WO2021000770A1 - Heterocyclic compound capable of enhancing immune activity, preparation method therefor and application in medicine - Google Patents

Abstract

A heterocyclic compound capable of enhancing immune activity, a preparation method therefor and an application in medicine. Specifically, provided is a compound represented by general formula (I), a preparation method therefor, and a pharmaceutical composition containing the derivative, as well as use thereof as a therapeutic agent, especially as a STING regulator and for treating STING-mediated diseases or disorders, such as inflammation, allergic and autoimmune diseases, infectious diseases, cancers, and precancerous syndromes.

Description

Heterocyclic compound capable of enhancing immune activity, its preparation method and its application in medicine Technical field

The present invention relates to the field of medicine, and relates to a compound represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and a therapeutic agent, especially its use as an STING modulator and treatment of STING-mediated Use of diseases or conditions, such as inflammation, allergic and autoimmune diseases, infectious diseases, cancer, precancerous syndromes.

Background technique

The human immune system can generally be divided into two types of systems, called "innate immunity" and "adaptive immunity". The innate immune system of the immune system is mainly responsible for the passage of many soluble factors (including the complement system and chemokine/cytokine system); these factors act on many different cell types, including mast cells, macrophages, dendritic cells and natural Kill cells to resist various pathogens such as viruses, bacteria, fungi and parasites. The adaptive immune system involves delayed and longer-lasting antibody responses and CD8 ⁺ and CD4 ⁺ T cell responses that play a key role in immune memory to antigens.

The innate immune system has no antigen specificity, but it does respond to multiple effect mechanisms. The mechanism by which the innate immune system mediates its response includes phagocytosis, activation of the complement system, and the production of soluble biologically active molecules such as cytokines or chemokines. By responding to the above-mentioned damage-related molecular patterns (DAMP) or pathogen-related molecular patterns (PAMP), the innate immune system can provide extensive protection to the body to resist a wide range of threats to the host. The innate immune system can detect free cytoplasmic DNA and RNA in PAMP and DAMP. It has recently been demonstrated that the main sensor for cytosolic DNA is cGAS (cyclic GMP-AMP synthase). After recognizing cytosolic DNA, cGAS catalyzes the production of cyclic dinucleotide 2'-3'cGAMP (CDN), which is an atypical second messenger that binds strongly to the ER-transmembrane adaptor protein STING. The conformational change occurs by cGAMP-bound STING, which transfers to the pernuclear compartment and induces the activation of key transcription factors IRF-3 and NF-κB. This leads to the strong induction of type I interferons and the production of pro-inflammatory cytokines such as IL-6, TNF-α and IFN-γ.

From a therapeutic point of view, type I interferon has antiviral activity and can inhibit the replication of human hepatitis B virus and hepatitis C virus. In addition, type I interferons and compounds that can induce the production of type I interferons can be used to treat human cancers. Such molecules may be used as anticancer agents with multiple active pathways. Interferon can directly inhibit the proliferation of human tumor cells and can act synergistically with various approved chemotherapeutics. Type I interferon can significantly enhance the anti-tumor immune response by inducing the activation of adaptive and innate immune cells. Finally, by regulating the expression of enzymes related to tissue remodeling, interferon can inhibit tumor invasiveness.

STING is considered to be the key adaptor protein in the cGAS-STING-IFN cascade, and the role of STING in the activation of the innate immune system against tumors has also been recognized. Xiang Zhou et al. (STING-mediated DNA sensing in cancer immunotherapy, Science China Life Sciences, Vol. 60, No. 6, pp563-574) believe that although STING has been proven to be necessary for innate immune activation triggered by cytosolic DNA However, the accumulated evidence obtained from various studies shows that the intrinsic correlation of STING-related signals in tumorigenesis can be observed. Recent studies have shown that tumor-derived DNA is present in the cytoplasm of certain antigen-presenting cells (such as tumor-infiltrating dendritic cells), which may be produced by tumor cell stress or cell death. This tumor-derived DNA is known to activate cGAS, which leads to the production of cyclic nucleotides that have been shown to activate STING, leading to the production of related type 1 interferons such as interferon beta (Woo, SR et al., Immunity (2014) 41: 830 -842). The downstream signal transduction pathways stimulated and produced by STING may also contribute to the recruitment of effector T cells into the inflamed tumor microenvironment (Woo, S.R. Trends in Immunol (2015) 36: 250-256). STING activation in the tumor microenvironment can induce an adaptive immune response, leading to anti-tumor activity. Therefore, in those STING-deficient tumors, by activating antigen-presenting cells and dendritic cells (APC and DC) and inducing adaptive immune responses, these tumors still have anti-tumor activity. With more and more data showing that the cGAS-STING cytosolic DNA sensory pathway has a significant ability to induce type I interferons, the development of STING activators has rapidly occupied an important position in the field of anti-tumor therapy today. In addition, several clinical trials using immunostimulatory adjuvants, especially agonistic and non-agonistic ligands of STING, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Xiang Zhou et al. summarized recent findings. These findings have pointed out that the STING pathway is an innate immune sensing mechanism that drives the production of type I interferon in the tumor environment. A better understanding of this approach can guide the further development of novel immunotherapy strategies for the treatment of cancer.

Due to easy hydrolysis in the body and very low permeability, natural cyclic dinucleotides (CDN) are not suitable for clinical development. Aduro Company modified the natural cyclic dinucleotide structure and replaced the phosphoric acid ester with phosphorothioate to obtain the compound ADU-S100 with higher druggability.

Injecting ADU-S00 into B16 melanoma and 4T1 breast cancer masses not only caused significant tumor suppression until the tumor disappeared, but also induced persistent antigen-specific T cell immunity of the immune system, resulting in tumor growth in other parts of the animal without injection of drugs Also suppressed. After intratumor injection, about 50% of the treated animals were tumor-free and survived more than 150 days (Cell Reports (2018) 25, 3074-3085). In addition, they are fully protected from the second tumor attack. These preclinical studies show that the systemic immunity induced by local tumor treatment can effectively induce the regression of distant tumors. Therefore, indirect action can promote systemic anti-tumor activity.

Compared with natural CDN, although the in vivo stability of ADU-S100 is greatly improved, it can still be detected only a few seconds after administration. Therefore, it is of great significance to develop new and more stable small molecule STING agonists.

International patent applications WO2014/093936, WO2014/189805, WO2013/185052 disclose certain cyclic dinucleotides and their use to induce immune responses via activation of STING.

International patent application WO2017/175156 discloses heterocyclic amides as modulators of STING and their preparation and medical use.

There is still a need for improved compounds for immune strategies to treat diseases (such as cancer) that may be difficult to treat with traditional treatment methods.

Summary of the invention

The object of the present invention is to provide a compound represented by general formula (I):

Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

among them:

X is selected from O, NR ^a and C(R ^a )(R ^b );

Y is selected from N and CR ^a ;

Is a 5-membered aryl group or a 5-membered heteroaryl group, U, V, and W are each independently selected from N, O and C;

R ¹ and R ² are each independently selected from a hydrogen atom, a cyano group, and -CON(R ^m )(R ⁿ );

R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen atom, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 3-6 membered heterocyclic, nitro, cyano,- C(O)R ^m , -OC(O)R ^m , -SR ^m , -S(O)R ^m , -S(O) ₂ R ^m , -S(O) ₂ N(R ^m )(R ⁿ ), -N(R ^m )(R ⁿ ), -N(R ^m )-C(O)R ⁿ , -C(O)-N(R ^m )(R ⁿ ), -(C ₁ -C ₆ Alkylene)-C(O)-N(R ^m )(R ⁿ ), -N(R ^m )-C(O)-N(R ^m )(R ⁿ ), -(C ₁ -C ₆ Alkyl)-N(R ^m )-C(O)-N(R ^m )(R ⁿ )、-(C ₁ -C ₆ alkylene)-S(O) ₂ -N(R ^m )(R ⁿ ) and -(C ₁ -C ₆ alkylene) -N(R ^m )(R ⁿ ), wherein the C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl and 3-6 membered heterocyclic group each Independently optionally substituted by one or more R ^c ;

R ⁷ and R ⁸ together with the connected atoms form a 5-7 membered heterocyclic group, wherein the 5-7 membered heterocyclic group is optionally substituted by one or more R ^c ;

Alternatively, one of R ⁷ and R ⁸ is selected from -(C ₁ -C ₆ alkylene) -N(R ^m )-S(O)-N(R ^m )(R ⁿ ), -(C ₁ -C ₆ alkylene)-N(R ^m )-S(O) ₂ -N(R ^m )(R ⁿ ), -(C ₂ -C ₆ alkenylene)-N(R ^m )-S(O) ^{-N (R m) (R n} ), - (C 2 -C 6 ^{alkynylene) -N (R m) -S (} O) -N (R m) (R n), - (C 2 -C ₆ ^{alkenylene) -N (R m) -S (} O) 2 -N (R m) (R n), - (C 2 -C 6 ^{alkynylene) -N (R m) -S (} O) ₂ -N(R ^m )(R ⁿ ) and -(C ₁ -C ₆ alkylene)-3-6-membered heterocyclic ring-S(O) ₂ -N(R ^m )(R ⁿ ), and R ⁷ And the other of R ⁸ is selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, halogen, halogenated C ₁ -C ₆ Alkyl, C _3-6 cycloalkyl, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 3-6 membered heterocyclic, nitro, cyano, -C (O)R ^m , -OC(O)R ^m , -SR ^m , -S(O)R ^m , -S(O) ₂ R ^m , -S(O) ₂ N(R ^m )(R ⁿ ) , -N(R ^m )(R ⁿ ), -N(R ^m )-C(O)R ⁿ , -C(O)-N(R ^m )(R ⁿ ), -(C ₁ -C ₆ Alkyl)-N(R ^m )(R ⁿ ), -C(O)-N(R ^m )(R ⁿ ), -(C ₁ -C ₆ alkylene)-C(O)-N(R ^m )(R ⁿ ), -N(R ^m )-C(O)-N(R ^m )(R ⁿ ), -(C ₁ -C ₆ alkylene)-N(R ^m )-C(O )-N(R ^m )(R ⁿ ), -(C ₁ -C ₆ alkylene)-S(O) ₂ -N(R ^m )(R ⁿ ), -(C ₁ -C ₆ alkylene )-N(R ^m )(R ⁿ ), -(C ₁ -C ₆ alkylene)-N(R ^m )-S(O)-N(R ^m )(R ⁿ ), -(C _1- C ₆ alkylene)-N(R ^m )-S(O) ₂ -N(R ^m )(R ⁿ ), -(C ₂ -C ₆ alkenylene)-N(R ^m )-S(O ^{) -N (R m) (R} n), - (C 2 -C 6 ^{alkynylene) -N (R m) -S (} O) -N (R m) (R n), - (C 2 - C ₆ ^{alkenylene) -N (R m) -S (} O) 2 -N (R m) (R ⁿ ) and -(C ₂ -C ₆ alkynylene)-N(R ^m )-S(O) ₂ -N(R ^m )(R ⁿ ), wherein the C ₁ -C ₆ alkylene , C ₂ -C ₆ alkenylene, C ₂ -C ₆ alkynylene, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy , Halo C ₁ -C ₆ alkyl, C _3-6 cycloalkyl, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl and 3-6 membered heterocyclic group each Independently optionally substituted by one or more R ^c ;

R ^a and R ^b are each independently selected from hydrogen atom, halogen, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 3-6 membered heterocyclic, nitro and cyano;

R ^{c is} selected from hydrogen atom, halogen, hydroxyl, amino, -N (R ^m ) (R ⁿ ), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _{3 -6} cycloalkyl, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 5-10 heterocyclic, amino, nitro and cyano; and

R ^m and R ⁿ are each independently selected from hydrogen atom, halogen, hydroxyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 5-10 heterocyclic, nitro and cyano;

Alternatively, R ^m and R ⁿ together with the attached nitrogen atom form a 5-7 membered heterocyclic group, wherein the 5-7 membered heterocyclic group is optionally substituted with one or more R ^c .

In a preferred embodiment, the compound represented by general formula (I) is a compound of general formula (I-1) and a compound of general formula (I-2):

Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

Wherein: X, Y, R ¹ -R ³ , R ⁵ , R ⁷ and R ⁸ are as defined in the general formula (I).

In another preferred embodiment, the compound represented by general formula (I) is a compound of general formula (I-1a) and a compound of general formula (I-2a):

Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof,

Wherein: R ³ , R ⁵ , R ⁷ and R ⁸ are as defined in the general formula (I).

In another preferred embodiment, in the compound represented by the general formula (I), one of R ⁷ and R ⁸ is selected from -(C ₁ -C ₆ alkylene)-N(R ^m )-S (O) ₂ -N(R ^m )(R ⁿ ) and -(C ₁ -C ₆ alkylene)-3-6-membered heterocyclic ring-S(O) ₂ -N(R ^m )(R ⁿ ), And the other of R ⁷ and R ⁸ is selected from a C ₁ -C ₆ alkyl group, wherein R ^m and R ⁿ are each independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group, or R ^m and R ⁿ are connected to The nitrogen atoms of together form a 5-7 membered heterocyclic group, preferably a 5-membered heterocyclic group or a 6-membered heterocyclic group, more preferably a pyrrolidinyl group or a morpholinyl group.

