Salt of KRAS g12d degradation agent, and preparation method therefor and use thereof

Abstract

The present invention relates to a salt of a KRAS G12D degradation agent, and a preparation method therefor and a use thereof, and in particular to a pharmaceutically acceptable salt of a compound as represented by formula I, and a crystal form thereof. These salts exhibit superior properties in at least one of the following aspects, thereby having better prospects for formulation: higher purity, less solvent residue, better storage stability or solution stability, and better solid stability / solid form.

Description

Salts of KRAS G12D degrading agent, their preparation methods and uses

[0001] Cross-reference to related applications

[0002] This disclosure is based on and claims priority to Chinese Patent Application No. 202410693209.4, filed on May 30, 2024, entitled “Salt of KRAS G12D Degrading Agent and its Preparation Method and Use”, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to salts of KRAS G12D degrading agents, methods for their preparation, and uses, and particularly to salts of compounds of formula I, methods for their preparation, and uses. Background Technology

[0004] The KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) gene belongs to the RAS family and is one of the most common gene mutations in human cancers. It encodes a small GTPase. The KRAS gene participates in kinase signaling pathways that control gene transcription, thereby regulating cell growth and differentiation. Intracellularly, the Kras protein alternates between inactive and activated states. When Kras binds to guanine diphosphate (GDP), it is inactive; when it binds to guanine triphosphate (GTP), it is activated and can activate downstream signaling pathways. Kras is inactive in most cells. When activated, it can activate downstream signaling pathways including the MAPK signaling pathway, the PI3K signaling pathway, and the Ral-GEF signaling pathway. These signaling pathways play important roles in promoting cell survival, proliferation, and cytokine release, thus influencing tumorigenesis and development.

[0005] In human cancers, KRAS gene mutations are found in nearly 90% of pancreatic cancers, approximately 30% to 40% of colon cancers, about 17% of endometrial cancers, and about 15% to 20% of lung cancers (mostly non-small cell lung cancer, NSCLC). It also occurs in other cancer types such as bile duct cancer, cervical cancer, bladder cancer, liver cancer, and breast cancer. In other words, a high proportion of these cancers contain Kras gene mutations. Most KRAS missense mutations occur at codon 12, resulting in a change from glycine to another amino acid. Depending on the specific mutation present, G12C, G12D, and G12R are the most common Kras mutations found in patients, such as KRAS. G12D and KRAS G12VMutations in both are found in approximately 90% of pancreatic cancers, while KRAS... G12D It is the most common Kras mutation in colorectal cancer.

[0006] Protein degradation-targeting chimeras (Protac) are one approach to controlling this degradation pathway (see Angew. Chem. Int. Ed. 2016, 55, 807–810, J. Med. Chem. 2018, 61, 444–452, etc.). Protac is not a traditional enzyme inhibitor; instead, it works by inducing selective intracellular proteolysis. Protac is a heterobifunctional small molecule composed of two active domains and a linker, capable of removing specific unwanted proteins. One of the two active domains of Protac binds to an E3 ubiquitin ligase, and the other binds to the target protein to be degraded. Recruiting the E3 ligase to the target protein leads to ubiquitination, followed by proteasome degradation of the target protein. Because Protac only needs to bind to its target protein with high selectivity (rather than inhibiting the enzymatic activity of the target protein), there are currently many efforts to reconstitute previously ineffective inhibitor molecules into next-generation drugs using Protac.

[0007] US patent application US20240059712A1 discloses a series of KRAS G12D degraders, including compound I. Biological evaluation results show that compound I exhibits high degradation rates of KRAS G12D protein in AsPc-1 cell lines, DC... 50 It exhibits good inhibitory activity against KRAS G12D at the nanomolar level.

[0008] For pharmaceutical formulations, the active pharmaceutical ingredient (API) should exhibit appropriate physical, physicochemical, and chemical properties. Furthermore, for industrial-scale synthesis, the API should be easily processed and produced on a large scale. In many cases, purifying crude products through complex, multi-step processes reduces yields and significantly increases production costs. Ideally, the API should also be easily post-processed, readily separable and purified, and able to achieve the required purity. It is well known that salting the free base form of the API can improve certain properties; however, selecting the appropriate salt for a specific API is not straightforward, as different salt forms can exhibit significantly different properties, such as varying solubility and chemical stability.

