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US-12624050-B2 - Three fused ring derivative-containing salt or crystal form and pharmaceutical composition thereof

US12624050B2US 12624050 B2US12624050 B2US 12624050B2US-12624050-B2

Abstract

A three fused ring derivative-containing salt and a crystal form thereof. In particular, the present invention relates to a compound having general formula (I), a crystal form thereof, a preparation method therefor, a pharmaceutical composition containing a therapeutically effective amount of the compound and the crystal form thereof, and use thereof in the preparation of a medicament for treating PI3K-mediated related diseases.

Inventors

  • Xiaolan Zhan
  • Linsong Guo

Assignees

  • SHANGHAI HANSOH BIOMEDICAL CO., LTD.
  • JIANGSU HANSOH PHARMACEUTICAL GROUP CO., LTD.

Dates

Publication Date
20260512
Application Date
20201119
Priority Date
20191125

Claims (20)

  1. 1 . An acid addition salt of a compound, wherein the specific structure of the compound is as follows: wherein, M is an inorganic acid or an organic acid, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid and phosphoric acid; the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfuric acid, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, embonic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; and y is an integer from 1 to 5.
  2. 2 . The acid addition salt according to claim 1 , wherein the acid addition salt is an ethanesulfonate, mesylate or sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide.
  3. 3 . The acid addition salt according to claim 2 , wherein the acid addition salt is
  4. 4 . A method for preparing the acid addition salt according to claim 1 , specifically comprising the following steps of: 1) weighing free base of the compound and adding an organic solvent to obtain a clear or suspended stock solution; 2) adding acid M into an organic solvent or water to obtain a counter ion acid solution; 3) adding the counter ion acid solution to the stock solution to obtain a salt solution, stirring the salt solution to precipitate a solid, and drying the solid.
  5. 5 . A crystal form of the acid addition salt according to claim 1 , wherein the crystal form is crystal form A of ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof comprises one or more diffraction peaks at 2θ of 6.8±0.2°, 13.4±0.2°, 14.7±0.2°, 19.5±0.2°, 20.1±0.2°, 23.9±0.2°, 24.4±0.2°, 25.0±0.2°, 23.0±0.2°, 23.6±0.2°, 9.3±0.2° and 17.3±0.2°; or, wherein the crystal form is crystal form A of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof comprises one or more diffraction peaks at 2θ of 6.1±0.2°, 7.5±0.2°, 8.0±0.2°, 14.9±0.2°, 23.8±0.2°, 8.4±0.2°, 18.8±0.2°, 20.7±0.2°, 22.3±0.2° and 22.8±0.2°; or, wherein the crystal form is crystal form B of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof comprises one or more diffraction peaks at 2θ of 24.4±0.2°, 13.3±0.2°, 23.8±0.2°, 20.3±0.2° 19.7±0.2°, 17.2±0.2°, 26.7±0.2°, 9.0±0.2°, 23.1±0.2°, 9.9±0.2°, 14.3±0.2° and 21.6±0.2°; or, wherein the crystal form is crystal form C of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof comprises one or more diffraction peaks at 2θ of 22.5±0.2°, 8.5±0.2°, 7.2±0.2°, 14.4±0.2°, 26.7±0.2°, 25.3±0.2°, 12.8±0.2°, 16.7±0.2°, 6.1±0.2°, 12.1±0.2°, 15.2±0.2° and 22.0±0.2°; or, wherein the crystal form is crystal form A of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof comprises one or more diffraction peaks at 2θ of 8.4±0.2°, 7.2±0.2°, 20.1±0.2°, 22.7±0.2°, 24.5±0.2°, 25.7±0.2°, 18.9±0.2°, 26.7±0.2°, 16.4±0.2°, 18.2±0.2°, 22.0±0.2° and 12.6±0.2°; or, wherein the crystal form is crystal form B of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof comprises one or more diffraction peaks at 2θ of 4.8±0.2°, 7.6±0.2°, 12.2±0.2°, 14.0±0.2°, 18.5±0.2°, 22.9±0.2°, 23.8±0.2° and 24.9±0.2°: or, wherein the crystal form is crystal form C of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof comprises one or more diffraction peaks at 2θ of 24.5±0.2°, 13.3±0.2°, 23.9±0.2°, 9.0±0.2°, 17.3±0.2° 19.4±0.2°, 26.9±0.2°, 20.4±0.2°, 17.7±0.2°, 9.9±0.2°, 20.0±0.2° and 28.3±0.2°; or, wherein the crystal form is crystal form D of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof comprises one or more diffraction peaks at 2θ of 7.6±0.2°, 22.5±0.2°, 8.9±0.2°, 15.0±0.2°, 23.9±0.2°, 26.6±0.2°, 24.6±0.2°, 5.8±0.2°, 12.9±0.2°, 19.9±0.2°, 20.7±0.2° and 11.6±0.2°; or, wherein the crystal form is crystal form E of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof comprises one or more diffraction peaks at 2θ of 17.7±0.2°, 23.5±0.2°, 24.8±0.2°, 9.9±0.2°, 22.6±0.2°, 21.2±0.2°, 19.1±0.2°, 29.4±0.2°, 16.9±0.2°, 28.4±0.2°, 17.3±0.2° and 24.5±0.2°.