In another preferred embodiment, in the compound represented by the general formula (I), wherein R ⁷ and R ⁸ together with the connected atoms form a 5-7 membered heterocyclic group, preferably a 6-membered heterocyclic group or 7 Membered heterocyclic group.

In another preferred embodiment, in the compound represented by the general formula (I), wherein R ^{3 is} selected from C ₁ -C ₆ alkyl and halo C ₁ -C ₆ alkyl.

In another preferred embodiment, in the compound represented by the general formula (I), wherein R ^{5 is} selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy.

Typical compounds of the present invention include but are not limited to:

Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

The present invention also relates to a method for preparing the compound represented by general formula (I), which comprises:

The compound of general formula (I-A) and the compound of general formula (I-B) undergo condensation reaction to obtain the compound of general formula (I),

Among them: X, Y,

R ¹ -R ⁸ are as defined in the general formula (I).

In a preferred embodiment, the compound of general formula (IA) and the compound of general formula (IB) undergo a condensation reaction in the presence of a condensing agent to obtain a compound of general formula (IC). Preferably, the condensing agent is selected from 2-(7). -Benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Amine hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N' -Tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N' -Tetramethylurea hexafluorophosphate, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-1- Tris(dimethylamino)phosphonium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinyl phosphorus hexafluorophosphate, most preferably 2-(7-benzotriazole oxide) )-N,N,N',N'-Tetramethylurea hexafluorophosphate (HATU).

The present invention also relates to a method for preparing the compound represented by general formula (I), which comprises:

The compound of general formula (I-C) and the compound of general formula (I-D) are reacted to obtain the compound of general formula (I),

Wherein: q is an integer of 1-6, L is a halogen, preferably a chlorine atom, R ⁸ is -(C ₁ -C ₆ alkylene) -N(R ^m )-S(O) ₂ -N(R ^m ) (R ⁿ ), X, Y,

R ¹ -R ⁷ , R ^m and R ⁿ are as defined in the general formula (I).

The present invention also relates to a method for preparing the compound represented by general formula (I), which comprises:

The compound of general formula (I-E) and the compound of general formula (I-D) are reacted to obtain the compound of general formula (I),

Wherein: q is an integer of 1-6, L is halogen, preferably the chlorine atom R ⁷ is -(C ₁ -C ₆ alkylene) -N(R ^m )-S(O) ₂ -N(R ^m )( R ⁿ ), X, Y,

R ¹ -R ⁶ , R ⁸ , R ^m and R ⁿ are as defined in the general formula (I).

The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by general formula (I) or its tautomers, mesosomes, racemates, enantiomers, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents or excipients.

The present invention also relates to the use of the compound represented by the general formula (I) or the pharmaceutical composition containing the same in the preparation of a medicine for the treatment of STING-mediated diseases or disorders. In a preferred embodiment, the STING-mediated disease or condition is selected from inflammatory diseases, allergic and autoimmune diseases, infectious diseases, cancer and precancerous syndromes.

The present invention also relates to the use of the compound represented by the general formula (I) or the pharmaceutical composition containing the same in the preparation of a medicine for treating cancer. Preferably, the cancer is selected from breast cancer, cervical cancer, colorectal cancer, and intrauterine cancer. Membrane cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer and urethral cancer.

The present invention also relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, which is used as a medicine.

The present invention also relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, which is used to treat STING-mediated diseases or conditions. In a preferred embodiment, the STING-mediated disease or condition is selected from inflammatory diseases, allergic and autoimmune diseases, infectious diseases, cancer and precancerous syndromes.

The present invention also relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, for the treatment of cancer, preferably, the cancer is selected from breast cancer, cervical cancer, colorectal cancer, endometrial cancer, glioblastoma, Head and neck cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer and urethral cancer.

The present invention also relates to a method for treating STING-mediated diseases or conditions, which comprises administering a therapeutically effective amount of a compound represented by the general formula (I) or its tautomers, mesosomes, or exogenous compounds to a desired patient. Rotates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them. In a preferred embodiment, the STING-mediated disease or condition is selected from inflammatory diseases, allergic and autoimmune diseases, infectious diseases, cancer and precancerous syndromes.

The present invention also relates to a method for treating cancer, comprising administering a therapeutically effective amount of a compound represented by general formula (I) or its tautomers, mesosomes, racemates, enantiomers to a desired patient Constructs, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them. Preferably, the cancer is selected from breast cancer, cervical cancer, colorectal cancer, and uterine cancer. Endometrial cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, and urethral cancer.

The compounds according to the present invention can be administered orally, sublingually, intraperitoneally, parenterally, subcutaneously, intramuscularly, intravenously, transdermally, topically, or rectally.

Among the pharmaceutical compounds of the present invention, for oral administration, sublingual administration, parenteral administration, subcutaneous administration, intramuscular administration, intravenous administration, transdermal administration, topical administration, or rectal administration, the active ingredient may be the same as conventional The pharmaceutical carriers are mixed together and administered to animals or humans in the form of administration units. Suitable administration unit forms include oral forms such as tablets, gel capsules, powders, granules and oral solutions or suspensions, sublingual or oral administration forms, parenteral, subcutaneous, intramuscular, intravenous, and nasal Intra or intraocular administration form and rectal administration form.

When the solid composition is prepared into a tablet form, the main active ingredient is mixed with pharmaceutical carriers such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like. The tablets may be coated with sucrose or other suitable materials or processed in such a way that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient.

A gel capsule preparation is obtained by mixing the active ingredient with a diluent and by pouring the obtained mixture into soft or hard capsules.

Preparations in the form of syrups or tinctures may contain the active ingredient together with sweetening agents, preservatives, and flavoring agents and appropriate coloring agents.

The water-dispersible powders or granules may contain active ingredients mixed with dispersing agents, wetting agents or suspending agents, and with flavoring or sweetening agents.

Suppositories are used for rectal administration and are prepared with adhesives that melt at rectal temperature, for example, cocoa butter or polyethylene glycol.

Aqueous suspension, isotonic physiological saline solution or sterile and injectable solution (which contains pharmacologically compatible dispersing agent and/or wetting agent) for parenteral, intranasal or intraocular Apply.

The active ingredient (possibly with one or more additive carriers) can also be formulated as microcapsules.

The compound of the present invention can be used at a dose between 0.01 mg/day and 1000 mg/day, provided in a single dose/day or administered in several doses throughout the day, for example, the same dose twice a day . The daily dose administered is advantageously between 0.1 mg and 1000 mg, even more advantageously between 2.5 mg and 50 mg. It may be necessary to use dosages outside of these ranges, and those skilled in the art themselves will be aware of this.

In a particular embodiment of the invention, the pharmaceutical composition may also be formulated for external administration. It can be introduced into the usual forms of the application type (ie, in particular lotions, foams, gels, dispersions, sprays), which have excipients, in particular It can penetrate the skin to improve the properties and accessibility of active ingredients. In addition to the compositions according to the invention, these compositions usually further comprise a physiologically acceptable medium, which usually comprises water or a solvent, for example, alcohol, ether or glycol. The composition may also include surfactants, preservatives, stabilizers, emulsifiers, thickeners, other active ingredients that produce complementary effects or possible synergistic effects, trace elements, essential oils, fragrances, colorants, collagen, Chemical or mineral filter.

definition

Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

Within the meaning of the present invention, "stereoisomers" refer to geometric isomers (or configuration isomers) or optical isomers.

"Geometric isomers" are caused by substituents at different positions on the double bond, which can then have the Z or E configuration, also called cis or trans.

"Optical isomers" are caused in particular by substituents at different steric positions on carbon atoms, said carbon atoms containing four different substituents. This carbon atom constitutes the chiral center or asymmetric center. Optical isomers include diastereomers and enantiomers. Optical isomers that are non-superimposable mirror images of each other are called "enantiomers". Optical isomers that are not superimposable mirror images of each other are called "diastereomers".

A mixture containing equal amounts of two separate enantiomeric forms of opposite chirality is called a "racemic mixture."

Within the meaning of the present invention, "tautomers" refer to structural isomers of compounds obtained by proton transfer rearrangement (prototropie), that is, by the migration of hydrogen atoms and the change of the position of the double bond. The different tautomers of the compound are generally mutually convertible and exist in the solution in a balanced manner in proportions, which may vary according to the solvent used, temperature or pH.

In the present invention, "pharmaceutically acceptable" is understood to mean that it is used to prepare pharmaceutical compositions, which are generally safe, non-toxic, biologically or otherwise satisfying and the combination The drug can be accepted for veterinary and human drug use.

In the present invention, the "pharmaceutically acceptable salt" of the compound is understood to refer to the following salt, which is a pharmaceutically acceptable (as defined herein) salt and which possesses the expected pharmacological activity of the parent compound. This salt includes:

(1) Acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, and ethanesulfonic acid , Fumaric acid, Glucoheptonic acid, Gluconic acid, Glutamic acid, Glycolic acid, Glycolic acid, 2-Hydroxyethanesulfonic acid, Lactic acid, Maleic acid, Malic acid, Mandelic acid, Methanesulfonic acid, Mucon Acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid and other acid addition salts; with

(2) When the acid protons present in the parent compound are replaced by metal ions, for example, alkali metal ions (such as Na ⁺ , K ⁺ or Li ⁺ ), alkaline earth metal ions (such as Ca ²⁺ or Mg ²⁺ ) or aluminum ions ; Or the salt formed when coordinated with an organic base or an inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

In the present invention, the term "halogen" means fluorine, bromine, chlorine or iodine atom.

The term "C _1-6 alkyl" refers to a saturated straight or branched hydrocarbon chain containing 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.

The term "C _1-6 alkylene" refers to a divalent hydrocarbon chain containing 1 to 6 carbon atoms. Representative examples include, but are not limited to, methylene (-CH ₂ -), 1,1-ethylene (-CH(CH ₃ )-), 1,2-ethylene (-CH ₂ CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3-propylene (- CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -) and 1,5-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -), etc.

The term "C _2-6 alkenyl" refers to a straight or branched hydrocarbon chain having at least one double bond and having 2 to 6 carbon atoms. Representative examples include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

The term "C _2-6 alkynyl" refers to a straight or branched hydrocarbon chain having at least one triple bond and having 2 to 6 carbon atoms. Representative examples include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

The term "C _1-6 alkoxy" refers to -O-(C _1-6 alkyl), wherein the definition of C _1-6 alkyl is as described above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like.

The term "halogenated C _1-6 alkyl" means that C _1-6 alkyl is substituted by one or more halogens, wherein C _1-6 alkyl and halogen are as defined above.

The term "C _3-6 cycloalkyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon system containing 3 to 6 carbon atoms. Representative examples include, but are not limited to, cyclohexyl, cyclopentyl, cyclobutyl, Cyclopropyl, cyclohexenyl, etc.

The term "3-6 membered heterocyclyl" refers to a heterocyclic group containing 3 to 6 ring atoms, of which 1-3 ring atoms are selected from nitrogen, oxygen or S(O) _m (wherein m is 0, 1, or 2) Atomized saturated or partially unsaturated monocyclic hydrocarbon systems, including 3-membered, 4-membered, 5-membered, and 6-membered heterocyclic groups. Representative examples include, but are not limited to, oxirane, pyrrolidinyl, and imidazolidine Group, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, etc.

The term "5-7 membered heterocyclyl" refers to a heterocyclic group containing 5 to 7 ring atoms, wherein 1-3 ring atoms are selected from nitrogen, oxygen or S(O) _m (wherein m is 0, 1, or 2). Atomized saturated or partially unsaturated monocyclic hydrocarbon systems, including 5-membered, 6-membered, and 7-membered heterocyclic groups. Representative examples include, but are not limited to, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, and tetrahydropyran Group, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, etc.

The term "C _5-10 aryl" refers to a 5- to 10-membered all-carbon monocyclic or fused polycyclic (that is, rings that share adjacent pairs of carbon atoms) groups with a conjugated π-electron system, including C ₆ aryl groups , C ₇ aryl, C ₈ aryl, C ₉ aryl, C ₁₀ aryl, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused on a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

The term "C _6-10 aryloxy" refers to -O-(C _6-10 alkyl), wherein the definition of C _6-10 alkyl is as described above.

The term "5-10 membered heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 10 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen, including 5-membered, 6-membered, 7-membered Member, 8-membered, 9-membered, 10-membered heteroaryl groups, preferably 5-membered or 6-membered heteroaryl groups containing 1 to 2 heteroatoms, such as quinolinyl, imidazolyl, furanyl, thienyl, thiazolyl, pyridine Azolyl, oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

The term "hydroxyl" refers to the -OH group.

The term "nitro" refers to -NO ₂ .

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

"Optional" or "optionally" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredients and thus the biological activity.

Detailed ways

By reading the following examples, those skilled in the art will better understand the present invention. These examples only serve to explain the invention.

The experimental methods that do not specify specific conditions in the embodiments of the present invention usually follow conventional conditions or the conditions suggested by the raw material or commodity manufacturers. Reagents without specific sources are conventional reagents purchased on the market.

All evaporations are performed in vacuum using a rotary evaporator.

The analysis sample was vacuum dried (1-5 mmHg) at room temperature. The monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC). Thin layer chromatography (TLC) was performed on a silica gel plate, and spots were observed by UV light (214 and 254 nm). Column purification and flash chromatography were performed using silica gel (200-300 mesh). The mixed solvent system is reported in volume ratio.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). (δ) is given in units of 10 ^-6 (ppm). The determination solvent is deuterated chloroform (CDCl ₃ ), deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) or deuterated acetonitrile (CD ₃ CN). The internal standard is tetramethylsilane (TMS). Use the following abbreviations: s is singlet, bs is broad singlet, d is doublet, t is triplet, qdt is quartet, m is multiplet or large peak, dd is double doublet, etc.