[0009] Furthermore, amorphous active pharmaceutical ingredients lack regular crystal structures and are often accompanied by other defects, such as poor product stability, solvent encapsulation, fine crystal particles that are difficult to filter, easy agglomeration, and poor flowability. Therefore, it is essential to improve the properties of compounds of formula I. Summary of the Invention

[0010] This disclosure relates to pharmaceutically acceptable salts of compounds of Formula I and their crystal forms, as well as methods of preparation and uses thereof. The pharmaceutically acceptable salts include hydrochlorides, sulfates, phosphates, p-toluenesulfonates, acetates, citrates, oxalates, malonates, salicylates, malates, lactates, aspartates, glutamates, fumarates, succinates, ascorbic acid salts, maleates, tartrates, sodium salts, potassium salts, methanesulfonates, or hydroxyethanesulfonates. These salts possess better properties in at least one of the following aspects, thus offering better formulation prospects: higher purity, lower solvent residue, better storage or solution stability, and better solid form.

[0011] In this disclosure, in particular the hydrochloride, sulfate, phosphate, p-toluenesulfonate, methanesulfonate, citrate, sodium salt and maleate of Formula I have better properties and thus better formulation prospects in at least one of the following aspects: higher purity, lower solvent residue, better storage stability or solution stability, better solid form.

[0012] In a first aspect of this disclosure, a salt of a compound of formula I is provided.

[0013] The pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, p-toluenesulfonate, methanesulfonate, citrate, sodium salt, maleate, fumarate, lactate, tartrate, malate, succinate, aspartate, glutamate, and potassium salt.

[0014] In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt, and optionally the molar ratio of compound I to hydrochloric acid is 1:0.5-1:3.

[0015] In some embodiments, the hydrochloride salt has characteristic peaks at diffraction angles of 4.349°, 5.611°, 7.862°, 9.918°, 13.018°, 14.356°, 17.913°, and 19.937° in an X-ray powder diffraction pattern obtained using Cu-Kα radiation, expressed in terms of diffraction angle 2θ, wherein the error range for each diffraction angle is ±0.2°.

[0016] In some embodiments, the pharmaceutically acceptable salt is a sulfate, and optionally the molar ratio of compound I to sulfuric acid is 1:0.5-1:2.

[0017] In some embodiments, the sulfate exhibits characteristic peaks at diffraction angles of 4.188°, 24.222°, 27.219°, 28.440°, 31.228°, 33.675°, 37.754°, and 39.695° in X-ray powder diffraction patterns obtained using Cu-Kα radiation, expressed as diffraction angles 2θ, with each diffraction angle having an error range of ±0.2°.

[0018] In some embodiments, the pharmaceutically acceptable salt is a phosphate, and optionally the molar ratio of compound I to phosphate is 1:0.3-1:2.

[0019] In some embodiments, the phosphate exhibits characteristic peaks at diffraction angles of 18.305°, 23.744°, 25.517°, 27.964°, 29.041°, 34.067°, 35.046°, 37.072°, 37.918°, and 38.766° in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, with each diffraction angle having an error range of ±0.2°.

[0020] In some embodiments, the pharmaceutically acceptable salt is p-toluenesulfonate, and optionally the molar ratio of compound of formula I to p-toluenesulfonate is 1:0.5-1:3.

[0021] In some embodiments, the p-toluenesulfonate exhibits characteristic peaks at diffraction angles of 4.010°, 10.956°, 11.787°, 13.339°, 16.141°, 17.313°, 18.599°, 24.114°, and 28.682° in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, with each diffraction angle having an error range of ±0.2°.

[0022] In some embodiments, the pharmaceutically acceptable salt is methanesulfonate A, methanesulfonate B, or methanesulfonate C, and optionally the molar ratio of compound of formula I to methanesulfonic acid is 1:0.5-1:3.

[0023] In some embodiments, the methanesulfonate A has characteristic peaks at diffraction angles of 6.528°, 9.755°, 13.321°, 14.061°, 16.021°, 16.445°, 17.821°, 18.810°, 19.389°, 19.741°, 21.981°, 24.375°, and 26.855° in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, where the error range for each diffraction angle is ±0.2°.

[0024] In some embodiments, the methanesulfonate B has characteristic peaks at diffraction angles of 7.340°, 10.799°, 14.682°, 17.946°, 19.676°, 20.328°, 21.144°, and 23.363° in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, wherein the error range for each diffraction angle is ±0.2°.

