Coumarin compound and pharmaceutically acceptable salt thereof as well as preparation method and application of coumarin compound and pharmaceutically acceptable salt

Abstract

The invention belongs to the technical field of medicinal chemistry and medicine, and particularly relates to a coumarin compound and pharmaceutically acceptable salt thereof as well as a preparation method and application of the coumarin compound. According to the compound, a coumarin mother nucleus is used as a skeleton, and target selectivity and binding efficiency are improved through multi-substituent collaborative design; a novel structure type and a practical scheme are provided for research and development of CDK9 targeted anti-cancer drugs, and important clinical value and application prospects are achieved.

Description

Technical Field

[0001] This invention belongs to the fields of medicinal chemistry and pharmaceutical technology, specifically relating to a coumarin compound and its pharmaceutically acceptable salt, as well as its preparation method and uses. Background Technology

[0002] Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, accounting for approximately 10%-20% of all breast cancer cases. Due to the lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), TNBC is insensitive to conventional endocrine therapy and anti-HER2 targeted therapy. Clinically, TNBC patients face severe challenges such as early recurrence, high metastatic potential, and extremely poor prognosis. Current treatment options are extremely limited, necessitating the development of new molecularly targeted therapies.

[0003] Among numerous potential targets, cyclin-dependent kinase 9 (CDK9) has attracted significant attention due to its central role in transcriptional regulation. CDK9 is the catalytic core of the positive transcription elongation factor b (P-TEFb) complex. By binding to Cyclin T, it phosphorylates serine 2 of the C-terminal domain (CTD) of RNA polymerase II (RNAP II), promoting the transition of transcription from the paused state to the elongation phase. Studies have shown that TNBC cells exhibit significant "transcription addiction," highly dependent on CDK9 to maintain the sustained expression of short-lived anti-apoptotic proteins and proliferation drivers such as c-Myc and MCL1. Furthermore, CDK9 also regulates the expression of transcription factors such as Snail1 and Twist1, promoting epithelial-mesenchymal transition (EMT), thereby driving tumor invasion and metastasis. Therefore, inhibiting CDK9 can not only indirectly block traditionally "undruggable" oncoprotein signaling but also inhibit tumor metastasis, demonstrating significant therapeutic potential.

[0004] Despite the significant efficacy of CDK9 inhibitors in preclinical models, the development of existing drugs still faces numerous challenges. Early pan-CDK inhibitors (such as Dinaciclib and CYC065), while having entered clinical trials, often resulted in severe off-target side effects such as cardiotoxicity and myelosuppression due to a lack of subtype selectivity. Although selectively improved inhibitors such as C35 and KB-0742 have emerged in recent years, achieving high activity, high subtype selectivity, and excellent pharmacokinetic properties simultaneously in a single molecule remains a major challenge in this field.

[0005] The root cause of this predicament lies in the complexity of CDK9 structural design. Unlike other members of the CDK family, CDK9's ATP-binding pocket lacks unique targeting residues (such as lysine in CDK1 / 2 / 5, histidine in CDK4 / 6, or cysteine ​​in CDK7 / 12 / 13), making precise selectivity through structure-based drug design (SBDD) exceptionally difficult. Currently, most strategies rely solely on utilizing the conformational plasticity of the glycine-rich ring (G-loop), and structural space exploration remains insufficient.

[0006] Therefore, there is an urgent need in this field to develop novel CDK9 inhibitors with novel structures, unique mechanisms, and excellent drug-like properties. Summary of the Invention

[0007] In view of the problems existing in the prior art, the purpose of this invention is to provide a coumarin compound and its pharmaceutically acceptable salt with high CDK9 inhibitory activity, high selectivity and easy preparation, as well as the preparation method and application of the compound and its pharmaceutically acceptable salt, so as to solve the problems of existing CDK9 inhibitors such as single structure, significant off-target effect, high preparation cost and poor penetration into solid tumors.

[0008] The present invention relates to a coumarin compound and a pharmaceutically acceptable salt thereof, the coumarin compound having the structure of formula (I): Formula (I).

[0009] Wherein, R1 is selected from , , , , , , , , , , , , , , , and ;

[0010] R1 is selected from: dimethylamino, oxetane-3-ylamino, 4-amino-4-methylpiperidin-1-yl, 4-methylpiperazin-1-yl, 4-methyl-1,4-diazaphen-1-yl, 2-methylpiperazin-1-yl, 4-methoxycarbonylpiperidin-1-yl, morpholino, 3-methylmorpholino, 2-methylmorpholino, 2-ethylmorpholino, 2-methylpyrrolidone-1-yl, or 3-oxa-8-azabicyclo[3.2.1]octane-8-yl.

[0011] R2 is selected from H, halogens (such as F, Cl), methyl (Me), and methoxy (OMe).

[0012] X is selected from CH, N, CF, CCl.

[0013] R3 is selected from , , , , , , , , ;

[0014] R3 is optionally a C3-C7 cycloalkyl group substituted with one or two halogens, or a 4-6 membered saturated heterocyclic group containing one or two heteroatoms and optionally protected by Boc. Preferably, it is specifically selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4,4-difluorocyclohexyl, tetrahydro-2-hydro-pyran-4-yl, piperidin-4-yl, and piperidin-3-yl.

[0015] Furthermore, the coumarin compound is selected from the following substances: .

[0016] The present invention relates to a method for preparing coumarin compounds and their pharmaceutically acceptable salts, comprising the following steps:

[0017] S1. Mix the compound shown in formula (M3), an amine nucleophile with or without a protecting group, and a first solvent to carry out a nucleophilic substitution reaction to obtain the first intermediate;

[0018] S2. The first intermediate, boryling agent, second catalyst, second basic agent and second solvent are mixed and boron esterification reaction is carried out to obtain the second intermediate;

[0019] S3. Mix the second intermediate, formula (M6) or haloaromatic (M5), third catalyst, third basic reagent and third solvent to carry out a cross-coupling reaction; then, react the product obtained from the cross-coupling reaction with an amide compound or an activated amino acid to obtain the third intermediate.

[0020] S4. The first intermediate, the boron-containing nucleophile shown in formula (M7), the fourth catalyst, the fourth basic reagent and the fourth solvent are mixed and subjected to a cross-coupling reaction to obtain the fourth intermediate.

[0021] S5. When there is no protecting group, the third intermediate and the fourth intermediate are coumarin compounds as shown in formula (I); when there is a protecting group, the protecting group in the third intermediate or the fourth intermediate containing the protecting group is removed to obtain the coumarin compound as shown in formula (I).

[0022] Formula (M3) R2 is selected from H, methyl, methoxy or halogen;

[0023] Formula (M5) , X is selected from N, CH, CF or CCl;

[0024] Formula (M6) , X is selected from N, CH, CF or CCl, R3 has the same structure as R3 in formula (I), and is selected from cycloalkyl or nitrogen-containing saturated heterocycles with / without protecting groups, and Boc is tert-butoxycarbonyl.

[0025] Formula (M7) X is selected from N, CH, CF or CCl.

[0026] The first intermediate has the structure shown in formula (M4):

[0027] Formula (M4); R1 replaces Cl in formula (M3), and R1 in formula (M4) is the same as R1 in formula (I); selected from dimethylamino, 4-tert-butoxycarbonylpiperazin-1-yl, 4-methylpiperazin-1-yl, piperazin-1-yl, morpholinyl, (R)-2-methylmorpholinyl, (S)-2-methylmorpholinyl, (R)-3-methylmorpholinyl, (S)-3-methylmorpholinyl, (R)-3-aminopyrrolidine-1-yl, (S)-3-aminopyrrolidine-1-yl, 2-oxa-6-azaspiro[3.3]heptane-6-yl and 3-oxa-8-azabicyclo[3.2.1]octane-8-yl.

[0028] The second intermediate has the structure shown in formula (M9):

[0029] In formula (M9), R1 is selected from various N-heterocycles in (M4).

[0030] The third intermediate has the structure shown in formula (M10) or formula (M11):

[0031] Formula (M10) Formula (M11);

[0032] In amide compounds or activated amino acids, the group introducing R3 is a cycloalkylformyl group or an N-protected amino acid acyl group. The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 4,4-difluorocyclohexyl; the N-protected amino acid acyl group is selected from N-Boc-(R)-piperidine-3-formyl, N-Boc-(S)-piperidine-3-formyl, N-Boc-(R)-prolyl and N-Boc-(S)-prolyl.

[0033] The fourth intermediate has the structure shown in formula (M12):

[0034] In formula (M12), R1 is selected from various N-heterocycles in (M4).

[0035] In step S1:

[0036] For every 1 mmol of the compound represented by formula (M3), use 2 mL to 10 mL of the first solvent, and the molar ratio of the compound represented by formula (M3) to the amine nucleophile is 1:(1.1-10.0).

[0037] Amine nucleophiles include aliphatic amines or cyclic amines; the first solvent is selected from one or more of DMSO, DMF, acetonitrile, and NMP;

[0038] The nucleophilic substitution reaction is carried out at temperatures ranging from 20℃ to 85℃ for 2 hours to 6 hours.

[0039] In step S2:

[0040] For every 1 mmol of the first intermediate, use 5 mL to 20 mL of the second solvent. The molar ratio of the first intermediate, the boryling agent, and the second catalyst is 1:(1.1-1.5):(0.02-0.1), and the molar ratio of the first intermediate to the second basic agent is 1:3.

[0041] The borizing agent is selected from pinacol diboronate ((Bpin)2) and / or pinacol isopropoxyboronate; the second catalyst is selected from one or more of Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(OAc)2 and Pd(amphos)Cl2; the second basic agent is selected from one or more of potassium acetate (KOAc), potassium carbonate and cesium carbonate; the second solvent is selected from one or more of 1,4-dioxane, DMSO, DMF and toluene.

[0042] The boron esterification reaction is carried out at a temperature of 90℃-100℃ for 6h-14h.

[0043] In step S3:

[0044] For every 1 mmol of the second intermediate, use 1 mL to 20 mL of the third solvent. The molar ratio of the second intermediate, the compound shown in formula (M6) or (M5), and the third catalyst is 1:(1.0-1.2):(0.02-0.1). The molar ratio of the second intermediate to the third basic reagent is 1:3.

[0045] The third catalyst is selected from one or more of Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(OAc)2 and Pd(amphos)Cl2; the third basic reagent is selected from one or more of potassium carbonate, potassium phosphate, sodium carbonate, cesium carbonate and cesium fluoride; the third solvent is selected from one or a mixture of one or more of 1,4-dioxane, water, ethanol, DMF and DME.

[0046] The cross-coupling reaction was carried out under inert gas protection at a temperature of 85℃-100℃ for 1-12 hours.

[0047] The amide compounds are selected from one or more of cyclopropionyl chloride, cyclobutyryl chloride, cyclopentyl chloride, cyclohexyl chloride and 4,4-difluorocyclohexanecarboxyl chloride;

[0048] The activated amino acid was prepared by reacting an N-protected amino acid with 1-chloro-N,N,2-trimethylpropyleneamine (Ghosez reagent) in situ at 0°C to room temperature; the N-protected amino acid was selected from N-Boc-piperidine-3-carboxylic acid or N-Boc-proline.

[0049] The (M5) haloaryrhine is selected from one or more of 2-amino-4-bromopyridine, 2-amino-4-iodo-5-fluoropyridine, 2-amino-4-bromo-5-chloropyridine and 2-amino-4-bromopyrimidine;

[0050] An organic base is also added during the amination reaction. The organic base is selected from one or more of pyridine, triethylamine and DIPEA. The conditions for the amination reaction include: reaction at 0°C to room temperature, and reaction time of 1-12 hours (preferably 2 hours).

[0051] The cross-coupling reaction also involves the addition of an alkaline substance, which is selected from one or more of potassium carbonate, potassium phosphate, sodium carbonate, cesium carbonate, and cesium fluoride.

[0052] In step S4:

[0053] For every 1 mmol of the first intermediate, use 1 mL to 20 mL of the fourth solvent. The molar ratio of the compound shown in formula (M7), the first intermediate, and the fourth catalyst is 1:(1.0-1.2):(0.02-0.1), and the molar ratio of the first intermediate to the fourth basic reagent is 1:3.

