WO2023202583A1

WO2023202583A1 - Fxr regulator and use thereof

Info

Publication number: WO2023202583A1
Application number: PCT/CN2023/089016
Authority: WO
Inventors: 焦宁; 豆晓东; 苏凌宇; 霍童雨; 刘雅萌
Original assignee: 北京大学
Priority date: 2022-04-18
Filing date: 2023-04-18
Publication date: 2023-10-26
Also published as: CN116903559A

Abstract

Disclosed are an FXR regulator and use thereof, and specifically disclosed are a compound represented by formula I, or a stereoisomer, a prodrug, a crystal form, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable ester of the compound.

Description

FXR regulators and their applications

Technical field

The present invention relates to the field of medicine, specifically to FXR modulators and their applications.

Background technique

Farnesoid X receptor (FXR) is a member of the nuclear receptors (NRs) superfamily. The nuclear receptor superfamily consists of 48 ligand-dependent transcription factors, which control the expression of specific genes, regulate physiological processes such as metabolism, development, and reproduction in mammals, and are related to a variety of human diseases, including inflammation, cancer, and reproductive disorders. , metabolic syndrome, cardiovascular disease, etc. The activity of the NRs superfamily can be regulated by binding to lipophilic small molecule ligands, which enter the lipid bilayer to regulate physiological activities inside and outside cells. Based on ligand selectivity, the NRs superfamily is generally divided into three categories: class I, class II, and class III. Class I is a classic endocrine nuclear receptor, with steroid hormones synthesized by endocrine glands as their ligands, including estrogen receptor (estrogen receptor, ER), progesterone receptor (progesterone receptor, PR), androgen receptor (androgen receptor, AR), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), these NRs bind to their target DNA sequences in the form of homodimers. Category II is orphan NRs for which no corresponding ligand has been found. They usually bind to DNA in the form of monomers or homodimers, such as retinoid-related orphan receptors (RORs) and nerve growth factors. IB (nerve growth factor IB, Nurr77), etc. Category III is the adopted orphan NRs, which are the type II orphan nuclear receptors for which ligands have recently been discovered, including farnesoid X receptor (FXR) and peroxisome proliferator. -activated receptors (PPARs), liver X receptors (liver X receptor, LXR) and retinoic acid X receptors (retinoid X receptor, RXR), etc.

In 1995, Seol et al. used a two-hybrid yeast system to identify a new protein that could interact with RXRα and named it RXR-interacting protein 14 (RIP14). In the same year, Forman et al. cloned the homologous gene of mouse RIP14 from a rat liver cDNA library and found that farnesol, an intermediate in the mevalonic acid pathway, could activate rat RIP14 at supraphysiological concentrations. Therefore, RIP14 was Renamed FXR. It is known that FXR has two genes, namely FXRα(NR1H4) and FXRβ(NR1H5). Existing studies have shown that FXRα plays an important role in various metabolic homeostasis and disease regulation. Unlike FXRα, FXRβ is a pseudogene in humans and primates, expressed in rodents, rabbits, and dogs, and its function and role are unclear. FXR is highly expressed in the liver, intestine, kidney, adrenal gland, and less expressed in adipose tissue and heart. The four FXRα isoforms are expressed in a tissue-specific manner. FXRα1 and FXRα2 are mainly expressed in the human liver, FXRα3 and FXRα4 are mainly expressed in the human kidney and colon, and all four isoforms are expressed in the human small intestine.

The protein structure of FXR consists of 486 amino acids. The full-length crystal structure has not yet been analyzed. However, multiple co-crystal structures of FXR-LBD (amino acid sequence 248-472) combined with ligands have been analyzed, which is the discovery of FXR ligands. and provide the basis for rational drug design. FXR plays an important role in various metabolic homeostasis and disease regulation, especially in glucose metabolism, cholesterol metabolism, lipid metabolism and bile acid metabolism. Part of the mechanism by which FXR exerts physiological functions is directly mediated by the binding of FXR/RXR heterodimers to the FXR response element (FXR-RE) in the target gene promoter. Others are regulated by downstream signaling factors, such as through the nucleus. The receptor SHP and fibroblast growth factor 15/19 (FGF15/19) inhibit the activity of CYP7A1, thereby inhibiting the synthesis of bile acids. Currently, drug research targeting FXR targets focuses on metabolic diseases. Mainly include hyperlipidemia, cholestasis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), diabetes, cardiovascular disease and obesity. In addition to the above-mentioned metabolism-related diseases, there are also relevant research reports on the therapeutic effects of FXR on intestinal diseases, inflammation and cancer.

FXR modulators include agonists and inhibitors (or antagonists), among which, agonist types such as steroids (such as primary BAs (CA and CDCA), and secondary BAs (DCA and LCA), INT-767, MFA -1, NIHS1600, TC-100, etc.) and non-steroidal (isoxazole derivatives-GW4064, aza [4,5-b]indole derivatives-WAY-362450, benzimidazole derivatives, Fexaramine derivatives, and anthranilic acid derivatives, etc.); types of antagonists include natural product FXR antagonists (such as Steroid derivatives, terpenoid derivatives, Tuberatolide derivatives, atractylodes derivatives, andrographolide derivatives, chalcone derivatives, phenol derivatives, etc.) and synthetic FXR antagonists (such as isoxazole Derivatives, 1,3,4-trisubstituted pyrazolone derivatives, 2,3,4-trisubstituted pyrazole compounds, pyrazole-4-carboxamide derivatives, phenylalkyl ether derivatives, 3-tert. Butyl benzoate/amide derivatives, benzimidazole derivatives, tert-butyl Benzene derivatives, oxadiazole derivatives, etc.).

However, those skilled in the art are still eager for a novel structure of FXR modulator for the research and treatment of metabolism-related diseases, cardiovascular diseases, liver diseases, cancer, intestinal diseases, inflammation and other diseases.

Contents of the invention

Through in-depth research and creative discovery, the inventor of the present application has obtained a novel structure of FXR modulator, which can be used to prevent and/or treat metabolic-related diseases, cardiovascular diseases, liver diseases, cancer, intestinal diseases, inflammation and other diseases. .

To this end, in the first aspect of the present invention, there is provided a compound represented by formula I, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable esters,

in:

L is selected from Among them, X is connected to the benzene ring, and Y is connected to R ⁴ ;

X is selected from

Y is selected from

R ⁵ is selected from hydrogen, C1-C6 alkyl;

R ^1a and R ^1b are each independently selected from hydrogen, halogen, C1-C6 alkoxy, -NR ^a R ^b ; or, R ^1a , R ^1b and the carbon atoms to which they are respectively connected together form a 5-6-membered heterogeneous ring;

R ^a and R ^b are each independently selected from C1-C6 alkyl groups, or R ^a , R ^b and the nitrogen atoms they are commonly connected to form a 4-7 membered nitrogen-containing heterocyclic ring;

R ² is selected from -(CH ₂ ) _n -R ⁶ ;

n is selected from 1, 2, 3, 4, 5, 6;

R ⁶ is selected from 5-6 membered heteroaryl, phenyl, C1-C6 alkyl, optionally, the 5-6 membered heteroaryl and phenyl are each independently substituted by R ^c ;

R ^c is selected from halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl;

R ³ is selected from phenyl, 5-6 membered heteroaryl, C1-C6 alkyl, -NR ^m R ⁿ , C3-C10 cycloalkyl, C1-C6 alkoxy, C2-C6 alkenyl, optionally , the phenyl group and the 5-6 membered heteroaryl group are each independently substituted by 1-2 groups selected from ^Rx ;

R ^m and R ⁿ are each independently selected from C1-C6 alkyl, or R ^m , R ⁿ and the nitrogen atoms they are jointly connected with form a 4-7 membered nitrogen-containing heterocyclic ring, optionally the 4-7 Any -CH ₂ - in the nitrogen-containing heterocycle is replaced by -O-;

R ^x is selected from halogen, nitro, C1-C6 alkyl, C1-C6 alkoxy, -NR ^s R ^t , C1-C6 haloalkyl;

R ^s and R ^t are each independently selected from C1-C6 alkyl;

R ⁴ is selected from:

1)

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are each independently selected from hydrogen, C1-C6 alkyl, halogen, carboxyl, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-N (R ^u )-, C1-C6 alkyl-C(=O)-C1-C6 alkyl, R ^v R ^w NC(=O)-N(R ^y )-, C1-C6 alkyl-OC(= O)-, C1-C6 alkyl-OC(=O)-C1-C6 alkyl, HO-C(=O)-C1-C6 alkyl, C1-C6 alkyl-OC(=O)-C1- C6 alkyl-C(=O)-N(R ^y )-, HO-C(=O)-C1-C6 alkyl-C(=O)-N(R ^y )-, C1-C6 alkyl- C(=O)-N(R ^y )-C(=O)-N(R ^y )-, C1-C6 alkyl-C(=O)-N(R ^y )-C(=O)-C1 -C6 alkyl, C1-C6 alkyl -C(=O)-C1-C6 alkyl-C(=O)-N(R ^y )-, R ^v R ^w NC(=O)-, C1-C6 Alkyl-C(=O)-N(R ^y )-C(=O)-, C1-C6 alkyl-C(=O)-, and R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ Not hydrogen at the same time;

R ^u is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;

R ^y is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;

R ^v and R ^w are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;

2)

X ¹ selected from

R ^z is selected from C1-C6 alkyl, C1-C6 alkyl-C(=O)-;

R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C1-C6 alkyl;

3)

X ² selected from

R ^q is selected from C1-C6 alkyl;

R ¹⁶ , R ¹⁷ , and R ¹⁸ are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl;

R ¹⁹ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl;

R ²⁰ is selected from carboxyl, C1-C6 alkyl-OC(=O)-, HO-C1-C6 alkyl,

Among them, X is And Y is When , the compound represented by formula I is not the following compound:

Some embodiments of the present invention provide compounds represented by formula I, or stereoisomers of said compounds, prodrug, crystalline form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable ester,

in:

X is selected from

Y is selected from

R ⁵ is selected from hydrogen, C1-C6 alkyl;

R ² is selected from -(CH ₂ ) _n -R ⁶ ;

n is selected from 1, 2, 3, 4, 5, 6;

R ^c is selected from halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl;

R ³ is selected from phenyl, 5-6-membered heteroaryl, C1-C6 alkyl, -NR ^m R ⁿ , optionally, the phenyl and 5-6-membered heteroaryl are each independently replaced by 1-2 Substituted with a group selected from R ^x ;

R ^m and R ⁿ are each independently selected from C1-C6 alkyl groups, or R ^m , R ⁿ and the nitrogen atoms they are commonly connected to form a 4-7 membered nitrogen-containing heterocyclic ring;

R ^s and R ^t are each independently selected from C1-C6 alkyl;

R ⁴ is selected from:

1)

R ^u is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;

R ^y is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;

2)

X ¹ selected from

R ^z is selected from C1-C6 alkyl, C1-C6 alkyl-C(=O)-;

3)

X ² selected from

R ^q is selected from C1-C6 alkyl;

R ¹⁹ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl;

R ²⁰ is selected from carboxyl, C1-C6 alkyl-OC(=O)-, HO-C1-C6 alkyl,

In some embodiments, L is Among them, X is connected to the benzene ring, and Y is connected to R ⁴ . In some embodiments, X is

In some embodiments, Y is selected from

In some embodiments, Y is

In some embodiments, ^R5 is selected from hydrogen, methyl, ethyl, n-propyl.

In some embodiments, R ^1a is selected from hydrogen, halogen, C1-C6 alkoxy, -NR ^a R ^b .

In some embodiments, R ^1a is selected from hydrogen, chlorine, methoxy, -NR ^a R ^b .

In some embodiments, R ^1a is selected from hydrogen, chlorine, methoxy,

In some embodiments, R ^lb is selected from hydrogen, C1-C6 alkoxy, -NR ^a R ^b .

In some embodiments, R ^lb is selected from hydrogen, methoxy, -NR ^a R ^b .

In some embodiments, R ^1b is selected from hydrogen, methoxy,

In some embodiments, R ^1a , R ^1b and the carbon atoms to which they are respectively connected form a 5-membered heterocyclic ring. Preferably, the 5-membered heterocyclic ring contains 1-2 (preferably 2) heteroatoms, preferably Ground, the heteroatom is selected from O, S.

In some embodiments, R ^1a , R ^1b , and the carbon atom to which they are respectively attached, together form

In some embodiments, R ^a and R ^b are each independently selected from C1-C6 alkyl, or R ^a , R ^b and the nitrogen atom to which they are commonly connected together form a 5-6 membered nitrogen-containing heterocyclic ring.

In some embodiments, R ^a and R ^b are each independently selected from C1-C6 alkyl, or R ^a , R ^b and the nitrogen atoms they are commonly connected to form a 5-6 membered nitrogen-containing saturated heterocyclic ring, preferably Preferably, the nitrogen-containing saturated heterocyclic ring contains 1-3 (such as 1) heteroatoms. Preferably, the heteroatoms are nitrogen atoms.

In some embodiments, R ^a , R ^b are each independently selected from methyl, ethyl, n-propyl, or R ^a , R ^b and the nitrogen atom to which they are commonly connected form

In some embodiments, n is selected from 1, 2, 3.

In some embodiments, n is selected from 1,2.

In some embodiments, n is 1.

In some embodiments, R ⁶ is selected from 5-membered heteroaryl, phenyl, C1-C6 alkyl, optionally, each of the 5-membered heteroaryl and phenyl is independently substituted by R ^c .

In some embodiments, R ⁶ is selected from furyl, thienyl, phenyl, C1-C6 alkyl, pyrrolyl, optionally, the furyl, thienyl, pyrrolyl are each independently substituted by R ^c .

In some embodiments, R ^is selected from furyl, thienyl, phenyl, C1-C6 alkyl, optionally, The furyl group and thienyl group are each independently substituted by R ^c .

In some embodiments, ^R is selected from optionally, Each is independently replaced by R ^c .

In some embodiments, ^R is selected from

In some embodiments, ^R6 is

In some embodiments, ^Rc is selected from halogen, nitro, cyano, C1-C6 alkyl.

In some embodiments, R ^c is selected from halogen, nitro, C1-C6 alkyl, C1-C6 haloalkyl.

In some embodiments, R ^c is selected from halogen, nitro, C1-C6 alkyl.

In some embodiments, ^Rc is selected from bromo, chlorine, nitro, methyl, trifluoromethyl.

In some embodiments, R ^c is selected from bromine, chlorine, nitro, methyl.

In some embodiments, ^Rc is selected from bromine, chlorine, methyl.

In some embodiments, ^R is selected from

In some embodiments, ^R2 is

In some embodiments, ^R3 is selected from phenyl, pyridyl, furyl, thienyl, C1-C6 alkyl, -NR ^m R ⁿ , C3-C6 cycloalkyl, C1-C6 alkoxy, C2- C6 alkenyl, optionally, the phenyl, pyridyl, furyl, and thienyl groups are each independently substituted by 1-2 groups selected from R ^x .

In some embodiments, R ³ is selected from phenyl, pyridyl, furyl, thienyl, C1-C6 alkyl, -NR ^m R ⁿ , optionally, the phenyl, pyridyl, furyl, thiophene Each group is independently substituted by 1-2 groups selected from ^Rx .

In some embodiments, ^R3 is selected from phenyl, pyridyl, furyl, thienyl, C1-C6 alkyl, -NR ^m R ⁿ , C3-C6 cycloalkyl, C1-C4 alkoxy, C2- C6 alkenyl, optionally, the phenyl and furyl groups are each independently substituted by 1-2 groups selected from ^Rx .

In some embodiments, R ³ is selected from phenyl, pyridyl, furyl, and thienyl. Optionally, each of the phenyl, pyridyl, furyl, and thienyl groups is independently selected from 1 to 2 R replaced by ^x group.

In some embodiments, R ³ is selected from phenyl, pyridyl, furyl, thienyl, C1-C6 alkyl, -NR ^m R ⁿ , optionally, each of the phenyl and furyl groups is independently replaced by 1 - Substituted by 2 groups selected from R ^x .

In some embodiments, R ³ is selected from phenyl, pyridyl, furyl, and thienyl. Optionally, the phenyl and furyl groups are each independently substituted by 1-2 groups selected from ^R .

In some embodiments, ^R3 is selected from methyl, -NR ^m R ⁿ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH ₂ ) ₃ CH ₃ , -CH＝CH ₂ , -C＝CH ₂ CH ₃ , -OC (CH ₃ ) ₃ , optionally, the Each is independently substituted by 1-2 groups selected from ^Rx .

In some embodiments, ^R3 is selected from methyl, -NR ^m R ⁿ , optionally, the Each is independently substituted by 1-2 groups selected from ^Rx .

In some embodiments, ^R3 is selected from Optionally, the Each is independently substituted by 1-2 groups selected from ^Rx .

In some embodiments, ^R3 is selected from Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH ₂ ) ₃ CH ₃ , -CH＝CH ₂ , -C＝CH ₂ CH ₃ , -OC(CH ₃ ) ₃ .

In some embodiments, ^R3 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, -(CH ₂ ) ₃ CH ₃ , -CH＝CH ₂ , -C＝CH ₂ CH ₃ , -OC(CH ₃ ) ₃ .

In some embodiments, ^R3 is selected from methyl,

In some embodiments, ^R3 is selected from

In some embodiments, R ^m and R ⁿ are each independently selected from C1-C6 alkyl, or R ^m , R ⁿ and the nitrogen atoms they are commonly connected together form a 5-6 membered nitrogen-containing heterocyclic ring, optionally Any one -CH ₂ - in the 5-6 membered nitrogen-containing heterocyclic ring is replaced by -O-.

In some embodiments, R ^m and R ⁿ are each independently selected from C1-C6 alkyl, or R ^m , R ⁿ and the nitrogen atom to which they are commonly connected together form a 5-6 membered nitrogen-containing heterocycle.

In some embodiments, R ^m and R ⁿ are each independently selected from C1-C6 alkyl, or R ^m , R ⁿ and the nitrogen atom to which they are commonly connected together form a 6-membered nitrogen-containing saturated heterocycle, optionally Any -CH ₂ - in the 6-membered nitrogen-containing heterocycle is substituted by -O-. Preferably, the nitrogen-containing saturated heterocycle contains 1-3 (such as 1) Heteroatom, preferably, the heteroatom is a nitrogen atom.

In some embodiments, R ^m and R ⁿ are each independently selected from C1-C6 alkyl, or R ^m , R ⁿ and the nitrogen atoms to which they are commonly connected form a 6-membered nitrogen-containing saturated heterocyclic ring, preferably, The nitrogen-containing saturated heterocyclic ring contains 1-3 (such as 1) heteroatoms. Preferably, the heteroatoms are nitrogen atoms.

In some embodiments, ^Rm , ^Rn are each methyl or ethyl, or, ^Rm , ^Rn and the nitrogen atoms to which they are commonly attached form

In some embodiments, R ^m , R ⁿ are both ethyl groups, or R ^m , R ⁿ and the nitrogen atoms to which they are commonly attached form

In some embodiments, ^Rx is selected from halogen, nitro, C1-C6 alkyl, C1-C6 alkoxy, -NR ^s R ^t .

In some embodiments, ^Rx is selected from fluorine, chlorine, methyl, methoxy, nitro, Trifluoromethyl, bromine.

In some embodiments, ^Rx is selected from fluorine, chlorine, methyl, methoxy, nitro, Trifluoromethyl.

In some embodiments, ^Rx is selected from fluorine, chlorine, methyl, methoxy, nitro,

In some embodiments, ^Rx is selected from chlorine, bromine.

In some embodiments, R ^s and R ^t are both methyl.

In some embodiments, R ⁸ and R ⁹ are each independently selected from hydrogen, C1-C6 alkyl, halogen, carboxyl, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-N(R ^u )-, C1-C6 alkyl-C(=O)-C1-C6 alkyl, R ^v R ^w NC(=O)-N(R ^y )-, C1-C6 alkyl-OC(=O)- , C1-C6 alkyl-OC(=O)-C1-C6 alkyl, HO-C(=O)-C1-C6 alkyl, C1-C6 alkyl-OC(=O)-C1-C6 alkyl -C(=O)-N(R ^y )-, HO-C(=O)-C1-C6 alkyl-C(=O)-N(R ^y )-, C1-C6 alkyl-C(= O)-N(R ^y )-C(=O)-N(R ^y )-, C1-C6 alkyl-C(=O)-N(R ^y )-C(=O)-C1-C6 alkyl Base, C1-C6 alkyl-C(=O)-C1-C6 alkyl-C(=O)-N(R ^y )-, R ^v R ^w NC(=O)-, C1-C6 alkyl- C(=O)-N(R ^y )-C(=O)-, C1-C6 alkyl-C(=O)-, and R ⁸ and R ⁹ are not hydrogen at the same time, R ⁷ , R ¹⁰ , R ¹¹ is hydrogen.

In some embodiments, R ⁹ is selected from hydrogen, carboxyl, C1-C6 alkyl-C(=O)-N(R ^u )-, C1-C6 alkyl-C(=O)-C1-C6 alkyl , R ^v R ^w NC(=O)-N(R ^y )-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-OC(=O)-C1-C6 alkyl, HO -C(=O)-C1-C6 alkyl, C1-C6 alkyl-OC(=O)-C1-C6 alkyl-C(=O)-N(R ^y )-, HO-C(=O )-C1-C6 alkyl-C(=O)-N(R ^y )-, C1-C6 alkyl-C(=O)-N(R ^y )- C(=O)-N(R ^y )-, C1-C6 alkyl-C(=O)-N(R ^y )-C(=O)-C1-C6 alkyl, C1-C6 alkyl-C (=O)-C1-C6 alkyl-C(=O)-N(R ^y )-, R ^v R ^w NC(=O)-, C1-C6 alkyl-C(=O)-N(R ^y )-C(=O)-, C1-C6 alkyl-C(=O)-, R ⁸ is selected from hydrogen, C1-C6 alkyl, halogen (preferably chlorine), C1-C6 haloalkyl, C1-C6 Alkyl -C(=O)-N(R ^u )-, and R ⁸ and R ⁹ are not hydrogen at the same time, and R ⁷ , R ¹⁰ and R ¹¹ are hydrogen.

In some embodiments, R ⁹ is selected from carboxyl, C1-C6 alkyl-C(=O)-N(R ^u )-, C1-C6 alkyl-C(=O)-C1-C6 alkyl, R ^v R ^w NC(=O)-N(R ^y )-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-OC(=O)-C1-C6 alkyl, HO-C (=O)-C1-C6 alkyl, C1-C6 alkyl-OC(=O)-C1-C6 alkyl-C(=O)-N(R ^y )-, HO-C(=O)- C1-C6 alkyl-C(=O)-N(R ^y )-, C1-C6 alkyl-C(=O)-N(R ^y )-C(=O)-N(R ^y )-, C1-C6 alkyl-C(=O)-N(R ^y )-C(=O)-C1-C6 alkyl, C1-C6 alkyl-C(=O)-C1-C6 alkyl-C( =O)-N(R ^y )-, R ^v R ^w NC(=O)-, C1-C6 alkyl-C(=O)-N(R ^y )-C(=O)-, C1-C6 Alkyl -C(=O)-, R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ are hydrogen.

In some embodiments, R ⁹ is selected from hydrogen, carboxyl, R ⁸ is selected from hydrogen, methyl, chlorine, Moreover, R ⁸ and R ⁹ are not hydrogen at the same time, and R ⁷ , R ¹⁰ and R ¹¹ are hydrogen.

In some embodiments, R ⁹ is selected from carboxyl, R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ are hydrogen.

In some embodiments, R ^is selected from hydrogen, C1-C6 alkyl.

In some embodiments, R ^is selected from hydrogen, methyl, trifluoromethyl.

In some embodiments, R ^is selected from hydrogen, methyl.

In some embodiments, R ^y is selected from hydrogen, C1-C6 alkyl.

In some embodiments, R ^y is selected from hydrogen, trifluoromethyl.

In some embodiments, ^Ry is hydrogen.

In some embodiments, R ^v , R ^w are each independently selected from hydrogen, C1-C6 alkyl.

In some embodiments, R ^v , R ^w are each independently selected from hydrogen, methyl, ethyl, trifluoromethyl.

In some embodiments, R ^v , R ^w are each independently selected from hydrogen, methyl, ethyl.

In some embodiments, As a whole, selected from the following:

In some embodiments, ^X1 is

In some embodiments, ^Rz is selected from methyl, acetyl.

In some embodiments, R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ are each hydrogen.

In some embodiments, as a whole, selected from

In some embodiments, ^X2 is

In some embodiments, each of R ¹⁶ , R ¹⁷ , and R ¹⁸ is independently selected from hydrogen, halogen, C1-C6 alkyl.

In some embodiments, R ¹⁶ , R ¹⁷ , and R ¹⁸ are each independently selected from hydrogen, halogen, C1-C6 haloalkyl.

In some embodiments, R ¹⁶ , R ¹⁷ , and R ¹⁸ are each independently selected from hydrogen and halogen.

In some embodiments, R ¹⁶ is selected from hydrogen, halogen, C1-C6 haloalkyl, and R ¹⁷ and R ¹⁸ are hydrogen.

In some embodiments, R ¹⁶ is selected from hydrogen, halogen, and R ¹⁷ and R ¹⁸ are hydrogen.

In some embodiments, R ¹⁶ is selected from hydrogen, chlorine, trifluoromethyl, and R ¹⁷ and R ¹⁸ are hydrogen.

In some embodiments, R ¹⁶ is selected from hydrogen, chlorine, and R ¹⁷ and R ¹⁸ are hydrogen.

In some embodiments, R ¹⁹ is selected from hydrogen, halogen, C1-C6 alkyl.

In some embodiments, R ¹⁹ is selected from hydrogen, chlorine, methyl, trifluoromethyl.

In some embodiments, R ¹⁹ is selected from hydrogen, chlorine, methyl.

In some embodiments, R ²⁰ is selected from carboxyl,

In some embodiments, as a whole, selected from

In the second aspect of the invention, the invention provides a compound represented by Formula I-1, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, or pharmaceutically acceptable solvent of the compound. compounds or pharmaceutically acceptable esters,

in:

X is selected from

Y is selected from

R ⁵ is selected from hydrogen, C1-C6 alkyl;

R ² is selected from -(CH ₂ ) _n -R ⁶ ;

n is selected from 1, 2, 3, 4, 5, 6;

R ^c is selected from halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl;

R ^s and R ^t are each independently selected from C1-C6 alkyl;

R ⁴ is selected from:

1)

R ^u is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;

R ^y is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;

2)

X ¹ selected from

R ^z is selected from C1-C6 alkyl, C1-C6 alkyl-C(=O)-;

3)

X ² selected from

R ^q is selected from C1-C6 alkyl;

R ¹⁹ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl;

R ²⁰ is selected from carboxyl, C1-C6 alkyl-OC(=O)-, HO-C1-C6 alkyl,

And, X is And Y is When , the compound represented by formula I-1 is not the following compound:

In some embodiments, L is Among them, X is connected to the benzene ring, and Y is connected to R ⁴ .

In some embodiments, X is

In some embodiments, Y is selected from

In some embodiments, Y is

In some embodiments, ^R5 is selected from hydrogen, methyl, ethyl, n-propyl.

In some embodiments, R ^1a is selected from hydrogen, chlorine, methoxy,

In some embodiments, R ^lb is selected from hydrogen, methoxy, -NR ^a R ^b .

In some embodiments, R ^1b is selected from hydrogen, methoxy,

In some embodiments, n is selected from 1, 2, 3.

In some embodiments, n is selected from 1,2.

In some embodiments, n is 1.

In some embodiments, R ⁶ is selected from furyl, thienyl, phenyl, C1-C6 alkyl, optionally, the furyl and thienyl are each independently substituted by R ^c .

In some embodiments, ^R is selected from

In some embodiments, ^R6 is

In some embodiments, ^Rc is selected from halogen, nitro, cyano, C1-C6 alkyl.

In some embodiments, R ^c is selected from halogen, nitro, C1-C6 alkyl.

In some embodiments, R ^c is selected from bromine, chlorine, nitro, methyl.

In some embodiments, ^R is selected from

In some embodiments, ^R2 is

In some embodiments, ^R3 is selected from phenyl, pyridyl, furyl, thienyl, optionally, Phenyl, pyridyl, furyl, and thienyl are each independently substituted by 1-2 groups selected from R ^x .

In some embodiments, ^R3 is selected from methyl,

In some embodiments, ^R3 is selected from

In some embodiments, R ^s and R ^t are both methyl.

In some embodiments, R ⁹ is selected from hydrogen, carboxyl, C1-C6 alkyl-C(=O)-N(R ^u )-, C1-C6 alkyl-C(=O)-C1-C6 alkyl , R ^v R ^w NC(=O)-N(R ^y )-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-OC(=O)-C1-C6 alkyl, HO -C(=O)-C1-C6 alkyl, C1-C6 alkyl-OC(=O)-C1-C6 alkyl-C(=O)-N(R ^y )-, HO-C(=O )-C1-C6 alkyl-C(=O)-N(R ^y )-, C1-C6 alkyl-C(=O)-N(R ^y )-C(=O)-N(R ^y ) -, C1-C6 alkyl-C(=O)-N(R ^y )-C(=O)-C1-C6 alkyl, C1-C6 alkyl-C(=O)-C1-C6 alkyl- C(=O)-N(R ^y )-, R ^v R ^w NC(=O)-, C1-C6 alkyl-C(=O)-N(R ^y )-C(=O)-, C1 -C6 alkyl-C(=O)-, R ⁸ is selected from hydrogen, C1-C6 alkyl, halogen (preferably chlorine), C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-N( R ^u )-, and R ⁸ and R ⁹ are not hydrogen at the same time, and R ⁷ , R ¹⁰ and R ¹¹ are hydrogen.

In some embodiments, R ^is selected from hydrogen, C1-C6 alkyl.

In some embodiments, R ^is selected from hydrogen, methyl, trifluoromethyl.

In some embodiments, R ^is selected from hydrogen, methyl.

In some embodiments, R ^y is selected from hydrogen, C1-C6 alkyl.

In some embodiments, R ^y is selected from hydrogen, trifluoromethyl.

In some embodiments, ^Ry is hydrogen.

In some embodiments, As a whole, selected from the following:

In some embodiments, ^X1 is

In some embodiments, ^Rz is selected from methyl, acetyl.

In some embodiments, R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ are each hydrogen.

In some embodiments, as a whole, selected from

In some embodiments, ^X2 is

In some embodiments, R ¹⁹ is selected from hydrogen, halogen, C1-C6 alkyl.

In some embodiments, R ¹⁹ is selected from hydrogen, chlorine, methyl.

In some embodiments, R ²⁰ is selected from carboxyl,

In some embodiments, as a whole, selected from

In the third aspect of the present invention, the present invention provides a compound represented by Formula I-1-1, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable salt, or pharmaceutically acceptable salt of the compound. solvates or pharmaceutically acceptable esters,

in:

R ² is selected from -(CH ₂ ) _n -R ⁶ ;

n is selected from 1, 2, 3, 4, 5, 6;

R ^c is selected from halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl;

R ³ is selected from phenyl, 5-6 membered heteroaryl, C1-C6 alkyl, -NR ^m R ⁿ , C3-C10 cycloalkyl, C1-C6 alkoxy, C2-C6 alkenyl, optionally , the phenyl group and the 5-6-membered heteroaryl group are each independently selected from 1-2 Substituted from a group of R ^x ;

R ^s and R ^t are each independently selected from C1-C6 alkyl;

R ⁴ is selected from:

1)

R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are each independently selected from hydrogen, C1-C6 alkyl, halogen, carboxyl, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-N (R ^u )-, C1-C6 alkyl-C(=O)-C1-C6 alkyl, R ^v R ^w NC(=O)-N(R ^y )-, C1-C6 alkyl-OC(= O)-, C1-C6 alkyl-OC(=O)-C1-C6 alkyl, HO-C(=O)-C1-C6 alkyl, C1-C6 alkyl-OC(=O)-C1- C6 alkyl-C(=O)-N(R ^y )-, HO-C(=O)-C1-C6 alkyl-C(=O)-N(R ^y )-, C1-C6 alkyl- C(=O)-N(R ^y )-C(=O)-N(R ^y )-, C1-C6 alkyl-C(=O)-N(R ^y )-C(=O)-C1 -C6 alkyl, C1-C6 alkyl -C(=O)-C1-C6 alkyl-C(=O)-N(R ^y )-, R ^v R ^w NC(=O)-, C1-C6 Alkyl-C(=O)-N(R ^y )-C(=O)-, and R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are not hydrogen at the same time;

R ^u is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;

R ^y is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;

2)

X ¹ selected from

R ^z is selected from C1-C6 alkyl, C1-C6 alkyl-C(=O)-;

3)

X ² selected from

R ^q is selected from C1-C6 alkyl;

R ¹⁹ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl;

R ²⁰ is selected from carboxyl, C1-C6 alkyl-OC(=O)-, HO-C1-C6 alkyl,

R ⁵ is selected from hydrogen, C1-C6 alkyl.

Some embodiments of the present invention provide a compound represented by formula I-1-1, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate of the compound. or a pharmaceutically acceptable ester,

in:

R ² is selected from -(CH ₂ ) _n -R ⁶ ;

n is selected from 1, 2, 3, 4, 5, 6;

R ^c is selected from halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl;

R ^m and R ⁿ are each independently selected from C1-C6 alkyl, or R ^m , R ⁿ and the nitrogens jointly connected to them The atoms together form a 4-7 membered nitrogen-containing heterocycle;

R ^s and R ^t are each independently selected from C1-C6 alkyl;

R ⁴ is selected from:

1)

R ^u is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;

R ^y is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;

2)

X ¹ selected from

R ^z is selected from C1-C6 alkyl, C1-C6 alkyl-C(=O)-;

3)

X ² selected from

R ^q is selected from C1-C6 alkyl;

R ¹⁹ is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl;

R ²⁰ is selected from carboxyl, C1-C6 alkyl-OC(=O)-, HO-C1-C6 alkyl,

R ⁵ is selected from hydrogen, C1-C6 alkyl.

In some embodiments, R ^1a is selected from hydrogen, chlorine, methoxy,

In some embodiments, R ^lb is selected from hydrogen, methoxy, -NR ^a R ^b .

In some embodiments, R ^1b is selected from hydrogen, methoxy,

In some embodiments, n is selected from 1, 2, 3.

In some embodiments, n is selected from 1,2.

In some embodiments, n is 1.

In some embodiments, ^R is selected from

In some embodiments, ^R6 is

In some embodiments, ^Rc is selected from halogen, nitro, cyano, C1-C6 alkyl.

In some embodiments, R ^c is selected from halogen, nitro, C1-C6 alkyl.

In some embodiments, R ^c is selected from bromine, chlorine, nitro, methyl.

In some embodiments, ^R is selected from

In some embodiments, ^R2 is

In some embodiments, ^R3 is selected from methyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH ₂ ) ₃ CH ₃ , -CH＝CH ₂ , -C＝CH ₂ CH ₃ ,

In some embodiments, ^R3 is selected from methyl,

In some embodiments, ^R3 is selected from

In some embodiments, ^Rm , ^Rn are each independently selected from C1-C6 alkyl, or, ^Rm , ^Rn and Together with the nitrogen atoms they are connected to, they form a 6-membered nitrogen-containing saturated heterocyclic ring. Preferably, the nitrogen-containing saturated heterocyclic ring contains 1-3 (such as 1) heteroatoms. Preferably, the heteroatoms are nitrogen atoms. .

In some embodiments, R ^s and R ^t are both methyl.

In some embodiments, R ⁸ and R ⁹ are each independently selected from hydrogen, C1-C6 alkyl, halogen, carboxyl, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-N(R ^u )-, C1-C6 alkyl-C(=O)-C1-C6 alkyl, R ^v R ^w NC(=O)-N(R ^y )-, C1-C6 alkyl-OC(=O)- , C1-C6 alkyl-OC(=O)-C1-C6 alkyl, HO-C(=O)-C1-C6 alkyl, C1-C6 alkyl-OC(=O)-C1-C6 alkyl -C(=O)-N(R ^y )-, HO-C(=O)-C1-C6 alkyl-C(=O)-N(R ^y )-, C1-C6 alkyl-C(= O)-N(R ^y )-C(=O)-N(R ^y )-, C1-C6 alkyl-C(=O)-N(R ^y )-C(=O)-C1-C6 alkyl Base, C1-C6 alkyl-C(=O)-C1-C6 alkyl-C(=O)-N(R ^y )-, R ^v R ^w NC(=O)-, C1-C6 alkyl- C(=O)-N(R ^y )-C(=O)-, and R ⁸ and R ⁹ are not hydrogen at the same time, and R ⁷ , R ¹⁰ and R ¹¹ are hydrogen.

In some embodiments, R ⁹ is selected from hydrogen, carboxyl, C1-C6 alkyl-C(=O)-N(R ^u )-, C1-C6 alkyl-C(=O)-C1-C6 alkyl , R ^v R ^w NC(=O)-N(R ^y )-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-OC(=O)-C1-C6 alkyl, HO -C(=O)-C1-C6 alkyl, C1-C6 alkyl-OC(=O)-C1-C6 alkyl-C(=O)-N(R ^y )-, HO-C(=O )-C1-C6 alkyl-C(=O)-N(R ^y )-, C1-C6 alkyl-C(=O)-N(R ^y )-C(=O)-N(R ^y ) -, C1-C6 alkyl-C(=O)-N(R ^y )-C(=O)-C1-C6 alkyl, C1-C6 alkyl-C(=O)-C1-C6 alkyl- C(=O)-N(R ^y )-, R ^v R ^w NC(=O)-, C1-C6 alkyl-C(=O)-N(R ^y )-C(=O)-, R ⁸ is selected from hydrogen, C1-C6 alkyl, halogen (preferably chlorine), C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-N(R ^u )-, and R ⁸ and R ⁹ are not at the same time is hydrogen, and R ⁷ , R ¹⁰ , and R ¹¹ are hydrogen.

In some embodiments, R ⁹ is selected from carboxyl, C1-C6 alkyl-C(=O)-N(R ^u )-, C1-C6 alkyl-C(=O)-C1-C6 alkyl, R ^v R ^w NC(=O)-N(R ^y )-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-OC(=O)-C1-C6 alkyl, HO-C (=O)-C1-C6 alkyl, C1-C6 alkyl-OC(=O)-C1-C6 alkyl-C(=O)-N(R ^y )-, HO-C(=O)- C1-C6 alkyl-C(=O)-N(R ^y )-, C1-C6 alkyl-C(=O)-N(R ^y )- C(=O)-N(R ^y )-, C1-C6 alkyl-C(=O)-N(R ^y )-C(=O)-C1-C6 alkyl, C1-C6 alkyl-C (=O)-C1-C6 alkyl-C(=O)-N(R ^y )-, R ^v R ^w NC(=O)-, C1-C6 alkyl-C(=O)-N(R ^y )-C(=O)-, R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ are hydrogen.

In some embodiments, As a whole, selected from the following:

In some embodiments, R ^is selected from hydrogen, C1-C6 alkyl.

In some embodiments, R ^is selected from hydrogen, methyl, trifluoromethyl.

In some embodiments, R ^is selected from hydrogen, methyl.

In some embodiments, R ^y is selected from hydrogen, C1-C6 alkyl.

In some embodiments, R ^y is selected from hydrogen, trifluoromethyl.

In some embodiments, ^Ry is hydrogen.

In some embodiments, R ^v , R ^w are each independently selected from hydrogen, methyl, ethyl, trifluoromethyl. In some embodiments, R ^v , R ^w are each independently selected from hydrogen, methyl, ethyl.

In some embodiments, ^X1 is

In some embodiments, ^Rz is selected from methyl, acetyl.

In some embodiments, R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ are each hydrogen.

In some embodiments, as a whole, selected from

In some embodiments, ^X2 is

In some embodiments, R ¹⁹ is selected from hydrogen, halogen, C1-C6 alkyl.

In some embodiments, R ¹⁹ is selected from hydrogen, chlorine, methyl.

In some embodiments, R ²⁰ is selected from carboxyl,

In some embodiments, as a whole, selected from

In some embodiments, ^R5 is selected from hydrogen, methyl, ethyl, n-propyl.

In some embodiments, ^R5 is selected from methyl, ethyl.

In the fourth aspect of the present invention, the present invention provides a compound represented by Formula I-1-2, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable salt, or pharmaceutically acceptable salt of the compound. solvates or pharmaceutically acceptable esters,

in:

R ^1a is selected from hydrogen and halogen;

R ^1b is selected from hydrogen and halogen;

R ² is selected from -(CH ₂ ) _n -R ⁶ ;

n is selected from 1, 2, 3, 4, 5, 6;

R ⁶ is selected from 5-6 membered heteroaryl;

R ³ is phenyl, and the phenyl group is optionally substituted by 1-2 groups selected from R ^x ;

R ^x is selected from halogen;

R ⁴ is

Among them, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are each independently selected from hydrogen, C1-C6 alkyl-C(=O)-N(R ^u )-, C1-C6 alkyl-C( =O)-, and R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are not hydrogen at the same time;

R ^u is selected from hydrogen, C1-C6 alkyl;

Moreover, the compound represented by formula I-1-2 is not the following compound:

In some embodiments, R ^1a is selected from hydrogen, chlorine.

In some embodiments, R ^lb is hydrogen.

In some embodiments, n is selected from 1, 2, 3.

In some embodiments, n is selected from 1,2.

In some embodiments, n is 1.

In some embodiments, R ^is selected from 5-membered heteroaryl.

In some embodiments, ^R6 is selected from furyl, thienyl.

In some embodiments, ^R is selected from

In some embodiments, ^R6 is

In some embodiments, ^R2 is

In some embodiments, ^Rx is selected from fluorine, chlorine.

In some embodiments, ^R3 is selected from

In some embodiments, R ⁹ is selected from C1-C6 alkyl-C(=O)-N(R ^u )-, C1-C6 alkyl-C(=O)-, R ⁷ , R ⁸ , R ¹⁰ , R ¹¹ is hydrogen.

In some embodiments, R ⁹ is selected from R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ are hydrogen.

In some embodiments, ^R is hydrogen.

In some embodiments, ^R4 is selected from

In the fifth aspect of the present invention, the present invention provides a compound represented by formula I-1-3, or the compound Stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates or pharmaceutically acceptable esters,

in:

R ^1a is selected from hydrogen and halogen;

R ^1b is selected from hydrogen and halogen;

R ² is selected from -(CH ₂ ) _n -R ⁶ ;

n is selected from 1, 2, 3, 4, 5, 6;

R ⁶ is selected from 5-6 membered heteroaryl;

R ^x is selected from halogen;

R ⁴ is

Among them, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ are each independently selected from hydrogen, C1-C6 alkyl-C(=O)-N( ^Ru )-, and R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are not hydrogen at the same time;

R ^u is selected from hydrogen, C1-C6 alkyl;

R ⁵ is selected from hydrogen, C1-C6 alkyl.

In some embodiments, R ^1a is selected from halogen.

In some embodiments, R ^1a is chlorine.

In some embodiments, R ^lb is hydrogen.

In some embodiments, n is selected from 1, 2, 3.

In some embodiments, n is selected from 1,2.

In some embodiments, n is 1.

In some embodiments, R ^is selected from 5-membered heteroaryl.

In some embodiments, ^R6 is selected from furyl, thienyl.

In some embodiments, ^R is selected from

In some embodiments, ^R6 is

In some embodiments, ^R2 is

In some embodiments, ^R3 is phenyl, optionally substituted with 1 group selected from ^Rx .

In some embodiments, ^R3 is

In some embodiments, ^Rx is chlorine.

In some embodiments, any one of R ⁸ and R ⁹ is selected from C1-C6 alkyl-C(=O)-N(R ^u )-, the other is hydrogen, and R ⁷ , R ¹⁰ , and R ¹¹ are hydrogen.

In some embodiments, any one of R ⁸ and R ⁹ is The other is hydrogen, and R ⁷ , R ¹⁰ and R ¹¹ are hydrogen.

In some embodiments, ^R is hydrogen.

In some embodiments, ^R4 is selected from

In some embodiments, ^R5 is selected from hydrogen, methyl, ethyl.

In the sixth aspect of the present invention, the present invention provides compounds represented by formula I-1-4, or stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, pharmaceutically acceptable salts, and solvates or pharmaceutically acceptable esters,

in:

R ^1a is selected from hydrogen and halogen;

R ^1b is selected from hydrogen and halogen;

R ² is selected from -(CH ₂ ) _n -R ⁶ ;

n is selected from 1, 2, 3, 4, 5, 6;

R ⁶ is selected from 5-6 membered heteroaryl;

R ^x is selected from halogen;

R ⁴ is

R ^u is selected from hydrogen, C1-C6 alkyl;

R ⁵ is selected from hydrogen, C1-C6 alkyl.

In some embodiments, R ^1a is selected from halogen.

In some embodiments, R ^1a is chlorine.

In some embodiments, R ^lb is hydrogen.

In some embodiments, n is selected from 1, 2, 3.

In some embodiments, n is selected from 1,2.

In some embodiments, n is 1.

In some embodiments, R ^is selected from 5-membered heteroaryl.

In some embodiments, ^R6 is selected from furyl, thienyl.

In some embodiments, ^R is selected from

In some embodiments, ^R6 is

In some embodiments, ^R2 is

In some embodiments, ^R3 is

In some embodiments, ^Rx is chlorine.

In some embodiments, R ⁹ is selected from C1-C6 alkyl-C(=O)-N( ^Ru )-, and R ⁷ , R ⁸ , R ¹⁰ , and R ¹¹ are hydrogen.

In some embodiments, ^R9 is R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ are hydrogen.

In some embodiments, ^R is hydrogen.

In some embodiments, ^R4 is

In some embodiments, ^R5 is selected from hydrogen, ethyl.

In the seventh aspect of the present invention, the present invention provides a compound represented by Formula I-2, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, or pharmaceutically acceptable solvent of the compound. compounds or pharmaceutically acceptable esters,

in:

R ^1a is selected from hydrogen, C1-C6 alkoxy;

R ^1b is selected from hydrogen, C1-C6 alkoxy;

R ² is selected from -(CH ₂ ) _n -R ⁶ ;

n is selected from 1, 2, 3, 4, 5, 6;

R ⁶ is selected from 5-6 membered heteroaryl;

R ^x is selected from halogen;

R ⁴ is

R ^u is selected from hydrogen, C1-C6 alkyl;

Moreover, the compound represented by formula I-2 is not the following compound:

In some embodiments, R ^1a is hydrogen.

In some embodiments, R ^1b is selected from C1-C6 alkoxy.

In some embodiments, R ^1b is methoxy.

In some embodiments, n is selected from 1, 2, 3.

In some embodiments, n is selected from 1,2.

In some embodiments, n is 1.

In some embodiments, R ^is selected from 5-membered heteroaryl.

In some embodiments, ^R6 is selected from furyl, thienyl.

In some embodiments, ^R is selected from

In some embodiments, ^R6 is

In some embodiments, ^R2 is

In some embodiments, ^Rx is chlorine.

In some embodiments, ^R3 is selected from

In some embodiments, ^R is hydrogen.

In some embodiments, ^R4 is selected from

In some embodiments, the aforementioned compounds are selected from the following:

In the eighth aspect of the present invention, the present invention provides a pharmaceutical composition, which contains the aforementioned compound, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable salt of the compound. Solvates or pharmaceutically acceptable esters, and optional pharmaceutically acceptable excipients.

The compounds of the present invention can be used as FXR modulators to prevent or treat FXR-related diseases. In some embodiments, the FXR modulator is an agonist. In some embodiments, the FXR modulator is an inhibitor (or antagonist).

Therefore, in the ninth aspect of the present invention, the present invention provides the aforementioned compound or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or The use of pharmaceutically acceptable esters in the preparation of medicines, or the use of the aforementioned pharmaceutical compositions in the preparation of medicines, or the compounds represented by the following formula II or the stereoisomers, prodrugs, crystal forms of the compounds, The use of pharmaceutically acceptable salts, pharmaceutically acceptable solvates or pharmaceutically acceptable esters in the preparation of medicaments for the treatment and/or prevention of diseases related to FXR receptors;

in:

R ^1' is selected from hydrogen, halogen, C1-C6 alkoxy, -NR ^a' R ^b' ;

R ^a' and R ^b' are each independently selected from hydrogen and C1-C6 alkyl;

R ^2' is selected from -(CH ₂ ) _n' -R ^5' ;

n' is selected from 0, 1, 2, 3, 4, 5, 6;

R ^5' is selected from 5-6 membered heteroaryl, phenyl, 5-6 membered saturated heterocycle, C3-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, Optionally, the phenyl group is substituted by a group selected from fluorine, chlorine, bromine, and iodine (preferably fluorine);

R ^3' is selected from phenyl, 5-6 membered heteroaryl, C1-C6 alkyl, -NR ^c' R ^d' , optionally, the phenyl group is selected from fluorine, chlorine, bromine, iodine (Preferably fluorine, chlorine) group substituted;

R ^c' and R ^d' are each independently selected from hydrogen, C1-C6 alkyl, and phenyl, and the phenyl group is optionally replaced by a group selected from C1-C6 alkoxy (preferably methoxy) replaced;

R ^4' is selected from C1-C6 alkyl.

In some embodiments, R ^1' is selected from hydrogen, chlorine, methoxy,

In some embodiments, R ^a' , R ^b' are each independently selected from C1-C6 alkyl.

In some embodiments, R ^a' , R ^b' are ethyl.

In some embodiments, n' is selected from 0, 1, 2, 3.

In some embodiments, n' is selected from 0, 1, 2.

In some embodiments, n' is selected from 0, 1.

In some embodiments, R ^5' is selected from furyl, phenyl, tetrahydrofuryl, C3-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, optionally, The phenyl group is substituted by a group selected from fluorine, chlorine, bromine, and iodine (preferably fluorine).

In some embodiments, R ^5' is selected from

In some embodiments, R ^2' is selected from

In some embodiments, R ^3' is selected from phenyl, furyl, thienyl, C1-C6 alkyl, ^-NRc'Rd ^' , optionally, the phenyl group is replaced by 1 selected from fluorine, chlorine , bromine, iodine (preferably fluorine, chlorine) groups substituted.

In some embodiments, any one of R ^c' and R ^d' is hydrogen, and the other is selected from C1-C6 alkyl, Phenyl, said phenyl optionally substituted by 1 group selected from C1-C6 alkoxy (preferably methoxy).

In some embodiments, any one of R ^c' and R ^d' is hydrogen, and the other is selected from

In some embodiments, R ^3' is selected from

In some embodiments, R ^4' is methyl.

In some embodiments, the compound represented by Formula II is selected from Formula II-1, II-2, II-3:

Among them, R ^1' , R ^2' , R ^3' and R ^4' are as defined above.

In some embodiments, the compound of Formula II is selected from the following:

In some embodiments, the disease associated with the FXR receptor is selected from metabolism-related diseases, cardiovascular disease, liver disease, cancer, kidney disease, enteropathy, inflammation, or any combination thereof.

In some embodiments, the metabolism-related disease is selected from the group consisting of glycolipid metabolism diseases, cholesterol metabolism diseases, lipid metabolism diseases, bile acid metabolism diseases, or any combination thereof.

In some embodiments, the glycolipid metabolism disease is selected from obesity, diabetes (such as type 2 diabetes), dyslipidemia, hyperlipidemia, hypercholesterolemia, cholestasis, non-alcoholic fatty liver disease, non-alcoholic fatty liver disease hepatitis or any combination thereof.

In some embodiments, the cardiovascular disease is selected from atherosclerosis, myocardial ischemia-reperfusion injury, or a combination thereof.

In some embodiments, the liver disease is selected from liver resection, liver injury, or a combination thereof.

In some embodiments, the cancer is selected from breast cancer, esophageal cancer, lung cancer, pancreatic cancer, kidney cancer, liver cancer, prostate cancer, or any combination thereof.

In some embodiments, the renal disease is selected from nephritis, nephrotic syndrome, atheroembolic renal disease, or any combination thereof.

In the tenth aspect of the present invention, the present invention provides the aforementioned compound or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable salt of the compound. The accepted ester, or the aforementioned pharmaceutical composition, or the compound represented by Formula II described in the aforementioned ninth aspect or the stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable salt of the compound Acceptable solvates or pharmaceutically acceptable esters for use in the treatment and/or prevention of diseases associated with the FXR receptor.

In some embodiments, the metabolism-related disease is selected from the group consisting of glucose and lipid metabolism diseases, cholesterol metabolism diseases, Lipid metabolism disease, bile acid metabolism disease, or any combination thereof.

