Coumarin compound and use thereof

Abstract

The present invention relates to the technical field of chemicals and pharmaceuticals. Disclosed are a coumarin compound and a use thereof. The present invention provides a coumarin compound represented by formula I, and some specific coumarin compounds. The compound and composition can effectively inhibit MEK or Ras-MAPK signaling pathways, can be used for preparing MEK or Ras-MAPK signaling pathway inhibitors, and provide a new way for treating MEK or Ras-MAPK signaling pathway-related diseases.

Description

Coumarin compounds and their uses Technical Field

[0001] This invention belongs to the field of chemical medicine, specifically relating to a class of coumarin compounds and their uses. Background Technology

[0002] MEK is a member of the mitogen-activated protein kinase family, participating in the Ras / Raf / MEK / ERK pathway (the classic MAPK signaling pathway) and mediating physiological processes such as cell proliferation, survival, differentiation, migration, and apoptosis. MEK inhibitors (PD0325901, CH4987655, trametinib, cobimetinib, selumetinib, etc.) have shown clinical efficacy against cancers with RAF mutations (such as BRAF-mutant malignant melanoma) as monotherapy or in combination with RAF inhibitors. Although several MEK inhibitors have received regulatory approval, these inhibitors have not yet met expectations for clinical efficacy. In many tumors carrying RAS or RAF mutations, anomalous activation often occurs with monotherapy of BRAF or MEK inhibitors. Therefore, existing MEK inhibitors generally suffer from insufficient activity and incomplete inhibition. Summary of the Invention

[0003] The purpose of this invention is to provide a class of coumarin compounds for the treatment of MEK and / or Ras-MAPK signaling-mediated diseases, thereby improving the aforementioned technical problems.

[0004] In a first aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, polymorph, or solvate thereof.

[0005] Among them, R1 is selected from C 1-4 Alkyl, C 3-6 Cycloalkyl groups and 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, and heterocyclic alkyl groups are optionally surrounded by 1-3 heteroatoms selected from deuterium, halogen, OH, NH2, CN, C. 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl and C 2-4 Group substitution of the alkynyl group;

[0006] X is selected from N and CH;

[0007] R2 is selected from H and halogens;

[0008] R 3a Selected from hydrogen, halogens, C 1-4 Alkyl, amino, cyano, C 2-4 The alkyl and nitro groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen and cyano groups;

[0009] R 3b Selected from hydrogen and halogens;

[0010] R 3c C 1-4 alkyl;

[0011] Ring A is selected from pyridine and pyridazine;

[0012] R4 is selected from deuterium and C. 1-4 Alkyl groups, OH, NH2, CN, and halogens;

[0013] n is an integer between 0 and 3;

[0014] The condition is that when ring A is pyridine, R 3a C 1-4 Alkyl group, wherein the alkyl group is substituted with 1-3 deuterium atoms.

[0015] In some specific embodiments of the present invention, in Formula I above, R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, tetrahydropyrrole, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and piperazine, and is optionally substituted by 1-3 groups selected from deuterium, F, Cl, Br, I, OH, NH2, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, vinyl, propenyl, allyl, ethynyl, propynyl, and propargyl.

[0016] X is selected from N and CH;

[0017] R2 is selected from F and Cl;

[0018] R 3a Selected from hydrogen, F, Cl, Br, I, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and CD3;

[0019] R 3b Selected from hydrogen, F, Cl, and Br;

[0020] R 3c It can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl;

[0021] Ring A is selected from pyridine and pyridazine;

[0022] R4 is selected from deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, OH, NH2, CN, F, Cl, Br, and I;

[0023] n is 0 or 1;

[0024] The condition is that when ring A is pyridine, R3a It is CD3.

[0025] In some specific embodiments of the present invention, the fragments in Formula I for

[0026] In some specific embodiments of the present invention, the fragments in Formula I for

[0027] This invention also provides specific compounds selected from:

[0028] In a second aspect, the present invention provides a pharmaceutical composition in which the active ingredient comprises a compound of formula I or a pharmaceutically acceptable salt, polymorph, or solvate thereof, supplemented by a pharmaceutically acceptable carrier.

[0029] The present invention also provides a method for preparing the pharmaceutical composition of the present invention, the method comprising mixing a compound of formula I or a pharmaceutically acceptable salt, polymorph, or solvate thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

[0030] In this invention, the pharmaceutically acceptable carrier is selected from any pharmaceutically acceptable excipient, and examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

[0031] Pharmaceutical compositions can be administered in any form, as long as they achieve the purpose of preventing, alleviating, preventing, or curing symptoms in human or animal patients. For example, they can be formulated into various suitable dosage forms depending on the route of administration.

[0032] In other embodiments, the administration of the compounds or pharmaceutical compositions of the present invention may be combined with other treatment methods. These other treatment methods may be selected from, but are not limited to, radiotherapy, chemotherapy, immunotherapy, or combinations thereof.

[0033] Thirdly, the present invention also provides a pharmaceutical formulation in which the active ingredient comprises the compound of the present invention, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, or a pharmaceutical composition of the present invention. In some embodiments, the formulation is in the form of a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form.

[0034] Fourthly, the present invention provides an article of manufacture, for example, provided in the form of a kit, comprising: (a) a first container; (b) a pharmaceutical composition contained in the first container, wherein the composition comprises any compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof; (c) optionally present instructions for use; and (d) a second container.

[0035] Fifthly, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts, polymorphs or solvates thereof, or pharmaceutical compositions of the present invention in the preparation of a medicament.

[0036] In some specific embodiments, the drug is used to treat and / or prevent MEK or Ras-MAPK-mediated diseases.

[0037] In a sixth aspect, the present invention provides a method of treating a disease, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, polymorph, or solvate thereof, or a pharmaceutical composition of the present invention to a subject in need.

[0038] In some specific embodiments, in the above-described uses of the prepared drug and methods for treating diseases, the disease is a MEK or Ras-MAPK mediated disease.

[0039] In some specific embodiments, in the above-described uses of the prepared drug and methods for treating diseases, the aforementioned MEK or Ras-MAPK-mediated diseases are tumors.

[0040] In some specific embodiments, in the above-described uses of the prepared medicine and methods for treating diseases, the tumor is breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumors, cholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell carcinoma, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.

[0041] The beneficial effects of this invention are:

[0042] This invention provides a class of coumarin compounds, as shown in Formula I, and some specific coumarin compounds. These compounds and compositions can effectively inhibit the MEK or Ras-MAPK signaling pathway and can be used to prepare MEK or Ras-MAPK signaling pathway inhibitors, providing a new approach for treating MEK or Ras-MAPK signaling pathway-related diseases.

[0043] Terminology definition:

[0044] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0045] In this invention, the terms "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted as indicating that the composition comprises "one or more" pharmaceutically acceptable excipients.

[0046] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein (in the form of “about a to b”, or equivalently, “approximately a to b”, or equivalently, “about ab”) should be understood to represent each numerical value and range encompassed within a wider range.

[0047] For example, the expression "C" 1-4 "This should be understood as encompassing any subrange and each point value, such as C." 2-4 C 3-4 C 1-2 C 1-3 C 1-4 And so on, as well as C1, C2, C3, C4, etc. For example, the expression "6-10 yuan" should be understood as covering any subrange and each point value within it, such as 6-7 yuan, 6-8 yuan, 6-7 yuan, etc., and 6, 7, 8, 9, 10 yuan, etc.

[0048] In this invention, unless otherwise stated, halogen refers to fluorine, chlorine, bromine or iodine.

[0049] In this invention, unless otherwise stated, "alkyl" includes straight-chain or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include 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 1-4 C in "alkyl" 1-4 It refers to a group that contains 1, 2, 3 or 4 carbon atoms arranged in a straight chain or branched chain.

[0050] In this invention, unless otherwise stated, "cycloalkyl," "carbocyclic," or "cycloalkylene" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings, or spirocyclic groups, such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, bicyclic [5.2.0]nonyl, decahydronaphthyl, etc. For example, "C 3-12 "Cycloalkyl" refers to a cycloalkyl group having 3 to 12 cyclic carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12). The cycloalkyl or cycloalkylene groups in this invention may optionally be substituted with one or more substituents described in this invention.

[0051] In this invention, unless otherwise stated, "heterocyclic alkyl," "heterocyclic alkylene," or "heterocycle" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic, e.g., fused, bridged, or spirocyclic) non-aromatic group whose ring atoms consist of a carbon atom and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur. Heterocyclic alkyl groups can be linked to the remainder of the molecule via any one ring atom, provided valence requirements are met. For example, "3-8 membered heterocyclic alkyl" refers to a heterocyclic alkyl group having 3 to 8 ring atoms. Common heterocyclic alkyl groups include (but are not limited to) ethylene oxide, oxocyclobutane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl, sulfolane, etc. The heterocyclic alkyl, heterocyclic alkylene, or heterocycle in this invention may optionally be substituted with one or more substituents (e.g., oxo groups) described in this invention.

[0052] In this invention, unless otherwise stated, "alkynyl" refers to a straight-chain or branched aliphatic hydrocarbon group having at least one C≡C triple bond. For example, "C 2-4 "Alynyl" refers to an alkynyl group having 2 to 4 carbon atoms. Common alkynyl groups include (but are not limited to) ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. The alkynyl group in this invention may optionally be substituted by one or more substituents described in this invention.

[0053] "Optional" or "optionally" means that the event or situation described below may, but does not necessarily, occur. For example, "the alkyl group may be substituted with a halogen" means that the alkyl group may, but does not necessarily, be substituted with a halogen, including cases where the alkyl group is substituted with a halogen and cases where the alkyl group is not substituted with a halogen.

[0054] In this invention, unless otherwise stated, "substituted" or "substituted" means that one or more hydrogen atoms in a group are substituted by the same or different substituents. Typical substituents include, but are not limited to, halogens (F, Cl, Br, or I), hydroxyl groups, amino groups, and C. 1-8 Alkyl, C 3-7 Cycloalkyl, -OR', -SR', =O, =S, -C(O)R', -C(S)R', =NR', -C(O)OR', -C(S)OR', -NR'R”, -C(O)NR'R”, cyano, nitro, -S(O)2R', -OS(O)2OR', -OS(O)2R', -OP(O)(OR')(OR”); wherein R' and R” are independently selected from -H, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups. In some embodiments, the substituents are independently selected from groups comprising -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH3, -SC2H5, formaldehyde, -C(O)CH3, cyano, nitro, -CF3, -OCF3, amino, dimethylamino, methylthio, sulfonyl, and acetyl groups.

[0055] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium). 2 H), tritium ( 3 H); carbon isotopes (e.g., H); 13 C and 14 C); isotopes of chlorine (e.g. 37 Cl); isotopes of iodine (e.g., Cl); 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g., ... 34 S).

[0056] In this invention, "polymorph" refers to different solid crystalline phases resulting from the presence of two or more different molecular arrangements in the solid state of certain compounds of this invention. Some compounds of this invention may exist in more than one crystal form, and this invention aims to include various crystal forms and mixtures thereof. Typically, crystallization produces solvates of the compounds of this invention. The term "solvate" as used in this invention refers to an aggregate comprising one or more molecules of the compound of this invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Therefore, the compounds of this invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., and corresponding solvated forms. The compounds of this invention can form true solvates, but in some cases, they may also remain only as indeterminate water or a mixture of water and a portion of indeterminate solvent. The compounds of this invention can react in a solvent or precipitate or crystallize from a solvent. The solvates of the compounds of this invention are also included within the scope of this invention. This invention also covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0057] In this invention, pharmaceutically acceptable salts include their acid addition salts and base addition salts. Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed by bases that form pharmaceutically acceptable salts. A review of suitable salts can be found, for example, in “Remington’s Pharmaceutical Sciences,” Mack Publishing Company, Easton, Pa., (2005); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use,” Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of this invention are known to those skilled in the art. “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecanoate, glycolate, gluconate, lactate, sebate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylic acid, and naphthalenedisulfonate. These salts can be prepared by methods known in this patent. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Preferred inorganic salts are ammonium salts, sodium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in this patent.

[0058] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0059] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form nitrogen oxides because nitrogen requires available lone pairs of electrons to be oxidized. Those skilled in the art will identify nitrogen-containing heterocycles capable of forming nitrogen oxides. They will also recognize that tertiary amines can form nitrogen oxides. Synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane.

[0060] In this application, "pharmaceutical composition" refers to a formulation of the compounds of the present invention with a medium generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, enhance the absorption of the active ingredient, and thereby exert its bioactivity.

[0061] In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is permitted by the relevant government regulatory authority or is acceptable for human or livestock use.

[0062] As used herein, the terms “drug combination,” “drug co-administration,” “combination therapy,” “administration of other treatments,” and “administration of other therapeutic agents” refer to pharmaceutical treatments achieved by mixing or combining more than one active ingredient, including fixed and non-fixed combinations of active ingredients. The term “fixed combination” refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or dosage form. The term “non-fixed combination” refers to the simultaneous, combined, or sequential administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity at variable intervals. These also apply to cocktail therapies, such as the administration of three or more active ingredients.

[0063] In this invention, unless otherwise stated, "treatment" means reversing, alleviating, or inhibiting the progression of a disease or condition or one or more symptoms of such a disease or condition, or preventing such a disease or condition or one or more symptoms of such a disease or condition.

[0064] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention. Attached Figure Description

[0065] Figure 1 shows the immunoblotting results of the compound in Example 5.

[0066] Figure 2 shows the effects of compounds 5 and 43 on Lewis lung cancer LLC (Kras) in mice. G12C and Nras Q61H (Image showing the in vivo drug efficacy results of a xenograft mouse model)

[0067] Figure 3 shows the effects of compounds from Examples 5 and 43 on human pancreatic cancer AsPC-1 (KRAS). G12D (Image showing the in vivo efficacy results of a mouse xenograft model)

[0068] Figure 4 shows the effect of the compound in Example 18 on human colon cancer HCT116 (KRAS). G13D (Image showing the in vivo drug efficacy results of a xenograft mouse model)

[0069] Figure 5 shows the effect of compound 18 on Lewis lung cancer LLC (Kras) in mice. G12C and Nras Q61H (Image showing the in vivo drug efficacy results of a xenograft mouse model)

[0070] Figure 6 shows the effect of the compound in Example 18 on human acute myeloid leukemia cells OCI-AML-3 (NRAS). Q61L (Image showing the in vivo drug efficacy results of a xenograft mouse model)

[0071] Figure 7 shows the effects of compounds 5 and 20 on human acute myeloid leukemia cells OCI-AML-3 (NRAS). Q61L (Image showing the in vivo drug efficacy results of a xenograft mouse model) Detailed Implementation

[0072] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in the art or in accordance with the product manual.

[0073] Table 1. Abbreviations and their meanings in this invention.

[0074] The structure of the compound described in this invention was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). Chemical shifts were expressed as 10⁻⁶. -6 (ppm) is given as the unit.

[0075] MS measurements were performed using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, signal: 6110).

[0076] HPLC determinations were performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfirc C18, 150X 4.6mm, 5µm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18, 150X 4.5mm, 5µm column).

[0077] The silica gel plates used for thin-layer chromatography are Qingdao Ocean GF254 silica gel plates. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15mm-0.2mm, while the silica gel plates used for thin-layer chromatography separation and purification of products have a diameter of 0.4mm-0.5mm.

[0078] Column chromatography typically uses Qingdao Marine 100-200 or 200-300 mesh silica gel as a carrier.

[0079] Unless otherwise specified in the following examples, all reactions are carried out under an argon or nitrogen atmosphere. An argon or nitrogen atmosphere refers to a reaction flask connected to an approximately 1L argon or nitrogen balloon. A hydrogen atmosphere refers to a reaction flask connected to an approximately 1L hydrogen balloon. Hydrogenation reactions are typically performed under vacuum, followed by hydrogen filling, and repeated three times.

[0080] Intermediate 1: Isopropylaminosulfonyl chloride

[0081] Isopropylamine (5.00 g, 84.59 mmol) was added to 20 mL of ultra-dry dichloromethane. After stirring for 10 min under nitrogen at -70 °C, sulfonyl chloride (10.38 g, 76.90 mmol) and DMAP (9.39 g, 76.90 mmol) were added. After reacting for 1 h, no purification was required, and the reaction solution was directly added to the next step.

[0082] Intermediate 2: Deuterated methylaminosulfonyl chloride

[0083] Add deuterated methylamine (2.80 g, 82.17 mmol) to 20 mL of ultra-dry acetonitrile, stir under nitrogen at 0 °C for 10 min, then add sulfonyl chloride (10.08 g, 74.70 mmol), react for 1 h, then transfer to 60 °C and continue reacting for 3 h. The reaction solution is evaporated to dryness and can be directly added to the next step without purification.

[0084] Intermediate 3: Cyclopropylaminosulfonyl chloride

[0085] Cyclopropylamine (5.00 g, 87.57 mmol) was added to 20 mL of ultra-dry dichloromethane. After stirring for 10 min under nitrogen at -70 °C, sulfonyl chloride (10.74 g, 79.61 mmol) and DMAP (9.73 g, 79.61 mmol) were added. After reacting for 1 h, no purification was required, and the reaction solution was directly added to the next step.

[0086] Intermediate 4: 2-Methoxyethylaminosulfonyl chloride

[0087] Add 2-methoxyethylamine (3.30 g, 43.93 mmol) to 20 mL of ultra-dry acetonitrile, stir under nitrogen at 0 °C for 10 min, then add sulfonyl chloride (5.63 g, 41.74 mmol), react for 1 h, then transfer to 60 °C and continue reacting for 3 h. The reaction solution is evaporated to dryness and can be directly added to the next step without purification.

[0088] Intermediate 5: Propyleneaminosulfonyl chloride

[0089] Add propargylamine (1.00 g, 18.15 mmol) to 20 mL of ultra-dry acetonitrile, stir under nitrogen at 0 °C for 10 min, then add sulfonyl chloride (4.90 g, 36.31 mmol), react for 1 h, then transfer to 60 °C and continue reacting for 3 h. The reaction solution is evaporated to dryness and can be directly added to the next step without purification.