[0054] The fourth catalyst is selected from one or more of Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(OAc)2 and Pd(amphos)Cl2; the fourth basic reagent is selected from one or more of potassium carbonate, potassium phosphate, sodium carbonate, cesium carbonate and cesium fluoride; the fourth solvent is selected from one or a mixture of one or more of 1,4-dioxane, water, ethanol, DMF and DME.

[0055] The cross-coupling reaction was carried out under inert gas protection at a temperature of 85℃-100℃ for 1-12 hours.

[0056] In step S5:

[0057] The conditions for removing the protecting group include: when the protecting group is tert-butyloxycarbonyl (Boc), the third or fourth intermediate containing the protecting group is reacted in a mixture of acidic reagent (selected from trifluoroacetic acid or hydrogen chloride) and organic solvent (such as dichloromethane) at 0°C to room temperature for 1 h to 12 h (preferably 1 h to 4 h). After the reaction is completed, the mixture is concentrated and purified to obtain the compound shown in formula (I).

[0058] The coumarin compounds and their pharmaceutically acceptable salts of the present invention can be used to prepare remedies for the prevention and / or treatment of diseases related to cyclin-dependent kinase 9 (CDK9).

[0059] CDK9-related diseases include leukemia, lymphoma, brain cancer, lung cancer, stomach cancer, esophageal cancer, skin cancer, colon cancer, rectal cancer, pancreatic cancer, myeloma, ovarian cancer, triple-negative breast cancer, testicular cancer, liver cancer, prostate cancer, and bladder cancer.

[0060] Leukemia includes acute lymphoblastic leukemia, acute myeloid leukemia, acute T-cell leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and chronic myeloid leukemia.

[0061] Through the above technical solution, the present invention provides a coumarin compound with potent CDK9 inhibitory activity. This compound uses a coumarin core as its backbone and improves target selectivity and binding efficiency through multi-substituent synergistic design. It provides a new structural type and practical solution for the development of CDK9-targeted anticancer drugs, and has important clinical value and application prospects. Attached Figure Description

[0062] Figure 1 This is a synthetic route diagram of the intermediates and coumarin compounds of this invention.

[0063] Figure 2 This is a synthetic route diagram of the intermediates and coumarin compounds of this invention.

[0064] Figure 3 This is a synthetic route diagram of the intermediates and coumarin compounds of this invention. Detailed Implementation

[0065] The technical solution of the present invention will be described in detail below with reference to embodiments and accompanying drawings. It should be understood that the specific embodiments described herein are for illustration and explanation only and are not intended to limit the present invention. All other embodiments obtained by those skilled in the art based on the present invention without inventive effort are within the protection scope of the present invention.

[0066] Unless otherwise specified, all technical and scientific terms used herein have their usual meanings in their respective fields. Where multiple definitions exist for a term, the definition used herein shall prevail.

[0067] The term "pharmaceutically acceptable" in this invention means that a compound or composition is chemically and / or toxicologically compatible with other components constituting the formulation and / or with humans or mammals for the prevention or treatment of diseases or conditions.

[0068] The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic acid or organic acid addition salt of the compounds of the present invention.

[0069] In this invention, when the name of a compound is inconsistent with its structural formula, the structural formula shall prevail.

[0070] This invention provides a coumarin compound and its pharmaceutically acceptable salt. The synthetic route of the coumarin compound is as follows: Figure 1 , Figure 2 , Figure 3 As shown, it has the structure shown in equation (I): Formula (I),

[0071] Wherein, R1 is selected from , , , , , , , , , , , , , , , and ;

[0072] R2 is selected from H, F, Cl, Me, OMe;

[0073] X is selected from CH, N, CF, CCl;

[0074] R3 is selected from , , , , , , , , .

[0075] The measured values ​​show that the coumarin compounds 30, 34, 35, 36, and 37 designed in this invention have potent CDK9 inhibitory activity. These compounds use a coumarin core as a backbone and improve target selectivity and binding efficiency through multi-substituent synergistic design. They provide new structural types and practical solutions for the development of CDK9-targeted anticancer drugs and play an important role in the preparation of drugs for the prevention or treatment of CDK9-related diseases.

[0076] In this invention, Represents a connection key.

[0077] Example 1

[0078] Preparation of the first intermediate M4 series (corresponding to step S1).

[0079] Synthetic route mapping: This preparation example specifically corresponds to step S1 in the invention description. Using the compound shown in formula (M3) as a starting material, a nucleophilic substitution reaction is carried out with the corresponding amine nucleophile to prepare the first intermediate (having the structure shown in formula M4). The relevant route is attached. Figure 1 and appendix Figure 2 As shown.

[0080] The general synthetic procedure for intermediates in the M4 series is as follows: Add the corresponding aliphatic amine (10.0 equivalents) to a DMSO (dimethyl sulfoxide, approximately 2 mL / mmol) solution of a 4-chlorocoumarin derivative (M3 series, 1 equivalent). Stir the reaction mixture at room temperature (rt) for 6 hours (some sterically hindered amines may require heating to 80°C, such as…). Figure 2 (As described above). After the reaction was complete, the mixture was poured into ice water and stirred vigorously to precipitate. The solid was collected by filtration and washed successively with 10% NaOH aqueous solution, 10% HCl aqueous solution (acid washing is omitted for products containing basic groups), and water. The solid was dried under vacuum to obtain the 4-amino-substituted coumarin intermediate, i.e., the first intermediate.

[0081] The specific synthesis is as follows: 4-(dimethylamino)coumarin (intermediate M4a) was performed according to the general procedure, using 4-chlorocoumarin (M3a) (259 mg, 1.0 mmol) and dimethylamine solution (excess) in DMSO (2 mL), and reacted at room temperature for 6 hours to obtain intermediate M4a (yield and appearance description), which was used directly without further purification.

[0082] 4-((R)-2-methylmorpholino)coumarin (intermediate M4i): Following standard procedure, 4-chlorocoumarin (M3a) (1.0 equivalent) and (R)-2-methylmorpholino (10.0 equivalent) were reacted in DMSO at room temperature for 6 hours to give intermediate M4i as a yellow solid. ESI-MS m / z 324.0 [M + H]+.

[0083] Example 2

[0084] Preparation of the second intermediate M9 (corresponding to step S2).

[0085] Synthetic route mapping: This preparation example involves the Miyaura borylation reaction. Specifically, the preparation of the M9 series corresponds to step S2 in the invention description (the first intermediate is borated to obtain the second intermediate, combined with the attached...). Figure 2 (As shown).

[0086] Second intermediate M9 ( Figure 2 The general synthetic steps (Miyaura borylation reaction) are as follows: The first intermediate (aryl halide, 1 equivalent, such as the M4 series) is dissolved in 1,4-dioxane, and pinacol diborate (B2Pin2, 1.2 equivalent), potassium acetate (KOAc, 3.0 equivalent), and palladium dichlorodi(triphenylphosphine) (Pd(PPh3)2Cl2, 0.05 equivalent) are added. Under N2 protection, the mixture is heated to 95°C and stirred for 12 hours. TLC shows that the reaction is complete. After cooling to room temperature, the inorganic solids are removed by filtration through a diatomaceous earth pad, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate) to give the corresponding borate intermediate, i.e., the second intermediate.

[0087] The specific synthesis is as follows: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3-chloro-6-((S)-3-methylmorpholinyl)coumarin (intermediate M9c): Following the general procedure, 4-bromo-3-chloro-6-((S)-3-methylmorpholinyl)coumarin (M4t) (1.0 g, equivalent to the stoichiometry), pinacol diborate (1.2 equivalents), potassium acetate (3.0 equivalents), and Pd(PPh3)2Cl2 (0.05 equivalents) were reacted in 1,4-dioxane at 95°C for 12 hours to obtain intermediate M9c, which is a pale yellow solid.

[0088] Example 3

[0089] The coupling and amination reactions that construct the target skeleton (corresponding to steps S3 and S4) are carried out.

[0090] Synthetic route mapping: This preparation example includes the core cross-coupling reaction (defined as general step A) and the subsequent amination reaction (defined as general step B).

[0091] General Step A (Suzuki cross-coupling, corresponding to the first half of step S3 or S4): Dissolve the aryl halide (1 equivalent, such as the first intermediate M4 series or the side chain precursor M6 series) and the corresponding borate ester coupling ligand (1.1 equivalent, such as the boron-containing reagent M7 or the second intermediate M9 series) in 1,4-dioxane (0.1-0.2 M), and add potassium carbonate (2.0 equivalent) and dichlorobis(triphenylphosphine)palladium (0.05 equivalent). The mixture is stirred and reacted at 85-95°C for 1-2 hours under N2 protection. After cooling to room temperature, dilute with ethyl acetate, filter through diatomaceous earth, concentrate and purify to obtain the corresponding coupling product.

[0092] General step B (amidation reaction, corresponding to the latter half of step S3): The intermediate containing a free amino group obtained through cross-coupling (such as the M10 series, 1 equivalent) and an organic base (such as triethylamine or pyridine) are dissolved in an organic solvent. The corresponding amide compound (such as acyl chloride reagents like cyclopentaneformyl chloride) or activated amino acid is slowly added at 0°C to room temperature, and the reaction is allowed to proceed for 1-12 hours. After the reaction is complete, the intermediate is extracted, concentrated, and purified to obtain the further modified third intermediate.

[0093] Example 4

[0094] Removal of protecting groups (general step C, corresponding to step S5)

[0095] Synthetic route mapping: This preparation example defines the operation of removing protecting groups such as tert-butyloxycarbonyl (Boc) (defined as general step C), which specifically corresponds to step S5 in the invention content.

[0096] General Step C (Deprotection): When the obtained third or fourth intermediate contains a tert-butyloxycarbonyl (Boc) protecting group, the intermediate containing this protecting group is placed in a mixture of an acidic reagent (selected from trifluoroacetic acid or hydrogen chloride) and an organic solvent (such as dichloromethane). The mixture is stirred and reacted at 0°C to room temperature for 1-12 hours (preferably 1-4 hours). After the reaction is complete, the reaction solution is concentrated under reduced pressure, and the residue is purified to obtain the compound of formula (I) after the protecting group has been removed.

[0097] Example 5

[0098] Preparation of side-chain coupling precursor M6 (providing raw materials for steps S3 / S4).

[0099] Synthetic route mapping: This preparation example primarily uses the compound shown in formula (M6), which can be used as a starting material to further prepare the boron-containing nucleophile (M7), or directly used for the coupling reaction in step S3 with the second intermediate. The synthetic route is attached. Figure 1 As shown.

[0100] Intermediate M6 ( Figure 1 The general synthetic steps for amide M6 are as follows: An aminoheteroaromatic hydrocarbon (1 equivalent) and pyridine (2.0 equivalent) are dissolved in anhydrous THF (tetrahydrofuran). Under nitrogen protection at 0°C, an acyl chloride (1.1 equivalent) is slowly added dropwise over 10 minutes. After the addition is complete, the reaction mixture is brought to room temperature and stirred for 2 hours. TLC indicates the reaction is complete. The solvent is removed under reduced pressure, and the residue is extracted between ethyl acetate and water. The organic phase is washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography to give the corresponding amide intermediate M6.

[0101] The specific synthesis is as follows: N-(4-bromopyridin-2-yl)cyclopropaneformamide (intermediate M6a): Following standard procedures, 4-bromopyridin-2-amine (compound M5a) (1.73 g, 10.0 mmol), pyridine (1.58 g, 20.0 mmol), and cyclopropionyl chloride (1.15 g, 11.0 mmol) were reacted in anhydrous THF (100 mL) at 0 °C to room temperature for 2 hours to give intermediate M6a (2.1 g, 87% yield) as a white solid. ESI-MS m / z 241.0 [M + H]+.

[0102] Example 6

[0103] Preparation of boron-containing nucleophile M7.

[0104] Synthetic route mapping: This preparation example involves the Miyaura borylation reaction. The preparation of M7 provides a boron-containing nucleophile for subsequent step S4 (in conjunction with the attached...). Figure 1 (As shown).

