Heterocyclic pyridine-7-ketone compound and medical application thereof

Abstract

The invention provides a heterocyclic pyridine-7-ketone compound and medical application thereof, in particular to a pyrrolopyridine-7-ketone compound and application of the pyrrolopyridine-7-ketone compound in preparation of drugs for treating diseases or symptoms mediated by hypoxia inducible factor-2 alpha and related diseases or symptoms. The compound provided by the invention has HIF-2 inhibitory activity, and shows VEGF (vascular endothelial growth factor) protein expression inhibitory activity in a human renal clear cell carcinoma cell strain 786-O. Overexpression and activation of HIF-2 alpha are main reasons causing VHL- / -clear cell renal cell carcinoma. Therefore, the compound can be applied to preparation of drugs for treating VHL deficiency or HIF-2alpha abnormal expression diseases including cancers, inflammations, autoimmune diseases and iron overload related diseases. Heterocyclic pyridine-7-ketone compound provided by the invention has a structure of general formula a: # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and relates to a heterocyclic pyridine-7-one compound and its pharmaceutical use, and is a pyrrolo pyridine-7-one compound and its application in the preparation of drugs for treating diseases or disorders mediated by hypoxia-inducible factor-2α (HIF-2α) and related diseases or disorders. Background Art

[0002] Renal cell carcinoma (RCC), also known as renal adenocarcinoma, is the third most common cancer in the urinary system and originates from the renal parenchymal urothelial system. In recent years, renal cell carcinoma has been highly prevalent globally. In 2020, more than 400,000 new cases were diagnosed worldwide, with approximately 180,000 deaths, and the incidence has been on the rise in the past decade. Renal cell carcinoma has multiple histological subtypes and can be classified into clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), chromophobe renal cell carcinoma (chRCC), etc. according to different genetic and molecular characteristics. Among them, ccRCC is the most common form of renal cancer, accounting for about 75% of all renal cell carcinoma cases. Currently, targeted therapeutic drugs for ccRCC include vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), mammalian target of rapamycin (mTOR) inhibitors, and immune checkpoint inhibitors (ICIs), but the emergence of drug resistance poses a greater challenge to clinical treatment.

[0003] Hypoxia-induced factors (HIFs) are a class of heterodimeric nuclear transcription factors belonging to the bHLH-PAS (basic loop-helix-loop PER-ARNT-SIM) transcription factor family.

[25] As key nuclear transcriptional regulatory factors, HIFs play a central role in multiple signal transduction pathways for cells to adapt to the hypoxic environment. This heterodimer consists of two subunits, HIF-α and aryl hydrocarbon receptor nuclear transcription factor (ARNT, also known as HIF-β). The HIF-α subunit has three subtypes, including HIF-1α, HIF-2α, and HIF-3α, which are oxygen-sensitive and can be degraded; while the ARNT subunit has only a single subtype for constitutive expression. Studies have shown that HIF-2 can regulate various physiological processes such as cell proliferation, metabolism, angiogenesis, and tumor metastasis, and is associated with poor prognosis in various cancers.

[0004] In ccRCC patients, the tumor suppressor gene (von Hippel-Lindau, VHL) located on chromosome 3 has a high frequency of mutation. The inactivation of the VHL gene leads to a decrease in the expression of the pVHL protein it encodes. As the substrate recognition subunit of the E3 ubiquitin ligase complex, VHL mediates the degradation of HIF-2α and regulates the cell's response to hypoxia. The loss of VHL function results in the over-accumulation of HIF-2α protein and the uncontrollable activation of downstream target genes under normoxic conditions, promoting tumorigenesis and development. Therefore, HIF-2α has become a new target for the treatment of clear cell renal carcinoma.

[0005] Currently, small molecule inhibitors targeting HIF-2α can specifically bind to the unique cavity of the PAS-B domain of HIF-2α and have high selectivity. Such as PT2385 (J. Med. Chem. 2018, 61, 9691), Belzutifan (MK-6482, PT2977) (J. Med. Chem. 2019, 62, 6876), THS-044 (J. Am. Chem. Soc. 2009, 131, 17647), 0X3 (J. Med. Chem. 2013, 56, 1739), and tetrazolo-hydropyrimidine derivatives (S,R)-37 (J. Med. Chem. 2015, 58, 5930), etc. Among them, Belzutifan, as a selective HIF-2α / ARNT dimerization inhibitor, was approved for marketing on August 31, 2021, for the treatment of recurrent glioblastoma, clear cell renal carcinoma associated with von Hippel-Lindau syndrome, etc. Small molecule inhibitors of HIF-2α have good clinical application prospects, but currently their structural types are relatively single. Searching for and discovering HIF-2α inhibitors with brand-new skeletons for the treatment of tumors such as clear cell renal carcinoma has important clinical significance. Summary of the Invention

[0006] Aiming at the characteristics of the existing HIF-2α inhibitors with fewer structural types, the purpose of the present invention is to provide a heterocyclic-fused pyridin-7-one compound.

[0007] On the one hand, the heterocyclic-fused pyridin-7-one compound provided by the present invention, or its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates, has the structure of general formula a: In formula a: L is selected from a chemical bond, -O-, or -NR 0 -; where R 0 is selected from hydrogen, deuterium or C 1-6 alkyl; X 1and X 2 are each independently selected from N or CH; R 1 、R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl; and R 1 、R 2 、R 3 、R 4 、R 5 are not simultaneously hydrogen; Alternatively, R 2 and R 3 together with the C atom to which they are attached form a 4- to 6-membered heterocyclic group; the 4- to 6-membered heterocyclic group is optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro or amino; and the 4- to 6-membered heterocyclic group is not piperidine or piperazinone; R 6 is selected from C 1-6 alkyl or C 1-6 haloalkyl; R 7 is selected from hydrogen, deuterium, C 1-6 alkyl or C 1-6 haloalkyl.

[0008] In some embodiments, the L is selected from a chemical bond or -O-.

[0009] In some embodiments, the R 6 、R 7 are each independently selected from hydrogen, methyl or ethyl.

[0010] In some embodiments, the R 1 、R 2 、R 3 、R 4 、R 5 are each independently selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl or difluoromethoxy; and R 1 、R 2 、R 3 、R 4 、R 5 are not simultaneously hydrogen.

[0011] In some embodiments, the R 2 and R 3Together with the connected C atom, it forms a 4-6 membered heterocyclic group; the 4-6 membered heterocyclic group is not piperidine or piperazinone.

[0012] In some embodiments, the 4-6 membered heterocyclic group is selected from tetrahydrofuran or dioxane.

[0013] Specifically, the compound of the present invention, or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate, is selected from the following compounds:

[0014] The above heterocyclic-fused pyrazol-7-one compounds can specifically bind to HIF-2α, inhibit the overexpression and activation of HIF-2α, so as to achieve the treatment and prevention of target diseases, such as diseases with VHL gene deletion or / and abnormal expression of HIF-2α.

[0015] On the other hand, the present invention provides a pharmaceutical composition, which comprises the above heterocyclic-fused pyrazol-7-one compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate, and a pharmaceutically acceptable carrier or excipient.

[0016] On another aspect, the present invention provides the use of the above heterocyclic-fused pyrazol-7-one compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate, or its pharmaceutical composition in the preparation of a drug for treating HIF-2α-mediated diseases.

[0017] On another aspect, the present invention provides the use of the above heterocyclic-fused pyrazol-7-one compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate, or its pharmaceutical composition in the treatment of HIF-2α-mediated diseases or disorders and related diseases or disorders.

[0018] The present invention also provides a method for treating a disease or disorder, the method comprising administering to a patient in need a therapeutically effective amount of the above heterocyclic-fused pyrazol-7-one compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate, or its pharmaceutical composition; the disease or disorder is selected from HIF-2α-mediated diseases or disorders and related diseases or disorders.

[0019] In some embodiments, the HIF-2α-mediated diseases or disorders and related diseases or disorders are selected from tumors, inflammatory and autoimmune diseases, and iron overload diseases.

[0020] In some embodiments, the tumor is selected from solid tumors with VHL gene deletion, including renal cancer, liver cancer, colorectal cancer, lung cancer, gastric cancer, breast cancer, ovarian cancer, cervical cancer, skin cancer, glioma, lymphoma or neuroblastoma.

[0021] When treating tumors, in addition to the single use of the above compounds, other anti-tumor drugs can also be selected for combined use. Other anti-tumor drugs include, but are not limited to, mitotic inhibitors (such as vinblastine, vindesine, etc.), tubulin depolymerization inhibitors (such as taxol), antimetabolites (such as 5-fluorouracil, methotrexate, cytarabine, etc.), alkylating agents (such as cisplatin, carboplatin, cyclophosphamide, etc.), intercalating antibiotics (such as aclarubicin, mitomycin, bleomycin, etc.), enzymes (such as asparaginase, etc.), topoisomerase inhibitors (such as etoposide, camptothecin, etc.).

[0022] In some embodiments, the inflammatory and autoimmune diseases are selected from asthma, nephritis, pneumonia, enteritis, dermatitis, arthritis, vasculitis, pancreatitis or trauma infection.

[0023] In some embodiments, the iron overload diseases are selected from hemochromatosis, polycythemia vera, Patau syndrome or β-thalassemia.

[0024] On the other hand, the present invention provides a method for preparing the compound. The heterocyclic-fused pyridin-7-one derivatives of general formula a structure are prepared through the following steps, but are not limited to the following methods.