The LC/MS instrument used is an Agilent 1200 series 6110 or 6120 mass spectrometer with electrospray ionization. Unless otherwise specified, the general LCMS conditions are as follows:

Method A: Agilent LCMS 1200-6110, column: Waters X-Bridge C18 (50 mm × 4.6 mm × 3.5 microns); column temperature: 40°C; flow rate: 1.5 mL/min; mobile phase: 95% within 0.8 minutes Change the mixed solvent of [water+0.05% trifluoroacetic acid] and 5% [acetonitrile+0.05% trifluoroacetic acid] to 0% [water+0.05% trifluoroacetic acid] and 100% [CH3CN+0.05% trifluoroacetic acid] Mix the solvent, then keep it under this condition for 0.4 minutes, and finally change it to 95% [water+0.05% trifluoroacetic acid] and 5% [CH3CN+0.05% trifluoroacetic acid], keep it for 0.01 minutes under this condition;

Method B: Agilent LCMS 1200-6110, column: Waters X-Bridge C18 (50 mm × 4.6 mm × 3.5 microns); column temperature: 40°C; flow rate: 2.0 mL/min; mobile phase: 95% within 1.6 minutes Change the mixed solvent of [water+0.05% trifluoroacetic acid] and 5% [acetonitrile+0.05% trifluoroacetic acid] to 0% [water+0.05% trifluoroacetic acid] and 100% [acetonitrile+0.05% trifluoroacetic acid] Mixed solvent, then under this condition for 1.4 minutes, and finally within 0.05 minutes it becomes a mixed solvent of 95% [water+0.05% trifluoroacetic acid] and 5% [acetonitrile+0.05% trifluoroacetic acid], under this condition Hold for 0.7 minutes;

Method C: Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm × 4.6 mm × 3.5 microns); column temperature: 40°C; flow rate: 2.0 mL/min; mobile phase: 95% within 1.6 minutes [Water+10mM ammonium bicarbonate] and 5% acetonitrile to 0% [water+10mM ammonium bicarbonate] and 100% acetonitrile, then keep under this condition for 1.4 minutes, and finally change to 95% [water+10mM] within 0.1 minutes Ammonium bicarbonate] and 5% acetonitrile and kept under these conditions for 0.7 minutes.

Nuclear magnetic resonance instrument: Bruker ARX-500 high-resolution mass spectrometer and Bruker ARX-400 high-resolution mass spectrometer.

MTT detection instrument: Thermo Scientific Multiskan GO full-wavelength microplate reader.

The thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ~ 0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm ~ 0.5mm.

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

Unless otherwise specified in the examples, the reactions are all carried out under an argon atmosphere or a nitrogen atmosphere.

Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

Unless otherwise specified in the examples, the reaction temperature is room temperature.

Example 1

2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-3,4-dihydro-5-oxa-1,2a-acenaphthylene-7-methan Amide 1

The first step: 4-chloro-3-hydroxy-5-nitrobenzamide 1-1

15g (65.2mmol) of 4-chloro-3-methoxy-5-nitrobenzamide 1-0 was dissolved in 326mL (326mmol) of 1M dichloromethane solution of boron tribromide and stirred at room temperature for 48 hours. TLC (ethyl acetate) detection, after the completion of the reaction, the reaction solution was poured into 1 kg of crushed ice, stirred, and extracted with ethyl acetate (3×50 mL), combined, dried, and spin-dried. 4-chloro-3-hydroxy-5-nitrobenzamide 1-1 (11 g) was obtained as an off-white solid with a yield of 78.0%. MS(ESI): 217.6 [M+1] ⁺ .

The second step: (2-(5-carbamoyl-2-chloro-3-nitrophenoxy)ethyl) tert-butyl carbamate 1-2

Dissolve 4g (18.6mmol) 4-chloro-3-hydroxy-5-nitrobenzamide 1-1, 5g (22mmol) (2-bromoethyl) tert-butyl carbamate and 12.8g (93mmol) potassium carbonate In 50 mL DMF, react at 120°C for 2 hours. TLC (ethyl acetate) detection, after the completion of the reaction, add 200 mL of water, stir for 30 minutes, separate the layers, extract with dichloromethane (3×25 mL), combine, dry, and spin dry to obtain a crude product. The crude product was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain (2-(5-carbamoyl-2-chloro-3-nitrophenoxy)ethyl) t-butyl carbamate 1 -2 (9.2g), orange-red solid, yield 100%. MS(ESI): 360.6 [M+1] ⁺ .

The third step: 3-(2-aminoethoxy)-4-chloro-5-nitrobenzamide 1-3

Dissolve 9.2g (25.5mmol) (2-(5-carbamoyl-2-chloro-3-nitrophenoxy)ethyl) tert-butyl carbamate 1-2 in 100mL 4M hydrogen chloride/dioxane In, stirring at room temperature overnight. TLC (ethyl acetate) detection, after the completion of the reaction, add 200 mL methyl tert-butyl ether, stir for 30 minutes, filter, wash, and drain. Obtained 3-(2-aminoethoxy)-4-chloro-5-nitrobenzamide 1-3 (7.1g) as yellowish white solid 7.1g with a yield of 100%. MS(ESI): 260.6 [M+1] ⁺ .

The fourth step: 5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 1-4

Dissolve 7.1g (27.4mmol) 3-(2-aminoethoxy)-4-chloro-5-nitrobenzamide 1-3 and 17.6g (137mmol) DIEA in 150mL ethanol, and react at 80℃ 16 hours. TLC (ethyl acetate) detection, after the completion of the reaction, the reaction solution was concentrated, water was added, ethyl acetate extraction (3×25 mL), combined, dried, and spin-dried. Obtained 5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 1-4 as an orange oil (8g) with a yield of 100%. MS(ESI): 224.2 [M+1] ⁺ .

The fifth step: 5-amino-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 1-5

Suspend 8g (35.6mmol) 5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 1-4 and 2g 10% Pd/C in 150mL Stir at room temperature overnight in ethanol. TLC (ethyl acetate) detection, after the completion of the reaction, filter, wash, spin-dry to obtain a crude product. The crude product was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain 5-amino-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 1 -5 is 5g of white solid, with a yield of 73.0%. MS(ESI): 192.2 [M+1] ⁺ .

The sixth step: 2-amino-3,4-dihydro-5-oxa-1,2a-diazepine-7-carboxamide 1-6

Dissolve 5g (25.8mmol) of 5-amino-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide 1-5 and 3.4g (28.4mmol) of bromoacetonitrile Stir in 100 mL of methanol at room temperature for 10 hours. TLC (dichloromethane: methanol = 5:1) detection, after the completion of the reaction, filter, wash, and drain. Obtained 2-amino-3,4-dihydro-5-oxa-1,2a-diazepine-7-carboxamide 1-6 as an off-white solid (2g) with a yield of 35.2%. MS (ESI): 219.2 [M+1] ⁺ .

The seventh step: 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-3,4-dihydro-5-oxa-1,2a-diazepine Acenaphthylene-7-carboxamide 1

100mg (0.45mmol) 2-amino-3,4-dihydro-5-oxa-1,2a-diazepine-7-carboxamide, 61mg (0.45mmol) 1-ethyl-3- Methyl-1H-pyrazole-5-carboxylic acid, 199mg (0.54mmol) HATU and 135mg (1.3mmol) triethylamine were dissolved in 2mL DMF and stirred at room temperature for 16 hours. TLC (dichloromethane: methanol = 5:1) detection, after the reaction is complete, add 10 mL of water, stir for 30 minutes, filter, wash, and drain. Obtain 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-3,4-dihydro-5-oxa-1,2a-acenaphthylene-7- Formamide 1 is a white solid 30 mg, with a yield of 18.8%. MS(ESI): 335.4 [M+1] ⁺ . ¹ H NMR (400MHz, DMSO) δ 12.67 (s, 1H), 7.91 (s, 1H), 7.57 (s, 1H), 7.30 (d, J = 14.8 Hz, 2H), 6.64 (s, 1H), 4.62 (d, J=7.1 Hz, 2H), 4.54 (s, 2H), 4.21 (s, 2H), 2.17 (s, 3H), 1.35 (t, J=7.1 Hz, 3H).

Following the procedure similar to Example 1, the 1-ethyl-3-methyl-1H-pyrazole in the seventh step was replaced by 3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid -5-carboxylic acid to obtain compound 2 as a white solid; replace the 1-ethyl-3-methyl- in the seventh step with 3-ethyl-1-methyl-1H-pyrazole-4-carboxylic acid 1H-pyrazole-5-carboxylic acid to obtain compound 3 as a white solid.

Example 4

1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd ]Zulene-4-carboxamide 4

The first step: (2-(5-carbamoyl-2-chloro-3-nitrophenoxy)propyl) tert-butyl carbamate 4-1

Dissolve 4g (18.6mmol) 4-chloro-3-hydroxy-5-nitrobenzamide 1-1, 5g (22mmol) (3-bromopropyl) t-butyl carbamate and 12.8g (93mmol) potassium carbonate In 50 mL DMF, react at 120°C for 2 hours. TLC (ethyl acetate) detection, after the completion of the reaction, add 200 mL of water, stir for 30 minutes, separate the layers, extract with dichloromethane (3×25 mL), combine the organic phases, dry, and spin dry to obtain a crude product. The crude product was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain 8.5 g of (2-(5-carbamoyl-2-chloro-3-nitrophenoxy)propyl) carbamate tert-butyl Ester 4-1 is an orange-red solid with a yield of 100%. MS(ESI): 374.8 [M+1] ⁺ .

Step 2: 3-(2-Aminopropoxy)-4-chloro-5-nitrobenzamide 4-2

8.5g (22.6mmol) (2-(5-carbamoyl-2-chloro-3-nitrophenoxy)propyl) tert-butyl carbamate was dissolved in 100mL 4M hydrogen chloride/dioxane, Stir at room temperature overnight. TLC (ethyl acetate) detection, after the completion of the reaction, 200 mL methyl tert-butyl ether was added, stirred for 30 minutes, filtered, washed, and drained. 10.1 g of 3-(2-aminopropoxy)-4-chloro-5-nitrobenzamide 4-2 was obtained as a yellow-white solid with a yield of 100%. MS(ESI): 274.8 [M+1] ⁺ .

The third step: 6-nitro-2,3,4,5-tetrahydrobenzo[b][1,4]gamorine-8-carboxamide 4-3

Dissolve 10.1g (17.4mmol) of 3-(2-aminoethoxy)-4-chloro-5-nitrobenzamide 4-2 and 13.6g (105mmol) of DIEA in 75mL DMSO, and react at 100°C for 16 hour. TLC (ethyl acetate) detection, after the completion of the reaction, the reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate (3×25 mL), combined, dried, and spin-dried. Obtained 4.3 g of 6-nitro-2,3,4,5-tetrahydrobenzo[b][1,4]gamorine-8-carboxamide 4-3 as an orange solid with a yield of 100%. MS(ESI): 238.4 [M+1] ⁺ .

The fourth step: 6-amino-2,3,4,5-tetrahydrobenzo[b][1,4]gamorine-8-carboxamide 4-4

Combine 4.3g (18.6mmol) 6-nitro-2,3,4,5-tetrahydrobenzo[b][1,4]gamorine-8-carboxamide 4-3 and 0.86g 10%Pd/ C was suspended in 150 mL of ethanol and stirred at room temperature overnight. TLC (ethyl acetate) detection, after the completion of the reaction, filter, wash, spin-dry to obtain a crude product. The crude product was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain 1.5 g of 6-amino-2,3,4,5-tetrahydrobenzo[b][1,4]gamorine-8 -Formamide 4-4 is a white solid with a yield of 38.7%. MS(ESI): 208.1 [M+1] ⁺ .

The fifth step: 1-amino-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-carboxamide 4-5

Mix 1.5g (7.2mmol) 6-amino-2,3,4,5-tetrahydrobenzo[b][1,4]gamorine-8-carboxamide 4-4 and 0.95g (7.9mmol) bromine Acetonitrile was dissolved in 20 mL of methanol and stirred at room temperature for 10 hours. TLC (dichloromethane: methanol = 5:1) detection, after the completion of the reaction, filter, wash, and drain. Obtained 1.7g of 1-amino-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-carboxamide 3-5 as white solid 1.7g, yield 100%. MS(ESI): 233.4 [M+1] ⁺ .

The sixth step: 1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9-dihydro-7H-6-oxa-2,9a-di Azabenzo[cd]azulene-4-carboxamide 4

1-Amino-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-carboxamide 3-6 (100mg, 0.43mmol) dissolved in 3mL DMF , Add 66mg (0.43mmol) 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid, 196mg (0.52mmol) HATU and 131mg (1.29mmol) triethylamine, heat to 90°C, react 16 After hours, cooling to room temperature, a solid precipitated out, filtered, washed with a small amount of methanol, and drained to obtain 25mg 1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9 -Dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-carboxamide 4 is a white solid with a yield of 15.76%. MS (ESI): 369.2 [M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ9.2(s,1H),7.79(s,1H),7.70(s,2H),7.2(s,1H),6.40(s,1H), 4.20(m,4H) ), 4.05-3.91 (m, 2H), 2.30 (s, 3H), 2.11 (q, J = 8.2 Hz, 2H), 1.29 (t, J = 8.2 Hz, 3H).