[0105] Boron-containing nucleophile M7 ( Figure 1 The general synthetic steps (Miyaura borylation reaction): side chain coupling with precursor M6 (1 equivalent, such as M6a, Figure 1The reagent was dissolved in 1,4-dioxane, and pinacol diboronate (B2Pin2, 1.2 equivalents), potassium acetate (KOAc, 3.0 equivalents), and palladium dichlorobis(triphenylphosphine) (Pd(PPh3)2Cl2, 0.05 equivalents) were added. Under N2 protection, the mixture was heated to 95°C and stirred for 12 hours. TLC showed the reaction was complete. After cooling to room temperature, the inorganic solids were removed by filtration through a diatomaceous earth mat, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the boron-containing nucleophile M7.

[0106] The specific synthesis is as follows: N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridin-2-yl)cyclopropaneformamide (containing boron nucleophile M7): Following standard procedures, N-(4-bromopyridin-2-yl)cyclopropaneformamide (M6a) (2.41 g, 10.0 mmol), pinacol diborate (3.05 g, 12.0 mmol), potassium acetate (2.94 g, 30.0 mmol), and Pd(PPh3)2Cl2 (351 mg, 0.5 mmol) were reacted in 1,4-dioxane (50 mL) at 95 °C for 12 h to give intermediate M7 (2.42 g, 84% yield) as a white solid. ESI-MS m / z 289.2 [M + H]+.

[0107] M3 and M5 are commercially available drugs purchased from Bid Bio.

[0108] In one specific embodiment of the present invention, the compound represented by formula (I) is selected from the following substances: .

[0109] The following describes the preparation and characterization of the target compounds 1-37 shown in formula (I).

[0110] Compound 1:

[0111] N-(4-(4-(dimethylamino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopropanecarboxamide (1) Following general procedure A, compound M4a was reacted with M7 to give title compound 1 as a white powder (yield: 65%). 1H NMR(400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.4 (d, J = 1.7 Hz, 1H), 8.4 (d, J = 5.2Hz, 1H), 8.0 (d, J = 2.2 Hz, 1H), 7.9 (dd, J = 8.6, 2.2 Hz, 1H), 7.5 (d, J =8.6 Hz, 1H), 7.5 (dd, J = 5.2, 1.7 Hz, 1H), 5.5 (s, 1H), 3.1 (s, 6H), 2.1 -2.0 (m, 1H), 0.9 - 0.8 (m, 4H); 13 C NMR (100 MHz, DMSO-d6) δ 172.8, 160.7, 159.7, 154.1, 152.8, 148.6, 147.8, 132.6, 129.8, 124.1, 118.1, 116.8, 116.1, 110.5, 91.8, 42.5 (2C), 14.2, 7.6 (2C). HRMS (ESI): m / z [M + H]+ Calculated C 20 H 20 N3O3, 350.1505; measured value, 350.1503.

[0112] Compound 2:

[0113] N-(4-(4-(4-amino-4-methylpiperidin-1-yl)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopropaneformamide (2) was prepared from M4b according to general step A, followed by general step C (deprotection). This sequence yielded title compound 2 as a white powder (yield: 38%). 1H NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.5 (d, J= 1.7 Hz, 1H), 8.4 (d, J = 5.2 Hz, 1H), 8.3 (s, 2H), 7.9 (dd, J = 8.5, 2.1Hz, 1H), 7.8 (d, J = 2.2 Hz, 1H), 7.5 (d, J = 8.6 Hz, 1H), 7.5 (dd, J = 5.2,1.7 Hz, 1H), 5.8 (s, 1H), 3.6 - 3.5 (m, 2H), 3.0 (m, 2H), 2.1 - 2.0 (m, 3H),2.0 - 1.9 (m, 2H), 1.4 (s, 3H), 0.9 - 0.8 (m, 4H); 13 C NMR (100 MHz, DMSO-d6) δ 173.4, 161.3, 160.5, 154.6, 153.5, 149.2, 148.3, 133.6, 130.6, 123.6, 118.8, 117.2, 116.8, 111.2, 97.6, 52.1, 46.8 (2C), 46.0, 34.9 (2C), 14.8, 8.3 (2C). HRMS (ESI): m / z [M + H]+ Calculated C 24 H 27 N4O3, 419.2083; Measured value, 419.2083.

[0114] Compound 3:

[0115] N-(4-(4-(4-methylpiperazin-1-yl)-2-oxo-2H-chromene-6-yl)pyridin-2-yl)cyclopropanecarboxamide (3) Following general procedure A, compound M4c was reacted with M7 to give title compound 3 as a white powder (yield: 72%). 1HNMR (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.5 (d, J = 1.7 Hz, 1H), 8.4 (d, J =5.3 Hz, 1H), 8.0 - 7.9 (m, 2H), 7.5 (d, J = 8.5 Hz, 1H), 7.5 (dd, J = 5.3,1.7 Hz, 1H), 5.8 (s, 1H), 3.3 - 3.3 (m, 4H), 2.6 - 2.5 (m, 4H), 2.3 (s, 3H),2.0 (tt, J = 7.4, 5.1 Hz, 1H), 0.9 - 0.8 (m, 4H); 13 C NMR (100 MHz, DMSO-d6) δ 172.8, 160.7, 160.1, 154.0, 152.9, 148.7, 147.6, 132.8, 129.9, 123.2, 118.1, 116.5, 116.2, 110.4, 96.8, 53.9 (2C), 50.4 (2C), 45.4, 14.1, 7.7 (2C). HRMS(ESI): m / z [M + H]+ Calculated C 23 H 25 N4O3, 405.1927; measured value, 405.1925.

[0116] Compound 4:

[0117] N-(4-(4-(4-methyl-1,4-diazaphen-1-yl)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopropanecarboxamide (4) Following general procedure A, compound M4d was reacted with M7 to give title compound 4 as a white powder (yield: 55%). 1 H NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.4 (m, 2H), 8.0 (d, J =2.1 Hz, 1H), 7.9 (dd, J = 8.6, 2.0 Hz, 1H), 7.5 - 7.4 (m, 2H), 5.5 (s, 1H),3.7 (dd, J = 6.2, 2.7 Hz, 2H), 3.6 (t, J = 5.6 Hz, 2H), 2.8 (s, 2H), 2.6 (s,2H), 2.3 (s, 3H), 2.1 - 2.0 (m, 3H), 0.9 - 0.8 (m, 4H);13 C NMR (100 MHz, DMSO-d6) δ 172.7, 160.8, 158.5, 154.1, 152.9, 148.6, 147.8, 132.3, 129.7, 124.4, 118.3, 116.8, 116.3, 110.4, 90.6, 57.4, 56.5, 51.4, 45.8, 37.9, 26.9, 14.1, 7.6 (2C). HRMS (ESI): m / z [M + H]+ Calculated C 24 H 27 N4O3, 419.2083; measured value, 419.2083.

[0118] Compound 5:

[0119] N-(4-(4-(2-methylpiperazin-1-yl)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopropaneformamide (5) was prepared from M4e according to general step A, followed by general step C. This sequence yielded the title compound 5 as a white powder (yield: 48%). 1 H NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.5 (d, J = 1.7 Hz, 1H), 8.4 (d, J = 5.6 Hz, 1H), 8.1 - 8.0 (m, 2H), 7.7 (dd, J = 5.7, 1.8 Hz, 1H),7.6 - 7.5 (m, 1H), 6.0 (s, 1H), 4.3 - 4.2 (m, 1H), 3.7 - 3.5 (m, 2H), 3.4 -3.3 (m, 2H), 3.3 - 3.1 (m, 2H), 2.2 - 2.1 (m, 1H), 1.3 (d, J = 6.7 Hz, 3H),1.0 - 0.8 (m, 4H); 13 C NMR (100 MHz, DMSO-d6) δ 172.5, 161.0, 159.4, 155.0, 151.8, 150.5, 146.0, 132.8, 130.9, 124.1, 118.9, 117.6, 117.1, 111.9, 101.5, 51.0, 46.8, 43.1, 42.5, 21.5, 14.3, 8.9 (2C). HRMS (ESI): m / z [M + H]+ Calculated C 23 H 25N4O3, 405.1927; measured value, 405.1920.

[0120] Compound 6:

[0121] N-(4-(4-(oxetane-3-ylamino)-2-oxo-2H-chromene-6-yl)pyridin-2-yl)cyclopropanecarboxamide (6) Following general procedure A, compound M4f was reacted with M7 to give title compound 6 as a white powder (yield: 66%). 1 H NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.5 (d, J = 2.2 Hz, 1H), 8.5 -8.4 (m, 2H), 8.3 (d, J = 5.3 Hz, 1H), 7.9 (dd, J = 8.6, 2.0 Hz, 1H), 7.5 (dd,J = 5.3, 1.7 Hz, 1H), 7.5 (d, J = 8.6 Hz, 1H), 5.0 (s, 1H), 4.9 (t, J = 6.6Hz, 2H), 4.9 - 4.7 (m, 1H), 4.7 (t, J = 6.0 Hz, 2H), 2.1 - 2.0 (m, 1H), 0.9 -0.8 (m, 4H); 13 C NMR (100 MHz, DMSO-d6) δ 172.7, 160.9, 153.5, 152.8, 151.9, 148.4, 148.1, 133.3, 130.4, 121.2, 117.8, 117.2, 114.5, 110.9, 83.0, 76.1 (2C), 47.1, 14.1, 7.6 (2C). HRMS (ESI): m / z [M + H] + calculated C 21 H 20 N3O4, 378.1454; measured value, 378.1457.

[0122] Compound 7:

[0123] Methyl 1-(6-(2-(cyclopropanecarbamoyl)pyridin-4-yl)-2-oxo-2H-chromen-4-yl)piperidine-4-carboxylic acid (7) Following general procedure A, compound M4g was reacted with M7 to give title compound 7 as a white powder (yield: 70%). 1H NMR (400 MHz, CDCl3) δ 8.8 (s, 1H), 8.6 - 8.5 (m, 1H), 8.3 (dd, J = 5.3,0.7 Hz, 1H), 7.9 (d, J = 2.2 Hz, 1H), 7.8 (dd, J = 8.6, 2.2 Hz, 1H), 7.4 (d,J = 8.6 Hz, 1H), 7.2 (dd, J = 5.4, 1.7 Hz, 1H), 5.8 (s, 1H), 3.8 (s, 3H), 3.7- 3.6 (m, 2H), 3.0 - 2.9 (m, 2H), 2.7 - 2.6 (m, 1H), 2.2 - 2.1 (m, 2H), 2.1 -2.0 (m, 2H), 1.7 - 1.6 (m, 1H), 1.2 - 1.1 (m, 2H), 1.0 - 0.9 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 174.6, 172.7, 162.1, 161.1, 154.8, 152.3, 149.7, 147.7, 133.5, 130.2, 123.6, 118.5, 117.2, 116.9, 111.7, 98.3, 52.0, 50.8 (2C), 40.7, 27.8 (2C), 16.0, 8.6 (2C). HRMS (ESI): m / z [M + Na]+ Calculated C 25 H 25 N3O5Na, 470.1692; Measured value, 470.1718.

[0124] Compound 8:

[0125] N-(4-(4-morpholino-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopropanecarboxamide (8) Following general procedure A, compound M4h was reacted with M7 to give title compound 8 as a white powder (yield: 75%). 1H NMR (400MHz, CDCl3) δ 8.6 (s, 1H), 8.5 (d, J = 1.7 Hz, 1H), 8.3 (d, J = 5.3 Hz, 1H), 7.9 (d, J = 2.2 Hz, 1H), 7.8 (dd, J = 8.6, 2.2 Hz, 1H), 7.4 (d, J = 8.6 Hz,1H), 7.2 (dd, J = 5.4, 1.7 Hz, 1H), 5.8 (s, 1H), 4.1 - 3.9 (m, 4H), 3.4 - 3.2(m, 4H), 1.7 - 1.5 (m, 1H), 1.2 - 1.1 (m, 2H), 1.0 - 0.8 (m, 2H); 13 C NMR (100MHz, CDCl3) δ 172.7, 161.9, 160.7, 154.8, 152.3, 149.5, 147.9, 133.6, 130.3, 123.5, 118.6, 117.1, 116.5, 111.7, 98.7, 66.3 (2C), 51.6 (2C), 16.0, 8.7 (2C). HRMS (ESI): m / z [M + H]+ Calculated C 22 H 22 N3O4, 392.1610; measured value, 392.1610.

