Pyrrolo[2,1-f][1,2,4]triazine compounds, their preparation methods and applications, intermediates, pharmaceutical compositions and cGAS agonists

Abstract

This invention discloses a compound of formula (I), and / or a pharmaceutically acceptable salt thereof, and / or a mixture of its racemic derivatives, hydrates, solvates, prodrugs, enantiomers, diastereomers, and tautomers, belonging to the field of pharmaceutical technology. This invention also discloses pharmaceutical compositions containing a compound of formula (I), and the use of the compound of formula (I) and / or a pharmaceutically acceptable salt thereof, and / or a mixture of its racemic derivatives, hydrates, solvates, prodrugs, enantiomers, diastereomers, and tautomers, and / or, said pharmaceutical compositions, in the preparation of cGAS agonists and in medicaments for treating diseases responsive to activation of the cGAS-STING signaling pathway.

Description

Technical Field

[0001] This invention belongs to the field of compound technology, specifically relating to pyrrolo[2,1- f [1,2,4] Triazine compounds, their preparation methods and applications, intermediates, pharmaceutical compositions and cGAS agonists. Background Technology

[0002] For understanding the technical content of this invention:

[0003] Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) is a receptor for DNA recognition in the innate immune system. It recognizes DNA in the cytoplasm, which originates from invading DNA viruses, bacteria, unstable genomes, tumor DNA, damaged mitochondria, micronuclei, and reverse transcription elements. When it binds to double-stranded DNA, cGAS undergoes a conformational change and becomes activated, catalyzing the synthesis of cyclic guanosine monophosphate adenosine monophosphate (cGAMP) from ATP and GTP. cGAMP can be recognized by the stimulator of interferon genes (STING). STING is a transmembrane protein located on the endoplasmic reticulum. After recognizing cGAMP, it undergoes a conformational change and becomes activated. The activated STING translocates to the Golgi apparatus, further recruiting TANK-binding kinase 1 and IκB kinase. These kinases phosphorylate interferon regulatory factor 3 (IRF3) and nuclear factor kappa-B (NF-κB) inhibitor IκBα, respectively. Phosphorylated IRF3 dimers and translocates into the nucleus, initiating the transcription of type I interferon genes. Phosphorylated IκBα promotes NF-κB nuclear translocation and initiates the transcription of various inflammatory factors, including IL-6, IL-1β, and TNF-α. These cytokines can promote the maturation, migration, and activation of immune cells such as dendritic cells, T cells, and natural killer cells, thereby generating effective anti-tumor immunity. The cGAS-STING signaling pathway plays an important role in the human body's defense against pathogen invasion, autoimmune diseases, neurodegenerative diseases, and tumor immunity. Developing cGAS-STING signaling pathway agonists has significant research value.

[0004] Relevant non-patent literature retrieved:

[0005] The journal or book title is "Cell Reports," and the article title is "Pharmacological boosting of cGAS activation sensitizes chemotherapy of enhancing antitumor immunity," volume number 42(3), publication date March 28, 2023. This article discloses that brinnib can directly target cGAS and activate the cGAS-STING signaling pathway, promoting antitumor immune response. Mechanistic studies show that the binding constant K of brinnib to cGAS is K. D It is 10.94 nM.

[0006] Currently, drug development targeting the cGAS-STING signaling pathway mainly focuses on the research and development of STING agonists. Most STING agonists are used in cancer treatment, but no STING agonists have been successfully marketed. This is because STING agonists often have poor drug-likeness and significant toxic side effects. Therefore, developing novel cGAS agonists has significant research value. Brinib is the only small molecule compound that can bind to and activate cGAS, obtained through high-throughput screening. However, systematic structure-activity relationship studies of brinib as a cGAS agonist are lacking, and there are currently no reports of rationally designed small molecule agonists targeting cGAS. Summary of the Invention

[0007] The purpose of this invention is to provide:

[0008] A pyrrolo[2,1- f [1,2,4] Triazine compounds, their preparation methods and applications, intermediates, pharmaceutical compositions, and cGAS agonists, and related technologies. This aims to address the current gaps in the development of specific cGAS agonists and the lack of rationally designed cGAS agonists.

[0009] Terminology Explanation:

[0010] Unless otherwise defined, all technical terms in this document have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent inventions, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0011] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, the singular is used in conjunction with the plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0012] The definition of standard chemical terms can be found in the reference "Basic Organic Chemistry (Volumes 1 & 2)" by Xing Qiyi, Higher Education Press, 3rd Edition, 2005-06.

[0013] Unless otherwise stated, conventional methods within the scope of the art, such as quenching, extraction, concentration, silica gel column chromatography, etc., shall be used.

[0014] Unless specifically defined herein, the use of all commercially available products herein employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.

[0015] The terms “optional / arbitrary” or “optionally / arbitrarily” mean that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation. For example, according to the definition below, “optionally substituted alkyl” means “unsubstituted alkyl” (an alkyl group not substituted by a substituent) or “substituted alkyl” (an alkyl group substituted by a substituent).

[0016] As used herein, the term "substituted" means that one or more hydrogen atoms have been removed from the chemical group and that it has been substituted by a substituent. As used herein, the term "substituent" has the common meaning known in the art and refers to a chemical moiety covalently attached to, or appropriately fused to, the parent group. As used herein, the terms "optionally substituted" or "optionally...substituted" mean that the chemical group may be without substituents (i.e., unsubstituted) or may have one or more substituents (i.e., substituted). It should be understood that substitution at a given atom is limited by the valence of the atom.

[0017] As used herein, the term "stereoisomer" refers to any of the various stereoisomer configurations (e.g., enantiomers, diastereomers, and racemates) of an asymmetric compound (e.g., a compound having one or more asymmetricly substituted carbon atoms or an "asymmetric center"). Compounds of this disclosure containing an asymmetric center can be separated by optical activity (enantiomers or diastereomers) or optical inactivation (racemate). The term "enantiomer" includes stereoisomer pairs that are not mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemate mixture". The term "diastereomer" refers to a stereoisomer having at least two asymmetric atoms that are not mirror images of each other. Certain compounds containing one or more asymmetric centers can produce enantiomers, diastereomers, or other stereoisomers, which can be defined with respect to absolute configuration at each asymmetric center as (R)- or (S)- according to the Cahn-Ingold-Prelog RS system. The term "or" can be used to indicate the absolute configuration of a resolved compound at the asymmetric center. Methods for preparing optically active forms from racemic mixtures are known in the art, such as by HPLC resolution or stereoselective synthesis.

[0018] As used herein, the term "tautomer" refers to a proton transfer tautomer comprising a proton-transfer tautomer of a compound in an isomeric protonated state having the same formula and total charge. Examples of proton transfer tautomers include, but are not limited to, keto-enol pairs, amide-imino pairs, lactam-lactamimide pairs, enamine-imide pairs, and cyclic forms in which the proton may occupy two or more positions in the heterocyclic system, such as 1H-imidazole and 3H-imidazole, 1 H -1,2,4-triazole, 2 H -1,2,4-triazole and 4 H -1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1 H -Pyrazole and 2 H -Pyrazole. Tautomers may be in equilibrium or spatially locked into one form by appropriate substitution. Unless otherwise stated, the compounds disclosed herein identified by name or structure as a particular tautomer form are intended to include other tautomer forms.

[0019] As used herein, the term "prodrug" refers to any compound or conjugate that releases an active parent drug when administered to an animal or human subject. Prodrugs can be prepared by modifying functional groups present in a compound in a manner that allows the modification to be cleaved by the parent compound under normal operating conditions or in vivo. Prodrugs include compounds in which a hydroxyl, amino, thiosulfate, or carboxyl group is bonded to any group such that, when administered to a mammalian subject, it can be cleaved to form a free hydroxyl, amino, thiosulfate, or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of compounds containing alcohol and amine functional groups. The preparation and use of prodrugs are discussed in Thiguchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Proceedings of the American Chemical Society (ACS) Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated in full.

[0020] As used herein, the term "polymorph" refers to the crystal form of the compound. It should be understood that the compound described may exist in many different crystal forms or polymorphs, or may be made in an amorphous form (i.e., a solid form without any defined crystal structure). Although such varied solid forms may have different pharmaceutical properties, it should be understood that any such crystal form constitutes a compound as described, i.e., it is included by a compound of formula (I). Similarly, pharmaceutically acceptable salts or solvates of compounds of formula (I) may exist as polymorphs, wherein any such polymorph is included by a pharmaceutically acceptable salt or pharmaceutically acceptable solvate of a compound of formula (I).

[0021] As used herein, the term "deuterated compound" refers to a deuterated compound formed by replacing one or more hydrogen atoms in a group of a compound of formula (I) with deuterium.

[0022] As used herein, the term "solvate" refers to an association formed by one or more solvent molecules with a compound of the present invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to an association formed when the solvent molecule is water. The term "hydrate" may be used when the solvent is water. In one embodiment, a molecule of the compound of the present invention may bind to one water molecule, such as a monohydrate; in another embodiment, a molecule of the compound of the present invention may bind to more than one water molecule, such as a dihydrate; and in yet another embodiment, a molecule of the compound of the present invention may bind to fewer than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compound.

[0023] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic alkali or acid. When the compounds of the present invention are acidic, their corresponding salts can be readily prepared from inorganic or organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (copper and cuprous), iron, ferrous, lithium, magnesium, manganese (manganese and manganese), potassium, sodium, zinc, etc. Preferred are ammonium, calcium, magnesium, potassium, and sodium salts. Salts prepared from organic bases include primary, secondary, and tertiary amines derived from natural and synthetic sources. Pharmaceutically acceptable, non-toxic organic bases that can form salts include arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds of the present invention are basic, their corresponding salts can be readily prepared from inorganic or organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethylsulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, viscous acid, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. In this invention, salts formed with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, maleic acid, fumaric acid, tartaric acid, lactic acid, citric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid, tannic acid, lithium, sodium, potassium, calcium, magnesium, and lysine are preferred.

[0024] As used in this article, the term "alkyl" refers to branched and straight-chain saturated hydrocarbons, including all isomers, comprising a specific number of carbon atoms. Common abbreviations for alkyl groups include methyl ("Me" or CH3), ethyl ("Et" or CH2CH3), propyl ("Pr" or CH2CH2CH3), butyl ("Pr" or CH2CH2CH3), etc.; and butyl ("Bu" or CH2CH2CH2CH3), etc.

[0025] The term "alkenyl" as used in this article refers to branched and straight-chain aliphatic hydrocarbon groups containing carbon-carbon double bonds.

[0026] As used in this article, the term "alkynyl" refers to a branched or straight-chain aliphatic hydrocarbon group with a carbon-carbon double bond. The term "carbonyl" is an organic functional group (C=O) formed by carbon and oxygen atoms linked by a double bond.

[0027] The terms “cycloalkyl” and “cycloalkenyl” used in this article refer to hydrocarbon groups having a monocyclic system of carbon atoms, whether saturated or unsaturated.

[0028] The term "aryl" as used in this article refers to an aromatic single or multi-carbon ring system, wherein in a multi-carbon ring system the carbon rings are fused or connected to each other by single bonds, and in the case of a multi-carbon ring, only one carbon ring needs to be an aromatic ring. Generally, aryl groups include phenyl, naphthyl, and biphenylene.

[0029] As used herein, the term "heterocyclic group" refers to a cyclic structure composed of carbon atoms and non-carbon atoms, with examples of non-carbon atoms such as nitrogen, oxygen, and sulfur. A heterocyclic group can be a monocyclic heterocyclic group with 4-8 ring atoms or a bicyclic heterocyclic group with 7-11 ring atoms. In a bicyclic heterocyclic group, only one ring needs to be heterocyclic; the other can be an aromatic or non-aromatic ring, containing or not containing heteroatoms. Furthermore, the bicyclic heterocyclic group can be a fused ring structure, a spirocyclic structure, or two heterocycles directly linked. Examples of heterocyclic groups include, but are not limited to, nitrogen-containing heterocyclic butyl, pyrrolyl, pyrrolinyl, tetrahydrofuranyl, dihydrofuranyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, and tetrahydrothiopheneyl.

[0030] As used herein, the term "heteroaryl" refers to an aromatic cyclic group containing 1-4 heteroatoms as ring members. Heteroatoms are nitrogen, oxygen, or sulfur. A heteroaryl can be a monocyclic heteroaryl with 5-7 ring atoms or a bicyclic heteroaryl with 7-11 ring atoms. In a bicyclic heteroaryl, only one ring needs to be a heteroaromatic ring; the other can be an aromatic or non-aromatic ring, containing or not containing heteroatoms. Furthermore, the bicyclic heteroaryl can have a fused ring structure, a spirocyclic structure, or two heterocycles directly linked. Examples of heteroaryl groups include, but are not limited to, pyrrole, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl, furanyl, thiophene, and indoleyl.

[0031] The term "halogen" as used in this article refers to fluorine, chlorine, bromine, and iodine [or fluorinated, chlorinated, brominated, and iodinated].

[0032] As used herein, the term "pharmaceutical-grade carrier" refers to a pharmaceutically acceptable material, composition, or mediator, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, for the transport or delivery of the compounds described herein from one location, body fluid, tissue, organ (internal or external), or part of the body to another location, body fluid, tissue, organ, or part of the body. A pharmaceutically acceptable carrier can be a mediator, diluent, excipient, or other material that can be used for contact with animal tissues without excessive toxicity or adverse effects. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, malt, astragalus gum, gelatin, Ringer's solution, alginate, isotonic saline, buffers, etc., as disclosed in Remington Pharmaceutical Sciences, Mark Publishing, New Jersey (1991).

[0033] Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered astragalus gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) (11) Diols, such as propylene glycol; (12) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (13) Esters, such as ethyl oleate and ethyl laurate; (14) Agar; (15) Buffers, such as magnesium hydroxide and aluminum hydroxide; (16) Alginate; (17) Pyrogenic water; (18) Isotonic saline; (19) Ringer's solution; (20) Alcohols, such as ethanol and propanol; (21) Phosphate buffer solutions; and (22) Other non-toxic and compatible substances used in pharmaceutical formulations, such as acetone.

[0034] The pharmaceutical composition may contain pharmaceutically acceptable excipients to approximate physiological conditions, such as pH adjusters and buffers, toxicity modifiers, etc., for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc.