Following the procedure similar to Example 4, the 1-ethyl-3-methyl-1H-pyrazole in the sixth step was replaced by 3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid -5-carboxylic acid to obtain compound 5 as a white solid; replace 1-ethyl-3-methyl- in the seventh step with 3-ethyl-1-methyl-1H-pyrazole-4-carboxylic acid 1H-pyrazole-5-carboxylic acid to obtain compound 6 as a white solid.

Example 7

7-(2-((N,N-Dimethylsulfamoyl)amino)ethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)- 1-Propyl-1H-benzo[d]imidazole-5-carboxamide 7

The first step: (2-(5-carbamoyl-2-chloro-3-nitrophenoxy)ethyl) tert-butyl carbamate 7-1

Suspend 4-chloro-3-hydroxy-5-nitrobenzamide 1-1 (2g, 9.3mmol), N-Boc-bromoethylamine (2.5g, 11mmol) and potassium carbonate (6.4g, 46.5mmol) In 25mL DMF, react at 120°C for 2 hours. TLC (ethyl acetate) detection showed that the reaction was complete, 100 mL of water was added, 100 mL of ethyl acetate was extracted twice, washed with water, dried with anhydrous sodium sulfate, and spin-dried. (2-(5-carbamoyl-2-chloro-3-nitrophenoxy)ethyl) tert-butyl carbamate 7-1 (2.75 g, 7.7 mmol) was obtained as an orange solid with a yield of 82.8%. MS (ESI): 360.1 [M+1] ⁺ .

The second step: (2-(5-carbamoyl-3-nitro-2-(propylamino)phenoxy)ethyl) tert-butyl carbamate 7-2

Combine (2-(5-carbamoyl-2-chloro-3-nitrophenoxy)ethyl) tert-butyl carbamate 7-1 (2.8g, 7.7mmol), propylamine (0.7g, 11.6mmol) And DIEA (2.9g, 23.1mmol) were dissolved in 30mL ethanol and reacted at 90°C for 12 hours. TLC (ethyl acetate) detection, after the completion of the reaction, cooled to 0 °C, the reaction system formed a precipitate, filtered, washed, and drained. Obtained (2-(5-carbamoyl-3-nitro-2-(propylamino)phenoxy)ethyl) tert-butyl carbamate 7-2 (2.5g, 6.5mmol), orange solid, yield The rate is 80.6%. MS(ESI): 383.4 [M+1] ⁺ .

The third step: (2-(3-amino-5-carbamoyl-2-(propylamino)phenoxy)ethyl) tert-butyl carbamate 7-3

Dissolve (2-(5-carbamoyl-3-nitro-2-(propylamino)phenoxy)ethyl) tert-butyl carbamate 7-2 (2.5g, 6.5mmol) in 150mL ethanol , Add 0.25 g of palladium on carbon, vent the air and then pass in hydrogen to react at room temperature for 12 hours. TLC (ethyl acetate) detection showed that the reaction was over, filtered, spin-dried, and purified by silica gel column (ethyl acetate). (2-(3-amino-5-carbamoyl-2-(propylamino)phenoxy)ethyl) tert-butyl carbamate 7-3 (2.0 g, 5.6 mmol) was obtained as a colorless oil, The yield was 83.3%. MS(ESI): 353.4 [M+1] ⁺ .

The fourth step: (2-((2-amino-5-carbamoyl-1-propyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)amino Tert-Butyl carboxylate 7-4

Combine (2-(3-amino-5-carbamoyl-2-(propylamino)phenoxy)ethyl) tert-butyl carbamate 7-3 (2g, 5.6mmol) and bromoacetonitrile (0.75g, 6.2mmol) was dissolved in 20mL methanol and stirred at room temperature for 12 hours. TLC (ethyl acetate) detection showed that the reaction was complete, methyl tert-butyl ether (60 mL) was added and stirred at room temperature for 30 minutes, filtered, washed, and drained. Obtained (2-((2-amino-5-carbamoyl-1-propyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl) tert-butyl carbamate 7-4 (2g , 5.2 mmol) white solid, yield 95.2%. MS(ESI): 378.2 [M+1] ⁺ .

The fifth step: (2-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl -1H-Benzo[d]imidazol-7-yl)oxy)tert-butyl)ethyl)tert-butyl carbamate 7-5

(2-((2-Amino-5-carbamoyl-1-propyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl) tert-butyl carbamate 7-4 (1g , 2.65mmol), 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (0.49g, 3.18mmol), HATU (1.5g, 3.9mmol) and triethylamine (0.53g, 5.3mmol) ) Dissolve in 5mL DMF and stir at room temperature for 12 hours. TLC (DCM:MeOH=10:1) was detected. After the reaction was completed, 20 mL of water was added and stirred for 30 minutes, filtered, washed, and drained. To obtain (2-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzo[d]imidazole -7-yl)oxy)tert-butyl)ethyl)carbamic acid tert-butyl 7-5 (1.2 g, 2.33 mmol) is a white solid, the yield is 88.2%. MS (ESI): 514.6 [M+1] ⁺ .

The sixth step: 7-(2-aminoethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H- Benzo[d]imidazole-5-carboxamide 7-6

Add (2-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzo[d]imidazole -7-yl)oxy)tert-butyl)ethyl)carbamate 7-5 (1.2g, 2.33mmol) was dissolved in 5mL 1M HCl/dioxane and stirred at room temperature for 12 hours. TLC (DCM:MeOH=10:1+Et ₃ N) was detected. After the reaction was completed, methyl tert-butyl ether (20 mL) was added and stirred for 30 minutes, filtered, washed, and drained. Obtain 7-(2-aminoethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzo[d]imidazole -5-carboxamide 7-6 (0.8 g, 1.93 mmol) is a white solid, with a yield of 72.7%. MS (ESI): 414.6 [M+1] ⁺ .

The seventh step: 7-(2-((N,N-dimethylsulfamoyl)amino)ethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole -5-carboxamido)-1-propyl-1H-benzo[d]imidazole-5-carboxamide 7

7-(2-Aminoethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzo[d]imidazole -5-carboxamide 7-6 (100mg, 0.24mmol), N,N-dimethylsulfonyl chloride (52mg, 0.36mg) and DIEA (92.8mg, 0.72mmol) were dissolved in 5mL of dichloromethane at 40°C React for 12 hours. TLC (DCM:MeOH=10:1) detection, after the reaction, the reaction solution was spin-dried to prepare TLC purification (DCM:MeOH=10:1). Obtain 7-(2-((N,N-dimethylsulfamoyl)amino)ethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -1-Propyl-1H-benzo[d]imidazole-5-carboxamide 7 (20mg, 0.038mmol) was a white solid 20mg, the yield was 18.1%. MS(ESI): 521.6[M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ 12.85 (s, 1H), 8.11 (s, 1H), 7.68-7.51 (m, 2H), 7.51-7.06 (m, 2H), 6.64 (s, 1H), 4.93 -4.51 (m, 2H), 4.51-4.02 (m, 4H), 3.45 (q, J = 7.8Hz, 2H), 2.70 (s, 6H), 2.18 (s, 3H), 1.82-1.70 (m, 2H) ), 1.36 (t, t = 7.8 Hz, 3H), 0.99 (t, J = 7.8 Hz, 3H).

Example 8

2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-((N-methylsulfamoyl)amino)ethoxy)-1-propane -1H-benzo[d]imidazole-5-carboxamide 8

7-(2-Aminoethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzo[d]imidazole -5-carboxamide 7-6 (100mg, 0.24mmol), N-methylsulfonyl chloride (46mg, 0.36mg) and DIEA (92.8mg, 0.72mmol) were dissolved in 5mL of dichloromethane and reacted at 40°C for 12 hour. TLC (DCM:MeOH=10:1) detection, after the reaction, the reaction solution was spin-dried to prepare TLC purification (DCM:MeOH=10:1). Obtain 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-((N-methylsulfamoyl)amino)ethoxy)-1- Propyl-1H-benzo[d]imidazole-5-carboxamide 8 (10 mg, 0.020 mmol), white solid, yield 9.1%. MS (ESI): 507.6 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ 8.03 (s, 1H), 7.69 (s, 1H), 7.50-7.31 (m, 2H), 7.25 (s, 1H), 6.84 (s, 1H), 6.65 (s ,1H),4.75-4.56(m,2H),4.49-4.38(m,2H),4.38-4.16(m,2H),3.33-3.24(m,2H),2.49(s,3H),2.19(s ,3H),2.06-1.91(m,1H),1.91-1.71(m,2H),1.42-1.31(m,3H),0.98-0.88(m,3H).

Example 9

2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl-7-(2-(sulfamoylamino)ethoxy)-1H-benzo [d]Imidazole-5-carboxamide 9

The first step: N-(2-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl -1H-Benzo[d]imidazol-7-yl)oxy)ethyl)sulfamoyl)tert-butyl carbamate 9-1

Dissolve chlorosulfonyl isocyanate (40mg, 0.28mmol) in 5mL of dichloromethane, add tert-butanol (23mg, 0.31mmol) dropwise, stir at room temperature for 2 hours, 7-(2-aminoethoxy)-2-( 1-Ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl-1H-benzo[d]imidazole-5-carboxamide 7-6 (100mg, 0.24mmol) was added The reaction solution was stirred at room temperature for 12 hours. TLC (DCM:MeOH=10:1) detection, after the completion of the reaction, the reaction solution was spin-dried. N-(2-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzo[d ]Imidazol-7-yl)oxy)ethyl)sulfamoyl)tert-butyl carbamate 9-1 (110 mg, 0.18 mmol), white solid, yield 84.6%. MS(ESI): 593.7 [M+1] ⁺ .

The second step: 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-7-(2-(sulfamoylamino) Ethoxy)-1H-benzo[d]imidazole-5-carboxamide 9

The N-(2-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzo(d ]Imidazol-7-yl)oxy)ethyl)sulfamoyl)tert-butyl carbamate 9-1 (110 mg, 0.16 mmol) was dissolved in HCl/dioxane (5 mL 1M) and stirred at room temperature for 12 hours. TLC (DCM: MeOH = 10: 1 + Et 3 N) is detected, after the completion of the reaction, methyl tert-butyl ether (20mL) was stirred for 30 minutes, filtered, washed and sucked dry. Obtain 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-7-(2-(sulfamoylamino)ethoxy)-1H-benzene And [d]imidazole-5-carboxamide (15 mg, 0.030 mmol) as a white solid 9. The yield is 16.7%. MS(ESI): 493.7 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ 9.12 (s, 1H), 7.69 (s, 1H), 7.50-7.31 (m, 2H), 7.25 (s, 1H), 6.84 (s, 1H), 6.65 (s ,1H),6.45(s,1H),4.75-4.56(m,2H),4.49-4.38(m,2H),4.38-4.16(m,2H),3.33-3.24(m,2H),2.19(s , 3H), 2.06-1.91 (m, 1H), 1.91-1.71 (m, 2H), 1.42-1.31 (m, 3H), 0.98-0.88 (m, 3H).

Example 10

1-(4-((N,N-Dimethylsulfamoyl)amino)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7 -Methoxy-1H-benzo[d]imidazole-5-carboxamide 10

The first step: (4-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)butyl) tert-butyl carbamate 10-1

4-chloro-3-methoxy-5-nitrobenzamide 1-0 (500mg, 2.17mmol) was dissolved in ethanol (20ml), and tert-butyl (4-aminobutyl) carbamate (730mg, 3.25mmol), DIEA (840mg, 6.5mmol), heated to 90°C under nitrogen protection, and reacted overnight. Cool to 0°C, stir for 2 hours, filter, wash with cold ethanol, and drain to obtain (4-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)butyl)carbamic acid Tert-butyl ester 10-1 (484mg, 1.26mmol), red solid, yield 58.3%. MS (ESI): 383.7 [M+1] ⁺ .

The second step: (4-((2-amino-4-carbamoyl-6-methoxyphenyl)amino)butyl) tert-butyl carbamate 10-2

(4-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)butyl) tert-butyl carbamate 10-1 (484mg, 1.26mmol) dissolved in ethanol (10ml) and In a mixed solution of ethyl acetate (10 ml), the system was replaced with nitrogen, palladium carbon (48 mg, 10% m/m) was added, the system was replaced with H ₂ , and the reaction was carried out at room temperature for 2 hours. Filter with diatomaceous earth, wash with a mixed solution of ethanol and ethyl acetate (1:1), and spin-dry the filtrate to obtain a crude product, which is obtained by silica gel column chromatography (eluent: methanol: dichloromethane = 1:10) (4-((2-Amino-4-carbamoyl-6-methoxyphenyl)amino)butyl) tert-butyl carbamate 10-2 (388mg, 1.09mmol), white solid, yield 87% . MS(ESI): 353.2 [M+1] ⁺ .

The third step: (4-(2-amino-5-carbamoyl-7-methoxy-1H-benzo[d]imidazol-1-yl)butyl)amino Tert-Butyl formate 10-3

(4-((2-Amino-4-carbamoyl-6-methoxyphenyl)amino)butyl) tert-butyl carbamate 10-2 (388mg, 0.99mmol) was dissolved in methanol (10ml), The system was replaced with nitrogen, cyanogen bromide (110 mg, 1.04 mmol) was added, and the reaction was carried out at room temperature overnight. A solid precipitated, filtered, the solid was washed with methanol, and drained to obtain (4-(2-amino-5-carbamoyl-7-methoxy-1H-benzo[d]imidazol-1-yl)butyl) Tert-butyl carbamate 10-3 (297 mg, 0.78 mmol) is a white solid with a yield of 79.62%. MS(ESI): 378.2 [M+1] ⁺ .