[0126] Compound 9:

[0127] (R)-N-(4-(4-(3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopropanecarboxamide (9) Following general procedure A, compound M4i was reacted with M7 to give title compound 9 as a white powder (yield: 73%). 1HNMR (400 MHz, CDCl3) δ 8.8 (s, 1H), 8.6 (d, J = 1.7 Hz, 1H), 8.3 (d, J = 5.3Hz, 1H), 7.9 (d, J = 2.2 Hz, 1H), 7.8 (dd, J = 8.6, 2.2 Hz, 1H), 7.4 (d, J =8.6 Hz, 1H), 7.2 (dd, J = 5.4, 1.7 Hz, 1H), 5.8 (s, 1H), 4.0 (dt, J = 11.5,3.3 Hz, 2H), 3.9 (ddt, J = 11.5, 9.8, 3.0 Hz, 2H), 3.7 (dd, J = 11.4, 3.1 Hz,1H), 3.6 (ddd, J = 12.9, 9.8, 3.3 Hz, 1H), 3.0 (dt, J = 12.7, 3.1 Hz, 1H),1.7 - 1.6 (m, 1H), 1.2 (d, J = 6.6 Hz, 3H), 1.2 - 1.1 (m, 2H), 1.0 - 0.8 (m,2H); 13 C NMR (100 MHz, CDCl3) δ 172.9, 161.8, 160.0, 154.9, 152.2, 149.8, 147.4, 133.4, 130.3, 123.6, 118.6, 117.1, 116.9, 111.7, 100.7, 71.0, 66.5, 53.7, 46.2, 16.0, 13.0, 8.7 (2C). HRMS (ESI): m / z [M + H]+ Calculated C 23 H 24 N3O4, 406.1767; measured value, 406.1769.

[0128] Compound 10:

[0129] (S)-N-(4-(4-(3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopropanecarboxamide (10) Following general procedure A, compound M4j was reacted with M7 to give white powder title compound 10 (yield: 71%). 1H NMR (400 MHz, CDCl3) δ 8.7 (s, 1H), 8.5 (d, J = 1.7 Hz, 1H), 8.3 (d, J =5.2 Hz, 1H), 7.9 (d, J = 2.3 Hz, 1H), 7.8 (dd, J = 8.6, 2.2 Hz, 1H), 7.4 (d,J = 8.6 Hz, 1H), 7.2 (dd, J = 5.1, 1.7 Hz, 1H), 5.8 (s, 1H), 4.0 (dt, J =11.5, 3.2 Hz, 2H), 3.9 - 3.8 (m, 2H), 3.7 (dd, J = 11.4, 3.1 Hz, 1H), 3.6(ddd, J = 12.9, 9.7, 3.3 Hz, 1H), 3.0 (dt, J = 12.7, 3.1 Hz, 1H), 1.7 - 1.6(m, 1H), 1.2 (d, J = 6.6 Hz, 3H), 1.2 - 1.1 (m, 2H), 1.0 - 0.9 (m, 2H); 13 CNMR (100 MHz, CDCl3) δ 172.8, 161.9, 160.1, 154.9, 152.3, 149.6, 147.4, 133.5, 130.3, 123.6, 118.6, 117.2, 116.9, 111.6, 100.6, 71.0, 66.5, 53.7, 46.2, 16.0, 13.0, 8.7 (2C). HRMS (ESI): m / z [M + H]+ Calculated value C 23 H 24 N3O4, 406.1767; measured value, 406.1763.

[0130] Compound 11:

[0131] (R)-N-(4-(4-(2-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopropanecarboxamide (11) Following general procedure A, compound M4k was reacted with M7 to give white powder title compound 11 (yield: 69%). 1H NMR (400 MHz, CDCl3) δ 8.6 (s, 1H), 8.6 (d, J = 1.7 Hz, 1H), 8.3 (d, J =5.3 Hz, 1H), 7.9 (d, J = 2.2 Hz, 1H), 7.8 (dd, J = 8.6, 2.2 Hz, 1H), 7.4 (d,J = 8.6 Hz, 1H), 7.2 (dd, J = 5.4, 1.7 Hz, 1H), 5.8 (s, 1H), 4.1 (ddd, J =11.7, 3.4, 1.5 Hz, 1H), 4.0 - 3.9 (m, 2H), 3.6 - 3.4 (m, 2H), 3.1 (td, J =12.0, 3.3 Hz, 1H), 2.7 (dd, J = 12.4, 10.1 Hz, 1H), 1.7 - 1.6 (m, 1H), 1.3(d, J = 6.2 Hz, 3H), 1.2 - 1.1 (m, 2H), 1.0 - 0.9 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 172.7, 161.9, 160.5, 154.8, 152.2, 149.6, 147.8, 133.5, 130.2, 123.6, 118.6, 117.1, 116.6, 111.7, 98.6, 71.4, 66.0, 57.5, 50.8, 18.8, 16.0, 8.7 (2C). HRMS (ESI): m / z [M + H]+ Calculated C 23 H 24 N3O4, 406.1767; measured value, 406.1766.

[0132] Compound 12:

[0133] (S)-N-(4-(4-(2-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopropanecarboxamide (12) Following general procedure A, compound M4l was reacted with M7 to give title compound 12 as a white powder (yield: 62%). 1H NMR (400 MHz, CDCl3) δ 8.9 (s, 1H), 8.6 (d, J = 1.7 Hz, 1H), 8.3 (d, J =5.4 Hz, 1H), 7.9 (d, J = 2.2 Hz, 1H), 7.8 (dd, J = 8.6, 2.2 Hz, 1H), 7.4 (d,J = 8.6 Hz, 1H), 7.3 (dd, J = 5.4, 1.7 Hz, 1H), 5.8 (s, 1H), 4.1 - 4.0 (m,1H), 4.0 - 3.9 (m, 2H), 3.5 (dt, J = 12.4, 2.2 Hz, 1H), 3.5 (dd, J = 12.4,2.2 Hz, 1H), 3.1 (td, J = 11.9, 3.3 Hz, 1H), 2.7 (dd, J = 12.4, 10.1 Hz, 1H), 1.7 - 1.6 (m, 1H), 1.3 (d, J = 6.2 Hz, 3H), 1.2 - 1.1 (m, 2H), 1.0 (dq, J =7.5, 4.0 Hz, 2H); 13 C NMR (100 MHz, CDCl3) δ 172.9, 161.8, 160.5, 155.0, 152.0, 150.2, 146.9, 133.2, 130.2, 123.6, 118.7, 117.0, 116.7, 111.8, 98.6, 71.4, 66.0, 57.5, 50.8, 18.8, 16.0, 8.9 (2C). HRMS (ESI): m / z [M + Na]+ Calculated C 23 H 23 N3O4Na, 428.1586; measured value, 428.1611.

[0134] Compound 13:

[0135] (R)-N-(4-(4-(2-ethylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopropanecarboxamide (13) Following general procedure A, compound M4m was reacted with M7 to give white powder title compound 13 (yield: 58%). 1H NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.4 (d, J = 1.7 Hz, 1H), 8.4 (d, J =5.2 Hz, 1H), 8.0 - 7.9 (m, 2H), 7.5 (d, J = 8.5 Hz, 1H), 7.5 (dd, J = 5.3,1.7 Hz, 1H), 5.8 (s, 1H), 3.9 (dd, J = 11.6, 2.6 Hz, 2H), 3.8 - 3.6 (m, 4H),3.2 (d, J = 12.4 Hz, 1H), 2.1 - 2.0 (m, 1H), 1.9 - 1.8 (m, 1H), 1.8 - 1.7 (m,1H), 0.9 - 0.8 (m, 4H), 0.8 (t, J = 7.5 Hz, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 172.8, 160.7, 159.4, 154.1, 152.9, 148.7, 147.6, 132.8, 130.0, 123.3, 118.2, 116.6, 116.2, 110.5, 97.2, 67.1, 65.5, 58.9, 45.3, 20.3, 14.2, 10.7, 7.7 (2C). HRMS (ESI): m / z [M + Na]+ Calculated C 24 H 25 N3O4Na, 442.1743; measured value, 442.1766.

[0136] Compound 14:

[0137] (S)-N-(4-(4-(2-ethylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopropanecarboxamide (14) Following general procedure A, compound M4n was reacted with M7 to give white powder title compound 14 (yield: 55%). 1H NMR (400 MHz, CDCl3) δ 8.7 (s, 1H), 8.6 (d, J = 1.7 Hz, 1H), 8.4 (d, J = 5,4 Hz, 1H), 7.9 (d, J = 2.2 Hz, 1H), 7.8 (dd, J = 8.6, 2.2 Hz, 1H), 7.4 (d, J= 8.6 Hz, 1H), 7.2 (dd, J = 5.4, 1.7 Hz, 1H), 5.8 (s, 1H), 4.0 - 3.8 (m, 4H), 3.7 - 3.5 (m, 2H), 3.1 (dt, J = 12.9, 2.6 Hz, 1H), 2.0 (ddt, J = 16.4, 14.5,7.4 Hz, 1H), 1.7 (ddq, J = 22.0, 8.2, 4.5 Hz, 2H), 1.2 - 1.1 (m, 2H), 1.0 -0.9 (m, 2H), 0.9 (t, J = 7.5 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 172.8, 162.0, 160.1, 155.0, 152.3, 149.8, 147.6, 133.3, 130.2, 123.7, 118.7, 117.1, 116.7, 111.7, 99.3, 67.8, 66.3, 60.1, 46.1, 20.2, 16.0, 11.1, 8.7 (2C). HRMS (ESI): m / z [M + H]+ Calculated C 24 H 26 N3O4, 420.1923; measured value, 420.1920.

[0138] Compound 15:

[0139] (R)-N-(4-(7-methyl-4-(3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopropanecarboxamide (15) Following general procedure A, compound M4o was reacted with M7 to give title compound 15 as a white powder (yield: 60%). 1H NMR (400 MHz, CDCl3) δ 9.0 (s, 1H), 8.3 (d, J = 5.2, 1H), 8.3 (d,J = 1.6 Hz, 1H), 7.4 (s, 1H), 7.2 (s, 1H), 7.0 (dd, J = 5.2, 1.6 Hz, 1H), 5.7(s, 1H), 4.0 - 3.9 (m, 2H), 3.8 (tdd, J = 11.7, 8.2, 2.9 Hz, 2H), 3.6 (dd, J= 11.3, 3.0 Hz, 1H), 3.5 (ddd, J = 13.0, 9.8, 3.3 Hz, 1H), 2.9 (dt, J = 12.3,2.9 Hz, 1H), 2.4 (s, 3H), 1.7 - 1.6 (m, 1H), 1.2 (d, J = 6.5 Hz, 3H), 1.1 -1.1 (m, 2H), 1.0 - 0.9 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 176.6, 172.9, 162.2, 160.2, 154.1, 151.6, 146.6, 140.0, 135.0, 125.3, 120.0, 119.3, 114.7, 114.5, 99.9, 71.0, 66.5, 53.5, 46.1, 20.7, 15.9, 12.9, 8.7 (2C). HRMS (ESI): m / z [M + H]+ Calculated C 24 H 26 N3O4, 420.1923; measured value, 420.1922.

[0140] Compound 16:

[0141] (R)-N-(4-(7-fluoro-4-(3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopropanecarboxamide (16) Following general procedure A, compound M4p was reacted with M7 to give title compound 16 as a white powder (yield: 63%). 1H NMR (400 MHz, CDCl3) δ 8.8 (s, 1H), 8.5 (d, J = 1.6 Hz, 1H), 8.3 (d, J = 5.3 Hz, 1H), 7.8 (d, J = 8.0 Hz, 1H), 7.3 (dd, J = 5.3, 1.6 Hz, 1H),7.2 (d, J = 10.4 Hz, 1H), 5.7 (s, 1H), 4.0 - 3.9 (m, 2H), 3.9 - 3.8 (m, 2H),3.7 (dd, J = 11.4, 3.0 Hz, 1H), 3.6 (ddd, J = 12.9, 9.8, 3.3 Hz, 1H), 2.9 (d,J = 12.7 Hz, 1H), 1.7 - 1.6 (m, 1H), 1.2 (d, J = 6.6 Hz, 3H), 1.2 - 1.0 (m,2H), 1.0 - 0.9 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 172.7, 161.6, 161.3 (d, J =257.9 Hz), 159.7, 155.5 (d, J = 13.0 Hz), 152.2, 147.7, 144.7, 127.0 (d, J =4.7 Hz), 122.8 (d, J = 14.1 Hz), 119.4 (d, J = 4.7 Hz), 113.6 (d, J = 3.1Hz), 113.5, 105.8 (d, J = 26.7 Hz), 99.6, 71.0, 66.4, 53.8, 46.1, 15.9, 13.0,8.6 (2C). HRMS (ESI): m / z [M + H] + calculated value C 23 H 23 FN3O4, 424.1673; Measured value, 424.1674.