[0025] 1. Synthesis method of compound I series:

[0026] The specific reaction process can be: 5-bromo-2-methoxy-4-methyl-3-nitropyridine (Ia) undergoes an acetal reaction with N,N-dimethylformamide dimethyl acetal to obtain an enamine intermediate Ib; The intermediate Ib undergoes nitro reduction and cyclization reactions to obtain a pyrrolo-pyridinone intermediate Ic; The intermediate Ic is protected by p-toluenesulfonyl and the methoxy group is removed by HBr to obtain an intermediate Ie; The intermediate Ie undergoes alkylation under the condition of NaH to obtain an N-alkyl substituted intermediate If; The intermediate If undergoes Suzuki coupling and deprotection under alkaline conditions to obtain the target compounds of series IA; The target compounds of series IA undergo alkylation to obtain the target compounds of series IB.

[0027] 2. Synthesis method of compound II series:

[0028] The specific reaction process can be as follows: 5-Bromo-4-methyl-3-nitropyridin-2(1H)-one (IIa) undergoes methylation, nitro reduction, and pentyl nitrite-mediated cyclization reaction to obtain intermediate IId; The intermediate IId undergoes SEM group protection, Suzuki coupling, and deprotection of the SEM protecting group with trifluoroacetic acid to obtain the target compounds of series II.

[0029] 3. Synthesis method of compound series III:

[0030] The specific reaction process can be as follows: 2,5-Dibromopyridine-3,4-diamine (IIIa) undergoes cyclization with formic acid to obtain the imidazopyridin-4-one intermediate IIIb; The intermediate IIIb undergoes SEM group protection, methylation, Suzuki coupling, and deprotection of the SEM protecting group with trifluoroacetic acid to obtain the target compounds of series III.

[0031] 4. Synthesis method of compound series IV:

[0032] The specific reaction process can be as follows: The intermediate Id reacts with bis(pinacolato)diboron to obtain the boronic acid intermediate IVa; The intermediate IVa reacts with hydrogen peroxide to obtain the intermediate IVb; The intermediate IVb then undergoes nucleophilic substitution with differently substituted fluorobenzenes to obtain the intermediate IVc; The intermediate IVc undergoes demethoxylation with hydrobromic acid, methylation, and deprotection with p-toluenesulfonyl to obtain the target compounds of series IV.

[0033] Unless otherwise specified, the general chemical terms used in the structural general formula have their usual meanings.

[0034] For example, unless otherwise specified, the term "halogen" used in the present invention refers to fluorine, chlorine, bromine, or iodine.

[0035] The term "chemical bond" refers to the direct connection of adjacent atoms.

[0036] In the present invention, unless otherwise specified, "alkyl" includes straight-chain or branched monovalent saturated hydrocarbon groups. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6"1-6" in "alkyl" refers to a group arranged in a straight-chain or branched-chain form containing 1, 2, 3, 4, 5, or 6 carbon atoms.

[0371] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched-chain alkyl, i.e., -O-alkyl.

[0038] The term "haloalkyl" refers to an alkyl in which one or more H have been replaced by halogen atoms.

[0039] The term "haloalkoxy" refers to an alkoxy in which one or more H have been replaced by halogen atoms.

[0040] The term "heterocyclic group" refers to a ring system having at least one cyclic alkyl or cyclic alkenyl containing a heterocyclic moiety, and the heteroatom is selected from N, O, and / or S. The heterocyclic group may include a monocyclic or polycyclic ring (e.g., having 2, 3, or 4 fused rings, spiro rings, bridged rings, etc.). The heterocyclic group may be connected to other parts of the compound via a ring-forming carbon atom or a ring-forming heteroatom. A 3- to 14-membered heterocyclic group is preferred, and "3- to 14-membered" in the 3- to 14-membered heterocyclic group refers to a heterocyclic group composed of 3 to 14 ring-forming atoms of C, N, O, or S; a 3- to 8-membered heterocyclic group is more preferred, and a 5- to 6-membered heterocyclic group is even more preferred; wherein the nitrogen or sulfur heteroatom may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized. Examples of these heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridine, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuryl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. The heterocyclic group may be fused to an aryl, heteroaryl, or cycloalkyl ring, and the ring connected to the parent structure is the heterocyclic group.

[0041] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.

[0042] When the compound provided by the present invention is an acid, its corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include salts such as aluminum, ammonium, calcium, copper (higher and lower valences), ferric, ferrous, lithium, magnesium, manganese (higher and lower valences), potassium, sodium, zinc, etc. Salts of ammonium, calcium, magnesium, potassium, and sodium are particularly preferred. Non-toxic organic bases capable of being derivatized into pharmaceutically acceptable salts include primary amines, secondary amines, and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins, as well as arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0043] When the compound provided by the present invention is a base, its corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclohexanesulfamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharic acid, trifluoroacetic acid, tartaric acid, and p-toluenesulfonic acid, etc. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, formic acid and hydrochloric acid.

[0044] Prodrugs of the compounds of the present invention are included within the scope of protection of the present invention. Generally, the prodrug refers to a functional derivative that can be easily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester, or other derivative of the compounds of the present application, which can directly or indirectly provide the compounds of the present application or their pharmaceutically active metabolites or residues after administration to a recipient.

[0045] The compounds of the present invention may contain one or more asymmetric centers and may thus give rise to diastereoisomers and optical isomers. The present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutical salts.

[0046] When the above compounds exist as tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutical salts, as well as their mixtures.

[0047] The present invention also includes atoms of all isotopes, whether in intermediates or final compounds. Atoms of isotopes include those having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0048] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the present application to an organism.

[0049] The "pharmaceutically acceptable carrier" described in the present invention refers to conventional pharmaceutical carriers in the pharmaceutical field, including conventional diluents in the pharmaceutical field, excipients such as water, fillers such as starch, binders such as cellulose derivatives, gelatin, etc., wetting agents such as glycerol, disintegrants such as agar, calcium carbonate, etc., absorption promoters such as quaternary ammonium compounds, surfactants such as cetyl alcohol, adsorption carriers such as kaolin and bentonite, lubricants such as talc powder, etc. If necessary, flavoring agents, sweetening agents, etc. can also be added.

[0050] The pharmaceutical preparation is suitable for administration by any appropriate route, such as oral (including buccal or sublingual administration), rectal administration, nasal administration, topical administration (including buccal, sublingual or transdermal administration), vaginal administration or parenteral administration (including subcutaneous injection, intramuscular injection, intravenous injection or intradermal injection) routes. These preparations can be prepared by any method known in the pharmaceutical field, such as by mixing the active ingredient with a carrier or excipient.

[0051] The term "treatment" generally refers to obtaining the desired pharmacological and / or physiological effect. This effect can be therapeutic depending on partially or completely stabilizing or curing the disease and / or side effects caused by the disease. "Treatment" as used herein encompasses any treatment of a patient's disease, including: (a) inhibiting the symptoms of the disease, i.e., preventing its development; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0052] The term "effective amount" means the amount of the compound of the present application that (i) treats or prevents a specific disease, condition or disorder, (ii) alleviates, improves or eliminates one or more symptoms of a specific disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition or disorder described herein. The amount of the compound of the present application constituting a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0053] Compared with the prior art, the present invention has the following technical effects: The above-mentioned compounds provided by the present invention have HIF-2 inhibitory activity and show inhibitory activity on the expression of VEGF protein in human renal clear cell carcinoma cell line 786-O. The overexpression and activation of HIF-2α are the main causes of VHL- / - clear cell renal cell carcinoma. Therefore, the above-mentioned compounds can be applied to the preparation of drugs for treating diseases caused by VHL deficiency or abnormal expression of HIF-2α, including cancer, inflammation, autoimmune diseases, and iron overload-related diseases. Detailed implementation mode

[0054] The present invention will be further described in conjunction with the embodiments. The specific embodiments included below are for illustrative purposes and should not be construed as limiting the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

[0055] Example 1: Synthesis of Series I Compounds

[0056] Step 1: (E)-2-(5-Bromo-2-methoxy-3-nitro-4-pyridinyl)-N,N-dimethylaniline (Ib) Dissolve 5-bromo-2-methoxy-4-methyl-3-nitropyridine (13.4 g, 0.054 mol) in DMF (110 mL), heat to 80 °C and stir for half an hour, slowly add N,N-dimethylformamide dimethyl acetal (60 mL), and react at 95 °C for 5 h. Cool the system to room temperature, pour it into ice water (300 mL), a red solid appears, filter by suction, wash the filter cake with water, and dry it under reduced pressure to obtain 16.4 g of a red solid, yield: 98%; 1 1H NMR (500 MHz, Chloroform-d) δ 8.11 (s, 1H), 6.99 (d, J = 13.5 Hz, 1H), 4.91 (d, J = 13.5 Hz, 1H), 3.94 (s, 3H), 2.92 (s, 6H); ESI-MS: m / z = 302.0 [M+H] + .

