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CN-121974891-A - Coumarin compound and pharmaceutically acceptable salt thereof, and preparation method and application thereof

CN121974891ACN 121974891 ACN121974891 ACN 121974891ACN-121974891-A

Abstract

The invention belongs to the technical field of pharmaceutical chemistry and medicine, and particularly relates to coumarin compounds and pharmaceutically acceptable salts thereof, and a preparation method and application thereof. The compound takes coumarin parent nucleus as a framework, improves target selectivity and binding efficiency through multi-substituent collaborative design, provides a new structure type and a practical scheme for research and development of CDK9 targeted anticancer drugs, and has important clinical value and application prospect.

Inventors

  • JIA JINGMING
  • WANG ANHUA
  • HUANG YAOGUANG

Assignees

  • 沈阳药科大学

Dates

Publication Date
20260505
Application Date
20260309

Claims (10)

  1. 1. Coumarin compound and pharmaceutically acceptable salts thereof, characterized in that the coumarin compound has the structure of formula (I): Formula (I) ; R 1 is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 And ; R 2 is selected from H, halogen, methyl, methoxy; x is selected from CH, N, CF, CCl; R 3 is selected from 、 、 、 、 、 、 、 、 。
  2. 2. A coumarin compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the coumarin compound is selected from the group consisting of: 。
  3. 3. The preparation method of the coumarin compound and the pharmaceutically acceptable salt thereof according to claim 1, wherein the preparation method of the coumarin compound comprises the following steps: s1, mixing a compound shown in a formula (M3), an amine nucleophilic reagent and a first solvent, and performing nucleophilic substitution reaction to obtain a first intermediate; S2, mixing the first intermediate, the boration reagent, the second catalyst, the second alkaline reagent and the second solvent, and performing a boration reaction to obtain a second intermediate; s3, mixing a second intermediate, a compound shown in the formula (M5) or (M6), a third catalyst, a third alkaline reagent and a third solvent for cross-coupling reaction, and carrying out amination reaction on a product obtained by the cross-coupling reaction and an amide compound or activated amino acid to obtain a third intermediate; S4, mixing the first intermediate, a boron-containing nucleophile shown in the formula (M7), a fourth catalyst, a fourth alkaline reagent and a fourth solvent, and performing cross coupling reaction to obtain a fourth intermediate; S5, when the protective group is not contained, the third intermediate and the fourth intermediate are the coumarin compound, and when the protective group is contained, the protective group of the third intermediate or the fourth intermediate containing the protective group is removed to obtain the coumarin compound; (M3) R 2 is selected from H, methyl, methoxy or halogen; (M5) 、 X is selected from N, CH, CF or CCl; (M6) 、 X is selected from N, CH, CF or CCl, R 3 is selected from cycloalkyl or nitrogen-containing saturated heterocycle, and Boc is tert-butoxycarbonyl; (M7) X is selected from N, CH, CF or CCl.
  4. 4. A process for the preparation of coumarin compounds and pharmaceutically acceptable salts thereof according to claim 3, wherein the first intermediate has the structure of formula (M4): (M4) ; The second intermediate has a structure represented by formula (M9): (M9) ; The third intermediate has a structure represented by formula (M10) or formula (M11): (M10) The, formula (M11) ; The fourth intermediate has a structure represented by formula (M12): (M12) ; R 1 is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 And 。
  5. 5. A process for the preparation of coumarin compounds and pharmaceutically acceptable salts thereof according to claim 3, wherein step S1 comprises the following steps: 2-10 mL of the first solvent is used for every 1mmol of the compound shown in the formula (M3), and the molar ratio of the compound shown in the formula (M3) to the amine nucleophilic reagent is 1 (1.1-10.0); The amine nucleophile comprises aliphatic amine or cyclic amine, and the first solvent is selected from one or more of DMSO, DMF, acetonitrile and NMP; The nucleophilic substitution reaction temperature is 20-85 ℃ and the time is 2-6 h.