In some embodiments, the cancer is selected from breast cancer, esophageal cancer, lung cancer, pancreatic cancer, liver cancer, kidney cancer, prostate cancer, or any combination thereof.

In an eleventh aspect of the present invention, the present invention provides a method for treating and/or preventing diseases related to FXR receptors, which includes: administering to a subject an effective amount of the aforementioned compound or a stereoisomer of the compound. body, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable ester, or the aforementioned pharmaceutical composition, or the formula II described in the ninth aspect A compound or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable ester of said compound.

Detailed ways

It is to be understood that the terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting. Additionally, although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described.

In the present invention, unless otherwise expressly stated, the description "... each independently selected from" used throughout this article may refer to specific options expressed between the same or different symbols in different groups. They do not affect each other, or it can also mean that in the same group, the specific options expressed by the same or different symbols do not affect each other.

Substituents of the compounds of the present invention are disclosed according to group type or range. In particular, the present invention includes each and every individual subcombination of the individual members of these radical classes and ranges. For example, the term "C1-C6 alkyl" refers specifically to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups.

The term "alkyl" is meant to include branched and straight chain saturated aliphatic hydrocarbon radicals having the specified number of carbon atoms. For example, "C1-C6 alkyl" refers to C1, C2, C3, C4, C5 and C6. In addition, for example, "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms, preferably "C1-C4 alkyl", more preferably "C1-C3 alkyl". Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl base, isopentyl, neopentyl), etc.

The term "alkoxy" refers to any of the above alkyl groups (eg, C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc.) connected to the remainder of the molecule through an oxygen atom (-O-).

The term "C1-C6 haloalkyl" refers to one or more hydrogen atoms in any of the above alkyl groups (such as C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc.) replaced by halogen (preferably fluorine, chlorine), for example, monofluoromethyl, difluoroethyl, trifluoromethyl, wait.

The term "C3-C6 cycloalkyl" refers to

Heteroatom refers to N, O or S.

Halogen refers to fluorine, chlorine, bromine or iodine.

The term "heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups having at least one heteroatom (N, O, or S) in at least one ring, 8- 1, 9- or 10-membered bicyclic groups and 11- to 14-membered tricyclic groups, the heteroatom-containing ring optionally also has 1, 2 or 3 selected from N, O or S of heteroatoms. Among them, substituted and unsubstituted aromatic 8-membered, 9-membered or 10-membered bicyclic groups having at least one heteroatom (N, O or S) in at least one ring and 11-membered to The 14-membered tricyclic group is the "condensed heteroaryl group". It is a bicyclic or tricyclic heteroaryl group and requires a bicyclic or tricyclic overall structure to form an aromatic system. The heteroaryl group can be attached at any available nitrogen or carbon atom of any ring. And those skilled in the art can understand that two adjacent atoms (preferably carbon atoms) are shared between each two rings in the fused ring.

Exemplary monocyclic heteroaryl groups include, but are not limited to: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thienyl, oxazolyl Diazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, etc.

Exemplary bicyclic heteroaryl groups include, but are not limited to: indolyl, 5-azaindolyl, pyrro[2,3-d]pyrimidinyl, 5,6-diazaindolyl, 6-azaindolyl Heteroindolyl, 7-azaindolyl, pyrazolo[3,4-b]pyridyl, pyrro[2,3-c]pyridazinyl, thieno[2,3-d]imidazolyl , Thieno[2,3-d]imidazolyl, pyrazolo[3,4-c]pyridyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzothienyl, quinolyl , isoquinolinyl, benzofuranyl, indolizinyl, quinoxalinyl, indazolyl, pyrrolopyrimidinyl, furopyridyl, isoindolyl, etc.

The terms "heterocycle", "heterocycle" or "heterocyclyl" are used interchangeably and refer to substituted and unsubstituted 3- to 7-membered (preferably 4-7-membered, more preferably 5-membered) 6-membered) monocyclic groups, 7- to 11-membered bicyclic groups, and 10- to 15-membered tricyclic groups, which may contain one or more double bonds, but do not constitute an aromatic ring; wherein at least A ring has at least one heteroatom (N, O or S). The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated or partially saturated and do not constitute an aromatic ring. Heterocyclic groups can be attached at any available nitrogen or carbon atom.

Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, tetrahydrofuranyl, piperidinyl, Piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinetrienyl, 1-pyridonyl, 4-piperidine Keto group, tetrahydropyranyl group, morpholinyl group, 1,3-dioxolyl group, etc., preferably such as

Among them, "saturated heterocycle" refers to the heterocycle defined above that does not contain unsaturated bonds, such as no double bonds. For example, "nitrogen-containing saturated heterocycle" can be

The term "substituted" means that any one or more hydrogens on a specified atom or group are replaced by a selected selection of the specified group, provided that the normal valence of the specified atom is not exceeded.

In the present invention, "R ³ is selected from phenyl, 5-6-membered heteroaryl, C1-C6 alkyl, -NR ^m R ⁿ , optionally, the phenyl and 5-6-membered heteroaryl are each independently "substituted by 1-2 groups selected from R ^x " means that the phenyl group or 5-6 membered heteroaryl group may be substituted or unsubstituted. Among them, "the phenyl group and the 5-6-membered heteroaryl group are each independently substituted by 1-2 groups selected from R ^x " means that the phenyl group, the 5-6-membered heteroaryl group The groups are each independently substituted by one group selected from R ^x , or the phenyl group and the 5- to 6-membered heteroaryl group are each independently substituted by two groups selected from R ^x . "The phenyl group and the 5-6 membered heteroaryl group are each independently substituted by two groups selected from R ^x ", wherein the two substituted groups of the phenyl group and the 5-6 membered heteroaryl group The groups may be the same or different. At the same time, the two groups selected from R ^x may be the same or different. For example, when the phenyl group and the 5-6-membered heteroaryl group are each independently substituted by two groups selected from ^Rx , and ^Rx is selected from fluorine, chlorine, methyl, methoxy, and nitro, The phenyl group can be substituted by fluorine or chlorine, or the phenyl group can be substituted by 2 chlorines; the 5-6-membered heteroaryl group can be substituted by fluorine or chlorine, or the 5-6 The 5-6-membered heteroaryl group may be substituted by 2 chlorines, or the 5-6-membered heteroaryl group may be substituted with methyl or methoxy, or the 5-6-membered heteroaryl group may be substituted with 2 methyl groups. replaced by base. Other similar definitions can be understood with reference to the foregoing content.

From all the above descriptions, it will be apparent to those skilled in the art that any group whose name is a compound name, such as "C1-C6 alkyl-OC(=O)-C1-C6 alkyl" or "C1-C6 alkyl" Oxygen-C1-C6 alkyl" shall refer to the moiety derived therefrom from left to right, for example, from "C1-C6 alkyl-OC(=O)-" substituted by "C1-C6 alkyl ” or constructed from “C1-C6 alkyl” substituted by “C1-C6 alkoxy”, where “C1-C6 alkyl” is as defined above. Specifically, "C1-C6 alkyl-OC(=O)-C1-C6 alkyl" may be, for example Alternatively, "C1-C6 alkoxy-C1-C6 alkyl" may be, for example Other similar composite groups can be understood with reference to the foregoing content.

In the present invention, the structural formula shown in formula I can be

In the present invention, for the structural formula shown in formula I If in some embodiments, R ^1a , R ^1b and the carbon atoms to which they are respectively attached, together, form It means that the heterocyclic ring Double bonds through the dotted line It is fused with the benzene ring in the parent core of the structural formula shown in formula I, that is, after fusion, the structural formula shown in formula I becomes

In the present invention, R ⁴ is selected from hour, Indicates the presence or absence of the oxo group, that is, can be

In the present invention, "treatment" generally refers to obtaining the desired pharmacological and/or physiological effects. The effect may be prophylactic in terms of completely or partially preventing the disease or its symptoms; and/or may be therapeutic in terms of partially or completely stabilizing or curing the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) preventing the disease or symptoms in a patient who is susceptible to the disease or symptoms but has not yet been diagnosed with the disease; (b) suppressing the symptoms of the disease, that is, to prevent its progression; or (c) to alleviate the symptoms of the disease; condition, i.e., causing the disease or symptoms to degenerate.

In the present invention, "subject" refers to a vertebrate animal. In certain embodiments, vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the mammal is a human.

In the present invention, "effective amount" refers to an amount that is effective in achieving the desired therapeutic or preventive effect at the necessary dose and time. The "therapeutically effective amount" of a substance/molecule of the invention may vary depending on factors such as the disease state, age, sex and weight of the individual and the ability of the substance/molecule to elicit the desired response in the individual. A therapeutically effective amount also encompasses an amount of the substance/molecule in which the therapeutically beneficial effects outweigh any toxic or harmful consequences. "Prophylactically effective amount" refers to an amount effective in the dosage and time necessary to achieve the desired preventive effect. Often, but not necessarily, the prophylactically effective amount will be less than the therapeutically effective amount because the prophylactic dose is administered to the subject prior to the onset of disease or in the early stages of the disease. In the case of cancer, a therapeutically effective amount of the drug reduces the number of cancer cells; reduces the size of the tumor; inhibits (i.e., somewhat slows, preferably halts) the infiltration of cancer cells into surrounding organs; inhibits (ie, somewhat slows, preferably halts) the infiltration of cancer cells into surrounding organs; ) Tumor metastasis; inhibiting tumor growth to a certain extent; and/or alleviating one or more symptoms related to cancer to a certain extent.

The pharmaceutical composition involved in the present invention may contain pharmaceutically acceptable excipients. The excipients include but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human albumin, and buffer substances such as phosphates. , glycerin, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal oxidation Silicon, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin and more.

The pharmaceutical composition of the present invention can be prepared in various forms according to different administration routes. For example, the pharmaceutical composition can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal administration, buccal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, peritoneal administration. Medications are administered intravenously, intrathecally, intraventricularly, intrasternally, and intracranially by injection or infusion, or by means of an explanted reservoir. Among them, oral or intravenous administration is preferred.

The compounds described in the present invention can optionally be used in combination with one or more other active ingredients, and their respective dosages and proportions can be adjusted by those skilled in the art according to specific diseases and patient conditions, as well as clinical needs.

As used herein, unless otherwise stated, the term "prodrug" refers to derivatives that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs undergo this reaction only under biological conditions to become active compounds, or they have no or only less activity in their unreacted form. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, ed., 5th edition).

Stereoisomers in the compounds described herein, when specifically designated by chemical name as the (R)- or (S)-isomer, shall be understood to mean that the predominant configuration is the (R)-isomer or (S)-isomer, respectively. S)-isomer. Any asymmetric carbon atom may be present in the (R)-, (S)- or (R, S)-configuration, preferably in the (R)- or (S)-configuration.

"Solvate" or "solvate" are used interchangeably and refer to a compound that exists in combination with a certain solvent molecule. The combination may include stoichiometric amounts of a certain solvent, such as a monohydrate or dihydrate, or may include any amount of water; as another example, methanol or ethanol may form an "alcoholate," which may also be stoichiometric or non-stoichiometric. The term "solvate" as used herein refers to a solid form, ie, a compound in solution in a solvent. Although it may be solvated, it is not a solvate as the term is used herein.

As used herein, the term "pharmaceutically acceptable salt" refers to (i) the acidic functional group (such as -COOH) present in the compound provided by the invention and the appropriate inorganic or organic cation (base) formed Salts, and include, but are not limited to, alkali metal salts, such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, etc.; other metal salts, such as aluminum salts, iron salts, zinc salts, copper salts, etc. salt, nickel salt, cobalt salt, etc.; inorganic alkali salts, such as ammonium salt; organic alkali salts, such as tert-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt , Ethylenediamine salt, N-methylglucosamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroplutide Caine salt, procaine salt, diethanolamine salt, N-benzyl-phenylethylamine salt, piperazine salt, tetramethylamine salt, tris(hydroxymethyl)aminomethane salt. And, (ii) salts formed by the basic functional groups (such as -NH ₂ ) present in the compounds provided by the invention and appropriate inorganic or organic anions (acids), and include, but are not limited to, hydrohalides, such as hydrogen Fluorate, hydrochloride, hydrobromide, hydroiodide, etc.; inorganic acid salts, such as nitrate, perchlorate, sulfate, phosphate, etc.; lower alkane sulfonate, such as methanesulfonate , triflate, ethanesulfonate, etc.; aryl sulfonates, such as benzenesulfonate, p-benzenesulfonate, etc.; organic acid salts, such as acetate, malate, fumarate , succinic acid Salt, citrate, tartrate, oxalate, maleate, etc.; amino acid salts, such as glycinate, trimethylglycinate, arginine, ornithine, glutamate, aspartate Salts, etc.

As used herein, the term "pharmaceutically acceptable ester" refers to the ester of -COOH present in the compounds provided by the present invention with an appropriate alcohol, or -OH present in the compounds provided by the present invention. Esters formed with appropriate acids such as carboxylic acids or oxygenated inorganic acids. Suitable ester groups include, but are not limited to, formate, acetate, propionate, butyrate, acrylate, ethyl succinate, stearate, or palmitate. Esters can undergo hydrolysis reactions in the presence of acids or bases to generate corresponding acids or alcohols.

As used herein, the term "crystalline form" refers to the crystal structure of a substance. During the crystallization of substances, due to the influence of various factors, the bonding methods within or between molecules change, resulting in different arrangements of molecules or atoms in the crystal lattice space, forming different crystal structures. The compound of the present invention can exist in one crystal structure or in multiple crystal structures, that is, it has "polymorphic form". The compounds of the invention may exist in different crystalline forms.

The present invention will be further explained below in conjunction with specific embodiments. Unless otherwise specified, the raw materials used in the following examples are all commercially available.

The synthetic routes of compounds F44-S1～F44-S5, F44-S35～F44-S39, F44-S43～F44-S59 and F44-S111～F44-S117 are shown in Scheme 1.1. First, o-nitrobenzaldehyde or substituted o-nitrobenzaldehyde and a substituted amine are reductively aminated in methanol to form intermediate M1. After intermediate M1 is condensed with a substituted acid chloride in dichloromethane to form intermediate M2, the nitro group is reduced to form intermediate M3. Intermediate M3 reacts with methyl iodide or ethyl iodide to produce intermediates M4 and M5. Intermediate M3 reacts with substituted acid chloride or substituted sulfonyl chloride to obtain compounds F44-S1 to F44-S5. Intermediates M4 and M5 are reacted with substituted acid chlorides or substituted sulfonyl chlorides to obtain compounds M6, F44-S9 to F44-S34. Intermediate M6 is hydrolyzed in a strong alkaline system to obtain compounds F44-S35～F44-S39, F44-S43～F44-S59 and F44-S111～F44-S117.

Scheme 1.1 Compounds F44-S1～F44-S5, F44-S9～F44-S34, F44-S35～F44-S39, F44-S43～F27-S59 and F44-S111～F44-S117. Reagents and reaction conditions: (a) substituted amine, sodium borohydride, methanol, reaction for 12 hours, yield: 47%; (b) substituted acid chloride, potassium carbonate, anhydrous dichloromethane, reaction for 12 hours, yield: 49 %; (c) hydrazine hydrate, 10% palladium on carbon, methanol, reaction for 12 hours, yield: 98%; (d) methyl iodide or ethyl iodide or substituted acid chloride or substituted sulfonyl chloride, potassium carbonate, anhydrous dichloride Methane, react for 12 hours, yield: 12-94%; (e) substituted acid chloride or substituted sulfonyl chloride, potassium carbonate, anhydrous dichloromethane, react for 12 hours, yield: 14-94%; (f) hydroxide Lithium, water/ethanol, heat to reflux for 1 hour, yield: 40-94%.

The above R ¹ is the same as the group represented by R ^1a or R ^1b above, and R ⁴ in the product obtained in step e is an ester group, and R ⁴ in the product obtained in step f is a carboxylic acid group.

The synthetic route of compound F44-S6 is shown in Scheme 1.2. Compound F44-S1 reacts with bromopropane under strong alkaline conditions to obtain compound F44-S6.

Scheme 1.2 Compound F44-S6. Reagents and reaction conditions: (a) Sodium hydride, N,N-dimethylformamide, bromopropane, reaction 12h, yield: 38%.

The synthetic routes of compounds F44-S7 and F44-S8 are shown in Scheme 1.3. Intermediate M3 and N-(4-formyl Phenyl)acetamide was dehydrated and condensed in methanol to obtain compound F44-S7. Compound F44-S7 was reduced in methanol to obtain compound F44-S8.

Scheme 1.3 Compounds F44-S7, F44-S8. Reagents and reaction conditions: (a) N-(4-formylphenyl)acetamide, methanol, reflux reaction for 36 hours, yield: 74%; (b) sodium borohydride, methanol, reaction for 12 hours, yield: 77% .

The synthetic route of compound F44-S40 is shown in Scheme 1.4. Intermediate M5 is condensed with 4-nitrobenzenesulfonyl chloride in anhydrous dichloromethane to form intermediate M20. Intermediate M20 is reduced in methanol to form intermediate M21. Intermediate M21 was combined with 2,2,6-trimethyl-4H-1,3-dioxin-4-one in tetrahydrofuran to obtain compound F44-S40.

Scheme 1.4 Compound F44-S40. Reagents and reaction conditions: (a) 4-acetamidobenzenesulfonyl chloride, potassium carbonate, anhydrous dichloromethane, reaction for 12 hours, yield: 33%; (b) sodium borohydride, methanol, reaction for 12 hours, yield: 76 %; (c) 2,2,6-trimethyl-4H-1,3-dioxin-4-one, sodium methoxide, tetrahydrofuran, reflux reaction for 48 hours, yield: 21%.

The synthetic routes of compounds F44-S41 and F44-S42 are shown in Scheme 1.5. Compound F44-S35 reacts with N,N'-carbonyldiimidazole and ammonia in tetrahydrofuran to obtain compound F44-S41. Compound F44-S41 was reacted with 4-dimethylaminopyridine, pyridine and acetyl chloride in anhydrous dichloromethane to obtain compound F44-S42.

Scheme 1.5 Compounds F44-S41, F44-S42. Reagents and reaction conditions: (a) N, N'-carbonyldiimidazole, ammonia, tetrahydrofuran, reaction for 36 hours, yield: 96%; (b) 4-dimethylaminopyridine, pyridine, acetyl chloride, anhydrous dichloromethane , reaction 12h, yield: 36%.

The synthetic route of compounds F44-S60～F44-S68 is shown in Scheme 2.1. Reductive amination of substituted o-/m-hydroxybenzaldehyde and furylmethylamine in formaldehyde produces intermediate M8. Intermediate M8 reacts with substituted benzoyl chloride in anhydrous dichloromethane to form intermediate M9. Intermediate M9 reacts with substituted benzenesulfonyl chloride in anhydrous dichloromethane to obtain F44-S60~F44-S68.

Scheme 2.1 Compounds F44-S60～F44-S68. Reagents and reaction conditions: (a) Furylmethylamine, sodium borohydride, methanol, reaction for 12 hours, yield: 61%; (b) substituted benzoyl chloride, pyridine, triethylamine, anhydrous dichloromethane, reaction for 3 hours , Yield: 29%; (c) Substituted benzenesulfonyl chloride, potassium carbonate, anhydrous dichloromethane, reaction for 12 hours, yield: 41-92%.

The synthetic route of compounds F44-S69'~F44-S110' is shown in Scheme 3.1. 2-Amino-5-chlorobenzonitrile is reduced in anhydrous tetrahydrofuran to generate intermediate M10. Intermediate M10 reacts with di-tert-butyl dicarbonate in anhydrous dichloromethane to form intermediate M11. Intermediate M11 reacts with ethyl iodide in acetonitrile to form intermediate M12. Intermediate M12 is condensed with ethyl 5-(chlorosulfonyl)-3-methylbenzofuran-2-carboxylate in dichloromethane to form intermediate M13, and then combined with trifluoroacetic acid in dichloromethane to form intermediate M14. . Intermediate M14 is reductively aminated with substituted aldehyde in methanol to form intermediate M15, and then reacted with substituted acid chloride or sulfonyl chloride and potassium carbonate in anhydrous dichloromethane to form intermediate M6. Intermediate M6 is hydrolyzed in a strong alkaline system to obtain compounds F44-S69'～F44-S99', F44-S100～F44-S110.

Scheme 3.1 Compounds F44-S69'～F44-S99', F44-S100～F44-S110. Reagents and reaction conditions: (a) Lithium aluminum tetrahydrogen, anhydrous tetrahydrofuran, heat to reflux for 4 hours, yield: 81%; (b) di-tert-butyl dicarbonate, triethylamine, anhydrous dichloromethane, reaction 12h, yield: 90%; (c) ethyl iodide, potassium carbonate, acetonitrile, react at 70°C for 12h, yield: 44%; (d) 5-(chlorosulfonyl)-3-methylbenzofuran- 2-Ethyl formate, potassium carbonate, anhydrous dichloromethane, reaction for 12 hours, yield: 76%; (e) trifluoroacetic acid, dichloromethane, reaction for 12 hours, yield: 99%; (f) substituted aldehydes , sodium borohydride, methanol, reaction 12h, yield: 14-70%; (g) substituted acid chloride or sulfonyl chloride, potassium carbonate, anhydrous dichloromethane, reaction 12h, yield: 35-99%; (h ) Lithium hydroxide, water/ethanol, heat to reflux for 1 hour, yield: 40-94%.

The synthetic route of compounds F44-S118~F44-S124 is shown in Scheme 4.1. After intermediate M1 and cyclopropylformyl chloride are reacted in dichloromethane to form intermediate M17, they are reduced in methanol to form intermediate M18. Intermediate M18 reacts with ethyl iodide in acetonitrile to form intermediate M19. Intermediate M19 and substituted sulfonyl chloride Condensation in anhydrous dichloromethane produces intermediate M6. Intermediate M6 is hydrolyzed in a strong alkaline system to obtain compounds F44-S118~F44-S124.

Scheme 4.1 Compounds F44-S118～F44-S124. Reagents and reaction conditions: (a) cyclopropylformyl chloride, potassium carbonate, anhydrous dichloromethane, reaction for 12 hours, yield: 95%; (b) hydrazine hydrate, 10% palladium on carbon, methanol, reaction for 12 hours, yield: :88%; (c) Iodoethane, potassium carbonate, anhydrous dichloromethane, react for 12 hours, yield: 79%; (d) Substituted sulfonyl chloride, potassium carbonate, anhydrous dichloromethane, react for 12 hours, yield: Yield: 16-51%; (f) Lithium hydroxide, water/ethanol, heat up to reflux reaction for 1 hour, yield: 78-94%.

R ⁴ in the product obtained in step f is an ester group, and R ⁴ in the product obtained in step g is a carboxylic acid group.

Example 1

N-(5-chloro-2-nitrobenzyl)-1-(furan-2-yl)methanamine (M1)

Add 5-chloro-2-nitrobenzaldehyde (1.86g, 10mmol) and 2-furylmethylamine (1.16g, 12mmol) to methanol (20mL) and stir at room temperature for 4h. Slowly add sodium borohydride under ice bath conditions. (0.57g, 15mmol) react at room temperature overnight. After the reaction is detected by TLC, add water to quench the reaction, distill the solvent under reduced pressure, add water (20mL) to dissolve, extract with ethyl acetate (20mL) three times, and use saturated sodium chloride aqueous solution for the organic phase. Wash and dry with anhydrous sodium sulfate. The crude product is separated by column chromatography (PE/EA=9/1~6/1) to obtain 2.50g of light yellow liquid with a yield of 47%. ¹ H NMR (400MHz, Chloroform-d) δ7.92(d,J＝8.7Hz,1H),7.69(d,J＝2.2Hz,1H),7.39–7.32(m,2H),6.30(dd,J ＝3.2,1.9Hz,1H),6.18 (d, J=3.2Hz, 1H), 4.05 (s, 2H), 3.81 (s, 2H). ¹³ C NMR (101MHz, Chloroform-d) δ 153.2, 147.2, 142.2, 139.9, 137.9, 131.0, 128.1, 126.4 ,110.3,107.5,49.5,45.8.

Example 2

2-Chloro-N-(5-chloro-2-nitrobenzyl)-N-(furan-2-ylmethyl)benzamide (M2)

Add N-(5-chloro-2-nitrobenzyl)-1-(furan-2-yl)methanamine (2.54g, 9.5mmol) and potassium carbonate (1.57g, 11.4mmol) into anhydrous dichloromethane (20 mL), slowly add o-chlorobenzoyl chloride (1.66 g, 9.5 mmol) under ice bath conditions, and react at room temperature overnight. After the reaction is detected by TLC, remove the solvent by distillation under reduced pressure, add water (20 mL) to dissolve, and dissolve in ethyl acetate. (20mL) was extracted three times, the organic phase was washed with saturated sodium chloride aqueous solution, and dried by adding anhydrous sodium sulfate. The crude product was separated by column chromatography (PE/EA=15/1~3/1) to obtain 1.88g of light yellow liquid, which was collected. The rate is 49%. ¹ H NMR(400MHz,Chloroform-d)δ8.28–6.77(m,8H),6.48–5.76(m,2H),5.62–3.86(m,4H). ¹³ C NMR(101MHz,Chloroform-d)δ169 .1,148.3,146.4,143.1,142.6,140.4,134.9,134.6,130.7,130.3,130.0,129.8,128.9,128.5,128.4,128.0,127.3,127.1,126.8,126.5,110. 5,109.7,49.0,46.0,45.8,41.7 .

Example 3

N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (M3)

2-Chloro-N-(5-chloro-2-nitrobenzyl)-N-(furan-2-ylmethyl)benzamide (1.62g, 4mmol), hydrazine hydrate (0.40g, 8mmol), 10% palladium on carbon (0.10g, 0.4mmol) was added to methanol (20mL) and heated to 50°C for reaction overnight. O-chlorobenzoyl chloride (1.66g, 9.5mmol) was slowly added dropwise under ice bath conditions, and reaction was carried out at room temperature overnight. TLC After the detection reaction is completed, filter with diatomaceous earth and evaporate under reduced pressure to remove the filtrate, add water (20 mL) to dissolve, extract three times with ethyl acetate (20 mL), and wash the organic phase with saturated sodium chloride aqueous solution. Add anhydrous sodium sulfate to dry, and the crude product is separated by column chromatography (PE/EA=3/1) to obtain 1.47g of light yellow solid, with a yield of 98%. ¹ H NMR(400MHz,Chloroform-d)δ7.98(d,J＝8.7Hz,1H),7.67(d,J＝1.6Hz,1H),7.54–7.43(m,2H),7.43–7.31(m ,4H),7.31–7.14(m,2H),6.26–6.14(m,1H),6.05(d,J＝3.1Hz,1H),5.40(d,J＝17.3Hz,1H),4.83(d, J＝17.5Hz, 1H), 4.44 (d, J＝15.9Hz, 1H), 4.24 (d, J＝15.9Hz, 1H). ¹³ C NMR (101MHz, Chloroform-d) δ 169.0, 149.1, 148.3, 146.3, 143.0,142.6,140.4,140.3,134.9,134.6,134.6,130.7,130.6,130.3,130.2,129.9,129.7,128.8,128.5,128.5,128.3,128.0,127.3,127.2,1 27.0,126.8,126.5,110.6,110.4, 109.7,49.0,46.0,45.7,41.6.

Example 4

N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S1)

N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (188 mg, 0.5 mmol), 4-acetamidobenzenesulfonyl chloride (117 mg, 0.5mmol), potassium carbonate (138mg, 1mmol) was added to anhydrous dichloromethane (2mL) and allowed to react at room temperature overnight. After the reaction was detected by TLC, the solvent was evaporated under reduced pressure, dissolved in water (5mL), and extracted with ethyl acetate (5mL). Wash the organic phase three times with saturated sodium chloride aqueous solution, add anhydrous sodium sulfate and dry. The crude product is separated by column chromatography (PE/EA=1/2) to obtain 34 mg of light yellow solid, with a yield of 12%. ¹ H NMR (400MHz, Chloroform-d) δ9.43 (s, 1H), 8.05 (s, 1H), 7.62 (d, J = 8.5Hz, 2H), 7.46 (dd, J = 29.5, 8.6Hz, 3H ),7.29(d,J＝15.2Hz,5H),7.20(s,1H),7.04–6.96(m,1H),6.26(s,1H),6.14–6.02(m,1H),4.50(d, J＝14.5Hz,1H),4.30–4.11(m,2H),3.93(d,J＝14.9Hz,1H),2.05(s,3H). ¹³ C NMR(101MHz,Chloroform-d)δ171.4,170.3, 148.1,143.5,142.5,135.2,134.3,131.6,131.1,130.6,130.1,129.9,129.8,129.0,128.4,128.0,127.4,124.9,119.3,110.8,110.1,60.6,44 .7,44.3,29.8,29.4,24.7, 21.2,14.3.HRMS(ESI)[M+H] ⁺ calcd for C ₂₇ H ₂₄ Cl ₂ N ₃ O ₅ S:572.0814; found:572.0823.

Example 5

N-(2-(4-acetamidobenzamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S2)

4-acetamidobenzenesulfonyl chloride (198mg, 1.1mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (209mg, 1.1mmol), 1-hydroxybenzotriazole (149mg, 1.1mmol), 4-dimethylaminopyridine (6mg, 0.05mmol) was added to anhydrous dichloromethane (1mL) and stirred at room temperature for 2h, then N,N-diisopropylethylamine (210mg, 1.5mmol) was added dropwise ), then add a solution of N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (187 mg, 0.5 mmol) in dichloromethane (1 mL) , after the TLC detection reaction is completed, the solvent is evaporated under reduced pressure, dissolved in water (5 mL), extracted three times with ethyl acetate (5 mL), the organic phase is washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the crude product is subjected to column chromatography After separation (PE/EA=1/2), 172 mg of light yellow solid was obtained, with a yield of 64%. ¹ H NMR(400MHz,Chloroform-d)δ10.84–10.04(m,1H),8.72(d,J＝20.6Hz,1H),8.29–7.83(m,3H),7.61–7.23(m,8H) ,7.21–7.08(m,1H),6.49–6.09(m,2H),5.23–4.18(m,4H),1.97(dd,J=11.3,3.9Hz,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ169.5,169.4,169.2,166.6,166.4,148.5,148.3,143.3,143.2,141.9,141.7,137.1,135.8,134.6,134.5,131.3,130.9,130.8,130.4,129.8, 129.7,129.7,129.5,1293,129.1 ,128.9,128.8,128.6,128.6,128.5,127.9,127.3,127.2,126.6,126.1,124.8,124.6,119.0,110.7,110.6,110.0,109.8,45.0,44.6,44.2,44. 1,24.3.HRMS(ESI)[ M+H] ⁺ calcd for C ₂₈ H ₂₄ Cl ₂ N ₃ O ₄ :536.1144; found:536.1148.

Example 6

N-(2-((4-acetaminophenyl)sulfonamido)benzyl)-2-fluoro-N-(furan-2-ylmethyl)benzamide (F44-S3)

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S1) The method used was to replace N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide with N-(2-aminobenzyl)-2- Fluoro-N-(furan-2-ylmethyl)benzamide, all other conditions were the same. 48 mg of colorless liquid was obtained, with a yield of 22%. ¹ H NMR (400MHz, Chloroform-d) δ9.63(d,J＝8.8Hz,1H),8.46(d,J＝7.1Hz,1H),7.74–7.62(m,2H),7.55(dt,J ＝17.0,8.9Hz,3H),7.38(s,3H),7.31–7.24(m,1H),7.23–7.02(m,4H),6.42–6.06(m,2H),4.47–4.16(m,4H ), 2.10 (s, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 169.5, 168.6, 158.3 (d, J = 247.2Hz, 1C), 148.3, 143.3, 142.6, 136.5, 134.2, 132.0 (d, J = 9.2Hz,1C),131.1,129.8,128.9,128.7(d,J＝2.5Hz,1C),128.3,126.7,124.8(d,J＝4.3Hz,1C),123.0(d,J＝17.4Hz,1C ),122.8,119.3,116.2(d,J=20.9Hz,1C),110.7,109.9,44.8,44.7,24.6. ¹⁹ F NMR (376MHz, CDCl ₃ )δ-114.4,-114.5.HRMS(ESI)[M +H] ⁺ calcd for C ₂₇ H ₂₅ N ₃ O ₅ FS:522.1499; found:522.1501.

Example 7

N-(2-((4-butylaminophenyl)sulfonylamino)benzyl)-2-fluoro-N-(furan-2-ylmethyl)benzamide (F44-S4)

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S1) The method used was to replace N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide with N-(2-aminobenzyl)-2- Fluoro-N-(furan-2-ylmethyl)benzamide, replace 4-acetamidobenzenesulfonyl chloride with 4-butylamidobenzenesulfonyl chloride, and keep the rest of the conditions the same. 60 mg of colorless liquid was obtained, with a yield of 27%. ¹ H NMR (400MHz, Chloroform-d) δ9.65 (s, 1H), 8.22 (s, 1H), 7.68 (d, J＝ 8.7Hz,2H),7.59(d,J＝8.7Hz,2H),7.53(d,J＝8.3Hz,1H),7.38(s,3H),7.31–7.24(m,1H),7.19(t, J＝7.5Hz,1H),7.16–6.99(m,3H),6.45–6.26(m,1H),6.18(d,J＝2.9Hz,1H),4.32(d,J＝29.0Hz,4H), 2.30 (t, J＝7.4Hz, 2H), 1.67 (q, J＝7.4Hz, 2H), 0.91 (t, J＝7.4Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 172.4, 168.6, 158.3 (d,J＝247.1Hz,1C),148.4,143.3,142.6,136.5,134.2,132.0(d,J＝5.6Hz,1C),129.8,128.7(d,J＝2.5Hz,1C),128.3,126.7 ,124.7,123.0(d,J＝17.4Hz,1C),122.7,119.3,116.2(d,J＝20.8Hz,1C),110.7,109.9,44.8,44.7,39.5,18.9,13.8. ¹⁹ F NMR (376MHz ,CDCl ₃ )δ-114.4,-114.5.HRMS(ESI)[M+H] ⁺ calcd for C ₂₉ H ₂₉ N ₃ O ₅ FS:550.1812; found:550.1816.

Example 8

N-(2-((4-butylaminophenyl)sulfonylamino)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S5)

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S1) The method used was to replace 4-acetamidobenzenesulfonyl chloride with 4-butylamidobenzenesulfonyl chloride, and the other conditions were the same. 37 mg of white solid was obtained, with a yield of 26%. ¹ H NMR (400MHz, Chloroform-d) δ9.42 (s, 1H), 7.93 (s, 1H), 7.65–7.49 (m, 4H), 7.41 (d, J = 8.7Hz, 1H), 7.34–7.22 (m,5H),7.18(d,J＝10.1Hz,1H),7.00(d,J＝2.3Hz,1H),6.25(dd,J＝3.2,1.9Hz,1H),6.09(d,J＝ 3.2Hz,1H),4.51(d,J＝14.7Hz,1H),4.28–4.07(m,2H),3.94(d,J＝14.8Hz,1H),2.22(t,J＝7.4Hz,2H) ,1.61(h,J＝7.4Hz,2H),0.86(t,J＝7.4Hz,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ172.2,170.2,148.1,143.5,142.6,135.2,134.3,134.2, 131.6,131.1,130.6,130.1,129.9,129.7,129.0,128.4,128.0,127.4,124.9,119.4,110.8,110.1,44.7,44.3,39.6,18.9,13.8.HRMS(ESI)[M+H] ⁺ calcd for C ₂₉ H ₂₈ Cl ₂ N ₃ O ₅ S:600.1133; found:600.1127.

Example 9

N-(2-((4-acetamido-N-propylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44 -S6)

N-(2-((4-acetylaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S1) (114 mg, 0.2 mmol), sodium hydride (10 mg, 0.2 mmol) was added to N, N-dimethylformamide (2 mL) under ice bath conditions, stirred at 0°C for 1 h, and bromopropane (37 mg, 0.3 mmol) was added at room temperature. The reaction was carried out overnight. After TLC detection, the solvent was evaporated under reduced pressure, dissolved in water (20 mL), and extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the crude product was passed through a column. Chromatographic separation (PE/EA=3/2) yielded 69 mg of light yellow solid with a yield of 38%. ¹ H NMR (400MHz, Chloroform-d) δ9.77(d,J＝9.3Hz,1H),7.91(d,J＝8.3Hz,2H),7.55(d,J＝8.7Hz,1H),7.43– 7.28(m,7H),7.24(s,1H),7.09(d,J＝2.1Hz,1H),6.38–6.31(m,1H),6.18(d,J＝3.0Hz,1H),4.57(d ,J＝14.6Hz,1H),4.34–4.14(m,2H),3.91(d,J＝14.6Hz,1H),3.68–3.60(m,2H),1.81(s,3H),1.48(dt, J＝14.9, 7.4Hz, 2H), 0.85 (d, J＝7.4Hz, 3H). ¹³ C NMR (101MHz, Chloroform-d) δ 170.1, 169.5, 148.0, 147.1, 143.4, 135.1, 134.1, 131.5, 131.0, 130.5,130.0,129.8,129.8,128.7,128.6,128.6,127.9,127.3,124.6,110.7,110.0,50.8,44.6,44.0,35.9,31.9,29.7,29.3,27.2,25.5,22.9 ,22.7,21.1,14.1, 11.2.HRMS(ESI)[M+H] ⁺ calcd for C ₃₀ H ₃₀ N ₃ O ₅ SCl ₂ :614.1283; found:614.1274.

Example 10

(E)-N-(2-((4-acetamidobenzylidene)amino)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44- S7)

N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (187 mg, 0.5 mmol), N-(4-formylphenyl) Acetamide (82 mg, 0.5 mmol) was added to methanol (1.5 mL) and refluxed for 36 hours. After TLC detection, the reaction was completed, and then cooled to room temperature to precipitate a white solid, which was filtered with suction. The filter residue was washed three times with methanol and dried to obtain 193 mg of white solid. Yield 74%. ¹ H NMR(400MHz,Chloroform-d)δ9.17(d,J＝23.6Hz,1H),8.19(d,J＝38.1Hz,1H),7.87–7.39(m,6H),7.38–7.00(m ,5H),6.88(dd,J＝36.2,8.5Hz,1H),6.50–5.84(m,2H),5.08(dd,J＝73.3,15.3Hz,1H),4.89–3.97(m,3H), 2.05 (d, J = 11.7Hz, 3H). ¹³ C NMR (101MHz, Chloroform-d) δ 169.5, 169.4, 169.3, 159.9, 159.6, 150.0, 149.1, 148.8, 148.7, 142.8, 142.3, 142.1, 141.9, 135. 4, 135.3,132.3,131.8,131.5,131.3,131.2,131.1,130.7,130.5,130.4,130.4,129.9,129.8,128.9,128.4,128.3,128.2,128.0,127.8,127.2,1 27.1,119.5,119.3,118.9,110.5, 110.4,109.4,109.0,47.6,45.5,43.7,41.5,24.4.HRMS(ESI)[M+H] ⁺ calcd for C ₂₈ H ₂₄ N ₃ O ₃ Cl ₂ :520.1195; found:520.1190.

Example 11

N-(2-((4-acetamidobenzyl)amino)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S8)

(E)-N-(2-((4-acetamidobenzylidene)amino)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (156 mg , 0.3 mmol) was added to methanol (1.5 mL), sodium borohydride (15 mg, 0.4 mmol) was slowly added under ice bath conditions, and the reaction was carried out at room temperature overnight. After TLC detection of the reaction, add water to quench the reaction, distill the solvent under reduced pressure, and add water. (5mL) was dissolved, and extracted three times with ethyl acetate (5mL). The organic phase was washed with saturated sodium chloride aqueous solution, dried by adding anhydrous sodium sulfate, and the crude product was separated by column chromatography (PE/EA=3/1~1/1) 121 mg of white solid was obtained, with a yield of 77%. ¹ H NMR (400MHz, Chloroform-d) δ8.44 (s, 1H), 7.39 (tt, J = 20.0, 12.4Hz, 7H), 7.20 (d, J = 7.7Hz, 2H), 7.09 (d, J ＝5.7Hz,2H),6.47(d,J＝8.6Hz,1H),6.33(s,1H),6.13(s,1H),5.91(s,1H),5.13(d,J＝14.6Hz,1H ), 4.44–4.07 (m, 5H), 2.00 (d, J = 25.4Hz, 3H). ¹³ C NMR (101MHz, Chloroform-d) δ 169.3, 169.0, 148.7, 145.7, 143.1, 137.4, 135.0, 134.4, 131.6 ,130.7,130.4,129.8,129.5,128.1,127.6,127.2,120.1,119.9,111.9,110.6,109.7,47.5,44.3,43.6,24.2.HRMS(ESI)[M+H] ⁺ calcd for C ₂₈ H ₂₆ N ₃ O ₃ Cl ₂ :522.1351; found:522.1345.

Example 12

2-Chloro-N-(5-chloro-2-(methylamino)benzyl)-N-(furan-2-ylmethyl)benzamide (M4)

Combine N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (374 mg, 1 mmol), paraformaldehyde (150 mg, 5 mmol), sodium methoxide (270mg, 5mmol) was added to methanol (2mL), heated to reflux and stirred for 4h, cooled to room temperature, slowly added sodium borohydride (190mg, 5mmol) under ice bath conditions, heated to reflux and reacted for 1h. After TLC detection, the pressure was reduced. The solvent was removed by distillation, dissolved in water (20 mL), and extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the crude product was separated by column chromatography (PE/EA=6/1 ) to obtain 2.50g of white solid, with a yield of 78%. ¹ H NMR (400MHz, Chloroform-d) δ7.29 (ddt, J＝9.4, 6.5, 3.6Hz, 3H), 7.22 (dd, J＝5.9, 3.5Hz, 2H), 7.09 (dd, J＝8.7, 2.5Hz,1H),6.93(d,J＝2.4Hz,1H),6.42(d,J＝8.7Hz,1H),6.23(dd,J＝3.0,1.9Hz,1H),6.02(d,J＝ 3.3Hz,1H),5.35(s,1H),5.08(d,J＝14.7Hz,1H),4.02(t,J＝13.4Hz,2H),3.94(d,J＝14.7Hz,1H),2.74 (s,3H). ¹³ C NMR (101MHz, Chloroform-d) δ169.1,148.9,146.9,143.0,135.2,131.5,130.5,130.4,129.7,129.5,128.1,127.1,119.6,119.4,110.5,110.4 ,109.5, 44.0,43.4,30.4.

Example 13

N-(2-((4-acetamido-N-methylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44 -S9)

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S1) The method used was to replace N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide with 2-chloro-N-(5-chloro-2 -(methylamino)benzyl)-N-(furan-2-ylmethyl)benzamide, all other conditions were the same. 255 mg of light yellow solid was obtained, with a yield of 88%. ¹ H NMR(400MHz,Chloroform-d)δ9.48–8.78(m,1H),7.66(dd,J＝30.0,8.3Hz,2H),7.49(d,J＝13.3Hz,3H),7.44–7.31 (m,4H),7.24(d,J＝39.2Hz,1H),7.04(d,J＝8.0Hz,1H),6.44–6.04(m,3H),5.61–4.12(m,4H),3.04( s,3H),2.09–1.95(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ169.8,169.7,169.6,149.8,148.6,148.5,143.4,143.2,143.0,142.6,138.8,138.8,138.4, 135.2,134.6,134.5,130.9,130.3,129.9,129.7,129.3,129.2,128.5,128.4,128.3,128.0,127.8,127.5,127.3,119.3,119.1,110.7,110.6,1 10.0,109.8,109.4,46.4,45.5, 45.1,44.5,39.0,29.7,24.5,24.4,24.2.HRMS(ESI)[M+H] ⁺ calcd for C ₂₈ H ₂₆ Cl ₂ N ₃ O ₅ S:586.0970; found:586.0979.

Example 14

N-(2-((3-acetamido-N-methylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44 -S10)

According to N-(2-((4-acetamido-N-methylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S9) was to replace 4-acetamidobenzenesulfonyl chloride with 3-acetamidobenzenesulfonyl chloride, and the other conditions were the same. 260 mg of white solid was obtained, with a yield of 89%. ¹ H NMR (400MHz, Chloroform-d) δ9.02 (d, J＝13.2Hz, 1H), 8.03–7.63 (m, 2H), 7.59–6.96 (m, 9H), 6.74–5.89 (m, 3H) ,5.57–4.00(m,4H),3.10(s,3H),2.03(d,J＝12.3Hz,3H). ¹³ C NMR(101MHz,Chloroform-d)δ169.5,149.7,148.7,143.0,142.9,142.5,139.5,139.4,139.3,139.1,138.4,138.1,136.2,135.1,134.6,130.7,130.6,130. 4,130.3,129.9,129.8, 129.5,129.4,128.6,128.4,127.9,127.6,127.4,127.3,124.4,124.3,123.1,123.0,119.0,110.6,110.5,109.8,109.6,109.4,46.2,45.5,44. 7,44.3,39.3,39.1,29.7, 29.3,29.3,29.1,27.2,24.2,24.2.HRMS(ESI)[M+H] ⁺ calcd for C ₂₈ H ₂₆ N ₃ O ₅ SCl ₂ :586.0970; found:586.0969.

Example 15

N-(2-(4-acetamido-N-methylbenzamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S11)

According to N-(2-((4-acetamido-N-methylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S9) is to replace 4-acetamidobenzenesulfonyl chloride with 4-acetamidobenzoyl chloride, and the other conditions are the same. 142 mg of light yellow solid was obtained, with a yield of 52%. ¹ H NMR(400MHz,Chloroform-d)δ8.81(s,1H),7.79–6.69(m,12H),6.40–5.80(m,2H),5.44–4.71(m,1H),4.23(dt, J＝84.5, 15.5Hz, 3H), 3.55–2.80 (m, 3H), 2.11–1.79 (m, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 170.2, 169.3, 148.4, 143.2, 143.1, 140.7, 134.8 ,133.9,130.8,130.7,130.2,130.0,129.9,129.4,128.9,128.7,128.2,127.9,127.3,118.3,110.7,110.6,109.7,109.5,45.4,43.6,38.1,24. 3,24.2.HRMS(ESI)[ M+H] ⁺ calcd for C ₂₉ H ₂₆ Cl ₂ N ₃ O ₄ :550.1300; found:550.1298.

Example 16

N-(2-(3-acetamido-N-methylbenzamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S12)

According to N-(2-((4-acetamido-N-methylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S9) was to replace 4-acetamidobenzenesulfonyl chloride with 3-acetamidobenzoyl chloride, and the other conditions were the same. 158 mg of light yellow solid was obtained, with a yield of 58%. ¹ H NMR(400MHz,Chloroform-d)δ9.08–8.51(m,1H),8.19–7.64(m,1H),7.62–6.89(m,10H),6.90–6.53(m,1H),6.49– 5.93(m,2H),5.51–4.75(m,1H),4.62(td,J＝20.6,18.3,12.1Hz,1H),4.53–4.15(m,2H),3.27(d,J＝19.7Hz, 3H),2.13–1.73(m,3H).13C NMR(101MHz,Chloroform-d)δ171.4,169.2,169.0,148.5,143.4,141.5,138.6,134.8,134.6,133.7,131.0,130.3,130.0,129. 1,128.8 ,128.3,128.2,128.1,128.1,127.3,126.8,123.1,120.7,119.2,110.7,109.9,109.7,109.5,47.5,47.3,46.1,45.7,37.4,37.1,24.1.HRMS(ESI)[ M+H] +calcd for C ₂₉ H ₂₆ Cl ₂ N ₃ O ₄ :550.1300; found:550.1306.

Example 17

N-(2-((4-acetamido-N-methylphenyl)sulfonamide)-5-chlorobenzyl)-2-fluoro-N-(furan-2-ylmethyl)benzamide (F44 -S13)

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S1) The method used was to replace N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide with N-(5-chloro-2-(methyl) Amino)benzyl)-2-fluoro-N-(furan-2-ylmethyl)benzamide, the other conditions are the same. 129 mg of white solid was obtained, with a yield of 57%. ¹ H NMR(400MHz,Chloroform-d)δ9.33–8.82(m,1H),7.58(dd,J＝23.5,8.5Hz,2H),7.50–7.32(m,3H),7.32–7.15(m, 4H),7.10(t,J＝8.7Hz,1H),7.00–6.91(m,1H),6.49–5.99(m,3H),5.42–4.12(m,4H),3.04–2.62(m,3H) ,1.96(d,J=17.6Hz,3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ169.8,169.6,168.1,168.0,158.2(d,J＝245.9Hz,1C),150.0,149.8,148.9,148.6,143.4,143.1,142.6,139.2,139.1,138.6,138.4,134.6,131 .8(d,J＝ 8.1Hz,1C),130.0,129.3,129.2,128.8(d,J＝3.0Hz,1C),128.4,128.4,128.3,128.2,127.9,127.5,124.9(d,J＝3.1Hz,1C),124.6( d,J＝3.0Hz,1C),123.8(d,J＝17.5Hz,1C),119.2,119.1,116.1(d,J＝20.8Hz,1C),110.6,110.5,109.8,109.5,109.2,108.9, 48.6,46.2,44.9,41.9,39.1,39.0,38.9,24.4,24.3. ¹⁹ F NMR (376MHz, CDCl ₃ )δ-114.4,-114.5,-115.1.HRMS(ESI)[MH] ^- calcd for C ₂₈ H ₂₄ N ₃ O ₅ FSCl:568.1109; found:568.1120.

Example 18

N-(2-((4-butylamino-N-methylphenyl)sulfonamide)-5-chlorobenzyl)-2-fluoro-N-(furan-2-ylmethyl)benzamide (F44-S14)

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S1) The method used was to replace N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide with N-(5-chloro-2-(methyl) Amino)benzyl)-2-fluoro-N-(furan-2-ylmethyl)benzamide, replace 4-acetamidobenzenesulfonyl chloride with 4-butylamidobenzenesulfonyl chloride, and other conditions are the same. 125 mg of light yellow liquid was obtained, with a yield of 52%. ¹ H NMR(400MHz,Chloroform-d)δ9.24–8.64(m,1H),7.82–7.62(m,2H),7.60–7.41(m,3H),7.41–7.24(m,4H),7.23– 7.17(m,1H),7.09–7.00(m,1H),6.60–5.99(m,3H),5.64–4.20(m,4H),3.13–2.77(m,3H),2.24(dt,J＝23.1 ,7.3Hz,2H),1.65(dp,J＝13.9,6.8Hz,2H),0.89(dt,J＝20.4,7.4Hz,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ172.7,172.5,168.0, 167.9,158.2(d,J＝245.8Hz,1C),149.8,148.9,148.6,143.4,143.3,143.1,143.0,142.9,142.5,142.4,140.2,139.2,139.0,138.6,138.4,134. 6,134.5,131.7( d,J＝7.8Hz,1C),129.9,129.3,129.2,128.8,128.8,128.6,128.4,128.2,127.9,127.5,127.4,124.9(d,J＝2.9Hz,1C),123.9(d,J＝ 17.7Hz,1C),119.2,119.0,116.1(d,J＝20.8Hz,1C),110.6,110.5,109.7,109.5,109.2,108.8,48.6,46.1,44.9,41.9,39.2,39.0,18.8,13.7, 13.6. ¹⁹ F NMR (376MHz, CDCl ₃ ) δ-114.4,-115.0.HRMS(ESI)[MH] ^- calcd for C ₃₀ H ₂₈ N ₃ O ₅ FSCl:596.1422; found:596.1431.

Example 19

N-(2-((4-butyrylamino-N-methylphenyl)sulfonylamino)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S15)

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S9) The method used was to replace 4-acetamidobenzenesulfonyl chloride with 4-butylamidobenzenesulfonyl chloride, and the other conditions were the same. 169 mg of white solid was obtained, with a yield of 92%. ¹ H NMR (400MHz, Chloroform-d) δ9.48–8.57 (m, 1H), 7.70 (dd, J＝34.8, 8.4Hz, 2H), 7.55–7.17 (m, 8H), 7.05 (d, J＝ 8.2Hz,1H),6.53–6.00(m,3H),5.68–4.04(m,4H),3.04(s,3H),2.35–2.08(m,2H),1.71–1.54(m,2H),0.95 –0.76(m,3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ172.9,172.5,169.6,169.6,149.8,148.5,143.5,143.4,143.2,143.0,142.6,139.3,138.8,138.4,135.2,13 4.6,134.5 ,130.9,130.6,130.3,130.2,129.9,129.6,129.3,129.2,128.4,128.3,128.2,128.0,127.8,127.5,127.3,119.3,119.1,110.7,110.6,110.0, 109.8,109.4,46.4,45.5,45.1 ,44.5,39.4,39.3,39.0,18.9,18.8,13.8,13.7.HRMS(ESI)[M+H] ⁺ calcd for C ₃₀ H ₃₀ Cl ₂ N ₃ O ₅ S:614.1283; found:614.1287.