  6. 6 . The acid addition salt according to claim 1 , wherein the acid addition salt is a hydrate or an anhydrate.
  7. 7 . The crystal form according to claim 5 , wherein the crystal form is crystal form A of ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof comprises two or three diffraction peaks at 2θ of 6.8±0.2°, 13.4±0.2°, 14.7±0.2° and 19.5±0.2°, optionally further comprises one or more diffraction peaks at 2θ of 20.1±0.2°, 23.9±0.2°, 24.4±0.2°, 25.0±0.2°, 23.0±0.2° and 23.6±0.2°; or, the X-ray powder diffraction pattern thereof has characteristic peaks at 13.4±0.2°, 14.7±0.2°, 19.5±0.2°, 20.1±0.2°, 23.0±0.2°, 23.9±0.2°, 24.4±0.2° and 25.0=0.2; or, the X-ray powder diffraction pattern thereof has characteristic peaks at 6.8±0.2°, 13.4±0.2°, 14.7±0.2°, 19.5±0.2°, 20.1±0.2°, 23.9±0.2°, 23.0±0.2° and 23.6±0.2°; or, the X-ray powder diffraction pattern thereof has characteristic peaks at 6.8±0.2°, 13.4±0.2°, 14.7±0.2°, 19.5±0.2°, 20.1±0.2°, 23.9±0.2°, 24.4±0.2° and 25.0±0.2°; or, the X-ray powder diffraction pattern thereof has characteristic peaks at 6.8±0.2°, 13.4±0.2°, 14.7±0.2°, 19.5±0.2°, 20.1±0.2°, 23.9±0.2°, 24.4±0.2°, 25.0±0.2°, 23.0±0.2° and 23.6±0.2°; or, wherein the crystal form is crystal form A of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof comprises two or three diffraction peaks at 2θ of 6.1±0.2°, 7.5±0.2° and 8.0±0.2°, optionally further comprises one or more diffraction peaks at 2θ of 14.9±0.2°, 18.8±0.2°, 20.7±0.2°, 22.3±0.2°, 22.8±0.2° and 23.8±0.2°; or, the X-ray powder diffraction pattern thereof has characteristic peaks at 6.1±0.2°, 7.5±0.2°, 8.0±0.2°, 14.9±0.2°, 18.8±0.2°, 22.3±0.2°, 22.8±0.2° and 23.8±0.2°; or, wherein the crystal form is crystal form B of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof comprises two or three diffraction peaks at 24.4±0.2°, 13.3±0.2° and 23.8±0.2°, optionally further comprises one or more diffraction peaks at 2θ of 9.0±0.2°, 9.9±0.2°, 26.7±0.2°, 17.2±0.2° and 23.1±0.2°; or, the X-ray powder diffraction pattern thereof has characteristic peaks at 24.4±0.2°, 13.3±0.2°, 23.8±0.2°, 9.0±0.2°, 9.9±0.2°, 26.7±0.2°, 17.2±0.2° and 23.1±0.2°; or, wherein the crystal form is crystal form C of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof comprises two or three diffraction peaks at 2θ of 22.5±0.2°, 8.5±0.2° and 7.2±0.2°, optionally further comprises one or more diffraction peaks at 2θ of 14.4±0.2°, 26.7±0.2°, 12.8±0.2°, 16.7±0.2° and 6.1±0.2°; or, the X-ray powder diffraction pattern thereof has characteristic peaks at 2θ of 22.5±0.2°, 8.5±0.2°, 7.2±0.2°, 14.4±0.2°, 26.7±0.2°, 12.8±0.2°, 16.7±0.2° and 6.1±0.2°; or, wherein the crystal form is crystal form A of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof comprises two or three diffraction peaks at 2θ of 8.4±0.2°, 7.2±0.2° and 20.1±0.2°, optionally further comprises one or more diffraction peaks at 2θ of 22.7±0.2°, 24.5±0.2°, 25.7±0.2°, 18.9±0.2° and 16.4±0.2°; or, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 8.4±0.2°, 7.2±0.2°, 20.1±0.2°, 22.7±0.2°, 24.5±0.2°, 25.7±0.2°, 18.9±0.2° and 16.4±0.2°; or, wherein the crystal form is crystal form B of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, for example, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 4.8±0.2°, 7.6±0.2°, 12.2±0.2°, 14.0±0.2°, 18.5±0.2°, 22.9±0.2°, 23.8±0.2° and 24.9±0.2°; or, wherein the crystal form is crystal form C of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof comprises two or three diffraction peaks at 2θ of 24.5±0.2°, 13.3±0.2° and 23.9±0.2°, optionally further comprises one or more diffraction peaks at 2θ of 9.0±0.2°, 17.3±0.2°, 19.4±0.2°, 17.7±0.2° and 9.9±0.2°; or, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 24.5±0.2°, 13.3±0.2°, 23.9±0.2°, 9.0±0.2°, 17.3±0.2°, 19.4±0.2°, 17.7±0.2° and 9.9±0.2°; or, wherein