[0090] Intermediate 6: Oxyhexacyclic butylaminosulfonyl chloride

[0091] Add 3-oxetane (1.00 g, 13.68 mmol) to 20 mL of ultra-dry dichloromethane, stir for 10 min under nitrogen at -70 °C, then add sulfonyl chloride (1.68 g, 12.44 mmol) and DMAP (1.52 g, 12.44 mmol). After reacting for 1 h, no purification is required, and the reaction solution is directly added to the next step.

[0092] Intermediate 7: Difluoroethylaminosulfonyl chloride

[0093] Add 2,2-difluoroethylamine (5.00 g, 61.68 mmol) to 20 mL of ultra-dry dichloromethane, stir for 10 min under nitrogen at -70 °C, then add sulfonyl chloride (7.91 g, 58.59 mmol) and DMAP (7.54 g, 61.68 mmol). After reacting for 1 h, no purification is required, and the reaction solution is directly added to the next step.

[0094] Intermediate 8: Trifluoroethylaminosulfonyl chloride

[0095] Add trifluoroethylamine (3.21 g, 32.31 mmol) to 20 mL of ultra-dry dichloromethane, stir for 10 min under nitrogen at -70 °C, then add sulfonyl chloride (3.92 g, 29.07 mmol) and DMAP (3.95 g, 32.31 mmol). After reacting for 1 h, no purification is required, and the reaction solution is directly added to the next step.

[0096] Example 1: 5-Fluoro-3-({3-fluoro-2-[(methylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyridazin-3-yl)oxy-4-methyl-2H-coumarin-2-one

[0097] Step 1: Synthesis of 2,3-difluoro-4-hydroxymethylpyridine

[0098] 2,3-Difluoropyridine-4-carboxylic acid (30.00 g, 188.56 mmol) and N,N'-carbonyldiimidazole (39.75 g, 245.13 mmol) were added to 300.00 mL of tetrahydrofuran. After stirring at room temperature for 3 h, an aqueous solution of sodium borohydride (14.27 g, 377.12 mmol) (30.00 mL) was added, and the reaction was continued at room temperature for 8 h. After the reaction was monitored by TLC until complete, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound in 65.3% yield.

[0099] Step 2: Synthesis of (2,3-difluoropyridin-4-yl)methanesulfonate

[0100] 2,3-Difluoro-4-hydroxymethylpyridine (17.87 g, 123.16 mmol) was dissolved in 200.00 mL of tetrahydrofuran and stirred at 0 °C for 10 min. After cooling, 2.2 M lithium tert-butoxide solution (83.97 mL, 184.73 mmol) was added, and the mixture was stirred for 1 h. Then, methanesulfonyl chloride (12.39 mL, 160.10 mmol) was added, and the mixture was stirred for another 3 h. After the reaction was confirmed to be complete by LC-MS, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was used for the next reaction without further purification.

[0101] Step 3: Synthesis of ethyl 2-((2,3-difluoropyridin-4-yl)methyl)-3-oxobutyrate

[0102] Ethyl acetoacetate (18.75 g, 144.08 mmol) was dissolved in 200.00 mL of tetrahydrofuran and stirred at 0 °C for 10 min. After cooling, 75.56 mL (166.24 mmol) of 2.2 M lithium tert-butoxide solution was added, and the reaction was carried out for 30 min. Then, (2,3-difluoropyridin-4-yl)methanesulfonate (24.74 g, 110.84 mmol) and sodium iodide (18.27 g, 121.91 mmol) were added, and the mixture was heated to 50 °C and reacted for another 2 h. After the reaction was completed by TLC, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound in 81.8% yield.

[0103] Step 4: Synthesis of 3-((2,3-difluoropyridin-4-yl)methyl)-5-fluoro-7-hydroxy-4-methyl-2H-coumarin-2-one

[0104] Ethyl 2-((2,3-difluoropyridin-4-yl)methyl)-3-oxobutyrate (3.00 g, 12.33 mmol) and 5-fluororesorcinol (2.37 g, 18.50 mmol) were dissolved in 30.00 mL of perchloric acid, and the mixture was heated to 50 °C and reacted for 2 h. After the reaction was complete as monitored by TLC, a large amount of water was added, and a large amount of solid precipitated. The solid was filtered, and the filter cake was dried to give the target compound in 90.2% yield.

[0105] Step 5: Synthesis of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-5-fluoro-7-hydroxy-4-methyl-2H-coumarin-2-one

[0106] 3-((2,3-difluoropyridin-4-yl)methyl)-5-fluoro-7-hydroxy-4-methyl-2H-coumarin-2-one (3.57 g, 11.11 mmol), triethylamine (7.72 mL, 55.56 mmol), and 2,4-dimethoxybenzylamine (6.50 g, 38.90 mmol) were added to 80.00 mL of N-methylpyrrolidone and reacted at 100 °C for 24 h. After the reaction was complete as monitored by LC-MS, a large amount of water was added, and the pH of the mixture was adjusted to neutral with 20% dilute hydrochloric acid. A large amount of solid precipitated, which was filtered. The filter cake was slurried with acetonitrile to obtain the target compound in 68.8% yield.

[0107] Step 6: Synthesis of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-5-fluoro-7-(pyridazin-3-yl)oxy-4-methyl-2H-coumarin-2-one

[0108] 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-5-fluoro-7-hydroxy-4-methyl-2H-coumarin-2-one (0.30 g, 0.64 mmol), 3-chloropyridazine (0.30 g, 2.63 mmol), cesium fluoride (0.15 g, 0.96 mmol), and potassium carbonate (0.18 g, 1.28 mmol) were added to 10.00 mL of anhydrous N,N-dimethylformamide and reacted at 100 °C for 16 h under sealed conditions. After the reaction was monitored by LC-MS until complete, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound in 43.3% yield.

[0109] Step 7: Synthesis of 3-((2-amino-3-fluoropyridin-4-yl)methyl)-5-fluoro-7-(pyridazin-3-yl)oxy-4-methyl-2H-coumarin-2-one

[0110] 1.00 mL of trifluoroacetic acid was added to a 10.00 mL solution of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-5-fluoro-7-(pyridazin-3-yl)oxy-4-methyl-2H-coumarin-2-one (156.26 mg, 0.28 mmol) in dichloromethane and reacted for 30 min. After the reaction was confirmed to be complete by TLC, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was filtered through diatomaceous earth, dried, and concentrated. The crude product was used for the next reaction without further purification.

[0111] Step 8: Synthesis of 5-fluoro-3-({3-fluoro-2-[(methylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyridazin-3-yl)oxy-4-methyl-2H-coumarin-2-one

[0112] 3-((2-amino-3-fluoropyridin-4-yl)methyl)-5-fluoro-7-(pyridazin-3-yl)oxy-4-methyl-2H-coumarin-2-one (100.70 mg, 0.24 mmol) was dissolved in anhydrous N,N-dimethylformamide (5.00 mL), and anhydrous pyridine (96.35 g, 1.22 mmol) and methylaminosulfonyl chloride (47.35 mg, 0.36 mmol) were added. The reaction was allowed to proceed at room temperature for 15 min. After the reaction was confirmed to be complete by TLC, a large amount of water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin-layer chromatography to obtain the target compound in 38.5% yield. LC-MS [M+H] + :m / z=500.1. 1 H NMR (400MHz, DMSO) δ10.32(s,1H),9.10(d,J=4.5Hz,1H),7.94(d,J=5.1Hz,1H),7.64–7.57 (m, 1H), 7.29 (d, J = 11.7Hz, 2H), 6.87 (d, J = 5.1Hz, 1H), 4.03 (s, 2H), 2.54 (d, J = 6.0Hz, 3H).

[0113] Example 2: 5-Fluoro-3-({3-fluoro-2-[(methanesulfonamide)amino]pyridin-4-yl}methyl)-7-[(6-fluoropyridazin-3-yl)oxy]-4-methyl-2H-coumarin-2-one

[0114] Step 1: Synthesis of 3-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-5-fluoro-7-((6-fluoropyridazine-3-yl)oxy)-4-methyl-2H-chromene-2-one

[0115] 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-5-fluoro-7-hydroxy-4-methyl-2H-coumarin-2-one (0.30 g, 0.64 mmol), 3,6-difluoropyridazine (0.30 g, 2.63 mmol), cesium fluoride (0.15 g, 0.96 mmol), and potassium carbonate (0.18 g, 1.28 mmol) were added to 10.00 mL of anhydrous N,N-dimethylformamide and reacted at 100 °C for 16 h under sealed conditions. After the reaction was monitored by LC-MS until complete, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound in 34.2% yield.

[0116] Step 2: Synthesis of 3-((2-amino-3-fluoropyridin-4-yl)methyl)-5-fluoro-7-((6-fluoropyridazin-3-yl)oxy)-4-methyl-2H-benzopyran-2-one

[0117] 1.00 mL of trifluoroacetic acid was added to a 10.00 mL solution of 3-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-5-fluoro-7-((6-fluoropyridazin-3-yl)oxy)-4-methyl-2H-chromene-2-one (156.26 mg, 0.28 mmol) in dichloromethane and reacted for 30 min. After the reaction was confirmed to be complete by TLC, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was filtered through diatomaceous earth, dried, and concentrated. The crude product was used for the next reaction without further purification.

[0118] Step 3: Synthesis of 5-fluoro-3-({3-fluoro-2-[(methylsulfonamide)amino]pyridin-4-yl}methyl)-7-[(6-fluoropyridazin-3-yl)oxy]-4-methyl-2H-coumarin-2-one

[0119] 3-((2-amino-3-fluoropyridin-4-yl)methyl)-5-fluoro-7-((6-fluoropyridazin-3-yl)oxy)-4-methyl-2H-benzopyran-2-one (100.70 mg, 0.24 mmol) was dissolved in anhydrous N,N-dimethylformamide (5.00 mL), and anhydrous pyridine (96.35 g, 1.22 mmol) and methylaminosulfonyl chloride (47.35 mg, 0.36 mmol) were added. The reaction was allowed to proceed at room temperature for 15 min. After the reaction was confirmed to be complete by TLC, a large amount of water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin-layer chromatography to obtain the target compound in 64.5% yield. LC-MS [M+H] + :m / z=508.1. 1 H NMR (400MHz, DMSO) δ10.34(s,1H),7.97–7.86(m,3H),7.39–7.24(m,2H),6.97(s,1H),6.86(s,1H),4.03(s,2H),2.56–2.51(m,6H).

[0120] Example 3: 6-Methyl-3-({3-fluoro-2-[(methylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyridazin-3-yl)oxy-4-methyl-2H-coumarin-2-one

[0121] Step 1: Synthesis of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-methyl-7-(pyridazin-3-yl)oxy-4-methyl-2H-coumarin-2-one

[0122] 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-5-fluoro-7-hydroxy-4-methyl-2H-coumarin-2-one (0.30 g, 0.64 mmol), 3-chloropyridazine (0.30 g, 2.63 mmol), cesium fluoride (0.15 g, 0.96 mmol), and potassium carbonate (0.18 g, 1.28 mmol) were added to 10.00 mL of anhydrous N,N-dimethylformamide and reacted at 100 °C for 16 h under sealed conditions. After the reaction was monitored by LC-MS until complete, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound in 43.3% yield.

[0123] Step 2: Synthesis of 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-methyl-7-(pyridazin-3-yl)oxy-4-methyl-2H-coumarin-2-one

[0124] 1.00 mL of trifluoroacetic acid was added to a 10.00 mL solution of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-methyl-7-(pyridazin-2-yl)oxy-4-methyl-2H-coumarin-2-one (156.26 mg, 0.28 mmol) in dichloromethane and reacted for 30 min. After the reaction was confirmed to be complete by TLC, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was filtered through diatomaceous earth, dried, and concentrated. The crude product was used for the next reaction without further purification.

[0125] Step 3: Synthesis of 6-methyl-3-({3-fluoro-2-[(methylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyridazin-3-yl)oxy-4-methyl-2H-coumarin-2-one

[0126] 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-methyl-7-(pyridazin-3-yl)oxy-4-methyl-2H-coumarin-2-one (100.70 mg, 0.24 mmol) was dissolved in anhydrous N,N-dimethylformamide (5.00 mL), and anhydrous pyridine (96.35 g, 1.22 mmol) and methylaminosulfonyl chloride (47.35 mg, 0.36 mmol) were added. The reaction was allowed to proceed at room temperature for 15 min. After the reaction was confirmed to be complete by TLC, a large amount of water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin-layer chromatography to obtain the target compound in 23.8% yield. LC-MS [M+H] + :m / z=486.2. 1 HNMR (400MHz, DMSO) δ10.33(s,1H),9.04(dd,J=4.5,1.2Hz,1H),7.93(d,J=4.5Hz,1H),7.88(s,1H),7.83(dd,J=8.9,4.5 Hz,1H),7.59(dd,J=8.9,1.2Hz,1H),7.32(s,1H),6.97(s,1H),6.82(s,1H),4.03(s,2H),2.53–2.51(m,6H),2.20(s,3H).

[0127] Example 4: 6-Methyl-3-({3-fluoro-2-[(methanesulfonamide)amino]pyridin-4-yl}methyl)-7-[(6-fluoropyridazin-2-yl)oxy]-4-methyl-2H-coumarin-2-one

[0128] This compound was prepared according to the method described in Example 2, with 5-fluororesorcinol replaced by 4-methylresorcinol in step four, yielding 55.8%. LC-MS [M+H] + :m / z=504.2. 1 H NMR (400MHz, DMSO) δ10.33(s,1H),7.92(d,J=4.8Hz,1H),7.86(d,J=8.5Hz,3H),7. 34(s,1H),7.10–6.76(m,2H),4.02(s,2H),2.51(s,3H),2.49(s,3H),2.22(s,3H).

[0129] Example 5: 6-(methyl-d3)-3-({3-fluoro-2-[(methanesulfonamide)amino]pyridin-4-yl}methyl)-7-[(3-fluoropyridin-2-yl)oxy]-4-methyl-2H-coumarin-2-one

[0130] Step 1: Synthesis of 2,4-dimethoxy-1-(methyl-d3)benzene

[0131] 2,4-Dimethoxybromobenzene (10.0 g, 46.1 mmol) was dissolved in THF (100 mL), and n-butyllithium (20.3 mL, 50.7 mmol) was added dropwise at -78 °C, with stirring at -78 °C for 0.5 h. CD3I (3.5 mL, 55.3 mmol) was then added, and the mixture was stirred at -78 °C for 2 h. The reaction was monitored by TLC until complete. The reaction solution was quenched in saturated ammonium chloride (30 mL), extracted with EA (3 x 30 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was used for the next reaction without further purification.

[0132] Step 2: Synthesis of 4-(methyl-d3)benzene-1,3-diol

[0133] 2,4-Dimethoxy-1-(methyl-d3)benzene (7.0 g, 45.1 mmol) was dissolved in DCM (100 mL), and boron tribromide (13.1 mL, 135.3 mmol) was added. The mixture was stirred at 0 °C for 3 h. After the reaction was detected by LC-MS, the solution was slowly poured into a saturated sodium bicarbonate solution to quench the reaction. After removing some of the product and impurities by EA extraction, the pH was adjusted to acidic, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained did not require purification and was used for the next reaction.

[0134] Step 3: Synthesis of 3-((2,3-difluoropyridin-4-yl)methyl)-7-hydroxy-4-methyl-6-(methyl-d3)-2H-coumarin-2-one

[0135] 4-(methyl-d3)benzene-1,3-diol (1.0 g, 7.9 mmol) and ethyl 2-((2,3-difluoropyridin-4-yl)methyl)-3-oxobutyrate (2.0 g, 7.9 mmol) were dissolved in perchloric acid (10.0 mL) and stirred at 25 °C for 2 h. After the reaction was complete, ice water was added to detect the reaction by LC-MS. The solid precipitated, was filtered, and the filter cake was dried to give the target compound in 99.3% yield.

[0136] Step 4: Synthesis of 3-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-7-hydroxy-4-methyl-6-(methyl-d3)-2H-coumarin-2-one

[0137] 3-((2,3-difluoropyridin-4-yl)methyl)-7-hydroxy-4-methyl-6-(methyl-d3)-2H-coumarin-2-one (2.5 g, 7.8 mmol) and 2,4-dimethoxybenzylamine (3.9 g, 23.4 mmol) were dissolved in NMP (50.0 mL), and TEA (5.4 mL, 39.0 mmol) was added. The mixture was stirred at 110 °C for 48 h. LC-MS showed that the reaction was complete, and dilute hydrochloric acid was added to adjust the pH to approximately 8. The precipitated solid was filtered, the filter cake was collected, and dried to give the target compound in 82.2% yield.

[0138] Step 5: Synthesis of 3-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-7-((3-fluoropyridin-2-yl)oxy)-4-methyl-6-(methyl-d3)-2H-coumarin-2-one

[0139] 3-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-7-hydroxy-4-methyl-6-(methyl-d3)-2H-coumarin-2-one (2.0 g, 4.3 mmol) and 2,3-difluoropyridine (0.98 g, 8.6 mmol) were dissolved in DMF (50.0 mL), and CsF (0.97 g, 6.4 mmol) and K2CO3 (1.8 g, 12.8 mmol) were added. The mixture was stirred at 140 °C for 15 h. After the reaction was monitored by LC-MS, the reaction solution was quenched in saturated ammonium chloride (30 mL), extracted with EA (3 x 40 mL), dried over sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (PE / EA = 1 / 1) to obtain the target compound in 98.6% yield.

[0140] Step 6: Synthesize 3-((2-amino-3-fluoropyridin-4-yl)methyl)-7-((3-fluoropyridin-2-yl)oxy)-4-methyl-6-(methyl-d3)-2H-coumarin-2-one.