The fourth step: (4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H- Benzo[d]imidazol-1-yl)butyl)tert-butyl carbamate 10-4

(4-(2-Amino-5-carbamoyl-7-methoxy-1H-benzo[d]imidazol-1-yl)butyl) tert-butyl carbamate 10-3 (297mg, 0.79mmol) Dissolve in DMF (5mL), add 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (122mg, 0.79mmol), HATU (361mg, 0.95mmol) and triethylamine (240mg, 2.37 mmol), heated to 90°C, reacted for 16 hours, cooled to room temperature, added 40ml of water, a solid precipitated out, filtered, washed with a small amount of methanol, and drained to obtain (4-(5-carbamoyl-2-(1- Ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d]imidazol-1-yl)butyl)tert-butyl carbamate 10-4( 330mg, 0.64mmol), white solid, yield 81%. MS(ESI): 514.3 [M+1] ⁺ .

The fifth step: 1-(4-aminobutyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzene And [d]imidazole-5-carboxamide 10-5

(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo(d)imidazole-1 -Butyl) tert-butyl carbamate 10-4 (330mg, 0.64mmol) was dissolved in hydrochloric acid/dioxane solution (4mL, 4M) and reacted at room temperature for 16 hours. A solid precipitated out, filtered and drained. Get 1-(4-aminobutyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d]imidazole- 5-formamide 10-5 (313 mg, 0.75 mmol), brown solid. MS (ESI): 414.7 [M+1] ⁺ .

The sixth step: 1-(4-((N,N-dimethylsulfamoyl)amino)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5- Carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide 10

Add 1-(4-aminobutyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d]imidazole- 5-formamide 10-5 (100mg, 0.24mmol), N,N-dimethylsulfamoyl chloride (35mg, 0.24mmol) and triethylamine (73mg, 0.72mmol) were dissolved in dichloromethane (3ml), React at room temperature for 16 hours. TLC (dichloromethane: methanol = 10:1) detection, after the reaction is complete, add 10ml of water and 10ml of dichloromethane, separate the liquids, collect the organic phase, dry with anhydrous sodium sulfate, evaporate to dryness, prepare liquid phase purification to obtain 1 -(4-((N,N-Dimethylsulfamoyl)amino)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7- Methoxy-1H-benzo[d]imidazole-5-carboxamide 10 (white solid, yield 16%). MS(ESI): 521.6[M+1] ⁺ .

¹ H NMR(400MHz,DMSO)δ11.90(s,1H),7.72(s,1H),7.65(s,1H),7.46(s,3H), 6.41(s,1H),4.2(m,4H) ), 3.85(s, 3H), 2.87(t, J = 7.8Hz, 2H), 2.75(s, 6H), 2.32(s, 3H), 1.70(m, 2H), 1.51(m, 2H), 1.28 (t, J=7.8 Hz, 3H).

Example 11

2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1-(4-((N-methylsulfamoyl)amino)butyl )-1H-Benzo[d]imidazole-5-carboxamide 11

Add 1-(4-aminobutyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d]imidazole- 5-formamide 10-5 (100mg, 0.24mmol), N-methylsulfonyl chloride (30mg, 0.24mmol) and triethylamine (73mg, 0.72mmol) were dissolved in dichloromethane (3ml) and reacted at room temperature 16 hour. TLC (dichloromethane: methanol = 10:1) detection, after the reaction is complete, add 10ml of water and 10ml of dichloromethane, separate the layers, dry the organic phase with anhydrous sodium sulfate, evaporate to dryness, prepare a plate to purify the 1-(4 -((N-methylsulfonyl)amino)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H- Benzo[d]imidazole-5-carboxamide 11 (18mg, 0.035mmol) was a white solid with a yield of 14.69%. MS (ESI): 507.6 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ 11.90 (s, 1H), 7.72 (s, 1H), 7.65 (br, 2H), 7.46 (s, 3H), 6.41 (s, 1H), 4.32 (m, 4H) ), 3.95(s, 3H), 2.77(t, J=7.8Hz, 2H), 2.75(s, 3H), 2.22(s, 3H), 1.80(m, 2H), 1.51(m, 2H), 1.28 (t, J=7.8 Hz, 3H).

Example 12

2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1-(4-(sulfamoylamino)butyl)-1H-benzo [d]Imidazole-5-carboxamide 12

Dissolve 35mg (0.26mmol) of chlorosulfonyl isocyanate and 22mg (0.29mmol) of tert-butanol in dichloromethane (5ml), cool to 0℃, react for 1 hour, add 1-(4-aminobutyl)-2 -(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide 10-5 (100mg, 0.24mmol ) And triethylamine (73mg, 0.72mmol), kept at 0°C and reacted for 3 hours. TLC (dichloromethane: methanol = 10:1) detection, after the reaction is complete, spin dry. Add 1ml of 4M hydrochloric acid/dioxane solution, stir at room temperature for 16 hours, a solid precipitated out, filtered and drained to obtain 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)- 7-Methoxy-1-(4-(sulfamoylamino)butyl)-1H-benzo[d]imidazole-5-carboxamide 12 (25mg, 0.051mmol) was a white solid with a yield of 20.99%. MS (ESI): 493.6 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ 11.90 (s, 1H), 7.72 (s, 1H), 7.65 (br, 1H), 7.46 (s, 3H), 6.41 (s, 1H), 4.32 (m, 4H) ),3.95(s,3H),2.97(t,J=7.8Hz,2H),2.42(s,3H),1.80(m,2H),1.51(m,2H),1.32(t,J=7.8Hz ,3H).

Example 13

7-(4-((N,N-Dimethylsulfamoyl)amino)butoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)- 1-Propyl-1H-benzo[d]imidazole-5-carboxamide 13

The first step: (2-(5-carbamoyl-2-chloro-3-nitrophenoxy)butyl) tert-butyl carbamate 13-1

Suspend 4-chloro-3-hydroxy-5-nitrobenzamide 1-1 (0.72g, 3.3mmol), N-Boc-bromobutylamine (1g, 4mmol) and potassium carbonate (2.2g, 16.5mmol) In DMF (10 mL), react at 120°C for 2 hours. TLC (ethyl acetate) detection, after the completion of the reaction, add water (50 mL), extract with ethyl acetate (50 mL) twice, wash with water, dry with anhydrous sodium sulfate, and spin dry. The obtained tert-butyl (2-(5-carbamoyl-2-chloro-3-nitrophenoxy)butyl)carbamate 13-1 (1.4 g, 3.6 mmol) was an orange solid with a yield of 100%. MS (ESI): 388.8 [M+1] ⁺ .

The second step: (2-(5-carbamoyl-3-nitro-2-(propylamino)phenoxy)butyl) tert-butyl carbamate 13-2

Combine (2-(5-carbamoyl-2-chloro-3-nitrophenoxy)butyl) tert-butyl carbamate 13-1 (1.4g, 3.6mmol), propylamine (0.3g, 5.4mmol) And DIEA (1.4g, 10.8mmol) was dissolved in ethanol (20mL) and reacted at 90°C for 12 hours. TLC (ethyl acetate) detection, after the completion of the reaction, cooling to 0 °C, solid precipitation, filtration, washing, and draining. Obtained (2-(5-carbamoyl-3-nitro-2-(propylamino)phenoxy)butyl) tert-butyl carbamate 13-2 (1.5g, 3.6mmol) as an orange solid. The rate is 99.3%. MS (ESI): 411.5 [M+1] ⁺ .

The third step: (4-(3-amino-5-carbamoyl-2-(propylamino)phenoxy)butyl) tert-butyl carbamate 13-3

(2-(5-carbamoyl-3-nitro-2-(propylamino)phenoxy)butyl) tert-butyl carbamate 13-2 (1.5g, 3.6mmol) was dissolved in ethanol ( 100mL), add palladium on carbon (0.15g, 10%), evacuate the air and bubbling in hydrogen for reaction for 12 hours. TLC (ethyl acetate) detection, after the completion of the reaction, filter, spin dry, and purify by silica gel column (ethyl acetate/hexane). (4-(3-Amino-5-carbamoyl-2-(propylamino)phenoxy)butyl) tert-butyl carbamate 13-3 (1g, 2.6mmol) was obtained as a colorless oil. The rate is 71.3%. MS(ESI): 381.5 [M+1] ⁺ .

The fourth step: (4-((2-amino-5-carbamoyl-1-propyl-1H-benzo[d]imidazol-7-yl)oxy)butyl)amino Tert-Butyl carboxylate 13-4

Combine (4-(3-amino-5-carbamoyl-2-(propylamino)phenoxy)butyl) tert-butyl carbamate 13-3 (1g, 2.6mmol) and bromoacetonitrile (0.35g, 2.9 mmol) was dissolved in methanol (10 mL) and stirred at room temperature for 12 hours. TLC (ethyl acetate) detection, after the completion of the reaction, methyl tert-butyl ether (40 mL) was added and stirred at room temperature for 30 minutes, filtered, washed, and drained. Obtained (4-((2-amino-5-carbamoyl-1-propyl-1H-benzo[d]imidazol-7-yl)oxy)butyl) tert-butyl carbamate 13-4 (1g , 2.4 mmol) is a white solid with a yield of 96.2%. MS(ESI): 406.5 [M+1] ⁺ .

The fifth step: (4-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl -1H-Benzo[d]imidazol-7-yl)oxy)tert-butyl)butyl)carbamate 13-5

Add (4-((2-amino-5-carbamoyl-1-propyl-1H-benzo[d]imidazol-7-yl)oxy)butyl) tert-butyl carbamate 13-4 (1g , 2.4mmol), 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (0.46g, 2.9mmol), HATU (1.3g, 3.3mmol) and triethylamine (0.49g, 4.8mmol) ) Was dissolved in DMF (5 mL) and stirred at room temperature for 12 hours. TLC (DCM:MeOH=10:1) was detected. After the reaction, water (20 mL) was added and stirred for 30 minutes, filtered, washed, and drained. To obtain (4-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzo[d]imidazole -7-yl)oxy)tert-butyl)butyl)carbamic acid tert-butyl ester 13-5 (1.2 g, 2.21 mmol) was a white solid with a yield of 88.2%. MS (ESI): 542.6 [M+1] ⁺ .

The sixth step: 7-(4-aminobutoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H- Benzo[d]imidazole-5-carboxamide 13-6

1.2g (4-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzo(d ]Imidazol-7-yl)oxy)tert-butyl)butyl)carbamate 13-5 (1.2g, 2.21mmol) was dissolved in HCl/dioxane (5mL, 4M) and stirred at room temperature for 12 hour. TLC (DCM: MeOH = 10: 1 + Et 3 N) is detected, after the completion of the reaction, methyl tert-butyl ether (20mL) was stirred for 30 minutes, filtered, washed and sucked dry. Obtain 7-(4-aminobutoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzo[d]imidazole -5-carboxamide 13-6 (0.8 g, 1.81 mmol) was a white solid with a yield of 72.7%. MS (ESI): 442.6 [M+1] ⁺ .

The seventh step: 7-(4-((N,N-dimethylsulfamoyl)amino)butoxy)-2-(1-ethyl-3-methyl-1H-pyrazole -5-carboxamido)-1-propyl-1H-benzo[d]imidazole-5-carboxamide 13

7-(4-Aminobutoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzo[d]imidazole -5-carboxamide 13-6 (100mg, 0.22mmol), N,N-dimethylsulfamoyl chloride (48mg, 0.34mg) and DIEA (85mg, 0.66mmol) were dissolved in dichloromethane (5mL), in React at 40°C for 12 hours. TLC (DCM:MeOH=10:1) detection, after the reaction, the reaction solution was spin-dried to prepare TLC purification (DCM:MeOH=10:1). Obtain 7-(4-((N,N-dimethylsulfamoyl)amino)butoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) -1-Propyl-1H-benzo[d]imidazole-5-carboxamide 13 (15mg, 0.027mmol) was a white solid with a yield of 12.1%. MS (ESI): 549.6 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ 12.82 (s, 1H), 8.03 (s, 1H), 7.65 (s, 1H), 7.40 (s, 1H), 7.34 (s, 1H), 7.31-7.20 (m ,1H),6.61(s,1H),4.51-4.62(m,2H),4.41-4.31(m,2H),4.30-4.15(m,2H),3.05-2.81(m,2H),2.66(s , 6H), 2.35 (s, 3H), 1.98-2.10 (m, 4H), 1.37 (t, J = 7.81 Hz, 3H), 0.92 (t, J = 7.81, Hz, 3H).

Example 14

2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(4-((N-methylsulfamoyl)amino)butoxy)-1-propane -1H-benzo[d]imidazole-5-carboxamide 14

Following the procedure similar to that in Example 13, the compound N,N-dimethylsulfamoyl chloride in the seventh step was replaced by the compound methylsulfamoyl chloride to obtain compound 14 as a white solid. MS (ESI): 535.6 [M+1] ⁺ .