[0025] In some embodiments, the methanesulfonate C exhibits characteristic peaks at diffraction angles of 5.447°, 13.829°, 19.545°, 20.459°, 21.291°, 23.469°, 25.642°, 26.650°, 28.460°, 31.652°, 32.305°, 33.290°, 34.232°, 34.995°, 36.548°, 37.918°, and 39.242° in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, expressed as a diffraction angle of 2θ, with each diffraction angle having an error range of ±0.2°.

[0026] In one embodiment, the pharmaceutically acceptable salt is a sodium salt, and optionally the molar ratio of compound I to Na is 1:0.5 to 1:1.5.

[0027] In some embodiments, the sodium salt exhibits characteristic peaks at diffraction angles of 7.634°, 10.930°, 12.896°, 17.970°, 18.403°, 19.969°, 25.615°, 29.243°, 30.325°, 30.504°, 33.427°, 34.595°, and 39.127° in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, expressed as a diffraction angle 2θ, with each diffraction angle having an error range of ±0.2°.

[0028] In some embodiments, the pharmaceutically acceptable salt is a citrate, and optionally the molar ratio of compound I to citric acid is 1:0.3-1:3.

[0029] In some embodiments, the citrate salt has characteristic peaks at diffraction angles of 8.694°, 21.586°, 24.032°, 26.599°, 27.131°, 28.226°, and 33.108° in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, with an error range of ±0.2° for each diffraction angle.

[0030] In some embodiments, the pharmaceutically acceptable salt is a maleate salt, and optionally the molar ratio of compound I to maleic acid is 1:0.5-1:3.

[0031] In some embodiments, the maleate salt has characteristic peaks at diffraction angles of 12.368°, 20.344°, 23.631°, 26.814°, 28.477°, 33.687°, 34.447°, and 37.611° in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, expressed in terms of diffraction angle 2θ, wherein the error range for each diffraction angle is ±0.2°.

[0032] In some embodiments, the pharmaceutically acceptable salt is fumarate, lactate, tartrate, malate, succinate, aspartate, glutamate, or potassium salt.

[0033] In a second aspect of this disclosure, a method for preparing a salt of a compound of formula I is provided.

[0034] In a third aspect of this disclosure, the use of pharmaceutically acceptable salts of compounds of formula I and their crystal forms in the preparation of KRAS G12D protein degrading agents is provided.

[0035] The hydrochloride, sulfate, phosphate, p-toluenesulfonate, methanesulfonate, sodium salt, and citrate salts of Compound I all exhibit good solution stability. Compared to the free base, lactate, aspartate, glutamate, and potassium salts of Compound I, the hydrochloride, sulfate, phosphate, p-toluenesulfonate, methanesulfonate, sodium salt, and citrate salts of Compound I have relatively better solid stability / solid form advantages. Furthermore, the solvent residue of the sulfate and sodium salts of Compound I is lower than that of the free base and its fumarate, lactate, tartrate, malate, and succinate salts, which is beneficial for subsequent process development and optimization. Attached Figure Description

[0036] Figure 1 shows the XRPD spectrum of Cu-Kα radiation of the compound of formula I.

[0037] Figure 2 shows the Cu-Kα radiation XRPD spectrum of the hydrochloride crystal form of compound I.

[0038] Figure 3 shows the Cu-Kα radiation XRPD spectrum of the sulfate crystal form of compound I.

[0039] Figure 4 shows the Cu-Kα radiation XRPD spectrum of the phosphate crystal form of compound I.

[0040] Figure 5 shows the Cu-Kα radiation XRPD spectrum of the citrate crystal form of compound I.

[0041] Figure 6 shows the Cu-Kα radiation XRPD spectrum of the compound of formula I for the toluenesulfonate crystal form.

[0042] Figure 7 shows the Cu-Kα radiation XRPD spectrum of the A crystal form of compound I methanesulfonate.

[0043] Figure 8 shows the Cu-Kα radiation XRPD spectrum of the B crystal form of compound I methanesulfonate.

[0044] Figure 9 shows the Cu-Kα radiation XRPD spectrum of the C crystal form of compound I methanesulfonate.

[0045] Figure 10 shows the XRPD spectrum of Cu-Kα radiation of the sodium salt crystal form of compound I.