[0141] 3-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-7-((3-fluoropyridin-2-yl)oxy)-4-methyl-6-(methyl-d3)-2H-coumarin-2-one (3.5 g, 6.221 mmol) was dissolved in DCM (5 mL), and TFA (5 mL, 65.296 mmol) was added. The mixture was stirred at 25 °C for 1 h. After the reaction was completed, the solution was concentrated under reduced pressure by LC-MS monitoring. A saturated sodium bicarbonate solution was added, and the solid precipitated. The solid was collected by filtration and dried to give the target compound in 97.4% yield.

[0142] Step 7: Synthesis of 6-(methyl-d3)-3-({3-fluoro-2-[(methanesulfonamide)amino]pyridin-4-yl}methyl)-7-[(3-fluoropyridin-2-yl)oxy]-4-methyl-2H-coumarin-2-one

[0143] 3-((2-amino-3-fluoropyridin-4-yl)methyl)-7-((3-fluoropyridin-2-yl)oxy)-4-methyl-6-(methyl-d3)-2H-coumarin-2-one (0.22 g, 0.533 mmol) was dissolved in ACN (5 mL) and DMA (5 mL), and pyridine (0.09 mL, 1.1 mmol) was added. Methylsulfonamide chloride (0.10 g, 0.800 mmol) was added at 0 °C, and the mixture was stirred at 25 °C for 20 min. After the reaction was monitored by LC-MS, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with EA, dried over sodium sulfate, and purified by column chromatography to obtain the target compound in 18.54% yield. LC-MS [M+H]+: m / z = 506.2. 1 H NMR (400MHz, DMSO) δ10.33(s,1H),7.91(m,3H),7.84(s,1H),7.30–7.19(m,2H),6. 97(q,J=4.9Hz,1H),6.82(t,J=4.9Hz,1H),4.01(s,2H),2.51(s,3H),2.49(s,3H).

[0144] Example 6: 6-(methyl-d3)-3-({3-fluoro-2-[(methylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyridazin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0145] Step 1: Synthesis of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-(methyl-d3)-7-(pyridazin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0146] 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-(methyl-d3)-7-hydroxy-4-methyl-2H-coumarin-2-one (0.30 g, 0.64 mmol), 3-chloropyridazine (0.30 g, 2.63 mmol), cesium fluoride (0.15 g, 0.96 mmol), and potassium carbonate (0.18 g, 1.28 mmol) were added to 10.00 mL of anhydrous N,N-dimethylformamide and reacted at 100 °C for 16 h under sealed conditions. After the reaction was monitored by LC-MS until complete, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound in 42.5% yield.

[0147] Step 2: Synthesis of 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-(methyl-d3)-7-(pyridazin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0148] 1.00 mL of trifluoroacetic acid was added to a 10.00 mL solution of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-(methyl-d3)-7-(pyridazin-2-yl)oxy-4-methyl-2H-coumarin-2-one (156.26 mg, 0.28 mmol) in dichloromethane and reacted for 30 min. After the reaction was confirmed to be complete by TLC, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was filtered through diatomaceous earth, dried, and concentrated. The crude product was used for the next reaction without further purification.

[0149] Step 3: Synthesis of 6-(methyl-d3)-3-({3-fluoro-2-[(methylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyridazin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0150] 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-(methyl-d3)-7-(pyridazin-2-yl)oxy-4-methyl-2H-coumarin-2-one (100.70 mg, 0.24 mmol) was dissolved in anhydrous N,N-dimethylformamide (5.00 mL), and anhydrous pyridine (96.35 g, 1.22 mmol) and methylaminosulfonyl chloride (47.35 mg, 0.36 mmol) were added. The reaction was allowed to proceed at room temperature for 15 min. After the reaction was complete as detected by TLC, a large amount of water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin-layer chromatography to obtain the target compound in 86.5% yield. LC-MS [M+H] + :m / z=489.1. 1H NMR (400MHz, DMSO) δ10.34(s,1H),9.14–8.87(m,1H),7.95(t,J=5.9Hz,1H),7.87(s,1H),7.83(dd,J=8.9,4.5Hz,1H),7.58(dd ,J=8.9,0.9Hz,1H),7.32(d,J=4.3Hz,1H),6.98(q,J=4.9Hz,1H),6.83(t,J=5.0Hz,1H),4.03(s,2H),2.52(s,3H),2.51(s,3H).

[0151] Example 7: 5-Fluoro-3-({2-fluoro-3-[(methylaminosulfonyl)amino]phenyl}methyl)-4-methyl-7-pyridazin-3-yloxy)-2H-benzodihydropyran-2-one

[0152] Step 1: Synthesis of 2-fluoro-3-nitrobenzyl methanesulfonate

[0153] 2-Fluoro-3-nitrobenzyl alcohol (15.00 g, 87.66 mmol) was dissolved in 200.00 mL of tetrahydrofuran and stirred at 0 °C for 10 min. After cooling, 2.2 M lithium tert-butoxide solution (59.77 mL, 131.49 mmol) was added, and the mixture was stirred for 1 h. Then, methanesulfonyl chloride (13.05 g, 113.96 mmol) was added, and the mixture was stirred for another 3 h. After the reaction was confirmed to be complete by LC-MS, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was used for the next reaction without further purification.

[0154] Step 2: Synthesis of ethyl 2-(2-fluoro-3-nitrophenylmethyl)-3-oxobutyrate

[0155] Ethyl acetoacetate (13.68 g, 105.18 mmol) was dissolved in 200.00 mL of tetrahydrofuran and stirred at 0 °C for 10 min. After cooling, 2.2 M lithium tert-butoxide solution (59.76 mL, 131.47 mmol) was added, and the reaction was carried out for 30 min. Then, 2-fluoro-3-nitrobenzyl methanesulfonate (21.84 g, 87.64 mmol) and sodium iodide (13.14 g, 87.64 mmol) were added, and the mixture was heated to 50 °C and reacted for another 2 h. After the reaction was completed by TLC, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound in 85.5% yield.

[0156] Step 3: Synthesis of 5-fluoro-3-(2-fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-2H-coumarin-2-one

[0157] Ethyl 2-(2-fluoro-3-nitrobenzyl)-3-oxobutyrate (3.00 g, 10.59 mmol) and 5-fluororesorcinol (2.03 g, 15.89 mmol) were dissolved in 30.00 mL of perchloric acid, and the mixture was heated to 50 °C and reacted for 2 h. After the reaction was complete as monitored by TLC, a large amount of water was added, and a large amount of solid precipitated. The solid was filtered, and the filter cake was dried to give the target compound in 95.6% yield.

[0158] Step 4: Synthesis of 5-fluoro-3-(2-fluoro-3-nitrobenzyl)-4-methyl-7-(pyridazin-3-yloxy)-2H-coumarin-2-one

[0159] 5-Fluoro-3-(2-fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-2H-coumarin-2-one (0.50 g, 1.44 mmol), 3-bromopyridazine (0.34 g, 2.16 mmol), potassium phosphate (0.92 g, 4.32 mmol), and tBuXPhos-Pd-G3 (0.23 g, 0.29 mmol) were added to 15.00 mL of ultra-dry toluene. The mixture was purged three times with nitrogen and reacted at 105 °C for 12 h under nitrogen protection. After the reaction was complete as monitored by TLC, 50.00 mL of ethyl acetate was added. The reaction solution was dissolved by sonication and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain the target compound in 35.5% yield.

[0160] Step 5: Synthesis of 3-(3-amino-2-fluorobenzyl)-5-fluoro-4-methyl-7-(pyridazin-3-yloxy)-2H-coumarin-2-one

[0161] 5-Fluoro-3-(2-Fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-2H-coumarin-2-one (0.22 g, 0.51 mmol) and palladium on carbon (0.05 g, 0.51 mmol) were added to 10.00 mL of methanol solution. The mixture was purged three times with hydrogen and reacted at room temperature for 2 h under hydrogen atmosphere. After the reaction was complete as monitored by LC-MS, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The crude product obtained did not require purification and was used for the next reaction.

[0162] Step 6: Synthesis of 5-fluoro-3-({3-fluoro-2-[(methanesulfonamide)amino]phenyl-4-yl}methyl)-7-(pyridazin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0163] 3-(3-amino-2-fluorobenzyl)-5-fluoro-4-methyl-7-(pyridazin-3-yloxy)-2H-coumarin-2-one (0.20 g, 0.51 mmol) was dissolved in anhydrous dichloromethane (5.00 mL), and anhydrous pyridine (129.17 mg, 1.63 mmol) and methylaminosulfonyl chloride (87.62 mg, 0.49 mmol) were added. The reaction was allowed to proceed at room temperature for 15 min. After TLC detection of complete reaction, a large amount of water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin-layer chromatography to give 5-fluoro-3-({3-fluoro-2-[(methylsulfonamide)amino]phenyl-4-yl}methyl)-7-(pyridazin-2-yl)oxy-4-methyl-2H-coumarin-2-one, in 45.6% yield. LC-MS [M+H] + :m / z=489.1. 1 H NMR(400MHz,DMSO)δ9.36(d,J=10.8Hz,1H),9.11–9.05(m,1H),7.86(m,1H),7.63(m,1H),7.33–7.17(m,4H ), 7.01 (q, J = 8.3Hz, 1H), 6.87 (t, J = 7.2Hz, 1H), 3.99 (s, 2H), 2.53 (d, J = 5.1Hz, 3H), 2.49 (d, J = 2.0Hz, 3H).

[0164] Example 8: N-(3-fluoro-4-((5-fluoro-4-methyl-7-((4-methylpyridazin-3-yl)oxy)-2-oxo-2H-benzopyran-3-yl)methyl)pyridin-2-yl)-N-methylthiodiamide

[0165] Step 1: Synthesis of 3-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-5-fluoro-4-methyl-7-((4-methylpyridazin-3-yl)oxy)-2H-benzopyran-2-one

[0166] 3-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-5-fluoro-7-hydroxy-4-methyl-2H-benzopyran-2-one (200 mg, 0.427 mmol), 3-chloro-4-methylpyridazine (81.418 μL, 0.854 mmol), tBuXPhos-Pd-G3 (33.96 mg, 0.043 mmol), and potassium phosphate (294.94 mg, 1.281 mmol) were dissolved in toluene (5 mL). The reaction was carried out overnight at 120 °C under a nitrogen atmosphere. The sample was concentrated under reduced pressure, mixed with silica gel, and subjected to column chromatography to obtain the target product 3-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-5-fluoro-4-methyl-7-((4-methylpyridazin-3-yl)oxy)-2H-benzopyran-2-one (96 mg, 0.176 mmol).

[0167] Step 2: Synthesis of 3-((2-amino-3-fluoropyridin-4-yl)methyl)-5-fluoro-4-methyl-7-((4-methylpyridazin-3-yl)oxy)-2H-benzopyran-2-one

[0168] 3-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-5-fluoro-4-methyl-7-((4-methylpyridin-3-yl)oxy)-2H-benzopyran-2-one (96 mg, 0.176 mmol) was dissolved in DCM (10 ml), and TFA (1 ml) was added. The reaction was carried out at room temperature for 3 h. The solution was concentrated under reduced pressure and adjusted to weakly alkaline with saturated sodium bicarbonate aqueous solution. The DCM was extracted three times, and the organic phases were combined and concentrated under reduced pressure to give the target compound 3-((2-amino-3-fluoropyridin-4-yl)methyl)-5-fluoro-4-methyl-7-((4-methylpyridin-3-yl)oxy)-2H-benzopyran-2-one (70 mg, 0.177 mmol).

[0169] Step 3: Synthesis of N-(3-fluoro-4-((5-fluoro-4-methyl-7-((4-methylpyridazin-3-yl)oxy)-2-oxo-2H-benzopyran-3-yl)methyl)pyridin-2-yl)-N-methylthiodiamide

[0170] 3-((2-amino-3-fluoropyridin-4-yl)methyl)-5-fluoro-4-methyl-7-((4-methylpyridazin-3-yl)oxy)-2H-benzopyran-2-one (70 mg, 0.177 mmol) was dissolved in DMA (5 mL) and ACN (5 mL), cooled to 0 °C, and methylaminosulfonyl chloride (22.923 μL, 0.266 mmol) was added. The mixture was then transferred to room temperature and reacted for 0.5 h. The reaction was monitored by lc-MS to ensure complete reaction of the starting material. The reaction was quenched with saturated sodium bicarbonate aqueous solution, extracted three times with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography to obtain the crude target compound. The crude product was prepared by TLC to obtain N-(3-fluoro-4-((5-fluoro-4-methyl-7-((4-methylpyridazin-3-yl)oxy)-2-oxo-2H-benzopyran-3-yl)methyl)pyridin-2-yl)-N-methylthiodiamide (20 mg). LC-MS [M+H] + :m / z=504.2. 1 H NMR (400MHz, DMSO) δ10.51–10.13(m,1H),8.93(d,J=4.7Hz,1H),7.94(d,J=4.7Hz,1H),7.71(dd,J= 4.7, 0.8Hz, 1H), 7.31–7.23 (m, 2H), 6.97 (s, 1H), 6.83 (br, J = 27.4Hz, 1H), 4.03 (s, 2H), 2.36 (s, 3H).

[0171] Example 9: 3-({2-chloro-3-[(methylaminosulfonyl)amino]phenyl}methyl)-5-fluoro-4-methyl-7-pyridazin-3-yloxy)-2H-benzodihydropyran-2-one

[0172] This compound was prepared according to the method described in Example 7, with 2-fluoro-3-nitrobenzyl alcohol replaced by 2-chloro-3-nitrobenzyl alcohol in the first step, yielding 40.6%. LC-MS [M+H] + :m / z=505.1. 1 H NMR(400MHz, DMSO)δ9.03(m,1H),8.94(s,1H),7.79(dd,J=9.0,4.6Hz,1H),7.60–7.52(m,1H),7.37–7.32(m,1H),7.26–7 .17(m,3H),7.11(t,J=8.0Hz,1H),6.79(dd,J=7.7,1.4Hz,1H),3.96(s,2H),2.50(d,J=4.4Hz,3H),2.38(d,J=5.9Hz,3H).

[0173] Example 10: 6-Fluoro-3-({3-fluoro-2-[(methylaminosulfonyl)amino]pyridin-4-yl}methyl)-4-methyl-7-pyridazin-3-yloxy)-2H-chromone

[0174] This compound was prepared according to the method described in Example 1, with 5-fluororesorcinol replaced by 4-fluororesorcinol in step four, yielding 55.8%. LC-MS [M+H] + :m / z=490.1. 1 H NMR (400MHz, DMSO) δ10.34(s,1H),9.07(dd,J=4.6,1.3Hz,1H),8.00–7.91(m,2H),7.87(dd,J=8.9,4.5Hz,1 H),7.72–7.64(m,2H),6.97(d,J=5.5Hz,1H),6.85(t,J=5.1Hz,1H),4.04(s,2H),2.52(s,3H),2.48(s,3H).

[0175] Example 11: 5-Fluoro-3-({3-fluoro-2-[(methylaminosulfonyl)amino]pyridin-4-yl}methyl)-4,6-dimethyl-7-pyridazin-3-yloxy)-2H-benzodihydropyran-2-one

[0176] Step 1: Synthesis of 3-((2,3-difluoropyridin-4-yl)methyl)-5-fluoro-6-methyl-7-hydroxy-4-methyl-2H-coumarin-2-one

[0177] Ethyl 2-((2,3-difluoropyridin-4-yl)methyl)-3-oxobutyrate (3.00 g, 12.33 mmol) and 5-fluoro-4-methylresorcinol (2.63 g, 18.50 mmol) were dissolved in 30.00 mL of perchloric acid, and the mixture was heated to 50 °C and reacted for 2 h. After the reaction was completed by TLC monitoring, a large amount of water was added, and a large amount of solid precipitated. The solid was filtered, and the filter cake was dried to give the target compound in 90.5% yield.

[0178] Step 2: Synthesis of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-5-fluoro-6-methyl-7-hydroxy-4-methyl-2H-coumarin-2-one

[0179] 3-((2,3-difluoropyridin-4-yl)methyl)-5-fluoro-6-methyl-7-hydroxy-4-methyl-2H-coumarin-2-one (3.72 g, 11.71 mmol), triethylamine (8.10 mL, 58.57 mmol), and 2,4-dimethoxybenzylamine (6.85 g, 40.99 mmol) were added to 80.00 mL of N-methylpyrrolidone, and the reaction was carried out at 100 °C for 24 h. After the reaction was monitored by LC-MS until complete, a large amount of water was added, and the pH of the mixture was adjusted to neutral with 20% dilute hydrochloric acid. A large amount of solid precipitated, which was filtered. The filter cake was slurried with acetonitrile to obtain the target compound in 60.2% yield.

[0180] Step 3: Synthesis of 3-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-5-fluoro-4,6-dimethyl-7-(pyridazin-3-yloxy)-2H-benzopyran-2-one

[0181] 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-5-fluoro-6-methyl-7-hydroxy-4-methyl-2H-coumarin-2-one (0.30 g, 0.64 mmol), 3-bromopyridazine (0.30 g, 2.63 mmol), cesium fluoride (0.15 g, 0.96 mmol), and potassium carbonate (0.18 g, 1.28 mmol) were added to 10.00 mL of anhydrous N,N-dimethylformamide and reacted at 100 °C for 16 h under sealed conditions. After the reaction was monitored by LC-MS until complete, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound in 57.4% yield.

[0182] Step 4: Synthesis of 3-((2-amino-3-fluoropyridin-4-yl)methyl)-5-fluoro-4,6-dimethyl-7-(pyridazin-3-yloxy)-2H-benzopyran-2-one

[0183] 1.00 mL of trifluoroacetic acid was added to a 10.00 mL solution of 3-((2-(((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-5-fluoro-4,6-dimethyl-7-(pyridazin-3-yloxy)-2H-benzopyran-2-one (236.01 mg, 0.42 mmol) in dichloromethane and reacted for 30 min. After the reaction was confirmed to be complete by TLC, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was filtered through diatomaceous earth, dried, and concentrated. The crude product was used for the next reaction without further purification.

