33: Preparation of Compound Int-33

Step 1: Under nitrogen protection, boron trifluoride ether (529 mg, 3.73 mmol) was added to 4-bromophenylacetic acid 33-1 (5.0 g, 23.3 mmol) and tertiary 2,2,2-trichloroethylimide A solution of butyl ester (10.2 g, 46.7 mmol) in tetrahydrofuran (50 mL) was stirred at room temperature for 16 hours. To the reaction mixture was added _NaHCO3 (500 mg) to quench the reaction, diluted with water (100 mL), then extracted with ethyl acetate (2 x 50 mL), the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The obtained crude product was separated and purified by reverse phase column (formic acid system) to obtain compound 33-2 (3.50 g, yield 55.4%) as a yellow oil. used directly in the next reaction.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.41 (m, 2H), 7.16-7.12 (m, 2H), 3.47 (s, 2H), 1.43 (s, 9H).

Step 2: Under nitrogen protection, compound 33-2 (3.00 g, 11.06 mmol), 2-vinylisoindoline-1,3-dione (1.92 g, 11.06 mmol), palladium acetate (74.52 mg, 331.92 μmol), triphenylphosphine (336.75 mg, 1.11 mmol) and N,N-diisopropylethylamine (4.29 g, 33.19 mmol) were added to acetonitrile (50 mL) and stirred at 90° C. for 16 hours. After cooling, the reaction mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was separated and purified by reverse phase column (formic acid system) to obtain compound 33-3 (1.80 g, yield 44.8%) as a yellow solid. LCMS[M+Na] ⁺ 386.1.

Step 3: Under argon protection, wet palladium/carbon (100 mg, 10% Pd) was added to a mixed solution of compound 33-3 (1.8 g, 4.95 mmol) in methanol (15 mL) and ethyl acetate (15 mL), After three hydrogen replacements, the mixture was stirred at room temperature at 50 psi for 12 hours. After the reaction was completed, it was filtered, and the filter cake was washed twice with methanol. The filtrates were combined and concentrated under reduced pressure to give crude compound 33-4 (1.80 g) as a yellow oil. LCMS[M+Na] ⁺ 388.1.

¹ H NMR (400MHz, CDCl ₃ )δ7.84-7.79(m,2H),7.73-7.66(m,2H),7.23-7.15(m,4H),3.94-3.88(m,2H),3.48(s , 2H), 3.00–2.93 (m, 2H), 1.42 (s, 9H).

Step 4: Compound 33-4 (500 mg, 1.37 mmol) was added to ethanol (5 mL), then 85% hydrazine hydrate (177.29 mg, 3.01 mmol) was added, and the mixture was stirred at 85° C. for 12 hours. After the completion of the reaction, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound 33-5 (370 mg) as a white solid. used directly in the next reaction. LCMS[M+H] ⁺ 236.1.

Step 5: Combine N,N-diisopropylethylamine (247.1 mg, 1.91 mmol) and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4- Fluorisoindoline 7-2 (264.0 mg, 0.96 mmol) was added to N,N-dimethylformamide (10 mL), stirred at 90°C for 0.5 h, and then compound 33-5 (270 mg, 1.15 mmol) was added , and stirred at 90 °C for 12 hours. After cooling, the reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (3 x 20 mL). The organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by reverse phase column (formic acid system) to obtain compound 33-6 (73.5 mg, yield 15.6%) as a yellow solid.

LCMS[M+Na] ⁺ 514.3.

Step 6: Compound 33-6 (95 mg, 193.3 μmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (3.08 g, 27.01 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was spun dry to obtain crude compound Int-33 (80 mg, yield 95.0%) as a yellow oil. used directly in the next reaction. LCMS[M+H] ⁺ 436.2.

Intermediate 34: Preparation of Compound Int-34

N,N-Diisopropylethylamine (320.5 mg, 2.48 mmol) was added to compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoro A solution of isoindoline 7-2 (342.5 mg, 1.24 mmol) in N,N-dimethylformamide (10 mL) was stirred at 90°C for 0.5 h, and then 2-(4-(aminomethyl)benzene was added base)acetic acid 34-1 (300.0 mg, 1.49 mmol), stirred at 90°C for 12 hours. After cooling, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (3×20 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by reverse phase column (formic acid system) to obtain compound Int-34 (77.8 mg, yield 14.9%) as a yellow solid. used directly in the next reaction. LCMS[M+H] ⁺ 422.0.

Intermediate 35: Preparation of Compound Int-35

Step 1: At room temperature, 3-bromophenylacetic acid 35-1 (5 g, 23.25 mmol) was dissolved in anhydrous methanol (50 mL), then concentrated sulfuric acid (920 mg, 9.38 mmol, 0.5 mL) was slowly added, and the reaction system was heated up Stir to 80°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (2×80 mL). The organic phases were combined, washed with saturated sodium bicarbonate solution (80 mL), and the layers were separated. The organic phase was washed with anhydrous sodium sulfate. dry. Filtration and concentration gave crude compound 35-2 (5.5 g) as a yellow oil. used directly in the next reaction.

Step 2: Under nitrogen protection, methyl 3-bromophenylacetate 35-2 (2.5 g, 10.91 mmol), (2-(9-borabicyclo[3.3.1]nonan-9-yl)ethyl)amino tert-Butyl formate 35-3 (5.79 g, 21.83 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex ((891.25 mg, 1.09 mmol) and cesium carbonate (7.11g, 21.83mmol) was dissolved in the mixed solvent of dioxane (50mL) and water (5mL), and the reaction system was warming up to 100 ° C and stirred for 2 hours. Cooled to room temperature, concentrated under reduced pressure to obtain the crude product. Phase separation and purification on silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-1:1) to obtain compound 35-4 (2.5 g, yield 78%).

Step 3: Compound 35-4 (0.5 g, 1.70 mmol) was dissolved in methanol (5 mL), 4M aqueous potassium hydroxide solution (10 mL) was added, and the reaction system was stirred at 85° C. for 3 hours. Cool to room temperature, add dropwise 1M hydrochloric acid (40 mL) to neutralize potassium hydroxide, add water (20 mL) to dilute, and extract with ethyl acetate (2×20 mL). The combined organic phases were washed twice with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration gave crude compound 35-5 (1.1 g) as a pale yellow oil. LCMS[M+K] ⁺ 318.0.

Step 4: Compound 35-5 (249.12 mg, 891.8 μmol), benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 (200 mg, 891.8 μmol), HATU (373.01 mg, 981.0 μmol) and N,N-diisopropylethylamine (345.79 mg, 2.68 mmol) were added to N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (2 x 20 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=1:0-1:3) to obtain compound 35-6 (0.15 g, yield 34.6%) as light brown oil. LCMS[M+H] ⁺ 486.3.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.33(d,J=8.3Hz,1H),8.62(s,1H),8.53(d,J=4.8Hz,1H),7.80(dt,J= 8.0, 2.0Hz, 1H), 7.59 (dd, J=7.3, 1.5Hz, 1H), 7.55–7.50 (m, 1H), 7.42 (dd, J=7.9, 4.8Hz, 1H), 7.32–7.18 (m ,3H),7.15–7.09(m,2H),7.05(d,J＝7.5Hz,1H),6.90(t,J＝5.6Hz,1H),6.65(t,J＝1.0Hz,1H),6.36 (d, J=8.1 Hz, 1H), 3.54 (s, 2H), 3.10 (q, J=6.9 Hz, 2H), 2.68–2.62 (m, 2H), 1.37 (s, 9H).

Step 5: Compound 35-6 (0.15 g, 308.91 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (770.00 mg, 6.75 mmol, 500.0 μL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude compound Int-35 as trifluoroacetate salt (0.2 g) as a brown oil. LCMS[M+H] ⁺ 386.1.

Intermediate 36: Preparation of Compound Int-36

Step 1: 2-Hydroxybenzaldehyde (2.17 g, 17.80 mmol) was added to 2-bromo-1-(pyridin-2-yl)ethanone 36-1 (5.00 g, 17.80 mmol) in N,N-dimethylene To the solution of methylformamide (20 mL), potassium carbonate (4.92 g, 35.59 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (3 x 20 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by reverse phase column to obtain compound 36-2 (3.10 g, yield 78.0%) as a brown solid. LCMS[M+H] ⁺ 224.2.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (dt, J=4.7, 1.4 Hz, 1H), 8.49 (d, J=1.0 Hz, 1H), 8.17-8.06 (m, 2H), 7.94 ( dd, J=7.8, 1.2Hz, 1H), 7.81-7.71 (m, 2H), 7.59 (ddd, J=8.4, 7.1, 1.3Hz, 1H), 7.40 (t, J=7.5Hz, 1H).

Step 2: Compound 36-2 (1.50 g, 6.72 mmol), tert-butylsulfinamide (741.13 mg, 6.11 mmol) and tetraethyl titanate (2.79 g, 12.23 mmol) were added to dichloromethane (50 mL) , and stirred at 40°C for 12 hours. The reaction mixture was diluted with water (80 mL), then extracted with dichloromethane (2 x 40 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-1:1) to obtain compound 36-3 (350 mg, yield 17.5%) as a yellow oil. LCMS[M+H] ⁺ 327.0.

Step 3: Sodium borohydride (69.54 mg, 1.84 mmol) was added to a solution of compound 36-3 (300 mg, 919.08 μmol) in methanol (5 mL) at 0°C, followed by stirring at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with water (5 mL). Diluted with water (10 mL), then extracted with ethyl acetate (2 x 10 mL), the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude compound 36-4 (540 mg) as a blue solid. used directly in the next reaction. LCMS[M+H] ⁺ 329.0.

Step 4: Compound 36-4 (70 mg, 213.14 μmol) was added to a solution of 4M HCl in methanol (4 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated and diluted with water (10 mL), adjusted to pH 8 with saturated sodium bicarbonate solution, then extracted with ethyl acetate (2×10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filter and concentrate. The crude compound Int-36 (40 mg, 83.7% yield) was obtained as a red oil. used directly in the next reaction. LCMS[M+H] ⁺ 225.0.

Intermediate 37: Preparation of Compound Int-37

Step 1: n-Butyllithium (2.5M, 4.11 mL) was slowly added dropwise to nitrogen-protected 1-methylindole 37-1 (1.22 g, 9.34 mmol) in anhydrous tetrahydrofuran (10 mL) at -78°C ) solution, the temperature was naturally raised to room temperature after dropping, and stirred for 0.5 hours. It was cooled to -78°C again, and a solution of nicotinaldehyde (1.00 g, 9.34 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise, and the mixture was naturally warmed to room temperature after dropping, and stirred for 3 hours. After completion of the reaction, the reaction was quenched with saturated NH ₄ Cl solution (20 mL), then extracted with ethyl acetate (3×30 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by reverse phase column to obtain compound 37-2 (1.69 g, yield 75.9%) as a yellow oil. LCMS[M+H] ⁺ 239.1.

Step 2: Active manganese dioxide (3.06 g, 35.25 mmol) was added to a solution of compound 37-2 (700 mg, 2.94 mmol) in anhydrous dichloromethane (20 mL) at room temperature, and stirred for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to give crude compound 37-3 (700 mg) as a yellow gum. used directly in the next reaction. LCMS[M+H] ⁺ 237.0.

Subsequent steps 3-5, using a method similar to the preparation of intermediate 36, gave compound Int-37 as a red oil. used directly in the next reaction. LCMS[M+H] ⁺ 238.2.

Intermediate 38: Preparation of Compound Int-38

Step 1: Compound 3-bromoxynil 38-1 (546 mg, 3 mmol) and tert-butyl acrylate (1.15 g, 9 mmol) were dissolved in N,N-dimethylformamide (10 mL), followed by adding tetrabutyl Ammonium bromide TBAB (1.16 g, 3.6 mmol), potassium carbonate (1.24 g, 9 mmol) and palladium acetate (34 mg, 0.15 mmol). It was heated to 120°C and stirred for 16 hours under nitrogen protection. After the reaction was completed, the reaction mixture was cooled to room temperature, ethyl acetate (50 mL) and water (20 mL) were added, extracted, and the layers were separated. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether/ethyl acetate, ethyl acetate%: 10%-50%) to obtain compound 38-2 (360 mg, yield 52.3%) as colorless oil.

Step 2: Compound 38-2 (180 mg, 0.78 mmol) was dissolved in methanol (5 mL), 7M _NH3/ MeOH (2 mL, 14.0 mmol) was added followed by Raney Ni (0.5 g). Hydrogenate with hydrogen balloon for 16 hours at room temperature. Filtration and concentration of the filtrate gave crude compound 38-3 (190 mg) as a colorless oil. used directly in the next reaction. LCMS[M+H] ⁺ 236.6.

Step 3: Compound 38-3 (160 mg, 0.69 mmol) and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7 -2 (190 mg, 0.69 mmol) was dissolved in N-methylpyrrolidone (4 mL), diisopropylethylamine (268 mg, 3.0 mmol) was added, and the mixture was heated and stirred at 90°C for 16 hours. After the reaction was completed, the reactant was cooled to room temperature, ethyl acetate (20 mL) and water (10 mL) were added, extracted, and the layers were separated. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether/ethyl acetate, ethyl acetate%: 20%-80%) to obtain compound 38-4 (130 mg, yield 38.3%) as a yellow oil. LCMS[M+ _NH4 ] ⁺ 509.4.

Step 4: Compound 38-4 (130 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL, 6.7 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, it was spin-dried under reduced pressure to obtain the crude compound Int-38 (95 mg) as a yellow oil. used directly in the next reaction. LCMS[M+H] ⁺ 436.5.

Intermediate 39: Preparation of Compound Int-39

In a similar manner to the preparation of intermediate 38, by using 2-bromo-6-cyanopyridine 39-1 as starting material, compound Int-39 was obtained. LCMS[M+H] ⁺ 437.5.

Intermediate 40: Preparation of Compound Int-40

In a similar manner to the preparation of intermediate 36, the compound was obtained by using the hydrobromide salt of 2-bromo-1-(pyridin-3-yl)ethanone 40-1 and 3-hydroxyisonicotinaldehyde 40-2 as starting materials Int-40. LCMS[M+H] ⁺ 226.0.

Intermediate 41: Preparation of Compound Int-41

In a similar manner to the preparation of intermediate 36, by using the hydrobromide salt of 2-bromo-1-(pyridin-3-yl)ethanone 40-1 and 3-hydroxypyridine-2-carbaldehyde 41-1 as starting materials, Compound Int-41 was obtained. LCMS[M+H] ⁺ 226.2.

Intermediate 42: Preparation of Compound Int-42

To 4-bromo-1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-isoindoline 1-3 (5.00 g, 14.8 mmol) at room temperature To a solution of N,N-dimethylformamide (30 mL), sodium sulfide (2.32 g, 29.6 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, it was diluted with ethyl acetate (30 mL), washed with 1M hydrochloric acid (2×30 mL) and water (50 mL) in turn, the final aqueous phase was extracted with ethyl acetate (2×20 mL), and all organic phases were combined, Dry over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was slurried with methanol (20 mL) to obtain the compound 4-mercapto-1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-isoindoline Int-42 (540 mg , yield 12.5%), yellow solid. LCMS[M+H] ⁺ 291.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 7.86-7.60 (m, 3H), 6.27 (brs, 1H), 5.13 (dd, J=12.7, 5.4Hz, 1H), 2.89 (ddd, J=17.0, 13.7, 5.4 Hz, 1H), 2.66–2.46 (m, 2H), 2.12–2.01 (m, 1H).

Intermediate 43: Preparation of Compound Int-43

Step 1: Methanesulfonyl chloride (246.75 mg, 2.15 mmol) was added dropwise to compound 8-2 (400 mg, 1.96 mmol) and triethylamine (594.46 mg, 5.87 mmol) in anhydrous dichloromethane (10 mL) at 0°C ) solution, and stirred at room temperature for 0.5 hours after dropping. After the reaction was completed, it was concentrated under reduced pressure to obtain the crude compound 43-1 (520 mg), which was directly used in the next reaction. LCMS[M+ _NH4 ] ⁺ 300.0.

Step 2: Compound 43-1 (145.90 mg, 516.72 μmol) was dissolved in N,N-dimethylformamide (5 mL), Int-42 (100 mg, 344.48 μmol) and potassium carbonate (71.41 mg, 516.72 μmol) were added sequentially μmol) and stirred at room temperature for 4 hours. TLC detected the formation of new substances. The reaction mixture was diluted with water (10 mL), then extracted with ethyl acetate (2 x 10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by reverse phase column to obtain compound 43-2 (30 mg, yield 18.3%) as a white solid. used directly in the next reaction. LCMS[M+Na] ⁺ 499.3.

Step 3: Compound 43-2 (30 mg, 62.95 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1.54 g, 13.51 mmol) was added, and the mixture was stirred at room temperature for 2 hours. TLC detected that the reaction was complete, and concentrated to obtain crude compound Int-43 (26 mg, yield 98.2%) as a yellow oil. used directly in the next reaction.

Intermediate 44: Preparation of Compound Int-44

Step 1: Compound benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 (253.59 mg, 1.13 mmol), 3-(((tert-butoxycarbonyl)amino)methyl)phenylacetic acid 44-1 (300 mg, 1.13 mmol), HATU (472.95 mg, 1.24 mmol) and N,N-diisopropylethylamine (438.44 mg, 3.39 mmol) were dissolved in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hours. After the reaction, water (15 mL) was added to the reaction solution for dilution, ethyl acetate (2×20 mL) was used for extraction, the organic phases were combined, washed once with saturated brine (20 mL), and the organic phase was dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by normal phase silica gel column to obtain compound 44-2 (500 mg, yield 93.8%) as a brown oil. LCMS[M+H] ⁺ 472.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.34 (d, J=8.2Hz, 1H), 8.62 (d, J=2.3Hz, 1H), 8.53 (dd, J=4.8, 1.6Hz, 1H) ,7.80(dt,J=8.2,2.1Hz,1H),7.62-7.59(m,1H),7.56-7.49(m,1H),7.42(dd,J=7.9,4.8Hz,1H),7.35(t , J=6.3Hz, 1H), 7.31–7.21 (m, 3H), 7.14 (brs, 2H), 7.09 (d, J=7.6Hz, 1H), 6.67 (t, J=1.0Hz, 1H), 6.35 (d, J=8.2 Hz, 1H), 4.09 (d, J=6.2 Hz, 2H), 3.56 (s, 2H), 1.38 (s, 9H).

Step 2: Compound 44-2 (500 mg, 1.06 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1.40 g, 12.28 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain the crude compound Int-44 (1.11 g) as a brown oil. used directly in the next reaction. LCMS[M+H] ⁺ 372.2.

Intermediate 45: Preparation of Compound Int-45

At room temperature, the compound benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 (674.77 mg, 3.01 mmol) and 4-hydroxymethylphenylacetic acid 45-1 (0.5 g, 3.01 mmol) were added To N,N-dimethylformamide (5 mL), HATU (1.26 g, 3.31 mmol) and N,N-diisopropylethylamine (1.17 g, 9.03 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (2×10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave compound Int-45 (473.2 mg, yield 42.2%). LCMS[M+H] ⁺ 373.0.

Intermediate 46: Preparation of Compound Int-46

In a similar manner to the preparation of intermediate 43, by using compound 12-3 as starting material, compound Int-46 was obtained. LCMS[M+H] ⁺ 421.2.

Intermediate 47: Preparation of Compound Int-47

Step 1: To 7-hydroxyheptanoic acid 47-1 (300 mg, 2.05 mmol), benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 (460.22 mg, 2.05 mmol) in N at room temperature , N-dimethylformamide (4 mL) solution was added HATU (858.34 mg, 2.26 mmol) and N,N-diisopropylethylamine (795.70 mg, 6.16 mmol, 1.07 mL). Stir at room temperature for 12 hours. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (3×5 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by reverse phase column to obtain compound 47-2 (309 mg, yield 42.7%) as a brown solid. LCMS[M+H] ⁺ 353.2.

Step 2: To a solution of compound 47-2 (150 mg, 425.62 μmol) and triethylamine (129.20 mg, 1.28 mmol, 177.72 μL) in anhydrous dichloromethane (5 mL) at 0° C. under the protection of N ₂ , add dropwise Methanesulfonyl chloride (300 mg, 2.62 mmol, 202.70 μL), the reaction mixture was stirred at room temperature for 1 hour, TLC showed the reaction was complete. The reaction mixture was concentrated to give crude compound Int-47 (183 mg, yield 99.9%) as a brown solid. used directly in the next reaction.

Intermediate 48: Preparation of Compound Int-48

Step 1: To a solution of compound 48-1 (3.00 g, 15.85 mmol) and triethylamine (4.81 g, 47.56 mmol) in anhydrous dichloromethane (50 mL) under the protection of N ₂ at 0 °C, methanesulfonic acid was added dropwise. Acid chloride (2.0 g, 17.44 mmol), the reaction mixture was stirred at room temperature for 0.5 h, TLC showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution (20 mL). The reaction mixture was then diluted with water (50 mL), extracted with dichloromethane (2 x 40 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude compound 48-2 (3.9 g, yield 92.0%) as a yellow oil. used directly in the next reaction. LCMS[M+Na] ⁺ 290.0.

Step 2: Compound 48-2 (138.14 mg, 516.72 μmol) was dissolved in N,N-dimethylformamide (4 mL), Int-42 (100 mg, 344.48 μmol) and potassium carbonate (71.41 mg, 516.72 μmol) were added sequentially ) and stirred at room temperature for 12 hours. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (2×10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by reverse phase column to obtain compound 48-3 (55 mg, yield 34.6%) as a yellow solid. LCMS[M+Na] ⁺ 484.2.

Step 3: Compound 48-3 (55 mg, 119.17 μmol) was added to anhydrous dichloromethane (6 mL), then trifluoroacetic acid (3.08 g, 27.01 mmol) was added, and the mixture was stirred at room temperature for 2 hours. TLC detected that the reaction was complete, and the reaction solution was concentrated to obtain crude compound 48-4 (87 mg) as a yellow solid. used directly in the next reaction.

Step 4: Compound 48-4 (70.00 mg, 147.2 μmol) was dissolved in tert-butanol (4 mL), followed by adding triethylamine (19.60 mg, 193.69 μmol) and tert-butyl acrylate (37.24 mg, 290.55 μmol), at 80° C. Heat and stir for 10 hours. After cooling, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (2 x 20 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by reverse phase column to obtain compound 48-5 (30 mg, yield 41.6%) as a yellow oil.

LCMS[M+H] ⁺ 490.3.

Step 5: Compound 48-5 (30 mg, 61.28 μmol) was added to anhydrous dichloromethane (3 mL), then trifluoroacetic acid (1.54 g, 13.51 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude compound Int-48 (26 mg, yield 77.5%) as a yellow oil. used directly in the next reaction.

Intermediate 49: Preparation of Compound Int-49

In a similar manner to the preparation of intermediate 34, compound Int-49 was obtained by using 3-(4-(aminomethyl)phenyl)propionic acid 49-1 as starting material. LCMS[M+H] ⁺ 436.1.

Intermediate 50: Preparation of Compound Int-50

In a similar manner to the preparation of intermediate 34, by using 4-(aminomethyl)benzoic acid 50-1 as starting material, compound Int-50 was obtained. LCMS[M+H] ⁺ 408.0.

Intermediate 51: Preparation of Compound Int-51

Step 1: At room temperature, benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 (674.77 mg, 3.01 mmol) and 4-hydroxymethylphenylacetic acid 51-1 (0.5 g, 3.01 mmol) were combined ) was dissolved in N,N-dimethylformamide (5 mL), then HATU (1.26 g, 3.31 mmol) and N,N-diisopropylethylamine (1.17 g, 9.03 mmol) were added, and the mixture was stirred at room temperature for 2 hours . The reaction mixture was diluted with water (10 mL), then extracted with ethyl acetate (2 x 10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude compound 51-2 (0.473 g, yield 42.2%). used directly in the next reaction. LCMS[M+H] ⁺ 373.0.

Step 2: To a solution of compound 51-2 (100 mg, 268.52 μmol) in dichloromethane (2 mL) at room temperature, manganese dioxide (280.14 mg, 3.22 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain the crude compound Int-51 (85 mg), which was directly used in the next reaction. LCMS[M+H] ⁺ 371.0.

Intermediate 52: Preparation of Compound Int-52

In a similar manner to the preparation of intermediate 37, by using benzo[d]thiazole 52-1 as starting material, compound Int-52 was obtained. LCMS[M+H] ⁺ 241.9.

Intermediate 53: Preparation of Compound Int-53

In a similar manner to the preparation of intermediate 37, by using benzo[d]furan and pyrimidine-5-carbaldehyde 53-1 as starting materials, compound Int-53 was obtained. LCMS[M+H] ⁺ 226.2.

Intermediate 54: Preparation of Compound Int-54

In a similar manner to the preparation of intermediate 37, by using benzo[b]thiophene 54-1 as starting material, compound Int-54 was obtained. LCMS[M+H] ⁺ 241.2.

Intermediate 55: Preparation of Compound Int-55

Step 1: Sodium nitrite (1.98 g, 28.6 mmol) was slowly added dropwise to hydrochloric acid (10 mL, 36% HCl) of dimethyl 3-aminophthalate 55-1 (5.0 g, 23.9 mmol) at 0°C ) and water (10 mL), and after stirring for 0.5 hour, potassium iodide (9.92 g, 59.8 mmol) was added, and stirring was continued at room temperature for 1 hour. After the reaction was completed, it was diluted with water (10 mL), extracted with ethyl acetate (2×20 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified with a normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=5:1-1:1) to obtain the compound 3-iodophthalate dimethyl 55-2 (4.0 g, yield 52.3%), white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.17 (dd, J=7.9, 1.1 Hz, 1H), 7.99 (dd, J=7.9, 1.1 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 3.85(s, 3H), 3.83(s, 3H).

Step 2: Under nitrogen protection, compound 55-2 (500 mg, 1.56 mmol), tert-butyl 4-aminophenylacetate (323.7 mg, 1.56 mmol), 2,2'-bis(diphenylphosphino)-1, 1'-Binaphthalene (BINAP) (48.6 mg, 78.1 μmol), Cesium Carbonate (712.5 mg, 2.19 mmol) and Tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ ) (42.9 mg, 46.8 μmol ) was added to anhydrous toluene (5 mL), heated and stirred at 120° C. for 16 hours. After cooling, the reaction mixture was filtered, and the filtrate was concentrated to obtain crude product. The crude product was separated and purified by reverse-phase column to obtain compound 55-3 (490 mg, yield 78.6%) as a yellow oil. LCMS[M+Na] ⁺ 422.3.

Step 3: To a solution of compound 55-3 (250 mg, 625.8 μmol) in 1,4-dioxane (1 mL), sodium hydroxide aqueous solution (5 M, 5 mL) was added, and the mixture was heated and stirred at 80° C. for 3 hours. After cooling, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 15 mL). The aqueous phase was adjusted to pH 5 and extracted with ethyl acetate (2×20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate to obtain crude product. The crude product was separated and purified by reverse phase column to obtain compound 55-4 (120 mg, yield 60.8%) as a yellow solid. LCMS[M+Na] ⁺ 337.9.

Step 4: Compound 55-4 (100 mg, 317.1 μmol) and 3-aminopiperidine-2,6-dione hydrochloride 55-5 (83.5 mg, 507.4 μmol) were added to pyridine (2 mL) at 120°C Heat and stir for 12 hours. After the reaction, it was diluted with ethyl acetate (30 mL), washed with 1M hydrochloric acid (2×30 mL) and water (2×30 mL), and the organic layer was dried over anhydrous sodium sulfate. Filtration and concentration gave crude compound Int-55 (135 mg) as a brown oil. used directly in the next reaction. LCMS[M+H] ⁺ 408.1.

Intermediate 56: Preparation of Compound Int-56

In a similar manner to the preparation of intermediate 37, by using benzo[d]oxazole 56-1 as starting material, compound Int-56 was obtained. LCMS[M+H] ⁺ 226.0.

Intermediate 57: Preparation of Compound Int-57

Step 1: 2-Fluoro-3-iodopyridine 57-1 (13.4 g, 60.09 mmol) and ethynyltrimethylsilane (9.03 g, 91.89 mmol, 12.73 mL) were dissolved in N,N-dimethylsilane at room temperature bis(triphenylphosphine) palladium(II) dichloride (2.68g, 3.82mmol), cuprous iodide (938.00mg, 4.93mmol) and triethylamine were added to the base formamide (200mL) under nitrogen protection (9.16 g, 90.50 mmol, 12.60 mL), and the reaction was stirred at room temperature for 6 hours. After the reaction was completed, filtered, the filtrate was diluted with water (200 mL), extracted with ethyl acetate (3×200 mL), the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether/ethyl acetate (V/V)=20/1～10/1) to obtain compound 57-2 (7.18 g, yield 61.8%) as a brown oil. LCMS[M+H] ⁺ 194.1.

Step 2: At 0°C, compound 57-2 (7 g, 36.21 mmol) was dissolved in tetrahydrofuran (100 mL) and water (10 mL), tetrabutylammonium fluoride solution (1 M, 36.2 mL) was slowly added, and stirred for 1 hour . The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (3×100 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude compound 57-3 (6.32 g) as a yellow oil. used directly in the next reaction.

Step 3: Compound 57-3 (4.39 g, 36.25 mmol) was dissolved in dimethyl sulfoxide (50 mL), sodium hydroxide (1.74 g, 43.50 mmol) was added, and the mixture was stirred at 80° C. for 12 hours. It was cooled to room temperature, diluted with saturated aqueous ammonium chloride solution (100 mL), extracted with ethyl acetate (3×100 mL), the organic layers were combined, washed with saturated brine (3×100 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether/ethyl acetate (V/V)=20/1～10/1) to obtain compound 57-4 (1.09 g, yield 25.2%) as a yellow oil.

¹ H NMR (400MHz, Chloroform-d) δ 8.32 (dd, J=4.9, 1.7Hz, 1H), 7.93 (dd, J=7.7, 1.7Hz, 1H), 7.70 (d, J=2.5Hz, 1H) ), 7.22 (dd, J=7.7, 4.9 Hz, 1H), 6.77 (d, J=2.5 Hz, 1H).

Step 4:

Under nitrogen protection, tert-butyllithium (1.3M, 6.59 mL) was slowly added dropwise to a solution of compound 57-4 (850 mg, 7.14 mmol) in anhydrous tetrahydrofuran (10 mL) at -78°C, and stirred for 15 minutes. A solution of nicotinaldehyde (917.16 mg, 8.56 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred for 15 minutes, then naturally warmed to room temperature and continued to be stirred for 3.5 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (50 mL) at 0 °C, diluted with water (20 mL), and extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether/ethyl acetate (V/V)=10/1～0/1) to obtain compound 57-5 (850 mg, yield 52.6%) as a yellow oil. LCMS[M+H] ⁺ 226.9.

Subsequent steps 5-8, using a method similar to the preparation of intermediate 37, gave compound Int-57. LCMS[M+H] ⁺ 226.0.