1H NMR (400MHz, DMSO) δ 10.16 (s, 1H), 8.02 (s, 1H), 7.67 (s, 1H), 7.51-7.38 (m, 2H), 6.94 (s, 1H), 6.51 (s, 1H), 4.75-4.53 (m, 2H), 4.42-4.25 (m, 2H), 4.25-4.10 (m, 2H), 3.01-2.85 (m, 2H), 2.46 (s, 3H), 2.18 (s, 3H), 1.77-1.69 (m, 4H), 1.69-1.52 (m, 2H), 1.42-1.31 (m, 3H), 1.03-0.84 (m, 3H).

Example 15

7-(3-((N,N-dimethylsulfamoyl)amino)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)- 1-Propyl-1H-benzo[d]imidazole-5-carboxamide 15

The first step: (3-(5-carbamoyl-2-chloro-3-nitrophenoxy)propyl) tert-butyl carbamate 15-1

4-chloro-3-hydroxy-5-nitrobenzamide 1-1 (1.0g, 4.62mmol) was dissolved in 15ml DMF, and (1.3mg, 5.54mmol) (5-bromopropyl) tert-butylamino was added Formate, (3.2mg, 23.1mmol) potassium carbonate, heated to 120°C and reacted for 4 hours. Cool to room temperature, add water (60ml) and dichloromethane (60ml), separate the liquids, extract the aqueous phase with dichloromethane (60ml), combine the organic phases, dry with anhydrous sodium sulfate, and evaporate to dryness (3-(5 -Carbamoyl-2-chloro-3-nitrophenoxy)propyl) tert-butyl carbamate 15-1 (1.2g, 3.2mmol) was a red solid with a yield of 69%. MS(ESI): 374.7 [M+1] ⁺ .

The second step: (3-(5-carbamoyl-3-nitro-2-(propylamino)phenoxy)propyl) tert-butyl carbamate 15-2

(3-(5-carbamoyl-2-chloro-3-nitrophenoxy)propyl) tert-butyl carbamate 15-1 (1.2g, 3.2mmol) was dissolved in ethanol (40ml) and added Propylamine (284mg, 4.81mmol), DIEA (1.244g, 9.63mmol), heated to 90°C under nitrogen protection, and reacted overnight. Cool to 0°C, stir for 2 hours, filter, wash with cold ethanol, and drain to obtain (3-(5-carbamoyl-3-nitro-2-(propylamino)phenoxy)propyl)carbamic acid The tert-butyl ester 15-2 (1.0 g, 2.5 mmol) was a red solid with a yield of 78.50%. MS(ESI): 397.4 [M+1] ⁺ .

The third step: (3-(3-amino-5-carbamoyl-2-(propylamino)phenoxy)propyl) tert-butyl carbamate 15-3

(3-(5-carbamoyl-3-nitro-2-(propylamino)phenoxy)propyl) tert-butyl carbamate 15-2 (1.0g, 2.52mmol) dissolved in ethanol (15ml) In a mixed solution with ethyl acetate (15 ml), the system was replaced with nitrogen, palladium carbon (100 mg, 10% m/m) was added, the system was replaced with H ₂ , and the reaction was carried out at room temperature for 2 hours. Filter with diatomaceous earth, wash with a 1:1 mixture of ethanol and ethyl acetate, and spin-dry the filtrate to obtain a crude product. The crude product is obtained by silica gel column chromatography (eluent: methanol: dichloromethane = 1:10). 3-(3-Amino-5-carbamoyl-2-(propylamino)phenoxy)propyl) tert-butyl carbamate 15-3 (0.6g, 1.6mmol) is a white solid, the yield is 64.97% . MS(ESI): 367.2 [M+1] ⁺ .

The fourth step: (3-((2-amino-5-carbamoyl-1-propyl-1H-benzo[d]imidazol-7-yl)oxy)propyl) Tert-Butyl carbamate 15-4

(3-(3-Amino-5-carbamoyl-2-(propylamino)phenoxy)propyl) tert-butyl carbamate 15-3 (0.6g, 1.64mmol) dissolved in methanol (10ml) , Replace the system with nitrogen, add cyanogen bromide (182 mg, 1.72 mmol), and react at room temperature overnight. A solid precipitated, filtered, the solid was washed with methanol, and drained to obtain (3-((2-amino-5-carbamoyl-1-propyl-1H-benzo[d]imidazol-7-yl)oxy) (Propyl) tert-butyl carbamate 15-4 (0.6 g, 1.53 mmol) is a white solid with a yield of 93%. MS(ESI): 392.2 [M+1] ⁺ .

The fifth step: (3-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl-1H- Benzo[d]imidazol-1-yl)oxy)propyl)tert-butyl carbamate 15-5

(3-((2-Amino-5-carbamoyl-1-propyl-1H-benzo(d)imidazol-7-yl)oxy)propyl) tert-butyl carbamate 15-4 (0.6g , 1.53mmol) was dissolved in DMF (10mL), added 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (236mg, 1.53mmol), HATU (700mg, 1.84mmol) and triethylamine (464mg, 4.59mmol), heated to 90°C, reacted for 16 hours, cooled to room temperature, added 80ml of water, a solid precipitated out, filtered, washed with a small amount of methanol, and drained to obtain (3-((5-carbamoyl- 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl-1H-benzo(d)imidazol-1-yl)oxy)propyl)carbamic acid Tert-butyl ester 15-5 (0.7 g, 1.33 mmol) was a white solid with a yield of 81%. MS(ESI): 528.4 [M+1] ⁺ .

The sixth step: 7-(3-aminopropoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl-1H-benzene And [d]imidazole-5-carboxamide 15-6

(3-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl-1H-benzo(d)imidazole-1 -Yl)oxy)propyl)carbamic acid tert-butyl ester 15-5 (0.7g, 1.33mmol) was dissolved in hydrochloric acid/dioxane solution (7mL, 4M), reacted at room temperature for 16 hours, a solid precipitated out, filtered , Drain it to get 7-(3-aminopropoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl-1H-benzo[ d] Imidazole-5-carboxamide 15-6 (580 mg, 1.35 mmol) is a brown solid. MS (ESI): 428.7 [M+1] ⁺ .

The seventh step: 7-(3-((N,N-dimethylsulfamoyl)amino)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazole -5-carboxamido)-1-propyl-1H-benzo[d]imidazole-5-carboxamide 15

The 7-(3-aminopropoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl-1H-benzo[d]imidazole- 5-formamide 15-6 (100mg, 0.23mmol), N,N-dimethylsulfamoyl chloride (33mg, 0.23mmol) and triethylamine (71mg, 0.70mmol) were dissolved in dichloromethane (3ml), Heat to 40°C and react for 16 hours. TLC (dichloromethane: methanol = 10:1) detection, after the reaction is complete, spin dry, prepare a plate and purify to obtain 7-(3-((N,N-dimethylsulfamoyl)amino)propoxy)- 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl-1H-benzo[d]imidazole-5-carboxamide 15 (36mg, 0.067mmol) It is a white solid with a yield of 28%. MS (ESI): 535.6 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ 12.61 (s, 1H), 7.79 (s, 2H), 7.37 (s, 2H), 6.86 (s, 2H), 3.97 (m, 6H), 2.87 (m, 2H) ),2.66(s,6H),2.30(s,3H),1.98(m,2H),1.70(m,2H),1.29(t,J=7.8Hz,3H),0.84(t,J=7.8Hz ,3H).

Following the procedure similar to that in Example 15, the N,N-dimethylsulfamoyl chloride in the seventh step was replaced by sulfamoyl chloride to obtain compound 16 as a pale yellow solid;

The N,N-dimethylsulfamoyl chloride in the seventh step was replaced by pyrrolidine-1-sulfonyl chloride to obtain compound 17 as a pale yellow solid.

The N,N-dimethylsulfamoyl chloride in the seventh step was replaced by morpholine-4-sulfonyl chloride to obtain compound 18 as a yellow solid.

The N,N-dimethylsulfamoyl chloride in the seventh step was replaced by methyl(propyl)sulfamoyl chloride to obtain compound 19 as a pale yellow solid.

The N,N-dimethylsulfamoyl chloride in the seventh step was replaced by diethylsulfamoyl chloride to obtain compound 20 as a white solid.

Example 21

1-(2-((N,N-Dimethylsulfamoyl)amino)ethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7 -Methoxy-1H-benzo[d]imidazole-5-carboxamide 21

The first step: (2-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)ethyl) tert-butyl carbamate 21-1

4-Chloro-3-methoxy-5-nitrobenzamide 1-0 (500mg, 2.17mmol) was dissolved in 20ml ethanol, and tert-butyl (5-aminoethyl) carbamate (521mg, 3.25mmol) ), DIEA (840 mg, 6.5 mmol), heated to 90° C. under the protection of nitrogen, and reacted overnight. Cool to 0°C, stir for 2 hours, filter, wash with cold ethanol, and drain to obtain (2-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)ethyl)carbamic acid Tert-butyl ester 21-1 (400 mg, 1.1 mmol) was a red solid with a yield of 52%. MS(ESI): 355.2 [M+1] ⁺ .

The second step: (2-((2-amino-4-carbamoyl-6-methoxyphenyl)amino)ethyl) tert-butyl carbamate 21-2

(2-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)ethyl) tert-butyl carbamate 21-1 (400mg, 1.1mmol) dissolved in ethanol (5ml) and In the mixed solution of ethyl acetate (5 ml), the system was replaced with nitrogen, palladium carbon (40 mg, 10% m/m) was added, the system was replaced with H ₂ , and the reaction was carried out at room temperature for 2 hours. Filter with diatomaceous earth, wash with a 1:1 mixture of ethanol and ethyl acetate, and spin-dry the filtrate to obtain a crude product. The crude product is obtained by silica gel column chromatography (eluent: methanol: dichloromethane = 1:10). Tert-butyl 2-((2-amino-4-carbamoyl-6-methoxyphenyl)amino)ethyl)carbamate 21-2 (230 mg, 0.66 mmol) was a white solid with a yield of 63%. MS(ESI): 325.2 [M+1] ⁺ .

The third step: (2-(2-amino-5-carbamoyl-7-methoxy-1H-benzo[d]imidazol-1-yl)ethylaminomethane Tert-butyl ester 21-3

(2-((2-Amino-4-carbamoyl-6-methoxyphenyl)amino)ethyl) tert-butyl carbamate 21-2 (230mg, 0.66mmol) was dissolved in methanol (10ml), The system was replaced with nitrogen, cyanogen bromide (73 mg, 0.69 mmol) was added, and the reaction was carried out at room temperature overnight. A solid precipitated, filtered, the solid was washed with methanol, and drained to obtain (2-(2-amino-5-carbamoyl-7-methoxy-1H-benzo[d]imidazol-1-yl)ethylamino Tert-butyl formate 21-3 (223 mg, 0.64 mmol) was a white solid with a yield of 90%. MS (ESI): 350.2 [M+1] ⁺ .

The fourth step: (2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy -1H-Benzo[d]imidazol-1-yl)ethyl)tert-butyl carbamate 21-4

(2-(2-Amino-5-carbamoyl-7-methoxy-1H-benzo[d]imidazol-1-yl) tert-butyl ethylcarbamate 21-3 (223mg, 0.64mmol) dissolved In DMF (5mL), add 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (99mg, 0.64mmol), HATU (293mg, 0.77mmol) and triethylamine (194mg, 1.92mmol) ), heated to 90°C, reacted for 16 hours, cooled to room temperature, added water (30mL), a solid precipitated out, filtered, washed with a small amount of methanol, and drained to obtain (2-(5-carbamoyl-2-(1 -Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)ethyl)tert-butyl carbamate 21- 4 (125 mg, 0.26 mmol) is a white solid with a yield of 40%. MS (ESI): 486.2 [M+1] ⁺ .

The fifth step: 1-(2-aminoethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H- Benzo[d]imidazole-5-carboxamide 21-5

(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo(d)imidazole- 1-yl) ethyl) tert-butyl carbamate 21-4 (125mg, 0.26mmol) was dissolved in hydrochloric acid/dioxane solution (2mL 4M), and reacted at room temperature for 16 hours. A solid precipitated out, filtered and drained. Get 1-(2-aminoethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole -5-carboxamide 21-5 (92mg, 0.24mmol) brown solid, yield 92%. MS(ESI): 386.7 [M+1] ⁺ .

The sixth step: 1-(2-((N,N-dimethylsulfamoyl)amino)ethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5- Carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide 21

Add 1-(2-aminoethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole -5-formamide 21-5 (92mg, 0.24mmol), N,N-dimethylsulfamoyl chloride (35mg, 0.24mmol) and triethylamine (73mg, 0.72mmol) dissolved in dichloromethane (3mL) , React at room temperature for 16 hours. TLC (dichloromethane: methanol = 10:1) detection, after the reaction is complete, add water (10mL) and dichloromethane (10mL), separate the layers, dry the organic phase with anhydrous sodium sulfate, evaporate to dryness, and prepare liquid phase purification Get 1-(2-((N,N-dimethylsulfamoyl)amino)ethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)- 7-Methoxy-1H-benzo[d]imidazole-5-carboxamide 21 (28 mg, 0.057 mmol) is a white solid with a yield of 23%. MS (ESI): 493.6 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ 12.3 (s, 1H), 7.74 (s, 1H), 7.37 (s, 2H), 6.81 (s, 2H), 4.53 (t, J = 7.5 Hz, 2H), 3.94(q,J=8.0Hz,2H),3,75(s,3H),3.15(s,2H),2.64(s,6H),2.29(s,3H),1.28(t,J=7.8Hz ,3H).