[0184] Step 5: Synthesis of 5-fluoro-3-({3-fluoro-2-[(methylaminosulfonyl)amino]pyridin-4-yl}methyl)-4,6-dimethyl-7-pyridazin-3-yloxy)-2H-benzodihydropyran-2-one

[0185] 3-((2-amino-3-fluoropyridin-4-yl)methyl)-5-fluoro-4,6-dimethyl-7-(pyridazin-3-yloxy)-2H-benzopyran-2-one (172.67 mg, 0.42 mmol) was dissolved in anhydrous N,N-dimethylformamide (5.00 mL), and anhydrous pyridine (96.35 g, 1.22 mmol) and methylaminosulfonyl chloride (83.21 mg, 0.63 mmol) were added. The reaction was allowed to proceed at room temperature for 15 min. After the reaction was confirmed to be complete by TLC, a large amount of water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin-layer chromatography to obtain the target compound in 38.8% yield. LC-MS [M+H] + :m / z=488.1. 1 HNMR (400MHz, DMSO) δ9.36(s,1H),9.03(dd,J=4.5,1.3Hz,1H),7.85(s,1H),7.82(dd,J=9.0,4.6Hz,1H),7.58(dd,J=8.9,1.3Hz,1H) ,7.32–7.26(m,2H),7.21(q,J=4.9Hz,1H),7.01(t,J=7.9Hz,1H),6.91–6.84(m,1H),3.99(s,2H),2.53(d,J=4.9Hz,3H),2.47(s,3H).

[0186] Example 12: 3-({2-fluoro-3-[(methylaminosulfonyl)amino]phenyl}methyl)-6-d3)methyl-4-methyl-7-pyridazin-3-yloxy)-2H-benzodihydropyran-2-one

[0187] This compound was prepared according to the method described in Example 7, with 5-fluororesorcinol replaced by 4-(methyl-d3)benzene-1,3-diol in step 3, yielding 57.4%. LC-MS [M+H] + :m / z=488.1. 1H NMR(400MHz,DMSO)δ9.36(s,1H),9.03(dd,J=4.5,1.3Hz,1H),7.85(s,1H),7.82(dd,J=9.0,4.6Hz,1H),7.58(dd,J=8.9,1.3Hz,1H), 7.32–7.26(m,2H),7.21(q,J=4.9Hz,1H),7.01(t,J=7.9Hz,1H),6.91–6.84(m,1H),3.99(s,2H),2.53(d,J=4.9Hz,3H),2.47(s,3H).

[0188] Example 13: 3-({2-chloro-3-[(methylaminosulfonyl)amino]phenyl}methyl)-6-d3)methyl-4-methyl-7-pyridazin-3-yloxy)-2H-benzodihydropyran-2-one

[0189] This compound was prepared according to the method described in Example 7, with 2-fluoro-3-nitrobenzyl alcohol replaced by 2-chloro-3-nitrobenzyl alcohol in the first step, and 5-fluororesorcinol replaced by 4-(methyl-d3)benzene-1,3-diol in the third step, yielding 30.2%. LC-MS [M+H] + :m / z=504.1. 1 H NMR (400MHz, DMSO) δ9.37(s,1H),9.07(dd,J=4.5,1.3Hz,1H),7.94(d,J=11.4Hz,1H),7.86(dd,J=9.0,4.5Hz,1H),7.72–7.63(m,2H ),7.29(td,J=7.9,1.7Hz,1H),7.22(q,J=5.0Hz,1H),7.02(t,J=7.9Hz,1H),6.92–6.86(m,1H),4.00(s,2H),2.53(d,J=5.0Hz,3H).

[0190] Example 14: 3-({2-fluoro-3-[(methylaminosulfonyl)amino]phenyl}methyl)-4-methyl-7-pyridazin-3-yloxy)-2H-benzodihydropyran-2-one

[0191] This compound was prepared according to the method described in Example 7, with 5-fluororesorcinol replaced by resorcinol in step 3, yielding 38.5%. LC-MS [M+H] + :m / z=471.1. 1H NMR (400MHz, DMSO) δ9.36(s,1H),9.07(dd,J=4.6,1.3Hz,1H),7.93(d,J=8.8Hz,1H),7.83(dd,J=8.9,4.6Hz,1H),7.57(dd,J=8.9,1.3Hz, 1H),7.37(d,J=2.4Hz,1H),7.32–7.13(m,3H),7.02(t,J=7.9Hz,1H),6.93–6.83(m,1H),3.99(s,2H),2.53(d,J=4.9Hz,3H),2.47(s,3H).

[0192] Example 15: 6-Ethyl-3-({3-fluoro-2-[(methylaminosulfonyl)amino]pyridin-4-yl}methyl)-4-methyl-7-pyridazin-3-yloxy)-2H-chromone

[0193] This compound was prepared according to the method described in Example 2, with 5-fluororesorcinol replaced by 6-ethylresorcinol in step four, yielding 75.8%. LC-MS [M+H] + :m / z=517.1. 1 H NMR (400MHz, DMSO) δ10.34(s,1H),7.99–7.88(m,3H),7.82(s,1H),7.32–7.21(m,2H),6.98(q,J=5.2Hz,1H ), 6.84 (t, J = 5.1Hz, 1H), 4.03 (s, 2H), 2.61 (q, J = 7.5Hz, 2H), 2.53 (d, J = 5.2Hz, 6H), 1.17 (t, J = 7.5Hz, 3H).

[0194] Example 16: 3-({2-fluoro-3-[(methylaminosulfonyl)amino]phenyl}methyl)-4,6-dimethyl-7-(pyridazin-3-yloxy)-2H-chroman-2-one

[0195] This compound was prepared according to the method described in Example 7, with 5-fluororesorcinol replaced by 4-methylresorcinol in step 3, yielding 37.4%. LC-MS [M+H] + :m / z=485.1. 1H NMR (400MHz, DMSO) δ9.36(s,1H),9.03(dd,J=4.5,1.3Hz,1H),7.85(s,1H),7.82(dd,J=9.0,4.6Hz,1H),7.58(dd,J=8.9,1.3Hz,1H),7.32– 7.26(m,2H),7.21(q,J=4.9Hz,1H),7.01(t,J=7.9Hz,1H),6.91–6.84(m,1H),3.99(s,2H),2.53(d,J=4.9Hz,3H),2.47(s,3H),2.19(s,3H).

[0196] Example 17: 3-({2-chloro-3-[(methylaminosulfonyl)amino]phenyl}methyl)-4,6-dimethyl-7-(pyridazin-3-yloxy)-2H-benzodihydropyran-2-one

[0197] This compound was prepared according to the method described in Example 7, with 2-fluoro-3-nitrobenzyl alcohol replaced by 2-chloro-3-nitrobenzyl alcohol in the first step and 5-fluororesorcinol replaced by 4-methylresorcinol in the third step, yielding 46.5%. LC-MS [M+H] + :m / z=501.1. 1 H NMR (400MHz, DMSO) δ9.37(s,1H),9.07(dd,J=4.5,1.3Hz,1H),7.94(d,J=11.4Hz,1H),7.86(dd,J=9.0,4.5Hz,1H),7.72–7.63(m,2H),7.2 9(td,J=7.9,1.7Hz,1H),7.22(q,J=5.0Hz,1H),7.02(t,J=7.9Hz,1H),6.92–6.86(m,1H),4.00(s,2H),2.53(d,J=5.0Hz,3H),2.46(s,3H).

[0198] Example 18: 6-Fluoro-3-({2-fluoro-3-[(methylaminosulfonyl)amino]phenyl}methyl)-4-methyl-7-pyridazin-3-yloxy)-2H-benzodihydropyran-2-one

[0199] This compound was prepared according to the method described in Example 7, with 5-fluororesorcinol replaced by 4-fluororesorcinol in step 3, yielding 33.5%. LC-MS [M+H] + :m / z=489.1. 1H NMR (400MHz, DMSO) δ9.37(s,1H),9.07(dd,J=4.5,1.3Hz,1H),7.94(d,J=11.4Hz,1H),7.86(dd,J=9.0,4.5Hz,1H),7.72–7.63(m,2H),7.2 9(td,J=7.9,1.7Hz,1H),7.22(q,J=5.0Hz,1H),7.02(t,J=7.9Hz,1H),6.92–6.86(m,1H),4.00(s,2H),2.53(d,J=5.0Hz,3H),2.46(s,3H).

[0200] Example 19: 3-({2-chloro-3-[(methylaminosulfonyl)amino]phenyl}methyl)-6-fluoro-4-methyl-7-pyridazin-3-yloxy)-2H-benzodihydropyran-2-one

[0201] This compound was prepared according to the method described in Example 7, with 2-fluoro-3-nitrobenzyl alcohol replaced by 2-chloro-3-nitrobenzyl alcohol in the first step and 5-fluororesorcinol replaced by 4-fluororesorcinol in the third step, yielding 38.1%. LC-MS [M+H] + :m / z=489.1. 1 H NMR (400MHz, DMSO) δ9.03(m,1H),8.94(s,1H),7.79(dd,J=9.0,4.6Hz,1H),7.60(dd,J=9.0,4.5Hz,1H),7.72–7.63(m,2H) ,7.29(m,1H),7.22(q,J=5.0Hz,1H),7.02(t,J=7.9Hz,1H),6.79(m,1H),3.88(s,2H),2.45(d,J=5.0Hz,3H),2.35(m,3H).

[0202] Example 20: 3-({3-fluoro-2-[(methylaminosulfonyl)amino]pyridin-4-yl}methyl)-4-methyl-7-pyridazin-3-yloxy)-2H-benzodihydropyran-2-one

[0203] This compound was prepared according to the method described in Example 1, with 5-fluororesorcinol replaced by resorcinol in step four, yielding 25.6%. LC-MS [M+H] + :m / z=472.1. 1H NMR (400MHz, DMSO) δ10.33(s,1H),9.07(dd,J=4.5,1.3Hz,1H),7.95(d,J=8.9Hz,2H),7.84(dd,J=8.9,4.6Hz,1H),7.58(d d,J=8.9,1.3Hz,1H),7.39(d,J=2.4Hz,1H),7.29(dd,J=8.8,2.3Hz,1H),6.84(d,J=5.0Hz,2H),4.03(s,2H),2.51(s,6H).

[0204] Example 21: 3-({2-fluoro-3-[(methylaminosulfonyl)amino]phenyl}methyl)-7-[(3-fluoropyridin-2-yl)oxy]-6-2H3)methyl-4-methyl-2H-benzodihydropyran-2-one

[0205] Step 1: Synthesis of 3-(2-fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-6-(methyl-d3)-2H-chromene-2-one

[0206] Ethyl 2-(2-fluoro-3-nitrobenzyl)-3-oxobutyrate (2 g, 7.06 mmol) and 4-(methyl-d3)benzene-1,3-diol (0.90 g, 7.06 mmol) were dissolved in perchloric acid (5 mL) and stirred at 25 °C for 12 h. The reaction was quenched by slowly adding 50 mL of distilled water, and a solid precipitated. The solid was filtered under reduced pressure, collected, and dried to give 3-(2-fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-6-(methyl-d3)-2H-chromene-2-one (2.3 g, 6.64 mmol, 94.1%). LC-MS [M+H] + :m / z=347.2.

[0207] Step 2: Synthesis of 3-(3-amino-2-fluorobenzyl)-7-hydroxy-4-methyl-6-(methyl-d3)-2H-chromen-2-one

[0208] 3-(2-fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-6-(methyl-d3)-2H-chromone-2-one (2.3 g, 6.64 mmol) was dissolved in MeOH (60 mL), Pd / C (0.71 g, 6.64 mmol) was added, and the mixture was substituted with H2 three times. The mixture was stirred at 25 °C for 3 h. The solution was filtered under reduced pressure, collected, and concentrated under reduced pressure to give 3-(3-amino-2-fluorobenzyl)-7-hydroxy-4-methyl-6-(methyl-d3)-2H-chromone-2-one (2 g, 6.32 mmol, 95.2%). LC-MS [M+H] + :m / z=317.1.

[0209] Step 3: Synthesis of benzyl (2-fluoro-3-((7-hydroxy-4-methyl-6-(methyl-d3)-2-oxo-2H-chromen-3-yl)methyl)phenyl)carbamate

[0210] 3-(3-amino-2-fluorobenzyl)-7-hydroxy-4-methyl-6-(methyl-d3)-2H-chromen-2-one (0.8 g, 2.53 mmol) was dissolved in DCM (20 mL), and DMAP (0.77 g, 6.32 mmol), TEA (1.1 mL, 7.59 mmol), and Cb2Cl (0.86 g, 5.06 mmol) were added. The mixture was stirred at 25 °C for 2 h. The reaction was quenched with saturated sodium bicarbonate solution, extracted with DCM, dried over sodium sulfate, and column chromatography was performed to obtain benzyl 2-fluoro-3-((7-hydroxy-4-methyl-6-(methyl-d3)-2-oxo-2H-chromen-3-yl)methyl)phenyl)carbamate (0.2 g, 0.44 mmol, 17.6%). LC-MS [M+H] + :m / z=451.2.

[0211] Step 4: Synthesis of 3-(3-amino-2-fluorobenzyl)-7-((3-fluoropyridin-2-yl)oxy)-4-methyl-6-(methyl-d3)-2H-chromen-2-one

[0212] Benzyl 2-fluoro-3-((7-hydroxy-4-methyl-6-(methyl-d3)-2-oxo-2H-chromene-3-yl)methyl)phenyl)carbamate (0.2 g, 0.44 mmol) and 2,3-difluoropyridine (0.10 g, 0.89 mmol) were dissolved in DMF (10 mL), and triethylamine (0.19 mL, 1.33 mmol) and cesium fluoride (0.13 g, 0.89 mmol) were added. The mixture was stirred at 100 °C for 15 h. The reaction was quenched with saturated ammonium chloride solution, extracted with EA, dried over sodium sulfate, and column chromatography was used to obtain 3-(3-amino-2-fluorobenzyl)-7-((3-fluoropyridin-2-yl)oxy)-4-methyl-6-(methyl-d3)-2H-chromene-2-one (0.1 g, 0.24 mmol, 54.75%). LC-MS [M+H] + :m / z=412.2.

[0213] Step 5: Synthesis of 3-({2-fluoro-3-[(methylaminosulfonyl)amino]phenyl}methyl)-7-[(3-fluoropyridin-2-yl)oxy]-6-d3)methyl-4-methyl-2H-benzodihydropyran-2-one

[0214] 3-(3-amino-2-fluorobenzyl)-7-((3-fluoropyridin-2-yl)oxy)-4-methyl-6-(methyl-d3)-2H-chromen-2-one (0.1 g, 0.24 mmol) was dissolved in acetonitrile (2 mL) and DMA (2 mL), and pyridine (0.06 mL, 0.73 mmol) was added. Methylsulfonamide chloride (0.05 g, 0.37 mmol) was added at 0 °C, and the reaction was quenched with saturated sodium bicarbonate solution after stirring at 25 °C for 20 min. The mixture was extracted with EA, dried over sodium sulfate, and prepared by reverse phase to give 3-({2-fluoro-3-[(methylaminosulfonyl)amino]phenyl}methyl)-7-[(3-fluoropyridin-2-yl)oxy]-6-d3)methyl-4-methyl-2H-benzodihydropyran-2-one (80 mg, 0.15 mmol, 60.8%). LC-MS [M+H] + :m / z=505.2. 1 H NMR(400MHz,DMSO)δ9.36(s,1H),7.97–7.87(m,2H),7.83(s,1H),7.33–7.17(m,4H),7.01 (t, J=7.9Hz, 1H), 6.87 (t, J=6.7Hz, 1H), 3.98 (s, 2H), 2.53 (d, J=5.0Hz, 3H), 2.46 (s, 3H).

[0215] Example 22: 6-Chloro-3-[[2-fluoro-3-(methylsulfonamide amino)phenyl]methyl]-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0216] This compound was prepared using the method described in Example 7, with 5-fluororesorcinol replaced by 4-chlororesorcinol in step 3, yielding 36.5%. LC-MS [M+H] + :m / z=505.1. 1 H NMR (400MHz, DMSO) δ9.30(s,1H),8.99(dd,J=4.6,1.3Hz,1H),8.04(s,1H),7.79(dd,J=9.0,4.5Hz,1H),7.64–7.55(m,2H),7.22(t d,J=7.8,1.7Hz,1H),7.15(q,J=5.0Hz,1H),6.99–6.92(m,1H),6.88–6.79(m,1H),3.94(s,2H),2.46(d,J=4.9Hz,3H),2.41(s,3H).

[0217] Example 23: 6-Chloro-3-({3-fluoro-2-[(methylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0218] Step 1: Synthesis of 3-((2,3-difluoropyridin-4-yl)methyl)-6-chloro-7-hydroxy-4-methyl-2H-coumarin-2-one

[0219] Ethyl 2-((2,3-difluoropyridin-4-yl)methyl)-3-oxobutyrate (3.00 g, 12.33 mmol) and 4-chlororesorcinol (3.00 g, 20.75 mmol) were dissolved in 30.00 mL of perchloric acid, and the mixture was heated to 50 °C and reacted for 2 h. After the reaction was completed by TLC monitoring, a large amount of water was added, and a large amount of solid precipitated. The solid was filtered, and the filter cake was dried to give the target compound in 87.3% yield.

[0220] Step 2: Synthesis of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-chloro-7-hydroxy-4-methyl-2H-coumarin-2-one

[0221] 3-((2,3-difluoropyridin-4-yl)methyl)-6-chloro-7-hydroxy-4-methyl-2H-coumarin-2-one (3.44 g, 10.19 mmol), triethylamine (8.10 mL, 58.57 mmol), and 2,4-dimethoxybenzylamine (6.85 g, 40.99 mmol) were added to 80.00 mL of N-methylpyrrolidone, and the mixture was reacted at 100 °C for 24 h. After the reaction was monitored by LC-MS until complete, a large amount of water was added, and the pH of the mixture was adjusted to neutral with 20% dilute hydrochloric acid. A large amount of solid precipitated, which was filtered. The filter cake was slurried with acetonitrile to obtain the target compound in 70.5% yield.