Intermediate 58: Preparation of Compound Int-58

Step 1: Di-tert-butyl dicarbonate (Boc ₂ O) (24.99 g, 114.50 mmol, 26.31 mL) and 4-(dimethylamino)pyridine (2.10 g, 17.16 mmol) were added to 4-iodophenylacetic acid 58 A solution of -1 (15 g, 57.24 mmol) in tert-butanol (100 mL) was stirred at room temperature for 3 hours. TLC detected the formation of new substances, and the crude product was obtained after the reaction mixture was concentrated. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-1:1) to obtain compound 58-2 (9.20 g, yield 50.5%) as a colorless oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.70-7.62 (m, 2H), 7.10-7.02 (m, 2H), 3.52 (s, 2H), 1.39 (s, 9H).

Step 2: Compound 58-2 (3.00 g, 9.43 mmol), ethynyltrimethylsilane (1.85 g, 18.86 mmol), triethylamine (18.18 g, 179.61 mmol), bis(triphenylphosphine)dichloro Palladium (II) (661.9 mg, 942.95 μmol) and cuprous iodide (179.6 mg, 942.95 μmol) were added to anhydrous tetrahydrofuran (25 mL) and stirred at room temperature for 6 hours under nitrogen protection. The reaction mixture was concentrated, and the crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-1:1) to obtain compound 58-3 (2.19 g, yield 80.5%), Yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.42-7.37(m,2H),7.27-7.22(m,2H),3.58(s,2H),1.38(s,9H),0.22(s,9H) ).

Step 3: Aqueous potassium carbonate solution (1 M, 5 mL) was added to a solution of compound 58-3 (1.36 g, 4.71 mmol) in anhydrous methanol (20 mL), and reacted at room temperature for 0.5 h. The reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (2 x 20 mL), and the organic layers were combined. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain crude compound 58-4 (790 mg, yield 77.5%) as a yellow oil. used directly in the next reaction.

¹ H NMR(400MHz, Chloroform-d)δ7.46-7.42(m,2H),7.25-7.21(m,2H),3.52(s,2H),3.06(s,1H),1.43(s,9H) . LCMS[M+H] ⁺ 217.2.

Step 4: Compound 58-4 (380 mg, 1.76 mmol), 4-bromo-1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-isoindoline 1-3 (592.34 mg, 1.76 mmol), triethylamine (727.0 mg, 7.18 mmol), bis(triphenylphosphine)palladium(II) dichloride (123.3 mg, 175.70 μmol) and cuprous iodide (66.9 mg, 351.40 μmol) was added to N,N-dimethylformamide (2 mL) solution, and stirred at 80° C. for 12 hours under nitrogen protection. After cooling to room temperature, the reaction mixture was diluted with water (10 mL), then extracted with ethyl acetate (2 x 10 mL), and the organic layers were combined. Dry over anhydrous sodium sulfate, filter, and concentrate to obtain crude product. The crude product was separated and purified by normal-phase silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-1:1) and reverse-phase column for secondary purification to obtain compound 58-5 (190 mg, yield 22.9%) , white solid. LCMS[M+ _NH4 ] ⁺ 490.2.

¹ H NMR (400MHz, Chloroform-d) δ 8.05 (brs, 1H), 7.83 (dd, J=2.5, 1.0Hz, 1H), 7.82-7.80 (m, 1H), 7.72 (dd, J=8.0, 7.2Hz, 1H), 7.64–7.57 (m, 2H), 7.33–7.26 (m, 2H), 5.01 (dd, J=12.3, 5.3Hz, 1H), 3.55 (s, 2H), 2.97–2.68 (m , 3H), 2.22–2.11 (m, 1H), 1.43 (s, 9H).

Step 5: Compound 58-5 (190 mg, 402.13 μmol) was added to anhydrous dichloromethane (6 mL), trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL) was added, and the mixture was stirred at room temperature for 2 hours. TLC detected that the reaction was complete, and the reaction mixture was concentrated to obtain the crude compound Int-58 (196 mg) as a yellow oil. used directly in the next reaction.

Intermediate 59: Preparation of Compound Int-59

Compound 4-(bromomethyl)phenylacetic acid 59-1 (150 mg, 654.82 μmol), Int-42 (190.09 mg, 654.82 μmol) and potassium carbonate (271.50 mg, 1.96 mmol) were added to N,N-dimethyl In formamide (5 mL), the mixture was stirred at 90°C for 8 hours. After the reaction, 1M aqueous hydrochloric acid was added to the reaction solution to adjust the pH to about 5, extracted with ethyl acetate (2×20 mL), the combined organic phases were washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave crude product. The crude product was separated and purified by reverse phase column to obtain compound Int-59 (203 mg, yield 70.7%) as a yellow solid. LCMS[M+H] ⁺ 439.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.32 (s, 1H), 11.11 (s, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.76 (t, J=7.7 Hz, 1H) ,7.62(d,J＝7.1Hz,1H),7.42(d,J＝7.8Hz,2H),7.23(d,J＝7.9Hz,2H),5.11(dd,J＝12.8,5.4Hz,1H) , 4.43 (s, 2H), 3.54 (s, 2H), 2.88 (ddd, J=16.6, 13.6, 5.3 Hz, 1H), 2.65–2.44 (m, 2H), 2.09–1.98 (m, 1H).

Intermediate 60: Preparation of Compound Int-60

Compound benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 (1.11 g, 4.95 mmol) and azidoacetic acid (500 mg, 4.95 mmol) were dissolved in N,N-dimethylformamide ( 5mL), add O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (2.07g, 5.44mmol ) and N,N-diisopropylethylamine (1.92 g, 14.84 mmol, 2.59 mL), and stirred at room temperature for 1 hour. After the reaction, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (2×10 mL), the organic layer was washed with saturated brine (2×10 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate (tetrahydrofuran was added during the concentration process, do not spin to dryness) to obtain the crude compound Int-60 (2.3 g) as a brown oil. used directly in the next reaction. LCMS[M+H] ⁺ 308.0.

Intermediate 61: Preparation of Compound Int-61

Compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7-2 (1 g, 3.62 mmol) and propargylamine (259.22 mg, 4.71 mmol, 301.42 μL) was added to N,N-dimethylformamide (15 mL), followed by N,N-diisopropylethylamine (935.80 mg, 7.24 mmol, 1.26 mL), heated at 90°C Stir for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (2×20 mL), the organic layer was washed with saturated brine (2×20 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was purified by reverse-phase column preparation to obtain compound Int-61 (0.234 g, yield 20.8%) as a yellow solid. LCMS[M+H] ⁺ 311.9.

Intermediate 62: Preparation of Compound Int-62

Step 1: At 0°C, tert-butyl 2-bromoacetate (964.21 mg, 4.94 mmol, 730.47 μL) was slowly added dropwise to tert-butyl (4-(methylamino)butyl)carbamate 62-1 (1 g , 4.94 mmol) and triethylamine (1.00 g, 9.89 mmol, 1.38 mL) in anhydrous tetrahydrofuran (10 mL), and stirred at room temperature for 36 hours. After the completion of the reaction, the reaction solution was diluted with water (15 mL), extracted with ethyl acetate (2×20 mL), the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=5:1 to 0:1) to obtain compound 62-2 (0.836 g, yield 53.4%) as a colorless oil.

¹ H NMR (400MHz, Chloroform-d) δ4.78(brs,1H), 3.16-3.07(m,4H), 2.51-2.43(m,2H), 2.33(s,3H), 1.50(p,J= 3.8Hz, 4H), 1.45(s, 9H), 1.42(s, 9H).

Step 2: Trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL) was added to a solution of compound 62-2 (0.836 g, 2.64 mmol) in anhydrous dichloromethane (6 mL) at room temperature, and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated to obtain crude compound 62-3 (0.4 g, yield 94.5%) as a colorless oil. used directly in the next reaction.

Step 3: At room temperature, compound 62-3 (191.41 mg, 1.19 mmol), 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisodi Indoline 7-2 (0.3 g, 1.09 mmol) and N,N-diisopropylethylamine (421.11 mg, 3.26 mmol, 567.53 μL) were dissolved in 1-methyl-2-pyrrolidone (3 mL), microwave Heating and stirring at 110°C for 2 hours. The reaction mixture was separated and purified with a reverse phase column to obtain compound Int-62 (0.04 g, yield 8.8%) as a yellow solid. LCMS[M+H] ⁺ 417.0.

Intermediate 63: Preparation of Compound Int-63

step 1:

Aqueous sodium hydroxide (3.98 g, 99.59 mmol) (100 mL) was added to a solution of 2-(methylamino)ethanol 63-1 (7.48 g, 99.59 mmol, 8 mL) in dichloromethane (100 mL), then slowly added A solution of chloroacetyl chloride (11.25 g, 99.59 mmol, 7.92 mL) in dichloromethane (100 mL) was stirred at room temperature for 34 hours. The organic phase was separated, washed once with saturated brine (50 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave a white oil. This was dissolved in ethanol (150 mL), potassium hydroxide (5.6 g, 99.81 mmol) was added as a solid, and the mixture was heated and stirred at 45° C. for 10 hours. After the completion of the reaction, the reaction solution was concentrated to obtain a crude compound 63-2 (15 g) as a yellow oil. used directly in the next reaction.

Step 2: Compound 63-2 (11.74 g, 101.97 mmol) and potassium hydroxide (5.6 g, 99.81 mmol) were dissolved in ethanol (150 mL), heated and stirred at 95° C. for 15 hours. After cooling to room temperature, di-tert-butyl dicarbonate (Boc ₂ O) (44 g, 201.61 mmol, 46.32 mL) was added, and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated, adjusted to pH=9 with saturated sodium bicarbonate solution, washed with ethyl acetate (2×50 mL), and the obtained aqueous phase was adjusted to pH=4 or so with dilute hydrochloric acid, and then used ethyl acetate ( 2×50 mL) extraction. The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 63-3 (3.5 g, yield 14.7%) as a colorless transparent oil.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.58 (brs, 1H), 4.00 (s, 2H), 3.54 (t, J=5.8Hz, 2H), 3.31 (t, J=5.8Hz, 2H) , 2.80(s, 3H), 1.38(s, 9H).

Step 3: At room temperature, compound 63-3 (2g, 8.57mmol), benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 (1.92g, 8.57mmol), HATU (3.59g, 9.43 mmol) and N,N-diisopropylethylamine (3.32 g, 25.72 mmol, 4.48 mL) were added to N,N-dimethylformamide (10 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was diluted with water (100 mL), then extracted with ethyl acetate (3×100 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=100:1～0:1) to obtain compound 63-4 (1.42 g, yield 37.7%) as a brown oil. LCMS[M+H] ⁺ 440.4.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.96 (d, J=8.5Hz, 1H), 8.67 (d, J=2.3Hz, 1H), 8.54 (dd, J=4.8, 1.6Hz, 1H) ,7.86(dt,J＝8.0,2.0Hz,1H),7.59(dd,J＝7.5,1.5Hz,1H),7.53(d,J＝8.2Hz,1H),7.43(dd,J＝7.9,4.7 Hz,1H),7.28(td,J=7.9,1.5Hz,1H),7.23(td,J=7.4,1.1Hz,1H),6.64(t,J=1.0Hz,1H),6.45(d,J ＝8.5Hz, 1H), 4.04(s, 2H), 3.58(t, J＝5.7Hz, 2H), 3.35(t, J＝5.7Hz, 2H), 2.80(s, 3H), 1.35(s, 9H ).

Step 4:

Trifluoroacetic acid (7.70 g, 67.53 mmol, 5 mL) was added to a solution of compound 63-4 (1.4 g, 3.19 mmol) in anhydrous dichloromethane (15 mL) at room temperature, and stirred for 1 hour. After the reaction, the reaction solution was concentrated to obtain the trifluoroacetic acid salt of the crude compound Int-63 (0.692 g, yield 47.9%) as a brown oil. used directly in the next reaction. LCMS[M+H] ⁺ 340.3.

Intermediate 64: Preparation of Compound Int-64

Step 1: Under nitrogen protection, compound 4-bromo-1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-isoindoline 1-3 (5g, 14.83 mmol), allyltributylstannane (7.37 g, 22.25 mmol, 6.82 mL) and tetrakistriphenylphosphine palladium (1.71 g, 1.48 mmol) were dissolved in N,N-dimethylformamide (30 mL), Heating and stirring at 100°C for 12 hours. After the reaction was completed, it was cooled to room temperature and filtered. The filtrate was diluted with water (50 mL), extracted with ethyl acetate (2×50 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=15:1 to 1:1) to obtain compound 64-1 (3.2 g, yield 72.3%) as a white solid. LCMS[M+H] ⁺ 299.2.

Step 2: At -78 °C, ozone was slowly passed into the solution of compound 64-1 (0.3 g, 1.01 mmol) in dichloromethane (50 mL), until the reaction solution turned light blue, then dimethyl sulfide was added (124.98 mg, 2.01 mmol, 147.73 μL), then the temperature was naturally raised to room temperature and stirred for 2 hours. After the completion of the reaction, the reaction solution was concentrated to obtain the crude compound Int-64 (0.4 g, crude product) as a yellow oil. used directly in the next reaction. LCMS[M+H] ⁺ 301.3.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 9.77 (s, 1H), 7.86–7.80 (m, 2H), 7.73–7.69 (m, 1H), 5.13 (dd, J = 13.1, 5.5 Hz, 1H), 4.28 (s, 2H), 2.94–2.83 (m, 1H), 2.65–2.51 (m, 2H), 2.10–1.99 (m, 1H).

Intermediate 65: Preparation of Compound Int-65

Step 1: Di-tert-butyl dicarbonate (Boc ₂ O) (1.63 g, 7.46 mmol) was added to compound 4-(methylamino)-1-butanol 65-1 (770 mg, 7.46 mmol) in dichloromethane (10 mL) solution was stirred at room temperature for 3 hours. After the reaction was completed, water (10 mL) was added to dilute, and the mixture was extracted with dichloromethane (2×10 mL). The organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=50:1 to 1:1) to obtain compound 65-2 (1.25 g, yield 82.4%) as a yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.38 (t, J=5.1 Hz, 1H), 3.39 (td, J=6.4, 5.1 Hz, 2H), 3.14 (t, J=7.1 Hz, 2H) , 2.74(s, 3H), 1.46(p, J=7.2Hz, 2H), 1.38(s, 9H), 1.38–1.30(m, 2H).

Step 2: At 0°C, methanesulfonyl chloride (290 mg, 2.53 mmol, 195.95 μL) was added to compound 65-2 (200 mg, 983.88 μmol) and triethylamine (298.68 mg, 2.95 mmol, 410.83 μL) in dichloromethane ( 10 mL) solution, and then stirred at room temperature for 0.5 h. After the reaction, the reaction solution was concentrated to obtain a crude compound 65-3 (720 mg, crude) as a yellow solid. used directly in the next reaction.

Step 3: To a solution of compound 65-3 (712.40 mg, 2.53 mmol) in acetonitrile (5 mL) was added cesium carbonate (707.10 mg, 2.17 mmol) and 4-mercapto-1,3-dioxo-2 at room temperature -(2,6-Dioxopiperidin-3-yl)-isoindoline Int-42 (210 mg, 723.40 μmol), and then heated and stirred at 50° C. for 3 hours. After completion of the reaction, the reaction solution was concentrated to obtain a crude product. The crude product was separated and purified by reverse phase column to obtain compound 65-4 (118 mg, yield 34.3%) as a yellow solid. LCMS[M+Na] ⁺ 498.2.

Step 4: Trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL) was added to a solution of compound 65-4 (170 mg, 357.48 μmol) in dichloromethane (6 mL) and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated to obtain crude compound 65-5 (250 mg) as a yellow oil. used directly in the next reaction.

Step 5: At 0°C, tert-butyl bromoacetate (249.38 mg, 1.28 mmol, 188.92 μL) was added to a mixture of compound 65-5 (240 mg, 639.25 μmol) and triethylamine (129.37 mg, 1.28 mmol, 177.95 μL). The solution in tetrahydrofuran (4 mL) was stirred at room temperature for 12 hours. Add water (20 mL) to dilute, extract with ethyl acetate (2×20 mL), combine the organic layers and dry over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was separated and purified by reverse phase column to obtain compound 65-6 (116 mg, yield 36.9%) as a yellow solid. LCMS[M+H] ⁺ 490.4.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 7.80-7.76 (m, 2H), 7.62 (dd, J=4.8, 3.2 Hz, 1H), 5.11 (dd, J=12.7 ,5.4Hz,1H),3.15(t,J＝7.3Hz,4H),2.89(ddd,J＝18.5,13.7,5.3Hz,1H),2.64–2.51(m,2H),2.27(s,3H) , 2.10–1.99 (m, 1H), 1.67 (q, J=7.3Hz, 2H), 1.64–1.53 (m, 2H), 1.40 (s, 9H).

Step 6: Trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL) was added to a solution of compound 65-6 (60 mg, 122.55 μmol) in dichloromethane (6 mL) and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated to obtain crude compound Int-65 (49 mg, yield 92.2%) as a yellow oil. used directly in the next reaction.

Intermediate 66: Preparation of Compound Int-66

Step 1: To a solution of ethylene glycol (4.17 g, 67.23 mmol, 3.76 mL) and tert-butyl 4-bromobutyrate 66-1 (5 g, 22.41 mmol) in toluene (50 mL) was added tetrabutylsulfuric acid at room temperature Ammonium hydrogen (7.61 g, 22.41 mmol) and sodium hydroxide (3.59 g, 89.64 mmol) were stirred at room temperature for 10 hours. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (2×50 mL), the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-1:1) to obtain compound 66-2 (280 mg, yield 6.1%) as a colorless oil.

¹ H NMR(400MHz, Chloroform-d)δ3.74-3.66(m,2H),3.56-3.45(m,4H),2.35-2.23(m,3H),1.93-1.81(m,2H),1.43( s, 9H).

Step 2: Under nitrogen protection, methanesulfonyl chloride (0.154g, 1.34mmol, 104.05μL) was added to compound 66-2 (250mg, 1.22mmol) and triethylamine (371.54mg, 3.67mmol, 511.06μL) at 0°C solution in anhydrous dichloromethane (10 mL), then stirred at room temperature for 0.5 h. After the reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate solution (20 mL) at 0°C, extracted with ethyl acetate (2×20 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude compound 66-3 (340 mg, crude) as a colorless oil. used directly in the next reaction.

Step 3: To a solution of compound 66-3 (233.43 mg, 826.75 μmol) in anhydrous acetonitrile (2 mL) was added cesium carbonate (404.06 mg, 1.24 mmol) and 4-mercapto-1,3-dioxo-2- (2,6-Dioxopiperidin-3-yl)-isoindoline Int-42 (120 mg, 413.37 μmol), heated and stirred at 50° C. for 3 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by reverse phase column to obtain compound 66-4 (30 mg, yield 15.2%) as a white solid. LCMS[M+Na] ⁺ 499.9.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 7.84-7.73 (m, 2H), 7.67-7.59 (m, 1H), 5.11 (dd, J=12.7, 5.4Hz, 1H ),3.66(t,J＝6.2Hz,2H),3.42(t,J＝6.3Hz,4H),2.95-2.83(m,1H),2.65-2.53(m,2H),2.21(t,J＝ 7.5Hz, 2H), 2.10–2.01 (m, 1H), 1.69 (p, J=6.9Hz, 2H), 1.38 (s, 9H).

Step 4: Trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL) was added to a solution of compound 66-4 (30 mg, 62.95 μmol) in anhydrous dichloromethane (6 mL) at room temperature, and stirred at room temperature for 2 hours. After the completion of the reaction, the reaction solution was concentrated to obtain the crude compound Int-66 (45 mg) as a yellow oil. used directly in the next reaction. LCMS[M+H] ⁺ 420.9.

Intermediate 67: Preparation of Compound Int-67

Step 1: A solution of 4-acetylphenylacetic acid 67-1 (500 mg, 2.81 mmol) in dimethyl sulfoxide (5 mL) was added to the enzyme CD-ATA-141 (500 mg), isopropylamine salt, at 15°C acid salt (2.68g, 28.06mmol) and (4-formyl-5-hydroxy-6-methylpyridin-3-yl)methyl phosphate dihydrogen hydrate (pyridoxal 5-phosphate) (25.00mg, 101.16 μmol) buffer solution (50 mL, 0.1 M triethanolamine solution pH=8.5), then adjusted with 1 M sodium hydroxide solution to pH=7.0-8.5, and stirred at 45° C. for 40 hours. After the completion of the reaction, the reaction solution was diluted with water (20 mL), filtered, and the filtrate was lyophilized to obtain a crude product. The crude product was separated and purified by reverse phase column to obtain compound 67-2 (192 mg, yield 38.4%) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.39 (d, J=7.6 Hz, 2H), 7.29 (d, J=7.3 Hz, 2H), 4.36-4.28 (m, 1H), 3.56 (s, 2H), 1.45 (d, J=6.3Hz, 3H).

Step 2: Compound 67-2 (155.59 mg, 868.15 μmol), 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7-2 (0.218 g, 789.23 μmol) and N,N-diisopropylethylamine (306.01 mg, 2.37 mmol, 412.41 μL) were added to a solution of N-methylpyrrolidone (3 mL) and heated at 110 °C with microwave Stir for 2 hours. After the reaction was completed, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (2×20 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was separated and purified by reverse phase column to obtain compound Int-67 (70 mg, yield 20.4%) as a yellow solid. LCMS[M+Na] ⁺ 458.2.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.11(s, 1H), 7.53-7.43(m, 1H), 7.35(d, J=7.9Hz, 2H), 7.25-7.18(m, 2H), 7.02(d,J＝7.1Hz,1H),6.88(dd,J＝8.6,4.2Hz,1H),6.68(dd,J＝7.6,2.2Hz,1H),5.07(dd,J＝12.8,5.4Hz ,1H),4.82(p,J＝6.1Hz,1H),3.52(s,2H),2.95–2.83(m,1H),2.64–2.52(m,2H),2.09–2.01(m,1H), 1.52 (d, J=6.7 Hz, 3H).

Intermediate 68: Preparation of Compound Int-68

Step 1: tert-Butyllithium (1.3 M, 9.0 mL) was slowly added dropwise to nitrogen protected 4-chlorofuro[3,2-c]pyridine 68-1 (1.5 g, 9.77 mmol) at -78 °C ) solution in anhydrous tetrahydrofuran (10 mL), stirred at -78 °C for 10 minutes, then added dropwise a solution of nicotinaldehyde (1.05 g, 9.77 mmol) in anhydrous tetrahydrofuran (8 mL), and stirred at -78 °C for 15 minutes after dropping, and naturally Warm to room temperature and continue stirring for 1 hour. After completion of the reaction, the reaction was quenched with saturated NH ₄ Cl solution (10 mL), then extracted with ethyl acetate (2×30 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-0:1) to obtain compound 68-2 (2.3 g, yield 90.3%) as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.69 (d, J=2.3Hz, 1H), 8.53 (dd, J=4.8, 1.7Hz, 1H), 8.25 (d, J=5.7Hz, 1H) ,7.86(dt,J＝8.1,2.1Hz,1H),7.69(dd,J＝5.7,1.0Hz,1H),7.41(ddd,J＝7.9,4.8,0.9Hz,1H),6.88(t,J = 1.0 Hz, 1H), 6.66 (d, J=5.0 Hz, 1H), 6.04 (d, J=5.0 Hz, 1H). LCMS[M+H] ⁺ 261.1.

Step 2: Zinc powder (1.87 g, 28.60 mmol) was added to a solution of compound 68-2 (1.2 g, 4.60 mmol) in glacial acetic acid (20 mL), and the reaction was stirred at 120° C. for 4 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=3:1-0:1) to obtain compound 68-3 (0.204 g, yield 19.6%) as a yellow oil. LCMS[M+H] ⁺ 227.1.

Subsequent steps 3-6, using a method similar to the preparation of intermediate 36, gave compound Int-68 as a yellow solid. used directly in the next reaction. LCMS[M+H] ⁺ 226.2.

Intermediate 69: Preparation of Compound Int-69

In a similar manner to the preparation of intermediate 61, by using 3-butyn-1-amine as starting material, compound Int-69 was obtained. LCMS[M+H] ⁺ 326.0.

Intermediate 70: Preparation of Compound Int-70

In a similar manner to the preparation of intermediate 60, by using 3-azidopropionic acid as starting material, compound Int-70 was obtained. LCMS[M+H] ⁺ 322.0.

Intermediate 71: Preparation of compound Int-71

Step 1: Dissolve methyl 2-(5-bromo-2-pyridyl)acetate 71-1 (0.6 g, 2.61 mmol) in anhydrous methanol (10 mL) solution, add lithium hydroxide monohydrate (0.11 g, 2.62 mmol) aqueous solution (1 mL), heated and stirred at 50°C for 1 hour. After the reaction was completed, it was cooled to room temperature, 1M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 3, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was slurried with acetone (50 mL) to obtain compound 71-2 (0.49 g, yield 86.1%) as a yellow solid. LCMS[M+H] ⁺ 216.1.

Step 2: Compound 71-2 (444.4 mg, 2.04 mmol), benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 (456.7 mg, 2.04 mmol), O-(7-aza Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (851.87 mg, 2.24 mmol) and N,N-diisopropylethylamine (789.70 mg, 6.11 mmol, 1.06 mL) was dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature for 2 hours. After the reaction, water (50 mL) was added to dilute, and then extracted with ethyl acetate (2×50 mL). The combined organic phase was washed with saturated brine (80 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Get crude. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=5:1 to 1:1) to obtain compound 71-3 (0.83 g, yield 93.6%) as a brown oil. LCMS[M+H] ⁺ 422.2.

Step 3: Compound 71-3 (0.6 g, 1.42 mmol), (((tert-butoxycarbonyl)amino)methyl)potassium trifluoroborate (673.69 mg, 2.84 mmol), 2-dicyclohexylphosphine-2, 6-Dimethoxybiphenyl (SPhos, 291.66 mg, 710.44 μmol), palladium acetate (31.90 mg, 142.09 μmol) and cesium carbonate (1.39 g, 4.26 mmol) were dissolved in 1,4-dioxane (30 mL) The mixed solution with water (8 mL) was heated and stirred at 100° C. for 36 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, the reaction solution was filtered, the filtrate was extracted with ethyl acetate (2×50 mL), the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=3:1 to 0:1) to obtain compound 71-4 (0.193 g, yield 28.8%) as a brown oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.39 (d, J=8.1 Hz, 1H), 8.66 (d, J=2.3 Hz, 1H), 8.53 (dd, J=4.8, 1.6 Hz, 1H) ,8.35(d,J＝2.3Hz,1H),7.83(dt,J＝7.6,2.0Hz,1H),7.64-7.50(m,3H),7.46-7.40(m,2H),7.31-7.20(m ,3H),6.72(t,J＝1.1Hz,1H),6.37(d,J＝8.1Hz,1H),4.11(d,J＝6.2Hz,2H),3.76(s,2H),1.38(s , 9H).

Step 4: Trifluoroacetic acid (770.0 mg, 6.75 mmol, 0.5 mL) was added to a solution of compound 71-4 (0.19 g, 402.09 μmol) in anhydrous dichloromethane (3 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and then saturated sodium bicarbonate solution was added to adjust the pH to 9, and then dichloromethane (2×10 mL) was added for extraction. The combined organic phases were washed with saturated brine (10 mL). Dry over sodium sulfate. Filtration and concentration of the filtrate gave compound Int-71 (0.13 g, yield 86.8%) as a brown oil. used directly in the next reaction. LCMS[M+H] ⁺ 373.3.

Intermediate 72: Preparation of Compound Int-72

Step 1: Under nitrogen protection, compound 58-4 (500 mg, 2.31 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborane (334.33 mg, 2.61 mmol, 379.06 μL), a mixed solution of bis(cyclopentadienyl)zirconium hydride chloride (61.71 mg, 231.19 μmol) and triethylamine (23.39 mg, 231.19 μmol, 32.18 μL) was heated and stirred at 70° C. for 12 hours. After the reaction was completed, the reaction mixture was diluted with water (10 mL), then extracted with ethyl acetate (2×10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=50:1 to 1:1) to obtain compound 72-1 (446 mg, yield 56.0%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ7.56-7.49(m, 2H), 7.33-7.21(m, 3H), 6.11(d, J=18.4Hz, 1H), 3.56(s, 2H), 1.39(s, 9H), 1.24(s, 12H).

Step 2: Under nitrogen protection, compound 72-1 (245.07 mg, 711.90 μmol), 4-bromo-1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)- Isoindoline 1-3 (200 mg, 593.25 μmol) and potassium carbonate (245.97 mg, 1.78 mmol) were added to a mixed solution of dioxane (5 mL) and water (1 mL), followed by bis(triphenylene) phosphine) palladium(II) dichloride (41.64 mg, 59.33 μmol), heated and stirred at 80° C. for 2 hours. The reaction was completed by TLC. The reaction mixture was diluted with water (30 mL), then extracted with ethyl acetate (2×30 mL). The organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude compound 72-2 (394 mg) as a yellow solid. used directly in the next reaction.

Step 3: Trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL) was added to a solution of compound 72-2 (200 mg, 421.49 μmol) in anhydrous dichloromethane (6 mL), and stirred at room temperature for 2 hours. TLC detected that the reaction was complete, and the reaction mixture was concentrated to obtain the crude compound Int-72 (264 mg) as a yellow oil. used directly in the next reaction.

Intermediate 73: Preparation of Compound Int-73

Step 1: Tetrakis(triphenylphosphine)palladium (1.91 g, 1.65 mmol) was added to methyl 2-(6-bromo-3-pyridyl)acetate 73-1 (1.9 g, 8.26 mmol) under nitrogen protection and a solution of zinc cyanide (1.90 g, 16.18 mmol) in N,N-dimethylformamide (10 mL), heated and stirred at 120° C. for 1 hour. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=50:1 to 1:1) to obtain compound 73-2 (0.768 g, yield 52.8%) as a yellow oil.

¹ H NMR (400MHz, Chloroform-d) δ8.61 (d, J=2.2Hz, 1H), 7.80 (dd, J=7.9, 2.3Hz, 1H), 7.67 (d, J=8.0Hz, 1H), 3.73(s, 3H), 3.72(s, 2H).

Step 2: Dissolve compound 73-2 (0.668 g, 3.79 mmol) in a mixed solution of anhydrous tetrahydrofuran (5 mL) and water (0.5 mL), add lithium hydroxide monohydrate (159.12 mg, 3.79 mmol), stir at room temperature 2 hours. After the reaction was completed, dilute hydrochloric acid solution was added to adjust pH=5, and concentrated under reduced pressure to obtain crude compound 73-3 (0.614 g, yield 99.9%) as a white solid. used directly in the next reaction.

Step 3: Compound 73-3 (614 mg, 3.79 mmol) and benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 (849.21 mg, 3.79 mmol) were added to N,N-dimethyl formamide (10 mL), followed by O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (1.58 g g, 4.17 mmol) and N,N-diisopropylethylamine (1.47 g, 11.36 mmol, 1.98 mL), and stirred at room temperature for 2 hours. After the reaction, the reaction solution was filtered, the filter cake was washed with ethyl acetate (3×10 mL), and the filtrate was concentrated to obtain the crude product. The crude product was separated and purified by reverse phase column to obtain compound 73-4 (800 mg, yield 57.4%) as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.50(d, J=8.0Hz, 1H), 8.72(s, 1H), 8.66(s, 1H), 8.64-8.58(m, 1H), 8.02- 7.92 (m, 3H), 7.61 (d, J=7.5Hz, 1H), 7.59–7.52 (m, 2H), 7.33–7.28 (m, 1H), 7.24 (t, J=7.4Hz, 1H), 6.73 (s, 1H), 6.42 (d, J=7.9 Hz, 1H), 3.80 (s, 2H).