Example 20

2-Chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan-2-ylmethyl)benzamide (M5)

Combine N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (374mg, 1mmol), iodoethane (156mg, 5mmol), potassium carbonate (690mg, 5mmol) was added to acetonitrile (2mL) and the temperature was raised Allow the reaction to reflux overnight. After TLC detection, the reaction is completed, then cool to room temperature, remove the solvent by distillation under reduced pressure, add water (20 mL) to dissolve, extract three times with ethyl acetate (20 mL), wash the organic phase with saturated sodium chloride aqueous solution, and add anhydrous sulfuric acid. After drying over sodium, the crude product was separated by column chromatography (PE/EA=8/1) to obtain 380 mg of light yellow solid, with a yield of 94%. ¹ H NMR (400MHz, Chloroform-d) δ7.49–7.37(m,3H),7.37–7.18(m,3H),7.17–7.02(m,1H),6.62(dd,J＝43.9,8.3Hz, 1H),6.42–6.31(m,1H),6.15(d,J＝3.2Hz,1H),5.58–5.31(m,1H),5.19(dd,J＝18.2,14.6Hz,1H),4.30–4.09 (m,3H),3.34–3.08(m,2H),1.37(q,J＝7.2Hz,3H). ¹³ C NMR(101MHz,Chloroform-d)δ169.0,168.9,149.3,149.0,147.6,146.2,143.0 ,142.9,135.6,135.4,132.4,131.7,130.5,130.5,130.4,130.4,129.9,129.8,129.7,129.5,128.2,128.1,127.2,127.1,119.6,119.3,118.1, 115.1,110.9,110.5,110.5,109.8 ,109.5,109.3,44.5,44.0,43.4,43.2,38.4,38.2,14.5,14.3.

Example 21

N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44 -S16)

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S1) The method used was to replace N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide with 2-chloro-N-(5-chloro-2 -(ethylamino)benzyl)-N-(furan-2-ylmethyl)benzamide, the temperature was raised to reflux, and the other conditions were the same. 149 mg of light yellow solid was obtained, with a yield of 50%. ¹ H NMR(400MHz,Chloroform-d)δ9.67–9.22(m,1H),7.77–7.61(m,2H),7.58–7.32(m,7H),7.30–6.99(m,2H),6.66– 5.96(m,3H),5.78–4.03(m,4H),3.86(dt,J＝14.4,7.2Hz,1H),3.30–2.73(m,1H),2.08–1.89(m,3H),1.09– 0.54(m,3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ169.9,169.8,169.7,149.5,148.6,148.5,143.4,143.4,143.1,142.8,142.5,140.5,140.1,136.2,136.0,13 5.0,134.8, 134.7,134.6,131.2,130.9,130.8,130.6,130.5,130.2,130.2,130.1,129.8,129.0,129.0,128.6,128.5,128.4,128.1,128.1,127.8,127.7, 127.6,127.4,127.3,127.3,127.1,119.2,119.2,119.0,110.6,110.5,110.0,109.4,46.7,46.4,46.2,45.6,45.3,45.1,24.3,24.2,24.1,13.5 ,13.4,12.8.HRMS( ESI)[M+H] ⁺ calcd for C ₂₉ H ₂₈ N ₃ O ₅ SCl ₂ :600.1127; found:600.1121.

Example 22

N-(2-(4-acetamido-N-ethylbenzamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S17)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with 4-acetamidobenzoyl chloride, and the other conditions were the same. 65 mg of light yellow solid was obtained, with a yield of 15%. ¹ H NMR (400MHz, Chloroform-d) δ8.39 (d, J＝55.7Hz, 1H), 7.66–6.97 (m, 12H), 6.48–5.81 (m, 2H), 5.42–4.74 (m, 1H) ,4.51–3.72(m,4H),3.70–3.39(m,1H),2.14–1.91(m,3H),1.26(t,J=7.1Hz,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ171 .3,169.4,169.2,149.3,148.6,143.2,140.2,134.2,134.0,130.9,130.7,130.3,129.9,129.5,128.4,128.3,127.5,127.3,118.3,110.7,110. 6,109.4,60.5,45.6,44.2,24.4 ,21.1,14.3,12.8.HRMS(ESI)[M+H] ⁺ calcd for C ₃₀ H ₂₈ Cl ₂ N ₃ O ₄ :564.1457; found:564.1458.

Example 23

N-(2-((4-acetamidobenzyl)(ethyl)amino)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S18 )

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with N-(4-bromomethylphenyl)acetamide, and the other conditions were the same. 129 mg of white solid was obtained, with a yield of 47%. ¹ H NMR (400MHz, Chloroform-d) δ8.85 (d, J＝7.9Hz, 1H), 7.58–7.25 (m, 7H), 7.23–7.11 (m, 2H), 7.10–6.84 (m, 3H) ,6.62–5.79(m,2H),5.42–4.49(m,2H),4.48–4.01(m,2H),3.79(dd,J＝92.5,8.3Hz,2H),2.75(dq,J＝73.3, 6.1, 5.0Hz, 2H), 2.02 (s, 3H), 0.81 (dt, J = 79.2, 7.0Hz, 3H). ¹³ C NMR (101MHz, Chloroform-d) δ 169.5, 169.4, 169.2, 169.2, 149.8, 149.0 ,148.2,147.8,142.9,142.4,137.7,137.6,135.3,135.2,135.1,134.2,133.4,132.9,130.6,130.4,130.3,130.3,129.9,129.8,129.7,129.6, 129.0,128.9,128.3,127.8,127.5 ,127.5,127.4,127.2,127.0,126.7,124.9,124.1,119.8,119.6,110.6,110.4,109.2,109.0,58.4,58.2,47.6,47.4,46.8,45.0,42.9,41.5,29 .6,24.2,11.9,11.8 .HRMS(ESI)[M+H] ⁺ calcd for C ₃₀ H ₃₀ N ₃ O ₃ Cl ₂ :550.1664; found:550.1661.

Example 24

N-(2-((3-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44 -S19)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with 3-acetamidobenzenesulfonyl chloride, and the other conditions were the same. 101 mg of white solid was obtained, with a yield of 56%. ¹ H NMR(400MHz,Chloroform-d)δ9.45–8.81(m,1H),8.14–7.49(m,3H),7.49–7.29(m,5H),7.25–6.98(m,3H),6.62– 5.88(m,3H),5.66–4.04(m,4H),3.99–3.45(m,1H),3.34–2.58(m,1H),2.10–1.73(m,3H),1.16–0.62(m,3H ). ¹³ C NMR (101MHz, Chloroform-d) δ169.6,169.6,149.9,149.6,148.9,148.8,142.9,142.8,142.4,139.5,139.5,135.8,135.2,134.8,130.6,130.2,129. 9,129.8,129.7, 129.4,129.4,129.2,128.8,128.7,127.8,127.4,127.3,127.2,124.3,124.2,123.1,122.9,122.8,118.8,118.8,110.6, 110.5,110.5,110.5,109.9,109.3,47.1,46.9,46.7,46.0,45.7,45.0,29.7,29.3,24.2,24.1,13.5,12.8.HRMS(ESI)[M+H] ⁺ calcd for C ₂₉ H ₂₈ N ₃ O ₅ SCl ₂ :600.1127; found:600.1125.

Example 25

2-Chloro-N-(5-chloro-2-((N-ethyl-4-(N-methylacetamido)phenyl)sulfonamide)benzyl)-N-(furan-2-ylmethyl )Benzamide (F44-S20)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with 4-(N-methylacetamido)benzenesulfonyl chloride, and the other conditions were the same. 45 mg of white solid was obtained, with a yield of 25%. ¹ H NMR(400MHz,Chloroform-d)δ7.79–7.55(m,2H),7.47(dd,J＝10.6,5.5Hz,2H),7.42–7.29(m,5H),7.29–6.98(m, 2H),6.64–5.97(m,3H),5.54–4.08(m,4H),4.04–3.58(m,1H),3.51–2.83(m,4H),1.94(d,J＝48.8Hz,3H) ,1.18–0.68(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ170.0,169.9,169.3,169.2,149.8,149.1,148.5,142.7,142.5,142.4,141.0,135.6,135.4,135.3, 135.1, 135.0,130.5,130.4,130.3,129.9,129.7,129.5,128.8,128.5,128.4,128.3,128.1,127.9,127.7,127.6,127.5,127.2,127.1,127.0,110.6,1 10.5,109.7,109.3,109.1,48.7, 47.0,46.8,46.6,45.9,45.7,44.8,44.7,37.9,37.4,29.7,29.3,27.2,25.5,22.7,22.6,14.1,13.6,12.8.HRMS(ESI)[M+H] ⁺ calcd for C ₃₀ H ₃₀ N ₃ O ₅ SCl ₂ :614.1283; found:614.1288.

Example 26

2-Chloro-N-(5-chloro-2-((N-ethyl-4-(2-oxopropyl)phenyl)sulfonamido)benzyl)-N-(furan-2-ylmethyl base) benzamide (F44-S21)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with 4-(2-oxopropyl)benzenesulfonyl chloride, and the other conditions were the same. 164 mg of white solid was obtained, with a yield of 55%. ¹ H NMR(400MHz,Chloroform-d)δ7.73–7.27(m,9H),7.25–7.01(m,2H),6.66–5.85(m,3H),5.57–4.02(m,4H),4.01– 3.44(m,3H),3.38–2.68(m,1H),2.18(d,J＝6.8Hz,3H),1.15–0.51(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ204.6,204.5 ,169.3,169.2,149.8,149.2,142.7,142.4,141.0,140.0,139.8,136.5,136.0,135.8,135.5,135.5,135.4,135.1,134.8,134.8,134.7,130.5, 130.4,130.2,130.2,129.9,129.8 ,129.6,128.8,128.6,128.4,128.2,128.2,128.0,127.7,127.6,127.5,127.3,127.2,127.1,127.0,110.6,110.5,109.7,109.4,109.3,109.3, 109.0,50.0,50.0,46.9,46.7 ,46.5,45.8,45.6,44.7,29.9,13.6,13.5,12.8.HRMS(ESI)[M+H] ⁺ calcd for C ₃₀ H ₂₉ N ₂ O ₅ SCl ₂ :599.1174; found:599.1171.

Example 27

N-(2-((4-acetamido-N-ethyl-3-methylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl) Benzamide (F44-S22)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with 4-acetamido-3-methylbenzenesulfonyl chloride, and the other conditions were the same. 72 mg of white solid was obtained, with a yield of 39%. ¹ H NMR (400MHz, Chloroform-d) δ8.28–7.81(m,2H),7.75–7.23(m,7H),7.21–6.99(m,2H),6.78–5.90(m,3H),5.60– 3.99(m,4H),3.98–3.49(m,1H),3.41–2.63(m,1H), 2.28–1.98(m,6H),1.37–0.90(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ169.5,169.2,149.7,148.9,142.8,142.8,142.4,140.8,140.8,140.7,136.6, 136.6,135.9,135.9,135.2,134.7,134.7,130.7,130.6,130.5,130.2,130.0,129.9,129.9,129.7,129.7,128.8,128.7,128.6,128.5,128.3,1 28.0,127.9,127.4,127.2,127.1, 127.0,126.5,124.5,123.5,122.5,110.6,110.5,109.8,109.2,46.6,46.4,45.9,45.6,44.9,44.8,24.2,23.8,18.1,18.0,17.9,17.8,13.5,13 .4,12.8.HRMS( ESI)[M+H] ⁺ calcd for C ₃₀ H ₃₀ N ₃ O ₅ SCl ₂ :614.1283; found:614.1294.

Example 28

N-(2-((4-acetamido-3-chloro-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzene Formamide (F44-S23)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with 4-acetamido-3-chlorobenzenesulfonyl chloride, and the other conditions were the same. 69 mg of white solid was obtained, with a yield of 36%. ¹ H NMR(400MHz,Chloroform-d)δ8.76–8.41(m,1H),7.95(d,J＝8.3Hz,1H),7.76–7.20(m,8H),7.19–7.02(m,1H) ,6.65–5.99(m,3H),5.51–4.16(m,4H),4.00–3.50(m,1H),3.36–2.78(m,1H),2.29(d,J＝5.3Hz,3H),1.29 –0.99(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ169.3,168.7,149.7,149.1,142.7,142.4,141.0,138.9,138.8,135.5,135.4,135.3,135.1,135.1,130.5, 130.4, 129.9,129.7,128.8,128.8,128.7,128.5,128.4,128.2,128.1,128.0,127.7,127.6,127.5,127.1,127.1,122.4,120.9,120.9,110.6,110.5,1 09.7,109.3,109.1,47.0,46.6, 45.9,45.8,44.9,44.7,25.0,13.6,13.5,12.8.HRMS(ESI)[M+H] ⁺ calcd for C ₂₉ H ₂₇ N ₃ O ₅ SCl ₃ :634.0737; found:634.0735.

Example 29

2-Chloro-N-(5-chloro-2-((4-(3,3-dimethylureido)-N-ethylphenyl)sulfonamido)benzyl)-N-(furan-2 -Methyl)benzamide (F44-S24)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with 4-(3,3-dimethylureido)benzenesulfonyl chloride, and the other conditions were the same. 71 mg of white solid was obtained, with a yield of 37%. ¹ H NMR (400MHz, Chloroform-d) δ7.73 (s, 1H), 7.61–7.40 (m, 5H), 7.40–7.13 (m, 5H), 7.05 (d, J = 7.3Hz, 1H), 6.61 –5.86(m,3H),5.76–3.94(m,4H),3.93–3.43(m,1H),3.04(ddd,J＝20.2,13.3,6.5Hz,1H),2.90(d,J＝18.1Hz ,6H),1.27–0.89(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ169.5,155.5,155.3,155.3,149.7,148.9,148.8,144.9,144.8,144.8,142.9,142.7,142.4,14 0.7 ,140.4,136.2,136.1,135.2,134.6,130.7,130.6,130.5,130.2,129.8,129.7,129.2,129.0,128.9,128.7,128.5,128.4,128.3,128.1,128.0, 127.7,127.5,127.4,127.2,127.1 ,127.0,118.9,118.8,118.7,110.6,110.5,109.8,109.2,46.7,46.4,46.3,45.9,45.5,45.0,44.8,36.5,36.4,13.4,13.3,12.8.HRMS(ESI)[M+H] ⁺ calcd for C ₃₀ H ₃₁ N ₄ O ₅ SCl ₂ :629.1392; found:629.1390.

Example 30

2-Chloro-N-(5-chloro-2-((N-ethyl-4-(3-ethylureido)phenyl)sulfonamido)benzyl)-N-(furan-2-ylmethyl base) benzamide (F44-S25)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with 4-(3-ethylureido)benzenesulfonyl chloride, and the other conditions were the same. 151 mg of white solid was obtained, with a yield of 80%. ¹ H NMR (400MHz, Chloroform-d) δ8.41 (d, J＝11.4Hz, 1H), 7.87–6.98 (m, 11H), 6.58–5.59 (m, 4H), 5.23–4.12(m,3H),3.77(d,J＝68.8Hz,1H),3.37–1.93(m,3H),1.40–0.44(m,6H). ¹³ C NMR(101MHz,Chloroform-d)δ170 .3,170.0,155.5,155.4,155.4,155.4,149.4,148.4,148.2,145.0,143.1,143.0,142.8,142.5,140.3,139.9,136.4,136.2,134.9,134.8,134. 5,131.1,130.9,130.3,130.1,129.9 ,129.1,129.1,129.0,128.5,128.3,128.1,127.8,127.5,127.4,127.4,127.3,127.2,117.4,110.6,110.5,110.0,109.5,46.6,46.3,46.2,46. 2,45.6,45.4,45.4,45.1 ,34.7,34.6,15.2,15.1,14.9,13.4,13.4,12.8.HRMS(ESI)[M+H] ⁺ calcd for C ₃₀ H ₃₁ N ₄ O ₅ SCl ₂ :629.1392; found:629.1390.

Example 31

4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl)benzene Ethyl formate (F44-S26)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with ethyl 4-(chlorosulfonyl)benzoate, and the other conditions were the same. 309 mg of white solid was obtained, with a yield of 50%. ¹ H NMR (400MHz, Chloroform-d) δ8.15 (dd, J＝22.3, 8.1Hz, 2H), 7.86–7.41 (m, 4H), 7.41–6.99 (m, 5H), 6.61–5.92 (m, 3H),5.52–4.14(m,6H),4.02–3.56(m,1H),3.45–2.81(m,1H),1.40(q,J＝6.8Hz,3H),1.17–0.45(m,3H) . ¹³ C NMR (101MHz, Chloroform-d) δ169.1,165.0,164.9,149.8,149.1,142.7,142.3,141.7,141.0,140.7,135.4,135.3,135.1,135.0,134.8,134.6,134. 5,130.5,130.4,130.2 ,130.1,130.0,129.8,129.6,128.8,128.6,128.5,128.3,128.0,128.0,127.7,127.6,127.5,127.1,127.1,127.0,110.6,110.5,109.7,109.3, 109.1,61.7,47.1,46.9,46.7 ,45.9,45.7,44.8,44.7,14.3,13.6,13.5,12.9.HRMS(ESI)[M+H] ⁺ calcd for C ₃₀ H ₂₉ N ₂ O ₆ SCl ₂ :615.1123; found:615.1124.

Example 32

2-(4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamate Acyl)phenyl)ethyl acetate (F44-S27)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with ethyl 2-(4-(chlorosulfonyl)phenyl)acetate, and the other conditions were the same. 273 mg of white solid was obtained, with a yield of 44%. ¹ H NMR(400MHz,Chloroform-d)δ7.80–7.55(m,2H),7.54–7.38(m,4H),7.38–7.29(m,3H),7.28–6.97(m,2H),6.91– 5.95(m,3H),5.69–3.79(m,7H),3.68(d,J＝12.0Hz,2H),3.34–2.74(m,1H),1.24(q,J＝6.9Hz,3H),1.12 –0.47(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ170.4,170.3,169.2,149.8,149.1,142.7,142.3,141.0,139.9,139.8,136.6,135.8,135.6,135.4,135.1, 134.7, 134.7,134.6,130.5,130.4,130.3,130.2,130.0,130.0,129.8,129.6,128.8,128.6,128.4,128.4,128.2,128.1,127.9,127.8,127.6,127.6,1 27.5,127.3,127.1,127.1,127.0, 110.5,110.5,109.7,109.3,109.1,61.1,46.9,46.6,46.4,45.8,45.6,44.8,44.7,40.9,40.9,14.1,13.5,12.8.HRMS(ESI)[M+H] ⁺ calcd for C ₃₁ H ₃₁ N ₂ O ₆ SCl ₂ :629.1280; found:629.1280.

Example 33

2-(4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamate Acyl)phenyl)-2-methylpropionic acid ethyl ester (F44-S28)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with 2-(4-(chlorosulfonyl)phenyl)-2-methylpropionic acid ethyl ester, and the other conditions were the same. 302 mg of white solid was obtained, with a yield of 46%. ¹ H NMR(400MHz,Chloroform-d)δ7.75–7.56(m,2H),7.54–7.40(m,4H),7.39– 7.01(m,5H),6.65–5.98(m,3H),5.61–4.19(m,4H),4.13(p,J＝6.9Hz,2H),4.03–3.56(m,1H),3.38–2.77( m,1H),1.59(d,J＝11.2Hz,6H),1.38–0.81(m,6H). ¹³ C NMR(101MHz,Chloroform-d)δ175.6,175.5,169.1,150.5,150.4,149.8,149.1, 142.6,142.3,141.0,136.2,135.9,135.7,135.6,135.4,135.2,134.7,134.7,130.4,130.3,130.2,129.8,129.6,128.8,128.6,128.4,128.1,1 27.8,127.5,127.5,127.3,127.1, 127.1,127.0,126.5,126.5,110.5,110.5,110.4,109.7,109.3,109.0,61.1,46.9,46.8,46.6,46.5,46.4,45.8,45.7,44.7,44.7,26.4,26.3,2 6.3,14.0,13.5, 12.8.HRMS(ESI)[M+H] ⁺ calcd for C ₃₃ H ₃₅ N ₂ O ₆ SCl ₂ :657.1593; found:657.1587.

Example 34

Ethyl 3-((4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethyl Sulfamoyl)phenyl)amino)-3-oxopropionate (F44-S29)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with ethyl 3-((4-(chlorosulfonyl)phenyl)amino)-3-oxopropionate, and the other conditions were the same. 69 mg of white solid was obtained, with a yield of 21%. ¹ H NMR (400MHz, Chloroform-d) δ9.99–9.57(m,1H),8.04–7.43(m,6H),7.42–6.99(m,5H),6.72–5.95(m,3H),5.67– 4.07(m,6H),3.97–3.61(m,1H),3.40(d,J＝28.8Hz,2H),3.21–2.77(m,1H),1.27(d,J＝6.1Hz,3H),1.10 –0.66(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ169.6,169.6,169.1,169.0,168.7,164.3,164.1,164.0,149.7,148.9,148.8,142.9,142.8,142.4,142.4, 142.3, 142.2,140.7,140.5,136.0,135.9,135.6,135.2,134.8,134.6,132.4,131.7,131.6,130.7,130.6,130.5,130.3,130.2,129.9,129.9,129.8,1 29.8,129.2,128.7,128.7,128.5, 128.4,128.1,128.0,127.7,127.6,127.5,127.4,127.3,127.1,127.0,119.5,119.4,110.6,110.5,109.8,109.3,62.0,61.9,61.8,61.8,46.8, 46.5,46.4,46.0,45.7, 45.0,44.9,42.4,42.2,42.1,35.9,31.9,29.8, 29.7,29.6,29.5,29.5,29.3,29.3,29.2,27.2,25.6,22.7,14.1,13.5,13.4,12.8.HRMS(ESI)[M+H] ⁺ calcd for C ₃₂ H ₃₂ N ₃ O ₇ SCl ₂ :672.1338; found:672.1342.

Example 35

N-(2-((4-(3-acetyluido)-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl )Benzamide (F44-S30)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with 4-(3-acetyluido)benzenesulfonyl chloride, and the other conditions were the same. 46 mg of white solid was obtained, with a yield of 24%. ¹ H NMR (400MHz, Chloroform-d) δ9.54–8.64(m,1H),7.79–7.11(m,10H),7.06(t,J＝8.8Hz,1H),6.75–5.86(m,3H) ,5.78–4.09(m,4H),3.97–3.54(m,1H),3.03(ddt,J＝26.0,13.1,6.7Hz,1H),2.25–1.85(m,3H),1.07–0.78(m, 3H). ¹³ C NMR (101MHz, Chloroform-d) δ169.8,169.8,169.7,169.5,169.5,149.7,148.8,148.6,143.3,143.1,143.0,142.8,142.5,140.6,140.1,136.2,1 36.0,135.2,135.2 ,134.7,134.6,134.6,130.9,130.8,130.7,130.7,130.5,130.3,130.2,129.9,129.9,129.8,129.3,129.1,129.0,128.6,128.4,128.4,128.0, 127.8,127.7,127.5,127.4,127.2 ,127.0,119.3,119.2,119.0,110.6,110.5,109.8,109.3,46.7,46.4,46.4,46.1,45.5,45.2,45.1,31.9,29.8,29.7,29.6,29.6,29.5,29.5,29 .3,29.3,29.2 ,27.2,25.6,24.4,24.2,24.1,22.7,14.1,13.5,13.3,12.8.HRMS(ESI)[M+H] ⁺ calcd for C ₃₀ H ₂₉ N ₄ O ₆ SCl ₂ :643.1185; found:643.1201.

Example 36

N-(2-((4-(2-acetamido-2-oxyethyl)-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan- 2-ylmethyl)benzamide (F44-S31)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with 4-(2-acetamido-2-oxyethyl)benzenesulfonyl chloride, and the other conditions were the same. 72 mg of white solid was obtained, with a yield of 23%. ¹ H NMR (400MHz, Chloroform-d) δ9.55 (d, J＝7.7Hz, 1H), 7.72–7.28 (m, 9H), 7.06 (t, J＝8.8Hz, 2H), 6.65–5.90 (m ,3H),5.50–4.06(m,4H),4.01–2.62(m,4H),2.27(s,3H),1.13–0.61(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ172. 1,170.7,169.5,149.7,149.0,142.8,142.7,142.4,140.9,139.4,139.3,135.8,135.5,135.3,134.8,130.6,130.5,130.4,130.3,129.9,129.7 ,128.8,128.6,128.5,128.4,128.2, 128.0,127.9,127.7,127.6,127.5,127.4,127.2,127.1,127.0,110.6,110.5,109.8,109.2,48.8,48.7,46.9,46.7,46.5,45.9,45.7,44.9,43. 4,43.4,31.9,29.7, ^found _{_} _{_} _{_} _{_} _{_} :642.1243.

Example 37

2-Chloro-N-(5-chloro-2-((N-ethyl-1-methyl-2-oxoindole)-5-sulfonamido)benzyl)-N-(furan-2-yl Methyl)benzamide (F44-S32)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with 1-methyl-2-oxoindoline-5-sulfonyl chloride, and the other conditions were the same. 26 mg of white solid was obtained, with a yield of 14%. ¹ H NMR (400MHz, Chloroform-d) δ7.86–7.28 (m, 7H), 7.11 (dt, J = 18.9, 8.3Hz, 2H), 6.95 –6.74(m,1H),6.69–5.97(m,3H),5.61–4.11(m,4H),4.08–3.66(m,1H),3.65–3.37(m,2H),3.24(d,J＝ 8.8Hz,4H),1.13–0.79(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ174.7,174.6,174.5,169.3,150.1,149.8,149.6,149.4,149.4,149.2,142.7,142.5,142. 3 ,137.5,135.9,134.8,131.0,130.6,130.4,130.3,129.9,129.9,129.7,129.4,128.9,128.7,128.5,128.3,128.2,127.8,127.5,127.2,127.0, 125.0,124.8,124.1,124.1,124.0 ,123.9,110.6,110.5,110.5,110.4,109.7,109.3,109.0,107.8,107.7,107.6,46.9,46.6,46.4,45.8,44.7,35.3,35.3,31.9,29.8,29.7,29.6 ,29.5,29.5,29.5 ,29.3,29.3,29.2,27.2,26.5,25.5,22.7,14.1,13.6,12.8.HRMS(ESI)[M+H] ⁺ calcd for C30H28N3O5SCl2:612.1127; found:612.1121.

Example 38

N-(2-((1-acetyl-N-ethylindoline)-5-sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzene Formamide (F44-S33)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with 1-acetylindoline-5-sulfonyl chloride, and the other conditions were the same. 46 mg of white solid was obtained, with a yield of 25%. ¹ H NMR (400MHz, Chloroform-d) δ8.25 (dd, J＝19.6, 8.0Hz, 1H), 7.78–6.99 (m, 10H), 6.79–5.86 (m, 3H), 5.58–4.19 (m, 4H),4.13(q,J＝8.9Hz,2H),3.95–3.55(m,1H),3.43–2.71(m,3H),2.50–2.07(m,3H),1.18–0.69(m,3H) . ¹³ C NMR (101MHz, Chloroform-d) δ169.5,169.3,150.1,149.8,149.5,149.2,147.0,142.7,142.5,142.4,142.2,141.0,138.8,137.5,136.0,134.7,132. 1,131.0,130.4,130.3 ,129.9,129.7,128.6,128.4,127.8,127.7,127.6,127.5,127.4,127.2,127.1,124.4,116.4,110.6,110.5,110.5,110.4,109.7,109.0,49.1,4 6.9,46.6,46.4,45.8,45.7 ,44.8,44.6,44.5,29.8,29.7,29.6,29.6,29.5,29.5,29.5,29.3,29.3,29.2,27.5,27.2,24.3,14.1,13.5,12.8.HRMS(ESI)[M+H] ⁺ calcd for C ₃₁ H ₃₀ N ₃ O ₅ SCl ₂ :626.1283; found:626.1280.

Example 39

5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl)- 3-Methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with ethyl 5-(chlorosulfonyl)-3-methylbenzofuran-2-carboxylate, and the other conditions were the same. 328 mg of white solid was obtained, with a yield of 49%. ¹ H NMR (400MHz, Chloroform-d) δ8.13–7.83(m,1H),7.82–7.43(m,4H),7.42–6.96(m,5H),6.66–5.91(m,3H),5.54– 4.15(m,6H),4.06–3.64(m,1H),3.41–2.85(m,1H),2.57(d,J＝14.5Hz,3H),1.45(td,J＝7.0,3.6Hz,3H) ,1.17–0.51(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ169.2,159.7,159.6,155.9,149.8,149.1,143.1,143.0,142.7,142.3,141.1,135.8,135.5,135.4, 134.8, 134.7,133.3,132.7,132.3,130.4,130.3,130.2,129.8,129.6,129.3,128.8,128.6,128.5,128.4,128.3,128.1,127.8,127.5,127.0,125.4,1 25.3,122.4,122.2,112.8,112.7, 110.5,110.4,109.6,109.3,109.0,61.5,61.5,47.0,46.7,46.5,45.9,45.7,44.8,44.7,14.3,13.6,13.5,12.8,9.3,9.3.HRMS(ESI)[M+H] ⁺ calcd for C ₃₃ H ₃₁ N ₂ O ₇ SCl ₂ :669.1229; found:669.1221.

Example 40

4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)benzene Formic acid (F44-S35)

4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylamino Ethyl sulfonyl benzoate (185 mg, 0.3 mmol) and lithium hydroxide (15 mg, 0.6 mmol) were dissolved in a mixed solution composed of ethanol (8 mL) and water (2 mL). Stir at 100°C for 1 hour. After the reaction is completed, TLC detection , the solvent was evaporated under reduced pressure, dissolved in water (10 mL), and the pH value was adjusted to 3.0 with 1M dilute hydrochloric acid. After standing for 5 hours, the solution was filtered under reduced pressure and dried to obtain 165 mg of white solid, with a yield of 94%. ¹ H NMR (400MHz, Chloroform-d) δ11.27(s,1H),8.37–7.58(m,4H),7.57–6.85(m,7H),6.67–5.91(m,3H),5.54–4.11( m,4H),3.84(d,J＝75.4Hz,1H),3.14(d,J＝92.6Hz,1H),1.25–0.35(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ169. 7,169.5,169.3,149.6,148.9,142.9,142.6,142.6,142.5,141.5,140.9,140.8,135.3,135.2,135.1,133.8,133.8,133.6,130.8,130.7,130.6 ,129.9,129.7,128.9,128.7,128.5, 128.5,128.1,127.9,127.7,127.2,127.1,110.6,110.5,109.6, 109.3,47.2,46.8,46.0, 44.8,13.6.hrms (ESI) ⁺ CALCD F. Calcd F OR C ₂₈ H ₂₅ N ₂ O ₆ SCl ₂ :587.0810; found:587.0814.

Example 41

2-(4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamate Acyl)phenyl)acetic acid (F44-S36)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)benzoic acid ethyl ester replaced with 2-(4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)methyl)benzoate) Amido)methyl)phenyl)-N-ethylsulfamoyl)phenyl)ethyl acetate, all other conditions were the same. 195 mg of white solid was obtained, with a yield of 81%. ¹ H NMR(400MHz,Chloroform-d)δ9.89(s,1H),7.75–7.53(m,2H),7.52–7.40(m,3H),7.39–7.29(m,4H),7.07(t, J＝10.5Hz,2H),6.49–6.03(m,3H),5.50–4.27(m,4H),4.23–3.80(m,1H),3.68(d,J＝11.7Hz,2H),3.28–2.81 (m,1H),1.11–0.51(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ175.0,169.6,149.6,149.0,142.7,142.4,140.8,139.3,139.1,136.8,135.8,135.8,135.7 ,135.5,135.1,134.9,134.8,130.5,130.4,130.3,130.1,130.0, 129.9,129.7,128.9,128.6,128.4,128.4,128.3,128.2,128.0,127.7,127.6,127.5,127.4,127.1,127.0,127.0,110.6,110.5,109.8,109.1,4 6.9,46.7,46.5,45.9,45.8, 45.0,44.8,40.8,13.5,12.8.HRMS(ESI)[M+H] ⁺ calcd for C ₂₉ H ₂₇ N ₂ O ₆ SCl ₂ :601.0967; found:601.0967.

Example 42

2-(4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamate Acyl)phenyl)-2-methylpropionic acid (F44-S37)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)benzoic acid ethyl ester replaced with 2-(4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)methyl)benzoate) Amido)methyl)phenyl)-N-ethylsulfamoyl)phenyl)-2-methylpropanoic acid ethyl ester, the other conditions were the same. 150 mg of white solid was obtained, with a yield of 80%. ¹ H NMR(400MHz,Chloroform-d)δ10.75(s,1H),7.91–7.29(m,9H),7.23–6.88(m,2H),6.62–6.38(m,1H),6.37–5.98( m,2H),5.42–4.10(m,4H),4.01–3.52(m,1H),3.42–2.65(m,1H),1.60(d,J＝10.8Hz,6H),1.13–0.44(m, 3H). ¹³ C NMR (101MHz, Chloroform-d) δ181.0,180.9,169.7,169.6,149.7,149.5,149.0,142.7,142.4,140.9,135.8,135.5,135.2,134.9,134.8,130.5,1 30.4,129.7,128.9 ,128.6,128.5,128.3,128.2,128.0,127.7,127.7,127.5,127.2,127.1,127.0,126.7,126.7,126.5,110.6,110.5,109.8,109.2,46.9,46.7,46 .5,45.9,45.8,44.9,44.8 ,26.3,26.2,13.6,12.8.HRMS(ESI)[M+H] ⁺ calcd for C ₃₁ H ₃₁ N ₂ O ₆ SCl ₂ :629.1280; found:629.1288.

Example 43

3-((4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylamino Sulfonyl)phenyl)amino)-3-oxopropionic acid (F44-S38)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-Ethylsulfamoyl)benzoic acid ethyl ester replaced with ethyl 3-((4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)) )benzamido)methyl)phenyl)-N-ethylsulfamoyl)phenyl)amino)-3-oxopropionate, the other conditions were the same. 134 mg of white solid was obtained, with a yield of 53%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.72–12.32(m,1H),7.77(dd,J＝23.7,8.4Hz,2H),7.67–7.13(m,9H),6.69–6.17(m ,3H),5.41–4.16(m,4H),3.81(s,1H),3.26–2.85(m,3H),1.04–0.31(m,3H). ¹³ C NMR (101MHz, DMSO-d ₆ )δ170 .8,169.3,169.1,168.2,149.8,149.0,144.0,143.7,143.2,142.8,135.6,135.1,135.0,133.4,133.1,130.9,130.7,129.6,129.4,129.3,128. 9,128.3,128.1,127.6,126.8,118.6 ,110.6,109.2,108.9,46.1,45.9,45.1,44.9,44.2,29.0,24.1,13.2,12.6.HRMS(ESI)[MH] ^- calcd for C ₃₀ H ₂₆ N ₃ O ₇ SCl ₂ :642.0869; found: 642.0873.

Example 44

5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)- 3-Methylbenzofuran-2-carboxylic acid (F44-S39)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate replaced with 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamide)) Methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2- Ethyl formate, other conditions were the same. 225 mg of white solid was obtained, with a yield of 88%. ¹ H NMR(400MHz,Chloroform-d)δ8.13–7.31(m,8H),7.12(d,J＝40.6Hz,2H),6.63–5.99(m,3H),5.50–4.34(m,4H) ,4.28–2.86(m,2H),2.59(d,J＝13.7Hz,3H),1.18–0.43(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ169.8,163.6,163.4,156.3,149.6 ,149.0,148.9,142.8,142.7,142.6,142.4,140.9,135.7,135.4,135.1,134.9,133.5,132.9,132.5,130.6,130.5,130.3,129.9,129.7,129.3, 128.9,128.6,128.5,128.4,128.2 ,127.9,127.6,127.5,127.4,127.2,127.1,122.6,122.5,113.0,113.0,110.6,110.5,109.8,109.2,47.1,46.8,46.6,46.0,45.9,45.1,44.9,1 3.6,13.5,12.9,9.5 ,9.5.HRMS(ESI)[M+H] ⁺ calcd for C ₃₁ H ₂₇ N ₂ O ₇ SCl ₂ :641.0916; found:641.0922.

Example 45

2-Chloro-N-(5-chloro-2-((N-ethyl-4-nitrophenyl)sulfonamido)benzyl)-N-(furan-2-ylmethyl)benzamide ( M20)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with 4-nitrobenzenesulfonyl chloride, and the other conditions were the same. 310 mg of white solid was obtained, with a yield of 33%.

Example 46

N-(2-((4-Amino-N-ethylphenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (M21 )

Follow the method used for N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (M3), Replace N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide with 2-chloro-N-(5-chloro-2-(( N-ethyl-4-nitrophenyl)sulfonamido)benzyl)-N-(furan-2-ylmethyl)benzamide, other conditions were the same. 142 mg of light yellow solid was obtained, with a yield of 76%.

Example 47

2-Chloro-N-(5-chloro-2-((N-ethyl-4-(3-oxobutylamido)phenyl)sulfonamido)benzyl)-N-(furan-2-yl Methyl)benzamide (F44-S40)

N-(2-((4-Amino-N-ethylphenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( 79mg, 0.14mmol), sodium methoxide (12mg, 0.14mmol), 2,2,6-trimethyl-4H-1,3-dioxin-4-one (24mg, 0.17mmol) were added to tetrahydrofuran (0.5mL) , reflux for 48 hours. After TLC detection, the solvent is evaporated under reduced pressure, dissolved in water (5 mL), extracted three times with ethyl acetate (5 mL), the organic phase is washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The crude product Separate by column chromatography (PE/EA=3/2~1/2) to obtain 19 mg of white solid, with a yield of 21%. ¹ H NMR (400MHz, Chloroform-d) δ7.99–6.91(m,11H),6.56–6.00(m,3H),5.60–3.45(m,7H),3.30–2.85(m,1H),2.42– 1.70(m,3H),1.17–0.85(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ202.3,169.5,165.2,148.7,142.1,141.2,134.2,134.3,133.3,131.1,129.8,129.4, 128.5,128.6,126.6,122.5,122.6,119.7,114.7,110.6,110.4,32.0,29.9,29.8,29.4,27.3,14.2.HRMS(ESI)[M+H] ⁺ calcd for C ₃₁ H ₃₀ N ₃ O ₆ SCl ₂ :642.1232; found:642.1232.

Example 48

N-(2-((4-Carbamoyl-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S41)

4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) Benzoic acid (788mg, 1.3mmol) and N,N'-carbonyldiimidazole (260mg, 1.6mmol) were added to tetrahydrofuran (25mL), stirred at 40°C overnight, and ammonia water (2mL) was added to react for 36h. After the reaction was completed, TLC was used to detect the reaction. The solvent was removed by pressure distillation, dissolved in water (5 mL), and extracted three times with ethyl acetate (5 mL). The organic phase was washed with saturated sodium chloride aqueous solution and dried by adding anhydrous sodium sulfate. The crude product was separated by column chromatography (PE/EA=1/ 2) Obtain 757 mg of white solid, with a yield of 96%. ¹ H NMR (400MHz, Chloroform-d) δ8.1–7.8(m,2H),7.7–6.9(m,10H),6.6–5.9(m,4H),5.6–4.1(m,4H),3.9( dq,J＝14.5,7.3Hz,1H),3.3–2.8(m,1H),1.2–0.4(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ169.5,167.9,149.7,148.8,143.0, 142.8,142.5,140.7,140.5,139.6,137.9,135.4,135.1,135.1,130.8,130.2,129.8,128.7,128.3,128.3,128.1,127.9,127.5,127.3,127.2,1 10.6,110.5,109.8,109.3,46.7, 46.0,45.7,44.9,13.6.HRMS(ESI)[M+H] ⁺ calcd for C ₂₈ H ₂₆ Cl ₂ N ₃ O ₅ S:586.0970; found:586.0966.

Example 49

N-(2-((4-(Acetylcarbamoyl)-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzene Formamide (F44-S42)

N-(2-((4-Carbamoyl-N-ethylphenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzyl Amide (58mg, 0.1mmol), 4-dimethylaminopyridine (1mg, 0.01mmol), pyridine (16mg, 0.2mmol), acetyl chloride (8mg, 0.1mmol) were added to anhydrous dichloromethane (0.5mL) and refluxed The reaction was carried out overnight. After TLC detection, the solvent was evaporated under reduced pressure, and water (5 mL) was added to dissolve. Extract three times with ethyl acetate (5 mL), wash the organic phase with saturated sodium chloride aqueous solution, and dry with anhydrous sodium sulfate. The crude product is separated by column chromatography (PE/EA=1/2) to obtain 23 mg of white solid, with a yield of 36%. . ¹ H NMR(400MHz,Chloroform-d)δ9.59–9.35(m,1H),8.01(q,J＝8.3Hz,2H),7.84–7.04(m,9H),6.54–5.99(m,3H) ,5.38–4.10(m,4H),4.01–3.62(m,1H),3.26(dt,J＝14.0,7.0Hz,1H),2.57(d,J＝14.3Hz,3H),1.18–0.71(m ,3H). ¹³ C NMR (101MHz, Chloroform-d) δ173.5,169.5,164.8,164.7,149.9,149.2,142.9,142.5,142.3,141.2,141.0,137.0,135.4,130.7,130.4,130.0, 129.8,128.8, 128.7,128.6,128.5,128.2,127.9,127.6,127.2,110.7,110.6,109.8,109.3,47.3,46.8,46.1,44.9,29.9,29.7,29.4,27.3,25.8,22.8,13.7. HRMS(ESI)[M +H] ⁺ calcd for C ₃₀ H ₂₉ Cl ₂ N ₃ O ₆ S:628.1076; found:628.1068.

Example 50

5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-5-methoxyphenyl)-N-ethylsulfamoyl )-3-Methylbenzofuran-2-carboxylic acid ethyl ester (M6-43)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide is replaced with 2-chloro-N-(2-(ethylamino)-4-methoxybenzyl)-N-(furan-2-ylmethyl)benzamide, All other conditions are the same. 188 mg of white solid was obtained, with a yield of 76%. ¹ H NMR(400MHz,Chloroform-d)δ8.16–7.87(m,1H),7.87–7.05(m,8H),7.04–6.81(m,1H),6.55–6.09(m,2H),6.08– 5.74(m,1H),5.47–4.92(m,1H),4.92–4.15(m,5H),4.02–3.67(m,1H),3.56(d,J＝10.6Hz,3H),3.31–2.83( m,1H),2.58(d,J＝18.3Hz,3H),1.45(td,J＝7.1,3.0Hz,3H),1.17–0.51(m,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ169 .2,159.8,159.7,158.9,158.7,155.9,155.9,150.2,149.6,142.9,142.4,142.1,138.1,137.8,135.7,135.3,133.6,132.6,130.7,130.2,130. 1, 129.7,129.4,129.3,129.2,128.9,128.3,128.1,127.6,127.3,127.3,127.0,126.8,125.5,125.4,122.5,122.4,114.3,113.9,113.4,113.1,1 12.7,112.5,110.5,110.4,109.4, 108.5,61.6,61.5,55.2,55.2,47.0,46.6,46.5,45.2,44.0,43.7,14.3,13.5,12.9,9.2.

Example 51

5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-5-methoxyphenyl)-N-ethylsulfamoyl )-3-methylbenzofuran-2-carboxylic acid (F44-S43)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)benzoic acid ethyl ester replaced with 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)- 5-Methoxyphenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester, the other conditions were the same. 150 mg of white solid was obtained, with a yield of 79%. ¹ H NMR(400MHz,Chloroform-d)δ11.69(s,1H),8.15–7.88(m,1H),7.87–7.51(m,3H),7.51–7.12(m,5H),6.92(d, J＝7.1Hz,1H),6.57–5.76(m,3H),5.52–4.96(m,1H),4.96–4.12(m,3H),4.07–3.68(m,1H),3.56(s,3H) ,3.10(d,J＝82.0Hz,1H),2.83–2.38(m,3H),1.46–0.96(m,2H),0.74(d,J＝91.3Hz,1H). ¹³ C NMR (101MHz, CDCl _3. 5,129.3,129.1,128.3,127.8, 127.6,127.1,127.0,126.9,126.7,122.8,122.6,114.3,114.0,113.7,113.3,112.7,110.6,110.5,109.6,108.8,55.3,55.3,47.1,46.6,45.5, 44.0,13.5,13.0,9.4. HRMS(ESI)[MH] ^- calcd for C ₃₂ H ₂₈ ClN ₂ O ₈ S:635.1255; found:635.1255.

Example 52

5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-4,5-dimethoxyphenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-44)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide replaced with 2-chloro-N-(2-(ethylamino)-4,5-dimethoxybenzyl)-N-(furan-2-ylmethyl)benzene Formamide, other conditions are the same. 220 mg of white solid was obtained, with a yield of 86%. ¹ H NMR(400MHz,Chloroform-d)δ8.20–7.89(m,1H),7.89–7.55(m,2H),7.54–6.68(m,6H),6.49–6.33(m,1H),6.33– 6.02(m,1H),5.86(d,J＝34.3Hz,1H),5.56–4.15(m,6H),4.06–3.68(m,4H),3.39(d,J＝18.5Hz,3H),3.28 –2.95(m,1H),2.69–2.47(m,3H),1.46(td,J＝7.1,2.9Hz,3H),1.06(dt,J＝21.2,7.1Hz,2H),0.81(d,J =34.5Hz, 1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ169.5,169.2,169.1,159.7,159.6,155.8,155.8,150.2,149.5,149.2,149.1,147.7,143.0,142.3,141.9,13 5.6,135.2, 133.9,131.7,131.6,130.3,130.0,129.8,129.5,129.3,129.2,129.1,129.0,128.7,128.3,127.7,127.3,127.1,126.9,125.3,125.2,122.5,1 22.4,122.3,112.6,112.4,110.7, 110.5,110.4,109.7,109.5,108.8,108.4,61.6,56.0,55.6,55.5,47.0,46.5,46.4,45.2,44.1,43.8,41.4,14.3,13.5,13.0,9.3,9.2.

Example 53

5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-4,5-dimethoxyphenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S44)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethyl The method used for sulfamoyl)benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl) ethyl)phenyl)-N-ethylsulfamoyl)benzoate was replaced with 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)) Methyl)-4,5-dimethoxyphenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate, the other conditions were the same. 171 mg of white solid was obtained, with a yield of 86%. ¹ H NMR(400MHz,Chloroform-d)δ11.40(s,1H),8.34–6.64(m,9H),6.63–5.70(m,3H),5.68–4.09(m,4H),3.93(s, 4H),3.40(d,J＝14.6Hz,3H),3.10(d,J＝51.9Hz,1H),2.70–2.39(m,3H),1.19–0.92(m,2H),0.83(d,J =40.9Hz, 1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ170.3,170.0,163.1,163.0,156.2,150.0,149.3,147.9,147.8,143.0,142.5,142.1,135.2,134.8,134.0,13 3.1,131.5, 130.6,130.1,130.0,129.6,129.4,129.2,129.0,128.5,127.6,127.2,127.0,126.7,126.6,122.7,122.6,112.8,112.6,110.9,110.6,110.5,1 09.8,109.1,108.7,56.1,55.7, 55.7,47.1,46.6,45.4,44.4,44.1,41.7,13.5,13.1,9.4.HRMS(ESI)[MH] ^- calcd for C ₃₃ H ₃₀ ClN ₂ O ₉ S:665.1361; found:665.1364.

Example 54

Ethyl 5-(N-(6-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)benzo[d][1,3]dioxolane- 5-yl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-45)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide was replaced with 2-chloro-N-((6-(ethylamino)benzo[d][1,3]dioxolane-5-yl)methyl)-N- (furan-2-ylmethyl)benzamide, all other conditions were the same. 210 mg of white solid was obtained, with a yield of 84%. ¹ H NMR(400MHz,Chloroform-d)δ8.21–7.88(m,1H),7.86–7.54(m,2H),7.52–7.32(m,4H),7.32–6.73(m,2H),6.50– 6.07(m,2H),6.07–5.70(m,3H),5.40–4.16(m,6H),4.00–3.57(m,1H),3.32–2.77(m,1H),2.59(d,J＝17.4 Hz,3H),1.45(td,J＝7.1,2.6Hz,3H),1.35–0.95(m,2H),0.75 (d, J=85.8Hz, 1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ169.5,169.3,159.8,159.7,155.9,155.9,150.0,149.4,148.1,146.7,142.9,142.5,142.1,135.5,133.7 , 133.1,132.8,130.3,130.1,130.0,129.8,129.5,129.3,128.9,128.3,127.6,127.1,127.0,125.5,125.4,122.4,122.2,112.8,112.7,110.5,1 10.4,109.4,108.7,107.9,107.5, 107.3,106.7,102.0,101.8,61.5,46.9,46.4,45.4,44.7,44.4,14.3,13.4,12.8,9.3,9.3.

Example 55

Ethyl 5-(N-(6-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)benzo[d][1,3]dioxolane- 5-yl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S45)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)benzoic acid ethyl ester replaced with ethyl 5-(N-(6-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl) )benzo[d][1,3]dioxolane-5-yl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester, the other conditions were the same. 173 mg of white solid was obtained, with a yield of 89%. ¹ H NMR(400MHz,Chloroform-d)δ11.49(s,1H),8.40–7.89(m,1H),7.88–7.55(m,2H),7.55–6.74(m,6H),6.63–5.57( m,5H),5.52–4.10(m,4H),3.81(d,J＝73.2Hz,1H),3.05(d,J＝82.2Hz,1H),2.59(d,J＝16.7Hz,3H), 1.19–0.48(m,3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ170.1,169.9,163.6,156.2,149.8,149.3,148.2,147.0,146.9,143.0,142.6,142.2,135.2,133.8,133 .0,130.5, 130.2,130.1,129.8,129.6,129.4,129.1,128.5,127.7,127.5,127.1,122.7,112.9,110.6,110.5,109.7,108.9,108.1,107.6,107.4,106.9,1 02.1,101.9,47.0,46.5,45.5, 44.6,13.5,9.5.HRMS(ESI)[MH] ^- calcd for C ₃₂ H ₂₆ ClN ₂ O ₉ S:649.1048; found:649.1046.

Example 56

5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-5-(dimethylamino)phenyl)-N- Ethyl sulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-46)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide replaced with 2-chloro-N-(4-(dimethylamino)-2-(ethylamino)benzyl)-N-(furan-2-ylmethyl)benzene Formamide, other conditions are the same. 68 mg of light yellow solid was obtained, with a yield of 91%. ¹ H NMR (400MHz, Chloroform-d) δ8.16–7.91(m,1H),7.90–7.09(m,8H),6.75(ddd,J＝28.9,8.7,2.3Hz,1H),6.59–5.95( m,2H),5.94–5.49(m,1H),5.43–4.16(m,6H),3.83(ddq,J＝72.8,14.4,7.4Hz,1H),3.36–2.90(m,1H),2.87– 2.31(m,9H),1.46(td,J＝7.1,2.2Hz,3H),1.14–0.57(m,3H). ¹³ C NMR(101MHz, CDCl ₃ )δ169.3,160.0,159.9,156.0,155.9,150.5 ,149.9,149.9,143.0,142.4,142.1,136.0,130.2,129.7,129.5,129.2,128.2,127.8,127.6,127.0,126.9,125.6,125.5,122.6,112.9,112.7, 112.5,111.4,110.5,110.5,61.7 ,61.7,46.7,40.5,40.3,14.4,13.6,9.4.

Example 57

5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-5-(dimethylamino)phenyl)-N-ethylamino Sulfonyl)-3-methylbenzofuran-2-carboxylic acid (F44-S46)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35) is to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)) Benzamido)methyl)phenyl)-N-ethylsulfamoyl)benzoic acid ethyl ester was replaced with 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl) )Benzoylamino)methyl)-5-(dimethylamino)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester, the other conditions were the same. 38 mg of white solid was obtained, with a yield of 59%. ¹ H NMR (400MHz, Chloroform-d) δ9.11 (s, 1H), 8.19–7.90 (m, 1H), 7.90–7.13 (m, 8H), 6.92 (d, J = 75.1Hz, 1H), 6.61 –5.67(m,3H),5.30(t,J＝15.7Hz,1H),4.92–4.08(m,3H),3.84(ddq,J＝75.8,14.4,7.5Hz,1H),3.36–2.98(m ,1H),2.88–2.47(m,8H),1.40–0.58(m,4H). ¹³ C NMR (101MHz, CDCl ₃ )δ169.8,163.0,156.3,156.3,150.3,149.6,143.0,142.9,142.6,142.2 ,135.6,133.3,130.5,129.8,129.3,128.4,127.8,127.2,127.0,126.8,122.8,112.7,110.7,110.6,109.7,46.8,45.5,41.0,29.8,13.8,13.2, 9.5.HRMS(ESI)[ MH] ^- calcd for C ₃₃ H ₃₁ ClN ₃ O ₇ S:648.1571; found:648.1566.