[0057] Step 2: 4-Bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (Ic) Dissolve compound Ib (16.0 g, 0.053 mmol), iron powder (16.0 g, 0.286 mmol), and ammonium chloride (16.0 g, 0.302 mmol) in methanol and water (450 and 60 mL), and reflux at heating for 7 h. Filter the system while it is hot, wash the filter cake with methanol (60 mL×3), concentrate the filtrate under reduced pressure, and purify it by silica gel column chromatography to obtain 11.1 g of a light brown solid, yield: 93%;1 1H NMR (500 MHz, Chloroform-d) δ 8.66 (s, 1H), 7.84 (s, 1H), 7.31 (t, J = 3.0 Hz, 1H), 6.58 - 6.57 (m, 1H), 4.08 (s, 3H); ESI-MS: m / z = 227.0 [M+H] + 。

[0058] Step 3: 4-Bromo-7-methoxy-1-(p-toluenesulfonyl)pyrrolo[2,3-c]pyridine (Id) At 0 °C, a solution of compound 1-31 (11.0 g, 0.048 mol) in anhydrous tetrahydrofuran (100 mL) was added dropwise via a constant pressure dropping funnel to a system of 60% sodium hydride (6.2 g, 0.154 mmol) in anhydrous tetrahydrofuran (100 mL). The mixture was stirred at room temperature for 1 h. It was cooled to 0 °C again, and a solution of p-toluenesulfonyl chloride (12.2 g, 0.064 mol) in anhydrous tetrahydrofuran (100 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. It was transferred to an ice bath, and saturated NH 4 Cl aqueous solution (200 mL) was added to quench the reaction. Ethyl acetate (200 mL × 3) was added for extraction. The organic layer was washed with saturated brine (200 mL), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 16.4 g of a light brown solid compound, yield: 89%; 1 1H NMR (500 MHz, Chloroform-d) δ 7.98 (d, J = 4.0 Hz, 1H), 7.91 (s, 1H), 7.79 - 7.76 (m, 2H), 7.31 - 7.28 (m, 2H), 6.70 (d, J = 4.0 Hz, 1H), 3.90 (s, 3H), 2.41 (s, 3H); ESI-MS: m / z = 381.0 [M+H] + 。

[0059] Step 4: 4-Bromo-1-(p-toluenesulfonyl)-6H-pyrrolo[2,3-c]pyridin-7-one (Ie) Compound 1-32 (16.4 g, 0.043 mol) was dissolved in ethanol (30 mL), and hydrobromic acid (40% aqueous solution, 175 mL) was added. The temperature was raised to 90 °C and the reaction was carried out for 2 h. TLC monitored the complete reaction of the raw materials. The system was cooled to 0 °C, filtered by suction, washed with water, and dried under reduced pressure to obtain 14.0 g of a white solid, yield 89%; 11H NMR (500 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.04 (d, J = 3.5 Hz, 1H), 7.97 - 7.93 (m, 2H), 7.43 - 7.39 (m, 2H), 7.36 (s, 1H), 6.60 (d, J = 3.5 Hz, 1H), 2.38 (s, 3H); ESI-MS: m / z = 367.0 [M+H] + 。

[0060] Step 5: 4-Bromo-7-methoxy-1-(p-toluenesulfonyl)pyrrolo[2,3-c]pyridine (If-1) At 0 °C, a solution of compound 1-31 (700 mg, 1.91 mmol) in anhydrous DMF (5 mL) was added dropwise to a system of 60% sodium hydride (95 mg, 2.38 mmol) in anhydrous DMF (5 mL). The mixture was stirred at room temperature for 15 min. Then it was cooled to 0 °C again, and iodomethane (237 μL, 3.81 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. It was transferred to an ice bath, quenched with water (10 mL), and extracted with ethyl acetate (10 mL × 3). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 771 mg of a light brown solid compound, yield: 85%; 1 1H NMR (500 MHz, Chloroform-d) δ 8.03 - 7.98 (m, 2H), 7.93 (d, J = 3.5 Hz, 1H), 7.32 - 7.28 (m, 2H), 7.17 (s, 1H), 6.50 (d, J = 3.5 Hz, 1H), 3.50 (s, 3H), 2.40 (s, 3H); ESI-MS: m / z = 381.0 [M+H] + 。

[0061] 4-Bromo-7-methoxy-1-(p-toluenesulfonyl)pyrrolo[2,3-c]pyridine (If-2) The synthesis method was the same as that of If-1, except that iodomethane was replaced with iodoethane (305 μL, 3.81 mmol), and 818 mg of a white solid was obtained, yield: 87%; 1 1H NMR (500 MHz, Chloroform-d) δ 7.94 - 7.87 (m, 2H), 7.73 (d, J = 3.5 Hz, 1H), 7.71 (s, 1H), 7.46 - 7.40 (m, 2H), 6.79 (d, J = 3.5 Hz, 1H), 3.00 (q, J = 8.0 Hz, 2H), 2.42 (s, 3H), 1.26 (t, J = 8.0 Hz, 3H); ESI-MS: m / z = 395.0 [M+H] + 。

[0062] Step 6: 4-(3,4-Dimethylphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Ig-1) Dissolve compound If-1 (152 mg, 0.4 mmol) and 3,4-dimethylphenylboronic acid (156 mg, 0.8 mmol) in 1,4-dioxane (2 mL), add 2 M aqueous potassium phosphate solution (600 μL, 1.2 mmol) and dichlorobis(tert-butyl)-(4-dimethylaminophenyl)phosphine palladium(II) (14 mg, 0.02 mmol), and heat to 80 °C for reaction overnight. After monitoring the reaction of the raw materials to completion by TLC, cool to room temperature, filter with suction and wash with water. Concentrate the filtrate under reduced pressure, add water (5 mL), extract with ethyl acetate (5 mL×3), combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 127 mg of a yellow oil. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 407 [M+H] + 。

[0063] 4-(2,3-Dimethylphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Ig-2) The synthesis method is the same as that of Ig-1. Replace 3,4-dimethylphenylboronic acid with 2,3-dimethylphenylboronic acid (156 mg, 0.8 mmol) to obtain 125 mg of a yellow oil. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 407 [M+H] + 。

[0064] 4-(3,5-Dimethoxyphenyl)-6-ethyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Ig-3) The synthesis method is the same as that of Ig-1. Replace 3,4-dimethylphenylboronic acid with 3,5-dimethoxyphenylboronic acid (145 mg, 0.8 mmol) to obtain 120 mg of a yellow oil. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 439 [M+H] + 。

[0065] 4-(2-Trifluoromethylphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Ig-4) The synthesis method is the same as that of Ig-1. Replace 3,4-dimethylphenylboronic acid with 2-(trifluoromethyl)phenylboronic acid (114 mg, 0.8 mmol) to obtain 129 mg of a yellow oil. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 447 [M+H] + 。

[0066] 4-(3-(Trifluoromethyl)phenyl)-6-methyl-1-(tosyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Ig-5) The synthesis method is the same as that of Ig-1. Replace 3,4-dimethylphenylboronic acid with 3-(trifluoromethyl)phenylboronic acid (152 mg, 0.8 mmol) to obtain 131 mg of a yellow oil. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 447 [M+H] + 。

[0067] 4-(4-(Trifluoromethyl)phenyl)-6-methyl-1-(tosyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Ig-6) The synthesis method is the same as that of Ig-1. Replace 3,4-dimethylphenylboronic acid with 4-(trifluoromethyl)phenylboronic acid (152 mg, 0.8 mmol) to obtain 133 mg of a yellow oil. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 447 [M+H] + 。

[0068] 4-(4-Fluorophenyl)-6-methyl-1-(tosyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Ig-7) The synthesis method is the same as that of Ig-1. Replace 3,4-dimethylphenylboronic acid with 4-fluorophenylboronic acid (112 mg, 0.8 mmol) to obtain 107 mg of a yellow oil. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 397 [M+H] + 。

[0069] 4-(4-Chlorophenyl)-6-methyl-1-(tosyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Ig-8) The synthesis method is the same as that of Ig-1. Replace 3,4-dimethylphenylboronic acid with 4-chlorophenylboronic acid (125 mg, 0.8 mmol) to obtain 114 mg of a yellow oil. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 413 [M+H] + 。

[0070] 4-(4-Methoxyphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Ig-9) The synthesis method is the same as that of Ig-1. Replace 3,4-dimethylphenylboronic acid with 4-methoxyphenylboronic acid (121 mg, 0.8 mmol) to obtain 119 mg of a yellow oil. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 409 [M+H] + .

[0071] 4-(3,5-Dimethylphenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one 4 (Ig-10) The synthesis method is the same as that of Ig-1. Replace 3,4-dimethylphenylboronic acid with 3,5-dimethylphenylboronic acid (156 mg, 0.8 mmol) to obtain 117 mg of a yellow oil. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 407 [M+H] + .

[0072] 4-(3-Chloro-4-fluorophenyl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Ig-11) The synthesis method is the same as that of Ig-1. Replace 3,4-dimethylphenylboronic acid with 3-chloro-4-fluorophenylboronic acid (140 mg, 0.8 mmol) to obtain 122 mg of a yellow oil. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 431 [M+H] + .

[0073] 4-(Benzo[d][1,3]dioxol-5-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Ig-12) The synthesis method is the same as that of Ig-1. Replace 3,4-dimethylphenylboronic acid with benzo[d][1,3]dioxol-5-boronic acid (135 mg, 0.8 mmol) to obtain 110 mg of a yellow oil. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 423 [M+H] + .