[0222] Step 3: Synthesis of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-chloro-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0223] 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-chloro-7-hydroxy-4-methyl-2H-coumarin-2-one (0.30 g, 0.62 mmol), 3-bromopyridazine (0.30 g, 1.89 mmol), potassium phosphate (0.3 g, 4.24 mmol), and tBuXPhos-Pd-G3 (0.13 g, 0.12 mmol) were added to 20.00 mL of anhydrous dioxane. The mixture was purged with nitrogen three times and reacted at 100 °C for 8 h. After the reaction was complete as monitored by LC-MS, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound in 70.3% yield.

[0224] Step 4: Synthesis of 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-chloro-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0225] 1.00 mL of trifluoroacetic acid was added to a 10.00 mL solution of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-chloro-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one (0.37 g, 0.66 mmol) in dichloromethane and reacted for 30 min. After the reaction was confirmed to be complete by TLC, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was filtered through diatomaceous earth, dried, and concentrated. The crude product was used for the next reaction without further purification.

[0226] Step 5: Synthesis of 6-chloro-3-({3-fluoro-2-[(methanesulfonamide)amino]pyridin-4-yl}methyl)-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0227] 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-chloro-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one (172.67 mg, 0.42 mmol) was dissolved in anhydrous N,N-dimethylformamide (5.00 mL), and anhydrous pyridine (96.35 g, 1.22 mmol) and methylaminosulfonyl chloride (83.21 mg, 0.63 mmol) were added. The reaction was allowed to proceed at room temperature for 15 min. After the reaction was complete as detected by TLC, a large amount of water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin-layer chromatography to obtain the target compound in 42.8% yield. LC-MS [M+H] + :m / z=506.1. 1H NMR (400MHz, DMSO) δ10.34(s,1H),9.05(dd,J=4.5,1.3Hz,1H),8.12(s,1H),7.97–7.80(m,2H),7.69–7.57(m ,2H),6.96(d,J=5.5Hz,1H),6.84(t,J=5.2Hz,1H),4.03(s,2H),2.51(d,J=3.3Hz,3H),2.49(d,J=1.9Hz,3H).

[0228] Example 24: 6-Fluoro-3-[[2-Fluoro-3-(Ethylsulfonamide amino)phenyl]methyl]-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0229] Step 1: Synthesis of 2-fluoro-3-nitrobenzyl methanesulfonate

[0230] 2-Fluoro-3-nitrobenzyl alcohol (15.00 g, 87.66 mmol) was dissolved in 200.00 mL of tetrahydrofuran and stirred at 0 °C for 10 min. After cooling, 2.2 M lithium tert-butoxide solution (59.77 mL, 131.49 mmol) was added, and the mixture was stirred for 1 h. Then, methanesulfonyl chloride (13.05 g, 113.96 mmol) was added, and the mixture was stirred for another 3 h. After the reaction was confirmed to be complete by LC-MS, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was used for the next reaction without further purification.

[0231] Step 2: Synthesis of ethyl 2-(2-fluoro-3-nitrophenylmethyl)-3-oxobutyrate

[0232] Ethyl acetoacetate (13.68 g, 105.18 mmol) was dissolved in 200.00 mL of tetrahydrofuran and stirred at 0 °C for 10 min. After cooling, 2.2 M lithium tert-butoxide solution (59.76 mL, 131.47 mmol) was added, and the reaction was carried out for 30 min. Then, 2-fluoro-3-nitrobenzyl methanesulfonate (21.84 g, 87.64 mmol) and sodium iodide (13.14 g, 87.64 mmol) were added, and the mixture was heated to 50 °C and reacted for another 2 h. After the reaction was completed by TLC, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound in 86.8% yield.

[0233] Step 3: Synthesis of 6-fluoro-3-(2-fluoro-3-nitrophenylmethyl)-7-hydroxy-4-methyl-2H-coumarin-2-one

[0234] Ethyl 2-(2-fluoro-3-nitrobenzyl)-3-oxobutyrate (3.00 g, 10.59 mmol) and 4-fluororesorcinol (2.03 g, 18.18 mmol) were dissolved in 30.00 mL of perchloric acid, and the mixture was heated to 50 °C and reacted for 2 h. After the reaction was completed by TLC monitoring, a large amount of water was added, and a large amount of solid precipitated. The solid was filtered, and the filter cake was dried to obtain the target compound in 95.6% yield.

[0235] Step 4: Synthesis of 6-fluoro-3-(2-fluoro-3-nitrophenylmethyl)-4-methyl-7-(pyridazin-3-yloxy)-2H-coumarin-2-one

[0236] 6-Fluoro-3-(2-fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-2H-coumarin-2-one (0.50 g, 1.44 mmol), 3-bromopyridazine (0.45 g, 2.16 mmol), potassium phosphate (0.46 g, 2.16 mmol), and tBuXPhos-Pd-G3 (0.23 g, 0.29 mmol) were added to 15.00 mL of anhydrous dioxane. The mixture was purged three times with nitrogen and reacted at 120 °C for 12 h under nitrogen protection. After the reaction was complete as monitored by TLC, 50.00 mL of ethyl acetate was added. The reaction solution was dissolved by sonication and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain the target compound in 60.7% yield.

[0237] Step 5: Synthesis of 6-fluoro-3-(3-amino-2-fluorobenzyl)-4-methyl-7-(pyridazin-3-yl)oxy-2H-coumarin-2-one

[0238] 6-fluoro-3-(2-fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-2H-coumarin-2-one (0.37 g, 0.81 mmol) was added to a mixture of 10.00 mL methanol and 10.00 mL water. Iron powder (0.5 g, 8.12 mmol) and ammonium chloride (0.5 g, 8.12 mmol) were added. The mixture was reacted at room temperature under hydrogen atmosphere for 2 h. After the reaction was complete as monitored by LC-MS, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The crude product obtained did not require purification and was used for the next reaction.

[0239] Step 6: Synthesis of 6-fluoro-3-({3-fluoro-2-[(ethylsulfonamide)amino]phenyl-4-yl}methyl)-7-(pyridazin-3-yl)oxy-4-methyl-2H-coumarin-2-one

[0240] The synthesized 6-fluoro-3-(3-amino-2-fluorobenzyl)-4-methyl-7-(pyridazin-3-yloxy)-2H-coumarin-2-one (0.34 g, 0.81 mmol) was dissolved in anhydrous dichloromethane (5.00 mL), and anhydrous pyridine (192.66 mg, 2.43 mmol) and ethylaminosulfonyl chloride (212.92 mg, 1.21 mmol) were added. The reaction was allowed to proceed at room temperature for 15 min. After the reaction was confirmed to be complete by TLC, a large amount of water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin-layer chromatography to obtain the target compound in 50.38% yield. LC-MS [M+H] + :m / z=503.1. 1 H NMR (400MHz, DMSO) δ9.34(s,1H),9.08(dd,J=4.5,1.2Hz,1H),7.94(d,J=11.4Hz,1H),7.87(dd,J=8.9,4.5Hz,1H),7.73–7.62(m,2H),7 .31(q,J=6.4Hz,2H),7.02(t,J=7.8Hz,1H),6.89(t,J=7.3Hz,1H),4.00(s,2H),2.97–2.90(m,2H),2.46(s,3H),0.99(t,J=7.2Hz,3H).

[0241] Example 25: 6-Fluoro-3-[[2-Fluoro-3-(isopropylsulfonamide amino)phenyl]methyl]-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0242] This compound was prepared using the method described in Example 24, replacing the ethylaminosulfonyl chloride in step 6 with intermediate 1, with a yield of 20.5%. LC-MS [M+H] + :m / z=517.1. 1 H NMR (400MHz, DMSO) δ9.36(s,1H),9.07(dd,J=4.6,1.1Hz,1H),7.94(d,J=11.4Hz,1H),7.86(dd,J=9.0,4.5Hz,1H),7.72–7.60 (m,2H),7.32(d,J=7.7Hz,2H),7.02(t,J=7.9Hz,1H),6.88(t,J=7.2Hz,1H),4.00(s,2H),2.45(s,3H),1.00(d,J=6.5Hz,6H).

[0243] Example 26: 6-Fluoro-3-({3-fluoro-2-[(ethylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0244] Step 1: Synthesis of 3-((2,3-difluoropyridin-4-yl)methyl)-6-chloro-7-hydroxy-4-methyl-2H-coumarin-2-one

[0245] Ethyl 2-((2,3-difluoropyridin-4-yl)methyl)-3-oxobutyrate (3.00 g, 12.33 mmol) and 4-chlororesorcinol (3.00 g, 20.75 mmol) were dissolved in 30.00 mL of perchloric acid, and the mixture was heated to 50 °C and reacted for 2 h. After the reaction was completed by TLC monitoring, a large amount of water was added, and a large amount of solid precipitated. The solid was filtered, and the filter cake was dried to give the target compound in 87.3% yield.

[0246] Step 2: Synthesis of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-fluoro-7-hydroxy-4-methyl-2H-coumarin-2-one

[0247] 3-((2,3-difluoropyridin-4-yl)methyl)-6-fluoro-7-hydroxy-4-methyl-2H-coumarin-2-one (3.44 g, 10.19 mmol), triethylamine (8.10 mL, 58.57 mmol), and 2,4-dimethoxybenzylamine (6.85 g, 40.99 mmol) were added to 80.00 mL of N-methylpyrrolidone, and the reaction was carried out at 100 °C for 24 h. After the reaction was monitored by LC-MS until complete, a large amount of water was added, and the pH of the mixture was adjusted to neutral with 20% dilute hydrochloric acid. A large amount of solid precipitated, which was filtered. The filter cake was slurried with acetonitrile to obtain the target compound in 70.5% yield.

[0248] Step 3: Synthesis of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-fluoro-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0249] 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-fluoro-7-hydroxy-4-methyl-2H-coumarin-2-one (0.30 g, 0.62 mmol), 3-bromopyridazine (0.30 g, 1.89 mmol), potassium phosphate (0.2 g, 0.96 mmol), and tBuXPhos-Pd-G3 (0.13 g, 0.12 mmol) were added to 20.00 mL of anhydrous dioxane. The mixture was purged with nitrogen three times and reacted at 100 °C for 8 h. After the reaction was complete as monitored by LC-MS, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound in 70.3% yield.

[0250] Step 4: Synthesis of 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-fluoro-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0251] 1.00 mL of trifluoroacetic acid was added to a 10.00 mL solution of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-fluoro-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one (0.37 g, 0.66 mmol) in dichloromethane and reacted for 30 min. After the reaction was confirmed to be complete by TLC, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was filtered through diatomaceous earth, dried, and concentrated. The crude product was used for the next reaction without further purification.

[0252] Step 5: Synthesis of 6-fluoro-3-({3-fluoro-2-[(ethylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0253] 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-fluoro-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one (172.67 mg, 0.42 mmol) was dissolved in anhydrous N,N-dimethylformamide (5.00 mL), and anhydrous pyridine (96.35 g, 1.22 mmol) and ethylaminosulfonyl chloride (83.21 mg, 0.63 mmol) were added. The reaction was allowed to proceed at room temperature for 15 min. After the reaction was confirmed to be complete by TLC, a large amount of water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin-layer chromatography to obtain the target compound in 44.8% yield. LC-MS [M+H] + :m / z=504.1. 1H NMR (400MHz, DMSO) δ10.33(s,1H),9.08(d,J=4.4Hz,1H),8.00–7.81(m,3H),7.76–7.62(m,2H),7.04(d,J= 42.9Hz, 1H), 6.82 (t, J = 5.0Hz, 1H), 4.03 (s, 2H), 2.93 (q, J = 7.2Hz, 2H), 2.48 (s, 3H), 1.02 (t, J = 7.2Hz, 3H).

[0254] Example 27: 6-Fluoro-3-({3-fluoro-2-[(isopropylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0255] This compound was prepared using the method described in Example 26, replacing the ethylaminosulfonyl chloride in step 6 with intermediate 1, with a yield of 10.5%. LC-MS [M+H] + :m / z=518.1. 1 H NMR (400MHz, DMSO) δ10.32(s,1H),9.08(d,J=4.4Hz,1H),7.99–7.92(m,2H),7.87(dd,J=8.9,4.5Hz,1H),7.68(dd, J=10.6,7.8Hz,2H),7.07(d,J=7.0Hz,1H),6.83(t,J=5.0Hz,1H),4.04(s,2H),2.48(s,3H),1.02(d,J=6.5Hz,6H).

[0256] Example 28: 6-Fluoro-3-[[2-Fluoro-3-(Deuterated Methylsulfonamide Amino)phenyl]methyl]-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0257] This compound was prepared using the method described in Example 24, replacing ethylaminosulfonyl chloride in step 6 with intermediate 2, with a yield of 18.6%. LC-MS [M+H] + :m / z=492.1. 1H NMR (400MHz, DMSO) δ9.36(s,1H),9.08(dd,J=4.5,1.1Hz,1H),7.95(d,J=11.4Hz,1H),7.87(dd,J=8.9,4.5Hz,1H),7.71– 7.63(m,2H),7.29(t,J=7.8Hz,1H),7.19(s,1H),7.02(t,J=7.9Hz,1H),6.89(t,J=7.2Hz,1H),4.00(s,2H),2.46(s,3H).

[0258] Example 29: 6-Fluoro-3-[[2-Fluoro-3-(cyclopropylsulfonamide amino)phenyl]methyl]-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0259] This compound was prepared using the method described in Example 24, replacing ethylaminosulfonyl chloride in step 6 with intermediate 3, with a yield of 23.6%. LC-MS [M+H] + :m / z=515.1. 1 H NMR (400MHz, DMSO) δ9.52(s,1H),9.07(dd,J=4.6,1.2Hz,1H),7.94(d,J=11.4Hz,1 H),7.86(dd,J=9.0,4.5Hz,1H),7.78(d,J=2.0Hz,1H),7.71–7.58(m,2H),7.31(t, J=7.7Hz,1H),7.01(t,J=7.9Hz,1H),6.86(t,J=7.2Hz,1H),4.00(s,2H),2.45(s,3 H), 2.35 (dq, J = 6.6, 3.3Hz, 1H), 0.52 (dd, J = 6.9, 4.5Hz, 2H), 0.43 (d, J = 3.4Hz, 2H).

[0260] Example 30: 6-Fluoro-3-({3-fluoro-2-[(cyclopropylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0261] This compound was prepared using the method described in Example 26, with the ethylaminosulfonyl chloride in step 6 replaced by intermediate 3, yielding 22.2%. LC-MS [M+H] + :m / z=516.1. 1H NMR (400MHz, DMSO) δ10.47(s,1H),9.07(d,J=4.4Hz,1H),7.96(d,J=11.5Hz,2H),7.86(dd,J=8.9,4.5Hz,1H) ,7.71–7.64(m,2H),7.54(s,1H),6.84(s,1H),4.04(s,2H),2.48(s,3H),2.32(s,1H),0.51(d,J=7.5Hz,4H).

[0262] Example 31: 6-Fluoro-3-[[2-Fluoro-3-(methoxyethylsulfonamide amino)phenyl]methyl]-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0263] This compound was prepared using the method described in Example 24, replacing the ethylaminosulfonyl chloride in step 6 with intermediate 4, with a yield of 50.5%. LC-MS [M+H] + :m / z=533.1. 1 H NMR (400MHz, DMSO) δ9.37 (s, 1H), 9.08 (dd, J = 4.5, 1.2Hz, 1H), 7.95 (d, J = 11. 4Hz,1H),7.86(dd,J=9.0,4.5Hz,1H),7.71–7.62(m,2H),7.49(t,J=5.9Hz,1H ),7.32(t,J=7.6Hz,1H),7.02(t,J=7.9Hz,1H),6.90(t,J=7.2Hz,1H),4.00(s ,2H),3.31(d,J=6.0Hz,2H),3.16(s,3H),3.05(q,J=6.0Hz,2H),2.46(s,3H).

[0264] Example 32: 6-Fluoro-3-({3-fluoro-2-[(methoxyethylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0265] This compound was prepared using the method described in Example 26, replacing the ethylaminosulfonyl chloride in step 6 with intermediate 4, with a yield of 48.6%. LC-MS [M+H] + :m / z=534.1. 1H NMR (400MHz, DMSO) δ10.43(s,1H),9.07(dd,J=4.5,1.2Hz,1H),7.98–7.90(m,2H),7.86(dd,J=8.9,4.5Hz,1H),7.75–7.62(m,2H), 7.04(t,J=6.0Hz,1H),6.85(t,J=5.0Hz,1H),4.04(s,2H),3.37(d,J=6.0Hz,2H),3.14(s,3H),3.06(q,J=5.9Hz,2H),2.48(s,3H).

[0266] Example 33: 6-Fluoro-3-[[2-Fluoro-3-(oxetane-3-ethylsulfonamide amino)phenyl]methyl]-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0267] This compound was prepared using the method described in Example 24, replacing ethylaminosulfonyl chloride in step 6 with intermediate 6, with a yield of 10.5%. LC-MS [M+H] + :m / z=531.1. 1 H NMR (400MHz, DMSO) δ9.50 (s, 1H), 9.08 (dd, J = 4.5, 1.2Hz, 1H), 8.32 (d, J = 8.1Hz ,1H),7.95(d,J=11.4Hz,1H),7.87(dd,J=9.0,4.5Hz,1H),7.72–7.62(m,2H),7 .32–7.25(m,1H),7.04(t,J=7.9Hz,1H),6.94(t,J=7.1Hz,1H),4.59(t,J=6.7H z, 2H), 4.46 (h, J = 7.0Hz, 1H), 4.33 (t, J = 6.3Hz, 2H), 4.00 (s, 2H), 2.46 (s, 3H).