Step 4: Under nitrogen protection, Raney nickel (300 mg) was added to compound 73-4 (300 mg, 814.36 μmol) and 25% ammonia water (1.09 g, 7.79 mmol, 1.20 mL) in anhydrous methanol solution (10 mL), After three hydrogen replacements, the mixture was stirred at room temperature for 6 hours under 15 psi of hydrogen. After the reaction was completed, filtered, the filter cake was washed twice with methanol (2×5 mL), and the filtrate was concentrated to obtain the crude compound Int-73 (277 mg) as a yellow oil. used directly in the next reaction. LCMS[M+H] ⁺ 373.2.

Intermediate 74: Preparation of Compound Int-74

Step 1: To a solution of compound 4-cyanophenylacetate 74-1 (0.5 g, 2.64 mmol) in N,N-dimethylformamide (10 mL) at 0°C, sodium hydride (116.26 mg) was added in portions. , 2.91 mmol, 60% purity), and then slowly dropwise added iodomethane (393.83 mg, 2.77 mmol, 172.73 μL), naturally warmed to room temperature, and stirred for 1 hour. After the reaction, water (50 mL) was added at 0°C to quench the reaction solution, then extracted with ethyl acetate (2×50 mL), the combined organic phases were washed with saturated brine (3×50 mL), and anhydrous sodium sulfate dry. Filtration and concentration of the filtrate gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=100:1 to 5:1) to obtain compound 74-2 (0.46 g, yield 85.6%) as colorless transparent oil .

¹ H NMR(400MHz, Chloroform-d)δ7.63-7.58(m,2H),7.43-7.39(m,2H),4.14-4.08(m,2H),3.75(q,J=7.2Hz,1H) , 1.50 (d, J=7.2 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H).

Step 2: Compound 74-2 (0.4 g, 1.97 mmol) was dissolved in tetrahydrofuran (4 mL), and an aqueous solution (4 mL) of sodium hydroxide (196.80 mg, 4.92 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, dilute acetic acid solution was added to adjust pH=4, then extracted with ethyl acetate (2×20 mL), the combined organic phases were washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude compound 74-3 (0.26 g) as a colorless transparent oil.

¹ H NMR (400MHz, DMSO-d ₆ )δ12.43(brs,1H),7.82-7.77(m,2H),7.52-7.47(m,2H),3.82(q,J=7.1Hz,1H), 1.38 (d, J=7.1 Hz, 3H).

Step 3: Compound 74-3 (0.26 g, 1.48 mmol), benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 (332.83 mg, 1.48 mmol), O-(7-aza Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (620.75 mg, 1.63 mmol) and N,N-diisopropylethylamine (575.45 mg, 4.45 mmol, 775.54 μL) was added to N,N-dimethylformamide (6 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (2×30 mL), the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was separated and purified by a normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=100:1 to 0:1) to obtain two groups of isomer compounds 74-4A (300 mg, yield 53.0%) and 74 -4B (250 mg, yield 44.2%), all were brown oil. Stereo configuration not determined.

74-4A: LCMS[M+H] ⁺ 382.1. t _R =0.543min.(

EVO C18 column, 2.1×30mm, 5μm, column temperature 40℃, mobile phase A: water (containing 0.0375% TFA), mobile phase B: acetonitrile (containing 0.01875% TFA), A%: 95%-5%, flow rate 1.5 mL/min, method duration 1.2min)

74-4B: LCMS[M+H] ⁺ 382.2. t _R =0.539min.(

Step 4: Under nitrogen protection, Raney nickel (0.3 g) was added to a solution of compound 74-4A (0.23 g, 603.00 μmol) and ammonia (1.40 g, 11.94 mmol, 1.53 mL, 30% purity) in methanol (3 mL) After three hydrogen replacements in the medium, the mixture was stirred at room temperature for 6 hours under 15 psi of hydrogen. After the reaction, filtered, the filter cake was washed twice with methanol (2×5 mL), and the filtrate was concentrated to obtain crude compound Int-74 (0.13 g, yield 55.9%) as a brown oil. used directly in the next reaction. LCMS[M+H] ⁺ 386.2.

Intermediate 75: Preparation of Compound Int-75

Under nitrogen protection, Raney nickel (0.3 g) was added to a solution of compound 74-4B (0.27 g, 707.87 μmol) and ammonia (1.64 g, 14.02 mmol, 1.80 mL, 30% purity) in methanol (3 mL), hydrogen After three displacements, it was stirred at room temperature for 6 hours under 15 psi of hydrogen. After the reaction, filtered, the filter cake was washed twice with methanol (2×5 mL), and the filtrate was concentrated to obtain crude compound Int-75 (0.21 g, yield 77.0%) as a brown oil. used directly in the next reaction. LCMS[M+H] ⁺ 386.1.

Intermediate 76: Preparation of Compound Int-76

step 1:

At -78 °C, n-butyllithium (2.5M, 1.78 mL) was slowly added dropwise to a nitrogen-protected solution of benzofuran (0.5 g, 4.23 mmol) in anhydrous tetrahydrofuran (10 mL), and stirred at -78 °C for 30 minutes, then add dropwise a solution of pyrimidine-2-carboxylate methyl ester 76-1 (584.61 mg, 4.23 mmol) in anhydrous tetrahydrofuran (2 mL), after dropping at -78 °C, stir for 15 minutes, naturally warm to room temperature, and continue to stir for 2 Hour. After the completion of the reaction, the reaction was quenched with saturated NH ₄ Cl solution (20 mL) at 0°C, then extracted with ethyl acetate (2×50 mL), the combined organic phases were washed with saturated brine (2×50 mL), and anhydrous sulfuric acid Sodium dry. Filtration and concentration of the filtrate gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=100:1-1:1) to obtain compound 76-2 (0.41 g, yield 43.2%) as a light brown solid. LCMS[M+H] ⁺ 225.1.

Subsequent steps 2-4 were carried out in a similar manner to the preparation of intermediate 37 to obtain crude compound Int-76 as a brown oil. LCMS[M- _NH2 ] ⁺ 209.3.

Intermediate 77: Preparation of Compound Int-77

step 1:

At -30°C, n-butyllithium (2.5M, 8.21 mL) was slowly added dropwise to a nitrogen-protected solution of 2,2,6,6-tetramethylpiperidine (2.90 g, 20.54 mmol, 3.49 mL) A solution of water in tetrahydrofuran (12 mL) was stirred at 0°C for 30 minutes. The temperature was lowered to -78°C, and a solution of pyridazine (1.97 g, 24.64 mmol) in anhydrous tetrahydrofuran (3 mL) and a solution of benzofuran-2-carbaldehyde 77-1 (3 g, 20.53 mmol, 2.48 mL) in anhydrous tetrahydrofuran were successively added dropwise. (3 mL) solution, and stirred at -78°C for 4 hours after completion of dropping. After the reaction was completed, the reaction was quenched with saturated NH ₄ Cl solution (30 mL) at 0° C., then extracted with ethyl acetate (2×30 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=50:1-1:1) to obtain compound 77-2 (1.72 g, yield 37.0%) as a yellow oil. LCMS[M+H] ⁺ 227.2.

Subsequent steps 2-5 were carried out in a similar manner to the preparation of intermediate 37 to obtain compound Int-77 as a yellow oil. LCMS[M- _NH2 ] ⁺ 209.1.

Intermediate 78: Preparation of Compound Int-78

Step 1: At room temperature, compound 2-[3-(hydroxymethyl)-1-bicyclo[1.1.1]pentyl]acetate tert-butyl ester 78-1 (50 mg, 235.53 μmol), 4-dimethylaminopyridine (1.44mg, 11.78μmol) and triethylamine (71.50mg, 706.60μmol, 98.35μL) were dissolved in anhydrous dichloromethane (4mL), then added p-toluenesulfonyl chloride (67.36mg, 353.30μmol), and stirred at room temperature for 12 Hour. After the reaction was completed, water (10 mL) was added to dilute, and dichloromethane (2×10 mL) was used for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude compound 78-2 (84 mg) as a yellow oil. used directly in the next reaction. LCMS[M+Na] ⁺ 389.2.

Step 2: Sodium azide (17.88 mg, 275.06 μmol) was added to a solution of compound 78-2 (84 mg, 229.21 μmol) in N,N-dimethylformamide (4 mL), and stirred at 60° C. for 12 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude compound 78-3 (150 mg), which was directly used in the next reaction.

Step 3: Under argon protection, wet palladium/carbon (100 mg, 10% Pd/C) was added to a solution of compound 78-3 (150 mg, 632.12 μmol) in methanol (3 mL), and after hydrogen replacement three times, 50 psi hydrogen was stirred at room temperature for 12 hours. After the reaction was completed, filtered, the filter cake was washed three times with methanol (3×15 mL), the filtrates were combined and concentrated under reduced pressure to obtain the crude compound 78-4 (110 mg) as a yellow oil. used directly in the next reaction.

Step 4: At room temperature, compound 78-4 (110 mg, 520.59 μmol), 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisodihydro Indole 7-2 (143.80 mg, 520.59 μmol) and N,N-diisopropylethylamine (134.56 mg, 1.04 mmol, 181.35 μL) were dissolved in dimethyl sulfoxide (2 mL) and heated at 130°C in microwave for 2 Hour. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was purified by reverse-phase preparative HPLC to give compound 78-5 (83 mg, 34.1% yield) as a yellow solid. LCMS[Mt-Bu+H] ⁺ 411.9.

Step 5: Compound 78-5 (83 mg, 177.54 μmol) was dissolved in dichloromethane (6 mL), then trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain crude compound Int-78 (32 mg, yield 43.8%). used directly in the next reaction.

Intermediate 79: Preparation of Compound Int-79

In a similar manner to the preparation of intermediate 37, by using thieno[2,3-b]pyridine as starting material, compound Int-79 was obtained. used directly in the next reaction.

Intermediate 80: Preparation of Compound Int-80

Step 1: At -78°C, n-butyllithium (2.5M, 71.11 mL) was slowly added dropwise to a nitrogen-protected solution of benzofuran (20 g, 169.30 mmol) in anhydrous tetrahydrofuran (200 mL). Warm to room temperature. After stirring for 30 minutes, the temperature was lowered to -78 °C again, and the solution of nicotinaldehyde 80-1 (18.13 g, 169.30 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise. Stir for 3 hours. After the reaction was complete, the reaction was quenched with saturated _NH4Cl solution (50 mL) at 0 °C. Diluted with water (100 mL), extracted with ethyl acetate (3×200 mL), combined organic phases and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude compound 80-2 (38 g, yield 99.6%) as a yellow oil. LCMS[M+H] ⁺ 226.0.

Step 2: Compound 80-2 (33 g, 146.51 mmol) was added to thionyl chloride (165 mL) at room temperature under nitrogen protection, and heated and stirred at 50° C. for 1 hour. Cooled to room temperature, concentrated under reduced pressure, the crude product was dissolved in dichloromethane (200 mL), and concentrated to dryness again. After repeating twice, crude compound 80-3 (35.7 g, yield 99.9%) was obtained as a yellow solid.

Step 3: Compound 80-3 (0.3 g, 1.23 mmol) was dissolved in tetrahydrofuran (5 mL), 30% aqueous methylamine solution (1.3 g, 12.6 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction, 1M hydrochloric acid solution was added to quench the reaction, water (20 mL) was added to dilute, and ethyl acetate (2×20 mL) was added for extraction. The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude compound Int-80 (0.235 g, yield 80.1%) as a brown oil. used directly in the next reaction. LCMS[M+H] ⁺ 239.3.

Intermediate 81: Preparation of Compound Int-81

Step 1: At -78°C, n-butyllithium (2.5M, 4.23mL) was slowly added dropwise to a nitrogen-protected solution of furan (653.87mg, 9.61mmol) in anhydrous tetrahydrofuran (15mL), stirred for 30 minutes , add dropwise a solution of 3-cyanopyridine 81-1 (1.00 g, 9.61 mmol) in anhydrous tetrahydrofuran (5 mL), stir at -78°C for 15 minutes after dropping, and then naturally warm to room temperature and continue stirring for 1 hour. After the completion of the reaction, the reaction was quenched with saturated NH ₄ Cl solution (10 mL) at 0°C, then the reaction solution was adjusted to pH=3 with 6M hydrochloric acid solution, extracted with ethyl acetate (3×30 mL), and the organic phases were combined, no Dry over sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was separated and purified by reverse phase column to obtain compound 81-2 (133 mg, yield 8.0%) as a yellow solid. LCMS[M+H] ⁺ 174.2.

Subsequent steps 2-4 were carried out in a similar manner to the preparation of intermediate 37 to obtain compound Int-81 as a yellow oil.

Intermediate 82: Preparation of Compound Int-82

Compounds 2-azidoacetic acid (71 mg, 702.55 μmol), Int-61 (170 mg, 540.43 μmol), sodium ascorbate (42.82 mg, 216.17 μmol) and copper sulfate pentahydrate (17.25 mg, 108.09 μmol) were added to tetrahydrofuran ( 1 mL), a mixed solution of tert-butanol (1 mL) and water (1 mL), and stirred at room temperature for 10 hours under nitrogen protection. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (2×10 mL), the organic layer was washed with saturated brine (2×10 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude compound Int-82 (300 mg) as a yellow solid. used directly in the next reaction.

Intermediate 83: Preparation of Compound Int-83

Step 1: tert-Butyl bromoacetate (1.26 g, 6.45 mmol), 1H-pyrazole-4-carbonitrile 83-1 (0.5 g, 5.37 mmol) and potassium carbonate (1.48 g, 10.74 mmol) were added to N,N - dimethylformamide (4 mL), stirred at room temperature for 3 hours. After the reaction, water (20 mL) was added to dilute the reaction solution, extracted with ethyl acetate (2×20 mL), the combined organic phases were washed with saturated brine (3×20 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude compound 83-2 (1.45 g) as a yellow liquid.

¹ H NMR (400 MHz, Chloroform-d) δ 7.92 (s, 1H), 7.81 (s, 1H), 4.84 (s, 2H), 1.47 (s, 9H).

Step 2: Under nitrogen protection, Raney nickel (0.8 g) was added to a solution of compound 83-2 (1.0 g, 4.83 mmol) and 30% ammonia water (2.25 g, 19.30 mmol, 2.48 mL) in methanol (6 mL), After three hydrogen replacements, it was stirred at room temperature for 6 hours under 15 psi of hydrogen. After the reaction was completed, filtered, the filter cake was washed twice with methanol (2×5 mL), and the filtrate was concentrated to obtain crude compound 83-3 (0.6 g) as a blue oil. used directly in the next reaction.

Step 3: Compound 83-3 (0.3 g, 1.42 mmol), 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7-2 (326.87 mg, 1.18 mmol) and N,N-diisopropylethylamine (305.89 mg, 2.37 mmol, 412.25 μL) were dissolved in dimethyl sulfoxide (2 mL), and stirred at 130°C with microwave heating for 2 hours . After completion of the reaction, water (10 mL) was added to dilute, extracted with ethyl acetate (2×10 mL), the combined organic phases were washed with saturated brine (2×10 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was separated and purified by normal phase silica gel column (petroleum ether:ethyl acetate (V/V)=5:1 to 1:1) to obtain compound 83-4 (0.35 g, yield 63.4%) as a green solid. LCMS[M+H] ⁺ 468.4.

Step 4: Compound 83-4 (0.35 g, 748 μmol) was dissolved in anhydrous dichloromethane (5 mL), trifluoroacetic acid (1.85 g, 16.21 mmol, 1.2 mL) was slowly added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain the crude compound Int-83 (0.48 g) as a green oil. used directly in the next reaction.

Intermediate 85: Preparation of Compound Int-85

Using compound 1H-pyrazole-3-carbonitrile as the initial raw material, compound Int-85 was prepared according to the method of compound Int-83, LCMS: m/z=412.1 (M+H) ⁺ .

Intermediate 86: Preparation of Compound Int-86

Step 1: Using 2-azidoacetic acid (92-1) and propargyl alcohol (92A) as raw materials and aqueous ethanol solution as solvent, the crude product of compound 92-2 was prepared with reference to the method of compound Int-82, which was directly used in the next step reaction.

Step 2: Compound 92-3 was prepared by using compound 92-2 as a raw material according to the method of compound Int-60, LCMS: m/z=364.0 (M+H) ⁺ .

Step 3: Compound Int-86 was prepared by using compound 92-3 as raw material according to the method of compound 43-1, LCMS: m/z=442.4 (M+H) ⁺ .

Intermediate 84.1: Preparation of Compound Int-84.1

Using compound 92-2 and compound Int-54 as raw materials, referring to step 2 and step 3 of Int-86, compound Int-84.1 was prepared, LCMS: m/z=458.3 (M+H) ⁺ .

Intermediate 87: Preparation of Compound Int-87

Using compound 98-1 as the starting material, compound Int-87 was prepared according to the method of compound Int-83, LCMS: m/z=412.1 (M+H) ⁺ .

Intermediate 88: Preparation of Compound Int-88

Step 1: Compound 97-2 was prepared by using compound 97-1 and compound a as raw materials according to the method of compound 83-2, LCMS: m/z=179.0 (M+H) ⁺ .

Step 2, Step 3, Step 4: Using Compound 97-2 as raw material, referring to Step 2, Step 3 and Step 4 of Compound Int-73 to prepare Compound Int-97, LCMS: m/z=343.9 (M-NH ₂ ) ⁺ .

Intermediate 89: Preparation of Compound Int-89

Compound Int-89 was prepared by using compound Int-40 and compound 92-2 as raw materials according to the method of compound Int-47, LCMS: m/z=443.1 (M+H) ⁺ .

Intermediate 111-4: Preparation of Compound 111-4

Step 1: Using compound 111-1 and compound 111-1-a as raw materials, compound 111-2 was prepared according to the method of compound Int-45, the reaction solution was concentrated under reduced pressure and purified by column chromatography (silica, PE:EA =3:1～0:1) to obtain compound 111-2.

Step 2: Compound 111-2 (800 mg, 2.64 mmol) was dissolved in dichloromethane (5 mL), then methoxycarbonyl-(triethylammonium)sulfonyl-azide (942.82 mg, 3.96 mmol) was added, and the mixture was Stir at 25°C for 12h. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by column chromatography (silica, PE:EA=5:1-0:1) to obtain compound 111-3 (370 mg, 1.30 mmol) as a butter. LCMS: m/z=230.1 (M-55) ⁺ .

Step 3: Compound 111-4 was prepared by referring to compound Int-15 in step 2 using compound 111-3 as raw material, LCMS: m/z=258.1 (M+H) ⁺ .

Intermediate 90: Preparation of Compound Int-90

Using compound 111-4 as raw material, compound Int-90 was prepared by referring to the method of compound Int-44, LCMS: m/z=364.1 (M+H) ⁺ .

Intermediate 93: Preparation of Compound Int-93

Step 1: Compound 148-2 was prepared by referring to the method of compound 83-2 using compound 148-1 and tert-butyl bromoacetate as raw materials, LCMS: m/z=155.1 (M-55) ⁺ .

Step 2: Compound 148-2 (700 mg, 3.33 mmol) and lenalidomide (863.26 mg, 3.33 mmol) were added to dichloromethane (7 mL) at 20°C, and acetic acid (12.25 mmol, 700.80 uL) was added and sodium borohydride acetate (2.82 g, 13.32 mmol), and the reaction was stirred for 2 hours. After the reaction, the reaction solution was filtered, the filtrate was concentrated, purified by reverse-phase preparation (formic acid system) and freeze-dried to obtain a white solid compound 148-3 (120 mg, 264.61 umol), LCMS: m/z=454.3 (M+H ) ⁺ .

Step 3: Using compound 148-3 as a raw material, referring to step 4 of compound Int-83, compound Int-93 was prepared, LCMS: m/z=398.1 (M+H) ⁺ .

Intermediate 112-2: Preparation of Compound 112-2

Step 1: Lawson's reagent (13.5 g, 33.38 mmol) was added to a solution of compound 111-2 (4.50 g, 14.84 mmol) in tetrahydrofuran (250 mL) at 25 °C, then the reaction was stirred at 50 °C for 12 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica, PE:EA=20:1-1:1) to obtain compound 112-1 (900 mg, 2.99 mmol) as a butter. LCMS: m/z=302.1 (M+H) ⁺ .

Step 2: Using compound 112-1 as a raw material, referring to compound Int-15 in step 2 to prepare compound 112-2, LCMS: m/z=274.1 (M+H) ⁺ .

Intermediate 94: Preparation of Compound Int-94

Using compound 112-2 as a raw material, compound Int-94 was prepared according to the method of compound Int-44, LCMS: m/z=380.1 (M+1) ⁺ .

Intermediate 95: Preparation of Compound Int-95

Using compound 149-1 as a raw material, referring to step 2, step 3 and step 4 of compound Int-83, compound Int-95 was prepared, LCMS: m/z=412.2 (M+H) ⁺ .

Intermediate 96: Preparation of Compound Int-96

Step 1: Di-tert-butyl dicarbonate (1.16 g, 5.30 mmol, 1.22 mL) and sodium hydroxide solution (4 M, 1.32 mL) were added to a solution of compound 134-1 (500 mg, 5.05 mmol) in water (5 mL), The reaction was stirred at 25°C for 2 hours. After the reaction, the reaction mixture was cooled to 0° C., adjusted to pH=4 with 1M dilute hydrochloric acid, a large amount of solid was precipitated, and the white solid compound 134-2 (600 mg, 3.01 mmol) was obtained after filtration. LC-MS: m/z=222.2(M+23) ⁺ .

Step 2, Step 3: Compound 134-4 was prepared by using compound 134-2 as a raw material according to the method of compound Int-15, LCMS: m/z=202.1 (M+H-56) ⁺ .

Intermediate 96: Preparation of Compound Int-96

Using compound 134-2 as a raw material, compound Int-96 was prepared according to the method of compound Int-44, LCMS: m/z=364.1 (M+H) ⁺ .

Example 1: Synthesis of compound HJM-001

Compound 6-4 (0.22 g, 1.0 mmol), Int-1 (0.40 g, 1.0 mmol), HATU (419.97 mg, 1.1 mmol) and DIPEA (389.32 mg, 3.0 mmol) were dissolved in DMF (12 mL) at room temperature was stirred at room temperature for 3 hours. After the reaction, water (10 mL) and ethyl acetate (10 mL) were added, and the mixture was extracted and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and rotated to dryness to obtain a crude product. The crude product was purified by reverse-phase preparative HPLC to give compound HJM-001 (42 mg, yield 6.9%) as a yellow solid. LCMS[M+H] ⁺ 605.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 9.01 (d, J=8.5Hz, 1H), 8.66 (d, J=2.3Hz, 1H), 8.53 (dt, J= 4.8, 1.8Hz, 1H), 7.89–7.77 (m, 4H), 7.57 (dd, J=7.6, 1.7Hz, 1H), 7.53 (d, J=8.1Hz, 1H), 7.44–7.39 (m, 1H) ), 7.30–7.19 (m, 2H), 6.61 (s, 1H), 6.44 (d, J=8.4Hz, 1H), 5.13 (dd, J=12.8, 5.4Hz, 1H), 4.10–3.99 (m, 2H), 3.67 (t, J=6.2Hz, 2H), 2.94–2.80 (m, 1H), 2.62 (t, J=7.0Hz, 2H), 2.59–2.53 (m, 1H), 2.53–2.46 (m , 1H), 2.10–1.99 (m, 1H), 1.88 (p, J=6.7Hz, 2H).

Example 2: Synthesis of compound HJM-002

Step 1: Compound 6-4 (144.9 mg, 0.65 mmol), Int-2 (258.7 mg, 0.65 mmol), HATU (270.2 mg, 0.71 mmol) and DIPEA (250.5 mg, 1.94 mmol) were dissolved in DMF at room temperature (5 mL) and stirred at room temperature for 12 hours. After the reaction was completed, water (20 mL) was added to quench, extracted twice with ethyl acetate (2×15 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and spin-dried to obtain the crude compound HJM-002-1 (390 mg, which was collected rate 99.5%), brown oil. LCMS[M+H] ⁺ 607.4.

Step 2: Under argon protection, wet palladium/carbon (400 mg, 10% Pd/C) was added to a solution of compound HJM-002-1 (340 mg, 0.56 mmol) in tetrahydrofuran (10 mL), and after hydrogen replacement three times, Stir at 40°C for 12 hours under 50 psi of hydrogen. After completion of the reaction, filter, and wash the filter cake with ethyl acetate three times (3×15 mL), the filtrates are combined, concentrated under reduced pressure and spin-dried to obtain the crude product. The crude product was purified by reverse-phase preparative HPLC to give compound HJM-002 (50 mg, yield 14.7%) as a yellow solid. LCMS[M+H] ⁺ 609.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 9.04 (d, J=8.5Hz, 1H), 8.82 (d, J=2.2Hz, 1H), 8.68 (dd, J= 5.2, 1.5Hz, 1H), 8.17 (dt, J=8.1, 1.9Hz, 1H), 7.79–7.70 (m, 2H), 7.72–7.64 (m, 2H), 7.59 (d, J=7.3Hz, 1H) ), 7.53(d, J＝8.1Hz, 1H), 7.32–7.26(m, 1H), 7.23(t, J＝7.4Hz, 1H), 6.65(s, 1H), 6.53(d, J＝8.3Hz ,1H),5.12(dd,J＝12.9,5.4Hz,1H),3.46(t,J＝6.6Hz,2H),3.01(t,J＝7.7Hz,2H),2.88(ddd,J＝17.4, 14.0, 5.4Hz, 1H), 2.65–2.49 (m, 2H), 2.09–2.01 (m, 1H), 1.65–1.54 (m, 4H), 1.37 (q, J=7.9Hz, 2H).

Example 3: Synthesis of compound HJM-003

Using a method similar to Example 1, by using 6-4 and Int-13 as starting materials, compound HJM-003 was obtained as a yellow solid. LCMS[M+H] ⁺ 611.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.02 (d, J=8.4 Hz, 1H), 8.73 (d, J=2.3 Hz, 1H), 8.60 (dd, J= 4.9,1.6Hz,1H),7.99(dt,J=8.0,2.0Hz,1H),7.78(dd,J=8.5,7.3Hz,1H),7.60-7.51(m,3H),7.49(d,J =8.6Hz,1H),7.43(d,J=7.2Hz,1H),7.28(dd,J=7.4,1.3Hz,1H),7.22(td,J=7.4,1.2Hz,1H),6.64(d , J＝1.1Hz, 1H), 6.48(d, J＝8.4Hz, 1H), 5.07(dd, J＝12.7, 5.4Hz, 1H), 4.22(t, J＝6.2Hz, 2H), 4.03(s ,2H),3.55(t,J＝6.2Hz,2H),2.87(ddd,J＝16.8,13.7,5.2Hz,1H),2.63–2.53(m,1H),2.53–2.42(m,1H), 2.06–1.96 (m, 1H), 1.88–1.69 (m, 4H).

Example 4: Synthesis of compound HJM-004

Using a method similar to Example 1, by using 6-4 and Int-3 as starting materials, compound HJM-004 was obtained as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 9.08 (d, J=8.3 Hz, 1H), 8.63 (d, J=2.3 Hz, 1H), 8.52 (dd, J= 4.8, 1.6Hz, 1H), 7.81 (dt, J=8.0, 2.0Hz, 1H), 7.77–7.70 (m, 2H), 7.68–7.62 (m, 1H), 7.56 (dd, J=7.5, 1.5Hz) ,1H),7.49(d,J＝8.1Hz,1H),7.41(dd,J＝7.9,4.8Hz,1H),7.26(td,J＝7.7,1.5Hz,1H),7.21(td,J＝ 7.4, 1.1Hz, 1H), 6.69(s, 1H), 6.39(d, J=8.2Hz, 1H), 5.12(dd, J=12.9, 5.4Hz, 1H), 3.61(t, J=6.1Hz, 2H), 3.38(td, J＝6.4, 1.9Hz, 2H), 3.01(t, J＝7.5Hz, 2H), 2.88(ddd, J＝17.4, 14.0, 5.4Hz, 1H), 2.64–2.53(m , 2H), 2.46 (d, J=6.2Hz, 2H), 2.11–1.96 (m, 1H), 1.69–1.42 (m, 4H).

LCMS[M+H] ⁺ 609.2.

Example 5: Synthesis of compound HJM-005

Using a method similar to Example 1, by using 6-4 and Int-4 as raw materials, compound HJM-005 was obtained as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.13(s, 1H), 9.14(d, J=8.2Hz, 1H), 8.67(s, 1H), 8.56(d, J=4.9Hz, 1H) ,7.89(dt,J＝8.0,1.9Hz,1H),7.85(dd,J＝5.9,2.7Hz,1H),7.83–7.77(m,2H),7.58(dd,J＝7.5,1.5Hz,1H) ), 7.53–7.46 (m, 2H), 7.26 (td, J=7.7, 1.6Hz, 1H), 7.24–7.19 (m, 1H), 6.71 (s, 1H), 6.41 (d, J=8.1Hz, 1H), 5.13(dd, J＝12.8, 5.4Hz, 1H), 3.73(t, J＝6.3Hz, 2H), 3.63(t, J＝6.8Hz, 2H), 2.95–2.80(m, 1H), 2.74(t,J＝6.9Hz,2H),2.65-2.56(m,1H),2.53(t,J＝6.3Hz,2H),2.52-2.46(m,1H),2.10-1.99(m,1H) . LCMS[M+H] ⁺ 605.4.

Example 6: Synthesis of compound HJM-006

Using a method similar to Example 1, by using 6-4 and Int-9 as starting materials, compound HJM-006 was obtained as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 9.09 (d, J=8.3 Hz, 1H), 8.62 (d, J=2.3 Hz, 1H), 8.51 (dd, J= 4.7, 1.6Hz, 1H), 7.81–7.73 (m, 2H), 7.59–7.56 (m, 1H), 7.50 (d, J=8.4Hz, 1H), 7.44–7.37 (m, 3H), 7.26 (td , J＝8.2, 1.6Hz, 1H), 7.20(t, J＝7.5Hz, 1H), 6.68(s, 1H), 6.38(d, J＝8.2Hz, 1H), 5.08(dd, J＝12.8, 5.4Hz, 1H), 4.20(t, J＝6.3Hz, 2H), 3.65(t, J＝6.1Hz, 2H), 3.57(t, J＝6.2Hz, 2H), 2.94–2.81(m, 1H) , 2.63–2.53 (m, 3H), 2.47–2.38 (m, 1H), 2.08–1.92 (m, 3H). LCMS[M+H] ⁺ 611.3.