[0046] Figure 11 shows the Cu-Kα radiation XRPD spectrum of the maleate crystal form of compound I. Detailed Implementation

[0047] To provide a clear and consistent understanding of the terminology used in this disclosure, some definitions are provided below. Furthermore, unless otherwise specified, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0048] As used in this article, the term "crystal form" or "crystal" refers to any solid material exhibiting a three-dimensional arrangement, which, in contrast to amorphous solid materials, produces characteristic XRPD patterns with clearly defined peaks.

[0049] As used in this article, the term "X-ray powder diffraction pattern (XRPD pattern)" refers to a pattern obtained according to Bragg's formula 2d sinθ = nλ (where λ is the wavelength of the X-rays). In diffraction techniques, n can be any positive integer, typically taking the first-order diffraction peak (n = 1). When X-rays are incident at a grazing angle θ (the complementary angle of the incident angle, also known as the Bragg angle) onto an atomic plane of a crystal or a partially crystal sample with a lattice spacing of d, the Bragg equation is satisfied, thus allowing the measurement of this set of X-ray powder diffraction patterns. XRPD patterns are usually characterized by peak position (x-axis) and / or peak intensity (y-axis).

[0050] As used herein, the term "2θ or 2θ angle" refers to the peak position, expressed in degrees (°), based on the setup in an X-ray diffraction experiment, and is typically the horizontal axis unit in a diffraction pattern. If the reflected beam is diffracted when the incident beam forms an angle θ with a lattice plane, the experimental setup requires recording the reflected beam at a 2θ angle. Unless otherwise specified, the error range for 2θ values ​​is ±0.2 degrees.

[0051] The chemical reactions in the specific embodiments of this disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of this disclosure and the reagents and materials required therefor. In order to obtain the compounds of this disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0052] The present disclosure will be described in detail below through embodiments, which are not intended to limit the present disclosure in any way.

[0053] All solvents used in this disclosure are commercially available and can be used without further purification.

[0054] Compounds are named in accordance with conventional naming principles in the field, and commercially available compounds are named according to the supplier's catalog.

[0055] In this disclosure, the purity of a product refers to its HPLC purity.

[0056] It should be understood that, within the scope of this disclosure, the above-described technical features and the technical features specifically described below (such as in the detailed embodiments) can be combined with each other to form new or preferred technical solutions. These will not be elaborated upon here.

[0057] To better understand this disclosure and to more clearly demonstrate how to implement it, features of embodiments according to this disclosure are now illustrated by way of example.

[0058] Comparative Example 1: Synthesis of Compound I (see Example 140 in the WO2024055112A1 publication, corresponding to Compound 2a in WO2024055112A1).

[0059] According to Example 140 in the WO2024055112A1 publication, after ionization and crystallization, compound of formula I was prepared.

[0060] The obtained solid sample was subjected to XRPD pattern by a Bruker D8 venture diffractometer (test conditions are detailed below), and its characteristic peak information is shown in Table 1 below.

[0061] XRPD: A Bruker D8 venture was used to analyze the samples, with a 2θ scan angle ranging from 3° to 42°, a scan step size of 0.02°, and a scan time of 0.2 s per step. The tube voltage and current were 40 kV and 40 mA, respectively. During sample preparation, an appropriate amount of sample was placed on the sample tray and flattened using a spoon or glass slide to ensure a smooth and flat surface. The resulting X-ray powder diffraction (XRPD) pattern is shown in Figure 1.

[0062] The XRPD spectrum analysis data of the product are shown in Table 1.

[0063] Table 1. XRPD characteristic peaks of compounds of formula I

[0064] The obtained solid sample was used 1 The residual solvent content detected by H NMR was 7.1% MTBE.

[0065] Example 1: Synthesis of the hydrochloride salt of compound I

[0066] At T = 25℃, 250 mg of compound I was added to 1.6 mL of ethanol / water (95:5, v:v) solution. After thorough stirring, 204.7 μL of hydrochloric acid solution [0.1 mL concentrated hydrochloric acid dissolved in 0.9 mL ethanol / water (95:5, v:v) solution] was added. The mixture was kept at this temperature and stirred for 4 days. The system was filtered to obtain a yellow solid. The solid was dried under vacuum at T = 30℃ for 3 hours, then further dried under vacuum at 50℃ for 2.5 hours. Purity: 95.8%; Solvent residue: 1.0% ethanol.

[0067] The obtained solid sample was subjected to XRPD pattern by Bruker D8 venture diffractometer (test conditions as above), as shown in Figure 2, and its characteristic peak information is shown in Table 2 below.