[0268] Example 34: 6-Fluoro-3-[[2-Fluoro-3-(propynesulfonamide amino)phenyl]methyl]-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0269] This compound was prepared using the method described in Example 24, replacing ethylaminosulfonyl chloride in step 6 with intermediate 5, with a yield of 14.7%. LC-MS [M+H] + :m / z=513.1. 1H NMR(400MHz, DMSO)δ9.49(s,1H),9.07(dd,J=4.5,1.2Hz,1H),7.97–7.83(m,3H),7.71–7.63(m,2H),7.36–7.27(m,1H),7 .02(t,J=7.8Hz,1H),6.90(t,J=7.1Hz,1H),4.00(s,2H),3.74(dd,J=5.9,2.5Hz,2H),3.11(t,J=2.5Hz,1H),2.46(s,3H).

[0270] Example 35: 6-Fluoro-3-[[2-Fluoro-3-(difluoroethylsulfonamide amino)phenyl]methyl]-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0271] This compound was prepared using the method described in Example 24, replacing ethylaminosulfonyl chloride in step 6 with intermediate 7, with a yield of 18.7%. LC-MS [M+H] + :m / z=539.1. 1 H NMR (400MHz, DMSO) δ9.56(s,1H),9.07(dd,J=4.5,1.2Hz,1H),8.01(t,J=6.3Hz,1H),7.95(d,J=11.4Hz,1H),7.87(dd,J=9.0,4.5Hz,1H),7 .74–7.56(m,2H),7.39–7.28(m,1H),7.04(t,J=7.9Hz,1H),6.94(t,J=7.2Hz,1H),5.98(tt,J=55.8,4.1Hz,1H),4.01(s,2H),2.46(s,3H).

[0272] Example 36: 6-Fluoro-3-[[2-Fluoro-3-(trifluoroethylsulfonamide amino)phenyl]methyl]-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0273] This compound was prepared using the method described in Example 24, replacing the ethylaminosulfonyl chloride in step 6 with intermediate 8, with a yield of 23.4%. LC-MS [M+H] + :m / z=557.1. 1H NMR(400MHz,DMSO)δ9.61(s,1H),9.11–9.03(m,1H),8.36(t,J=6.8Hz,1H),7.95(d,J=11.4Hz,1H),7.87(dd,J=9.0,4.5Hz,1H), 7.76–7.60(m,2H),7.37–7.26(m,1H),7.05(t,J=7.9Hz,1H),6.95(t,J=7.2Hz,1H),4.01(s,2H),3.77–3.65(m,2H),2.46(s,3H).

[0274] Example 37: 6-nitro-3-[[2-fluoro-3-(methylsulfonamide amino)phenyl]methyl]-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0275] Step 1: Synthesis of 3-((2,3-difluoropyridin-4-yl)methyl)-7-hydroxy-4-methyl-2H-coumarin-2-one

[0276] Methyl 2-((2,3-difluoropyridin-4-yl)methyl)-3-oxobutyrate (3.00 g, 12.33 mmol) and resorcinol (2.04 g, 18.50 mmol) were dissolved in 30.00 mL of perchloric acid, and the mixture was heated to 50 °C and reacted for 2 h. After the reaction was complete as monitored by TLC, a large amount of water was added, and a large amount of solid precipitated. The solid was filtered, and the filter cake was dried to give the target compound in 90.5% yield.

[0277] Step 2: Synthesis of 3-((2,3-difluoropyridin-4-yl)methyl)-7-hydroxy-4-methyl-6-nitro-2H-coumarin-2-one

[0278] 3-((2,3-difluoropyridin-4-yl)methyl)-7-hydroxy-4-methyl-2H-coumarin-2-one (3.00 g, 9.89 mmol) was dissolved in 45.00 mL of glacial acetic acid and heated at 50 °C with stirring until fully dissolved. Calcium nitrate (1.62 g, 9.89 mmol) was added, and the reaction solution slowly turned yellow. The reaction was monitored when the solution turned orange-yellow. After the reaction was complete as monitored by LC-MS, water was added, and a large amount of solid precipitated. The target compound was obtained by filtration with a yield of 34.83%.

[0279] Step 3: Synthesis of 3-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-7-hydroxy-4-methyl-6-nitro-2H-coumarin-2-one

[0280] 3-((2,3-difluoropyridin-4-yl)methyl)-7-hydroxy-4-methyl-6-nitro-2H-coumarin-2-one (3.00 g, 8.61 mmol), triethylamine (3.58 mL, 25.84 mmol), and 2,4-dimethoxybenzylamine (4.32 g, 25.84 mmol) were dissolved in NMP solution (45 mL), the tube was sealed, and the reaction was carried out overnight at 120 °C. After the reaction was monitored by LC-MS to be complete, a large amount of water was added to adjust the pH to neutral, and a yellow solid precipitated. The solid was filtered, and the filter cake was slurried with diethyl ether to give a yellow solid product with a yield of 28.12%.

[0281] Step 4: Synthesis of 3-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-4-methyl-6-nitro-7-(pyridazin-3-yloxy)-2H-coumarin-2-one

[0282] 3-((2-((2,4-dimethoxybenzyl)amino)-3-fluoropyridin-4-yl)methyl)-7-hydroxy-4-methyl-6-nitro-2H-coumarin-2-one (1.00 g, 2.02 mmol), 3-bromopyridazine (0.64 g, 4.04 mmol), potassium phosphate (0.70 g, 3.03 mmol), and tBuXPhos-Pd-G3 (0.16 g, 0.20 mmol) were added to 20.00 mL of anhydrous dioxane. The mixture was purged with nitrogen three times and reacted at 100 °C for 8 h. After the reaction was complete as monitored by LC-MS, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound in 69.11% yield.

[0283] Step 5: Synthesis of 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-nitro-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0284] 2.00 mL of trifluoroacetic acid was added to a 10.00 mL solution of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-nitro-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one (0.30 g, 0.52 mmol) in dichloromethane and reacted for 30 min. After the reaction was confirmed to be complete by TLC, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was filtered through diatomaceous earth, dried, and concentrated. The crude product was used for the next reaction without further purification.

[0285] Step 6: Synthesis of 6-nitro-3-({3-fluoro-2-[(ethylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0286] 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-nitro-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one (50.00 mg, 0.12 mmol) was dissolved in anhydrous N,N-dimethylformamide (5.00 mL), and anhydrous pyridine (28.03 mg, 0.35 mmol) and methylaminosulfonyl chloride (15.30 mg, 0.12 mmol) were added. The reaction was carried out at room temperature for 15 min. After the reaction was complete as monitored by TLC, a large amount of water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin-layer chromatography to obtain the target compound in 81.97% yield. LC-MS [M+H] + :m / z=517.1. 1 H NMR (400MHz, DMSO) δ10.35(s,1H),9.06(d,J=4.2Hz,1H),8.65(s,1H),7.94(d,J=5.1Hz,1H),7.88(dd,J=9.0,4.5Hz,1H ),7.80(s,1H),7.74–7.70(m,1H),6.98(d,J=5.2Hz,1H),6.89(t,J=5.0Hz,1H),4.06(s,2H),2.56(s,3H),2.52(s,3H).

[0287] Example 38: 6-amino-3-[[2-fluoro-3-(hydroxyethylsulfonamide amino)phenyl]methyl]-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0288] 6-Nitro-3-({3-fluoro-2-[(methoxyethylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one (0.05 g, 0.10 mmol) was dissolved in 10.00 mL of methanol. Stannous chloride (36.71 mg, 0.20 mmol) was added at room temperature. The reaction was heated to 50 °C and continued for 3 h. LC-MS was used for monitoring. After the reaction was complete, the mixture was quenched with water, extracted, and evaporated to dryness. Thin-layer chromatography was used to purify the target compound, with a yield of 53.88%. LC-MS [M+H] + :m / z=486.1. 1H NMR (400MHz, DMSO) δ8.64(d,J=9.5Hz,2H),8.59(s,1H),7.91(d,J=5.1Hz,1H),7.43(dd,J=9.0,4.4Hz,1H ),7.33(dd,J=9.1,1.3Hz,1H),6.87(s,2H),6.78(t,J=5.0Hz,1H),3.97(s,2H),2.54(s,3H),2.41(s,3H).

[0289] Example 39: 6-Cyano-3-[[2-fluoro-3-(methylsulfonamide amino)phenyl]methyl]-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0290] Step 1: Synthesis of 6-bromo-3-(2-fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-2H-coumarin-2-one

[0291] Ethyl 2-(2-fluoro-3-nitrobenzyl)-3-oxobutyrate (5.00 g, 17.65 mmol) and bromo-fluororesorcinol (5.00 g, 26.45 mmol) were dissolved in 30.00 mL of methanesulfonic acid and reacted at room temperature for 2 h. After the reaction was complete as monitored by TLC, a large amount of water was added, and a large amount of solid precipitated. The solid was filtered, and the filter cake was dried to give the target compound in 41.64% yield.

[0292] Step 2: Synthesis of 6-bromo-3-(2-fluoro-3-nitrobenzyl)-4-methyl-7-(pyridazin-3-yloxy)-2H-coumarin-2-one

[0293] 6-fluoro-3-(2-fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-2H-coumarin-2-one (4.00 g, 9.80 mmol), 3-bromopyridazine (3.12 g, 19.60 mmol), potassium phosphate (3.38 g, 14.70 mmol), and tBuXPhos-Pd-G3 (1.56 g, 1.96 mmol) were added to 100.00 mL of anhydrous dioxane. The mixture was purged three times with nitrogen and reacted at 120 °C for 12 h under nitrogen protection. After the reaction was complete as monitored by TLC, 50.00 mL of ethyl acetate was added. The reaction solution was dissolved by sonication and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain the target compound in 52.46% yield.

[0294] Step 3: Synthesis of 6-vinyl-3-(3-amino-2-fluorobenzyl)-4-methyl-7-(pyridazin-3-yl)oxy-2H-coumarin-2-one

[0295] 6-Bromo-3-(2-fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-2H-coumarin-2-one (2.40 g, 4.94 mmol) was added to 50.00 mL of dioxane solution, followed by the addition of tributylvinyltin (1.56 g, 4.94 mmol) and bis(triphenylphosphine)palladium dichloride (0.35 g, 0.49 mmol). The reaction was carried out overnight at 100 °C under nitrogen atmosphere. After the reaction was completed as monitored by LC-MS, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain the target compound in 88.82% yield.

[0296] Step 4: 3-(2-fluoro-3-nitrobenzyl)-4-methyl-2-oxo-7-(pyridazine-3-yloxy)-2H-coumarin-6-carboxaldehyde

[0297] The synthesized 6-vinyl-3-(3-amino-2-fluorobenzyl)-4-methyl-7-(pyridazin-3-yloxy)-2H-coumarin-2-one (1.80 g, 4.15 mmol) was dissolved in acetone (20.00 mL), potassium osmium tetroxide (120.00 mg, 0.41 mmol) was added, and the mixture was stirred for 15 min. Then, an aqueous solution of sodium periodate (1.78 g, 8.31 mmol) was added, and the mixture was reacted at room temperature for 6 h. After the reaction was confirmed to be complete by TLC, a large amount of sodium sulfite aqueous solution was added to quench the reaction. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography to obtain the target compound in 71.90% yield.

[0298] Step 5: Synthesis of 3-(2-fluoro-3-nitrobenzyl)-4-methyl-2-oxo-7-(pyridazin-3-yloxy)-2H-coumarin-6-carboxynitrile

[0299] 3-(2-fluoro-3-nitrobenzyl)-4-methyl-2-oxo-7-(pyridazin-3-yloxy)-2H-coumarin-6-carboxaldehyde (200.00 mg, 0.46 mmol) was dissolved in a very small amount of dioxane (1.00 mL), and 3.00 mL of ammonia and iodine (233.00 mg, 0.92 mmol) were added. The reaction was allowed to proceed overnight at room temperature. After the reaction was monitored by LCMS until complete, it was quenched with sodium thiosulfate. The mixture was extracted three times with ethyl acetate, and the organic phases were combined and purified by column chromatography to obtain the target compound in 50.35% yield.

[0300] Step 6: Synthesis of 3-(3-amino-2-fluorobenzyl)-4-methyl-2-oxo-7-(pyridazine-3-yloxy)-2H-coumarin-6-carboxynitrile

[0301] 3-(2-fluoro-3-nitrobenzyl)-4-methyl-2-oxo-7-(pyridazin-3-yloxy)-2H-coumarin-6-carboxynitrile (100.00 mg, 0.23 mmol) was dissolved in 3.00 mL of methanol and 3.00 mL of aqueous solution. Iron powder (100.00 mg, 1.79 mmol) and ammonium chloride (100.00 mg, 1.87 mmol) were added, and the reaction was carried out overnight at 80 °C. After the reaction was monitored by LCMS until complete, the mixture was filtered and extracted three times with dichloromethane. The organic phases were combined to obtain the target compound in 80.88% yield.

[0302] Step 7: Synthesis of 6-formonitrile-3-[[2-fluoro-3-(hydroxyethylsulfonamide amino)phenyl]methyl]-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0303] 3-(3-amino-2-fluorobenzyl)-4-methyl-2-oxo-7-(pyridazin-3-yloxy)-2H-coumarin-6-carboxynitrile (100.00 mg, 0.25 mmol) was dissolved in anhydrous dichloromethane (5.00 mL), and anhydrous pyridine (58.97 mg, 0.75 mmol) and methylaminosulfonyl chloride (32.20 mg, 0.25 mmol) were added. The reaction was carried out at room temperature for 15 min. After the reaction was complete as monitored by TLC, a large amount of water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin-layer chromatography to obtain the target compound in 24.36% yield. LC-MS [M+H] + :m / z=496.1. 1 H NMR (400MHz, DMSO) δ9.37(s,1H),9.13(d,J=4.5Hz,1H),8.56(s,1H),7.92(dd,J=8.9,4.6Hz,1H),7.77(d,J=8.8Hz,1H),7.68(s,1H),7. 29(t,J=7.8Hz,1H),7.21(q,J=4.9Hz,1H),7.02(t,J=7.9Hz,1H),6.91(t,J=7.2Hz,1H),4.00(s,2H),2.53(d,J=4.9Hz,3H),2.49(s,3H).

[0304] Example 40: 6-Trideuterated methyl-3-[[2-fluoro-3-(hydroxyethylsulfonamide amino)phenyl]methyl]-7-(fluoropyridine)oxy-4-methyl-2H-coumarin-2-one

[0305] 3-((2-amino-3-fluoropyridin-4-yl)methyl)-7-((3-fluoropyridin-2-yl)oxy)-4-methyl-6-(trideuteratedmethyl)-2H-coumarin-2-one (0.11 g, 0.21 mmol) was dissolved in 10.00 mL of dichloromethane, and anhydrous pyridine (58.97 mg, 0.75 mmol) and intermediate 3 (32.20 mg, 0.25 mmol) were added. The reaction was carried out at room temperature for 15 min. After the reaction was complete as monitored by TLC, a large amount of water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin-layer chromatography to obtain the target compound in 11.26% yield. LC-MS [M+H] + :m / z=532.1. 1 H NMR(400MHz,DMSO)δ10.49(s,1H),7.96–7.87(m,3H),7.85(s,1H),7.49(s,1H),7.28–7.2 0(m,2H),6.79(s,1H),4.02(s,2H),2.49(s,3H),2.34–2.29(m,1H),0.51(d,J=7.4Hz,4H).

[0306] Example 41: 1-(4-{[6-(d3)methyl-7-[(3-fluoropyridin-2-yl)oxy]-4-methyl-2-oxomylidene-3-yl]methyl}-3-fluoropyridin-2-yl)-N-ethylazanesulfonyl

[0307] The compound 6-(d3)methyl-3-[(2-amino-3-fluoropyridin-4-yl)methyl]-7-[(3-fluoropyridin-2-yl)oxy]-4-methyl-2H-chromen-2-one (0.07 g, 0.170 mmol) was dissolved in ACN (3 mL) and DMA (3 mL), pyridine (0.041 mL, 0.509 mmol) was added, and ethylsulfonamide chloride (0.05 g, 0.339 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 20 min. The reaction was quenched with saturated sodium bicarbonate solution, extracted with EA, dried over sodium sulfate, and the mixture was prepared by reverse reaction to give compound 1-(4-{[6-(d3)methyl-7-[(3-fluoropyridin-2-yl)oxy]-4-methyl-2-oxomylidene-3-yl]methyl}-3-fluoropyridin-2-yl)-N-ethylazanesulfonyl (18.00 mg, 0.035 mmol, 20.41%). LC-MS [M+H] + :m / z=520.2. 1HNMR (400MHz, DMSO) δ10.27 (d, J=38.5Hz, 1H), 7.97–7.74 (m, 4H), 7.35–7.13 (m, 2H), 7.04 (d, J= 7.7Hz, 1H), 6.76 (s, 1H), 4.01 (s, 2H), 2.92 (q, J = 7.2Hz, 2H), 2.48 (s, 3H), 1.01 (t, J = 7.2Hz, 3H).

[0308] Example 42: 6-Fluoro-3-[[2-Fluoro-3-(oxetane-3-ethylsulfonamide amino)phenyl]methyl]-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one

[0309] 6-Fluoro-3-[[2-Fluoro-3-(oxetanebutylethylsulfonamide amino)phenyl]methyl]-7-(pyridazine)oxy-4-methyl-2H-coumarin-2-one was prepared using the method described in Example 26, with the ethylaminosulfonyl chloride in step 5 replaced by intermediate 6, yielding 7.5%. LC-MS [M+H] + :m / z=532.1.

[0310] Example 43: 6-Methyl-3-({3-fluoro-2-[(methylsulfonamide)amino]pyridin-4-yl}methyl)-7-[(3-fluoropyridin-2-yl)oxy]-4-methyl-2H-coumarin-2-one

[0311] Step 1: Synthesis of 3-((2,3-difluoropyridin-4-yl)methyl)-6-methyl-7-hydroxy-4-methyl-2H-coumarin-2-one

[0312] Ethyl 2-((2,3-difluoropyridin-4-yl)methyl)-3-oxobutyrate (3.00 g, 12.33 mmol) and 4-methylresorcinol (2.63 g, 18.50 mmol) were dissolved in 30.00 mL of perchloric acid, and the mixture was heated to 50 °C and reacted for 2 h. After the reaction was completed by TLC monitoring, a large amount of water was added, and a large amount of solid precipitated. The solid was filtered, and the filter cake was dried to give the target compound in 90.5% yield.