Example 7: Synthesis of compound HJM-007

Using a method similar to Example 1, by using 6-4 and Int-8 as starting materials, compound HJM-007 was obtained as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.12 (d, J=8.3 Hz, 1H), 8.67 (d, J=2.2 Hz, 1H), 8.54 (dd, J= 4.9, 1.6Hz, 1H), 7.85 (dd, J=6.2, 4.1Hz, 1H), 7.59–7.47 (m, 3H), 7.45 (dd, J=8.0, 4.8Hz, 1H), 7.26 (td, J ＝7.7,1.6Hz,1H),7.20(td,J＝7.4,1.2Hz,1H),7.03(d,J＝8.6Hz,1H),7.00(d,J＝7.0Hz,1H),6.70(s ,1H),6.62(t,J＝5.6Hz,1H),6.42(d,J＝8.3Hz,1H),5.04(dd,J＝12.9,5.4Hz,1H),3.64(t,J＝6.2Hz ,2H),3.45(t,J＝6.1Hz,2H),3.30(q,J＝6.4Hz,2H),2.87(ddd,J＝17.3,14.0,5.4Hz,1H),2.62–2.51(m, 3H), 2.49–2.44 (m, 1H), 2.06–1.97 (m, 1H), 1.77 (p, J=6.4Hz, 2H). LCMS[M+H] ⁺ 610.2.

Example 8: Synthesis of compound HJM-008

Synthesized in a similar manner to Example 1, by using 6-4 and Int-5 as starting materials and using 0.05% hydrochloric acid as aqueous phase in preparative HPLC purification, the hydrochloride salt of compound HJM-008 was obtained as a white solid. LCMS[M+H] ⁺ 609.2.

¹ H NMR(500MHz,Methanol-d ₄ )δ8.96(s,1H),8.83(d,J=5.6Hz,1H),8.70(dd,J=8.2,1.5Hz,1H),8.12(dd, J=8.1, 5.8Hz, 1H), 7.74 (dd, J=8.5, 7.3Hz, 1H), 7.56 (d, J=7.8Hz, 1H), 7.46–7.38 (m, 3H), 7.29 (t, J =7.5Hz,1H),7.22(t,J=7.5Hz,1H),6.81-6.76(m,1H),6.61(s,1H),5.09-5.03(m,1H),4.19(td,J= 6.2, 2.5Hz, 2H), 2.87–2.77 (m, 1H), 2.74–2.64 (m, 2H), 2.43–2.35 (m, 2H), 2.12–2.06 (m, 1H), 1.86–1.78 (m, 2H), 1.75–1.67 (m, 2H), 1.59–1.51 (m, 2H), 1.46–1.37 (m, 2H).

Example 9: Synthesis of compound HJM-009

Using a method similar to Example 1, by using 6-4 and Int-11 as starting materials, compound HJM-009 was obtained as a yellow solid. LCMS[M+H] ⁺ 611.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 9.09 (d, J=8.1 Hz, 1H), 8.77 (d, J=2.2 Hz, 1H), 8.66 (dd, J= 5.2,1.6Hz,1H),8.09(dt,J＝8.0,2.0Hz,1H),7.80(dd,J＝8.5,7.2Hz,1H),7.66(dd,J＝8.0,5.0Hz,1H), 7.62-7.55(m, 1H), 7.55-7.47(m, 2H), 7.45(d, J=7.2Hz, 1H), 7.28(td, J=7.5, 1.5Hz, 1H), 7.22(td, J= 7.4, 1.2Hz, 1H), 6.69(s, 1H), 6.46(d, J=8.1Hz, 1H), 5.07(dd, J=12.9, 5.4Hz, 1H), 4.36–4.30(m, 2H), 3.77–3.71 (m, 2H), 3.50 (t, J=6.4Hz, 2H), 2.87 (ddd, J=17.2, 14.0, 5.3Hz, 1H), 2.63–2.54 (m, 1H), 2.54–2.44 ( m, 1H), 2.35–2.28 (m, 2H), 2.05–1.95 (m, 1H), 1.78 (p, J=6.9Hz, 2H).

Example 10: Synthesis of compound HJM-010

Compounds Int-15 (42 mg, 0.15 mmol), Int-17 (67 mg, 0.17 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.9 mmol) were dissolved in DMF (3 mL), HATU (68 mg) was added , 0.18 mmol), after stirring at room temperature for 3 hours. The reaction was complete as detected by LCMS and filtered. The filtrate was purified by reverse-phase preparative HPLC (acetonitrile/0.05% aqueous hydrochloric acid) to give the hydrochloride salt of compound HJM-010 (22 mg, yield 21.7%) as a yellow solid. LCMS[M+H] ⁺ 609.9.

¹ H NMR (500MHz, Methanol-d ₄ ) δ 9.26 (s, 1H), 9.02-8.93 (m, 2H), 8.19 (dd, J=8.1, 5.7Hz, 1H), 7.67 (dd, J=7.9 ,1.2Hz,1H),7.62(d,J＝8.3Hz,1H),7.54(dd,J＝8.6,7.1Hz,1H),7.41(ddd,J＝8.6,7.2,1.3Hz,1H),7.31 (t, J=7.5Hz, 1H), 7.23(s, 1H), 7.03(t, J=7.7Hz, 2H), 6.37(s, 1H), 5.04(ddd, J=12.6, 5.5, 1.2Hz, 1H), 3.97–3.86 (m, 2H), 3.34 (t, J=6.6Hz, 2H), 3.26 (td, J=6.8, 1.6Hz, 2H), 2.90–2.79 (m, 1H), 2.78–2.62 (m, 2H), 2.14–2.05 (m, 1H), 1.71–1.51 (m, 4H).

Example 11: Synthesis of compound HJM-011

Using a method similar to Example 10, by using Int-15 and Int-17 as starting materials, the hydrochloride salt of compound HJM-011 was obtained as a yellow solid. LCMS[M+H] ⁺ 610.7.

¹ H NMR(500MHz,Methanol-d ₄ )δ9.34(s,1H),9.09(d,J=8.1Hz,1H),9.03(d,J=5.5Hz,1H),8.28(dd,J= 8.2, 5.6Hz, 1H), 7.77 (t, J=7.9Hz, 1H), 7.66 (dd, J=7.8, 3.8Hz, 1H), 7.62 (d, J=8.4Hz, 1H), 7.44–7.39 ( m, 3H), 7.29(t, J=7.6Hz, 1H), 7.27(s, 1H), 6.47(s, 1H), 5.07(ddd, J=14.9, 12.6, 5.3Hz, 1H), 4.23(t , J=5.9Hz, 2H), 4.05–3.95 (m, 2H), 3.32 (t, J=7.6Hz, 2H), 2.92–2.78 (m, 1H), 2.78–2.61 (m, 2H), 2.13– 2.06 (m, 1H), 1.87 (p, J=6.4 Hz, 2H), 1.73 (p, J=6.8 Hz, 2H).

Example 12: Synthesis of compound HJM-012

Using a method similar to Example 10, by using Int-15 and Int-18 as starting materials, the hydrochloride salt of compound HJM-012 was obtained as a yellow solid. LCMS[M+H] ⁺ 608.8.

¹ H NMR(500MHz, Methanol-d ₄ )δ9.32(s,1H),9.06(d,J=8.1Hz,1H),9.02(d,J=5.4Hz,1H),8.26(dd,J= 8.1, 5.4Hz, 1H), 7.73–7.66 (m, 3H), 7.65–7.60 (m, 2H), 7.42 (t, J=7.7Hz, 1H), 7.32 (t, J=7.5Hz, 1H), 7.27(s, 1H), 6.44(s, 1H), 5.11(dd, J=12.7, 5.3Hz, 1H), 4.00–3.87(m, 2H), 3.19(t, J=6.9Hz, 2H), 3.08 (t, J=7.7Hz, 2H), 2.92–2.82 (m, 1H), 2.79–2.65 (m, 2H), 2.17–2.09 (m, 1H), 1.66 (p, J=7.4Hz, 2H), 1.52 (p, J=7.0 Hz, 2H), 1.38 (p, J=7.5 Hz, 2H).

Example 13: Synthesis of compound HJM-013

At room temperature, compound Int-19 (10.0 mg, 20.3 μmol, TFA salt), Int-20 (14.5 mg, 33.8 μmol), HATU (15.4 mg, 40.5 μmol) and DIPEA (13.1 mg, 101 μmol) were mixed and dissolved in sequence. Stir in DMF (1 mL) for 16 hours. After the reaction was detected by LCMS, it was filtered, and the filtrate was directly purified by reverse-phase preparative HPLC (acetonitrile/0.05% aqueous hydrochloric acid solution) to obtain the hydrochloride salt of compound HJM-013 (4.5 mg, yield 32.5%) as a pale yellow solid. LCMS[M+H] ⁺ 609.6.

¹ H NMR(500MHz,Methanol-d ₄ )δ8.65(d,J=2.2Hz,1H),8.45(dd,J=5.2,1.5Hz,1H),7.96(dq,J=7.9,1.8Hz, 1H), 7.50 (dd, J=7.5, 1.5Hz, 1H), 7.47 (ddd, J=8.5, 7.1, 1.7Hz, 1H), 7.41 (ddd, J=7.6, 5.0, 2.4Hz, 1H), 7.37 (d, J=8.0Hz, 1H), 7.21 (td, J=7.9, 1.5Hz, 1H), 7.17 (td, J=7.4, 1.1Hz, 1H), 7.03–6.95 (m, 2H), 6.72 ( s, 1H), 5.13 (s, 1H), 5.04 (dd, J=12.5, 5.5Hz, 1H), 3.38–3.33 (m, 4H), 2.96–2.79 (m, 3H), 2.78–2.64 (m, 2H), 2.44 (t, J=6.5Hz, 2H), 2.12–2.05 (m, 1H), 1.83 (p, J=6.7Hz, 2H).

Example 14: Synthesis of compound HJM-014

In a similar manner to Example 13, by using Int-19 and Int-21 as starting materials, the hydrochloride salt of compound HJM-014 was obtained as a white solid. LCMS: [M+H] ⁺ 610.6.

¹ H NMR(500MHz,Methanol-d ₄ )δ8.75(s,1H),8.55(s,1H),8.08(d,J=7.8Hz,1H),7.75(ddd,J=8.5,7.2,1.3 Hz, 1H), 7.59–7.53 (m, 1H), 7.53–7.44 (m, 2H), 7.44 (dd, J=7.3, 1.3Hz, 1H), 7.38 (dd, J=8.5, 1.6Hz, 1H) ,7.29(t,J＝7.7Hz,1H),7.22(t,J＝7.5Hz,1H),6.88(s,1H),5.37–5.32(m,1H),5.10(ddd,J＝12.6,5.5 ,1.9Hz,1H),4.29(t,J＝5.7Hz,2H),3.51-3.47(m,2H),2.89-2.61(m,5H),2.27(t,J＝7.4Hz,2H),2.13 -2.06(m, 3H).

Example 15: Synthesis of compound HJM-015

Compound Int-22 (16 mg, 0.044 mmol), compound Int-23 (16 mg, 0.044 mmol) and N,N-diisopropylethylamine (56 mg, 0.44 mmol) were dissolved in dichloromethane (2 mL) and N, HATU (20 mg, 0.053 mmol) was added to N-dimethylformamide (1 mL), stirred at room temperature for 3 hours, and filtered. After the filtrate was concentrated, it was purified by reverse-phase preparative HPLC (acetonitrile/0.05% aqueous hydrochloric acid) to give the hydrochloride salt of compound HJM-015 (9.6 mg, 31.8% yield) as a yellow solid. LCMS[M+H] ⁺ 609.8.

¹ H NMR(500MHz,Methanol-d ₄ )δ9.34(s,1H),9.08(d,J=8.4Hz,1H),8.99(d,J=5.7Hz,1H),8.23(dd,J= 8.3, 5.7Hz, 1H), 7.65 (d, J=7.8Hz, 1H), 7.60 (d, J=8.3Hz, 1H), 7.50 (dd, J=8.6, 7.1Hz, 1H), 7.41–7.37 ( m, 1H), 7.33–7.26 (m, 2H), 7.03 (d, J=8.6Hz, 1H), 7.01 (d, J=7.4Hz, 1H), 6.48 (d, J=3.2Hz, 1H), 5.05 (dd, J=12.8, 5.4Hz, 1H), 3.67–3.57 (m, 1H), 3.59–3.50 (m, 1H), 3.34 (t, J=6.9Hz, 2H), 3.33–3.21 (m, 2H), 2.85 (ddd, J=17.4, 13.9, 5.4Hz, 1H), 2.79–2.62 (m, 2H), 2.36 (t, J=7.2Hz, 2H), 2.14–2.05 (m, 1H), 1.92 (p, J=7.0 Hz, 2H).

Example 16: Synthesis of compound HJM-016

In a similar manner to Example 15, by using Int-22 and Int-24 as starting materials, the hydrochloride salt of compound HJM-016 was obtained as a yellow solid. LCMS[M+H] ⁺ 610.7.

¹ H NMR(500MHz,Methanol-d ₄ )δ9.32(s,1H),9.05(d,J=8.2Hz,1H),8.99(d,J=5.5Hz,1H),8.23(dd,J= 8.2, 5.6Hz, 1H), 7.76–7.72 (m, 1H), 7.66 (dt, J=7.8, 1.5Hz, 1H), 7.61 (d, J=8.4Hz, 1H), 7.45–7.36 (m, 3H) ), 7.33–7.27 (m, 2H), 6.46 (s, 1H), 5.10 (dd, J=12.7, 5.4Hz, 1H), 4.23 (t, J=5.9Hz, 2H), 3.71–3.61 (m, 1H), 3.61–3.51 (m, 1H), 3.37–3.22 (m, 2H), 2.87 (ddd, J=17.5, 14.0, 5.3Hz, 1H), 2.78–2.62 (m, 2H), 2.51 (t, J = 7.3Hz, 2H), 2.18-2.07 (m, 3H).

Example 17: Synthesis of compound HJM-017

Compound Int-25 (24.5 mg, 0.077 mmol), compound Int-26 (22 mg, 0.064 mmol) and N,N-diisopropylethylamine (50 mg, 0.38 mmol) were dissolved in N,N dimethylformamide (3 mL), HATU (30 mg, 0.077 mmol) was added, the mixture was stirred at room temperature for 3 hours, and then filtered. The filtrate was purified by reverse-phase preparative HPLC (acetonitrile/0.05% aqueous hydrochloric acid) to give compound HJM-017 as the hydrochloride salt (6.2 mg, yield 14.2%) as a yellow solid. LCMS[M+H] ⁺ 609.7.

¹ H NMR (500MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 10.54 (brs, 1H), 9.01 (d, J=2.3Hz, 1H), 8.70 (dd, J=4.9, 1.6Hz, 1H), 8.39 (dt, J=8.1, 1.9Hz, 1H), 8.16 (t, J=5.8Hz, 1H), 7.71–7.68 (m, 1H), 7.65–7.56 (m, 3H), 7.39–7.33 (m,1H),7.32–7.26(m,2H),7.12(d,J=8.5Hz,1H),7.04(d,J=7.1Hz,1H),6.67(brs,1H),6.07(s, 1H), 5.03 (dd, J=12.6, 5.5Hz, 1H), 3.50–3.47 (m, 2H), 3.14 (q, J=6.5Hz, 2H), 3.00–2.83 (m, 3H), 2.66–2.53 (m, 2H), 2.40 (t, J=6.6 Hz, 2H), 2.07-2.00 (m, 1H), 1.93 (p, J=7.1 Hz, 2H).

Example 18: Synthesis of compound HJM-018

Using a method similar to Example 17, by using Int-25 and Int-27 as starting materials, the hydrochloride salt of compound HJM-018 was obtained as a yellow solid. LCMS[M+H] ⁺ 610.6.

¹ H NMR (500MHz, DMSO-d ₆ )δ11.56-10.12(m, 2H), 9.01(s, 1H), 8.70(d, J=4.9Hz, 1H), 8.38(d, J=8.0Hz, 1H), 8.04 (t, J=5.8Hz, 1H), 7.69 (d, J=7.7Hz, 1H), 7.67–7.62 (m, 2H), 7.57 (d, J=8.3Hz, 1H), 7.38– 7.25(m, 5H), 6.07(s, 1H), 5.12(dd, J=12.8, 5.5Hz, 1H), 3.88–3.77(m, 2H), 3.09(q, J=6.5Hz, 2H), 2.99 –2.88(m,3H),2.78–2.71(m,1H),2.57–2.50(m,1H),2.24(t,J=7.8Hz,2H),2.08–2.02(m,1H),1.90(p , J=7.1Hz, 2H).

Example 19: Synthesis of compound HJM-019

Step 1: Compound benzofuran-2-yl(pyridin-3-yl)methanamine 6-4 dihydrochloride (130 mg, 0.437 mmol) and triethylamine (100 mg, 1 mmol) were dissolved in dichloromethane (5 mL) ), bromoacetyl chloride (95 mg, 0.6 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature overnight. Spin to dryness under reduced pressure, and the obtained crude product was separated and purified by normal phase silica gel column (petroleum ether/ethyl acetate, ethyl acetate%: 50%-100%) to obtain compound HJM-019-1 (105 mg, yield 69.6%), Colorless oil. LCMS[M+H] ⁺ 347.3.

Step 2: Compound Int-28 (40 mg, 0.085 mmol) and compound HJM-019-1 (28 mg, 0.081 mmol) were dissolved in N-methylpyrrolidone (3 mL), and N,N-diisopropylethylamine was added (68 μL, 0.41 mmol) and potassium iodide (18.6 mg, 0.112 mmol), the mixture was heated to 80° C., stirred for 16 hours and filtered. The filtrate was purified by reverse-phase preparative HPLC (acetonitrile/0.05% aqueous hydrochloric acid) to give the hydrochloride salt of compound HJM-019 (5.4 mg, yield 9.4%) as a yellow solid. LCMS[M+H] ⁺ 635.7.

¹ H NMR(500MHz,Methanol-d ₄ )δ9.07(s,1H),8.89(d,J=5.6Hz,1H),8.78(d,J=8.3Hz,1H),8.16(dd,J= 8.1, 5.6Hz, 1H), 7.60 (d, J=7.7Hz, 1H), 7.57 (dd, J=8.5, 7.1Hz, 1H), 7.46 (d, J=8.4Hz, 1H), 7.33 (ddd, J=8.4,7.2,1.3Hz,1H),7.26(td,J=7.6,1.0Hz,1H),7.12(d,J=8.5Hz,1H),7.07(d,J=7.0Hz,1H), 6.90(s,1H),6.73(s,1H),5.06(dd,J=12.6,5.5Hz,1H),4.16(q,J=16.1Hz,2H),3.69(dd,J=26.8,11.7Hz ,2H),3.33(d,J＝6.6Hz,2H),3.21-3.08(m,2H),2.92-2.81(m,1H),2.79-2.65(m,2H),2.16-1.99(m,4H ), 1.72–1.59 (m, 2H).

Example 20: Synthesis of Compound HJM-020

Synthesized by a method similar to Example 1, by using 6-4 and Int-29 as starting materials, and using 0.05% hydrochloric acid as aqueous phase during preparative HPLC purification, the hydrochloride salt of compound HJM-020 was obtained as a yellow solid. LCMS[M+H] ⁺ 649.8.

¹ H NMR (500MHz, Methanol-d ₄ )δ9.10(s,1H),8.89(d,J=5.7Hz,1H),8.83-8.76(m,1H),8.17(dd,J=8.2,5.7 Hz, 1H), 7.60 (dd, J=7.8, 1.2Hz, 1H), 7.54 (dd, J=8.5, 7.1Hz, 1H), 7.46 (d, J=8.3Hz, 1H), 7.36–7.29 (m ,1H),7.27–7.23(m,1H),7.05–7.01(m,2H),6.93(s,1H),6.74(s,1H),5.05(dd,J=12.7,5.5Hz,1H), 4.26–4.12 (m, 2H), 3.66 (dd, J=29.5, 11.9Hz, 2H), 3.42–3.34 (m, 2H), 3.20–3.11 (m, 2H), 2.90–2.81 (m, 1H), 2.77–2.64 (m, 2H), 2.13–2.06 (m, 1H), 2.06–2.00 (m, 2H), 1.82–1.56 (m, 5H).

Example 21: Synthesis of compound HJM-021

Using a method similar to Example 1, by using 6-4 and Int-12 as starting materials, compound HJM-021 was obtained as a yellow solid. LCMS[M+H] ⁺ 610.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.02 (d, J=8.5Hz, 1H), 8.75 (d, J=2.2Hz, 1H), 8.62 (dd, J= 4.9, 1.5Hz, 1H), 8.03 (dt, J=8.1, 1.9Hz, 1H), 7.62–7.49 (m, 4H), 7.32–7.23 (m, 1H), 7.22 (td, J=7.4, 1.1Hz) ,1H),7.08(d,J＝8.6Hz,1H),7.00(d,J＝7.0Hz,1H),6.64(d,J＝1.1Hz,1H),6.56(brs,1H),6.49(d , J=8.4Hz, 1H), 5.04 (dd, J=12.8, 5.4Hz, 1H), 4.02 (s, 2H), 3.60–3.47 (m, 2H), 3.35–3.27 (m, 2H), 2.95– 2.81 (m, 1H), 2.63–2.50 (m, 2H), 2.06–1.97 (m, 1H), 1.66–1.57 (m, 4H).

Example 22: Synthesis of compound HJM-022

Compound Int-32 (200 mg, 0.43 mmol), and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7-2 (118.69 mg, 0.43 mmol) was added to N,N-dimethylformamide (3 mL), followed by N,N-diisopropylethylamine (374.2 μL, 2.15 mmol), and reacted at 90° C. for 12 hours. The reaction mixture was diluted with water (10 mL), then extracted with ethyl acetate (3 x 10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The obtained crude product was purified by preparative HPLC to obtain compound HJM-022 (31 mg, yield 11.9%) as a yellow solid. LCMS[M+H] ⁺ 608.4.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 9.14 (d, J=8.1 Hz, 1H), 8.71 (d, J=5.5 Hz, 2H), 7.67 (d, J= 5.4Hz, 2H), 7.62–7.50 (m, 3H), 7.32–7.20 (m, 2H), 7.06 (d, J=8.6Hz, 1H), 7.02 (d, J=7.1Hz, 1H), 6.74 ( s, 1H), 6.51 (brs, 1H), 6.46 (d, J=8.1Hz, 1H), 5.04 (dd, J=12.8, 5.4Hz, 1H), 3.31–3.21 (m, 2H), 2.95–2.79 (m, 1H), 2.63–2.48 (m, 2H), 2.26 (t, J=7.4Hz, 2H), 2.06–1.98 (m, 1H), 1.61–1.50 (m, 4H), 1.40–1.25 (m , 4H).

Example 23: Synthesis of compound HJM-023

Compound 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline 7-2 (10 mg, 0.036 mmol) and compound Int-30 (22 mg, 0.037 mmol) was dissolved in N-methylpyrrolidone (2 mL), N,N-diisopropylethylamine (18 mg, 0.14 mmol) was added, and the mixture was heated to 95°C and stirred for 16 hours. After the reaction was completed, it was cooled to room temperature and filtered. The filtrate was purified by reverse-phase preparative HPLC (acetonitrile/0.05% aqueous hydrochloric acid) to give the hydrochloride salt of compound HJM-023 (13.5 mg, 57.7% yield) as a yellow solid. LCMS[M+H] ⁺ 649.7.

¹ H NMR(500MHz,Methanol-d ₄ )δ9.02(s,1H),8.88(d,J=5.6Hz,1H),8.77(d,J=8.2Hz,1H),8.18(dd,J= 8.2, 5.7Hz, 1H), 7.91–7.71 (m, 1H), 7.66–7.51 (m, 2H), 7.46 (dd, J=8.3, 3.6Hz, 1H), 7.35–7.28 (m, 1H), 7.28 –7.12(m, 2H), 6.84(s, 1H), 6.65(s, 1H), 5.07(dd, J=12.5, 5.4Hz, 1H), 4.10(t, J=5.9Hz, 1H), 3.85( t,J＝6.4Hz,1H),3.80(d,J＝12.5Hz,1H),3.67(d,J＝12.0Hz,1H),3.44(t,J＝5.9Hz,1H),3.35(t, J=6.5Hz, 1H), 3.15–3.00 (m, 2H), 2.92–2.81 (m, 1H), 2.79–2.64 (m, 2H), 2.44–2.36 (m, 2H), 2.19–1.93 (m, 4H), 1.76–1.58 (m, 2H).

Example 24: Synthesis of compound HJM-024

Synthesized by a method similar to Example 1, by using 6-4 and Int-31 as starting materials, and using 0.05% hydrochloric acid as aqueous phase during preparative HPLC purification, the hydrochloride salt of compound HJM-024 was obtained as a yellow solid. LCMS[M+H] ⁺ 650.6.

¹ H NMR(500MHz,Methanol-d ₄ )δ9.08(d,J=2.0Hz,1H),8.88(d,J=5.7Hz,1H),8.79(dt,J=8.4,1.8Hz,1H) ,8.16(dd,J=8.3,5.7Hz,1H),7.64-7.57(m,2H),7.46(d,J=8.2Hz,1H),7.34-7.30(m,1H),7.25(t,J =7.5Hz,1H),7.21(d,J=8.5Hz,1H),7.13(d,J=7.1Hz,1H),6.90(s,1H),6.73(s,1H),5.07(dd,J =12.8,5.5Hz,1H),4.20-4.09(m,2H),3.86(t,J=6.4Hz,2H),3.78-3.60(m,8H),3.50(t,J=6.4Hz,2H) , 2.93–2.81 (m, 1H), 2.79–2.62 (m, 2H), 2.15–2.06 (m, 1H).

Example 25: Synthesis of compound HJM-025

Using a method similar to Example 1, by using 6-4 and Int-33 as starting materials, compound HJM-025 was obtained as a yellow solid. LCMS[M+H] ⁺ 642.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 9.34 (d, J=8.3 Hz, 1H), 8.63 (d, J=2.3 Hz, 1H), 8.52 (dd, J= 4.9,1.6Hz,1H),7.80(dt,J=8.0,2.0Hz,1H),7.62-7.50(m,3H),7.41(dd,J=7.9,4.8Hz,1H),7.28(td,J ＝7.9, 1.5Hz, 1H), 7.23(s, 5H), 7.16(d, J＝8.6Hz, 1H), 7.03(d, J＝7.0Hz, 1H), 6.66(s, 1H), 6.58(t ,J=5.9Hz,1H),6.36(d,J=8.1Hz,1H),5.04(dd,J=12.8,5.4Hz,1H),3.55(s,2H),3.54–3.49(m,2H) , 2.94–2.79 (m, 3H), 2.63–2.42 (m, 2H), 2.06–1.95 (m, 1H).

Example 26: Synthesis of compound HJM-026

Using a method similar to Example 1, by using 6-4 and Int-34 as starting materials, compound HJM-026 was obtained as a yellow solid. LCMS[M+H] ⁺ 628.4.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 9.36 (d, J=8.2 Hz, 1H), 8.68 (s, 1H), 8.59 (d, J=4.8 Hz, 1H) ,7.93(dt,J=8.1,1.9Hz,1H),7.58(dd,J=7.4,1.5Hz,1H),7.55-7.46(m,3H),7.32-7.18(m,7H),7.02(d ,J=7.1Hz,1H),6.94(d,J=8.6Hz,1H),6.66(s,1H),6.38(d,J=8.0Hz,1H),5.07(dd,J=12.9,5.4Hz , 1H), 4.52 (d, J=5.8Hz, 2H), 3.55 (s, 2H), 2.95–2.82 (m, 1H), 2.65–2.51 (m, 2H), 2.09–2.00 (m, 1H).

Example 27: Synthesis of compound HJM-027

In a similar manner to Example 1, by using HJM-027-1 and Int-7 as starting materials, compound HJM-027 was obtained as a yellow solid. LCMS[M+H] ⁺ 622.5.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.07 (d, J=8.2 Hz, 1H), 8.67 (d, J=2.3 Hz, 1H), 8.49 (dd, J= 4.8, 1.6Hz, 1H), 7.84 (dt, J=8.0, 2.0Hz, 1H), 7.59–7.52 (m, 3H), 7.39 (dd, J=7.9, 4.8Hz, 1H), 7.28–7.22 (m ,1H),7.18(td,J＝7.4,1.1Hz,1H),7.06(d,J＝8.6Hz,1H),7.01(d,J＝7.0Hz,1H),6.58(d,J＝8.2Hz ,1H),6.51(t,J＝5.9Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H),3.77(s,3H),3.24(q,J＝6.7Hz,2H),2.95 –2.82(m,1H),2.63-2.45(m,2H),2.22(t,J=7.3Hz,2H),2.06-1.97(m,1H),1.53(p,J=7.3Hz,4H), 1.38–1.21 (m, 4H).

Example 28: Synthesis of compound HJM-028

Using a method similar to Example 1, by using 6-4 and Int-10 as starting materials, compound HJM-028 was obtained as a yellow solid. LCMS[M+H] ⁺ 610.4.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.05 (d, J=8.3 Hz, 1H), 8.63 (d, J=2.3 Hz, 1H), 8.52 (dd, J= 4.8, 1.7Hz, 1H), 7.80 (dt, J=8.0, 2.0Hz, 1H), 7.61–7.54 (m, 2H), 7.53–7.49 (m, 1H), 7.41 (dd, J=7.9, 4.7Hz) ,1H),7.27(td,J＝7.9,1.6Hz,1H),7.22(td,J＝7.4,1.2Hz,1H),7.13(d,J＝8.6Hz,1H),7.03(d,J＝ 7.0Hz, 1H), 6.66(s, 1H), 6.60(t, J=5.7Hz, 1H), 6.37(d, J=8.3Hz, 1H), 5.05(dd, J=12.9, 5.4Hz, 1H) ,3.55(t,J＝5.4Hz,2H),3.47-3.40(m,4H),2.92-2.80(m,1H),2.62-2.44(m,2H),2.30(t,J＝7.4Hz,2H ), 2.05–1.96 (m, 1H), 1.78 (p, J=6.9Hz, 2H).

Example 29: Synthesis of compound HJM-029

At room temperature, compound Int-6 (775 mg, 2.22 mmol), 4-bromo-1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-isoindoline 1-3 (500 mg, 1.48 mmol), cuprous iodide (58.3 mg, 306.1 μmol), bis(triphenylphosphine)palladium(II) dichloride (104.1 mg, 148.3 μmol) and triethylamine (3.64 g) , 35.9 mmol, 5 mL) was dissolved in N,N-dimethylformamide (10 mL), and stirred at 80 °C for 12 hours under nitrogen protection. After the reaction was completed, it was filtered, the filtrate was diluted with water (50 mL), and then extracted with ethyl acetate (2×15 mL). The organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was purified by preparative HPLC to give compound HJM-029 (120 mg, yield 13.4%) as an off-white solid. LCMS[M+H] ⁺ 605.4.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.14 (s, 1H), 9.29 (d, J=8.0 Hz, 1H), 8.97 (d, J=2.2 Hz, 1H), 8.84 (d, J= 5.4Hz, 1H), 8.50 (d, J=8.1Hz, 1H), 7.99 (dd, J=8.1, 5.5Hz, 1H), 7.91 (dd, J=6.4, 2.1Hz, 1H), 7.89–7.82 ( m, 2H), 7.59 (dd, J=7.6, 1.4Hz, 1H), 7.53 (d, J=8.1Hz, 1H), 7.29 (td, J=7.9, 1.5Hz, 1H), 7.23 (td, J =7.4,1.1Hz,1H),6.75(s,1H),6.59(d,J=8.0Hz,1H),5.15(dd,J=12.8,5.4Hz,1H),4.45(s,2H),3.60 (t, J=6.3Hz, 2H), 2.96–2.82 (m, 1H), 2.65–2.43 (m, 2H), 2.41–2.31 (m, 2H), 2.10–2.01 (m, 1H), 1.84 (p , J=6.8Hz, 2H).