[0035] In a first aspect, the present invention provides:

[0036] A pyrrolo[2,1- f [1,2,4] Triazine compounds are compounds of formula (I) and / or their pharmaceutically acceptable salts, deuterated derivatives, hydrates, polymorphs, solvates, prodrugs, stereoisomers and tautomers;

[0037]

[0038] Where X is selected from N, O, and S;

[0039] R1 is a C group selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 Heterocyclic alkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 One or more of the following groups: alkynyl, alkyl monosubstituted amino, alkyl disubstituted amino, alkoxy, alkyl carbonyloxy, cycloalkyl carbonyloxy, heteroaryl carbonyloxy, alkoxy carbonyl, cycloalkoxy carbonyl, heteroaryloxy carbonyl, alkyl carbonylamine, cycloalkyl carbonylamine, heteroaryl carbonylamine, amino carbonyl, alkoxyformamide, alkimidyl, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxy carbonyl, carboxyalkoxy, and carboxyalkylformyloxy;

[0040] R2, R3, R4, R5, R6, and R7 may be the same or different, and each is independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 Heterocyclic alkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10One or more of the following groups: alkynyl, alkyl monosubstituted amino, alkyl disubstituted amino, alkoxy, alkyl carbonyloxy, cycloalkyl carbonyloxy, heteroaryl carbonyloxy, alkoxy carbonyl, cycloalkoxy carbonyl, heteroaryloxy carbonyl, alkyl carbonylamine, cycloalkyl carbonylamine, heteroaryl carbonylamine, amino carbonyl, alkoxyformamide, alkimidyl, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphate group, polyhydroxyalkoxy carbonyl, carboxyalkoxy, and carboxyalkylformyloxy, or R3 and R4 forming a substituted or unsubstituted C group through coupling. 4-10 The aryl ring structure, or the formation of substituted or unsubstituted C 2-10 The ring structure of heteroaryl groups, or the substituted or unsubstituted C4 and R5 through coupling. 4-10 The aryl ring structure, or the formation of substituted or unsubstituted C 2-10 The ring structure of the heteroaryl group; or R5 and R6 forming a substituted or unsubstituted C through coupling. 4-10 The aryl ring structure, or the formation of substituted or unsubstituted C 2-10 The ring structure of the heteroaryl group; or R6 and R7 forming a substituted or unsubstituted C through coupling. 4-10 The aryl ring structure, or the formation of substituted or unsubstituted C 2-10 The ring structure of heteroaryl groups;

[0041] The substituents in the substituted groups are selected from one or more of the following: halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, alkoxyacyl, alkanoyloxy, aryl, heterocyclic, alkyl monosubstituted amino, alkyl disubstituted amino, alkoxy, alkyl carbonyloxy, cycloalkyl carbonyloxy, heterocyclic carbonyloxy, alkoxycarbonyl, cycloalkoxycarbonyl, heterocyclic carbonyloxy, alkylcarbonylamine, cycloalkylcarbonylamine, heterocyclic carbonylamine, aminocarbonyl, alkoxyformamide, alkoxymercapto, hydroxyalkoxy, sugar residue, sulfonic acid, phosphoric acid, polyhydroxyalkoxycarbonyl, carboxyalkoxy, and carboxyalkylformyloxy.

[0042] Among them, the technical feature “pyrrolo[2,1-f][1,2,4]triazine compound” is preferably: a compound of formula (II) and / or its pharmaceutically acceptable salt, deuterated product, hydrate, polymorph, solvate, prodrug, stereoisomer and tautomer;

[0043]

[0044] Among them, R1, R3, R4, R5, R6, and R7 are defined in the same way as in equation (I).

[0045] Among them, the preferred technical feature "R1" is: H, , , , , , , or “ " " represents the connection site.

[0046] Among them, the technical feature "R3" is preferably: hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 Heterocyclic alkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 One or more of the following groups: alkynyl, alkyl monosubstituted amino, alkyl disubstituted amino, alkoxy, alkyl carbonyloxy, cycloalkyl carbonyloxy, heteroaryl carbonyloxy, alkoxy carbonyl, cycloalkoxy carbonyl, heteroaryl carbonyloxy, alkyl carbonylamine, cycloalkyl carbonylamine, heteroaryl carbonylamine, amino carbonyl, alkoxyformamide, alkoxymeryl, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphate group, polyhydroxyalkoxycarbonyl, carboxyalkoxy, and carboxyalkylformyloxy.

[0047] Among them, the technical feature "R4" is preferably: hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 Heterocyclic alkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 One or more of the following groups: alkynyl, alkyl monosubstituted amino, alkyl disubstituted amino, alkoxy, alkyl carbonyloxy, cycloalkyl carbonyloxy, heteroaryl carbonyloxy, alkoxy carbonyl, cycloalkoxy carbonyl, heteroaryl carbonyloxy, alkyl carbonylamine, cycloalkyl carbonylamine, heteroaryl carbonylamine, amino carbonyl, alkoxyformamide, alkoxymeryl, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphate group, polyhydroxyalkoxycarbonyl, carboxyalkoxy, and carboxyalkylformyloxy.

[0048] Among them, the preferred technical feature "R5" is: hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 Heterocyclic alkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C1-8 heteroaryl, C 2-10 alkenyl, C 2-10 One or more of the following groups: alkynyl, alkyl monosubstituted amino, alkyl disubstituted amino, alkoxy, alkyl carbonyloxy, cycloalkyl carbonyloxy, heteroaryl carbonyloxy, alkoxy carbonyl, cycloalkoxy carbonyl, heteroaryl carbonyloxy, alkyl carbonylamine, cycloalkyl carbonylamine, heteroaryl carbonylamine, amino carbonyl, alkoxyformamide, alkoxymeryl, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphate group, polyhydroxyalkoxycarbonyl, carboxyalkoxy, and carboxyalkylformyloxy.

[0049] Among them, the preferred technical feature "R6" is: hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 Heterocyclic alkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 One or more of the following groups: alkynyl, alkyl monosubstituted amino, alkyl disubstituted amino, alkoxy, alkyl carbonyloxy, cycloalkyl carbonyloxy, heteroaryl carbonyloxy, alkoxy carbonyl, cycloalkoxy carbonyl, heteroaryl carbonyloxy, alkyl carbonylamine, cycloalkyl carbonylamine, heteroaryl carbonylamine, amino carbonyl, alkoxyformamide, alkoxymeryl, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphate group, polyhydroxyalkoxycarbonyl, carboxyalkoxy, and carboxyalkylformyloxy.

[0050] Among them, the preferred technical feature "R7" is: hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 Heterocyclic alkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 One or more of the following groups: alkynyl, alkyl monosubstituted amino, alkyl disubstituted amino, alkoxy, alkyl carbonyloxy, cycloalkyl carbonyloxy, heteroaryl carbonyloxy, alkoxy carbonyl, cycloalkoxy carbonyl, heteroaryl carbonyloxy, alkyl carbonylamine, cycloalkyl carbonylamine, heteroaryl carbonylamine, amino carbonyl, alkoxyformamide, alkoxymeryl, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphate group, polyhydroxyalkoxycarbonyl, carboxyalkoxy, and carboxyalkylformyloxy.

[0051] The preferred technical feature is "pyrrolo[2,1-f][1,2,4]triazine compound".

[0052]

[0053]

[0054] The technical feature “pharmaceutical acceptable salt” is selected from: inorganic acid salts or organic acid salts.

[0055] The technical feature “inorganic acid salt” is selected from salts formed from any one of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid.

[0056] The technical feature “organic acid salt” is selected from any one of acetic acid, trifluoroacetic acid, malonic acid, citric acid, tartaric acid, pyruvic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, mandelic acid, lactic acid and p-toluenesulfonic acid.

[0057] Based on further solutions to the technical problems of the present invention, or simultaneous solutions to multiple technical problems, the preferred solution in the technical solution provided in the first aspect of the present invention includes:

[0058] First preferred option: the pyrrolo[2,1- f [1,2,4] Triazine compounds are compounds of formula (II) and / or their pharmaceutically acceptable salts, deuterated derivatives, hydrates, polymorphs, solvates, prodrugs, stereoisomers and tautomers;

[0059]

[0060] R1, R3, R4, R5, R6, and R7 are defined the same as in equation (I). This technical solution solves the technical problem of "providing a pyrrolo[2,1- f Based on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0061] Second preferred option: R1 is H, , , , , , , or “ "" represents the connection site; R3, R4, R5, R6, and R7 may be the same or different, and each is independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C.1-6 Alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 Heterocyclic alkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 One or more of the following groups are included: alkynyl, alkyl monosubstituted amino, alkyl disubstituted amino, alkoxy, alkyl carbonyloxy, cycloalkyl carbonyloxy, heteroaryl carbonyloxy, alkoxy carbonyl, cycloalkoxy carbonyl, heteroaryl carbonyloxy, alkyl carbonylamine, cycloalkyl carbonylamine, heteroaryl carbonylamine, amino carbonyl, alkoxyformamide, alkimidyl, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphate group, polyhydroxyalkoxy carbonyl, carboxylalkoxy, and carboxylalkylformyloxy. This technical solution addresses the technical problem of "providing a pyrrolo[2,1- f Based on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0062] The third preferred option: the pyrrolo[2,1- f [1,2,4] Triazine compounds are selected from any of the following compounds and / or their pharmaceutically acceptable salts, deuterated derivatives, hydrates, polymorphs, solvates, prodrugs, stereoisomers, and tautomers:

[0063]

[0064]

[0065] This technical solution addresses the technical problem of "providing a pyrrolo[2,1- f Based on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0066] The fourth preferred option: the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt. This technical solution solves the technical problem of "providing a pyrrolo[2,1- f Based on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0067] The fifth preferred option: the inorganic acid salt is selected from any one of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. This technical solution solves the technical problem of "providing a pyrrolo[2,1-f Based on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0068] The sixth preferred option: the organic acid salt is selected from any one of acetic acid, trifluoroacetic acid, malonic acid, citric acid, tartaric acid, pyruvic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, mandelic acid, lactic acid, and p-toluenesulfonic acid. This technical solution solves the technical problem of "providing a pyrrolo[2,1- f Based on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0069] Secondly, the present invention provides:

[0070] A method for preparing the above-mentioned pyrrolo[2,1- f [1,2,4] An intermediate of triazine compounds, the structural formula of which is shown in formula (Ⅲ):

[0071]

[0072] Where R1 is -OH or -COOH; R3, R4, R5, R6, and R7 are defined in the same way as in equation (I).

[0073] Thirdly, the present invention provides:

[0074] A method for preparing the above-mentioned pyrrolo[2,1- f [1,2,4] The preparation method of triazine compounds involves using reaction route 1 to synthesize compounds CA1-CA22; reaction route 2 to synthesize compounds CA23-CA24; reaction route 3 to synthesize compounds CA25-CA28; and reaction route 4 to synthesize compounds CA29-CA32.

[0075] Reaction route 1 is as follows:

[0076] ;

[0077] Reaction route 2 is as follows:

[0078] ;

[0079] Reaction route 3 is as follows:

[0080] ;

[0081] Reaction route 4 is as follows:

[0082] .

[0083] The technical feature "reaction route 1 includes the following steps": Compound 1 reacts with methylmagnesium bromide to generate compound 2; compound 2 is oxidized by H2O2 to compound 3; compound 3 reacts with pivaloyl chloride to obtain compound 4; compound 4 reacts with POCl3 to obtain compound 5; compound 5 undergoes a substitution reaction with compound 6 to obtain compound 7; compound 7 undergoes ester hydrolysis in NaOH aqueous solution to obtain compound 8; finally, compound 8 reacts with (… R )-Propylene oxide or ( S The reaction with propylene oxide yields compounds CA1-CA22; * represents the chiral center.

[0084] The technical feature “reaction route 2 includes the following steps”: compound 1 reacts with POCl3 to obtain compound 9; compound 9 undergoes a substitution reaction to obtain compound 10; compound 10 is subjected to ester hydrolysis in NaOH aqueous solution to obtain compound 11; finally, compound 11 is condensed with the corresponding amine compound to obtain compounds CA23 and CA24.

[0085] Among them, the technical feature “reaction route 3 includes the following steps”: compound 8 undergoes a substitution reaction with 2-bromoethanol or 3-bromopropanol to obtain compounds CA25-CA28.

[0086] The technical feature “reaction route 4 includes the following steps”: compound 5 undergoes a substitution reaction with primary amine compound 12 to obtain compound 13; compound 13 undergoes ester hydrolysis to obtain compound 14; finally, compound 14 reacts with (… R The reaction of )-propane, 2-bromoethanol or 3-bromopropanol yields compounds CA29-CA32; * represents the chiral center.

[0087] Based on further solutions to the technical problems of the present invention, or simultaneous solutions to multiple technical problems, the preferred solution in the technical solution provided in the third aspect of the present invention includes:

[0088] First preferred option: Reaction route 1 includes the following steps: Compound 1 reacts with methylmagnesium bromide to generate compound 2; compound 2 is oxidized by H2O2 to compound 3; compound 3 reacts with pivaloyl chloride to obtain compound 4; compound 4 reacts with POCl3 to obtain compound 5; compound 5 undergoes a substitution reaction with compound 6 to obtain compound 7; compound 7 undergoes ester hydrolysis in NaOH aqueous solution to obtain compound 8; finally, compound 8 reacts with (… R )-Propylene oxide or ( S The reaction of )-propane yields compounds CA1-CA22; * represents the chiral center. This technical solution solves the technical problem of "providing a pyrrolo[2,1-f Based on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0089] The second preferred option: Reaction route 2 includes the following steps: Compound 1 reacts with POCl3 to obtain compound 9; compound 9 undergoes a substitution reaction to obtain compound 10; compound 10 undergoes ester hydrolysis in NaOH aqueous solution to obtain compound 11; finally, compound 11 condenses with the corresponding amine compound to obtain compounds CA23 and CA24. This technical solution solves the technical problem of "providing a pyrrolo[2,1- f Based on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0090] The third preferred option: Reaction route 3 includes the following steps: Compound 8 undergoes a substitution reaction with 2-bromoethanol or 3-bromopropanol to obtain compounds CA25-CA28. This technical solution solves the technical problem of "providing a pyrrolo[2,1- f Based on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0091] The fourth preferred option: Reaction route 4 includes the following steps: Compound 5 undergoes a substitution reaction with primary amine compound 12 to obtain compound 13; compound 13 undergoes ester hydrolysis to obtain compound 14; finally, compound 14 reacts with (… R The reaction of propylene oxide, 2-bromoethanol, or 3-bromopropanol yields compounds CA29-CA32; * represents a chiral center. This technical solution addresses the technical problem of "providing a pyrrolo[2,1- f Based on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0092] Fourthly, the present invention provides:

[0093] A pharmaceutical composition comprising pyrrolo[2,1- f [1,2,4] Triazine compounds.

[0094] Fifthly, the present invention provides:

[0095] A cGAS agonist comprising the above-mentioned pyrrolo[2,1- f[1,2,4] Triazine compounds, or the above-mentioned pharmaceutical compositions.

[0096] Sixthly, the present invention provides:

[0097] The above-mentioned pyrrolo[2,1- f [1,2,4] The use of triazine compounds, and / or the above-described pharmaceutical compositions, in the preparation of a medicament for treating diseases that respond to the cGAS-STING pathway.

[0098] The technical feature "diseases" include: inflammatory diseases, autoimmune diseases, cancer, infectious diseases, and cardiovascular and cerebrovascular diseases.

[0099] The technical features “inflammatory diseases and autoimmune diseases” are selected from: rheumatoid arthritis, chronic obstructive pulmonary disease, allergic rhinitis, asthma, lupus erythematosus, psoriasis and multiple sclerosis.

[0100] The technical feature “cancer” is selected from solid tumors or hematologic malignancies, specifically leukemia, multiple myeloma, and lymphoma.