[0074] 4-(2,3-Dihydrobenzo[b][1,4]dioxan-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Ig-13) The synthesis method is the same as that of Ig-1. Replace 3,4-dimethylphenylboronic acid with benzo-1,4-dioxane-6-boronic acid (144 mg, 0.8 mmol) to obtain 119 mg of a yellow oil. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 437 [M+H] + 。

[0075] 4-(3,4-Dimethylphenyl)-6-ethyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Ig-14) The synthesis method is the same as that of Ig-1. Replace compound If-1 with If-2 (157 mg, 0.4 mmol) to obtain 111 mg of a yellow oil. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 421 [M+H] + 。

[0076] 4-(4-Fluorophenyl)-6-ethyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Ig-15) The synthesis method is the same as that of Ig-15. Replace 3,4-dimethylphenylboronic acid with 4-chlorophenylboronic acid (125 mg, 0.8 mmol) to obtain 117 mg of a yellow oil. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 411.1 [M+H] + 。

[0077] 4-(4-Methoxyphenyl)-6-ethyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (Ig-16) The synthesis method is the same as that of Ig-15. Replace 3,4-dimethylphenylboronic acid with 4-chlorophenylboronic acid (125 mg, 0.8 mmol) to obtain 121 mg of a yellow oil. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 423.1 [M+H] + 。

[0078] Step 7: 4-(3,4-Dimethylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IA-1) Dissolve compound Ig-1 in methanol (2 mL), add potassium hydroxide (112 mg, 2 mmol), and heat to 50 °C for 1 h. Cool to room temperature, concentrate under reduced pressure, add water (5 mL) to the system, extract with ethyl acetate (5 mL × 3), wash the organic layer with saturated brine (5 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by column chromatography to obtain 57 mg of a white solid. The two-step yield is 56%;1 H NMR (500 MHz, DMSO-d 6 ) δ 12.13 (s, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.34 (t, J = 3.0 Hz, 1H), 7.31 - 7.29 (m, 2H), 7.21 (d, J = 8.0 Hz, 1H), 6.42 - 6.40 (m, 1H), 3.58 (s, 3H), 2.28 (s, 3H), 2.26 (s, 3H); 13 C NMR (125 MHz, DMSO-d 6 ) δ 154.51, 136.94, 135.14, 135.09, 130.26, 129.06, 128.83, 127.78, 127.40, 125.14, 123.83, 115.28, 102.68, 35.98, 20.01, 19.54; ESI-MS: m / z = 253.1 [M + H] + 。

[0079] 4-(2,3-Dimethylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IA-2) The synthesis method is the same as that of IA-1. Replace compound Ig-1 with Ig-2 to obtain 49 mg of white solid. Two-step yield: 49%; 1 H NMR (500 MHz, DMSO-d6) δ 12.06 (s, 1H), 7.25 (t, J = 3.0 Hz, 1H), 7.19 (d, J = 7.0 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 7.0 Hz, 1H), 7.07 (s, 1H), 5.89 (dd, J = 3.0, 2.0 Hz, 1H), 3.55 (s, 3H), 2.30 (s, 3H), 2.07 (s, 3H); 13 C NMR (125 MHz, DMSO) δ 154.60, 137.24, 136.99, 135.34, 130.79, 129.35, 128.71, 128.40, 127.26, 125.72, 123.19, 115.81, 102.93, 35.94, 20.75, 17.32; ESI-MS: m / z = 275.1 [M + H] + 。

[0080] 4-(3,5-Dimethoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IA-3) The synthesis method is the same as that of IA-1. Replace compound Ig-1 with Ig-3 to obtain 44 mg of white solid. The two-step yield is 39%; 1 H NMR(500MHz,DMSO-d6)δ12.11(s,1H),7.34(t,J=3.0Hz,1H),7.32(s,1H),7.15-7.10(m,2H),7.04(d,J=8.5Hz,1H),6.48-6.45(m,1H),3.83(s,3H),3.80(s,3H),3.58(s,3H). 13 C NMR(125MHz,DMSO-d6)δ154.48,149.35,148.33,130.35,129.11,127.70,127.41,123.82,119.84,115.23,112.61,111.63,102.69,56.06,55.96,35.96,27.17;ESI-MS:m / z=285.1[M+H] + 。

[0081] 4-(2-Trifluoromethylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IA-4) The synthesis method is the same as that of IA-1. Replace compound Ig-1 with Ig-4 to obtain 51 mg of white solid. The two-step yield is 44%; 1 H NMR(500MHz,DMSO-d6)δ12.13(s,1H),7.86(d,J=8.0Hz,1H),7.73(t,J=8.0Hz,1H),7.63(t,J=8.0Hz,1H),7.50(d,J=8.0Hz,1H),7.26(t,J=2.5Hz,1H),7.12(s,1H),5.86-5.85(m,1H),3.54(s,3H); 13 C NMR(125MHz,DMSO-d6)δ154.66,136.02,133.49,132.71,130.97,129.76(q,J=220.0Hz),128.87,128.79(q,J=28.5Hz),128.72,127.39,126.72(q,J=5.0Hz),123.08,112.66,103.16,102.34,93.56,36.02;ESI-MS:m / z=293.1[M+H] + 。

[0082] 4-(3-Trifluoromethylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IA-5) The synthesis method is the same as that of IA-1. Replace compound Ig-1 with Ig-5 to obtain 60 mg of a white solid. The two-step yield is 51%; 1 H NMR (500 MHz, DMSO-d6) δ 12.22 (s, 1H), 7.95 - 7.91 (m, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.75 - 7.68 (m, 2H), 7.55 (s, 1H), 7.39 (t, J = 3.0 Hz, 1H), 6.43 - 6.42 (m, 1H), 3.60 (s, 3H); 13 C NMR (125 MHz, DMSO-d6) δ 154.58, 138.75, 130.01 (q, J = 31.5 Hz), 129.87 (q, J = 220.0 Hz), 127.97, 127.85, 125.81, 123.86 (q, J = 4.0 Hz), 123.81, 123.72 (q, J = 4.0 Hz), 123.64, 113.51, 102.17, 36.03; ESI-MS: m / z = 293.1 [M + H] + 。

[0083] 4-(4-Trifluoromethylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IA-6) The synthesis method is the same as that of IA-1. Replace compound Ig-1 with Ig-6 to obtain 55 mg of a white solid. The two-step yield is 47%; 1 H NMR (500 MHz, DMSO-d6) δ 12.22 (s, 1H), 7.86 - 7.79 (m, 4H), 7.54 (s, 1H), 7.39 (t, J = 3.0 Hz, 1H), 6.50 - 6.49 (m, 1H), 3.60 (s, 3H); 13 C NMR (125 MHz, DMSO-d6) δ 154.59, 141.88, 128.71 (q, J = 220.0 Hz), 128.30, 128.22, 127.83, 127.44 (q, J = 31.5 Hz), 126.10 (q, J = 4.0 Hz), 125.97 (q, J = 4.0 Hz), 123.83, 113.60, 102.43, 99.99, 36.10; ESI-MS: m / z = 293.1 [M + H] + 。

[0084] 4-(4-Fluorophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IA-7) The synthesis method was the same as that of IA-1. Compound Ig-1 was replaced with Ig-7 to obtain 49 mg of a white solid. The two-step yield was 51%; 1 1H NMR (500 MHz, DMSO-d6) δ 12.17 (s, 1H), 7.66 - 7.59 (m, 2H), 7.37 (s, 1H), 7.36 (t, J = 2.5 Hz, 1H), 7.33 - 7.26 (m, 2H), 6.41 - 6.40 (m, 1H), 3.58 (s, 3H). 13 13C NMR (125 MHz, DMSO-d6) δ 161.68 (d, J = 242.0 Hz), 154.53, 134.04, 134.01, 129.59 (d, J = 7.9 Hz), 128.84, 128.37, 127.58, 123.79, 116.03 (d, J = 21.1 Hz), 114.17, 102.44, 35.99; ESI-MS: m / z = 243.1 [M+H] + 。

[0085] 4-(4-Chlorophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IA-8) The synthesis method was the same as that of IA-1. Compound Ig-1 was replaced with Ig-8 to obtain 38 mg of a white solid. The two-step yield was 37%; 1 1H NMR (500 MHz, DMSO-d6) δ 12.19 (s, 1H), 7.64 - 7.60 (m, 2H), 7.53 - 7.49 (m, 2H), 7.42 (s, 1H), 7.37 (t, J = 3.0 Hz, 1H), 6.44 - 6.43 (m, 1H), 3.59 (s, 3H). 13 13C NMR (125 MHz, DMSO-d6) δ 154.54, 136.52, 131.72, 129.39, 129.20, 128.68, 128.56, 127.66, 123.81, 113.87, 102.44, 36.03; ESI-MS: m / z = 259.1 [M+H] + 。

[0086] 4-(4-Methoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IA-9) The synthesis method was the same as that of IA-1. Compound Ig-1 was replaced with Ig-9 to obtain 36 mg of a white solid. The two-step yield was 35%;1 1H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 7.53 - 7.49 (m, 2H), 7.34 (t, J = 3.0 Hz, 1H), 7.28 (s, 1H), 7.05 - 7.01 (m, 2H), 6.41 - 6.40 (m, 1H), 3.80 (s, 3H), 3.58 (s, 3H). 13 13C NMR (125 MHz, DMSO-d6) δ 158.72, 154.48, 129.97, 129.12, 128.87, 127.56, 127.39, 123.83, 114.98, 114.66, 102.58, 55.60, 35.95; ESI-MS: m / z = 255.1 [M + H] + 。

[0087] 4-(3-Chloro-4-fluorophenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IA-10) The synthesis method is the same as that of IA-1. Replace compound Ig-1 with Ig-12 to obtain 47 mg of white solid. Two-step yield: 43%; 1 1H NMR (500 MHz, DMSO-d6) δ 12.21 (s, 1H), 7.75 (dd, J = 7.0, 2.5 Hz, 1H), 7.62 - 7.59 (m, 1H), 7.52 - 7.48 (m, 1H), 7.47 (s, 1H), 7.37 (t, J = 3.0 Hz, 1H), 6.43 - 6.42 (m, 1H), 3.58 (s, 3H). 13 13C NMR (125 MHz, DMSO-d6) δ 157.60, 155.64, 154.53, 135.54, 129.11, 128.42, 128.27, 127.76, 123.74, 120.19, 117.54, 112.82, 102.26, 36.02; ESI-MS: m / z = 277.1 [M + H] + 。