[0068] Table 2. XRPD characteristic peaks of hydrochloride crystal forms

[0069] Example 2: Synthesis of sulfate of compound I

[0070] At T=25℃, 250 mg of compound I was added to 1.8 mL of acetone. After thorough stirring, 123.1 μL of acetone-sulfuric acid solution (0.1 mL sulfuric acid dissolved in 0.9 mL acetone) was added. The mixture was kept at this temperature and stirred for 4 days. The system was then filtered to obtain a bright yellow solid. The solid was dried under vacuum at T=30℃ for 3 hours, and then further dried under vacuum at 50℃ for 2.5 hours. Purity: 93.9%; Solvent residue: 0.4% acetone.

[0071] The obtained solid sample was subjected to XRPD pattern by Bruker D8 venture diffractometer (test conditions as above), as shown in Figure 3, and its characteristic peak information is shown in Table 3 below.

[0072] Table 3. XRPD characteristic peaks of sulfate crystal forms

[0073] Example 3: Synthesis of phosphate of compound I

[0074] At T = 25℃, 250 mg of compound I was added to 1.6 mL of ethanol / water (95:5, v:v) solution. After thorough stirring, 154.4 μL of phosphoric acid solution [0.1 mL of phosphoric acid dissolved in 0.9 mL of ethanol / water (95:5, v:v) solution] was added. The mixture was kept at this temperature and stirred for 4 days. The system was filtered, and the solid was dried under vacuum at T = 30℃ for 3 hours, then further dried under vacuum at 50℃ for 2.5 hours to obtain a yellow solid. Purity: 94.6%; Solvent residue: 1.0% ethanol.

[0075] The obtained solid sample was subjected to XRPD pattern by Bruker D8 venture diffractometer (test conditions as above), as shown in Figure 4, and its characteristic peak information is shown in Table 4 below.

[0076] Table 4. XRPD characteristic peaks of phosphate crystal forms

[0077] Example 4: Synthesis of citrate of Formula I

[0078] At T=25℃, 250 mg of compound I was added to 1.6 mL of ethanol / water (95:5, v:v) solution. After thorough stirring, 44 mg of citric acid solid was added to the solution system. The mixture was kept warm and stirred for 4 days. The system was filtered, and the solid was dried under vacuum at T=30℃ for 3 hours, then dried under vacuum at T=50℃ for 2.5 hours to obtain a yellow solid. Purity: 94.7%; Solvent residue: 1.3% ethanol.

[0079] The obtained solid sample was subjected to XRPD pattern by Bruker D8 venture diffractometer (test conditions as above), as shown in Figure 5, and its characteristic peak information is shown in Table 5 below.

[0080] Table 5. XRPD characteristic peaks of citrate crystal forms

[0081] Example 5: Synthesis of p-Toluenesulfonate of Formula I

[0082] At T=25℃, 30 mg of compound I was added to 1.8 mL of acetone solution and stirred thoroughly. Then, about 6 mg of p-toluenesulfonic acid was added and stirred at T=50℃ for 2 h. After stirring at T=25℃ for 4 days, the system was filtered. The solid was dried under vacuum at T=30℃ for 4 hours to obtain a bright yellow solid. Purity: 95.0%; Solvent residue: 1.6% acetone.

[0083] The obtained solid sample was subjected to XRPD pattern by Bruker D8 venture diffractometer (test conditions as above), as shown in Figure 6, and its characteristic peak information is shown in Table 6 below.

[0084] Table 6. XRPD characteristic peaks of p-toluenesulfonate crystal forms

[0085] Example 6: Synthesis of Methanesulfonate A, a compound of formula I

[0086] At T = 25℃, 250 mg of compound I was added to 1.6 mL of ethanol / water (95:5, v:v) solution. After thorough stirring, 148.3 μL of methanesulfonic acid solution [0.1 mL of methanesulfonic acid dissolved in 0.9 mL of ethanol / water (95:5, v:v) solution] was added. The mixture was kept at this temperature and stirred for 4 days. The system was filtered, and the solid was dried under vacuum at T = 30℃ for 3 hours, then further dried under vacuum at 50℃ for 2.5 hours to obtain a bright yellow solid A; purity: 95.6%; solvent residue: 0.9% ethanol.

[0087] The obtained solid sample A was subjected to XRPD pattern by a Bruker D8 venture diffractometer (test conditions as above), as shown in Figure 7, and its characteristic peak information is shown in Table 7 below.