  6. 6. A process for the preparation of coumarin compounds and pharmaceutically acceptable salts thereof according to claim 3, wherein step S2 comprises the following steps: 5mL-20mL of the second solvent is used for each 1mmol of the first intermediate, the molar ratio of the first intermediate to the boration reagent to the second catalyst is 1 (1.1-1.5): (0.02-0.1), and the molar ratio of the first intermediate to the second alkaline reagent is 1:3; The boration reagent is selected from pinacol ester of biboronate ((Bpin) 2) and/or pinacol ester of isopropoxycarbonate, the second catalyst is selected from one or more of Pd (PPh 3 ) 2 Cl 2 、Pd(dppf)Cl 2 、Pd(OAc) 2 ) and Pd (amphos) Cl 2 , the second alkaline reagent is selected from one or more of potassium acetate, potassium carbonate and cesium carbonate, and the second solvent is selected from one or more of 1, 4-dioxane, DMSO, DMF and toluene; The temperature of the boron esterification reaction is 90-100 ℃ and the time is 6-14 h.
  7. 7. A process for the preparation of coumarin compounds and pharmaceutically acceptable salts thereof according to claim 3, wherein step S3 comprises the following steps: 1mL-20mL of the third solvent is used for every 1mmol of the second intermediate, the molar ratio of the second intermediate, the compound shown in the formula (M5) or the formula (M6) to the third catalyst is 1 (1.0-1.2): 0.02-0.1, and the molar ratio of the second intermediate to the third alkaline reagent is 1:3; The third catalyst is selected from one or more of Pd (PPh 3 ) 2 Cl 2 、Pd(dppf)Cl 2 、Pd(OAc) 2 and Pd (amphos) Cl 2 ), the third alkaline reagent is selected from one or more of potassium carbonate, potassium phosphate, sodium carbonate, cesium carbonate and cesium fluoride, and the third solvent is selected from one or more of 1, 4-dioxane, water, ethanol, DMF and DME; the cross coupling reaction is carried out under the protection of inert gas, the reaction temperature is 85 ℃ to 100 ℃ and the reaction time is 1h to 12h; the amide compound is one or more selected from cyclopropanecarbonyl chloride, cyclobutanecarbonyl chloride, cyclopentanecarbonyl chloride, cyclohexanecarbonyl chloride and 4, 4-difluoro-cyclohexanecarbonyl chloride; The activated amino acid is generated in situ by reacting an N-protected amino acid with 1-chloro-N, N, 2-trimethylpropenamine at 0 ℃ to room temperature, wherein the N-protected amino acid is selected from N-Boc-piperidine-3-carboxylic acid or N-Boc-proline; the temperature of the amination reaction is 0 ℃ to room temperature, and the reaction time is 1h-12h.
  8. 8. A process for the preparation of coumarin compounds and pharmaceutically acceptable salts thereof according to claim 3, wherein step S4 comprises the following steps: 1mL-20mL of fourth solvent is used for each 1mmol of the first intermediate, the mol ratio of the compound shown in the formula (M7), the first intermediate and the fourth catalyst is 1 (1.0-1.2): (0.02-0.1), and the mol ratio of the first intermediate to the fourth alkaline reagent is 1:3; The fourth catalyst is selected from one or more of Pd (PPh 3 ) 2 Cl 2 、Pd(dppf)Cl 2 、Pd(OAc) 2 and Pd (amphos) Cl 2 ), the fourth alkaline reagent is selected from one or more of potassium carbonate, potassium phosphate, sodium carbonate, cesium carbonate and cesium fluoride, and the fourth solvent is selected from one or more of 1, 4-dioxane, water, ethanol, DMF and DME; the cross coupling reaction is carried out under the protection of inert gas, the reaction temperature is 85-100 ℃ and the time is 1-12 h.
  9. 9. A process for the preparation of coumarin compounds and pharmaceutically acceptable salts thereof according to claim 3, wherein step S5 comprises the following steps: When the protecting group is tert-butyloxycarbonyl Boc, the third intermediate or the fourth intermediate containing the protecting group is reacted in a mixed system of an acidic reagent and an organic solvent at 0 ℃ to room temperature for 1 to 12 hours, and after the reaction is finished, the coumarin compound is obtained through concentration and purification.
  10. 10. The use of a coumarin compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the coumarin compound or the pharmaceutically acceptable salt thereof is used in the manufacture of a medicament for the prophylaxis and/or treatment of cyclin dependent kinase 9, CDK9, associated diseases; CDK 9-related disorders include leukemia, lymphoma, brain, lung, stomach, esophagus, skin, colon, rectum, pancreas, myeloma, ovary, triple negative breast, testis, liver, prostate and bladder.