[0088] 4-(3,5-Dimethoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IA-11) The synthesis method is the same as that of IA-1. Replace compound Ig-1 with Ig-11 to obtain 45 mg of white solid. Two-step yield: 45%; 11H NMR (500 MHz, DMSO-d6) δ 12.11 (s, 1H), 7.34 (t, J = 3.0 Hz, 1H), 7.32 (s, 1H), 7.15 - 7.10 (m, 2H), 7.04 (d, J = 8.5 Hz, 1H), 6.48 - 6.45 (m, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 3.58 (s, 3H). 13 13C NMR (125 MHz, DMSO-d6) δ 154.48, 149.35, 148.33, 130.35, 129.11, 127.70, 127.41, 123.82, 119.84, 115.23, 112.61, 111.63, 102.69, 56.06, 55.96, 35.96, 27.17; ESI-MS: m / z = 285.1 [M+H] + 。

[0089] 4-(Benzo[d][1,3]dioxol-5-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IA-12) The synthesis method is the same as that of IA-1. Replace compound Ig-1 with Ig-13 to obtain 47 mg of white solid. The two-step yield is 44%; 1 1H NMR (500 MHz, DMSO-d6) δ 12.11 (s, 1H), 7.33 (t, J = 3.0 Hz, 1H), 7.30 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 7.06 (dd, J = 8.0, 2.0 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.40 - 6.39 (m, 1H), 6.06 (s, 2H), 3.56 (s, 3H). 13 13C NMR (125 MHz, DMSO-d6) δ 154.48, 148.10, 146.65, 131.65, 128.99, 127.94, 127.43, 123.77, 121.12, 115.02, 109.01, 108.20, 102.56, 101.48, 35.96; ESI-MS: m / z = 269.1 [M+H] + 。

[0090] 4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IA-13) The synthesis method is the same as that of IA-1. Replace compound Ig-1 with Ig-14 to obtain 35 mg of white solid. The two-step yield is 31%; 11H NMR (500 MHz, DMSO-d6) δ 12.09 (s, 1H), 7.32 (t, J = 3.0 Hz, 1H), 7.28 (s, 1H), 7.05 - 7.03 (m, 2H), 6.94 - 6.92 (m, 1H), 6.39 - 6.38 (m, 1H), 4.28 (s, 4H), 3.56 (s, 3H). 13 13C NMR (125 MHz, DMSO-d6) δ 154.46, 143.96, 142.91, 130.89, 129.91, 128.95, 127.79, 127.42, 123.78, 120.68, 117.76, 116.15, 114.71, 102.50, 99.99, 64.61, 35.96; ESI-MS: m / z = 283.1 [M + H] + 。

[0091] 4-(3,4-Dimethylphenyl)-6-ethyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IA-14) The synthesis method is the same as that of IA-1. Replace compound Ig-1 with Ig-15 to obtain 48 mg of white solid. The two-step yield: 45%; 1 1H NMR (500 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.33 (t, J = 3.0 Hz, 1H), 7.31 (dd, J = 7.5, 2.0 Hz, 1H), 7.29 (s, 1H), 7.21 (d, J = 7.5 Hz, 1H), 6.42 - 6.41 (m, 1H), 4.06 (q, J = 7.0 Hz, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 1.28 (t, J = 7.0 Hz, 3H); 13 13C NMR (125 MHz, DMSO-d6) δ 153.84, 136.93, 135.15, 135.11, 130.24, 128.94, 128.84, 127.40, 126.50, 125.17, 123.92, 115.65, 102.63, 42.90, 19.97, 19.52, 15.63; ESI-MS: m / z = 267.1 [M + H] + 。

[0092] 4-(4-Fluorophenyl)-6-ethyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IA-15) The synthesis method is the same as that of IA-1. Replace compound Ig-1 with Ig-16 to obtain 40 mg of a white solid. The two-step yield is 39%; ESI-MS: m / z = 257.1 [M+H] + 。

[0093] 4-(4-Methoxyphenyl)-6-ethyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IA-16) The synthesis method is the same as that of IA-1. Replace compound Ig-1 with Ig-17 to obtain 45 mg of a white solid. The two-step yield is 42%; ESI-MS: m / z = 269.1 [M+H] + 。

[0094] Step 8: 4-(3,4-Dimethylphenyl)-1,6-dimethyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IB-1) At 0 °C, a solution of compound IA-1 (50 mg, 0.2 mmol) in anhydrous DMF (1 mL) was added dropwise to a system of 60% sodium hydride (20 mg, 0.3 mmol) in anhydrous DMF (1 mL). The mixture was stirred at room temperature for 15 min. Then it was cooled to 0 °C again, and iodomethane (25 μL, 0.4 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. Water (2 mL) was slowly added under an ice bath to quench the reaction, and the mixture was extracted with ethyl acetate (2 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 38 mg of a white solid. The yield was 71%; 1 HNMR (500 MHz, DMSO-d6) δ 7.32 - 7.31 (m, 2H), 7.27 - 7.25 (m, 1H), 7.26 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.34 (d, J = 3.0 Hz, 1H), 4.11 (s, 3H), 3.53 (s, 3H), 2.27 (s, 3H), 2.25 (s, 3H); 13 CNMR (125 MHz, DMSO-d6) δ 155.16, 136.91, 135.18, 134.84, 132.45, 130.21, 130.13, 128.89, 128.16, 125.20, 122.53, 115.22, 101.27, 35.94, 35.90, 19.94, 19.49; ESI-MS: m / z = 267.1 [M+H] + 。

[0095] 4-(4-Fluorophenyl)-1,6-dimethyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IB-2) The synthesis method is the same as that of IB-1. Replace compound IA-1 with IA-7 (48 mg, 0.2 mmol) to obtain 31 mg of a white solid, yield: 61%; ESI-MS: m / z = 257.1 [M+H] + 。

[0096] 4-(4-Methoxyphenyl)-1,6-dimethyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IB-3) The synthesis method is the same as that of IB-1. Replace compound IA-1 with IA-9 (51 mg, 0.2 mmol) to obtain 34 mg of a white solid, yield: 63%; ESI-MS: m / z = 269.1 [M+H] + 。

[0097] 4-(3,4-Dimethylphenyl)-1-ethyl-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IB-4) The synthesis method is the same as that of IB-1. Replace methyl iodide with ethyl iodide (32 μL, 0.4 mmol) to obtain 38 mg of a white solid, yield: 67%; 1 H NMR (500 MHz, DMSO-d6) δ 7.39 (d, J = 3.0 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.28 - 7.26 (m, 1H), 7.27 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.36 (d, J = 3.0 Hz, 1H), 4.56 (q, J = 7.0 Hz, 2H), 3.55 (s, 3H), 2.27 (s, 3H), 2.25 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H); 13 C NMR (125 MHz, DMSO-d6) δ 154.71, 136.87, 135.15, 134.89, 130.96, 130.43, 130.20, 128.95, 128.10, 125.24, 121.73, 115.25, 101.45, 43.26, 35.98, 19.92, 19.47, 18.14; ESI-MS: m / z = 281.2 [M+H] + 。

[0098] 4-(4-Fluorophenyl)-1-ethyl-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IB-5) The synthesis method is the same as that of IB-4. Replace compound IA-1 with IA-7 (48 mg, 0.2 mmol) to obtain 33 mg of a white solid, two-step yield: 61%; ESI-MS: m / z = 271.1 [M+H]+ .

[0099] 4-(4-Methoxyphenyl)-1-ethyl-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IB-6) The synthesis method is the same as that of IB-4. Replace compound IA-1 with IA-9 (51 mg, 0.2 mmol) to obtain 32 mg of a white solid. The two-step yield is 59%; ESI-MS: m / z = 283.1 [M+H] + .

[0100] Step 9: 4-(3,4-Dimethylphenyl)-7-methoxy-1H-pyrrolo[2,3-c]pyridine (Ig-18) The synthesis method is the same as that of Ig-1. Replace compound If-1 with Ic (90 mg, 0.4 mmol) to obtain 59 mg of a brown solid. The yield is 59%; 1 1H NMR (500 MHz, DMSO-d6) δ 11.85 (s, 1H), 7.69 (s, 1H), 7.48 (t, J = 3.0 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.35 (dd, J = 8.0, 2.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.56 - 6.55 (m, 1H), 4.04 (s, 3H), 2.30 (s, 3H), 2.27 (s, 3H). ESI-MS: m / z = 253.1 [M+H] + .