the crystal form is crystal form D of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof comprises two or three diffraction peaks at 2θ of 7.6±0.2°, 22.5±0.2° and 8.9±0.2°, optionally further comprises one or more diffraction peaks at 2θ of 15.0±0.2°, 26.6±0.2°, 5.8±0.2°, 12.9±0.2° and 11.6±0.2°; or, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 7.6±0.2°, 22.5±0.2°, 8.9±0.2°, 15.0±0.2°, 26.6±0.2°, 5.8±0.2°, 12.9±0.2° and 11.6±0.2°; or, wherein the crystal form is crystal form E of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof comprises two or three diffraction peaks at 2θ of 17.7±0.2°, 23.5±0.2° and 24.8±0.2°, optionally further comprises one or more diffraction peaks at 2θ of 9.9±0.2°, 22.6±0.2°, 21.2±0.2°, 19.1±0.2° and 29.4±0.2°; or, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 17.7±0.2°, 23.5±0.2°, 24.8±0.2°, 9.9±0.2°, 22.6±0.2°, 21.2±0.2°, 19.1±0.2° and 29.4±0.2°.
  8. 8 . The crystal form according to claim 5 , wherein the crystal form is crystal form A of ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 6.8±0.2°, 9.3±0.2°, 13.4±0.2° and 14.7±0.2°; or, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 6.8±0.2° and 13.4±0.2°; the crystal form is crystal form A of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 6.1±0.2° and 8.0±0.2°; the crystal form is crystal form B of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 13.3±0.2° and 23.1±0.2°; the crystal form is crystal form C of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 7.2±0.2° and 22.5±0.2°; the crystal form is crystal form A of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 8.4±0.2° and 20.1±0.2°; the crystal form is crystal form B of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 4.8±0.2° and 7.6±0.2°; the crystal form is crystal form C of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 13.3±0.2° and 24.5±0.2°; the crystal form is crystal form D of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 7.6±0.2° and 15.0±0.2°; the crystal form is crystal form E of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 9.9±0.2° and 22.6±0.2°.
  9. 9 . A method for preparing the crystal form according to claim 5 , comprising: 1) weighing an appropriate amount of free base and suspending it with a poor solvent; 2) weighing an appropriate amount of acid M and dissolving it with an organic solvent; 3) adding the solution in step 2) to the suspension in step 1), and stirring the resulting mixture to precipitate a solid; 4) optionally, adding an organic solvent to the solid obtained in step 3), and stirring the resulting mixture to precipitate a crystal; 5) stirring and cooling the mixture, followed by precipitating a crystal to obtain the target product; wherein, the poor solvent is one or more selected from the group consisting of alcohols, esters, ketones, ethers, benzenes, amides and nitriles; wherein, the organic solvent in step 2) is one or more selected from the group consisting of alcohols, esters, hydrocarbons, ketones, ethers, benzenes, amides and nitriles; wherein the organic solvent in step 4) is one or more selected from the group consisting of alcohols, esters and ethers.
  10. 10 . A method for preparing the crystal form according to claim 5 , comprising: 1) weighing an appropriate amount of salt of the compound and suspending it with a poor solvent; 2) shaking the suspension obtained above; 3) centrifuging the above suspension, removing the supernatant, and vacuum-drying the remaining solid to obtain the target product; wherein, the poor solvent is one or more selected from the group consisting of alcohols, ketones, esters, ethers, benzenes, amides and nitriles.
  11. 11 . A method for preparing the crystal form according to claim 5 , comprising: weighing an appropriate amount of salt of the compound, and exposing the salt of the compound to a certain humidity for a certain period of time; wherein, the humidity is RH=70% to 95%.