Description

Coumarin compound and pharmaceutically acceptable salt thereof, and preparation method and application thereof Technical Field The invention belongs to the technical field of pharmaceutical chemistry and medicine, and particularly relates to coumarin compounds and pharmaceutically acceptable salts thereof, and a preparation method and application thereof. Background Triple Negative Breast Cancer (TNBC) is the most aggressive subtype of breast cancer, accounting for about 10% -20% of all breast cancer cases. TNBC is insensitive to both conventional endocrine and anti-HER 2 targeted therapies due to the lack of expression of Estrogen Receptor (ER), progestogen Receptor (PR) and human epidermal growth factor receptor 2 (HER 2). Clinically, TNBC patients face serious challenges of early recurrence, high metastatic potential and extremely poor prognosis, and currently, treatment approaches are extremely limited, and development of new molecular targeted therapeutic strategies is urgently needed. Among the many potential targets, cyclin-dependent kinase 9 (CDK 9) is of great interest due to its central role in transcriptional regulation. CDK9 is the catalytic core of the positive transcription elongation factor b (P-TEFb) complex, and by binding to Cyclin T, phosphorylates serine 2 sites of the RNA polymerase II (RNAP II) carboxy-terminal domain (CTD), facilitating transcription from a suspended state into an elongation phase. Studies have shown that TNBC cells exhibit significant "transcriptional addiction" properties, and are highly dependent on CDK9 to maintain sustained expression of short-lived anti-apoptotic proteins such as c-Myc, MCL1, and proliferation-driving factors. In addition, CDK9 also regulates expression of transcription factors such as Snail1 and Twist1, and promotes epithelial-to-mesenchymal transition (EMT), thereby driving invasion and metastasis of tumors. Therefore, inhibiting CDK9 can not only indirectly block the oncoprotein signal of traditional 'non-patent medicine', but also inhibit tumor metastasis, and has great therapeutic potential. Although CDK9 inhibitors show significant efficacy in preclinical models, the development of existing drugs still faces serious difficulties. Early pan CDK inhibitors (e.g., dinaciclib, CYC) entered clinical trials but, due to lack of subtype selectivity, often resulted in serious off-target side effects such as cardiotoxicity, myelosuppression, etc. Despite the recent advent of inhibitors with improved selectivity, such as C35, KB-0742, etc., achieving both high activity, high subtype selectivity and good pharmacokinetic properties in a single molecule remains a significant challenge in this field. The root cause of this dilemma is the complexity of the CDK9 structural design. Unlike other members of the CDK family, the ATP binding pocket of CDK9 lacks unique targeting residues (e.g., lysine in CDK1/2/5, histidine in CDK4/6, or cysteine in CDK 7/12/13), which makes achieving precise selectivity through structure-based drug design (SBDD) exceptionally difficult. Currently, most strategies rely solely on conformational plasticity using glycine-rich rings (G-loop), and the structural space mining is not yet adequate. In view of this, there is a strong need in the art to develop novel CDK9 inhibitors that are novel in structure, unique in mechanism and possess excellent drug properties. Disclosure of Invention Aiming at the problems in the prior art, the invention aims to provide coumarin compounds and pharmaceutically acceptable salts thereof which have high-efficiency CDK9 inhibition activity and high selectivity and are easy to prepare, and a preparation method and application of the coumarin compounds and pharmaceutically acceptable salts thereof, so as to solve the problems of single structure, obvious off-target effect, high preparation cost, poor solid tumor penetrability and the like of the existing CDK9 inhibitor. The coumarin compound and the pharmaceutically acceptable salt thereof have the structure shown in the formula (I): Formula (I). Wherein R 1 is selected from、、、、、、、、、、、、、、、And; R 1 is selected from dimethylamino, oxetan-3-ylamino, 4-amino-4-methylpiperidin-1-yl, 4-methylpiperazin-1-yl, 4-methyl-1, 4-diaza-1-yl, 2-methylpiperazin-1-yl, 4-methoxycarbonylpiperidin-1-yl, morpholinyl, 3-methylmorpholino, 2-ethylmorpholinyl, 2-methylpyrrolidin-1-yl, or 3-oxa-8-azabicyclo [3.2.1] oct-8-yl. R 2 is selected from H, halogen (such as F, cl), methyl (Me), methoxy (OMe). X is selected from CH, N, CF, CCl. R 3 is selected from、、、、、、、、; R 3 is C3-C7 cycloalkyl optionally substituted by 1 to 2 halogen, 4-6 membered saturated heterocyclyl containing 1 to 2 heteroatoms optionally protected by Boc. Preferably, the specific group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-difluorocyclohexyl, tetrahydro-2-hydro-pyran-4-yl, piperidin-3-yl. Further, the coumarin compound is selected from the following substances: 。 the pr