Deuterated RAS inhibitor drug and application

Abstract

The invention discloses a deuterated RAS inhibitor which is shown in the following formula I. The invention relates to the deuterated RAS inhibitor and a pharmaceutical composition and application thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to deuterated RAS inhibitor drugs and uses. Background Art

[0002] Pancreatic cancer is one of the most deadly malignancies and is often diagnosed at an advanced stage, when patients respond poorly to standard chemotherapy and have a very high mortality rate.

[0003] Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, accounting for about 92% of all pancreatic cancer cases. RAS, as the first oncogene discovered in the human body, has always been a research hotspot for drug development. There are three RAS genes in the human body, namely HRAS, KRAS, and NRAS. RAS has GTPase activity. When RAS binds to GTP, RAS is in an active state, and when it binds to GDP, it is in an inactive state. It acts as a molecular switch in the transduction process of RAS-mediated cell signals (RAS / RAF / MEK / ERK and PI3K / AKT signaling pathways), thereby regulating cell differentiation, proliferation and apoptosis. In human tumorigenesis, more than 30% are related to the activation of RAS genes. RMC-6236 is an oral, multi-targeted RAS inhibitor that can block the proliferation and survival signals of cancer cells by inhibiting signal transduction in the RAS (ON) state, showing a wide range of anti-tumor activity.

[0004] Deuterated drugs, that is, new drug molecules in which one or more carbon-hydrogen bonds of a drug molecule are replaced with carbon-deuterium bonds, can improve the pharmacokinetic properties of the original drugs, thereby overcoming the original defects of the drugs such as easy metabolism and large side effects.

[0005] The present invention is a deuterated RAS inhibitor drug, which can further improve the pharmacokinetic properties of current RAS inhibitor drugs, reduce the dosage and possible toxic side effects. Summary of the invention

[0006] The present invention provides a deuterated compound of a RAS inhibitor, its stereoisomers, tautomers and pharmaceutically acceptable salts thereof, which can further improve the pharmacokinetic properties of the deuterated compound of a RAS inhibitor, its stereoisomers, tautomers and pharmaceutically acceptable salts thereof, and reduce the dosage and possible toxic side effects.

[0007] In order to achieve the above-mentioned object, the present invention provides a deuterated compound of a RAS inhibitor as shown in the following formula I, its stereoisomers, tautomers and pharmaceutically acceptable salts thereof:

[0008]

[0009] The deuterated compounds of the RAS inhibitors of the present invention, their stereoisomers, tautomers and pharmaceutically acceptable salts thereof, include the following structures:

[0010]

[0011] The deuterated compound of the RAS inhibitor of the present invention, its stereoisomers, tautomers and pharmaceutically acceptable salts thereof, wherein the pharmaceutically acceptable salt is selected from methanesulfonate, maleate, hydrochloride or phosphate.

[0012] The deuterated compound, its stereoisomers, tautomers and pharmaceutically acceptable salts described in the present invention include their use in preparing drugs for preventing and / or treating RAS-mediated diseases.

[0013] RAS inhibitors are provided herein and are known to those skilled in the art. RAS inhibitors refer to inhibitors that target, i.e., selectively bind or inhibit the GDP-bound inactive state of RAS. Inhibiting the GDP-bound inactive state of RAS includes, for example, isolating the inactive state by inhibiting the exchange of GDP with GTP, thereby inhibiting RAS from assuming an active conformation. In certain embodiments, RAS inhibitors may also bind or inhibit the GTP-bound active state of RAS.

[0014] The deuterated compound, its stereoisomer, tautomer and pharmaceutically acceptable salt thereof described in the present invention comprises the deuterated compound, its stereoisomer, tautomer and pharmaceutically acceptable salt thereof as active ingredients and a pharmaceutically acceptable carrier.

[0015] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures and other mixtures. In addition, asymmetric carbon atoms may represent substituents, such as alkyl. All isomers and their mixtures are included in the present invention.

[0016] According to the present invention, the ratio of isomers contained in the mixture of isomers can be various. For example, in the mixture of only two isomers, there can be the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present invention. Similar ratios that are easily understood by ordinary technicians in this profession, and ratios for more complex mixtures of isomers are also within the scope of the present invention.

[0017] The pharmaceutical composition of the deuterated compound and the pharmaceutically acceptable salt thereof of the present invention is selected from capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories or patches.

[0018] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0019] (1) The compounds provided by the present invention have excellent KRAS G12C Inhibitory activity;

[0020] (2) The present invention provides a class of deuterated compounds, their stereoisomers, tautomers and pharmaceutically acceptable salts thereof, which further improve the pharmacokinetic properties of RAS inhibitors, reduce the dosage and possible toxic side effects. DETAILED DESCRIPTION

[0021] The present invention will be further described below in conjunction with the examples. The present invention will be further described below in conjunction with the specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0022] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only. Specific embodiments

[0024] Example 1

[0025] General synthetic method

[0026]

[0027] The synthesis of intermediate 1-E can be prepared by referring to the synthesis method of intermediate 4 in patent CN116457358.