[0101] The technical feature “leukemia” is selected from: acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, and chronic myeloid leukemia.

[0102] The technical feature “lymphoma” is selected from: Hodgkin lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, follicular lymphoma, B-cell lymphoma, cellular lymphoma, and diffuse large B-cell lymphoma.

[0103] The technical feature “infectious diseases” includes: bacterial infections, fungal infections, viral infections, and parasitic infections.

[0104] The technical feature “cardiovascular and cerebrovascular diseases” includes: acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary heart disease, restenosis and vascular stenosis, as well as traumatic brain injury, stroke and ischemia-reperfusion injury.

[0105] Based on further solutions to the technical problems of the present invention, or simultaneous solutions to multiple technical problems, the preferred solution in the technical solution provided in the sixth aspect of the present invention includes:

[0106] The first preferred solution: The diseases include inflammatory diseases, autoimmune diseases, cancer, infectious diseases, and cardiovascular and cerebrovascular diseases. This technical solution addresses the technical problem of "providing a pyrrolo[2,1- fBased on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0107] The second preferred option: The inflammatory diseases and autoimmune diseases mentioned are all rheumatoid arthritis, chronic obstructive pulmonary disease, allergic rhinitis, asthma, lupus erythematosus, psoriasis, and multiple sclerosis. This technical solution solves the technical problem of "providing a pyrrolo[2,1- f Based on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0108] The third preferred option: The cancer is a solid tumor or a hematologic malignancy, selected from leukemia, multiple myeloma, and lymphoma. This technical solution addresses the technical problem of "providing a pyrrolo[2,1- f Based on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0109] The fourth preferred option: The leukemia is acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, and chronic myeloid leukemia. This technical solution solves the technical problem of "providing a pyrrolo[2,1- f Based on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0110] The fifth preferred option: the lymphoma is Hodgkin's lymphoma, non-Hodgkin's lymphoma, mantle cell lymphoma, follicular lymphoma, B-cell lymphoma, cellular lymphoma, and diffuse large B-cell lymphoma. This technical solution addresses the technical problem of "providing a pyrrolo[2,1- f Based on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0111] The sixth preferred solution: The infectious diseases include bacterial infections, fungal infections, viral infections, and parasitic infections. This technical solution addresses the technical problem of "providing a pyrrolo[2,1- fBased on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0112] The seventh preferred option: The cardiovascular and cerebrovascular diseases include acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary heart disease, restenosis and vascular stenosis, as well as traumatic brain injury, stroke and ischemia-reperfusion injury. This technical solution addresses the technical problem of "providing a pyrrolo[2,1- f Based on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0113] In a seventh aspect, the present invention provides:

[0114] The above-mentioned pyrrolo[2,1- f [1,2,4] The use of triazine compounds, and / or the above-described pharmaceutical compositions, in the preparation of an immune adjuvant for enhancing the therapeutic effect of a vaccine drug.

[0115] Among them, the technical feature "immune adjuvant" is: a non-specific immune enhancer that effectively strengthens the immune response or changes the type of immune response when injected into the body together with or before the antigen.

[0116] Based on further solutions to the technical problems of the present invention, or simultaneous solutions to multiple technical problems, the preferred solution in the technical solution provided in the seventh aspect of the present invention includes:

[0117] The first preferred option is that the immune adjuvant is a non-specific immune enhancer that effectively strengthens the immune response or alters the type of immune response, either together with or pre-injected into the body. This technical solution addresses the technical problem of "providing a pyrrolo[2,1- f Based on the "triazine compounds" [1,2,4], the technical problems of "the current lack of development of specific cGAS agonists and the lack of rational design of cGAS agonists" have been further solved.

[0118] Embodiments 1-32 of this invention at least support the protection scope of claim 1.

[0119] Regarding the claim 1:

[0120] Technical feature "the pyrrolo[2,1- f[1,2,4] Triazine compounds are compounds of formula (I) and / or their pharmaceutically acceptable salts, deuterated derivatives, hydrates, polymorphs, solvates, prodrugs, stereoisomers and tautomers;

[0121]

[0122] Where X is selected from N, O, and S;

[0123] R1 is a C group selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 Heterocyclic alkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 One or more of the following groups: alkynyl, alkyl monosubstituted amino, alkyl disubstituted amino, alkoxy, alkyl carbonyloxy, cycloalkyl carbonyloxy, heteroaryl carbonyloxy, alkoxy carbonyl, cycloalkoxy carbonyl, heteroaryloxy carbonyl, alkyl carbonylamine, cycloalkyl carbonylamine, heteroaryl carbonylamine, amino carbonyl, alkoxyformamide, alkimidyl, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxy carbonyl, carboxyalkoxy, and carboxyalkylformyloxy;

[0124] R2, R3, R4, R5, R6, and R7 may be the same or different, and each is independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 Heterocyclic alkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 One or more of the following groups: alkynyl, alkyl monosubstituted amino, alkyl disubstituted amino, alkoxy, alkyl carbonyloxy, cycloalkyl carbonyloxy, heteroaryl carbonyloxy, alkoxy carbonyl, cycloalkoxy carbonyl, heteroaryloxy carbonyl, alkyl carbonylamine, cycloalkyl carbonylamine, heteroaryl carbonylamine, amino carbonyl, alkoxyformamide, alkimidyl, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphate group, polyhydroxyalkoxy carbonyl, carboxyalkoxy, and carboxyalkylformyloxy, or R3 and R4 forming a substituted or unsubstituted C group through coupling. 4-10 The aryl ring structure, or the formation of substituted or unsubstituted C 2-10 The ring structure of heteroaryl groups, or the substituted or unsubstituted C4 and R5 through coupling.4-10 The aryl ring structure, or the formation of substituted or unsubstituted C 2-10 The ring structure of the heteroaryl group; or R5 and R6 forming a substituted or unsubstituted C through coupling. 4-10 The aryl ring structure, or the formation of substituted or unsubstituted C 2-10 The ring structure of the heteroaryl group; or R6 and R7 forming a substituted or unsubstituted C through coupling. 4-10 The aryl ring structure, or the formation of substituted or unsubstituted C 2-10 The ring structure of heteroaryl groups;

[0125] The substituents in the substituted groups are selected from one or more of the following: halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, alkoxyacyl, alkanoyloxy, aryl, heterocyclic, alkyl monosubstituted amino, alkyl disubstituted amino, alkoxy, alkyl carbonyloxy, cycloalkyl carbonyloxy, heterocyclic carbonyloxy, alkoxycarbonyl, cycloalkoxycarbonyl, heterocyclic carbonyloxy, alkyl carbonylamine, cycloalkyl carbonylamine, heterocyclic carbonylamine, amino carbonyl, alkoxyformamide, alkoxymeryl, hydroxyalkoxy, sugar residue, sulfonic acid, phosphoric acid, polyhydroxyalkoxycarbonyl, carboxyalkoxy, and carboxyalkylformyloxy, which are derived from the common features of the compounds CA1-CA32, etc., as explained above and / or in Examples 1-32. Therefore, those skilled in the art can reasonably infer that the technical feature "the pyrrolo[2,1- f [1,2,4] Triazine compounds are compounds of formula (I) and / or their pharmaceutically acceptable salts, deuterated derivatives, hydrates, polymorphs, solvates, prodrugs, stereoisomers and tautomers; "the pyrrolo[2,1- f [1,2,4] Triazine compounds are the subordinate concepts of "compounds of formula (I) and / or their pharmaceutically acceptable salts, deuterated derivatives, hydrates, polymorphs, solvates, prodrugs, stereoisomers and tautomers", "the pyrrolo[2,1- f [1,2,4] Triazine compounds are compounds of formula (I) and / or their pharmaceutically acceptable salts, deuterated derivatives, hydrates, polymorphs, solvates, prodrugs, stereoisomers and tautomers. This is essentially equivalent to the technical means used to replace "the pyrrolo[2,1-]" within the scope of conventional technical means and common knowledge based on existing technology. f [1,2,4]The technical means of “the triazine compound being a compound of formula (I) and / or its pharmaceutically acceptable salt, deuterated product, hydrate, polymorph, solvate, prodrug, stereoisomer and tautomer” should all fall within the protection scope of claim 1.

[0126] Embodiments 1-32 of this invention at least support the protection scope of claim 2.

[0127] Technical feature "the pyrrolo[2,1- f [1,2,4] Triazine compounds are compounds of formula (II) and / or their pharmaceutically acceptable salts, deuterated derivatives, hydrates, polymorphs, solvates, prodrugs, stereoisomers and tautomers;

[0128]

[0129] Where R1, R3, R4, R5, R6, and R7 are the same as those defined in formula (I), they are derived from the common features of the compounds CA1-CA32, etc., as explained above and / or in Examples 1-32. Therefore, those skilled in the art can reasonably infer that the technical feature "the pyrrolo[2,1- f [1,2,4] Triazine compounds are compounds of formula (II) and / or their pharmaceutically acceptable salts, deuterated derivatives, hydrates, polymorphs, solvates, prodrugs, stereoisomers and tautomers; "the pyrrolo[2,1- f [1,2,4] Triazine compounds are the subordinate concepts of "compounds of formula (II) and / or their pharmaceutically acceptable salts, deuterated derivatives, hydrates, polymorphs, solvates, prodrugs, stereoisomers and tautomers", and "the pyrrolo[2,1- f [1,2,4] Triazine compounds are compounds of formula (II) and / or their pharmaceutically acceptable salts, deuterated derivatives, hydrates, polymorphs, solvates, prodrugs, stereoisomers and tautomers. This is essentially equivalent to the technical means used to replace "the pyrrolo[2,1-]" within the scope of conventional technical means and common knowledge based on existing technology. f [1,2,4]The technical means of “the triazine compound being a compound of formula (II) and / or its pharmaceutically acceptable salt, deuterated product, hydrate, polymorph, solvate, prodrug, stereoisomer and tautomer” shall all fall within the protection scope of claim 1 and claim 2.

[0130] Embodiments 1-32 of this invention at least support the protection scope of claim 3.

[0131] Technical feature "R1 is H, , , , , , , or “ "" represents the connection site; R3, R4, R5, R6, and R7 may be the same or different, and each is independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 Heterocyclic alkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 The term "one or more of the following groups" is derived from the common features of compounds CA1-CA32, as explained above and / or in Examples 1-32. Therefore, those skilled in the art can reasonably infer that the technical feature "R1 is H, , , , , , , or “ "" represents the connection site; R3, R4, R5, R6, and R7 may be the same or different, and each is independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 Heterocyclic alkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 One or more of the following: alkynyl, alkyl monosubstituted amino, alkyl disubstituted amino, alkoxy, alkyl carbonyloxy, cycloalkyl carbonyloxy, heteroaryl carbonyloxy, alkoxy carbonyl, cycloalkoxy carbonyl, heteroaryloxy carbonyl, alkyl carbonylamine, cycloalkyl carbonylamine, heteroaryl carbonylamine, amino carbonyl, alkoxyformamide, alkimidyl, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphoric acid group, polyhydroxyalkoxy carbonyl, carboxyalkoxy, and carboxyalkylformyloxy; "The R1 is H, , , , , , , or “ "" represents the connection site; R3, R4, R5, R6, and R7 may be the same or different, and each is independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 Heterocyclic alkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 The sub-concept of "one or more of the following": alkynyl, alkyl monosubstituted amino, alkyl disubstituted amino, alkoxy, alkyl carbonyloxy, cycloalkyl carbonyloxy, heteroaryl carbonyloxy, alkoxy carbonyl, cycloalkoxy carbonyl, heteroaryl carbonyloxy, alkyl carbonylamine, cycloalkyl carbonylamine, heteroaryl carbonylamine, amino carbonyl, alkoxyformamide, alkimidyl, hydroxyalkoxy, sugar residue, sulfonic acid group, phosphate group, polyhydroxyalkoxy carbonyl, carboxyalkoxy, and carboxyalkylformyloxy; "R1 is H..." , , , , , , or “ "" represents the connection site; R3, R4, R5, R6, and R7 may be the same or different, and each is independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 Heterocyclic alkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10The technical means are essentially equivalent to "one or more of the following": alkyne group, alkyl monosubstituted amino group, alkyl disubstituted amino group, alkoxy group, alkyl carbonyloxy group, cycloalkyl carbonyloxy group, heteroaryl carbonyloxy group, alkoxy carbonyl group, cycloalkoxy carbonyl group, heteroaryl carbonyloxy group, alkyl carbonylamine group, cycloalkyl carbonylamine group, heteroaryl carbonylamine group, amino carbonyl group, alkoxyformamide group, alkimido group, hydroxyalkoxy group, sugar residue, sulfonic acid group, phosphate group, polyhydroxyalkoxy carbonyl group, carboxyalkoxy group, and carboxyalkylformyloxy group. Based on the existing level of technology and within the scope of conventional technical means and common knowledge, "R1 is H" can be replaced. , , , , , , or “ "" represents the connection site; R3, R4, R5, R6, and R7 may be the same or different, and each is independently selected from hydrogen, halogen, nitro, cyano, amino, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, carboxyl, ester, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 cycloalkyl, substituted or unsubstituted C 1-6 Heterocyclic alkyl, substituted or unsubstituted C 4-10 aryl, substituted or unsubstituted C 1-8 heteroaryl, C 2-10 alkenyl, C 2-10 The technical means of "one or more of the following" should all fall within the protection scope of claim 3.

[0132] Embodiments 1-32 of this invention at least support the protection scope of claim 4.

[0133] Technical feature "the pyrrolo[2,1- f [1,2,4] Triazine compounds are selected from any of the following compounds and / or their pharmaceutically acceptable salts, deuterated derivatives, hydrates, polymorphs, solvates, prodrugs, stereoisomers, and tautomers:

[0134]

[0135]

[0136] "" is derived from the common features of the compounds CA1-CA32, etc., as explained above and / or in Examples 1-32.

[0137] Embodiments 1-32 of this invention at least support the protection scope of claim 5.

[0138] The technical feature “the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt” is derived from the common features of the corresponding technical feature compounds CA1-CA32 in the foregoing explanation and / or Examples 1-32. Therefore, those skilled in the art can reasonably presume that the subordinate concepts of the technical feature “the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt”, the essentially equivalent technical means of “the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt”, and the technical means that can replace A within the scope of conventional technical means and common knowledge based on the existing level of technology should all fall within the protection scope of claim 5.

[0139] Embodiments 1-32 of this invention at least support the protection scope of claim 6.

[0140] The technical feature "the inorganic acid salt is selected from any one of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid" is derived from the common features of the corresponding technical feature compounds CA1-CA32 in the foregoing explanation and / or Examples 1-32. Therefore, those skilled in the art can reasonably infer that the subordinate concepts of the technical feature "the inorganic acid salt is selected from any one of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid," the essentially equivalent technical means of "the inorganic acid salt is selected from any one of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid," and the technical means that can replace "the inorganic acid salt is selected from any one of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid" based on the existing technical level and conventional technical means and common knowledge should all fall within the protection scope of claim 6.