Example 30: Synthesis of Compound HJM-030

In a similar manner to Example 23, by using 7-2 and Int-35 as starting materials, compound HJM-030 was obtained as a yellow solid. LCMS[M+H] ⁺ 642.4.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.34 (d, J=8.3 Hz, 1H), 8.63 (d, J=2.3 Hz, 1H), 8.52 (dd, J= 4.8, 1.6Hz, 1H), 7.80 (dt, J=8.0, 2.0Hz, 1H), 7.60–7.54 (m, 2H), 7.52 (d, J=8.1Hz, 1H), 7.41 (dd, J=7.9 ,4.7Hz,1H),7.30-7.20(m,4H),7.18-7.11(m,3H),7.03(d,J＝7.0Hz,1H),6.66(s,1H),6.60(t,J＝ 5.9Hz,1H),6.36(d,J=8.2Hz,1H),5.05(dd,J=12.8,5.4Hz,1H),3.56(s,2H),3.50(q,J=6.8Hz,2H) , 2.93–2.81 (m, 3H), 2.63–2.45 (m, 2H), 2.06–1.96 (m, 1H).

Example 31: Synthesis of compound HJM-031

In a similar manner to Example 1, by using Int-36 and Int-7 as starting materials, compound HJM-031 was obtained as a yellow solid. LCMS[M+H] ⁺ 608.3.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 8.97 (d, J=8.5Hz, 1H), 8.54 (dd, J=5.2, 1.8Hz, 1H), 7.84 (td, J=7.7, 1.8Hz, 1H), 7.61–7.52 (m, 2H), 7.51 (d, J=7.9Hz, 1H), 7.48 (d, J=8.0Hz, 1H), 7.34 (ddd, J=7.6 ,4.8,1.1Hz,1H),7.24(td,J＝7.7,1.7Hz,1H),7.20(td,J＝7.4,1.3Hz,1H),7.06(d,J＝8.6Hz,1H),7.01 (d, J=7.0Hz, 1H), 6.64 (s, 1H), 6.51 (t, J=6.0Hz, 1H), 6.35 (d, J=8.4Hz, 1H), 5.05 (dd, J=12.9, 5.4Hz, 1H), 3.25 (q, J=6.7Hz, 2H), 2.95–2.81 (m, 1H), 2.63–2.43 (m, 2H), 2.26 (t, J=7.3Hz, 2H), 2.10– 1.97 (m, 1H), 1.60–1.48 (m, 4H), 1.39–1.23 (m, 4H).

Example 32: Synthesis of compound HJM-032

In a similar manner to Example 1, by using Int-37 and Int-7 as starting materials, compound HJM-032 was obtained as a yellow solid. LCMS[M+H] ⁺ 621.5.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 8.91 (d, J=8.3 Hz, 1H), 8.62 (d, J=2.3 Hz, 1H), 8.53 (dd, J= 4.8,1.6Hz,1H),7.78(dt,J=8.0,2.0Hz,1H),7.57(dd,J=8.6,7.0Hz,1H),7.46-7.40(m,3H),7.13(ddd,J =8.2,7.0,1.3Hz,1H),7.07(d,J=8.6Hz,1H),7.04–6.96(m,2H),6.52(t,J=5.9Hz,1H),6.44(d,J= 8.2Hz, 1H), 5.86(s, 1H), 5.05(dd, J=12.9, 5.4Hz, 1H), 3.65(s, 3H), 3.26(q, J=6.7Hz, 2H), 2.95–2.82( m, 1H), 2.63–2.45 (m, 2H), 2.21 (td, J=7.3, 3.2Hz, 2H), 2.08–1.98 (m, 1H), 1.55 (p, J=7.0Hz, 4H), 1.40 -1.21 (m, 4H).

Example 33: Synthesis of Compound HJM-033

Using a method similar to Example 23, by using 7-2 and Int-14 as starting materials, and using 0.1% formic acid as aqueous phase in preparative HPLC purification, compound HJM-033 as a formate salt was obtained as a white solid. LCMS[M+H] ⁺ 623.5.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.16 (d, J=8.3 Hz, 1H), 8.62 (d, J=2.3 Hz, 1H), 8.51 (dd, J= 4.8, 1.6Hz, 1H), 8.17 (s, 1H), 7.79 (dt, J=8.0, 2.0Hz, 1H), 7.57 (dd, J=7.5, 1.5Hz, 1H), 7.55–7.47 (m, 2H) ),7.39(dd,J=7.9,4.8Hz,1H),7.25(td,J=7.9,1.6Hz,1H),7.20(td,J=7.4,1.2Hz,1H),7.01(d,J= 8.8Hz, 1H), 6.98 (d, J=7.2Hz, 1H), 6.73–6.67 (m, 2H), 6.37 (d, J=8.2Hz, 1H), 5.05 (dd, J=12.9, 5.4Hz, 1H), 3.25 (q, J=6.6Hz, 2H), 2.87 (ddd, J=17.3, 13.9, 5.5Hz, 1H), 2.66–2.46 (m, 4H), 2.41 (q, J=6.5Hz, 4H) ), 2.20 (s, 3H), 2.06–1.97 (m, 1H), 1.68 (p, J=6.8Hz, 2H).

Example 34: Synthesis of compound HJM-034

Synthesized in a similar manner to Example 1, by using 6-4 and Int-38 as starting materials, and using 0.05% hydrochloric acid as aqueous phase in preparative HPLC purification, the hydrochloride salt of compound HJM-034 was obtained as a white solid. LCMS[M+H] ⁺ 642.7.

¹ H NMR(500MHz,Methanol-d ₄ )δ8.67(d,J=5.5Hz,1H),8.62(s,1H),8.05(d,J=8.0Hz,1H),7.78(dd,J= 8.2, 5.5Hz, 1H), 7.53 (dt, J=7.6, 1.3Hz, 1H), 7.44–7.37 (m, 2H), 7.30–7.19 (m, 5H), 7.16–7.12 (m, 1H), 6.98 (d, J=7.2Hz, 1H), 6.91 (d, J=8.5Hz, 1H), 6.54 (dt, J=3.1, 0.9Hz, 1H), 6.47 (s, 1H), 5.04 (dd, J= 12.7, 5.5Hz, 1H), 4.44(s, 2H), 2.96(t, J=7.3Hz, 2H), 2.89-2.78(m, 1H), 2.76-2.67(m, 2H), 2.66(t, J = 7.3Hz, 2H), 2.11–2.05 (m, 1H).

Example 35: Synthesis of compound HJM-035

Synthesized in a similar manner to Example 1, by using 6-4 and Int-39 as starting materials, and using 0.05% hydrochloric acid as aqueous phase in preparative HPLC purification, the hydrochloride salt of compound HJM-035 was obtained as a yellow solid. LCMS[M+H] ⁺ 643.6.

¹ H NMR(500MHz,Methanol-d ₄ )δ8.95(dd,J=8.5,2.0Hz,1H),8.86(d,J=5.7Hz,1H),8.67(tt,J=8.2,1.8Hz, 1H), 8.40 (td, J=8.0, 1.1Hz, 1H), 8.18–8.09 (m, 1H), 7.91–7.82 (m, 2H), 7.60–7.54 (m, 1H), 7.49 (dd, J= 8.5,7.2Hz,1H),7.46–7.40(m,1H),7.31(ddt,J=8.4,7.2,1.6Hz,1H),7.24(t,J=7.5Hz,1H),7.07(t,J ＝6.8Hz,1H),6.96(d,J＝8.5Hz,1H),6.82(d,J＝19.1Hz,1H),6.54(d,J＝10.0Hz,1H),5.10(ddd,J＝12.4 ,5.5,3.6Hz,1H),5.04(s,2H),3.40(t,J＝6.6Hz,2H),3.03(t,J＝6.3Hz,2H),2.89–2.79(m,1H),2.78 – 2.64 (m, 2H), 2.15 – 2.04 (m, 1H).

Example 36: Synthesis of compound HJM-036

Under nitrogen protection, to a solution of compound HJM-029 (70.0 mg, 115.8 μmol) in tetrahydrofuran (2 mL), wet palladium/carbon (200 mg, 10% Pd) was added, and hydrogen was replaced three times. Hour. Filter through celite, wash the filter cake twice with tetrahydrofuran, combine the filtrates and spin dry to obtain the crude product. The crude product was purified by reverse-phase preparative HPLC to give compound HJM-036 (11.0 mg, yield 15.6%) as a white solid. LCMS[M+H] ⁺ 609.4.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 9.06 (d, J=8.4 Hz, 1H), 8.63 (d, J=2.3 Hz, 1H), 8.52 (dd, J= 4.8, 1.6Hz, 1H), 7.80 (dt, J=8.0, 2.0Hz, 1H), 7.77–7.70 (m, 2H), 7.66 (dd, J=5.6, 3.3Hz, 1H), 7.58 (dd, J ＝7.5, 1.5Hz, 1H), 7.50 (d, J＝8.0Hz, 1H), 7.41 (dd, J＝7.9, 4.8Hz, 1H), 7.26 (td, J＝7.7, 1.5Hz, 1H), 7.21 (td, J＝7.4, 1.2Hz, 1H), 6.66 (t, J＝1.0Hz, 1H), 6.38 (d, J＝8.2Hz, 1H), 5.12 (dd, J＝12.9, 5.4Hz, 1H) ,3.05(t,J＝7.6Hz,2H),2.88(ddd,J＝17.3,14.0,5.4Hz,1H),2.65–2.45(m,2H),2.30(t,J＝7.4Hz,2H), 2.11–1.99 (m, 1H), 1.87–1.69 (m, 4H).

¹ H NMR (400MHz, DMSO-d ₆ +D ₂ O) δ 8.58 (d, J=2.3 Hz, 1H), 8.48 (dd, J=4.8, 1.6 Hz, 1H), 7.79 (dt, J=8.0 ,2.0Hz,1H),7.75–7.67(m,2H),7.63(dd,J=6.4,2.4Hz,1H),7.56(dd,J=7.5,1.9Hz,1H),7.46(d,J= 8.2Hz, 1H), 7.40 (ddd, J=7.9, 4.8, 0.8Hz, 1H), 7.25 (td, J=7.7, 1.6Hz, 1H), 7.20 (td, J=7.4, 1.2Hz, 1H), 6.66(t,J＝1.0Hz,1H),6.33(s,1H),5.08(dd,J＝12.8,5.5Hz,1H),3.32(q,J＝6.1Hz,4H),3.01(t,J =7.6Hz,2H),2.84(ddd,J=17.1,13.9,5.4Hz,1H),2.64-2.43(m,2H),2.28(td,J=7.3,1.8Hz,2H),2.07-1.99( m, 1H), 1.82–1.68 (m, 4H).

Example 37: Synthesis of Compound HJM-037

In a similar manner to Example 1, by using Int-40 and Int-7 as starting materials, compound HJM-037 was obtained as a yellow solid. LCMS[M+H] ⁺ 609.4.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09(s, 1H), 9.12(d, J=8.2Hz, 1H), 8.96(s, 1H), 8.66(s, 1H), 8.56(dd, J=5.0, 1.6Hz, 1H), 8.40 (d, J=5.3Hz, 1H), 7.84 (dt, J=8.0, 2.0Hz, 1H), 7.73 (dd, J=5.3, 1.0Hz, 1H), 7.57(dd,J＝8.6,7.1Hz,1H),7.45(dd,J＝8.0,4.7Hz,1H),7.07(d,J＝8.6Hz,1H),7.02(d,J＝7.0Hz,1H) ),6.86(t,J＝1.0Hz,1H),6.52(t,J＝5.9Hz,1H),6.47(d,J＝8.2Hz,1H),5.05(dd,J＝12.9,5.3Hz,1H) ),3.26(q,J＝6.7Hz,2H),2.88(ddd,J＝17.4,14.1,5.5Hz,1H),2.63–2.44(m,2H),2.25(t,J＝7.4Hz,2H) , 2.07–1.98 (m, 1H), 1.61–1.49 (m, 4H), 1.39–1.26 (m, 4H).

Example 38: Synthesis of Compound HJM-038

In a similar manner to Example 1, by using Int-41 and Int-7 as starting materials, compound HJM-038 was obtained as a yellow solid. LCMS[M+H] ⁺ 609.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09(s, 1H), 9.10(d, J=8.2Hz, 1H), 8.71(s, 1H), 8.60(d, J=5.0Hz, 1H) ,8.49(d,J＝4.8Hz,1H),7.98(dt,J＝8.3,1.2Hz,1H),7.94(dt,J＝8.1,1.9Hz,1H),7.57(dd,J＝8.6,7.0 Hz,1H),7.52(dd,J=8.0,4.9Hz,1H),7.31(dd,J=8.4,4.8Hz,1H),7.07(d,J=8.6Hz,1H),7.02(d,J ＝7.0Hz,1H),6.89(s,1H),6.51(t,J＝5.0Hz,1H),6.47(d,J＝8.2Hz,1H),5.05(dd,J＝12.9,5.4Hz,1H) ),3.26(q,J＝5.6Hz,2H),2.88(ddd,J＝17.4,14.1,5.5Hz,1H),2.64–2.42(m,2H),2.25(t,J＝7.4Hz,2H) , 2.09–1.95 (m, 1H), 1.62–1.48 (m, 4H), 1.42–1.21 (m, 4H).

Example 39: Synthesis of Compound HJM-039

In a similar manner to Example 1, by using 6-4 and Int-43 as starting materials, compound HJM-039 was obtained as a yellow solid. LCMS[M+H] ⁺ 627.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 9.12 (d, J=8.3 Hz, 1H), 8.63 (d, J=2.3 Hz, 1H), 8.51 (dd, J= 4.8, 1.7Hz, 1H), 7.79 (dt, J=7.9, 2.0Hz, 1H), 7.76–7.71 (m, 1H), 7.67 (d, J=8.1Hz, 1H), 7.61–7.54 (m, 2H) ),7.48(d,J＝8.0Hz,1H),7.39(dd,J＝7.9,4.8Hz,1H),7.25(td,J＝7.7,1.6Hz,1H),7.19(t,J＝7.3Hz ,1H),6.68(s,1H),6.40(d,J＝8.2Hz,1H),5.11(dd,J＝12.7,5.4Hz,1H),3.66(t,J＝6.1Hz,2H),3.51 (t, J=6.0Hz, 2H), 3.10 (t, J=7.3Hz, 2H), 2.89 (ddd, J=16.7, 13.7, 5.4Hz, 1H), 2.64–2.46 (m, 4H), 2.11– 2.01 (m, 1H), 1.86 (p, J=6.3Hz, 2H).

Example 40: Synthesis of Compound HJM-040

In a similar manner to Example 23, by using 7-2 and Int-44 as starting materials, compound HJM-040 was obtained as a yellow solid. LCMS[M+H] ⁺ 628.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 9.33 (d, J=8.2 Hz, 1H), 8.61 (d, J=2.3 Hz, 1H), 8.52 (dd, J= 4.8,1.6Hz,1H),7.78(dt,J=7.9,2.0Hz,1H),7.58(dd,J=7.4,1.5Hz,1H),7.54-7.50(m,1H),7.47(dd,J =8.5,7.1Hz,1H),7.40(dd,J=7.9,4.8Hz,1H),7.30–7.16(m,7H),7.01(d,J=7.0Hz,1H),6.93(d,J= 8.6Hz, 1H), 6.65 (s, 1H), 6.34 (d, J=8.1Hz, 1H), 5.07 (dd, J=12.9, 5.4Hz, 1H), 4.52 (d, J=6.2Hz, 2H) , 3.57 (s, 2H), 2.89 (ddd, J=17.2, 14.0, 5.4 Hz, 1H), 2.64–2.43 (m, 2H), 2.09–1.98 (m, 1H).

Example 41: Synthesis of compound HJM-041

At room temperature, compound Int-45 (50 mg, 134.26 μmol) and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline 5 -1 (36.82 mg, 134.26 μmol) was added to dry tetrahydrofuran (1 mL), followed by diisopropyl azodicarboxylate (81.45 mg, 402.78 μmol) and triphenylphosphine (105.64 mg, 402.78 μmol), The reaction was stirred at room temperature for 5 hours under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3×10 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was purified by preparative HPLC to give compound HJM-041 (10.49 mg, yield 12.0%) as a yellow solid. LCMS[M+H] ⁺ 629.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 9.36 (d, J=8.2 Hz, 1H), 8.63 (d, J=2.3 Hz, 1H), 8.52 (dd, J= 4.8, 1.6Hz, 1H), 7.83–7.77 (m, 2H), 7.61–7.56 (m, 2H), 7.53 (d, J=8.1Hz, 1H), 7.48–7.39 (m, 4H), 7.34–7.31 (m, 2H), 7.28 (td, J=7.8, 1.5Hz, 1H), 7.23 (td, J=7.4, 1.2Hz, 1H), 6.66 (s, 1H), 6.36 (d, J=8.2Hz, 1H), 5.35(s, 2H), 5.09(dd, J=12.9, 5.4Hz, 1H), 3.60(s, 2H), 2.88(ddd, J=17.4, 14.1, 5.4Hz, 1H), 2.63–2.44 (m, 2H), 2.09–2.00 (m, 1H).

Example 42: Synthesis of compound HJM-042

Using a method similar to Example 1, by using 6-4 and Int-46 as starting materials, compound HJM-042 was obtained as a yellow solid. LCMS[M+H] ⁺ 627.4.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 9.02 (d, J=8.4Hz, 1H), 8.70 (d, J=2.3Hz, 1H), 8.61-8.54 (m, 1H),7.95(dt,J=8.1,1.9Hz,1H),7.74(s,1H),7.73(s,1H),7.61-7.57(m,2H),7.55-7.47(m,2H),7.27 (td, J=7.7, 1.5Hz, 1H), 7.22 (t, J=7.4Hz, 1H), 6.64 (s, 1H), 6.46 (d, J=8.4Hz, 1H), 5.11 (dd, J= 12.7, 5.4Hz, 1H), 4.02 (s, 2H), 3.52 (t, J=5.6Hz, 2H), 3.15 (t, J=6.9Hz, 2H), 2.88 (ddd, J=16.7, 13.6, 5.4 Hz, 1H), 2.64–2.44 (m, 2H), 2.09–2.01 (m, 1H), 1.78–1.68 (m, 4H).

Example 43: Synthesis of Compound HJM-043

Compounds Int-47 (111.23 mg, 258.36 μmol) and Int-42 (50 mg, 172.24 μmol) were added to acetonitrile (2 mL), then potassium carbonate (35.7 mg, 258.36 μmol) was added, and the mixture was heated and stirred at 50° C. for 4 hours. After the reaction was completed, the reaction solution was diluted with water (5 mL), extracted with ethyl acetate (3×5 mL), the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and concentration gave crude product. The crude product was purified by preparative HPLC to give compound HJM-043 (6.2 mg, yield 5.8%) as a yellow solid. LCMS[M+H] ⁺ 625.5.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 9.04 (d, J=8.4Hz, 1H), 8.63 (d, J=2.4Hz, 1H), 8.52 (dd, J= 4.8, 1.6Hz, 1H), 7.80 (dt, J=7.7, 1.7Hz, 1H), 7.76 (d, J=7.2Hz, 1H), 7.74–7.68 (m, 1H), 7.62 (d, J=7.2 Hz, 1H), 7.62–7.55 (m, 1H), 7.51 (d, J=8.1Hz, 1H), 7.41 (dd, J=8.0, 4.7Hz, 1H), 7.26 (td, J=7.8, 1.6Hz) ,1H),7.21(td,J＝7.4,1.2Hz,1H),6.65(t,J＝1.0Hz,1H),6.37(d,J＝8.4Hz,1H),5.11(dd,J＝12.8, 5.5Hz, 1H), 3.09 (t, J=7.2Hz, 2H), 2.93–2.82 (m, 1H), 2.64–2.39 (m, 2H), 2.24 (t, J=7.3Hz, 2H), 2.09– 2.01 (m, 1H), 1.69–1.59 (m, 2H), 1.59–1.52 (m, 2H), 1.48–1.38 (m, 2H), 1.33–1.26 (m, 2H).

Example 44: Synthesis of Compound HJM-044

Using a method similar to Example 1, by using 6-4 and Int-48 as starting materials, compound HJM-044 was obtained as a yellow solid. LCMS[M+H] ⁺ 640.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 9.15 (d, J=8.3 Hz, 1H), 8.61 (d, J=2.3 Hz, 1H), 8.50 (dd, J= 4.8, 1.6Hz, 1H), 7.79 (dt, J=8.0, 2.0Hz, 1H), 7.70 (dd, J=8.2, 7.1Hz, 1H), 7.63 (d, J=8.1Hz, 1H), 7.60– 7.53 (m, 2H), 7.48 (d, J=7.9Hz, 1H), 7.42–7.37 (m, 1H), 7.24 (dd, J=7.3, 1.7Hz, 1H), 7.19 (tt, J=7.3, 1.2Hz, 1H), 6.70(t, J=1.0Hz, 1H), 6.38(d, J=8.2Hz, 1H), 5.11(dd, J=12.7, 5.4Hz, 1H), 3.05(t, J= 7.1Hz, 2H), 2.89 (ddd, J=16.7, 13.7, 5.3Hz, 1H), 2.67–2.50 (m, 4H), 2.47 (t, J=6.9Hz, 2H), 2.42 (t, J=6.8 Hz, 2H), 2.21 (s, 3H), 2.09–2.01 (m, 1H), 1.77 (p, J=6.7Hz, 2H).

Example 45: Synthesis of compound HJM-045

In a similar manner to Example 1, by using 6-4 and Int-49 as starting materials, compound HJM-045 was obtained as a yellow solid. LCMS[M+H] ⁺ 642.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 9.05 (d, J=8.3 Hz, 1H), 8.57 (d, J=2.3 Hz, 1H), 8.52 (dd, J= 4.8,1.6Hz,1H),7.72(dt,J＝7.9,2.0Hz,1H),7.58(dd,J＝7.5,1.6Hz,1H),7.52-7.46(m,2H),7.39(dd,J = 7.9, 4.8Hz, 1H), 7.30–7.21 (m, 4H), 7.21–7.14 (m, 3H), 7.01 (d, J=7.1Hz, 1H), 6.96 (d, J=8.6Hz, 1H) ,6.59(d,J＝1.0Hz,1H),6.36(d,J＝8.2Hz,1H),5.07(dd,J＝12.9,5.4Hz,1H),4.51(d,J＝5.9Hz,2H) , 2.94–2.85 (m, 1H), 2.83 (t, J=7.4Hz, 2H), 2.64–2.49 (m, 4H), 2.09–2.00 (m, 1H).

Example 46: Synthesis of compound HJM-046

Using a method similar to Example 1, by using 6-4 and Int-50 as starting materials, compound HJM-046 was obtained as a yellow solid. LCMS[M+H] ⁺ 614.2.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 9.55 (d, J=8.1 Hz, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.60 (dd, J= 4.9, 1.6Hz, 1H), 8.02 (dt, J=8.1, 2.0Hz, 1H), 7.91 (d, J=8.3Hz, 2H), 7.59 (dd, J=7.6, 1.5Hz, 1H), 7.56– 7.45(m, 5H), 7.33(t, J=6.4Hz, 1H), 7.28(dd, J=7.9, 1.6Hz, 1H), 7.23(td, J=7.4, 1.2Hz, 1H), 7.02(d ,J=7.0Hz,1H),6.91(d,J=8.6Hz,1H),6.66(t,J=1.0Hz,1H),6.64(d,J=8.3Hz,1H),5.07(dd,J =12.9,5.4Hz,1H),4.63(d,J=6.1Hz,2H),2.89(ddd,J=17.2,14.0,5.4Hz,1H),2.65–2.48(m,2H),2.12–1.97( m, 1H).

Example 47: Synthesis of compound HJM-047

At room temperature, compound Int-51 (50 mg, 134.99 μmol) and lenalidomide (35 mg, 134.99 μmol) were added to a mixed solvent of methanol (1 mL) and 1,2-dichloroethane (1 mL), and added dropwise. Acetic acid (8.11 mg, 134.99 μmol) was stirred at room temperature for 0.5 h. Sodium cyanoborohydride (25.45 mg, 404.97 μmol) was added, and the mixture was stirred at room temperature for 0.5 hours. Quenched with saturated ammonium chloride solution (1 mL), the reaction was concentrated to give crude product. The crude product was purified by preparative HPLC to give compound HJM-047 (44.80 mg, yield 54.1%) as a white solid. LCMS[M+H] ⁺ 614.4.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.01(s, 1H), 9.33(d, J=8.3Hz, 1H), 8.62(s, 1H), 8.53(d, J=4.8Hz, 1H) ,7.79(dt,J＝8.0,2.0Hz,1H),7.57(dt,J＝7.6,0.9Hz,1H),7.54–7.47(m,1H),7.41(dd,J＝7.9,4.8Hz,1H) ), 7.34–7.14 (m, 7H), 6.91 (dd, J=7.5, 0.8Hz, 1H), 6.65–6.64 (m, 1H), 6.62 (d, J=8.0Hz, 1H), 6.38–6.28 ( m, 2H), 5.11 (dd, J=13.3, 5.1Hz, 1H), 4.35 (s, 2H), 4.34–4.14 (m, 2H), 3.54 (s, 2H), 2.92 (ddd, J=18.1, 13.5, 5.4Hz, 1H), 2.66–2.58 (m, 1H), 2.38–2.25 (m, 1H), 2.09–2.00 (m, 1H).

Example 48: Synthesis of Compound HJM-048

In a similar manner to Example 1, by using Int-52 and Int-7 as starting materials, compound HJM-048 was obtained as a yellow solid. LCMS[M+H] ⁺ 625.1.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09(s, 1H), 9.32(d, J=8.2Hz, 1H), 8.77(s, 1H), 8.61(d, J=4.3Hz, 1H) ,8.08(dd,J＝8.1,1.3Hz,1H),8.00(d,J＝8.2Hz,1H),7.92(d,J＝7.7Hz,1H),7.60–7.52(m,2H),7.49( td, J=7.7, 1.4Hz, 1H), 7.43 (td, J=7.6, 1.3Hz, 1H), 7.07 (d, J=8.6Hz, 1H), 7.02 (d, J=7.0Hz, 1H), 6.62 (d, J=8.1Hz, 1H), 6.52 (brs, 1H), 5.05 (dd, J=12.9, 5.4Hz, 1H), 3.27 (q, J=5.8Hz, 2H), 2.94–2.82 (m , 1H), 2.63–2.50 (m, 2H), 2.31–2.23 (m, 2H), 2.07–1.97 (m, 1H), 1.64–1.51 (m, 4H), 1.42–1.27 (m, 4H).

Example 49: Synthesis of Compound HJM-049

In a similar manner to Example 1, by using Int-53 and Int-7 as starting materials, compound HJM-049 was obtained as a yellow solid. LCMS[M+H] ⁺ 609.4.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.08(s,1H),9.16(s,1H),9.10(d,J=8.1Hz,1H),8.87(s,2H),7.63-7.50( m,3H),7.29(td,J=7.8,1.6Hz,1H),7.23(td,J=7.4,1.2Hz,1H),7.07(d,J=8.6Hz,1H),7.02(d,J ＝7.0Hz,1H),6.71(t,J＝1.0Hz,1H),6.51(t,J＝5.9Hz,1H),6.44(d,J＝8.1Hz,1H),5.05(dd,J＝12.9 ,5.4Hz,1H),3.26(q,J＝6.7Hz,1H),2.88(ddd,J＝18.4,14.0,5.4Hz,1H),2.63–2.49(m,2H),2.24(t,J＝ 7.3Hz, 2H), 2.06–1.98 (m, 1H), 1.61–1.49 (m, 4H), 1.39–1.23 (m, 4H).

Example 50: Synthesis of Compound HJM-050

In a similar manner to Example 1, by using Int-54 and Int-7 as starting materials, compound HJM-050 was obtained as a yellow solid. LCMS[M+H] ⁺ 624.5.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.10 (d, J=8.5 Hz, 1H), 8.71 (d, J=2.3 Hz, 1H), 8.58 (dd, J= 4.9,1.6Hz,1H),7.94(dt,J=8.0,2.0Hz,1H),7.88(dd,J=6.9,2.0Hz,1H),7.79-7.73(m,1H),7.57(dd,J =8.6,7.1Hz,1H),7.51(dd,J=7.9,4.9Hz,1H),7.36-7.28(m,2H),7.09-7.05(m,2H),7.02(d,J=7.0Hz, 1H), 6.54–6.48 (m, 2H), 5.05 (dd, J=12.9, 5.4Hz, 1H), 3.26 (q, J=6.3Hz, 2H), 2.88 (ddd, J=17.4, 14.1, 5.5Hz , 1H), 2.63–2.49 (m, 2H), 2.28–2.19 (m, 2H), 2.07–1.98 (m, 1H), 1.62–1.48 (m, 4H), 1.40–1.24 (m, 4H).

Example 51: Synthesis of compound HJM-051

In a similar manner to Example 1, by using 6-4 and Int-55 as starting materials, compound HJM-051 was obtained as a yellow solid. LCMS[M+H] ⁺ 614.4.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 9.37 (d, J=8.2 Hz, 1H), 8.69 (d, J=2.3 Hz, 1H), 8.58 (dd, J= 4.9,1.6Hz,1H),8.39(s,1H),7.92(dt,J=8.0,2.0Hz,1H),7.63–7.49(m,4H),7.38(d,J=8.6Hz,1H), 7.34–7.21(m,7H),6.69(t,J=1.1Hz,1H),6.41(d,J=8.1Hz,1H),5.12(dd,J=12.9,5.4Hz,1H),3.59(s , 2H), 2.90 (ddd, J=17.3, 14.0, 5.5Hz, 1H), 2.65–2.49 (m, 2H), 2.11–2.02 (m, 1H).

Example 52: Synthesis of compound HJM-052

In a similar manner to Example 1, by using Int-56 and Int-7 as starting materials, compound HJM-052 was obtained as a yellow solid. LCMS[M+H] ⁺ 609.4.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09(s, 1H), 9.23(d, J=7.9Hz, 1H), 8.73(s, 1H), 8.58(d, J=4.8Hz, 1H) ,7.94(dt,J＝8.0,2.0Hz,1H),7.71(td,J＝6.9,2.4Hz,2H),7.57(dd,J＝8.6,7.1Hz,1H),7.49(dd,J＝7.9 ,4.8Hz,1H),7.38(tt,J＝7.4,5.7Hz,2H),7.07(d,J＝8.6Hz,1H),7.01(d,J＝7.0Hz,1H),6.53(t,J =1.0Hz,1H),6.50(d,J=7.9Hz,1H),5.05(dd,J=12.9,5.4Hz,1H),3.26(q,J=6.5Hz,2H),2.88(ddd,J =17.4,14.0,5.5Hz,1H),2.63-2.48(m,2H),2.25(t,J=7.3Hz,2H),2.06-1.98(m,1H),1.55(p,J=7.2Hz, 4H), 1.39–1.26 (m, 4H).