  12. 12 . A method for preparing the crystal form according to claim 5 , comprising: 1) weighing an appropriate amount of free base and suspending it with a poor solvent; 2) weighing an appropriate amount of acid M and dissolving it with an organic solvent; 3) adding the solution in step 2) to the suspension in step 1), and heating the reaction; 4) optionally, adding an organic solvent to the solution in step 3); 5) optionally, adding a salt of the compound to the solution in step 4); 6) cooling the mixture to precipitate a crystal; wherein, the poor solvent is one or more selected from the group consisting of alcohols, ketones, esters, ethers, benzenes, amides and acetonitrile; wherein, the organic solvent in step 2) is selected from alcoholic solvents; wherein, the heating temperature in step 3) is 30 to 80° C.; wherein, the organic solvent in step 4) is one or more selected from the group consisting of alcohols, esters and ethers.
  13. 13 . A pharmaceutical composition, comprising a therapeutically effective amount of the acid addition salt according to claim 1 and or more pharmaceutically acceptable carriers or excipients.
  14. 14 . The pharmaceutical composition according to claim 13 , wherein the acid addition salt is wherein, M is selected from the group consisting of sulfuric acid, tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, fumaric acid and methanesulfonic acid.
  15. 15 . The crystal form according to claim 8 , wherein the crystal form is crystal form A of ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 17.3±0.2°, 19.5±0.2°, 20.8±0.2°, 23.9±0.2° and 25.0±0.2°; or, the X-ray powder diffraction pattern thereof also has one or two diffraction peaks at 2θ of 14.7±0.2° and 19.5±0.2°; the crystal form is crystal form A of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 6.1±0.2°, 7.5±0.2°, 8.0±0.2°, 14.9±0.2° and 23.8±0.2°; the crystal form is crystal form B of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 9.0±0.2°, 13.3±0.2°, 19.7±0.2° and 23.1±0.2°; the crystal form is crystal form C of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 7.2±0.2°, 14.4±0.2°, 22.5±0.2° and 26.7±0.2°; the crystal form is crystal form A of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 7.2±0.2°, 8.4±0.2°, 20.1±0.2° and 22.7±0.2°; the crystal form is crystal form B of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 12.2±0.2°, 14.0±0.2°, 18.5±0.2°, 22.9±0.2° and 23.8±0.2°; the crystal form is crystal form C of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 9.0±0.2°, 13.3±0.2°, 17.3±0.2° and 24.5±0.2°; the crystal form is crystal form D of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 7.6±0.2°, 15.0±0.2°, 22.5±0.2° and 23.9±0.2°; the crystal form is crystal form E of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof has diffraction peaks at 2θ of 9.9±0.2°, 17.7±0.2°, 22.6±0.2° and 24.8±0.2°.
  16. 16 . The crystal form according to claim 15 , wherein the crystal form is crystal form A of ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 9.8±0.2°, 18.4±0.2°, 19.1±0.2°, 20.1±0.2°, 23.0±0.2°, 23.6±0.2°, 24.4±0.2°, 27.3±0.2° and 30.7±0.2°; or, the X-ray powder diffraction pattern thereof also has one or more diffraction peaks at 20) (±0.2° of 20.1±0.2°, 23.9±0.2°, 24.4±0.2° and 25.0±0.2°; the crystal form is crystal form A of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 8.4±0.2°, 18.8±0.2°, 20.7±0.2°, 22.3±0.2° and 22.8±0.2°; the crystal form is crystal form B of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 9.9±0.2°, 17.2±0.2°, 20.3±0.2° and 26.7±0.2°; the crystal form is crystal form C of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 6.1±0.2°, 12.8±0.2°, 16.7±0.2° and 20.8±0.2°; the crystal form is crystal form A of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 5.8±0.2°, 16.4±0.2°, 18.9±0.2° and 26.7±0.2°; the crystal form is crystal form B of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern is substantially as shown in FIG. 8 ; the crystal form is crystal form C of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 9.9±0.2°, 17.7±0.2°, 19.4±0.2° and 26.9±0.2°; the crystal form is crystal form D of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 5.8±0.2°, 12.9±0.2°, 19.9±0.2° and 26.6±0.2°; the crystal form is crystal form E of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 16.9±0.2°, 21.2±0.2°, 23.5±0.2° and 29.4±0.2°.