[0028] The synthesis of intermediate 1-I can be prepared by referring to the synthesis method of intermediate 5 in patent CN116457358.

[0029] Synthesis of intermediate 1-J

[0030] To a THF solution (10 mL) of intermediate 1-I (1 mmol) was added sodium hydrogen sulfide (4 mmol, 4 eq) at 0°C, and the mixture was reacted at room temperature for half an hour. Deuterated iodomethane was added and the reaction was continued for 2 hours. After the reaction was completed as monitored by TLC, water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (10 mL*2), washed with water (20 mL*2), washed with saturated salt (20 mL), dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain intermediate 1-J.

[0031] Synthesis of compounds

[0032] It can be prepared by the synthesis method of Example A120 in reference patent CN116457358. 1 H NMR (500 MHz, DMSO-d6) δ 8.53 (d, J = 4.8 Hz, 1H), 8.47 (dd, J = 6.2, 4.2 Hz, 2H), 7.80 (s,1H), 7.73 (dd, J = 4.0, 2.2 Hz, 1H), 7.56 (d, J = 5.0 Hz, 1H), 7.22 (d, J =2.5 Hz, 1H), 5.56 (t, J = 2.5 Hz, 1H), 5.10 (d, J = 7.5 Hz, 1H), 4.26-4.14(m, 5H), 3.57 (s, 1H), 3.28-3.25 (m, 4H), 3.24 (s, 3H), 3.21-3.15 (m, 1H), 2.94 (d, J = 9.0 Hz, 1H), 2.78-2.73 (m, 1H), 2.52-3.47 (m, 4H), 2.10-2.06 (m,1H), 1.79 (s, 1H), 1.51-1.49 (m, 1H), 1.34-1.32 (m, 3H), 1.08-1.07 (m, 4H), 0.91-0.87 (m, 7H), 0.57-0.54 (m, 1H), 0.34 (s, 3H).

[0033] Example 2

[0034]

[0035] Synthesis of intermediate 2-A

[0036] To a THF solution (10 mL) of intermediate 1-A (1 mmol) was added sodium hydrogen sulfide (4 mmol, 4 eq) at 0°C, and the mixture was reacted at room temperature for half an hour. Deuterated iodomethane was added and the reaction was continued for 2 hours. After the reaction was completed as monitored by TLC, water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (10 mL*2), washed with water (20 mL*2), washed with saturated salt (20 mL), dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain intermediate 2-A.

[0037] Synthesis of compounds

[0038] Referring to the synthesis method of Example 1, the intermediate 1-B is replaced by 2-A, and the deuterated iodomethane in the synthesis method of intermediate 1-J is replaced by iodomethane, so as to obtain Example 2. 1 H NMR (500 MHz, DMSO-d6)) δ 8.50 (d, J = 4.5Hz, 1H), 8.45 (dd, J = 6.2, 4.2 Hz, 2H), 7.81 (s, 1H), 7.75 (dd, J = 4.0, 2.1Hz, 1H), 7.51 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 2.5 Hz, 1H), 5.52 (t, J = 2.5Hz, 1H), 5.12 (d, J = 7.5 Hz, 1H), 4.23-4.12 (m, 5H), 3.52 (s, 1H), 3.28-3.24(m, 4H), 3.20-3.15 (m, 1H), 2.93 (d, J = 9.0 Hz, 1H), 2.72-2.70 (m, 1H), 2.52-3.47 (m, 4H), 2.22 (s, 3H), 2.10-2.04 (m, 1H), 1.78 (s, 1H), 1.50-1.49(m, 1H), 1.34-1.31 (m, 3H), 1.08-1.07 (m, 4H), 0.92-0.87 (m, 7H), 0.57-0.54(m, 1H), 0.33 (s, 3H).

[0039] Example 3

[0040] Synthesis of compounds

[0041] Referring to the synthesis method of Example 1, Example 3 can be prepared by replacing intermediate 1-B with 2-A. 1H NMR (500MHz, DMSO-d6) δ 8.52 (d, J = 4.8 Hz, 1H), 8.46 (dd, J = 6.2, 4.2 Hz, 2H), 7.81 (s, 1H), 7.72 (d, J = 4.0 Hz, 1H), 7.53 (d, J = 5.0 Hz, 1H), 7.24 (d, J= 2.5 Hz, 1H), 5.53 (t, J = 2.5 Hz, 1H), 5.09 (d, J = 7.5 Hz, 1H), 4.26-4.15(m, 5H), 3.56 (s, 1H), 3.29-3.25 (m, 4H), 3.21-3.16 (m, 1H), 2.95 (d, J = 9.0Hz, 1H), 2.78-2.72 (m, 1H), 2.53-3.47 (m, 4H), 2.11-2.06 (m, 1H), 1.79 (s,1H), 1.52-1.49 (m, 1H), 1.33-1.32 (m, 3H), 1.10-1.07 (m, 4H), 0.91-0.88(m,7H), 0.57-0.54 (m, 1H), 0.34 (s, 3H).