[0142] Compound 17:

[0143] (R)-N-(4-(7-chloro-4-(3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopropanecarboxamide (17) Following general procedure A, compound M4q was reacted with M7 to give title compound 17 as a white powder (yield: 52%). 1H NMR (400 MHz, CDCl3) δ 9.8 (s, 1H), 8.4 (d, J = 1.6 Hz, 1H), 8.3 (d, J = 5.0 Hz, 1H), 7.6 (s, 1H), 7.5 (s, 1H), 7.2 (dd, J = 5.3, 1.6 Hz, 1H),5.8 (s, 1H), 4.0 - 3.9 (m, 2H), 3.8 - 3.8 (m, 2H), 3.7 (d, J = 10.7 Hz, 1H),3.5 (t, J = 10.8 Hz, 1H), 2.9 (d, J = 12.5 Hz, 1H), 1.8 - 1.7 (m, 1H), 1.2(d, J = 5.8 Hz, 3H), 1.1 - 1.0 (m, 2H), 1.0 - 0.9 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 173.2, 161.3, 159.5, 154.2, 152.0, 149.1, 146.2, 135.3, 133.5, 127.0, 120.2, 119.3, 115.6, 115.1, 100.6, 71.0, 66.4, 53.7, 46.2, 15.8, 13.0, 8.8 (2C). HRMS (ESI): m / z [M + H]+ Calculated C 23 H 23 ClN3O4, 440.1377; Measured value, 440.1378.

[0144] Compound 18:

[0145] (R)-N-(4-(7-methoxy-4-(3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopropanecarboxamide (18) Compound M4r was reacted with M7 according to general procedure A to give white powder title compound 18 (yield: 50%). 1H NMR (400 MHz, CDCl3) δ 10.5 (s, 1H), 8.5 (d, J = 1.6 Hz, 1H), 8.2 (d, J = 5.4 Hz, 1H), 7.6 (s, 1H), 7.3 (dd, J = 5.5, 1.6 Hz, 1H), 6.9 (s,1H), 5.7 (s, 1H), 4.0 - 3.9 (m, 2H), 3.9 (s, 3H), 3.9 - 3.8 (m, 2H), 3.7 (dd,J = 11.4, 2.9 Hz, 1H), 3.6 - 3.5 (m, 1H), 2.9 (dt, J = 12.6, 3.0 Hz, 1H), 1.8- 1.7 (m, 1H), 1.2 (d, J = 6.5 Hz, 3H), 1.1 - 1.0 (m, 2H), 1.0 - 0.9 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 173.3, 162.4, 160.5, 159.4, 156.4, 152.1, 148.7, 145.3, 126.8, 124.1, 120.0, 114.9, 109.8, 100.2, 97.7, 71.0, 66.5, 56.2, 53.7, 46.0, 15.4, 12.9, 8.6 (2C). HRMS (ESI): m / z [M + H]+ Calculated C 24 H 26 N3O5, 436.1872; measured value, 436.1865.

[0146] Compound 19:

[0147] (R)-N-(4-(4-(3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopentanecarboxamide (19) Following general step B, amine intermediate M10a was reacted with cyclopentanecarboxyl chloride to give title compound 19 as a white powder (yield: 72%). 1H NMR (400 MHz, DMSO-d6) δ 10.6 (s, 1H), 8.5 (d, J = 1.8 Hz, 1H), 8.4 (d, J = 5.2 Hz, 1H), 8.0 - 7.9 (m, 2H), 7.5 (d, J = 8.5 Hz, 1H), 7.5 (dd,J = 5.3, 1.8 Hz, 1H), 5.8 (s, 1H), 4.0 - 3.9 (m, 3H), 3.8 - 3.7 (m, 1H), 3.6(dd,J = 11.3, 2.4 Hz, 1H), 3.6 - 3.5 (m, 1H), 3.0 (d, J = 13.1 Hz, 1H), 3.0- 2.9 (m, 1H), 1.9 - 1.8 (m, 2H), 1.8 - 1.6 (m, 4H), 1.6 - 1.5 (m, 2H), 1.2(d, J = 6.6 Hz, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 176.1, 161.2, 159.9, 154.6, 153.6, 149.1, 148.1, 133.4, 130.5, 123.6, 118.7, 117.1, 116.8, 111.0, 99.4, 70.6, 66.2, 53.7, 46.2, 45.4, 29.7 (2C), 24.8 (2C), 13.0. HRMS (ESI): m / z [M+ H]+ Calculated C 25 H 28 N3O4, 434.2080; measured value, 434.2082.

[0148] Compound 20:

[0149] (R)-N-(4-(4-(3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclohexaneformamide (20) Following general step B, amine intermediate M10a was reacted with cyclohexaneformyl chloride to give title compound 20 as a white powder (yield: 75%). 1H NMR (400 MHz, CDCl3) δ 8.8 (s, 1H), 8.7 (d, J = 1.6 Hz, 1H), 8.3 (d, J = 5.5 Hz, 1H), 8.0 (d, J = 2.2 Hz, 1H), 7.8 (dd, J = 8.8, 2.2 Hz, 1H), 7.5 (d, J = 8.6 Hz, 1H), 7.3 - 7.3 (m, 1H), 5.8 (s, 1H), 4.1 - 4.0 (m,2H), 3.9 - 3.8 (m, 2H), 3.8 (dd, J = 11.4, 3.0 Hz, 1H), 3.6 (ddd, J = 12.9,9.7, 3.3 Hz, 1H), 3.0 (d, J = 12.7 Hz, 1H), 2.4 (t, J = 11.7 Hz, 1H), 2.0 (d,J = 12.8 Hz, 2H), 1.9 (d, J = 12.5 Hz, 2H), 1.7 (d, J = 11.5 Hz, 1H), 1.6 (q,J = 12.9 Hz, 2H), 1.4 - 1.3 (m, 3H), 1.2 (d, J = 6.5 Hz, 3H); 13 C NMR (100MHz, CDCl3) δ 175.5, 161.7, 160.0, 155.1, 151.9, 150.7, 145.9, 133.0, 130.3, 123.8, 118.7, 117.1, 117.0, 112.0, 100.8, 71.0, 66.5, 53.7, 46.6, 46.2, 29.4(2C), 25.6(2C), 25.5, 13.0. HRMS (ESI): m / z [M + H]+ Calculated C 26 H 30 N3O4, 448.2236; Measured value, 448.2236.

[0150] Compound 21:

[0151] (R)-N-(4-(4-(3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cycloheptaneformamide (21) Following general step B, amine intermediate M10a was reacted with cycloheptaneformyl chloride to give title compound 21 as a white powder (yield: 71%). 1H NMR (400 MHz, CDCl3) δ 8.6 (d, J = 1.6 Hz, 1H), 8.4 (s, 1H),8.3 (d, J = 5.3, Hz, 1H), 7.9 (d, J = 2.2 Hz, 1H), 7.8 (dd, J = 8.6, 2.2 Hz,1H), 7.4 (d, J = 8.6 Hz, 1H), 7.2 (dd, J = 5.3, 1.7 Hz, 1H), 5.8 (s, 1H), 4.1- 4.0 (m, 2H), 4.0 - 3.8 (m, 2H), 3.7 (dd, J = 11.4, 3.0 Hz, 1H), 3.6 (ddd, J= 12.9, 9.8, 3.3 Hz, 1H), 3.0 (dt, J = 12.6, 3.1 Hz, 1H), 2.5 - 2.4 (m, 1H), 2.1 - 2.0 (m, 2H), 1.9 - 1.7 (m, 4H), 1.7 - 1.5 (m, 6H), 1.3 - 1.2 (m, 3H); 13 C NMR (100 MHz, CDCl3) δ 176.2, 161.9, 160.1, 154.8, 152.7, 149.3, 148.2, 133.7, 130.3, 123.6, 118.5, 117.2, 116.9, 111.7, 100.6, 71.0, 66.5, 53.7, 48.3, 46.2, 31.4 (2C), 28.2 (2C), 26.5 (2C), 13.0. HRMS (ESI): m / z [M + H] + calculated C 27 H 32 N3O4, 462.2393; measured value, 462.2385.

[0152] Compound 22:

[0153] (R)-4,4-difluoro-N-(4-(4-(3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclohexane-1-carboxamide (22) Following general step B, the amine intermediate M10a was reacted with 4,4-difluorocyclohexanecarboxyl chloride to give the title compound 22 as a white powder (yield: 78%). 1H NMR (400 MHz, CDCl3) δ 8.6 (s, 1H), 8.6(d, J = 1.6 Hz, 1H), 8.4 (d, J = 5.3 Hz, 1H), 7.9 (d, J = 2.2 Hz, 1H), 7.8(dd, J = 8.6, 2.2 Hz, 1H), 7.4 (d, J = 8.6 Hz, 1H), 7.3 (dd, J = 5.3, 1.6 Hz,1H), 5.8 (s, 1H), 4.1 - 4.0 (m, 2H), 4.0 - 3.8 (m, 2H), 3.8 (dd, J = 11.4,3.0 Hz, 1H), 3.6 (ddd, J = 13.0, 9.8, 3.3 Hz, 1H), 3.0 (dt, J = 12.7, 3.1 Hz,1H), 2.5 - 2.4 (m, 1H), 2.3 - 2.2 (m, 2H), 2.1 - 1.9 (m, 4H), 1.9 - 1.7 (m,2H), 1.3 (d, J = 6.5 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 173.2, 161.9, 160.1, 154.8, 152.4, 149.4, 148.3, 133.5, 130.2, 123.6, 118.6, 117.5, 116.9, 111.8, 100.6, 71.0, 66.5, 53.7, 46.2, 43.6, 32.7 (t, J = 24.5 Hz), 25.8 (2C), 25.7 (2C), 13.0. HRMS (ESI): m / z [M + H]+ Calculated C 26 H 28 F2N3O4, 484.2048; Measured value, 484.2047.

[0154] Compound 23:

[0155] (R)-N-(5-fluoro-4-(4-(3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopentanecarboxamide (23) Following general step B, amine intermediate M10b was reacted with cyclopentanecarboxyl chloride to give title compound 23 as a white powder (yield: 85%). 1H NMR (400 MHz, CDCl3) δ 8.5 (d, J = 6.0 Hz, 1H), 8.2 (d, J= 2.3 Hz, 1H), 8.1 (s, 1H), 8.0 (d, J = 1.9, 1H), 7.8 (dd, J = 8.5, 1.9 Hz,1H), 7.4 (d, J = 8.6 Hz, 1H), 5.8 (s, 1H), 4.1 - 4.0 (m, 2H), 3.9 - 3.8 (m,2H), 3.7 (dd, J = 11.4, 2.6 Hz, 1H), 3.6 (ddd, J = 13.0, 9.8, 3.1 Hz, 1H),3.0 (dt, J = 13.1, 2.9 Hz, 1H), 2.8 - 2.7 (m, 1H), 2.0 - 1.9 (m, 4H), 1.8 -1.7 (m, 2H), 1.7 - 1.6 (m, 2H), 1.2 (d, J = 6.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 175.0, 161.9, 160.0, 154.8, 153.4 (d, J = 251.4 Hz), 148.4 (d, J =2.9 Hz), 136.7 (d, J = 10.9 Hz), 136.2 (d, J = 28.5 Hz), 131.9 (d, J = 2.5Hz), 128.4, 125.8, 118.4 (d, J = 5.4 Hz), 116.6, 113.8, 100.5, 71.0, 66.5,53.7, 46.8, 46.1, 30.4 (2C), 26.0 (2C), 13.0. HRMS (ESI): m / z [M + H] + calculated value C 25 H 27 FN3O4, 452.1986; Measured value, 452.1986.