Following the procedure similar to Example 21, the tert-butyl (2-aminoethyl)carbamate in the first step was replaced by tert-butyl (3-aminopropyl)carbamate to obtain compound 22 as a white solid; The procedure was similar to that of Example 22, replacing the N,N-dimethylsulfamoyl chloride in the sixth step with sulfamoyl chloride to obtain compound 23 as a white solid.

Example 24

7-(3-((N,N-Dimethylsulfamoyl)amino)propoxy)-2-(1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5- Carboxamido)-1-propyl-1H-benzo[d]imidazole-5-carboxamide 24

The first step: 1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxylic acid methyl ester 24-1

3-Methyl-1H-pyrazole-5-carboxylic acid methyl ester 24-0 (200mg, 1.4mmol), fluoroethanol (110.7mg, 1.7mmol), triphenylphosphine (550mg, 2.1mmol) were dissolved in tetrahydrofuran ( 20 mL), cool to 0°C, add dimethyl azodicarboxylate (365 mg, 2.1 mmol) dropwise, and stir at room temperature for 12 hours. TLC (ethyl acetate: petroleum ether = 1:1) detection, after the completion of the reaction, add 100 mL of water, extract with ethyl acetate (50 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, and spin dry to obtain a crude product. The crude product was suspended in 100 mL petroleum ether, stirred for 30 minutes, filtered, washed, combined the mother liquor, and spin-dried to obtain methyl 1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxylate 24- 1 (370 mg) is a yellow solid with a yield of 100%. MS(ESI): 187.2 [M+1] ⁺ .

The second step: 1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxylic acid 24-2

The 1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxylic acid methyl ester 24-1 (370mg, 1.97mmol) was dissolved in sodium hydroxide (5mL, 10%) and methanol (5m ), stirring at room temperature for 12 hours. TLC (ethyl acetate: petroleum ether = 1:1) detection. After the reaction, adjust pH=3-4, extract with ethyl acetate (50 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, and spin dry. The obtained 1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxylic acid 24-2 was 220 mg of a white solid with a yield of 59.4%. MS(ESI): 187.2 [M+1] ⁺ .

The third step: (3-((5-carbamoyl-2-(1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl -1H-Benzo[d]imidazol-7-yl)oxy)propyl)tert-butyl carbamate 24-3

Add (3-((2-amino-5-carbamoyl-1-propyl-1H-benzo[d]imidazol-7-yl)oxy)propyl) tert-butyl carbamate 15-4 (619mg , 1.58mmol), 1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxylic acid 24-2 (300mg, 1.74mmol), HATU (900mg, 2.37mmol) and triethylamine (480mg, 4.74mmol) was dissolved in DMF (10m) and reacted at 90°C for 12 hours. TLC (dichloromethane: methanol=10:1) was detected. After the reaction, water (100 mL) was added, extracted with ethyl acetate (50 mL×2), the organic phases were combined, dried with anhydrous sodium sulfate, and spin-dried. Obtain (3-((5-carbamoyl-2-(1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl-1H-benzo [d] Imidazol-7-yl) oxy) propyl) tert-butyl carbamate 24-3 was 0.7 g of brown oil, and the yield was 91.1%. MS (ESI): 546.6 [M+1] ⁺ .

The fourth step: 7-(3-aminopropoxy)-2-(1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxamido)-1-propan -1H-benzo[d]imidazole-5-carboxamide 24-4

Add (3-((5-carbamoyl-2-(1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl-1H-benzo [d] Imidazol-7-yl)oxy)propyl) tert-butyl carbamate 24-3 (0.7 mg, 1.28 mmol) was dissolved in 2M HCl/dioxane (10 mL) and stirred at room temperature for 12 hours. TLC (dichloromethane: methanol = 10:1) was detected. After the reaction was completed, 30 mL of methyl tert-butyl ether was added, stirred for 30 minutes, filtered, and washed. Obtain 7-(3-aminopropoxy)-2-(1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzene And [d]imidazole-5-carboxamide 24-4 is a white solid 0.4g, the yield is 51.2%, MS (ESI): 446.6[M+1] ⁺ .

1H NMR(400MHz,DMSO)δ8.57(s,1H), 8.06(s,4H), 7.68(s,1H), 7.43(s,1H), 7.35(s,1H), 6.70(s,1H) , 4.99(s, 1H), 4.92(s, 1H), 4.88-4.81(m, 1H), 4.47-4.20(m, 4H), 3.01(m, 2H), 2.20(s, 3H), 2.18-2.08 (m, 2H), 1.90-1.63 (m, 2H), 0.83 (t, J=7.8 Hz, 3H).

The fifth step: 7-(3-((N,N-dimethylsulfamoyl)amino)propoxy)-2-(1-(2-fluoroethyl)-3-methyl -1H-pyrazole-5-carboxamide)-1-propyl-1H-benzo[d]imidazole-5-carboxamide 24

Add 7-(3-aminopropoxy)-2-(1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzene And [d] imidazole-5-carboxamide 24-4 (107mg, 0.24mmol), N,N-dimethylsulfamoyl chloride (35mg, 0.24mmol) and triethylamine (73mg, 0.72mmol) were dissolved in dichloride In methane (3 mL), react at room temperature for 16 hours. TLC (dichloromethane: methanol = 10:1) detection, after the reaction is complete, add water (10mL) and dichloromethane (10mL), separate the layers, dry the organic phase with anhydrous sodium sulfate, evaporate to dryness, and prepare liquid phase purification 7-(3-((N,N-dimethylsulfamoyl)amino)propoxy)-2-(1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5 -Carboxamido)-1-propyl-1H-benzo[d]imidazole-5-carboxamide 24 (42 mg, 0.076 mmol) white solid, yield 31%. MS(ESI): 553.2 [M+1] ⁺ .

1H NMR (400MHz, DMSO) δ 12.81 (s, 1H), 8.09 (s, 1H), 7.68 (s, 1H), 7.53-7.16 (m, 3H), 6.69 (s, 1H), 5.05-4.67 ( m, 4H), 4.39-4.18 (m, 4H), 2.67 (s, 7H), 2.19 (s, 3H), 2.11-1.85 (m, 3H), 1.85-1.71 (m, 2H), 0.88 (t, J=7.8Hz, 3H).

Example 25

7-((1-(N,N-Dimethylsulfamoyl)pyrrolidin-3-yl)methoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5- Carboxamido)-1-propyl-1H-benzo[d]imidazole-5-carboxamide 25

The first step: tert-butyl 3-((5-carbamoyl-2-chloro-3-nitrophenoxy)methyl)pyrrolidine-1-carboxylate 25-1

Combine 4-chloro-3-hydroxy-5-nitrobenzamide 1-1 (0.5g, 2.3mmol), tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate (0.73g, 2.7mmol) Suspend with potassium carbonate (1.5g, 11.5mmol) in DMF (10mL) and react at 120°C for 2 hours. TLC (EA) detection, after the completion of the reaction, add 80 mL of water, extract with ethyl acetate (80 mL×2), wash with water, dry with anhydrous sodium sulfate, and spin dry. The obtained tert-butyl 3-((5-carbamoyl-2-chloro-3-nitrophenoxy)methyl)pyrrolidine-1-carboxylate 25-1 was 1.1 g of an orange solid with a yield of 100%. MS (ESI): 400.1 [M+1] ⁺ .

Step 2: Tertiary 3-((5-carbamoyl-3-nitro-2-(propylamino)phenoxy)methyl)pyrrolidine-1-carboxylic acid Butyl ester 25-2

Combine 3-((5-carbamoyl-2-chloro-3-nitrophenoxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester 25-1 (1.1g, 2.7mmol), propylamine (0.24g , 4.1mmol) and DIEA (1.0g, 8.1mmol) were dissolved in ethanol (20mL) and reacted at 90°C for 12 hours. TLC (EA) detection. After the reaction is over, cool to 0°C, filter, wash, and drain. Obtained 3-((5-carbamoyl-3-nitro-2-(propylamino)phenoxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester 25-2 as an orange solid 0.9g, yield 81.8%. MS(ESI): 425.5 [M+1] ⁺ .

The third step: tertiary 3-((3-amino-5-carbamoyl-2-(propylamino)phenoxy)methyl)pyrrolidine-1-carboxylic acid Butyl ester 25-3

Dissolve 3-((5-carbamoyl-3-nitro-2-(propylamino)phenoxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester 25-2 (0.9g, 2.1mmol) In ethanol (50 mL), palladium on carbon (0.09 g, 10%) was added, and the air was evacuated, and then hydrogen was introduced for reaction for 12 hours. TLC (EA) detection, after the completion of the reaction, filter, spin dry, and purify by silica gel column (EA). Obtained 3-((3-amino-5-carbamoyl-2-(propylamino)phenoxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester 25-3 as a colorless oily substance 0.9g, The rate is 100%. MS(ESI): 393.5 [M+1] ⁺ .

The fourth step: 3-((2-amino-5-carbamoyl-1-propyl-1H-benzo[d]imidazol-7-yl)oxy)methyl)pyrrole Tert-butyl alkane-1-carboxylate 25-4

Combine 3-((3-amino-5-carbamoyl-2-(propylamino)phenoxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester 25-3 (0.9g, 2.3mmol) and bromine Acetonitrile (0.27 g, 2.5 mmol) was dissolved in methanol (10 mL) and stirred at room temperature for 12 hours. TLC (EA) detection, after the completion of the reaction, 50mL methyl tert-butyl ether was added and stirred at room temperature for 30 minutes, filtered, washed, and drained. 3-((2-Amino-5-carbamoyl-1-propyl-1H-benzo[d]imidazol-7-yl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester 25- 4 is a white solid (0.5 g, 1.2 mmol) with a yield of 51.5%. MS(ESI): 418.5 [M+1] ⁺ .

The fifth step: 3-(((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl-1H-benzene And [d]imidazol-7-yl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester 25-5

3-((2-Amino-5-carbamoyl-1-propyl-1H-benzo[d]imidazol-7-yl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester 25- 4 (0.5g, 1.2mmol), 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (0.22g, 1.43mmol), HATU (0.68g, 1.8mmol) and triethylamine (0.36 g, 3.6 mmol) was dissolved in DMF (5 mL) and stirred at room temperature for 12 hours. TLC (DCM:MeOH=10:1) was detected. After the reaction, 20 mL of water was added and stirred for 30 minutes, filtered, washed, and drained. Obtain 3-(((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl-1H-benzo[d]imidazole- 7-yl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester 25-5 (0.6 g, 1.08 mmol) was a white solid with a yield of 85.7%. MS (ESI): 554.7 [M+1] ⁺ .

The sixth step: 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-7-(pyrrolidin-3-ylmethoxy Yl)-1H benzo[d]imidazole-5-carboxamide 25-6

To 3-(((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl-1H-benzo[d]imidazole- 7-yl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester 25-5 was dissolved in (0.6g, 1.08mmol), HCl/dioxane (5mL, 1M) was added, and the mixture was stirred at room temperature for 12 hours. TLC (DCM: MeOH = 10: 1 + Et 3 N) is detected, after the completion of the reaction, methyl tert-butyl ether (20mL) was stirred for 30 minutes, filtered, washed and sucked dry. Obtain 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-7-(pyrrolidin-3-ylmethoxy)-1H benzo(d ] Imidazole-5-carboxamide 25-6 (0.4 g, 0.88 mmol) was a white solid with a yield of 79.2%. MS(ESI): 454.7 [M+1] ⁺ .

The seventh step: 7-((1-(N,N-dimethylsulfamoyl)pyrrolidin-3-yl)methoxy)-2-(1-ethyl-3-methyl -1H-pyrazole-5-carboxamide)-1-propyl-1H-benzo[d]imidazole-5-carboxamide 25

The 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-7-(pyrrolidin-3-ylmethoxy)-1H benzo(d ] Imidazole-5-carboxamide 25-6 (100mg, 0.24mmol), N,N-dimethylsulfonyl chloride 25-6 (47mg, 0.33mg) and DIEA (85mg, 0.66mmol) dissolved in dichloromethane (5mL ), react at 40°C for 12 hours. TLC (DCM:MeOH=10:1) detection, after the reaction, the reaction solution was spin-dried to prepare TLC purification (DCM:MeOH=10:1). Obtain 7-((1-(N,N-dimethylsulfamoyl)pyrrolidin-3-yl)methoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5 -Carboxamido)-1-propyl-1H-benzo[d]imidazole-5-carboxamide 25 (10 mg, 0.017 mmol) was a white solid with a yield of 8.9%. MS (ESI): 561.7 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ 12.84 (s, 1H), 8.09 (s, 1H), 7.72 (s, 1H), 7.46 (s, 1H), 7.35 (s, 1H), 6.63 (s, 1H) ), 4.42-4.08 (m, 4H), 3.60-3.47 (m, 2H), 3.09-2.80 (m, 2H), 2.76 (s, 6H), 2.55 (s, 2H), 2.18 (s, 4H), 2.08-1.71 (m, 4H), 1.41-1.31 (t, J=7.8 Hz, 3H), 1.01-0.88 (t, J=7.8 Hz, 3H).

