WO2020151682A1 - Macrocyclic immunomodulator - Google Patents

Abstract

Disclosed are a compound shown in Formula (I), a tautomer or enantiomer thereof, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, as a macrocyclic immunomodulator. Experimental results indicated that the compound of the present invention is capable of effective binding with STING, and has a good effect in the agonization of a STING protein. Thus, the compound of the present invention functions as a STING agonist and can be used to treat various related diseases. The compound provided in the present invention has promising prospects in the preparation of medicaments for treating diseases associated with STING activity, particularly in the preparation of medicaments for treating inflammation, autoimmune diseases, infectious diseases, cancer, or precancerous syndromes.

Description

A macrocyclic immunomodulator Technical field

The invention belongs to the field of medicine and relates to a macrocyclic immunomodulator.

Background technique

The human immune system can generally be divided into "innate immunity" and "adaptive immunity" systems. The innate immune system plays an important role in fighting infections, inhibiting tumor growth, and the pathogenesis of autoimmune diseases. It mainly recognizes pathogenic microorganisms and cancer cell components through pattern recognition receptors, initiates downstream signaling pathways, and finally induces cytokine expression. Kill pathogenic microorganisms and cancer cell components, and adapt to the immune system to promote the production of antibodies and specific T lymphocytes.

STING (interferon gene stimulating factor, TMEM173, MITA, etc.) is a key node molecule in the intracellular response to DNA invasion. Under the stimulation of cytoplasmic DNA, it recognizes the signal of cytoplasmic DNA receptor and plays a key role in the process of inducing interferon production. . After the host cell's DNA recognition receptor recognizes exogenous or endogenous "non-self" DNA, it transmits the signal to the node molecule STING, and then STING rapidly dimerizes and transfers from the endoplasmic reticulum to the perinuclear body. The activation of STING leads to the up-regulation of IRF3 and NKκB pathways, which leads to the induction of interferon-β and other cytokines.

Compounds that induce human interferon can be used to treat various diseases, including allergic diseases and other inflammatory diseases, allergic rhinitis and asthma, infectious diseases, neurodegenerative diseases, precancerous syndromes and cancer, and can also be used as immunity Composition or vaccine adjuvant. Therefore, activation of STING is a potential method for treating related type 1 IFN pathway diseases (including inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, and precancerous syndromes).

Summary of the invention

The present invention provides a compound represented by formula I or its tautomers, enantiomers, or pharmaceutically acceptable salts, crystal forms, hydrates or solvates thereof:

among them,

R ¹ and R ² are each independently selected from hydrogen and C ₁ ～C ₆ alkyl groups;

R ^{3 is} selected from hydrogen, C ₁ ～C ₆ alkyl, halogen;

R ^{4 is} selected from hydrogen, C ₁ ～C ₆ alkyl, halogen or none;

R ^{5 is} selected from hydrogen, C ₁ ～C ₆ alkyl;

X ^{2 is} selected from C or N;

Ring B is selected from ^a benzene ring substituted with 0 to 4 Ra, and ^a 5- to 6-membered aromatic heterocyclic ring substituted with 0 to 4 Ra;

R ^{a is} selected from halogen, hydroxy, amino, and C ₁ to C ₆ alkyl optionally substituted by 0 to 4 R ^b ;

R ^{b is} selected from halogen, hydroxyl, amino, C ₁ ～C ₆ alkoxy;

X is selected from -O-, -S-, -S(O) _n -or none; n is 1 or 2;

L ^1, L ² are each independently selected from 0 to 4 substituents R ⁱ is C ₁ ~ C ₁₀ alkylene group, and is substituted with 0 to 4 R ⁱ alkenylene substituted C ₂ ~ C _10, wherein, when R ⁱ when there are at least two, L ^1, L R ^{i 2} may be linked to form a 3 to 10-membered ring;

R ^{i is} selected from -OR ^j , halogen, -CN, C ₁ ～C ₆ alkyl;

R ^{j is} selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

Z is selected from -O-, -C(O)-,

R ^c and R ^d are independently selected from hydrogen, C ₁ ～C ₆ alkyl, halogen substituted C ₁ ～C ₆ alkyl, -C(O)R ^k or none, or R ^c and ^Rd are connected to them nitrogen atom to form a substituted 0-4 R ^e 3 to 8-membered heterocyclic ring optionally alkane, substituted with 0 to 4 R ^e 3-10-membered heteroaryl ring;

R ^k is selected from 0 to 4 R ^m substituted 5- to 6-membered cycloalkyl, substituted with 0 to 4 R ^m substituted 5- to 6-membered heterocyclic group; R ^m is selected from C ₁ ~ C ₆ alkyl , C ₁ ～C ₆ alkyl substituted by halogen;

R ^g and R ^h are independently selected from -C(O)-, -C(O)O- or none;

R ^{e is} selected from -OR ^f -, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

R ^{f is} selected from hydrogen, C ₁ to C ₆ alkyl, and halogen substituted C ₁ to C ₆ alkyl.

Further, the compound is represented by formula I:

among them,

R ¹ and R ² are each independently selected from hydrogen and C ₁ ～C ₆ alkyl groups;

R ^{3 is} selected from hydrogen, C ₁ ～C ₆ alkyl, halogen;

R ^{4 is} selected from hydrogen, C ₁ ～C ₆ alkyl, halogen or none;

R ^{5 is} selected from hydrogen, C ₁ ～C ₆ alkyl;

X ^{2 is} selected from C or N;

Ring B is selected from ^a benzene ring substituted with 0 to 4 Ra, and ^a 5- to 6-membered aromatic heterocyclic ring substituted with 0 to 4 Ra;

R ^{a is} selected from C ₁ to C ₆ alkyl groups optionally substituted by 0 to 4 R ^b ;

R ^{b is} selected from halogen, hydroxyl, amino, C ₁ ～C ₆ alkoxy;

X is selected from -O-, -S- or none;

L ^1, L ² are each independently selected from 0 to 4 substituents R ⁱ is C ₁ ~ C ₁₀ alkylene group, wherein, when at least two R ^i, L ^1, L R ^{i 2} may be connected Form a 3-10 membered ring;

R ^{i is} selected from -OR ^j , halogen, -CN, C ₁ ～C ₆ alkyl;

R ^{j is} selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

Z is selected from -O-, -C(O)-,

R ^c and R ^d are independently selected from hydrogen, C ₁ ～C ₆ alkyl, halogen substituted C ₁ ～C ₆ alkyl or none, or R ^c and R ^d are connected to the nitrogen atom to which they are connected to form a 0～ 4 R ^e is optionally substituted 3 to 8-membered heterocyclic ring alkane, substituted with 0 to 4 R ^e 3-10-membered heteroaryl ring;

R ^g and R ^h are independently selected from -C(O)-, -C(O)O- or none;

R ^{e is} selected from -OR ^f -, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

R ^{f is} selected from hydrogen, C ₁ to C ₆ alkyl, and halogen substituted C ₁ to C ₆ alkyl.

Further, the compound is represented by formula II:

Ring B is selected from

R ⁶ , R ⁷ , and R ⁸ are each independently selected from hydrogen, and C ₁ to C ₆ alkyl optionally substituted with 0 to 4 R ^b ;

R ^{b is} selected from halogen, hydroxyl, amino, C ₁ ～C ₆ alkoxy;

R ¹ and R ² are each independently selected from hydrogen and C ₁ ～C ₆ alkyl groups;

R ³ and R ⁴ are each independently selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen;

R ^{5 is} selected from hydrogen, C _1-6 alkyl;

L ^1, L ² are each independently selected from 0 to 4 substituents R ⁱ is C ₁ ~ C ₁₀ alkylene group, wherein, when at least two R ^i, L ^1, L R ^{i 2} may be connected Form a 3-10 membered ring;

R ^{i is} selected from -OR ^j , halogen, -CN, C ₁ ～C ₆ alkyl;

R ^{j is} selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

Z is selected from -O-, -C(O)-, -C(O)NR-, -NR-,

R is selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

R ^c and R ^d are independently selected from hydrogen, C ₁ -C ₆ alkyl or none, or R ^c and R ^d are connected with the nitrogen atom to which they are attached to form ^3-8 optionally substituted with 0-4 R ^e Membered heterocyclic alkane, 3-10 membered heteroaromatic ring optionally substituted by 0-4 R ^e ;

R ^{e is} selected from -OR ^f -, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

R ^{f is} selected from hydrogen, C ₁ to C ₆ alkyl, and halogen substituted C ₁ to C ₆ alkyl.

Further, the Z is -O-.

Further, the compound represented by formula II is:

Further, the compound is represented by formula III:

R ¹ and R ² are each independently selected from hydrogen and C ₁ ～C ₆ alkyl groups;

R ³ and R ⁴ are each independently selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen;

R ^{5 is} selected from hydrogen, C _1-6 alkyl;

Ring B is selected from

R ⁶ , R ⁷ , and R ⁸ are each independently selected from hydrogen, and C ₁ to C ₆ alkyl optionally substituted with 0 to 4 R ^b ;

R ^{b is} selected from halogen, hydroxyl, amino, C ₁ ～C ₆ alkoxy;

R ^c and R ^d are independently selected from hydrogen, C ₁ -C ₆ alkyl or none, or R ^c and R ^d are connected with the nitrogen atom to which they are attached to form an optionally substituted with 0 to 4 R ^e

0-4 is optionally substituted with R ^e

0-4 is optionally substituted with R ^e

R ^g and R ^h are independently selected from -C(O)-, -C(O)O- or none;

L ^1, L ² are each independently selected from 0 to 4 substituents R ⁱ is C ₁ ~ C ₁₀ alkylene group, wherein, when at least two R ^i, L ^1, L R ^{i 2} may be connected Form a 3-10 membered ring;

R ^{i is} selected from -OR ^j , halogen, -CN, C ₁ ～C ₆ alkyl;

R ^{j is} selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

R ^{e is} selected from -OR ^f -, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

R ^{f is} selected from hydrogen, C ₁ to C ₆ alkyl, and halogen substituted C ₁ to C ₆ alkyl.

Further, the compound represented by formula III is:

Further, the compound is represented by formula IV:

Ring B is selected from

R ⁶ , R ⁷ , and R ⁸ are each independently selected from hydrogen, and C ₁ to C ₆ alkyl optionally substituted with 0 to 4 R ^b ;

R ^{b is} selected from halogen, hydroxyl, amino, C ₁ ～C ₆ alkoxy;

R ¹ and R ² are each independently selected from hydrogen and C ₁ ～C ₆ alkyl groups;

R ³ and R ⁴ are each independently selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen;

R ^{5 is} selected from hydrogen, C ₁ ～C ₆ alkyl;

L ^1, L ² are each independently selected from 0 to 4 substituents R ⁱ is C ₁ ~ C ₁₀ alkylene group, wherein, when at least two R ^i, L ^1, L R ^{i 2} may be connected Form a 3-10 membered ring;

R ^{i is} selected from -OR ^j , halogen, -CN, C ₁ ～C ₆ alkyl;

R ^{j is} selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

Z is selected from -O-, -C(O)-, -C(O)NR-, -NR-,

R is selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

R ^c and R ^d are independently selected from hydrogen, C ₁ -C ₆ alkyl or none, or R ^c and R ^d are connected with the nitrogen atom to which they are attached to form ^3-8 optionally substituted with 0-4 R ^e Membered heterocyclic alkane, 3-10 membered heteroaromatic ring optionally substituted by 0-4 R ^e ;

R ^{e is} selected from -OR ^f -, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

R ^{f is} selected from hydrogen, C ₁ to C ₆ alkyl, and halogen substituted C ₁ to C ₆ alkyl.

Further, the compound is represented by formula V:

Ring B is selected from

R ⁶ , R ⁷ , and R ⁸ are each independently selected from hydrogen, and C ₁ to C ₆ alkyl optionally substituted with 0 to 4 R ^b ;

R ^{b is} selected from halogen, hydroxyl, amino, C ₁ ～C ₆ alkoxy;

R ¹ and R ² are each independently selected from hydrogen and C ₁ ～C ₆ alkyl groups;

R ³ and R ⁴ are each independently selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen;

R ^{5 is} selected from hydrogen, C ₁ ～C ₆ alkyl;

L ^1, L ² are each independently selected from 0 to 4 substituents R ⁱ is C ₁ ~ C ₁₀ alkylene group, wherein, when at least two R ^i, L ^1, L R ^{i 2} may be connected Form a 3-10 membered ring;

R ^{i is} selected from -OR ^j , halogen, -CN, C ₁ ～C ₆ alkyl;

R ^{j is} selected from hydrogen, C ₁ to C ₆ alkyl, and halogen substituted C ₁ to C ₆ alkyl.

Further, the compound represented by formula V is:

Further, the compound is represented by formula VI:

among them,

Ring B is selected from ^a 5-membered nitrogen-containing aromatic heterocyclic ring substituted with 0 to 3 Ra;

R ^{a is} selected from halogen, hydroxyl, amino, and C ₁ to C ₆ alkyl optionally substituted by 0 to 3 R ^b ;

R ^{b is} selected from halogen and hydroxyl;

R ¹ and R ² are each independently selected from hydrogen and C ₁ ～C ₆ alkyl groups;

R ³ and R ⁴ are each independently selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen;

R ^{5 is} selected from hydrogen, C ₁ ～C ₆ alkyl;

L ^1, L ² are each independently selected from substituted with 0 to 4 R ⁱ C ₁ ~ C ₆ alkylene group, and is substituted with 0 to 4 R ⁱ substituents of C ₂ ~ C ₆ alkenylene group,

R ^{i is} selected from halogen, -CN, C ₁ ～C ₆ alkyl;

X is selected from -O-, -S-, -S(O) _n -or none, n is 1 or 2;

Z is selected from -O-, -C(O)-,

R ^c, R ^d each independently selected from hydrogen, C ₁ ~ C ₆ alkyl, halo-substituted C ₁ ~ C ₆ alkyl, -C (O) R ^k, or no; R ^K is selected from 0 to 4 R ^m substituted 5- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl substituted with 0 to 4 R ^m ; R ^{m is} selected from C ₁ ～C ₆ alkyl, halogen substituted C ₁ ～C ₆ alkane base;

R ^g and R ^h are independently selected from -C(O)-, -C(O)O- or none.

Further, it is characterized by:

Ring B is selected from

R ⁶ , R ⁷ , and R ⁸ are each independently selected from hydrogen, halogen, hydroxyl, amino, and C ₁ ～C ₂ alkyl optionally substituted with 0 to 3 R ^b ;

R ^{b is} selected from halogen and hydroxyl;

R ¹ and R ² are each independently selected from hydrogen and C ₁ ～C ₃ alkyl groups;

R ³ and R ⁴ are each independently selected from hydrogen, C ₁ ～C ₃ alkyl, and halogen;

R ^{5 is} selected from hydrogen, C ₁ ～C ₃ alkyl;

L ^1, L ² are each independently selected from substituted with 0 to 2 R ⁱ C ₁ ~ C ₃ alkylene group, and is substituted with 0 to 2 substituents R ⁱ of C ₂ ~ C ₃ alkenylene group,

R ^{i is} selected from halogen, -CN, C ₁ ～C ₃ alkyl;

X is selected from -O-, -S-, -S(O) _n -or none, n is 1 or 2;

Z is selected from -O-, -C(O)-,

Preferably, Z is -O-;

R ^c, R ^d each independently selected from hydrogen, C ₁ ~ C ₃ alkyl group, halogen-substituted C ₁ ~ C ₃ alkyl, -C (O) R ^k, or no; R ^K is selected from 0 to 2 R ^m substituted 5- to 6-membered cycloalkyl, piperidine ring substituted with 0 to 2 R ^m ; R ^{m is} selected from C ₁ ～C ₃ alkyl, halogen substituted C ₁ ～C ₃ alkyl;

R ^g and R ^h are independently selected from -C(O)-, -C(O)O- or none.

Further, the compound is:

In some embodiments of the present invention, for the compounds of Formula I, B ring is preferably substituted with from 0 to 4 substituents R ^a nitrogen-containing aromatic 5-membered heterocyclic ring, R ^a is selected from halogen, halo substituted with 0 to 4 Substituted C ₁ ～C ₆ alkyl group, L ^{1 is} selected from C ₂ ～C ₆ alkylene, C ₂ ～C ₆ alkenylene group, L ^{2 is} selected from C ₂ ～C ₆ alkylene, Z is selected From -O-, -C(O)-, -NHC(O)O-, -NR ^c -, -C(O)NH-, R ^{c is} selected from hydrogen, C ₁ ～C ₆ alkyl, halogen substituted C ₁ ~ C ₆ ^{alkyl, -C (O) R k,} R k is selected from substituted with 0 to 2 R ^m 5 to 6-membered cycloalkyl, substituted with 0 to 2 substituents R ^m is 5 to 6-membered Heterocycloalkyl, R ^{m is} selected from C ₁ ～C ₆ alkyl and halogen substituted C ₁ ～C ₆ alkyl.

In some embodiments of the present invention, the compound of Formula I, B is more preferably a ring substituted with 0-3 R ^a pyrrole, substituted with 0 to 3 R ^a substituted pyrazole, substituted with 0 to 3 R ^a substituted imidazole, substituted with 0 to 3 R ^a substituted thiazole is substituted with 0 to 3 R ^a substituted isothiazole, substituted with 0 to 3 R ^a substituted oxazole, substituted with 0 to 3 R ^a is isoxazole, R ^a is selected from halo, substituted with 0 to 3 halo C ₁ ~ C ₆ alkyl group.

The present invention also provides the use of the above-mentioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite in the preparation of activating STING drugs .

The present invention also provides the compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite for preparing and treating diseases related to STING activity Use in medicine.

Further, the diseases related to STING activity are one or more of diseases related to inflammatory, autoimmune diseases, infectious diseases, cancer, and precancerous syndromes.

The present invention also provides the above-mentioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite for preparing treatment of inflammation, autoimmunity Use in medicine for diseases, infectious diseases, cancer or precancerous syndromes.

The present invention also provides the use of the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite in the preparation of an immune adjuvant.

The present invention also provides a drug, which is based on the above-mentioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite A preparation prepared with pharmaceutically acceptable excipients.

Experimental results show that the compound of the present invention can effectively bind to STING and has a good STING protein agonistic function. Therefore, the compounds of the present invention can be used as STING agonists and used to treat various related diseases. The compound provided by the present invention has very good application prospects in the preparation of drugs for treating diseases related to STING activity, especially in the preparation of drugs for treating inflammatory, autoimmune diseases, infectious diseases, cancer or precancerous syndromes.

The diseases related to STING activity defined in the present invention are diseases in which STING plays an important role in the pathogenesis of the disease.

Diseases related to STING activity include inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, and precancerous syndromes.

"Cancer" or "malignant tumor" refers to any of a variety of diseases characterized by uncontrolled abnormal proliferation of cells, the ability of affected cells to spread to other locations locally or through the bloodstream and lymphatic system The body (i.e. metastasis) and any of many characteristic structural and/or molecular characteristics. "Cancer cells" refer to cells that undergo the early, middle or late stages of tumor progression in multiple steps. Cancers include sarcoma, breast cancer, lung cancer, brain cancer, bone cancer, liver cancer, kidney cancer, colon cancer and prostate cancer. In some embodiments, the compound of formula I is used to treat a cancer selected from colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma. In some embodiments, the cancer is selected from melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer. In some embodiments, the cancer being treated is a metastatic cancer.

Inflammatory diseases include a variety of conditions characterized by histopathological inflammation. Examples of inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, Airway inflammation and interstitial cystitis caused by house dust mites. There is a significant overlap between inflammatory diseases and autoimmune diseases. Some embodiments of the present invention relate to the treatment of the inflammatory disease asthma. The immune system is usually involved in inflammatory diseases, which are manifested in allergic reactions and some myopathy. Many immune system diseases lead to abnormal inflammation.

The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) naming system.

Regarding the definitions of terms used in the present invention: Unless otherwise specified, the initial definitions of groups or terms provided herein are applicable to the groups or terms throughout the specification; for terms not specifically defined herein, it should be based on the disclosure and context , Give them the meaning that those skilled in the art can give them.

"Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

The minimum and maximum content of carbon atoms in a hydrocarbon group are indicated by prefixes. For example, the prefixes _Ca to _Cb alkyl groups indicate any alkyl groups containing "a" to "b" carbon atoms. Thus, for example, a C ₁ to C ₆ alkyl group refers to an alkyl group containing 1 to 6 carbon atoms.

In the present invention, "alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, the C ₁ to C ₆ alkyl group refers to an alkyl group having 1 to 6 carbon atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) Base) and hexyl. The alkyl group may also be part of another group, such as a C ₁ to C ₆ alkoxy group.

In the present invention, the C _a -C _b alkoxy group refers to a group obtained by connecting an alkyl group containing "a" to "b" carbon atoms to the corresponding oxygen atom.

In the present invention, "C ₁ ~ C ₁₀ alkylene group" refers to a divalent having 1 to 10 carbon atoms, saturated aliphatic hydrocarbon. Alkylene groups include branched and straight chain hydrocarbyl groups. For example, "(C ₁ -C ₆ )alkylene" is meant to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene and the like. Therefore, the term "propylene" can be exemplified by the following structure:

Likewise, the term "dimethyl butylene" can be exemplified by any of the following structures, for example:

In addition, the term "(C ₁ -C ₆ )alkylene" is meant to include such branched hydrocarbon groups, such as cyclopropylmethylene, which can be exemplified by the following structure:

Similarly, "C ₂ -C ₁₀ alkenylene" refers to an aliphatic hydrocarbon group having 2 to 10 carbon atoms and containing one or more carbon-carbon double bonds. Alkenylene groups include branched and straight chain groups. The carbon-carbon double bonds in the alkenylene group include cis double bonds and trans double bonds.

In the present invention, "halogen" means a halogen group: fluorine, chlorine, bromine or iodine.

The term "pharmaceutically acceptable" means that a certain carrier, carrier, diluent, excipient, and/or the formed salt is usually chemically or physically compatible with other ingredients constituting a certain pharmaceutical dosage form, and physiologically Compatible with the receptor.