[0101] Step 10: 4-(3,4-Dimethylphenyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IB-7) The synthesis method is the same as that of Ie. Replace compound Id with Ig-18 (55 mg, 0.22 mmol) to obtain 45 mg of a brown solid. The yield is 85%; 1 1H NMR (500 MHz, DMSO-d 6 ) δ 12.11 (s, 1H), 11.10 (d, J = 5.0 Hz, 1H), 7.34 (t, J = 3.0 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.27 (dd, J = 7.5, 2.0 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 5.0 Hz, 1H), 6.42 - 6.41 (m, 1H), 2.28 (s, 3H), 2.25 (s, 3H); 1313C NMR (125 MHz, DMSO-d6) δ 154.87, 136.94, 135.27, 135.04, 130.28, 129.87, 128.84, 127.21, 125.11, 124.04, 122.40, 115.51, 102.86, 19.97, 19.51; ESI-MS: m / z = 239.1 [M+H] + 。

[0102] Example 2: Synthesis of Series II Compounds

[0103] Step 1: 5-Bromo-1,4-dimethyl-3-nitropyridin-2(1H)-one (IIb) Dissolve 5-bromo-4-methyl-3-nitropyridin-2-ol (IIa, 1.17 g, 5.0 mmol) in DMF, and successively add potassium carbonate (1.04 g, 7.5 mmol) and potassium iodide (465 μL, 7.5 mmol). Stir at room temperature for 2 h. Pour the system into ice water, filter the precipitated brown solid by suction, wash the filter cake with water, and dry it under reduced pressure to obtain 1.07 g of brown solid. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 247.0 [M+H] + 。

[0104] Step 2: 3-Amino-5-bromo-1,4-dimethylpyridin-2(1H)-one (IIc) Dissolve compound IIb (1.07 g, 4.3 mmol), iron powder (1.22 g, 22 mmol), and ammonium chloride (465 mg, 8.6 mmol) in a mixed solvent (methanol:tetrahydrofuran:water = 21:21:7 mL), and reflux at heating for 2 h. Filter the system by suction while it is hot, wash the filter cake with methanol. After the filtrate is concentrated under reduced pressure and purified by column chromatography, 715 mg of yellow solid is obtained. The two-step yield is 66%; 1 1H NMR (500 MHz, DMSO-d6) δ 7.73 (s, 1H), 4.73 (s, 2H), 3.47 (s, 3H), 2.18 (s, 3H). ESI-MS: m / z = 217.0 [M+H] + 。

[0105] Step 3: 4-Bromo-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (IId) Compound IIc (690 mg, 3.2 mmol) and potassium acetate (374 mg, 3.8 mmol) were dissolved in toluene (15 mL), acetic anhydride (896 μL, 9.6 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. When the reaction of the starting materials was monitored by TLC to be complete, amyl nitrite (641 μL, 4.8 mmol) was added dropwise, and the mixture was heated to 80 °C and stirred for 24 h. After the reaction of the intermediate was monitored by TLC to be complete, the solvent was evaporated under reduced pressure. Water (20 mL) and ethyl acetate (20 mL × 3) were added to the system for extraction, and saturated brine (20 mL) was used for washing. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, a crude product was obtained. It was dissolved in methanol (20 mL), 2N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for 1 h. After the system was concentrated under reduced pressure, water (20 mL) and ethyl acetate (20 mL × 3) were added for extraction, and saturated brine (20 mL) was used for washing. After drying over anhydrous sodium sulfate, concentrating under reduced pressure and purification by column chromatography, 328 mg of a yellow solid was obtained, yield: 36%; 1 H NMR (500 MHz, DMSO-d6) δ 14.42 (s, 1H), 7.87 (s, 1H), 7.62 (s, 1H), 3.34 (s, 3H). ESI-MS: m / z = 228.0 [M + H] + 。

[0106] Step 4: 4-Bromo-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (IIe) At 0 °C, a solution of compound IId (320 mg, 1.1 mmol) in anhydrous DMF (3 mL) was added dropwise to a system of 60% sodium hydride (84 mg, 1.7 mmol) in anhydrous DMF (3 mL). The mixture was stirred at room temperature for 30 min. After cooling to 0 °C again, 2-(trimethylsilyl)ethoxymethyl chloride (298 μL, 1.3 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 h. It was transferred to an ice bath, water (5 mL) was slowly added to quench the reaction, and ethyl acetate (5 mL × 3) was added for extraction and washed with saturated brine. After drying over anhydrous sodium sulfate, concentrating under reduced pressure and purification by column chromatography, 274 mg of a white solid was obtained, yield: 69%; 1 H NMR (500 MHz, Chloroform-d) δ 7.92 (s, 1H), 7.71 (s, 1H), 5.98 (s, 2H), 3.76 (s, 3H), 3.33 (t, J = 8.5 Hz, 2H), 0.79 (t, J = 8.5 Hz, 2H), 0.06 (s, 9H). ESI-MS: m / z = 358.1 [M + H] + 。

[0107] Step 5: 4-(3,4-Dimethylphenyl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (IIf-1) N 2 Under protection, dissolve compound IIe (270 mg, 0.75 mmol) and 3,4-dimethylphenylboronic acid (123 mg, 0.83 mmol) in a mixed solvent (1,4-dioxane: water = 8 mL: 2 mL), add sodium carbonate (342 mg, 3.2 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (21 mg, 0.075 mmol) and tris(dibenzylideneacetone)dipalladium (21 mg, 0.023 mmol), and heat to 65 °C for reaction for 4.5 h. Cool to room temperature, filter with suction and wash with water. Concentrate the filtrate under reduced pressure, add water (10 mL) and ethyl acetate (10 mL × 3) for extraction, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure and purify by column chromatography to obtain 149 mg of a white solid, yield: 52%; 1 1H NMR (500 MHz, Chloroform-d) δ 7.82 (s, 1H), 7.62 (s, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 7.15 (s, 1H), 3.83 (s, 3H), 3.33 (t, J = 8.5 Hz, 2H), 2.34 (s, 3H), 2.32 (s, 3H), 0.79 (t, J = 8.5 Hz, 2H), 0.07 (s, 9H). ESI-MS: m / z = 384.2 [M+H] + 。

[0108] 4-(4-Fluorophenyl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (IIf-2) The synthesis method is the same as that of IIf-1. Replace 3,4-dimethylphenylboronic acid with 4-fluorophenylboronic acid (116 mg, 0.83 mmol) to obtain 183 mg of a white solid, yield: 49%; ESI-MS: m / z = 374.2 [M+H] + 。

[1091] 4-(4-Methoxyphenyl)-6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (IIf-3) The synthesis method was the same as that of IIf-1. Replace 3,4-dimethylphenylboronic acid with 4-methoxyphenylboronic acid (126 mg, 0.83 mmol) to obtain 181 mg of a white solid, yield: 47%; ESI-MS: m / z = 386.2 [M+H] + 。

[0120] Step 6: 4-(3,4-Dimethylphenyl)-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (II-1) To compound IIf-1 (140 mg, 0.36 mmol), add 5 mL of trifluoroacetic acid dropwise and stir at room temperature for 0.5 h. After monitoring the reaction of the raw materials to completion by TLC, evaporate the solvent. Add methanol (5 mL) and ammonia water (0.5 mL), stir at room temperature for 0.5 h, and a white solid precipitates. After evaporating the solvent from the system, add water (5 mL) and ethyl acetate (5 mL×3) for extraction, wash with saturated brine (5 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 28 mg of a white solid, yield: 30%; 1 1H NMR (500 MHz, DMSO-d6) δ 14.19 (s, 1H), 8.05 (s, 1H), 7.44 (s, 1H), 7.41 (s, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 3.60 (s, 3H), 2.30 (s, 3H), 2.26 (s, 3H); 13 13C NMR (125 MHz, DMSO-d6) δ 153.54, 137.27, 135.68, 134.02, 133.89, 131.88, 130.48, 128.70, 128.46, 124.81, 124.01, 113.45, 36.02, 19.98, 19.56; ESI-MS: m / z = 255.1 [M+H] + 。

[0121] 4-(4-Fluorophenyl)-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (II-2) The synthesis method was the same as that of II-1. Replace compound IIf-1 with IIf-2 (134 mg, 0.36 mmol) to obtain 109 mg of a white solid, yield: 45%; ESI-MS: m / z = 244.1 [M+H] + 。

[0122] 4-(4-Methoxyphenyl)-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (II-3) The synthesis method is the same as that of II-1, replacing compound IIf-1 with IIf-3 (139 mg, 0.36 mmol), to obtain 105 mg of a white solid, yield: 41%; ESI-MS: m / z = 256.1 [M+H] + 。

[0123] Example 3: Synthesis of Series III Compounds

[0124] Step 1: 7-Bromo-3,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one (IIIb) Dissolve 2,5-dibromopyridine-3,4-diamine (IIIa, 1.06 g, 3.97 mmol) in HCOOH (3 mL), and reflux at 100 °C for 6 h. Concentrate under reduced pressure, and the crude product is purified by column chromatography to obtain 594 mg of a gray solid, yield: 70%; ESI-MS: m / z = 214.0 [M+H] + 。

[0125] Step 2: 7-Bromo-3-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[4,5-c]pyridin-4-one (IIIc) Dissolve compound IIIb-1 (400 mg, 1.87 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (467 mg, 2.80 mmol) in DMF, add TEA (567 mg, 5.61 mmol), and heat to 80 °C for reaction for 3 h. Cool to room temperature, add water (20 mL) and ethyl acetate (20 mL × 3) for extraction, combine the organic layers, wash with water (20 mL) and saturated brine (20 mL), dry over anhydrous sodium sulfate and concentrate under reduced pressure to obtain 712 mg of a yellow liquid. The crude product is used in the next step without further purification; ESI-MS: m / z = 344.0 [M+H] + 。

[0126] Step 3: 7-Bromo-5-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazo[4,5-c]pyridin-4-one (IIId) At 0 °C, a solution of compound IIIc (643 mg, 1.87 mmol) in anhydrous DMF (3 mL) was added dropwise to a system of anhydrous THF (3 mL) containing 60% sodium hydride (149 mg, 2.24 mmol). The mixture was stirred at room temperature for 30 minutes. Then it was transferred to 0 °C, and iodomethane (795 mg, 5.60 mmol) was added dropwise. The reaction was carried out at room temperature for 1 h. The reaction was quenched by slowly adding water (10 mL), and the mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 660 mg of a brown liquid. The crude product was used in the next step without further purification; ESI-MS: m / z = 358.1 [M+H] + 。