  17. 17 . The crystal form according to claim 16 , wherein the crystal form is crystal form A of ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 10.5±0.2°, 17.5±0.2°, 26.9±0.2°, 27.7±0.2°, 28.6±0.2°, 29.6±0.2°, 35.7±0.2° and 37.6±0.2°; or, the X-ray powder diffraction pattern thereof also has one or two diffraction peaks at 23.0±0.2° and 23.6±0.2°; the crystal form is crystal form A of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 13.5±0.2° and 25.2±0.2°; the crystal form is crystal form B of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 14.3±0.2°, 21.6±0.2°, 23.8±0.2° and 28.4±0.2°; the crystal form is crystal form C of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 8.5±0.2°, 15.2±0.2°, 22.0±0.2° and 25.3±0.2°; the crystal form is crystal form A of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 12.6±0.2°, 14.7±0.2°, 17.2±0.2° and 25.1±0.2°; the crystal form is crystal form C of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 14.3±0.2°, 18.6±0.2°, 28.3±0.2° and 37.5±0.2°; the crystal form is crystal form D of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 8.9±0.2°, 16.8±0.2°, 20.7±0.2° and 24.6±0.2°; the crystal form is crystal form E of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 17.3±0.2°, 19.1±0.2°, 28.4±0.2° and 30.5±0.2°.
  18. 18 . The crystal form according to claim 17 , wherein the crystal form is crystal form A of ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has one or two diffraction peaks at 9.3±0.2° and 17.3±0.2°; the crystal form is crystal form A of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof is substantially as shown in FIG. 4 ; the crystal form is crystal form B of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 24.4±0.2°, 30.5±0.2° and 32.6±0.2°; the crystal form is crystal form C of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 12.1±0.2°, 19.1±0.2° and 23.8±0.2°; the crystal form is crystal form A of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 14.4±0.2°, 18.2±0.2°, 24.5±0.2° and 25.7±0.2°; the crystal form is crystal form C of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 16.7±0.2°, 20.0±0.2°, 20.4±0.2°, 24.0±0.2° and 30.4±0.2°; the crystal form is crystal form D of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 10.1±0.2°, 11.6±0.2°, 17.4±0.2°, 18.2±0.2°, 19.1±0.2°, 21.9±0.2°, 25.4±0.2° and 27.7±0.2°; the crystal form is crystal form E of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 14.1±0.2°, 16.2±0.2°, 19.6±0.2°, 20.7±0.2°, 24.5±0.2° and 26.5±0.2°.
  19. 19 . The crystal form according to claim 18 , wherein the crystal form is crystal form A of ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 9.8±0.2°, 18.4±0.2°, 19.1±0.2°, 23.6±0.2°, 27.3±0.2° and 30.7±0.2°; the crystal form is crystal form B of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof is substantially as shown in FIG. 5 ; the crystal form is crystal form C of mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof is substantially as shown in FIG. 6 ; the crystal form is crystal form A of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof is substantially as shown in FIG. 7 ; the crystal form is crystal form C of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof is substantially as shown in FIG. 9 ; the crystal form is crystal form D of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof is substantially as shown in FIG. 10 ; the crystal form is crystal form E of sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof is substantially as shown in FIG. 11 .
  20. 20 . The crystal form according to claim 19 , wherein the crystal form is crystal form A of ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern thereof also has diffraction peaks at 2θ of 10.5±0.2°, 17.5±0.2°, 26.9±0.2°, 27.7±0.2°, 28.6±0.2°, 29.6±0.2°, 35.7±0.2° and 37.6±0.2°.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a U.S. National Phase of International PCT Application No. PCT/CN2020/130035 filed Nov. 19, 2020, which claims priority to Chinese Patent Application Serial No. 201911168310.3 filed Nov. 25, 2019, the contents of each application are incorporated herein by reference in their entireties. FIELD OF THE INVENTION The present invention belongs to the field of drug synthesis, and specifically relates to a salt of three ring fused derivative salt and a crystal form thereof, a preparation method and use thereof. BACKGROUND OF THE INVENTION The phosphatidylinositol 3-kinase (PI3K) protein family is classified into four