[0156] Compound 24:

[0157] (R)-N-(5-chloro-4-(4-(3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclopentanecarboxamide (24) Following general step B, the amine intermediate M10c was reacted with cyclopentanecarboxyl chloride to give the title compound 24 as a white powder (yield: 77%). 1H NMR (400 MHz, CDCl3) δ 8.9 (s, 1H), 8.5 (s, 1H), 8.3 (s,1H), 7.8 (d, J = 2.1 Hz, 1H), 7.7 (dd, J = 8.6, 1.9 Hz, 1H), 7.5 (d, J = 8.6Hz, 1H), 5.8 (s, 1H), 4.0 (t, J = 12.0 Hz, 2H), 3.9 - 3.8 (m, 2H), 3.7 - 3.7(m, 1H), 3.6 (s, 1H), 2.9 (d, J = 12.6 Hz, 1H), 2.8 (p, J = 8.0 Hz, 1H), 2.0(d, J = 8.6 Hz, 2H), 1.9 (dq, J = 13.6, 7.3 Hz, 2H), 1.8 (d, J = 8.6 Hz, 2H), 1.7 - 1.6 (m, 2H), 1.2 (d, J = 6.4 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 175.5, 161.7, 159.9, 154.8, 149.9, 145.3, 132.2, 131.4, 129.9, 125.8, 124.5, 118.2, 116.5, 115.8, 100.8, 71.0, 66.5, 53.5, 46.9, 46.2, 30.4 (2C), 26.0 (2C), 13.0. HRMS (ESI): m / z [M + H]+ Calculated C 25 H 27 ClN3O4, 468.1690; Measured value, 468.1693.

[0158] Compound 25:

[0159] (R)-N-(6-(4-(3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyrimidin-4-yl)cyclopentaneformamide (25) Following general step B, amine intermediate M10d was reacted with cyclopentaneformyl chloride to give title compound 25 as a white powder (yield: 65%). 1H NMR (400 MHz, CDCl3) δ 8.9 (s, 1H), 8.7 (d, J = 1.3 Hz, 1H), 8.5 (d, J = 2.2 Hz, 1H), 8.2 (dd, J = 8.7, 2.2 Hz, 1H), 8.1 (s, 1H), 7.4 (d,J = 8.7 Hz, 1H), 5.8 (s, 1H), 4.2 - 4.0 (m, 2H), 4.0 - 3.9 (m, 2H), 3.8 - 3.7(m, 1H), 3.7 - 3.5 (m, 1H), 3.0 (dt, J = 12.8, 3.0 Hz, 1H), 2.9 - 2.7 (m,1H), 2.1 - 1.9 (m, 4H), 1.9 - 1.8 (m, 2H), 1.8 - 1.6 (m, 2H), 1.3 - 1.2 (m,3H); 13 C NMR (100 MHz, CDCl3) δ 176.0, 163.9, 161.9, 160.2, 158.4, 158.2, 156.0, 132.3, 130.3, 124.3, 118.4, 116.8, 105.2, 100.1, 71.0, 66.5, 53.7, 47.0, 46.0, 30.3 (2C), 26.0 (2C), 13.0. HRMS (ESI): m / z [M + H]+ Calculated C 24 H 27 N4O4, 435.2032; measured value, 435.2027.

[0160] Compound 26:

[0161] (R)-N-(5-fluoro-4-(4-(3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclohexaneformamide (26) Following general step B, amine intermediate M10b was reacted with cyclohexaneformyl chloride to give title compound 26 as a white powder (yield: 70%). 1H NMR (400 MHz, CDCl3) δ 8.5 (d, J = 6.2 Hz, 1H), 8.2 (d, J= 2.4 Hz, 1H), 8.2 (s, 1H), 8.0 - 7.9 (m, 1H), 7.9 - 7.8 (m, 1H), 7.4 (d, J =8.7 Hz, 1H), 5.8 (s, 1H), 4.0 (ddd, J = 11.2, 7.4, 3.2 Hz, 2H), 3.9 (tdd, J =14.1, 8.4, 3.4 Hz, 2H), 3.7 (dd, J = 11.2, 2.9 Hz, 1H), 3.6 (ddd, J = 13.0,9.8, 3.3 Hz, 1H), 3.0 (dt, J = 12.7, 3.1 Hz, 1H), 2.3 (tt, J = 11.7, 3.5 Hz,1H), 2.0 - 2.0 (m, 2H), 1.9 (dt, J = 12.6, 3.2 Hz, 2H), 1.8 - 1.7 (m, 1H),1.6 (qd, J = 12.1, 3.2 Hz, 2H), 1.4 - 1.3 (m, 3H), 1.2 (s, 3H); 13 C NMR (100MHz, CDCl3) δ 174.7, 161.9, 160.0, 154.7, 153.4 (d, J = 251.8 Hz), 148.4,136.7 (d, J = 10.8 Hz), 136.2 (d, J = 28.4 Hz), 131.9 (d, J = 3.3 Hz), 128.4,125.7 (d, J = 5.1 Hz), 118.4, 116.6, 113.8, 100.4, 71.0, 66.5, 53.7, 46.4,46.1, 29.5 (2C), 25.6 (2C), 24.9, 13.0. HRMS (ESI): m / z [M + H] + Calculated value C 26 H 29 FN3O4, 466.2142; Measured value, 466.2144.

[0162] Compound 27:

[0163] (R)-N-(5-fluoro-4-(4-(3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide (27) Following general step B, amine intermediate M10b was reacted with tetrahydro-2H-pyran-4-carboxyl chloride to give title compound 27 as a white powder (yield: 68%). 1 H NMR (400 MHz, CDCl3) δ 8.5 (d,J = 6.1Hz, 1H), 8.3 (d, J = 2.4 Hz, 1H), 8.2 (s, 1H), 8.0 - 7.9 (m, 1H), 7.9 - 7.8(m, 1H), 7.5 (d, J = 8.6 Hz, 1H), 5.8 (s, 1H), 4.1 - 4.0 (m, 2H), 4.0 - 4.0(m, 2H), 4.0 - 3.8 (m, 2H), 3.7 (dd, J = 11.4, 2.9 Hz, 1H), 3.6 - 3.4 (m,3H), 3.0 - 2.9 (m, 1H), 2.6 - 2.5 (m, 1H), 2.0 - 1.8 (m, 4H), 1.2 (d, J = 6.6Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 172.9, 161.8, 159.9, 154.9, 153.5 (d, J = 252.7 Hz), 148.0, 135.8 (d, J = 28.4 Hz), 131.9 (d, J = 3.2 Hz), 128.2, 125.8 (d, J = 4.7 Hz), 118.5, 116.7, 115.0, 114.0, 100.6, 71.0, 67.1 (2C), 66.5, 53.7, 46.1, 43.1, 29.0 (2C), 13.0. HRMS (ESI): m / z [M + H]+ Calculated C 25 H 27 FN3O5, 468.1935; Measured value, 468.1939.

[0164] Compound 28:

[0165] (R)-N-(5-fluoro-4-(4-(3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)piperidin-4-carboxamide (28) was prepared from M9a and M6b via general step A, followed by deprotection via general step C. This sequence yielded the title compound 28 as a white powder (yield: 35%). 1 H NMR (400 MHz, DMSO-d6) δ 10.6 (s, 1H), 8.4 (d, J = 2.3 Hz, 1H), 8.4 (d, J = 6.3 Hz, 1H), 7.9 (s, 1H), 7.9 (d, J =8.9 Hz, 1H), 7.6 (d, J = 8.6 Hz, 1H), 5.8 (s, 1H), 4.0 (d, J = 6.6 Hz, 1H), 3.9 - 3.8 (m, 2H), 3.8 - 3.5 (m, 5H), 3.1 - 3.0 (m, 2H), 3.0 (s, 1H), 2.7 -2.6 (m, 2H), 1.7 (d, J = 12.6 Hz, 2H), 1.5 (q, J = 12.5 Hz, 2H), 1.2 (d, J =6.5 Hz, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 174.9, 161.2, 159.9, 154.6, 153.1(d, J = 249.0 Hz), 149.6 (d, J = 2.2 Hz), 136.9 (d, J = 27.1 Hz), 135.9 (d, J= 10.3 Hz), 132.2, 128.5, 126.0 (d, J = 3.2 Hz), 118.6, 116.6, 114.0, 99.4,70.6, 66.2, 53.6, 45.2, 42.7, 40.5 (2C), 29.5 (2C), 13.3. HRMS (ESI): m / z [M+ H]+ Calculated value C 25 H 28 FN4O4, 467.2095; Measured value, 467.2097.

[0166] Compound 29:

[0167] (R)-N-(5-fluoro-4-(4-((R)-3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)piperidine-3-carboxamide (29) was prepared from M9a and M6c via general step A, followed by deprotection via general step C. This sequence yielded the title compound 29 as a white powder (yield: 38%). 1 H NMR (400 MHz, CD3OD) δ 8.4 (d, J = 6.1 Hz, 1H), 8.3 (d, J = 2.4 Hz, 1H), 8.1 (s, 1H), 7.9 (d, J = 8.6 Hz, 1H), 7.5 (d, J= 8.6 Hz, 1H), 5.9 (s, 1H), 4.0 (dd, J = 11.8, 3.1 Hz, 3H), 3.8 (t, J = 10.7Hz, 1H), 3.7 - 3.6 (m, 2H), 3.4 (d, J = 5.9 Hz, 2H), 3.2 - 3.0 (m, 3H), 2.2(t, J = 8.9 Hz, 1H), 2.1 - 1.8 (m, 4H), 1.3 (d, J = 6.7 Hz, 3H); 13 C NMR (100MHz, CD3OD) δ 173.5, 164.1, 162.0, 154.4 (d, J = 251.5 Hz), 153.8, 149.9,138.0 (d, J = 27.7 Hz), 137.5 (d, J = 28.7 Hz), 133.2 (d, J = 4.0 Hz), 130.1,127.2 (d, J = 3.5 Hz), 127.1, 119.4, 115.5, 100.2, 71.9, 67.6, 55.2, 49.8,46.0, 45.1, 40.6, 27.3, 22.1, 13.3. HRMS (ESI): m / z [M + H] + Calculated value C 25 H 28 FN4O4, 467.2095; Measured value, 467.2095.

[0168] Compound 30:

[0169] (S)-N-(5-fluoro-4-(4-((R)-3-methylmorpholino)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)piperidin-3-carboxamide (30) was prepared from amines M9a and M6d via general step A, followed by deprotection via general step C. This sequence yielded the title compound 30 as a white powder (yield: 46%). 1 H NMR (400 MHz, CD3OD) δ 8.4 (d, J = 6.2 Hz,1H), 8.3 (d, J = 2.5 Hz, 1H), 8.1 - 8.0 (m, 1H), 7.9 - 7.9 (m, 1H), 7.5 (d, J= 8.7 Hz, 1H), 5.8 (s, 1H), 4.1 - 3.9 (m, 3H), 3.8 (td, J = 10.9, 2.7 Hz,1H), 3.8 - 3.7 (m, 1H), 3.7 - 3.6 (m, 1H), 3.2 - 3.0 (m, 2H), 3.0 (d, J =12.8 Hz, 1H), 2.9 (t, J = 11.1 Hz, 1H), 2.6 (d, J = 10.5 Hz, 1H), 2.1 - 2.0(m, 2H), 1.8 (q, J = 10.2 Hz, 2H), 1.6 - 1.6 (m, 1H), 1.3 (d, J = 6.6 Hz,3H); 13 C NMR (100 MHz, CD3OD) δ 175.7, 164.2, 162.0, 155.9 (d, J = 251.7 Hz), 154.8 (d, J = 251.1 Hz), 150.2 (d, J = 3.1 Hz), 137.8 (d, J = 28.1 Hz), 137.4(d, J = 27.9 Hz), 133.3 (d, J = 3.5 Hz), 130.9, 127.1 (d, J = 4.3 Hz), 119.3,117.9, 115.4, 100.0, 71.9, 67.6, 55.2, 49.8, 47.0, 46.7, 45.0, 28.9, 23.8, 13.2. HRMS (ESI): m / z [M + H] + calculated value C 25 H 28 FN4O4Na, 489.1914; Measured value, 489.1936.