Example 58

Ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-5-(ethyl(methyl)amino)phenyl) -N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-47)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide replaced with 2-chloro-N-(4-(ethyl(methyl)amino)-2-(ethylamino)benzyl)-N-(furan-2-ylmethyl base) benzamide, the other conditions are the same. 158 mg of light yellow solid was obtained, with a yield of 98%. ¹ H NMR (400MHz, Chloroform-d) δ8.31–7.02(m,9H),6.85–6.59(m,1H),6.53–6.04(m,2H),5.84–5.47(m,1H),5.46– 4.16(m,6H),3.84(ddq,J＝73.6,14.3,7.1Hz,1H),3.36–2.89(m,3H),2.69–2.45(m,6H),1.46(td,J＝7.1,2.6 Hz, 3H), 1.19–0.56 (m, 6H). ¹³ C NMR (101MHz, CDCl ₃ ) δ169.2,159.9,159.8,155.8,155.8,150.5,149.9,148.6,142.9,142.3,142.0,138.1,137.8,136 .0 ,135.6,130.1,130.1,129.6,129.4,129.1,128.2,127.7,127.3,126.9,126.9,125.6,125.5,122.6, 113.1,112.6,112.4,111.1,110.5,110.4,109.3,61.6,46.6,46.6,46.5,37.1,37.1,14.3,13.6,11.1,9.3.

Example 59

Ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-5-(ethyl(methyl)amino)phenyl) -N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S47)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)benzoic acid ethyl ester replaced with ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl) )-5-(ethyl(methyl)amino)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester, the other conditions were the same. 106 mg of white solid was obtained, with a yield of 69%. ¹ H NMR(400MHz,Chloroform-d)δ11.09(s,1H),8.21–7.07(m,10H),7.04–5.78(m,3H),5.64–4.11(m,4H),3.87(d, J＝80.8Hz,1H),3.25(d,J＝39.9Hz,3H),2.82(d,J＝57.7Hz,3H),2.51(d,J＝9.8Hz,3H),1.29–0.89(m, 5H), 0.75 (d, J=75.8Hz, 1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ169.7,162.4,156.1,156.0,150.0,149.1,143.8,142.7,142.2,138.8,135.2,130.6,130.4, 130.2,129.7,129.5,128.9,127.7,127.2,127.0,125.3,122.4,113.2,112.8,110.6,110.5,109.7,109.1,46.7,45.7,13.7,13.1,10.8,10.6,9 .4,9.4.HRMS(ESI) [MH] ^- calcd for C ₃₄ H ₃₃ ClN ₃ O ₇ S:662.1728; found:662.1735.

Example 60

5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-5-(diethylamino)phenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-48)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide replaced with 2-chloro-N-(4-(diethylamino)-2-(ethylamino)benzyl)-N-(furan-2-ylmethyl)benzamide , other conditions are consistent. 252 mg of light yellow solid was obtained, with a yield of 99%. ¹ H NMR(400MHz,Chloroform-d)δ8.25–7.03(m,9H),6.78–6.54(m,1H),6.50–6.02(m,2H),5.67(dd,J＝34.6,23.2Hz, 1H),5.44–4.16(m,6H),3.85(ddq,J＝74.5,14.3,7.3Hz,1H),3.44–2.83(m,5H),2.56(d,J＝20.3Hz,3H),1.45 (td,J＝7.1,2.4Hz,3H),1.18–0.65(m,9H). ¹³ C NMR (101MHz, CDCl ₃ )δ169.1,159.8,159.7,155.7,155.7,150.4,149.9,147.4,142.8,142.2 ,141.8,138.1,137.8,135.9,135.5,134.6,133.6,130.0,130.0,129.5,129.4,129.1,128.3,127.7,127.1,127.0,126.8,126.8,125.5,125.4, 124.2,122.4,112.5,112.1,110.6 ,110.4,110.3,109.1,108.2,61.5,47.2,46.6,44.9,44.0,44.0,43.3,14.3,13.6,13.1,12.3,12.3,9.2.

Example 61

5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-5-(diethylamino)phenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S48)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-Ethylsulfamoyl)benzoic acid ethyl ester was replaced with 5-(N-(2-((2-chloro-N-(furan) Ethyl (pyran-2-ylmethyl)benzoylamino)methyl)-5-(diethylamino)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate ester, other conditions are the same. 166 mg of white solid was obtained, with a yield of 66%. ¹ H NMR(400MHz,Chloroform-d)δ11.96(s,1H),8.27–7.06(m,10H),7.03–6.04(m,3H),5.57–4.16(m,4H),3.92(d, J＝87.5Hz,1H),3.74–2.80(m,5H),2.49(s,3H),1.32–0.57(m,9H).HRMS(ESI)[MH] ^- calcd for C ₃₄ H ₃₃ ClN ₃ O ₇ S: 662.1728; found: 662.1735. ¹³ C NMR (101MHz, CDCl ₃ ) δ169.6,162.3,156.0,150.0,149.2,144.5,142.6,142.2,138.8,135.3,135.1,130.6,129.8,12 9.6,128.5,127.7, 127.2,126.9,126.7,124.6,124.3,122.2,113.0,112.7,110.6,110.5,109.7,109.1,47.1,46.9,46.7,45.8,13.6,13.1,11.5,11.0,9.4,9.4.H RMS(ESI)[MH ] ^- calcd for C ₃₅ H ₃₅ ClN ₃ O ₇ S:676.1884; found:676.1891.

Example 62

Ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-5-(ethyl(propyl)amino)phenyl) -N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-49)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide replaced with 2-chloro-N-(4-(ethyl(propyl)amino)-2-(ethylamino)benzyl)-N-(furan-2-ylmethyl base) benzamide, the other conditions are the same. 180 mg of light yellow solid was obtained, with a yield of 96%. ¹ H NMR (400MHz, Chloroform-d) δ8.19–7.87(m,1H),7.87–7.08(m,8H),6.77–6.53(m,1H),6.52–6.03(m,2H),5.60( dd,J＝32.6,22.4Hz,1H),5.40–4.17(m,6H),3.86(ddq,J＝73.0,14.3,7.4Hz,1H),3.37–2.97(m,3H),2.97–2.72( m,2H),2.55(d,J＝20.2Hz,3H),1.45(td,J＝7.2,2.3Hz,3H),1.17(ddt,J＝70.1,14.5,7.9Hz,4H),0.90(d , J＝7.4Hz, 4H), 0.65 (t, J＝7.4Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ169.1,159.8,159.7,155.7,155.7,150.5,149.9,147.6,142.8, 142.2,141.8,138.1,137.8,135.9,135.6,133.6,130.0,130.0,129.6,129.4,129.1,129.0,128.3,127.7,127.1,127.0,126.8,125.5,125.4,1 22.4,112.5,111.9,110.5,110.4, 110.3,109.1,108.5,61.5,51.8,51.8,46.7,44.9,44.6,20.4,20.4,14.3,13.6,13.1,12.0,12.0,11.0,11.0,9.3,9.2.

Example 63

Ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-5-(ethyl(propyl)amino)phenyl) -N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S49)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)benzoic acid ethyl ester replaced with ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl) )-5-(ethyl(propyl)amino)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester, the other conditions were the same. 110 mg of white solid was obtained, with a yield of 64%. ¹ H NMR(400MHz,Chloroform-d)δ10.37(s,1H),8.46–7.10(m,10H),7.10–5.62(m,4H),5.49–4.16(m,4H),3.87(d, J＝77.1Hz, 1H), 3.54–2.26 (m, 9H), 1.00 (q, J＝92.2, 78.6Hz, 8H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 169.8, 162.9, 162.7, 156.1, 150.2, 149.5,142.5,142.1,138.5,138.1,135.5,135.2,133.2,130.4,129.6,127.9,127.3,127.1,127.0,122.6,112.6,110.5,46.7,45.4,29.7,13.7 ,13.2,11.1,9.4.HRMS( ESI)[MH] ^- calcd for C ₃₆ H ₃₇ ClN ₃ O ₇ S:690.2041; found:690.2028.

Example 64

5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-5-(dipropylamino)phenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-50)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S364), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide replaced with 2-chloro-N-(4-(dipropylamino)-2-(ethylamino)benzyl)-N-(furan-2-ylmethyl)benzene Formamide, other conditions are the same. 318 mg of light yellow solid was obtained, with a yield of 96%. ¹ H NMR (400MHz, Chloroform-d) δ8.15–7.68 (m, 2H), 7.57 (ddd, J = 35.7, 20.3, 9.0Hz, 2H), 7.45–7.11 (m, 5H), 6.76–6.51 ( m,1H),6.51–6.01(m,2H),5.71–5.41(m,1H),5.38–4.16(m,6H),3.87(ddq,J＝71.0,14.3,7.2Hz,1H),3.48– 3.06(m,1H),2.90(ddd,J＝19.5,9.3,5.7Hz,4H),2.66–2.47(m,3H),1.45(td,J＝7.2,2.0Hz,3H),1.29(dt, J＝15.3,7.5Hz,4H),1.16–0.74(m,3H),0.66(t,J＝7.4Hz,6H). ¹³ C NMR (101MHz, CDCl ₃ )δ169.1,159.8,159.7,155.8,150.5, 149.9,147.8,142.8,142.2,141.9,137.8,136.0,135.6,133.6,130.0,129.6,129.4,129.1,128.2,127.8,127.1,126.8,125.5,125.4,122.3,1 12.5,111.9,110.3,108.5,61.5, 52.5,52.5,46.8,45.0,20.2,20.1,14.3,13.6,13.1,11.0,11.0,9.3,9.2.

Example 65

5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-5-(dipropylamino)phenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S50)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35) is to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)) Benzamido)methyl)phenyl)-N-ethylsulfamoyl)benzoic acid ethyl ester was replaced with 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl) )Benzoylamino)methyl)-5-(dipropylamino)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester, the other conditions were the same. 93 mg of white solid was obtained, with a yield of 40%. ¹ H NMR(400MHz,Chloroform-d)δ11.46(s,1H),8.22–7.10(m,10H),7.07–6.02(m,3H),5.48–4.16(m,4H),3.90(d, J＝70.1Hz,1H),3.18(d,J＝143.4Hz,5H),2.53(d,J＝11.0Hz,3H),1.93–0.98(m,6H),0.76(d,J＝45.2Hz, 7H). ¹³ C NMR (101MHz, CDCl ₃ ) δ173.0,169.6,162.8,155.9,150.0,149.2,144.0,142.5,142.0,138.4,138.0,135.2,133.0,130.4,129.6,128.4,126 .8,125.0,122.3, 112.7,110.4,109.5,108.8,46.8,29.6,19.6,13.6,13.1,10.9,10.9,9.3.HRMS(ESI)[MH] ^- calcd for C ₃₇ H ₃₉ ClN ₃ O ₇ S:704.2197; found:704.2195.

Example 66

Ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-5-(pyrrolidin-1-yl)phenyl)- N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-51)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide replaced with 2-chloro-N-(2-(ethylamino)-4-(pyrrolidin-1-yl)benzyl)-N-(furan-2-ylmethyl) ) benzamide, other conditions are the same. 180 mg of light yellow solid was obtained, with a yield of 81%. ¹ H NMR (400MHz, Chloroform-d) δ8.17–7.04 (m, 9H), 6.66–6.45 (m, 1H), 6.33 (t, J = 25.5Hz, 2H), 5.52 (dd, J = 40.2, 27.3Hz,1H),5.34–4.86(m,1H),4.86–4.13(m,5H),3.99–3.58(m,1H),3.35–2.92(m,3H),2.92–2.68(m,2H) ,2.54(d,J＝21.0Hz,3H),1.85(s,4H),1.43(td,J＝7.1,2.4Hz,3H),1.13–0.56(m,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ169.2,159.8,159.8,155.9,155.9,150.5,150.0, 147.4,142.9,142.3,142.0,137.8,136.0,135.6,133.3,130.1,129.6,129.0,128.2,127.7,127.6,126.9,126.8,125.5,125.5,122.6,112.5,1 12.3,112.1,110.4,110.4,108.6, 61.6,47.4,46.5,25.3,14.4,13.5,9.3.

Example 67

Ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-5-(pyrrolidin-1-yl)phenyl)- N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S51)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)benzoic acid ethyl ester replaced with ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl) )-5-(pyrrolidin-1-yl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester, the other conditions were the same. 153 mg of white solid was obtained, with a yield of 87%. ¹ H NMR(400MHz,Chloroform-d)δ10.58(s,1H),8.37–7.01(m,9H),6.99–5.96(m,3H),5.95–5.40(m,1H),5.39–4.04( m,4H),3.82(d,J＝65.1Hz,1H),2.93(d,J＝67.6Hz,4H),2.53(s,3H),1.88(s,4H),1.53–0.21(m,4H ). ¹³ C NMR (101MHz, Chloroform-d) δ169.9,162.9,162.8,156.1,150.2,149.6,147.4,143.0,142.4,142.1,135.4,135.1,130.3,129.7,129.1,128.4,127. 8,126.9,126.6, 126.4,122.8,112.5,112.3,110.5,109.5,108.9,47.5,46.6,25.3,13.6,13.1,9.4.HRMS(ESI)[MH] ^- calcd for C ₃₅ H ₃₃ ClN ₃ O ₇ S:674.1728; found: 674.1735.

Example 68

Ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-5-(piperidin-1-yl)phenyl)- N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-52)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide replaced with 2-chloro-N-(2-(ethylamino)-4-(piperidin-1-yl)benzyl)-N-(furan-2-ylmethyl) ) benzamide, other conditions are the same. 91 mg of light yellow solid was obtained, with a yield of 75%. ¹ H NMR (400MHz, Chloroform-d) δ8.12–7.77 (m, 1H), 7.65 (ddd, J = 37.4, 15.8, 8.1Hz, 2H), 7.52–7.08 (m, 6H), 6.90 (dt, J＝8.9,4.8Hz,1H),6.35(t,J＝23.9Hz,2H),6.02–5.62(m,1H),5.42–4.15(m,6H),3.84(ddd,J＝75.2,13.1, 7.1Hz,1H),3.35–2.93(m,1H),2.93–2.65(m,4H),2.64–2.47(m,3H),1.61–1.37(m,9H),1.35–1.16(m,1H) ,0.95–0.42(m,2H). ¹³ C NMR (101MHz, CDCl ₃ )δ172.5,169.3,159.9,159.9,156.0,156.0,151.6,150.4,149.9,143.0,142.4,142.1,136.0,133.2,13 0.2,130.1 ,129.7,129.3,129.2,128.3,128.0,127.7,127.4,127.3,127.0,126.9,125.5,122.7,117.0,116.4,115.1,115.1,112.6,110.5,110.5,110.5, 108.8,61.7,50.1,50.0,46.6 ,45.2,25.5,25.5,24.1,24.1,24.1,14.4,13.6,9.4,9.4.

Example 69

Ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-5-(piperidin-1-yl)phenyl)- N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S52)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)benzoic acid ethyl ester replaced with ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl) )-5-(piperidin-1-yl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester, the other conditions were the same. 65 mg of white solid was obtained, with a yield of 73%. ¹ H NMR(400MHz,Chloroform-d)δ10.28(s,1H),8.17–6.95(m,10H),6.93–5.76(m,3H),5.23–3.89(m,4H),3.55(d, J＝197.4Hz, 1H), 2.95 (s, 4H), 2.53 (d, J＝7.3Hz, 3H), 1.93–0.47 (m, 10H). ¹³ C NMR (101MHz, CDCl ₃ ) δ173.1, 169.7, 162.7 ,156.1,150.2,149.5,144.0,142.6,132.8,130.5,129.6,127.3,127.1,127.0,122.7,112.6,110.6,46.6,29.8,25.0,24.7,13.7,9.5.HRMS(ESI)[ MH] ^-calcd for C ₃₇ H ₃₉ ClN ₃ O ₇ S:688.1884; found:688.1890.

Example 70

5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-4-(dimethylamino)phenyl)-N-ethylamino Sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-53)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide replaced with 2-chloro-N-(5-(dimethylamino)-2-(ethylamino)benzyl)-N-(furan-2-ylmethyl)benzene Formamide, other conditions are the same. 436 mg of light yellow solid was obtained, with a yield of 48%. ¹ H NMR(400MHz,Chloroform-d)δ8.13–7.86(m,1H),7.86–7.52(m,2H),7.51–7.14(m,5H),7.03–6.52(m,1H),6.51– 6.00(m,4H),5.63–4.71(m,2H),4.47(qd,J＝7.2,2.7Hz,4H),3.82(ddq,J＝70.8,13.9,7.0Hz,1H),2.98(s, 7H), 2.58 (d, J＝18.9Hz, 3H), 1.45 (td, J＝7.1, 2.7Hz, 3H), 1.15–0.59 (m, 3H). ¹³ C NMR (101MHz, Chloroform-d) δ169. 4,159.9,159.8,155.9,155.8,150.5,150.4, 150.2,149.7,142.8,142.3,142.0,139.0,136.0,135.4,130.2,130.2,130.0,129.8,129.5,129.3,129.1,128.5,128.0,127.8,127.3,127.3,1 27.1,126.8,125.7,125.6,125.3, 124.7,122.4,122.3,112.6,112.4,111.0,110.8,110.5,110.4,109.4,108.8,108.5,61.5,61.5,47.1,46.5,45.4,44.6,40.5,40.3,14.4,13.6 ,13.5,13.0,9.3.

Example 71

5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-4-(dimethylamino)phenyl)-N-ethylamino Sulfonyl)-3-methylbenzofuran-2-carboxylic acid (F44-S53)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)benzoic acid ethyl ester replaced with 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)- 4-(Dimethylamino)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester, the other conditions were the same. 249 mg of white solid was obtained, with a yield of 75%. ¹ H NMR(400MHz,Chloroform-d)δ9.42(s,1H),8.37–5.96(m,13H),5.66–5.06(m,1H),5.05–4.60(m,2H),4.50(dd, J＝33.6,14.1Hz,1H),3.84(d,J＝74.2Hz,1H),3.04(s,7H),2.56(d,J＝14.7Hz,3H),1.49–0.49(m,3H). ¹³ C NMR (101MHz, Chloroform-d) δ170.0,162.3,156.0,149.9,149.2,143.0,142.5,142.1,135.1,134.8,133.8,133.0,130.5,130.4,129.2,128.2,127.7, 127.2,126.9,126.3, 126.2,122.5,112.5,110.5,109.7,108.9,46.5,45.6,44.9,41.8,40.9,13.5,12.9,9.3.HRMS(ESI)[MH] ^- calcd for C ₃₃ H ₃₁ ClN ₃ O ₇ S:648.1571; found:648.1581.

Example 72

Ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-4-(ethyl(methyl)amino)phenyl) -N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-54)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide replaced with 2-chloro-N-(5-(ethyl(methyl)amino)-2-(ethylamino)benzyl)-N-(furan-2-ylmethyl base) benzamide, the other conditions are the same. 480 mg of light yellow solid was obtained, with a yield of 62%. ¹ H NMR(400MHz,Chloroform-d)δ8.13–7.86(m,1H),7.86–7.51(m,2H),7.51–7.14(m,5H),7.02–6.50(m,1H),6.49– 6.03(m,4H),5.57–4.15(m,6H),3.81(dtd,J＝70.1,14.3,13.6,7.2Hz,1H),3.40(q,J＝7.2,6.4Hz,2H),2.93( s,4H),2.57(d,J＝20.1Hz,3H),1.45(td,J＝7.1,2.6Hz,3H),1.21–0.54(m,6H).13C NMR(101MHz,Chloroform-d)δ169 .4,169.3,159.8,159.8,155.8,155.8,150.3,149.7,149.1,149.0,148.8,142.8,142.4,142.2,142.0,139.0,136.0,135.4,134.3,133.3,130. 5,130.2,129.9,129.7,129.5,129.3 ,129.1,128.4,128.0,127.7,127.2,127.0,126.8,125.6,125.5,124.8,124.3,122.5,122.4,122.2,112.5,112.4,110.7,110.5,110.4,109.4, 108.7,108.5,61.5,61.4,47.0 ,46.6,46.5,45.3,44.5,37.5,37.4,14.3,13.6,13.4,13.0,11.5,11.4,9.3.

Example 73

Ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-4-(ethyl(methyl)amino)phenyl) -N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S54)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethyl The method used for sulfamoyl)benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl) ethyl)phenyl)-N-ethylsulfamoyl)benzoate was replaced with ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoyl) Amino)methyl)-4-(ethyl(methyl)amino)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester, the other conditions were the same. 352 mg of white solid was obtained, with a yield of 98%. ¹ H NMR (400MHz, Chloroform-d) δ9.33 (s, 1H), 8.54–6.90 (m, 9H), 6.43 (td, J = 95.0, 87.8, 53.1Hz, 4H), 5.63–4.20 (m, 4H),3.84(d,J＝65.0Hz,1H),3.44(s,2H),3.09(d,J＝87.7Hz,4H),2.57(s,3H),1.09(d,J＝52.3Hz, 6H). ¹³ C NMR (101MHz, Chloroform-d) δ169.8,162.3,155.8,149.9,149.1,148.3,147.8,143.3,142.4,142.0,135.1,134.7,133.7,133.0,130.4,129.6,1 29.2,128.2,127.6 ,127.0,125.7,122.3,112.4,110.4,109.5,108.8,47.8,47.0,46.4,44.8,41.4,38.4,37.8,13.4,12.9,11.2,9.2.HRMS(ESI)[MH] ^- calcd for C ₃₄ H ₃₃ ClN ₃ O ₇ S:662.1728; found:648.1741.

Example 74

5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-4-(diethylamino)phenyl)-N-ethylamino Sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-55)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide was replaced with 2-chloro-N-(5-(diethylamino)-2-(ethylamino)benzyl)-N-(furan-2-ylmethyl)benzamide , other conditions are consistent. 538 mg of light yellow solid was obtained, with a yield of 75%. ¹ H NMR(400MHz,Chloroform-d)δ8.13–7.51(m,3H),7.50–7.14(m,5H),7.00–6.50(m,1H),6.50–6.24(m,3H),6.24– 6.03(m,1H),5.61–4.22(m,6H),4.03–3.62(m,1H),3.37(d,J＝7.5Hz,4H),3.27–2.92(m,1H),2.57(d, J＝20.9Hz, 3H), 1.45 (td, J＝7.1, 2.5Hz, 3H), 1.18 (q, J＝7.0Hz, 6H), 1.12–0.64 (m, 3H). ¹³ C NMR (101MHz, Chloroform -d)δ169.2,159.8,159.7,155.8,155.7,150.3, 149.6,147.9,147.6,142.7,142.3,142.2,141.9,139.0,135.9,135.4,130.1,129.7,129.5,129.2,129.0,128.3,128.1,128.0,127.7,127.1,1 26.9,126.8,125.6,125.5,124.2, 123.7,122.4,122.2,112.4,112.3,110.4,110.3,110.0,109.3,108.5,61.4,61.4,46.4,44.5,44.3,44.1,14.3,13.5,13.4,13.0,12.6,12.5,9 .2.

Example 75

5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-4-(diethylamino)phenyl)-N-ethylamino Sulfonyl)-3-methylbenzofuran-2-carboxylic acid (F44-S55)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)benzoic acid ethyl ester replaced with 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)- 4-(diethylamino)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester, the other conditions were the same. 243 mg of white solid was obtained, with a yield of 72%. ¹ H NMR(400MHz,Chloroform-d)δ8.71–7.86(m,2H),7.85–5.95(m,12H),5.65–4.10(m,4H),4.05–3.78(m,1H),3.78– 3.27(m,4H),3.28–2.91(m,1H),2.71–2.43(m,3H),1.45–0.57(m,9H). ¹³ C NMR(101MHz,Chloroform-d)δ163.1,156.2,156.1, 150.3,149.5,142.6,142.2,135.6,135.2,130.6,130.5,129.9,129.5,129.3,128.5,127.4,127.3,127.0,126.5,122.7,112.6,110.6,110.6,1 09.8,108.9,68.0,47.2,46.6, 45.7,45.1,25.7,13.7,13.6,13.2,12.5,12.2,9.5.HRMS(ESI)[MH] ^- calcd for C ₃₅ H ₃₅ ClN ₃ O ₇ S:676.1884; found:676.1895.

Example 76

Ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-4-(ethyl(propyl)amino)phenyl) -N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-56)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide replaced with 2-chloro-N-(5-(ethyl(propyl)amino)-2-(ethylamino)benzyl)-N-(furan-2-ylmethyl base) benzamide, the other conditions are the same. 140 mg of light yellow solid was obtained, with a yield of 81%. ¹ H NMR(400MHz,Chloroform-d)δ8.12–7.51(m,3H),7.34(tdd,J＝28.6,22.9,7.9Hz,5H),6.97–6.49(m,1H),6.49–5.95( m,4H),5.51–4.14(m,6H),3.79(ddq,J＝62.3,14.4,7.1Hz,1H),3.58–3.31(m,2H),3.22(s,3H),2.69–2.46( m,3H),1.62(ddt,J＝11.3,7.4,3.7Hz,2H),1.45(td,J＝7.1,2.1Hz,3H),1.17(q,J＝6.8Hz,3H),1.11–0.75 (m,6H). ¹³ C NMR (101MHz, CDCl ₃ ) δ169.3,159.9,159.9,155.9,155.9,150.4,149.8,148.0,142.8,142.3,142.0,139.0,136.1,135.5,130.2,129.8,1 29.4,129.1 ,128.4,128.2,127.8,127.3,127.0,126.9,125.7,125.6,124.3,123.8,122.6,122.4,112.4,110.5,110.4,110.1,109.8,109.3,108.6,61.5,5 2.1,52.0,46.6,45.3,45.0 ,44.9,44.6,41.2,20.8,14.4,13.6,13.1,12.4,12.4,11.5,9.3.

Example 77

Ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-4-(ethyl(propyl)amino)phenyl) -N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S56)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35) is to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)) Benzamido)methyl)phenyl)-N-ethylsulfamoyl)benzoic acid ethyl ester was replaced with ethyl 5-(N-(2-((2-chloro-N-(furan-2-yl) Methyl)benzoylamino)methyl)-4-(ethyl(propyl)amino)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate, All other conditions are the same. 108 mg of white solid was obtained, with a yield of 78%. ¹ H NMR (400MHz, Chloroform-d) δ10.57(s,1H),8.54–6.91(m,10H),6.59–6.18(m,3H),5.53–4.22(m,4H),4.07–2.94( m,6H),2.75–2.42(m,3H),1.63(s,2H),1.30–0.54(m,10H). ¹³ C NMR(101MHz,CDCl ₃ )δ170.0,169.8,162.8,156.3,156.1,150.1 ,149.3,143.1,142.7,142.2,135.1,130.5,129.9,129.5,129.3,129.2,128.6,127.8,127.3,127.0,126.3,122.6,112.6,110.6,109.9,109.0, 47.1,46.8,46.6,45.8,45.2 ,13.7,13.1,11.4,11.3,9.4.HRMS(ESI)[MH] ^- calcd for C ₃₆ H ₃₇ ClN ₃ O ₇ S:690.2041; found:690.2048.

Example 78

5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-4-(dipropylamino)phenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-57)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide replaced with 2-chloro-N-(5-(dipropylamino)-2-(ethylamino)benzyl)-N-(furan-2-ylmethyl)benzene Formamide, other conditions are the same. 70 mg of light yellow solid was obtained, with a yield of 60%. ¹ H NMR(400MHz,Chloroform-d)δ8.10–7.51(m,3H),7.50–7.11(m,5H),6.96–6.48(m,1H),6.47–5.99(m,4H),5.42– 4.17(m,6H),3.79(ddq,J＝64.0,14.5,7.2Hz,1H),3.39–2.93(m,5H),2.68–2.50(m,3H),1.62(q,J＝7.4Hz, 4H), 1.45 (td, J＝7.1, 2.4Hz, 3H), 0.95 (dt, J＝12.2, 7.3Hz, 8H), 0.74 (s, 1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 169.3, 160.0 ,160.0,156.0,155.9,150.5,149.9,148.2,142.9, 142.0,139.1,136.1,135.6,130.3,129.8,129.2,128.4,128.1,127.9,127.3,126.9,125.8,125.7,124.4,123.8,122.6,122.4,112.5,110.6,1 10.5,110.2,108.7,61.6,61.6, 52.9,52.7,46.6,45.4,41.2,20.5,14.4,13.7,13.2,11.5,11.5,9.4.

Example 79

5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-4-(dipropylamino)phenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S57)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)benzoic acid ethyl ester replaced with 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)- 4-(Dipropylamino)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester, the other conditions were the same. 54 mg of white solid was obtained, with a yield of 77%. ¹ H NMR(400MHz,Chloroform-d)δ9.29(s,1H),8.10–6.09(m,13H),5.46–4.15(m,4H),4.11–3.63(m,1H),3.16(d, J=97.4Hz, 5H), 2.72–2.38 (m, 3H), 1.96–0.81 (m, 13H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 169.8, 163.1, 156.3, 150.3, 142.7, 142.2, 135.2, 130.7 ,129.9,129.6,128.6,127.9,127.4,127.0,122.7,110.7,46.7,13.7,13.2,11.5,11.3,9.5.HRMS(ESI)[MH] ^- calcd for C ₃₇ H ₃₉ ClN ₃ O ₇ S:704.2197 ;found:704.2208.

Example 80

Ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-4-(pyrrolidin-1-yl)phenyl)- N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-58)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide replaced with 2-chloro-N-(2-(ethylamino)-5-(pyrrolidin-1-yl)benzyl)-N-(furan-2-ylmethyl) ) benzamide, other conditions are the same. 87 mg of light yellow solid was obtained, with a yield of 93%. ¹ H NMR(400MHz,Chloroform-d)δ10.58(s,1H),8.37–7.01(m,9H),6.99–5.96(m,3H),5.95–5.40(m,1H),5.39–4.04( m,4H),3.82(d,J＝65.1Hz,1H),2.93(d,J＝67.6Hz,4H),2.53(s,3H),1.88(s,4H),1.53–0.21(m,4H ). ¹³ C NMR (101MHz, CDCl ₃ ) δ169.9,162.9,162.8,156.1,150.2,149.6,147.4,143.0,142.4,142.1,135.4,135.1,130.3,129.7,129.1,128.4,127.8, 126.9,126.6,126.4 ,122.8,112.5,112.3,110.5,109.5,108.9,47.5,46.6,25.3,13.6,13.1,9.4.HRMS(ESI)[MH] ^- calcd for C ₃₅ H ₃₃ ClN ₃ O ₇ S:674.1728; found:674.1735 .Example 81

Ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-4-(pyrrolidin-1-yl)phenyl)- N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S58)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)benzoic acid ethyl ester replaced with ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl) )-4-(pyrrolidin-1-yl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester, the other conditions were the same. 15 mg of white solid was obtained, with a yield of 56%. ¹ H NMR(400MHz,Chloroform-d)δ10.58(s,1H),8.37–7.01(m,9H),6.99–5.96(m,3H),5.95–5.40(m,1H),5.39–4.04(m, 4H),3.82(d,J＝65.1Hz,1H),2.93(d,J＝67.6Hz,4H),2.53(s,3H),1.88(s,4H),1.53–0.21(m,4H). ¹³ C NMR (101MHz, CDCl ₃ ) δ169.9,162.9,162.8,156.1,150.2,149.6,147.4,143.0,142.4,142.1,135.4,135.1,130.3,129.7,129.1,128.4,127.8,12 6.9,126.6,126.4,122.8 ,112.5,112.3,110.5,109.5,108.9,47.5,46.6,25.3,13.6,13.1,9.4.HRMS(ESI)[MH] ^- calcd for C ₃₅ H ₃₃ ClN ₃ O ₇ S:674.1728; found:674.1735.

Example 82

Ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-4-(piperidin-1-yl)phenyl)- N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-59)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide replaced with 2-chloro-N-(2-(ethylamino)-5-(piperidin-1-yl)benzyl)-N-(furan-2-ylmethyl) ) benzamide, other conditions are the same. 87 mg of light yellow solid was obtained, with a yield of 93%. ¹ H NMR (400MHz, Chloroform-d) δ8.11–7.51(m,3H),7.51–6.79(m,6H),6.67–6.48(m,1H),6.48–5.96(m,3H),5.57– 4.13(m,6H),3.97–3.59(m,1H),3.19(t,J＝5.4Hz,5H),2.71–2.48(m,3H),1.66(dt,J＝33.5,5.1Hz,6H) ,1.45(td,J＝7.1,2.7Hz,3H),1.13–0.59(m,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ169.5,160.0,159.9,156.0,155.9,152.1,151.8,150.4,149.7 ,142.9,142.4,142.1,139.5,139.1,136.0,135.4,134.3,130.3,129.9,129.6,129.4,129.2,128.5,128.0,127.7,127.4,127.3,127.1,126.9, 125.7,125.6,122.5,122.4,114.9 ,114.5,114.2,112.7,112.5,110.6,110.5,109.6,108.9,108.5,61.6,61.6,49.9,49.7,47.1,46.6,45.4,44.5,25.8,25.7,24.3,24.2,14.4,1 3.7,13.5,13.0 ,9.5,9.4.

Example 83

Ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-4-(piperidin-1-yl)phenyl)- N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S59)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)benzoic acid ethyl ester replaced with ethyl 5-(N-(2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl) )-4-(piperidin-1-yl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester, the other conditions were the same. 62 mg of white solid was obtained, with a yield of 75%. ¹ H NMR(400MHz,Chloroform-d)δ10.18(s,1H),8.23–7.09(m,10H),6.66–5.95(m,3H),5.65–4.15(m,4H),4.08–2.86( m,6H),2.72–2.44(m,3H),2.03–1.19(m,6H),1.12–0.57(m,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ162.9,156.2,150.2,149.3,143.5 ,142.7,142.3,135.4,130.7,130.0,129.5,129.4,129.3,127.4,127.0,126.0,122.6,112.7,110.6,110.0,47.2,46.6,45.8,25.3,13.7,13.1, 9.5.HRMS(ESI)[ MH] ^- calcd for C ₃₆ H ₃₅ ClN ₃ O ₇ S:688.1884; found:688.1895.

Example 84

4-Chloro-2-(((furan-2-ylmethyl)amino)methyl)phenol (M8)

Follow the method used for N-(5-chloro-2-nitrobenzyl)-1-(furan-2-yl)methanamine (M1), replacing 5-chloro-2-nitrobenzaldehyde with 5-chloro- 2-Hydroxybenzaldehyde, all other conditions were the same. 1.44g of yellow solid was obtained, with a yield of 61%. ¹ H NMR (400MHz, Chloroform-d) δ7.39 (d, J＝1.9Hz, 1H), 7.11 (dd, J＝8.6, 2.7Hz, 1H), 6.93 (d, J＝2.6Hz, 1H), 6.77(d,J＝8.7Hz,1H),6.34(dd,J＝3.2,1.8 Hz, 1H), 6.21 (d, J = 3.2Hz, 1H), 3.89 (s, 2H), 3.79 (s, 2H). ¹³ C NMR (101MHz, Chloroform-d) δ 156.9, 151.6, 142.5, 128.6, 128.3 ,123.6,123.5,117.8,110.4,108.3,50.7,44.2.

Example 85

2-Chloro-N-(5-chloro-2-hydroxybenzyl)-N-(furan-2-ylmethyl)benzamide (M9)

Add 4-chloro-2-(((furan-2-ylmethyl)amino)methyl)phenol (948mg, 4mmol) and triethylamine (606mg, 6mmol) into anhydrous dichloromethane (15mL), and ice it Slowly add o-chlorobenzoyl chloride (700 mg, 4 mmol) under bath conditions and react at room temperature for 3 hours. After TLC detection, the solvent is evaporated under reduced pressure, dissolved in water (20 mL), and extracted three times with ethyl acetate (20 mL). The organic phase Wash with saturated sodium chloride aqueous solution, add anhydrous sodium sulfate and dry. The crude product is separated by column chromatography (PE/EA=6/1) to obtain 439 mg of white solid, with a yield of 29%. ¹ H NMR (400MHz, Chloroform-d) δ9.25 (s, 1H), 7.37 (dtd, J＝20.3, 7.0, 2.0Hz, 5H), 7.17 (dd, J＝8.7, 2.6Hz, 1H), 7.00 (d,J＝2.6Hz,1H),6.90(d,J＝8.7Hz,1H),6.38–6.30(m,1H),6.24(d,J＝3.3Hz,1H),4.82(d,J＝ 14.8Hz,1H),4.44–4.22(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ170.7,155.0,148.1,143.3,134.1,131.0,131.0,130.7,130.1,129.9,128.0,127.2,123 .8 ,122.8,119.0,110.7,110.1,45.2,44.5.

Example 86

4-Chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl 4-acetylamidobenzene sulfonate (F44-S60)

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzene Method used for formamide (F44-S1), replacing N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide with 2-chloro-N -(5-chloro-2-hydroxybenzyl)-N-(furan-2-ylmethyl)benzamide, all other conditions were the same. 137 mg of white solid was obtained, with a yield of 48%. ¹ H NMR (400MHz, Chloroform-d) δ9.32 (d, J＝13.2Hz, 1H), 7.76–7.52 (m, 4H), 7.50–7.31 (m, 5H), 7.31–7.04 (m, 2H) ,6.82(d,J＝8.7Hz,1H),6.39–6.05(m,2H),4.96(d,J＝16.0Hz,1H),4.45(t,J＝20.6Hz,1H),4.35(d, J＝16.0Hz,1H),4.27–4.08(m,1H),2.07–1.95(m,3H). ¹³ C NMR(101MHz,Chloroform-d)δ169.8,169.5,149.2,148.1,146.0,145.8,144.8, 143.2,142.6,134.7,134.6,133.1,132.1,131.6,130.9,130.8,130.3,130.2,130.0,129.9,129.6,129.5,129.1,129.1,128.7,128.6,128.3,1 28.2,127.6,127.4,124.0,123.7, 119.2,119.1,110.5,110.0,109.5,46.5,45.6,42.7,41.6,24.3,14.2.HRMS(ESI)[M+H] ⁺ calcd for C ₂₇ H ₂₃ N ₂ O ₆ SCl ₂ :573.0654; found:573.0660 .

Example 87

2-((3-Fluoro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl 4-acetylbenzene sulfonate (F44-S61)

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S1) The method used was to replace N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide with 3-fluoro-N-(furan-2-yl). Methyl)-N-(2-hydroxybenzyl)benzamide, replace 4-acetamidobenzenesulfonyl chloride with 4-acetylbenzenesulfonyl chloride, and the remaining conditions are the same. 104 mg of white solid was obtained, with a yield of 80%. ¹ H NMR (400MHz, Chloroform-d) δ8.21–7.82 (m, 4H), 7.49–7.04 (m, 9H), 6.26 (d, J = 50.5Hz, 2H), 4.39 (d, J = 90.9Hz ,4H),2.66(d,J＝2.6Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ169.5,168.6,158.3(d,J＝247.2Hz,1C),148.3,143.3,142.6,136.5,134.2 ,132.0(d,J＝9.2Hz,1C),131.1,129.8,128.9,128.7(d,J＝2.5Hz,1C),128.3,126.7,124.8(d,J＝4.3Hz,1C),123.0(d , J＝17.4Hz, 1C), 122.8, 119.3, 116.2 (d, J＝ 20.9Hz, 1C), 110.7, 109.9, 44.8, 44.7, 26.6. ¹⁹ F NMR (376MHz, CDCl ₃ ) δ- 114.4,-114.5.

Example 88

4-Chloro-2-((2,6-dichloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl 4-acetamidobenzene sulfonate (F44-S62)

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S1) The method used was to replace N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide with 2,6-dichloro-N-(5- Chloro-2-hydroxybenzyl)-N-(furan-2-ylmethyl)benzamide, all other conditions were the same. 223 mg of white solid was obtained, with a yield of 74%. ¹ H NMR (400MHz, Chloroform-d) δ8.91 (d, J＝22.2Hz, 1H), 7.75–7.53 (m, 4H), 7.53–7.06 (m, 6H), 6.82 (dd, J＝43.7, 8.8Hz,1H),6.47–5.97(m,2H),4.73(d,J＝17.9Hz,2H),4.24(d,J＝32.1Hz,2H),2.05(d,J＝22.3Hz,3H) . ¹³ C NMR (101MHz, Chloroform-d) δ169.6,169.4,166.5,166.4,149.0,147.5,145.8,145.7,144.6,144.5,143.2,142.5,134.0,133.8,133.1,133.0,132. 1,132.0,131.9,131.1 ,131.0,131.0,129.6,129.5,129.3,129.1,128.4,124.1,123.5,119.2,119.1,110.6,110.3,109.8,46.0,45.5,43.4,41.7,24.4,24.4.HRMS(ESI) [M+H] ⁺ calcd for C ₂₇ H ₂₂ N ₂ O ₆ SCl ₃ :607.0264; found:607.0264.

Example 89

4-Chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl 4-butyrylamidobenzenesulfonate (F44-S63)

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzene Method used for formamide (F44-S1), replacing N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide with 2-chloro-N -(5-Chloro-2-hydroxybenzyl)-N-(furan-2-ylmethyl)benzamide, replacing 4-acetamidobenzenesulfonyl chloride with 4-butylamidobenzenesulfonyl chloride, all other conditions are the same consistent. 141 mg of white solid was obtained, with a yield of 47%. ¹ H NMR (400MHz, Chloroform-d) δ9.18 (d, J＝24.6Hz, 1H), 7.71 (dd, J＝26.0, 8.6Hz, 2H), 7.63 (d, J＝8.5Hz, 2H), 7.51–7.31(m,5H),7.31–7.05(m,2H),6.79(dd,J＝24.2,8.7Hz,1H),6.46–5.92(m,2H),5.01(d,J＝16.0Hz, 1H),4.46(d,J＝16.1Hz,1H),4.36(d,J＝15.9Hz,1H),4.19(q,J＝19.6,15.4Hz,1H),2.29–2.11(m,2H), 1.61 (dp, J＝14.4, 7.1Hz, 2H), 0.86 (dt, J＝14.7, 7.3Hz, 3H). ¹³ C NMR (101MHz, Chloroform-d) δ 172.8, 172.7, 169.5, 169.4, 149.2, 148.1, 146.0,145.8,144.9,143.1,142.6,134.8,134.6,133.1,132.2,131.6,130.9,130.8,130.3,130.3,130.0,129.9,129.6,129.5,129.1,129.0,1 28.7,128.5,128.3,128.1,128.0, 127.6,127.4,127.3,124.0,123.6,119.3,119.2,110.5,110.0,109.5,46.5,45.7,42.7,41.6,39.1,18.6,13.6.HRMS(ESI)[M+H] ⁺ calcd for C ₂₉ H ₂₇ N ₂ O ₆ SCl ₂ :601.0967; found:601.0963.

Example 90

4-Chloro-2-((2,6-dichloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl 4-butyrylamidobenzene sulfonate (F44-S64)

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S1) The method used was to replace N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide with 2,6-dichloro-N-(5- Chloro-2-hydroxybenzyl)-N-(furan-2-ylmethyl)benzamide, replace 4-acetamidobenzenesulfonyl chloride with 4-butylamidobenzenesulfonyl chloride, and other conditions are the same. 131 mg of white solid was obtained, with a yield of 41%. ¹ H NMR (400MHz, Chloroform-d) δ9.04 (d, J＝12.7Hz, 1H), 7.85–7.46 (m, 5H), 7.45–7.21 (m, 4H), 7.20–7.07 (m, 1H) ,6.79(dd,J＝56.8,8.6Hz,1H),6.50–5.98(m,2H),4.77(d,J＝33.5Hz,2H),4.27(d,J＝24.8Hz,2H),2.23( ¹³ C NMR(101MHz,Chloroform-d)δ172.7,172.6,166.5,166.4,148.9,147.5,145.8,144.8,143.2,142.6,134.1,133.8,133.1,132.9,132.1,132.1,131.8,131. 2,131.0,129.6,129.5, 129.5,129.3,129.1,128.4,128.2,124.1,123.5,119.3,119.1,110.6,110.3,109.8,46.0,45.6,43.5,41.7,39.2,18.7,13.7,13.7.HRMS(ESI)[M+ H] ⁺ calcd for C ₂₉ H ₂₆ N ₂ O ₆ SCl ₃ :635.0577; found:635.0565.

Example 91

5-((2,6-Dichloro-N-(furan-2-ylmethyl)benzamido)methyl)-2-methoxyphenyl 4-acetamidyl benzene sulfonate (F44-S66 )

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S1) The method used was to replace N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide with 2,6-dichloro-N-(furan- 2-ylmethyl)-N-(3-hydroxy-4-methoxybenzyl)benzamide, other conditions were the same. 230 mg of white solid was obtained, with a yield of 83%. ¹ H NMR(400MHz,Chloroform-d)δ9.07(d,J＝20.1Hz,1H),7.78–7.63(m,4H),7.41–7.22(m,5H),7.08(d,J＝8.6Hz ,1H),6.80(t,J＝8.7Hz,1H),6.39–6.05(m,2H),4.66(d,J＝40.0Hz,2H),4.21(d,J＝6.3Hz,2H),3.53 (d, J＝16.2Hz, 3H), 2.10 (d, J＝2.3Hz, 3H). ¹³ C NMR (101MHz, Chloroform-d) δ 169.7, 169.6, 166.0, 165.8, 151.7, 151.2, 149.2, 148.1, 144.2 ,144.0,143.1,142.5,138.3,138.1,134.3,134.3,132.1,131.8,131.0,130.9,129.7,129.6,129.5,128.4,128.4,128.3,127.1,124.5,124.3, 118.8,118.8,113.0,112.7,110.6 ,110.5,110.0,109.6,55.8,55.7,50.7,46.6,44.0,39.4,24.5.HRMS(ESI)[M+H] ⁺ calcd for C ₂₈ H ₂₅ N ₂ O ₇ SCl ₂ :603.0760; found:603.0758.

Example 92

5-((2-Chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)-2-methoxyphenyl4-butyrylamidobenzene Sulfonate (F44-S67)

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S1) The method used was to replace N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide with 2-chloro-N-(furan-2-yl). Methyl)-N-(3-hydroxy-4-methoxybenzyl)benzamide, replacing 4-acetamidobenzenesulfonyl chloride with 4-butylamidobenzenesulfonyl chloride, and remaining the same. 263 mg of white solid was obtained, with a yield of 88%. ¹ H NMR(400MHz,Chloroform-d)δ8.85(d,J＝16.1Hz,1H),7.71(d,J＝4.1Hz,4H),7.49–6.75(m,8H),6.54–5.93(m ,2H),5.05(dd,J＝108.5,15.0Hz,1H),4.43–4.03(m,3H),3.53(d,J＝8.4Hz,3H),2.26(td,J＝7.5,2.5Hz, 2H), 1.66 (h, J = 7.4Hz, 2H), 0.90 (t, J = 7.3Hz, 3H). ¹³ C NMR (101MHz, Chloroform-d) δ 172.6, 172.5, 168.9, 168.8, 151.5, 151.2, 149.5 ,148.7,144.2,144.1,143.1,142.6,138.4,138.2,135.3,135.2,130.7,130.6,130.4,130.3,129.9,129.8,129.7,129.7,129.5,129.4,128.7, 128.2,128.0,127.9,127.8,127.5 ,127.4,127.3,124.2,123.5,118.9,118.8,113.0,112.9,110.5,110.5,109.6,109.3,55.8,55.7,50.6,46.1,44.2,39.7,39.2,18.7,13.7.HRMS( ESI)[M+ H] ⁺ calcd for C ₃₀ H ₃₀ N ₂ O ₇ SCl:597.1462; found:597.1456.

Example 93

5-((2,6-Dichloro-N-(furan-2-ylmethyl)benzamido)methyl)-2-methoxyphenyl 4-butylamidobenzene sulfonate (F44- S68)

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S1) The method used was to replace N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide with 2,6-dichloro-N-(furan- 2-ylmethyl)-N-(3-hydroxy-4-methoxybenzyl)benzamide, 4-acetamidobenzenesulfonyl chloride was replaced with 4-butylamidobenzenesulfonyl chloride, and the remaining conditions were the same. 291 mg of white solid was obtained, with a yield of 92%. ¹ H NMR (400MHz, Chloroform-d) δ9.00 (d, J＝19.6Hz, 1H), 7.79–7.66 (m, 4H), 7.43–7.05 (m, 6H), 6.81 (t, J＝8.2Hz ,1H),6.38–6.02(m,2H),4.68(d,J＝37.6Hz,2H),4.21(d,J＝8.4Hz,2H),3.53(d,J＝13.6Hz,3H),2.29 (td, J＝7.6, 1.8Hz, 2H), 1.67 (hd, J＝7.4, 1.7Hz, 2H), 0.91 (t, J＝7.4Hz, 3H). ¹³ C NMR (101MHz, Chloroform-d) δ172 .7,172.6,165.9,165.8,151.6,151.2,149.2,148.1,144.3,144.1,143.1,142.5,138.3,138.0,134.4,134.3,132.1,131.8,131.0,130.9,129. 7,129.6,129.4,129.3,128.4,128.4 ,128.3,127.0,124.5,124.3,118.8,118.8,113.0,112.7,110.6,110.5,110.0,109.6,55.7,55.6,50.7,46.6,44.0,39.4,39.2,18.7,13.7.HRMS( ESI)[M+ H] ⁺ calcd for C ₃₀ H ₂₉ N ₂ O ₇ SCl ₂ :631.1073; found:631.1072.

Example 94

5-((2-Chloro-N-(furan-2-ylmethyl)benzamido)methyl)-2-methoxyphenyl 4-acetylamidobenzene sulfonate (F44-B19)

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S1) The method used was to replace N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide with 2-chloro-N-(furan-2-yl). Methyl)-N-(3-hydroxy-4-methoxybenzyl)benzamide, other conditions were the same. 230 mg of white solid was obtained, with a yield of 83%.

Example 95

5-((2-Chloro-N-(furan-2-ylmethyl)benzamido)methyl)-2-methoxyphenyl 4-acetylamidobenzene sulfonate (F44-S65)

According to N-(2-((4-acetaminophenyl)sulfonamido)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (F44-S1) The method used was to replace N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide with 2-chloro-N-(furan-2-yl). Methyl)-N-(3-hydroxy-4-methoxybenzyl)benzamide, other conditions were the same. 230 mg of white solid was obtained, with a yield of 83%. ¹ H NMR(400MHz,Chloroform-d)δ9.21(d,J＝18.1Hz,1H),7.70(d,J＝10.6Hz,4H),7.48–6.73(m,8H),6.51–5.98(m ,2H),5.04(dd,J＝106.7,15.1Hz,1H),4.43–4.06(m,3H),3.51(d,J＝4.7Hz,3H),2.07(s,3H). ¹³ C NMR( 101MHz,Chloroform-d)δ169.7,169.7,169.0,168.9,151.5,151.2,149.5,148.6,144.2,144.1,143.1,142.6,138.3,138.1,135.2,130.7,130.7,130.3, 130.3,129.9,129.8,129.7, 129.5,129.4,128.7,128.2,128.1,127.8,127.8,127.5,127.4,127.3,124.2,123.5,118.8,118.8,113.0,112.9,110.6,110.5,109.6,109.3,5 5.8,55.7,50.6,46.2,44.3, 39.8,24.4.HRMS(ESI)[M+H] ⁺ calcd for C ₂₈ H ₂₆ N ₂ O ₇ SCl:569.1149; found:569.1145.

Example 96

2-(Aminomethyl)-4-chloroaniline (M10)

Lithium aluminum tetrahydrogen (3.80g, 100mmol) was added into the reaction flask. After argon protection, anhydrous tetrahydrofuran (50mL) was added, and then anhydrous 2-amino-5-chlorobenzonitrile (7.65g, 50mmol) was slowly added dropwise. Aqueous tetrahydrofuran (50mL) solution was heated to reflux and reacted for 4 hours. After TLC detection, water was slowly added to quench the reaction. After filtration, the solution was taken, the solvent was evaporated under reduced pressure, dissolved in water (50mL), and extracted with ethyl acetate (50mL). Three times, the organic phase was washed with saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, and the crude product was separated by column chromatography (DCM/CH ₃ OH = 10/1 ~ 5/1) to obtain 6.34g of white solid, with a yield of 81%. .