The terms "salts" and "pharmaceutically acceptable salts" refer to the above-mentioned compounds or their stereoisomers, acid and/or basic salts formed with inorganic and/or organic acids and bases, and also include zwitterionic salts (internal Salt), also includes quaternary ammonium salts, such as alkyl ammonium salts. These salts can be directly obtained in the final isolation and purification of the compound. It can also be obtained by mixing the above-mentioned compound, or its stereoisomers, with a certain amount of acid or base appropriately (for example, equivalent). These salts may form a precipitate in the solution and be collected by filtration, or recovered after evaporation of the solvent, or prepared by freeze-drying after reaction in an aqueous medium. The salt in the present invention can be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, butane Acid salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.

In certain embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compound of the present invention can be used in combination with any other active agent to prepare drugs or pharmaceutical compositions for regulating cell functions or treating diseases. If a group of compounds are used, these compounds can be administered to the subject simultaneously, separately or sequentially.

Obviously, according to the above content of the present invention, according to common technical knowledge and conventional means in the field, various other modifications, substitutions or changes can be made without departing from the above basic technical idea of the present invention.

Hereinafter, the above-mentioned content of the present invention will be further described in detail through specific implementations in the form of examples. However, it should not be understood that the scope of the aforementioned subject matter of the present invention is limited to the following examples. All technologies implemented based on the foregoing content of the present invention belong to the scope of the present invention.

detailed description

The raw materials and equipment used in the present invention are all known products and can be obtained by purchasing commercially available products.

The structure of the compound of the present invention was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). NMR is measured with (Bruker AvanceIII 400 and Bruker Avance 300) nuclear magnetometer, and the solvent is deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) , The internal standard is tetramethylsilane (TMS).

The LC-MS measurement uses Shimadzu LC-MS 2020 (ESI).

Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A) was used for HPLC measurement.

Gilson GX-281 reverse-phase preparative chromatography was used for reverse-phase preparative chromatography.

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications for thin layer chromatography separation and purification products are 0.4mm～0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from Anaiji Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology and other companies.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.

The hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.

There is no special description in the examples, and the reaction is carried out under a nitrogen atmosphere.

There is no special description in the examples, and the solution refers to an aqueous solution.

There are no special instructions in the examples, and the reaction temperature is room temperature.

No special instructions in the examples, M is mole per liter.

Room temperature is the most suitable reaction temperature, ranging from 20°C to 30°C.

DCM: refers to dichloromethane.

DMF: refers to N,N-dimethylformamide.

DMSO: refers to dimethyl sulfoxide.

DIPEA: refers to diisopropylethylamine.

HATU: refers to 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

Pd(dppf)Cl ₂ : refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.

TFA: refers to trifluoroacetic acid.

NBS: refers to N-bromosuccinimide.

1. Synthesis of intermediate 4-chloro-3-hydroxy-5-nitrobenzamide:

Step 1: Synthesis of 4-chloro-3-methoxy-5-nitrobenzamide

A (18.5 g, 75.3 mmol) was added to a single-neck flask containing ammonia water (200 mL) and stirred at 60° C. for 3 h. The reaction solution was concentrated to 100 mL, cooled and filtered, and the solid was washed with ice water. After drying, 4-chloro-3-methoxy-5-nitrobenzamide (12.5 g, 54.1 mmol) was obtained as a brown solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) δ 8.29 (s, 1H), 8.04 (d, 1H), 7.87 (d, 1H), 7.78 (s, 1H), 4.01 (s, 3H).

MS(ESI) m/z=231 [M+H] ⁺ .

Step 2: Synthesis of 4-chloro-3-hydroxy-5-nitrobenzamide

Under an ice bath, b (12.5 g, 54.1 mmol) was dispersed in dry DCM (150 mL), and boron tribromide (200 mL, 1M) was slowly added dropwise to it. After the addition, the ice bath was removed, protected by nitrogen, and reacted overnight at room temperature. After the reaction was complete, the reaction solution was poured into ice water, stirred vigorously for 30 minutes, filtered, and the filter cake was washed with water. After the filter cake was dried, 4-chloro-3-hydroxy-5-nitrobenzamide (10g, 46.2mmol , 85.3% yield), pale yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 11.73 (s, 1H), δ 8.21 (s, 1H), 7.92 (s, 1H), 7.80 (s, 1H), 7.66 (s, 1H).

MS (ESI) m/z=217 [M+H] ⁺ .

2. Synthesis of intermediate 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate:

Step 1: Synthesis of 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl chloride

1-Ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (4g, 25.9mmol) was dispersed in dry DCM (80mL), and oxalyl chloride (3.9g, 31.1 mmol) and a catalytic amount of DMF. After reacting for 1 hour at room temperature, the volatiles were removed by rotary evaporation under reduced pressure. DCM (20mL) was added to the crude product, and the solvent was removed by rotary evaporation to obtain 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl chloride (4.46g, 100% yield), which was used directly in the next step reaction.

Step 2: Synthesis of 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate

At 0°C, g (4.46g, 25.9mmol) was dissolved in dry acetone (20mL) and added dropwise to potassium thiocyanate (5g, 51.5mmol) in acetone (100mL) solution, stirred at room temperature for 3h, the reaction system The inorganic salt was removed by filtration, and the crude product after the filtrate was concentrated was purified by silica gel column (eluent ethyl acetate/petroleum ether, v/v=1/15) to obtain 1-ethyl-3-methyl-1H-pyrazole- 5-carbonyl isothiocyanate h (4g, 20.4mmol, 78.7%), a clear brownish yellow liquid.

MS(ESI) m/z=196 [M+H] ⁺ .

3. Synthesis of intermediate 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate:

Step 1: Synthesis of 4-ethyl-2-methylthiazole-5-carboxylic acid chloride

4-ethyl-2-methylthiazole-5-carboxylic acid (2g, 11.7mmol) was dispersed in dry DCM (40ml), and oxalyl chloride (1.9g, 15.1mmol) and Catalytic amount of DMF. After reacting for 1 hour at room temperature, the volatiles were removed by rotary evaporation under reduced pressure. DCM (20ml) was added to the crude product, and the solvent was removed by rotary evaporation to obtain 4-ethyl-2-methylthiazole-5-carboxylic acid chloride (2.2g, 100% yield), which was directly used in the next reaction.

Step 2: Synthesis of 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate

At 0°C, 4-ethyl-2-methylthiazole-5-carbonyl chloride (2.2g, 11.7mmol) was dissolved in dry acetone (10mL) and added dropwise to potassium thiocyanate (2.3g, 23.4mmol) In acetone (50mL) solution, stirred at room temperature for 3h, the reaction system was filtered to remove inorganic salts, and the crude product after concentrated filtrate was purified by silica gel column (eluent ethyl acetate/petroleum ether, v/v=1/15) to obtain 4-Ethyl-2-methylthiazole-5-carbonyl isothiocyanate (2.15g, 10.2mmol, yield 87%), clear brownish yellow liquid.

MS(ESI) m/z=213 [M+H] ⁺ .

4. Synthesis of intermediate 4-ethyl-2-methyloxazole-5-carbonyl isothiocyanate

Step 1: Synthesis of methyl 2-chloro-3-oxopentanoate

Add SO ₂ Cl ₂ (7.2g, 58mmol) dropwise into a solution of methyl 3-oxopentanoate (5g, 38mmol) in dichloromethane (100mL) in an ice bath, warm to room temperature and stir for 4h, react The liquid was washed with saturated sodium carbonate solution, the separated organic phase was washed with saturated brine, and then dried over anhydrous sodium sulfate. The filtrate obtained by filtration was spin-dried to obtain the compound methyl 2-chloro-3-oxopentanoate (6g, 36.5mmol ), a colorless oil, used directly in the next reaction.

MS (ESI) m/z = 166.0 [M+H] ⁺ .

Step 2: Synthesis of 2-acetoxy-3-oxopentanoic acid methyl ester

In an ice bath, TEA (12.5mL) was added dropwise to a solution of acetic acid (12.5mL) in DMF (63mL). After warming to room temperature, methyl 2-chloro-3-oxopentanoate (6g, 36.5 mmol) was added to the reaction solution and stirred at room temperature overnight. TLC monitors that the reaction is complete, the reaction solution is poured into water, extracted with dichloromethane, the combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate obtained by filtration is spin-dried to obtain the compound 2-acetoxy-3-oxo Methyl valerate (3.0 g, 15.9 mmol), a yellow oil, was directly used in the next reaction.

Step 3: Synthesis of 4-ethyl-2-methyloxazole-5-carboxylic acid methyl ester

Methyl 2-acetoxy-3-oxopentanoate (3.0 g, 15.9 mmol) was dissolved in acetic acid (50 mL), and then ammonium acetate (9.8 g, 127.6 mmol) was added. The mixture was heated to 120°C and stirred at this temperature for 4 hours. After the reaction solution was concentrated, diluted with water, extracted with ethyl acetate, the separated organic phase was washed with water and saturated brine successively, and then dried over anhydrous sodium sulfate, the filtrate obtained by filtration was spin-dried, and the crude product was separated and purified with a silica gel column (elution Agent: petroleum ether/ethyl acetate, 9/1) to obtain methyl 4-ethyl-2-methyloxazole-5-carboxylate (0.52 g, 3.1 mmol).

MS(ESI)m/z＝170.1[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ ): δ (ppm) 3.89 (s, 3H), 2.84 (q, J = 7.6 Hz, 2H), 2.50 (s, 3H), 1.23 (t, J = 7.6 Hz, 3H ).

Step 4: Synthesis of 4-ethyl-2-methyloxazole-5-carboxylic acid

Dissolve 4-ethyl-2-methyloxazole-5-carboxylic acid methyl ester (323mg, 1.9mmol) in THF/MeOH (10mL/5mL), add hydrated lithium hydroxide (160mg, 3.8mmol) at room temperature Stir overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The separated aqueous phase was adjusted to pH 2.0 with HCl (2M), and then extracted with ethyl acetate. The organic phase obtained again was dried with anhydrous sodium sulfate, filtered and spin-dried to obtain 4-ethyl-2-methyloxazole-5-carboxylic acid (220 mg, 1.42 mmol) as a white solid.

MS (ESI) m/z = 156.1 [M+H] ⁺ .

Step 5: Synthesis of 4-ethyl-2-methyloxazole-5-carbonyl isothiocyanate

4-ethyl-2-methyloxazole-5-carboxylic acid (220mg, 1.42mmol) was dispersed in dry THF (10mL), and oxalyl chloride (270mL, 2.13mmol) and Catalytic amount of DMF. After 30 minutes of reaction at room temperature, the volatiles were removed by rotary evaporation under reduced pressure. DCM (20 mL) was added to the crude product, and the crude product obtained after the solvent was removed by rotary evaporation was directly used in the next reaction.

At 0℃, the yellow oil was dissolved in dry acetone (10mL) and added dropwise to the solution of potassium thiocyanate (276mg, 2.84mmol) in acetone (15mL), stirred at room temperature for 3h, the reaction system The inorganic salt was removed by filtration, washed with n-hexane, and the crude product after concentrated filtrate was purified by silica gel column (eluent ethyl acetate/petroleum ether, v/v=1/7) to obtain 4-ethyl-2-methyloxazole -5-carbonyl isothiocyanate (176 mg, 63%), clear light yellow liquid.

MS(ESI)m/z＝197.0[M+H] ⁺

5. Synthesis of the intermediate compound 3-bromo-4-fluoro-5-nitrobenzoic acid methyl ester

Step 1: Synthesis of 3-bromo-4-fluoro-5-nitrobenzoic acid

Disperse 4-fluoro-3-nitrobenzoic acid (50 g, 270 mmol) in concentrated sulfuric acid (200 ml), and add NBS (47.5 g, 270 mmol). Warm up to 75°C and stir overnight. After cooling to room temperature, slowly poured into ice water and stirred, a light yellow solid precipitated out, the solid was filtered out and dried to obtain the target compound (66 g).

Step 2: Synthesis of methyl 3-bromo-4-fluoro-5-nitrobenzoate

In an ice bath, thionyl chloride (44.5 g, 373.5 mmol) was added dropwise to a solution of 3-bromo-4-fluoro-5-nitrobenzoic acid (66 g, 249 mmol) in methanol (400 ml). Raise to 75°C and stir overnight. Concentrate to about 100 ml of the remaining solvent. After cooling, the solid continues to precipitate out. The solid is filtered and dried to obtain methyl 3-bromo-4-fluoro-5-nitrobenzoate (56g).

6. Synthesis of the intermediate compound 4-chloro-3-hydroxy-5-nitrobenzoic acid methyl ester

Methyl 4-chloro-3-methoxy-5-nitrobenzoate (10g, 40.7mmol) was dispersed in anhydrous dichloromethane (100mL), and boron tribromide ( 40.8g, 162.8mmol), after dripping, slowly rise to room temperature and stir overnight. After the reaction was completed, methanol was slowly added dropwise to quench under an ice bath, and then it was spin-dried. Methanol (100 mL) and concentrated sulfuric acid (0.2 mL) were added thereto, and the reaction solution was heated to 75° C. and stirred overnight. After cooling, the solvent was removed by concentration under reduced pressure, and 150 mL of water was added. After ultrasonic dispersion, filtration, the solid was washed with water again, and the solid was dried to obtain methyl 4-chloro-3-hydroxy-5-nitrobenzoate (8.89g , 38.4mmol, yield 94%).

Example 1

Step 1: Synthesis of 3-bromo-4-fluoro-5-nitrobenzoic acid

At room temperature, 4-fluoro-3-nitrobenzoic acid (18.7 g, 101.02 mmol) and NBS (17.98 g, 101.02 mmol) were added to concentrated sulfuric acid (40 mL), and the temperature was raised to 65° C. and the reaction was stirred for 16 h. After the reaction was completed, water was added to precipitate a solid, filtered, and the filter cake was washed with water and dried to obtain 3-bromo-4-fluoro-5-nitrobenzoic acid (Compound 1a) (19g, 71.97mmol) as a pale yellow solid. Yield: 71%.

MS(ESI) m/z=265 [M+H] ⁺ .

Step 2: Synthesis of methyl 3-bromo-4-fluoro-5-nitrobenzoate

Under ice bath, add thionyl chloride (8mL, 110mmol) dropwise to 3-bromo-4-fluoro-5-nitrobenzoic acid (19g, 71.97mmol) in methanol (150mL) solution, and increase the temperature after adding The reaction was stirred at 70°C for 16h. After the reaction is complete, spin dry methanol, dissolve the crude product with ethyl acetate, wash with water and saturated brine, dry and filter with anhydrous sodium sulfate, spin dry to obtain methyl 3-bromo-4-fluoro-5-nitrobenzoate ( Compound 1b) (18 g, 64.74 mmol), pale yellow solid, yield: 89%.

MS(ESI) m/z=279 [M+H] ⁺ .

Step 3: Synthesis of methyl 3-bromo-4-((3-((tert-butoxycarbonyl)amino)propyl)amino)-5-nitrobenzoate

At room temperature, 3-bromo-4-fluoro-5-nitrobenzoic acid methyl ester (1.25g, 7.19mmol) and tert-butyl-(3-aminopropyl) carbamate (2g, 7.19mmol) DMF (20 mL) was added, and DIPEA (2.8 g, 21.57 mmol) was added, and the mixture was stirred and reacted at room temperature for 0.5 h. After the reaction is completed, add water and ethyl acetate extraction (50mL x 3), combine the organic phases and wash with water and saturated brine, spin dry the solvent to obtain 3-bromo-4-((3-((tert-butoxycarbonyl)amino )Propyl)amino)-5-nitrobenzoic acid methyl ester (compound 1c) (2.55 g, 5.92 mmol) yellow solid, yield 82%.

MS(ESI) m/z=433 [M+H] ⁺ .

Step 4: (E)-3-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)-4-((3-((tert-butoxycarbonyl)amino) Synthesis of propyl)amino)-5-methylnitrobenzene

At room temperature, add compound 1c (500mg, 1.16mmol), tert-butyl acrylate (180mg, 1.4mmol) and potassium carbonate (320mg, 2.31mmol) to toluene (5mL), replace the air with nitrogen and add Pd(dppf) Cl ₂ (85mg, 0.116mmol), after nitrogen exchange, the temperature was raised to 100°C and the reaction was stirred for 16h. After the reaction is complete, cool to room temperature, add water and extract with ethyl acetate (20mL x 3), combine the organic phases and wash with water and saturated brine, spin off the solvent, and purify by silica gel column (eluent: ethyl acetate/petroleum) Ether, v/v=1/15) to obtain (E)-3-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)-4-((3-(( Tert-Butoxycarbonyl)amino)propyl)amino)-5-methyl nitrobenzene (compound 1d) (400 mg, 0.834 mmol), pale yellow solid, yield: 72%.

MS(ESI) m/z=480 [M+H] ⁺ .

Step 5: 3-Amino-5-(3-(tert-butoxy)-3-oxopropyl)-4-((3-((tert-butoxycarbonyl)amino)propyl)amino)benzoic acid Synthesis of methyl ester

To the methanol and ethyl acetate solution of compound 1d (200mg, 0.417mmol) was added 10% palladium on carbon (20mg), hydrogenated and reduced for 3h, filtered to remove the palladium on carbon, and the filtrate was concentrated to obtain 3-amino-5-(3- (Tert-Butoxy)-3-oxopropyl)-4-((3-((tert-butoxycarbonyl)amino)propyl)amino)methyl benzoate (Compound 1e) (184mg, 0.407mmol) , Directly used in the next reaction.

MS(ESI) m/z=452 [M+H] ⁺ .

Step 6: 7-(3-(tert-butoxy)-3-oxopropyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-(1-ethyl- Synthesis of 3-methyl-1H-pyrazole-5-methyl)carboxamido)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester

Under an ice bath, compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (80mg, 0.41mmol) was added dropwise to compound 1e (180mg, 0.399mmol) in DMF (3mL ) In the solution, react for 0.5h. Then HATU (160mg, 0.421mmol) and N,N-diisopropylethylamine (110mg, 0.851mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. The reaction solution was separated by reverse phase MPLC (eluent acetonitrile/water = 1/2, v/v) to obtain 7-(3-(tert-butoxy)-3-oxopropyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2- (1-Ethyl-3-methyl-1H-pyrazole-5-methyl)carboxamido)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (Compound 1f) (240mg, 0.391mmol ), white solid, yield 96%.

MS(ESI) m/z=613 [M+H] ⁺ .

Step 7: 3-(1-(3-Aminopropyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-5-(methoxycarbonyl)- Synthesis of 1H-Benzo[d]imidazol-7-yl)propionic acid

In an ice bath, add TFA (1 mL) to 1f (230 mg, 0.375 mmol) of DCM (2 mL), and react at room temperature for 1 h. After the reaction is complete, spin dry to obtain crude 3-(1-(3-aminopropyl) -2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-5-(methoxycarbonyl)-1H-benzo[d]imidazol-7-yl)propionic acid (Compound 1g) (300mg), used directly in the next step.

MS (ESI) m/z=457 [M+H] ⁺ .

Step 8: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-oxo-7,8,9,10,11,12-hexahydro-6H- Synthesis of 2,9,12a-triazepane[cd]]indene-4-carboxylic acid methyl ester

Under ice bath, HATU (170mg, 0.372mmol) and DIPEA (145mg, 1.12mmol) were added to 1g (170mg, 0.372mmol) of DMF (2mL) and DCM (4mL) solution, stirred for 0.5h, after the reaction was completed, water was added It was extracted with ethyl acetate (10mLx3), the combined organic phases were washed with water and saturated brine, and the solvent was spin-dried to obtain 1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)- 8-oxo-7,8,9,10,11,12-hexahydro-6H-2,9,12a-triazacycloheptane[cd]indene-4-carboxylic acid methyl ester (compound 1h) (110mg, 0.25mmol), white solid, yield 67%.

MS(ESI) m/z=439 [M+H] ⁺ .

Step 9: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-oxo 7,8,9,10,11,12 hexahydro-6H-2, Synthesis of 9,12a-triazacyclodecane benzo[cd]indene-4-carboxylic acid

Compound 1h (100 mg, 0.228 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and methanol (1 mL), and then lithium hydroxide (50 mg, 1.14 mmol) in water (2 mL) was added. The reaction solution was stirred at room temperature for 2h. Dilute with water and spin dry the organic solvent, extract once with ethyl acetate, acidify the aqueous phase with dilute hydrochloric acid (1M) to pH≈4, extract with ethyl acetate (10mL x 3), combine the organic phases and wash with water and saturated brine, and spin. Dry solvent to obtain 1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-oxo 7,8,9,10,11,12 hexahydro-6H-2, 9,12a-Triazacyclodecane benzo[cd]indene-4-carboxylic acid (Compound 1i) (74 mg, 0.174 mmol), white solid, yield 76.3%.

MS (ESI) m/z = 425 [M+H] ⁺ .

Step 10: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-oxo 7,8,9,10,11,12 hexahydro-6H-2, Synthesis of 9,12a-triazacyclodecane benzo[cd]indene-4-carboxamide

Under an ice bath, HATU (73 mg, 0.192 mmol) was added to a solution of compound 1i (70 mg, 0.165 mmol) in DMF (2 mL). After 15 min, DIPEA (65 mg, 0.5 mmol) and ammonium chloride (30 mg, 0.56 mmol) were added. After reacting for 1 h, the reaction solution was separated by reverse phase MPLC (eluent acetonitrile/water=1/1, v/v) to obtain compound 1 (10.69 mg) as a white solid with a yield of 14%.