Example 53: Synthesis of compound HJM-053

In a similar manner to Example 1, by using Int-57 and Int-7 as starting materials, compound HJM-053 was obtained as a yellow solid. LCMS[M+H] ⁺ 609.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.38 (d, J=8.1 Hz, 1H), 9.05 (d, J=2.0 Hz, 1H), 8.91 (dd, J= 5.7, 1.4Hz, 1H), 8.64 (dt, J=8.2, 1.8Hz, 1H), 8.27 (dd, J=4.8, 1.7Hz, 1H), 8.11–8.06 (m, 2H), 7.57 (dd, J ＝8.6,7.0Hz,1H),7.34(dd,J＝7.6,4.9Hz,1H),7.07(d,J＝8.6Hz,1H),7.01(d,J＝7.0Hz,1H),6.85(d , J＝1.0Hz, 1H), 6.67(d, J＝8.0Hz, 1H), 5.05(dd, J＝12.8, 5.4Hz, 1H), 3.26(t, J＝7.1Hz, 2H), 2.88(ddd , J=17.2, 14.0, 5.4Hz, 1H), 2.63–2.45 (m, 2H), 2.32–2.24 (m, 2H), 2.06–1.98 (m, 1H), 1.62–1.48 (m, 4H), 1.40 -1.22 (m, 4H).

Example 54: Synthesis of compound HJM-054

Using a method similar to Example 1, by using 6-4 and Int-58 as starting materials, compound HJM-054 was obtained as a yellow solid. LCMS[M+H] ⁺ 623.4.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.15 (s, 1H), 9.43 (d, J=8.1 Hz, 1H), 8.70 (s, 1H), 8.60 (d, J=5.0 Hz, 1H) ,8.00–7.87(m,4H),7.63–7.52(m,5H),7.40(d,J=8.1Hz,2H),7.30(td,J=7.7,1.5Hz,1H),7.24(td,J ＝7.4,1.1Hz,1H),6.70(s,1H),6.42(d,J＝8.0Hz,1H),5.18(dd,J＝12.9,5.4Hz,1H),3.67(s,2H),2.90 (ddd, J=17.4, 13.9, 5.5 Hz, 1H), 2.66-2.53 (m, 2H), 2.14-2.04 (m, 1H).

Example 55: Synthesis of compound HJM-055

Under the protection of argon, Lindela catalyst (50.0 mg, 10% Pd) was added to a solution of compound HJM-054 (50 mg, 80.31 μmol) in anhydrous tetrahydrofuran (2 mL), and after hydrogen replacement three times, at 20 °C, Stir under 1 atmosphere of hydrogen for 2 hours. After the reaction was completed, it was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to give compound HJM-055 (3.09 mg, yield 6.1%) as a white solid. LCMS[M+H] ⁺ 625.4.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 9.34 (d, J=8.2 Hz, 1H), 8.60 (d, J=2.3 Hz, 1H), 8.53 (dd, J= 5.0,1.7Hz,1H),7.78(dd,J=7.8,4.5Hz,2H),7.58(t,J=7.7Hz,2H),7.50(dd,J=10.6,8.0Hz,2H),7.41( dd,J=7.9,4.8Hz,1H),7.32-7.13(m,6H),7.09(d,J=12.3Hz,1H),6.91(d,J=12.3Hz,1H),6.66(s,1H) ), 6.35(d, J=8.2Hz, 1H), 5.16(dd, J=12.9, 5.4Hz, 1H), 3.55(s, 2H), 2.98–2.83(m, 1H), 2.65–2.48(m, 2H), 2.13–2.02 (m, 1H).

Example 56: Synthesis of compound HJM-056

Under the protection of argon, wet palladium on carbon (100 mg, 10% Pd) was added to a solution of compound HJM-054 (50 mg, 80.31 μmol) in anhydrous tetrahydrofuran (2 mL), and after hydrogen replacement three times, at 40 °C, 1 Stir under atmospheric hydrogen for 12 hours. After the reaction was completed, it was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to give compound HJM-056 (10 mg, yield 19.9%) as a white solid. LCMS[M+H] ⁺ 627.3.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 9.32 (d, J=8.2 Hz, 1H), 8.62 (d, J=2.3 Hz, 1H), 8.53 (dd, J= 4.9, 1.7Hz, 1H), 7.82–7.66 (m, 4H), 7.60 (d, J=7.5Hz, 1H), 7.53 (d, J=8.1Hz, 1H), 7.42 (dd, J=7.9, 4.8 Hz,1H),7.32–7.16(m,6H),6.66(s,1H),6.36(d,J=8.2Hz,1H),5.15(dd,J=12.9,5.4Hz,1H),3.54(s , 2H), 3.32–3.24 (m, 2H), 2.96–2.81 (m, 3H), 2.65–2.51 (m, 2H), 2.13–2.01 (m, 1H).

Example 57: Synthesis of compound HJM-057

In a similar manner to Example 1, by using Int-54 and Int-34 as starting materials, compound HJM-057 was obtained as a yellow solid. LCMS[M+H] ⁺ 644.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 9.37 (dd, J=8.3, 2.1 Hz, 1H), 8.70 (s, 1H), 8.58 (d, J=4.9 Hz, 1H), 7.91 (dd, J=13.1, 7.6Hz, 2H), 7.74 (dd, J=6.0, 3.8Hz, 1H), 7.54–7.46 (m, 2H), 7.37–7.17 (m, 7H), 7.08 (s,1H),7.02(dd,J=7.0,2.0Hz,1H),6.95(dd,J=8.6,2.0Hz,1H),6.48(d,J=8.3Hz,1H),5.07(dd, J=12.8, 5.4Hz, 1H), 4.53 (d, J=6.0Hz, 2H), 3.55 (s, 2H), 2.97–2.83 (m, 1H), 2.65–2.44 (m, 2H), 2.12–1.95 (m, 1H).

Example 58: Synthesis of Compound HJM-058

In a similar manner to Example 1, by using 6-4 and Int-59 as starting materials, compound HJM-058 was obtained as a yellow solid. LCMS[M+H] ⁺ 645.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 9.36 (d, J=8.1 Hz, 1H), 8.68 (d, J=2.3 Hz, 1H), 8.58 (dd, J= 4.9, 1.6Hz, 1H), 7.91 (d, J=8.0Hz, 1H), 7.82 (d, J=8.1Hz, 1H), 7.79–7.73 (m, 1H), 7.62 (d, J=7.2Hz, 1H), 7.61–7.58 (m, 1H), 7.55–7.47 (m, 2H), 7.41 (d, J=8.1Hz, 2H), 7.32–7.19 (m, 4H), 6.66 (s, 1H), 6.38 (d, J=8.1Hz, 1H), 5.11 (dd, J=12.8, 5.4Hz, 1H), 4.42 (s, 2H), 3.57 (s, 2H), 2.88 (ddd, J=16.7, 13.9, 5.5 Hz, 1H), 2.63–2.51 (m, 2H), 2.09–2.00 (m, 1H).

Example 59: Synthesis of compound HJM-059

Compounds Int-60 (64.17 mg, 208.81 μmol), Int-61 (50 mg, 160.62 μmol), sodium ascorbate (12.73 mg, 64.25 μmol) and copper sulfate pentahydrate (5.13 mg, 32.12 μmol) were added to tetrahydrofuran (1 mL) , a mixed solution of tert-butanol (1 mL) and water (1 mL), and stirred at room temperature for 10 hours under nitrogen protection. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (2×10 mL), the organic layer was washed with saturated brine (2×10 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave crude product. The crude product was purified by preparative HPLC to give compound HJM-059 (12.3 mg, yield 12.3%) as a yellow solid. LCMS[M+H] ⁺ 619.1.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.09(s,1H),9.63(d,J=8.0Hz,1H),8.71(brs,1H),8.59(brs,1H),8.01(s, 1H), 7.90(d, J=8.0Hz, 1H), 7.64-7.48(m, 4H), 7.33-7.27(m, 1H), 7.24(td, J=7.4, 1.1Hz, 1H), 7.19(d , J=8.5Hz, 1H), 7.11–7.06(m, 1H), 7.05(d, J=7.1Hz, 1H), 6.77(s, 1H), 6.40(d, J=8.0Hz, 1H), 5.25 (d, J=2.5Hz, 2H), 5.05 (dd, J=12.9, 5.3Hz, 1H), 4.61 (d, J=5.4Hz, 2H), 2.95–2.81 (m, 1H), 2.63–2.51 ( m, 2H), 2.07–1.98 (m, 1H).

Example 60: Synthesis of compound HJM-060

Using a method similar to Example 1, using 6-4 and Int-62 as raw materials, compound HJM-060 was obtained as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 8.84 (d, J=8.6 Hz, 1H), 8.65 (d, J=2.3 Hz, 1H), 8.52 (dd, J= 4.9, 1.6Hz, 1H), 7.87–7.77 (m, 1H), 7.60–7.47 (m, 3H), 7.40 (dd, J=8.0, 4.8Hz, 1H), 7.29–7.18 (m, 2H), 7.04 (d, J=8.6Hz, 1H), 7.00 (d, J=7.0Hz, 1H), 6.65 (s, 1H), 6.52 (t, J=5.9Hz, 1H), 6.41 (d, J=8.5Hz) ,1H),5.04(dd,J＝12.9,5.4Hz,1H),3.28-3.21(m,2H),3.09(s,2H),2.93-2.81(m,1H),2.64-2.45(m,2H) ), 2.41 (t, J=6.4Hz, 2H), 2.24 (s, 3H), 2.07–1.96 (m, 1H), 1.58–1.44 (m, 4H).

LCMS[M+H] ⁺ 623.3.

Example 61: Synthesis of compound HJM-061

At room temperature, Int-63 (226.7 mg, 0.5 mmol), Int-64 (150.1 mg, 0.5 mmol), and glacial acetic acid (150.0 mg, 2.50 mmol, 142.85 μL) were added to 1,2-dichloroethane ( 8 mL), and after stirring for 0.5 hours, sodium triacetoxyborohydride (106.0 mg, 0.5 mmol) was added to the reaction solution, and stirring was continued for 2.5 hours. After completion of the reaction, the reaction solution was concentrated to obtain a crude product. The crude product was purified by preparative HPLC (hydrochloric acid system) to give the hydrochloride salt of compound HJM-061 (2.6 mg, yield 0.8%) as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.13(s, 1H), 10.36(s, 1H), 9.46(d, J=8.5Hz, 1H), 8.92(s, 1H), 8.71(s, 1H), 8.30 (s, 1H), 7.92–7.66 (m, 4H), 7.64–7.46 (m, 2H), 7.35–7.18 (m, 2H), 6.72 (s, 1H), 6.58 (d, J= 8.3Hz, 1H), 5.20–5.06 (m, 1H), 4.17 (s, 2H), 3.91–3.83 (m, 2H), 3.55–3.26 (m, 6H), 2.98–2.79 (m, 4H), 2.64 –2.47(m,2H),2.09–1.97(m,1H). LCMS[M+H] ⁺ 624.5.

Example 62: Synthesis of Compound HJM-062

Using a method similar to Example 1, using 6-4 and Int-65 as starting materials, compound HJM-062 was obtained as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 8.88 (s, 1H), 8.65 (d, J=2.4Hz, 1H), 8.52 (dd, J=4.8, 1.7Hz, 1H), 7.83(d, J=7.9Hz, 1H), 7.78–7.70 (m, 2H), 7.62–7.56 (m, 2H), 7.51 (d, J=8.0Hz, 1H), 7.41 (dd, J ＝8.0, 4.8Hz, 1H), 7.26(t, J＝7.5Hz, 1H), 7.21(t, J＝7.3Hz, 1H), 6.66(s, 1H), 6.41(d, J＝8.4Hz, 1H) ), 5.11(dd, J=12.8, 5.4Hz, 1H), 3.19–3.06 (m, 4H), 2.94–2.82 (m, 1H), 2.70–2.42 (m, 4H), 2.26 (s, 3H), 2.10–2.00 (m, 1H), 1.70–1.54 (m, 4H). LCMS[M+H] ⁺ 640.2.

Example 63: Synthesis of compound HJM-063

Using a method similar to Example 1, using 6-4 and Int-66 as raw materials, compound HJM-063 was obtained as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 9.11 (d, J=8.2 Hz, 1H), 8.76 (d, J=2.2 Hz, 1H), 8.66 (dd, J= 5.1, 1.5Hz, 1H), 8.08(d, J=8.0Hz, 1H), 7.77(s, 1H), 7.76(s, 1H), 7.65(dd, J=7.9, 5.0Hz, 1H), 7.62( t, J=4.1Hz, 1H), 7.59 (dd, J=7.4, 1.5Hz, 1H), 7.52 (d, J=8.1Hz, 1H), 7.28 (dd, J=7.7, 1.5Hz, 1H), 7.22(td,J＝7.4,1.2Hz,1H),6.69(s,1H),6.46(d,J＝8.1Hz,1H),5.11(dd,J＝12.7,5.4Hz,1H),3.65(t , J＝6.2Hz, 2H), 3.43(t, J＝6.4Hz, 2H), 3.31(t, J＝6.2Hz, 2H), 2.88(ddd, J＝16.7, 13.6, 5.3Hz, 1H), 2.64 – 2.50 (m, 2H), 2.34 – 2.27 (m, 2H), 2.09 – 2.00 (m, 1H), 1.77 (p, J=6.8 Hz, 2H). LCMS[M+H] ⁺ 627.0.

Example 64: Synthesis of Compound HJM-064

Using a method similar to Example 1, using 6-4 and Int-67 as starting materials, compound HJM-064 was obtained as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ 11.11(s, 1H), 9.35(d, J=8.2Hz, 1H), 8.68(s, 1H), 8.58(s, 1H), 7.91(d, J=7.8Hz, 1H), 7.57 (dd, J=7.5, 4.4Hz, 1H), 7.55–7.42 (m, 3H), 7.38–7.31 (m, 2H), 7.32–7.18 (m, 4H), 7.02 (d, J=7.1Hz, 1H), 6.87 (dd, J=8.6, 3.5Hz, 1H), 6.70–6.63 (m, 2H), 6.38 (d, J=8.1Hz, 1H), 5.07 (dd, J=12.9, 5.4Hz, 1H), 4.81 (p, J=6.8Hz, 1H), 3.55 (s, 2H), 2.97–2.82 (m, 1H), 2.63–2.50 (m, 2H), 2.09–1.99 (m, 1H), 1.51 (d, J=6.7Hz, 3H). LCMS[M+H] ⁺ 642.1.

Example 65: Synthesis of compound HJM-065

Using a method similar to Example 1, using Int-68 and Int-7 as raw materials, compound HJM-065 was obtained as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.08 (d, J=8.3 Hz, 1H), 8.90 (d, J=0.9 Hz, 1H), 8.64 (d, J= 2.3Hz, 1H), 8.54 (dd, J=4.8, 1.6Hz, 1H), 8.43 (d, J=5.7Hz, 1H), 7.82 (dt, J=8.0, 2.0Hz, 1H), 7.62 (dt, J=5.7, 1.0Hz, 1H), 7.57 (dd, J=8.6, 7.1Hz, 1H), 7.43 (dd, J=7.9, 4.7Hz, 1H), 7.07 (d, J=8.6Hz, 1H), 7.02(d,J＝7.0Hz,1H),6.80(t,J＝1.1Hz,1H),6.52(t,J＝6.0Hz,1H),6.43(d,J＝8.3Hz,1H),5.05( dd, J=12.9, 5.3Hz, 1H), 3.26 (q, J=6.8Hz, 2H), 2.88 (ddd, J=17.3, 14.0, 5.4Hz, 1H), 2.64–2.47 (m, 2H), 2.24 (t, J=7.3Hz, 2H), 2.08–1.98 (m, 1H), 1.60–1.49 (m, 4H), 1.40–1.22 (m, 4H).

LCMS[M+H] ⁺ 609.4.

Example 66: Synthesis of compound HJM-066

Using a method similar to Example 59, using Int-60 and Int-69 as starting materials, compound HJM-066 was obtained as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ 11.08(s, 1H), 9.64(d, J=8.0Hz, 1H), 8.71(brs, 1H), 8.59(brs, 1H), 7.95(s, 1H), 7.90(d, J＝8.0Hz, 1H), 7.65-7.47(m, 4H), 7.30(td, J＝7.7, 1.4Hz, 1H), 7.25(td, J＝7.5, 1.1Hz, 1H) ),7.14(d,J＝8.6Hz,1H),7.03(d,J＝7.0Hz,1H),6.78(s,1H),6.74(t,J＝6.1Hz,1H),6.40(d,J ＝7.9Hz,1H),5.25(d,J＝2.4Hz,2H),5.04(dd,J＝13.0,5.4Hz,1H),3.59(d,J＝6.7Hz,2H),2.95(t,J = 7.2 Hz, 2H), 2.92-2.80 (m, 1H), 2.62-2.51 (m, 2H), 2.06-1.95 (m, 1H). LCMS[M+H] ⁺ 633.0.

Example 67: Synthesis of compound HJM-067

Using a method similar to Example 59, using Int-70 and Int-69 as starting materials, compound HJM-067 was obtained as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ 11.07(s, 1H), 9.22(d, J=8.2Hz, 1H), 8.56(d, J=2.3Hz, 1H), 8.51(d, J= 4.8Hz, 1H), 7.82(s, 1H), 7.72(d, J=8.0Hz, 1H), 7.61–7.56(m, 2H), 7.50(d, J=8.1Hz, 1H), 7.39(dd, J=7.9, 4.8Hz, 1H), 7.26(t, J=7.7Hz, 1H), 7.21(t, J=7.4Hz, 1H), 7.11(d, J=8.6Hz, 1H), 7.04(d, J=7.1Hz, 1H), 6.73(t, J=6.1Hz, 1H), 6.64(s, 1H), 6.36(d, J=8.1Hz, 1H), 5.05(dd, J=12.9, 5.4Hz, 1H), 4.57 (t, J=6.7Hz, 2H), 3.54 (q, J=6.8Hz, 2H), 2.94–2.81 (m, 5H), 2.62–2.51 (m, 2H), 2.06–1.98 (m , 1H). LCMS[M+H] ⁺ 647.1.

Example 68: Synthesis of Compound HJM-068

Using a method similar to Example 59, using Int-70 and Int-61 as starting materials, compound HJM-068 was obtained as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.20 (d, J=8.2 Hz, 1H), 8.56 (d, J=2.3 Hz, 1H), 8.52 (dd, J= 4.8, 1.6Hz, 1H), 7.92 (s, 1H), 7.71 (dt, J=7.9, 2.0Hz, 1H), 7.60–7.48 (m, 3H), 7.39 (dd, J=7.9, 4.8Hz, 1H) ), 7.27 (td, J=7.7, 1.6Hz, 1H), 7.22 (td, J=7.4, 1.2Hz, 1H), 7.15 (d, J=8.6Hz, 1H), 7.08–7.02 (m, 2H) ,6.63(s,1H),6.34(d,J=8.1Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),4.62–4.51(m,4H),2.94–2.83(m,3H ), 2.63–2.51 (m, 2H), 2.06–1.97 (m, 1H). LCMS[M+H] ⁺ 633.0.

Example 69: Synthesis of compound HJM-069

In a similar manner to Example 23, by using 7-2 and Int-71 as starting materials, compound HJM-069 was obtained as a yellow solid. LCMS[M+H] ⁺ 629.4.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 9.49 (d, J=8.2 Hz, 1H), 8.74 (d, J=2.3 Hz, 1H), 8.65 (d, J= 2.2Hz, 1H), 8.61 (dd, J=4.9, 1.6Hz, 1H), 8.02–7.93 (m, 2H), 7.63–7.47 (m, 5H), 7.35 (t, J=6.4Hz, 1H), 7.29(dd,J＝7.7,1.6Hz,1H),7.24(td,J＝7.4,1.2Hz,1H),7.05(d,J＝7.1Hz,1H),7.01(d,J＝8.6Hz,1H) ),6.74(s,1H),6.41(d,J＝8.0Hz,1H),5.07(dd,J＝12.9,5.4Hz,1H),4.64(d,J＝6.1Hz,2H),3.89(s , 2H), 2.89 (ddd, J=18.0, 13.8, 5.4Hz, 1H), 2.63–2.50 (m, 2H), 2.09–1.98 (m, 1H).

Example 70: Synthesis of Compound HJM-070

Using a method similar to Example 1, by using 6-4 and Int-72 as starting materials, compound HJM-070 was obtained as a yellow solid. LCMS[M+H] ⁺ 625.2.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.15 (s, 1H), 9.56 (d, J=8.0 Hz, 1H), 8.90 (d, J=2.1 Hz, 1H), 8.77 (d, J= 5.3Hz, 1H), 8.37–8.29 (m, 2H), 8.11 (d, J=16.5Hz, 1H), 7.91–7.78 (m, 3H), 7.70–7.53 (m, 5H), 7.37 (d, J ＝7.9Hz, 2H), 7.31(t, J＝7.6Hz, 1H), 7.25(t, J＝7.4Hz, 1H), 6.74(s, 1H), 6.54(d, J＝8.0Hz, 1H), 5.17(dd,J=12.9,5.4Hz,1H),3.65(s,2H),2.91(ddd,J=17.8,13.9,5.4Hz,1H),2.65–2.53(m,2H),2.12–2.04( m, 1H).

Example 71: Synthesis of compound HJM-071

Using a method similar to Example 23, using 7-2 and Int-73 as starting materials, compound HJM-071 was obtained as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 9.69 (d, J=7.9 Hz, 1H), 8.92 (s, 1H), 8.78 (d, J=5.4 Hz, 1H) ,8.64(s,1H),8.36(d,J＝8.1Hz,1H),8.05(d,J＝8.1Hz,1H),7.86(t,J＝6.9Hz,1H),7.64(d,J＝ 8.3Hz, 1H), 7.62–7.59 (m, 1H), 7.57–7.51 (m, 2H), 7.46 (s, 1H), 7.31 (dd, J=7.8, 1.5Hz, 1H), 7.25 (t, J ＝7.3Hz,1H),7.09(d,J＝7.1Hz,1H),7.02(d,J＝8.6Hz,1H),6.77(s,1H),6.53(d,J＝7.9Hz,1H), 5.09(dd, J＝12.9, 5.4Hz, 1H), 4.80(s, 2H), 3.80(s, 2H), 2.90(ddd, J＝17.4, 13.9, 5.5Hz, 1H), 2.65–2.53(m, 2H), 2.09–2.00 (m, 1H). LCMS[M+H] ⁺ 629.2.

Example 72: Synthesis of Compound HJM-072

Using a method similar to Example 23, using 7-2 and Int-74 as starting materials, compound HJM-072 was obtained as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ )δ 11.09(s, 1H), 9.21(d, J=8.1Hz, 1H), 8.51-8.47(m, 2H), 7.65(d, J=8.1Hz, 1H), 7.62–7.57 (m, 1H), 7.55–7.48 (m, 2H), 7.35–7.20 (m, 7H), 7.18 (t, J=6.2Hz, 1H), 7.02 (d, J=7.1Hz) ,1H),6.96(d,J＝8.6Hz,1H),6.66(s,1H),6.34(d,J＝8.0Hz,1H),5.07(dd,J＝12.8,5.4Hz,1H),4.52 (d, J=5.8Hz, 2H), 3.80 (q, J=6.9Hz, 1H), 2.89 (ddd, J=17.9, 13.9, 5.2Hz, 1H), 2.64–2.53 (m, 2H), 2.09– 1.99 (m, 1H), 1.37 (d, J=7.0Hz, 3H). LCMS[M+H] ⁺ 642.2.

Example 73: Synthesis of Compound HJM-073

In a similar manner to Example 23, by using 7-2 and Int-75 as starting materials, compound HJM-073 was obtained as a yellow solid. LCMS[M+H] ⁺ 642.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.18 (d, J=8.2Hz, 1H), 8.65 (d, J=2.3Hz, 1H), 8.56 (dd, J= 4.8, 1.6Hz, 1H), 7.87–7.80 (m, 1H), 7.51–7.44 (m, 3H), 7.42 (d, J=8.1Hz, 1H), 7.32 (s, 4H), 7.27–7.16 (m ,3H),7.02(d,J＝7.0Hz,1H),6.98(d,J＝8.6Hz,1H),6.43(s,1H),6.33(d,J＝8.1Hz,1H),5.07(dd , J=12.9, 5.4Hz, 1H), 4.54 (d, J=6.2Hz, 2H), 3.79 (q, J=6.9Hz, 1H), 2.89 (ddd, J=17.9, 13.9, 5.4Hz, 1H) , 2.63–2.52 (m, 2H), 2.10–2.00 (m, 1H), 1.33 (d, J=7.0Hz, 3H).

Example 74: Synthesis of Compound HJM-074

Using a method similar to Example 1, using Int-76 and Int-7 as raw materials, compound HJM-074 was obtained as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09(s, 1H), 8.98(d, J=8.4Hz, 1H), 8.84(s, 1H), 8.82(s, 1H), 7.61-7.52( m, 2H), 7.52–7.44 (m, 2H), 7.25 (td, J=7.7, 1.6Hz, 1H), 7.20 (t, J=7.2Hz, 1H), 7.06 (d, J=8.6Hz, 1H) ),7.01(d,J＝7.0Hz,1H),6.70(s,1H),6.51(t,J＝5.9Hz,1H),6.40(d,J＝8.3Hz,1H),5.05(dd,J =12.9,5.4Hz,1H),3.26(q,J=6.8Hz,2H),2.88(ddd,J=17.5,14.1,5.4Hz,1H),2.63–2.51(m,2H),2.26(td, J=7.2, 3.4Hz, 2H), 2.08-1.98 (m, 1H), 1.59-1.46 (m, 4H), 1.40-1.22 (m, 4H).

LCMS[M+H] ⁺ 609.0.

Example 75: Synthesis of compound HJM-075

In a similar manner to Example 1, by using Int-77 and Int-7 as starting materials, compound HJM-075 was obtained as a yellow solid. LCMS[M+H] ⁺ 609.0.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.21 (dd, J=4.8, 1.8 Hz, 1H), 9.17 (d, J=8.3 Hz, 1H), 7.85-7.72 ( m, 2H), 7.62–7.53 (m, 2H), 7.53–7.47 (m, 1H), 7.27 (td, J=7.7, 1.6Hz, 1H), 7.22 (td, J=7.4, 1.2Hz, 1H) ,7.07(d,J＝8.6Hz,1H),7.01(d,J＝7.0Hz,1H),6.72(t,J＝1.0Hz,1H),6.59(d,J＝8.2Hz,1H),6.51 (brs, 1H), 5.05 (dd, J=12.9, 5.4Hz, 1H), 3.29–3.21 (m, 2H), 2.88 (ddd, J=17.4, 14.0, 5.4Hz, 1H), 2.63–2.50 (m ,2H),2.27(t,J＝7.4,1.8Hz,2H),2.07–1.98(m,1H),1.55(t,J＝7.4Hz,4H),1.30(d,J＝9.9Hz,4H) .

Example 76: Synthesis of Compound HJM-076

Using a method similar to Example 1, using 6-4 and Int-78 as starting materials, compound HJM-076 was obtained as a yellow solid. LCMS[M+H] ⁺ 618.4.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09(s, 1H), 9.02(d, J=8.3Hz, 1H), 8.68(s, 1H), 8.58(d, J=4.7Hz, 1H) ,7.91(d,J＝7.9Hz,1H),7.60-7.46(m,4H),7.30-7.19(m,2H),7.08-7.00(m,2H),6.63(s,1H),6.46(brs ,1H),6.39(d,J＝8.1Hz,1H),5.06(dd,J＝13.1,5.3Hz,1H),3.38(d,J＝5.3Hz,2H),2.93–2.82(m,1H) , 2.64–2.51 (m, 2H), 2.42 (s, 2H), 2.08–1.99 (m, 1H), 1.60 (s, 6H).

Example 77: Synthesis of compound HJM-077

In a similar manner to Example 1, by using Int-79 and Int-34 as starting materials, compound HJM-077 was obtained as a yellow solid. LCMS[M+H] ⁺ 645.5.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.10(s, 1H), 9.40(d, J=8.4Hz, 1H), 8.68(d, J=2.3Hz, 1H), 8.56(d, J= 4.8Hz, 1H), 8.50 (dd, J=4.7, 1.6Hz, 1H), 8.14 (dd, J=8.1, 1.6Hz, 1H), 7.87 (d, J=8.0Hz, 1H), 7.52–7.43 ( m, 2H), 7.40(dd, J=8.0, 4.6Hz, 1H), 7.32–7.24(m, 4H), 7.21(t, J=6.1Hz, 1H), 7.07(s, 1H), 7.01(d ,J=7.1Hz,1H),6.95(d,J=8.6Hz,1H),6.49(d,J=8.3Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.53(d , J=6.2Hz, 2H), 3.60–3.48 (m, 2H), 2.95–2.83 (m, 1H), 2.63–2.51 (m, 2H), 2.09–1.99 (m, 1H).

Example 78: Synthesis of Compound HJM-078

In a similar manner to Example 1, by using Int-80 and Int-34 as starting materials, compound HJM-078 was obtained as a yellow solid. LCMS[M+H] ⁺ 642.5.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.10(s, 1H), 8.58(d, J=4.7Hz, 1H), 8.49(s, 1H), 7.71(d, J=8.0Hz, 1H) ,7.61(d,J＝7.6Hz,1H),7.56(d,J＝8.2Hz,1H),7.50(t,J＝7.8Hz,1H),7.45(dd,J＝7.9,4.8Hz,1H) ,7.35–7.18(m,7H),7.10(s,1H),7.02(d,J=7.1Hz,1H),6.97(d,J=8.6Hz,1H),6.75(s,1H),5.07( dd, J=12.9, 5.4Hz, 1H), 4.54 (d, J=6.1Hz, 2H), 3.92–3.78 (m, 2H), 2.95 (s, 3H), 2.93–2.84 (m, 1H), 2.64 – 2.53 (m, 2H), 2.09 – 2.00 (m, 1H).

Example 79: Synthesis of Compound HJM-079

In a similar manner to Example 1, by using Int-81 and Int-34 as starting materials, compound HJM-079 was obtained as a yellow solid. LCMS[M+H] ⁺ 578.4.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 9.17 (d, J=8.3 Hz, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.48 (dd, J= 4.8,1.6Hz,1H),7.69(dt,J=8.1,2.0Hz,1H),7.63(d,J=1.8Hz,1H),7.50(dd,J=8.6,7.1Hz,1H),7.36( dd,J=7.9,4.8Hz,1H),7.28(d,J=7.9Hz,2H),7.24–7.17(m,3H),7.01(d,J=7.1Hz,1H),6.94(d,J ＝8.6Hz,1H),6.40(dd,J＝3.4,1.9Hz,1H),6.19-6.14(m,2H),5.06(dd,J＝13.0,5.4Hz,1H),4.52(d,J＝ 6.2Hz, 2H), 3.50 (s, 2H), 2.95–2.84 (m, 1H), 2.64–2.52 (m, 2H), 2.09–1.99 (m, 1H).