Example 97

(2-Amino-5-chlorobenzoyl)carbamic acid tert-butyl ester (M11)

Add 2-(aminomethyl)-4-chloroaniline (M10) (6.34g, 40mmol) and triethylamine (4.44g, 44mmol) into anhydrous dichloromethane (100mL), and slowly add dropwise under ice bath conditions Di-tert-butyl dicarbonate (8.72g, 40mmol) was reacted at room temperature overnight. After TLC detection, the solvent was evaporated under reduced pressure, dissolved in water (50mL), extracted three times with ethyl acetate (50mL), and the organic phase was chlorinated with saturated chlorine. Wash with sodium aqueous solution, add anhydrous sodium sulfate and dry. The crude product is separated by column chromatography (PE/EA=10/1~3/1) to obtain 9.29g of light yellow solid, with a yield of 90%.

Example 98

tert-Butyl(5-chloro-2-(ethylamino)benzyl)carbamate (M12)

Add (2-amino-5-chlorobenzoyl)carbamic acid tert-butyl ester (M11) (4.65g, 18mmol), iodoethane (14.0g, 90mmol), potassium carbonate (12.4g, 90mmol) to acetonitrile (100mL ), react overnight at 70°C. After TLC detection, the solvent is evaporated under reduced pressure, dissolved in water (50 mL), extracted three times with ethyl acetate (50 mL), the organic phase is washed with saturated sodium chloride aqueous solution, and anhydrous sodium sulfate is added. dry, The crude product was separated by column chromatography (PE/EA=20/1) to obtain 2.23g of light yellow solid, with a yield of 44%.

Example 99

5-(N-(2-((tert-butoxycarbonyl)amino)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid Ethyl ester (M13)

According to 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl)-N-ethylsulfamoyl) The method used for -3-methylbenzofuran-2-carboxylic acid ethyl ester (F44-S34), 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan- 2-ylmethyl)benzamide was replaced with tert-butyl(5-chloro-2-(ethylamino)benzyl)carbamate (M12), and the other conditions were the same. 3.28g of light yellow solid was obtained, with a yield of 76%.

Example 100

5-(N-(2-((Aminomethyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate (M14)

5-(N-(2-(((tert-butoxycarbonyl)amino)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2- Ethyl formate (M13) (3.28g, 6mmol) and trifluoroacetic acid (5mL) were added to dichloromethane (25mL), and the reaction was carried out at room temperature overnight. After the reaction was detected by TLC, the solvent was evaporated under reduced pressure, and water (20mL) was added to dissolve. Extract three times with ethyl acetate (20 mL), wash the organic phase with saturated sodium chloride aqueous solution, and dry with anhydrous sodium sulfate. The crude product is separated by column chromatography (DCM/CH ₃ OH = 10/1) to obtain 2.70 g of light yellow solid. The yield is 99%.

Example 101

5-(N-(4-Chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate (M15 -69)

5-(N-(2-((Aminomethyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M14) (225 mg ,0.5mmol), pivaldehyde (52mg, 0.6mmol), add methanol (10mL) and stir at room temperature for 4h, slowly add sodium borohydride (30mg, 0.8mmol) under ice bath conditions and react at room temperature overnight. TLC detects that the reaction is completed. , add water to quench the reaction, distill the solvent under reduced pressure, add water (20 mL) to dissolve, extract three times with ethyl acetate (20 mL), wash the organic phase with saturated sodium chloride aqueous solution, add anhydrous sodium sulfate and dry, the crude product is separated by column chromatography (PE/EA=3/1) obtained 166 mg of light yellow solid, yield 64%.

Example 102

5-(N-(4-chloro-2-((2-chloro-N-neopentylbenzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzo Furan-2-carboxylic acid ethyl ester (M6-69)

Ethyl 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate ( M15-69) (166mg, 0.32mmol), potassium carbonate (66mg, 0.48mmol) was added to anhydrous dichloromethane (10mL), o-chlorobenzoyl chloride (67mg, 0.38mmol) was slowly added dropwise under ice bath conditions, at room temperature The reaction was carried out overnight. After TLC detection, the solvent was evaporated under reduced pressure, dissolved in water (20 mL), and extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the crude product was passed through a column. Chromatographic separation (PE/EA=3/1) gave 192 mg of white solid, with a yield of 91%. ¹ H NMR(400MHz,Chloroform-d)δ8.05–7.83(m,1H),7.83–7.56(m,2H),7.55–7.10(m,4H),7.03(dd,J＝19.2,6.9Hz, 2H),6.42–6.13(m,1H),5.47–4.54(m,2H),4.47(q,J＝7.1Hz,1H),4.34–3.93(m,3H),3.77(ddd,J＝46.2, 13.0,7.5Hz,1H),3.64–2.92(m,1H),2.83(dd,J＝12.6,6.3Hz,1H),2.59(d,J＝12.0Hz,3H),1.35(dt, J＝79.7,7.1Hz,3H),1.15(d,J＝11.3Hz,8H),0.96–0.61(m,2H),0.34(t,J＝6.8Hz,1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ170.1,160.0,159.7,156.0,143.1,142.8,142.3,141.7,136.3,135.2,135.0,134.8,132.4,130.0,129.8,129.5,129.4,129.3,128.3,127. 8,127.7,127.6,127.1,126.8, 125.6,125.3,122.3,112.8,61.6,60.3,57.2,52.3,51.4,46.5,35.0,28.8,28.6,14.3,14.2,12.4,9.3,9.2.

Example 103

5-(N-(4-chloro-2-((2-chloro-N-neopentylbenzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzo Furan-2-carboxylic acid (F44-S69')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-Ethylsulfamoyl)ethyl benzoate (F44-S26) was replaced with 5-(N-(4-chloro-2-((2-chloro-N-neopentylbenzoylamino)methyl) (base)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-69), and other conditions were consistent. 140 mg of white solid was obtained, with a yield of 76%. ¹ H NMR (400MHz, Chloroform-d) δ7.89 (d, J＝18.4Hz, 1H), 7.61 (d, J＝22.4Hz, 2H), 7.43–6.89 (m, 6H), 6.43–6.06 (m ,1H),5.08(dd,J＝78.9,17.0Hz,1H),4.73(dd,J＝96.5,17.4Hz,1H),4.48–3.51(m,2H),3.50–2.75(m,2H), 2.58 (s, 3H), 1.17 (s, 9H), 0.81 (d, J = 74.6Hz, 2H), 0.34 (s, 1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ171.3, 170.8, 163.4, 156.2, 143.4,142.1,141.4,135.8,135.3,135.1,135.0,132.4,132.3,130.5,130.3,129.9,129.5,128.4,127.8,127.2,126.9,126.3,122.5,57.6,51 .6,46.6,35.1,28.7,28.5, 13.0,12.5,9.5.HRMS(ESI)[MH] ^- calcd for C ₃₁ H ₃₁ Cl ₂ N ₂ O ₆ S:629.1280; found:629.1278.

Example 104

5-(N-(4-chloro-2-(((5-methylfuran-2-yl)methyl)amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Ethyl benzofuran-2-carboxylate (M15-70)

According to ethyl 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate ( The method used in M15-69) was to replace pivaldehyde with 5-methylfuranaldehyde, and the other conditions were the same. 190 mg of white solid was obtained, with a yield of 70%.

Example 105

5-(N-(4-chloro-2-(((5-methylfuran-2-yl)methyl)amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Ethyl benzofuran-2-carboxylate (M6-70)

According to 5-(N-(4-chloro-2-((2-chloro-N-neopentylbenzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene The method used for furan-2-carboxylic acid ethyl ester (M6-69), 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl )-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-69) replaced with 5-(N-(4-chloro-2-(((5-methylfuran-2-yl)methyl) )Amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-70), the other conditions were the same. 180 mg of white solid was obtained, with a yield of 75%. ¹ H NMR(400MHz,Chloroform-d)δ8.07–7.86(m,1H),7.86–7.61(m,2H),7.61–7.29(m,5H),7.10–6.97(m,1H),6.51– 5.72(m,3H),5.44–4.78(m,2H),4.76–4.09(m,4H),3.88(d,J＝75.3Hz,1H),3.40–2.81(m,1H),2.68–2.50( m,3H),2.27(s,3H),1.45(td,J＝7.0,3.4Hz,3H),1.10(dt,J＝14.8,6.8Hz,2H),0.69(d,J＝98.9Hz,1H ). ¹³ C NMR (101MHz, CDCl ₃ ) δ169.2,159.8,159.7,156.0,152.4,147.7,147.1,143.0,141.3,141.2,135.7,135.5,135.4,134.9,134.8,134.7,133.3, 132.8,132.7,132.4 ,131.8,131.0,130.4,129.8,129.6,129.3,128.9,128.5,128.3,127.6,127.5,127.4,127.3,127.0,126.9,126.5,125.5,125.4,122.4,122.3, 112.8,110.6,110.0,106.5,106.3 ,61.6, 47.0,46.8,46.5,46.1,45.0,44.8,14.3,13.5,9.3,9.3.

Example 106

5-(N-(4-chloro-2-(((5-methylfuran-2-yl)methyl)amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Benzofuran-2-carboxylic acid (F44-S70')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-(((5-methylfuran-2-yl)methyl) Amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-70), the other conditions were the same. 140 mg of white solid was obtained, with a yield of 76%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.20–7.80(m,2H),7.78–7.13(m,7H),6.81–5.76(m,3H),5.48–4.12(m,4H),4.05 –2.95(m,2H),2.59(d,J＝15.6Hz,3H),2.23(d,J＝12.0Hz,3H),1.12–0.41(m,3H). ¹³ C NMR(101MHz,DMSO)δ168 .1,160.9,155.4,151.9,147.9,147.0,143.9,140.7,135.9,135.4,135.3,135.1,133.5,133.2,132.4,132.0,131.7,130.8,129.6,129.4,129. 3,128.6,128.3,127.9,127.5,126.9 ,126.8,124.3,122.2,113.0,110.1,106.6,106.4,13.3,13.1,9.0.HRMS(ESI)[MH] ^- calcd for C ₃₂ H ₂₇ Cl ₂ N ₂ O ₇ S:653.0916; found:653.0912.

Example 107

5-(N-(2-(((5-bromofuran-2-yl)methyl)amino)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methyl Benzofuran-2-carboxylic acid ethyl ester (M15-71)

According to ethyl 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate ( The method used in M15-69) was to replace pivaldehyde with 5-bromo-2-furancarbaldehyde, and the other conditions were the same. 42 mg of white solid was obtained, with a yield of 14%.

Example 108

5-(N-(2-((N-((5-bromofuran-2-yl)methyl)-2-chlorobenzoylamino)methyl)-4-chlorophenyl)-N-ethyl Ethyl sulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-71)

According to 5-(N-(4-chloro-2-((2-chloro-N-neopentylbenzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene The method used for furan-2-carboxylic acid ethyl ester (M6-69), 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl )-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-69) replaced with 5-(N-(2-(((5-bromofuran-2-yl)methyl)amino)methyl )-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-71), the other conditions were the same. 45 mg of white solid was obtained, with a yield of 86%. ¹ H NMR (400MHz, Chloroform-d) δ8.09–7.84(m,1H),7.74(q,J＝11.5,10.2Hz,1H),7.70–7.44(m,3H),7.44–7.27(m, 3H),7.12–7.02(m,1H),6.53–6.00(m,3H),5.39–4.00(m,7H),3.31–2.87(m,1H),2.63–2.51(m,3H),1.46( td,J＝7.1,3.5Hz,1H),1.30–0.48(m,5H). ¹³ C NMR (101MHz, CDCl ₃ )δ169.5,160.3,156.2,152.1,151.2,143.0,141.1,135.9,135.3,135.1, 130.7,130.4,129.7,129.5,129.4,129.3,128.8,128.6,128.3,127.7,127.6,127.3,127.2,126.0,125.9,122.6,113.0,112.9,112.8,112.5,1 12.3,61.8,52.5,47.2,46.8, 45.6,44.5,14.5,13.7,9.5,0.1.

Example 109

5-(N-(2-((N-((5-bromofuran-2-yl)methyl)-2-chlorobenzoylamino)methyl)-4-chlorophenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S72)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-Ethylsulfamoyl)benzoic acid ethyl ester (F44-S26) was replaced with 5-(N-(2-((N-((5-bromofuran-2-yl)methyl)methyl)-2- Chlorobenzamido)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-71), other conditions are the same . 28 mg of white solid was obtained, with a yield of 65%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.17–7.79(m,2H),7.74–7.07(m,7H),6.75–6.14(m,3H),5.42–4.28(m,4H),4.05 –2.82(m,3H),2.64–2.42(m,4H),1.23(s,1H). ¹³ C NMR(101MHz,DMSO)δ160.8,155.3,152.2,143.9,135.0,134.8,133.2,131.6,131.0, 130.8,129.7,129.3,128.0,127.6,126.8,124.2,122.2,121.3,113.0,112.9,112.5,112.4,112.0,13.3,9.0.HRMS(ESI)[MH] ^- calcd for C ₃₁ H ₂₄ BrCl ₂ N ₂ O ₇ S:716.9859; found:716.9862.

Example 110

5-(N-(2-(((3-bromofuran-2-yl)methyl)amino)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methyl Benzofuran-2-carboxylic acid ethyl ester (M15-72)

According to ethyl 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate ( The method used in M15-69) was to replace pivaldehyde with 3-bromo-2-furancarbaldehyde, and the other conditions were the same. 68 mg of white solid was obtained, with a yield of 22%.

Example 111

5-(N-(2-((N-((3-bromofuran-2-yl)methyl)-2-chlorobenzoylamino)methyl)-4-chlorophenyl)-N-ethyl amino Sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-72)

According to 5-(N-(4-chloro-2-((2-chloro-N-neopentylbenzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene The method used for furan-2-carboxylic acid ethyl ester (M6-69), 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl )-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-69) replaced with 5-(N-(2-(((3-bromofuran-2-yl)methyl)amino)methyl )-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-72), the other conditions were the same. 86 mg of white solid was obtained, with a yield of 99%. ¹ H NMR(400MHz,Chloroform-d)δ8.07–7.70(m,2H),7.69–7.29(m,7H),7.14–6.16(m,3H),5.47–4.80(m,2H),4.79– 3.52(m,5H),3.37–2.84(m,1H),2.58(d,J＝10.7Hz,3H),1.46(td,J＝7.1,2.5Hz,3H),1.12(dt,J＝33.6, 6.4Hz, 2H), 0.69 (d, J = 85.1Hz, 1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 169.4, 159.9, 159.8, 156.1, 147.1, 146.6, 143.2, 143.1, 135.7, 135.5, 135.0, 134.9 ,134.4,133.2,132.4,132.3,131.4,130.6,130.5,130.4,129.8,129.4,129.0,128.9,128.6,128.4,128.1,127.9,127.6,127.4,127.2,127.1, 127.0,126.7,125.6,125.5,122.4 ,114.1,112.9,112.8,100.1,61.7,61.7,46.7,14.4,13.8,9.5,9.4.

Example 112

5-(N-(2-((N-((3-bromofuran-2-yl)methyl)-2-chlorobenzoylamino)methyl)-4-chlorophenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S71)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35) is to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)) Benzamido)methyl)phenyl)-N-ethylsulfamoyl)benzoic acid ethyl ester (F44-S26) was replaced with 5-(N-(2-((N-((3-bromofuran- 2-yl)methyl)-2-chlorobenzoylamino)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate ethyl ester (M6-72), other conditions are the same. 28 mg of white solid was obtained, with a yield of 65%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.23–6.30(m,12H),5.67–4.08(m,4H),4.01–3.59(m,1H),3.36–2.93(m,1H),2.62 –2.51(m,3H),1.10–0.40(m,3H). ¹³ C NMR(101MHz,DMSO)δ168.2,166.8,160.9,155.3,147.0,144.3,144.0,135.5,134.9,134.9,133.5,131.6,131.0 ,130.8,129.7,129.3,129.3,128.0,127.6,126.6,123.9,122.0,113.8,112.9,112.8,99.3,98.9,46.3,13.4,9.0,9.0.HRMS(ESI)[MH] ^- calcd for C ₃₁ H ₂₄ BrCl ₂ N ₂ O ₇ S:716.9865; found:716.9862.

Example 113

5-(N-(4-chloro-2-(((thiophen-2-ylmethyl)amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2 -Ethyl formate (M15-73)

According to ethyl 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate ( The method used in M15-69) was to replace pivaldehyde with 2-thiophenecarbaldehyde, and the other conditions were the same. 152 mg of white solid was obtained, with a yield of 56%.

Example 114

5-(N-(4-chloro-2-((2-chloro-N-(thiophen-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)- 3-Methylbenzofuran-2-carboxylic acid ethyl ester (M6-73)

According to 5-(N-(4-chloro-2-((2-chloro-N-neopentylbenzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene The method used for furan-2-carboxylic acid ethyl ester (M6-69) is to 5-(N-(4-chloro-2-((neopentylamino) (methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-69) was replaced with 5-(N-(4-chloro-2- (((thiophen-2-ylmethyl)amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate (M15-73), remaining conditions All consistent. 182 mg of white solid was obtained, with a yield of 95%. ¹ H NMR (400MHz, Chloroform-d) δ7.95 (d, J＝54.4Hz, 1H), 7.82–7.18 (m, 8H), 7.13–6.74 (m, 3H), 6.55–6.17 (m, 1H) ,5.62–5.06(m,1H),5.03–4.44(m,4H),4.00(d,J＝2.8Hz,1H),3.97–3.65(m,1H),3.34–2.83(m,1H),2.58 (d, J＝11.2Hz, 3H), 1.52–0.92 (m, 5H), 0.63 (d, J＝61.6Hz, 1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ171.0,169.0,160.1,160.0,159.7 ,159.7,156.0,143.1,143.0,142.8,142.8,140.9,138.5,138.4,135.8,135.5,135.0,132.4,132.3,130.6,130.3,129.7,129.4,129.3,128.8, 128.5,128.3,127.9,127.6,127.4 ,127.2,127.2,127.0,126.9,126.9,126.6,126.0,125.8,125.7,125.5,125.4,122.3,112.8,61.6,61.6,60.3,52.3,46.5,21.0,14.3,14.2,9. 3,9.3,9.3.

Example 115

5-(N-(4-chloro-2-((2-chloro-N-(thiophen-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)- 3-Methylbenzofuran-2-carboxylic acid (F44-S77)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((2-chloro-N-(thiophen-2-ylmethyl)) Benzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-73), the other conditions were the same. 136 mg of white solid was obtained, with a yield of 77%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.45–6.73 (m, 12H), 6.56 (d, J = 43.1Hz, 1H), 5.60–4.28 (m, 4H), 3.77 (d, J = 75.6 Hz,1H),3.37–2.83(m,1H),2.55(d,J＝10.9Hz,3H),1.09–0.26(m,3H). ¹³ C NMR(101MHz,DMSO)δ168.6,161.4,155.8,144.9 ,139.2,136.1,135.5,135.4,134.1,133.7,132.1,131.5,131.3,130.2,129.8,129.7,129.6,128.6,128.0,127.5,127.1,127.0,126.8,124.2, 124.1,122.5,113.4,113.3,46.5 , 9.5.HRMS(ESI)[MH] ^- calcd for C ₃₁ H ₂₅ Cl ₂ N ₂ O ₆ S ₂ :655.0531; found:655.0530.

Example 116

5-(N-(4-chloro-2-(((5-methylthiophen-2-yl)methyl)amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Ethyl benzofuran-2-carboxylate (M15-74)

According to ethyl 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate ( The method used in M15-69) was to replace pivaldehyde with 5-methyl-2-thiophenecarboxaldehyde, and the other conditions were the same. 87 mg of white solid was obtained, with a yield of 31%.

Example 117

5-(N-(4-chloro-2-((2-chloro-N-((5-methylthiophen-2-yl)methyl)benzoylamino)methyl)phenyl)-N-ethyl Ethyl sulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-74)

According to 5-(N-(4-chloro-2-((2-chloro-N-neopentylbenzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene The method used for furan-2-carboxylic acid ethyl ester (M6-69), 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl )-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-69) replaced with 5-(N-(4-chloro-2-((((5-methylthiophen-2-yl)methyl) )Amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-74), the other conditions were the same. 68 mg of brown solid was obtained, with a yield of 61%. ¹ H NMR(400MHz,Chloroform-d)δ8.05–7.86(m,1H),7.77–7.43(m,4H),7.41–7.31(m,2H),7.26–6.96(m,2H),6.94– 6.47(m,2H),6.47–6.20(m,1H),5.47–4.26(m,4H),4.08–3.59(m,4H),3.32–2.83(m,1H),2.58(d,J＝11.8 Hz, 3H), 2.47 (d, J = 13.0Hz, 3H), 2.12–0.42 (m, 5H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 169.1, 160.3, 160.2, 156.1, 143.0, 142.9, 141.1, 140.8 ,136.0,135.8,135.5,135.1,134.5,133.2,132.6, 132.3,131.4,130.7,130.6,130.4,129.8,129.4,129.1,128.8,128.5,128.4,127.9,127.8,127.6,127.3,127.0,126.7,126.0,125.8,125.0,1 24.7,122.6,122.5,112.9,52.5, 52.5,48.3,46.6,15.5,15.5,13.7,9.4,9.4.

Example 118

5-(N-(4-chloro-2-((2-chloro-N-((5-methylthiophen-2-yl)methyl)benzoylamino)methyl)phenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S78)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-Ethylsulfamoyl)ethyl benzoate (F44-S26) was replaced with 5-(N-(4-chloro-2-((2-chloro-N-((5-methylthiophene-2) -ethyl)methyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-74), the other conditions are the same . 53 mg of light yellow solid was obtained, with a yield of 79%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.06 (d, J＝35.0Hz, 1H), 7.85 (dd, J＝23.3, 8.1Hz, 1H), 7.76–7.04 (m, 7H), 6.97– 6.36(m,3H),5.50–4.20(m,4H),4.06–2.30(m,9H),0.95(d,J＝63.2Hz,2H). ¹³ C NMR(101MHz,DMSO)δ160.8,155.4,143.8 ,140.0,139.8,136.3,135.5,135.0,133.3,131.7,131.1,130.8,129.7,129.2,129.1,127.5,127.2,127.0,126.8,125.1,124.6,124.4,124.3, 113.0,112.9,15.0,9.0.HRMS (ESI)[MH] ^- calcd for C ₃₂ H ₂₇ Cl ₂ N ₂ O ₆ S ₂ :669.0688; found:669.0684.

Example 119

5-(N-(4-chloro-2-((((4-methylthiophen-2-yl)methyl)amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Ethyl benzofuran-2-carboxylate (M15-75)

According to ethyl 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate ( The method used in M15-69) was to replace pivaldehyde with 4-methyl-2-thiophenecarboxaldehyde, and the other conditions were the same. 126 mg of white solid was obtained, with a yield of 45%.

Example 120

5-(N-(4-chloro-2-((2-chloro-N-((4-methylthiophen-2-yl)methyl)benzoylamino)methyl)phenyl)-N-ethyl Ethyl sulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-75)

According to 5-(N-(4-chloro-2-((2-chloro-N-neopentylbenzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene The method used for furan-2-carboxylic acid ethyl ester (M6-69), 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl )-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-69) replaced with 5-(N-(4-chloro-2-((((4-methylthiophen-2-yl)methyl) )Amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-75), the other conditions were the same. 173 mg of purple solid was obtained, with a yield of 99%. ¹ H NMR(400MHz,Chloroform-d)δ8.09–7.86(m,1H),7.81–7.41(m,4H),7.41–7.13(m,4H),7.10–6.77(m,2H),6.49– 6.16(m,1H),5.58–4.20(m,6H),3.83(ddd,J＝69.7,13.2,7.0Hz,1H),3.35–2.77(m,1H),2.58(d,J＝12.4Hz, 3H), 2.28–1.96 (m, 4H), 1.46 (td, J＝7.1, 3.0Hz, 3H), 1.04 (dt, J＝50.2, 7.1Hz, 2H). ¹³ C NMR (101MHz, CDCl ₃ ) δ169 .1,159.8,159.8,156.0,143.1,143.1,141.0,138.2,138.1,137.2,135.8,135.5,135.0,134.2,133.0,132.4,132.1,131.2,130.6,130.4,130. 1,129.7,129.4,129.3,128.9,128.5 ,128.4,127.9,127.7,127.5,127.2,127.1,126.9,126.6,125.5,125.4,122.5,122.4,121.2,120.8,112.8,61.7,61.6,46.5,15.7,15.6,14.4, 13.5,9.4,9.4.

Example 121

5-(N-(4-chloro-2-((2-chloro-N-((4-methylthiophen-2-yl)methyl)benzoylamino)methyl)phenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S79)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-Ethylsulfamoyl)ethyl benzoate (F44-S26) was replaced with 5-(N-(4-chloro-2-((2-chloro-N-((4-methylthiophene-2) -ethyl)methyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-75), the other conditions are the same . 114 mg of light pink solid was obtained, with a yield of 77%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.23–7.94 (m, 1H), 7.85 (dd, J = 23.2, 8.2Hz, 1H), 7.76–6.34 (m, 10H), 5.66–4.90 (m ,1H),4.88–4.23(m,3H),3.82(d,J＝73.7Hz,1H),3.41–2.83(m,1H),2.57(d,J＝13.3Hz,3H),2.15(d, J＝22.3Hz,3H),1.12–0.31(m,3H). ¹³ C NMR(101MHz,DMSO)δ160.7,160.7,155.4,143.7,138.5,136.9,136.4,135.6,135.0,134.9,133.6,133.3,131.7 ,131.0,130.8,129.8,129.7,129.2,129.2,128.1,127.7,127.5,127.1,126.8,124.5,124.4,122.3,121.5,121.2,113.0,112.9,46.0,15.3,15 .3,9.0,9.0.HRMS(ESI )[MH] ^- calcd for C ₃₂ H ₂₇ Cl ₂ N ₂ O ₆ S ₂ :669.0688; found:669.0693.

Example 122

5-(N-(4-chloro-2-(((3-methylthiophen-2-yl)methyl)amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Ethyl benzofuran-2-carboxylate (M15-76)

According to ethyl 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate ( The method used in M15-69) was to replace pivaldehyde with 3-methyl-2-thiophenecarboxaldehyde, and the other conditions were the same. 151 mg of white solid was obtained, with a yield of 54%.

Example 123

5-(N-(4-chloro-2-((2-chloro-N-((3-methylthiophen-2-yl)methyl)benzoylamino)methyl)phenyl)-N-ethyl Ethyl sulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-76)

According to 5-(N-(4-chloro-2-((2-chloro-N-neopentylbenzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene The method used for furan-2-carboxylic acid ethyl ester (M6-69), 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl )-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-69) replaced with 5-(N-(4-chloro-2-(((3-methylthiophen-2-yl)methyl) )Amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-76), the other conditions were the same. 173 mg of purple solid was obtained, with a yield of 96%. ¹ H NMR(400MHz,Chloroform-d)δ8.04–7.86(m,1H),7.78–7.55(m,3H),7.47–7.17(m,5H),7.17–6.69(m,2H),6.57– 6.19(m,1H),5.56–5.04(m,1H),5.02–3.44(m,6H),3.38–2.81(m,1H),2.58(d,J＝8.9Hz,3H),2.38–1.53( m,3H),1.46(t,J=7.1Hz,3H),1.23–0.33(m,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ166.9,159.8,159.7,156.0,156.0,143.1,143.1,143.0 ,142.5,136.3,135.6,135.4,135.1,135.0,135.0,132.9,132.7,132.3,132.0,131.9,131.2,131.1,130.9,130.9,130.5,130.2,130.1,129.8, 129.7,129.4,129.3,128.5,128.3 ,128.3,127.8,127.5,127.1,127.0,126.9,126.6,125.4,125.4,124.2,122.3,112.9,112.8,61.6,61.6,47.0,46.5,39.1,14.4,13.8,13.6,13 .3,9.4,9.3.

Example 124

5-(N-(4-chloro-2-((2-chloro-N-((3-methylthiophen-2-yl)methyl)benzoylamino)methyl)phenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S80)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-Ethylsulfamoyl)ethyl benzoate (F44-S26) was replaced with 5-(N-(4-chloro-2-((2-chloro-N-((3-methylthiophene-2) -ethyl)methyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-76), the other conditions are the same . 99 mg of light pink solid was obtained, with a yield of 55%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.38–6.34 (m, 12H), 5.53–2.47 (m, 9H), 2.27–0.15 (m, 6H). ¹³ C NMR (101MHz, DMSO) δ 166. 8,160.8,160.7,155.4,143.7,142.9,136.7,135.5,135.5,135.1,133.2,132.6,132.2,131.6,130.9,129.8,129.7,129.4,129.3,129.2,128.9 ,127.7,127.5,127.2,126.8,124.5, 124.4,124.2,122.2,113.0,112.9,48.0,46.3,46.0,13.4,13.4,12.9,9.0,9.0.HRMS(ESI)[MH] ^- calcd for C ₃₂ H ₂₇ Cl ₂ N ₂ O ₆ S ₂ :669.0688 ;found:669.0695.

Example 125

5-(N-(4-chloro-2-(((5-bromothiophen-2-yl)methyl)amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Benzofuran-2-carboxylic acid ethyl ester (M15-77)

According to ethyl 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate ( The method used in M15-69) was to replace pivaldehyde with 5-bromothiophene-2-carbaldehyde, and the other conditions were the same. 74 mg of white solid was obtained, with a yield of 24%.

Example 126

5-(N-(4-chloro-2-((2-chloro-N-((5-bromothiophen-2-yl)methyl)benzoylamino)methyl)phenyl)-N-ethyl ammonia sulfate Acyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-77)

According to 5-(N-(4-chloro-2-((2-chloro-N-neopentylbenzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene The method used for furan-2-carboxylic acid ethyl ester (M6-69), 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl )-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-69) replaced with 5-(N-(4-chloro-2-(((5-bromothiophen-2-yl)methyl) Amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-77), the other conditions were the same. 68 mg of white solid was obtained, with a yield of 74%. ¹ H NMR(400MHz,Chloroform-d)δ8.10–7.29(m,8H),7.26–7.02(m,2H),6.96–6.51(m,2H),6.50–6.15(m,1H),5.46– 4.44(m,4H),4.06–3.73(m,3H),3.32–2.83(m,1H),2.59(d,J＝11.6Hz,3H),1.52–1.16(m,2H),1.10(t, J＝6.9Hz, 1H), 1.04–0.79 (m, 1H), 0.64 (d, J＝55.9Hz, 2H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 169.6, 169.2, 160.3, 160.2, 156.2, 143.0, 140.9,140.3,135.9,135.6,135.2,133.4,132.5,132.4,131.5,130.8,130.6,129.9,129.8,129.5,129.3,129.0,128.6,128.4,128.1,127.6,1 27.5,127.3,127.2,127.1,126.8, 125.8,122.5,113.0,61.8,52.5,48.5,47.9,46.7,44.6,14.5,13.7,13.0,9.5,9.4.

Example 127

5-(N-(4-chloro-2-((2-chloro-N-((5-bromothiophen-2-yl)methyl)benzoylamino)methyl)phenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S83)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4- Chloro-2-((2-chloro-N-((5-bromothiophen-2-yl)methyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl benzofuran-2-carboxylic acid ethyl ester (M6-77), and the other conditions are consistent. 41 mg of white solid was obtained, with a yield of 62%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.27–6.20(m,12H),5.46–4.26(m,4H),4.03–2.35(m,6H),1.24(s,1H). ¹³ C NMR (101MHz, DMSO) δ161.0,155.3,141.0,135.6,134.6,133.6,131.6,130.9,130.2,129.7,129.5,129.4,128.5,128.2,127.6,127.0,126.6,122.1,112. 9,111.7,47.8,46.0,9.0 .HRMS(ESI)[MH] ^- calcd for C ₃₁ H ₂₄ BrCl ₂ N ₂ O ₆ S ₂ :732.9648; found:732.9642.

Example 128

5-(N-(4-chloro-2-((((4-bromothiophen-2-yl)methyl)amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Benzofuran-2-carboxylic acid ethyl ester (M15-78)

According to ethyl 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate ( The method used in M15-69) was to replace pivaldehyde with 4-bromothiophene-2-carbaldehyde, and the other conditions were the same. 108 mg of white solid was obtained, with a yield of 35%.

Example 129

5-(N-(4-chloro-2-((2-chloro-N-((4-bromothiophen-2-yl)methyl)benzoylamino)methyl)phenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-78)

According to 5-(N-(4-chloro-2-((2-chloro-N-neopentylbenzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene The method used for furan-2-carboxylic acid ethyl ester (M6-69), 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl )-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-69) replaced with 5- (N-(4-chloro-2-(((4-bromothiophen-2-yl)methyl)amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzo Furan-2-carboxylic acid ethyl ester (M15-78), other conditions are the same. 80 mg of white solid was obtained, with a yield of 62%. ¹ H NMR(400MHz,Chloroform-d)δ8.08–7.86(m,1H),7.80–7.29(m,6H),7.27–7.04(m,3H),7.03–6.54(m,1H),6.53– 6.13(m,1H),5.55–4.32(m,4H),4.08–3.70(m,4H),3.32–2.84(m,1H),2.59(d,J＝9.8Hz,3H),2.11–0.39( m,5H). ¹³ C NMR (101MHz, CDCl ₃ ) δ169.3,160.3,160.2,156.1,143.0,135.9,135.7,135.1,132.5,132.2,131.4,130.9,130.6,130.3,130.0,129.4,12 8.7,128.6, 128.1,127.6,127.4,127.3,127.1,126.7,125.8,123.6,122.6,122.5,112.9,109.1,52.5,52.5,46.7,13.6,9.4,9.4.

Example 130

5-(N-(4-chloro-2-((2-chloro-N-((4-bromothiophen-2-yl)methyl)benzoylamino)methyl)phenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S78')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) was replaced with 5-(N-(4-chloro-2-((2-chloro-N-((4-bromothiophene-2- (methyl)methyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-78), and the other conditions were consistent. 52 mg of white solid was obtained, with a yield of 71%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.35–7.15 (m, 10H), 6.98 (d, J = 47.8Hz, 1H), 6.77–6.33 (m, 1H), 5.63–4.23 (m, 4H) ),4.16–2.22(m,6H),1.29–0.78(m,2H). ¹³ C NMR(101MHz,DMSO)δ160.7,155.4,143.7,140.9,135.6,134.8,134.6,133.6,133.3,131.7,131.2, 130.9,129.8,129.5,129.2,129.1,128.2,127.6,126.8,124.4,123.9,122.3,113.0,112.9,108.2,107.7,46.0,9.0.HRMS(ESI)[MH] ^- calcd for C ₃₁ H ₂₄ BrCl ₂ N ₂ O ₆ S ₂ :732.9636; found:732.9634.

Example 131

5-(N-(4-chloro-2-((((1-methyl-1H-pyrrol-2-yl)methyl)amino)methyl)phenyl)-N-ethylsulfamoyl)- 3-Methylbenzofuran-2-carboxylic acid ethyl ester (M15-79)

According to ethyl 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate ( The method used in M15-69) was to replace pivaldehyde with N-methyl-2-pyrrolecarbaldehyde, and the other conditions were the same. 137 mg of white solid was obtained, with a yield of 50%.

Example 132

5-(N-(4-chloro-2-((2-chloro-N-((1-methyl-1H-pyrrol-2-yl)methyl)benzoylamino)methyl)phenyl)- N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-79)

According to 5-(N-(4-chloro-2-((2-chloro-N-neopentylbenzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene The method used for furan-2-carboxylic acid ethyl ester (M6-69), 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl )-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-69) was replaced with 5-(N-(4-chloro-2-((((1-methyl-1H-pyrrol-2-yl) )methyl)amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-79), the other conditions were the same. 172 mg of white solid was obtained, with a yield of 99%. ¹ H NMR(400MHz,Chloroform-d)δ8.13–6.93(m,10H),6.71–6.44(m,1H),6.30–5.93(m,2H),5.52–5.11(m,1H),5.10– 4.65(m,1H),4.48(qd,J＝7.1,2.1Hz,3H),4.15–3.57(m,3H),3.29(s,1H),3.22–2.75(m,1H),2.58(d, J＝9.1Hz, 3H), 1.46 (td, J＝7.1, 2.2Hz, 3H), 1.34–0.33 (m, 4H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 169.4, 166.8, 159.8, 156.0, 143.2, 143.1,143.1,142.6,141.3,135.6,135.3,135.2,135.0,134.9,132.4,131.2,131.0,130.9,130.5,130.3,130.2,129.8,129.5,129.4,128.4, 128.3,128.1,127.6,127.4,127.2,127.1,127.0,126.9,125.5,125.4,123.7,122.3,113.0,112.8,107.2,61.6,61.6,60.4,47.0,46.5,39.1,3 4.4,33.7,21.1,14.4, 14.2,13.6,13.4,9.4,9.4,9.4.

Example 133

5-(N-(4-chloro-2-((2-chloro-N-((1-methyl-1H-pyrrol-2-yl)methyl)benzoylamino)methyl)phenyl)- N-Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S79')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-Ethylsulfamoyl)ethyl benzoate (F44-S26) was replaced with 5-(N-(4-chloro-2-((2-chloro-N-((1-methyl-1H- Pyrrol-2-yl)methyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-79), the rest The conditions are the same. 107 mg of pink solid was obtained, with a yield of 65%. ¹ H NMR(400MHz,Chloroform-d)δ10.44(s,1H),8.07–7.80(m,1H),7.79–6.95(m,9H),6.58(d,J＝67.0Hz,1H),6.30 –5.93(m,2H),5.53–5.17(m,1H),5.12–3.97(m,3H),3.71(d,J＝49.5Hz,2H),3.34–2.75(m,2H),2.58(d , J＝7.3Hz, 3H), 1.37–0.81 (m, 2H), 0.56 (d, J＝128.5Hz, 2H). ¹³ C NMR (101MHz, CDCl ₃ ) δ169.9,167.4,163.7,156.2,143.4,142.2 ,141.0,135.7,135.3,135.1,135.0,134.8,132.6,132.4,131.5,131.0,130.7,130.3,130.2,129.9,129.6,129.5,128.6,128.3,128.2,127.7, 127.1,127.0,126.4,123.8,123.1 ,122.4,112.9,111.7,108.3,107.3,47.0,46.5,44.9,39.3,34.5,33.7,13.6,13.5,13.2,12.6,9.5,0.1.HRMS(ESI)[MH] ^- calcd for C ₃₂ H ₂₈ Cl ₂ N ₃ O ₆ S:652.1076; found:652.1074.

Example 134

5-(N-(2-((Benzylamino)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate (M15-80 )

According to ethyl 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate ( The method used in M15-69) was to replace pivaldehyde with benzaldehyde, and the other conditions were the same. 260 mg of white solid was obtained, with a yield of 38%.

Example 135

5-(N-(2-((N-benzyl-2-chloroamino)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2 -Ethyl formate (M6-80)

According to 5-(N-(4-chloro-2-((2-chloro-N-neopentylbenzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene The method used for furan-2-carboxylic acid ethyl ester (M6-69), 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl )-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-69) replaced with 5-(N-(2-((benzylamino)methyl)-4-chlorophenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-80), other conditions were the same. 156 mg of white solid was obtained, with a yield of 87%. ¹ H NMR(400MHz,Chloroform-d)δ8.05–7.79(m,1H),7.79–7.61(m,1H),7.56(s,1H),7.48–7.00(m,11H),6.38(dd, J＝75.4,11.9Hz,1H),5.64–4.61(m,2H),4.53(s,1H),4.51–4.30(m,3H),3.96–3.54(m,1H),3.33–2.82(m, 1H),2.55(d,J＝8.1Hz,3H),1.44(td,J＝7.1,2.4Hz,3H),0.92(d,J＝122.9Hz,2H),0.52(d,J＝69.7Hz, 1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ169.6,159.8,159.7,156.0,143.1,143.0,141.0,136.3,135.6,135.5,135.0,134.9,132.4,130.4,129.8,129.4,129 .3,128.7,127.8, 127.6,127.4,127.1,127.0,125.5,125.4,122.4,112.8,112.8,63.6,61.6,61.6,60.6,46.4,41.7,34.1,14.5,14.4,14.1,9.3,9.3.

Example 136

5-(N-(2-((N-benzyl-2-chloroamino)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2 -Carboxylic acid (F44-S80')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(2-((N-benzyl-2-chloroamino)methyl)-4-chlorobenzene) (ethyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-80), and the other conditions were consistent. 116 mg of white solid was obtained, with a yield of 78%. ¹ H NMR(400MHz,Chloroform-d)δ9.31(s,1H),8.09–7.81(m,1H),7.80–6.99(m,13H),6.63–6.20(m,1H),5.69–5.09( m,1H),5.02–4.11(m,3H),3.96–3.52(m,1H),3.32–2.78(m,1H),2.57(d,J＝8.4Hz,3H),1.17–0.34(m, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ170.2,163.6,163.4,156.3,143.0,142.9,140.8,136.0,135.8,135.5,135.2,135.0,132.5,130.6,130.5,129.9,129 .4,129.4,128.8, 128.0,127.7,127.5,127.4,127.2,127.0,122.7,113.0,46.5,9.5,9.5.HRMS(ESI)[MH] ^- calcd for C ₃₃ H ₂₇ Cl ₂ N ₂ O ₆ S:649.0967; found:649.0967.

Example 137

5-(N-(4-Chloro-2-((phenythylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate (M15- 81)

According to 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran The method used for pyran-2-carboxylic acid ethyl ester (M15-69) was to replace pivaldehyde with phenylacetaldehyde, and the other conditions were the same. 520 mg of white solid was obtained, with a yield of 44%.

Example 138

5-(N-(4-chloro-2-((2-chloro-N-phenylethylbenzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzo Furan-2-carboxylic acid ethyl ester (M6-81)

According to 5-(N-(4-chloro-2-((2-chloro-N-neopentylbenzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene The method used for furan-2-carboxylic acid ethyl ester (M6-69), 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl )-3-Methylbenzofuran-2-carboxylic acid ethyl ester (M15-69) replaced with 5-(N-(4-chloro-2-((phenythylamino)methyl)phenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-81), the other conditions were the same. 348 mg of white solid was obtained, with a yield of 87%. ¹ H NMR (400MHz, Chloroform-d) δ8.14–7.83(m,1H),7.80–7.72(m,1H),7.70–7.22(m,6H),7.22–6.76(m,6H),6.35( d,J＝8.5Hz,1H),5.63–4.37(m,4H),4.33–3.28(m,3H),3.28–2.68(m,3H),2.56(d,J＝16.3Hz,3H),1.51 –1.34(m,3H),1.14(t,J＝6.2Hz,2H),0.64(d,J＝78.5Hz,1H). ¹³ C NMR(101MHz, CDCl ₃ )δ169.4,159.7,159.7,156.0,156.0 ,143.1,141.5,138.6,137.8,136.0,135.8,135.5,135.0,133.3,132.5,130.3,130.0,129.7,129.5,129.4,129.0,128.9,128.6,128.0,127.9, 127.7,127.2,127.0,126.5,125.5 ,125.4,122.4,112.9,61.6,50.5,49.0,47.2,46.6,44.0,41.7,34.8,33.3,14.4,13.8,9.4.

Example 139

5-(N-(4-chloro-2-((2-chloro-N-phenylethylbenzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzo Furan-2-carboxylic acid (F44-S81')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-Ethylsulfamoyl)ethyl benzoate (F44-S26) was replaced with 5-(N-(4-chloro-2-((2-chloro-N-phenylethylbenzamido))methyl (base)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-81), and the other conditions were consistent. 218 mg of light yellow solid was obtained, with a yield of 66%. ¹ H NMR (400MHz, Chloroform-d) δ9.77 (s, 1H), 8.20–6.79 (m, 14H), 6.31 (dd, J = 52.0, 7.3Hz, 1H), 5.77–4.43 (m, 2H) ,4.17(d,J＝84.8Hz,1H),3.89–3.27(m,2H),3.26–2.72(m,3H),2.58(d,J＝16.6Hz,3H),1.16(s,2H), 0.67 (d, J=84.3Hz, 1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ170.1,162.8,162.6,156.2,143.0,143.0,141.1,138.4,137.6,135.9,135.5,135.1,133.1,132.3, 130.5 ,130.0,129.7,129.4,129.0,128.8,128.5,128.0,127.7,127.3,127.1,126.6,126.5,122.5,113.0,50.6,49.1,47.1,46.6,44.2,34.7,33.2,1 3.7,12.9,9.4,9.4 .HRMS(ESI)[MH] ^- calcd for C ₃₄ H ₂₉ Cl ₂ N ₂ O ₆ S:663.1123; found:663.1127.

Example 140

5-(N-(2-(((5-bromofuran-2-yl)methyl)amino)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methyl Benzofuran-2-carboxylic acid (F44-S82')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-Ethylsulfamoyl)benzoate ethyl ester (F44-S26) was replaced with 5-(N-(2- ((((5-bromofuran-2-yl)methyl)amino)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl Ester (M15-71), other conditions are the same. 220 mg of white solid was obtained, with a yield of 76%.

Example 141

5-(N-(2-((N-((5-bromofuran-2-yl)methyl)acetamido)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3 -Methylbenzofuran-2-carboxylic acid ethyl ester (M6-83)

According to 5-(N-(2-((N-((5-bromofuran-2-yl)methyl)-2-chlorobenzoylamino)methyl)-4-chlorophenyl)-N- The method used for ethyl sulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-71) was to replace o-chlorobenzoyl chloride with acetyl chloride, and the other conditions were the same. 237 mg of white solid was obtained, with a yield of 73%. ¹ H NMR (400MHz, Chloroform-d) δ7.99 (dd, J＝14.3, 2.0Hz, 1H), 7.77–7.62 (m, 2H), 7.21–7.01 (m, 2H), 6.45–6.18 (m, 3H),5.12(dd,J＝47.2,17.4Hz,1H),4.85–4.26(m,4H),4.02(s,3H),3.16(ddq,J＝19.7,13.6,6.9Hz,1H),2.52 (d, J＝62.9Hz, 5H), 2.11 (d, J＝56.7Hz, 2H), 1.54–1.43 (m, 1H), 1.07 (dt, J＝15.5, 7.1Hz, 3H). ¹³ C NMR ( 101MHz, CDCl ₃ )δ171.4,171.3,160.0,159.6,156.6,156.0,155.9,152.7,152.0,142.9,142.8,141.7,141.1,135.7,135.6,135.1,134.8,133.1,13 2.3,129.4,129.3,129.3,128.4 ,128.3,128.1,127.8,127.5,127.1,127.1,127.0,126.7,125.7,125.6,122.4,122.3,121.8,121.0,112.8,112.2,112.1,111.8,111.8,61.5,5 2.3,48.9,46.9,46.7,45.4 ,44.9,41.8,21.7,21.4,14.3,13.5,13.5,9.3,9.2.

Example 142

5-(N-(2-((N-((5-bromofuran-2-yl)methyl)acetamido)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3 -Methylbenzofuran-2-carboxylic acid (F44-S83')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(2-((N-((5-bromofuran-2-yl)methyl)acetamido) Methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-83), the other conditions were the same. 143 mg of white solid was obtained, with a yield of 46%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.13 (s, 1H), 7.88 (t, J = 9.8 Hz, 1H), 7.78–7.63 (m, 1H), 7.26 (dd, J = 18.6, 7.8 Hz,1H),7.05(d,J＝26.7Hz,1H),6.69–6.55(m,1H),6.45(td,J＝25.5,24.9,2.9Hz,2H),5.04–4.43(m,4H) ,3.95(dp,J＝14.2,6.9Hz,1H),3.22(dt,J＝15.6,8.0Hz,1H),2.58(d,J＝16.8Hz,3H),2.30(d,J＝37.4Hz, 2H), 2.07 (s, 1H), 1.00 (q, J = 6.7Hz, 3H). ¹³ C NMR (101MHz, DMSO) δ170.8, 170.5, 160.7, 155.5, 155.4, 153.1, 152.9, 143.6, 141.6, 141.2, 135.8,135.7,133.7,133.3,132.4,131.9,129.3,129.2,127.9,127.4,127.0,126.8,126.7,126.0,124.6,122.4,122.2,121.1,120.6,113.0,1 12.4,112.3,111.9,111.5,48.5, 46.3,46.2,45.3,45.2,41.7,21.5,21.2,13.3,13.1,9.0.HRMS(ESI)[MH] ^- calcd for C ₂₆ H ₂₃ BrClN ₂ O ₇ S:621.0098; found:621.0098.

Example 143

5-(N-(2-((N-((5-bromofuran-2-yl)methyl)pivaloylamino)methyl)-4-chlorophenyl)-N-ethylsulfamoyl) -Ethyl 3-methylbenzofuran-2-carboxylate (M6-84)

According to 5-(N-(2-((N-((5-bromofuran-2-yl)methyl)-2-chlorobenzoylamino)methyl)-4-chlorophenyl)-N- The method used for ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-71) was to replace o-chlorobenzoyl chloride with pivaloyl chloride, and the other conditions were the same. 293 mg of white solid was obtained, with a yield of 84%. ¹ H NMR (400MHz, Chloroform-d) δ7.98 (d, J＝2.0Hz, 1H), 7.78–7.57 (m, 2H), 7.17 (s, 1H), 7.07 (dd, J＝8.3, 2.4Hz ,1H),6.37–6.22(m,3H),5.49–4.43(m,4H),4.07–3.76(m,4H),3.13(dq,J＝13.6,6.9Hz,1H),2.60(s,3H ),1.57–1.28(m,9H),1.23(d,J＝3.8Hz,2H),1.09(t,J＝7.1Hz,3H). ¹³ C NMR(101MHz, CDCl ₃ )δ178.7,160.3,156.2, 143.0,141.8,135.9,135.2,129.5,128.5,127.7,127.4,125.9,122.4,113.0,112.5,112.1,111.6,110.6,57.4,52.5,47.0,39.4,28.5,14.5,1 3.7,9.5.

Example 144

5-(N-(2-((N-((5-bromofuran-2-yl)methyl)pivaloylamino)methyl)-4-chlorophenyl)-N-ethylsulfamoyl) -3-Methylbenzofuran-2-carboxylic acid (F44-S84')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(2-((N-((5-bromofuran-2-yl)methyl)methyl)pivaloyl Amino)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-84), the other conditions were the same. 30 mg of light yellow solid was obtained, with a yield of 9%.

Example 145

5-(N-(2-((1-((5-bromofuran-2-yl)methyl)-3,3-dimethylureido))methyl)-4-chlorophenyl)-N -Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-85)

According to 5-(N-(2-((N-((5-bromofuran-2-yl)methyl)-2-chlorobenzoylamino)methyl)-4-chlorophenyl)-N- The method used for ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-71) was to replace o-chlorobenzoyl chloride with dimethylcarbamoyl chloride, and the other conditions were the same. 203 mg of white solid was obtained, with a yield of 60%. ¹ H NMR (400MHz, Chloroform-d) δ7.98 (d, J = 2.0Hz, 1H), 7.72 (dd, J = 8.8, 1.5Hz, 1H), 7.65 (d, J = 8.8Hz, 1H), 7.49(d,J＝2.1Hz,1H),7.12–7.03(m,1H),6.39(dd,J＝8.4,2.9Hz,1H),6.35(d,J＝3.2Hz,1H),6.24(d ,J＝3.2Hz,1H),4.79(d,J＝18.1Hz,1H),4.63(d,J＝18.0Hz,1H),4.55–4.08(m,3H),4.07–3.68(m,4H) ,3.17(dq,J＝13.7,6.8Hz,1H),2.92(s,6H),2.60(s,3H),1.47(t,J＝7.1Hz,1H),1.06(t,J＝7.1Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ164.5,160.1,159.7,156.0,153.8,143.1,142.8,142.4,135.8,135.0,133.0,132.9,129.4,129.3,128.5,127.7,127 .4,127.2,127.1, 125.7,125.4,122.3,120.6,112.8,112.3,111.9,61.6,52.3,49.2,46.8,45.1,38.6,14.3,13.5,9.3,9.3.