MS(ESI) m/z=424 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ(ppm) 1.35(t,J=7.2Hz,3H)1.91～2.09(m,2H)2.18(s,3H)2.76～2.87(m,2H)2.98 ～3.11(m,2H)4.56～4.65(m,4H)6.63(s, 1H)7.31(s,1H)7.60(s,1H)7.87(s,2H)7.91(s,1H)

Example 2

Step 1: Synthesis of tert-butyl (3-(3-(benzyloxy)propoxy)propyl)carbamate

Under an ice bath, sodium hydride (550 mg, 13.7 mmol) was added to a mixed solvent of tert-butyl (3-hydroxypropyl) carbamate (2 g, 11.42 mmol) in DMF (8 mL) and tetrahydrofuran (16 mL). After stirring for 30 minutes, 3-benzyloxy bromopropane (3.66 g, 15.989 mmol) was added, and the temperature was raised to room temperature to react for 10 h. After the reaction is complete, add water, extract with ethyl acetate (50mL x 3), combine the organic phase and spin-dry the solvent, and separate the crude product by column chromatography (eluent: ethyl acetate/petroleum ether = 1/10, v/v). Color oil (3-(3-(benzyloxy)propoxy)propyl) tert-butyl carbamate (Compound 2a) (1.23g, 3.8mmol), yield 33%.

MS(ESI) m/z=324 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl (3-(3-hydroxypropoxy)propyl)carbamate

Palladium on carbon (10%, 80mg) was added to the methanol and ethyl acetate solution of compound 2a (800mg, 2.47mmol), hydrogenated and reduced for 3h, filtered to remove the palladium on carbon, and the filtrate was concentrated to obtain (3-(3-hydroxypropoxy) (Yl)propyl)tert-butyl carbamate (compound 2b) (519 mg, 2.227 mmol), yield 90%. Used directly in the next reaction.

MS(ESI) m/z=234 [M+H] ⁺ .

Step 3: Synthesis of (3-(3-(5-carbamoyl-2-chloro-3-nitrophenoxy)propoxy)propyl) tert-butyl carbamate

At room temperature, compound 2b (510mg, 2.19mmol) and 4-chloro-3-hydroxy-5-nitrobenzamide (500mg, 2.3mmol) were dissolved in dry tetrahydrofuran (20mL). After replacing the air with nitrogen, add triphenyl Phosphine (907 mg, 3.45 mmol) and diisopropyl azodicarboxylate (700 mg, 3.45 mmol) were added and the reaction was stirred for 10 h. After the reaction is complete, add water and ethyl acetate extraction (20mL x 3), combine the organic phase and spin-dry the solvent, and separate the crude product by column chromatography (eluent ethyl acetate/petroleum ether = 1/2, v/v) to obtain 3-( 3-(5-carbamoyl-2-chloro-3-nitrophenoxy)propoxy)propyl)tert-butyl carbamate (compound 2c) (750 mg, 1.736 mmol), the yield was 75%.

MS(ESI) m/z=432[M+H] ⁺ .

Step 4: Synthesis of 3-(3-(3-aminopropoxy)propoxy)-4-chloro-5-nitrobenzamide

TFA (3mL) was added to compound 2c (740mg, 1.716mmol) in DCM (6mL), and reacted at room temperature for 1 h. After the reaction was complete, it was spin-dried. The crude product was adjusted to pH≈8 with saturated sodium bicarbonate solution and extracted with ethyl acetate ( 20mLx3), the combined organic phase was washed with saturated brine, then dried and spin-dried to obtain 3-(3-(3-aminopropoxy)propoxy)-4-chloro-5-nitrobenzamide (compound 2d ) (555mg, 1.68mmol) was used directly in the next step.

MS (ESI) m/z=332 [M+H] ⁺ .

Step 5: 10-Nitro-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxacycloundecane-12-carboxamide Synthesis

At room temperature, 3-(3-(3-aminopropoxy)propoxy)-4-chloro-5-nitrobenzamide (200mg, 0.604mmol) and potassium carbonate (100mg, 0.725mmol) were dissolved in In DMF (120 mL), the temperature was raised to 90° C. and the reaction was stirred for 20 h. After the reaction is complete, the solvent is spin-dried, the ethyl acetate (50 mL) is dissolved, washed with water and saturated brine, and spin-dried to obtain 10-nitro-3,4,6,7,8,9-hexahydro-2H-benzo [b] [1,8,4] Dioxazepine-12-carboxamide (Compound 2e) (177 mg, 0.597 mmol), the yield was 99%, and it was used directly in the next step.

MS(ESI) m/z=296 [M+H] ⁺ .

Step 6: 10-Amino-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxacycloundecane-12-carboxamide synthesis

Palladium on carbon (10%, 20mg) was added to the methanol and ethyl acetate solution of 2e (170mg, 0.574mmol), hydrogenated and reduced for 3h, the palladium on carbon was filtered off, and the filtrate was concentrated to obtain 10-amino-3,4,6,7 ,8,9-hexahydro-2H-benzo[b][1,8,4]dioxanundecane-12-carboxamide (compound 2f) (150 mg, 0.566 mmol), the yield was 98%. Used directly in the next reaction.

MS(ESI) m/z=266 [M+H] ⁺ .

Step 7: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-6,10-dioxa Synthesis of 2,13a-diazacycloundecanebenzo[cd]indene-4-carboxamide

Under an ice bath, compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (80 mg, 0.41 mmol) was added dropwise to compound 2f (108 mg, 0.407 mmol) in DMF (3 mL ) In the solution, react for 0.5h. Then HATU (160mg, 0.421mmol) and N,N-diisopropylethylamine (105mg, 0.814mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was complete, it was purified by reverse phase HPLC to obtain compound 2 (8.7mg, Yield 5%), white solid.

MS(ESI) m/z=427 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ(ppm) 1.35(t,J=7.2Hz,3H)1.86～1.96(m,4H)2.17(s,3H)3.33～3.35(m,2H)3.61 ～3.75(m,2H)4.38～4.47(m,2H)4.47～4.55(m,2H)4.61(q,J1＝14Hz,J2＝7.2Hz,2H)6.64(s,1H)7.35(s,1H) 7.45(s, 1H)7.67(s,1H)7.98(s,1H)12.85(s,1H).

Example 3

In an ice bath, compound 1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (64 mg, 0.3 mmol) was added dropwise to compound 2f (80 mg, 0.3 mmol) ) In DMF (3mL) solution for 0.5h. Then HATU (114mg, 0.3mmol) and N,N-diisopropylethylamine (77mg, 0.6mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was complete, it was purified by reverse phase HPLC to obtain compound 3 (19.2mg, Yield 14.4%).

MS(ESI)m/z=445[M+H] ⁺

¹ H NMR (400MHz, MeOD): δ (ppm) 7.64-7.65 (m, 1H), 7.46 (m, 1H), 6.78 (s, 1H), 5.03-5.06 (t, J = 5.2 Hz, 1H), 4.97-5.00(t,J=5.2Hz,1H), 4.84-4.85(t,J=5.2Hz,1H), 4.72-4.75(t,J=5.2Hz,1H), 4.66(s,2H), 4.48 (s,2H), 3.80(s,2H), 3.50-3.52(t,J=3.6Hz,2H), 2.28(s,3H), 2.02-2.05(m,4H).

Example 4

Under an ice bath, compound 1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (44 mg, 0.226 mmol) was added dropwise to compound 2f (60 mg, 0.226 mmol) ) In DMF (3mL) solution for 0.5h. Then HATU (86mg, 0.226mmol) and N,N-diisopropylethylamine (58mg, 0.452mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was complete, it was purified by reverse phase HPLC to obtain compound 4 (9.9mg, Yield 10.3%).

MS(ESI)m/z=428[M+H] ⁺

¹ H NMR (400MHz, MeOD): δ (ppm) 7.65 (s, 1H), 7.47 (s, 1H), 4.59-4.75 (m, 2H), 4.42-4.55 (m, 2H), 3.71-3.90 (m , 2H), 3.50-3.51 (m, 2H), 3.08-3.15 (m, 2H), 2.52 (s, 3H), 2.00-2.08 (m, 4H), 1.28-1.32 (m, 3H).

Example 5

In an ice bath, compound 1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (64 mg, 0.3 mmol) was added dropwise to compound 2f (80 mg, 0.3 mmol) ) In DMF (3mL) solution for 0.5h. Then HATU (114mg, 0.3mmol) and N,N-diisopropylethylamine (77mg, 0.6mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was complete, it was purified by reverse phase HPLC to obtain compound 5 (55mg, yield) Rate 41.4%).

MS(ESI)m/z=444[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 12.80 (s, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.35-7.45 (m, 2H), 4.41-4.47 (m, 4H) ), 3.67(s,2H),3.34-3.35(m,2H),3.17-3.23(m,2H),2.61(s,3H),1.90(m,4H),1.21-1.25(t,J=7.6 Hz, 3H).

Example 6

Under an ice bath, compound 3-(difluoromethyl)-1-ethyl-1H-pyrazole-5-carbonyl isothiocyanate (52 mg, 0.226 mmol) was added dropwise to compound 2f (60 mg, 0.226 mmol) In DMF (3mL) solution, react for 0.5h. Then HATU (86mg, 0.226mmol) and N,N-diisopropylethylamine (58mg, 0.452mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was complete, it was purified by reverse phase HPLC to obtain compound 6 (41mg, yield Rate 39.4%).

MS(ESI)m/z=463[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ): δ (ppm) 12.93 (s, 1H), 7.64-7.65 (m, 1H), 7.46 (m, 1H), 6.78 (s, 1H), 5.76 (s, 1H),4.72-4.75(m,2H),4.42-4.45(m,4H), 3.60-3.77(m,2H),3.34-3.38(m,2H),1.87-1.99(m,4H),1.39- 1.43(t,J=7.2Hz,3H).

Example 7

Step 1: Synthesis of tert-butyl (3-(2-(benzyloxy)ethoxy)propyl)carbamate

Under an ice bath, sodium hydride (550 mg, 13.7 mmol) was added to a mixed solvent of tert-butyl (3-hydroxypropyl) carbamate (2 g, 11.42 mmol) in DMF (8 mL) and tetrahydrofuran (16 mL). After stirring for 30 minutes, 3-benzyloxy bromoethane (3.42 g, 15.99 mmol) was added, and the temperature was raised to room temperature to react for 10 h. After the reaction is complete, add water, extract with ethyl acetate (50mLx3), combine the organic phases and spin-dry the solvent, and separate the crude product by column chromatography (eluent: ethyl acetate/petroleum ether = 1/10, v/v) to obtain a colorless oil Compound tert-butyl 3-(2-(benzyloxy)ethoxy)propyl)carbamate 7a (1.23g, 3.98mmol), the yield was 34.9%.

MS(ESI) m/z=310 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl (3-(2-hydroxyethoxy)propyl)carbamate

To the methanol and ethyl acetate solution of compound 7a (1.2g, 3.88mmol) was added 10% palladium on carbon (120mg), hydrogenated and reduced for 3h, filtered to remove the palladium on carbon, and the filtrate was concentrated to obtain (3-(2-hydroxyethoxy (Yl)propyl) tert-butyl carbamate 7b (760 mg, 3.49 mmol), the yield was 90%. Used directly in the next reaction.

MS(ESI) m/z=220 [M+H] ⁺ .

Step 3: Synthesis of (tert-butyl(3-(2-(5-carbamoyl-2-chloro-3-nitrophenoxy)ethoxy)propyl)carbamate

At room temperature, compound 7b (510mg, 2.19mmol) and 4-chloro-3-hydroxy-5-nitrobenzamide (500mg, 2.3mmol) were dissolved in dry tetrahydrofuran (20mL). After replacing the air with nitrogen, add triphenyl Phosphine (907mg, 3.45mmol) and diisopropyl azodicarboxylate (700mg, 3.45mmol) were added and the reaction was stirred for 10h. After the reaction is complete, add water and ethyl acetate extraction (20mL x 3), combine the organic phase and spin-dry the solvent, and separate the crude product by column chromatography (eluent ethyl acetate/petroleum ether = 1/2, v/v) to obtain (tert-butyl The yield of 3-(2-(5-carbamoyl-2-chloro-3-nitrophenoxy)ethoxy)propyl)carbamate 7c (750 mg, 1.736 mmol) was 75%.

MS(ESI) m/z=418 [M+H] ⁺ .

Step 4: Synthesis of 3-(2-(3-aminopropoxy)ethoxy)-4-chloro-5-nitrobenzamide

TFA (3mL) was added to compound 2c (740mg, 1.716mmol) in DCM (6mL), and reacted at room temperature for 1 h. After the reaction was complete, it was spin-dried. The crude product was adjusted to pH≈8 with saturated sodium bicarbonate solution and extracted with ethyl acetate ( 20mLx3), the combined organic phase was washed with saturated brine, then dried and spin-dried to obtain 3-(2-(3-aminopropoxy)ethoxy)-4-chloro-5-nitrobenzamide 7d (555mg , 1.68mmol) used directly in the next step.

MS(ESI) m/z=318 [M+H] ⁺ .

Step 5: Synthesis of 9-nitro-2,3,5,6,7,8-hexahydrobenzo[E][1,4,7]dioxazepine-11-carboxamide

At room temperature, 3-(3-(3-aminopropoxy)propoxy)-4-chloro-5-nitrobenzamide (200mg, 0.604mmol) and potassium carbonate (100mg, 0.725mmol) were dissolved in In DMF (120 mL), the temperature was raised to 90° C. and the reaction was stirred for 20 h. After the reaction is complete, the solvent is spin-dried, ethyl acetate (50mL) is dissolved, washed with water and saturated brine, and spin-dried to obtain 9-nitro-2,3,5,6,7,8-hexahydrobenzo[E] [1,4,7] Dioxazepine-11-carboxamide 7e (177 mg, 0.597 mmol), the yield was 99%, and it was used directly in the next step.

MS (ESI) m/z=282 [M+H] ⁺ .

Step 6: Synthesis of 9-amino-2,3,5,6,7,8-hexahydrobenzo[E][1,4,7]dioxazepine-11-carboxamide

Palladium on carbon (10%, 20mg) was added to the methanol and ethyl acetate solution of 2e (170mg, 0.574mmol), hydrogenated and reduced for 3h, the palladium on carbon was filtered off, and the filtrate was concentrated to obtain 9-amino-2,3,5,6 ,7,8-Hexahydrobenzo[E][1,4,7]dioxazepine-11-carboxamide 7f (150mg, 0.566mmol), the yield is 98%. Used directly in the next reaction.

MS(ESI) m/z=252 [M+H] ⁺ .

Step 7: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,10,11,12tetrahydro-7H-6,9-dioxa2,12a Synthesis of -diazadecane benzo[cd]indene-4-carboxamide

In an ice bath, compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (80mg, 0.41mmol) was added dropwise to compound 7f (108mg, 0.407mmol) in DMF (3mL ) In the solution, react for 0.5h. Then HATU (160mg, 0.421mmol) and N,N-diisopropylethylamine (105mg, 0.814mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was complete, it was purified by reverse phase HPLC to obtain compound 7 (8.7mg, Yield 5%), white solid.

MS (ESI) m/z=413 [M+H] ⁺ .

Example 8

Step 1: Synthesis of 2-(3-((tert-butoxycarbonyl)amino)propoxy)ethyl methanesulfonate

(3-(2-Hydroxyethoxy)propyl) tert-butyl carbamate (1.15g, 5.25mmol) was dissolved in DCM (30mL), TEA (2.2mL, 15.8mmol) was added, and the methyl ester was added dropwise under ice cooling. Sulfonyl chloride (0.49mL, 6.30mmol), stirred under ice bath for 2 hours, the reaction was completed. Water was added to separate the DCM phase, the aqueous layer was extracted twice with DCM, the combined organic phases were dried and then spin-dried to obtain compound 8a (1.6 g). Yield: 103%. Used directly in the next step.

MS (ESI) m/z=298 [M+H] ⁺ .

Step 2: Synthesis of S-(2-(3-((tert-butoxycarbonyl)amino)propoxy)ethyl)ethanethiol ester

Compound 8a (1.6 g, 5.39 mmol) was dissolved in DMF (20 mL), potassium thioacetate (1.23 g, 10.77 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction is complete, add water, extract with ethyl acetate (20mL x3), combine the organic phases and dry, and concentrate the crude product obtained after purification by column chromatography (PE:EA=5:1) to obtain compound 8b (1.31g) as a pale yellow oil , Yield: 87.8%.

MS (ESI) m/z=278 [M+H] ⁺ .

Step 3: Synthesis of S-(2-(3-aminopropoxy)ethyl)ethanethiol ester

Compound 8b (1.31 g, 4.73 mmol) was dissolved in DCM (30 mL), TFA (5 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain the synthesis 8c of compound S-(2-(3-aminopropoxy)ethyl)ethanethiol ester, which was directly used in the next reaction.

MS (ESI) m/z=178 [M+H] ⁺ .

Step 4: Synthesis of methyl 4-((3-(2-(acetylthio)ethoxy)propyl)amino)-3-bromo-5-nitrobenzoate

Compound 8c (837 mg, 4.73 mmol) was dissolved in DMF (20 mL), and methyl 3-bromo-4-fluoro-5-nitrobenzoate (850 mg, 3.09 mmol) and TEA (1.96 mL, 14.2 mmol) were added at room temperature. Stir overnight. Dilute with water, extract with ethyl acetate (20mL*3), combine the organic phases, dry and concentrate. The crude product is purified by column chromatography (PE:EA=5:1) to give 4-((3-(2-( Acetylthio)ethoxy)propyl)amino)-3-bromo-5-nitrobenzoic acid methyl ester 8d (1.183g), yield: 84.9%.

MS (ESI) m/z=435 [M+H] ⁺ .

Step 5: Synthesis of methyl 3-bromo-4-((3-(2-mercaptoethoxy)propyl)amino)-5-nitrobenzoate

Compound 8d (1.1 g, 2.53 mmol) was dissolved in MeOH (20 mL), MeONa (410 mg, 7.6 mmol) was added under ice-bath cooling, and stirred for 1 h. The reaction was completed. Add dilute hydrochloric acid (3M) to adjust to pH≈4, spin dry, add water to dissolve the residue, extract with ethyl acetate (15mL*3), combine the organic phases, dry and spin dry to give 3-bromo-4-((3-( 2-Mercaptoethoxy)propyl)amino)-5-nitrobenzoic acid methyl ester 8e (980 mg) is a yellow solid, which is directly used in the next step, yield: 98.7%.

MS (ESI) m/z=393 [M+H] ⁺ .

Step 6: Synthesis of 9-nitro-2,3,5,6,7,8-hexahydrobenzo[e][1,4,7]oxathiacridine-11-carboxylic acid methyl ester

Compound 8e (980mg, 2.49mmol) was dissolved in 1,4-dioxane (30mL), under nitrogen protection, Xantphos (288mg, 0.498mmol), DIPEA (1.23mL, 7.47mmol) and Pd ₂ (dba ) ₃ (228mg, 0.249mmol), react overnight at 100°C. The insoluble matter was removed by filtration, and the crude product obtained after concentration was purified by column chromatography (PE:EA=5:1 to 3:1) to obtain 9-nitro-2,3,5,6,7,8-hexahydrobenzo [e] [1,4,7]oxathiacridine-11-carboxylic acid methyl ester 8f (180mg) yellow solid, yield: 23.2%.

MS(ESI) m/z=313 [M+H] ⁺ .

Step 7: Synthesis of 9-amino-2,3,5,6,7,8-hexahydrobenzo[e][1,4,7]oxythiazine-11-carboxylic acid methyl ester

Compound 8f (50 mg, 0.16 mmol) was suspended in MeOH (8 mL), and an aqueous solution of Na ₂ S ₂ O ₄ (139 mg, 0.80 mmol) was added dropwise under ice-bath cooling, and the mixture was stirred at room temperature for 2 h. The reaction was complete. The insoluble matter was removed by filtration, the filtrate was spin-dried, the residue was dissolved in water, and then extracted with ethyl acetate (10mL*3), the combined organic phases were dried and spin-dried to obtain 9-amino-2,3,5,6,7,8 -Hexahydrobenzo[e][1,4,7]oxythiazine-11-carboxylic acid methyl ester 8g (45mg), used directly in the next step.

MS (ESI) m/z=283 [M+H] ⁺ .

Step 8: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,10,11,12-tetrahydro-7H-9-oxa-6-thia Synthesis of -2,12a-Diazacyclodecene[cd]indene-4-carboxylic acid ethyl ester

Compound 8g (45mg, 0.16mmol) dissolved in 5mL DMF, add 1-ethyl-3-methyl-5-pyrazolecarboxylic acid isothiocyanate (32mg, 0.16mmol) under ice bath, stir for 10min, then send to LCMS , Showing that the reaction is complete. Add HATU (67 mg, 0.176 mmol) and DIPEA (0.85 mL, 0.48 mmol), and stir overnight at room temperature. Dilute with water, extract with ethyl acetate (10mL x 2), combine the organic phases, dry, and spin dry to obtain 1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,10 ,11,12-Tetrahydro-7H-9-oxa-6-thia-2,12a-diazacyclodecene[cd]indene-4-carboxylic acid ethyl ester 8h (62mg) yellow solid, used directly To the next step.

MS(ESI) m/z=444 [M+H] ⁺ .

Step 9: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,10,11,12-tetrahydro-7H-9-oxa-6-thia Synthesis of -2,12a-diazacyclodecene[cd]indene-4-carboxylic acid

Compound 8h (62mg, 0.14mmol) was dissolved in 5mL MeOH/H2O (10:1) mixed solvent, and hydrated lithium hydroxide (59mg, 1.4mmol) was added, and the mixture was heated to 40°C and reacted overnight. After cooling to room temperature, add dilute hydrochloric acid (1M) to adjust to Ph～4, spin dry. The residue was dissolved in water, extracted with ethyl acetate (10mL x 2), combined the organic phases, dried, and spin-dried to obtain 1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8 ,10,11,12-Tetrahydro-7H-9-oxa-6-thia-2,12a-diazacyclodecene[cd]indene-4-carboxylic acid 8i (42 mg), used directly Next reaction.

MS(ESI) m/z=430 [M+H] ⁺ .

Step 10: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,10,11,12-tetrahydro-7H-9-oxa-6-thia Synthesis of -2,12a-diazacyclodecene[cd]indene-4-carboxamide

Compound 8i (42mg, 0.1mmol) was dissolved in DMF (3mL), TEA (0.55mL, 0.4mmol), HATU (57mg, 0.15mmol) were added successively, stirred at room temperature for 30min, and then ammonium chloride (18mg, 0.3mmol) ), stirring overnight at room temperature. The reaction solution was purified by reverse phase prep-HPLC to obtain compound 8 (10 mg).