[0141] Embodiments 1-32 of this invention at least support the protection scope of claim 7.

[0142] The technical feature "the organic acid salt is selected from any one of acetic acid, trifluoroacetic acid, malonic acid, citric acid, tartaric acid, pyruvic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, mandelic acid, lactic acid, and p-toluenesulfonic acid" is derived from the common features of the corresponding technical feature compounds CA1-CA32 in the foregoing explanation and / or Examples 1-32. Therefore, those skilled in the art can reasonably infer that the technical feature "the organic acid salt is selected from any one of acetic acid, trifluoroacetic acid, malonic acid, citric acid, tartaric acid, pyruvic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, mandelic acid, lactic acid, and p-toluenesulfonic acid" and "the organic acid salt is selected from any one of acetic acid, trifluoroacetic acid, malonic acid, citric acid, tartaric acid, pyruvic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, mandelic acid, lactic acid, and p-toluenesulfonic acid" are subordinate concepts, .... All technical means that are substantially equivalent to the salts formed from any one of trifluoroacetic acid, malonic acid, citric acid, tartaric acid, pyruvic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, mandelic acid, lactic acid, and p-toluenesulfonic acid, and technical means that can replace the salts formed from any one of acetic acid, trifluoroacetic acid, malonic acid, citric acid, tartaric acid, pyruvic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, mandelic acid, lactic acid, and p-toluenesulfonic acid, based on existing technical levels and conventional technical means and common knowledge, should fall within the protection scope of claim 7.

[0143] Embodiments 1-32 of this invention at least support the protection scope of claim 8.

[0144] Technical features “used for the preparation of the above-mentioned pyrrolo[2,1- f [1,2,4] An intermediate of triazine compounds, the structural formula of which is shown in formula (Ⅲ):

[0145]

[0146] Wherein, R1 is -OH or -COOH; R3, R4, R5, R6, and R7 are the same as defined in formula (I), and are derived from the common features of the compounds CA1-CA32, etc., as explained above and / or in Examples 1-32. Therefore, those skilled in the art can reasonably infer that the technical feature "used to prepare the above-mentioned pyrrolo[2,1- f [1,2,4] intermediates of triazine compounds, "used to prepare the above-mentioned pyrrolo[2,1- f The concept of "intermediate of triazine compounds" and "used to prepare the above-mentioned pyrrolo[2,1- fThe technical means that are basically equivalent to the intermediates of triazine compounds [1,2,4] and can replace the above-mentioned pyrrolo[2,1-] within the scope of conventional technical means and common knowledge based on the current level of technology. f The technical means of “intermediates of triazine compounds” [1,2,4] should all fall within the protection scope of claim 8.

[0147] Embodiments 1-32 of this invention at least support the protection scope of claim 9.

[0148] Technical features: "Reaction route 1 synthesizes compounds CA1-CA22; reaction route 2 synthesizes compounds CA23-CA24; reaction route 3 synthesizes compounds CA25-CA28; reaction route 4 synthesizes compounds CA29-CA32."

[0149] Reaction route 1 is as follows:

[0150] ;

[0151] Reaction route 2 is as follows:

[0152] ;

[0153] Reaction route 3 is as follows:

[0154] ;

[0155] Reaction route 4 is as follows:

[0156] "

[0157] The compounds CA1-CA32, etc., described in the foregoing explanation and / or Examples 1-32, are derived from common features. Therefore, those skilled in the art can reasonably infer that the technical features “using reaction route 1 to synthesize compounds CA1-CA22; reaction route 2 to synthesize compounds CA23-CA24; reaction route 3 to synthesize compounds CA25-CA28; reaction route 4 to synthesize compounds CA29-CA32” and “using reaction route 1 to synthesize compounds CA1-CA22; reaction route 2 to synthesize compounds CA23-CA24; reaction route 3 to synthesize compounds CA25-CA28; reaction route 4 to synthesize compounds CA29-CA32” are subordinate concepts, and “using reaction route 1 to synthesize compounds” are also subordinate concepts. All technical means that are essentially equivalent to “using reaction route 1 to synthesize compound CA1-CA22; reaction route 2 to synthesize compound CA23-CA24; reaction route 3 to synthesize compound CA25-CA28; reaction route 4 to synthesize compound CA29-CA32”, and technical means that can replace “using reaction route 1 to synthesize compound CA1-CA22; reaction route 2 to synthesize compound CA23-CA24; reaction route 3 to synthesize compound CA25-CA28; reaction route 4 to synthesize compound CA29-CA32” based on existing technology, conventional technical means, and common knowledge, should fall within the protection scope of claim 9.

[0158] Embodiments 1-32 of this invention at least support the protection scope of claim 10.

[0159] Technical features: "Reaction route 1 includes the following steps: Compound 1 reacts with methylmagnesium bromide to generate compound 2; compound 2 is oxidized by H2O2 to compound 3; compound 3 reacts with pivaloyl chloride to obtain compound 4; compound 4 reacts with POCl3 to obtain compound 5; compound 5 undergoes a substitution reaction with compound 6 to obtain compound 7; compound 7 undergoes ester hydrolysis in NaOH aqueous solution to obtain compound 8; finally, compound 8 reacts with ( R )-Propylene oxide or ( S The reaction of compound 1 with propylene oxide yields compounds CA1-CA22; * represents a chiral center, which is derived from the common features of compounds CA1-CA32, etc., as explained above and / or in Examples 1-32. Therefore, those skilled in the art can reasonably infer that the technical feature "reaction route 1" includes the following steps: compound 1 reacts with methylmagnesium bromide to generate compound 2; compound 2 is oxidized by H2O2 to compound 3; compound 3 reacts with pivaloyl chloride to obtain compound 4; compound 4 reacts with POCl3 to obtain compound 5; compound 5 undergoes a substitution reaction with compound 6 to obtain compound 7; compound 7 undergoes ester hydrolysis in NaOH aqueous solution to obtain compound 8; finally, compound 8 reacts with ( R )-Propylene oxide or (S The reaction of compound 1 with propylene oxide yields compound CA1-CA22; * represents the chiral center. Reaction route 1 includes the following steps: compound 1 reacts with methylmagnesium bromide to generate compound 2; compound 2 is oxidized by H2O2 to compound 3; compound 3 reacts with pivaloyl chloride to obtain compound 4; compound 4 reacts with POCl3 to obtain compound 5; compound 5 undergoes a substitution reaction with compound 6 to obtain compound 7; compound 7 undergoes ester hydrolysis in NaOH aqueous solution to obtain compound 8; finally, compound 8 reacts with (… R )-Propylene oxide or ( S The reaction of compound 1 with propylene oxide yields compounds CA1-CA22; * represents the hyposide concept of the chiral center. Reaction route 1 includes the following steps: Compound 1 reacts with methylmagnesium bromide to generate compound 2; compound 2 is oxidized by H2O2 to compound 3; compound 3 reacts with pivaloyl chloride to obtain compound 4; compound 4 reacts with POCl3 to obtain compound 5; compound 5 undergoes a substitution reaction with compound 6 to obtain compound 7; compound 7 undergoes ester hydrolysis in NaOH aqueous solution to obtain compound 8; finally, compound 8 reacts with (… R )-Propylene oxide or ( S The reaction of compound 1 with propylene oxide yields compounds CA1-CA22; * represents the chiral center. The reaction route 1, which is essentially equivalent to the reaction of compound 1 with methylmagnesium bromide, yields compound 2; compound 2 is oxidized by H2O2 to compound 3; compound 3 reacts with pivaloyl chloride to yield compound 4; compound 4 reacts with POCl3 to yield compound 5; compound 5 undergoes a substitution reaction with compound 6 to yield compound 7; compound 7 undergoes ester hydrolysis in NaOH aqueous solution to yield compound 8; finally, compound 8 reacts with ( R )-Propylene oxide or ( S The technical means of reacting propylene oxide to obtain compounds CA1-CA22; *, representing the chiral center, should all fall within the protection scope of claim 10.

[0160] Embodiments 1-32 of this invention at least support the protection scope of claim 11.

[0161] The technical feature “Reaction route 2 includes the following steps: Compound 1 reacts with POCl3 to obtain Compound 9; Compound 9 undergoes a substitution reaction to obtain Compound 10; Compound 10 undergoes ester hydrolysis in NaOH aqueous solution to obtain Compound 11; Finally, Compound 11 condenses with the corresponding amine compound to obtain Compounds CA23 and CA24” is summarized from the common features of the corresponding technical feature compounds CA1-CA32 in the foregoing explanation and / or Examples 1-32. Therefore, those skilled in the art can reasonably presume that the technical feature “Reaction route 2 includes the following steps: Compound 1 reacts with POCl3 to obtain Compound 9; Compound 9 undergoes a substitution reaction to obtain Compound 10; Compound 10 undergoes ester hydrolysis in NaOH aqueous solution to obtain Compound 11; Finally, Compound 11 condenses with the corresponding amine compound to obtain Compounds CA23 and CA24” is a subordinate concept, and “Reaction route 2 includes the following steps: Compound 1 reacts with POCl3 to obtain Compound 9; Compound 9 undergoes a substitution reaction to obtain Compound 10; Compound 10 undergoes ester hydrolysis in NaOH aqueous solution to obtain Compound 11; Finally, Compound 11 condenses with the corresponding amine compound to obtain Compounds CA23 and CA24” is a subordinate concept, and “Reaction route 2 includes the following steps: The technical means that are essentially equivalent to "reaction route 2, which includes the following steps: reaction of compound 1 with POCl3 to obtain compound 9; substitution reaction of compound 9 to obtain compound 10; ester hydrolysis of compound 10 in NaOH aqueous solution to obtain compound 11; and finally, condensation of compound 11 with the corresponding amine compound to obtain compounds CA23 and CA24", and which can replace "reaction route 2, which includes the following steps: reaction of compound 1 with POCl3 to obtain compound 9; substitution reaction of compound 9 to obtain compound 10; ester hydrolysis of compound 10 in NaOH aqueous solution to obtain compound 11; and finally, condensation of compound 11 with the corresponding amine compound to obtain compounds CA23 and CA24", should all fall within the protection scope of claim 11.

[0162] Embodiments 1-32 of this invention at least support the protection scope of claim 12.

[0163] The technical feature “Reaction route 3 includes the following steps: Compound 8 undergoes a substitution reaction with 2-bromoethanol or 3-bromopropanol to obtain compounds CA25-CA28” is summarized from the common features of the corresponding technical feature compounds CA1-CA32 in the foregoing explanation and / or Examples 1-32. Therefore, those skilled in the art, through reasonable presumption, can determine that the subordinate concepts of the technical feature "reaction route 3 includes the following steps: compound 8 undergoes a substitution reaction with 2-bromoethanol or 3-bromopropanol to obtain compound CA25-CA28", the essentially equivalent technical means of "reaction route 3 includes the following steps: compound 8 undergoes a substitution reaction with 2-bromoethanol or 3-bromopropanol to obtain compound CA25-CA28", and the technical means that can replace "reaction route 3 includes the following steps: compound 8 undergoes a substitution reaction with 2-bromoethanol or 3-bromopropanol to obtain compound CA25-CA28" based on the existing level of technology and conventional technical means and common knowledge, should all fall within the protection scope of claim 12.

[0164] Embodiments 1-32 of this invention at least support the protection scope of claim 13.

[0165] Technical feature "Reaction route 4 includes the following steps: Compound 5 undergoes a substitution reaction with primary amine compound 12 to obtain compound 13; compound 13 undergoes ester hydrolysis to obtain compound 14; finally, compound 14 reacts with ( R The reaction of propylene oxide, 2-bromoethanol, or 3-bromopropanol yields compounds CA29-CA32; * represents a chiral center, derived from the common features of compounds CA1-CA32 described above and / or in Examples 1-32. Therefore, those skilled in the art can reasonably infer that technical feature “reaction route 4 includes the following steps: compound 5 undergoes a substitution reaction with primary amine compound 12 to obtain compound 13; compound 13 undergoes ester hydrolysis to obtain compound 14; finally, compound 14 reacts with ( R The reaction of propylene oxide, 2-bromoethanol, or 3-bromopropanol yields compounds CA29-CA32; * represents a chiral center. Reaction route 4 includes the following steps: compound 5 undergoes a substitution reaction with primary amine compound 12 to yield compound 13; compound 13 undergoes ester hydrolysis to yield compound 14; finally, compound 14 reacts with (… RThe reaction of propylene oxide, 2-bromoethanol, or 3-bromopropanol yields compounds CA29-CA32; * represents the hyposide concept of "chiral center"; reaction route 4 includes the following steps: compound 5 undergoes a substitution reaction with primary amine compound 12 to yield compound 13; compound 13 undergoes ester hydrolysis to yield compound 14; finally, compound 14 reacts with ( R The reaction of propylene oxide, 2-bromoethanol, or 3-bromopropanol yields compounds CA29-CA32; * represents the chiral center. The basic equivalent technical means, based on existing technology and within the bounds of conventional techniques and common knowledge, can replace the reaction route 4, which includes the following steps: Compound 5 undergoes a substitution reaction with primary amine compound 12 to obtain compound 13; compound 13 undergoes ester hydrolysis to obtain compound 14; finally, compound 14 reacts with ( R The reaction of propylene oxide, 2-bromoethanol or 3-bromopropanol to obtain compounds CA29-CA32; *, representing the chiral center, should all fall within the protection scope of claim 13.

[0166] Embodiments 1-32 of this invention at least support the protection scope of claim 14.

[0167] Technical feature: "A pharmaceutical composition comprising the above-mentioned pyrrolo[2,1- f [1,2,4] Triazine compounds” are derived from the common features of the corresponding technical feature compounds CA1-CA32, etc., explained above and / or in Examples 1-32. Therefore, those skilled in the art can reasonably infer that the technical feature “a pharmaceutical composition comprising the above-mentioned pyrrolo[2,1- f [1,2,4] Triazine compounds", "A pharmaceutical composition comprising the above-mentioned pyrrolo[2,1- f The subcategory of "[1,2,4]triazine compounds", "a pharmaceutical composition comprising the above-mentioned pyrrolo[2,1- f [1,2,4] Triazine compounds" are essentially equivalent to the technical means, and can replace "a pharmaceutical composition containing the above-mentioned pyrrolo[2,1-] within the scope of conventional technical means and common knowledge based on the existing technical level. f The technical means of “triazine compounds” [1,2,4] should all fall within the protection scope of claim 14.

[0168] Embodiments 1-32 of this invention at least support the protection scope of claim 15.