Example 146

5-(N-(2-((1-((5-bromofuran-2-yl)methyl)-3,3-dimethylureido))methyl)-4-chlorophenyl)-N -Ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S85')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-Ethylsulfamoyl)benzoate ethyl ester (F44-S26) was replaced with 5-(N-(2- ((1-((5-bromofuran-2-yl)methyl)-3,3-dimethylureido))methyl)-4-chlorophenyl)-N-ethylsulfamoyl)- 3-Methylbenzofuran-2-carboxylic acid ethyl ester (M6-85), the other conditions are the same. 162 mg of white solid was obtained, with a yield of 50%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.13 (s, 1H), 7.88 (d, J = 8.7Hz, 1H), 7.68 (d, J = 8.7Hz, 1H), 7.39 (s, 1H) ,7.25(d,J＝8.3Hz,1H),6.62(d,J＝8.5Hz,1H),6.48(d,J＝2.8Hz,1H),6.45–6.25(m,1H),4.56(q, J＝17.6Hz,2H),4.31(dd,J＝75.6,16.1Hz,2H),3.89(dd,J＝13.2,7.0Hz,1H),3.22(dd,J＝13.1,6.7Hz,1H), 2.86 (s, 6H), 2.59 (s, 3H), 0.96 (t, J = 6.9Hz, 3H). ¹³ C NMR (101MHz, DMSO) δ 163.6, 160.7, 155.4, 153.8, 143.4, 142.4, 135.8, 133.4, 132.4,129.4,129.2,127.4,126.9,124.7,122.2,120.4,113.0,112.4,111.6,56.1,48.1,46.2,45.6,18.6,13.3,9.0.HRMS(ESI)[MH] ^- calcd for C ₂₇ H _{2 6} BrClN ₃ O ₇ S: 650.0363; found: 650.0364.

Example 147

5-N(-(2-((N-((5-bromofuran-2-yl)methyl)piperidine-1-carboxamido)methyl)-4-chlorophenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-86)

According to 5-(N-(2-((N-((5-bromofuran-2-yl)methyl)-2-chlorobenzoylamino)methyl)-4-chlorophenyl)-N- The method used for ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-71) was to replace o-chlorobenzoyl chloride with 1-piperidine acid chloride, and the other conditions were the same. 214 mg of white solid was obtained, with a yield of 59%. ¹ H NMR(400MHz,Chloroform-d)δ7.98(s,1H),7.75–7.40(m,3H),7.12–7.02(m,1H),6.45–6.21(m,3H),4.80–4.11( m,3H),4.10–3.66(m,6H),3.56–3.10(m,4H),2.88–1.89(m,5H),1.61(s,4H),1.46(t,J＝7.1Hz,1H) ,1.28(dt,J＝17.7,7.2Hz,1H),1.04(dt,J＝13.7,7.1Hz,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ164.3,160.1,155.9,155.9,155.8,153.8, 143.9,142.8,142.4,135.8,135.6,134.9,134.6,133.0,130.2,129.2,129.2,128.6,127.7,127.5,127.4,127.2,127.0,125.7,122.3,122.2,1 20.6,120.5,112.8,112.8,112.2, 111.8,111.6,109.9,61.5,52.3,49.0,47.9,46.8,46.7,46.0,45.0, 41.7,25.6,24.6,14.3,13.5,13.5,9.3.

Example 148

5-N(-(2-((N-((5-bromofuran-2-yl)methyl)piperidine-1-carboxamido)methyl)-4-chlorophenyl)-N-ethyl Sulfamoyl)-3-methylbenzofuran-2-carboxylic acid (F44-S86')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-N(-(2-((N-((5-bromofuran-2-yl)methyl)piperidine- 1-Carboxylamino)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-86), the other conditions were the same. 158 mg of light yellow solid was obtained, with a yield of 46%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.04(s,1H),7.94–7.55(m,3H),7.22(s,1H),6.66–6.28(m,3H),4.72–3.69(m ,6H),3.21(s,4H),2.55(s,4H),1.22(d,J＝235.9Hz,8H). ¹³ C NMR(101MHz,DMSO)δ163.8,161.8,155.7,154.1,153.1,145.6, 142.8,141.1,136.4,136.3,133.8,133.7,132.6,129.9,129.4,128.5,127.8,127.2,126.8,123.4,122.3,121.5,120.9,113.2,113.0,112.8,1 11.9,48.4,47.8,46.6,46.3, 46.1,44.3,25.7,24.6,13.7,9.5.HRMS(ESI)[MH] ^- calcd for C ₃₀ H ₃₀ BrClN ₃ O ₇ S:690.0676; found:690.0682.

Example 149

5-(N-(2-((N-((5-bromofuran-2-yl)methyl)morpholine-4-carboxamide)methyl)-4-chlorophenyl)-N-ethylamino Sulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-87)

According to 5-(N-(2-((N-((5-bromofuran-2-yl)methyl)-2-chlorobenzoylamino)methyl)-4-chlorophenyl)-N- The method used for ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-71) was to replace o-chlorobenzoyl chloride with 4-morpholinecarbonyl chloride, and the other conditions were the same. 240 mg of white solid was obtained, with a yield of 66%. ¹ H NMR (400MHz, Chloroform-d) δ7.98 (s, 1H), 7.74–7.62 (m, 2H), 7.40 (d, J = 2.1Hz, 1H), 7.11 (dd, J = 8.4, 2.0Hz ,1H),6.43–6.29(m,2H),6.25(d,J＝3.2Hz,1H),4.87(d,J＝18.0Hz,1H),4.69(d,J＝18.0Hz,1H),4.58 –4.08(m,3H),4.08–3.60(m,8H),3.34(s,4H),3.15(dq,J＝13.7,6.8Hz,1H),2.60(s,3H),1.47(t,J =7.1Hz, 1H), 1.07 (t, J = 7.1Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ164.0,160.0,159.6,155.9,153.3,143.0,142.8,141.8,135.9,134.9,132.7, 132.6,129.3,129.2,128.4,127.5,127.4,127.1,127.0,125.6,125.3,122.2,120.7,112.7,112.3,111.9,66.4,61.5,52.3,49.1,47.3,46.7,4 4.5,14.3,13.4,9.3, 9.2.

Example 150

5-(N-(2-((N-((5-bromofuran-2-yl)methyl)morpholine-4-carboxamide)methyl)-4-chlorophenyl)-N-ethylamino Sulfonyl)-3-methylbenzofuran-2-carboxylic acid (F44-S87')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(2-((N-((5-bromofuran-2-yl)methyl)morpholine- 4-Carboxamide)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methyl benzofuran-2-carboxylic acid ethyl ester (M6-87), and the other conditions are consistent. 189 mg of white solid was obtained, with a yield of 54%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.05(s,1H),7.85(d,J＝8.6Hz,1H),7.63(d,J＝8.6Hz,1H),7.35(s,1H) ,7.27(d,J＝8.3Hz,1H),6.61(d,J＝8.4Hz,1H),6.55–6.46(m,1H),6.42(s,1H),4.85–4.53(m,2H), 4.38(dd,J＝84.7,16.1Hz,2H),3.90(dd,J＝12.8,6.8Hz,1H),3.66(s,4H),3.45–3.06(m,5H),2.58(d,J＝ 13.7Hz, 3H), 0.96 (t, J = 6.6Hz, 3H). ¹³ C NMR (101MHz, DMSO) δ163.3,161.7,155.1,153.4,146.5,142.0,136.0,133.4,131.8,129.8,129.4,127.6, 126.8,126.1,121.8,120.6,112.7,112.5,111.8,65.9,48.0,47.1,46.2,45.3,13.3,9.1.HRMS(ESI)[MH] ^- calcd for C ₂₉ H ₂₈ BrClN ₃ O ₈ S:692.0469; found:692.0467.

Example 151

5-(N-(2-((N-((5-bromofuran-2-yl)methyl)furan-2-carboxamide)methyl)-4-chlorophenyl)-N-ethylsulfamate Acyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-88)

According to 5-(N-(2-((N-((5-bromofuran-2-yl)methyl)-2-chlorobenzoylamino)methyl)-4-chlorophenyl)-N- The method used for ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-71) was to replace o-chlorobenzoyl chloride with furancarbonyl chloride, and the other conditions were the same. 261 mg of white solid was obtained, with a yield of 74%. ¹ H NMR(400MHz,Chloroform-d)δ8.09–7.94(m,1H),7.77–7.61(m,2H),7.59–7.00(m,4H),6.74–6.14(m,4H),5.72– 4.08(m,5H),4.06–3.89(m,3H),3.19(s,1H),2.69–1.97(m,4H),1.47(td,J＝7.1,2.4Hz,1H),1.33–1.08( m,3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ160.5,160.0,159.7,156.0,152.4,144.5,143.1,142.8,141.4,135.7,134.9,129.4,129.3,128.3,127.7,127.2,12 7.1,125.7, 125.4,122.4,117.3,113.0,112.8,112.3,111.5,61.5,52.3,46.8,41.6,14.3,14.1,13.5,9.3,9.3.

Example 152

5-(N-(2-((N-((5-bromofuran-2-yl)methyl)furan-2-carboxamide)methyl)-4-chlorophenyl)-N-ethylsulfamate acyl methyl)-3-methylbenzofuran-2-carboxylic acid (F44-S88')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(2-((N-((5-bromofuran-2-yl)methyl)furan-2) -Carboxamide)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-88), the other conditions were the same. 91 mg of white solid was obtained, with a yield of 27%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.09 (s, 1H), 7.95–7.75 (m, 2H), 7.66 (d, J = 8.4Hz, 1H), 7.34–7.01 (m, 3H), 6.77–6.56(m,2H),6.47(d,J＝18.9Hz,2H),4.88(s,4H),3.94(dd,J＝12.6,6.8Hz,1H),3.23(dd,J＝12.2, 6.3Hz, 1H), 2.57 (d, J = 18.5Hz, 3H), 1.01 (t, J = 6.2Hz, 3H). ¹³ C NMR (101MHz, DMSO) δ 161.4, 159.8, 155.2, 152.6, 146.5, 145.7, 145.6,141.1,135.8,133.3,131.8,129.6,129.3,127.7,126.3,122.4,121.9,116.8,112.8,112.5,111.7,46.3,13.3,9.0.HRMS(ESI)[MH] ^- calcd for C _{2 9} H ₂₃ BrClN ₂ O ₈ S:673.0047; found:673.0052.

Example 153

5-(N-(2-((N-((5-bromofuran-2-yl)methyl)thiophene-2-carboxamide)methyl)-4-chlorophenyl)-N-ethylsulfamate Acyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-89)

According to 5-(N-(2-((N-((5-bromofuran-2-yl)methyl)-2-chlorobenzoylamino)methyl)-4-chlorophenyl)-N- The method used for ethyl sulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-71), o-chlorobenzyl The acid chloride was replaced with thiophenecarboxylic acid chloride, and the remaining conditions were the same. 300 mg of white solid was obtained, with a yield of 83%. ¹ H NMR(400MHz,Chloroform-d)δ8.00(s,1H),7.75–7.44(m,3H),7.34(s,1H),7.27–6.88(m,2H),6.54–6.13(m, 3H),5.77–4.08(m,5H),4.01(s,3H),3.16(dq,J＝13.3,6.2Hz,1H),2.60(s,4H),1.47(td,J＝6.9,3.1Hz ,1H),1.17(dt,J=70.3,7.2Hz,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ165.0,160.0,159.6,156.5,155.9,142.8,141.1,136.8,135.8,135.0,130.1,129.3 ,129.3,129.2,128.5,127.9,127.3,127.2,127.1,125.7,125.4,122.3,121.3,112.8,112.3,112.3,111.9,110.2,67.9,61.5,57.0,52.3,46.7 ,14.3,13.5,9.3,9.3 .

Example 154

5-(N-(2-((N-((5-bromofuran-2-yl)methyl)thiophene-2-carboxamide)methyl)-4-chlorophenyl)-N-ethylsulfamate Acyl)-3-methylbenzofuran-2-carboxylic acid (F44-S89')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(2-((N-((5-bromofuran-2-yl)methyl)thiophene-2) -Carboxamide)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-89), the other conditions were the same. 213 mg of light yellow solid was obtained, with a yield of 62%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.12 (s, 1H), 8.01–7.53 (m, 4H), 7.36–7.13 (m, 3H), 6.66 (d, J = 7.4Hz, 1H), 6.49(d,J＝9.7Hz,2H),5.50–4.65(m,4H),4.10–3.77(m,1H),3.23(dd,J＝13.1,6.9Hz,1H),2.62(s,3H) ,1.00(s,3H). ¹³ C NMR(101MHz,DMSO)δ164.1,161.3,155.3,152.4,145.2,140.9,137.0,135.8,133.5,131.8,130.8,129.6,129.4,129.2,127.9,127 .6,126.5, 126.4,123.1,122.1,121.0,112.8,112.5,112.3,46.3,13.3,9.1.HRMS(ESI)[MH] ^- calcd for C ₂₉ H ₂₃ BrClN ₂ O ₇ S ₂ :688.9819; found:688.9825.

Example 155

5-(N-(4-chloro-2-(((furan-2-ylmethyl)amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2 -Ethyl formate (M16)

According to ethyl 5-(N-(4-chloro-2-((neopentylamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate ( The method used in M15-69) was to replace pivaldehyde with furfural, and the other conditions were the same. 2.46g of white solid was obtained, with a yield of 74%.

Example 156

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene Furan-2-carboxylic acid ethyl ester (M6-90)

According to 5-(N-(2-((N-((5-bromofuran-2-yl)methyl)acetamido)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)- The method used for 3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-83), 5-(N-(2-(((5-bromofuran-2-yl)methyl)amino)methyl )-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M15-71) was replaced with 5-(N-(4-chloro-2- (((furan-2-ylmethyl)amino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M16), all other conditions are the same . 230 mg of white solid was obtained, with a yield of 80%. ¹ H NMR(400MHz,Chloroform-d)δ7.98(d,J＝14.2Hz,1H),7.77–7.62(m,2H),7.37(d,J＝38.2Hz,1H),7.20–6.99(m ,2H),6.45–6.21(m,3H),5.09(dd,J＝52.4,17.5Hz,1H),4.88–4.39(m,5H),3.98(ddd,J＝25.4,12.7,7.7Hz,1H ),3.16(ddq,J＝32.3,13.5,6.8Hz,1H),2.60(s,3H),2.30(d,J＝104.4Hz,3H),1.46(t,J＝7.1Hz,3H),1.05 (T, J = 6.9Hz, 3H). ¹³ C NMR (101MHz, CDCL ₃ ) Δ171.4,171.3,159.5,155.9,150.4,149.9,142.9.5,142.8.8,141.2,13 5.6, 135.5,135.1,134.7,133.0,132.1,129.3,129.2,128.3,128.2,127.9,127.7,127.3,127.0,126.9,126.6,125.3,125.2,122.2,122.2,112.7,1 12.7,110.3,110.3,108.9,108.7, 61.5,61.4,48.6,46.7,46.5,45.6,45.1,41.7,21.6,21.4,14.2,13.4,13.3,9.2.

Example 157

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene Furan-2-carboxylic acid (F44-S90')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)) Methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-90), the other conditions were the same. 206 mg of white solid was obtained, with a yield of 95%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.11 (s, 1H), 7.88 (d, J = 9.0Hz, 1H), 7.63 (d, J = 39.0Hz, 2H), 7.28 (dd, J = 18.9,8.5Hz,1H),7.11(d,J＝29.6Hz,1H),6.62(d,J＝8.1Hz,1H),6.40(t,J＝21.3Hz,2H),5.06–4.45(m, 4H),3.96(s,1H),3.24(s,1H),2.61(s,3H),2.38(s,2H),2.08(s,1H),1.00(s,3H). ¹³ C NMR(101MHz ,DMSO)δ171.0,170.6,161.3,155.3,150.7,150.5,145.1,143.1,142.6,141.8,141.3,135.9,135.8,133.8,133.4,132.3,131.7,129.6,129.3,12 8.0,127.5,126.9,126.5,126.1 ,123.2,122.2,122.0,112.9,110.6,108.8,108.5,48.4,46.4,45.3,45.1,41.6,21.6,21.3,13.3,13.2,9.1.HRMS(ESI)[MH] ^- calcd for C ₂₆ H ₂₄ ClN ₂ O ₇ S:543.0993; found:543.0995.

Example 158

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)pivalamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Benzofuran-2-carboxylic acid ethyl ester (M6-91)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90) was to replace acetyl chloride with pivaloyl chloride, and the other conditions were the same. 190 mg of white solid was obtained, with a yield of 62%. ¹ H NMR (400MHz, Chloroform-d) δ7.97 (s, 1H), 7.74–7.59 (m, 2H), 7.34 (s, 1H), 7.19 (s, 1H), 7.07 (d, J = 8.2Hz ,1H),6.45–6.29(m,2H),6.26(s,1H),5.57–3.85(m,7H),3.14(dq,J＝13.4,6.7Hz,1H),2.60(s,3H), 1.46 (t, J=7.1Hz, 3H), 1.38 (s, 8H), 1.26 (s, 1H), 1.05 (t, J=7.1Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 159.7, 156.0 ,143.1,142.1,141.8,135.7,135.0,129.4,128.4,127.4,127.1,125.4,122.2,112.8,110.4,108.5,61.6,46.8,39.2,28.4,14.3,13.4,9.3.

Example 159

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)pivalamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Benzofuran-2-carboxylic acid (F44-S91')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl))pivalamido) )methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-91), the other conditions were the same. 158 mg of white solid was obtained, with a yield of 90%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.05 (s, 1H), 7.85 (d, J = 8.4Hz, 1H), 7.62 (d, J = 11.5Hz, 2H), 7.26 (d, J = 7.4Hz,1H),7.06(s,1H),6.62(d,J＝8.2Hz,1H),6.41(s,1H),6.29(s,1H),5.18–4.80(m,2H),4.73– 4.28(m,2H),3.90(dd,J＝13.4,7.0Hz,1H), 3.20(dd,J=13.6,7.0Hz,1H),2.59(s,3H),1.32(s,9H),0.94(s,3H). ¹³ C NMR(101MHz,DMSO)δ177.1,161.6,155.2,150.6 H RMS(ESI)[MH] ^- calcd for C ₂₉ H ₃₀ ClN ₂ O ₇ S:585.1462; found:585.1465.

Example 160

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)pentanolamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene Furan-2-carboxylic acid ethyl ester (M6-92)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90) was to replace acetyl chloride with n-valeryl chloride, and the other conditions were the same. 160 mg of white solid was obtained, with a yield of 93%. ¹ H NMR (400MHz, Chloroform-d) δ7.99 (d, J＝12.7Hz, 1H), 7.78–7.60 (m, 2H), 7.44–7.29 (m, 1H), 7.14 (s, 1H), 7.06 (dd,J＝24.9,8.4Hz,1H),6.43–6.22(m,3H),5.11(dd,J＝48.1,17.6Hz,1H),4.89–4.36(m,4H),4.04–3.88(m ,2H),3.16(ddq,J＝33.5,13.5,6.9Hz,1H),2.70(td,J＝7.4,3.3Hz,1H),2.60(s,3H),2.35(hept,J＝7.6Hz, 1H), 2.19–1.24 (m, 7H), 1.06 (t, J＝6.2Hz, 3H), 0.94 (dt, J＝31.5, 7.3Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 174.0, 174.0 ,160.0,159.7,159.6,156.0,155.9,150.7,150.1,143.1,143.0,142.9,142.5,142.1,142.1,141.6,135.7,135.6,135.1,134.8,133.2,132.3, 129.4,129.3,129.2,128.5,128.3 ,127.9,127.7,127.3,127.2,127.1,127.0,126.8,125.6,125.4,125.3,122.3,122.3,112.8,112.8,110.4,110.4,108.8,108.7,61.5,61.5,52 .3,47.8,46.9,46.6,45.4 ,45.0,42.0,32.7,27.3,27.3,22.5,22.3,14.3,13.8,13.8,13.5,13.3,9.3,9.2.

Example 161

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)pentanolamino)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene Furan-2-carboxylic acid (F44-S92')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)valeramide)) Methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-92), other conditions were consistent. 141 mg of white solid was obtained, with a yield of 92%. ¹ H NMR (400MHz, Chloroform-d) δ7.95(d,J＝6.7Hz,1H),7.64(d,J＝15.6Hz,2H),7.35(d,J＝38.7Hz,1H),7.19– 6.95(m,2H),6.42–6.02(m,3H),5.25–4.38(m,6H),3.12(ddd,J＝28.0,12.9,6.7Hz,1H),2.84–2.68(m,1H), 2.60(d,J＝7.4Hz,3H),2.39(p,J＝7.6Hz,1H),1.73(dp,J＝30.0,7.5Hz,2H),1.40(ddq,J＝40.3,14.5,7.2Hz ,2H),1.04(t,J＝6.9Hz,2H),0.92(dt,J＝32.3,7.3Hz,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ175.1,156.1,156.0,150.4,149.7,144.4 ,142.8,142.4,141.7,141.3,135.8,135.7,135.3,134.9,132.9,132.1,129.8,129.7,128.3,127.9,127.6,126.9,125.3,122.4,112.9,110.5, 109.2,109.0,48.2,46.9,46.7 ,45.7,45.1,42.4,32.9,27.6,27.5,22.6,22.4,13.9,13.9,13.5,13.5,9.4.HRMS(ESI)[MH] ⁺ calcd for C ₂₉ H ₃₀ ClN ₂ O ₇ S:585.1462; found :585.1465.

Example 162

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acrylamide)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene Furan-2-carboxylic acid ethyl ester (M6-93)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90), replacing acetyl chloride with acryloyl chloride, All other conditions are the same. 101 mg of white solid was obtained, with a yield of 91%. ¹ H NMR (400MHz, Chloroform-d) δ7.99 (d, J = 12.7Hz, 1H), 7.73 (dd, J = 14.4, 9.2Hz, 1H), 7.65 (d, J = 8.9Hz, 1H), 7.37(d,J＝36.0Hz,1H),7.16(s,1H),7.12–7.02(m,1H),7.02–6.29(m,5H),5.90–5.67(m,1H),5.20(dd, J＝57.4,17.6Hz,1H),4.91–4.45(m,3H),4.02(s,4H),3.16(ddq,J＝33.3,13.5,6.8Hz,1H),2.60(s,3H),1.26 (s, 1H), 1.07 (t, J = 7.0Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 167.3, 167.1, 160.1, 156.1, 150.4, 149.9, 143.0, 142.8, 142.4, 141.8, 141.5, 135.8 ,135.5,135.3,135.0,133.3,132.4,129.9,129.4,129.2,128.5,128.2,128.1,127.9,127.6,127.3,127.0,125.7,122.5,112.9,110.5,109.2, 108.9,52.4,47.9,47.0,46.7 ,46.0,45.0,42.5,29.7,13.5,13.4,9.3.

Example 163

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acrylamide)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene Furan-2-carboxylic acid (F44-S93')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acrylamide)) Methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-93), other conditions were consistent. 66 mg of white solid was obtained, with a yield of 69%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.08 (s, 1H), 7.86 (d, J = 8.7Hz, 1H), 7.77–7.49 (m, 2H), 7.31–7.19 (m, 1H), 7.09(d,J＝18.9Hz,1H),6.58(t,J＝8.4Hz,1H),6.36(t,J＝28.0Hz,2H),5.03–4.50(m,4H),3.90(dd,J ＝12.9,6.9Hz,1H),3.71(t,J＝5.9Hz,1H),3.49(q,J＝6.9Hz,1H),3.20(tt,J＝11.9,6.8Hz,1H),2.89(t ,J＝6.0Hz,1H),2.57(s,3H),0.96(t,J＝6.9Hz,3H). ¹³ C NMR(101MHz,DMSO)δ171.6,171.1,161.0,155.3,150.6,150.5,144.5, 143.1,142.6,141.6,141.2,135.9,135.6,133.6,133.3,132.3,129.4,129.3,127.5,126.7,126.6,123.7,122.2,122.1,112.9,110.5,108.7,1 08.4, 66.4,66.0,65.6,65.4,47.3,46.3,45.1,44.4,41.7,32.9,15.1,15.1,13.3,13.1,9.0.HRMS(ESI)[MH] ⁺ calcd for C ₂₇ H ₂₄ ClN ₂ O ₇ S: 555.0993; found:555.0989.

Example 164

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)methacrylamide)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Ethyl benzofuran-2-carboxylate (M6-94)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90) was to replace acetyl chloride with methacryloyl chloride, and the other conditions were the same. 107 mg of white solid was obtained, with a yield of 94%. ¹ H NMR (400MHz, Chloroform-d) δ7.98 (s, 1H), 7.70 (s, 1H), 7.64 (d, J = 8.7Hz, 1H), 7.38 (s, 1H), 7.29–6.93 (m ,2H),6.44–6.23(m,3H),5.42–4.30(m,6H),4.02(s,3H),3.93(dd,J＝12.9,7.1Hz,1H),3.16(s,1H), 2.59(s,3H),2.31–0.78(m,8H). ¹³ C NMR (101MHz, CDCl ₃ ) δ173.5,160.2,156.1,142.9,141.8,135.7,129.4,128.6,127.3,125.8,122.5,112.9,110. 5 ,109.2,52.4,46.9,20.8,13.4,9.4.

Example 165

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)methacrylamide)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Benzofuran-2-carboxylic acid (F44-S94')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)methacrylamide) (methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzene and furan-2-carboxylic acid ethyl ester (M6-94), and the other conditions are the same. 73 mg of white solid was obtained, with a yield of 72%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.15–8.02(m,1H),7.85(d,J＝8.6Hz,1H),7.73–6.88(m,4H),6.71–6.19(m,3H ),5.57–4.28(m,6H),3.88(dq,J＝14.3,7.3Hz,1H),3.30–3.07(m,1H),2.57(d,J＝3.1Hz,3H),2.51(s, 1H),2.00(s,2H),1.04–0.90(m,3H). ¹³ C NMR(101MHz,DMSO)δ177.8,172.3,161.1,155.2,150.0,145.0,141.3,139.9,135.8,129.5,129.3,127.9 ^found _{_} _{_} _{_} _{_} :569.1151.

Example 166

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)-2,2-dimethylpropionamido)methyl)phenyl)-N-ethylsulfamate Acyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-95)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90) was to replace acetyl chloride with chloropivaloyl chloride, and the other conditions were the same. 168 mg of white solid was obtained, with a yield of 92%. ¹ H NMR (400MHz, Chloroform-d) δ7.97 (s, 1H), 7.66 (q, J = 8.9Hz, 2H), 7.31 (d, J = 30.3Hz, 2H), 7.09 (d, J = 8.1 Hz,1H),6.41–6.24(m,3H),5.81–4.28(m,5H),4.27–3.89(m,3H),3.86(d,J＝11.0Hz,1H),3.75(d,J＝ 11.0Hz,1H),3.13(dq,J＝13.6,6.8Hz,1H),2.60(s,3H),1.47(d,J＝6.6Hz,8H),1.05(t,J＝7.3Hz,3H) . ¹³ C NMR (101MHz, CDCl ₃ ) δ175.4,160.1,159.7,156.0,150.3,143.1,142.9,142.2,141.2,135.7,135.1,129.4,129.3,128.3,127.6,127.3,127.2, 127.1,125.7,125.4, 122.3,122.2,112.8,110.5,108.9,61.6,54.0,52.3,48.0,46.8,44.5,24.1,23.6,14.3,13.4,9.3,9.3.

Example 167

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)-2,2-dimethylpropionamido)methyl)phenyl)-N-ethylsulfamate Acyl)-3-methylbenzofuran-2-carboxylic acid (F44-S95')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl))-2,2 -Dimethylpropionamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-95), other conditions were the same. 149 mg of white solid was obtained, with a yield of 93%. ¹ H NMR (400MHz, Chloroform-d) δ7.92 (s, 1H), 7.63 (s, 2H), 7.37–7.19 (m, 2H), 7.07 (d, J = 6.8Hz, 1H), 6.32 (dd ,J＝19.6,5.5Hz,3H),5.39(s,1H),5.20–4.53(m,4H),3.81(dd,J＝39.0,10.6Hz,2H),3.09(s,1H),2.58( s,3H),1.48(s,6H),1.02(s,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ175.9,164.5,156.0,150.1,144.6,142.4,141.0,135.8,135.1,132.2,129.7, 128.4,127.8,127.3,126.9,125.2,122.2,112.9,110.6,109.1,54.0,48.1,46.8,44.7,24.2,23.8,13.4,9.4.HRMS(ESI)[MH] ⁺ calcd for C ₂₉ H ₂₉ Cl ₂ N ₂ O ₇ S:619.1073; found:619.1075.

Example 168

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Ethyl benzofuran-2-carboxylate (M6-96)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90) was to replace acetyl chloride with cyclopropylformyl chloride, and the other conditions were the same. 162 mg of white solid was obtained, with a yield of 97%. ¹ H NMR(400MHz,Chloroform-d)δ7.98(d,J＝12.3Hz,1H),7.80–7.60(m,2H),7.36(d,J＝40.0Hz,1H),7.28–7.00(m ,2H),6.46–6.18(m,3H),5.23(dd,J＝147.6,17.6Hz,1H),4.80 (ddd,J＝22.4,17.4,8.0Hz,2H),4.46(dd,J＝15.2,8.9Hz,2H),4.06–3.88(m,2H),3.16(ddq,J＝33.5,13.7,6.8Hz ,1H),2.59(s,3H),1.46(t,J＝7.1Hz,2H),1.34–0.98(m,7H),0.90(s,1H),0.79(d,J＝7.0Hz,1H) . ¹³ C NMR (101MHz, CDCl ₃ ) δ174.5,174.4,160.0,159.7,156.0,156.0,150.7,150.4,143.1,143.1,142.5,142.2,142.1,141.8,135.7,135.5,135.1, 134.8,133.2,132.4, 129.4,129.3,128.5,128.1,127.9,127.7,127.4,127.3,127.1,127.0,125.6,125.3,122.3,112.8,110.4,110.4,108.9,108.5,61.6,52.3,48. 0,46.9,46.6,46.0,44.9, 42.6,31.8,29.6,29.6,22.6,14.3,13.5,13.4,11.5,11.4,9.3,9.2,8.4,8.2,7.9.

Example 169

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Benzofuran-2-carboxylic acid (F44-S96')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl))cyclopropanecarboxamide (methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-96), and the other conditions were consistent. 122 mg of white solid was obtained, with a yield of 79%. ¹ H NMR (400MHz, Chloroform-d) δ7.81 (d, J＝8.5Hz, 1H), 7.70–7.42 (m, 2H), 7.40–7.13 (m, 2H), 7.07–6.94 (m, 1H) ,6.31(d,J＝9.8Hz,2H),6.25(s,1H),5.48–4.37(m,5H),3.06(s,1H),2.46(d,J＝20.4Hz,3H),1.26( s,2H),1.11(s,1H),1.05–0.95(m,3H),0.90(s,1H),0.84–0.65(m,1H). ¹³ C NMR(101MHz, CDCl ₃ )δ175.1,155.8, 155.6,150.6,150.0,142.8,142.4,141.6,135.8,135.7,135.2,134.9,132.1,129.9,127.8,127.3,126.6,112.9,110.6,110.5,109.2,108.7,4 8.2,46.8,46.3,45.1,42.9, 32.0,29.8,29.4,22.8,14.2,13.5,11.7,11.6,9.3,8.5.HRMS(ESI)[MH] ⁺ calcd for C ₂₈ H ₂₆ ClN ₂ O ₇ S:569.1149; found:569.1153.

Example 170

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclobutanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3- Methylbenzofuran-2-carboxylic acid ethyl ester (M6-97)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90) was to replace acetyl chloride with cyclobutylformyl chloride, and the other conditions were the same. 162 mg of white solid was obtained, with a yield of 94%. ¹ H NMR(400MHz,Chloroform-d)δ7.98(d,J＝6.6Hz,1H),7.76–7.68(m,1H),7.68–7.61(m,1H),7.35(d,J＝35.9Hz ,1H),7.15–6.98(m,2H),6.43–6.16(m,3H),5.04(dd,J＝26.4,17.6Hz,1H),4.94–4.25(m,4H),4.03–3.89(m ,2H),3.79–3.03(m,2H),2.60(d,J＝4.9Hz,3H),2.57–1.78(m,7H),1.46(t,J＝7.1Hz,2H),1.06(q, J=6.6Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ175.5,175.3,160.0,159.7,159.6,156.0,155.9,150.7,150.0,143.1,143.0,142.9,142.5,142.1,142.1,141 .6,135.6 ,135.6,135.1,134.8,133.2,132.3,129.4,129.3,129.2,128.5,128.2,127.6,127.6,127.2,127.1,127.0,126.9,125.7,125.6,125.4,125.3, 122.3,112.8,112.8,110.4,110.3 ,108.7,61.6,61.5,52.3,47.2,46.9,46.6,45.4,44.5,41.8,37.1,36.9,25.6,25.5,24.8,24.7,18.0,17.8,14.3,13.5,13.3,9.3.

Example 171

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclobutanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3- Methylbenzofuran-2-carboxylic acid (F44-S97')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethyl The method used for sulfamoyl)benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl) ethyl)phenyl)-N-ethylsulfamoyl)benzoate (F44-S26) was replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)) Cyclbutanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-97), the other conditions were the same. 151 mg of white solid was obtained, with a yield of 98%. ¹ H NMR (400MHz, Chloroform-d) δ7.90 (d, J = 6.1Hz, 1H), 7.63 (d, J = 12.4Hz, 2H), 7.33 (d, J = 33.2Hz, 1H), 7.14– 6.94(m,2H),6.60–6.20(m,3H),5.12–4.24(m,6H),3.51(dp,J＝171.5,9.1,8.6Hz,1H),3.23–2.95(m,1H), 2.51(dd,J＝32.4,13.4Hz,4H),2.41–2.15(m,2H),2.04(dd,J＝18.6,8.8Hz,1H),1.93(dt,J＝17.5,9.5Hz,1H) ,1.17–0.81(m,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ176.2,176.1,156.0,155.8,150.5,149.6,145.1,142.8,142.3,141.7,141.4,135.7,135.2,134.9,13 2.7,132.1 ,129.8,129.7,128.3,127.8,127.5,126.9,124.7,122.2,112.9,110.6,110.5,109.0,108.9,47.4,46.7,45.6,44.6,42.1,37.3,37.0,25.7,25 .2,24.9,18.1,17.9 ,13.5,13.4,9.4.HRMS(ESI)[MH] ⁺ calcd for C ₂₉ H ₂₈ ClN ₂ O ₇ S:583.1306; found:583.1318.

Example 172

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopentanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3- Methylbenzofuran-2-carboxylate (M6-98)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90) was to replace acetyl chloride with cyclopentylformyl chloride, and the other conditions were the same. 158 mg of white solid was obtained, with a yield of 90%. ¹ H NMR(400MHz,Chloroform-d)δ7.98(d,J＝9.7Hz,1H),7.77–7.60(m,2H),7.36(d,J＝37.1Hz,1H),7.19–6.98(m ,2H),6.45–6.19(m,3H),5.15(dd,J＝81.2,17.6Hz,1H),4.93–4.31(m,4H),4.03–3.87(m,2H),3.41–2.78(m ,2H),2.60(d,J＝3.4Hz,3H),2.13–1.50(m,9H),1.46(t,J＝7.1Hz,2H),1.05(q,J＝6.6Hz,3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ177.4,177.3,160.1,159.7,159.7,156.0,156.0,150.8,150.2,143.2,143.1, 142.9,142.6,142.1,141.9,135.7,135.6,135.1,134.8,133.4,133.3,132.5,132.4,129.4,129.4,129.3,128.6,128.2,127.7,127.3,127.1,1 27.0,125.7,125.4,125.4,122.4, 122.3,112.8,112.8,110.5,110.4,108.7,108.6,61.6,61.5,52.3,47.7,46.9,46.7,45.6,44.9,42.2,41.2,41.0,31.1,30.9,30.5,30.4,26.3 ,26.2,26.1, 14.3,13.5,13.3,9.3.

Example 173

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopentanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3- Methylbenzofuran-2-carboxylic acid (F44-S98')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl))cyclopentanemethyl Amido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-98), the other conditions were the same. 145 mg of white solid was obtained, with a yield of 96%. ¹ H NMR (400MHz, Chloroform-d) δ7.93 (s, 1H), 7.65 (s, 2H), 7.34 (d, J = 38.0Hz, 1H), 7.20–6.94 (m, 2H), 6.41–6.29 (m,2H),6.27(s,1H),5.36–4.66(m,5H),4.58(s,1H),3.46–2.67(m,2H),2.66–1.49(m,10H),1.03(t , J=6.3Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ178.2,178.1,164.2,156.0,155.9,150.6,149.8,144.8,142.8,142.3,141.8,141.7,135.8,135.7,135.2,1 34.9, 132.8,132.1,129.8,129.7,128.3,127.9,127.5,127.0,125.0,122.3,112.9,110.6,110.5,109.0,108.9,47.9,46.9,46.7,45.8,45.1,42.5,4 1.4,41.2,31.1,30.9, 30.6,26.3,26.2,13.5,13.4,9.4.HRMS(ESI)[MH] ⁺ calcd for C ₃₀ H ₃₀ ClN ₂ O ₇ S:597.1462; found:597.1469.

Example 174

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclohexanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3- Methylbenzofuran-2-carboxylate (M6-99)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90) was to replace acetyl chloride with cyclohexylformyl chloride, and the other conditions were the same. 132 mg of white solid was obtained, with a yield of 99%. ¹ H NMR (400MHz, Chloroform-d) δ7.99 (dd, J＝7.3, 1.8Hz, 1H), 7.72 (ddd, J＝17.2, 8.8, 1.9Hz, 1H), 7.65 (dd, J＝8.8, 5.9Hz,1H),7.43–7.29(m,1H),7.17–6.97(m,2H),6.43–6.18(m,3H),5.13(dd,J＝64.0,17.6Hz,1H),4.90–4.32 (m,3H),4.02(s,4H),3.15(ddq,J＝36.1,13.6,6.9Hz,1H),3.00–2.37(m,4H),2.02–1.16(m,11H),1.06(td , J=7.1, 3.5Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ177.2,160.2,160.1,156.1,156.0,150.8,150.2,142.9,142.8,142.7,142.2,142.1,135.7,135.6,135 .2, 134.9,133.4,132.4,129.4,129.3,128.6,128.2,127.8,127.7,127.3,127.2,126.9,125.8,125.7,122.4,112.9,110.5,110.4,108.7,108.7,5 2.4,47.6,47.0,46.7,45.3, 44.9,42.1,40.8,40.6,30.0,29.8,29.4,29.3,26.0,25.8,25.7,25.6,13.6,13.4,9.3.

Example 175

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclohexanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3- Methylbenzofuran-2-carboxylic acid (F44-S99')

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl))cyclohexanemethyl) Amido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-99), other conditions were the same. 99 mg of white solid was obtained, with a yield of 85%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.08 (d, J = 5.3Hz, 1H), 7.86 (d, J = 8.7Hz, 1H), 7.77–7.39 (m, 2H), 7.23 (td, J＝10.5,8.5,5.4Hz,1H),6.96(s,1H),6.57(t,J＝8.2Hz,1H),6.49–6.16(m,2H),5.11–4.44(m,4H),3.92 (ddq,J＝20.6,14.4,7.3,6.8Hz,1H),3.43–3.11(m,1H),2.95(t,J＝10.3Hz,1H),2.57(s,3H),1.90–1.52(m ,5H),1.41(tt,J＝26.1,12.1Hz,3H),1.28–1.03(m,2H),0.96(q,J＝7.2Hz,3H). ¹³ C NMR(101MHz,DMSO)δ176.2,175.7 ,161.1,155.3,155.2,150.7,150.6,144.8,143.1,142.6,141.8,135.8,135.6,133.5,133.2,132.3,131.5,129.5,129.4,129.3,127.8,127.3, 126.6,126.4,126.0,123.3,122.1 ,122.0,112.9,110.5,110.5,108.6,108.3,47.4,46.2,45.2,44.5,41.8,29.4,29.4,29.3,29.1,25.5,25.4,25.1,13.3,13.1,9.0.HRMS(ESI)[MH] ⁺ calcd for C ₃₁ H ₃₂ ClN ₂ O ₇ S:611.1619; found:611.1624.

Example 176

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)-3,3-dimethylureido)methyl)phenyl)-N-ethylsulfamoyl )-3-Methylbenzofuran-2-carboxylic acid ethyl ester (M6-100)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90) was to replace acetyl chloride with dimethylcarbamoyl chloride, and the other conditions were the same. 175 mg of white solid was obtained, with a yield of 58%. ¹ H NMR (400MHz, Chloroform-d) δ7.97 (s, 1H), 7.76–7.67 (m, 1H), 7.64 (d, J = 8.7Hz, 1H), 7.50–7.43 (m, 1H), 7.34 (s,1H),7.11–7.01(m,1H),6.39(d,J＝8.4Hz,1H),6.34–6.22(m,2H),4.77–4.61(m,2H),4.60–4.39(m ,3H),4.18(d,J＝15.7Hz,1H),3.90(dq,J＝14.4,7.2Hz,1H),3.18(dq,J＝13.7,6.8Hz,1H),2.93(s,6H) ,2.59(s,3H),1.46(t,J＝7.1Hz,3H),1.03(t,J＝7.1Hz,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ164.6,159.7,155.9,151.3,143.0 ,142.6,142.0,135.6,134.8,133.0,129.3,128.6,127.8,127.2,127.0,125.4,122.2,112.7,110.4,108.7,61.5,48.8,46.7,45.4,38.6,14.3, 13.3,9.3.

Example 177

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)-3,3-dimethylureido)methyl)phenyl)-N-ethylsulfamoyl )-3-methylbenzofuran-2-carboxylic acid (F44-S100)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl))-3,3 -Dimethylureido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-100), other conditions were the same. 138 mg of white solid was obtained, with a yield of 83%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.97 (s, 1H), 7.80 (d, J = 8.6Hz, 1H), 7.59 (s, 2H), 7.35 (s, 1H), 7.24 (d, J＝7.9Hz,1H),6.59(d,J＝8.4Hz,1H),6.40(s,1H),6.30(s,1H),4.51(s,2H),4.44(d,J＝16.0Hz, 1H),4.20(d,J＝15.9Hz,1H),3.84(dq,J＝14.7,7.5Hz,1H),3.20(dq,J＝13.7,6.8Hz,1H),2.86(s,6H), 2.57(s,3H),0.92(s,3H). ¹³ C NMR(101MHz,DMSO)δ163.7,162.4,154.9,151.2,148.2,142.6,142.6,135.9,133.2,131.7,130.0,129.5,127.3,126.9 , 125.5,121.4,120.0,112.5,110.5,108.5,47.8,46.1,45.7,38.2,13.2,9.0.HRMS(ESI)[MH] ^- calcd for C ₂₇ H ₂₇ ClN ₃ O ₇ S:572.1258; found:572.1263.

Example 178

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)piperidin-1-carboxamido)methyl)phenyl)-N-ethylsulfamoyl)- 3-Methylbenzofuran-2-carboxylic acid ethyl ester (M6-101)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Method used for benzofuran-2-carboxylic acid ethyl ester (M6-90), replacing acetyl chloride with 1-pipericomoyl Chlorine, other conditions are the same. 195 mg of white solid was obtained, with a yield of 61%. ¹ H NMR (400MHz, Chloroform-d) δ7.94 (s, 1H), 7.67 (d, J = 10.1Hz, 1H), 7.60 (t, J = 6.4Hz, 1H), 7.36 (d, J = 8.9 Hz,1H),7.29(d,J＝8.5Hz,1H),7.02(d,J＝8.3Hz,1H),6.36(d,J＝8.4Hz,1H),6.28(d,J＝10.2Hz, 1H),6.23(d,J＝9.5Hz,1H),4.84–4.49(m,2H),4.45(q,J＝7.0Hz,2H),4.18–3.79(m,4H),3.29(s,3H ), 3.16 (dd, J＝13.5, 6.3Hz, 2H), 2.56 (s, 3H), 1.68–1.38 (m, 8H), 0.99 (q, J＝7.0Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ164.5,160.1,159.8,156.0,153.5,151.4,144.0,143.0,142.8,142.7,142.0,141.9,135.7,135.6,134.8,134.7,133.2,130.4,129.3,12 9.3,128.7,127.9,127.5,127.2 ,127.1,127.0,125.8,125.5,122.3,112.8,112.8,110.4,110.2,108.5,107.2,61.6,52.3,48.6,48.0,48.0,47.9,46.9,46.7,46.1,45.6,25.8 ,25.6,24.8,24.7 ,14.3,13.6,13.4,9.3.

Example 179

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)piperidin-1-carboxamido)methyl)phenyl)-N-ethylsulfamoyl)- 3-Methylbenzofuran-2-carboxylic acid (F44-S101)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)piperidine)) -Carboxamido)methyl)phenyl)-N-methylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-101), the other conditions were the same. 159 mg of light yellow solid was obtained, with a yield of 86%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.03 (s, 1H), 7.84 (d, J = 8.7Hz, 1H), 7.62 (d, J = 13.8Hz, 2H), 7.32 (s, 1H) ,7.25(d,J＝7.7Hz,1H),6.61(d,J＝8.1Hz,1H),6.41(s,1H),6.29(s,1H),4.48(d,J＝38.9Hz,3H) ,4.21(d,J＝15.9Hz,1H),3.94–3.78(m,1H),3.27(s,5H),2.58(s,3H),1.55(s,6H),0.94(s,3H). ¹³ C NMR (101MHz, DMSO) δ163.5,161.7,155.1,151.2,146.5,142.7,142.7,135.9,133.3,132.1,129.7,129.6,127.3,126.8,126.0,121.7,112.7,110. 5,108.4,47.5,47.4, 46.2,46.0,25.3,24.2, 13.3,9.1.HRMS(ESI)[MH] ^- calcd for C ₃₀ H ₃₁ ClN ₃ O ₇ S:612.1571; found:612.1573.

Example 180

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)morpholin-4-carboxamido)methyl)phenyl)-N-ethylsulfamoyl)- 3-Methylbenzofuran-2-carboxylic acid ethyl ester (M6-102)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90) was to replace acetyl chloride with 4-morpholine carbonyl chloride, and the other conditions were the same. 234 mg of white solid was obtained, with a yield of 73%. ¹ H NMR(400MHz,Chloroform-d)δ7.97(s,1H),7.73–7.61(m,2H),7.41–7.33(m,2H),7.13–7.04(m,1H),6.38(d, J＝8.5Hz,1H),6.30(dd,J＝9.0,2.4Hz,2H),4.87–4.65(m,2H),4.59(d,J＝15.7Hz,1H),4.48(q,J＝7.0 Hz,2H),4.18(d,J＝15.7Hz,1H),3.92(dq,J＝14.5,7.2Hz,1H),3.74(dq,J＝17.2,6.4Hz,4H),3.36(t,J ＝8.3Hz,4H),3.15(dq,J＝13.6,6.8Hz,1H),2.59(s,3H),1.46(t,J＝7.1Hz,3H),1.03(t,J＝7.1Hz,3H ). ¹³ C NMR (101MHz, CDCl ₃ ) δ164.1,159.6,155.9,150.9,143.0,142.1,142.1,135.8,134.8,132.7,129.3,128.4,127.6,127.3,127.0,125.3,122.2, 112.7,110.4,108.9 ,66.4,61.5,48.6,47.4,46.6,45.0,14.2,13.3,9.2.

Example 181

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)morpholin-4-carboxamido)methyl)phenyl)-N-ethylsulfamoyl)- 3-Methylbenzofuran-2-carboxylic acid (F44-S102)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35) is to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)) Benzamido)methyl)phenyl)-N-ethylsulfamoyl)benzoic acid ethyl ester (F44-S26) was replaced with 5-(N-(4-chloro-2-((N-(furan- 2-ylmethyl)morpholine-4-carboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-102), All other conditions are the same. 145 mg of white solid was obtained, with a yield of 65%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.08 (s, 1H), 7.94–7.77 (m, 1H), 7.61 (s, 2H), 7.29 (d, J = 26.6Hz, 2H), 6.62 ( s,1H),6.37(d,J＝33.1Hz,2H),4.89–4.07(m,4H),3.87(s,1H),3.65(s,4H),3.30(s,5H),2.59(s ,3H),0.93(s,3H). ¹³ C NMR(101MHz,DMSO)δ163.4,161.3,155.2,150.9,145.1,142.7,142.2,135.9,133.3,132.1,129.5,127.4,126.8,126.4,123.1 ,121.9 ,112.8,110.5,108.7,65.9,47.5,47.1,46.2,45.6,13.2,9.0.HRMS(ESI)[MH] ^- calcd for C ₂₉ H ₂₉ ClN ₃ O ₈ S:614.1364; found:614.1371.

Example 182

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)furan-2-carboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3 -Methylbenzofuran-2-carboxylate (M6-103)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90) was to replace acetyl chloride with furancarbonyl chloride, and the other conditions were the same. 270 mg of white solid was obtained, with a yield of 87%. ¹ H NMR (400MHz, Chloroform-d) δ8.01 (s, 1H), 7.73 (d, J = 8.7Hz, 1H), 7.65 (d, J = 8.7Hz, 1H), 7.52–6.99 (m, 5H ),6.57–6.23(m,4H),5.63–4.44(m,6H),3.98(dd,J＝14.6,8.9Hz,1H),3.18(s,1H),2.60(s,3H),1.46( t, J＝7.1Hz, 3H), 1.08 (t, J＝6.9Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 160.5, 159.6, 156.4, 155.8, 150.1, 147.0, 144.4, 142.9, 142.3, 141.5 ,135.6,134.8,129.3,129.2,128.3,127.5,127.0,125.3,122.2,117.1,112.8,112.7,111.3,110.4,110.2,61.4,46.6,14.2,13.3,9.2,9.1.

Example 183

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)furan-2-carboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3 -Methylbenzofuran-2-carboxylic acid (F44-S103)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)furan-2- Carboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-103), the other conditions were the same. 225 mg of light yellow solid was obtained, with a yield of 88%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.06–7.79(m,3H),7.64(d,J＝8.0Hz,2H),7.43–7.05(m,3H),6.83–6.54(m,2H ),6.41(d,J＝16.7Hz,2H),4.86(s,4H),3.93(dd,J＝13.7,7.3Hz,1H),3.23(dd,J＝13.8,7.4Hz,1H),2.58 (d, J＝15.4Hz, 3H), 1.00 (s, 3H). ¹³ C NMR (101MHz, DMSO) δ162.3,160.0,155.0,150.2,148.3,146.7,145.6,143.0,141.3,136.0,133.5,131.5, 130.1,129.4,127.8,126.5,125.7,121.6,120.1,116.7,112.6,111.7,110.7,109.0,46.3,13.3,9.1.HRMS(ESI)[MH] ^- calcd for C ₂₉ H ₂₄ ClN ₂ O ₈ S: 595.0942; found:595.0945.

Example 184

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)thiophene-2-carboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3 -Methylbenzofuran-2-carboxylate (M6-104)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90) was to replace acetyl chloride with thiophenecarboxylic acid chloride, and the other conditions were the same. 112 mg of white solid was obtained, with a yield of 35%. ¹ H NMR (400MHz, Chloroform-d) δ7.99 (s, 1H), 7.71 (d, J = 8.7Hz, 1H), 7.64 (d, J = 8.7Hz, 1H), 7.55–7.20 (m, 4H ),7.17–7.06(m,1H),7.02(s,1H),6.49–6.24(m,3H),4.97(dd,J＝48.4, 13.8Hz,2H),4.48(q,J＝7.1Hz,2H),3.94(dq,J＝14.5,7.2Hz,1H),3.16(s,1H),2.60(s,3H),2.35(s, 2H), 1.46 (t, J = 7.1Hz, 3H), 1.04 (t, J = 6.9Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 171.2, 170.7, 164.9, 159.6, 155.9, 149.9, 143.0, 142.4,141.3,137.1,135.8,135.0,129.8,129.3,129.2,128.5,127.7,127.4,127.1,125.3,122.3,112.8,110.5,109.4,63.5,61.5,60.5,60.4 ,46.6,41.6,34.0,14.4, 14.3,14.1,13.3,9.3.

Example 185

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)thiophene-2-carboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3 -Methylbenzofuran-2-carboxylic acid (F44-S104)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)thiophene-2- Carboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-104), the other conditions were the same. 164 mg of white solid was obtained, with a yield of 99%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.12(s,1H),8.01–7.37(m,5H),7.36–7.01(m,3H),6.66(s,1H),6.42(s,2H ), 4.84 (d, J = 52.3Hz, 4H), 3.93 (s, 1H), 3.23 (s, 1H), 2.62 (s, 3H), 0.98 (s, 3H). ¹³ C NMR (101MHz, DMSO) δ164.1,161.2,155.3,149.9,145.0,143.1,141.0,137.1,135.9,133.5,131.9,130.7,129.5,129.4,129.2,127.5,126.5,123.3,122.1,112.9, 110.6,109.2,46.3,13.2,9.1. HRMS(ESI)[MH] ^- calcd for C ₂₉ H ₂₄ ClN ₂ O ₇ S ₂ :611.0713; found:611.0721.