MS(ESI) m/z=429 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 8.05-7.98 (m, 3H), 7.41 (s, 1H), 6.15-6.12 (m, 1H), 4.61-4.58 (m ,2H),4.21--4.18(m,1H),3.87-3.84(m,1H),3.75-3.73(m,1H),3.14-3.05(m,2H),2.86-2.75(m,2H),2.34 -2.31(m,1H),2.07(s,3H),2.05-1.95(m,1H),1.35(t,J=7.5Hz,3H).

Example 9

Step 1: Synthesis of 4-((tert-butyldimethylsilyl)oxy)butan-2-ol

To a solution of butane-1,3-diol (5g, 55.48mmol) in dichloromethane (100mL) was added tert-butyldimethylchlorosilane (8.36g, 55.48mmol) and imidazole (4.53g, 66.58mmol) , Stir overnight at room temperature. The reaction solution was poured into water, the separated organic phase was washed with water and saturated brine, dried and concentrated to obtain 4-((tert-butyldimethylsilyl)oxy)butan-2-ol 9a (13.89g) . No further purification was used directly in the next reaction.

MS (ESI) m/z=205 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl (3-((4-((tert-butyldimethylsilyl)oxy)but-2-yl)oxy)propyl)carbamate

Under an ice bath, sodium hydride (1.4 g, 35.23 mmol) was added to a DMF (100 mL) solution of compound 9a (6 g, 29.36 mmol), and the mixture was stirred for 0.5 h. Then, tert-butyl 3-bromopropyl)carbamate (9.09 g, 38.2 mmol) was warmed to room temperature and stirred overnight. After quenching with saturated ammonium chloride, the reaction solution was poured into water, extracted with ethyl acetate (100mL x 3), the combined organic phases were washed with water and saturated brine, dried and concentrated to obtain (3-((4-((叔Butyldimethylsilyl)oxy)but-2-yl)oxy)propyl)t-butyl carbamate 9b (8.28g) was directly used in the next reaction.

MS (ESI) m/z=362 [M+H] ⁺ .

Step 3: Synthesis of tert-butyl (3-((4-hydroxybut-2-yl)oxy)propyl)carbamate

At room temperature, to a tetrahydrofuran (80 mL) solution of compound 9b (8.28 g, 22.9 mmol) was added TBAF (34.35 mmol, 1M tetrahydrofuran solution). The reaction solution was raised to 55°C and stirred overnight. The reaction solution was poured into water, extracted with ethyl acetate (100 mL x 3), the organic phase was washed with saturated brine, dried and spin-dried. The crude product was purified by silica gel column (elution machine: petroleum ether/ethyl acetate=1/1, v/v) to obtain (3-((4-hydroxybut-2-yl)oxy)propyl) t-butyl carbamate Ester 9c (1.86 g).

MS(ESI) m/z=248 [M+H] ⁺ .

Step 4: Synthesis of tert-butyl (3-((4-(5-carbamoyl-2-chloro-3-nitrophenoxy)but-2-yl)oxy)propyl)carbamate

At room temperature, compound 9c (600mg, 2.42mmol) and 4-chloro-3-hydroxy-5-nitrobenzamide (420mg, 1.94mmol) were dissolved in dry tetrahydrofuran (20mL). After replacing the air with nitrogen, add triphenyl Phosphine (1.14 g, 4.36 mmol) and diisopropyl azodicarboxylate (880 mg, 4.36 mmol). Then the temperature was raised to 60°C and the reaction was stirred overnight. After the reaction is complete, add water and ethyl acetate extraction (20mL x 3), combine the organic phase and spin-dry the solvent, and separate the crude product by column chromatography (eluent dichloromethane/methanol=50/1, v/v) to obtain (3-( (4-(5-carbamoyl-2-chloro-3-nitrophenoxy)but-2-yl)oxy)propyl)tert-butyl carbamate 9d (320 mg, yield 29.6%).

MS(ESI) m/z=446 [M+H] ⁺ .

Step 5: Synthesis of 3-(3-(3-aminopropoxy)butoxy)-4-chloro-5-nitrobenzamide

TFA (3mL) was added to compound 9d (320mg, 0.72mmol) in DCM (10mL), and reacted at room temperature for 1 h. After the reaction was complete, it was spin-dried under reduced pressure to obtain 3-(3-(3-aminopropoxy)butoxy Yl)-4-chloro-5-nitrobenzamide 9e (350mg, trifluoroacetate), used directly in the next step.

MS (ESI) m/z=346 [M+H] ⁺ .

Step 6: 4-Methyl-10-nitro-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxaundecane- Synthesis of 12-formamide

At room temperature, compound 9e (350 mg (70% purity), 0.72 mmol) and potassium carbonate (76 mg, 1.1 mmol) were dissolved in DMF (150 mL), and the temperature was raised to 90° C. and the reaction was stirred for 3 h. After the reaction is complete, the solvent is spin-dried, the ethyl acetate (50mL) is dissolved and washed with water and saturated brine, and spin-dried and passed through a normal phase silica gel column (eluent: dichloromethane/methanol=100/3, v/v) Purified to obtain 4-methyl-10-nitro-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxaundecane-12 -Formamide 9f (200 mg, 90% yield).

MS(ESI) m/z=310 [M+H] ⁺ .

Step 7: 10-Amino-4-methyl-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxaundecane-12 -Synthesis of formamide

Palladium on carbon (10%, 20mg) was added to the methanol solution of 9f (127mg, 0.41mmol), hydrogenated and reduced for 3h, the palladium on carbon was filtered off, and the filtrate was concentrated to obtain 10-amino-4-methyl-3,4,6, 7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxaundecane-12-carboxamide 9g (90mg, 78.7% yield). Used directly in the next reaction.

MS (ESI) m/z=280 [M+H] ⁺ .

Step 8: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl 7,8,9,11,12,13 hexahydro-6,10- Synthesis of Dioxa-2,13a-Diazacycloundecane[CD]Indene-4-Carboxamide

Under an ice bath, compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (62 mg, 0.0.32 mmol) was added dropwise to compound 9 g (90 mg, 0.32 mmol) in DMF ( 3mL) solution, react for 0.5h. Then HATU (147mg, 0.38mmol) and N,N-diisopropylethylamine (82mg, 0.64mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was complete, it was purified by reverse phase HPLC to obtain compound 9 (33mg, yield) Rate 23%), white solid.

MS(ESI) m/z=441 [M+H] ⁺ .

Example 9-1

Step 1: Synthesis of 4-((triphenylmethyl)oxy)butan-2-ol

To a solution of butane-1,3-diol (50g, 554.8mmol) in dichloromethane (750mL) was added trimethylchloromethane (8.36g, 154.8mmol), triethylamine (140mL, 665.8mmol) and 4 -Dimethylaminopyridine (1.3g, 10.6mmol), stirred overnight at room temperature. The reaction solution was poured into water, the separated organic phase was washed with water and saturated brine, dried and concentrated, and separated by column chromatography (petroleum ether/ethyl acetate=20/1, 10/1, v/v) to obtain 4 -((Triphenylmethyl)oxy)butan-2-ol 9-1a (110g, 59.6%), a colorless transparent oily substance.

MS (ESI) m/z=333.0 [M+H] ⁺ .

Step 2: Synthesis of 1-tert-butyldimethylsilyl-3-((4-(trityloxy)butan-2-yl)oxy)propan-1-ol

Under an ice bath, sodium hydride (9 g, 225 mmol) was added to a DMF (500 mL) solution of compound 9-1a (50 g, 150.0 mmol), and stirred for 0.5 h. Then 3-bromopropoxy(tert-butyl)dimethylsilane (45.5g, 180mmol) and tetrabutylammonium iodide (5.5g, 15mmol) were added sequentially. After the reaction solution was raised to room temperature, it was heated to 80°C and stirred overnight. After quenching with saturated ammonium chloride, the reaction solution was poured into water, extracted with ethyl acetate (600mL*3), the combined organic phases were washed with water and saturated brine, dried and concentrated to obtain the crude product, which was separated by silica gel column (petroleum ether/ Ethyl acetate = 20/1-10/1, v/v) Purification to obtain 9-1b (14g, 18.5%) as a colorless oil.

MS (ESI) m/z=505.0 [M+H] ⁺ .

Step 3: Synthesis of 3-((4-(Trityloxy)butan-2-yl)oxy)propan-1-ol

At room temperature, to a tetrahydrofuran (50 mL) solution of compound 9-1b (14 g, 27.78 mmol) was added TBAF (33 mmol, 1 M tetrahydrofuran solution). Stir overnight. The reaction solution was poured into water, extracted with ethyl acetate (100 mL*3), the organic phase was washed with saturated brine, dried and spin-dried. The crude product was purified by silica gel column (eluent: petroleum ether/ethyl acetate=70/30, v/v) to obtain 9-1c (7.7 g, 74%) as a colorless oil.

MS(ESI) m/z=391.0 [M+H] ⁺ .

Step 4: Synthesis of 3-((4-(trityloxy)butan-2-yl)oxy)propan-1-ol p-toluenesulfonate

At room temperature, compound 9-1c (7.5 g, 19.23 mmol) was dissolved in a mixture of dichloromethane (20 mL) and pyridine (20 mL), and p-toluenesulfonyl chloride (4.03 g, 21.15 mmol) was added. The reaction solution was stirred overnight at room temperature. After the reaction was completed, it was concentrated. The dichloromethane and pyridine were removed by rotating. The mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was concentrated, and the insoluble matter was filtered off. g), no further purification is used directly in the next reaction. .

MS (ESI) m/z=545.0 [M+H] ⁺ .

Step 5: Synthesis of tert-butyl (3-(((4-(trityloxy)butan-2-yl)oxy)propyl)carbamic acid

Compound 9-1d (8.75g, 16.7mmol) was dissolved in DMF (80mL), K2CO3 (4.6g, 33.5mmol), bis(tert-butoxycarbonyl)amine (4.0g, 18.5mmol) and methyl iodide ( 20mg). Heat to 80°C and react overnight. After the reaction is complete, dilute with water and extract with ethyl acetate. Combine the organic phases and spin-dry the crude product, which is purified by silica gel column (elution machine: petroleum ether/ethyl acetate=100/5, v/ v) 9-1e (2.9g, 34%) was obtained as a colorless oil.

MS (ESI) m/z=590.0 [M+H] ⁺ .

Step 6: Synthesis of tert-butyl (3-((4-hydroxybut-2-yloxy)propyl)carbamic acid

At room temperature, formic acid (2 mL) was added dropwise to a solution of 9-1e (2.9 g, 5.0 mmol) in dichloromethane (30 mL), and the reaction was stirred at room temperature for 3 h. After the reaction is complete, dilute with water and extract with dichloromethane. The combined organic phases are washed with water and saturated brine, spin-dried and passed through a normal phase silica gel column (eluent: petroleum ether/ethyl acetate = 70/30, v/v ) Purification to obtain 9-1f (1.2 g, 57% yield) as a colorless oil.

MS (ESI) m/z=348.0 [M+H] ⁺ .

Step 7: Synthesis of methyl 3-(3-(3-(((tert-butoxycarbonyl)amino)propoxy)butoxy)-4-chloro-5-nitrobenzoate

At room temperature, compound 9-1f (600mg, 2.42mmol) and methyl 4-chloro-3-hydroxy-5-nitrobenzoate (562mg, 2.43mmol) were dissolved in dry tetrahydrofuran (10mL), and the air was replaced with nitrogen. Triphenylphosphine (1.15 g, 4.37 mmol) and diisopropyl azodicarboxylate (4 mg, 4.37 mmol) were added. Then the temperature was raised to 60°C and the reaction was stirred overnight. After the reaction is complete, add water and ethyl acetate extraction (20mL x 3), combine the organic phase and spin-dry the solvent, and separate the crude product by column chromatography (eluent petroleum ether/ethyl acetate=85/15, v/v) to obtain 9-1g (1.91g, crude product contains triphenylphosphine oxide), yellow oil.

MS(ESI) m/z=462.0 [M+H] ⁺ .

Step 8: Synthesis of methyl 3-(3-(3-aminopropoxy)butoxy)-4-chloro-5-nitrobenzoate

Under an ice bath, TFA (2 mL) was added dropwise to a dichloromethane (10 mL) solution of compound 9-1 g (1.9 g crude product, 2.38 mmol), and reacted at room temperature for 2 h. After the reaction is complete, spin off the solvent and dry to obtain the compound 3-(3-(3-aminopropoxy)butoxy)-4-chloro-5-nitrobenzoic acid methyl ester 9-1h (1.39g, crude) , Yellow oil. Used directly in the next reaction.

MS (ESI) m/z=362.0 [M+H] ⁺ .

Step 9: (S)-4-methyl-10-nitro-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxazepine Synthesis of Heteroundecene-12-Methyl Carboxylate

At room temperature, compound 9-1h (1.39 g (70% purity), 3.85 mmol) and potassium carbonate (797 mg, 5.77 mmol) were dissolved in DMF (400 mL), and the temperature was raised to 60° C. and the reaction was stirred overnight. After the reaction is complete, the solvent is spin-dried, the ethyl acetate (50mL) is dissolved and washed with water and saturated brine, and spin-dried and passed through a normal phase silica gel column (eluent: dichloromethane/methanol=100/3, v/v) After purification, 802 mg of the racemate obtained was purified and separated by SFC to obtain 9-1i (300 mg) as an orange solid.

MS (ESI) m/z=325.0 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO)δ8.50(t,J=6.2Hz,1H), 8.21(d,J=1.9Hz,1H), 7.48(d,J=1.8Hz,1H), 4.55-4.45( m,1H),4.22–4.09(m,1H),3.94(td,J=10.3,2.4Hz,1H), 3.82(s,3H), 3.68–3.51(m,2H), 3.44–3.34(m, 1H), 3.19–3.07(m,1H), 1.96–1.62(m,4H), 1.13(d,J=6.3Hz,3H)

Step 10: (S)-4-Methyl-10-amino-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxazepine Synthesis of Heteroundecene-12-Methyl Carboxylate

Palladium-carbon (10%, 113mg) was added to the mixed solution of 9-1i (300mg, 0.93mmol) in methanol (15mL) and tetrahydrofuran (15mL), hydrogenated and reduced for 3h, the palladium-carbon was filtered off, and the filtrate was concentrated to obtain 9-1l ( 300mg, crude product). Used directly in the next reaction.

MS(ESI) m/z=295.0 [M+H] ⁺ .

Step 11: (S)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexa Synthesis of Methyl Hydro-6,10-Dioxa-2,13a-Diazacyclobenzo[cd]indan-4-carboxylate

Under an ice bath, compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (33 mg, 0.17 mmol) was added dropwise to compound 9-11 (50 mg, 0.17 mmol) in DMF (2mL) in the solution, react for 0.5h. Then HATU (77mg, 0.20mmol) and N,N-diisopropylethylamine (43mg, 0.34mmol) were added to the reaction solution, and stirring was continued at room temperature for 3 hours. After the reaction was completed, it was filtered and washed with water to obtain compound 9-1m (77mg, Crude product), white solid.

MS(ESI) m/z=456.0 [M+H] ⁺ .

Step 12: (S)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexa Synthesis of Hydrogen-6,10-Dioxa-2,13a-Diazacyclobenzo[cd]indan-4-carboxylic acid

Compound 9-1m (77mg, 0.17mmol) was dissolved in 5mL MeOH/H2O (10:1) mixed solvent, and hydrated lithium hydroxide (70mg, 1.7mmol) was added, and the mixture was heated to 65 degrees and reacted for 5 hours. After cooling to room temperature, dilute with water and extract with ethyl acetate. Add dilute hydrochloric acid (3M) to the separated aqueous phase to adjust to pH: 3～2. The precipitated white solid is filtered and dried to obtain 9-1n (55mg, 73% yield) , White solid.

MS (ESI) m/z=442.0 [M+H] ⁺ .

Step 13: (S)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexa Synthesis of Hydrogen-6,10-Dioxa-2,13a-Diazacyclobenzo[cd]indan-4-carboxamide

Compound 9-1n (55mg, 0.12mmol) was dissolved in DMF (2mL), DIPEA (31mg, 0.24mmol), HATU (55mg, 0.14mmol) were added successively, stirred at room temperature for 30min, and then ammonium bicarbonate (19.7mg, 0.25mmol), stirred overnight at room temperature. The reaction solution was diluted with water, and a white solid precipitated out, which was collected by filtration and washed with water three times to obtain 9-1 (47.79 mg, 86% yield).

MS (ESI) m/z=443.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO) δ 12.81 (s, 1H), 7.96 (s, 1H), 7.65 (s, 1H), 7.43 (s, 1H), 7.33 (s, 1H), 6.62 (s, 1H) ), 4.71–4.53(m,4H), 4.39–4.29(m,1H), 4.18(t,J=10.1Hz,1H), 3.65–3.53(m,1H), 3.48(s,1H), 3.30– 3.23(m,1H),2.17(s,3H),1.99–1.84(m,3H),1.79(d,J=14.6Hz,1H),1.35(t,J=7.1Hz,3H),1.17(d ,J=6.3Hz,3H).

Example 9-2

Step 1: (R)-4-methyl-10-nitro-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxazepine Synthesis of Heteroundecene-12-Methyl Carboxylate

At room temperature, compound 9-1h (1.39 g (70% purity), 3.85 mmol) and potassium carbonate (797 mg, 5.77 mmol) were dissolved in DMF (400 mL), and the temperature was raised to 60° C. and the reaction was stirred overnight. After the reaction is complete, the solvent is spin-dried, the ethyl acetate (50mL) is dissolved and washed with water and saturated brine, and spin-dried and passed through a normal phase silica gel column (eluent: dichloromethane/methanol=100/3, v/v) Purification, the obtained racemate was purified and separated by SFC to obtain 9-2a (300mg) as an orange solid.

MS (ESI) m/z=325.0 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO)δ8.50(t,J=6.2Hz,1H), 8.21(d,J=1.9Hz,1H), 7.48(d,J=1.8Hz,1H), 4.55-4.46( m,1H), 4.21-4.09(m,1H), 3.99-3.89(m,1H), 3.82(s,3H), 3.65-3.52(m,2H), 3.42--3.34(m,1H), 3.20- 3.06(m,1H),1.96-1.62(m,4H), 1.13(d,J=6.3Hz,3H).

Step 2: (R)-4-methyl-10-amino-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxazepine Synthesis of Heteroundecene-12-Methyl Carboxylate

Palladium on carbon (10%, 113mg) was added to the mixed solution of 9-2a (300mg, 0.93mmol) in methanol (15mL) and tetrahydrofuran (15mL), hydrogenated and reduced for 3h, the palladium on carbon was filtered off, and the filtrate was concentrated to obtain 9-2b( 307mg, crude product). Used directly in the next reaction.

MS(ESI) m/z=295.0 [M+H] ⁺ .

Step 3: (R)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexa Synthesis of Methyl Hydro-6,10-Dioxa-2,13a-Diazacyclobenzo[cd]indan-4-carboxylate

Under an ice bath, compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (33 mg, 0.17 mmol) was added dropwise to compound 9-2b (50 mg, 0.17 mmol) in DMF (2mL) in the solution, react for 0.5h. Then HATU (77mg, 0.20mmol) and N,N-diisopropylethylamine (43mg, 0.34mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was completed, it was filtered and washed with water to obtain compound 9-2c (74mg, Crude product), white solid.

MS(ESI) m/z=456.0 [M+H] ⁺ .

Step 4: (R)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexa Synthesis of Hydrogen-6,10-Dioxa-2,13a-Diazacyclobenzo[cd]indan-4-carboxylic acid

Compound 9-2c (74 mg, 0.16 mmol) was dissolved in 5 mL of a mixed solvent of MeOH/H2O (10:1), and hydrated lithium hydroxide (70 mg, 1.7 mmol) was added, and the mixture was heated to 65 degrees and reacted for 5 hours. After cooling to room temperature, dilute with water and extract with ethyl acetate. Add dilute hydrochloric acid (3M) to the separated aqueous phase to adjust to pH: 3～2. The precipitated white solid is filtered and dried to obtain 9-2d (64mg, 85% yield) , White solid.

MS (ESI) m/z=442.0 [M+H] ⁺ .

Step 5: (R)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexa Synthesis of Hydrogen-6,10-Dioxa-2,13a-Diazacyclobenzo[cd]indan-4-carboxamide

Compound 9-2d (64mg, 0.14mmol) was dissolved in DMF (2mL), DIPEA (36mg, 0.28mmol), HATU (66mg, 0.17mmol) were added successively, stirred at room temperature for 30min, and then ammonium bicarbonate (22mg, 0.28mmol) was added. mmol) and stirred overnight at room temperature. The reaction solution was diluted with water, and a white solid precipitated out, which was collected by filtration and washed with water three times to obtain 9-2 (58 mg, 90% yield).

MS (ESI) m/z=441.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO) δ 12.81 (s, 1H), 7.96 (s, 1H), 7.66 (s, 1H), 7.43 (s, 1H), 7.33 (s, 1H), 6.62 (s, 1H) ), 4.71–4.53(m,4H), 4.35(dt,J=5.2,4.1Hz,1H), 4.18(t,J=9.8Hz,1H), 3.65–3.53(m,1H),3.53–3.42( m,1H),3.29–3.22(m,1H),2.17(s,3H),1.98–1.83(m,3H),1.83–1.72(m,1H),1.35(t,J=7.1Hz,3H) ,1.17(d,J=6.3Hz,3H).

Example 10

Step 1: Synthesis of methyl 3-amino-5-bromo-4-((3-((tert-butoxycarbonyl)amino)propyl)amino)benzoate

Compound 1c (600 mg, 1.39 mmol) was dissolved in methanol (10 mL), the solution was cooled to 0° C., and then ammonia (2.5 mL) and an aqueous solution (5 mL) of sodium dithionite (1.2 g, 6.9 mmol) were added in sequence. The reaction mixture was stirred at 0°C for 1 hour, and the color of the reaction solution changed from orange-red to white. The reaction solution was evaporated to remove methanol, then diluted with water, and extracted with ethyl acetate (20mL×4). The separated organic phase was washed with saturated brine (20mL×2), dried with anhydrous sodium sulfate, filtered, and then spin-dried to obtain the compound 10a (440 mg, 79% yield).