[0127] Step 4: 7-(3,4-Dimethylphenyl)-5-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazo[4,5-c]pyridin-4-one (IIIe-1) N 2 Under N protection, compound IIId (200 mg, 0.56 mmol) and 3,4-dimethylphenylboronic acid (100 mg, 0.67 mmol) were dissolved in dioxane (10 mL) and water (2 mL). Cs 2 CO 3 (546 mg, 1.68 mmol) and Pd(dppf) 2 Cl 2 ·CH 2 Cl 2 (41 mg, 0.056 mmol) were added, and the mixture was heated to 90 °C for 2 h. After cooling to room temperature, water (10 mL) and ethyl acetate (10 mL × 3) were added for extraction. The combined organic layers were washed with water and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 88 mg of a white solid. The overall yield for three steps was 41%; ESI-MS: m / z = 384.2 [M+H] + 。

[0128] 7-(4-Fluorophenyl)-5-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazo[4,5-c]pyridin-4-one (IIIe-2) The synthesis method was the same as that of IIf-1, except that 3,4-dimethylphenylboronic acid was replaced with 4-fluorophenylboronic acid (94 mg, 0.67 mmol), to obtain 88 mg of a white solid. The overall yield for three steps was 42%; ESI-MS: m / z = 374.2 [M+H] + 。

[0129] 7-(4-Methoxyphenyl)-5-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)imidazo[4,5-c]pyridin-4-one (IIIe-3) The synthesis method is the same as that of IIf-1. Replace 3,4-dimethylphenylboronic acid with 4-methoxyphenylboronic acid (101 mg, 0.67 mmol) to obtain 86 mg of a white solid. The three-step yield is 40%; ESI-MS: m / z = 386.2 [M+H] + 。

[0130] Step 5: 7-(3,4-Dimethylphenyl)-5-methyl-3H-imidazo[4,5-c]pyridin-4-one (III-1) The synthesis method is the same as that of II-1. Replace compound IIf-1 with IIIe-1 (85 mg, 0.22 mmol) to obtain 25 mg of a white solid. The yield is 45%; ESI-MS: m / z = 255.1 [M+H] + 。

[0131] 7-(4-Fluorophenyl)-5-methyl-3H-imidazo[4,5-c]pyridin-4-one (III-2) The synthesis method is the same as that of II-1. Replace compound IIf-1 with IIIe-1 (82 mg, 0.22 mmol) to obtain 26 mg of a white solid. The yield is 49%; ESI-MS: m / z = 244.1 [M+H] + 。

[0132] 7-(4-Methoxyphenyl)-5-methyl-3H-imidazo[4,5-c]pyridin-4-one (III-3) The synthesis method is the same as that of II-1. Replace compound IIf-1 with IIIe-1 (85 mg, 0.22 mmol) to obtain 22 mg of a white solid. The yield is 39%; ESI-MS: m / z = 256.1 [M+H] + 。

[0133] Example 4: Synthesis of Series IV Compounds

[0134] Step 1: (7-Methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridin-4-yl)boronic acid (IVa) N 2Under protection, dissolve compound Id (1.91 g, 5 mol) in 1,4-dioxane (50 mL), add bis(pinacolato)diboron (1.65 g, 6.5 mol), potassium acetate (1.23 g, 12.5 mol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (366 mg, 0.5 mol), heat to 90 °C and react for 4 h. After cooling to room temperature, rotary evaporate to dryness, add water (30 mL) and ethyl acetate (30 mL × 3) for extraction, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure and purify by column chromatography to obtain 1.40 g of a colorless oily liquid, yield: 81%; 1 H NMR (500 MHz, DMSO-d6) δ 8.06 - 8.04 (m, 2H), 8.01 (s, 1H), 7.44 - 7.42 (m, 2H), 7.15 (d, J = 3.5 Hz, 1H), 6.97 (d, J = 3.5 Hz, 1H), 4.82 (s, 2H), 3.95 (s, 3H), 2.42 (s, 3H). ESI-MS: m / z = 347.1 [M + H] + 。

[0135] Step 2: 7-Methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridin-4-ol (IVb) At 0 °C, dropwise add an aqueous solution of potassium peroxymonosulfate (1.35 g, 3.9 mol) in water (10 mL) to a system of compound IVa (1.35 g, 3.9 mol) in acetone (10 mL), stir at room temperature for 30 min. Add ethyl acetate (15 mL × 3) for extraction, wash with saturated brine (15 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure and purify by column chromatography to obtain 584 mg of a colorless oily liquid, yield: 47%; 1 H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.93 (d, J = 3.5 Hz, 1H), 7.83 - 7.79 (m, 2H), 7.45 - 7.41 (m, 2H), 7.36 (s, 1H), 6.86 (d, J = 3.5 Hz, 1H), 3.71 (s, 3H), 2.37 (s, 3H); ESI-MS: m / z = 319.1 [M + H] + 。

[0136] Step 3: 4-(4-Chloro-3-fluorophenoxy)-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine (IVc-1) N 2Under protection, compound IVb (160 mg, 5 mmol), 2,4-difluorochlorobenzene (659 μL, 6 mmol), potassium phosphate (210 mg, 10 mmol), picolinic acid (45 μL, 0.1 mmol) and copper(I) iodide (5 mg, 0.25 mmol) were dissolved in anhydrous DMSO (10 mL), and the temperature was raised to 90 °C and reacted overnight. After cooling to room temperature, water (15 mL) and ethyl acetate (15 mL × 3) were added for extraction. The organic layers were combined, washed with water (15 mL × 2) and saturated brine (15 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography to obtain 735 mg of a white solid, yield: 33%; 1 H NMR (500 MHz, Chloroform-d) δ 7.84 - 7.81 (m, 2H), 7.68 (s, 1H), 7.46 - 7.45 (m, 2H), 7.37 - 7.36 (m, 1H), 7.31 - 7.30 (m, 1H), 7.17 (d, J = 3.0 Hz, 1H), 6.53 (d, J = 3.0 Hz, 1H), 3.90 (s, 3H), 2.45 (s, 3H). ESI-MS: m / z = 447.1 [M+H] + 。

[0137] 4-(3-Chloro-5-fluorophenoxy)-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine (IVc-2) The synthesis method was the same as that of IVc-1, replacing 2,4-difluorochlorobenzene with 3,5-difluorochlorobenzene (671 μL, 6 mmol), to obtain 690 mg of a white solid, yield: 31%; 1 H NMR (500 MHz, Chloroform-d) δ 7.81 - 7.79 (m, 2H), 7.51 (t, J = 2.0 Hz, 1H), 7.42 - 7.40 (m, 1H), 7.40 - 7.37 (m, 1H), 7.36 - 7.33 (m, 2H), 7.32 (s, 1H), 7.21 (d, J = 3.0 Hz, 1H), 6.69 (d, J = 3.0 Hz, 1H), 3.90 (s, 3H), 2.47 (s, 3H). ESI-MS: m / z = 447.1 [M+H] + 。

[0138] Step 4: 4-(4-Chloro-3-fluorophenoxy)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IVd-1) The synthesis method was the same as that of Ie. Compound Id was replaced with IVc-1 (730 mg, 1.64 mmol) to obtain 628 mg of a white solid. The crude product was used in the next reaction without further purification; ESI-MS: m / z = 433.0 [M+H] + 。

[0139] 4-(3-Chloro-5-fluorophenoxy)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IVd-2) The synthesis method was the same as that of Ie. Compound Id was replaced with IVc-2 (680 mg, 1.52 mmol) to obtain 415 mg of a white solid. Yield: 63%; 1 H NMR (500 MHz, DMSO-d6) δ 11.21 (d, J = 6.0 Hz, 1H), 7.91 - 7.89 (m, 2H), 7.86 - 7.84 (m, 2H), 7.83 - 7.80 (m, 1H), 7.67 (d, J = 3.0 Hz, 1H), 7.51 - 7.48 (m, 2H), 6.78 (d, J = 6.0 Hz, 1H), 6.34 (d, J = 3.0 Hz, 1H), 2.43 (s, 3H). ESI-MS: m / z = 433.0 [M+H] + 。

[0140] Step 5: 4-(4-Chloro-3-fluorophenoxy)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IVe-1) The synthesis method was the same as that of If-1. Compound Ie was replaced with IVd-1 (628 mg, 1.45 mmol) to obtain 250 mg of a white solid. Two-step yield: 34%; 1 H NMR (500 MHz, Chloroform-d) δ 7.83 - 7.82 (m, 2H), 7.45 - 7.43 (m, 1H), 7.36 - 7.34 (m, 2H), 7.30 - 7.27 (m, 1H), 7.22 - 7.19 (m, 1H), 7.04 (d, J = 3.0 Hz, 1H), 6.88 (s, 1H), 6.20 (d, J = 3.0 Hz, 1H), 3.48 (s, 3H), 2.47 (s, 3H). ESI-MS: m / z = 447.1 [M+H] + 。

[0141] 4-(3-Chloro-5-fluorophenoxy)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IVe-2) The synthesis method is the same as that of If-1. Replace compound Ie with IVd-2 (405 mg, 0.94 mmol) to obtain 255 mg of a white solid, yield: 61%; 1 H NMR (500 MHz, Chloroform-d) δ 7.84 - 7.81 (m, 2H), 7.51 - 7.50 (m, 1H), 7.43 - 7.38 (m, 2H), 7.38 - 7.34 (m, 2H), 7.08 (d, J = 3.0 Hz, 1H), 6.92 (s, 1H), 6.27 (d, J = 3.0 Hz, 1H), 3.50 (s, 3H), 2.48 (s, 3H). ESI-MS: m / z = 447.1 [M + H] + 。

[0142] Step 6: 4-(4-Chloro-3-fluorophenoxy)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IV-1) The synthesis method is the same as that of IA-1. Replace compound Ig-1 with IVe-1 (240 mg, 0.54 mmol) to obtain 20 mg of a white solid, yield: 13%; 1 H NMR (500 MHz, DMSO-d6) δ 8.91 (s, 1H), 7.64 - 7.62 (m, 1H), 7.55 - 7.52 (m, 1H), 7.38 - 7.37 (m, 1H), 7.10 (d, J = 3.0 Hz, 1H), 6.67 (s, 1H), 6.59 (d, J = 3.0 Hz, 1H), 2.65 (s, 3H); 13 C NMR (125 MHz, DMSO-d6) δ 165.76, 161.57, 157.90 (d, J = 245.0 Hz), 136.99, 132.45, 127.44, 126.09, 126.02, 124.62, 120.20 (d, J = 20.0 Hz), 117.75 (d, J = 22.5 Hz), 116.92, 111.39, 26.41; HRMS (ESI): Calcd for C 14 H 10 ClFN 2 O 2 [M + H] + 293.0488, found 293.0481.