Example 186

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)pyridinecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Benzofuran-2-carboxylic acid ethyl ester (M6-105)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90) was to replace acetyl chloride with 2-pyridylcarbonyl chloride, and the other conditions were the same. 174 mg of white solid was obtained, with a yield of 55%. ¹ H NMR (400MHz, Chloroform-d) δ8.55 (dd, J＝78.9, 4.5Hz, 1H), 7.97 (d, J＝29.0Hz, 1H), 7.89–7.33 (m, 7H), 7.06 (ddd ,J＝8.3,5.5,2.5Hz,1H),6.45–6.37(m,1H),6.34(d,J＝8.5Hz,1H),6.26–6.15(m,1H),5.21(dd,J＝30.3 ,17.1Hz,1H),5.10–4.84(m,2H),4.61–4.44(m,3H),3.91(ddd,J＝47.2,13.0,7.3Hz,1H),3.17(ddq,J＝60.5,13.6 ,6.8Hz,1H),2.59(d,J＝6.0Hz,3H),1.46(t,J＝7.0Hz,3H),1.02(dt,J＝76.3,7.1Hz,3H). ¹³ C NMR (101MHz , CDCl ₃ )δ169.6,169.3,159.8,159.8,156.0,154.1,153.4,150.3,148.1,148.1,143.1,142.4,142.2,141.8,141.6,137.0,136.9,135.7,135.5, 135.0,134.8,133.2,132.7, 129.4,128.6,128.0,127.6,127.5,127.2,127.1,125.5,125.4,124.8,124.7,124.2,124.1,122.4,122.3,112.8,112.8,110.5,110.4,109.2,1 08.8,61.6,49.2,46.9,46.6, 46.2,46.0,42.5,14.4,13.5,13.2,9.4.

Example 187

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)pyridinecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Benzofuran-2-carboxylic acid (F44-S105)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)pyridinecarboxamide) )Methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzo Furan-2-carboxylic acid ethyl ester (M6-105), other conditions are the same. 116 mg of white solid was obtained, with a yield of 91%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.63 (dd, J＝82.7, 4.9Hz, 1H), 8.22–7.19 (m, 9H), 6.61 (dd, J＝32.9, 8.4Hz, 1H), 6.50–6.05(m,2H),5.23–4.33(m,4H),3.89(ddq,J＝63.6,14.6,7.4Hz,1H),3.19(ddq,J＝58.0,13.8,6.9Hz,1H), 2.66–2.52(m,3H),1.34–0.65(m,3H). ¹³ C NMR(101MHz,DMSO)δ169.1,168.8,160.9,155.4,153.7,153.5,150.1,150.0,148.4,148.3,144.0,143.0, 142.7,141.2,141.0,137.6,137.5,135.9,135.6,133.4,132.2,131.9,129.3,129.0,127.8,127.6,127.2,126.7,126.5,125.0,124.9,124.2,1 23.6,123.2,122.2,113.0,110.5, 108.8,108.7,48.4,46.3,46.1,45.7,45.3,41.8,13.3,12.9,9.0.HRMS(ESI)[MH] ^- calcd for C ₃₀ H ₂₅ ClN ₃ O ₇ S:606.1102; found:606.1098.

Example 188

5-(N-(2-((5-bromo-N-(furan-2-ylmethyl)furan-2-carboxamido)methyl)-4-chlorophenyl)-N-ethylsulfamate Acyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-106)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90) was to replace acetyl chloride with 5-bromofuran-2-carbonyl chloride, and the other conditions were the same. 194 mg of white solid was obtained, with a yield of 98%. ¹ H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.73(d,J＝8.7Hz,1H),7.65(d,J＝8.7Hz,1H),7.41–6.99(m,4H ),6.39(d,J＝8.1Hz,3H),6.33(s,1H),5.74–3.88(m,8H),3.19(s,1H),2.60(s,3H),1.46(t,J＝ 7.1Hz, 2H), 1.09 (t, J = 7.0Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 160.0, 159.6, 156.0, 149.9, 148.7, 143.0, 142.8, 142.5, 141.3, 135.7, 134.9, 129.3 ,129.2,128.4,127.6,127.2,127.0,125.7,125.3,125.0,122.4,122.3,119.4,113.5,112.8,110.5,109.4,61.5,52.3,46.8,14.3,13.5,9.3,9 .2.

Example 189

5-(N-(2-((5-bromo-N-(furan-2-ylmethyl)furan-2-carboxamido)methyl)-4-chlorophenyl)-N-ethylsulfamate Acyl)-3-methylbenzofuran-2-carboxylic acid (F44-S106)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(2-((5-bromo-N-(furan-2-ylmethyl)furan-2- Carboxamido)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-106), the other conditions were the same. 164 mg of white solid was obtained, with a yield of 88%. ¹ H NMR (400MHz, Chloroform-d) δ8.00 (s, 1H), 7.72 (d, J = 8.9Hz, 1H), 7.65 (d, J = 8.8Hz, 1H), 7.23 (d, J = 105.1 Hz,4H),6.56–6.36(m,3H),6.32(s,1H),5.57–4.52(m,4H),3.97(dd,J＝13.0,7.0Hz,1H),3.17(s,1H) ,2.62(s,3H),1.09(t,J=7.1Hz,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ163.6,156.2,149.7,148.4,143.7,142.6,141.1,135.8,135.1,129.6,128.5 ,127.8,127.2,126.2,125.6,122.5,120.2,113.8,112.9,110.6,109.9,49.2,46.8,13.5,9.5.HRMS(ESI)[MH] ⁺ calcd for C ₂₉ H ₂₃ Cl ₂ BrN ₂ O ₈ S :673.0047; found:673.0044.

Example 190

5-(N-(4-chloro-2-((5-chloro-N-(furan-2-ylmethyl)thiophene-2-carboxamido)methyl)phenyl)-N-ethylsulfamate Acyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-107)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90) was to replace acetyl chloride with 5-chlorothiophene-2-carboxylic acid chloride, and the other conditions were the same. 174 mg of white solid was obtained, with a yield of 92%. ¹ H NMR(400MHz,Chloroform-d)δ7.99(s,1H),7.71(d,J＝8.8Hz,1H),7.65(d,J＝8.8Hz,1H),7.55– 6.96(m,4H),6.84(s,1H),6.49–6.36(m,2H),6.34(s,1H),6.04–3.78(m,8H),3.15(dq,J＝13.5,6.8Hz, 1H), 2.61 (s, 3H), 1.46 (t, J = 7.1Hz, 2H), 1.05 (t, J = 7.2Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 163.7, 160.1, 159.7, 156.0 ,149.7,143.1,142.9,142.6,141.0,136.3,135.9,135.3,135.1,129.4,129.3,129.1,128.5,127.9,127.3,127.2,127.1,126.6,125.7,125.4, 122.4,122.3,112.9,110.6,109.6 ,61.6,52.4,46.7,14.3,13.4,9.3,9.3.

Example 191

5-(N-(4-chloro-2-((5-chloro-N-(furan-2-ylmethyl)thiophene-2-carboxamido)methyl)phenyl)-N-ethylsulfamate Acyl)-3-methylbenzofuran-2-carboxylic acid (F44-S107)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((5-chloro-N-(furan-2-ylmethyl)) Thiophene-2-carboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-107), the other conditions were the same. 149 mg of white solid was obtained, with a yield of 89%. ¹ H NMR (400MHz, Chloroform-d) δ7.89 (s, 1H), 7.61 (s, 2H), 7.43–7.03 (m, 4H), 6.81 (s, 1H), 6.36 (dd, J＝25.6, 9.5Hz,3H),5.00–4.38(m,4H),3.89(s,1H),3.08(s,1H),2.54(s,3H),1.01(s,3H). ¹³ C NMR(101MHz,CDCl _3. 9,110.7,109.8,46.7,29.7, 13.4,9.4.HRMS(ESI)[MH] ⁺ calcd for C ₂₉ H ₂₃ Cl ₂ N ₂ O ₇ S ₂ :645.0324; found:645.0322.

Example 192

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)-2-phenylacetamido)methyl)phenyl)-N-ethylsulfamoyl)- 3-Methylbenzofuran-2-carboxylic acid ethyl ester (M6-108)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90) was to replace acetyl chloride with phenylacetyl chloride, and the other conditions were the same. 176 mg of white solid was obtained, with a yield of 97%. ¹ H NMR (400MHz, Chloroform-d) δ7.96 (d, J＝8.6Hz, 1H), 7.74–7.59 (m, 2H), 7.44–7.18 (m, 6H), 7.03 (dd, J＝17.0, 9.2Hz,2H),6.33(d,J＝6.5Hz,2H),6.26(d,J＝6.9Hz,1H),5.15(dd,J＝77.5,17.6Hz,1H),4.87–4.74(m, 1H),4.73–4.51(m,1H),4.51–3.79(m,6H),3.77(s,1H),3.13(ddq,J＝33.5,13.4,6.7Hz,1H),2.58(d,J＝ 5.0Hz, 3H), 1.45 (t, J = 7.2Hz, 2H), 1.02 (dt, J = 14.1, 7.1Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 171.9, 171.9, 160.0, 159.7, 159.6 ,156.0,155.9,150.4,149.8,143.1,143.0,142.9,142.7,142.1,141.8,141.0,135.6,135.5,135.0,134.9,134.8,134.5,133.2,133.1,132.2, 129.4,129.3,129.0,128.9,128.8 ,128.4,128.2,127.8,127.7,127.3,127.1,127.0,126.9,126.8,125.7,125.6,125.4,125.3,122.4,122.3,112.8,112.8,110.5,110.4,108.9, 108.9,61.5,61.5,52.3,48.2 ,46.8,46.6,45.3,45.0,42.0,40.9,40.4,14.3,13.5,13.3,9.2,9.2.

Example 193

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)-2-phenylacetamido)methyl)phenyl)-N-ethylsulfamoyl)- 3-Methylbenzofuran-2-carboxylic acid (F44-S108)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl))-2-benzene) Acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Benzofuran-2-carboxylic acid ethyl ester (M6-108), other conditions are the same. 160 mg of white solid was obtained, with a yield of 95%. ¹ H NMR (400MHz, Chloroform-d) δ7.87 (s, 1H), 7.59 (s, 2H), 7.28 (ddt, J＝39.3, 26.7, 8.0Hz, 6H), 6.99 (q, J＝10.6, 8.8Hz,2H),6.55–6.01(m,3H),5.27–4.31(m,6H),4.09(q,J＝15.1Hz,1H),3.07(d,J＝22.8Hz,1H),2.51( d, J＝12.3Hz, 3H), 1.09–0.70 (m, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ172.8,155.9,155.7,150.1,149.4,145.3,142.9,142.3,141.4,140.7,135.8, 135.7,135.1,134.9,134.6,134.2,132.6,131.9,129.8,129.8,129.1,128.8,128.6,127.6,127.2,127.0,126.7,124.3,122.2,112.8,110.6,1 10.5,109.2,109.2,48.4,46.8, 45.5,45.0,42.2,41.0,40.6,13.5,13.4,9.3.HRMS(ESI)[MH] ⁺ calcd for C ₃₂ H ₂₈ ClN ₂ O ₇ S:619.1306; found:619.1306.

Example 194

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)methylsulfonamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Ethyl benzofuran-2-carboxylate (M6-109)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90) was to replace acetyl chloride with methanesulfonyl chloride, and the other conditions were the same. 100 mg of white solid was obtained, with a yield of 86%. ¹ H NMR (400MHz, Chloroform-d) δ7.95(d,J＝1.4Hz,1H),7.72(d,J＝1.7Hz,2H),7.65(d,J＝8.7Hz,1H),7.54– 7.40(m,1H),7.07(dd,J＝8.5,2.4Hz,1H),6.42(d,J＝3.1Hz,1H),6.39–6.34(m,1H),6.30(d,J＝8.5Hz ,1H),4.88(d,J＝17.2Hz,1H),4.71(d,J＝17.2Hz,1H),4.56(d,J＝16.3Hz,1H),4.31(d,J＝16.3Hz,1H ),4.02(s,4H),3.15(dq,J＝13.8,6.9Hz,1H),2.84(s,3H),2.59(s,3H),1.06(t,J＝7.1Hz,3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ160.2,156.1,149.3,143.1,142.9,141.1,135.6,135.2,132.5,129.4,128.9,128.0,127.3,125.8,122.6,112.9,110.7,110.5 ,52.4,47.1,46.8, 43.9,39.0,13.5,9.3.

Example 195

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)methylsulfonamido)methyl)phenyl)-N-ethylsulfamoyl)-3- Methylbenzofuran-2-carboxylic acid (F44-S109)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)methyl)methylsulfonamide (methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-109), and the other conditions were consistent. 71 mg of white solid was obtained, with a yield of 75%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.00 (d, J＝1.9Hz, 1H), 7.83 (d, J＝8.7Hz, 1H), 7.64 (s, 1H), 7.60 (dd, J＝ 8.7,2.0Hz,1H),7.42(d,J＝2.3Hz,1H),7.23(dd,J＝8.5,2.4Hz,1H),6.52(d,J＝8.6Hz,1H),6.39(d, J＝2.0Hz,2H),4.69(d,J＝17.7Hz,1H),4.58(d,J＝17.6Hz,1H),4.48(d,J＝16.0Hz,1H),4.39(d,J＝ 16.0Hz,1H),3.90(dq,J＝14.6,7.3Hz,1H),3.18(dq,J＝13.7,6.8Hz,1H),3.02(s,3H),2.55(s,3H),0.95( t, J＝7.1Hz, 3H). ¹³ C NMR (101MHz, DMSO) δ161.6,155.1,149.3,146.8,143.4,141.4,135.5,133.2,131.5,129.8,128.9,127.7,127.5,126.0,121.7,12 1.3, 112.7,110.6,110.1,47.2,46.2,44.4,13.2,9.0.HRMS(ESI)[MH] ⁺ calcd for C ₂₅ H ₂₄ ClN ₂ O ₈ S ₂ :579.0663; found:579.0667.

Example 196

5-(N-(2-(((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3- Methylbenzofuran-2-carboxylic acid ethyl ester (M6-110)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)acetamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl The method used for benzofuran-2-carboxylic acid ethyl ester (M6-90), replacing acetyl chloride with dicarbonate tert-butyl ester, other conditions are the same. 105 mg of white solid was obtained, with a yield of 90%. ¹ H NMR (400MHz, Chloroform-d) δ7.99 (s, 1H), 7.71 (s, 1H), 7.63 (d, J = 8.8Hz, 1H), 7.35 (s, 1H), 7.21 (s, 1H) ),7.08–6.99(m,1H),6.36(s,1H),6.28(d,J＝11.1Hz,2H),4.97–4.61(m,2H),4.45(q,J＝18.2,15.2Hz, 2H),4.01(s,3H),3.92(dq,J＝14.3,7.2Hz,1H),3.17(s,1H),2.59(s,3H),1.49(d,J＝36.7Hz,9H), 1.04 (t, J=7.0Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ160.2,156.1,142.9,134.8,129.3,127.3,125.9,122.4,112.8,110.3,80.6,52.4,46.8,28.4,13.5 ,9.3.

Example 197

5-(N-(2-(((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)methyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3- Methylbenzofuran-2-carboxylic acid (F44-S110)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(2-((tert-butoxycarbonyl)(furan-2-ylmethyl)amino)methyl (ethyl)-4-chlorophenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylate (M6-110), and the other conditions were consistent. 81 mg of white solid was obtained, with a yield of 80%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.10(d,J＝1.6Hz,1H),7.88(d,J＝8.8Hz,1H),7.65(d,J＝7.4Hz,1H),7.61 –7.51(m,1H),7.23(dd,J＝8.5,2.4Hz,1H),7.06(s,1H),6.57(d,J＝8.4Hz,1H),6.39(s,1H),6.27( s,1H),4.58(td,J＝45.7,41.8,15.1Hz,4H),3.88(dd,J＝12.7,6.7Hz,1H),3.20(dq,J＝13.2,6.3Hz,1H),2.57 (s, 3H), 1.40 (d, J = 53.8Hz, 9H), 0.95 (s, 3H). ¹³ C NMR (101MHz, DMSO) δ 160.7, 155.4, 143.6, 142.6, 142.1, 133.1, 132.2, 129.3, 129.2 ,127.4,126.8,126.6,124.5,122.2,113.0,110.4,79.7,46.2,27.9,13.2,9.0.HRMS(ESI)[MH] ⁺ calcd for C ₂₉ H ₃₀ ClN ₂ O ₈ S:601.1411; found:601.1417 .

Example 198

5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)- 1,3-Dimethyl-1H-indole-2-carboxylic acid ethyl ester (M6-111)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with ethyl 5-(chlorosulfonyl)-1,3-dimethyl-1H-indole-2-carboxylate, and the other conditions were the same. 160 mg of white solid was obtained, with a yield of 23%. ¹ H NMR (400MHz, Chloroform-d) δ8.08–7.86 (m, 1H), 7.77–7.47 (m, 2H), 7.46–7.32 (m, 5H), 7.19 (d, J = 33.8Hz, 1H) ,7.03(q,J＝8.5,7.3Hz,1H),6.53–6.03(m,3H),5.47–4.17(m,6H),4.07–3.68(m,4H),3.23–2.81(m,1H) ,2.64–2.45(m,3H),1.44(td,J＝7.1,3.4Hz,3H),1.05(dt,J＝22.4,6.8Hz,2H),0.64(d,J＝75.2Hz,1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ169.3,162.3,162.3,149.8,149.2,142.6,142.3,141.1,139.9,136.2,135.9,135.4,134.6,134.5,130.4,129.8,129.6,12 8.9,128.7,128.6,128.5 ,128.2,127.8,127.6,127.5,127.4,127.3,127.0,126.3,123.8,123.8,122.5,122.4,121.7,121.6,110.5,110.4,110.4,109.7,109.0,60.9,6 0.9,46.8,46.5,46.3,45.8 ,44.7,32.5,14.3,13.5,12.8,10.8,10.7.

Example 199

5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)- 1,3-Dimethyl-1H-indole-2-carboxylic acid (F44-S111)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35) is to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)) Benzamido)methyl)phenyl)-N-ethylsulfamoyl)benzoic acid ethyl ester (F44-S26) was replaced with 5-(N-(4-chloro-2-((2-chloro-N -(Furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)-1,3-dimethyl-1H-indole-2-carboxylic acid ethyl ester ( M6-111), other conditions are the same. 137 mg of white solid was obtained, with a yield of 85%. ¹ H NMR (400MHz, Chloroform-d) δ8.19–7.84(m,1H),7.81–6.94(m,9H),6.66–5.93(m,3H),5.57–4.55(m,3H),4.44( s,1H),4.27–3.73(m,4H),2.88(d,J＝218.7Hz,4H),1.15–0.44(m,3H). ¹³ C NMR(101MHz, CDCl ₃ )δ166.9,166.8,149.2, 142.8,141.1,140.5,136.3,130.6,129.7,129.1,128.6,127.5,127.2,126.7,126.5,124.5,122.9,110.6,46.5,46.0,44.9,32.8,13.6,11.0.H RMS(ESI)[MH] ^- calcd for C ₃₂ H ₂₈ N ₃ O ₆ SCl ₂ :652.1076; found:652.1077.

Example 200

5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)benzene Furan-2-carboxylic acid ethyl ester (M6-112)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with ethyl 5-(chlorosulfonyl)benzofuran-2-carboxylate, and the other conditions were the same. 78 mg of light yellow solid was obtained, with a yield of 28%. ¹ H NMR(400MHz,Chloroform-d)δ8.21–7.86(m,1H),7.85–7.57(m,3H),7.56–7.33(m,5H),7.26–6.99(m,2H),6.58– 5.99(m,3H),5.48–4.15(m,6H),4.04–3.66(m,1H),3.36–2.83(m,1H),1.44(td,J＝7.1,3.6Hz,3H),1.17– 0.49(m,3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ158.9,158.9,157.3,150.1,149.9,149.6,149.2,148.0,147.9,142.8,142.6,137.3,135.7,135.4,135.0,13 3.5,133.1, 130.5,130.4,129.7,128.9,128.5,128.3,127.8,127.6,127.1,127.0,127.0,126.9,124.1,113.7,113.7,113.6,113.6,113.1,112.9,110.6,1 10.6,110.5,110.5,109.7,62.1, 47.1,46.7,46.0,45.7,44.7,14.4,13.7.

Example 201

5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)benzene Furan-2-carboxylic acid (F44-S112)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)) Benzamido)methyl)phenyl)-N-ethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester (M6-112), other conditions were the same. 63 mg of white solid was obtained, with a yield of 84%. ¹ H NMR(400MHz,Chloroform-d)δ8.14–7.86(m,1H),7.82–7.57(m,3H),7.41(d,J＝37.0Hz,5H),7.26–6.97(m,2H) ,6.59–5.98(m,3H),5.54–4.11(m,4H),4.02–3.70(m,1H),3.29–2.88(m,1H),1.14–0.52(m,3H). ¹³ C NMR( 101MHz, CDCl ₃ )δ170.0,157.4,149.8,149.6,149.2,148.9,142.9,142.7,140.9,138.6,135.7,135.1,133.4,130.7,129.8,129.0,127.7,127.2,12 4.2,114.6,113.2,110.6,110.0 ,46.7,29.8,13.6.HRMS(ESI)[MH] ^- calcd for C ₃₀ H ₂₃ N ₂ O ₇ SCl ₂ :625.0603; found:625.0607.

Example 202

6-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)- 3-Methylbenzofuran-2-carboxylic acid ethyl ester (M6-113)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with 6-(chlorosulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester, and the other conditions were the same. 148 mg of light yellow solid was obtained, with a yield of 15%. ¹ H NMR (400MHz, Chloroform-d) δ7.93–7.52(m,3H),7.51–7.32(m,5H),7.25(s,1H),7.05(dd,J＝15.0,7.7Hz,1H) ,6.54–6.05(m,3H),5.42–4.17(m,6H),4.04–3.67(m,1H),3.38–2.87(m,1H),2.61(d,J＝9.1Hz,3H),1.54 –1.38(m,3H),1.06(dt,J＝22.6,6.8Hz,2H),0.65(d,J＝73.3Hz,1H). ¹³ C NMR(101MHz, CDCl ₃ )δ169.3,159.8,159.8,159.7 ,153.0,152.9,150.1,149.8,149.5,149.1,144.0,142.7,142.5,142.2,141.0,136.4,136.0,135.6,135.0,134.9,133.1,133.0,132.8,130.4, 130.3,129.9,129.6,128.8,128.5 ,128.3,128.0,127.9,127.5,127.1,127.0,124.9,122.6,121.7,121.6,112.6,110.6,110.5,110.5,110.4,109.7,109.4,109.1,61.7,47.1,46 .7,45.9,45.6,44.7,14.3 ,13.6,12.9,9.3,9.3.

Example 203

6-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)- 3-Methylbenzofuran-2-carboxylic acid (F44-S113)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 6-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)) Benzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-113), the other conditions were the same. 118 mg of white solid was obtained, with a yield of 86%. ¹ H NMR(400MHz,Chloroform-d)δ7.94–7.32(m,8H),7.27–6.97(m,2H),6.66–5.93(m,3H),5.50–4.16(m,4H),4.05– 3.66(m,1H),3.39–2.82(m,1H),2.62(d,J＝8.6Hz,3H),1.14–0.49(m,3H). ¹³ C NMR(101MHz, CDCl ₃ )δ169.9,163.3, 163.2,163.0,153.3,153.2,149.8,149.5,149.2,148.9,143.9,143.7,142.8,142.6,142.5,140.8,138.5,136.6,136.2,135.0,133.0,132.9,1 30.7,129.7,128.9,128.6,128.3, HRMS(ES) I)[MH] ^- calcd for C ₃₁ H ₂₅ N ₂ O ₇ SCl ₂ :639.0760; found:639.0764.

Example 204

6-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)benzene Furan-2-carboxylic acid ethyl ester (M6-114)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with 6-(chlorosulfonyl)benzofuran-2-carboxylic acid ethyl ester, and the other conditions were the same. 181 mg of light yellow solid was obtained, with a yield of 35%. ¹ H NMR(400MHz,Chloroform-d)δ7.99–7.73(m,2H),7.73–7.55(m,2H),7.51–7.32(m,5H),7.28–6.98(m,2H),6.62– 6.01(m,3H),5.41–4.16(m,6H),3.99–3.52(m,1H),3.34–2.90(m,1H),1.48–1.41(m,3H),1.07(dt,J＝22.4 ,6.9Hz,2H),0.66(d,J=71.1Hz,1H). ¹³ C NMR (101MHz, CDCl ₃ )δ158.9,158.8,154.4,154.3,150.1,149.5,149.2,149.0,142.8,142.5,136.0, 135.0,131.0,130.8,130.5,130.3,129.7,128.9,127.9,127.6,127.2,127.1,123.4,123.3,123.3,113.1,112.9,110.6,110.5,110.5,109.7,6 2.1,46.7,45.9,45.6,14.3, 13.6,13.0.

Example 205

6-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)benzene Furan-2-carboxylic acid (F44-S114)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-Ethylsulfamoyl)ethyl benzoate (F44-S26) was replaced with 6-(N-(4- Chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)benzofuran-2-carboxylate (M6-114), other conditions are the same. 57 mg of white solid was obtained, with a yield of 33%. ¹ H NMR(400MHz,Chloroform-d)δ8.00–7.29(m,9H),7.25–6.98(m,2H),6.58–5.98(m,3H),5.49–4.16(m,4H),4.00– 3.66(m,1H),3.31–2.90(m,1H),1.13–0.51(m,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ170.0,154.5,149.2,148.9,142.9,142.7,140.8,136.5, 135.2,131.0,130.7,129.8,129.0,127.2,123.2,113.9,113.0,110.6,110.0,46.8,29.8,13.6.HRMS(ESI)[MH] ^- calcd for C ₃₀ H ₂₃ N ₂ O ₇ SCl ₂ :625.060 3 ;found:625.0609.

Example 206

5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)benzene And [b]thiophene-2-carboxylic acid ethyl ester (M6-115)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with ethyl 5-(chlorosulfonyl)benzo[b]thiophene-2-carboxylate, and the other conditions were the same. 70 mg of light yellow solid was obtained, with a yield of 10%. ¹ H NMR (400MHz, Chloroform-d) δ8.29–8.02(m,2H),8.01–7.89(m,1H),7.77–7.63(m,1H),7.62–7.42(m,2H),7.41– 7.32(m,3H),7.26–6.99(m,2H),6.55–6.03(m,3H),5.48–4.17(m,6H),4.03–3.69(m,1H),3.35–2.88(m,1H ), 1.47–1.40 (m, 3H), 1.14–0.96 (m, 2H), 0.66 (d, J = 71.8Hz, 1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ162.1, 162.1, 150.2, 149.6, 149.2 ,146.1,146.0,145.8,142.8,142.6,138.3,138.2,137.3,137.0,136.8,135.7,135.4,135.0,134.5,134.1,130.5,130.4,130.3,130.2,130.2, 129.7,128.9,128.0,127.8,127.6 ,127.3,127.1,125.9,125.8,125.2,125.1,125.1,125.0,123.5,123.4,110.6,110.5,110.5,109.8,62.2,62.1,60.4,47.1,46.7,45.9,45.6,2 9.7,21.1,14.4,14.3 ,13.7.

Example 207

5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)benzene And[b]thiophene-2-carboxylic acid (F44-S115)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)) Benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)benzo[b]thiophene-2-carboxylic acid ethyl ester (M6-115), other conditions were the same. 50 mg of white solid was obtained, with a yield of 78%. ¹ H NMR(400MHz,Chloroform-d)δ8.31–7.79(m,3H),7.69(d,J＝15.1Hz,1H),7.59–7.31(m,5H),7.07(dd,J＝17.7, 9.1Hz,2H),6.59–5.96(m,3H),5.50–4.16(m,4H),4.06–3.70(m,1H),3.12(d,J＝90.0Hz,1H),1.18–0.47(m ,3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ170.0,166.1,149.9,149.3,149.0,146.5,142.9,142.7,138.7,138.4,135.1,131.3,130.6,129.8,129.0,128.6,12 7.2,126.0,110.6 ,47.2,46.7,13.7.HRMS(ESI)[MH] ^- calcd for C ₃₀ H ₂₃ N ₂ O ₆ SCl ₂ :641.0375; found:641.0378.

Example 208

6-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)benzene And [b]thiophene-2-carboxylic acid ethyl ester (M6-S203)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with 6-(chlorosulfonyl)benzo[b]thiophene-2-carboxylic acid ethyl ester, and the other conditions were the same. 83 mg of light yellow solid was obtained, with a yield of 12%. ¹ H NMR(400MHz,Chloroform-d)δ8.26–8.04(m,2H),8.02–7.91(m,1H),7.75– 7.60(m,1H),7.59–7.43(m,2H),7.39–7.31(m,3H),7.26–6.97(m,2H),6.53–6.05(m,3H),5.45–4.17(m,6H ),4.04–3.71(m,1H),3.31–2.99(m,1H),1.42(dd,J＝7.0,3.6Hz,3H),1.09(tt,J＝17.4,6.9Hz,2H),0.66( d, J＝71.9Hz, 1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ169.4,162.0,162.0,161.9,150.1,149.8,149.5,149.2,142.8,142.6,141.6,141.5,138.6,138.5,138.4 ,137.2 ,135.6,135.5,135.1,130.5,130.3,129.7,129.6,129.5,129.5,128.9,128.5,128.0,127.8,127.6,127.4,127.3,127.1,126.0,125.8,123.9, 123.8,123.7,123.5,123.5,110.6 ,110.5,110.5,109.8,109.5,62.2,62.1,60.4,47.2,46.7,45.9,45.6,44.7,29.7,21.1,14.3,14.3,13.7.

Example 209

6-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)benzene And[b]thiophene-2-carboxylic acid (F44-S203)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 6-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)) Benzamido)methyl)phenyl)-N-ethylsulfamoyl)benzo[b]thiophene-2-carboxylic acid ethyl ester (M6-116), other conditions were the same. 58 mg of white solid was obtained, with a yield of 75%. ¹ H NMR(400MHz,Chloroform-d)δ8.28–7.89(m,3H),7.86–7.29(m,7H),7.13–6.97(m,1H),6.72–5.86(m,3H),5.48– 4.16(m,4H),3.89(d,J＝70.0Hz,1H),3.14(d,J＝85.9Hz,1H),1.24–0.44(m,3H). ¹³ C NMR (101MHz, CDCl ₃ )δ170 .0,165.8,149.3,149.0,142.9,142.7,142.1,141.8,141.7,140.9,138.7,138.6,135.7,135.2,130.5,129.8,129.0,128.6,127.7,127.2,126. 2,123.8,123.6,110.6,46.8,29.8 ,13.7.HRMS(ESI)[MH] ^- calcd for C ₃₀ H ₂₃ N ₂ O ₆ SCl ₂ :641.0375; found:641.0371.

Example 210

5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)- 3-Methylbenzo[b]thiophene-2-carboxylic acid ethyl ester (M6-S201)

According to N-(2-((4-acetamido-N-ethylphenyl)sulfonamide)-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide ( The method used in F44-S16) was to replace 4-acetamidobenzenesulfonyl chloride with ethyl 5-(chlorosulfonyl)-3-methylbenzo[b]thiophene-2-carboxylate, and the other conditions were the same. 46 mg of light yellow solid was obtained, with a yield of 13.4%. ¹ H NMR(400MHz,Chloroform-d)δ8.18–7.97(m,1H),7.97–7.83(m,1H),7.83–7.29(m,7H),7.06(dt,J＝18.6,8.7Hz, 1H),6.65–5.99(m,3H),5.51–4.49(m,3H),4.46–4.17(m,3H),4.01–3.69(m,1H),3.28–2.88(m,1H),2.84– 2.69(m,3H),1.43(td,J＝7.1,3.6Hz,3H),1.08(dq,J＝19.1,6.9Hz,2H),0.65(d,J＝67.8Hz,1H). ¹³ C NMR (101MHz, CDCl ₃ )δ162.9,149.9,149.3,144.5,144.3,142.8,142.6,141.0,140.0,130.5,130.4,130.0,129.8,128.9,128.6,127.6,127.1,125.5,12 5.3,125.3,124.2,123.4, 110.6,109.8,61.8,47.1,46.6,44.8,29.8,14.4,13.7,13.3.

Example 211

5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl)- 3-Methylbenzo[b]thiophene-2-carboxylic acid (F44-S201)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)) Benzamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzo[b]thiophene-2-carboxylic acid ethyl ester (M6-117), other conditions were the same. 20 mg of white solid was obtained, with a yield of 43%. ¹ H NMR (400MHz, Chloroform-d) δ8.24–7.29 (m, 8H), 7.15 (d, J = 67.4Hz, 2H),6.67–5.90(m,3H),5.42–4.14(m,4H),4.05–3.68(m,1H),3.09(d,J＝89.6Hz,1H),2.74(dd,J＝15.1, 7.9Hz, 3H), 1.07 (dt, J＝15.1, 7.0Hz, 2H), 0.67 (d, J＝74.4Hz, 1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 167.7, 149.9, 149.2, 144.9, 144.8 , 142.9,141.2,140.1,135.2,130.6,128.6,127.27.2,124.4, 123.5, 110.6,47.7, 29.8, 13.4.4.4.4.4.4.4.4.4.4.4.4.4.4.4.4.4.4.4.4.4.4.4.4.4.4.4.4.HRMS (ESI) [MH] ^-Calcd for C ₃₁ H 31 H 31 H 31 H 31 H ₂₅ n ₂ O ₆ S ₂ Cl ₂ :655.0531; found:655.0532.

Example 212

N-(5-chloro-2-nitrobenzyl)-N-(furan-2-ylmethyl)cyclopropanecarboxamide (M17)

Follow the procedure used for 2-chloro-N-(5-chloro-2-nitrobenzyl)-N-(furan-2-ylmethyl)benzamide (M2), substituting o-chlorobenzoyl chloride for cyclopropyl chloride. Formyl chloride, other conditions are the same. 15.8g of light yellow solid was obtained, with a yield of 95%.

Example 213

N-(2-amino-5-chlorophenyl)-N-(furan-2-ylmethyl)cyclopropanecarboxamide (M18)

According to the method used for N-(2-amino-5-chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (M3), 2-chloro-N-(5-chloro -2-nitrobenzyl)-N-(furan-2-ylmethyl)benzamide (M2) is replaced with N-(5-chloro-2-nitrobenzyl)-N-(furan-2- Methyl)cyclopropanecarboxamide (M17), the other conditions were the same. 12.7g of light yellow solid was obtained, with a yield of 88%.

Example 214

N-(5-chloro-2-(ethylamino)benzyl)-N-(furan-2-ylmethyl)cyclopropanecarboxamide (M19)

According to the method used for 2-chloro-N-(5-chloro-2-(ethylamino)benzyl)-N-(furan-2-ylmethyl)benzamide (M5), N-(2-amino -5-Chlorobenzyl)-2-chloro-N-(furan-2-ylmethyl)benzamide (M3) is replaced with N-(2-amino-5-chlorophenyl)-N-(furan- 2-ylmethyl)cyclopropanecarboxamide (M18), other conditions were the same. 11.0 g of light yellow solid was obtained, with a yield of 79%.

Example 215

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Ethylbenzo[b]thiophene-2-carboxylate (M6-118)

N-(5-chloro-2-(ethylamino)benzyl)-N-(furan-2-ylmethyl)cyclopropanecarboxamide (M19) (332 mg, 1.0 mmol), 5-(chlorosulfonyl )-3-methylbenzo[b]thiophene-2-carboxylic acid ethyl ester (383 mg, 1.2 mmol), potassium carbonate (207 mg, 2.0 mmol) were added to anhydrous dichloromethane (2 mL), and the temperature was raised to reflux overnight. , after the TLC detection reaction is completed, the solvent is evaporated under reduced pressure, dissolved in water (5 mL), extracted three times with ethyl acetate (5 mL), the organic phase is washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the crude product is subjected to column chromatography After separation (PE/EA=4/1), 138 mg of light yellow solid was obtained, with a yield of 20%. ¹ H NMR(400MHz,Chloroform-d)δ8.16–8.03(m,1H),7.94(dd,J＝8.4,3.7Hz,1H),7.77–7.60(m,1H),7.45–7.23(m, 2H),7.18–7.05(m,1H),6.48–6.21(m,3H),5.25(dd,J＝140.1,17.7Hz,1H),4.95–4.71(m,2H),4.69–4.37(m, 3H),4.07–3.87(m,1H),3.15(ddt,J＝28.9,12.9,6.9Hz,1H),2.83–2.71(m,3H),1.94(ddt,J＝191.0,8.0,3.5Hz, 1H), 1.44 (t, J＝7.1Hz, 3H), 1.09 (dt, J＝26.1, 5.8Hz, 5H), 0.92–0.76 (m, 2H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 174.6, 174.5 ,162.7,162.6,151.1,150.7,150.4,144.5,144.4,142.6,142.2,142.2,142.1,141.8,140.8,140.8,139.9,137.1,135.7,135.5,135.2,134.9, 134.3,133.5, 130.0,129.9,129.0,128.5,128.1,127.9,127.7,127.5,127.4,127.3,127.0,125.3,125.2,124.1,124.0,123.4,123.2,110.5,110.4,108.9,1 08.7,108.6,61.7,61.7,48.0, 46.9,46.6,46.0,44.9,42.6,42.4,14.3,13.5,13.4,13.2,11.6,11.4,8.5,8.2,8.0.

Example 216

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Benzo[b]thiophene-2-carboxylic acid (F44-S118)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl))cyclopropanecarboxamide (methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzo[b]thiophene-2-carboxylic acid ethyl ester (M6-118), and the other conditions were consistent. 121 mg of light yellow solid was obtained, with a yield of 94%. ¹ H NMR(400MHz,Chloroform-d)δ8.24–7.29(m,8H),7.15(d,J＝67.4Hz,2H),6.67–5.90(m,3H),5.42–4.14(m,4H) ,4.05–3.68(m,1H),3.09(d,J＝89.6Hz,1H),2.74(dd,J＝15.1,7.9Hz,3H),1.07(dt,J＝15.1,7.0Hz,2H), 0.67 (d, J=74.4Hz, 1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ167.7,149.9,149.2,144.9,144.8,142.9,141.2,140.1,135.2,130.6,128.6,127.7,127.2,125.5, 124.4 ,123.5,110.6,47.2,46.7,29.8,13.7,13.4.HRMS(ESI)[MH] ^- calcd for C ₃₁ H ₂₅ N 2 _O ₆ S ₂ Cl ₂ :655.0531; found:655.0532.

Example 217

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-1,3 -Dimethyl-1H-indole-2-carboxylic acid ethyl ester (M6-119)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3- Method used for methylbenzo[b]thiophene-2-carboxylic acid ethyl ester (M6-118), replacing 5-(chlorosulfonyl)-3-methylbenzo[b]thiophene-2-carboxylic acid ethyl ester with 5-(Chlorosulfonyl)-1,3-dimethyl-1H-indole-2-carboxylic acid ethyl ester, the other conditions are the same. 270 mg of light yellow solid was obtained, with a yield of 40%. ¹ H NMR (400MHz, Chloroform-d) δ7.98 (dd, J＝12.6, 1.8Hz, 1H), 7.53 (ddd, J＝16.1, 8.8, 1.8Hz, 1H), 7.43–7.31 (m, 2H) ,7.19(dd,J＝43.5,2.1Hz,1H),7.03(ddd,J＝26.4,8.4,2.3Hz,1H),6.47–6.22(m,3H),5.25(dd,J＝143.4,17.7Hz ,1H),4.96–4.39(m,5H),4.06–3.90(m,4H),3.10(ddd,J＝23.7,12.9,6.8Hz,1H),2.54(d,J＝5.7Hz,3H), 2.25–1.67(m,1H),1.45(t,J＝7.1Hz,3H),1.16–0.97(m,5H),0.92–0.75(m,2H). ¹³ C NMR (101MHz, CDCl ₃ )δ174. 4,174.3,162.1,162.1,150.6,150.4,142.3,142.1,142.0,141.6,139.8,139.7,136.0,135.8,134.6,134.3,128.5,128.2,127.6,127.6,127.4 ,127.2,127.1,126.8,126.2,123.7, 122.3,121.4,110.3,110.2,108.7,108.4,60.8,47.9,46.6,46.3,45.8,44.7,42.4,32.4,14.2,13.3,13.2,11.4,11.2,10.6,8.3,8.1,7.8.

Example 218

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-1,3 -Dimethyl-1H-indole-2-carboxylic acid (F44-S119)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4- Chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-1,3-dimethyl-1H-indole Indole-2-carboxylic acid ethyl ester (M6-119), other conditions are the same. 224 mg of light yellow solid was obtained, with a yield of 87%. ¹ H NMR (400MHz, Chloroform-d) δ8.02 (d, J＝7.1Hz, 1H), 7.47 (dd, J＝49.0, 8.1Hz, 2H), 7.34 (d, J＝31.1Hz, 1H), 7.25–6.96(m,2H),6.51–6.18(m,3H),5.24(dd,J＝154.3,17.4Hz,1H),4.90–4.40(m,3H),4.19–3.75(m,4H), 3.10(ddd,J＝19.3,12.6,6.7Hz,1H),2.62(d,J＝9.3Hz,3H),1.95(d,J＝186.1Hz,1H),1.21–0.75(m,7H). ¹³ C NMR (101MHz, CDCl ₃ ) δ175.2,150.7,150.4,142.7,142.4,141.8,140.4,136.1,135.0,134.8,128.4,128.1,127.7,127.2,126.6,124.3,122.9,110.6 ,110.5,109.1,108.8, 48.3,46.9,46.6,42.9,32.8,13.5,11.8,11.6,11.0,8.8,8.5,8.3.HRMS(ESI)[MH] ^- calcd for C ₂₉ H ₂₉ N ₃ O ₆ SCl:582.1466; found:582.1475.

Example 219

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)benzo[b ] Thiophene-2-carboxylic acid ethyl ester (M6-120)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3- Method used for methylbenzo[b]thiophene-2-carboxylic acid ethyl ester (M6-118), replacing 5-(chlorosulfonyl)-3-methylbenzo[b]thiophene-2-carboxylic acid ethyl ester with 5-(Chlorosulfonyl)benzo[b]thiophene-2-carboxylic acid ethyl ester, other conditions are the same. 249 mg of light yellow solid was obtained, with a yield of 37%. ¹ H NMR (400MHz, Chloroform-d) δ8.20 (d, J＝13.6Hz, 1H), 8.11 (d, J＝6.1Hz, 1H), 8.00 (dd, J＝8.5, 5.3Hz, 1H), 7.67(dd,J＝13.7,9.3Hz,1H),7.50–7.18(m,2H),7.18–7.05(m,1H),6.49–6.22(m,3H),5.25(dd,J＝150.2,17.7 Hz,1H),4.81(td,J＝21.3,20.2,6.0Hz,2H),4.71–4.38(m,3H),4.09–3.86(m,1H),3.18(ddp,J＝26.6,13.6,6.9 ,5.7Hz,1H),1.94(dtt,J＝193.5,8.1,4.6Hz,1H),1.43(t,J＝7.1Hz,3H),1.17–1.00(m,5H),0.94–0.75(m, 2H). ¹³ C NMR (101MHz, CDCl ₃ ) δ174.4,174.3,161.8,161.7,150.6,150.3,145.9,145.7,142.4,142.1,142.0,141.6,138.1,138.0,136.9,136.7,135 .5,135.3,135.0, 134.8, 134.7,133.9,130.0,130.0,128.4,128.0,127.7,127.4,127.1,125.6,125.6,124.8,123.5,110.4,110.3,108.8,108.4,62.0,47.9,46.8,46.6 ,45.8,44.8,42.4,14.2, 13.4,13.3,11.4,11.2,8.4,8.1,7.8.

Example 220

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-1,3 -Dimethyl-1H-indole-2-carboxylic acid (F44-S120)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl))cyclopropanecarboxamide (methyl)phenyl)-N-ethylsulfamoyl)benzo[b]thiophene-2-carboxylic acid ethyl ester (M6-120), and other conditions were consistent. 184 mg of light yellow solid was obtained, with a yield of 78%. ¹ H NMR(400MHz,Chloroform-d)δ8.21–7.32(m,4H),7.22–6.87(m,2H),6.60–5.97(m,3H),5.11(dd,J＝236.0,16.8Hz, 2H),4.76–4.40(m,2H),3.92(d,J＝31.2Hz,1H),3.10(s,1H),1.91(d,J＝189.6Hz,1H),0.95(q,J＝57.2 , 55.5Hz, 7H). ¹³ C NMR (101MHz, CDCL ₃ ) Δ175.2,150.6,142.8,141.6,138.8,135.2,110.6,108.8.8.3,46.9.9.6, 11.6,8.6.H RMS (RMS ESI)[MH] ^- calcd for C ₂₇ H ₂₄ N ₂ O ₆ S ₂ Cl:571.0764; found:571.0768.

Example 221

6-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)benzo[b ] Thiophene-2-carboxylic acid ethyl ester (M6-121)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3- Method used for methylbenzo[b]thiophene-2-carboxylic acid ethyl ester (M6-118), replacing 5-(chlorosulfonyl)-3-methylbenzo[b]thiophene-2-carboxylic acid ethyl ester with 6-(Chlorosulfonyl)benzo[b]thiophene-2-carboxylic acid ethyl ester, other conditions are the same. 340 mg of light yellow solid was obtained, with a yield of 51%. ¹ H NMR (400MHz, Chloroform-d) δ8.20 (d, J＝10.6Hz, 1H), 8.12 (s, 1H), 8.01 (dd, J＝8.4, 4.5Hz, 1H), 7.72–7.54 (m ,1H),7.43–7.00(m,3H),6.50–6.20(m,3H),5.24(dd,J＝154.3,17.7Hz,1H),4.81(ddd,J＝23.9,18.0,7.5Hz,2H ),4.71–4.35(m,3H),4.14–3.85(m,1H),3.19(ddt,J＝26.7,12.9,5.7Hz,1H),1.95(dtt,J＝192.7,8.1,4.6Hz,1H ),1.43(t,J＝7.1Hz,3H),1.18–0.99(m,5H),0.93–0.75(m,2H). ¹³ C NMR (101MHz, CDCl ₃ )δ174.3,174.2,161.6,161.6,150.5 ,150.3,142.4,142.1,141.9,141.5,141.4,138.5,138.3,135.7,135.4,135.2,134.9,134.8,134.7,129.3,128.4,128.1,127.6,127.3,127.0, 125.9,123.5,123.2,123.2,110.3 ,110.2,108.8,108.4,61.9,61.9,47.8,46.8,46.6,45.8,44.7,42.4,14.1,13.3,13.2,11.4,11.2,8.3,8.1,7.8.

Example 222

6-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-1,3 -Dimethyl-1H-indole-2-carboxylic acid (F44-S121)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 6-(N-(4-chloro-2-((N-(furan-2-ylmethyl))cyclopropanecarboxamide (methyl)phenyl)-N-ethylsulfamoyl)benzo[b]thiophene-2-carboxylic acid ethyl ester (M6-121), and other conditions were consistent. 275 mg of light yellow solid was obtained, with a yield of 84%. ¹ H NMR(400MHz,Chloroform-d)δ8.20–7.30(m,4H),7.23–6.84(m,2H),6.27(dd,J＝19.8,9.9Hz,3H),5.47–4.37(m, 4H), 3.93 (d, J＝31.0Hz, 1H), 3.11 (s, 1H), 1.90 (d, J＝188.2Hz, 1H), 1.25–0.48 (m, 7H). ¹³ C NMR (101MHz, CDCl ₃ )δ175.2, 150.6,142.8,142.4,141.6,135.3,123.5,110.6,109.3,48.3,46.9,42.9,13.6,11.8,8.7.HRMS(ESI)[MH] ^- calcd for C ₂₇ H ₂₄ N ₂ O ₆ S ₂ Cl: 571.0764; found:571.0770.

Example 223

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)benzofuran- 2-Ethyl formate (M6-122)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3- Method used for methylbenzo[b]thiophene-2-carboxylic acid ethyl ester (M6-118), replacing 5-(chlorosulfonyl)-3-methylbenzo[b]thiophene-2-carboxylic acid ethyl ester with 5-(Chlorosulfonyl)benzofuran-2-carboxylic acid ethyl ester, other conditions are the same. 210 mg of light yellow solid was obtained, with a yield of 28%. ¹ H NMR(400MHz,Chloroform-d)δ8.19–8.00(m,1H),7.82–7.67(m,2H),7.61(d,J＝4.4Hz,1H),7.45–7.19(m,2H) ,7.16–7.06(m,1H),6.50–6.19(m,3H),5.24(dd,J＝150.8,17.7Hz,1H),4.93–4.41(m,5H),4.09–3.85(m,1H) ,3.16(ddt,J＝26.8,11.9,6.9Hz,1H),1.93(dtt,J＝193.2,8.1,4.1Hz,1H),1.45(t,J＝7.1Hz,3H),1.16–1.00(m ,5H),0.93–0.75(m,2H). ¹³ C NMR (101MHz, CDCl ₃ ) δ174.4,174.4,158.7,158.6,157.2,157.1,150.6,150.3,147.9,147.8,142.5,142.1,142.0,141. 7, 135.6,135.4,135.0,134.7,133.7,132.9,128.4,128.0,127.8,127.7,127.4,127.2,127.1,126.8,123.9,123.8,113.5,113.5,113.0,113.0,1 10.4,110.3,108.9,108.5,62.0, 61.9,47.9,46.8,46.6,45.9,44.8,42.5,14.2,13.4,13.3,11.4,11.3,8.4,8.2,8.1,7.9.

Example 224

5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)benzofuran- 2-Carboxylic acid (F44-S122)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl))cyclopropanecarboxamide (methyl)phenyl)-N-ethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester (M6-122), and the other conditions were consistent. 169 mg of light yellow solid was obtained, with a yield of 84%. ¹ H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.77–7.28(m,4H),7.25–6.94(m,2H),6.63–5.95(m,3H),5.47–4.42( m,4H),3.94(ddd,J＝36.5,12.0,6.7Hz,1H),3.12(dq,J＝19.2,6.2Hz,1H),1.93(d,J＝190.9Hz,1H),1.22–0.75 (m,7H). ¹³ C NMR (101MHz, CDCl ₃ ) δ175.4,157.4,150.5,150.1,142.8,142.4,141.6,135.8,135.6,135.3,135.0,132.9,128.0,127.6,124.1,113.2,1 10.6,109.3 ,108.9,48.3,46.8,45.1,43.0,13.6,13.5,11.8,11.7,8.6.HRMS(ESI)[MH] ^- calcd for C ₂₇ H ₂₄ N ₂ O ₇ SCl:555.0993; found:555.1000.

Example 225

6-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Ethyl benzofuran-2-carboxylate (M6-123)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3- Method used for methylbenzo[b]thiophene-2-carboxylic acid ethyl ester (M6-118), replacing 5-(chlorosulfonyl)-3-methylbenzo[b]thiophene-2-carboxylic acid ethyl ester with 6-(Chlorosulfonyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester, the other conditions are the same. Obtained 222 mg of light yellow solid, yield 29%. ¹ H NMR (400MHz, Chloroform-d)δ7.85(d,J＝15.6Hz,1H),7.78(dd,J＝8.3,4.4Hz,1H),7.66–7.54(m,1H),7.44–7.21(m,2H), 7.17–7.06(m,1H),6.59–6.11(m,3H),5.24(dd,J＝144.0,17.6Hz,1H),4.96–4.71(m,2H),4.70–4.33(m,3H), 4.08–3.85(m,1H),3.32–3.04(m,1H),2.63(s,3H),2.24–1.66(m,1H),1.46(t,J＝7.1Hz,3H),1.16–0.99( m,5H),0.94–0.76(m,2H). ¹³ C NMR (101MHz, CDCl ₃ ) δ174.5,174.5,174.4,159.7,159.6,152.8,150.9,150.6,150.3,144.0,143.9,142.4,142.3,142. 2 ,142.0,141.9,141.6,139.2,136.8,135.8,135.5,135.2,135.0,134.7,133.1,132.9,128.9,128.3,128.0,127.8,127.8,127.7,127.5,127.1, 126.8,126.8,124.7,122.5,122.4 ,121.7,121.6,112.5,112.4,110.4,110.3,110.3,108.9,108.6,108.5,61.6,61.5,47.9,46.9,46.7,45.9,44.8,42.5,42.4,14.2,13.4,13.3, 11.4,11.3,11.2 ,9.2,8.4,8.3,8.2,8.1,7.9.