MS(ESI)m/z=402.1[M+H] ⁺

Step 2: 7-Bromo-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) Synthesis of -1H-benzo[d]imidazole-5-carboxylic acid methyl ester

Under an ice bath, compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (214 mg, 1.1 mmol) was added dropwise to compound 10a (440 mg, 1.1 mmol) in DMF (5 mL ) In the solution, react for 0.5h. Then HATU (493mg, 1.3mmol) and N,N-diisopropylethylamine (284mg, 2.2mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. The reaction solution was separated by reverse phase MPLC (eluent acetonitrile/water = 1/2, v/v) to obtain compound 10b (560 mg, yield 90%).

MS(ESI) m/z=563.1 [M+H] ⁺ .

Step 3: 7-Bromo-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-(1-ethyl-3-methyl-N-((2-(trimethylform Synthesis of (silyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester

At room temperature, DIPEA (503 mg, 3.9 mmol) was added to 10b (550 mg, 0.98 mmol) DMF (5 mL), and the temperature was raised to 40° C. to react overnight. The reaction solution was poured into water, extracted with ethyl acetate (5mL*3), the combined organic phases were washed with water and saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound 10c (640mg, yield 94%), directly Used in the next step.

MS (ESI) m/z=693.2 [M+H] ⁺ .

Step 4: (E)-7-(4-(tert-butoxy)-4-oxobut-1-en-1-yl)-1-(3-((tert-butoxycarbonyl)amino)propane Yl)-2-(1-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester

At room temperature, add palladium acetate (1.03g, 4.6mmol), 2-dicyclohexylphosphorus-2,4,6-triisopropyl to 10c (640mg, 0.92mmol) of N,N-dimethylacetamide Diphenyl (86 mg, 0.18 mmol) and DIPEA (356 mg, 2.76 mmol). After nitrogen replacement, the inert atmosphere was maintained and the temperature was raised to 110° C., and the reaction was carried out for 18 hours. The reaction solution was poured into water, extracted with ethyl acetate (10mL*3), the combined organic phases were washed with water and saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by a silica gel column (petroleum ether/ethyl acetate) Ester = 1/1) to obtain compound 10c (400 mg, yield 70%).

MS(ESI) m/z=625.3 [M+H] ⁺ .

Step 5: (E)-4-(1-(3-aminopropyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-5-(methoxy Carbonyl)-1H-benzo[d]imidazol-7-yl)but-3-enoic acid

Under an ice bath, TFA (5 mL) was added to a solution of 10c (254 mg, 0.4 mmol) in dichloromethane (5 mL). It was heated to room temperature and stirred overnight, the solvent was spin-dried, and the excess trifluoroacetic acid was removed under reduced pressure with an oil pump. The obtained compound 10d (235 mg, 100% yield) was directly used in the next step.

MS(ESI)m/z=469.2[M+H] ⁺

Step 6: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-oxo 8,9,10,11,12,13-hexahydro-2,10 Synthesis of ,13a-triazol[cd]indene-4-carboxylic acid methyl ester

Compound 10d (235 mg, 0.4 mmol) was dissolved in DMF (10 mL), and DIPEA (258 mg, 2.0 mmol) and HBTU (167 mg, 0.44 mmol) were added. React at room temperature for 2h, pour the reaction solution into water, extract with ethyl acetate (10mL*3), combine the organic phases, wash with water and saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain the crude product, which is purified by silica gel column (oil Ether/ethyl acetate = 1/2) to obtain compound 10e (84 mg, yield 45%).

MS(ESI)m/z=451.2[M+H] ⁺

Step 7: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-oxo 8,9,10,11,12,13-hexahydro-2,10 Synthesis of ,13a-triazol[cd]indene-4-carboxylic acid

Compound 10e (84 mg, 0.18 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and methanol (1 mL), and then lithium hydroxide (76 mg, 1.8 mmol) in water (2 mL) was added. The reaction solution was stirred at room temperature for 16 hours. Dilute the organic solvent with water and spin dry the organic solvent, acidify the aqueous phase with dilute hydrochloric acid (1M) to pH≈4, extract with ethyl acetate (10mL x 3), combine the organic phases and wash with water and saturated brine, and spin dry the solvent to obtain compound 10f (65mg , The yield is 83%)

MS (ESI) m/z = 437.2 [M+H] ⁺ .

Step 8: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-oxo 8,9,10,11,12,13-hexahydro-2,10 Synthesis of ,13a-triazol[cd]indene-4-carboxamide

Under an ice bath, HATU (68 mg, 0.18 mmol) was added to a solution of compound 10f (65 mg, 0.15 mmol) in DMF (2 mL). After 15 min, DIPEA (58 mg, 0.45 mmol) and ammonium chloride (29 mg, 0.54 mmol) were added. After reacting for 1 h, the reaction solution was separated by reverse phase MPLC (eluent acetonitrile/water=1/1, v/v) to obtain compound 10g (26mg, yield 33%).

MS (ESI) m/z = 436.2 [M+H] ⁺ .

Step 9: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-oxo-6,7,8,9,10,11,12,13-A Synthesis of hydrogen-2,10,13a-triazacycloaryl[cd]indene-4-carboxamide

At room temperature, palladium/carbon (10%, 10 mg) was added to a methanol (5 mL) solution of 10 g (24 mg, 0.055 mmol), and the hydrogenation reaction was carried out for 1 h. The palladium carbon was removed by filtration, and the solvent was spin-dried to obtain compound 10 (10 mg, yield 42%).

MS(ESI)m/z=438.2[M+H] ⁺

¹ H NMR (400MHz, MeOD): δppm 7.96 (s, 1H), 7.87 (s, 1H), 7.75 (s, 1H), 6.82 (s, 1H), 4.73 (q, J = 6.8, 14Hz, 2H) ,4.44(s,2H),3.14(s,2H),2.32(s,3H),2.26(m,2H),1.47(t,J=7.2Hz,3H),1.30-1.35(m,2H)

Example 11

Step 1: (S)-1-(1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12 Synthesis of ,13-hexahydro-6,10-dioxa-2,13a-diaza heterocyclic benzo[cd]indan-4-carboxylic acid methyl ester

Under an ice bath, compound 1-ethyl-3-methyl 4-fluoro-1H-pyrazole-5-carbonyl isothiocyanate (215 mg, 1.01 mmol) was added dropwise to compound (S)-10-amino- 4-methyl-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxaazacycloundecene-12-carboxylic acid methyl The ester (277 mg, 0.92 mmol) in DMF (4 mL) was reacted for 0.5 h. Then HATU (420mg, 1.1mmol) and N,N-diisopropylethylamine (237mg, 1.84mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was completed, it was filtered and washed with water to obtain compound 11a (380mg, crude) , White solid.

MS (ESI) m/z=474.0 [M+H] ⁺ .

Step 2: (S)-1-(1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12 Synthesis of ,13-hexahydro-6,10-dioxa-2,13a-diaza heterocyclic benzo[cd]indan-4-carboxylic acid

Compound 11a (374mg, 0.79mmol) was dissolved in 30mL MeOH/H2O (10:1) mixed solvent, added with hydrated lithium hydroxide (329mg, 7.9mmol), heated to 65°C and reacted for 5h. After cooling to room temperature, dilute with water and extract with ethyl acetate. Add dilute hydrochloric acid (3M) to the separated aqueous phase to adjust to pH: 3～2. The precipitated white solid is filtered and dried to obtain 11b (247mg, 68% yield), white solid.

MS (ESI) m/z=460.0 [M+H] ⁺ .

Step 3: (S)-1-(1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12 Synthesis of ,13-hexahydro-6,10-dioxa-2,13a-diaza heterocyclic benzo[cd]indan-4-carboxamide

Compound 11b (247mg, 0.53mmol) was dissolved in DMF (4mL), DIPEA (130mg, 1.0mmol), HATU (241mg, 0.63mmol) were added successively, stirred at room temperature for 30min, and then ammonium bicarbonate (85mg, 1.0mmol) was added , Stir overnight at room temperature. The reaction solution was diluted with water, and a white solid precipitated out, which was collected by filtration and washed with water three times to obtain 11 (195 mg, 80% yield).

MS(ESI) m/z=459.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO) δ 12.83 (s, 1H), 7.97 (s, 1H), 7.66 (s, 1H), 7.44 (s, 1H), 7.34 (s, 1H), 4.77--4.58 (m ,2H),4.58–4.44(m,2H), 4.34(d,J=12.6Hz,1H), 4.18(t,J=10.1Hz,1H), 3.65–3.52(m,1H), 3.47(s, 1H), 3.30–3.19(m,1H), 2.15(s,3H),1.99–1.69(m,4H), 1.33(t,J=7.1Hz,3H),1.16(d,J=6.2Hz,3H ).

Example 12

Step 1: (R)-1-(1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12 Synthesis of ,13-hexahydro-6,10-dioxa-2,13a-diaza heterocyclic benzo[cd]indan-4-carboxylic acid methyl ester

Under an ice bath, compound 1-ethyl-3-methyl 4-fluoro-1H-pyrazole-5-carbonyl isothiocyanate (215 mg, 1.01 mmol) was added dropwise to compound (R)-10-amino- 4-methyl-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxaazacycloundecene-12-carboxylic acid methyl The ester (306 mg, 0.92 mmol) in DMF (4 mL) was reacted for 0.5 h. Then HATU (420mg, 1.1mmol) and N,N-diisopropylethylamine (237mg, 1.84mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was completed, it was filtered and washed with water to obtain compound 12a (370mg, crude) , White solid.

MS (ESI) m/z=474.0 [M+H] ⁺ .

Step 2: (R)-1-(1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12 Synthesis of ,13-hexahydro-6,10-dioxa-2,13a-diaza heterocyclic benzo[cd]indan-4-carboxylic acid

Compound 12a (363mg, 0.77mmol) was dissolved in 30mL MeOH/H2O (10:1) mixed solvent, and hydrated lithium hydroxide (352mg, 7.8mmol) was added, and the mixture was heated to 65 degrees and reacted for 5 hours. After cooling to room temperature, dilute with water and extract with ethyl acetate. Add dilute hydrochloric acid (3M) to the separated aqueous phase to adjust to pH: 3～2. The precipitated white solid is filtered and dried to obtain 12b (250mg, 77% yield), white solid.

MS (ESI) m/z=460.0 [M+H] ⁺ .

Step 3: (R)-1-(1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12 Synthesis of ,13-hexahydro-6,10-dioxa-2,13a-diaza heterocyclic benzo[cd]indan-4-carboxamide

Compound 12b (250mg, 0.54mmol) was dissolved in DMF (4mL), DIPEA (139mg, 1.0mmol), HATU (246mg, 0.65mmol) were added in sequence, stirred at room temperature for 30min, and then ammonium bicarbonate (86mg, 1.0mmol) was added , Stir overnight at room temperature. The reaction solution was diluted with water, and a white solid precipitated out, which was collected by filtration and washed with water three times to obtain 12 (196 mg, 80% yield).

¹ H NMR(400MHz,DMSO)δ12.86(s,1H),7.97(s,1H),7.66(s,1H),7.44(s,1H),7.34(s,1H),4.74-4.58(m ,2H),4.58–4.47(m,2H), 4.41–4.28(m,1H), 4.18(t,J=10.1Hz,1H), 3.65–3.53(m,1H),3.53–3.42(m,1H) ), 3.30–3.22(m,1H),2.01–1.86(m,2H),1.85–1.66(m,2H),1.33(t,J=7.1Hz,3H),1.16(d,J=6.3Hz, 3H).

Example 13

Step 1: (S)-1-(4-ethyl-2-methylthiazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexahydro-6, Synthesis of 10-Dioxazole-2,13a-Diazol[cd]indene 4-Carboxylate

Under an ice bath, compound 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate (107 mg, 0.50 mmol) was added dropwise to compound (S)-10-amino-4-methyl-3, 4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxaazacycloundecene-12-carboxylic acid methyl ester (153mg, 0.46mmol) In DMF (4mL) solution, react for 0.5h. Then HATU (210mg, 0.55mmol) and N,N-diisopropylethylamine (118mg, 0.90mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was completed, it was filtered and washed with water to obtain compound 13a (185mg, crude) , White solid.

MS (ESI) m/z=473.0 [M+H] ⁺ .

Step 2: (S)-1-(4-ethyl-2-methylthiazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexahydro-6, Synthesis of 10-Dioxazole-2,13a-Diazol[cd]indene 4-carboxylic acid

Compound 13a (181 mg, 0.39 mmol) was dissolved in 15 mL of a mixed solvent of MeOH/H2O (10:1), and hydrated lithium hydroxide (176 mg, 3.9 mmol) was added, and the mixture was heated to 65 degrees and reacted for 5 hours. After cooling to room temperature, dilute with water and extract with ethyl acetate. Add dilute hydrochloric acid (3M) to the separated aqueous phase to adjust to pH: 3～2. The precipitated white solid is filtered and dried to obtain 13b (125mg, 77% yield), white solid.

MS(ESI) m/z=459.0 [M+H] ⁺ .

Step 3: (S)-1-(4-ethyl-2-methylthiazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexahydro-6, Synthesis of 10-Dioxazole-2,13a-Diazol[cd]indene 4-Carboxamide

Compound 13b (125mg, 0.27mmol) was dissolved in DMF (3mL), DIPEA (70mg, 0.5mmol), HATU (123mg, 0.33mmol) were added in sequence, stirred at room temperature for 30min, then ammonium bicarbonate (43mg, 0.33mmol) was added , Stir overnight at room temperature. The reaction solution was diluted with water, and a white solid precipitated out, which was collected by filtration and washed with water three times to obtain 13 (98 mg, 80% yield).

MS(ESI) m/z=458.0 [M+H] ⁺ .

Example 14

Step 1: (R)-1-(4-ethyl-2-methylthiazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexahydro-6, Synthesis of 10-Dioxazole-2,13a-Diazol[cd]indene 4-Carboxylate

Under an ice bath, compound 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate (110 mg, 0.52 mmol) was added dropwise to compound (R)-10-amino-4-methyl-3, Methyl 4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxaazacycloundecene-12-carboxylate (139mg, 0.47mmol) In DMF (4mL) solution, react for 0.5h. Then HATU (214mg, 0.56mmol) and N,N-diisopropylethylamine (121mg, 0.94mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was completed, it was filtered and washed with water to obtain compound 13a (175mg, crude) , White solid.

MS (ESI) m/z=473.0 [M+H] ⁺ .

Step 2: (R)-1-(4-ethyl-2-methylthiazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexahydro-6, Synthesis of 10-Dioxazole-2,13a-Diazol[cd]indene 4-carboxylic acid

Compound 14a (90 mg, 0.19 mmol) was dissolved in 10 mL of a mixed solvent of MeOH/H ₂ O (10:1), lithium hydroxide hydrate (88 mg, 1.95 mmol) was added, and the mixture was heated to 65 degrees and reacted for 5 hours. After cooling to room temperature, dilute with water and extract with ethyl acetate. Add dilute hydrochloric acid (3M) to the separated aqueous phase to adjust to pH: 3～2. The precipitated white solid is filtered and dried to obtain 14b (63mg, 76% yield), white solid.

MS(ESI) m/z=459.0 [M+H] ⁺ .

Step 3: (R)-1-(4-ethyl-2-methylthiazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexahydro-6, Synthesis of 10-Dioxazole-2,13a-Diazol[cd]indene 4-Carboxamide

Compound 14b (63mg, 0.14mmol) was dissolved in DMF (3mL), and DIPEA (40mg, 0.3mmol), HATU (62mg, 0.16mmol) were added in sequence, stirred at room temperature for 30min, and then ammonium bicarbonate (13mg, 0.165mmol) was added , Stir overnight at room temperature. The reaction solution was diluted with water, and a white solid precipitated out, which was collected by filtration and washed with water three times to obtain 14 (49 mg, 80% yield).

MS(ESI)m/z=458.0[M+H] ⁺

Example 15

Step 1: Synthesis of methyl 3-bromo-4-((3-hydroxypropyl)amino)-5-nitrobenzoate

At room temperature, the compound 3-hydroxypropylamine (622mg, 8.29mmol) and DIPEA (1.78g, 13.8mmol) were added dropwise to the compound 3-bromo-4-fluoro-5-nitrobenzoic acid methyl ester (1.92g, 6.9mmol) In DMF (10 mL) solution, react for 3 hours. After the reaction was completed, it was diluted with water and extracted with dichloromethane. The combined organic phase was washed with water, washed with saturated brine, dried and concentrated to obtain compound 15a (2.1 g, crude product) as a yellow oil. Used directly in the next reaction.

MS (ESI) m/z=334.0 [M+H] ⁺ .

Step 2: Synthesis of methyl 3-amino-5-bromo-4-((3-hydroxypropyl)amino)benzoate

Under ice bath, add ammonia water (5mL, 33mmol) to compound 15a (1.1g, 3.3mmol) in MeOH (20mL) solvent, 5min later, add sodium hydroxide (2.87g, 16.5mmol) aqueous solution (6mL), gradually increase After reaching room temperature and stirring for 2h, the reaction is complete, dilute with water, extract with dichloromethane, add water to the separated organic phase, wash with saturated brine, dry and concentrate with anhydrous sodium sulfate to obtain 15b (772mg, 77% yield), yellow oil Things. It was used directly in the next reaction without purification.

MS (ESI) m/z=304.0 [M+H] ⁺ .

Step 3: 7-Bromo-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(3-hydroxypropyl)-1H-benzo[d]imidazole Synthesis of -5-carboxylic acid methyl ester

Under an ice bath, compound 1-ethyl-3-methyl 4-fluoro-1H-pyrazole-5-carbonyl isothiocyanate (545 mg, 2.79 mmol) was added dropwise to compound 15b (770 mg, 2.54 mmol) In DMF (10 mL) solution, react for 0.5 h. Then HATU (1.16mg, 1.1mmol) and N,N-diisopropylethylamine (655mg, 5.08mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was completed, it was filtered and washed with water to obtain compound 15c (765mg, crude ), light pink solid.

MS (ESI) m/z=465.0 [M+H] ⁺ .

Step 4: 7-Bromo-2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxy Synthesis of Amido)-1-(3-hydroxypropyl)-1H-benzo[d]imidazole 5-carboxylate

At room temperature, to a solution of compound 15c (765mg, 1.65mmol) in tetrahydrofuran (15mL) was added cesium carbonate (1.6g, 4.97mmol), (2-(chloromethoxy)ethyl)trimethylsilane (550mg, 3.3mmol) ). Stir overnight. After the reaction was completed, the reaction solution was concentrated, and the obtained crude product was purified by silica gel column (eluent: dichloromethane/methanol=95/5, v/v) to obtain 15d (570 mg, 58% yield), an off-white solid.

MS (ESI) m/z=594.0 [M+H] ⁺ .

Step 5: 7-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-2-(1-ethyl-3-methyl-N-((2-(tri (Methylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)-1-(3-hydroxypropyl)-1H-benzo[d]imidazole-5-carboxylic acid methyl Synthesis of ester

At room temperature, compound 15d (270mg, 0.45mmol) was dissolved in N,N-dimethylformamide (5mL) solution, N-tert-butoxycarbonylpropynamide (106mg, 0.68mmol), Pd(PPh ₃ ) ₂ Cl ₂ (16 mg, 0.02 mmol), tri-tert-butylphosphorus (10% toluene solution, 37 mg, 0.04 mmol), cuprous iodide (8.7 mg, 0.04 mmol) and DIPEA (117 mg, 0.91 mmol). The mixture was replaced with nitrogen for 5 times, heated to 85°C under nitrogen protection and stirred overnight at this temperature. After the reaction was completed, it was concentrated and dried to obtain a crude product, which was purified by silica gel column (eluent: dichloromethane/methanol=92/8, v/v) 15e (76mg, 25% yield) was obtained as a white solid.

MS (ESI) m/z=669.0 [M+H] ⁺ .

Step 6: 7-(3-((tert-butoxycarbonyl)amino)propyl)-2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethyl (Oxy)methyl)-1H-pyrazole-5-carboxamido-1-(3-hydroxypropyl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester

Compound 15e (76mg, 0.11mmol) was dissolved in methanol (8mL), Pd/C (20mg,) was added, and after hydrogen replacement, stirred at room temperature for 48h under the protection of a hydrogen balloon. After the reaction was completed, Pd/C was removed by filtration, and the filtrate was spin-dried to obtain 15f (68 mg, yield 89%) as a colorless oil.

MS (ESI) m/z=673.0 [M+H] ⁺ .

Step 7: 7-(3-((tert-butoxycarbonyl)amino)propyl)-2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethyl Oxy)methyl)-1H-pyrazole-5-carboxamido-1-(3-((((4-nitrophenoxy)carbonyl)oxy)propyl)-1H-benzo(d ] Synthesis of imidazole-5-carboxylic acid methyl ester

Under an ice bath, phenyl p-nitrochloroformate (18 mg, 0.09 mmol) and pyridine (13 mg, 0.16 mmol) were added to a solution of 15f (68 mg, 0.08 mmol) in dichloromethane (10 mL). The temperature was raised to room temperature between, and the reaction was stirred for 3h. After the reaction was completed, the organic phase was removed by distillation under reduced pressure, and the crude product obtained was purified by TLC (developer: dichloromethane/methanol=15/1, v/v) silica gel plate to obtain 15 g (32 mg, 49% yield) , A colorless oil.

MS (ESI) m/z=838.0 [M+H] ⁺ .

Step 8: 7-(3-Aminopropyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(3-((((4-nitro (Phenoxy)carbonyl)oxy)propyl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester

At room temperature, trifluoroacetic acid (1mL) was added dropwise to a solution of compound 15g (32mg, 0.02mmol) in dichloromethane (3mL), stirred at room temperature for 2h, after the reaction was completed, the organic phase was spun off and dried to obtain 15h (35mg, Crude product), yellow oil.

MS(ESI) m/z=608.0 [M+H] ⁺ .