[0313] Step 2: Synthesis of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-methyl-7-hydroxy-4-methyl-2H-coumarin-2-one

[0314] 3-((2,3-difluoropyridin-4-yl)methyl)-6-methyl-7-hydroxy-4-methyl-2H-coumarin-2-one (3.72 g, 11.71 mmol), triethylamine (8.10 mL, 58.57 mmol), and 2,4-dimethoxybenzylamine (6.85 g, 40.99 mmol) were added to 80.00 mL of N-methylpyrrolidone, and the mixture was reacted at 100 °C for 24 h. After the reaction was monitored by LC-MS until complete, a large amount of water was added, and the pH of the mixture was adjusted to neutral with 20% dilute hydrochloric acid. A large amount of solid precipitated, which was filtered. The filter cake was slurried with acetonitrile to obtain the target compound in 59.2% yield.

[0315] Step 3: Synthesis of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-methyl-7-((3-fluoropyridin-2-yl)oxy)-4-methyl-2H-coumarin-2-one

[0316] 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-methyl-7-hydroxy-4-methyl-2H-coumarin-2-one (0.30 g, 0.64 mmol), 2,3-difluoropyridine (0.30 g, 2.63 mmol), cesium fluoride (0.15 g, 0.96 mmol), and potassium carbonate (0.18 g, 1.28 mmol) were added to 10.00 mL of anhydrous N,N-dimethylformamide and reacted at 100 °C for 16 h under sealed conditions. After the reaction was monitored by LC-MS until complete, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound in 65.9% yield.

[0317] Step 4: Synthesis of 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-methyl-7-((3-fluoropyridin-2-yl)oxy)-4-methyl-2H-coumarin-2-one

[0318] 1.00 mL of trifluoroacetic acid was added to a 10.00 mL solution of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-methyl-7-((3-fluoropyridin-2-yl)oxy)-4-methyl-2H-coumarin-2-one (236.01 mg, 0.42 mmol) in dichloromethane and reacted for 30 min. After the reaction was confirmed to be complete by TLC, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was filtered through diatomaceous earth, dried, and concentrated. The crude product was used for the next reaction without further purification.

[0319] Step 5: Synthesis of 6-methyl-3-({3-fluoro-2-[(methanesulfonamide)amino]pyridin-4-yl}methyl)-7-[(3-fluoropyridin-2-yl)oxy]-4-methyl-2H-coumarin-2-one

[0320] 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-methyl-7-((3-fluoropyridin-2-yl)oxy)-4-methyl-2H-coumarin-2-one (172.67 mg, 0.42 mmol) was dissolved in anhydrous N,N-dimethylformamide (5.00 mL), and anhydrous pyridine (96.35 g, 1.22 mmol) and methylaminosulfonyl chloride (83.21 mg, 0.63 mmol) were added. The reaction was allowed to proceed at room temperature for 15 min. After the reaction was confirmed to be complete by TLC, a large amount of water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin-layer chromatography to obtain the target compound in 48.8% yield. LC-MS [M+H] + :m / z=503.1. 1 H NMR (400MHz, DMSO) δ10.34(s,1H),8.03–7.88(m,3H),7.85(d,J=0.9Hz,1H),7.32–7.19(m,2H),6.97( q,J=5.1Hz,1H),6.83(t,J=5.1Hz,1H),4.02(s,2H),2.52(d,J=5.2Hz,3H),2.49(s,3H),2.20(s,3H).

[0321] Comparative compound 1 (D1): 6-fluoro-3-({3-fluoro-2-[(methylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0322] Step 1: Synthesis of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-fluoro-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0323] 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-fluoro-7-hydroxy-4-methyl-2H-coumarin-2-one (0.30 g, 0.64 mmol), 2-chloropyrimidine (0.30 g, 2.63 mmol), cesium fluoride (0.15 g, 0.96 mmol), and potassium carbonate (0.18 g, 1.28 mmol) were added to 10.00 mL of anhydrous N,N-dimethylformamide and reacted at 100 °C for 16 h under sealed conditions. After the reaction was monitored by LC-MS until complete, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound in 43.3% yield.

[0324] Step 2: Synthesis of 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-fluoro-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0325] 1.00 mL of trifluoroacetic acid was added to a 10.00 mL solution of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-fluoro-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one (156.26 mg, 0.28 mmol) in dichloromethane and reacted for 30 min. After the reaction was confirmed to be complete by TLC, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was filtered through diatomaceous earth, dried, and concentrated. The crude product was used for the next reaction without further purification.

[0326] Step 3: Synthesis of 6-fluoro-3-({3-fluoro-2-[(methylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0327] 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-fluoro-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one (100.70 mg, 0.24 mmol) was dissolved in anhydrous N,N-dimethylformamide (5.00 mL), and anhydrous pyridine (96.35 g, 1.22 mmol) and methylaminosulfonyl chloride (47.35 mg, 0.36 mmol) were added. The reaction was allowed to proceed at room temperature for 15 min. After the reaction was confirmed to be complete by TLC, a large amount of water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin-layer chromatography to obtain the target compound in 66.5% yield. LC-MS [M+H] + :m / z=490.1. 1H NMR(400MHz,DMSO-d6)δ10.35(d,J=5.4Hz,1H),8.02-7.90(m,4H),7.64(d,J=6.8Hz,1H),7.34-7.2 4(m,1H),6.98(q,J=5.6,5.2Hz,1H),6.85(t,J=5.1Hz,1H),4.03(s,2H),2.52(s,3H),2.48(s,3H).

[0328] Comparative compound 2 (D2): 8-methyl-3-({3-fluoro-2-[(methylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0329] Step 1: Synthesis of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-8-methyl-7-hydroxy-4-methyl-2H-coumarin-2-one

[0330] Ethyl 2-((2,3-difluoropyridin-4-yl)methyl)-3-oxobutyrate (3.00 g, 12.33 mmol) and 2-methylresorcinol (2.63 g, 18.50 mmol) were dissolved in 30.00 mL of perchloric acid, and the mixture was heated to 50 °C and reacted for 2 h. After the reaction was complete as monitored by TLC, a large amount of water was added, and a large amount of solid precipitated. The solid was filtered, and the filter cake was dried to give the target compound in 92.1% yield.

[0331] Step 2: Synthesis of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-8-methyl-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0332] 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-8-methyl-7-hydroxy-4-methyl-2H-coumarin-2-one (0.30 g, 0.64 mmol), 2-chloropyrimidine (0.30 g, 2.63 mmol), cesium fluoride (0.15 g, 0.96 mmol), and potassium carbonate (0.18 g, 1.28 mmol) were added to 10.00 mL of anhydrous N,N-dimethylformamide and reacted at 100 °C for 16 h under sealed conditions. After the reaction was monitored by LC-MS until complete, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound in 42.5% yield.

[0333] Step 3: Synthesis of 3-((2-amino-3-fluoropyridin-4-yl)methyl)-8-methyl-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0334] 1.00 mL of trifluoroacetic acid was added to a 10.00 mL solution of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-8-methyl-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one (156.26 mg, 0.28 mmol) in dichloromethane and reacted for 30 min. After the reaction was confirmed to be complete by TLC, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was filtered through diatomaceous earth, dried, and concentrated. The crude product was used for the next reaction without further purification.

[0335] Step 4: Synthesis of 8-methyl-3-({3-fluoro-2-[(methanesulfonamide)amino]pyridin-4-yl}methyl)-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0336] 3-((2-amino-3-fluoropyridin-4-yl)methyl)-8-methyl-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one (100.70 mg, 0.24 mmol) was dissolved in anhydrous N,N-dimethylformamide (5.00 mL), and anhydrous pyridine (96.35 g, 1.22 mmol) and methylaminosulfonyl chloride (47.35 mg, 0.36 mmol) were added. The reaction was allowed to proceed at room temperature for 15 min. After the reaction was complete as detected by TLC, a large amount of water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin-layer chromatography to obtain the target compound in 73.3% yield. LC-MS [M+H] + :m / z=486.1. 1 H NMR (400MHz, DMSO) δ10.34(s,1H),8.67(d,J=4.8Hz,2H),7.94(d,J=5.1Hz,1H),7.78(d,J=8.8Hz,1H),7.32(t,J=4.8Hz,1H),7. 24(d,J=8.8Hz,1H),6.98(q,J=4.9Hz,1H),6.85(t,J=5.0Hz,1H),4.04(s,2H),2.52(d,J=5.2Hz,3H),2.49(s,3H),2.14(s,3H).

[0337] Comparative compound 3 (D3): 6-methyl-3-({3-fluoro-2-[(methylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0338] Step 1: Synthesis of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-methyl-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0339] 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-methyl-7-hydroxy-4-methyl-2H-coumarin-2-one (0.30 g, 0.64 mmol), 2-chloropyrimidine (0.30 g, 2.63 mmol), cesium fluoride (0.15 g, 0.96 mmol), and potassium carbonate (0.18 g, 1.28 mmol) were added to 10.00 mL of anhydrous N,N-dimethylformamide and reacted at 100 °C for 16 h under sealed conditions. After the reaction was monitored by LC-MS until complete, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound in 43.5% yield.

[0340] Step 2: Synthesis of 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-methyl-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0341] 1.00 mL of trifluoroacetic acid was added to a 10.00 mL solution of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-methyl-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one (156.26 mg, 0.28 mmol) in dichloromethane and reacted for 30 min. After the reaction was confirmed to be complete by TLC, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was filtered through diatomaceous earth, dried, and concentrated. The crude product was used for the next reaction without further purification.

[0342] Step 3: Synthesis of 6-methyl-3-({3-fluoro-2-[(methylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0343] 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-methyl-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one (100.70 mg, 0.24 mmol) was dissolved in anhydrous N,N-dimethylformamide (5.00 mL), and anhydrous pyridine (96.35 g, 1.22 mmol) and methylaminosulfonyl chloride (47.35 mg, 0.36 mmol) were added. The reaction was allowed to proceed at room temperature for 15 min. After the reaction was confirmed to be complete by TLC, a large amount of water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin-layer chromatography to obtain the target compound in 83.3% yield. LC-MS [M+H] + :m / z=486.1. 1 H NMR (400MHz, DMSO) δ10.34(s,1H),8.67(d,J=4.8Hz,2H),8.02–7.75(m,2H),7.42–7.24(m,2H) ,7.12–6.92(m,1H),6.83(s,1H),4.03(s,2H),2.53(d,J=4.7Hz,3H),2.49(s,3H),2.16(s,3H).

[0344] Comparative compound 4 (D4): 5-methyl-3-({3-fluoro-2-[(methylsulfonamide)amino]pyridin-4-yl}methyl)-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0345] Step 1: Synthesis of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-5-methyl-7-hydroxy-4-methyl-2H-coumarin-2-one

[0346] Ethyl 2-((2,3-difluoropyridin-4-yl)methyl)-3-oxobutyrate (3.00 g, 12.33 mmol) and 5-methylresorcinol (2.63 g, 18.50 mmol) were dissolved in 30.00 mL of perchloric acid, and the mixture was heated to 50 °C and reacted for 2 h. After the reaction was complete as monitored by TLC, a large amount of water was added, and a large amount of solid precipitated. The solid was filtered, and the filter cake was dried to obtain the target compound in 88.1% yield.

[0347] Step 2: Synthesis of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-5-methyl-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0348] 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-5-methyl-7-hydroxy-4-methyl-2H-coumarin-2-one (0.30 g, 0.64 mmol), 2-chloropyrimidine (0.30 g, 2.63 mmol), cesium fluoride (0.15 g, 0.96 mmol), and potassium carbonate (0.18 g, 1.28 mmol) were added to 10.00 mL of anhydrous N,N-dimethylformamide and reacted at 100 °C for 16 h under sealed conditions. After the reaction was monitored by LC-MS until complete, a large amount of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target compound in 43.5% yield.

[0349] Step 3: Synthesis of 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-methyl-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0350] 1.00 mL of trifluoroacetic acid was added to a 10.00 mL solution of 3-((2-((2,4-dimethoxyphenyl)amino)-3-fluoropyridin-4-yl)methyl)-6-methyl-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one (156.26 mg, 0.28 mmol) in dichloromethane and reacted for 30 min. After the reaction was confirmed to be complete by TLC, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was filtered through diatomaceous earth, dried, and concentrated. The crude product was used for the next reaction without further purification.

[0351] Step 4: Synthesis of 6-methyl-3-({3-fluoro-2-[(methanesulfonamide)amino]pyridin-4-yl}methyl)-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one

[0352] 3-((2-amino-3-fluoropyridin-4-yl)methyl)-6-methyl-7-(pyrimidin-2-yl)oxy-4-methyl-2H-coumarin-2-one (100.70 mg, 0.24 mmol) was dissolved in anhydrous N,N-dimethylformamide (5.00 mL), and anhydrous pyridine (96.35 g, 1.22 mmol) and methylaminosulfonyl chloride (47.35 mg, 0.36 mmol) were added. The reaction was allowed to proceed at room temperature for 15 min. After the reaction was confirmed to be complete by TLC, a large amount of water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin-layer chromatography to obtain the target compound in 76.5% yield. LC-MS [M+H] + :m / z=486.1. 1H NMR (400MHz, DMSO) δ10.31(s,1H),8.69(d,J=4.8Hz,2H),7.92(d,J=4.9Hz,1H),7.33(t,J=4.8Hz,1H),7.21(s,1H),7.04 –7.00(m,1H),6.96(d,J=4.8Hz,1H),6.75(t,J=4.4Hz,1H),3.96(s,2H),2.47(d,J=4.0Hz,3H),2.39(s,3H),2.31(s,3H).

[0353] Bioactivity test

[0354] 1. Inhibitory activity of the compound against AsPC-1 cells

[0355] Human pancreatic cancer cell line AsPC-1 was cultured in appropriate media containing 10% fetal bovine serum and penicillin / streptomycin at 37°C with 5% CO2. The cytotoxicity of the target compounds to AsPC-1 cells was investigated using CCK-8. Approximately 4000 cells were seeded per well in 96-well plates. After cell attachment, 200 μL of fresh medium containing different concentrations of the compounds was added. After 72 hours of incubation, 10 μL of CCK-8 was added to each well, and incubation continued for another 2 hours. The plates were shaken for approximately 20 seconds, and absorbance was measured at 450 nm using a microplate reader. Reference compounds NST-628 and VS-6766 were purchased from MedChemExpress Shanghai. Reference compound Ref-1 was synthesized according to the method described in Example 3 of patent WO2023143206.

[0356] The experimental results are shown in Table 2.

[0357] Table 2 Results of cell inhibitory activity tests of the compounds

[0358] Conclusion: The compounds of the present invention significantly inhibit the antiproliferative activity of AsPC-1 cells. The antitumor activity of the compounds in preferred embodiments 5, 12, 13, 16, 17, 18, 19, 21, 24, 25, 26, 28, 29, 39, and 41 is significantly better than that of the reference compounds NST-628, VS-6766, Ref-1, D1, D2, D3, and D4.

[0359] 2. Affinity assay for the interaction between MEK1 and BRAF and CRAF proteins

[0360] The TR-FRET Binding method was used to test the affinity of MEK1 for interaction with BRAF and CRAF proteins.

[0361] The reagents and materials are shown in Table 3:

[0362] Table 3 Reagent Materials

[0363] The experimental steps are as follows:

[0364] 1) Prepare 1x kinase buffer and stop solution: 1x kinase buffer, 50mM HEPES pH 7.5, 50mM NaCl, 5mM MgCl2, 1mM DTT, 1mM ATP, 0.01% Triton X-100, 0.1% BSA.

[0365] 2) Compound Preparation: The initial concentration of the compound for detection was 10 μM, prepared to a 100-fold concentration, i.e., 1000 μM. Take 5 μl of the 10 mM compound and add 45 μl of 100% DMSO to prepare a 1000 μM compound solution. Add 50 μl of the 100-fold compound solution to the second well of a 96-well plate, and 30 μl of 100% DMSO to the other wells. Take 10 μl of the compound from the second well and add it to the third well, and so on, performing 4-fold dilutions for a total of 10 concentrations. Transfer 40 μl of 100% DMSO to two empty wells as controls (no compound and no enzyme added); use an Echo to transfer 200 nmol of the compound to a 384-well plate.

[0366] 3) Prepare 4x kinase solutions: Prepare 4x BRAF and CRAF kinase solutions using 1x kinase buffer. Transfer 5 μl of the 4x enzyme solution to a 384-well plate. Centrifuge at 1000 rpm for 1 minute and incubate at room temperature. Prepare 4x MAP2K1 (MEK1) kinase solutions using 1x kinase buffer. Transfer 5 μl of the 4x enzyme solution to a 384-well plate. Centrifuge at 1000 rpm for 1 minute and incubate at room temperature.

[0367] 4) Prepare 2x stop solution: Use 1x kinase buffer, add MAb Anti GST-Tb cryptate and His-XL665 to prepare 2x stop solution. Transfer 10 μl of stop solution to the wells of a 384-well plate, centrifuge at 1000 rpm for 1 minute, and let stand at room temperature for 1 hour.

[0368] 5) Data reading: Read sample values ​​in Envision.

[0369] 6) Calculate the ratio of replicated fluorescence readings (Lantha signal (665nm / 615nm)). Convert the above data to the inhibition percentage using the formula: Percent inhibition = (max - Lantha signal) / (max - min) * 100, where "min" is the reading of the control well without enzyme reaction; "max" is the reading of the control well with DMSO added. Import the data into MS Excel, IC... 50 The results were obtained using the curve fitting formula from XLFit Excel add-in version 5.4.0.8: Y = Bottom + (Top - Bottom) / (1 + (IC50 / X)^HillSlope).