[0088] Table 7. XRPD characteristic peaks of methanesulfonate A

[0089] Example 7: Synthesis of Methanesulfonate B, a compound of Formula I

[0090] At T=25℃, 250 mg of compound I was added to 1.8 mL of acetone solution and stirred thoroughly. Then, 160.8 μL of methanesulfonic acid solution [0.1 mL of methanesulfonic acid dissolved in 0.9 mL of acetone solution] was added, and the mixture was kept at this temperature and stirred for 4 days. The system was filtered, and the solid was dried under vacuum at T=30℃ for 3 hours, and then dried under vacuum at T=50℃ for 2.5 hours to obtain a bright yellow solid B; purity: 95.5%.

[0091] The obtained solid sample B was subjected to XRPD pattern by Bruker D8 venture diffractometer (test conditions as above), as shown in Figure 8, and its characteristic peak information is shown in Table 8 below.

[0092] Table 8. XRPD characteristic peaks of methanesulfonate B

[0093] Example 8: Synthesis of Methanesulfonate C of Formula I

[0094] At T=25℃, 250 mg of compound I was added to 1.8 mL of THF solution and stirred thoroughly. Then, 162 μL of methanesulfonic acid solution [0.1 mL methanesulfonic acid dissolved in 0.9 mL THF solution] was added, and the mixture was kept at this temperature and stirred for 4 days. The system was filtered, and the solid was dried under vacuum at T=30℃ for 3 hours, then further dried under vacuum at 50℃ for 2.5 hours to obtain a bright yellow solid C; purity: 95.4%.

[0095] The obtained solid sample C was subjected to XRPD pattern by a Bruker D8 venture diffractometer (test conditions as above), as shown in Figure 9, and its characteristic peak information is shown in Table 9 below.

[0096] Table 9. XRPD characteristic peaks of methanesulfonate C

[0097] Example 9: Synthesis of sodium salt of compound I

[0098] At T=25℃, 250 mg of compound I was added to 1.9 mL of acetone and stirred thoroughly for 10 min. An aqueous solution of sodium carbonate (24.2 mg) (0.1 mL) was added to the suspension and stirred thoroughly at 25℃ for 4 days. The system was filtered to obtain a filter cake, which was then vacuum dried at 30℃ for 3 hours, heated to 50℃ and dried for another 2.5 hours to obtain a yellow solid. Purity: 94.7%; Solvent residue: 0.3% acetone.

[0099] The obtained solid sample was subjected to XRPD pattern by Bruker D8 venture diffractometer (test conditions as above), as shown in Figure 10, and its characteristic peak information is shown in Table 10 below.

[0100] Table 10. XRPD characteristic peaks of sodium salt

[0101] Example 10: Synthesis of maleate of Formula I

[0102] At T=25℃, 250 mg of compound I was added to 1.8 mL of acetone and stirred thoroughly for 10 min. 30.6 mg of maleic acid was added to the suspension and stirred thoroughly at 25℃ for 4 days. The system was filtered to obtain a filter cake, which was then vacuum dried at 30℃ for 3 hours, heated to 50℃ and dried for another 2.5 hours to obtain a yellow solid; purity: 95.2%.

[0103] The obtained solid sample was subjected to XRPD pattern by Bruker D8 venture diffractometer (test conditions as above), as shown in Figure 11, and its characteristic peak information is shown in Table 11 below.

[0104] Table 11. Characteristic peaks of maleate XRPD

[0105] Example 11: Synthesis of fumarate of Formula I

[0106] Using 30 mg of compound I as a starting material, it was added to 1.6 mL of ethanol / water (95:5, v:v) solution. After thorough stirring, 1 mol equivalent of fumaric acid relative to 30 mg of compound I was added, and the target product was synthesized by a method similar to that in Example 6. Purity: 93.0%; Solvent residue: 1.0% ethanol.

[0107] Example 12: Synthesis of lactate of Formula I

[0108] The target product was synthesized using a method similar to that in Example 10, except that maleic acid was replaced with lactic acid. Purity: 93.4%; Solvent residue: 3.2% acetone.

[0109] Example 13: Synthesis of tartrate of Formula I

[0110] The target product was synthesized using a method similar to that in Example 8, except that methanesulfonic acid was replaced with tartaric acid. Purity: 94.3%.