[0169] Technical feature: "A cGAS agonist comprising the above-mentioned pyrrolo[2,1- f[1,2,4] Triazine compounds or the above-described pharmaceutical compositions, and one or more pharmaceutically acceptable carriers,” are derived from the common features of the corresponding technical feature compounds CA1-CA32, etc., explained above and / or in Examples 1-32. Therefore, those skilled in the art can reasonably infer that the technical feature “a cGAS agonist comprising the above-described pyrrolo[2,1- f [1,2,4] Triazine compounds or the above-described pharmaceutical compositions, and one or more pharmaceutically acceptable carriers; "a cGAS agonist comprising the above-described pyrrolo[2,1- f [1,2,4] Triazine compounds or the above-described pharmaceutical compositions, and one or more pharmaceutically acceptable carriers” are subordinate concepts, “a cGAS agonist comprising the above-described pyrrolo[2,1- f [1,2,4] Triazine compounds or the above-mentioned pharmaceutical compositions, and one or more pharmaceutically acceptable carriers” are essentially equivalent technical means, and can replace “a cGAS agonist containing the above-mentioned pyrrolo[2,1-] within the scope of conventional technical means and common knowledge based on the existing level of technology. f [1,2,4] Triazine compounds or the above-mentioned pharmaceutical compositions, as well as one or more pharmaceutically acceptable carriers, shall all fall within the protection scope of claim 15.

[0170] Embodiments 1-32 of this invention at least support the protection scope of claim 16.

[0171] Technical feature “the pyrrolo[2,1- f [1,2,4] Triazine compounds, and / or the above-described pharmaceutical compositions, in the preparation of a medicament for treating diseases responsive to the cGAS-STING pathway,” are derived from the common features of the compounds CA1-CA32, etc., as explained above and / or in Examples 1-32. Therefore, those skilled in the art can reasonably presume that the technical feature “the pyrrolo[2,1- f [1,2,4] Triazine compounds, and / or the above-described pharmaceutical compositions, in the preparation of a medicament for treating diseases responsive to the cGAS-STING pathway, “the pyrrolo[2,1- f The subconcept of "[1,2,4] triazine compounds, and / or the above-described pharmaceutical compositions, in the preparation of a medicament for treating diseases responsive to the cGAS-STING pathway", and "the pyrrolo[2,1- fThe use of [1,2,4] triazine compounds, and / or the above-described pharmaceutical compositions, in the preparation of medicaments for treating diseases responsive to the cGAS-STING pathway, is essentially equivalent to the technical means, and can replace the pyrrolo[2,1-] within the scope of conventional techniques and common knowledge based on the existing level of technology. f The technical means of “using triazine compounds and / or the above-mentioned pharmaceutical compositions in the preparation of medicaments for treating diseases that respond to the cGAS-STING pathway” should all fall within the protection scope of claim 16.

[0172] Embodiments 1-32 of this invention at least support the protection scope of claim 17.

[0173] The technical feature "the disease includes inflammatory diseases, autoimmune diseases, cancer, infectious diseases, and cardiovascular diseases" is derived from the common features of the corresponding technical feature compounds CA1-CA32 in the foregoing explanation and / or Examples 1-32. Therefore, those skilled in the art can reasonably presume that the technical feature "the disease includes inflammatory diseases, autoimmune diseases, cancer, infectious diseases, and cardiovascular diseases," the subordinate concepts of "the disease includes inflammatory diseases, autoimmune diseases, cancer, infectious diseases, and cardiovascular diseases," the essentially equivalent technical means of "the disease includes inflammatory diseases, autoimmune diseases, cancer, infectious diseases, and cardiovascular diseases," and the technical means that can replace "the disease includes inflammatory diseases, autoimmune diseases, cancer, infectious diseases, and cardiovascular diseases" based on the existing level of technology and within the scope of conventional technical means and common knowledge, should all fall within the protection scope of claim 17.

[0174] Embodiments 1-32 of this invention at least support the protection scope of claim 18.

[0175] The technical feature “the inflammatory diseases and autoimmune diseases mentioned are all rheumatoid arthritis, chronic obstructive pulmonary disease, allergic rhinitis, asthma, lupus erythematosus, psoriasis and multiple sclerosis” is derived from the common features of the corresponding technical feature compounds CA1-CA32 in the foregoing explanation and / or Examples 1-32. Therefore, based on reasonable presumption, those skilled in the art can determine that the subordinate concepts of the technical feature "the inflammatory diseases and autoimmune diseases are all rheumatoid arthritis, chronic obstructive pulmonary disease, allergic rhinitis, asthma, lupus erythematosus, psoriasis and multiple sclerosis", the technical means that are essentially equivalent to "the inflammatory diseases and autoimmune diseases are all rheumatoid arthritis, chronic obstructive pulmonary disease, allergic rhinitis, asthma, lupus erythematosus, psoriasis and multiple sclerosis", and the technical means that can replace "the inflammatory diseases and autoimmune diseases are all rheumatoid arthritis, chronic obstructive pulmonary disease, allergic rhinitis, asthma, lupus erythematosus, psoriasis and multiple sclerosis" based on the existing technical level and within conventional technical means and common knowledge, should all fall within the protection scope of claim 8.

[0176] Embodiments 1-32 of this invention at least support the protection scope of claim 19.

[0177] The technical feature "the cancer is a solid tumor or a hematologic malignancy, selected from leukemia, multiple myeloma, and lymphoma" is derived from the common features of the corresponding technical feature compounds CA1-CA32 in the foregoing explanation and / or Examples 1-32. Therefore, those skilled in the art can reasonably presume that the subordinate concepts of the technical feature "the cancer is a solid tumor or a hematologic malignancy, selected from leukemia, multiple myeloma, and lymphoma," the essentially equivalent technical means of "the cancer is a solid tumor or a hematologic malignancy, selected from leukemia, multiple myeloma, and lymphoma," and the technical means that can replace "the cancer is a solid tumor or a hematologic malignancy, selected from leukemia, multiple myeloma, and lymphoma" based on the existing technical level and within conventional technical means and common knowledge should all fall within the protection scope of claim 19.

[0178] Embodiments 1-32 of this invention at least support the protection scope of claim 20.

[0179] The technical feature “the leukemia is acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia and chronic myeloid leukemia” is derived from the common features of the corresponding technical feature compounds CA1-CA32 in the foregoing explanation and / or Examples 1-32. Therefore, based on reasonable presumption, those skilled in the art can determine that the subordinate concepts of the technical feature "the leukemia is acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, and chronic myeloid leukemia", the technical means that are essentially equivalent to "the leukemia is acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, and chronic myeloid leukemia", and the technical means that can replace "the leukemia is acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, and chronic myeloid leukemia" based on the existing technical level and within the scope of conventional technical means and common knowledge, should all fall within the protection scope of claim 20.

[0180] Embodiments 1-32 of this invention at least support the protection scope of claim 21.

[0181] The technical feature "the lymphoma is Hodgkin lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, follicular lymphoma, B-cell lymphoma, cellular lymphoma, and diffuse large B-cell lymphoma" is derived from the common features of the corresponding technical feature compounds CA1-CA32, etc., explained above and / or in Examples 1-32. Therefore, those skilled in the art can reasonably infer that the technical feature "the lymphoma is Hodgkin lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, follicular lymphoma, B-cell lymphoma, cellular lymphoma, and diffuse large B-cell lymphoma" and "the lymphoma is Hodgkin lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, follicular lymphoma, B-cell lymphoma, cellular lymphoma, and diffuse large B-cell lymphoma" are subordinate concepts, and that "the lymphoma is Hodgkin lymphoma" is a type of Hodgkin lymphoma. All technical means that are essentially equivalent to "non-Hodgkin lymphoma, mantle cell lymphoma, follicular lymphoma, B-cell lymphoma, cellular lymphoma, and diffuse large B-cell lymphoma" and technical means that can replace "the lymphoma is Hodgkin lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, follicular lymphoma, B-cell lymphoma, cellular lymphoma, and diffuse large B-cell lymphoma" based on existing technology, conventional technical means, and common knowledge should fall within the protection scope of claim 21.

[0182] Embodiments 1-32 of this invention at least support the protection scope of claim 22.

[0183] The technical feature "the infectious disease includes bacterial infection, fungal infection, viral infection and parasitic infection" is derived from the common features of the corresponding technical feature compounds CA1-CA32 in the foregoing explanation and / or Examples 1-32. Therefore, those skilled in the art can reasonably presume that the subordinate concepts of the technical feature "the infectious disease includes bacterial infection, fungal infection, viral infection and parasitic infection," the essentially equivalent technical means of "the infectious disease includes bacterial infection, fungal infection, viral infection and parasitic infection," and the technical means that can replace "the infectious disease includes bacterial infection, fungal infection, viral infection and parasitic infection" based on the existing level of technology and within the scope of conventional technical means and common knowledge, should all fall within the protection scope of claim 22.

[0184] Embodiments 1-32 of this invention at least support the protection scope of claim 23.

[0185] The technical feature “the cardiovascular and cerebrovascular diseases include acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary heart disease, restenosis and vascular stenosis, as well as traumatic brain injury, stroke and ischemia-reperfusion injury” is summarized from the common features of the corresponding technical feature compounds CA1-CA32 in the foregoing explanation and / or Examples 1-32. Therefore, those skilled in the art can reasonably presume that the technical feature "the cardiovascular and cerebrovascular diseases include acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary heart disease, restenosis and vascular stenosis, as well as traumatic brain injury, stroke and ischemia-reperfusion injury" is a subordinate concept of "the cardiovascular and cerebrovascular diseases include acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary heart disease, restenosis and vascular stenosis, as well as traumatic brain injury, stroke and ischemia-reperfusion injury". All technical means that are essentially equivalent to "heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary heart disease, restenosis and vascular stenosis, as well as traumatic brain injury, stroke and ischemia-reperfusion injury" and technical means that can replace "the cardiovascular and cerebrovascular diseases including acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary heart disease, restenosis and vascular stenosis, as well as traumatic brain injury, stroke and ischemia-reperfusion injury" based on existing technology and conventional technical means and common knowledge should fall within the protection scope of claim 23.

[0186] Embodiments 1-32 of this invention at least support the protection scope of claim 24.

[0187] Technical feature “the pyrrolo[2,1- f The use of [1,2,4] triazine compounds, and / or the above-mentioned pharmaceutical compositions, in the preparation of medicaments for enhancing the therapeutic effect of vaccine drugs, is derived from the common features of the corresponding technical feature compounds CA1-CA32, etc., explained above and / or in Examples 1-32. Therefore, those skilled in the art can reasonably infer that the technical feature "the pyrrolo[2,1- f [1,2,4] Triazine compounds, and / or the above-described pharmaceutical compositions, in the preparation of a medicament for use as an immune adjuvant to enhance the therapeutic effect of a vaccine drug; "The pyrrolo[2,1- f The subconcept of "[1,2,4] triazine compounds, and / or the above-described pharmaceutical compositions, in the preparation of medicaments for enhancing the therapeutic effect of vaccine drugs", and "the pyrrolo[2,1- f The use of [1,2,4] triazine compounds, and / or the above-mentioned pharmaceutical compositions, in the preparation of pharmaceuticals as immune adjuvants for enhancing the therapeutic effect of vaccine drugs, is essentially equivalent to the technical means, and can replace the pyrrolo[2,1-] within the scope of conventional technical means and common knowledge based on the existing level of technology. f The technical means of “using triazine compounds and / or the above-mentioned pharmaceutical compositions in the preparation of an immune adjuvant for enhancing the therapeutic effect of a vaccine drug” should all fall within the protection scope of claim 24.

[0188] Embodiments 1-32 of this invention at least support the protection scope of claim 25.

[0189] The technical feature “the immune adjuvant is a non-specific immune enhancer that, together with or pre-injected into the body with the antigen, effectively enhances the strength of the immune response or alters the type of the immune response” is derived from the common features of the corresponding technical feature compounds CA1-CA32, etc., explained above and / or in Examples 1-32. Therefore, those skilled in the art can reasonably presume that the subordinate concepts of the technical feature “the immune adjuvant is a non-specific immune enhancer that, together with or pre-injected into the body with the antigen, effectively enhances the strength of the immune response or alters the type of the immune response”, the essentially equivalent technical means of “the immune adjuvant is a non-specific immune enhancer that, together with or pre-injected into the body with the antigen, effectively enhances the strength of the immune response or alters the type of the immune response”, and the technical means that can replace “the immune adjuvant is a non-specific immune enhancer that, together with or pre-injected into the body with the antigen, effectively enhances the strength of the immune response or alters the type of the immune response” based on the existing level of technology and conventional technical means and common knowledge, should all fall within the protection scope of claim 25.

[0190] The beneficial effects of this invention are as follows:

[0191] The present invention has at least the following beneficial effects:

[0192] Compared with the prior art, the present invention has better technical effects in terms of cGAS activation activity and cGAS binding activity of the target compound.

[0193] According to experimental tests, the cGAS activation activity of the target compound is significantly better than that of the lead compound Brinib.

[0194] According to experimental tests, the present invention makes the cGAS binding activity of the target compound significantly better than that of the lead compound Brinib. Detailed Implementation

[0195] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0196] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all instruments, devices, equipment, reagents, products, etc., used in the embodiments of the present invention are obtained through conventional commercial means.

[0197] Example 1

[0198] The structural formula of compound CA1:

[0199]

[0200] The preparation method of compound CA1 is as follows:

[0201] (1) Preparation of compound 2:

[0202]

[0203] Weigh out compound 1 (5-methyl-4-oxo-3,4-dihydropyrrolo[2,1- f [1,2,4]Triazine-6-carboxylic acid ethyl ester (2.2 g, 10.0 mmol) was placed in a two-necked flask, and 15 mL of dry THF was added. After purging with argon several times, 13.3 mL of methylmagnesium bromide (40.0 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction was allowed to proceed to room temperature for 12 h. The reaction solution was quenched with saturated ammonium chloride aqueous solution, and then extracted three times with ethyl acetate. The organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was washed with 50 mL of a 1:1 mixture of petroleum ether and ethyl acetate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give a pale yellow solid (compound 2) in 78.2% yield.

[0204] (2) Preparation of compound 3:

[0205]

[0206] Compound 2 (1.0 g, 5.0 mmol) was weighed and dissolved in 30 mL of THF. 30% hydrogen peroxide (H₂O₂, 4.8 mL, 50.0 mmol) was added at 0 °C, and stirring was continued for 30 min. Then, while maintaining 0 °C, 10 mL of an aqueous solution of methanesulfonic acid (CH₃SO₃H, 4.8 g, 50.0 mmol) was added dropwise, and stirring was continued for 1 h. The reaction solution was quenched with 15 mL of 10% sodium sulfite aqueous solution. 50 mL of saturated brine was added, and the solution was extracted three times with 100 mL of ethyl acetate. The organic phases were combined. The organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 0.5 g of a yellow solid (compound 3), with a yield of 65.1%.

[0207] (3) Preparation of compound 4:

[0208]

[0209] Compound 3 (0.7 g, 4.0 mmol) was weighed and placed in a two-necked flask. 20 mL of THF was added, followed by DIPEA (0.6 g, 4.8 mmol). Pivaloyl chloride (0.50 g, 4.4 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. 50 mL of saturated brine was added to the reaction mixture, followed by extraction three times with 50 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 0.4 g of a pale yellow solid (compound 4), with a yield of 40.1%.