Example 80: Synthesis of Compound HJM-080

In a similar manner to Example 1, by using Int-57 and Int-34 as starting materials, compound HJM-080 was obtained as a yellow solid. LCMS[M+H] ⁺ 629.0.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.10(s, 1H), 9.39(d, J=8.2Hz, 1H), 8.66(d, J=2.4Hz, 1H), 8.56(d, J= 4.8Hz, 1H), 8.26 (dd, J=4.9, 1.7Hz, 1H), 8.06 (dd, J=7.6, 1.7Hz, 1H), 7.86 (dt, J=8.1, 2.0Hz, 1H), 7.53– 7.43(m, 2H), 7.33(dd, J=7.7, 4.9Hz, 1H), 7.29(d, J=8.1Hz, 2H), 7.24(d, J=8.1Hz, 2H), 7.21(t, J ＝6.4Hz,1H),7.01(d,J＝7.1Hz,1H),6.94(d,J＝8.6Hz,1H),6.75(s,1H),6.40(d,J＝8.1Hz,1H), 5.07(dd,J＝12.9,5.4Hz,1H),4.52(d,J＝6.1Hz,2H),3.56(s,2H),2.89(ddd,J＝17.3,14.0,5.3Hz,1H),2.64 –2.52 (m, 2H), 2.09–2.00 (m, 1H).

Example 81: Synthesis of Compound HJM-081

In a similar manner to Example 1, by using Int-54 and Int-82 as starting materials, compound HJM-081 was obtained as a yellow solid. LCMS[M+H] ⁺ 635.2.

¹ H NMR (400MHz, DMSO-d ₆ )δ11.08(s, 1H), 9.64(d, J=8.1Hz, 1H), 8.73(s, 1H), 8.60(s, 1H), 8.01(s, 1H), 7.98–7.88 (m, 2H), 7.79 (d, J=7.5Hz, 1H), 7.57 (t, J=7.8Hz, 1H), 7.52 (dd, J=7.9, 4.9Hz, 1H), 7.40–7.29 (m, 2H), 7.22 (s, 1H), 7.20 (d, J=8.6Hz, 1H), 7.11–7.06 (m, 1H), 7.05 (d, J=7.1Hz, 1H), 6.51 (d, J＝8.2Hz, 1H), 5.25 (d, J＝3.4Hz, 2H), 5.05 (dd, J＝12.8, 5.4Hz, 1H), 4.61 (d, J＝5.2Hz, 2H), 2.94 – 2.82 (m, 1H), 2.62 – 2.52 (m, 2H), 2.06 – 1.97 (m, 1H).

Example 82: Synthesis of Compound HJM-082

Using a method similar to Example 1, by using 6-4 and Int-83 as starting materials, compound HJM-082 was obtained as a yellow solid. LCMS[M+H] ⁺ 618.2.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 9.47 (d, J=8.1 Hz, 1H), 8.72 (d, J=2.3 Hz, 1H), 8.62 (dd, J= 4.9,1.6Hz,1H),7.97(d,J=8.0Hz,1H),7.71(s,1H),7.64-7.58(m,1H),7.60-7.51(m,3H),7.46(s,1H) ),7.30(td,J=7.7,1.5Hz,1H),7.25(td,J=7.5,1.0Hz,1H),7.15(d,J=8.6Hz,1H),7.03(d,J=7.1Hz ,1H),6.89–6.85(m,1H),6.75(s,1H),6.41(d,J=7.9Hz,1H),5.04(dd,J=12.8,5.4Hz,1H),4.92(d, J=2.8Hz, 2H), 4.38 (d, J=4.4Hz, 2H), 2.88 (ddd, J=16.9, 13.7, 5.4Hz, 1H), 2.62–2.52 (m, 2H), 2.06–1.98 (m , 1H).

Example 83: Synthesis of Compound HJM-083

In a similar manner to Example 1, by using Int-57 and Int-82 as starting materials, compound HJM-083 was obtained as a yellow solid. LCMS[M+H] ⁺ 620.0.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 9.67 (d, J=8.0Hz, 1H), 8.68 (d, J=2.4Hz, 1H), 8.56 (dd, J= 4.8,1.6Hz,1H),8.27(dd,J=4.9,1.7Hz,1H),8.09(dd,J=7.7,1.7Hz,1H),8.01(s,1H),7.86(dt,J=7.9 ,2.1Hz,1H),7.60–7.53(m,1H),7.45(dd,J=7.9,4.8Hz,1H),7.35(dd,J=7.6,4.9Hz,1H),7.19(d,J= 8.6Hz, 1H), 7.08(t, J＝6.1Hz, 1H), 7.05(d, J＝7.1Hz, 1H), 6.85(s, 1H), 6.42(d, J＝7.9Hz, 1H), 5.26 (s, 2H), 5.05 (dd, J=12.9, 5.4Hz, 1H), 4.61 (d, J=6.1Hz, 2H), 2.94–2.82 (m, 1H), 2.63–2.51 (m, 2H), 2.06–1.98 (m, 1H).

Example 84: Synthesis of Compound HJM-084

Using compound Int-84.1 as raw material, compound HJM-084 was prepared by referring to the method of compound HJM-43, LCMS: m/z=652.4 (M+H) ⁺ .

1H NMR (400MHz, DMSO-d6) δ11.11(s, 1H), 9.73(d, J=8.3Hz, 1H), 8.85(s, 1H), 8.76-8.64(m, 1H), 8.15(d, J=7.5Hz, 1H), 8.09(s, 1H), 7.94(t, J=7.4Hz, 2H), 7.81-7.76(m, 2H), 7.70(dd, J=5.3, 6.8Hz, 1H), 7.63(d,J＝7.1Hz,1H),7.41-7.31(m,2H),7.24(s,1H),6.57(d,J＝8.0Hz,1H),5.26(d,J＝4.0Hz,2H ), 5.11(dd, J=5.4, 12.9Hz, 1H), 4.52(s, 2H), 2.92-2.83(m, 1H), 2.63-2.54(m, 2H), 2.08-1.99(m, 1H).

Example 85: Compound N-(benzofuran-2-yl(pyridin-3-yl)methyl)-2-(3-((((2-(2,6-dioxopiperidin-3-yl) )-1,3-dioxoisoindolin-4-yl)amino)methyl)-1H-pyrazol-1-yl)acetamide (HJM-085) synthesis

Using compound Int-85 and compound 6-4 as raw materials, compound HJM-085 was prepared according to the method of Example 1, LCMS: m/z=618.2(M+H) ⁺ .

¹ H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.47(d,J=8.0Hz,1H),8.70(s,1H),8.59(d,J=4.5Hz,1H), 7.91(d,J＝8.0Hz,1H),7.67(d,J＝2.1Hz,1H),7.61(d,J＝7.3Hz,1H),7.57-7.46(m,3H),7.34-7.20(m ,2H),7.11(d,J＝8.6Hz,1H),7.06-6.93(m,2H),6.76(s,1H),6.41(d,J＝8.0Hz,1H),6.20(d,J＝ 2.1Hz,1H),5.05(dd,J=5.4,12.8Hz,1H),4.94(d,J=1.4Hz,2H),4.46(d,J=4.8Hz,2H),2.95-2.81(m, 1H), 2.56(s, 2H), 2.08-1.96(m, 1H).

Example 86: N-(benzofuran-2-yl(pyridin-3-yl)methyl)-2-(4-((((2-(2,6-dioxopiperidin-3-yl)) Synthesis of -1,3-dioxoisoindolin-4-yl)thio)methyl)-1H-1,2,3-triazol-1-yl)acetamide (HJM-086)

Using compounds Int-86 and Int-42 as raw materials, the compound HJM-086 was prepared according to the method of compound HJM-43, LCMS: m/z=636.2 (M+H) ⁺ .

¹ H NMR(400MHz, DMSO-d6)δ11.21-10.99(m,1H),9.63(d,J=8.0Hz,1H),8.66(d,J=1.9Hz,1H),8.58-8.51(m ,1H),8.09(s,1H),7.94(d,J=8.1Hz,1H),7.87-7.74(m,2H),7.68-7.59(m,2H),7.54(d,J=7.9Hz, 1H), 7.44(dd, J＝4.8, 7.9Hz, 1H), 7.34-7.20(m, 2H), 6.76(s, 1H), 6.38(d, J＝7.9Hz, 1H), 5.25(d, J ＝1.6Hz, 2H), 5.11(dd, J＝5.4, 12.8Hz, 1H), 4.52(s, 2H), 2.93-2.82(m, 1H), 2.62-2.55(m, 2H), 2.07-2.00( m, 1H).

Example 87: N-(benzofuran-2-yl(pyridin-3-yl)methyl)-2-(4-((((2-(2,6-dioxopiperidin-3-yl)) Synthesis of -1,3-dioxoisoindolin-4-yl)amino)methyl)-1H-imidazol-1-yl)acetamide (HJM-087)

Using compound Int-87 as raw material, compound HJM-087 was prepared with reference to Example 1, LCMS: m/z=618.3 (M+H) ⁺ .

¹ H NMR(400MHz, DMSO-d6)δ11.10(s,1H),9.48(d,J=8.1Hz,1H),8.67(d,J=2.1Hz,1H),8.55(d,J=1.5 ,4.8Hz,1H),7.83(d,J=7.4Hz,1H),7.66(s,1H),7.63-7.52(m,3H),7.44(d,J=4.8,7.9Hz,1H),7.33 -7.17(m, 3H), 7.10(s, 1H), 7.04(d, J=7.0Hz, 1H), 6.90(t, J=5.6Hz, 1H), 6.75(s, 1H), 6.39(d, J＝8.0Hz, 1H), 5.06(d, J＝5.4, 12.8Hz, 1H), 4.91-4.76(m, 2H), 4.39(d, J＝5.5Hz, 2H), 3.01-2.76(m, 1H) ), 2.63-2.53 (m, 2H), 2.09-2.01 (m, 1H).

Example 88: N-(benzofuran-2-yl(pyridin-3-yl)methyl)-2-(3-((((2-(2,6-dioxopiperidin-3-yl)) Synthesis of -1,3-Dioxisoindolin-4-yl)amino)methyl)-1H-pyrrol-1-yl)acetamide (HJM-088)

Using compound Int-97 and compound 7-2 as raw materials, compound HJM-088 was prepared according to the method of compound 83-4, LCMS: m/z=617.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 9.34 (d, J=8.1 Hz, 1H), 8.67 (d, J=1.8 Hz, 1H), 8.59-8.55 (m, 1H), 7.87(d, J=7.9Hz, 1H), 7.61(d, J=7.5Hz, 1H), 7.56-7.46(m, 3H), 7.31-7.21(m, 2H), 7.14(d, J =8.5Hz,1H),7.04-6.98(m,1H),6.77-6.62(m,4H),6.38(d,J=8.1Hz,1H),6.03-6.00(m,1H),5.04(dd, J=5.3, 12.8Hz, 1H), 4.67-4.62(m, 2H), 4.32-4.26(m, 2H), 2.94-2.81(m, 1H), 2.61-2.53(m, 2H), 2.05-1.98( m, 1H).

Example 89: 2-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)thio)methyl) -1H-1,2,3-Triazol-1-yl)-N-(furo[2,3-b]pyridin-2-yl(pyridin-3-yl)methyl)acetamide (HJM-089) Synthesis

Using compound Int-89 as raw material, compound HJM-089 was prepared according to the method of compound HJM-043, LCMS: m/z=637.1 (M+H) ⁺ .

¹ H NMR(400MHz, DMSO-d6)δ11.23-10.99(m,1H),9.68(d,J=8.0Hz,1H),8.69(d,J=2.5Hz,1H),8.58-8.54(m ,1H),8.27(dd,J＝1.6,4.8Hz,1H),8.12-8.07(m,2H),7.94(d,J＝8.0Hz,1H),7.86(d,J＝7.6Hz,1H) ,7.78(t,J＝7.7Hz,1H),7.63(d,J＝7.1Hz,1H),7.45(dd,J＝5.1,7.8Hz,1H),7.35(dd,J＝4.8,7.7Hz, 1H), 6.86(s, 1H), 6.42(d, J=7.6Hz, 1H), 5.27(s, 2H), 5.15-5.08(m, 1H), 4.52(s, 2H), 2.63-2.53(m , 3H), 2.0-2.01(m, 1H).

Example 90: N-(benzofuran-2-yl(pyridin-3-yl)methyl)-2-(5-((((2-(2,6-dioxopiperidin-3-yl)) Synthesis of -1,3-dioxoisoindolin-4-yl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide (HJM-090)

Using compound Int-90 and compound 7-2 as raw materials, compound HJM-090 was prepared according to the method of compound HJM-023, LCMS: m/z=620.2 (M+H) ⁺ .

1H NMR(400MHz, DMSO-d6)δ11.19-11.00(m,1H),9.57(d,J=8.0Hz,1H),8.66(d,J=2.1Hz,1H),8.55(d,J= 1.6,4.8Hz,1H),7.85-7.81(m,1H),7.64-7.53(m,3H),7.44(d,J=4.7,7.9Hz,1H),7.32-7.21(m,3H),7.19 -7.08(m, 2H), 6.76(s, 1H), 6.37(d, J=6.9Hz, 1H), 5.09(d, J=5.3, 12.8Hz, 1H), 4.86(d, J=6.5Hz, 2H), 4.05(s, 2H), 2.92-2.84(m, 1H), 2.62-2.54(m, 2H), 2.10-2.03(m, 1H).

Example 91: 2-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl) Synthesis of -1H-imidazol-1-yl)-N-(furo[2,3-b]pyridin-2-yl(pyridin-3-yl)methyl)acetamide (HJM-091)

Compound HJM-091 was prepared by using compound Int-87 and compound Int-40 as raw materials according to the method of Example 1, LCMS: m/z=619.2(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d6)δ11.10(s, 1H), 9.52(d, J=8.0Hz, 1H), 8.69(d, J=2.1Hz, 1H), 8.56(d, J=1.4 ,4.8Hz,1H),8.27(d,J＝5.0Hz,1H),8.09(d,J＝1.6,7.7Hz,1H),7.85(d,J＝8.0Hz,1H),7.63-7.54(m ,2H),7.45(t,J＝6.2Hz,1H),7.34(t,J＝6.3Hz,1H),7.19(d,J＝8.6Hz,1H),7.08(s,1H),7.05(d , J＝6.9Hz, 1H), 6.88(t, J＝5.7Hz, 1H), 6.84(s, 1H), 6.43(d, J＝8.1Hz, 1H), 5.05(d, J＝5.4, 12.8Hz) ,1H),4.88-4.78(m,2H),4.38(d,J=5.5Hz,2H),2.97-2.79(m,1H),2.63-2.53(m,2H),2.16-1.88(m,1H ).

Example 92: N-(benzofuran-2-yl(pyridazin-3-yl)methyl)-2-(4-((((2-(2,6-dioxopiperidin-3-yl)) Synthesis of -1,3-Dioxisoindolin-4-yl)amino)methyl)-1H-imidazol-1-yl)acetamide (HJM-092)

Compound HJM-092 was prepared by using compound Int-87 and compound Int-77 as raw materials according to the method of Example 1, LCMS: m/z=619.3 (M+H) ⁺ .

¹ H NMR(400MHz,DMSO-d6)δ11.08(s,1H),9.63(d,J=8.0Hz,1H),9.24(d,J=1.6,4.9Hz,1H),7.87(d,J =1.6,8.6Hz,1H),7.78(d,J=5.0,8.5Hz,1H),7.64-7.51(m,4H),7.32-7.16(m,3H),7.07(s,1H),7.03( d, J＝7.0Hz, 1H), 6.87(t, J＝5.6Hz, 1H), 6.81(s, 1H), 6.60(d, J＝8.0Hz, 1H), 5.05(d, J＝5.4, 12.8 Hz, 1H), 4.90-4.79(m, 2H), 4.37(d, J=5.5Hz, 2H), 2.94-2.83(m, 1H), 2.63-2.53(m, 2H), 2.08-1.98(m, 1H).

Example 93: N-(benzofuran-2-yl(pyridin-3-yl)methyl)-2-(4-(((((2-(2,6-dioxopiperidin-3-yl) )-1-oxoisoindol-4-yl]amino)methyl)-1H-imidazol-1-yl)acetamide (HJM-093) synthesis

Using compound Int-93 and compound 6-4 as raw materials, compound HJM-093 was prepared according to the method of Example 1, m/z=604.1 (M+H) ⁺ .

¹ H NMR(400MHz, DMSO-d6)δ11.00(s,1H),9.44(d,J=8.3Hz,1H),8.65(d,J=2.0Hz,1H),8.54(dd,J=1.4 ,4.8Hz,1H),7.84-7.79(m,1H),7.63-7.50(m,3H),7.42(dd,J=4.8,7.9Hz,1H),7.32-7.19(m,3H),6.99( s,1H),6.92(d,J=7.3Hz,1H),6.82(d,J=8.1Hz,1H),6.74(s,1H),6.37(d,J=8.3Hz,1H),5.97( t, J=5.5Hz, 1H), 5.10(dd, J=4.9, 13.3Hz, 1H), 4.78(s, 2H), 4.28-4.12(m, 4H), 2.99-2.85(m, 1H), 2.61 (d, J=17.3 Hz, 2H), 2.08-1.95 (m, 1H).

Example 94: N-[benzofuran-2-yl(3-pyridinyl)methyl]-2-[5-[[[[2-(2,6-dioxo-3-piperidinyl)-1 Synthesis of ,3-dioxo-isoindol-4-yl]amino]methyl]-1,3,4-thiadiazol-2-yl]acetamide (HJM-094)

Using compound Int-94 and compound 7-2 as raw materials, compound HJM-094 was prepared according to the method of compound HJM-023, LCMS: m/z=636.2 (M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d6)δ11.10(s, 1H), 9.59(d, J=7.75Hz, 1H), 8.63(d, J=2.13Hz, 1H), 8.53(m, 1H), 7.80(m,1H),7.55-7.62(m,2H),7.46-7.53(m,2H),7.41(m,1H),7.20-7.30(m,2H),7.11(m,2H),6.71( s, 1H), 6.37(d, J=7.88Hz, 1H), 5.07(m, 1H), 4.96(d, J=6.50Hz, 2H), 4.19(s, 2H), 2.83-2.95(m, 1H) ),2.54-2.63(m,2H),1.99-2.10(m,1H).

Example 95: N-(benzofuran-2-yl(pyridin-3-yl)methyl)-2-(4-(((2-(2,6-dioxopiperidin-3-yl)- Synthesis of 1,3-Dioxisoindolin-5-yl)amino)methyl)-1H-imidazol-1-yl)acetamide (HJM-095)

Using compound Int-95 and compound 6-4 as raw materials, compound HJM-095 was prepared according to the method of Example 1, LCMS: m/z=618.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.05 (s, 1H), 9.45 (d, J=8.1 Hz, 1H), 8.66 (d, J=2.1 Hz, 1H), 8.54 (dd, J= 1.6,4.8Hz,1H),7.82(dd,J=1.7,7.8Hz,1H),7.64-7.50(m,4H),7.48-7.37(m,2H),7.33-7.20(m,2H),7.07 -7.01(m,2H),6.93(dd,J=2.1,8.4Hz,1H),6.74(s,1H),6.37(d,J=8.1Hz,1H),5.02(dd,J=5.4,12.7 Hz, 1H), 4.80(s, 2H), 4.25(d, J=5.4Hz, 2H), 2.94-2.80(m, 1H), 2.61-2.54(m, 2H), 2.04-1.93(m, 1H) .

Example 96:

Using compound Int-96 and compound 7-2 as raw materials, compound HJM-096 was prepared according to the method of compound HJM-023, LCMS: m/z=620.2 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 9.74 (d, J=7.88Hz, 1H), 8.67 (d, J=2.25Hz, 1H), 8.56 (m, 1H) ,7.80-7.87(m,1H),7.60-7.65(m,1H),7.51-7.58(m,2H),7.44(m,1H),7.27-7.32(m,1H),7.22-7.27(m, 2H), 7.05-7.15(m, 2H), 6.78(s, 1H), 6.38(d, J=7.88Hz, 1H), 5.63(s, 2H), 5.07(m, 1H), 4.87(d, J =6.38Hz,2H),2.79-2.96(m,1H),2.55-2.64(m,2H),1.99-2.06(m,1H).

Synthesis of Control Compounds

Control Compound 1: Synthesis of Compound Ref-1

step 1:

At room temperature, compound (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-( 4-Methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-amide hydrochloride Ref-1-1 (100 mg, 0.22 mmol), 4,7-dioxadecanedioic acid (116 mg, 0.56 mmol), HOAt (36.7 mg, 0.26 mmol), EDCI.HCl (51.6 mg, 0.26 mmol), N-methylmorpholine (114 mg, 1.10 mmol) were dissolved in anhydrous dichloromethane (15 mL), stirred at room temperature 6h. After the reaction was detected by LCMS, a small amount of water was added to quench the reaction and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase preparative HPLC (acetonitrile/(water + 0.05% HCl), 10%-100%), and lyophilized to give compound Ref-1-2 (80 mg, yield 57%) as a white solid. LCMS[M+H] ⁺ 633.6.

¹ H NMR(500MHz,Methanol-d ₄ )δ8.87(s,1H),7.47-7.39(m,4H),5.01(q,J=6.5Hz,1H),4.64(s,1H),4.57( t, J=8.1Hz, 1H), 4.43(s, 1H), 3.87(d, J=11.0Hz, 1H), 3.78-3.69(m, 5H), 3.65-3.56(m, 4H), 2.65(s ,2H),2.53(t,J=6.2Hz,2H),2.48(s,3H),2.23–2.16(m,1H),1.99–1.92(m,1H),1.51(d,J=6.8Hz, 3H), 1.05 (s, 9H).

Step 2: At room temperature, compound Ref-1-2 (20mg, 0.03mmol), compound 6-4 dihydrochloride (9mg, 0.03mmol), HOAt (5.2mg, 0.04mmol), EDCI.HCl (7.3mg , 0.04 mmol), N-methylmorpholine (15 mg, 0.15 mmol) was dissolved in anhydrous DMF (2 mL) and stirred at room temperature for 6 h. After the reaction was detected by LCMS, the reaction solution was purified by reverse-phase preparative HPLC (acetonitrile/(water + 0.05% HCl), 10%-100%), and lyophilized to obtain the hydrochloride of compound Ref-1 (13 mg, yield 49.5%), white solid. LCMS[M+H] ⁺ 839.4.

¹ H NMR(500MHz,Methanol-d ₄ )δ9.69(s,1H),9.00(d,J=7.7Hz,1H),8.92-8.87(m,1H),8.71(t,J=9.5Hz, 1H), 8.17–8.09 (m, 1H), 7.61 (d, J=7.7Hz, 1H), 7.54–7.45 (m, 5H), 7.33 (t, J=7.9Hz, 1H), 7.26 (t, J ＝7.4Hz,1H),6.87(d,J＝3.6Hz,1H),6.64(d,J＝9.1Hz,1H),5.00(q,J＝6.8Hz,1H),4.63(d,J＝3.9 Hz, 1H), 4.60–4.53 (m, 1H), 4.42 (s, 1H), 3.88 (d, J=11.2Hz, 1H), 3.83–3.68 (m, 5H), 3.68–3.58 (m, 4H) , 2.73–2.65 (m, 1H), 2.62–2.50 (m, 6H), 2.23–2.14 (m, 1H), 1.98–1.89 (m, 1H), 1.49 (d, J=6.9Hz, 3H), 1.05 (s, 9H).

Control Compound 2: Synthesis of Compound Ref-2

The hydrochloride salt of compound Ref-2 was obtained as a white solid by a method similar to that of control compound 1 _by using 1,4-succinic acid as a starting material. LCMS[M+H] ⁺ 751.8.

¹ H NMR (500MHz, DMSO-d ₆ )δ9.32(d,J=4.0Hz,1H),9.05(s,1H),9.03(s,1H),8.89(d,J=5.0Hz,1H) ,8.60(d,J＝7.8Hz,1H),8.40(d,J＝7.6Hz,1H),8.06(t,J＝6.8Hz,1H),7.87(t,J＝8.8Hz,1H),7.61 (d, J=7.6Hz, 1H), 7.55 (d, J=8.4Hz, 1H), 7.44 (d, J=7.6Hz, 2H), 7.38 (d, J=7.8Hz, 2H), 7.31 (t ,J=7.6Hz,1H),7.25(t,J=7.4Hz,1H),6.80(s,1H),6.59(d,J=7.8Hz,1H),4.91(p,J=6.9Hz,1H) ), 4.51(d, J＝9.1Hz, 1H), 4.42(t, J＝8.0Hz, 1H), 4.28(s, 1H), 3.60(q, J＝10.6Hz, 2H), 2.62–2.52(m , 2H), 2.46(s, 3H), 2.45–2.37(m, 2H), 2.06–1.97(m, 1H), 1.83–1.73(m, 1H), 1.37(d, J=6.8Hz, 3H), 0.90 (d, J=18.3 Hz, 9H).

Pharmacological activity and application

The activity of the compounds of the present invention can be demonstrated using the following assays.

1. Smad3 luciferase reporter gene activity detection

Human renal epithelial cells HEK293T stably expressing pGL4.48[luc2P/SBE/Hygro] plasmid (Promega, product number E3671) were cultured in petri dishes with 10% fetal bovine serum (FBS, Gibco, product number 10099141) , 0.1% penicillin/streptomycin solution (P/S) in DMEM (Gibco, product number 12100046), placed in a sterile incubator with a temperature of 37° C., a relative humidity of 95%, and 5% CO ₂ . Cells in exponential growth phase were taken and seeded into a 384-well plate (Corning, product number 3572) at a density of 5000 cells/well, and 40 μL of medium was added to each well. After 24 hours, various concentrations of compounds disclosed herein were added to the wells seeded with cells (9 concentration gradients for each compound, the highest detection concentration was 10 μM, 3-fold dilution), and the final concentration of DMSO was 1%. After 20 hours, 1 ng/ml TGF-beta1 (R&D SYSTEM, product number 240-B) was added. After 4 hours, 10 μL of ONE-Glo ^™ luciferase reporter gene detection reagent (Progema, product number E6110) was added, and the fluorescent signal was read using Cytation3 (BioTek). The data were fitted to dose-response curves using GraphPad prisim5 to obtain _IC50 values for the test compounds.

Table 1 IC50 values of Smad3 luciferase reporter gene activity of some compounds of the present invention

A:<100nM; B:100-1000nM; C:1000-5000nM; D:>5000nM

2. Western blotting and Western-blot determination of SMAD3 protein abundance

Human renal epithelial cells HEK293T were cultured in petri dishes in DMEM (Gibco, product number) containing 10% fetal bovine serum (FBS, Gibco, product number 10099141) and 0.1% penicillin/streptomycin solution (P/S). 12100046), placed in a sterile incubator with a temperature of 37°C, a relative humidity of 95%, and 5% _CO2 . Cells in the exponential growth phase were taken and seeded into a 24-well plate (Corning, product number 3524) at a density of 15,000 cells/well, and 1 mL of medium was added to each well. After 24 hours, different concentrations of the compounds disclosed herein were added to the wells inoculated with cells (5 concentration gradients were set for each compound, the highest detection concentration was 10 μM, 10-fold gradient dilution), and the final concentration of DMSO was 0.1%. After 24 hours, cells were lysed in SDS lysis solution (1.45 g SDS, 0.2 g Tris base, 6 mL glycerol, 20 mg bromophenol blue, 310 _mg DTT, _d2H2O in 40 mL) by standard molecular biology techniques. Western blot was used to detect and analyze the level of SMAD3. The cell lysate was boiled at 95°C for 8 minutes. After mixing and centrifugation, the total cell protein in the lysate was transferred to NC membrane (GE, product number 1060002) by SDS-PAGE (GenScript, product number M00654) and blotting. Incubate in blocking buffer (TAKARA, product number T7131A) for 60 minutes at room temperature, and incubate with primary antibody overnight at 4°C. Antibodies used are: anti-SMAD3 (#9523S, 1:1000), anti-Actin (#5125S, 1:10000) ) (all purchased from Cell Signaling Technology). Wash three times with TBST at room temperature for 10 min each. Afterwards, incubation was performed for 60 minutes in blocking buffer containing secondary antibody (#7074S, 1:10000, purchased from Cell Signaling Technology) at room temperature. Washed three times with TBST at room temperature for 10 min each; finally developed with chemiluminescent substrate and imaged using Azure c300.

As shown in the accompanying drawings, some compounds of the present invention can effectively degrade SMAD3 protein. As shown in Figure 1, the representative compounds of the present invention HJM-001, HJM-004, HJM-007, HJM-008, HJM-025 and HJM-026 can effectively degrade SMAD3 protein. With the increase of compound concentration, SMAD3 protein more degradation. Especially for HJM-025 and HJM-026, the _DC50 value is about 100 nM.

The above content is a further detailed description of the present invention in combination with specific preferred embodiments, and it cannot be considered that the specific implementation of the present invention is limited to these descriptions. For those of ordinary skill in the technical field of the present invention, without departing from the concept of the present invention, some simple deductions or substitutions can be made, which should be regarded as belonging to the protection scope of the present invention.