[0370] The experimental results are shown in Table 4:

[0371] Table 4. Affinity test results of MEK1 interaction with BRAF and CRAF proteins.

[0372] Conclusion: The compounds of this invention promote the formation of MEK1 / BRAF and MEK1 / CRAF ternary complexes, exert the properties of molecular glue, and the effect is significantly better than that of the reference compound VS-6766.

[0373] 3. Immunoblotting experiment of the compound in Example 5

[0374] Protein samples were extracted using RIPA lysis buffer (BioSharp, China). Cellular proteins were separated by 10% SDS-PAGE and transferred to polyvinylidene fluoride membranes (Millipore, IRL). The membranes were blocked in a 5% skim milk solution dissolved in PBST. The membranes were incubated overnight at 4°C with the following primary antibodies: MEK1 / 2 (D1A5) rabbit monoclonal antibody (CST Biotech, USA), phosphate-MEK1 (S217 / 221)(41G9) rabbit monoclonal antibody (CST Biotech, USA), ERK1 / 2 rabbit monoclonal antibody (ZENBIO, China), phosphate-Erk1 (T202 / Y204) + Erk2 (T185 / Y187) (Abways, China), GAPDH (Abways, China), and β-actin (Abways, China). Compound VS-6766 was purchased from MedChemExpress, Shanghai. Wash the membrane four times with PBST, then incubate for 45 minutes with horseradish peroxidase-linked secondary antibody (diluted with 5% milk). Use SuperKine. TMSpecific bands were detected using West Femto's highest-sensitivity substrate (Abbkine, USA), and images were taken using a ChemiScope 6100 (clinx, China). KRAS-mutant colon cancer cells HCT116 were treated with VS6766 and the compound from Example 5 for 4 hours, and the phosphorylation status of MEK and ERK at different concentrations was analyzed (Figure 1A). HCT116 cells were then treated with 3 nM of the compound from Example 5 and 300 nM of the reference compound VS6766 for 96 hours, and the changes in MEK and ERK phosphorylation levels were analyzed (Figure 1B). As shown in Figure 1, after 4 hours of treatment with the compound from Example 5 and VS-6766, the phosphorylation levels of MEK and ERK in HCT116 cells were significantly reduced, and the inhibitory effect of the compound was significantly better than that of VS-6766. In addition, after 96 hours of treatment with 3nM of the compound from Example 5 and 300nM of the reference compound VS6766, the inhibitory effects of the compounds on MEK and ERK phosphorylation did not change significantly, but the MEK phosphorylation level recovered significantly after treatment with VS-6766.

[0375] Conclusion: The compound in Example 5 exhibits stronger inhibitory effects and longer duration of inhibition on the RAF / MEK / ERK pathway, significantly outperforming the reference compound VS-6766.

[0376] 4. Evaluation of the distribution of the compound in mouse brain tissue and plasma

[0377] Experimental procedure: Weigh the compound, add a small amount of DMSO, then add sodium chloride solution for injection to prepare a solution of 0.5 mg / mL. -1 A solution of the compound, ready for administration. For male mice, administer at 5 mg / kg. -1 The drug was administered orally. Whole brain and whole blood samples were collected at 1 h and 6 h post-administration (n=2). Whole blood was centrifuged at 3500 rpm for 15 min, and the supernatant plasma was collected. The weight of centrifuge tube M1, the weight of the centrifuge tube containing whole brain (M2), the weight of the centrifuge tube after homogenization with water (M3), and the weight of the centrifuge tube containing 30 μL of homogenate (M4) were collected. 30 μL of plasma and 30 μL of brain homogenate were placed in centrifuge tubes, and 120 μL of acetonitrile containing 20 ng·ml⁻¹ internal standard SAHA was added to precipitate. The mixture was vortexed for 30 s and centrifuged at 13000 rpm for 15 min. The supernatant was collected and injected into sample vials for analysis. Standard curve range: 10–10000 ng·ml⁻¹. -1 Drug content in the brain = measured value × 0.03 × (M3-M1) / [(M2-M1) × (M3-M4)].

[0378] The experimental results are shown in Table 5.

[0379] Table 5. Results of compound administration to mouse brain tissue and plasma distribution.

[0380] Conclusion: Some compounds of the present invention have good brain penetration potential. In particular, the brain-blood ratios of the compounds of Example 5 and Example 21 are significantly better than that of the reference compound NST-628.

[0381] 5. Pharmacokinetic evaluation in mice

[0382] Experimental purpose: To understand the pharmacokinetics of the compounds.

[0383] Experimental basis: Technical Guidelines for Non-clinical Pharmacokinetic Studies of Chemical Drugs, 2014.

[0384] Experimental protocol: The pharmacokinetics of the compounds were investigated by oral administration (5 mg·kg -1 ) to mice.

[0385] Sample preparation: Weighed compounds were dissolved in DMSO and then added with sodium chloride injection solution to prepare a compound solution of 0.5 mg·mL -1 for use in drug administration.

[0386] Sample collection: Three male Balb / c mice (Chengdu Dashuo Experimental Animal Co., Ltd., License No.: SCXK(Sichuan)2020-030) were orally administered (PO) at 5 mg·kg -1 . Approximately 0.05 mL of blood was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 24 h, and 48 h after administration. The collected blood was centrifuged at 3500 rpm for 15 min, and the supernatant plasma was collected and stored at -40 °C for later measurement. The plasma drug concentration was quantitatively analyzed by LC-MS / MS, and pharmacokinetic parameters such as peak time (C max ), area under the curve (AUC (0-t) ), half-life (T 1 / 2 ), clearance rate (CL), and volume of distribution (V dss ) were calculated.

[0387] The results of pharmacokinetic evaluation are shown in Table 6.

[0388] Table 6 Pharmacokinetic test results of compounds in Balb / c mice

[0389] Conclusion: Some compounds of the present invention have good pharmacokinetic properties in Balb / c mice, including good oral bioavailability, exposure, half-life, clearance rate, and area under the curve, etc.

[0390] 6. Compounds of Example 5 and 43 in mouse Lewis lung cancer LLC (Kras G12Cand Nras Q61H In vivo efficacy evaluation of xenograft mouse models

[0391] Experimental method: Female nude mice (NU / NU, 4-6 weeks old) were subcutaneously injected with LLC cells (5 x 10⁻⁶ cells) into the right abdomen. 5 / each). When the average tumor size is 250mm 3 (V=L*W 2 / 2) Mice were randomly divided into different treatment groups, with 6 mice in each group, including a control group, an NST-628 treatment group (6 mg / kg, suspended in 1% DMSO, 1% anhydrous ethanol and 98% saline), administered orally once daily; an Example 43 compound treatment group (3 mg / kg, suspended in 1% DMSO, 1% anhydrous ethanol and 98% saline), administered orally once daily; and an Example 5 compound treatment group (3 mg / kg, suspended in 1% DMSO, 1% anhydrous ethanol and 98% saline), administered orally once daily, for a total of 23 days. Tumor size and body weight were measured during treatment. Nude mice were sacrificed after 23 days.

[0392] The experimental results are shown in Figure 2. The antitumor efficacy of compound 5, administered orally at 3 mg / kg once daily, was superior to that of reference compound NST-628, administered orally at 6 mg / kg once daily. The antitumor efficacy of compound 5, administered orally at 3 mg / kg once daily, was superior to that of compound 43, administered orally at 3 mg / kg once daily, and there was no significant change in mouse body weight during the treatment period.

[0393] 7. Examples 5 and 43: Effects of compounds on human pancreatic cancer AsPC-1 (KRAS) G12D In vivo efficacy evaluation in mouse xenograft model

[0394] Experimental methods: Female nude mice (NU / NU, 4-6 weeks old) were subcutaneously injected with AsPC-1 cells (5 x 10⁻⁶ cells) into the right abdomen. 6 / each). When the average tumor size is 200mm 3 (V=L*W 2 / 2) Mice were randomly divided into different treatment groups, with 6 mice in each group, including a control group, an NST-628 treatment group (3 mg / kg, suspended in 1% DMSO, 1% anhydrous ethanol and 98% saline), administered orally once daily; an example 43 compound treatment group (1 mg / kg, suspended in 1% DMSO, 1% anhydrous ethanol and 98% saline), administered orally once daily; and an example 5 compound treatment group (1 mg / kg, suspended in 1% DMSO, 1% anhydrous ethanol and 98% saline), administered orally once daily, for a total of 45 days. Tumor size and body weight were measured during treatment. Nude mice were sacrificed after 45 days.

[0395] The experimental results are shown in Figure 3. The antitumor efficacy of compound 5, administered orally at 1 mg / kg once daily, was superior to that of reference compound NST-628, administered orally at 3 mg / kg once daily. The antitumor efficacy of compound 5, administered orally at 1 mg / kg once daily, was superior to that of compound 43, administered orally at 1 mg / kg once daily, and there was no significant change in mouse body weight during the treatment period.

[0396] 8. Example 18 Compound's effect on human colon cancer HCT116 (KRAS) G13D In vivo efficacy evaluation of xenograft mouse models

[0397] Experimental methods: Female nude mice (NU / NU, 4-6 weeks old) were subcutaneously injected with HCT116 cells (4.0 × 10⁻⁶) in the right abdomen. 6 / each). When the tumor size reaches 100-200mm 3 (V=L*W 2 In step 2), mice were randomly divided into different treatment groups, with 6 mice in each group. These included a control group, a NST-628 3 mg / kg treatment group (suspended in 1% DMSO, 1% anhydrous ethanol, and 98% saline), administered orally once daily; a Compound 18 1.5 mg / kg treatment group (suspended in 1% DMSO, 1% anhydrous ethanol, and 98% saline), a Compound 18 5 mg / kg treatment group (suspended in 1% DMSO, 1% anhydrous ethanol, and 98% saline), and a Compound 18 15 mg / kg treatment group (suspended in 1% DMSO, 1% anhydrous ethanol, and 98% saline). All medications were administered orally once daily for 36 days. Tumor size and body weight were measured during treatment.

[0398] The experimental results are shown in Figure 4. In Example 18, the antitumor efficacy of compound NST-628 administered orally once daily at doses of 1.5 mg / kg, 5 mg / kg, and 15 mg / kg was significantly better than that of compound NST-628 administered orally once daily at doses of 3 mg / kg. Furthermore, the body weight of mice in the treatment groups did not change significantly during the treatment period, demonstrating good safety.

[0399] 9. Example 18 Compound's effect on Lewis lung cancer LLC (Kras) in mice G12C and Nras Q61H In vivo efficacy evaluation of xenograft mouse models

[0400] Experimental method: Female nude mice (NU / NU, 4-6 weeks old) were subcutaneously injected with LLC cells (5 x 10⁻⁶ cells) into the right abdomen. 5 / each). When the average tumor size is 250mm 3 (V=L*W 2 / 2) Mice were randomly divided into different treatment groups, with 6 mice in each group, including a control group, a NST-628 6 mg / kg treatment group (suspended in 1% DMSO, 1% anhydrous ethanol and 98% saline), administered orally once daily; a Compound 18 3 mg / kg treatment group (suspended in 1% DMSO, 1% anhydrous ethanol and 98% saline), and a Compound 18 6 mg / kg treatment group (suspended in 1% DMSO, 1% anhydrous ethanol and 98% saline). Administered orally once daily for 16 days. Tumor size and body weight were measured during treatment. Nude mice were sacrificed after 16 days.

[0401] The experimental results are shown in Figure 5. In Example 18, the antitumor efficacy of compound 3 mg / kg and 6 mg / kg administered orally once daily was significantly better than that of reference compound NST-628 administered orally once daily at 6 mg / kg. Furthermore, the weight of mice in the treatment groups did not change significantly during the treatment period, demonstrating good therapeutic safety.

[0402] 10. Example 18: The effect of compound 18 on human acute myeloid leukemia cells OCI-AML-3 (NRAS) Q61L In vivo efficacy evaluation of xenograft mouse models

[0403] Experimental methods: Female nude mice (Balb / c-nude, 4-6 weeks old) were subcutaneously injected with OCI-AML-3 cells (1 x 10^6 cells) into the right abdomen. 6 / each). When the average tumor size is 120mm 3 (V=L*W 2 / 2) Mice were randomly divided into different treatment groups, with 6 mice in each group, including a control group, a NST-628 6 mg / kg treatment group (suspended in 1% DMSO, 1% anhydrous ethanol and 98% saline), administered orally once daily; a Compound 18 3 mg / kg treatment group (suspended in 1% DMSO, 1% anhydrous ethanol and 98% saline), and a Compound 18 6 mg / kg treatment group (suspended in 1% DMSO, 1% anhydrous ethanol and 98% saline). Administered orally once daily for 17 days. Tumor size and body weight were measured during treatment. Nude mice were sacrificed after 17 days.

[0404] The experimental results are shown in Figure 6. In Example 18, the antitumor efficacy of compound 3 mg / kg and 6 mg / kg administered orally once daily was significantly better than that of reference compound NST-628 administered orally once daily at 6 mg / kg. Furthermore, the weight of mice in the treatment groups did not change significantly during the treatment period, demonstrating good therapeutic safety.

[0405] 11. Examples 5 and 20: Effects of compounds on human acute myeloid leukemia cells OCI-AML-3 (NRAS) Q61L In vivo efficacy evaluation of xenograft mouse models

[0406] Experimental methods: Female nude mice (Balb / c-nude, 4-6 weeks old) were subcutaneously injected with OCI-AML-3 cells (1 x 10^6 cells) into the right abdomen. 6 / each). When the average tumor size is 120mm 3 (V=L*W 2 / 2) Mice were randomly divided into different treatment groups, with 6 mice in each group, including a control group, a treatment group receiving 125 mg / kg of reference compound IMM-1-104 (suspended in 1% DMSO, 1% anhydrous ethanol, and 98% saline), administered orally twice daily, and a treatment group receiving 3 mg / kg of reference compound VS-6766 (suspended in 1% DMSO, 1% anhydrous ethanol, and 98% saline), administered orally once daily. Treatment groups for Compound 5 (5 mg / kg, 10 mg / kg, and 5 mg / kg, suspended in 1% DMSO, 1% anhydrous ethanol, and 98% saline), and treatment groups for Compound 20 (3 mg / kg and 10 mg / kg, suspended in 1% DMSO, 1% anhydrous ethanol, and 98% saline), were administered orally once daily for 17 days. Tumor size and body weight were measured during treatment. Nude mice were sacrificed after 17 days. The compound IMM-1-104 was synthesized using the same method as compound 9 in patent WO2021142144.

[0407] The experimental results are shown in Figure 7. In Example 20, the antitumor efficacy of compounds administered orally at 3 mg / kg and 10 mg / kg once daily was significantly better than that of the reference compound VS6766 administered orally at 3 mg / kg once daily and IMM-1-104 administered orally at 125 mg / kg twice daily. Furthermore, there was no significant change in body weight in the treated mice, demonstrating good therapeutic safety. In Example 5, the antitumor efficacy of compounds administered orally at 10 mg / kg and 20 mg / kg once daily was significantly better than that of the reference compound VS6766 administered orally at 3 mg / kg once daily and IMM-1-104 administered orally at 125 mg / kg twice daily. Furthermore, there was no significant change in body weight in the treated mice, demonstrating good therapeutic safety.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, polymorph, or solvate thereof. in, R1 is selected from C 1-4 Alkyl, C 3-6 Cycloalkyl groups and 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, and heterocyclic alkyl groups are optionally surrounded by 1-3 heteroatoms selected from deuterium, halogen, OH, NH2, CN, C. 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl and C 2-4 Group substitution of the alkynyl group; X is selected from N and CH; R2 is selected from H and halogens; R 3a Selected from hydrogen, halogens, C 1-4 Alkyl, amino, cyano, C 2-4 The alkyl and nitro groups are optionally substituted with 1 to 3 groups selected from deuterium, halogen, and cyano groups; R 3b Selected from hydrogen and halogens; R 3c C 1-4 alkyl; Ring A is selected from pyridine and pyridazine; R4 is selected from deuterium and C. 1-4 Alkyl groups, OH, NH2, CN, and halogens; n is an integer between 0 and 3; The condition is that when ring A is pyridine, R 3a C 1-4 Alkyl group, wherein the alkyl group is substituted with 1-3 deuterium atoms.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, wherein, R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, tetrahydropyrrole, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and piperazinyl, and is optionally substituted by 1 to 3 groups selected from deuterium, F, Cl, Br, I, OH, NH2, CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, vinyl, propenyl, allyl, ethynyl, propynyl, and propargyl; X is selected from N and CH; R2 is selected from F and Cl; R 3a Selected from hydrogen, F, Cl, Br, I, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and CD3; R 3b Selected from hydrogen, F, Cl, and Br; R 3c It can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; Ring A is selected from pyridine and pyridazine; R4 is selected from deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, OH, NH2, CN, F, Cl, Br, and I; n is 0 or 1; The condition is that when ring A is pyridine, R 3a It is CD3.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, wherein, Fragment in Equation I for 4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, wherein, Fragment in Equation I for 5. The compound according to claim 1, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, wherein, The compound is selected from:

6. A pharmaceutical composition wherein the active ingredient comprises the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt, polymorph, or solvate thereof, and is supplemented with a pharmaceutically acceptable carrier or excipient.

7. Use of the compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, or the pharmaceutical composition of claim 7, in the preparation of a medicament for the treatment and / or prevention of MEK or Ras-MAPK-mediated diseases.

8. The use according to claim 7, wherein the MEK or Ras-MAPK-mediated disease is a tumor; preferably, the tumor is breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumors, cholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell carcinoma, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.

9. A method for treating MEK or Ras-MAPK-mediated diseases, the method comprising administering a therapeutically effective amount of the compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt, polymorph, or solvate thereof, or the pharmaceutical composition of claim 6, to a subject in need.

10. The method according to claim 9, wherein the MEK or Ras-MAPK-mediated disease is a tumor; preferably, the tumor is breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumors, cholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell carcinoma, squamous cell carcinoma of the lung, lichen keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.

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