[0210] (4) Preparation of compound 5:

[0211]

[0212] Weigh 0.5 g (2.0 mmol) of compound 4 into a single-necked flask, add 10.0 mL of acetonitrile, then add DIPEA (0.3 g, 2.6 mmol), and slowly add phosphorus oxychloride (POCl3, 0.8 g, 5.0 mmol). The reaction mixture is heated to 80 °C and reacted overnight. After cooling to room temperature, the solvent and most of the phosphorus oxychloride are removed by concentration under reduced pressure. The mixture is then extracted three times with 100 mL of saturated ammonium bicarbonate aqueous solution and 100 mL of ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product is purified by silica gel column chromatography to give 0.4 g of a white solid (compound 5), with a yield of 83.0%.

[0213] (5) Preparation of compound 7a:

[0214]

[0215] Compound 5 (0.1 g, 0.4 mmol) and compound 6a (0.1 g, 0.50 mmol) were weighed and placed in a single-necked flask. Acetonitrile (10 mL) was added, followed by 1,4-diazabicyclo[2.2.2]octane (DABCO, 0.1 g, 0.70 mmol). The reaction was carried out at room temperature for 1 h. The mixture was extracted three times with 50 mL of saturated brine and 50 mL of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 0.15 g of a white solid (compound 7a), with a yield of 65.5%.

[0216] (6) Preparation of compound 8a:

[0217]

[0218] Compound 7a (0.2 g, 0.5 mmol) was weighed into a single-necked flask, and 10 mL of acetonitrile was added. Sodium methoxide (CH3ONa, 0.06 g, 1.04 mmol) was weighed and suspended in 0.5 mL of methanol (CH3OH). The methanol solution of sodium methoxide was added to the reaction mixture, and the reaction was carried out at room temperature for 2 h. 50 mL of saturated saline solution was added, and the pH was adjusted to neutral with 1 M dilute hydrochloric acid solution. 50 mL of ethyl acetate was added, and the mixture was extracted three times. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 0.09 g of a white solid (compound 8a), with a yield of 45.4%.

[0219] (7) Preparation of compound CA1:

[0220]

[0221] Compound 8a (0.12 g, 0.34 mmol) was weighed and placed in a pressure-resistant tube. 5 mL of acetonitrile was added, followed by DIPEA (0.1 g, 1.0 mmol) and (R)-propylene oxide (0.1 g, 1.7 mmol). The mixture was heated to 50 °C and reacted overnight. The solvent and low-boiling-point substances were removed by vacuum concentration. The mixture was extracted three times with 50 mL of saturated brine and 100 mL of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 0.07 g of a white solid (compound CA1), with a yield of 50.1%.

[0222] 1 H NMR (400 MHz, DMSO- d 6) d 10.95 (s, 1H), 7.89 (s, 1H), 7.84 (s, 1H),7.72 (q, J = 4.6 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 6.88(dd, J = 8.6, 2.4 Hz, 1H), 4.92 (d, J = 4.8 Hz, 1H), 4.00 (p, J = 5.3 Hz, 1H), 3.94- 3.81 (m, 2H), 3.40 (s, 2H), 2.53 (d, J = 4.5 Hz, 3H), 2.41 (s, 3H), 2.37 (s, 3H), 1.18 (d, J= 6.3 Hz, 3H).

[0223] 13 C NMR (101 MHz, DMSO- d 6) δ 171.53, 162.07, 148.46, 144.82, 144.74,135.25, 133.30, 129.18, 114.92, 111.09, 111.04, 110.70, 105.91, 105.79,100.23, 76.79, 65.00, 31.94, 26.13, 20.53, 12.05, 9.05.

[0224] Example 2

[0225] The structural formula of compound CA2:

[0226]

[0227] The preparation method of compound CA2 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA2) with a yield of 50.5%.

[0228] 1 H NMR (400 MHz, DMSO- d 6) d 1 H NMR (400 MHz, DMSO- d 6) d 9.78 (s, 1H), 8.72 (q, J = 4.7 Hz, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.74 - 7.71 (m, 2H), 7.51 (s,1H), 7.44 (dd, J = 8.9, 2.4 Hz, 1H), 4.91 (d, J = 4.8 Hz, 1H), 4.02 (h, J = 5.6 Hz,1H), 3.94 - 3.81 (m, 2H), 2.83 (d, J = 4.6 Hz, 3H), 2.39 (s, 3H), 1.20 (d, J =6.3 Hz, 3H).

[0229] 13 C NMR (101 MHz, DMSO- d 6) d 162.02, 158.65, 152.30, 151.11, 148.60, 147.92, 144.60, 128.35, 121.84, 116.02, 112.90, 110.90, 109.52, 106.15, 100.44, 76.82, 64.95, 26.21, 20.53, 8.84.

[0230] Example 3

[0231] The structural formula of compound CA3:

[0232]

[0233] The preparation method of compound CA3 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA3) with a yield of 45.3%.

[0234] 1 H NMR (400 MHz, DMSO- d 6) d 10.98 (s, 1H), 7.93 (t, J = 5.9 Hz, 1H), 7.89(s, 1H), 7.85 (s, 1H), 7.38 - 7.37 (m, 2H), 7.25 (s, 1H), 6.98 (d, J = 8.6 Hz,1H), 4.02 (m, 2H), 3.86 (m 2H), 3.29 (q, J = 6.9 Hz, 2H), 2.79 (t, J = 7.4 Hz, 2H), 2.42 (s, 3H), 1.78 (s, 3H), 1.18 (d, J = 6.4 Hz, 3H).

[0235] 13 C NMR (101 MHz, DMSO- d 6) d 169.49, 162.17, 148.48, 144.81, 144.70, 134.52, 127.98, 124.74, 116.14, 112.84, 112.24, 111.11, 111.09, 105.83, 100.30, 76.81, 64.99, 26.82, 25.56, 23.14, 20.53, 8.90.

[0236] Example 4

[0237] The structural formula of compound CA4:

[0238]

[0239] The preparation method of compound CA4 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA4) with a yield of 45.6%.

[0240] 1 H NMR (400 MHz, DMSO- d 6) d 7.96 (q, J = 4.7 Hz, 1H), 7.93 (s, 1H), 7.90(s, 1H), 7.83 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.28(dd, J = 8.5, 2.1 Hz, 1H), 6.98 (s, 1H), 4.92 (d, J = 4.8 Hz, 1H), 3.99 (p, J = 5.1Hz, 1H), 3.91-3.82 (m, 2H), 2.84 (d, J = 4.6 Hz, 3H), 2.66 (s, 3H), 2.40 (s, 3H), 1.19 (d, J = 6.3 Hz, 3H).

[0241] 13 C NMR (101 MHz, DMSO- d 6) δ 163.65, 161.50, 158.89, 153.20, 148.87,148.63, 144.54, 124.23, 121.09, 118.31, 113.05, 110.90, 106.15, 106.03,100.50, 76.82, 65.00, 26.56, 20.50, 14.15, 8.87.

[0242] Example 5

[0243] The structural formula of compound CA5:

[0244]

[0245] The preparation method of compound CA5 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA5) with a yield of 51.2%.

[0246] 1 H NMR (400 MHz, DMSO- d6 ) d 7.97 (q, J = 4.7 Hz, 1H), 7.93 (s, 1H), 7.89(s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.25 (dd, J = 8.5, 2.1Hz, 1H), 4.92 (d, J = 4.8 Hz, 1H), 4.00 (p, J = 5.1 Hz, 1H), 3.92-3.83 (m, 2H), 2.83 (d, J = 4.6 Hz, 3H), 2.64 (s, 3H), 2.41 (s, 3H), 1.18 (d, J = 6.3 Hz, 3H).

[0247] 13 C NMR (101 MHz, DMSO- d 6) δ 163.66, 161.53, 158.88, 153.20, 148.89,148.64, 144.54, 124.24, 121.07, 118.33, 113.07, 110.88, 106.19, 106.03,100.43, 76.83, 64.98, 26.55, 20.52, 14.15, 8.88.

[0248] Example 6

[0249] The structural formula of compound CA6:

[0250]

[0251] The preparation method of compound CA6 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA6) with a yield of 50.6%.

[0252] 1H NMR (400 MHz, DMSO- d 6) d 8.75 (q, J = 4.7 Hz, 1H), 7.94 (s, 1H), 7.89(s, 1H), 7.76 - 7.69 (m, 2H), 7.53 (s, 1H), 7.41 (dd, J = 8.9, 2.4 Hz, 1H), 4.92 (d, J = 4.8 Hz, 1H), 4.01 (h, J = 5.6 Hz, 1H), 3.95 - 3.81 (m, 2H), 2.82 (d, J = 4.6 Hz, 3H), 2.41 (s, 3H), 1.19 (d, J = 6.3 Hz, 3H).

[0253] 13 C NMR (101 MHz, DMSO- d 6) d 161.55, 158.80, 152.27, 151.08, 148.64, 147.97, 144.56, 128.37, 121.86, 116.04, 112.92, 110.88, 109.56, 106.18, 100.47, 76.84, 64.98, 26.23, 20.51, 8.84.

[0254] Example 7

[0255] The structural formula of compound CA7:

[0256]

[0257] The preparation method of compound CA7 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA7) with a yield of 46.8%.

[0258] 1 H NMR (400 MHz, DMSO- d 6) d 8.58 (s, 1H), 8.34 (d, J = 4.6 Hz, 1H), 7.93(bs, 2H), 7.89 (s, 1H), 7.74 (d, J= 8.9 Hz, 1H), 7.34 (d, J = 6.4 Hz, 1H), 4.92(d, J = 4.9 Hz, 1H), 4.01 (m, 1H), 3.95 - 3.81 (m, 2H), 2.79 (d, J = 4.6 Hz, 3H), 2.42 (s, 3H), 1.19 (d, J = 6.3 Hz, 3H).

[0259] 13 C NMR (101 MHz, DMSO- d 6) d 162.61, 161.61, 152.70, 149.10, 148.62, 148.20, 144.56, 126.40, 120.18, 117.65, 115.21, 112.83, 110.89, 106.16, 100.48, 76.83, 64.98, 26.07, 20.52, 8.84.

[0260] Example 8

[0261] The structural formula of compound CA8:

[0262]

[0263] The preparation method of compound CA8 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA8) with a yield of 34.4%.

[0264] 1 H NMR (400 MHz, DMSO- d 6) d 11.45 (bs, 1H), 10.39 (s, 1H),8.58 (s, 1H),8.34 (d, J = 4.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.33 (dd, J = 8.3, 1.8 Hz, 1H), 4.03 (m, 1H), 3.95 - 3.82 (m, 2H), 2.80 (s,3H), 2.41 (s, 3H), 1.18 (d, J = 6.3 Hz, 3H).

[0265] 13 C NMR (101 MHz, DMSO -d 6) d 174.11, 162.90, 155.5, 148.9, 146.7, 146.0, 138.3, 132.5, 132.78, 119.5, 116.8, 116.5, 116.2, 107.8, 76.83, 64.98, 24.0, 20.50, 8.83.

[0266] Example 9

[0267] The structural formula of compound CA9:

[0268]

[0269] The preparation method of compound CA9 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA9) with a yield of 41.2%.

[0270] 1 H NMR (400 MHz, DMSO- d 6) δ 8.94 (dd, J = 4.3, 1.8 Hz, 1H), 8.39 (d, J =8.4 Hz, 1H), 8.11 (d, J = 9.1 Hz, 1H), 7.96 (s, 2H), 7.93 (s, 1H), 7.77 (dd, J =9.1, 2.6 Hz, 1H), 7.59 (dd, J = 8.3, 4.2 Hz, 1H), 4.93 (d, J = 4.8 Hz, 1H), 4.08- 3.95 (m, 1H), 3.89 (m, 1H), 2.44 (s, 3H), 1.19 (d, J = 6.3 Hz, 2H).

[0271] 13 C NMR (101 MHz, DMSO -d 6) d161.20, 150.93, 149.65, 148.74, 146.25, 144.50, 136.21, 130.88, 128.81, 126.04, 122.44, 119.44, 110.85, 106.39, 100.53, 76.85, 64.99, 20.52, 8.86.

[0272] Example 10

[0273] The structural formula of compound CA10:

[0274]

[0275] The preparation method of compound CA10 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA10) with a yield of 34.5%.

[0276] 1 H NMR (400 MHz, DMSO- d 6) δ 8.94 (dd, J = 4.3, 1.8 Hz, 1H), 8.39 (d, J =8.4 Hz, 1H), 7.29 (dd, J = 8.3, 4.2 Hz, 1H), 6.64 (s, 1H), 6.60 (bs, 1H), 6.52(s, 1H), 4.93 (d, J = 4.8 Hz, 1H), 4.08 - 3.95 (m, 1H), 3.89 (m, 2H), 3.04 (t, J = 6.2 Hz, 2H), 2.80 ( J = 6.3 Hz, 2H), 2.44 (s, 3H), 1.94 (m, 2H), 1.19 (d, J =6.3 Hz, 2H).

[0277] 13 C NMR (101 MHz, DMSO -d 6) d 161.20, 153.91, 148.65, 145.74, 144.53, 136.21, 130.88, 128.81, 122.44, 119.44, 116.5, 114.6, 76.85, 64.99, 41.8, 27.3, 22.6, 20.52, 8.86.

[0278] Example 11

[0279] The structural formula of compound CA11:

[0280]

[0281] The preparation method of compound CA11 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA11) with a yield of 52.2%.

[0282] 1 H NMR (400 MHz, DMSO- d 6) d 11.83 (s, 1H), 8.19 (s, 1H), 7.93 (s, 1H), 7.92 (s, 1H), 7.89 (s, 1H), 7.57 (s, 1H), 6.49 (s, 1H), 4.92 (d, J = 4.9 Hz, 1H), 4.00 (p, J = 6.1 Hz, 1H), 3.95 - 3.81 (m, 2H), 2.43 (s, 3H), 1.18 (d, J =6.4 Hz, 3H).

[0283] 13 C NMR (101 DMSO- d 6) d 161.91, 148.63, 146.71, 144.56, 142.77, 137.19, 128.36, 121.75, 120.15, 110.89, 106.16, 100.53, 100.51, 76.85, 64.98, 20.52, 8.90.

[0284] Example 12

[0285] The structural formula of compound CA12:

[0286]

[0287] The preparation method of compound CA12 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA12) with a yield of 53.1%.

[0288] 1 H NMR (400 MHz, DMSO- d 6) d 8.95 (dd, J = 4.2, 1.8 Hz, 1H), 8.40 (d, J = 8.4Hz, 1H), 8.15 (d, J = 9.0 Hz, 1H), 7.95 (s, 2H), 7.91 (s, 1H), 7.80 (dd, J = 9.1, 2.6 Hz, 1H), 7.52 (dd, J = 8.3, 4.2 Hz, 1H), 4.91 (d, J = 4.8 Hz, 1H), 4.00 -3.91 (m, 1H), 3.90 (m, 1H), 2.41 (s, 3H), 1.26 (d, J = 6.3 Hz, 2H).

[0289] 13 C NMR (101 MHz, DMSO -d 6) d 160.21, 151.24, 149.12, 148.14, 146.15, 144.10, 137.61, 131.11, 128.43, 126.20, 122.24, 119.51, 111.05, 106.21, 100.12, 77.02, 65.12, 20.21, 8.85.