major classes: I, II, III and IV, and is involved in the regulation of various cellular functions such as cell growth, proliferation, differentiation, survival, glucose metabolism and the like. The four classes of PI3K proteins have different structures and functions, among which the most widely studied is the Class I PI3K, which is further classified into four subtypes: PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ. Among them, PI3Kα is activating mutated and amplified in a variety of tumors, and is closely related to the onset and development of tumors. It has been reported that PI3Kβ can activate platelets and plays an important role in the onset and development of thrombosis and other diseases. PI3Kδ and PI3Kγ are mainly expressed in the blood system and are closely related to the immune system and the onset of inflammation. In addition, PI3Kγ is closely related to blood pressure stability and smooth muscle contraction. PI3Kα is activating mutated and amplified in a variety of tumors and is a driver of tumorigenesis. PI3Kα is a heterodimer consisting of a p110 catalytic subunit and a p85 regulatory subunit. PI3Kα is activated by receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). After activation, it catalyzes the production of phosphatidylinositol 3 phosphate (PIP3) from phosphatidylinositol 2 phosphate (PIP2), and PIP3 can further activate protein kinase B (PKB, also known as AKT) and its downstream signaling pathways. A variety of cell growth factors, such as epidermal growth factor (EGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and insulin, can all activate PI3Kα, thereby activating downstream proliferation signaling pathways in cells. Abnormal activation of PI3Kα can lead to rapid cell proliferation, thereby causing tumorigenesis. PI3Kα has been an important target for tumor drug research and development, but most compounds are broad-spectrum inhibitors of PI3Ks, resulting in serious side effects in clinical research, which severely limits the development of PI3Ks inhibitors. Current studies have determined that most of the side effects of broad-spectrum PI3Ks inhibitors are caused by the inhibition of PI3Kβ, PI3Kδ and PI3Kγ subtypes. Among them, PI3Kβ plays an important role in the mechanism of the side effects of thrombocytopenia and thrombosis. Inhibition of PI3Kδ can lead to immune system abnormalities. Autoimmune and infectious toxicities such as pneumonia, hepatitis and diarrhea/enteritis are closely related to the inhibition of PI3Kδ targets. PI3Kγ is closely related to blood pressure stability and smooth muscle contraction, and is a major target that causes the side effect of hypertension. Therefore, the development of highly active and selective PI3Kα inhibitors can further improve the anti-tumor effect of PI3Kα inhibitors and reduce or eliminate the various serious side effects such as inflammation, thrombocytopenia, hypertension and the like, which are caused by inhibition of other subtypes. The PI3Kα selective inhibitor BYL-719 developed by Novartis is currently in the phase III clinical study, the PI3Kα selective inhibitor MLN1117 developed by Takeda has entered the phase II clinical study, and the selective inhibitor GDC-0077 developed by Genentech has also been in phase I clinical study. International applications WO2010029082A1 and WO2011022439A1 have reported compounds related to PI3Kα selective inhibitors, but later studies have shown that none of the compounds have high cellular activity, which affects their clinical anti-tumor effects. Therefore, there is an urgent need to develop PI3Kα selective inhibitors with high activity and high selectivity. PI3Kα selective inhibitors can be used to treat a variety of multiple tumors with PI3Kα activating mutations or amplifications, and have great value of clinical application. The PCT patent applications (application numbers: PCT/CN2019/088788 and PCT/CN2019/104558) of Jiangsu Hansoh Pharmaceutical Group Co., Ltd. disclose a series of structures of three ring fused derivative inhibitors. In subsequent research and development, in order to make the products easy to handle, filter and dry and to improve the solubility of the products, and to seek for suitable features of easy storage, long-term stability