[0042] Test Example 1: KRAS G12C Inhibitory activity test

[0043] 1. Reagents and consumables

[0044]

[0045] 2. Instruments

[0046] Centrifuge (Manufacturer: Eppendorf, Model: 5430)

[0047] Microplate reader (Manufacturer: Perkin Elmer, Model: EnVision)

[0048] 3. Experimental methods

[0049] The test compound was prepared with DMSO, diluted in proportion and added to 384 wells. Diluent buffer was used to prepare a 4-fold final concentration of Tag1-SOS1 solution. 2.5 μL of a 4-fold final concentration of Tag1-SOS1 solution was added to the 384 wells. Diluent buffer was used to prepare a 4-fold final concentration of Tag2-KRAS-G12C solution. The 384-well plate was centrifuged at 1000 rpm for 30 seconds, shaken evenly, and incubated at room temperature for 15 minutes. Detection buffer was used to prepare a 1-fold final concentration of Anti-Tag1-TB3+ solution and a 1-fold final concentration of Anti-Tag2-XL665 solution. After mixing, 5 μL was added to each well. The 384-well plate was centrifuged at 1000 rpm for 30 seconds, shaken evenly, and incubated at room temperature for 2 hours. Read the results with an ELISA reader, Em665 / 620.

[0050]

[0051] The above table shows that Example compounds 1-3 all exhibit excellent KRAS G12C Inhibitor activity: compared with the positive drug RMC-6236, the activity of the compounds in Example 1 and Example 3 was increased by two times, and the activity gain was significant.

[0052] Experimental Example 2: Pharmacokinetics of Compounds

[0053] 1. Experimental instruments and materials

[0054] High-speed refrigerated centrifuge, vortex oscillator (Vortex Genius3), high-speed centrifuge (Eppendorf5415D), disposable syringes, pipettes (Eppendorf), SD male rats used in the experiment were purchased from Yangzhou University, EDTA-K2 vacuum blood collection tubes, and normal saline. All rats in the oral group fasted for 12 hours before administration, and had free access to water and food during administration.

[0055] (II) Experimental steps

[0056] Example 1 or RMC-6236 was dissolved in DMSO / solutol / water (10 / 10 / 80) to prepare a clear solution. The compound was administered orally at a dose of 25 mg / kg, and the compound was administered orally at a dose of 5 mg / kg. At 2 min, 10 min, 30 min, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 16 h, and 24 h after the administration of the tail vein, 0.5 mL of blood was continuously collected from the venous plexus of the fundus into a heparin tube. At 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 16 h, and 24 h after the administration of the gastric administration, 0.5 mL of blood was continuously collected from the venous plexus of the fundus into a heparin tube. The samples were heated at 8000r, 4 0 After centrifugation at -20 °C for 10 min, 0.15 mL of upper plasma was collected. 0 The samples were stored at 4 °C and then analyzed by LC-MS / MS. The data were analyzed by WinNolin non-compartmental model to obtain key pharmacokinetic parameters.

[0057] (III) Experimental results

[0058] Table 1 Pharmacokinetic parameters

[0059]

[0060] Compared with the positive drug RMC-6236, the half-life of Example 1 after oral administration is doubled, and the peak concentration is also significantly increased, which can effectively improve the dosage of RMC-6236, thereby reducing the toxic and side effects of high-dose administration of RMC-6236.

[0061] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A deuterated compound of a RAS inhibitor of formula I, its stereoisomers, tautomers and pharmaceutically acceptable salts thereof, in, R1 and R2 are independently selected from hydrogen or deuterium, and R1 and R2 are not hydrogen.

2. The deuterated compound, its stereoisomers, tautomers and pharmaceutically acceptable salts thereof according to claim 1, characterized in that: The compound is selected from the following structures: 。 3. The deuterated compound, its stereoisomers, tautomers and pharmaceutically acceptable salts thereof according to claim 1, characterized in that The pharmaceutically acceptable salt is selected from methanesulfonate, maleate, hydrochloride or phosphate.

4. Use of the deuterated compound according to claim 1, its stereoisomers, tautomers and pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing and / or treating RAS-mediated diseases.

5. A pharmaceutical composition, characterized in that The pharmaceutical composition is composed of the deuterated compound according to claim 1, its stereoisomers, tautomers and pharmaceutically acceptable salts thereof as active ingredients and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 5, characterized in that The pharmaceutical composition is selected from capsules, powders, tablets, granules, pills, injections, syrups, oral solutions, inhalants, ointments, suppositories or patches.

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