[0143] 4-(3-Chloro-5-fluorophenoxy)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (IV-2) The synthesis method was the same as that of IA-1. Compound Ig-1 was replaced with IVe-2 (250 mg, 0.56 mmol) to obtain 16 mg of a white solid. Yield: 10%; 1 H NMR (500 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.51 - 7.50 (m, 1H), 7.49 - 7.42 (m, 2H), 6.90 (d, J = 3.0 Hz, 1H), 6.79 (s, 1H), 6.77 (d, J = 3.0 Hz, 1H), 3.85 (s, 3H); HRMS (ESI): Calcd for C 14 H 10 ClFN 2 O 2 [M + H] + 293.0488, found 293.0488.

[0144] Example 5: VEGF Elisa experiment of the compounds (heterocyclic-fused pyrazol-7-one) of the present invention In this example, PT2385 was used as a positive control, and the VEGF protein inhibitory activity of some of the above compounds against the human renal clear cell carcinoma cell line 786-O was evaluated by VEGF Elisa Assay. Other compounds of the present invention have similar beneficial effects to the compounds listed below, but this should not be construed as the compounds of the present invention having only the following beneficial effects.

[0145] 786-O cells in the logarithmic growth phase were seeded in a 96-well plate (Fisher ScientifIAc), 7500 cells per well (180 μL / well). After culturing for 8 hours, 20 μL of the compound stock solution (dissolved in DMSO, concentration 10 mmol / L) was added to each well to make the final concentration 10 μM, and 3 parallel replicates were set. Approximately 24 hours later, the culture medium was removed by aspiration and 180 μL of growth medium was provided to each well. 20 μL of freshly prepared 10x test compound stock solution was added to each well. The cells were cultured for 24 hours under hypoxic conditions (1% oxygen + 5% carbon dioxide + 94% nitrogen), and then the cell culture medium was removed. The VEGF concentration was determined using an ELISA kit purchased from R&D Systems. The reaction was terminated by adding 50 μL of Celltiter Glo reagent to each well, and the microplate was gently shaken to ensure full termination of the reaction. A Celltiter-Glo luminescent cell viability assay (Promega) was performed on the plate seeded with cells, and then the absorbance of each well was immediately measured at a wavelength of 450 nm using a microplate reader. The data was analyzed by GraphPadPrism using equations such as dose-response-inhibition (four-parameter) to calculate the EC 50 value, and the results are shown in Table 1.

[0146] Table 1 VEGF protein inhibitory activities of some heterocyclic-fused pyrazol-7-one compounds Compound <![CDATA[EC 50 (μM)]]> Compound <![CDATA[EC 50 (μM)]]> IA-1 +++ IA-2 ++ IA-5 ++ IA-8 +++ IA-9 ++++ IA-11 ++++ IA-12 ++++ IA-13 ++++ IB-3 ++ II-1 ++ II-3 +++ III-2 ++ III-3 +++ PT2385 ++++

Note

[0147] From the experimental results in Table 1, it can be seen that most compounds exhibit strong inhibitory activities against VEGF protein expression and have good application prospects.

[0148] Example 6: Luciferase experiment of the compounds (heterocyclic-fused pyrazol-7-one) of the present invention The luciferase LUC gene was stably transfected into 786-O cells (purchased from ATCC) using Lipofectamine 3000 transfection reagent (purchased from Invitrogen) to construct HIF-2α reporter gene cells (786-O-HIF2α-Luc cells). The experiment was carried out when the 786-O-HIF2α-Luc cells were in the logarithmic growth phase. The medium (RPMI MEDIUM 1640, purchased from Invitrogen) was discarded, and the cells were rinsed three times with PBS; trypsin (TrypLE, purchased from Invitrogen) was added to digest the cells, and the digestion was terminated by washing the cells with the medium, 10% fetal bovine serum, and 1% penicillin and streptomycin. The cells were collected by centrifugation, rinsed twice with PBS to remove phenol red in the medium, and resuspended to an appropriate concentration. The cell density and viability were detected, and the cells could be used for the experiment only when the cell viability was above 90%. The gradient concentration compounds were transferred into 384-well plates using an Echo550 (non-contact acoustic pipetting system, purchased from Labcyte), 25 nL / well; the cells were seeded into 384-well plates, 4500 cells / well, with 25 μL of medium, so that the final concentrations of the compounds were 10000, 3333, 1111, 370, 123, 41.1, 13.7, 4.6, 1.5, 0.5 nM. The cells were placed in an environment of 37 °C and 5% CO 2 and cultured for 18 - 20 h; the Steady-GloTM luciferase assay system (purchased from Promega) was added to the 384-well plates, 25 μL / well; the luminescence value was detected using Envision. The inhibition rate % was calculated according to the RLU (Record Luminescence) signal value of each well, and then the IC 50 of the corresponding compounds was calculated by fitting with Graphpad 8.0. The results are shown in Table 2.

[0149] Table 2 HIF-2α protein inhibitory activities of related compounds Compound <![CDATA[IC 50 (μM)]]> Compound <![CDATA[IC 50 (μM)]]> IA-1 ++ IA-2 ++ IA-8 ++ IA-9 ++++ IA-11 ++++ IA-12 ++++ IA-13 ++++ II-3 ++ III-3 +++ PT2385 ++++

Note

[0150] As can be seen from the experimental results in Table 2, most of the compounds showed strong inhibitory activity against HIF-2α expression and had the potential for further development.

[0151] In the present invention, the raw materials and equipment used, unless otherwise specified, are common raw materials and equipment in the art; the methods used in the present invention, unless otherwise specified, are conventional methods in the art.

[0152] The above are only the preferred embodiments of the present invention and do not impose any limitations on the present invention. Any simple modifications, changes, and equivalent transformations made to the above embodiments based on the technical essence of the present invention still fall within the protection scope of the technical solution of the present invention.

Claims

1. A heterocyclic pyridin-7-one compound, including its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates, having the following general formula a structure: In formula a: L is selected from a chemical bond, -O-, or -NR0-; wherein R0 is selected from hydrogen, deuterium or C 1-6 alkyl; X1 and X2 are independently selected from N or CH; R1, R2, R3, R4, and R5 are independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Haloalkyl; and R1, R2, R3, R4, and R5 are not hydrogen at the same time; Alternatively, R2 and R3 together with the C atom to which they are attached form a 4-6 membered heterocyclic group; the 4-6 membered heterocyclic group is optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, hydroxyl, cyano, nitro or amino; The 4-6 membered heterocyclic group is not piperidine or piperazinone; R6 is selected from C 1-6 Alkyl or C 1-6 Haloalkyl; R7 is selected from hydrogen, deuterium, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

2. The compound according to claim 1, characterized in that The L is selected from a chemical bond or -O-.

3. The compound according to claim 1, characterized in that The R6 and R7 are independently selected from hydrogen, methyl or ethyl.

4. The compound according to claim 1, characterized in that The R1, R2, R3, R4, and R5 are independently selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl, or difluoromethoxy; and R1, R2, R3, R4, and R5 are not hydrogen at the same time.

5. The compound according to claim 1, characterized in that The R2 and R3 and the C atom to which they are connected together form a 4-6 membered heterocyclic group; the 4-6 membered heterocyclic group is not piperidine or piperazinone.

6. The compound according to claim 5, characterized in that The 4-6 membered heterocyclic group is selected from tetrahydrofuran or dioxane.

7. The compound according to claim 1, characterized in that The heterocyclic pyridin-7-one compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate is selected from the following compounds:

8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a compound according to any one of claims 1 to 7 or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

9. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating HIF-2α-mediated diseases.

10. The use according to claim 9, characterized in that The HIF-2α-mediated disease is selected from tumors, inflammatory and autoimmune diseases, and iron overload diseases; The tumor is selected from solid tumors with VHL gene deletion, including renal cancer, liver cancer, colorectal cancer, lung cancer, gastric cancer, breast cancer, ovarian cancer, cervical cancer, skin cancer, glioma, lymphoma or neuroblastoma; The inflammatory and autoimmune diseases are selected from asthma, nephritis, pneumonia, enteritis, dermatitis, arthritis, vasculitis, pancreatitis or traumatic infection; The iron overload disease is selected from hemochromatosis, polycythemia, Partau syndrome or beta-thalassemia.

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