[0170] Compound 31:

[0171] N-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-yl)-2-oxo-2H-chromen-6-yl)-5-fluoropyridin-2-yl)cyclohexaneformamide (31) was reacted with cyclohexaneformyl chloride according to general step A to give title compound 31 as a white powder (yield: 62%). 1 H NMR (400 MHz, CDCl3) δ 8.6 (d, J= 6.2 Hz, 1H), 8.2 (d, J = 2.5 Hz, 1H), 8.1 (t, J = 1.8 Hz, 1H), 7.8 (dt, J =8.7, 1.6 Hz, 1H), 7.4 (d, J = 8.6 Hz, 1H), 5.7 (s, 1H), 4.1 (d, J = 4.4 Hz,2H), 4.0 (d, J = 10.9 Hz, 2H), 3.8 - 3.7 (m, 2H), 2.3 (ddt, J = 11.5, 6.9,3.4 Hz, 1H), 2.2 - 2.1 (m, 2H), 2.1 (d, J = 9.2 Hz, 2H), 2.0 (d, J = 13.2 Hz,2H), 1.9 (dd, J = 8.0, 4.6 Hz, 2H), 1.7 (d, J = 11.0 Hz, 1H), 1.6 - 1.5 (m,2H), 1.4 - 1.2 (m, 3H); 13 C NMR (100 MHz, CDCl3) δ 174.8, 162.2, 157.8, 154.9,153.4 (d, J = 251.5 Hz), 148.3, 137.1 (d, J = 12.3 Hz), 135.7 (d, J = 28.7Hz), 131.9 (d, J = 3.9 Hz), 128.0, 126.0 (d, J = 4.9 Hz), 118.4, 116.6,113.9, 94.8, 72.1 (2C), 60.5 (2C), 46.4, 29.5 (2C), 25.9 (2C), 25.6, 25.5(2C). HRMS (ESI): m / z [M + H]+ Calculated value C27H29FN3O4, 478.2142; Measured value, 478.2139.

[0172] Compound 32:

[0173] (R)-N-(5-fluoro-4-(4-(2-methylpyrrolidin-1-yl)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclohexaneformamide (32) was reacted with cyclohexaneformyl chloride according to general step A to give title compound 32 as a white powder (yield: 66%). 1 H NMR (400 MHz, CDCl3) δ 8.5 (d, J = 6.2 Hz,1H), 8.3 - 8.2 (m, 3H), 7.8 - 7.7 (m, 1H), 7.4 (d, J = 8.6 Hz, 1H), 5.4 (s,1H), 4.1 - 4.0 (m, 1H), 4.0 (td, J = 9.8, 6.2 Hz, 1H), 3.8 (ddd, J = 9.9,7.4, 2.4 Hz, 1H), 2.4 - 2.3 (m, 2H), 2.1 - 2.0 (m, 1H), 2.0 (dd, J = 13.6,3.4 Hz, 2H), 1.9 - 1.7 (m, 5H), 1.5 (qd, J = 12.2, 3.3 Hz, 2H), 1.4 - 1.3 (m,1H), 1.3 (d, J = 6.0 Hz, 3H), 1.3 - 1.3 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ174.7, 162.6, 155.7, 154.8, 153.4 (d, J = 251.3 Hz), 148.4, 137.0 (d, J =11.4 Hz), 136.2 (d, J = 28.3 Hz), 131.5 (d, J = 3.0 Hz), 127.7, 126.7 (d, J =4.2 Hz), 118.4, 117.3, 113.9, 89.5, 56.3, 54.2, 46.4, 34.1, 29.5 (2C), 25.6(2C), 25.5, 24.9, 18.8. HRMS (ESI): m / z [M + H] + Calculated value C 26 H 29 FN3O3, 450.2193; measured value, 450.2194.

[0174] Compound 33:

[0175] (S)-N-(5-fluoro-4-(4-(2-methylpyrrolidin-1-yl)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)cyclohexaneformamide (33) was reacted with cyclohexaneformyl chloride according to general procedure A to give title compound 33 as a white powder (yield: 64%). 1 H NMR (400 MHz, CDCl3) δ 8.5 (d, J = 6.2 Hz,1H), 8.2 (d, J = 7.4 Hz, 1H), 8.2 - 8.1 (m, 2H), 7.8 - 7.7 (m, 1H), 7.4 (d, J= 8.6 Hz, 1H), 5.4 (s, 1H), 4.0 (dq, J = 12.4, 6.0 Hz, 1H), 4.0 (td, J = 9.8,6.1 Hz, 1H), 3.9 - 3.8 (m, 1H), 2.4 - 2.3 (m, 2H), 2.1 - 2.0 (m, 1H), 2.0 -2.0 (m, 2H), 1.9 - 1.7 (m, 5H), 1.6 - 1.5 (m, 2H), 1.4 - 1.3 (m, 1H), 1.3 (d,J = 6.0 Hz, 3H), 1.3 - 1.3 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 174.8, 162.5,155.7, 154.9, 153.4 (d, J = 251.1 Hz), 148.3 (d, J = 2.8 Hz), 137.4 (d, J =10.9 Hz), 135.8 (d, J = 28.0 Hz), 131.5 (d, J = 3.0 Hz), 127.5, 126.7 (d, J =4.5 Hz), 118.5 (d, J = 4.5 Hz), 117.3, 114.0, 89.5, 56.3, 54.3, 46.4, 34.1,29.5 (2C), 25.6 (2C), 25.5, 24.9, 18.8. HRMS (ESI): m / z [M + H] + calculated value C 26 H 29 FN3O3, 450.2193; Measured value, 450.2197.

[0176] Compound 34:

[0177] (R)-N-(5-fluoro-4-(4-((S)-2-methylpyrrolidin-1-yl)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)piperidin-3-carboxamide (34) was prepared from borate esters M9d and M6c via general step A, followed by deprotection via general step C. This sequence yielded the title compound 34 as a white powder (yield: 52%). The absolute configuration was confirmed by X-ray diffraction analysis of its N-Boc protected precursor M11d. 1 H NMR (400 MHz, CD3OD) δ 8.4 - 8.3 (m, 2H), 8.3 (d, J =2.4 Hz, 1H), 7.9 - 7.8 (m, 1H), 7.5 (d, J = 8.6 Hz, 1H), 5.4 (s, 1H), 4.3 -4.1 (m, 1H), 4.0 (td, J = 9.6, 6.2 Hz, 1H), 3.9 - 3.8 (m, 1H), 3.1 (dd, J =12.3, 3.7 Hz, 1H), 3.0 - 2.9 (m, 1H), 2.9 - 2.8 (m, 1H), 2.7 - 2.6 (m, 2H),2.4 - 2.3 (m, 1H), 2.2 - 2.0 (m, 2H), 1.9 - 1.7 (m, 4H), 1.7 - 1.5 (m, 1H),1.3 (d, J = 6.1 Hz, 3H); 13 C NMR (100 MHz, CD3OD) δ 175.6, 165.3, 157.7, 155.9, 154.9 (d, J = 251.0 Hz), 150.1, 137.8 (d, J = 10.9 Hz), 137.6 (d, J = 26.8 Hz), 133.1, 129.7, 128.3 (d, J = 3.9 Hz), 119.5, 118.4, 115.5, 88.5, 57.9, 55.5, 49.6, 46.6, 44.8, 35.0, 28.8, 28.0, 26.2, 19.0. HRMS (ESI): m / z[M + H] + Calculated C 25 H 28 FN4O3, 451.2145; Measured value, 451.2145.

[0178] Compound 35:

[0179] (R)-N-(5-fluoro-4-(4-((R)-2-methylpyrrolidin-1-yl)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)piperidin-3-carboxamide (35) was prepared from borate esters M9d and M6d via general step A, followed by deprotection via general step C. This sequence yielded the title compound 35 as a white powder (yield: 43%). 1 H NMR (400 MHz, CD3OD) δ 8.4 - 8.3(m, 3H), 7.9 (d, J = 8.7 Hz, 1H), 7.5 (d, J = 8.6 Hz, 1H), 5.4 (s, 1H), 4.2(q, J = 6.6 Hz, 1H), 4.0 (td, J = 9.6, 6.3 Hz, 1H), 3.9 - 3.8 (m, 1H), 3.4 -3.3 (m, 2H), 3.3 (s, 1H), 3.1 (t, J = 10.4 Hz, 1H), 3.1 (s, 1H), 2.4 - 2.3(m, 1H), 2.2 - 2.0 (m, 2H), 2.0 - 1.7 (m, 5H), 1.3 (d, J = 6.1 Hz, 3H); 13 CNMR (100 MHz, CD3OD) δ 173.4, 165.3, 157.6, 155.9, 154.6 (d, J = 250.9 Hz), 149.8, 137.9 (d, J = 13.1 Hz), 137.7 (d, J = 3.1 Hz), 133.0 (d, J = 3.1 Hz),129.6, 128.3 (d, J = 4.0 Hz), 119.5, 118.4, 115.6, 88.6, 57.9, 55.5, 46.0,45.1, 40.6, 35.0, 27.3, 26.2, 22.1, 19.0. HRMS (ESI): m / z [M + H]+ Calculated value C 25 H 28 FN4O3, 451.2145; Measured value, 451.2145.

[0180] Compound 36:

[0181] (S)-N-(5-fluoro-4-(4-((S)-2-methylpyrrolidin-1-yl)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)piperidin-3-carboxamide (36) was prepared from borate esters M9c and M6c via general step A, followed by deprotection via general step C. This sequence yielded the title compound 36 as a white powder (yield: 45%). 1 H NMR (400 MHz, DMSO-d6) δ 10.9(s, 1H), 8.4 (d, J = 2.2 Hz, 1H), 8.3 (d, J = 6.3 Hz, 1H), 8.2 - 8.2 (m, 1H),7.8 - 7.8 (m, 1H), 7.5 (d, J = 8.6 Hz, 1H), 5.3 (s, 1H), 4.2 - 4.1 (m, 1H), 3.9 (td, J = 9.6, 6.3 Hz, 1H), 3.7 (td, J = 8.0, 4.1 Hz, 1H), 3.0 - 2.9 (m,1H), 2.8 (d, J = 11.9 Hz, 1H), 2.7 (t, J = 10.4 Hz, 1H), 2.6 - 2.5 (m, 2H), 2.3 - 2.2 (m, 1H), 2.0 - 1.9 (m, 1H), 1.9 (d, J = 8.8 Hz, 1H), 1.8 (dq, J =9.5, 5.7 Hz, 1H), 1.7 - 1.6 (m, 1H), 1.6 - 1.5 (m, 2H), 1.5 - 1.3 (m, 1H), 1.2 (d, J = 5.9 Hz, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 174.4, 161.2, 155.3,154.6, 153.1 (d, J = 249.6 Hz), 149.5 (d, J = 2.8 Hz), 136.8 (d, J = 27.1Hz), 136.3 (d, J = 11.5 Hz), 131.9, 127.9, 127.1 (d, J = 3.9 Hz), 118.6,117.2, 114.1, 88.3, ​​56.3, 54.0, 49.0, 46.3, 43.7, 33.9, 28.1, 25.2, 19.0.HRMS (ESI): m / z [M + H]+ Calculated value C 25 H 28FN4O3, 451.2145; Measured value, 451.2145.