[0290] Example 13

[0291] The structural formula of compound CA13:

[0292]

[0293] The preparation method of compound CA13 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA13) with a yield of 56.6%.

[0294] 1 H NMR (400 MHz, DMSO- d 6) d 8.04 (s, 1H), 7.99 (s, 1H), 7.96 (m, 2H), 7.91 (s, 1H), 7.44 (s, 1H), 7.42 (s, 1H), 7.40 (s, 1H), 4.92 (d, J= 4.8 Hz,1H), 4.00 (m, 1H), 3.87 (m, 2H), 2.39 (s, 3H), 1.18 (d, J = 6.3 Hz, 3H).

[0295] 13 C NMR (101 MHz, DMSO- d 6) d 167.58, 160.85, 154.19, 148.77, 144.47,132.34, 129.53 (x2), 122.36 (x2), 110.84, 106.35, 100.46, 76.84, 64.97,20.50, 8.81.

[0296] Example 14

[0297] The structural formula of compound CA14:

[0298]

[0299] The preparation method of compound CA14 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA14) with a yield of 60.1%.

[0300] 1 H NMR (400 MHz, DMSO- d 6) d 10.06 (s, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.66 (s, 1H), 7.64 (s, 1H), 7.24 (s, 1H), 7.22 (s, 1H), 4.91 (d, J = 4.8 Hz, 1H), 3.99 (p, J = 6.0 Hz, 1H), 3.93 - 3.79 (m, 2H), 2.38 (s, 3H), 2.06 (s, 3H), 1.17 (d, J = 6.3 Hz, 3H).

[0301] 13 C NMR (101 MHz, DMSO- d 6) d168.73, 161.40, 148.58, 146.99, 144.59,137.50, 122.72 (x2), 120.38 (x2), 110.86, 106.11, 100.36, 76.81, 64.96,24.43, 20.51, 8.83.

[0302] Example 15

[0303] The structural formula of compound CA15:

[0304]

[0305] The preparation method of compound CA15 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA15) with a yield of 37.8%.

[0306] 1 H NMR (400 MHz, DMSO- d 6) d 11.07 (d, J = 7.1 Hz, 1H), 7.89 (d, J = 2.6 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.34 (m, 2H), 6.95 (td, J = 8.0, 2.4 Hz, 1H), 4.91(d, J = 4.8 Hz, 1H), 4.62 (d, J = 9.6 Hz, 2H), 4.00 (p, J = 5.2 Hz, 1H), 3.90 (m,1H), 3.86 - 3.81 (m, 2H), 3.78 (m, 1H), 2.90 (t, J = 5.8 Hz, 1H), 2.78 (t, J =5.8 Hz, 1H), 2.41 (s, 3H), 2.12 (d, J = 14.9 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H).

[0307] 13 C NMR (101 MHz, DMSO- d 6) d169.53, 162.11, 148.47, 144.82, 134.62, 134.11, 125.72, 115.65, 111.69, 111.08, 110.46, 106.84, 106.54, 105.80, 100.26, 76.81, 64.99, 43.86, 24.23, 22.40, 21.99, 20.53, 8.90.

[0308] Example 16

[0309] The structural formula of compound CA16:

[0310]

[0311] The preparation method of compound CA16 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA16) with a yield of 36.9%.

[0312] 1 H NMR (400 MHz, DMSO- d 6) d 11.06 (s, 1H), 7.89 (s, 1H), 7.84 (s, 1H),7.36 - 7.28 (m, 2H), 6.94 (d, J = 8.6 Hz, 1H), 4.90 (bs, 1H), 4.51 (bs, 2H), 4.07 - 3.96 (m, 1H), 3.87 (m, 2H), 3.71 (t, J = 5.8 Hz, 2H), 2.80 (t, J = 5.8 Hz,2H), 2.41 (s, 2H), 1.43 (s, 9H), 1.18 (d, J = 6.3 Hz, 3H).

[0313] 13 C NMR (101 MHz, DMSO- d 6) δ 162.15, 154.73, 148.47, 144.82, 134.76,134.10, 125.75, 115.59, 111.70, 111.11, 110.40, 106.68, 105.81, 100.29,79.41, 76.82, 64.99, 28.58, 26.82, 23.62, 20.53, 8.89.

[0314] Example 17

[0315] The structural formula of compound CA17:

[0316]

[0317] The preparation method of compound CA17 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA17) with a yield of 39.4%.

[0318] 1 H NMR (400 MHz, DMSO- d 6) d 7.93 (t, J = 5.9 Hz, 1H), 7.89 (s, 1H), 7.85(s, 1H), 7.72 (q, J = 4.6 Hz, 1H), 7.38 - 7.37 (m, 2H), 7.25 (s, 1H), 6.98 (d, J = 8.6 Hz, 1H), 4.91 (d, J = 4.8 Hz, 1H), 3.99 (p, J = 6.0 Hz, 1H), 3.93 - 3.79(m, 2H), 2.69 (t, J = 7.4 Hz, 2H), 2.52 (d, J = 4.5 Hz, 3H), 2.26, (t, J = 7.4 Hz, 2H), 1.78 (s, 3H), 1.18 (d, J = 6.4 Hz, 3H).

[0319] 13 C NMR (101 MHz, DMSO- d 6) d 171.39, 162.17, 148.48, 144.81, 144.70, 134.52, 127.98, 124.74, 116.14, 112.84, 112.24, 111.11, 111.09, 105.83, 100.30, 76.81, 64.99, 35.12, 26.82, 25.56, 21.14, 8.90.

[0320] Example 18

[0321] The structural formula of compound CA18:

[0322]

[0323] The preparation method of compound CA18 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA18) with a yield of 44.1%.

[0324] 1 H NMR (400 MHz, DMSO- d 6) d 8.57 (s, 1H), 8.33 (d, J = 4.6 Hz, 1H), 7.94(bs, 2H), 7.90 (s, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.34 (d, J = 6.4 Hz, 1H), 4.92(d, J = 4.9 Hz, 1H), 4.01 (m, 1H), 3.95 - 3.81 (m, 2H), 2.79 (d, J = 4.6 Hz, 3H), 2.42 (s, 3H), 1.19 (d, J = 6.3 Hz, 3H).

[0325] 13 C NMR (101 MHz, DMSO- d 6) d 162.60, 161.60, 152.70, 149.10, 148.61, 148.20, 144.56, 126.40, 120.18, 117.65, 115.21, 112.82, 110.89, 106.16, 100.48, 76.83, 64.98, 26.08, 20.53, 8.85.

[0326] Example 19

[0327] The structural formula of compound CA19:

[0328]

[0329] The preparation method of compound CA19 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA19) with a yield of 47.2%.

[0330] 1H NMR (400 MHz, DMSO- d 6) d 7.98 (q, J = 4.7 Hz, 1H), 7.93 (s, 1H), 7.90(s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H), 7.26 (dd, J = 8.5, 2.1Hz, 1H), 4.91 (d, J = 4.8 Hz, 1H), 4.01 (p, J = 5.1 Hz, 1H), 3.94-3.83 (m, 2H), 2.84 (d, J = 4.6 Hz, 3H), 2.65 (s, 3H), 2.40 (s, 3H), 1.19 (d, J = 6.3 Hz, 3H).

[0331] 13 C NMR (101 MHz, DMSO- d 6) d 163.65, 161.52, 158.87, 153.21, 148.88, 148.65, 144.54, 124.24, 121.07, 118.33, 113.07, 110.88, 106.19, 106.03, 100.43, 76.83, 64.99, 26.55, 20.52, 14.15, 8.89.

[0332] Example 20

[0333] The structural formula of compound CA20:

[0334]

[0335] The preparation method of compound CA20 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA20) with a yield of 52.1%.

[0336] 1 H NMR (400 MHz, DMSO- d 6) d 8.74 (q, J= 4.7 Hz, 1H), 7.94 (s, 1H), 7.89(s, 1H), 7.76 - 7.69 (m, 2H), 7.53 (s, 1H), 7.41 (dd, J = 8.9, 2.4 Hz, 1H), 4.91 (d, J = 4.8 Hz, 1H), 4.00 (h, J = 5.6 Hz, 1H), 3.93 - 3.82 (m, 2H), 2.81 (d, J = 4.6 Hz, 3H), 2.40 (s, 3H), 1.20 (d, J = 6.3 Hz, 3H).

[0337] 13 C NMR (101 MHz, DMSO- d 6) d 161.53, 158.78, 152.25, 151.05, 148.63, 147.98, 144.58, 128.39, 121.84, 116.06, 112.91, 110.88, 109.56, 106.18, 100.47, 76.84, 64.98, 26.23, 20.51, 8.85.

[0338] Example 21

[0339] The structural formula of compound CA21:

[0340]

[0341] The preparation method of compound CA21 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA21) with a yield of 53.5%.

[0342] 1 H NMR (400 MHz, DMSO- d 6) d 10.94 (s, 1H), 7.89 (s, 1H), 7.84 (s, 1H),7.73 (q, J = 4.6 Hz, 1H), 7.32 (d, J = 2.5 Hz, 1H), 7.26 (d, J = 8.6 Hz, 1H), 6.89(dd, J= 8.6, 2.4 Hz, 1H), 4.91 (d, J = 4.8 Hz, 1H), 4.01 (p, J = 5.3 Hz, 1H), 3.94- 3.85 (m, 2H), 3.41 (s, 2H), 2.55 (d, J = 4.5 Hz, 3H), 2.41 (s, 3H), 2.39 (s, 3H), 1.20 (d, J = 6.3 Hz, 3H).

[0343] 13 C NMR (101 MHz, DMSO- d 6) δ 171.52, 162.06, 148.45, 144.83, 144.76,135.24, 133.31, 129.19, 114.94, 111.10, 111.04, 110.70, 105.91, 105.79,100.23, 76.79, 65.00, 31.94, 26.12, 20.54, 12.05, 9.04.

[0344] Example 22

[0345] The structural formula of compound CA22:

[0346]

[0347] The preparation method of compound CA22 is similar to that in Example 1, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA22) in 50.1% yield.

[0348] 1 H NMR (400 MHz, DMSO- d 6) d 11.82 (s, 1H), 8.19 (s, 1H), 7.93 (s, 1H), 7.92 (s, 1H), 7.89 (s, 1H), 7.57 (s, 1H), 6.49 (s, 1H), 4.92 (d, J = 4.9 Hz, 1H), 4.00 (p, J = 6.1 Hz, 1H), 3.95 - 3.81 (m, 2H), 2.42 (s, 3H), 1.19 (d, J =6.4 Hz, 3H).

[0349] 13 C NMR (101 DMSO- d 6) d 161.90, 148.62, 146.70, 144.56, 142.76, 137.20, 128.35, 121.71, 120.25, 110.94, 106.20, 100.57, 100.58, 76.90, 64.98, 20.62, 8.95.

[0350] Example 23

[0351] The structural formula of compound CA23:

[0352]

[0353] The preparation method of compound CA23 is as follows:

[0354] (1) Preparation of compound 9:

[0355]

[0356] Compound 1 (0.7 g, 3.0 mmol) was weighed and placed in a single-necked flask. 15 mL of acetonitrile was added, followed by DIPEA (0.5 g, 3.0 mmol). Phosphorus oxychloride (1.1 g, 7.5 mmol) was slowly added under stirring. After the addition was complete, the temperature was raised to 80 °C and the reaction was allowed to proceed overnight. After cooling to room temperature, the solvent and most of the phosphorus oxychloride were removed by concentration under reduced pressure. The mixture was then extracted with 100 mL of saturated ammonium bicarbonate aqueous solution and 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 0.5 g of a white solid (compound 9), with a yield of 68.0%.

[0357] (2) Preparation of compound 10:

[0358]

[0359] Compound 9 (0.1 g, 0.5 mmol) and compound 6e (0.1 g, 0.5 mmol) were weighed and placed in a single-necked flask. 10 mL of acetonitrile was added, followed by the addition of 1,4-diazabicyclo[2.2.2]octane (DABCO, 0.1 g, 0.7 mmol). The mixture was reacted at room temperature for 1 h. The mixture was extracted three times with 50 mL of saturated brine and 50 mL of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 0.1 g of a white solid (compound 10), with a yield of 56.1%.

[0360] (3) Preparation of compound 11:

[0361]

[0362] Compound 10 (0.2 g, 0.5 mmol) was weighed into a single-necked flask, 10 mL of THF was added, followed by 0.1 g, 2.5 mmol of NaOH. The mixture was heated to 50 °C and reacted overnight. After the reaction, glacial acetic acid was added to adjust the pH to neutral, followed by extraction with 100 mL of saturated brine and 100 mL of ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate, and filtered. The concentrated brownish-yellow oil was dried under vacuum and used directly in the next step.

[0363] (4) Preparation of compound CA23:

[0364]

[0365] Compound 11 (0.2 g, 0.5 mmol) was weighed into a single-necked flask, 10 mL of DMF was added, followed by 2-ethanolamine (0.04 g, 0.6 mmol), then HATU (0.2 g, 0.6 mmol) and DIPEA (0.1 g, 1.0 mmol). The mixture was reacted at room temperature for 4 h. After the reaction was complete, the mixture was extracted with saturated brine and ethyl acetate, and the organic layer was collected. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to give 0.07 g of a white solid (compound CA23), with a yield of 35.5%.

[0366] 1 H NMR (400 MHz, DMSO- d 6) d 8.67 (s, 1H), 8.56 (s, 1H), 8.41 (d, J = 4.6Hz, 1H), 8.01 (bs, 2H), 7.93 (s, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 6.4Hz, 1H), 4.82 (s, 1H), 3.82 (t, J = 6.3 Hz, 2H), 3.01 (t, J = 6.2 Hz, 2H), 2.79(d, J = 4.6 Hz, 3H), 2.62 (s, 3H), 2.41 (s, 3H).

[0367] 13 C NMR (101 MHz, DMSO- d 6) d 167.31, 163.67, 162.11, 151.72, 151.11, 149.12, 149.10, 144.86, 126.21, 120.88, 118.15, 115.62, 113.13, 111.24, 106.26, 100.61, 75.42, 44.16, 26.05, 20.22, 11.89.

[0368] Example 24

[0369] The structural formula of compound CA24:

[0370]

[0371] The preparation method of compound CA24 is similar to that in Example 23, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA24) with a yield of 36.7%.

[0372] 1 H NMR (400 MHz, DMSO- d 6) d 11.85 (s, 1H), 8.95 (s, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.88 (s, 1H), 7.62 (s, 1H), 6.56 (s, 1H), 4.92(d, J = 4.9 Hz, 1H), 3.91 - 3.80 (m, 2H), 3.01 (t, J = 6.2 Hz (2H), 2.43 (s, 3H).

[0373] 13 C NMR (101 DMSO- d 6) d 167.12, 161.83, 148.56, 146.67, 144.52, 142.71, 137.21, 128.36, 121.51, 120.11, 110.82, 107.11, 100.31, 100.22, 66.85, 44.18, 12.52.