Step 9: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-10-oxo-6,7,8,9,10,12,13,14-A Synthesis of Methyl Hydro-11-oxa-2,9,14a-triazacyclododecyl[cd]indene-4-carboxylate

At room temperature, DIPEA (13 mg, 0.1 mmol) was added dropwise to a solution of compound 15h (35 mg crude product, 0.02 mmol) in acetonitrile (5 mL), and reacted at room temperature for 5 hours. After the reaction is complete, after the reaction is complete, the organic phase is removed by distillation under reduced pressure, and the obtained crude product is purified by TLC (developing solvent: dichloromethane/methanol=15/1, v/v) silica gel plate to obtain 15i (10mg, crude product) ), yellow oil.

MS (ESI) m/z=469.0 [M+H] ⁺ .

Step 10: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-10-oxo-6,7,8,9,10,12,13,14-A Synthesis of hydrogen-11-oxa-2,9,14a-triazacyclododecyl[cd]indan-4-carboxylic acid

At room temperature, compound 15i (10 mg (70% purity), 0.01 mmol) was dissolved in ammonia water (5 mL), and the temperature was raised to 90° C. and the reaction was stirred overnight. After the reaction was completed, the solvent was spin-dried and dried to obtain 15j (15mg, cupin) as a yellow oil. It was used directly in the next reaction without purification.

MS(ESI) m/z=455.0 [M+H] ⁺ .

Step 11: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-10-oxo-6,7,8,9,10,12,13,14-A Synthesis of hydrogen-11-oxa-2,9,14a-triazacyclododecyl[cd]indan-4-carboxamide

(Boc) ₂ O (3 mg, 0.015 mmol), pyridine (one drop) and NH ₄ HCO ₃ (2 mg, 0.02 mmol) were added to a 15h (15 mg, crude product, 0.01 mmol) solution of dioxane (3 mL). Stir overnight at room temperature. After the reaction is complete, spin off the solvent. The crude product is subjected to preparative thin-layer chromatography (developing solvent: dichloromethane/methanol=15/1, v/v) and then MPLC (eluent: water/acetonitrile) , Compound 15 (3.5 mg, 77% yield) was obtained as a white solid.

MS (ESI) m/z=454.0 [M+H] ⁺ .

Example 16

Step 1: Synthesis of 4-methyl-2-phenyl-1,3-dioxane

Under nitrogen protection, 1,3-butanediol (15g, 167mmol), benzaldehyde (17.7g, 167mmol), anhydrous sodium sulfate (40g, 333mmol), p-toluenesulfonic acid (2.9g, 17mmol) were dissolved in DCM (200mL), react at room temperature for 10h. After the reaction is completed, the inorganic salt is filtered, and the organic phase is spin-dried to obtain 16a (29 g, 163 mmol) with a yield of 97%.

MS (ESI) m/z=179 [M+H] ⁺ .

Step 2: Synthesis of 3-(benzyloxy)butan-1-ol

Under the protection of nitrogen, the temperature of 16a (17.8g, 100mmol) in DCM (200mL) was cooled to -78°C, DIBAL-H (100mL, 1M dichloromethane solution, 100mmol) was slowly added dropwise, and the temperature was raised to room temperature to react for 10h. After the reaction is complete, add sodium sulfate decahydrate to quench the reaction, filter the inorganic salt, spin the organic phase to dry the solvent, and separate the crude product by column chromatography (eluent: ethyl acetate/petroleum ether = 1/4, v/v) to obtain 16b (14.7g, 81mmol), the yield is 82%.

MS(ESI) m/z=181 [M+H] ⁺ .

Step 3: Synthesis of tert-butyl (3-(3-(benzyloxy)butoxy)propyl)carbamate

Under an ice bath, sodium hydride (107 mg, 2.66 mmol) was added to 16b (400 mg, 2.22 mmol) in a mixed solvent of DMF (8 mL) and tetrahydrofuran (16 mL). After stirring for 30 minutes, N-tert-butoxycarbonyl propyl bromide 16c (635 mg, 2.66 mmol) was added, and the temperature was raised to room temperature to react for 10 h. After the reaction is complete, add water, extract with ethyl acetate (50mL x 3), combine the organic phase and spin-dry the solvent, and separate the crude product by column chromatography (eluent: ethyl acetate/petroleum ether = 1/10, v/v) to obtain 16d (847g, 2.51mmol), yield 57%.

MS (ESI) m/z=338 [M+H] ⁺ .

Step 4: Synthesis of tert-butyl (3-(3-hydroxybutoxy)propyl)carbamate

Palladium on carbon (10%, 80mg) was added to the methanol and ethyl acetate solution of compound 16d (847mg, 2.51mmol), hydrogenated and reduced for 3h, filtered to remove the palladium on carbon, and the filtrate was concentrated to obtain 16e (562mg, 2.27mmol). The rate is 99%. Used directly in the next reaction.

MS(ESI) m/z=248 [M+H] ⁺ .

Step 5: Synthesis of (3-(3-(5-carbamoyl-2-chloro-3-nitrophenoxy)propoxy)propyl) tert-butyl carbamate

At room temperature, compound 16e (562mg, 2.27mmol) and 4-chloro-3-hydroxy-5-nitrobenzamide (491mg, 2.27mmol) were dissolved in dry tetrahydrofuran (20mL). After replacing the air with nitrogen, add triphenyl Phosphine (894 mg, 3.41 mmol) and diisopropyl azodicarboxylate (689 mg, 3.41 mmol) were added and the reaction was stirred for 10 h. After the reaction is complete, add water and ethyl acetate extraction (20mL x 3), combine the organic phase and spin-dry the solvent, the crude product is separated by column chromatography (eluent ethyl acetate/petroleum ether = 1/2, v/v) to obtain 16f (900mg , 2.01 mmol) yield 92%.

MS(ESI) m/z=446 [M+H] ⁺ .

Step 6: Synthesis of 3-((4-(3-aminopropoxy)but-2-yl)oxy)-4-chloro-5-nitrobenzamide

TFA (20mL) was added to compound 16f (900mg, 2.01mmol) in DCM (20mL), and reacted at room temperature for 1 h. After the reaction was complete, it was spin-dried. The crude product was adjusted to pH≈8 with saturated sodium bicarbonate solution, and extracted with ethyl acetate ( 20 mL×3), the combined organic phase was washed with saturated brine, dried and then spin-dried to obtain 16 g (377 mg, 1.09 mmol) with a yield of 54%, which was directly used in the next step.

MS (ESI) m/z=346 [M+H] ⁺ .

Step 7: 2-Methyl-10-nitro-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxaazacycloundecane Synthesis of Alkyl-12-Carboxamide

At room temperature, 16 g (377 mg, 1.09 mmol) and potassium carbonate (301 mg, 2.18 mmol) were dissolved in DMF (120 mL), and the temperature was raised to 90° C. and the reaction was stirred for 20 h. After the reaction was completed, the solvent was spin-dried, ethyl acetate (50 mL) was dissolved, washed with water and saturated brine, and spin-dried to obtain 16h (366 mg, 1.09 mmol) with a yield of 99%, which was used directly in the next step.

MS(ESI) m/z=310 [M+H] ⁺ .

Step 8: 2-Methyl-10-amino-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxaazacycloundecane Synthesis of Alkyl-12-Carboxamide

Palladium on carbon (10%, 20mg) was added to the 16h (336mg, 1.09mmol) methanol and ethyl acetate solution, hydrogenated and reduced for 3h, the palladium on carbon was filtered off, and the filtrate was concentrated to obtain 16i (272mg, 0.975mmol) with a yield of 89 %. Used directly in the next reaction.

MS (ESI) m/z=280 [M+H] ⁺ .

Step 9: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-7,8,9,11,12,13-hexahydro-6, Synthesis of 10-Dioxa-2,13a-Diazacycloundecanebenzo[cd]indene-4-carboxamide

In an ice bath, compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (35mg, 0.18mmol) was added dropwise to compound 16i (50mg, 0.18mmol) in DMF (3mL ) In the solution, react for 0.5h. Then HATU (75mg, 0.20mmol) and N,N-diisopropylethylamine (46mg, 0.36mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was complete, it was purified by reverse phase HPLC to obtain compound 16 (5.5mg, Yield 7.1%).

MS(ESI)m/z=441[M+H] ⁺

¹ H NMR (400M, DMSO-d6) δ 12.84 (s, 1H), 7.97-8.04 (m, 1H), 7.62-7.67 (m, 1H), 7.42-7.48 (m, 1H), 7.31-7.38 ( m,1H),6.63(s,1H),4.92-4.98(m,1H),4.76-4.84(m,1H),4.56-4.66(m,2H),4.24-4.30(m,1H),3.94- 4.01(m,1H),3.07-3.21(m,2H),2.17(s,3H),1.85-2.11(m,4H),1.61-1.69(m,1H),1.52(d,J=6.08Hz, 3H), 1.35(t, J=7.08Hz, 3H).

Example 17

Step 1: 1-(4-Ethyl-2-(fluoromethyl)thiazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-6,10-dioxazole- Synthesis of 2,13a-diazacyclohexyl[cd]indene 4-carboxamide

Under an ice bath, compound 4-ethyl-2-(fluoromethyl)thiazole-5-carbonyl isothiocyanate (23 mg, 0.1 mmol) was added dropwise to compound 2f (27 mg, 0.1 mmol) in DMF (3 mL) In the solution, react for 0.5h. Then HATU (46mg, 0.12mmol) and N,N-diisopropylethylamine (26mg, 0.2mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was complete, it was purified by reverse phase MPLC to obtain compound 17 (20mg, yield Rate 43%).

MS(ESI)m/z=462[M+H] ⁺

¹ H NMR(400M,DMSO-d6)δ12.86(s,1H),7.85-8.11(m,1H), 7.60-7.72(m,1H),7.43-7.55(m,1H),7.31-7.41( m,1H),5.65-5.78(m,1H),5.53-5.64(m,1H),4.33-4.64(m,4H),3.63-3.74(m,1H),3.21-3.29(m,2H), 1.82-2.00 (m, 2H), 1.20-1.32 (m, 3H).

Example 18

Under an ice bath, compound 2-(difluoromethyl)-4-ethylthiazole-5-carbonyl isothiocyanate (25 mg, 0.1 mmol) was added dropwise to compound 2f (27 mg, 0.1 mmol) in DMF ( 3mL) solution, react for 0.5h. Then HATU (46mg, 0.12mmol) and N,N-diisopropylethylamine (26mg, 0.2mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was complete, it was purified by reverse phase HPLC to obtain compound 18 (8.5mg, Yield 17.7%).

MS(ESI)m/z=480[M+H] ⁺

¹ H NMR(400M,DMSO-d6)δ12.91(s,1H),7.95-8.03(m,1H),7.65-7.70(m,1H),7.44-7.50(m,1H),7.14-7.44( m,2H),4.40-4.58(m,4H),3.64-3.76(m,2H),3.25-3.31(m,2H),1.86-1.99(m,2H),1.27(t,J=7.48Hz, 3H).

Example 19

Under an ice bath, compound 1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (21 mg, 0.1 mmol) was added dropwise to compound 2f (27 mg, 0.1 mmol) In DMF (3mL) solution, react for 0.5h. Then HATU (46mg, 0.12mmol) and N,N-diisopropylethylamine (26mg, 0.2mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was complete, it was purified by reverse phase HPLC to obtain compound 19 (6.6mg, Yield 14.9%).

MS(ESI)m/z=445[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )12.85(s,1H),7.98(s,1H),7.67(s,1H),7.45(s,1H),7.35(s,1H),4.55～4.40( m,6H),3.75～3.70(m,2H),2.16(s,3H),1.92～1.90(m,4H),1.34(t,J=7.2Hz,3H)

Example 20

Under an ice bath, compound 1-ethyl-4-chloro-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (23 mg, 0.1 mmol) was added dropwise to compound 2f (27 mg, 0.1 mmol) In DMF (3mL) solution, react for 0.5h. Then HATU (46mg, 0.12mmol) and N,N-diisopropylethylamine (26mg, 0.2mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h. After the reaction was complete, it was purified by reverse phase HPLC to obtain compound 20 (5.8mg, Yield 12.6%).

MS(ESI)m/z=461[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )12.96(s,1H),7.99(s,1H),7.69(s,1H),7.47(s, 1H),7.36(s,1H),4.55～4.45( m,6H),3.79～3.74(m,2H),2.17(s,3H),1.94～1.90(m,4H),1.36(t,J=7.2Hz,3H)

Example 21

Step 1: Synthesis of benzyl (3-((tert-butoxycarbonyl)amino)propylbenzyl(3-((tert-butyldimethylsilyl)oxy)propyl)carbamate

At room temperature, to a solution of N-BOC propylene diamine (2.1 g, 12 mmol) in acetonitrile, DIPEA (3.1 g, 24 mmol) and O-TBS bromopropane (2.0 g, 7.9 mmol) were added. The reaction solution was raised to 80°C and reacted for 4 hours. After cooling to room temperature, benzyloxycarbonyl succinimide (2.98 g, 12 mmol) was continued to react for 3 h. The solvent was spin-dried and purified by silica gel column (petroleum ether/ethyl acetate = 5/1) to obtain compound 21a (2.4g, 62%)

MS(ESI)m/z=481.3[M+H] ⁺

Step 2: Synthesis of benzyl (3-((tert-butoxycarbonyl)amino)propyl)(3-hydroxypropyl)carbamate

Dissolve compound 21a (2.4g, 5mmol) in tetrahydrofuran (5mL), then add tetrabutylammonium fluoride (10mL, 1M), react for 2h, then spin off the tetrahydrofuran, and dissolve the crude product in ethyl acetate with water , Washed with saturated brine, concentrated and purified by silica gel column (petroleum ether/ethyl acetate=2/3) to obtain compound 21b (1.3g, yield 70%)

MS(ESI)m/z=367.2[M+H] ⁺

Step 3: 3-(3-(((Benzyloxy)carbonyl)(3-((tert-butoxycarbonyl)amino)propyl)amino)propoxy)-4-chloro-5-nitrobenzoic acid Synthesis of methyl ester

21b (400mg, 1.09mmol) and methyl 4-chloro-3-hydroxy-5-nitrobenzoate (252mg, 1.09mmol) were dissolved in dry tetrahydrofuran (10mL), and then triphenylphosphine (428mg, 1.63 mmol). After the ice bath was reduced to 0°C, diisopropyl azodicarboxylate (440 mg, 2.18 mmol) was added under nitrogen protection. Then it was raised to room temperature and reacted for 18h. After rotary drying and column purification (petroleum ether/ethyl acetate=3/2), compound 21c (600 mg, yield 94%) was obtained.

MS(ESI)m/z=580.2[M+H] ⁺

Step 4: Synthesis of methyl 3-(3-((3-aminopropyl)((benzyloxy)carbonyl)amino)propoxy)-4-chloro-5-nitrobenzoate

In an ice bath, add trifluoroacetic acid (5mL) to 21c (600mg, 1.03mmol) in dichloromethane (10mL) solution, warm to room temperature and react for 1h, spin off the solvent, and remove excess trifluoroacetic acid with an oil pump. Compound 21d (700 mg, yield 100%).

MS(ESI)m/z=480.2[M+H] ⁺

Step 5: 5-benzyl12-methyl10-nitro-3,4,6,7,8,9-hexahydrobenzo[b][1,4,8] diazacycloundecane -5,12(2H)-Dicarboxylic acid ester synthesis

Dissolve 21d (700mg, 1.03mmol) in DMF (100mL), add potassium carbonate (569mg, 4.12mmol), raise the temperature to 90°C for 16 hours, spin dry the solvent, add ethyl acetate to dissolve, wash with water to remove inorganic salts, The organic phase was spin-dried to obtain the crude product and purified by silica gel column (petroleum ether/ethyl acetate = 2/1) to obtain compound 21e (230 mg, yield 50%)

MS(ESI)m/z=444.1[M+H] ⁺

Step 6: 5-benzyl 12-methyl 10-amino-3,4,6,7,8,9-hexahydrobenzo[b][1,4,8] oxadiazacycloundecane- Synthesis of 5,12(2H)-Dicarboxylate

21e (230mg, 0.52mmol) was dissolved in methanol (5mL) and tetrahydrofuran (5mL), and ammonia (1mL) was added under ice bath. After 10 min, an aqueous solution (2 mL) of sodium dithionite (452 mg, 2.6 mmol) was added to the reaction solution. After half an hour, the reaction was complete, extracted with ethyl acetate, and the organic phase was dried with water, saturated brine, and anhydrous sodium sulfate, filtered and concentrated to obtain compound 21f (190mg, yield 88%)

MS(ESI)m/z=414.2[M+H] ⁺

Step 7: 10-((Benzyloxy)carbonyl)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,10,11,12,13 Synthesis of -hexahydro-7H-6-oxa-2,10,13a-triazaheterocyclyl[cd]indene-4-carboxylic acid methyl ester

Under an ice bath, add 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (85 mg, 0.46 mmol) to a DMF (10 mL) solution of 21f (190 mg, 0.46 mmol) . Ten minutes later, DIPEA (148 mg, 1.15 mmol) and HATU (194 mg, 0.51 mmol) were added. After reacting for 2 hours, DMF was spin-dried, and ethyl acetate was added to precipitate a solid. The solid was collected by filtration to obtain compound 21g (200 mg, yield 74%).

MS(ESI)m/z=575.2[M+H] ⁺

Step 8: 10-((Benzyloxy)carbonyl)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,10,11,12,13 Synthesis of -hexahydro-7H-6-oxa-2,10,13a-triazaheterocyclyl[cd]indene-4-carboxylic acid 21g (200mg, 0.34mmol) was dissolved in methanol (3mL) and tetrahydrofuran 3mL) was added hydrated lithium hydroxide (74mg, 1.7mmol). Raise to 75°C and react for 2h. After cooling, the pH was adjusted to about 3 with dilute hydrochloric acid (1M), a solid was precipitated, and the solid was filtered and dried to obtain compound 21h (160 mg, yield 84%).

MS(ESI)m/z=561.2[M+H] ⁺

Step 9: 10-((Benzyloxy)carbonyl)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,10,11,12,13 Synthesis of -hexahydro-7H-6-oxa-2,10,13a-triazaheterocyclyl[cd]indene-4-carboxamide

Under an ice bath, HATU (106 mg, 0.28 mmol), DIPEA (108 mg, 0.84 mmol) and ammonium chloride (74 mg, 1.4 mmol) were added to a 21h (160 mg, 0.28 mmol) DMF (5 mL) solution. After 2 hours of reaction, DMF was spin-dried, ethyl acetate was dissolved and washed with water and saturated brine, and the organic phase was spin-dried to obtain compound 21i (130 mg, yield 82%).

MS(ESI)m/z=560.2[M+H] ⁺

Step 10: 1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,10,11,12,13-hexahydro-7H-6-oxa-2 Synthesis of ,10,13a-triazaheterocyclyl[cd]indene-4-carboxamide

Disperse 21i (130 mg, 0.23 mmol) in dichloromethane (5 mL), add hydrobromic acid/acetic acid (33%, 5 mL), and react at room temperature for 1 h. The solvent was spin-dried to obtain the crude product (140 mg, hydrobromide and containing acetic acid), 50 mg of the crude product was separated and purified by preparative HPLC to obtain compound 21 (22 mg).

MS(ESI)m/z=426.2[M+H] ⁺

¹ H NMR (400MHz, DMSO): δppm 8.06(s,1H), 7.73(s,1H), 7.54(s,1H), 7.40(s,1H), 6.72(s,1H), 4.62-4.55(m ,6H), 3.20(s,br,2H), 2.94(s,br,2H), 2.19-2.13(m,5H), 2.08(s,br,2H), 1.36(t,J=7.4,3H) .

Example 22

Step 1: Synthesis of tert-butyl (3-(3-(benzyloxy)propoxy)propyl)carbamate

Under an ice bath, sodium hydride (550 mg, 13.7 mmol) was added to a mixed solvent of tert-butyl (3-hydroxypropyl) carbamate (2 g, 11.42 mmol) in DMF (8 mL) and tetrahydrofuran (16 mL). After stirring for 30 minutes, 3-benzyloxy bromopropane (3.66 g, 15.989 mmol) was added, and the temperature was raised to room temperature to react for 10 h. After the reaction is complete, add water, extract with ethyl acetate (50mL x 3), combine the organic phase and spin-dry the solvent, and separate the crude product by column chromatography (eluent: ethyl acetate/petroleum ether = 1/10, v/v). Colored oil (3-(3-(benzyloxy)propoxy)propyl) tert-butyl carbamate (Compound 22a) (1.23g, 3.8mmol), yield 33%.

MS(ESI) m/z=324 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl (3-(3-hydroxypropoxy)propyl)carbamate

Palladium on carbon (10%, 80mg) was added to the methanol and ethyl acetate solution of compound 22a (800mg, 2.47mmol), hydrogenated and reduced for 3h, filtered to remove the palladium on carbon, and the filtrate was concentrated to obtain (3-(3-hydroxypropoxy) (Yl)propyl) tert-butyl carbamate (compound 22b) (519 mg, 2.227 mmol), yield 90%. Used directly in the next reaction.

MS(ESI) m/z=234 [M+H] ⁺ .

Step 3: Synthesis of 3-(3-tert-butoxycarbonylamino)propoxy)propyl methanesulfonate

Under ice bath, dissolve compound 22b (800mg, 3.43mmol) and triethylamine (1.43mL, 10.3mmol) in DCM (20mL), slowly drop in methanesulfonyl chloride (0.3mL, 4.12mmol), after dripping Warm to room temperature and react overnight. LCMS showed that the reaction was complete, the reaction solution was washed with water, dried and then spin-dried to obtain methanesulfonic acid-3-(3-tert-butoxycarbonylamino)propoxy)propyl ester (compound 22c) (1.35g, 4.34mmol). The rate is 126% and it is directly used in the next reaction.

MS (ESI) m/z=312 [M+H] ⁺ .