[0111] Example 14: Synthesis of malate, a compound of formula I

[0112] The target product was synthesized using a method similar to that in Example 11, except that fumaric acid was replaced with malic acid. Purity: 94.5%; Solvent residue: 0.9% ethanol.

[0113] Example 15: Synthesis of Succinate, a compound of formula I

[0114] The target product was synthesized using a method similar to that in Example 11, except that fumaric acid was replaced with succinic acid. Purity: 93.5%; Solvent residue: 2.1% ethanol.

[0115] Example 16: Synthesis of aspartic acid salt of compound I

[0116] The target product was obtained by synthesizing a product using a method similar to that in Example 11, except that fumaric acid was replaced with aspartic acid.

[0117] Example 17: Synthesis of glutamate from Formula I

[0118] The target product was obtained by synthesizing fumaric acid in a manner similar to that in Example 11, but with glutamic acid substituted for fumaric acid.

[0119] Example 18: Synthesis of potassium salt of Formula I compound

[0120] The target product was obtained by synthesizing the product using a method similar to that in Example 11, except that fumaric acid was replaced with potassium carbonate.

[0121] Test Example: Comparative Study of Chemical Stability of Salt Forms

[0122] Stability study of ethanol / water (95:5, v:v) system

[0123] Experimental procedure: Approximately 15 mg of different salt forms of compound I and 15 mg of compound I were added to 0.15 mL of ethanol / water (95:5, v:v) solution, suspended and stirred. The mixture was kept at 20–30 °C and stirred for 4 days. After filtration, the purity of the solid was determined by HPLC. The physical properties of the substances were observed and recorded. “-” indicates that no record was made.

[0124] Experimental results:

[0125] Experimental conclusion:

[0126] The hydrochloride, phosphate, citrate, and methanesulfonate salts of compound I exhibit significantly better stability in ethanol / water (95:5, v:v) solution than the compound of formula I in the same solution. Furthermore, the hydrochloride, phosphate, citrate, and methanesulfonate salts of compound I demonstrate better solid stability / solid form compared to the compounds of formula I, as well as their lactate, aspartate, glutamate, and potassium salts.

[0127] Stability of 2-acetone system

[0128] Experimental procedure: Approximately 15 mg of different salt forms of compound I and 15 mg of compound I were added to 0.15 mL of acetone solution, suspended and stirred. The mixture was kept at 20–30 °C and stirred for 4 days. After filtration, the purity was determined by HPLC. The speciation of the substances was observed and recorded. “-” indicates that no record was made.

[0129] Experimental results:

[0130] Experimental conclusion:

[0131] The sulfate, p-toluenesulfonate, citrate, and sodium salts of compound I exhibit significantly better stability in acetone solution than the compound of formula I itself. Furthermore, the sulfate, p-toluenesulfonate, and citrate of compound I demonstrate better solid stability / solid form compared to the compound of formula I, as well as its aspartate, glutamate, and potassium salts.

[0132] 3RH high humidity environment stability

[0133] Experimental procedure: Approximately 15 mg of different salt forms of compound I and 15 mg of compound I were added and placed in an open container at 25℃ / 92.5%RH for one week under high humidity. After filtration, the purity of the solid was determined by HPLC.

[0134] Experimental results:

[0135] Experimental conclusion:

[0136] The hydrochloride and methanesulfonate A of compound I, especially methanesulfonate A, exhibit significantly better stability under relatively high humidity conditions than compound I under relatively high humidity conditions.

[0137] Although the invention has been described in detail with reference to embodiments thereof, these embodiments are provided for illustration and not limitation. Other embodiments that can be obtained according to the principles of the invention fall within the scope defined by the claims of the invention.

Claims

1. A pharmaceutically acceptable salt of a compound of Formula I: ###00001### Formula I and crystalline forms thereof. wherein The pharmaceutically acceptable salts are selected from hydrochloride, sulfate, phosphate, p-toluenesulfonate, methanesulfonate, citrate, sodium salt, maleate, fumarate, lactate, tartrate, malate, succinate, aspartate, glutamate, and potassium salts.

2. The pharmaceutically acceptable salt and the crystal form thereof according to claim 1, wherein, The pharmaceutically acceptable salt is a hydrochloride salt, preferably the hydrochloride salt having characteristic peaks at diffraction angles of 4.349°, 5.611°, 7.862°, 9.918°, 13.018°, 14.356°, 17.913° and 19.937° in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, wherein the error range for each diffraction angle is ±0.2°.