[0374] Example 25

[0375] The structural formula of compound CA25:

[0376]

[0377] The preparation method of compound CA25 is as follows:

[0378]

[0379] Compound 8e (0.4 g, 1.0 mmol) was weighed and placed in a two-necked flask. 10 mL of DMF was added, followed by ethanolamine (0.2 g, 1.3 mmol), and then cesium carbonate (CS₂CO₃, 0.5 g, 1.5 mmol). The reaction was allowed to proceed at room temperature for 4 h. After the reaction was complete, 5 mL of 1 M dilute hydrochloric acid aqueous solution was added to quench the reaction. Extraction was then performed by adding 50 mL of saturated brine and 100 mL of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to give 0.1 g of a white solid (compound CA₂₅), with a yield of 24.7%.

[0380] 1 H NMR (400 MHz, DMSO- d 6) d 7.98 (s, 1H), 7.84 (s, 1H), 7.81 (s, 1H),7.74 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.21 (d, J = 8.5 Hz, 1H), 4.52 (t, J = 5.3Hz, 1H), 4.13 - 4.05 (m, 2H), 3.52 (q, J = 6.0 Hz, 2H), 2.81 (d, J = 4.5 Hz, 3H), 2.63 (s, 3H), 2.39 (s, 3H).

[0381] 13 C NMR (101 MHz, DMSO d 6) d 163.62, 161.50, 158.84, 153.22, 148.83, 148.51, 144.50, 124.23, 121.02, 118.30, 113.10, 110.84, 106.01, 105.89, 100.31, 68.30, 57.62, 32.61, 26.57, 14.11.

[0382] Example 26

[0383] The structural formula of compound CA26:

[0384]

[0385] The preparation method of compound CA26 is similar to that in Example 25, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA26) with a yield of 26.1%.

[0386] 1 H NMR (400 MHz, DMSO- d 6) d 7.97 (s, 1H), 7.92 (s, 1H), 7.89 (s, 1H),7.79 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.25 (d, J = 8.5 Hz, 1H), 4.58 (t, J = 5.3Hz, 1H), 4.14 - 4.08 (m, 2H), 3.59 (q, J = 6.0 Hz, 2H), 2.82 (d, J = 4.5 Hz, 3H), 2.64 (s, 3H), 2.39 (s, 3H), 1.90 (p, J = 5.9 Hz, 2H).

[0387] 13 C NMR (101 MHz, DMSO d 6) d 163.66, 161.51, 158.88, 153.20, 148.89, 148.52, 144.52, 124.24, 121.07, 118.33, 113.07, 110.89, 106.08, 106.03, 100.36, 68.35, 57.67, 32.66, 26.55, 14.15, 8.84.

[0388] Example 27

[0389] The structural formula of compound CA27:

[0390]

[0391] The preparation method of compound CA27 is similar to that in Example 25, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA27) with a yield of 23.4%.

[0392] 1 H NMR (400 MHz, DMSO- d 6) d 11.82 (s, 1H), 8.19 (d, J = 2.5 Hz, 1H), 7.94(d, J = 2.5 Hz, 1H), 7.92 (s, 1H), 7.89 (s, 1H), 7.57 (t, J = 3.0 Hz, 1H), 6.54 -6.42 (m, 1H), 4.91 (t, J = 5.5 Hz, 1H), 4.06 (t, J = 4.9 Hz, 2H), 3.76 (q, J = 5.1Hz, 2H), 2.43 (s, 3H).

[0393] 13 C NMR (101 MHz, DMSO d 6) d 161.91, 148.60, 146.71, 144.57, 142.77, 137.19, 128.37, 121.75, 120.15, 110.92, 106.17, 100.53, 73.33, 60.12, 24.14.

[0394] Example 28

[0395] The structural formula of compound CA28:

[0396]

[0397] The preparation method of compound CA28 is similar to that in Example 25, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA28) with a yield of 25.3%.

[0398] 1 H NMR (400 MHz, DMSO- d 6) d9.51 (s, 1H), 8.41 (s, 1H), 8.20 (s, 1H),7.84 (s, 1H), 7.81 - 7.71 (m, 1H), 7.44 (s, 1H), 6.74 - 6.58 (m, 1H), 4.67 -4.47 (m, 1H), 4.14 (t, J = 6.3 Hz, 2H), 3.65 - 3.49 (m, 2H), 1.89 (p, J = 6.2 Hz, 2H), 1.55 (s, 3H).

[0399] 13 C NMR (101 MHz, DMSO- d 6) d 150.06, 149.98, 149.43, 145.16, 143.62, 133.74, 129.90, 122.04, 116.90, 114.43, 106.99, 103.16, 100.58, 68.37, 57.58, 32.62, 8.28.

[0400] Example 29

[0401] The structural formula of compound CA29:

[0402]

[0403] The preparation method of compound CA29 is as follows:

[0404] (1) Preparation of compound 13a:

[0405]

[0406] Compound 5 (0.5 g, 2.0 mmol) and compound 12a (0.4 g, 2.0 mmol) were weighed into a single-necked flask, and 10 mL of DMF was added, followed by DABCO (0.2 g, 2.0 mmol). The mixture was stirred at room temperature for 3 h. After the reaction was complete, 100 mL of saturated brine and 100 mL of ethyl acetate were added, and the mixture was extracted. The organic layer was collected, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 13a 0.6 g, with a yield of 59.2%.

[0407] (2) Preparation of compound CA29:

[0408]

[0409] Similar to the method for preparing compound CA1 from compound 8a in Example 1, the reactants were simply changed. After purification by column chromatography, a brown solid (compound CA29) was obtained, with a yield of 41.1%.

[0410] 1 H NMR (400 MHz, DMSO- d 6) d 8.64 (s, 1H), 8.07 (q, J = 4.7 Hz, 1H), 7.91(s, 1H), 7.85 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.42(dd, J = 8.5, 2.1 Hz, 1H), 4.81 (d, J = 4.8 Hz, 1H), 4.31 (p, J = 5.1 Hz, 1H),3.91-3.86 (m, 2H), 2.82 (d, J = 4.6 Hz, 3H), 2.64 (s, 3H), 2.40 (s, 3H), 1.19(d, J = 6.3 Hz, 3H).

[0411] 13 C NMR (101 MHz, DMSO- d 6) δ 160.21, 158.13, 155.22, 152.21, 147.21,145.24, 143.45, 124.13, 121.10, 118.30, 114.07, 111.01, 106.42, 106.11,100.13, 76.81, 65.00, 26.55, 20.51, 14.16, 8.88.

[0412] Example 30

[0413] The structural formula of compound CA30:

[0414]

[0415] The preparation method of compound CA30 is similar to that in Example 29, except that the reactants are changed. Silica gel column chromatography yielded a brown solid (compound CA30) with a yield of 38.2%.

[0416] Example 31

[0417] The structural formula of compound CA31:

[0418]

[0419] The preparation method of compound CA31 is as follows:

[0420]

[0421] The preparation method of compound CA31 is similar to that in Example 25, except that the reactants are changed. After purification by column chromatography, a brown solid (compound CA31) is obtained with a yield of 23.4%.

[0422] 1 H NMR (400 MHz, DMSO- d 6) d 11.82 (s, 1H), 8.64 (s, 1H), 8.20 (d, J = 2.5Hz, 1H), 8.01 (s, 1H), 7.94 (d, J = 2.5 Hz, 1H), 7.93 (s, 1H), 7.61 (t, J = 3.0Hz, 1H), 6.51 - 6.42 (m, 1H), 4.90 (t, J = 5.5 Hz, 1H), 4.04 (t, J = 4.9 Hz, 2H), 3.78 (q, J = 5.1 Hz, 2H), 2.40 (s, 3H).

[0423] 13 C NMR (101 MHz, DMSO -d 6) d 160.51, 146.92, 146.11, 143.14, 142.02, 136.67, 128.30, 120.12, 119.89, 110.41, 105.62, 100.13, 73.33, 60.12, 24.14.

[0424] Example 32

[0425] The structural formula of compound CA32:

[0426]

[0427] The preparation method of compound CA32 is similar to that in Example 31, except that the reactants are changed. Silica gel column chromatography yielded a white solid (compound CA32) with a yield of 28.7%.

[0428] 1 H NMR (400 MHz, DMSO- d 6) d 11.82 (s, 1H), 8.64 (s, 1H), 8.20 (s, 1H),8.01 (s, 1H), 7.84 (s, 1H), 7.91 - 7.84 (m, 1H), 7.54 (s, 1H), 6.74 - 6.58(m, 1H), 4.67 - 4.47 (m, 1H), 4.14 (t, J = 6.3 Hz, 2H), 3.65 - 3.49 (m, 2H), 2.30 (s, 3H), 1.89 (p, J = 6.2 Hz, 2H).

[0429] 13 C NMR (101 MHz, DMSO- d 6) d 151.12, 150.48, 149.72, 145.26, 144.12, 134.04, 131.10, 122.74, 117.21, 114.82, 107.45, 103.09, 100.72, 68.12, 58.18, 32.09, 8.28.

[0430] Detection Example 1

[0431] In vitro activation activity assay of the target compound for cGAS.

[0432] qRT-PCR test Ifnb The expression level method was used to evaluate the activity of the target compound CA1-32 in activating cGAS protein in different cells. The specific steps were as follows:

[0433] (1) Cell treatment: PC-9 cells (purchased from the Cell Bank of the Chinese Academy of Sciences) were treated at a concentration of 5 × 10⁶ cells / year. 5Cells were incubated at a density of [number] cells / mL in six-well plates in DMEM medium (Gibco, 11965092) containing 10% fetal bovine serum (Gibco, A5256701) and 1% penicillin-streptomycin (Beyotime, C0222). After cell adhesion, cells were co-treated with cisplatin (MedChemExpress, HY-17394) and the target compound for 48 h. Cells were divided into the following groups: blank group (1% DMSO treatment); cisplatin group (10 μM cisplatin treatment); brinanib group (5 μM brinanib treatment); cisplatin + brinanib group (10 μM cisplatin and 5 μM brinanib co-treatment); and cisplatin + target compound group (10 μM cisplatin and 5 μM target compound co-treatment). Cisplatin was dissolved in DMF, and the final concentration after addition to the medium was 1%; both brinanib and the target compound were dissolved in DMSO, and the final concentration after addition to the medium was 1%.

[0434] (2) RNA extraction: After treatment, the cells were washed once with PBS. 1 mL of TriZol (Invitrogen, 15596026CN) was added to each group, and the mixture was pipetted and incubated at room temperature for 10 min. 200 μL of chloroform was added, mixed, and incubated on ice for 15 min. Then, the cells were centrifuged at 4 °C and 12000 rpm / min for 15 min. The upper aqueous phase was collected, and an equal volume of isopropanol was added. The mixture was inverted in the same direction and allowed to stand for 10 min. The cells were centrifuged at 4 °C and 10000 rpm / min for 10 min, the supernatant was removed, and the white precipitate at the bottom of the tube was collected. 75% ethanol was added, the mixture was gently mixed, and the cells were centrifuged at 4 °C and 12000 rpm / min for 3 min. The supernatant was removed. This process was repeated once, and an appropriate amount of double-distilled water was added. The OD value was measured.

[0435] (2) Reverse transcription: Genomic DNA was removed using 5×g DNA digester Mix (Yeasen, 11141ES10), and 4×Hifair was added. ® III. SuperMix plus (Yeasen, 11141ES10) reverse transcribes RNA into cDNA.

[0436] (3) q-PCR: using Hieff UNICON ® Gene expression was quantitatively analyzed using Universal Blue qPCR SYBR Green Master Mix (Yeasen, 11184ES03). Ifnb The relative mRNA content compared with the internal reference β- actin The ratio is expressed as .

[0437] Verification of technical effectiveness and / or analysis of technical problem solving

[0438] The test results are shown in Table 1. As can be seen from Table 1, most of the compounds in the table exhibited cGAS agonist activity and could increase intracellular cGAS activity in PC-9 cells. Ifnb The relative contents of the compounds were as follows. Among them, compounds CA7, CA19, CA26, and CA28 showed stronger activity and better cGAS activating activity, which was superior to the lead compound brinnib.

[0439] Table 1. cGAS agonist activity of the target compounds

[0440]

[0441] Note: "++" means >15; "++" means 5-15; "+" means <5.

[0442] Detection Example 2

[0443] In vitro binding activity test of the target compound with cGAS.

[0444] The binding affinity of target compounds CA1, CA3, CA5, CA6, CA8, CA11, and CA16 to human cGAS protein was determined using isothermal titration calorimetry. The binding affinity was expressed as K0. D express.

[0445] Verification of technical effectiveness and / or analysis of technical problem solving

[0446] The test results are shown in Table 2. As can be seen from Table 2, some of the tested compounds exhibited high cGAS binding activity. The binding constants K of compounds CA3, CA6, CA8, and CA11 with the cGAS protein are... D Between 1 and 5 μM, the binding constant K of compounds CA5 and CA16 to cGAS protein is... D It has a molecular weight of less than 1 μM and exhibits strong binding activity.

[0447] Table 2. cGAS binding activity of the target compounds

[0448]

[0449] Note: "++" represents K D (μM) < 1; "++" represents K D (μM) is between 1 and 5; "+" indicates between 5 and 10.

[0450] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A pyrrolo[2,1- f [1,2,4] Triazine compounds, characterized in that, Selected from any of the following compounds and / or their pharmaceutically acceptable salts: 。 2. The pyrrolo[2,1-] according to claim 1 f [1,2,4] Triazine compounds, characterized in that, The pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt.

3. The pyrrolo[2,1-] according to claim 2 f [1,2,4] Triazine compounds, characterized in that, The inorganic acid salt is selected from any one of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid.

4. The pyrrolo[2,1-] according to claim 2 f [1,2,4] Triazine compounds, characterized in that, The organic acid salt is selected from any one of acetic acid, trifluoroacetic acid, malonic acid, citric acid, tartaric acid, pyruvic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, mandelic acid, lactic acid, and p-toluenesulfonic acid.

5. A method for preparing pyrrolo[2,1-] according to any one of claims 1-4 f [1,2,4] The method for synthesizing triazine compounds involved using reaction route 1 to synthesize compounds CA1, CA6-CA10, and CA18-CA21; reaction route 3 to synthesize compound CA26; and reaction route 4 to synthesize compound CA29. Reaction route 1 is as follows: ； Reaction route 3 is as follows: ； Reaction route 4 is as follows: ； R3, R4, R5, R6, and R7 are the same as those defined in claim 1.

6. A pharmaceutical composition, characterized in that, Contains pyrrolo[2,1-] as described in any one of claims 1-4 f [1,2,4] Triazine compounds.

7. A cGAS agonist, characterized in that, Contains pyrrolo[2,1-] as described in any one of claims 1-4 f [1,2,4] Triazine compounds or the pharmaceutical composition of claim 6, and one or more pharmaceutically acceptable carriers.

8. A pyrrolo[2,1-] as described in any one of claims 1-4 f [1,2,4] Use of triazine compounds or the pharmaceutical composition of claim 6 in the preparation of a medicament for treating diseases that have an agonistic response to the cGAS-STING pathway.

Images