Step 4: Synthesis of acetic acid-3-(3-tert-butoxycarbonylamino)propoxy)propylthioester

Compound 22c (1.35 g, 4.34 mmol) was dissolved in DMF (20 mL), potassium thioacetate (0.94 g, 8.68 mmol) was added and stirred at room temperature overnight. LCMS showed that the reaction was complete. Pour the reaction into water, extract with ethyl acetate (3x 40mL), combine the ethyl acetate layers, dry and spin dry, and purify by column chromatography (eluent: ethyl acetate/petroleum ether = 1/5, v/v ) (Ninhydrin color development) to give a yellow oil acetic acid-3-(3-tert-butoxycarbonylamino)propoxy)propylthioester (compound 22d) (1.062g, 3.65mmol), yield 84%.

MS (ESI) m/z=292 [M+H] ⁺ .

Step 5: Synthesis of acetic acid-3-(3-aminopropoxy)propylthioester

At room temperature, compound 22d (1.062 g, 3.65 mmol) was added to a mixed solvent of dichloromethane (20 mL) and trifluoroacetic acid (4 mL), and stirred overnight. LCMS showed that the reaction was complete, the reaction solution was directly spin-dried to obtain the trifluoroacetate salt of acetic acid-3-(3-aminopropoxy)propylthioester (compound 22e) (1.11g, 3.65mmol), the yield was 100% .

MS(ESI) m/z=192 [M+H] ⁺ .

Step 6: Synthesis of methyl 4-(3-(3-ethylthiopropoxy)propylamino)-3-bromo-5-nitrobenzoate

The trifluoroacetate (1.11g, 3.65mmol) of compound 22e was dissolved in DMF (15mL), and methyl 3-bromo-4-fluoro-5-nitrobenzoate (1.00g, 3.65mmol) was added at room temperature. ) And triethylamine (1.51mL, 10.95mmol), stirred overnight at room temperature. LCMS showed that the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate (3x40mL), combined the ethyl acetate layer, dried, spin-dried, and purified by column chromatography (eluent: ethyl acetate/petroleum ether = 1/6 ,v/v) to give 4-(3-(3-ethylthiopropoxy)propylamino)-3-bromo-5-nitrobenzoic acid methyl ester (compound 22f) (1.52g, 3.39mmol), The yield was 92.8%.

MS (ESI) m/z=448 [M+H] ⁺ .

Step 7: Synthesis of methyl 4-(3-(3-mercaptopropoxy)propylamino)-3-bromo-5-nitrobenzoate

Compound 22f (1.52 g, 3.39 mmol) was dissolved in methanol (40 mL), sodium methoxide (366 mg, 6.79 mmol) was added under ice bath, and stirred under ice bath for 30 minutes. LCMS showed that the reaction was complete. Add 1M HCl to adjust to acidity and spin dry. The residue was dissolved in water and ethyl acetate (50 mL), the ethyl acetate layer was separated, dried and then spin-dried to obtain 4-(3-(3-mercaptopropoxy)propylamino)-3-bromo-5-nitro Methyl benzoate (compound 22g) (1.30g, 3.19mmol), yield 94.3%.

MS (ESI) m/z=406 [M+H] ⁺ .

Step 8: 10-Nitro-3,4,6,7,8,9-hexahydro-2H-benzo[f][1,5,8]oxazepine-12-formic acid methyl Synthesis of ester

At room temperature, compound 22g (1.30g, 3.19mmol) was dissolved in dioxane (80mL), and N,N-diisopropylethylamine (1.58mL, 9.57mmol), Xantphos (369mg, 0.638mmol), Pd2(dba)3 (292mg, 0.319mmol), the temperature was raised to 100°C and reacted overnight. LCMS showed that the reaction was complete. Transitionally remove insoluble materials, spin the filtrate to dryness, and purify by column chromatography (eluent: ethyl acetate/petroleum ether = 1/5 to 1/3, v/v) to obtain 10-nitro-3,4,6,7 ,8,9-hexahydro-2H-benzo[f][1,5,8]oxthiazepine-12-methyl carboxylate (compound 22h) (570mg, 1.74mmol), yield 54.7 %.

MS(ESI) m/z=327 [M+H] ⁺ .

Step 9: 10-Amino-3,4,6,7,8,9-hexahydro-2H-benzo[f][1,5,8]oxazepine-12-methyl carboxylate Synthesis

Suspend compound 22h (400mg, 1.23mmol) in methanol (30mL), add ammonia water (1mL) under ice bath, drop in aqueous solution (5mL) of sodium dithionite (1.07g, 6.14mmol), and warm to room temperature after dripping After stirring for 2 hours, LCMS showed that the reaction was complete. The insoluble matter was removed by filtration, the filtrate was spin-dried, the residue was re-dissolved in water and ethyl acetate (50 mL), the ethyl acetate layer was separated, dried, and spin-dried to obtain 10-amino-3,4,6,7,8,9 -Hexahydro-2H-benzo[f][1,5,8]oxazepine-12-methyl carboxylate (Compound 22i) (320mg, 1.08mmol), the yield is 88.1%.

MS(ESI) m/z=297 [M+H] ⁺ .

Step 10: 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a Synthesis of Methyl Diazacycloundec[cd]indene-4-carboxylate

Compound 22i (160mg, 0.54mmol) was dissolved in DMF (5mL), and 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate (126mg, 0.594mmol) was added under ice bath cooling. After reacting for 30 minutes, LCMS showed that the addition was complete, HATU (226 mg, 0.594 mmol) and N,N-diisopropylethylamine (0.28 mL, 1.62 mmol) were added, and the mixture was heated to room temperature and stirred overnight. LCMS showed that the reaction was complete. The precipitated solid was filtered. The filter cake was washed once with DMF (1mL) and petroleum ether (20mL). After drying, 1-(4-ethyl-2-methylthiazole-5-carboxamido) was obtained. -7,8,9,11,12,13-hexahydro-10-oxo-6-thio-2,13a-diaza heteroundec[cd]indene-4-carboxylic acid methyl ester (compound 22j) (140mg , 0.295mmol), the yield is 54.6%.

MS (ESI) m/z=475 [M+H] ⁺ .

Step 11: 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a Synthesis of -Diazacycloundec[cd]indene-4-carboxylic acid

Compound 22j (70 mg, 0.148 mmol) was suspended in methanol (5 mL), water (1 mL) and lithium hydroxide monohydrate (62 mg, 1.48 mmol) were added, and the temperature was raised to 40° C. and stirred overnight. LCMS showed that the reaction was complete. Add 1M HCl to adjust to acidity, spin dry the solvent. The residue was redissolved in water and dichloromethane (30 mL), the dichloromethane layer was separated, dried and then spin-dried to obtain 1-(4-ethyl-2-methylthiazole-5-carboxamido)-7,8 ,9,11,12,13-hexahydro-10-oxo-6-thio-2,13a-diaza heteroundec[cd]indene-4-carboxylic acid (compound 22k) (61mg, 0.133mmol), yield The rate is 81.8%.

MS (ESI) m/z=461 [M+H] ⁺ .

Step 12: 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a Synthesis of -Diazacycloundec[cd]indene-4-carboxamide

Dissolve compound 22k (61mg, 0.133mmol) in DMF (5mL), add N,N-diisopropylethylamine (0.09mL, 0.532mmol), HATU (76mg, 0.20mmol), and stir at room temperature for 30 minutes Ammonium chloride (21mg, 0.398mmol) was added and stirred overnight at room temperature. LCMS showed that the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate (3x30mL), combined the ethyl acetate layers, dried and spin-dried, purified by prep-HPLC to obtain 1-(4-ethyl-2-methylthiazole- 5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxo-6-thio-2,13a-diaza heteroundec[cd]indene-4-carboxamide ( Compound 22) (23.5 mg, 0.051 mmol), the yield was 28%.

MS(ESI) m/z=460 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.93 (s, 1H), 8.07 (s, 1H), 7.97 (d, J = 16.7 Hz, 2H), 7.40 (s, 1H), 5.53 (s, 1H), 4.19(s, 1H), 3.21(s, 4H), 3.22-3.15(m, 1H), 2.99(s, 1H), 2.61(s, 3H), 2.29(s, 1H), 1.96(s ,1H),1.62(s,2H),1.53(s,1H),1.24(t,J=7.3Hz,4H).

Example 23

Step 1: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxy-6-sulfur Synthesis of -2,13a-Diazacycloundec[cd]indene-4-carboxylic acid methyl ester

Compound 22i (160mg, 0.54mmol) was dissolved in DMF (5mL), and 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (116mg, 0.594mmol) was added under ice cooling, The reaction was carried out under ice bath for 30 minutes. After LCMS showed that the addition was complete, HATU (226 mg, 0.594 mmol) and N,N-diisopropylethylamine (0.28 mL, 1.62 mmol) were added, and the mixture was heated to room temperature and stirred overnight. LCMS showed that the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate (3x30mL), combined the ethyl acetate layer, dried and spin-dried to obtain 1-(1-ethyl-3-methyl-1H-pyrazole-5) -Carboxamido)-7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a-diaza heteroundec[cd]indene-4-carboxylic acid methyl ester ( Compound 23a) (335 mg, 0.733 mmol), the yield was 136%.

MS(ESI) m/z=458 [M+H] ⁺ .

Step 2: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxy-6-sulfur Synthesis of -2,13a-diazaheteroundec[cd]indene-4-carboxylic acid

Compound 23a (190 mg, 0.416 mmol) was suspended in methanol (5 mL), water (1 mL) and lithium hydroxide monohydrate (175 mg, 4.16 mmol) were added, and the temperature was raised to 50° C. and stirred overnight. LCMS showed that the reaction was complete. Add 1M HCl to adjust to acidity, spin dry the solvent. The residue was re-dissolved in water and ethyl acetate (30 mL), the ethyl acetate layer was separated, dried and then spin-dried to obtain 1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a-diaazacycloundec[cd]indene-4-carboxylic acid (compound 23b) (148mg, 0.334 mmol), the yield is 80.4%.

MS(ESI) m/z=444 [M+H] ⁺ .

Step 3: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxy-6-sulfur Synthesis of -2,13a-diazaheteroundec[cd]indene-4-carboxamide

Dissolve compound 23b (148mg, 0.334mmol) in DMF (5mL), add N,N-diisopropylethylamine (0.22mL, 1.336mmol), HATU (190mg, 0.501mmol), stir at room temperature for 30 minutes Ammonium chloride (53 mg, 1.00 mmol) was added and stirred overnight at room temperature. LCMS showed that the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate (3x30mL), combined the ethyl acetate layer, dried and spin-dried, purified by prep-HPLC to obtain 1-(1-ethyl-3-methyl-1H -Pyrazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a-diaza heteroundec[cd]indene-4 -Formamide (Compound 23) (17.5 mg, 0.040 mmol), yield 11.4%.

MS(ESI) m/z=443 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.96 (s, 1H), 8.08 (s, 1H), 7.99 (d, J = 10.0 Hz, 2H), 7.40 (s, 1H), 6.65 (s, 1H), 5.52(s, 1H), 4.62(q, J=7.2Hz, 2H), 4.25(s, 1H), 3.73(s, 1H), 3.57(s, 1H), 3.26(s, 1H), 3.17(s, 1H), 2.98(s, 1H), 2.25(s, 1H), 2.18(s, 3H), 1.97(s, 1H), 1.63(s, 1H), 1.53(s, 1H), 1.36 (t,J=7.1Hz,3H).

Example 24

Step 1: 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a -Diazacycloundec[cd]indene-4-carboxylic acid methyl ester-6,6-dioxide synthesis

Compound 22j (70 mg, 0.147 mmol) was dissolved in dichloromethane (10 mL), m-chloroperoxybenzoic acid (51 mg, 0.295 mmol) was added, and the mixture was stirred at room temperature overnight. LCMS showed that the reaction was complete, the reaction solution was washed with water, the organic layer was separated, dried and then spin-dried to obtain 1-(4-ethyl-2-methylthiazol-5-carboxamido)-7,8,9,11, 12,13-hexahydro-10-oxo-6-sulfur-2,13a-diaza heteroundec[cd]indene-4-carboxylic acid methyl ester-6,6-dioxide (compound 24a) (76mg, 0.15mmol), the yield is 101.7%.

MS(ESI) m/z=507 [M+H] ⁺ .

Step 2: 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a -Diazacycloundec[cd]indene-4-carboxylic acid-6,6-dioxide synthesis

Compound 24a (76 mg, 0.15 mmol) was suspended in methanol (5 mL), water (1 mL) and lithium hydroxide monohydrate (63 mg, 1.5 mmol) were added, and the temperature was raised to 50° C. and stirred overnight. LCMS showed that the reaction was complete. Add 1M HCl to adjust to acidity, spin dry the solvent. The residue was redissolved in water and ethyl acetate (30 mL), the ethyl acetate layer was separated, dried and then spin-dried to obtain 1-(4-ethyl-2-methylthiazole-5-carboxamido)-7,8 ,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a-diazepine undec[cd]indene-4-carboxylic acid-6,6-dioxide (compound 24b) (25mg, 0.051mmol), the yield is 34%.

MS (ESI) m/z=493 [M+H] ⁺ .

Step 3: 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a -Diazacycloundec[cd]indene-4-carboxamide-6,6-dioxide synthesis

Dissolve compound 24b (25mg, 0.051mmol) in DMF (5mL), add N,N-diisopropylethylamine (0.033mL, 0.204mmol), HATU (29mg, 0.077mmol), stir at room temperature for 30 minutes Ammonium chloride (8mg, 0.152mmol) was added and stirred overnight at room temperature. LCMS showed that the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate (3x30mL), combined the ethyl acetate layers, dried and spin-dried, purified by prep-HPLC to obtain 1-(4-ethyl-2-methylthiazole- 5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxo-6-thio-2,13a-diaza heteroundec[cd]indene-4-carboxamide- 6,6-Dioxide (Compound 24) (0.9 mg, 0.0018 mmol), yield 3.6%.

MS (ESI) m/z=492 [M+H] ⁺ .

¹ H NMR(400MHz,Methanol-d ₄ )δ8.42(d,J＝1.6Hz,1H), 8.22(d,J＝1.7Hz,1H), 5.60(s,1H), 5.36(t,J＝ 4.8Hz, 1H),, 3.37(s, 3H), 2.72(s, 3H), 2.34(s, 3H), 2.21(s, 2H), 1.79(s, 1H), 1.62(s, 1H), 1.43 (s,1H),1.37–1.28(m,1H),0.92(t,J=6.7Hz,3H)

Example 25

Step 1: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxy-6-sulfur Synthesis of -2,13a-Diazacycloundecyl[cd]indene-4-carboxylic acid methyl ester-6-oxide

Compound 23a (136 mg, 0.298 mmol) was dissolved in dichloromethane (5 mL), m-chloroperoxybenzoic acid (61 mg, 0.357 mmol) was added under ice-cooling, and stirred under ice-bath for 3 hours. LCMS showed that the reaction was complete, the reaction solution was washed with a saturated sodium bicarbonate solution, the organic layer was separated, dried and then spin-dried to obtain 1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a-diaza heteroundec[cd]indene-4-carboxylic acid methyl ester-6-oxide ( Compound 25a) (50mg, 0.106mmol), yield 35.5%.

MS(ESI) m/z=474 [M+H] ⁺ .

Step 2: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxy-6-sulfur Synthesis of -2,13a-diazaheteroundec[cd]indene-4-carboxylic acid-6-oxide

Compound 25a (50 mg, 0.106 mmol) was suspended in methanol (5 mL), water (1 mL) and lithium hydroxide monohydrate (45 mg, 1.06 mmol) were added, and the temperature was raised to 50° C. and stirred overnight. LCMS showed that the reaction was complete. Add 1M HCl to adjust to acidity, spin dry the solvent. The residue was re-dissolved in water and ethyl acetate (30 mL), the ethyl acetate layer was separated, dried and then spin-dried to obtain 1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a-diazaheteroundec[cd]indene-4-carboxylic acid-6-oxide (compound 25b ) (50mg, 0.11mmol), yield 103%.

MS(ESI) m/z=460 [M+H] ⁺ .

Step 3: 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxy-6-sulfur Synthesis of -2,13a-diazaheteroundec[cd]indene-4-carboxamide-6-oxide

Dissolve compound 25b (50mg, 0.11mmol) in DMF (5mL), add N,N-diisopropylethylamine (0.07mL, 0.44mmol), HATU (63mg, 0.165mmol), stir at room temperature for 30 minutes Ammonium chloride (18mg, 0.33mmol) was added and stirred overnight at room temperature. LCMS showed that the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate (3x30mL), combined the ethyl acetate layer, dried and spin-dried, purified by prep-HPLC to obtain 1-(1-ethyl-3-methyl-1H -Pyrazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a-diaza heteroundec[cd]indene-4 -Formamide-6-oxide (Compound 25) (0.9 mg, 0.002 mmol), the yield is 1.8%.

MS(ESI) m/z=459 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.08 (s, 1H), 8.30 (d, J = 15.1 Hz, 2H), 8.15 (s, 1H), 7.56-7.46 (m, 1H), 6.67 ( s, 1H), 4.74 (t, J = 12.6 Hz, 1H), 4.61 (p, J = 7.0, 6.6 Hz, 2H), 4.42–4.33 (m, 1H), 4.04 (s, 1H), 3.54 (t ,J=10.6Hz,1H),3.48(t,J=5.3Hz,2H),3.18(d,J=6.6Hz,1H),2.27(s,1H),2.19(s,3H),2.00(dt ,J＝13.2,6.3Hz,1H),1.75(d,J＝15.2Hz,1H),1.36(t,J＝7.1Hz,3H),1.24(s,2H)

Example 26

Step 1: 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-8,10,11,12-tetrahydro-7H-9-oxy-6-sulfur-2,12a-di Synthesis of azepine[cd]indene-4-carboxylic acid methyl ester

Compound 8g (120mg, 0.425mmol) was dissolved in DMF (5mL), and 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate (90mg, 0.425mmol) was added under cooling in an ice bath. After reacting for 30 minutes, LCMS showed that the addition was complete, HATU (178 mg, 0.468 mmol) and N,N-diisopropylethylamine (0.23 mL, 1.28 mmol) were added, and the mixture was heated to room temperature and stirred overnight. LCMS showed that the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate (3x30mL), combined the ethyl acetate layer, dried and spin-dried to obtain 1-(4-ethyl-2-methylthiazole-5-carboxamide )-8,10,11,12-tetrahydro-7H-9-oxo-6-thio-2,12a-diazepine[cd]indene-4-carboxylic acid methyl ester (compound 26a) (220mg, 0.478 mmol), the yield is 112%.

MS (ESI) m/z=461 [M+H] ⁺ .

Step 2: 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-8,10,11,12-tetrahydro-7H-9-oxy-6-sulfur-2,12a-di Synthesis of azepine[cd]indene-4-carboxylic acid

Compound 26a (220 mg, 0.478 mmol) was suspended in methanol (10 mL), water (2 mL) and lithium hydroxide monohydrate (201 mg, 4.78 mmol) were added, and the temperature was raised to 40° C. and stirred overnight. LCMS showed that the reaction was complete. Add 1M HCl to adjust to acidity, spin dry the solvent. The residue was redissolved in water and dichloromethane (30 mL), the dichloromethane layer was separated, dried and then spin-dried to obtain 1-(4-ethyl-2-methylthiazole-5-carboxamido)-8,10 ,11,12-Tetrahydro-7H-9-oxo-6-thio-2,12a-diazepine[cd]indene-4-carboxylic acid (compound 26b) (80mg, 0.179mmol), yield 37.5% .

MS(ESI) m/z=447 [M+H] ⁺ .

Step 3: 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-8,10,11,12-tetrahydro-7H-9-oxy-6-sulfur-2,12a-di Synthesis of azepine[cd]indene-4-carboxamide

Dissolve compound 26b (80mg, 0.179mmol) in DMF (5mL), add triethylamine (0.1mL, 0.716mmol), HATU (102mg, 0.0.269mmol), stir at room temperature for 30 minutes and add ammonium chloride (29mg , 0.538mmol), stirred overnight at room temperature. LCMS showed that the reaction was complete, the reaction solution was poured into water, extracted with ethyl acetate (3x30mL), combined the ethyl acetate layers, dried and spin-dried, purified by prep-HPLC to obtain 1-(4-ethyl-2-methylthiazole- 5-carboxamido)-8,10,11,12-tetrahydro-7H-9-oxo-6-thio-2,12a-diazepine[cd]indene-4-carboxamide (compound 26) (6mg, 0.013mmol), the yield is 7.5%.

MS(ESI) m/z=446 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.98 (s, 1H), 8.08-7.93 (m, 3H), 7.41 (s, 1H), 6.18-6.07 (m, 1H), 4.16-4.07 (m , 1H), 3.86 (dt, J = 10.5, 3.9 Hz, 1H), 3.74 (d, J = 9.5 Hz, 1H), 3.19 (q, J = 7.7 Hz, 2H), 3.10 (dt, J = 13.9, 4.1Hz, 2H), 2.89 (s, 1H), 2.73 (s, 1H), 2.60 (s, 3H), 2.34 (s, 1H), 2.04 (s, 1H), 1.23 (t, J = 7.5 Hz, 3H).

Example 27

Acetic acid was added to the methanol (2 mL) solution of 21 (20 mg, 0.047 mmol) until the pH was about 4, and then the formaldehyde alcohol solution (1 mL) was added. After reacting for 0.5h at room temperature, sodium cyanoborohydride (15 mg, 0.24 mmol), after the reaction is complete, purified by preparative HPLC to obtain compound 27 (8 mg, yield 38%)

MS (ESI) m/z=440.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO): δppm 12.79 (s, 1H), 7.96 (s, 1H), 7.67 (s, 1H), 7.46 (s, 1H), 7.33 (s, 1H), 6.65 (s, 1H) ), 4.73 (t, J = 6.52, 1H), 4.63 (q, J = 6.57, 2H), 4.54 (m, 2H), 2.28-2.22 (m, 5H), 2.18 (s, 3H), 1.87-1.83 (m, 2H), 1.80-1.76 (m, 2H), 1.36 (t, J = 6.87, 3H).