[0182] Compound 37:

[0183] (S)-N-(5-fluoro-4-(4-((R)-2-methylpyrrolidin-1-yl)-2-oxo-2H-chromen-6-yl)pyridin-2-yl)piperidin-3-carboxamide (37) was prepared from borate esters M9c and M6d via general step A, followed by deprotection via general step C. This sequence yielded the title compound 37 as a white powder (yield: 51%). 1 H NMR (400 MHz, DMSO-d6) δ 11.0(s, 1H), 9.1 (s, 2H), 8.5 (d, J = 2.1 Hz, 1H), 8.3 - 8.2 (m, 2H), 7.8 (d, J =8.6 Hz, 1H), 7.5 (d, J = 8.6 Hz, 1H), 5.3 (s, 1H), 4.2 (q, J = 6.6 Hz, 1H), 3.9 (td, J = 9.4, 6.2 Hz, 1H), 3.7 (dd, J = 9.6, 6.2 Hz, 1H), 3.3 (d, J =10.2 Hz, 1H), 3.2 - 3.1 (m, 1H), 3.0 (s, 2H), 2.9 (s, 1H), 2.2 (t, J = 6.8Hz, 1H), 2.1 - 1.9 (m, 2H), 1.9 - 1.5 (m, 5H), 1.2 (d, J = 5.9 Hz, 3H); 13 CNMR (100 MHz, DMSO-d6) δ 172.1, 161.2, 155.3, 154.7, 153.3 (d, J = 250.2 Hz), 149.1 (d, J = 2.3 Hz), 137.0 (d, J = 27.2 Hz), 136.4 (d, J = 11.7 Hz), 131.9,127.8, 127.2 (d, J = 3.5 Hz), 118.6, 117.2, 114.4, 88.4, 56.3, 54.0, 44.3,43.3, 33.9, 26.7, 25.2, 21.6, 19.0. HRMS (ESI): m / z [M + H]+ Calculated value C 25 H 28 FN4O3, 451.2145; measured value, 451.2140.

[0184] The properties of compounds 1-37 were tested.

[0185] (1) Evaluation of the inhibitory activity of compounds 1-37 on CDK9 and CDK2:

[0186] The tested compounds were compounds 1-37, and the control sample Dinaciclib, a classic CDK2 / 9 inhibitor, was purchased from Bide Pharmaceuticals (BD630863); the control sample KB-074, a clinical investigational CDK9 inhibitor, was purchased from Bide Pharmaceuticals (BD01574850).

[0187] Kinase Glo assay was performed in a yellow 96-well plate using assay buffer. 1 μL (10 μM) of the analyte compound (dissolved in DMSO and then diluted to the desired concentration with kinase buffer) and 2 μL (5 ng) of the enzyme were added to each well, followed by 2 μL of a stoichiometric mixture containing 0.2 μg of substrate and 25 μM ATP. After incubation at room temperature for 60 minutes, the enzymatic reaction was stopped with 5 μL of kinase Glo reagent, and any remaining ATP was removed. After incubation at room temperature for another 40 minutes, the ADP generated in the reaction was converted to ATP using the kinase assay reagent. The luminescence value was recorded using a multi-plate reader after 30 minutes. The control samples were treated in the same manner. The results are shown in Table 1.

[0188] (2) Evaluation of the anti-proliferation activity of compounds 1-37:

[0189] The control sample KB-074, a clinically investigated CDK9 inhibitor, was purchased from Bidex Pharmaceuticals (BD01574850). In vitro antiproliferative activity was assessed using the MTT assay to evaluate cytotoxicity. Specific steps included:

[0190] The antiproliferative activity of the compounds was assessed using the MTT assay. MDA-MB-231 cells (2000 cells / well) were seeded in 96-well plates and allowed to adhere overnight. Cells were then exposed to different concentrations of the compounds for 72 h. MTT solution (20 μL, 0.5 mg / mL) was added to each well, and cells were incubated with MTT at 37°C for 4 h. After aspirating the supernatant, DMSO (150 μL) was added, and absorbance was read at 490 nm. All assays were repeated in triplicate. Control samples were treated in the same manner. GraphPadprism 8.0 software was used to determine the linear regression parameters and calculate the IC50. 50 Values. The results are shown in Table 1.

[0191] Table 1. CDK9 / CDK2 inhibitory activity and antiproliferative activity against MDA-MB-231 of compounds 1-37

[0192] a IC 50 The value is calculated from the data points obtained by averaging the values ​​of repeated holes. b GI 50 The values ​​were calculated from the average of the data points obtained from the replicate wells. The values ​​of MDA-MB-231 cells were determined using the MTT assay after 72 hours of treatment. Data are the mean ± standard deviation of at least two to three independent experiments.

[0193] As shown in Table 1, most of the compounds prepared in this invention can effectively inhibit CDK9 activity, with IC values ​​less than 10 nM, and exhibit high selectivity for CDK2 (CDK2 activity greater than 10 nM, demonstrating high selectivity). The coumarin compounds of this invention possess potent and highly selective CDK9 inhibitory activity, specifically blocking CDK9-mediated transcriptional regulatory pathways. Pharmaceutically acceptable salts also possess this function, providing high-quality candidate molecules for the development of CDK9-targeting anticancer drugs. Therefore, most of the compounds prepared in this invention can effectively inhibit the proliferation of triple-negative breast cancer.

[0194] The preferred embodiments of the present invention have been described in detail above with reference to the accompanying drawings. However, the present invention is not limited to the specific details of the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0195] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

[0196] Furthermore, various different embodiments of the present invention can be combined in any way, as long as they do not violate the spirit of the present invention, they should also be considered as the content protected by the present invention.

Claims

1. A coumarin compound and its pharmaceutically acceptable salt, characterized in that, The coumarin compounds have the structure of formula (I): Equation (I) ; R1 is selected from , , , , , , , , , , , , , , , and ; R2 is selected from H, halogen, methyl, and methoxy. X is selected from CH, N, CF, and CCl; R3 is selected from , , , , , , , , .

2. The coumarin compound and its pharmaceutically acceptable salt according to claim 1, characterized in that, The coumarin compounds are selected from the following substances: 。 3. The method for preparing a coumarin compound and its pharmaceutically acceptable salt according to claim 1, characterized in that, The preparation method of the coumarin compounds includes the following: S1. The compound shown in formula (M3), an amine nucleophile, and a first solvent are mixed and subjected to a nucleophilic substitution reaction to obtain the first intermediate; S2. The first intermediate, boryling agent, second catalyst, second basic agent and second solvent are mixed and boron esterification reaction is carried out to obtain the second intermediate; S3. Mix the second intermediate, the compound of formula (M5) or (M6), the third catalyst, the third basic reagent and the third solvent to carry out a cross-coupling reaction; and amination the product obtained from the cross-coupling reaction with an amide compound or an activated amino acid to obtain the third intermediate. S4. The first intermediate, the boron-containing nucleophile shown in formula (M7), the fourth catalyst, the fourth basic reagent and the fourth solvent are mixed and cross-coupled to obtain the fourth intermediate. S5. When there is no protecting group, the third and fourth intermediates are the product coumarin compounds; when there is a protecting group, the protecting group of the third or fourth intermediate containing the protecting group is removed to obtain the product coumarin compounds. Formula (M3) R2 is selected from H, methyl, methoxy or halogen; Formula (M5) , X is selected from N, CH, CF or CCl; Formula (M6) , X is selected from N, CH, CF or CCl, R3 is selected from cycloalkyl or nitrogen-containing saturated heterocycle, and Boc is tert-butoxycarbonyl; Formula (M7) X is selected from N, CH, CF or CCl.

4. The method for preparing a coumarin compound and its pharmaceutically acceptable salt according to claim 3, characterized in that, The first intermediate has the structure shown in formula (M4): Formula (M4) ; The second intermediate has the structure shown in formula (M9): Formula (M9) ; The third intermediate has the structure shown in formula (M10) or formula (M11): Formula (M10) Formula (M11) ; The fourth intermediate has the structure shown in formula (M12): Formula (M12) ; R1 is selected from , , , , , , , , , , , , , , , and .

5. The method for preparing a coumarin compound and its pharmaceutically acceptable salt according to claim 3, characterized in that, Step S1 includes the following: Use 2 mL to 10 mL of the first solvent for every 1 mmol of the compound represented by formula (M3), and the molar ratio of the compound represented by formula (M3) to the amine nucleophile is 1:(1.1-10.0). Amine nucleophiles include aliphatic amines or cyclic amines; the first solvent is selected from one or more of DMSO, DMF, acetonitrile, and NMP; The nucleophilic substitution reaction is carried out at temperatures ranging from 20℃ to 85℃ for 2 hours to 6 hours.

6. The method for preparing a coumarin compound and its pharmaceutically acceptable salt according to claim 3, characterized in that, Step S2 includes the following: Use 5 mL to 20 mL of the second solvent for every 1 mmol of the first intermediate. The molar ratio of the first intermediate, the boryling agent, and the second catalyst is 1:(1.1-1.5):(0.02-0.1), and the molar ratio of the first intermediate to the second basic agent is 1:

3. The borizing agent is selected from pinacol diboronate ((Bpin)2) and / or pinacol isopropoxyboronate; the second catalyst is selected from one or more of Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(OAc)2 and Pd(amphos)Cl2; the second basic agent is selected from one or more of potassium acetate, potassium carbonate and cesium carbonate; the second solvent is selected from one or more of 1,4-dioxane, DMSO, DMF and toluene. The boron esterification reaction is carried out at a temperature of 90℃-100℃ for 6h-14h.

7. The method for preparing a coumarin compound and its pharmaceutically acceptable salt according to claim 3, characterized in that, Step S3 includes the following: Use 1 mL to 20 mL of third solvent for every 1 mmol of second intermediate. The molar ratio of second intermediate, compound of formula (M5) or formula (M6), and third catalyst is 1:(1.0-1.2):(0.02-0.1). The molar ratio of second intermediate to third basic reagent is 1:

3. The third catalyst is selected from one or more of Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(OAc)2 and Pd(amphos)Cl2; the third basic reagent is selected from one or more of potassium carbonate, potassium phosphate, sodium carbonate, cesium carbonate and cesium fluoride; the third solvent is selected from one or a mixture of one or more of 1,4-dioxane, water, ethanol, DMF and DME. The cross-coupling reaction was carried out under inert gas protection at a temperature of 85℃-100℃ for 1-12 hours. The amide compounds are selected from one or more of cyclopropionyl chloride, cyclobutyryl chloride, cyclopentyl chloride, cyclohexyl chloride and 4,4-difluorocyclohexanecarboxyl chloride; The activated amino acid is generated in situ by reacting an N-protected amino acid with 1-chloro-N,N,2-trimethylpropenylamine at 0°C to room temperature; the N-protected amino acid is selected from N-Boc-piperidine-3-carboxylic acid or N-Boc-proline. The amination reaction is carried out at a temperature of 0°C to room temperature for 1-12 hours.

8. The method for preparing a coumarin compound and its pharmaceutically acceptable salt according to claim 3, characterized in that, Step S4 includes the following: For every 1 mmol of the first intermediate, use 1 mL to 20 mL of the fourth solvent. The molar ratio of the compound shown in formula (M7), the first intermediate, and the fourth catalyst is 1:(1.0-1.2):(0.02-0.1), and the molar ratio of the first intermediate to the fourth basic reagent is 1:

3. The fourth catalyst is selected from one or more of Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd(OAc)2 and Pd(amphos)Cl2; the fourth basic reagent is selected from one or more of potassium carbonate, potassium phosphate, sodium carbonate, cesium carbonate and cesium fluoride; the fourth solvent is selected from one or a mixture of one or more of 1,4-dioxane, water, ethanol, DMF and DME. The cross-coupling reaction was carried out under inert gas protection at a temperature of 85℃-100℃ for 1-12 hours.

9. The method for preparing a coumarin compound and its pharmaceutically acceptable salt according to claim 3, characterized in that, Step S5 includes the following: The method for removing the protecting group includes the following: when the protecting group is tert-butyloxycarbonyl Boc, the third or fourth intermediate containing the protecting group is reacted in a mixture of acidic reagent and organic solvent at 0°C to room temperature for 1-12 hours. After the reaction is completed, the product coumarin compound is obtained by concentration and purification.

10. The use of a coumarin compound and its pharmaceutically acceptable salt according to claim 1, characterized in that, The coumarin compounds and their pharmaceutically acceptable salts are used to prepare drugs for the prevention and / or treatment of cyclin-dependent kinase 9 (CDK9)-related diseases. CDK9-related diseases include leukemia, lymphoma, brain cancer, lung cancer, stomach cancer, esophageal cancer, skin cancer, colon cancer, rectal cancer, pancreatic cancer, myeloma, ovarian cancer, triple-negative breast cancer, testicular cancer, liver cancer, prostate cancer, and bladder cancer.

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