3. The pharmaceutically acceptable salt and the crystal form thereof according to claim 1, wherein, The pharmaceutically acceptable salt is a sulfate, preferably the sulfate having characteristic peaks at diffraction angles of 4.188°, 24.222°, 27.219°, 28.440°, 31.228°, 33.675°, 37.754° and 39.695° in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, where the error range for each diffraction angle is ±0.2°.

4. The pharmaceutically acceptable salt and the crystal form thereof according to claim 1, wherein, The pharmaceutically acceptable salt is a phosphate, preferably the phosphate exhibiting characteristic peaks at diffraction angles of 18.305°, 23.744°, 25.517°, 27.964°, 29.041°, 34.067°, 35.046°, 37.072°, 37.918°, and 38.766° in X-ray powder diffraction patterns obtained using Cu-Kα radiation, with each diffraction angle having an error range of ±0.2°.

5. The pharmaceutically acceptable salt and the crystal form thereof according to claim 1, wherein, The pharmaceutically acceptable salt is p-toluenesulfonate, preferably p-toluenesulfonate, which, in the X-ray powder diffraction pattern obtained using Cu-Kα radiation and expressed in terms of diffraction angle 2θ, has characteristic peaks at diffraction angles of 4.010°, 10.956°, 11.787°, 13.339°, 16.141°, 17.313°, 18.599°, 24.114°, and 28.682°, with an error range of ±0.2° for each diffraction angle.

6. The pharmaceutically acceptable salt and the crystal form thereof according to claim 1, wherein, The pharmaceutically acceptable salts are mesylate A, mesylate B, or mesylate C. Preferably, the methanesulfonate A, in the X-ray powder diffraction pattern obtained using Cu-Kα radiation and expressed in 2θ angles, exhibits characteristic peaks at diffraction angles of 6.528°, 9.755°, 13.321°, 14.061°, 16.021°, 16.445°, 17.821°, 18.810°, 19.389°, 19.741°, 21.981°, 24.375°, and 26.855°, with an error range of ±0.2° for each diffraction angle; preferably, the methanesulfonate B, in the X-ray powder diffraction pattern obtained using Cu-Kα radiation and expressed in 2θ angles, exhibits characteristic peaks at diffraction angles of 7.340°, 10.799°, 14.682°, 17.946°, 19.676°, and 26.855°, respectively. Characteristic peaks are observed at diffraction angles of 20.328°, 21.144°, and 23.363°, with an error range of ±0.2° for each diffraction angle. Preferably, the methanesulfonate C exhibits characteristic peaks at diffraction angles of 5.447°, 13.829°, 19.545°, 20.459°, 21.291°, 23.469°, 25.642°, 26.650°, 28.460°, 31.652°, 32.305°, 33.290°, 34.232°, 34.995°, 36.548°, 37.918°, and 39.242° in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, expressed in terms of diffraction angle 2θ. The error range for each diffraction angle is ±0.2°.

7. The pharmaceutically acceptable salt and the crystal form thereof according to claim 1, wherein, The pharmaceutically acceptable salt is a sodium salt, preferably the sodium salt having characteristic peaks at diffraction angles of 7.634°, 10.930°, 12.896°, 17.970°, 18.403°, 19.969°, 25.615°, 29.243°, 30.325°, 30.504°, 33.427°, 34.595°, and 39.127° in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, expressed as a diffraction angle of 2θ, with each diffraction angle having an error range of ±0.2°.

8. The pharmaceutically acceptable salt and the crystal form thereof according to claim 1, wherein, The pharmaceutically acceptable salt is citrate, and preferably, the citrate has characteristic peaks at diffraction angles of 8.694°, 21.586°, 24.032°, 26.599°, 27.131°, 28.226°, and 33.108° in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, expressed in terms of diffraction angle 2θ, wherein the error range for each diffraction angle is ±0.2°.

9. The pharmaceutically acceptable salt and its crystal form according to claim 1, wherein, The pharmaceutically acceptable salt is a maleate salt, preferably the maleate salt having characteristic peaks at diffraction angles of 12.368°, 20.344°, 23.631°, 26.814°, 28.477°, 33.687°, 34.447°, and 37.611° in the X-ray powder diffraction pattern obtained using Cu-Kα radiation, where the error range for each diffraction angle is ±0.2°.

10. Use of the pharmaceutically acceptable salt and its crystal form as described in any one of claims 1 to 9 in the preparation of KRAS G12D protein degrading agent.

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