Example 28

Dissolve 1-methylpiperidine-4-carboxylic acid (8mg, 0.056mmol) in DMF (2mL), add HATU (21mg, 0.056mmol) and DIPEA (12mg, 0.094mmol) at room temperature and stir for 1h, then add 21 (20mg, 0.047mmol) was added to the reaction solution. The reaction was complete after two hours, and the reaction solution was purified by preparative HPLC to obtain compound 28 (4.8 mg, yield 15%)

MS (ESI) m/z = 551.3 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO): δppm 7.99 (s, 1H), 7.69 (s, 1H), 7.55 (s, 0.3H), 7.51 (s, 0.8H), 7.35 (s, 1H), 6.75 (s) ,0.7H), 6.75(s,0.3H), 4.62(q,J=7.28,4H), 4.46-4.36(m,3H), 4.29-4.24(m,2H), 4.20-4.15(m,1H) , 3.72-3.67(m,0.6H), 3.56-3.50(m,2H), 3.49-3.39(m,3H), 3.35-3.29(m,0.4H), 3.09-2.94(m,3H), 2.79- 2.75(m,3H), 2.21-2.18(m,3H), 2.16-2.10(m,2H), 2.05-1.95(m,2H), 1.94-1.80(m,4H), 1.36(t,J=7.28 ,3H).

Hereinafter, the beneficial effects of the present invention are illustrated by way of test examples.

Test Example 1. Binding affinity test of the compound of the present invention and Sting protein

(1) Experimental method

The protein thermal transfer test (TSA) was used to determine the binding affinity of the compound to the Sting protein. The 100ug/ml Sting protein was combined with different concentrations of the compound in 20mM Hepes, 150mM NaCl, 1mM MgCl ₂ , 1mM DTT, and pH=7.5 buffer. Mix 5X SYPRO Orange dyes, measure the dissolution curve of the protein on a qPCR instrument, fit the Tm value with the Protein Thermal Shift Software 1.3 software, calculate the difference between the Tm of the protein when different concentrations of compound and no compound are added, according to _Δ Tm as the compound concentration The change fitting obtains the dissociation constant Kd. The lower the Kd, the stronger the binding affinity of the compound to the Sting protein.

(2) Experimental results

Table 1 The binding affinity of the compound and Sting protein

Compound	Kd
2	+++
3	+++
4	++
5	+++
6	+++
7	++
9	+++
13	+++
16	+++
17	+++
19	+++
20	+++
twenty one	+
twenty two	++
twenty three	++
27	+
28	++

The Kd value of each compound is determined according to the following instructions:

"+" means that the Kd value is greater than 100μM and less than 500μM;

"++" means that the Kd value is less than 100μM and greater than 50μM;

"+++" means Kd value is less than 50μM;

The above experimental results show that the compound of the present invention has a good ability to bind to the Sting protein, especially the compounds 2-6, 9, 13, 16, 17, 19, 20, 23, 28. Therefore, the compound of the present invention can be used as an effective STING protein regulator.

Test Example 2. Test of the agonistic function of the compound of the present invention on Sting protein

(1) Experimental method

In this experiment, the function of sting agonist was evaluated by detecting the changes of CXCL10 (IP10) cytokines produced by THP1 cells (Shanghai Cell Bank) stimulated by compounds in the peripheral blood mononuclear cell line. On the first day of the experiment, the ELISA plate was coated according to the instructions of the IP10 ELISA detection kit (BD, #550926). Dissolve the compound DMSO into a stock solution and dilute it with culture medium to a 2X working concentration, add it to a 96-well plate, 100μL per well; take the THP1 cells in the logarithmic growth phase to count, and dilute to a concentration of 2*10 ⁶ /mL, add the above containing In a 96-well plate of the compound, 100 μL per well, mix well, and incubate in a 37°C, 5% CO ₂ incubator for 18 hours. On the second day, take the above cell culture supernatant, 100μL per well, test according to the instructions of the IP10ELISA detection kit (BD, #550926), read the OD450 value, convert it to IP10 concentration according to the standard curve, and use GraphPad 5.0 to fit the agent effect curve Calculate the EC ₅₀ value. EC ₅₀ concentration for the half-maximal effect (concentration for 50% of maximal effect , EC50) refers to a drug concentration effective to cause 50% of individuals.

(2) Experimental results

Table 2 Effects of compounds on CXCL10 (IP10) cytokines

Compound	EC 50
2	++
4	++
9-1	+++
9-2	++
11	+++
12	++
19	++
20	++
twenty two	+
twenty three	++
27	+

The EC ₅₀ value of each compound is determined according to the following instructions:

"+" means the EC ₅₀ value is greater than 10μM and less than 50μM;

"++" means the EC ₅₀ value is less than 10μM and greater than 1μM;

"+++" means that the EC ₅₀ value is less than 1μM;

The above experimental results show that the compound of the present invention has a good activity of stimulating THP1 cells to produce CXCL10 (IP10) cytokines, and has a good STING protein agonistic function, especially the compound 2, 4, 9-1, 9-2, 11, 12 , 19, 20, 23.

In summary, the present invention provides a compound with a novel structure shown in formula I. Experimental results show that the compound of the present invention can effectively bind to STING and has a good STING protein agonistic function. Therefore, the compounds of the present invention can be used as STING agonists and used to treat various related diseases. The compound provided by the present invention has a very good application prospect in the preparation of drugs for treating diseases related to STING activity, especially in the preparation of drugs for treating inflammatory, autoimmune diseases, infectious diseases, cancer or precancerous syndromes.

Claims (19)

1. The compound represented by Formula I or its tautomers, enantiomers, or pharmaceutically acceptable salts, crystal forms, hydrates or solvates thereof:

   

   among them,

   R ¹ and R ² are independently selected from hydrogen, C ₁ ～C ₆ alkyl, cyano, nitro, hydroxyl, amino, C ₁ ～C ₆ alkoxy, C ₁ ～C ₆ alkylamino, halogen substituted The C ₁ ～C ₆ alkyl group;

   R ^{3 is} selected from hydrogen, C ₁ ～C ₆ alkyl, halogen;

   R ^{4 is} selected from hydrogen, C ₁ ～C ₆ alkyl, halogen, cyano, nitro, hydroxyl, amino, C ₁ ～C ₆ alkoxy, C ₁ ～C ₆ alkylamino, halogen substituted C ₁ ～C ₆ alkyl or none;

   R ^{5 is} selected from hydrogen, C ₁ ～C ₆ alkyl;

   X ^{2 is} selected from C or N;

   Ring B is selected from ^a benzene ring substituted with 0 to 4 Ra, and ^a 5- to 6-membered aromatic heterocyclic ring substituted with 0 to 4 Ra;

   R ^{a is} selected from halogen, hydroxy, amino, and C ₁ to C ₆ alkyl optionally substituted by 0 to 4 R ^b ;

   R ^{b is} selected from halogen, hydroxyl, amino, C ₁ ～C ₆ alkoxy;

   X is selected from -O-, -S-, -S(O) _n -or none; n is 1 or 2;

   L ^1, L ² are each independently selected from 0 to 4 substituents R ⁱ is C ₁ ~ C ₁₀ alkylene group, and is substituted with 0 to 4 R ⁱ alkenylene substituted C ₂ ~ C _10, wherein, when R ⁱ when there are at least two, L ^1, L R ^{i 2} may be linked to form a 3 to 10-membered ring;

   R ^{i is} selected from -OR ^j , halogen, -CN, C ₁ ～C ₆ alkyl;

   R ^{j is} selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

   Z is selected from -O-, -C(O)-,

   

   R ^c and R ^d are independently selected from hydrogen, C ₁ ～C ₆ alkyl, halogen substituted C ₁ ～C ₆ alkyl, -C(O)R ^k or none, or R ^c and ^Rd are connected to them nitrogen atom to form a substituted 0-4 R ^e 3 to 8-membered heterocyclic ring optionally alkane, substituted with 0 to 4 R ^e 3-10-membered heteroaryl ring;

   R ^k is selected from 0 to 4 R ^m substituted 5- to 6-membered cycloalkyl, substituted with 0 to 4 R ^m substituted 5- to 6-membered heterocyclic group; R ^m is selected from C ₁ ~ C ₆ alkyl , C ₁ ～C ₆ alkyl substituted by halogen;

   R ^g and R ^h are independently selected from -C(O)-, -C(O)O- or none;

   R ^{e is} selected from -OR ^f -, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

   R ^{f is} selected from hydrogen, C ₁ to C ₆ alkyl, and halogen substituted C ₁ to C ₆ alkyl.
2. The compound or its tautomers, enantiomers, or pharmaceutically acceptable salts, crystal forms, hydrates or solvates thereof according to claim 1, characterized in that: the compound is of formula I shows:

   

   among them,

   R ¹ and R ² are each independently selected from hydrogen and C ₁ ～C ₆ alkyl groups;

   R ^{3 is} selected from hydrogen, C ₁ ～C ₆ alkyl, halogen;

   R ^{4 is} selected from hydrogen, C ₁ ～C ₆ alkyl, halogen or none;

   R ^{5 is} selected from hydrogen, C ₁ ～C ₆ alkyl;

   X ^{2 is} selected from C or N;

   Ring B is selected from ^a benzene ring substituted with 0 to 4 Ra, and ^a 5- to 6-membered aromatic heterocyclic ring substituted with 0 to 4 Ra;

   R ^{a is} selected from C ₁ to C ₆ alkyl groups optionally substituted by 0 to 4 R ^b ;

   R ^{b is} selected from halogen, hydroxyl, amino, C ₁ ～C ₆ alkoxy;

   X is selected from -O-, -S- or none;

   L ^1, L ² are each independently selected from 0 to 4 substituents R ⁱ is C ₁ ~ C ₁₀ alkylene group, wherein, when at least two R ^i, L ^1, L R ^{i 2} may be connected Form a 3-10 membered ring;

   R ^{i is} selected from -OR ^j , halogen, -CN, C ₁ ～C ₆ alkyl;

   R ^{j is} selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

   Z is selected from -O-, -C(O)-,

   

   R ^c and R ^d are independently selected from hydrogen, C ₁ ～C ₆ alkyl, halogen substituted C ₁ ～C ₆ alkyl or none, or R ^c and R ^d are connected to the nitrogen atom to which they are connected to form a 0～ 4 R ^e is optionally substituted 3 to 8-membered heterocyclic ring alkane, substituted with 0 to 4 R ^e 3-10-membered heteroaryl ring;

   R ^g and R ^h are independently selected from -C(O)-, -C(O)O- or none;

   R ^{e is} selected from -OR ^f -, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

   R ^{f is} selected from hydrogen, C ₁ to C ₆ alkyl, and halogen substituted C ₁ to C ₆ alkyl.
3. The compound according to claim 2 or its tautomer, enantiomer, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, characterized in that: the compound is of the formula II shows:

   

   Ring B is selected from

   

   R ⁶ , R ⁷ , and R ⁸ are each independently selected from hydrogen, and C ₁ to C ₆ alkyl optionally substituted with 0 to 4 R ^b ;

   R ^{b is} selected from halogen, hydroxyl, amino, C ₁ ～C ₆ alkoxy;

   R ¹ and R ² are each independently selected from hydrogen and C ₁ ～C ₆ alkyl groups;

   R ³ and R ⁴ are each independently selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen;

   R ^{5 is} selected from hydrogen, C _1-6 alkyl;

   L ^1, L ² are each independently selected from 0 to 4 substituents R ⁱ is C ₁ ~ C ₁₀ alkylene group, wherein, when at least two R ^i, L ^1, L R ^{i 2} may be connected Form a 3-10 membered ring;

   R ^{i is} selected from -OR ^j , halogen, -CN, C ₁ ～C ₆ alkyl;

   R ^{j is} selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

   Z is selected from -O-, -C(O)-, -C(O)NR-, -NR-,

   

   R is selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

   R ^c and R ^d are independently selected from hydrogen, C ₁ -C ₆ alkyl or none, or R ^c and R ^d are connected with the nitrogen atom to which they are attached to form ^3-8 optionally substituted with 0-4 R ^e Membered heterocyclic alkane, 3-10 membered heteroaromatic ring optionally substituted by 0-4 R ^e ;

   R ^{e is} selected from -OR ^f -, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

   R ^{f is} selected from hydrogen, C ₁ to C ₆ alkyl, and halogen substituted C ₁ to C ₆ alkyl.
4. The compound or its tautomers, enantiomers, or pharmaceutically acceptable salts, crystal forms, hydrates or solvates thereof according to claim 3, characterized in that: said Z is- O-.
5. The compound according to claim 3 or its tautomers, enantiomers, or pharmaceutically acceptable salts, crystal forms, hydrates or solvates thereof, characterized in that: the formula II The compound is shown as:

   

   
6. The compound according to claim 2 or its tautomer, enantiomer, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, characterized in that: the compound is of the formula As shown in III:

   

   

   R ¹ and R ² are each independently selected from hydrogen and C ₁ ～C ₆ alkyl groups;

   R ³ and R ⁴ are each independently selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen;

   R ^{5 is} selected from hydrogen, C _1-6 alkyl;

   Ring B is selected from

   

   R ⁶ , R ⁷ , and R ⁸ are each independently selected from hydrogen, and C ₁ to C ₆ alkyl optionally substituted with 0 to 4 R ^b ;

   R ^{b is} selected from halogen, hydroxyl, amino, C ₁ ～C ₆ alkoxy;

   R ^c and R ^d are independently selected from hydrogen, C ₁ -C ₆ alkyl or none, or R ^c and R ^d are connected with the nitrogen atom to which they are attached to form an optionally substituted with 0 to 4 R ^e

   

   0-4 is optionally substituted with R ^e

   

   0-4 is optionally substituted with R ^e

   

   R ^g and R ^h are independently selected from -C(O)-, -C(O)O- or none;

   L ^1, L ² are each independently selected from 0 to 4 substituents R ⁱ is C ₁ ~ C ₁₀ alkylene group, wherein, when at least two R ^i, L ^1, L R ^{i 2} may be connected Form a 3-10 membered ring;

   R ^{i is} selected from -OR ^j , halogen, -CN, C ₁ ～C ₆ alkyl;

   R ^{j is} selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

   R ^{e is} selected from -OR ^f -, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

   R ^{f is} selected from hydrogen, C ₁ to C ₆ alkyl, and halogen substituted C ₁ to C ₆ alkyl.
7. The compound or its tautomers, enantiomers, or pharmaceutically acceptable salts, crystal forms, hydrates or solvates thereof according to claim 6, characterized in that: the formula III The compound is shown as:

   
8. The compound according to claim 2 or its tautomer, enantiomer, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, characterized in that: the compound is of the formula IV shows:

   

   

   Ring B is selected from

   

   R ⁶ , R ⁷ , and R ⁸ are each independently selected from hydrogen, and C ₁ to C ₆ alkyl optionally substituted with 0 to 4 R ^b ;

   R ^{b is} selected from halogen, hydroxyl, amino, C ₁ ～C ₆ alkoxy;

   R ¹ and R ² are each independently selected from hydrogen and C ₁ ～C ₆ alkyl groups;

   R ³ and R ⁴ are each independently selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen;

   R ^{5 is} selected from hydrogen, C ₁ ～C ₆ alkyl;

   L ^1, L ² are each independently selected from 0 to 4 substituents R ⁱ is C ₁ ~ C ₁₀ alkylene group, wherein, when at least two R ^i, L ^1, L R ^{i 2} may be connected Form a 3-10 membered ring;

   R ^{i is} selected from -OR ^j , halogen, -CN, C ₁ ～C ₆ alkyl;

   R ^{j is} selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

   Z is selected from -O-, -C(O)-, -C(O)NR-, -NR-,

   

   R is selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

   R ^c and R ^d are independently selected from hydrogen, C ₁ -C ₆ alkyl or none, or R ^c and R ^d are connected with the nitrogen atom to which they are attached to form ^3-8 optionally substituted with 0-4 R ^e Membered heterocyclic alkane, 3-10 membered heteroaromatic ring optionally substituted by 0-4 R ^e ;

   R ^{e is} selected from -OR ^f -, C ₁ ～C ₆ alkyl, and halogen substituted C ₁ ～C ₆ alkyl;

   R ^{f is} selected from hydrogen, C ₁ to C ₆ alkyl, and halogen substituted C ₁ to C ₆ alkyl.
9. The compound according to claim 8 or its tautomer, enantiomer, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, characterized in that: the compound is of the formula V shows:

   

   Ring B is selected from

   

   R ⁶ , R ⁷ , and R ⁸ are each independently selected from hydrogen, and C ₁ to C ₆ alkyl optionally substituted with 0 to 4 R ^b ;

   R ^{b is} selected from halogen, hydroxyl, amino, C ₁ ～C ₆ alkoxy;

   R ¹ and R ² are each independently selected from hydrogen and C ₁ ～C ₆ alkyl groups;

   R ³ and R ⁴ are each independently selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen;

   R ^{5 is} selected from hydrogen, C ₁ ～C ₆ alkyl;

   L ^1, L ² are each independently selected from 0 to 4 substituents R ⁱ is C ₁ ~ C ₁₀ alkylene group, wherein, when at least two R ^i, L ^1, L R ^{i 2} may be connected Form a 3-10 membered ring;

   R ^{i is} selected from -OR ^j , halogen, -CN, C ₁ ～C ₆ alkyl;

   R ^{j is} selected from hydrogen, C ₁ to C ₆ alkyl, and halogen substituted C ₁ to C ₆ alkyl.
10. The compound according to claim 9 or its tautomers, enantiomers, or pharmaceutically acceptable salts, crystal forms, hydrates or solvates thereof, characterized in that: the formula V The compound is shown as:

    
11. The compound or its tautomers, enantiomers, or pharmaceutically acceptable salts, crystal forms, hydrates or solvates thereof according to claim 1, characterized in that: the compound is of formula VI shows:

    

    among them,

    Ring B is selected from ^a 5-membered nitrogen-containing aromatic heterocyclic ring substituted with 0 to 3 Ra;

    R ^{a is} selected from halogen, hydroxyl, amino, and C ₁ to C ₆ alkyl optionally substituted by 0 to 3 R ^b ;

    R ^{b is} selected from halogen and hydroxyl;

    R ¹ and R ² are each independently selected from hydrogen and C ₁ ～C ₆ alkyl groups;

    R ³ and R ⁴ are each independently selected from hydrogen, C ₁ ～C ₆ alkyl, and halogen;

    R ^{5 is} selected from hydrogen, C ₁ ～C ₆ alkyl;

    L ^1, L ² are each independently selected from substituted with 0 to 4 R ⁱ C ₁ ~ C ₆ alkylene group, and is substituted with 0 to 4 R ⁱ substituents of C ₂ ~ C ₆ alkenylene group,

    R ^{i is} selected from halogen, -CN, C ₁ ～C ₆ alkyl;

    X is selected from -O-, -S-, -S(O) _n -or none, n is 1 or 2;

    Z is selected from -O-, -C(O)-,

    

    R ^c, R ^d each independently selected from hydrogen, C ₁ ~ C ₆ alkyl, halo-substituted C ₁ ~ C ₆ alkyl, -C (O) R ^k, or no; R ^K is selected from 0 to 4 R ^m substituted 5- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl substituted with 0 to 4 R ^m ; R ^{m is} selected from C ₁ ～C ₆ alkyl, halogen substituted C ₁ ～C ₆ alkane base;

    R ^g and R ^h are independently selected from -C(O)-, -C(O)O- or none.
12. The compound or its tautomers, enantiomers, or pharmaceutically acceptable salts, crystal forms, hydrates or solvates thereof according to claim 11, characterized in that:

    Ring B is selected from

    

    R ⁶ , R ⁷ , and R ⁸ are each independently selected from hydrogen, halogen, hydroxyl, amino, and C ₁ ～C ₂ alkyl optionally substituted with 0 to 3 R ^b ;

    R ^{b is} selected from halogen and hydroxyl;

    R ¹ and R ² are each independently selected from hydrogen and C ₁ ～C ₃ alkyl groups;

    R ³ and R ⁴ are each independently selected from hydrogen, C ₁ ～C ₃ alkyl, and halogen;

    R ^{5 is} selected from hydrogen, C ₁ ～C ₃ alkyl;

    L ^1, L ² are each independently selected from substituted with 0 to 2 R ⁱ C ₁ ~ C ₃ alkylene group, and is substituted with 0 to 2 substituents R ⁱ of C ₂ ~ C ₃ alkenylene group,

    R ^{i is} selected from halogen, -CN, C ₁ ～C ₃ alkyl;

    X is selected from -O-, -S-, -S(O) _n -or none, n is 1 or 2;

    Z is selected from -O-, -C(O)-,

    

    Preferably, Z is -O-;

    R ^c, R ^d each independently selected from hydrogen, C ₁ ~ C ₃ alkyl group, halogen-substituted C ₁ ~ C ₃ alkyl, -C (O) R ^k, or no; R ^K is selected from 0 to 2 R ^m substituted 5- to 6-membered cycloalkyl, piperidine ring substituted with 0 to 2 R ^m ; R ^{m is} selected from C ₁ ～C ₃ alkyl, halogen substituted C ₁ ～C ₃ alkyl;

    R ^g and R ^h are independently selected from -C(O)-, -C(O)O- or none.
13. The compound according to claim 12, or a tautomer, enantiomer, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, wherein the compound is:

    

    
14. The compound of any one of claims 1-13, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite is used in the preparation of activated STING class Use in medicine.
15. The compound according to any one of claims 1-13, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite is used in the preparation of therapeutic and STING Use in medicine for activity-related diseases.
16. The use according to claim 15, wherein the disease related to STING activity is one or more of diseases related to inflammatory, autoimmune diseases, infectious diseases, cancer, and precancerous syndromes. Kind.
17. The compound according to any one of claims 1-13, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite is used in the preparation of therapeutic inflammatory , Use in medicine for autoimmune diseases, infectious diseases, cancer or precancerous syndrome.
18. The compound according to any one of claims 1 to 13, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite is used in the preparation of immune adjuvants Use in.
19. A drug, characterized in that it is a compound according to any one of claims 1-13, or a stereoisomer, or a pharmaceutically acceptable salt, or a solvate, or a precursor thereof Drugs, or their metabolites, plus pharmaceutically acceptable auxiliary materials.