Claims

A compound of formula (X), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

in,

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L is NR";

wherein R" is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

X1 is CR X1 or N ;

X2 is CR X2 or N ;

X3 is CR X3 or N;

X4 is CR X4 or N;

X5 is CR X5 or N;

wherein R X1 , R X2 , R X3 , R X4 and R X5 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

Y 1 is CR Y1 or N;

Y2 is O, S or NR Y2 ;

wherein R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

R Y2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 1 and R 2 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

Or R1 and R2 are connected, and together with the atoms to which they are connected form

where Z 1 is CR Z1 or N;

Z2 is CR Z2 or N ;

Z 3 is CR Z3 or N;

Z 4 is CR Z4 or N;

wherein R Z1 , R Z2 , R Z3 and R Z4 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L 1 is CR 1 R 1 ';

L 2 is O, S, NR 2 ″ or CR 2 R 2 ′;

L 3 is O, S, NR 3 "or CR 3 R 3 ';

L 4 is O, S, NR 4 "or CR 4 R 4 ';

L 5 is O, S, NR 5 "or CR 5 R 5 ';

L 6 is O, S, NR 6 "or CR 6 R 6 ';

L 7 is O, S, NR 7 "or CR 7 R 7 ';

or L 1 , L 5 and L 6 are each independently absent;

Or -L 6 -L 7 - combines to form -CH=CH- or -C≡C-;

Or the substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene base or 5-7 membered heteroarylene;

Or the substituents of L 2 and L 4 are connected, and together with L 2 , L 3 and L 4 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene or 5 -7-membered heteroarylene;

Or the substituents of L 3 and L 5 are connected and together with L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene or 5 -7-membered heteroarylene;

Or -L 2 -L 3 -L 4 - represents a C 5-7 cycloalkylene group, a 5-7-membered heterocyclylene group, a C 6-10 -membered arylene group or a 5-7-membered heteroarylene group;

Or -L 3 -L 4 -L 5 -represents a C 5-7 cycloalkylene group, a 5-7-membered heterocyclylene group, a C 6-10 -membered arylene group or a 5-7-membered heteroarylene group;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 , and R 7 ′ are independently is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

Or R 2 and R 2 ', R 3 and R 3 ', R 4 and R 4 ', R 5 and R 5 ', R 6 and R 6 ', R 7 and R 7 ' combine to form =0;

R 2 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 3 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 4 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 5 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 6 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 7 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

The condition is that two adjacent atoms cannot be heteroatoms at the same time;

Ra is selected from D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

n is 0, 1, 2, 3 or 4.
A compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

in,

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L is NR";

wherein R" is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

X1 is CR X1 or N ;

X2 is CR X2 or N ;

X3 is CR X3 or N;

X4 is CR X4 or N;

X5 is CR X5 or N;

wherein R X1 , R X2 , R X3 , R X4 and R X5 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

Y 1 is CR Y1 or N;

Y2 is O, S or NR Y2 ;

wherein R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

R Y2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 1 and R 2 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

Or R1 and R2 are connected, and together with the atoms to which they are connected form

where Z 1 is CR Z1 or N;

Z2 is CR Z2 or N ;

Z 3 is CR Z3 or N;

Z 4 is CR Z4 or N;

wherein R Z1 , R Z2 , R Z3 and R Z4 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L 1 is CR 1 R 1 ';

L 2 is O, S, NR 2 ″ or CR 2 R 2 ′;

L 3 is O, S, NR 3 "or CR 3 R 3 ';

L 4 is O, S, NR 4 "or CR 4 R 4 ';

L 5 is O, S, NR 5 "or CR 5 R 5 ';

L 6 is O, S, NR 6 "or CR 6 R 6 ';

L 7 is O, S, NR 7 "or CR 7 R 7 ';

or L 1 , L 5 and L 6 are each independently absent;

Or -L 6 -L 7 - combines to form -CH=CH- or -C≡C-;

Or the substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene base or 5-7 membered heteroarylene;

Or the substituents of L 2 and L 4 are connected, and together with L 2 , L 3 and L 4 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene or 5 -7-membered heteroarylene;

Or the substituents of L 3 and L 5 are connected and together with L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene or 5 -7-membered heteroarylene;

Or -L 2 -L 3 -L 4 - represents a C 5-7 cycloalkylene group, a 5-7 membered heterocyclylene group, a C 6-10 arylene group or a 5-7 membered heteroarylene group;

Or -L 3 -L 4 -L 5 -represents a C 5-7 cycloalkylene group, a 5-7-membered heterocyclylene group, a C 6-10 -membered arylene group or a 5-7-membered heteroarylene group;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 , and R 7 ′ are independently is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

Or R 2 and R 2 ', R 3 and R 3 ', R 4 and R 4 ', R 5 and R 5 ', R 6 and R 6 ', R 7 and R 7 ' combine to form =0;

R 2 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 3 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 4 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 5 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 6 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 7 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

The condition is that two adjacent atoms cannot be heteroatoms at the same time.
The compound of claim 1 or 2, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein W is C=O.
3. The compound of any one of claims 1-3, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L is NH.
The compound of any one of claims 1-4, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X is N .
The compound of any one of claims 1-5, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Y 1 is CR Y1 , preferably CH.
The compound of any one of claims 1-6, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Y is O or S, preferably O.
The compound of any one of claims 1-7 , or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R and R 2 are connected, and together with the atoms they are connected to form
Preferably, Z 1 , Z 2 , Z 3 and Z 4 are respectively CR Z1 , CR Z2 , CR Z3 and CR Z4 , preferably all CH; preferably, Z 1 , Z 2 , Z 3 and Z 4 are respectively CH, CH, CH, and N.
The compound of any one of claims 1-8 , or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L is O , S or CR 2 R 2 '; L 3 is O, S or CR 3 R 3 '; L 4 is O, S or CR 4 R 4 '; L 5 is O, S or CR 5 R 5 '; L 6 is O, S or CR 6 R 6 ′.
The compound of any one of claims 1-9, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L is O , S, NH or CH 2 ; or -L 6 -L 7 - combine to form -CH=CH- or -C≡C-.
The compound of any one of claims 1-10, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L and L The substituents of 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form a C 6-10 aryl ring or a 5-7 membered heteroarylene, preferably 1,4-phenylene, 2, 5-pyridylene, 1,4-pyrazolyl, 1,3-pyrazolyl, 1,3-pyrrolidine, 1,4-triazolyl, 2,5-thiadiazole or tetrazolium.
The compound of any one of claims 1-11, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein L and L The substituents of 4 are attached and together with L 2 , L 3 and L 4 form C 6-10 arylene or 5-7 membered heteroarylene, preferably 1,3-phenylene or 1,4-trisylene Azazolyl.
The compound of any one of claims 1-12, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein -L 2 - L 3 -L 4 - represents C 5-7 cycloalkylene,
or C 6-10 arylene, preferably
The compound of any one of claims 1-13, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is a compound of the formula :

wherein each group is as defined in claims 1-13.
The compound of any one of claims 1-14, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is of formula (II ) or (II-a) compounds:

in,

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L is NR";

wherein R" is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

X1 is CR X1 or N ;

X2 is CR X2 or N ; preferably N;

X3 is CR X3 or N;

X4 is CR X4 or N;

X5 is CR X5 ;

wherein R X1 , R X2 , R X3 , R X4 and R X5 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

Y 1 is CR Y1 or N;

Y2 is O, S or NR Y2 ;

wherein R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

R Y2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

Z1 is CR Z1 or N ;

Z2 is CR Z2 or N ;

Z 3 is CR Z3 or N;

Z 4 is CR Z4 or N;

wherein R Z1 , R Z2 , R Z3 and R Z4 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L 2 is O, S, NR 2 ″ or CR 2 R 2 ′;

L 3 is O, S, NR 3 "or CR 3 R 3 ';

L 4 is O, S, NR 4 "or CR 4 R 4 ';

L 5 is O, S, NR 5 "or CR 5 R 5 ';

L 1 and L 6 are CR 1 R 1 ' and CR 6 R 6 ', respectively;

or L 1 , L 5 and L 6 are each independently absent;

Or the substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene base or 5-7 membered heteroarylene;

Or the substituents of L 2 and L 4 are connected, and together with L 2 , L 3 and L 4 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene or 5 -7-membered heteroarylene;

Or the substituents of L 3 and L 5 are connected and together with L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene or 5 -7-membered heteroarylene;

Or -L 2 -L 3 -L 4 - represents a C 5-7 cycloalkylene group, a 5-7 membered heterocyclylene group, a C 6-10 arylene group or a 5-7 membered heteroarylene group;

Or -L 3 -L 4 -L 5 -represents a C 5-7 cycloalkylene group, a 5-7-membered heterocyclylene group, a C 6-10 -membered arylene group or a 5-7-membered heteroarylene group;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl ;

Or R 2 and R 2 ', R 3 and R 3 ', R 4 and R 4 ', R 5 and R 5 ', R 6 and R 6 ' combine to form =0;

R 2 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 3 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 4 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 5 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

The condition is that two adjacent atoms cannot be heteroatoms at the same time.
The compound of claim 15, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is CRR' or C=O;

wherein R and R' are independently selected from H or D;

L is NH;

X1 is CR X1 or N ;

X2 is CR X2 or N ; preferably N;

X3 is CR X3 or N;

X4 is CR X4 or N;

X5 is CR X5 ;

wherein R X1 , R X2 , R X3 , R X4 and R X5 are independently selected from H or D;

Y 1 is CR Y1 or N;

Y2 is O, S or NR Y2 ;

wherein R Y1 is independently selected from H or D;

R Y2 is selected from H or C 1-6 alkyl;

Z1 is CR Z1 or N ;

Z2 is CR Z2 or N ;

Z 3 is CR Z3 or N;

Z 4 is CR Z4 or N;

wherein R Z1 , R Z2 , R Z3 and R Z4 are independently selected from H or D;

L 2 is O, NR 2 "or CR 2 R 2 ';

L 3 is O, NR 3 "or CR 3 R 3 ';

L 4 is O, NR 4 "or CR 4 R 4 ';

L 1 , L 5 and L 6 are CR 1 R 1 ', CR 5 R 5 ' and CR 6 R 6 ', respectively;

or L 1 , L 5 and L 6 are each independently absent;

Or the substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form 1,4-phenylene or

Or the substituents of L 2 and L 4 are connected, and together with L 2 , L 3 and L 4 form 1,3-phenylene;

Or the substituents of L 3 and L 5 are connected, and together with L 3 , L 4 and L 5 form 1,3-phenylene or 2,6-pyridylene;

Or -L 2 -L 3 -L 4 - represents 1,4-phenylene,

Or -L 3 -L 4 -L 5 - represents 1,4-phenylene;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D;

R 2 " is selected from H or C 1-6 alkyl;

R 3 " is selected from H or C 1-6 alkyl;

R 4 " is selected from H or C 1-6 alkyl;

The condition is that two adjacent atoms cannot be heteroatoms at the same time.
The compound of any one of claims 1-14, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is of formula (II -1) or (II-1-a) compound:

in,

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

X1 is CR X1 or N ;

X2 is CR X2 or N ; preferably N;

X3 is CR X3 or N;

X4 is CR X4 or N;

X5 is CR X5 ;

wherein R X1 , R X2 , R X3 , R X4 and R X5 are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

Y1 is CR Y1 ;

Y2 is O, S or NR Y2 ;

wherein R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

R Y2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

Z 4 is CR Z4 or N;

wherein R Z4 is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L 2 is O, S, NR 2 ″ or CR 2 R 2 ′;

L 3 is O, S or CR 3 R 3 ';

L 4 is O, S or CR 4 R 4 ';

L 1 , L 5 and L 6 are CR 1 R 1 ', CR 5 R 5 ' and CR 6 R 6 ', respectively; or L 5 is absent;

Or the substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene or C 6-10 arylene base;

Or the substituents of L 2 and L 4 are connected, and together with L 2 , L 3 and L 4 form a C 5-7 cycloalkylene group, a 5-7 membered heterocyclylene group or a C 6-10 arylene group ;

Or -L 2 -L 3 -L 4 - represents C 5-7 cycloalkylene, C 6-10 arylene or

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl ;

R 2 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

The condition is that when Y 2 is O, L 1 , L 2 , L 3 , L 4 , L 5 and L 6 cannot be CH 2 at the same time;

The condition is that two adjacent atoms cannot be heteroatoms at the same time.
The compound of claim 17, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is CRR' or C=O;

wherein R and R' are independently selected from H or D;

X1 is CR X1 or N ;

X2 is CR X2 or N ; preferably N;

X3 is CR X3 or N;

X4 is CR X4 or N;

X5 is CR X5 ;

wherein R X1 , R X2 , R X3 , R X4 and R X5 are independently selected from H or D;

Y1 is CR Y1 ;

Y2 is O, S or NR Y2 ;

wherein R Y1 is independently selected from H or D;

R Y2 is selected from H or C 1-6 alkyl;

Z 4 is CR Z4 or N;

wherein R Z4 is selected from H or D;

L 2 is O, NR 2 "or CR 2 R 2 ';

L 3 is O or CR 3 R 3 ';

L 4 is O or CR 4 R 4 ';

L 1 , L 5 and L 6 are CR 1 R 1 ', CR 5 R 5 ' and CR 6 R 6 ', respectively; or L 5 is absent;

Or the substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form 1,4-phenylene or

Or the substituents of L 2 and L 4 are connected, and together with L 2 , L 3 and L 4 form 1,3-phenylene;

or -L 2 -L 3 -L 4 - represents 1,4-phenylene or

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D;

R 2 " is selected from H or C 1-6 alkyl;

The condition is that when Y 2 is O, L 1 , L 2 , L 3 , L 4 , L 5 and L 6 cannot be CH 2 at the same time;

The condition is that two adjacent atoms cannot be heteroatoms at the same time.
The compound of any one of claims 1-14, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is of formula (II -2) or (II-2-a) compound:

in,

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

Y1 is CR Y1 ;

Y2 is O, S or NR Y2 ;

wherein R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

R Y2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

Z 4 is CR Z4 or N;

wherein R Z4 is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L 2 is O, S, NR 2 ″ or CR 2 R 2 ′;

L 3 is O, S or CR 3 R 3 ';

L 1 , L 4 , L 5 and L 6 are CR 1 R 1 ', CR 4 R 4 ', CR 5 R 5 ' and CR 6 R 6 ', respectively;

Or the substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene or C 6-10 arylene base;

Or the substituents of L 2 and L 4 are connected, and together with L 2 , L 3 and L 4 form a C 5-7 cycloalkylene group, a 5-7 membered heterocyclylene group or a C 6-10 arylene group ;

Or -L 2 -L 3 -L 4 - represents C 5-7 cycloalkylene, C 6-10 arylene or

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl ;

Or R 2 and R 2 ', R 3 and R 3 ', R 4 and R 4 ', R 5 and R 5 ', R 6 and R 6 ' combine to form =0;

R 2 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

The condition is that when Y 2 is O, L 1 , L 2 , L 3 , L 4 , L 5 and L 6 cannot be CH 2 at the same time;

The condition is that two adjacent atoms cannot be heteroatoms at the same time.
The compound of claim 19, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is CRR' or C=O;

wherein R and R' are independently selected from H or D;

Y1 is CR Y1 ;

Y2 is O, S or NR Y2 ;

wherein R Y1 is independently selected from H or D;

R Y2 is selected from H or C 1-6 alkyl;

Z 4 is CR Z4 or N;

wherein R Z4 is selected from H or D;

L 2 is O, NR 2 "or CR 2 R 2 ';

L 3 is O or CR 3 R 3 ';

L 1 , L 4 , L 5 and L 6 are CR 1 R 1 ', CR 4 R 4 ', CR 5 R 5 ' and CR 6 R 6 ', respectively;

Or the substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form 1,4-phenylene;

Or the substituents of L 2 and L 4 are connected, and together with L 2 , L 3 and L 4 form 1,3-phenylene;

or -L 2 -L 3 -L 4 - represents 1,4-phenylene or

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D;

R 2 " is selected from H or C 1-6 alkyl;

The condition is that when Y 2 is O, L 1 , L 2 , L 3 , L 4 , L 5 and L 6 cannot be CH 2 at the same time;

The condition is that two adjacent atoms cannot be heteroatoms at the same time.
The compound of claim 19, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

Y1 is CR Y1 ;

wherein R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

Y 2 is O or S;

Z 4 is CR Z4 or N;

wherein R Z4 is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L 1 , L 2 , L 3 , L 4 , L 5 and L 6 are CR 1 R 1 ′, CR 2 R 2 ′, CR 3 R 3 ′, CR 4 R 4 ′, CR 5 R 5 ′ and CR, respectively 6R6 ';

Or the substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene or C 6-10 arylene base;

Or -L 2 -L 3 -L 4 - represents a C 5-7 cycloalkylene group, a 5-7 membered heterocyclic group or a C 6-10 arylene group;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl ;

Or R 2 and R 2 ', R 3 and R 3 ', R 4 and R 4 ', R 5 and R 5 ', R 6 and R 6 ' combine to form =0;

The condition is that when Y 2 is O, L 1 , L 2 , L 3 , L 4 , L 5 and L 6 cannot be CH 2 at the same time.
The compound of claim 21, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is CRR' or C=O;

wherein R and R' are independently selected from H or D;

Y1 is CR Y1 ;

wherein R Y1 is independently selected from H or D;

Y 2 is O or S;

Z 4 is CR Z4 or N;

wherein R Z4 is selected from H or D;

L 1 , L 2 , L 3 , L 4 , L 5 and L 6 are CR 1 R 1 ′, CR 2 R 2 ′, CR 3 R 3 ′, CR 4 R 4 ′, CR 5 R 5 ′ and CR, respectively 6R6 ';

Or the substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form 1,4-phenylene;

Or -L 2 -L 3 -L 4 - represents 1,4-phenylene;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D;

The condition is that when Y 2 is O, L 1 , L 2 , L 3 , L 4 , L 5 and L 6 cannot be CH 2 at the same time.
The compound of any one of claims 1-14, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is of formula (III -3) or (III-a) compound:

in,

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L 2 is O, S, NR 2 ″ or CR 2 R 2 ′;

L 3 is O, S, NR 3 "or CR 3 R 3 ';

L 4 is O, S, NR 4 "or CR 4 R 4 ';

L 5 is O, S, NR 5 "or CR 5 R 5 ';

L 1 and L 6 are CR 1 R 1 ' and CR 6 R 6 ', respectively;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl ;

Or R 2 and R 2 ', R 3 and R 3 ', R 4 and R 4 ', R 5 and R 5 ', R 6 and R 6 ' combine to form =0;

R 2 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 3 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 4 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 5 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

The condition is that two adjacent atoms cannot be heteroatoms at the same time.
The compound of claim 23, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is C=O;

L 2 is O or CR 2 R 2 ';

L 3 is O, NR 3 "or CR 3 R 3 ';

L 1 , L 4 , L 5 and L 6 are CR 1 R 1 ', CR 4 R 4 ', CR 5 R 5 ' and CR 6 R 6 ', respectively;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D;

R 3 " is selected from H or C 1-6 alkyl;

The condition is that two adjacent atoms cannot be heteroatoms at the same time.
The compound of claim 23, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L 3 is O, S or CR 3 R 3 ';

L 1 , L 2 , L 4 , L 5 and L 6 are CR 1 R 1 ′, CR 2 R 2 ′, CR 4 R 4 ′, CR 5 R 5 ′ and CR 6 R 6 ′, respectively;

wherein R 1 , R 1 ', R 2 , R 2 ', R 4 , R 4 ', R 5 , R 5 ', R 6 and R 6 ' are independently selected from H, D, halogen, C 1-6 alkanes group or C 1-6 haloalkyl;

Or R 2 and R 2 ', R 3 and R 3 ', R 4 and R 4 ', R 5 and R 5 ', R 6 and R 6 ' combine to form =O.
The compound of claim 25, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is C=O;

L 3 is O or CR 3 R 3 ';

L 1 , L 2 , L 4 , L 5 and L 6 are CR 1 R 1 ′, CR 2 R 2 ′, CR 4 R 4 ′, CR 5 R 5 ′ and CR 6 R 6 ′, respectively;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D.
The compound of claim 23, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L 3 is O or S;

L 1 , L 2 , L 4 , L 5 and L 6 are CR 1 R 1 ′, CR 2 R 2 ′, CR 4 R 4 ′, CR 5 R 5 ′ and CR 6 R 6 ′, respectively;

wherein R 1 , R 1 ', R 2 , R 2 ', R 4 , R 4 ', R 5 , R 5 ', R 6 and R 6 ' are independently selected from H, D, halogen, C 1-6 alkanes group or C 1-6 haloalkyl;

Or R 2 and R 2 ', R 3 and R 3 ', R 4 and R 4 ', R 5 and R 5 ', R 6 and R 6 ' combine to form =O.
The compound of claim 27, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is C=O;

L 3 is O;

L 1 , L 2 , L 4 , L 5 and L 6 are CR 1 R 1 ′, CR 2 R 2 ′, CR 4 R 4 ′, CR 5 R 5 ′ and CR 6 R 6 ′, respectively;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D.
The compound of any one of claims 1-14, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is of formula (IV -3) Compounds:

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L 2 is O, S, NR 2 ″ or CR 2 R 2 ′;

L 3 is O, S, NR 3 "or CR 3 R 3 ';

L 4 is O, S, NR 4 "or CR 4 R 4 ';

L 5 is O, S, NR 5 "or CR 5 R 5 ';

L 1 and L 6 are CR 1 R 1 ' and CR 6 R 6 ', respectively;

Or the substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene, C 6-10 arylene base or 5-7 membered heteroarylene;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl ;

Or R 2 and R 2 ', R 3 and R 3 ', R 4 and R 4 ', R 5 and R 5 ', R 6 and R 6 ' combine to form =0;

R 2 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 3 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 4 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 5 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

The condition is that two adjacent atoms cannot be heteroatoms at the same time.
The compound of claim 29, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is C=O;

L 2 is O or CR 2 R 2 ';

L 3 is O or CR 3 R 3 ';

L 4 is O or CR 4 R 4 ';

L 1 , L 5 and L 6 are CR 1 R 1 ', CR 5 R 5 ' and CR 6 R 6 ', respectively;

Or the substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form 1,4-phenylene, 2,5-pyridylene, 1,4-pyrazolyl , 1,3-pyrazolylidene, 1,3-pyrrolidene, 1,4-triazolylidene, 2,5-thiadiazolylidene or tetrazolylidene;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D;

The condition is that two adjacent atoms cannot be O at the same time.
The compound of claim 29, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L 2 is O, S or CR 2 R 2 ';

L 3 is O, S or CR 3 R 3 ';

L 1 , L 4 , L 5 and L 6 are CR 1 R 1 ', CR 4 R 4 ', CR 5 R 5 ' and CR 6 R 6 ', respectively;

Or the substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene or C 6-10 arylene base;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl ;

Or R 2 and R 2 ', R 3 and R 3 ', R 4 and R 4 ', R 5 and R 5 ', R 6 and R 6 ' combine to form =0;

The condition is that two adjacent atoms cannot be heteroatoms at the same time.
The compound of claim 31, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is C=O;

L 2 is O or CR 2 R 2 ';

L 3 is O or CR 3 R 3 ';

L 1 , L 4 , L 5 and L 6 are CR 1 R 1 ', CR 4 R 4 ', CR 5 R 5 ' and CR 6 R 6 ', respectively;

Or the substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form 1,4-phenylene;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D;

The condition is that two adjacent atoms cannot be O at the same time.
The compound of claim 29, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L 3 is O, S or CR 3 R 3 ';

L 1 , L 2 , L 4 , L 5 and L 6 are CR 1 R 1 ′, CR 2 R 2 ′, CR 4 R 4 ′, CR 5 R 5 ′ and CR 6 R 6 ′, respectively;

Or the substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form C 5-7 cycloalkylene, 5-7 membered heterocyclylene or C 6-10 arylene base;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl ;

Or R 2 and R 2 ', R 3 and R 3 ', R 4 and R 4 ', R 5 and R 5 ', R 6 and R 6 ' combine to form =O.
The compound of claim 31, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is C=O;

L 3 is O or CR 3 R 3 ';

L 1 , L 2 , L 4 , L 5 and L 6 are CR 1 R 1 ′, CR 2 R 2 ′, CR 4 R 4 ′, CR 5 R 5 ′ and CR 6 R 6 ′, respectively;

Or the substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form 1,4-phenylene;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D.
The compound of any one of claims 1-14, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is of formula (V -2) or (V-2-a) compound:

in,

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

Y1 is CR Y1 ;

Y2 is O, S or NR Y2 ;

wherein R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

R Y2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

L 1 is CR 1 R 1 ';

L 5 is CR 5 R 5 ';

L 6 is CR 6 R 6 ' or absent;

L 7 is O, S, NR 7 "or CR 7 R 7 ';

The substituents of L 2 and L 5 are connected and together with L 2 , L 3 , L 4 and L 5 form C 6-10 arylene, 5-7 membered heteroarylene or
Preferably C 6-10 arylene or 5-7 membered heteroarylene;

Or the substituents of L 2 and L 4 are connected, and together with L 2 , L 3 and L 4 form a C 6-10 arylene group or a 5-7 membered heteroarylene group;

Or -L 2 -L 3 -L 4 - represents C 6-10 arylene, 5-7 membered heteroarylene or

wherein R 1 , R 1 ', R 5 , R 5 ', R 6 , R 6 ', R 7 and R 7 ' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkane base;

R 7 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
The compound of claim 35, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is CRR' or C=O;

wherein R and R' are independently selected from H or D;

Y1 is CR Y1 ;

Y 2 is O or S;

wherein R Y1 is independently selected from H or D;

L 1 is CR 1 R 1 ';

L 5 is CR 5 R 5 ';

L 6 is CR 6 R 6 ' or absent;

L 7 is O, S, NR 7 "or CR 7 R 7 ';

The substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form 1,4-phenylene, 1,4-triazolylylene or
1,4-phenylene or 1,4-triazolylylene is preferred;

Or the substituents of L 2 and L 4 are connected, and together with L 2 , L 3 and L 4 form 1,3-phenylene;

or -L 2 -L 3 -L 4 - represents 1,4-phenylene or

wherein R 1 , R 1 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 and R 7 ′ are independently selected from H or D;

R 7 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
The compound of claim 35, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

Y1 is CR Y1 ;

Y2 is O, S or NR Y2 ;

wherein R Y1 is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

R Y2 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

L 1 is CR 1 R 1 ';

L 5 is CR 5 R 5 ';

L 6 is CR 6 R 6 ′;

L 7 is S or NR 7 ";

The substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form a C 6-10 arylene group or a 5-7 membered heteroarylene group;

Or -L 2 -L 3 -L 4 - represents a C 6-10 arylene group or a 5-7 membered heteroarylene group;

wherein R 1 , R 1 ', R 5 , R 5 ', R 6 and R 6 ' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

R 7 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
The compound of claim 37, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is CRR' or C=O;

wherein R and R' are independently selected from H or D;

Y1 is CR Y1 ;

Y 2 is O or S;

wherein R Y1 is independently selected from H or D;

L 1 is CR 1 R 1 ';

L 5 is CR 5 R 5 ';

L 6 is CR 6 R 6 ′;

L 7 is S or NH;

The substituents of L 2 and L 5 are connected, and together with L 2 , L 3 , L 4 and L 5 form 1,4-phenylene or 1,4-triazolylylene;

Or -L 2 -L 3 -L 4 - represents 1,4-phenylene;

wherein R 1 , R 1 ′, R 5 , R 5 ′, R 6 and R 6 ′ are independently selected from H or D.
The compound of any one of claims 1-14, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is of formula (V -3) or (V-3-a) compound:

in,

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L 2 is O, S, NR 2 "or CR 2 R 2 ';

L 3 is O, S, NR 3 "or CR 3 R 3 ';

L 4 is O, S, NR 4 "or CR 4 R 4 ';

L 5 is O, S, NR 5 "or CR 5 R 5 ';

L 6 is O, S, NR 6 "or CR 6 R 6 ';

L 1 and L 7 are CR 1 R 1 ' and CR 7 R 7 ', respectively;

Or -L 6 -L 7 - combines to form -CH=CH- or -C≡C-;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 , and R 7 ′ are independently is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

Or R 2 and R 2 ', R 3 and R 3 ', R 4 and R 4 ', R 5 and R 5 ', R 6 and R 6 ', R 7 and R 7 ' combine to form =0;

R 2 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 3 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 4 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 5 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

R 6 " is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;

The condition is that two adjacent atoms cannot be heteroatoms at the same time.
The compound of claim 39, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is C=O;

L 2 is O or CR 2 R 2 ';

L 3 is O or CR 3 R 3 ';

L 4 is O or CR 4 R 4 ';

L 1 , L 5 , L 6 and L 7 are CR 1 R 1 ', CR 5 R 5 ', CR 6 R 6 ' and CR 7 R 7 ', respectively;

Or -L 6 -L 7 - combines to form -C≡C-;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 , and R 7 ′ are independently is selected from H or D;

The condition is that two adjacent atoms cannot be O at the same time.
The compound of claim 39, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L 2 is O or S;

L 1 , L 3 , L 4 and L 5 are CR 1 R 1 ', CR 3 R 3 ', CR 4 R 4 ' and CR 5 R 5 ', respectively;

-L 6 -L 7 - combines to form -CH=CH- or -C≡C-;

wherein R 1 , R 1 ', R 3 , R 3 ', R 4 , R 4 ', R 5 and R 5 ' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkane base;

Or R 3 and R 3 ′, R 4 and R 4 ′, R 5 and R 5 ′ combine to form =O.
The compound of claim 41, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is C=O;

L 2 is O;

L 1 , L 3 , L 4 and L 5 are CR 1 R 1 ', CR 3 R 3 ', CR 4 R 4 ' and CR 5 R 5 ', respectively;

-L 6 -L 7 - combines to form -C≡C-;

wherein R 1 , R 1 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 and R 5 ′ are independently selected from H or D.
The compound of claim 41, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L 2 is O, S or CR 2 R 2 ';

L 3 is O, S or CR 3 R 3 ';

L 1 , L 4 , L 5 , L 6 and L 7 are CR 1 R 1 ′, CR 4 R 4 ′, CR 5 R 5 ′, CR 6 R 6 ′ and CR 7 R 7 ′, respectively;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 , and R 7 ′ are independently is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

Or R 2 and R 2 ', R 3 and R 3 ', R 4 and R 4 ', R 5 and R 5 ', R 6 and R 6 ', R 7 and R 7 ' combine to form =0;

The condition is that two adjacent atoms cannot be heteroatoms at the same time.
The compound of claim 43, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is C=O;

L 2 is O or CR 2 R 2 ';

L 3 is O or CR 3 R 3 ';

L 1 , L 4 , L 5 , L 6 and L 7 are CR 1 R 1 ′, CR 4 R 4 ′, CR 5 R 5 ′, CR 6 R 6 ′ and CR 7 R 7 ′, respectively;

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 , and R 7 ′ are independently is selected from H or D;

The condition is that two adjacent atoms cannot be O at the same time.
The compound of claim 39, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is CRR' or C=O;

wherein R and R' are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;

L 3 is O or S;

L 1 , L 2 , L 4 , L 5 , L 6 and L 7 are CR 1 R 1 ′, CR 2 R 2 ′, CR 4 R 4 ′, CR 5 R 5 ′, CR 6 R 6 ′ and CR, respectively 7R7 ';

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 and R 7 ′ are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl ;

Or R 2 and R 2 ', R 4 and R 4 ', R 5 and R 5 ', R 6 and R 6 ', R 7 and R 7 ' combine to form =O.
The compound of claim 45, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

W is C=O;

L 3 is O;

L 1 , L 2 , L 4 , L 5 , L 6 and L 7 are CR 1 R 1 ′, CR 2 R 2 ′, CR 4 R 4 ′, CR 5 R 5 ′, CR 6 R 6 ′ and CR, respectively 7R7 ';

wherein R 1 , R 1 ′, R 2 , R 2 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 , R 6 ′, R 7 and R 7 ′ are independently selected from H or D.
The compound of claim 1, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is selected from the group consisting of:
A pharmaceutical composition comprising a compound of any one of claims 1-47, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, and pharmaceutically acceptable excipients.
The compound of any one of claims 1-47, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the drug of claim 48 Use of the composition in the preparation of a medicament for treating and/or preventing Smad3 protein-mediated diseases.
A method for treating and/or preventing Smad3 protein-mediated diseases in a subject, comprising administering to the subject a compound according to any one of claims 1-47 or a tautomer, stereoisomer thereof An isomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition of claim 48.
The compound of any one of claims 1-47, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the drug of claim 48 A composition for treating and/or preventing Smad3 protein-mediated diseases.
The use according to claim 49 or the method of 50 or the use of the compound or pharmaceutical composition of 51, wherein the disease mediated by Smad3 protein is selected from autoimmune disease, inflammation, tissue fibrosis, tumor and the like.