Biological activity detection

Test Example 1: Determination of Stimulating THP1 Cells to Produce Interferon β

material:

Material name	supplier	Product number
RPMI 1640 medium	invitrogen	A10491-01
FBS	invitrogen	10099141
ADU-S100	Chemietek	To
Human IFN-beta DuoSet ELISA	R&D	DY814-05
DuoSet ELISA Auxiliary Kit 2	R&D	DY008

Testing procedure:

first day:

1. Cell and compound processing

-The compound to be tested is prepared as a 10 mM DMSO solution and diluted 3 times with DMSO to prepare a solution of 3.3 mM, 1.1 mM, 0.4 mM, 0.1 mM, 0.033 mM, 0.0137 mM and 0.0046 mM

-Assay medium: RPMI1640 medium and 0.5% HIFBS

-Add 98μL THP1 suspension to 100,000 cells per well in a 96-well plate.

-Add 2uL of the test compound prepared above to each well, and test each compound twice.

-Incubate for 5 hours in a cell culture incubator

-Harvest the cell supernatant, centrifuge at 200×g for 5 minutes and store at -80°C

2. Coat plate

-Add 100ul/well of the diluted capture antibody to the ELISA plate, seal the plate and incubate overnight at room temperature

Day 2: ELISA test.

1. Clean and process the board

-Wash the plate 3 times with 300 μl/well of 1X wash buffer.

-Add 300 μl of reagent diluent to each well and incubate for 1.5 hours at room temperature.

-Wash the plate 3 times with washing buffer in an amount of 300 μl per well.

2. Sample preparation

-Collect the cell supernatant and centrifuge for 3 minutes (2000g)

3. Add sample

-Add 100ul of the prepared sample to each well of the ELISA plate, and incubate at room temperature for 2 hours.

4. Wash and add detection antibody solution

-Wash the plate 3 times with 300 μl/well of 1X wash buffer.

-Add 100 μl of detection antibody solution to each well and incubate at room temperature for 2 hours.

5. Wash and add HRP antibody solution

-Wash the plate 3 times with washing buffer in an amount of 300 μl per well.

-Add 100μl of HRP antibody solution to each well and incubate for 20 minutes at room temperature.

6. Wash and add substrate solution

-Wash the plate 3 times with 300 μl/well of 1X wash buffer.

-Add 100 μl of substrate to each well and incubate for 20 minutes at room temperature.

7. Read the data

-Do not wash, directly add 50μl stop solution, and read the plate within 5 minutes (OD450)

Compound	EC 50 (μM)
ADU-S100	4.2
Example 1	42
Example 2	80
Example 3	100
Example 4	12
Example 5	60
Example 6	300
Example 7	12
Example 8	14.6
Example 9	300
Example 10	124
Example 11	300
Example 12	300
Example 13	4.2
Example 14	3.9
Example 15	3.3
Example 16	4.1
Example 17	2.1
Example 18	4.2
Example 19	8.2
Example 20	2.2
Example 21	300
Example 22	12.7
Example 23	300
Example 25	Untested
Example 25	1.8

Conclusion: The compound of the present invention has excellent activity and can effectively activate and stimulate THP1 cells to produce interferon β, thereby having excellent anti-inflammatory and anti-tumor activities.

Test Example 2: Determination of solubility

Steps:

1. Establishment of standard curve:

1) Take 2 mg of the sample and dissolve it in 400 μL of DMSO solvent to prepare a 5 mg/ml solution.

2) Take 200 μL of 5 mg/ml solution and add 200 μL of DMSO solvent to prepare a 2.5 mg/ml solution.

3) Take 200 μL of 2.5 mg/ml solution and add 200 μL of DMSO solvent to prepare a 1.25 mg/ml solution.

4) Take 200 μL of 1.25 mg/ml solution and add 200 μL of DMSO solvent to prepare a 0.625 mg/ml solution.

5) Take 200 μL of 0.625 mg/ml solution and add 200 μL of DMSO solvent to prepare a 0.32 mg/ml solution.

6) Take 200 μL 0.32 mg/ml solution and add 200 μL DMSO solvent to prepare a 0.16 mg/ml solution.

7) Take a sample of 1μL volume and inject it into HPLC to obtain the peak of the sample and measure the integral of the peak

8) Using the concentration as the abscissa and the peak integration as the ordinate, plot the standard curve.

2. Measure the solubility of the sample:

1) Dissolve 2 mg of sample with 100 μL PEG400, mix well, and then add 150 μL PBS. Vortex for 10 minutes, then shake on a shaker for 1 hour.

2) Centrifuge in a centrifuge for 30 minutes (3000rpm).

3) Take 20μL of clear solution, add 20μL DMSO, and mix well.

4) Take a sample with a volume of 1 μL, inject it into the HPLC, obtain the sample peak, and measure the peak integral.

Obtain the concentration from the standard curve

Conclusion: The compound of the present invention has good solubility and is beneficial to absorption in the body. More importantly, it can be formulated into a solution for intratumoral injection to improve the efficacy.

Claims (13)

1. A compound represented by general formula (I):

   

   Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

   among them:

   X is selected from O, NR ^a and C(R ^a )(R ^b );

   Y is selected from N and CR ^a ;

   

   Is a cyclopentadienyl group or a 5-membered heteroaryl group, U, V, and W are each independently selected from N, O and C;

   R ¹ and R ² are each independently selected from a hydrogen atom, a cyano group, and -CON(R ^m )(R ⁿ );

   R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen atom, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 3-6 membered heterocyclic, nitro, cyano,- C(O)R ^m , -OC(O)R ^m , -SR ^m , -S(O)R ^m , -S(O) ₂ R ^m , -S(O) ₂ N(R ^m )(R ⁿ ), -N(R ^m )(R ⁿ ), -N(R ^m )-C(O)R ⁿ , -C(O)-N(R ^m )(R ⁿ ), -(C ₁ -C ₆ Alkylene)-C(O)-N(R ^m )(R ⁿ ), -N(R ^m )-C(O)-N(R ^m )(R ⁿ ), -(C ₁ -C ₆ Alkyl)-N(R ^m )-C(O)-N(R ^m )(R ⁿ )、-(C ₁ -C ₆ alkylene)-S(O) ₂ -N(R ^m )(R ⁿ ) and -(C ₁ -C ₆ alkylene) -N(R ^m )(R ⁿ ), wherein the C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl and 3-6 membered heterocyclic group each Independently optionally substituted by one or more R ^c ;

   R ⁷ and R ⁸ together with the connected atoms form a 5-7 membered heterocyclic group, wherein the 5-7 membered heterocyclic group is optionally substituted by one or more R ^c ;

   Alternatively, one of R ⁷ and R ⁸ is selected from -(C ₁ -C ₆ alkylene) -N(R ^m )-S(O)-N(R ^m )(R ⁿ ), -(C ₁ -C ₆ alkylene)-N(R ^m )-S(O) ₂ -N(R ^m )(R ⁿ ), -(C ₂ -C ₆ alkenylene)-N(R ^m )-S(O) ^{-N (R m) (R n} ), - (C 2 -C 6 ^{alkynylene) -N (R m) -S (} O) -N (R m) (R n), - (C 2 -C ₆ ^{alkenylene) -N (R m) -S (} O) 2 -N (R m) (R n), - (C 2 -C 6 ^{alkynylene) -N (R m) -S (} O) ₂ -N(R ^m )(R ⁿ ) and -(C ₁ -C ₆ alkylene)-3-6-membered heterocyclic ring-S(O) ₂ -N(R ^m )(R ⁿ ), and R ⁷ And the other of R ⁸ is selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, halogen, halogenated C ₁ -C ₆ Alkyl, C _3-6 cycloalkyl, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 3-6 membered heterocyclic, nitro, cyano, -C (O)R ^m , -OC(O)R ^m , -SR ^m , -S(O)R ^m , -S(O) ₂ R ^m , -S(O) ₂ N(R ^m )(R ⁿ ) , -N(R ^m )(R ⁿ ), -N(R ^m )-C(O)R ⁿ , -C(O)-N(R ^m )(R ⁿ ), -(C ₁ -C ₆ Alkyl)-N(R ^m )(R ⁿ ), -C(O)-N(R ^m )(R ⁿ ), -(C ₁ -C ₆ alkylene)-C(O)-N(R ^m )(R ⁿ ), -N(R ^m )-C(O)-N(R ^m )(R ⁿ ), -(C ₁ -C ₆ alkylene)-N(R ^m )-C(O )-N(R ^m )(R ⁿ ), -(C ₁ -C ₆ alkylene)-S(O) ₂ -N(R ^m )(R ⁿ ), -(C ₁ -C ₆ alkylene )-N(R ^m )(R ⁿ ), -(C ₁ -C ₆ alkylene)-N(R ^m )-S(O)-N(R ^m )(R ⁿ ), -(C _1- C ₆ alkylene)-N(R ^m )-S(O) ₂ -N(R ^m )(R ⁿ ), -(C ₂ -C ₆ alkenylene)-N(R ^m )-S(O ^{) -N (R m) (R} n), - (C 2 -C 6 ^{alkynylene) -N (R m) -S (} O) -N (R m) (R n), - (C 2 - C ₆ ^{alkenylene) -N (R m) -S (} O) 2 -N (R m) (R ⁿ ) and -(C ₂ -C ₆ alkynylene)-N(R ^m )-S(O) ₂ -N(R ^m )(R ⁿ ), wherein the C ₁ -C ₆ alkylene , C ₂ -C ₆ alkenylene, C ₂ -C ₆ alkynylene, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy , Halo C ₁ -C ₆ alkyl, C _3-6 cycloalkyl, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl and 3-6 membered heterocyclic group each Independently optionally substituted by one or more R ^c ;

   R ^a and R ^b are each independently selected from hydrogen atom, halogen, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 3-6 membered heterocyclic, nitro and cyano;

   R ^{c is} selected from hydrogen atom, halogen, hydroxyl, amino, -N (R ^m ) (R ⁿ ), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _{3 -6} cycloalkyl, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 5-10 heterocyclic, amino, nitro and cyano; and

   R ^m and R ⁿ are each independently selected from hydrogen atom, halogen, hydroxyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 5-10 heterocyclic, nitro and cyano;

   Alternatively, R ^m and R ⁿ together with the attached nitrogen atom form a 5-7 membered heterocyclic group, wherein the 5-7 membered heterocyclic group is optionally substituted with one or more R ^c .
2. The compound represented by general formula (I) according to claim 1, which is a compound of general formula (I-1) and a compound of general formula (I-2):

   

   Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof,

   Wherein: X, Y, R ¹ -R ³ , R ⁵ , R ⁷ and R ^{8 are} as defined in claim 1.
3. The compound represented by general formula (I) according to claim 1 or 2, which is a compound of general formula (I-1a) and a compound of general formula (I-2a):

   

   Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof,

   Wherein: R ³ , R ⁵ , R ⁷ and R ^{8 are} as defined in claim 1.
4. The compound represented by the general formula (I) according to any one of claims 1 to 3, wherein one of R ⁷ and R ⁸ is selected from -(C ₁ -C ₆ alkylene)-N(R ^m ) -S(O) ₂ -N(R ^m )(R ⁿ ) and -(C ₁ -C ₆ alkylene)-3-6-membered heterocyclic ring-S(O) ₂ -N(R ^m )(R ⁿ ), and the other of R ⁷ and R ⁸ is selected from a C ₁ -C ₆ alkyl group, wherein R ^m and R ⁿ are each independently selected from a hydrogen atom and a C ₁ -C ₆ alkyl group, or R ^m and R ⁿ and The connected nitrogen atoms together form a 5-7 membered heterocyclic group, preferably a 5-membered heterocyclic group or a 6-membered heterocyclic group, more preferably a pyrrolidinyl group or a morpholinyl group.
5. The compound represented by the general formula (I) according to any one of claims 1-3, wherein R ⁷ and R ⁸ together with the connected atoms form a 5-7 membered heterocyclic group, preferably a 6-membered heterocyclic group Or a 7-membered heterocyclic group.
6. The compound represented by the general formula (I) according to any one of claims 1 to 5, wherein R ^{3 is} selected from C ₁ -C ₆ alkyl and halogenated C ₁ -C ₆ alkyl.
7. The compound represented by the general formula (I) according to any one of claims 1-6, wherein R ^{5 is} selected from C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy.
8. The compound represented by general formula (I) according to any one of claims 1-7, which is selected from:

   

   

   
9. A method for preparing the compound represented by general formula (I) according to claim 1, which comprises:

   

   The compound of general formula (I-A) and the compound of general formula (I-B) undergo condensation reaction to obtain the compound of general formula (I),

   Among them: X, Y,

   

   R ¹ -R ^{8 are} as defined in claim 1.
10. A pharmaceutical composition comprising a therapeutically effective amount of the compound represented by the general formula (I) according to any one of claims 1-8 and a pharmaceutically acceptable carrier, diluent or excipient.
11. Use of the compound represented by the general formula (I) according to any one of claims 1-8 or the pharmaceutical composition according to claim 10 in the preparation of a medicament for the treatment of STING-mediated diseases or disorders .
12. The use according to claim 11, wherein the disease or condition is selected from the group consisting of inflammatory diseases, allergic and autoimmune diseases, infectious diseases, cancer and precancerous syndromes.
13. The use of the compound represented by the general formula (I) according to any one of claims 1-8 or the pharmaceutical composition according to any one of claim 10 in the preparation of a medicine for the treatment of cancer, preferably, The cancer is selected from breast cancer, cervical cancer, colorectal cancer, endometrial cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, ovarian cancer, pancreatic cancer, prostate cancer, Skin cancer and urethral cancer.