Example 226

6-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3-methyl Benzofuran-2-carboxylic acid (F44-S123)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 6-(N-(4-chloro-2-((N-(furan-2-ylmethyl))cyclopropanecarboxamide (methyl)phenyl)-N-ethylsulfamoyl)-3-methylbenzofuran-2-carboxylic acid ethyl ester (M6-123), and the other conditions were consistent. 177 mg of light yellow solid was obtained, with a yield of 84%. ¹ H NMR (400MHz, Chloroform-d) δ7.87 (d, J = 9.9 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.58 (dd, J = 15.4, 8.1 Hz, 1H), 7.35(d,J＝44.5Hz,1H),7.25–6.97(m,2H),6.53–6.12(m,3H),5.25(dd,J＝148.3,17.5Hz,1H),4.95–4.35(m, 3H),3.95(ddt,J＝34.0,13.2,6.9Hz,1H),3.15(ddq,J＝26.1,12.9,6.8,6.3Hz,1H),2.65(s,3H),2.24–1.66(m, 1H),1.21–0.78(m,7H). ¹³ C NMR (101MHz, CDCl ₃ ) δ175.5,175.4,153.3,150.8,150.6,142.8,142.4,142.3,141.6,135.5,135.4,133.4,127.4,122.7 ,121.9 , 112.9,110.7,110.6,109.3,108.9,48.3,47.1,46.9,45.1,43.0,13.5,11.8,11.7,9.5,8.6.HRMS(ESI)[MH] ^- calcd for C ₂₈ H ₂₆ N ₂ O ₇ SCl: 569.1149; found:569.1153.

Example 227

6-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)benzofuran- 2-Ethyl formate (M6-124)

According to 5-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)-3- Method used for methylbenzo[b]thiophene-2-carboxylic acid ethyl ester (M6-118), replacing 5-(chlorosulfonyl)-3-methylbenzo[b]thiophene-2-carboxylic acid ethyl ester with 6-(Chlorosulfonyl)methylbenzofuran-2-carboxylic acid ethyl ester, the other conditions are the same. 55 mg of light yellow solid was obtained, with a yield of 16%. ¹ H NMR (400MHz, Chloroform-d) δ7.92 (d, J＝16.8Hz, 1H), 7.83 (dd, J＝8.3, 4.4Hz, 1H), 7.67–7.56 (m, 2H), 7.36–7.23 (m,2H),7.10(tt,J＝8.5,5.0Hz,1H),6.47–6.22(m,3H),5.25(dd,J＝134.4,17.6Hz,1H),4.93–4.30(m,5H ),4.07–3.85(m,1H),3.29–3.06(m,1H),2.21–1.63(m,1H),1.45(t,J＝7.1Hz,3H),1.16–1.01(m,5H), 0.84 (dd, J=38.0, 7.0Hz, 2H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 174.8, 174.7, 158.9, 158.8, 154.4, 151.1, 150.8, 150.5, 149.1, 149.0, 142.6, 142.4, 142.3, 14 2.2 ,142.1,141.8,139.5,136.9,136.5,136.0,135.6,135.4,135.3,135.0,131.2,131.0,129.1,128.5,128.1,128.0,127.8,127.7,127.5,127.4, 127.0,127.0,123.5,123.3,123.2 ,113.1,113.1,113.0,112.9,110.6,110.5,110.4,109.0,108.8,108.7,108.5,62.2,62.2,48.0,47.1,46.8,46.1,45.0,42.7,42.5,29.8,14.4 ,13.6,13.5,13.5 ,11.6,11.5,11.4,8.6,8.5,8.3,8.2,8.0.

Example 228

6-(N-(4-chloro-2-((N-(furan-2-ylmethyl)cyclopropanecarboxamido)methyl)phenyl)-N-ethylsulfamoyl)methylbenzo Furan-2-carboxylic acid (F44-S124)

According to 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzoylamino)methyl)phenyl)-N-ethylsulfamoyl) The method used for benzoic acid (F44-S35), 4-(N-(4-chloro-2-((2-chloro-N-(furan-2-ylmethyl)benzamido)methyl)phenyl )-N-ethylsulfamoyl)ethyl benzoate (F44-S26) replaced with 6-(N-(4-chloro-2-((N-(furan-2-ylmethyl))cyclopropanecarboxamide (methyl)phenyl)-N-ethylsulfamoyl)benzofuran-2-carboxylic acid ethyl ester (M6-124), and the other conditions were consistent. 39 mg of light yellow solid was obtained, with a yield of 78%. ¹ H NMR (400MHz, Chloroform-d) δ7.91 (d, J＝7.8Hz, 1H), 7.86–7.72 (m, 1H), 7.72–7.45 (m, 2H), 7.41–7.29 (m, 1H) ,7.25–6.95(m,2H),6.58–6.09(m,3H),5.23(dd,J＝160.6,17.1Hz,1H),4.97–4.34(m,3H),3.95(ddt,J＝35.5, 14.3, 7.1Hz, 1H), 3.15 (ddd, J＝20.9, 13.1, 7.1Hz, 1H), 2.25–1.64 (m, 1H), 1.22–0.76 (m, 7H). ¹³ C NMR (101MHz, CDCl ₃ )δ175.7,175.5,154.5,150.8,150.5,142.5,142.3,141.5,139.1,135.5,131.3,123.6,113.6,113.1,110.7,110.6,110.6,109.3,109.1,48.3,4 6.9,42.9,29.8,13.6,11.9 ,11.7,8.6.HRMS(ESI)[MH] ^- calcd for C ₂₇ H ₂₄ N ₂ O ₇ SCl:555.0993; found:555.0991.

In addition, the following compounds can be prepared by referring to the above-mentioned synthesis methods.

In addition, the inventor of the present application also prepared the following compounds by referring to the above-mentioned synthesis method.

biologically active part

1.1 FXR activity evaluation

FXR activity was evaluated by time-resolved fluorescence resonance energy transfer (TR-FRET) experiment, using LanthaScreen ^TM TR-FRET FXR co-activation experiment kit (ThermoFisher, Cat. PV4833). For agonist screening, take a 384-well black plate (Coring), add 10 μL of Complete Coregulator buffer G containing the corresponding concentration of the compound to be tested, 5 μL of 20nM FXR-LBD Complete Coregulator buffer G, and 5 μL of 2.0 μM Fluorescein-SRC2-2/20nM Tb into each well. -anti-GST antibody Complete Coregulator buffer G, after incubation at room temperature for 1 hour, the fluorescence value at 520nm and 495nm is detected by a microplate reader. The measured value is expressed as 520nm/495nm. There were three duplicate wells for each compound, with CDCA as the positive compound and DMSO as the solvent control. For antagonist screening, take a 384-well black plate (Coring), add 5 μL of Complete Coregulator buffer G containing the corresponding concentration of the compound to be tested, 5 μL of 20nM FXR-LBD Complete Coregulator buffer G, and 5 μL of 200 μM CDCA FXR-LBD Complete Coregulator buffer G into each well. 5μL 2.0μM Fluorescein-SRC2-2/20nM Tb-anti-GST antibody Complete Coregulator buffer G, incubate at room temperature for 10h, and screen with agonists.

Compounds with lower EC ₅₀ values in the above experiments have better FXR antagonist activity.

1.2 Cell culture and passage

The human embryonic kidney cell line HEK293A was subcultured in MEM medium containing penicillin (final concentration: 100 U/mL), streptomycin (final concentration: 100 μg/mL) and 10% FBS, placed in 95% air and 5 Incubate at 37°C in a humidified atmosphere of % carbon dioxide. When the cells are 90% confluent, discard the old culture medium and wash the cells twice with 2 mL of PBS. After discarding the PBS, add 2 mL of 0.25% trypsin-0.25% EDTA mixed digestion solution and observe under a microscope. When the cells become round, Quickly add 2mL Complete medium was used to terminate digestion, and cells were collected by gently pipetting. Centrifuge at 800 rpm, 4°C for 5 minutes, discard the supernatant, resuspend the cells in complete culture medium, culture in separate bottles, and change the medium every other day.

The human hepatoma cell line HepG2 was subcultured in DMEM medium containing penicillin (final concentration: 100 U/mL), streptomycin (final concentration: 100 μg/mL) and 10% FBS, and was the same as HEK293A subculture.

1.3 Cell proliferation inhibition experiment

The cell proliferation inhibitory ability of compounds was detected by MTT assay. HepG2 and HEK293 cells were seeded in a 96-well plate at a density of 30%. After incubation for 18 hours to allow the cells to adhere, the original culture medium was removed and a given concentration of the compound to be tested was added to each well. An equal amount of DMSO was added to the control group. Three replicate wells were set up for each compound. After 48 hours of administration, the cell viability was detected by the MTT method. The blank group was the well where no cells were added, and then the OD value was read at 490 nm with a microplate reader. The calculation formula of cell viability is: cell viability (%) = (OD _{to be tested} - OD _blank ) / (OD _control - OD _blank ) × 100.

In the above experiments, compounds with high HEK293 cell viability and high CC ₅₀ values have better safety. Compounds with higher inhibition rates on HepG2 cells and lower EC ₅₀ values can better inhibit the proliferation of tumor cells.

1.4 Cell TC/TG detection

Cellular TC/TG was detected using Nanjing Jiancheng TG test kit and TC test kit. HepG2 cells were incubated with 0.5 mmol/L FFA (oleic acid and palmitate mixed at a ratio of 2:1) and solvent or compounds of different concentrations (20 μM, 40 μM, 80 μM) for 24 h. Aspirate the culture medium and wash the cells with 0.01M, pH 7.4 PBS. Scrape the cells with a cell scraper, add 2-5mL, 0.01M, pH 7.4 PBS, collect the cell suspension, centrifuge at 1000×g, 4℃ for 10 minutes to collect the cells, and add 300-500μL homogenization medium according to ¹⁰⁶ cells. Add isopropyl alcohol at a certain ratio, perform mechanical homogenization, and fully disrupt until there is no obvious cell precipitation. Centrifuge at 10000×g, 4°C for 10 minutes, take the supernatant and place it on ice for testing. Take 2.5 μL of distilled water, standards or samples, mix them with 250 μL of distilled water, incubate at 37°C for 10 minutes, and measure the absorbance value of each well with a microplate reader at 510 nm. TC/TG concentration calculation formula: sample concentration (mmol/g protein) = (OD _sample -OD _blank )/(OD _standard -OD _blank ) × standard concentration (mmol/L)/protein concentration (g protein/L).

BCA method protein quantification

Preparation of protein standard: a. Add 1.2 mL of protein standard preparation solution into a tube of protein standard (30 mg BSA), fully dissolve it and prepare a 25 mg/mL protein standard solution. b. Take an appropriate amount of 25mg/mL Protein standard, diluted to a final concentration of 0.5 mg/mL. Preparation of BCA working solution: According to the number of samples, prepare an appropriate amount of BCA working solution by adding 50 volumes of BCA reagent A and 1 volume of BCA reagent B (50:1), and mix thoroughly. Determination of protein concentration: a. Add 0, 1, 2, 4, 8, 12, 16, and 20 μL of standard into the standard wells of the 96-well plate, and add standard diluent to make up to 20 μL, which is equivalent to the concentration of the standard. They are 0, 0.025, 0.05, 0.1, 0.2, 0.3, 0.4, and 0.5 mg/mL respectively. b. Add appropriate volume of sample to the sample well of the 96-well plate. If the sample is less than 20 μL, add standard diluent to make up to 20 μL. c. Add 200 μL BCA working solution to each well and place at 37°C for 20-30 minutes. d. Use a microplate reader to measure the absorbance at the wavelength of A562nm. e. Calculate the protein concentration of the sample based on the standard curve and the sample volume used.

In the above experiments, compounds with higher TC/TG reduction rates and lower EC ₅₀ values can better reduce the fat content in the blood and/or liver.

1.5 Animal experiments on acute hyperlipidemia

Male C57BL/6 mice were randomly divided into 8 groups, Control group, Model group, SIPI-7623 group (10mg/kg, 30mg/kg and 100mg/kg) and test substance group (3 doses). The Model group, SIPI-7623 group and test group were intraperitoneally injected with 600mg/kg Triton WR-1339, and the Control group was injected with the same volume of normal saline. The compounds were administered intragastrically 1 hour before and 23 hours after the induction agent injection, and blood and tissue samples were collected 1 hour later.

1.6 High-fat diet animal experiments

Male C57BL/6 mice were randomly divided into 6 groups, Control group, HFD group, SIPI-7623 group (40 mg/kg) and test substance group (3 doses). The control group was given a normal diet, and the HFD group, SIPI-7623 group and test substance group were given a high-fat diet. The Control group and HFD group were given solvent by gavage, and the other groups were given corresponding doses of compounds. The mouse body weight was recorded every day. After 8 weeks of oral administration of the compound, blood and tissue samples were collected. The ingredients of high-fat diet are shown in Table 1.1.

Table 1.1 Formula composition of mouse normal chow (Standard chow) and high fat diet (High fat diet)

1.7 Animal experiments on diet-induced obesity

Male C57BL/6 mice were divided into 2 groups, the Control group was fed a normal diet, and the HFD group was given a high-fat diet. After 12 weeks of high-fat diet, the HFD group was randomly divided into 9 groups: HFD group, test substance group (3 doses), SIPI-7623 (40mg/kg), Atorvastatin (10mg/kg) and test substance (10mg/kg). kg)+Atorvastatin(10mg/kg). The Control group and HFD group were given solvent by gavage, and the other groups were given corresponding doses of compounds. The body weight of the mice was recorded weekly. After 8 weeks of oral administration of the compound, blood and tissue samples were collected. The ingredients of high-fat diet are shown in Table 1.1.

1.8 db/db mouse animal experiment

Male db/db mice were randomly divided into 5 groups, and the experimental groups were db/db group, test substance group (3 doses) and pioglitazone (7 mg/kg). The db/db group was given intragastric treatment with solvent, and the other groups were given intragastric treatment with corresponding compounds for 4 weeks. The body weight of the mice was recorded weekly, and fasting blood glucose was measured. Four weeks after compound administration, blood and tissue samples were collected for subsequent experiments.

1.9 Mouse blood glucose measurement

1. Roche blood glucose meter includes: blood glucose meter, blood collection pen, and blood glucose test strips.

2. Wipe the tail tip of the mouse with an alcohol cotton ball, open the sampling needle on the lancing pen, and prick the tail tip of the mouse; dip the blood glucose test paper into the tail tip blood, and the blood must completely cover the test area of the test paper; turn on the blood glucose meter and collect the blood glucose The test strip is inserted into the blood glucose meter to read and record the blood glucose value. The sampling needle and blood glucose test paper should be replaced before measuring blood glucose in each mouse.

2.0 Glucose tolerance test (Glucose tolerance test, GTT)

The glucose tolerance test was performed on the 5th week after intragastric administration of the test substance (the 17th week of the experiment). After the mice were fasted for 16 hours, glucose (1.5g/kg) was injected intraperitoneally. The blood glucose levels of the mice were measured with a blood glucose meter at 0, 15, 30, 60, 90, and 120 minutes after glucose injection.

2.1 Insulin tolerance test (ITT)

The insulin tolerance test was performed on the 6th week after intragastric administration of the test substance (the 18th week of the experiment). After the mice were fasted for 4 hours, insulin (1 U/kg) was injected intraperitoneally. The blood glucose levels of the mice were measured with a blood glucose meter at 0, 15, 30, 60, 90, and 120 minutes after insulin injection.

2.2 Animal materials

1. After weighing the mice, anesthetize them by intraperitoneal injection of sodium pentobarbital.

2. Take blood from the inner canthus, take 20 μL of whole blood, dilute it with whole blood diluent, and conduct routine blood tests; the remaining whole blood is allowed to stand at room temperature for 2 hours, 3000 rpm, 4°C, and centrifuged for 10 minutes, and the upper serum is taken for blood biochemical testing.

3. After collecting blood from the mice, open the chest and abdominal cavities and remove the liver, intestines, white fat and brown adipose tissue respectively.

4. Separate a part of the liver and fix it in 4% formaldehyde for paraffin sectioning and frozen sectioning. The remaining tissue is frozen at -80°C.

5. After washing the intestinal tissue with PBS, scrape the intestinal epithelial cells and freeze them at -80°C.

6. Weigh the white adipose and brown adipose tissue.

2.3 Detection of cholesterol and triglycerides in liver

1. Take an appropriate amount of liver tissue, add grinding beads and use PBS as buffer to homogenize the tissue.

2. Divide the homogenate into two parts, add one part to chloroform and methanol for extraction, and measure cholesterol and triglycerides. Add 4 times the volume of chloroform-methanol extract (chloroform:methanol=2:1) to one of the tubes, vortex to mix thoroughly, let stand until layered, centrifuge at 2000 rpm, 4°C for 30 minutes, suck out the lower liquid and place it in a new tube. Centrifuge the tube, evaporate the clean solvent in a vacuum concentrator, add an appropriate amount of 3% Triton X-100, and dissolve in a constant temperature water bath shaker at 50-60°C. Determine concentration using TC and TG kits.

5. Take another tube of homogenate, centrifuge at 12000 rpm, 4°C for 15 minutes, take the supernatant, and use the BCA kit to measure the protein concentration.

6. Lipid content = lipid concentration/protein concentration

2.4 Oil Red O staining of liver

1. Take fresh liver tissue from the same part and size and fix it in 4% neutral formaldehyde. Send it to a testing company to prepare sections and stain with Oil Red O.

2. Take back the prepared slices, scan them with a scanner and take pictures.

2.5 Tissue HE staining

1. Take fresh liver tissue of the same size from the same part, place it in 4% neutral formaldehyde and fix it, then send it to a testing company to prepare sections and perform HE staining.

2. Take back the prepared slices, scan them with a scanner and take pictures.

Results and discussion

FXR antagonist activity results and discussion

A:0.1μM<IC ₅₀ <10μM

B:10μM<IC ₅₀ <50μM

C:50μM<IC ₅₀ <100μM

Table 1.2 FXR antagonist activity of the compounds of the present invention

Table 1.3 FXR antagonist activity of the compounds of the present invention

^a Data are expressed as the geometric mean of at least two independent runs. ^b Z-GS, SIPI-7623 and
Centatin is a positive control. SIPI-7623 is in Phase I clinical research and Centatin is in Phase III clinical research.

Experimental results show that the compound of the present invention has one or more of the following effects:

(1) Has good FXR antagonist activity;

(2) Has good safety;

(3) Can improve glucose tolerance;

(4) Can improve insulin resistance;

(5) Can lower blood sugar levels;

(6) Can lower blood lipid levels;

(7) It can reduce the fat content in the liver;

(8) Can inhibit the proliferation of tumor cells.

In summary, the compounds of the present invention can be used as FXR modulators for preventing and/or treating FXR-related diseases, such as tumors or metabolic diseases.

Although the specific embodiments of the present invention have been described in detail, those skilled in the art will understand that various modifications and substitutions can be made to those details based on all teachings that have been disclosed, and these changes are within the scope of the present invention. . The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims

A compound represented by formula I, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable ester of said compound,

in:

L is selected from Among them, X is connected to the benzene ring, and Y is connected to R 4 ;

Preferably, L is Among them, X is connected to the benzene ring, and Y is connected to R 4 ;

X is selected from

Preferably, X is

Y is selected from

Preferably, Y is selected from

More preferably, Y is

R 5 is selected from hydrogen, C1-C6 alkyl;

Preferably, R 5 is selected from hydrogen, methyl, ethyl, n-propyl;

R 1a and R 1b are each independently selected from hydrogen, halogen, C1-C6 alkoxy, -NR a R b ; or, R 1a , R 1b and the carbon atoms to which they are respectively connected together form a 5-6-membered heterogeneous ring;

Preferably, R 1a is selected from hydrogen, halogen, C1-C6 alkoxy, -NR a R b ;

More preferably, R 1a is selected from hydrogen, chlorine, methoxy, -NR a R b ;

Most preferably, R 1a is selected from hydrogen, chlorine, methoxy,

Preferably, R 1b is selected from hydrogen, C1-C6 alkoxy, -NR a R b ;

More preferably, R 1b is selected from hydrogen, methoxy, -NR a R b ;

Most preferably, R 1b is selected from hydrogen, methoxy,

Preferably, R 1a , R 1b and the carbon atoms to which they are respectively connected form a 5-membered heterocyclic ring. Preferably, the 5-membered heterocyclic ring contains 1-2 (preferably 2) heteroatoms. Preferably, the 5-membered heterocyclic ring contains 1-2 (preferably 2) heteroatoms. The heteroatoms are selected from O and S;

More preferably, R 1a , R 1b and the carbon atoms to which they are respectively connected together form

Most preferably, R 1a , R 1b and the carbon atoms to which they are respectively connected together form

R a and R b are each independently selected from C1-C6 alkyl groups, or R a , R b and the nitrogen atoms they are commonly connected to form a 4-7 membered nitrogen-containing heterocyclic ring;

Preferably, R a and R b are each independently selected from C1-C6 alkyl groups, or R a , R b and the nitrogen atoms they are commonly connected together form a 5-6 membered nitrogen-containing heterocyclic ring;

More preferably, R a and R b are each independently selected from C1-C6 alkyl groups, or R a , R b and the nitrogen atoms they are commonly connected to form a 5-6 membered nitrogen-containing saturated heterocyclic ring, preferably, The nitrogen-containing saturated heterocyclic ring contains 1-3 (such as 1) heteroatoms. Preferably, the heteroatoms are nitrogen atoms;

Most preferably, R a and R b are each independently selected from methyl, ethyl, n-propyl, or R a , R b and the nitrogen atom they are commonly connected to form

R 2 is selected from -(CH 2 ) n -R 6 ;

n is selected from 1, 2, 3, 4, 5, 6;

Preferably, n is selected from 1, 2, and 3;

More preferably, n is selected from 1 and 2;

Most preferably, n is 1;

R 6 is selected from 5-6 membered heteroaryl, phenyl, C1-C6 alkyl, optionally, the 5-6 membered heteroaryl and phenyl are each independently substituted by R c ;

Preferably, R 6 is selected from 5-membered heteroaryl, phenyl, C1-C6 alkyl, optionally, the 5-membered heteroaryl and phenyl are each independently substituted by R c ;

More preferably, R 6 is selected from furyl, thienyl, phenyl, C1-C6 alkyl, pyrrolyl, optionally, the furyl, thienyl, pyrrolyl are each independently substituted by R c ;

Further preferably, R 6 is selected from optionally, Each is independently replaced by R c ;

More preferably, R 6 is selected from

Most preferably, R6 is

R c is selected from halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl;

Preferably, R c is selected from halogen, nitro, C1-C6 alkyl, C1-C6 haloalkyl;

More preferably, R c is selected from bromine, chlorine, nitro, methyl, and trifluoromethyl;

More preferably, R c is selected from bromine, chlorine, and methyl;

Preferably, R 2 is selected from

More preferably, R 2 is

R 3 is selected from phenyl, 5-6 membered heteroaryl, C1-C6 alkyl, -NR m R n , C3-C10 cycloalkyl, C1-C6 alkoxy, C2-C6 alkenyl, optionally , the phenyl group and the 5-6 membered heteroaryl group are each independently substituted by 1-2 groups selected from Rx ;

Preferably, R 3 is selected from phenyl, pyridyl, furyl, thienyl, C1-C6 alkyl, -NR m R n , C3-C6 cycloalkyl, C1-C6 alkoxy, C2-C6 alkenyl , optionally, the phenyl, pyridyl, furyl, and thienyl groups are each independently substituted by 1-2 groups selected from R x ;

Or preferably, R 3 is selected from phenyl, pyridyl, furyl, and thienyl. Optionally, the phenyl, pyridyl, furyl, and thienyl groups are each independently replaced by 1-2 selected from R x replaced by a group;

More preferably, R 3 is selected from phenyl, pyridyl, furyl, thienyl, C1-C6 alkyl, -NR m R n , C3-C6 cycloalkyl, C1-C4 alkoxy, C2-C6 alkene group, optionally, the phenyl group and furyl group are each independently substituted by 1-2 groups selected from R x ;

Or more preferably, R 3 is selected from phenyl, pyridyl, furyl, and thienyl. Optionally, the phenyl and furyl groups are each independently substituted by 1-2 groups selected from R x ;

Further preferably, R 3 is selected from methyl, -NR m R n , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) 3 CH 3 , -CH＝CH 2 , -C＝CH 2 CH 3 , -OC (CH 3 ) 3 , optionally, the Each is independently substituted by 1-2 groups selected from R x ;

Or further preferably, R 3 is selected from Optionally, the Each is independently substituted by 1-2 groups selected from R x ;

Most preferably, R3 is selected from methyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) 3 CH 3 , -CH＝CH 2 , -C＝CH 2 CH 3 , -OC(CH 3 ) 3 ;

Or most preferably, R3 is selected from Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) 3 CH 3 , -CH＝CH 2 , -C＝CH 2 CH 3 , -OC(CH 3 ) 3 ;

Or most preferably, R3 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, -(CH 2 ) 3 CH 3 , -CH＝CH 2 , -C＝CH 2 CH 3 , -OC(CH 3 ) 3 ;

R m and R n are each independently selected from C1-C6 alkyl, or R m , R n and the nitrogen atoms they are jointly connected with form a 4-7 membered nitrogen-containing heterocyclic ring, optionally the 4-7 Any -CH 2 - in the nitrogen-containing heterocycle is replaced by -O-;

Preferably, R m and R n are each independently selected from C1-C6 alkyl, or R m , R n and the nitrogen atoms they are commonly connected together form a 5-6 membered nitrogen-containing heterocyclic ring, optionally as described Any one -CH 2 - in the 5-6 membered nitrogen-containing heterocycle is replaced by -O-;

More preferably, R m and R n are each independently selected from C1-C6 alkyl, or R m , R n and the nitrogen atoms they are commonly connected together form a 6-membered nitrogen-containing saturated heterocyclic ring, optionally said Any one -CH 2 - in the 6-membered nitrogen-containing heterocycle is substituted by -O-. Preferably, the nitrogen-containing saturated heterocycle contains 1-3 (such as 1) heteroatoms. Preferably, the heteroatoms is a nitrogen atom;

Most preferably, R m and R n are both methyl or ethyl, or R m , R n and the nitrogen atoms they are commonly connected to form

R x is selected from halogen, nitro, C1-C6 alkyl, C1-C6 alkoxy, -NR s R t , C1-C6 haloalkyl;

Preferably, Rx is selected from fluorine, chlorine, methyl, methoxy, nitro, Trifluoromethyl, bromine;

Preferably, Rx is selected from chlorine and bromine;

R s and R t are each independently selected from C1-C6 alkyl;

Preferably, R s and R t are both methyl;

R 4 is selected from:

1)

R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, C1-C6 alkyl, halogen, carboxyl, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-N (R u )-, C1-C6 alkyl-C(=O)-C1-C6 alkyl, R v R w NC(=O)-N(R y )-, C1-C6 alkyl-OC(= O)-, C1-C6 alkyl-OC(=O)-C1-C6 alkyl, HO-C(=O)-C1-C6 alkyl, C1-C6 alkyl-OC(=O)-C1- C6 alkyl-C(=O)-N(R y )-, HO-C(=O)-C1-C6 alkyl-C(=O)-N(R y )-, C1-C6 alkyl- C(=O)-N(R y )-C(=O)-N(R y )-, C1-C6 alkyl- C(=O)-N(R y )-C(=O)-C1-C6 alkyl, C1-C6 alkyl-C(=O)-C1-C6 alkyl-C(=O)-N( R y )-, R v R w NC(=O)-, C1-C6 alkyl-C(=O)-N(R y )-C(=O)-, C1-C6 alkyl-C(= O)-, and R 7 , R 8 , R 9 , R 10 , and R 11 are not hydrogen at the same time;

Preferably, R 8 and R 9 are each independently selected from hydrogen, C1-C6 alkyl, halogen, carboxyl, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-N(R u )-, C1-C6 alkyl-C(=O)-C1-C6 alkyl, R v R w NC(=O)-N(R y )-, C1-C6 alkyl-OC(=O)-, C1- C6 alkyl-OC(=O)-C1-C6 alkyl, HO-C(=O)-C1-C6 alkyl, C1-C6 alkyl-OC(=O)-C1-C6 alkyl-C( =O)-N(R y )-, HO-C(=O)-C1-C6 alkyl-C(=O)-N(R y )-, C1-C6 alkyl-C(=O)- N(R y )-C(=O)-N(R y )-, C1-C6 alkyl-C(=O)-N(R y )-C(=O)-C1-C6 alkyl, C1 -C6 alkyl-C(=O)-C1-C6 alkyl-C(=O)-N(R y )-, R v R w NC(=O)-, C1-C6 alkyl-C(= O)-N(R y )-C(=O)-, C1-C6 alkyl-C(=O)-, and R 8 and R 9 are not hydrogen at the same time, R 7 , R 10 , R 11 are hydrogen ;

More preferably, R 9 is selected from hydrogen, carboxyl, C1-C6 alkyl-C(=O)-N(R u )-, C1-C6 alkyl-C(=O)-C1-C6 alkyl, R v R w NC(=O)-N(R y )-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-OC(=O)-C1-C6 alkyl, HO-C (=O)-C1-C6 alkyl, C1-C6 alkyl-OC(=O)-C1-C6 alkyl-C(=O)-N(R y )-, HO-C(=O)- C1-C6 alkyl-C(=O)-N(R y )-, C1-C6 alkyl-C(=O)-N(R y )-C(=O)-N(R y )-, C1-C6 alkyl-C(=O)-N(R y )-C(=O)-C1-C6 alkyl, C1-C6 alkyl-C(=O)-C1-C6 alkyl-C( =O)-N(R y )-, R v R w NC(=O)-, C1-C6 alkyl-C(=O)-N(R y )-C(=O)-, C1-C6 Alkyl-C(=O)-, R 8 is selected from hydrogen, C1-C6 alkyl, halogen (preferably chlorine), C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-N(R u )-, and R 8 and R 9 are not hydrogen at the same time, R 7 , R 10 and R 11 are hydrogen;

Or more preferably, R 9 is selected from carboxyl, C1-C6 alkyl-C(=O)-N(R u )-, C1-C6 alkyl-C(=O)-C1-C6 alkyl, R v R w NC(=O)-N(R y )-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-OC(=O)-C1-C6 alkyl, HO-C( =O)-C1-C6 alkyl, C1-C6 alkyl-OC(=O)-C1-C6 alkyl-C(=O)-N(R y )-, HO-C(=O)-C1 -C6 alkyl-C(=O)-N(R y )-, C1-C6 alkyl-C(=O)-N(R y )-C(=O)-N(R y )-, C1 -C6 alkyl-C(=O)-N(R y )-C(=O)-C1-C6 alkyl, C1-C6 alkyl-C(=O)-C1-C6 alkyl-C(= O)-N(R y )-, R v R w NC(=O)-, C1-C6 alkyl-C(=O)-N(R y )-C(=O)-, C1-C6 alkyl Group -C(=O)-, R 7 , R 8 , R 10 , R 11 are hydrogen;

Most preferably, R 9 is selected from hydrogen, carboxyl, R 8 is selected from hydrogen, methyl, chlorine, And R 8 and R 9 are not hydrogen at the same time, and R 7 , R 10 and R 11 are hydrogen;

Or most preferably, R 9 is selected from carboxyl, R 7 , R 8 , R 10 and R 11 are hydrogen;

R u is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;

Preferably, R u is selected from hydrogen, methyl, and trifluoromethyl;

R y is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;

Preferably, R y is selected from hydrogen and trifluoromethyl;

R v and R w are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;

Preferably, R v and R w are each independently selected from hydrogen, methyl, ethyl, and trifluoromethyl;

Most preferably, As a whole, selected from the following:

Or, choose from:

2)

X 1 selected from

Preferably, X 1 is

R z is selected from C1-C6 alkyl, C1-C6 alkyl-C(=O)-;

Preferably, Rz is selected from methyl and acetyl;

R 12 , R 13 , R 14 and R 15 are each independently selected from hydrogen and C1-C6 alkyl;

Preferably, R 12 , R 13 , R 14 and R 15 are all hydrogen;

Most preferably, as a whole, selected from

3)

X 2 selected from

Preferably, X 2 is

R q is selected from C1-C6 alkyl;

R 16 , R 17 , and R 18 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl;

Preferably, R 16 , R 17 , and R 18 are each independently selected from hydrogen, halogen, and C1-C6 haloalkyl;

More preferably, R 16 is selected from hydrogen, halogen, C1-C6 haloalkyl, R 17 and R 18 are hydrogen;

Most preferably, R 16 is selected from hydrogen, chlorine, and trifluoromethyl, and R 17 and R 18 are hydrogen;

R 19 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl;

Preferably, R 19 is selected from hydrogen, chlorine, methyl, and trifluoromethyl;

R 20 is selected from carboxyl, C1-C6 alkyl-OC(=O)-, HO-C1-C6 alkyl,

Preferably, R 20 is selected from carboxyl,

Most preferably, as a whole, selected from

Most preferably, as a whole, selected from

Most preferably, as a whole, selected from

Among them, X is And Y is When , the compound represented by formula I is not the following compound:
The compound according to claim 1, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable ester of the compound, wherein, The compound has the structure shown in formula I-1:

in:

The definitions of X, Y, R 1a , R 1b , R 2 , R 3 and R 4 are as defined in claim 1,

And, X is And Y is When , the compound represented by formula I-1 is not the following compound:
The compound according to claim 1, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable ester of the compound, wherein, The compound has the structure shown in formula I-1-1:

in:

The definitions of R 1a , R 1b , R 2 and R 5 are as defined in claim 1;

R 3 is selected from phenyl, 5-6 membered heteroaryl, C1-C6 alkyl, -NR m R n , C3-C10 cycloalkyl, C1-C6 Alkoxy group, C2-C6 alkenyl group, optionally, the phenyl group and 5-6 membered heteroaryl group are each independently substituted by 1-2 groups selected from R x ;

Preferably, R 3 is selected from phenyl, pyridyl, furyl, thienyl, C1-C6 alkyl, -NR m R n , C3-C6 cycloalkyl, C1-C6 alkoxy, C2-C6 alkenyl , optionally, the phenyl, pyridyl, furyl, and thienyl groups are each independently substituted by 1-2 groups selected from R x ;

Or preferably, R 3 is selected from phenyl, pyridyl, furyl, and thienyl. Optionally, the phenyl, pyridyl, furyl, and thienyl groups are each independently replaced by 1-2 selected from R x replaced by a group;

More preferably, R 3 is selected from phenyl, pyridyl, furyl, thienyl, C1-C6 alkyl, -NR m R n , C3-C6 cycloalkyl, C1-C4 alkoxy, C2-C6 alkene group, optionally, the phenyl group and furyl group are each independently substituted by 1-2 groups selected from R x ;

Or more preferably, R 3 is selected from phenyl, pyridyl, furyl, and thienyl. Optionally, the phenyl and furyl groups are each independently substituted by 1-2 groups selected from R x ;

Further preferably, R 3 is selected from methyl, -NR m R n , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) 3 CH 3 , -CH＝CH 2 , -C＝CH 2 CH 3 , -OC (CH 3 ) 3 , optionally, the Each is independently substituted by 1-2 groups selected from R x ;

Or further preferably, R 3 is selected from Optionally, the Each is independently substituted by 1-2 groups selected from R x ;

Most preferably, R3 is selected from methyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) 3 CH 3 , -CH＝CH 2 , -C＝CH 2 CH 3 , -OC(CH 3 ) 3 ;

Or most preferably, R3 is selected from Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) 3 CH 3 , -CH＝CH 2 , -C＝CH 2 CH 3 , -OC(CH 3 ) 3 ;

Or most preferably, R3 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, -(CH 2 ) 3 CH 3 , -CH＝CH 2 , -C＝CH 2 CH 3 , -OC(CH 3 ) 3 ;

The definitions of R m , R n and R x are as defined in claim 1;

R 4 is selected from:

1)

R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, C1-C6 alkyl, halogen, carboxyl, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-N (R u )-, C1-C6 alkyl-C(=O)-C1-C6 alkyl, R v R w NC(=O)-N(R y )-, C1-C6 alkyl-OC(= O)-, C1-C6 alkyl-OC(=O)-C1-C6 alkyl, HO-C(=O)-C1-C6 alkyl, C1-C6 alkyl-OC(=O)-C1- C6 alkyl-C(=O)-N(R y )-, HO-C(=O)-C1-C6 alkyl-C(=O)-N(R y )-, C1-C6 alkyl- C(=O)-N(R y )-C(=O)-N(R y )-, C1-C6 alkyl-C(=O)-N(R y )-C(=O)-C1 -C6 alkyl, C1-C6 alkyl -C(=O)-C1-C6 alkyl-C(=O)-N(R y )-, R v R w NC(=O)-, C1-C6 Alkyl-C(=O)-N(R y )-C(=O)-, and R 7 , R 8 , R 9 , R 10 , and R 11 are not hydrogen at the same time;

Preferably, R 8 and R 9 are each independently selected from hydrogen, C1-C6 alkyl, halogen, carboxyl, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-N(R u )-, C1-C6 alkyl-C(=O)-C1-C6 alkyl, R v R w NC(=O)-N(R y )-, C1-C6 alkyl-OC(=O)-, C1- C6 alkyl-OC(=O)-C1-C6 alkyl, HO-C(=O)-C1-C6 alkyl, C1-C6 alkyl-OC(=O)-C1-C6 alkyl-C( =O)-N(R y )-, HO-C(=O)-C1-C6 alkyl-C(=O)-N(R y )-, C1-C6 alkyl-C(=O)- N(R y )-C(=O)-N(R y )-, C1-C6 alkyl-C(=O)-N(R y )-C(=O)-C1-C6 alkyl, C1 -C6 alkyl-C(=O)-C1-C6 alkyl-C(=O)-N(R y )-, R v R w NC(=O)-, C1-C6 alkyl-C(= O)-N(R y )-C(=O)-, and R 8 and R 9 are not hydrogen at the same time, and R 7 , R 10 and R 11 are hydrogen;

More preferably, R 9 is selected from hydrogen, carboxyl, C1-C6 alkyl-C(=O)-N(R u )-, C1-C6 alkyl-C(=O)-C1-C6 alkyl, R v R w NC(=O)-N(R y )-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-OC(=O)-C1-C6 alkyl, HO-C (=O)-C1-C6 alkyl, C1-C6 alkyl-OC(=O)-C1-C6 alkyl-C(=O)-N(R y )-, HO-C(=O)- C1-C6 alkyl-C(=O)-N(R y )-, C1-C6 alkyl-C(=O)-N(R y )-C(=O)-N(R y )-, C1-C6 alkyl-C(=O)-N(R y )-C(=O)-C1-C6 alkyl, C1-C6 alkyl-C(=O)-C1-C6 alkyl-C( =O)-N(R y )-, R v R w NC(=O)-, C1-C6 alkyl-C(=O)-N(R y )-C(=O)-, R is selected from 8 From hydrogen, C1-C6 alkyl, halogen (preferably chlorine), C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-N(R u )-, and R 8 and R 9 are not hydrogen at the same time , R 7 , R 10 , R 11 are hydrogen;

Or more preferably, R 9 is selected from carboxyl, C1-C6 alkyl-C(=O)-N(R u )-, C1-C6 alkyl-C(=O)-C1-C6 alkyl, R v R w NC(=O)-N(R y )-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-OC(=O)-C1-C6 alkyl, HO-C( =O)-C1-C6 alkyl, C1-C6 alkyl-OC(=O)-C1-C6 alkyl-C(=O)-N(R y )-, HO-C(=O)-C1 -C6 alkyl-C(=O)-N(R y )-, C1-C6 alkyl-C(=O)-N(R y )-C(=O)-N(R y )-, C1 -C6 alkyl-C(=O)-N(R y )-C(=O)-C1-C6 alkyl, C1-C6 alkyl-C(=O)-C1-C6 alkyl-C(= O)-N(R y )-, R v R w NC(=O)-, C1-C6 alkyl-C(=O)-N(R y )-C(=O)-, R 7 , R 8 , R 10 and R 11 are hydrogen;

Most preferably, R 9 is selected from hydrogen, carboxyl, R 8 is selected from hydrogen, methyl, chlorine, And R 8 and R 9 are not hydrogen at the same time, and R 7 , R 10 and R 11 are hydrogen;

Or most preferably, R 9 is selected from carboxyl, R 7 , R 8 , R 10 and R 11 are hydrogen;

Most preferably, As a whole, selected from the following:

Or, choose from:

The definitions of R u , R v , R w and R y are as defined in claim 1;

2)

The definitions of X 1 , R 12 , R 13 , R 14 and R 15 are as defined in claim 1;

3)

The definitions of X 2 , R 16 , R 17 , R 18 and R 20 are as defined in claim 1.
The compound according to claim 1, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable ester of the compound, wherein, The compound has the structure shown in formula I-1-2:

in:

R 1a is selected from hydrogen and halogen;

Preferably, R 1a is selected from hydrogen and chlorine;

R 1b is selected from hydrogen and halogen;

Preferably, R 1b is hydrogen;

R 2 is selected from -(CH 2 ) n -R 6 ;

n is selected from 1, 2, 3, 4, 5, 6;

Preferably, n is selected from 1, 2, and 3;

More preferably, n is selected from 1 and 2;

Most preferably, n is 1;

R 6 is selected from 5-6 membered heteroaryl;

Preferably, R 6 is selected from 5-membered heteroaryl;

More preferably, R 6 is selected from furyl and thienyl;

Further preferably, R 6 is selected from

Most preferably, R6 is

Preferably, R 2 is

R 3 is phenyl, and the phenyl group is optionally substituted by 1-2 groups selected from R x ;

R x is selected from halogen;

Preferably, Rx is selected from fluorine and chlorine;

Preferably, R 3 is selected from

R 4 is

Among them, R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, C1-C6 alkyl-C(=O)-N(R u )-, C1-C6 alkyl-C( =O)-, and R 7 , R 8 , R 9 , R 10 , and R 11 are not hydrogen at the same time;

Preferably, R 9 is selected from C1-C6 alkyl-C(=O)-N(R u )-, C1-C6 alkyl-C(=O)-, R 7 , R 8 , R 10 , R 11 is hydrogen;

More preferably, R 9 is selected from R 7 , R 8 , R 10 and R 11 are hydrogen;

R u is selected from hydrogen, C1-C6 alkyl;

Preferably, R u is hydrogen;

Preferably, R 4 is selected from

Moreover, the compound represented by formula I-1-2 is not the following compound:
The compound according to claim 1, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable ester of the compound, wherein, The compound has the structure shown in formula I-1-3:

in:

R 1a is selected from hydrogen and halogen;

Preferably, R 1a is selected from halogen;

More preferably, R 1a is chlorine;

R 1b is selected from hydrogen and halogen;

Preferably, R 1b is hydrogen;

R 2 is selected from -(CH 2 ) n -R 6 ;

n is selected from 1, 2, 3, 4, 5, 6;

Preferably, n is selected from 1, 2, and 3;

More preferably, n is selected from 1 and 2;

Most preferably, n is 1;

R 6 is selected from 5-6 membered heteroaryl;

Preferably, R 6 is selected from 5-membered heteroaryl;

More preferably, R 6 is selected from furyl and thienyl;

Further preferably, R 6 is selected from

Most preferably, R6 is

Preferably, R 2 is

R 3 is phenyl, and the phenyl group is optionally substituted by 1-2 groups selected from R x ;

Preferably, R 3 is a phenyl group, and the phenyl group is optionally substituted by a group selected from R x ;

More preferably, R 3 is

R x is selected from halogen;

Preferably, R x is chlorine;

R 4 is

Among them, R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, C1-C6 alkyl-C(=O)-N( Ru )-, and R 7 , R 8 , R 9 , R 10 and R 11 are not hydrogen at the same time;

Preferably, any one of R 8 and R 9 is selected from C1-C6 alkyl-C(=O)-N(R u )-, the other is hydrogen, R 7 , R 10 , and R 11 are hydrogen;

More preferably, any one of R 8 and R 9 is The other is hydrogen, R 7 , R 10 and R 11 are hydrogen;

R u is selected from hydrogen, C1-C6 alkyl;

Preferably, R u is hydrogen;

Preferably, R 4 is selected from

R 5 is selected from hydrogen, C1-C6 alkyl;

Preferably, R5 is selected from hydrogen, methyl, ethyl.
The compound according to claim 1, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable ester of the compound, wherein, The compound has the structure shown in formula I-1-4:

in:

R 1a is selected from hydrogen and halogen;

Preferably, R 1a is selected from halogen;

More preferably, R 1a is chlorine;

R 1b is selected from hydrogen and halogen;

Preferably, R 1b is hydrogen;

R 2 is selected from -(CH 2 ) n -R 6 ;

n is selected from 1, 2, 3, 4, 5, 6;

Preferably, n is selected from 1, 2, and 3;

More preferably, n is selected from 1 and 2;

Most preferably, n is 1;

R 6 is selected from 5-6 membered heteroaryl;

Preferably, R 6 is selected from 5-membered heteroaryl;

More preferably, R 6 is selected from furyl and thienyl;

Further preferably, R 6 is selected from

Most preferably, R6 is

Preferably, R 2 is

R 3 is phenyl, and the phenyl group is optionally substituted by 1-2 groups selected from R x ;

Preferably, R 3 is a phenyl group, and the phenyl group is optionally substituted by a group selected from R x ;

More preferably, R 3 is

R x is selected from halogen;

Preferably, R x is chlorine;

R 4 is

Among them, R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, C1-C6 alkyl-C(=O)-N( Ru )-, and R 7 , R 8 , R 9 , R 10 and R 11 are not hydrogen at the same time;

Preferably, R 9 is selected from C1-C6 alkyl-C(=O)-N(R u )-, R 7 , R 8 , R 10 , and R 11 are hydrogen;

More preferably, R 9 is R 7 , R 8 , R 10 and R 11 are hydrogen;

R u is selected from hydrogen, C1-C6 alkyl;

Preferably, R u is hydrogen;

Preferably, R 4 is

R 5 is selected from hydrogen, C1-C6 alkyl;

Preferably, R5 is selected from hydrogen and ethyl.
The compound according to claim 1, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable ester of the compound, wherein, The compound has the structure shown in formula I-2:

in:

R 1a is selected from hydrogen, C1-C6 alkoxy;

Preferably, R 1a is hydrogen;

R 1b is selected from hydrogen, C1-C6 alkoxy;

Preferably, R 1b is selected from C1-C6 alkoxy;

More preferably, R 1b is methoxy;

R 2 is selected from -(CH 2 ) n -R 6 ;

n is selected from 1, 2, 3, 4, 5, 6;

Preferably, n is selected from 1, 2, and 3;

More preferably, n is selected from 1 and 2;

Most preferably, n is 1;

R 6 is selected from 5-6 membered heteroaryl;

Preferably, R 6 is selected from 5-membered heteroaryl;

More preferably, R 6 is selected from furyl and thienyl;

Further preferably, R 6 is selected from

Most preferably, R6 is

Preferably, R 2 is

R 3 is phenyl, and the phenyl group is optionally substituted by 1-2 groups selected from R x ;

R x is selected from halogen;

Preferably, R x is chlorine;

Preferably, R 3 is selected from

R 4 is

Among them, R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, C1-C6 alkyl-C(=O)-N( Ru )-, and R 7 , R 8 , R 9 , R 10 and R 11 are not hydrogen at the same time;

Preferably, R 9 is selected from C1-C6 alkyl-C(=O)-N(R u )-, R 7 , R 8 , R 10 , and R 11 are hydrogen;

More preferably, R 9 is selected from R 7 , R 8 , R 10 and R 11 are hydrogen;

R u is selected from hydrogen, C1-C6 alkyl;

Preferably, R u is hydrogen;

Preferably, R 4 is selected from

Moreover, the compound represented by formula I-2 is not the following compound:
The compound according to any one of claims 1 to 7, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable salt of the compound An ester, wherein the compound is selected from the following:
Pharmaceutical composition, comprising the compound of any one of claims 1 to 8, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate of the compound or pharmaceutically acceptable esters, and optional pharmaceutically acceptable excipients.
The compound of any one of claims 1-8 or the stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable ester of the compound Use in the preparation of medicines, or the use of the pharmaceutical composition according to claim 9 in the preparation of medicines, or the compound represented by the following formula II or the stereoisomer, prodrug, crystal form, pharmaceutical The use of acceptable salts, pharmaceutically acceptable solvates or pharmaceutically acceptable esters in the preparation of medicaments for the treatment and/or prevention of diseases related to FXR receptors;

Preferably, the disease related to the FXR receptor is selected from the group consisting of metabolic related diseases, cardiovascular diseases, hepatic Heart disease, cancer, kidney disease, intestinal disease, inflammation or any combination thereof;

Preferably, the metabolism-related disease is selected from the group consisting of glucose and lipid metabolism diseases, cholesterol metabolism diseases, lipid metabolism diseases, bile acid metabolism diseases or any combination thereof;

Preferably, the glycolipid metabolism disease is selected from obesity, diabetes (such as type 2 diabetes), dyslipidemia, hyperlipidemia, hypercholesterolemia, cholestasis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis or any combination thereof;

Preferably, the cardiovascular disease is selected from atherosclerosis, myocardial ischemia-reperfusion injury or a combination thereof;

Preferably, the liver disease is selected from liver resection, liver injury or a combination thereof;

Preferably, the cancer is selected from breast cancer, esophageal cancer, lung cancer, pancreatic cancer, kidney cancer, liver cancer, prostate cancer or any combination thereof;

Preferably, the renal disease is selected from nephritis, nephrotic syndrome, atheroembolic renal disease or any combination thereof;

in:

R 1' is selected from hydrogen, halogen, C1-C6 alkoxy, -NR a' R b' ;

Preferably, R 1' is selected from hydrogen, chlorine, methoxy,

R a' and R b' are each independently selected from hydrogen and C1-C6 alkyl;

Preferably, R a' and R b' are each independently selected from C1-C6 alkyl;

More preferably, R a' and R b' are ethyl;

R 2' is selected from -(CH 2 ) n' -R 5' ;

n' is selected from 0, 1, 2, 3, 4, 5, 6;

Preferably, n' is selected from 0, 1, 2, 3;

More preferably, n' is selected from 0, 1, 2;

Most preferably, n' is selected from 0, 1;

R 5' is selected from 5-6 membered heteroaryl, phenyl, 5-6 membered saturated heterocycle, C3-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, Optionally, the phenyl group is substituted by a group selected from fluorine, chlorine, bromine, and iodine (preferably fluorine);

Preferably, R 5' is selected from furyl, phenyl, tetrahydrofuryl, C3-C6 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, optionally, the phenyl The group is substituted by a group selected from fluorine, chlorine, bromine, and iodine (preferably fluorine);

More preferably, R 5' is selected from

Preferably, R 2' is selected from

R 3' is selected from phenyl, 5-6 membered heteroaryl, C1-C6 alkyl, -NR c' R d' , optionally, the phenyl group is selected from fluorine, chlorine, bromine, iodine (Preferably fluorine, chlorine) group substituted;

Preferably, R 3' is selected from phenyl, furyl, thienyl, C1-C6 alkyl, -NR c' R d' , optionally, the phenyl group is selected from fluorine, chlorine, bromine, Substituted with iodine (preferably fluorine, chlorine) groups;

R c' and R d' are each independently selected from hydrogen, C1-C6 alkyl, and phenyl, and the phenyl group is optionally replaced by a group selected from C1-C6 alkoxy (preferably methoxy) replaced;

Preferably, any one of R c' and R d' is hydrogen, and the other is selected from C1-C6 alkyl and phenyl, and the phenyl group is optionally replaced by one selected from C1-C6 alkoxy (preferably methoxy) group substituted;

More preferably, any one of R c' and R d' is hydrogen, and the other is selected from

More preferably, R 3' is selected from

R 4' is selected from C1-C6 alkyl;

Preferably, R 4' is methyl.
The use according to claim 10, wherein the compound represented by formula II is selected from the group consisting of formula II-1, II-2 and II-3:

Wherein, R 1' , R 2' , R 3' and R 4' are defined as in claim 10.
The use according to any one of claims 10-11, wherein the compound represented by formula II is selected from the following: