Patent Publication Number: US-2022213066-A1

Title: Salts of a class of pyrimidine compounds, polymorphs, and pharmaceutical compositions thereof, preapration methods therefor and uses thereof

Description:
TECHNICAL FIELD 
     The present invention relates to salts and polymorphs of a pyrimidine compound, and a pharmaceutical composition containing the same, a method for preparing various salts and polymorphs, and their use in preparing a pharmaceutical composition. 
     BACKGROUND 
     Epidermal growth factor receptor (EGFR) is a receptor tyrosine protein kinase, which is a transmembrane protein belonging to the erbB receptor family 
     EGFR regulates cell proliferation, survival, adhesion, migration and differentiation. It is over-activated or continuously activated in a variety of tumor cells, such as lung cancer, breast cancer, prostate cancer cells and the like. Abnormal activation of EGFR plays a key role in tumor transformation and growth. Blocking the activation of EGFR has been clinically proven to be one of the effective treatment methods for targeting tumor cells. EGFR is expressed in 50% of NSCLC (non-small cell lung cancer) patients. This makes EGFR and its family members the main candidates for targeted therapy. Gefitinib and Erlotinib are the first-generation small molecule EGFR inhibitors, mainly used to treat advanced NSCLC. It has clinically shown that gefitinib or erlotinib is effective for approximately 10% of white NSCLC patients and approximately 35% of Asian NSCLC patients. Analysis results show that most NSCLC patients with EGFR activating mutations have a significantly higher response rate to EGFR-tyrosine kinase inhibitors (TKI) compared with NSCLC patients with wild type EGFR. 
     However, clinical studies have shown that many patients quickly (12-14 months) develop resistance to these small molecule EGFR inhibitors, that is, acquired drug resistance. The gatekeeper residue T790M mutation is a mutation point in the exon 20 of EGFR, and it is one of the main mechanisms causing drug resistance. It has achieved great success by recent research on a new generation of inhibitors against these EGFR mutations. Afatinib is a potent and irreversible dual inhibitor of EGFR and human epidermal growth factor receptor 2 (HER2) tyrosine kinase. Other highly active, irreversible inhibitors with similar multi targets, such as Canertinib, Dacomitinib are also in late-stage clinical trials. These new second-generation irreversible inhibitors have a potent inhibitory effect on EGFR L858R and T790M mutations, and have significant effects on cancer patients who are already resistant to gefitinib or erlotinib. However, these second-generation inhibitors of EGFR mutant also have potent inhibitory effect on wild-type EGFR (WT-EGFR). Clinical studies have proven that the inhibition on wild-type EGFR can cause drug toxicity and side effects in most patients, for example, some patients encounter skin rash or diarrhea. 
     To overcome the toxicity and side effects of these second-generation EGFR inhibitors, it is necessary to reduce the inhibitory effect on wild-type EGFR (WT-EGFR). The new generation of EGFR inhibitors should maintain strong inhibition on EGFR L858R activating mutant, Exon19 deletion activating mutant and T790M resistance mutant, while having relatively weak inhibitory effect on WT-EGFR and other tyrosine protein kinase receptors. Without concerns on the side effects of second-generation EGFR mutant inhibitors such as afatinib, this kind of compounds can be used for the treatment of cancer patients with EGFR L858R activating mutant and Exon19 deletion activating mutant, and for the treatment of cancer patients with EGFR-T790M mutant who are resistant to the first generation of EGFR inhibitors such as gefitinib, erlotinib or icotinib. 
     Chinese patent application CN105085489A relates to a class of pyrimidine or pyridine compounds, and their pharmaceutically acceptable salts, stereoisomers, prodrugs and solvates, their preparation methods, pharmaceutical compositions and medical uses. This application shows many pyrimidine or pyridine compounds having high inhibitory activity against EGFR mutants (one or more mutants, such as EGFR L858R activating mutant, Exon19 deletion activating mutant and/or T790M resistance mutant), while having relatively low inhibitory activity against wild-type EGFR. 
     Compound 1 (see Example 104 of CN105085489A) as shown below, the compound described in CN105085489A, has good biological activity and safe toxicity parameters. This class of compounds has a good function in the treatment of cancers with EGFR activating mutants and/or EGFR drug-resistant mutations. CN105085489A describes the synthesis of Compound 1 and methanesulfonate thereof. In order to further improve the physicochemical properties of Compound 1, such as stability, hygroscopicity, solubility, etc., which may be beneficial to its production, preparation, synthesis, and/or pharmaceutical applications, the present inventor has developed a novel salt form and a polymorphism of Compound 1 after conducting in-depth research. 
     
       
         
         
             
             
         
       
     
     DESCRIPTION 
     One of the objects of the present invention is to provide a salt form of a pyrimidine Compound 1, preferably its p-toluenesulfonate, benzenesulfonate, succinate, hydrochloride, phosphate, sulfate, or hydrobromide, for example, a salt form and/or crystalline form thereof prepared in Examples 1-9. 
     The Compound 1 described herein refers to a compound with the following structure: 
     
       
         
         
             
             
         
       
     
     The “salts” described herein include pharmaceutically acceptable salts as well as pharmaceutically unacceptable salts. It is not preferable to apply the pharmaceutically unacceptable salts to patients, but these salts can be used to provide pharmaceutical intermediates and bulk pharmaceutical forms. 
     Compound 1 can form a salt with one or two equivalents of acid (abbreviated as mono-salt or di-salt), for example, its hydrobromide can be monohydrobromide or dihydrobromide. Generally, when preparing a salt form of Compound 1, the corresponding mono- or di-salt can be generated by controlling the molar ratio of the compound to the corresponding acid. However, it is difficult to completely control the equivalent of 1:1 or 1:2 during actual operation, and in large-scale preparations, due to the locally excessive presence of acid or Compound 1, a mixture of a mono-salt and a di-salt may be formed. Because the physical and chemical properties of a mono-salt are different from those of a di-salt, the formation of this mixture will result in non-uniform properties of the final product. Therefore, it will bring great convenience to the preparation and production if the formation of a certain salt type is relatively easily controlled, and final products with uniform qualities can be obtained more easily. The inventor has discovered by accident that for p-toluenesulfonate, benzenesulfonate, succinate, hydrochloride, phosphate, and sulfate of Compound 1, a mono-salt can be formed in high yields at a molar ratio of the compound to the corresponding acid of slightly less than 1:1, such as 1:1.1 (acid excess), so the scale-up process is simplified and the efficiency is improved. 
     As described herein, compared with Compound 1, some salt forms of Compound 1, such as hydrochloride, phosphate, p-toluenesulfonate, benzenesulfonate, succinate, sulfate, hydrobromide (including monohydrobromide or dihydrobromide), have more or less improved water solubility, and some polymorphs of these salt forms (especially p-toluenesulfonate crystalline form I, benzenesulfonate crystalline form I, phosphate crystalline form I, etc.) have properties such as high stability, low moisture absorption, which is beneficial to the production and preparation of Compound 1, and is of great significance to its final marketization. 
     In some embodiments, the present invention provides a p-toluenesulfonate of Compound 1, preferably a crystalline form I of p-toluenesulfonate of Compound 1. In the present application, the crystalline form I of p-toluenesulfonate of Compound 1 refers to a crystalline form with one or more of the following characteristics: 1) its X-ray powder diffraction pattern has diffraction peaks at least at one or more positions (1, 2, 3, 4, 5, or 6) of 7.22, 7.90, 9.30, 10.46, 14.64, 15.36, ±0.2° 2θ; 2) its DSC graph has an endothermic peak with an onset temperature of 161.54° C.±5° C. In the crystalline form I of p-toluenesulfonate of Compound 1, the molar ratio of Compound 1 to p-toluenesulfonic acid is about 1:1. In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of p-toluenesulfonate of Compound 1 has 6 or more (such as 10, 16, or 20) X-ray diffraction peaks shown in the table below: 
     
       
         
           
               
               
               
               
               
               
               
             
               
                   
                   
               
               
                   
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
               
               
                   
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 7.221 
                 13.478 
                 17.536 
                 20.498 
                 23.679 
                 28.449 
               
               
                   
                 7.904 
                 14.638 
                 18.385 
                 21.368 
                 24.457 
                 29.728 
               
               
                   
                 9.293 
                 15.36 
                 19.004 
                 22.224 
                 25.408 
                 30.176 
               
               
                   
                 10.459 
                 15.708 
                 19.25 
                 22.529 
                 26.66 
                 31.107 
               
               
                   
                 12.015 
                 16.892 
                 20.231 
                 23.184 
                 27.37 
               
               
                   
                   
               
            
           
         
       
     
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of p-toluenesulfonate of Compound 1 has the main peaks in  FIG. 14 , that is, having peaks at the corresponding 2θ angle ±0.2°, however, the intensities of the peaks might be different from those in  FIG. 14 . The main peak of the X-ray powder diffraction pattern herein means a peak in the X-ray powder diffraction pattern with a relative intensity of 20% or more, for example, a peak with a relative intensity of 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more, or 100%, preferably 30% or more, more preferably 50% or more. 
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of p-toluenesulfonate of Compound 1 is substantially the same as that in  FIG. 14 . The substantially the same X-ray powder diffraction pattern means that the 2θ angles of the diffraction peaks in two patterns are substantially the same within the experimental error range, however, the intensities of the peaks might be different. Preferably, the DSC graph of the crystalline form is also substantially the same as that in  FIG. 15 . The substantially the same DSC graph means that the endothermic peaks in two graphs, such as their starting temperatures, are substantially the same within the experimental error range. 
     In some embodiments, the present invention provides a crystalline form I of p-toluenesulfonate of Compound 1 with high purity, for example, in some embodiments, Compound 1 is predominantly present (for example, in about 80 wt %, about 90 wt %, about 95 wt %, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the high-purity substance in the form of crystalline form I of its p-toluenesulfonate. 
     The crystalline form I of p-toluenesulfonate of Compound 1 can be usually obtained by the following method: Compound 1 and p-toluenesulfonic acid are mixed in a suitable solvent at a molar ratio of about 1:1, and then the p-toluenesulfonate salt of Compound 1 crystalizes. In some embodiments, the molar ratio of Compound 1 to p-toluenesulfonic acid may be slightly less than 1:1 (acid excess), for example, about 1:1.1; about 1:1.15; about 1:1.2. The solvent can be one or more organic solvents, such as acetone. In some embodiments, both the salt-forming reaction and crystallization can be carried out under stirring at room temperature. A typical method for preparing the crystalline form I of p-toluenesulfonate of Compound 1 is described in details in example 3. 
     The crystalline form I of p-toluenesulfonate of Compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition. Preferably, Compound 1 is predominantly present (for example, in about 80 wt %, about 90 wt %, about 95 wt %, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the pharmaceutical composition in the form of crystalline form I of its p-toluenesulfonate. In some cases, Compound 1 is the sole active substance in the pharmaceutical composition. In some cases, the pharmaceutical composition contains a therapeutically or preventively effective amount of Compound 1, for example, for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein. 
     In some embodiments, the present invention provides a benzenesulfonate of Compound 1, preferably a crystalline form I of benzenesulfonate of Compound 1. As used herein, the crystalline form I of benzenesulfonate of Compound 1 refers to a crystalline form with one or more of the following characteristics: 1) its X-ray powder diffraction pattern has diffraction peaks at least at one or more positions (1, 2, 3, 4, or 5, preferably 5) of 8.41, 16.53, 18.78, 21.18, 23.16, ±0.2°, 2θ; 2) its DSC graph has an endothermic peak with an onset temperature of 155.49° C.±5° C. In the crystalline form I of benzenesulfonate of Compound 1, the molar ratio of Compound 1 to benzenesulfonic acid is about 1:1. In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of benzenesulfonate of Compound 1 has 6 or more (such as 10, 16, or 20) X-ray diffraction peaks as shown in the table below: 
     
       
         
           
               
               
               
               
               
               
               
             
               
                   
                   
               
               
                   
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
               
               
                   
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 7.675 
                 13.3 
                 17.122 
                 21.177 
                 24.769 
                 30.277 
               
               
                   
                 8.411 
                 14.595 
                 17.728 
                 21.532 
                 25.162 
                 33.549 
               
               
                   
                 10.009 
                 15.523 
                 18.196 
                 22.191 
                 25.846 
                 34.355 
               
               
                   
                 10.494 
                 15.89 
                 18.782 
                 23.163 
                 26.396 
                 34.441 
               
               
                   
                 10.766 
                 16.534 
                 19.181 
                 24.082 
                 27.523 
                 39.824 
               
               
                   
                 11.143 
                 16.845 
                 20.084 
                 24.415 
                 29.625 
               
               
                   
                   
               
            
           
         
       
     
     In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form I of benzenesulfonate of Compound 1 has diffraction peaks at 7.68, 8.41, 14.60, 15.52, 16.53, 16.85, 17.73, 18.78, 20.08, 21.18, 23.16, 24.42, and 24.76, ±0.2° 2θ. 
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of benzenesulfonate of Compound 1 has the main peaks in  FIG. 19 , that is, having peaks at the corresponding 2θ angle ±0.2°, however, the intensities of the peaks might be different from those shown in  FIG. 19 , for example, a peak with a relative intensity of 20% or more, for example, a peak with a relative intensity of 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more, or 100%, preferably 30% or more, more preferably 50% or more. 
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of benzenesulfonate of Compound 1 is substantially the same as that in  FIG. 19 . Preferably, the DSC graph of the crystalline form is also substantially the same as that in  FIG. 20 . 
     In some embodiments, the present invention provides a crystalline form I of benzenesulfonate of Compound 1 with high purity. For example, in some embodiments, Compound 1 is predominantly present (for example, in about 80 wt %, about 90 wt %, about 95 wt %, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the high-purity substance in the form of crystalline form I of its benzenesulfonate. 
     The crystalline form I of benzenesulfonate of Compound 1 can usually be obtained by the following method: Compound 1 and p-benzenesulfonic acid are mixed in an appropriate solvent at a molar ratio of about 1:1, and then the form I of benzenesulfonate of Compound 1 crystallizes. In some embodiments, the molar ratio of Compound 1 to benzenesulfonic acid may be slightly less than 1:1 (acid excess), for example, about 1:1.1; about 1:1.15; about 1:1.2. The solvent can be one or more organic solvents, such as acetone, acetonitrile. In some embodiments, both the salt-forming reaction and crystallization can be carried out under stirring at room temperature. In some embodiments, the solvent used in the salt-forming reaction may be different from that used in the crystallization. A typical method for preparing the crystalline form I of benzenesulfonate of Compound 1 is described in details in example 4. 
     The crystalline form I of benzenesulfonate of Compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition. Preferably, Compound 1 is predominantly present (for example, in about 80wt %, about 90wt %, about 95wt %, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the pharmaceutical composition in the form of crystalline form I of its benzenesulfonate. In some cases, Compound 1 is the sole active substance in the pharmaceutical composition. In some cases, the pharmaceutical composition contains a therapeutically or preventively effective amount of Compound 1, for example, for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein. 
     In some embodiments, the present invention provides a succinate of Compound 1, preferably a crystalline form I of succinate of Compound 1. As used herein, the crystalline form I of succinate of Compound 1 refers to a crystalline form with one or more of the following characteristics: 1) its X-ray powder diffraction pattern has diffraction peaks at least at one or more positions (1, 2, 3, 4, or 5, preferably 5) of 7.38, 10.21, 11.59, 17.55, 23.38, ±0.2° 2θ; 2) its DSC graph has an endothermic peak with an onset temperature of 108.3° C.±5° C. In the crystalline form I of succinate of Compound 1, the molar ratio of Compound 1 to succinic acid is about 1:1. In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of succinate of Compound 1 has 6 or more (such as 10, 16, or 20) X-ray diffraction peaks shown in the table below: 
     
       
         
           
               
               
               
               
               
               
               
             
               
                   
                   
               
               
                   
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
               
               
                   
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 6.946 
                 13.549 
                 17.811 
                 21.142 
                 25.463 
                 29.9 
               
               
                   
                 7.376 
                 13.952 
                 18.449 
                 21.864 
                 25.892 
                 30.547 
               
               
                   
                 9.175 
                 14.89 
                 18.642 
                 22.144 
                 26.463 
                 31.357 
               
               
                   
                 9.674 
                 15.942 
                 19.051 
                 23.376 
                 27.119 
                 31.958 
               
               
                   
                 10.209 
                 16.57 
                 19.42 
                 24.111 
                 27.829 
                 33.223 
               
               
                   
                 10.672 
                 16.859 
                 19.595 
                 24.402 
                 28.567 
                 35.668 
               
               
                   
                 11.594 
                 17.554 
                 20.418 
                 24.975 
                 29.326 
                 36.201 
               
               
                   
                   
               
            
           
         
       
     
     In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form I of succinate of Compound 1 has diffraction peaks at 7.38, 9.18, 9.67, 10.21, 10.67, 11.59, 13.55, 14.89, 16.86, 17.55, 19.05, 19.42, 19.60, 23.38, 24.11, 24.40, 27.83, 29.90, and 30.55, ±0.2° 2θ. 
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of succinate of Compound 1 has the main peaks in  FIG. 24 , that is, having peaks at the corresponding 2θ angle ±0.2°, however, the intensities of the peaks might be different from those shown in  FIG. 24 , for example, a peak with a relative intensity of 20% or more, for example, a peak with a relative intensity of 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more, or 100%, preferably 30% or more, more preferably 50% or more. 
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of succinate of Compound 1 is substantially the same as that in  FIG. 24 . Preferably, the DSC graph of the crystalline form is also substantially the same as that in  FIG. 25 . 
     In some embodiments, the present invention provides a crystalline form I of succinate of Compound 1 with high purity. For example, in some embodiments, Compound 1 is predominantly present (for example, in about 80 wt %, about 90 wt %, about 95 wt %, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the high-purity substance in the form of crystalline form I of its succinate. 
     The crystalline form I of succinate of Compound 1 can usually be obtained by the following method: Compound 1 and succinic acid are mixed in a suitable solvent at a molar ratio of about 1:1, and then the form I of succinate of Compound 1 crystallizes. In some embodiments, the molar ratio of Compound 1 to succinic acid may be slightly less than 1:1 (acid excess), for example, about 1:1.1; about 1:1.15; about 1:1.2. The solvent can be one or more organic solvents, such as acetone and acetonitrile. In some embodiments, both the salt-forming reaction and crystallization can be carried out under stirring at room temperature. In some embodiments, the solvent used in the salt-forming reaction may be different from that used in the crystallization. A typical method for preparing the crystalline form I of succinate of Compound 1 is described in details in Example 5. 
     The crystalline form I of succinate of Compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition. Preferably, Compound 1 is predominantly present (for example, in about 80 wt %, about 90 wt %, about 95 wt %, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the pharmaceutical composition in the form of crystalline form I of its succinate. In some cases, Compound 1 is the sole active substance in the pharmaceutical composition. In some cases, the pharmaceutical composition contains a therapeutically or preventively effective amount of Compound 1, for example, for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein. 
     In some embodiments, the present invention provides a crystalline form II of succinate of Compound 1. As used herein, the crystalline form II of succinate of Compound 1 refers to a crystalline form with one or more of the following characteristics: 1) its X-ray powder diffraction pattern has diffraction peaks at least at one or more positions (1, 2, 3, 4, 5, 6, 7, or 8, preferably 5 or more, more preferably, 8) of 7.32, 9.02, 9.65, 10.09, 11.63, 17.53, 19.47, 23.45, ±0.2° 2θ; 2) its DSC graph has an endothermic peak with an onset temperature of 139.9° C.±5° C. In the crystalline form II of succinate of Compound 1, the molar ratio of Compound 1 to succinic acid is about 1:1. In some embodiments, the X-ray powder diffraction pattern of the crystalline form II of succinate of Compound 1 has 8 or more (such as 10, 16, or 20) X-ray diffraction peaks shown in the table below: 
     
       
         
           
               
               
               
               
               
               
               
             
               
                   
                   
               
               
                   
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
               
               
                   
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 6.89 
                 13.881 
                 18.644 
                 22.561 
                 25.942 
                 30.688 
               
               
                   
                 7.321 
                 14.734 
                 18.945 
                 23.148 
                 26.482 
                 31.826 
               
               
                   
                 8.014 
                 15.781 
                 19.474 
                 23.454 
                 26.897 
                 33.307 
               
               
                   
                 9.022 
                 16.446 
                 19.702 
                 23.786 
                 27.402 
                 34.561 
               
               
                   
                 9.652 
                 16.774 
                 20.376 
                 24.171 
                 28.108 
                 35.276 
               
               
                   
                 10.087 
                 17.534 
                 21.106 
                 24.428 
                 29.431 
                 36.167 
               
               
                   
                 10.51 
                 17.821 
                 21.8 
                 24.839 
                 29.892 
                 36.427 
               
               
                   
                 11.63 
                 18.131 
                 22.293 
                 25.349 
                 30.33 
                 39.608 
               
               
                   
                 13.604 
               
               
                   
                   
               
            
           
         
       
     
     In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form II of succinate of Compound 1 has diffraction peaks at 7.32, 9.02, 9.65, 10.09, 10.51, 11.63, 13.60, 14.73, 16.45, 16.77, 17.53, 18.13, 19.47, 19.70, 23.45, 23.79, and 24.43, ±0.2° 2θ. 
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form II of succinate of Compound 1 has the main peaks in  FIG. 29 , that is, having peaks at the corresponding 2θ angle ±0.2, however, the intensities of the peaks might be different from those shown in  FIG. 29 , for example, a peak with a relative intensity of 20% or more, for example, a peak with a relative intensity of 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more, or 100%, preferably 30% or more, more preferably 50% or more. 
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form II of succinate of Compound 1 is substantially the same as that in  FIG. 29 . Preferably, the DSC graph of the crystalline form is also substantially the same as that in  FIG. 30 . 
     In some embodiments, the present invention provides a crystalline form II of succinate of Compound 1 with high purity. For example, in some embodiments, Compound 1 is predominantly present (for example, in about 80 wt %, about 90 wt %, about 95 wt %, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the high-purity substance in the form of crystalline form II of its succinate. 
     The crystalline form II of succinate of Compound 1 can usually be obtained by the following method: Compound 1 and succinic acid are mixed in a suitable solvent at a molar ratio of about 1:1, and then the form II of succinate of Compound 1 crystallizes. In some embodiments, the molar ratio of Compound 1 to succinic acid may be slightly less than 1:1 (acid excess), for example, about 1:1.1; about 1:1.15; about 1:1.2. The solvent can be one or more organic solvents, such as ethyl acetate, 2-butanone. In some embodiments, both the salt-forming reaction and crystallization can be carried out under stirring at room temperature. In some embodiments, the solvent used in the salt-forming reaction may be different from that used in the crystallization. A typical method for preparing the crystalline form II of succinate of Compound 1 is described in details in Example 6. 
     The crystalline form II of succinate of Compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition. Preferably, Compound 1 is predominantly present (for example, in about 80 wt %, about 90 wt %, about 95 wt %, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the pharmaceutical composition in the form of crystalline form II of its succinate. In some cases, Compound 1 is the sole active substance in the pharmaceutical composition. In some cases, the pharmaceutical composition contains a therapeutically or preventively effective amount of Compound 1, for example, for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein. 
     In some embodiments, the present invention provides a hydrochloride of Compound 1, preferably a crystalline form III of hydrochloride of Compound 1. As used herein, the crystalline form III of hydrochloride of Compound 1 refers to a crystalline form with one or more of the following characteristics: 1) its X-ray powder diffraction pattern has diffraction peaks at least at one or more positions (1, 2, 3, 4, 5, 6, 7, or 8, preferably 5 or more, more preferably, 8) of 6.39, 7.35, 10.03, 11.48, 15.27, 21.04, 21.87, 23.35, 24.94, ±0.2° 2θ; 2) its DSC graph has an endothermic peak with an onset temperature of 270.75° C.±5° C. In the crystalline form III of hydrochloride of Compound 1, the molar ratio of Compound 1 to hydrochloric acid is about 1:1. In some embodiments, the X-ray powder diffraction pattern of the crystalline form III of hydrochloride of Compound 1 has 8 or more (such as 10, 16, or 20) X-ray diffraction peaks shown in the table below: 
     
       
         
           
               
               
               
               
               
               
               
             
               
                   
                   
               
               
                   
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
               
               
                   
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 6.385 
                 13.255 
                 19.4 
                 22.134 
                 26.206 
                 29.921 
               
               
                   
                 7.353 
                 14.632 
                 20.042 
                 22.745 
                 26.789 
                 31.559 
               
               
                   
                 7.872 
                 15.266 
                 20.313 
                 23.353 
                 27.255 
                 32.794 
               
               
                   
                 10.033 
                 15.657 
                 20.694 
                 23.621 
                 27.481 
                 33.388 
               
               
                   
                 11.483 
                 16.947 
                 21.037 
                 24.101 
                 27.875 
                 37.271 
               
               
                   
                 12.445 
                 18.181 
                 21.485 
                 24.944 
                 28.937 
                 39.086 
               
               
                   
                 12.977 
                 18.713 
                 21.867 
               
               
                   
                   
               
            
           
         
       
     
     In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form III of hydrochloride of Compound 1 has diffraction peaks at 6.39, 7.35, 7.87, 10.03, 11.48, 15.27, 21.04, 21.87, 22.13, 22.74, 23.35, 24.94 and 26.79, ±0.2° 2θ. 
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form III of hydrochloride of Compound 1 has the main peaks in  FIG. 4 , that is, having peaks at the corresponding 2θ angle ±0.2°, however, the intensities of the peaks might be different from those shown in  FIG. 4 , for example, a peak with a relative intensity of 20% or more, for example, a peak with a relative intensity of 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more, or 100%, preferably 30% or more, more preferably 50% or more. 
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form III of hydrochloride of Compound 1 is substantially the same as that in  FIG. 4 . Preferably, the DSC graph of the crystalline form is also substantially the same as that in  FIG. 5 . 
     In some embodiments, the present invention provides a crystalline form III of hydrochloride of Compound 1 with high purity, for example, in some embodiments, Compound 1 is predominantly present (for example, in about 80 wt %, about 90 wt %, about 95 wt %, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the high-purity substance in the form of crystalline form III of its hydrochloride. 
     The crystalline form III of hydrochloride of Compound 1 can usually be obtained by the following method: Compound 1 and hydrochloric acid are mixed in a suitable solvent at a molar ratio of about 1:1, and then the form III of hydrochloride of Compound 1 crystallizes. In some embodiments, the molar ratio of Compound 1 to hydrochloric acid may be slightly less than 1:1 (acid excess), for example, about 1:1.1; about 1:1.15; about 1:1.2. The solvent can be one or more organic solvents, such as acetonitrile and dichloromethane. In some embodiments, both the salt-forming reaction and crystallization can be carried out under stirring at room temperature. In some embodiments, the solvent used in the salt-forming reaction may be different from that used in the crystallization. A typical method for preparing the crystalline form III of hydrochloride of Compound 1 is described in details in Example 1. 
     The crystalline form III of hydrochloride of Compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition. Preferably, Compound 1 is predominantly present (for example, in about 80 wt %, about 90 wt %, about 95 wt %, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the pharmaceutical composition in the form of crystalline form III of its hydrochloride. In some cases, Compound 1 is the sole active substance in the pharmaceutical composition. In some cases, the pharmaceutical composition contains a therapeutically or preventively effective amount of Compound 1, for example, for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein. 
     In some embodiments, the present invention provides a phosphate of Compound 1, preferably a crystalline form I of phosphate of Compound 1. As used herein, the crystalline form I of phosphate of Compound 1 refers to a crystalline form with one or more of the following characteristics: 1) its X-ray powder diffraction pattern has diffraction peaks at least at one or two positions (preferably 2) of 8.14, 16.32, ±0.2° 2θ; 2) its DSC graph has an endothermic peak with an onset temperature of 234.95° C.±5° C. In the crystalline form I of phosphate of Compound 1, the molar ratio of Compound 1 to phosphoric acid is about 1:1. In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of phosphate of Compound 1 has 4 or more (such as 6, 10, or 20) X-ray diffraction peaks shown in the table below: 
     
       
         
           
               
               
               
               
               
               
               
             
               
                   
                   
               
               
                   
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
               
               
                   
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 8.144 
                 13.554 
                 17.395 
                 20.994 
                 24.015 
                 29.882 
               
               
                   
                 8.573 
                 14.334 
                 17.752 
                 21.366 
                 24.715 
                 31.536 
               
               
                   
                 9.48 
                 14.767 
                 18.48 
                 22.361 
                 26.218 
                 32.976 
               
               
                   
                 10.988 
                 15.671 
                 19.362 
                 22.992 
                 26.91 
                 37.285 
               
               
                   
                 12.698 
                 16.316 
                 20.389 
                 23.451 
                 29.013 
                 39.543 
               
               
                   
                   
               
            
           
         
       
     
     In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form I of phosphate of Compound 1 has diffraction peaks at 8.14, 16.32, 17.75 and 20.99, ±0.2° 2θ. 
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of phosphate of Compound 1 has the main peaks in  FIG. 9 , that is, having peaks at the corresponding 2θangle ±0.2°, however, the intensities of the peaks might be different from those shown in  FIG. 9 , for example, a peak with a relative intensity of 20% or more, for example, a peak with a relative intensity of 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more, or 100%, preferably 30% or more, more preferably 50% or more. 
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of phosphate of Compound 1 is substantially the same as that in  FIG. 9 . Preferably, the DSC graph of the crystalline form is also substantially the same as that in  FIG. 10 . 
     In some embodiments, the present invention provides a crystalline form I of phosphate of Compound 1 with high purity. For example, in some embodiments, Compound 1 is predominantly present (for example, in about 80 wt %, about 90 wt %, about 95 wt %, or more, or other forms of Compound 1 that cannot be detected by XRPD) in high-purity substance in the form of crystalline form I of its phosphate. 
     The crystalline form I of phosphate of Compound 1 can usually be obtained by the following method: Compound 1 and phosphoric acid are mixed in a suitable solvent at a molar ratio of about 1:1, and then the form I of phosphate of Compound 1 crystallizes. In some embodiments, the molar ratio of Compound 1 to phosphoric acid can be slightly less than 1:1 (acid excess), for example, about 1:1.1; about 1:1.15; about 1:1.2. The solvents can be one or more organic solvent, such as acetone. In some embodiments, both the salt-forming reaction and crystallization can be carried out under stirring at room temperature. In some embodiments, the solvent used in the salt-forming reaction may be different from that used in the crystallization. A typical method for preparing the crystalline form I of phosphate of Compound 1 is described in details in Example 2. 
     The crystalline form I of phosphate of Compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition. Preferably, Compound 1 is predominantly present (for example, in about 80 wt %, about 90 wt %, about 95 wt %, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the pharmaceutical composition in the form of crystalline form I of its phosphate. In some cases, Compound 1 is the sole active substance in the pharmaceutical composition. In some cases, the pharmaceutical composition contains a therapeutically or preventively effective amount of Compound 1, for example, for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein. 
     In some embodiments, the present invention provides a sulfate of Compound 1, preferably a crystalline form I of sulfate of Compound 1. As used herein, the crystalline form I of sulfate of Compound 1 refers to a crystalline form having one or more of the following characteristics: 1) its X-ray powder diffraction pattern has diffraction peaks at least at one or more (preferably 2 or 3) 10.28, 18.34, 20.64, ±0.2° 2θ; 2) its DSC graph has an endothermic peak with an onset temperature of 255.89° C.±5° C. In the crystalline form I of sulfate of Compound 1, the molar ratio of Compound 1 to sulfuric acid is about 1:1. In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of sulfate of Compound 1 has 4 or more (such as 6, 10, or 20) X-ray diffraction peaks shown in the table below: 
     
       
         
           
               
               
               
               
               
               
               
             
               
                   
                   
               
               
                   
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
               
               
                   
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 9.039 
                 14.239 
                 20.141 
                 21.943 
                 27.196 
                 31.141 
               
               
                   
                 9.49 
                 15.432 
                 20.411 
                 22.45 
                 28.534 
                 32.097 
               
               
                   
                 10.275 
                 18.342 
                 20.635 
                 22.792 
                 30.647 
                 33.216 
               
               
                   
                 11.809 
                 19.085 
                 21.261 
                 24.479 
               
               
                   
                   
               
            
           
         
       
     
     In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form I of sulfate of Compound 1 has diffraction peaks at 9.04, 10.28, 18.34, 20.41, 20.64, 27.20 and 28.53, ±0.2° 2θ. 
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of sulfate of Compound 1 has the main peaks in  FIG. 32 , that is, having peaks at the corresponding 2θ angle ±0.2°, however, the intensities of the peaks might be different from those shown in  FIG. 32 , for example, a peak with a relative intensity of 20% or more, for example, a peak with a relative intensity of 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more, or 100%, preferably 30% or more, more preferably 50% or more. 
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of sulfate of Compound 1 is substantially the same as that in  FIG. 32 . Preferably, the DSC graph of the crystalline form is also substantially the same as that in  FIG. 33 . 
     In some embodiments, the present invention provides a crystalline form I of sulfate of Compound 1 with high purity, for example, in some embodiments, Compound 1 is predominantly present (for example, in about 80 wt %, about 90 wt %, about 95 wt %, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the high-purity substance in the form of crystalline form I of its sulfate. 
     The crystalline form I of sulfate of Compound 1 can usually be obtained by the following method: Compound 1 and sulfuric acid are mixed in a suitable solvent at a molar ratio of about 1:1, and then the form I of sulfate of Compound 1 crystallizes. In some embodiments, the molar ratio of Compound 1 to sulfuric acid may be slightly less than 1:1 (acid excess), for example, about 1:1.1; about 1:1.15; about 1:1.2. The solvent can be one or more organic solvents, such as ethyl acetate. In some embodiments, both the salt-forming reaction and crystallization can be carried out under stirring at room temperature. In some embodiments, the solvent used in the salt-forming reaction may be different from that used in the crystallization. A typical method for preparing the crystalline form I of sulfate of Compound 1 is described in details in Example 7. 
     The crystalline form I of sulfate of Compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition. Preferably, Compound 1 is predominantly present (for example, in about 80 wt %, about 90 wt %, about 95 wt %, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the pharmaceutical composition in the form of crystalline form I of its sulfate. In some cases, Compound 1 is the sole active substance in the pharmaceutical composition. In some cases, the pharmaceutical composition contains a therapeutically or preventively effective amount of Compound 1, for example, for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein. 
     In some embodiments, the present invention provides a hydrobromide of Compound 1, such as a crystalline form I of monohydrobromide of Compound 1. As used herein, the crystalline form I of monohydrobromide of Compound 1 refers to a crystalline form with one or more of the following characteristics: 1) its X-ray powder diffraction pattern has diffraction peaks at least at one or two positions of 6.10, 24.73 ±0.2° 2θ; 2) its DSC graph has two endothermic peaks. In the crystalline form I of monohydrobromide of Compound 1, the molar ratio of Compound 1 to hydrobromic acid is about 1:1. In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of monohydrobromide of Compound 1 has 4 or more (such as 6, 10, or 20) X-ray diffraction peaks shown in the table below: 
     
       
         
           
               
               
               
               
               
               
               
             
               
                   
                   
               
               
                   
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
               
               
                   
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 3.67 
                 13.07 
                 17.703 
                 23.634 
                 28.981 
                 31.923 
               
               
                   
                 6.104 
                 14.58 
                 19.27 
                 24.73 
                 29.532 
                 37.951 
               
               
                   
                 10.262 
                 15.651 
                 20.057 
                 26.032 
                 30.584 
                 39.358 
               
               
                   
                 12.251 
                 16.739 
                 21.916 
                 26.437 
                 31.816 
               
               
                   
                   
               
            
           
         
       
     
     In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form I of monohydrobromide of Compound 1 has diffraction peaks at 6.10, 12.25, 13.07, 14.58, 15.65, 16.74, 19.27, 20.06, 21.92, 24.73, 26.03 and 26.44, ±0.2° 2θ. 
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of monohydrobromide of Compound 1 has the main peaks in  FIG. 37 , that is, having peaks at the corresponding 2θ angle ±0.2°, however, the intensities of the peaks might be different from those shown in  FIG. 37 , for example, a peak with a relative intensity of 20% or more, for example, a peak with a relative intensity of 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more, or 100%, preferably 30% or more, more preferably 50% or more. 
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of monohydrobromide of Compound 1 is substantially the same as that in  FIG. 37 . Preferably, the DSC graph of the crystalline form is also substantially the same as that in  FIG. 38 . 
     In some embodiments, the present invention provides a crystalline form I of monohydrobromide of Compound 1 with high purity, for example, in some embodiments, Compound 1 is predominantly present (e.g., in about 80 wt %, about 90 wt %, about 95 wt %, or more, or other forms of Compound 1 not detectable by XRPD) in the high-purity substance in the form of crystalline form I of its monohydrobromide. 
     The crystalline form I of monohydrobromide of Compound 1 can usually be obtained by the following method: Compound 1 and hydrobromic acid are mixed in a suitable solvent at a molar ratio of about 1:1, and then the form I of monohydrobromide of Compound 1 crystallizes. In some embodiments, the molar ratio of Compound 1 to hydrobromic acid may be slightly less than 1:1 (acid excess), for example, about 1:1.1; about 1:1.15; about 1:1.2. The solvent can be one or more organic solvents, such as acetone. In some embodiments, both the salt-forming reaction and crystallization can be carried out under stirring at room temperature. In some embodiments, the solvent used for the salt formation reaction may be different from that used in the crystallization. A typical method for preparing the crystalline form I of monohydrobromide of Compound 1 is described in details in Example 8. 
     The crystalline form I of monohydrobromide of Compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition. Preferably, Compound 1 is predominantly present (for example, in about 80 wt %, about 90 wt %, about 95 wt %, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the pharmaceutical composition in the form of crystalline form I of its monohydrobromide. In some cases, Compound 1 is the sole active substance in the pharmaceutical composition. In some cases, the pharmaceutical composition contains a therapeutically or preventively effective amount of Compound 1, for example, for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein. 
     In some embodiments, the present invention provides a crystalline form I of dihydrobromide of Compound 1. As used herein, the crystalline form I of dihydrobromide of Compound 1 refers to a crystalline form with one or more of the following characteristics: 1) its X-ray powder diffraction pattern has diffraction peaks at least at one or more positions (such as 1, 2, 3, or 4) of 6.28, 13.12, 19.30, 25.34, ±0.2° 2θ; 2) its DSC graph has two endothermic peaks with onset temperatures at 193.38° C.±5° C. and 230.24° C.±5° C. respectively. In the crystalline form I of dihydrobromide of Compound 1, the molar ratio of Compound 1 to hydrobromic acid is about 1:2. In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of dihydrobromide of Compound 1 has 6 or more (such as 8, 12, or 20) X-ray diffraction peaks shown in the table below: 
     
       
         
           
               
               
               
               
               
               
               
             
               
                   
                   
               
               
                   
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
                 Angle 
               
               
                   
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
                 2θ/° 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 6.276 
                 12.071 
                 18.953 
                 22.87 
                 28.58 
                 33.849 
               
               
                   
                 7.329 
                 12.603 
                 19.305 
                 23.626 
                 29.384 
                 34.543 
               
               
                   
                 7.771 
                 13.122 
                 19.605 
                 24.148 
                 30.618 
                 35.211 
               
               
                   
                 9.38 
                 14.575 
                 20.387 
                 25.341 
                 31.164 
                 36.629 
               
               
                   
                 9.69 
                 16.777 
                 20.662 
                 25.61 
                 31.832 
                 38.6 
               
               
                   
                 10.493 
                 17.067 
                 21.148 
                 26.424 
                 32.348 
                 39.414 
               
               
                   
                 11.591 
                 18.236 
                 21.954 
                 27.78 
                 33.126 
               
               
                   
                   
               
            
           
         
       
     
     In some preferred embodiments, the X-ray powder diffraction pattern of the crystalline form I of dihydrobromide of Compound 1 has diffraction peaks at 6.28, 13.12, 16.78, 18.95, 19.30, 21.95, 23.63, 25.34, 25.61 and 26.42, ±0.2° 2θ. 
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of dihydrobromide of Compound 1 has the main peaks in  FIG. 40 , that is, having peaks at the corresponding 2θ angle ±0.2°, however, the intensities of the peaks might be different from those shown in  FIG. 40 , for example, a peak with a relative intensity of 20% or more, for example, a peak with a relative intensity of 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more, or 100%, preferably 30% or more, more preferably 50% or more. 
     In some embodiments, the X-ray powder diffraction pattern of the crystalline form I of dihydrobromide of Compound 1 is substantially the same as that in  FIG. 40 . Preferably, the DSC graph of the crystalline form is also substantially the same as that in  FIG. 41 . 
     In some embodiments, the present invention provides a crystalline form I of dihydrobromide of Compound 1 with high-purity, for example, in some embodiments, Compound 1 is predominantly present (for example, in about 80 wt %, about 90 wt %, about 95 wt %, or more, or other forms of Compound 1 not detectable by XRPD) in the high-purity substance in the form of crystalline form I of its dihydrobromide. 
     The crystalline form I of dihydrobromide of Compound 1 can usually be obtained by the following method: Compound 1 and hydrobromic acid are mixed in a suitable solvent at a molar ratio of about 1:2, and then the form I of dihydrobromide of Compound 1 crystallizes. The solvent can be one or more organic solvents, such as acetone and acetonitrile. In some embodiments, both the salt-forming reaction and crystallization can be carried out under stirring at room temperature. In some embodiments, the solvent used for the salt formation reaction may be different from that used in the crystallization. A typical method for preparing the crystalline form I of dihydrobromide of Compound 1 is described in details in Example 9. 
     The crystalline form I of dihydrobromide of Compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition. Preferably, Compound 1 is predominantly present (for example, in about 80 wt %, about 90 wt %, about 95 wt %, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the pharmaceutical composition in the form of crystalline form I of its dihydrobromide. In some cases, Compound 1 is the sole active substance in the pharmaceutical composition. In some cases, the pharmaceutical composition contains a therapeutically or preventively effective amount of Compound 1, for example, for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein. 
     In some embodiments, the present invention provides a pharmaceutical composition comprising any one or more of the salt forms or crystalline forms described herein and a pharmaceutically acceptable carrier or diluent. Excipients, binders, lubricants, disintegrating agents, coloring agents, flavoring agents, emulsifiers, surfactants, solubilizers, suspending agents, isotonic agents, buffers, preservatives, antioxidants, stabilizers, absorption promoters, etc. which are commonly used in the medical field can also be used in appropriate combinations as needed. 
     The pharmaceutical composition of the present invention can be in any available dosage form, for example, tablets, capsules and the like. In the case of preparing a tablet-type solid composition, the main active ingredient component can be mixed with a pharmaceutical carrier, such as starch, lactose, magnesium stearate, etc., and the tablet can be coated with sugar or other suitable substances, or it is processed so that the tablet has a prolonged or delayed releasing effect and the tablet releases a predetermined amount of active ingredient in a continuous manner. In the case of preparing a capsule-type solid composition, a capsule can be obtained by mixing the active ingredient with a diluent, and filling the resulting mixture into capsules. In some embodiments, the pharmaceutical composition of the present invention can also be in other dosage forms, such as granules, powders, or syrups and the like which are administered orally, or injections, powder injections, sprays, or suppositories and the like, which are non-orally administered. These preparations can be prepared by conventional methods. 
     In some embodiments, the salt, crystalline form, and/or pharmaceutical composition of Compound 1 of the present invention can be used for preparing a drug for the treatment or prevention a disorder or disease mediated by activating or resistant mutant form of EGFR, for example, mediated by L858R activating mutant, Exon19 deletion activating mutant and/or T790M resistance mutant of EGFR. In some embodiments, the disorder or disease is cancer. In some embodiments, the disorder or disease includes, but is not limited to: ovarian cancer, cervical cancer, colorectal cancer (e.g., colon adenocarcinoma), breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin&#39;s lymphoma, gastric cancer, lung cancer (for example, non-small cell lung cancer), hepatocellular carcinoma, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, intrauterine membrane cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma or mesothelioma. 
     In the present invention, the activating mutant or resistant mutant form of EGFR may be, for example, L858R activating mutant, Exon19 deletion activating mutant and/or T790M resistance mutant. Therefore, the disorder or disease mediated by the activating mutant or resistant mutant form of EGFR may be, for example, a disorder or disease mediated by L858R activating mutant, Exon19 deletion activating mutant and/or T790M resistance mutant. 
     The salt, crystalline form, and/or pharmaceutical composition of Compound 1 of the present invention can be specifically used in the prevention or treatment of diseases mediated by the activating mutant or resistant mutant form of EGFR, for example, in the prevention or treatment of diseases, disorders or conditions mediated by L858R activating mutant, Exon19 deletion activating mutant and/or T790M resistance mutant, for example, it can be used in the prevention or treatment in cancer patients who have been resistant to gefitinib, erlotinib, or ectinib. 
     In another aspect of the present invention, it provides a combined treatment method for cancer, comprising administering a therapeutically effective amount of the salt, crystalline form of Compound 1, and/or pharmaceutical composition thereof of the present invention to an individual in need thereof, with the combination of conventional surgery or radiotherapy or chemotherapy or immuno-tumor therapy. The chemotherapy or immuno-tumor therapy may be administered together, simultaneously, sequentially, or separately with the application of the salt, crystalline form, and/or pharmaceutical composition of Compound 1 of the present invention, and they may include but are not limited to one or more of the following types of anti-tumor agents: alkylating agents (e.g. carboplatin, oxaliplatin, cisplatin, cyclophosphamide, nitrosoureas, mechlorethamine, melphalan), antimetabolites (e.g. gemcitabine), and antifolates (e.g. 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, hydroxyurea), topoisomerase inhibitors (e.g. etorposide, topotecan, camptothecin), anti-mitotic agents (e.g. vincristine, vinblastine, vinorelbine, paclitaxel, taxotere), anti-tumor antibiotics (e.g. doxorubicin, bleomycin, doxorubicin, daunorubicin, mitomycin C, actinomycin), anti-estrogens (e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene), antiandrogens (e.g. bicalutamide, flutamide, nilutamide), LHRH antagonists or LHRH agonists (e.g. goserelin, leuprolide, and buserelin), aromatase inhibitors (such as anastrozole, letrozole), CYP17 lyase inhibitors (such as abiraterone), anti-erbB2 antibody trastuzumab [Herceptin], anti-EGFR antibody cetuximab [Erbitux]; tyrosine kinase, serine/threonine kinase inhibitors (e.g., imatinib and nilotinib, sorafenib, trametinib, crizotinib); cyclin-dependent kinase inhibitors (such as CDK4 inhibitor palbociclib), anti-human vascular endothelial cell growth factor antibody bevacizumab (Avastin) and VEGF receptor tyrosine kinase inhibitor (apatinib), immuno-oncology therapy, such as anti PD-1 antibody (pembrolizumab, nivolumab), anti-PD-L1 antibody, anti-LAG-3 antibody, anti-CTLA-4 antibody, anti-4-1BB antibody, anti-GITR antibody, anti-ICOS antibody, interleukin-2. 
    
    
     
       DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is the XRPD pattern of Compound 1; 
         FIG. 2  is the DSC and TGA graphs of Compound 1; 
         FIG. 3  is the NMR spectrum of Compound 1; 
         FIG. 4  is the XRPD pattern of the crystalline form III of hydrochloride of Compound 1; 
         FIG. 5  is the DSC and TGA graphs of the crystalline form III of hydrochloride of Compound 1; 
         FIG. 6  is the 1H NMR spectrum of the crystalline form III of hydrochloride of Compound 1; 
         FIG. 7  is the DVS plot of the crystalline form III of hydrochloride of Compound 1; 
         FIG. 8  is the XPRD overlapping pattern of the crystalline form III of hydrochloride of Compound 1 before and after the DVS test; 
         FIG. 9  is the XRPD pattern of the crystalline form I of phosphate of Compound 1; 
         FIG. 10  is the DSC and TGA graphs of the crystalline form I of phosphate of Compound 1; 
         FIG. 11  is the 1H NMR spectrum of the crystalline form I of phosphate of Compound 1; 
         FIG. 12  is the DVS plot of the crystalline form I of phosphate of Compound 1; 
         FIG. 13  is the XPRD overlapping pattern of the crystalline form I of phosphate of Compound 1 before and after DVS test; 
         FIG. 14  is the XRPD pattern of the crystalline form I of p-toluenesulfonate of Compound 1; 
         FIG. 15  is the DSC and TGA graphs of the crystalline form I of p-toluenesulfonate of Compound 1; 
         FIG. 16  is the 1H NMR spectrum of the crystalline form I of p-toluenesulfonate of Compound 1; 
         FIG. 17  is the DVS plot of the crystalline form I of p-toluenesulfonate of Compound 1; 
         FIG. 18  is the XRPD overlapping pattern of the crystalline form I of p-toluenesulfonate of Compound 1 before and after DVS test; 
         FIG. 19  is the XRPD pattern of the crystalline form I of benzenesulfonate of Compound 1; 
         FIG. 20  is the DSC and TGA graphs of the crystalline form I of benzenesulfonate of Compound 1; 
         FIG. 21  is the 1H NMR spectrum of the crystalline form I of benzenesulfonate of Compound 1; 
         FIG. 22  is the DVS plot of the crystalline form I of benzenesulfonate of Compound 1; 
         FIG. 23  is the XPRD overlapping pattern of the crystalline form I of benzenesulfonate of Compound 1 before and after DVS test; 
         FIG. 24  is the XRPD pattern of the crystalline form I of succinate of Compound 1; 
         FIG. 25  is the DSC and TGA graphs of the crystalline form I of succinate of Compound 1; 
         FIG. 26  is the 1H NMR spectrum of the crystalline form I of succinate of Compound 1; 
         FIG. 27  is the DVS plot of the crystalline form I of succinate of Compound 1; 
         FIG. 28  is the XPRD overlapping pattern of the crystalline form I of succinate of Compound 1 before and after DVS test; 
         FIG. 29  is the XRPD pattern of the crystalline form II of succinate of Compound 1; 
         FIG. 30  is the DSC and TGA graphs of the crystalline form II of succinate of Compound 1; 
         FIG. 31  is the 1H NMR spectrum of the crystalline form II of succinate of Compound 1; 
         FIG. 32  is the XRPD pattern of the crystalline form I of sulfate of Compound 1; 
         FIG. 33  is the DSC and TGA graphs of the crystalline form I of sulfate of Compound 1; 
         FIG. 34  is the 1H NMR spectrum of the crystalline form I of sulfate of Compound 1; 
         FIG. 35  is the DVS plot of the crystalline form I of sulfate of Compound 1; 
         FIG. 36  is the XPRD overlapping pattern of the crystalline form I of sulfate of Compound 1 before and after DVS test; 
         FIG. 37  is the XRPD pattern of the crystalline form I of monohydrobromide of Compound 1; 
         FIG. 38  is the DSC and TGA graphs of the crystalline form I of monohydrobromide of Compound 1; 
         FIG. 39  is the 1H NMR spectrum of the crystalline form I of monohydrobromide of Compound 1; 
         FIG. 40  is the XRPD pattern of the crystalline form I of dihydrobromide of Compound 1; 
         FIG. 41  is the DSC and TGA graphs of the crystalline form I of dihydrobromide of Compound 1; 
         FIG. 42  is the 1H NMR spectrum of the crystalline form I of dihydrobromide of Compound 1. 
     
    
    
     ADVANTAGEOUS EFFECTS 
     The inventor has discovered by accident that for p-toluenesulfonate, benzenesulfonate, succinate, hydrochloride, phosphate, and sulfate of Compound 1, a mono-salt can be formed in high yields at a molar ratio of the compound to the corresponding acid of slightly less than 1:1, such as 1:1.1 (acid excess), so the process scale-up is simplified and the efficiency is improved. 
     In addition, as detailed herein, compared with Compound 1, some salt forms of Compound 1, such as hydrochloride, phosphate, p-toluenesulfonate, benzenesulfonate, succinate, sulfate, hydrobromide (including monohydrobromide or dihydrobromide), have more or less improved water solubility, and some polymorphs of these salt forms (especially p-toluenesulfonate crystalline form I, benzenesulfonate crystalline form I, phosphate crystalline form I, etc.) have properties such as high stability, low moisture absorption, which is beneficial to the production and preparation of Compound 1, and is of great significance to its final marketization. 
     DETAILED EMBODIMENTS 
     The present invention is further illustrated by the following examples. The following examples are just used to more specifically illustrate the preferred embodiments of the present invention, and are not used to limit the technical solutions of the present invention. 
     In the following examples,    
     The instrument used in  1 H-NMR analysis was a Bruker Advance 300 equipped with a B-ACS 120 automatic sampling system. 
     The solid samples were analyzed with a powder X-ray diffraction analyzer (Bruker D8 advance). The instrument is equipped with a LynxEye detector. The 20 scan angle range is 3° to 40°, and the step size is 0.02°. When measuring the sample, the light tube voltage and light tube current were 40 KV and 40 mA, respectively. 
     The instrument used in thermogravimetric analysis (TGA) was Discovery TGA 55 (TA Instruments, US). The sample was placed in a balanced open aluminum sample pan, and the sample was automatically weighed in the TGA furnace. The sample was heated to the final temperature at a rate of 10° C./min 
     The instrument used in differential scanning calorimetry (DSC) was TA Instruments Q200 or Discovery DSC 250. After the sample was accurately weighed, it was placed in a DSC sample pan with a pierced lid, and the mass of the sample was accurately recorded. The sample was heated to the final temperature at a heating rate of 10° C./min. 
     The instrument used in dynamic vapor absorption and desorption analysis (DVS) was DVS Intrinsic (SMS, UK). The sample was placed in the sample basket of the instrument for automatic weighing, then heated to 40° C., and dried under a nitrogen stream to a dm/dt of less than 0.002%. The measurement was started after the temperature was dropped to 25° C., The instrument parameters were as follows. 
     Time per step: 60 min
 
Sample temperature: 25° C.
 
Cycle: entire cycle
 
     Adsorption: 0, 10, 20, 30, 40, 50, 60, 70, 80, 90 
     Desorption: 80, 70, 60, 50, 40, 30, 20, 10, 0 
     Data storage rate: 5 s
 
Total flow rate: 200 sccm
 
Total flow rate after the test: 200 sccm
 
     Characterization of Compound 1 
     The initial drug 1 is a crystal with good crystallinity ( FIG. 1 ), and its melting point is 146° C. as shown in DSC ( FIG. 2 ). The sample has no residual solvent and almost no weight loss at temperatures lower than 200° C. as shown in  1 H-NMR and TGA ( FIG. 3 ). The results show that the sample is an anhydrous crystal, named as crystalline form I. 
     Preparation of Various Salt Forms 
     Example 1. Crystalline Form III of Hydrochloride 
     1 (31.21 mg, 1.0 eq) was dissolved in a mixed solvent of acetonitrile and dichloromethane (48 v, 3/1), and hydrochloric acid (1.1 eq) was added under stirring at 50° C. After the reaction solution was cooled to room temperature, the solution was stirred for 30 minutes. Then the resulting clear solution was concentrated to about 32 v with N 2  stream, and a solid precipitated out immediately. The resulting suspension was stirred overnight at room temperature, and a solid was collected by filtration, and dried under vacuum at 50° C. for about 4 hours to obtain a crystalline form III of hydrochloride, which sample, an off-white solid, was characterized by XRPD, DSC, TGA, DVS and  1 H-NMR, respectively. 
     The crystalline form III of hydrochloride is a crystal with a high melting point (273° C.,  FIG. 5 ) (Table 1 and  FIG. 4 ). The sample is slightly hygroscopic, with a weight gain of about 1.86% under 80% relative humidity ( FIG. 7 ). The sample has no residual solvent and no significant weight loss at temperature lower than 200° C. as shown in  1 H-NMR and TGA ( FIG. 5  and  FIG. 6 ), indicating that the sample is an anhydrous crystal. The crystalline form of the sample does not change after the DVS test ( FIG. 8 ). 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 List of XRPD diffraction peaks of the crystalline form  
               
               
                 III of hydrochloride 
               
            
           
           
               
               
               
               
               
               
            
               
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
               
               
                 2θ/° 
                 % 
                 2θ/° 
                 % 
                 2θ/° 
                 % 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 6.385 
                 35.9 
                 18.713 
                 27.2 
                 24.944 
                 100 
               
               
                 7.353 
                 98.4 
                 19.4 
                 23.2 
                 26.206 
                 25.1 
               
               
                 7.872 
                 44.9 
                 20.042 
                 21.1 
                 26.789 
                 48 
               
               
                 10.033 
                 52.2 
                 20.313 
                 22.4 
                 27.255 
                 28 
               
               
                 11.483 
                 71.5 
                 20.694 
                 23.7 
                 27.481 
                 21.1 
               
               
                 12.445 
                 25.1 
                 21.037 
                 87.3 
                 27.875 
                 14 
               
               
                 12.977 
                 20.8 
                 21.485 
                 21.4 
                 28.937 
                 11.9 
               
               
                 13.255 
                 17.2 
                 21.867 
                 73.6 
                 29.921 
                 13.7 
               
               
                 14.632 
                 17.9 
                 22.134 
                 33 
                 31.559 
                 14.5 
               
               
                 15.266 
                 67.5 
                 22.745 
                 32.7 
                 32.794 
                 32.2 
               
               
                 15.657 
                 17.4 
                 23.353 
                 67 
                 33.388 
                 13.2 
               
               
                 16.947 
                 15.8 
                 23.621 
                 24.8 
                 37.271 
                 11.3 
               
               
                 18.181 
                 29 
                 24.101 
                 14.2 
                 39.086 
                 9.8 
               
               
                   
               
            
           
         
       
     
     Example 2. Crystalline Form I of Phosphate 
     1 (30.20 mg, 1.0 eq) was dissolved in acetone (26 v), and phosphoric acid (1.1 eq) was added under stirring at room temperature, and a viscous substance immediately precipitated out. After stirring for 2 hours, a solid precipitated out. After the suspension was stirred at room temperature for 3 hours, a solid was collected by filtration and dried in vacuum at 50° C. overnight to obtain crystalline form I of phosphate, which sample, an off-white solid, was characterized by XRPD, DSC, TGA, DVS and  1 H-NMR, respectively. 
     The crystalline form I of phosphate is a crystal with high crystallinity (Table 2 and  FIG. 9 ) and high melting point (238° C.,  FIG. 10 ). The sample is slightly hygroscopic, with a weight gain of about 0.61% under 80% relative humidity ( FIG. 12 ). The sample has 0.7% residual solvent, and no significant weight loss at temperatures lower than 150° C. as shown in  1 H-NMR and TGA ( FIG. 10  and  FIG. 11 ), indicating that the sample is an anhydrous crystal. The crystalline form of the sample does not change after the DVS test ( FIG. 13 ). 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 List of XRPD diffraction peaks of crystalline form I of phosphate 
               
            
           
           
               
               
               
               
               
               
            
               
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
               
               
                 2θ/° 
                 % 
                 2θ/° 
                 % 
                 2θ/° 
                 % 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 8.144 
                 100 
                 17.395 
                 4.6 
                 24.015 
                 4.3 
               
               
                 8.573 
                 10 
                 17.752 
                 12.6 
                 24.715 
                 5 
               
               
                 9.48 
                 8.1 
                 18.48 
                 6.6 
                 26.218 
                 5.4 
               
               
                 10.988 
                 5.1 
                 19.362 
                 4.3 
                 26.91 
                 2.1 
               
               
                 12.698 
                 4 
                 20.389 
                 4.8 
                 29.013 
                 2.9 
               
               
                 13.554 
                 6.5 
                 20.994 
                 15.7 
                 29.882 
                 3.3 
               
               
                 14.334 
                 4 
                 21.366 
                 11.9 
                 31.536 
                 2.3 
               
               
                 14.767 
                 3.6 
                 22.361 
                 4.7 
                 32.976 
                 2.4 
               
               
                 15.671 
                 4.8 
                 22.992 
                 7.3 
                 37.285 
                 2.2 
               
               
                 16.316 
                 24.5 
                 23.451 
                 7.9 
                 39.543 
                 2.3 
               
               
                   
               
            
           
         
       
     
     Example 3. Crystalline Form I of p-toluenesulfonate 
     1 (31.60 mg, 1.0 eq) was dissolved in acetone (25 v), and p-toluenesulfonic acid (1.1 eq) was added under stirring at room temperature. After about 2 minutes, a solid precipitated out. The suspension was stirred at room temperature for about 6 hours, and a solid was collected by filtration and dried overnight at 50° C. under vacuum to obtain a crystalline form I of p-toluenesulfonate, which sample, an off-white solid, was characterized by XRPD, DSC, TGA, DVS and  1 H-NMR, respectively. 
     The crystalline form I of p-toluenesulfonate is a crystal with a melting point of 172° C. ( FIG. 15 ) (Table 3 and  FIG. 14 ). The sample is slightly hygroscopic, with a weight gain of about 0.55% under 80% relative humidity ( FIG. 17 ). The sample has no significant weight loss at temperatures lower than 200° C. as shown in TGA ( FIG. 15 ); the sample has about 0.3% residual solvent, and the ratio of free base to p-toluenesulfonic acid is 1:1 as shown in  1 H-NMR ( FIG. 16 ). The sample may be an anhydrous crystal. The crystalline form of the sample does not change after the DVS test ( FIG. 18 ). 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 List of XRPD diffraction peaks of crystalline form I 
               
               
                 of p-toluenesulfonate 
               
            
           
           
               
               
               
               
               
               
            
               
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
               
               
                 2θ/° 
                 % 
                 2θ/° 
                 % 
                 2θ/° 
                 % 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 7.221 
                 100 
                 17.536 
                 6.7 
                 23.679 
                 14.2 
               
               
                 7.904 
                 18.5 
                 18.385 
                 11.8 
                 24.457 
                 4.5 
               
               
                 9.293 
                 18.7 
                 19.004 
                 10.4 
                 25.408 
                 5.8 
               
               
                 10.459 
                 15.6 
                 19.25 
                 7.3 
                 26.66 
                 7.1 
               
               
                 12.015 
                 6.3 
                 20.231 
                 8.4 
                 27.37 
                 5.1 
               
               
                 13.478 
                 4.5 
                 20.498 
                 9.5 
                 28.449 
                 4.3 
               
               
                 14.638 
                 23.3 
                 21.368 
                 16.3 
                 29.728 
                 6.1 
               
               
                 15.36 
                 24.7 
                 22.224 
                 7.6 
                 30.176 
                 4.1 
               
               
                 15.708 
                 9.2 
                 22.529 
                 6.5 
                 31.107 
                 3.7 
               
               
                 16.892 
                 5.2 
                 23.184 
                 4.4 
               
               
                   
               
            
           
         
       
     
     Example 4. Crystalline Form I of Benzenesulfonate 
     1 (19.51 mg, 1.0 eq) was dissolved in acetone (40 v), and benzenesulfonic acid (1.0 eq) was added under stirring at room temperature. The reaction solution was still clear after stirring for 3 hours. It was blown dry with N 2  stream. The resulting viscous substance was suspended in acetonitrile (50 v) at room temperature and slurried overnight. A solid was collected by filtration and dried under vacuum at 50° C. for about 4 hours to obtain a crystalline form I of benzenesulfonate, which sample, a white solid, was characterized by XRPD, DSC, TGA, DVS and  1 H-NMR, respectively. 
     The crystalline form I of benzenesulfonate is a crystal with a melting point of 165° C. ( FIG. 20 ) (Table 4 and  FIG. 19 ). The sample is slightly hygroscopic, with a weight gain of about 0.41% under 80% relative humidity ( FIG. 22 ). The sample has no significant weight loss at temperatures lower than 180° C. as shown in TGA ( FIG. 20 ); the sample has no residual solvent, and the ratio of free base to benzenesulfonic acid was 1:1 as shown in  1 H-NMR ( FIG. 21 ). The sample is an anhydrous crystal, and the crystalline form of the sample does not change after the DVS test ( FIG. 23 ). 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 List of XRPD diffraction peaks of crystalline form I of 
               
               
                 benzenesulfonate 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
               
               
                   
                 2θ/° 
                 % 
                 2θ/° 
                 % 
                 2θ/° 
                 % 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 7.675 
                 36.4 
                 17.122 
                 14.6 
                 24.769 
                 31.4 
               
               
                   
                 8.411 
                 55.9 
                 17.728 
                 32.9 
                 25.162 
                 21 
               
               
                   
                 10.009 
                 13.3 
                 18.196 
                 13.1 
                 25.846 
                 12.8 
               
               
                   
                 10.494 
                 18.3 
                 18.782 
                 56.9 
                 26.396 
                 23 
               
               
                   
                 10.766 
                 12.8 
                 19.181 
                 14.4 
                 27.523 
                 15.3 
               
               
                   
                 11.143 
                 23.7 
                 20.084 
                 39.8 
                 29.625 
                 28 
               
               
                   
                 13.3 
                 28.4 
                 21.177 
                 55.7 
                 30.277 
                 12.2 
               
               
                   
                 14.595 
                 44.3 
                 21.532 
                 29.5 
                 33.549 
                 10.2 
               
               
                   
                 15.523 
                 33.7 
                 22.191 
                 26.5 
                 34.355 
                 11.4 
               
               
                   
                 15.89 
                 10.1 
                 23.163 
                 100 
                 34.441 
                 11.4 
               
               
                   
                 16.534 
                 56.4 
                 24.082 
                 19.6 
                 39.824 
                 10.9 
               
               
                   
                 16.845 
                 47 
                 24.415 
                 34.7 
               
               
                   
                   
               
            
           
         
       
     
     Example 5. Crystalline Form I of Succinate 
     1 (31.3 mg, 1.0 eq) was dissolved in acetone (26 v), and succinic acid (1.1 eq, 0.6 M in methanol) was added under stirring at room temperature. The reaction solution was still clear after stirring for 2 hours. It was blown dry with N 2  stream. The resulting viscous substance was suspended and slurried in acetonitrile (16 v) at room temperature for 2 hours. A solid was collected by filtration and dried under vacuum at 50° C. overnight to obtain a crystalline form I of succinate, which sample, an off-white solid, was characterized by XRPD, DSC, TGA, DVS and  1 H-NMR, respectively. 
     The crystalline form I of succinate is a crystal with high crystallinity (Table 5 and  FIG. 24 ), and with a melting point of 144° C. ( FIG. 25 ). The sample is slightly hygroscopic, with a weight gain of about 0.57% under 80% relative humidity ( FIG. 27 ).The sample loses about 1.4% in weight between 87 and 157° C. as shown in TGA ( FIG. 25 ), and the sample has about 1% residual solvent, and the ratio of free base to succinic acid is 1:1 as shown in  1 H-NMR ( FIG. 26 ). The sample is an anhydrous crystal, and the crystalline form of the sample does not change after DVS test ( FIG. 28 ). 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 List of XRPD diffraction peaks of crystalline form I of succinate 
               
            
           
           
               
               
               
               
               
               
            
               
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
               
               
                 2θ/° 
                 % 
                 2θ/° 
                 % 
                 2θ/° 
                 % 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 6.946 
                 18.5 
                 17.811 
                 20.6 
                 25.463 
                 13.2 
               
               
                 7.376 
                 100 
                 18.449 
                 27.6 
                 25.892 
                 20.7 
               
               
                 9.175 
                 46.2 
                 18.642 
                 23.2 
                 26.463 
                 17.2 
               
               
                 9.674 
                 34.8 
                 19.051 
                 31.8 
                 27.119 
                 22.5 
               
               
                 10.209 
                 56.1 
                 19.42 
                 47.3 
                 27.829 
                 31.6 
               
               
                 10.672 
                 35 
                 19.595 
                 49.9 
                 28.567 
                 10 
               
               
                 11.594 
                 56.8 
                 20.418 
                 13.2 
                 29.326 
                 17.8 
               
               
                 13.549 
                 33.4 
                 21.142 
                 16.9 
                 29.9 
                 31.1 
               
               
                 13.952 
                 17.4 
                 21.864 
                 13 
                 30.547 
                 44.8 
               
               
                 14.89 
                 31.5 
                 22.144 
                 24.1 
                 31.357 
                 10.7 
               
               
                 15.942 
                 10.2 
                 23.376 
                 93.8 
                 31.958 
                 12.7 
               
               
                 16.57 
                 20.2 
                 24.111 
                 41.3 
                 33.223 
                 12.3 
               
               
                 16.859 
                 30.4 
                 24.402 
                 30.8 
                 35.668 
                 9.7 
               
               
                 17.554 
                 56.8 
                 24.975 
                 23.6 
                 36.201 
                 12.7 
               
               
                   
               
            
           
         
       
     
     Example 6. Crystalline Form II of Succinate 
     1 (30.2 mg, 1.0 eq) was dissolved in ethyl acetate (33 v), and succinic acid (1.1 eq, 0.6 M in methanol) was added under stirring at 35° C. The reaction solution was still clear after stirring for 2 hours. It was blown dry with N 2  stream. The resulting viscous substance was suspended and slurried in 2-butanone (16 v) at room temperature overnight. A solid was collected by filtration and dried under vacuum at 50° C. for about 4 hours to obtain a crystalline form II of succinate, which sample, a white solid, was characterized by XRPD, DSC, TGA and  1 H-NMR, respectively. 
     The crystalline form II of succinate is a crystalline with high crystallinity (Table 6 and  FIG. 29 ), with a melting point of 141° C. ( FIG. 30 ). The sample has a weight loss of about 1.9% between 102 and 157° C. as shown in TGA ( FIG. 30 ); the sample has about 2% residual 2-butanone, and the ratio of free base to succinic acid is 1:1 as shown in  1 H-NMR ( FIG. 31 ). The sample is an anhydrous crystal. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 List of XRPD diffraction peaks of crystalline form II of succinate 
               
            
           
           
               
               
               
               
               
               
            
               
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
               
               
                 2θ/° 
                 % 
                 2θ/° 
                 % 
                 2θ/° 
                 % 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 6.89 
                 21.4 
                 18.644 
                 25.4 
                 26.482 
                 15.5 
               
               
                 7.321 
                 100 
                 18.945 
                 24.9 
                 26.897 
                 16 
               
               
                 8.014 
                 10.2 
                 19.474 
                 68.2 
                 27.402 
                 21.6 
               
               
                 9.022 
                 69 
                 19.702 
                 37.8 
                 28.108 
                 7 
               
               
                 9.652 
                 65.1 
                 20.376 
                 13.9 
                 29.431 
                 14.8 
               
               
                 10.087 
                 70.4 
                 21.106 
                 16.4 
                 29.892 
                 19 
               
               
                 10.51 
                 39.4 
                 21.8 
                 15.7 
                 30.33 
                 17.4 
               
               
                 11.63 
                 86.7 
                 22.293 
                 10.6 
                 30.688 
                 28.3 
               
               
                 13.604 
                 33.5 
                 22.561 
                 12.6 
                 31.826 
                 7.2 
               
               
                 13.881 
                 24.4 
                 23.148 
                 28 
                 33.307 
                 9.9 
               
               
                 14.734 
                 30.7 
                 23.454 
                 87.2 
                 34.561 
                 6 
               
               
                 15.781 
                 11.8 
                 23.786 
                 30.7 
                 35.276 
                 7 
               
               
                 16.446 
                 35 
                 24.171 
                 23.5 
                 36.167 
                 6.7 
               
               
                 16.774 
                 44.3 
                 24.428 
                 32.2 
                 36.427 
                 6.1 
               
               
                 17.534 
                 52.1 
                 24.839 
                 20.8 
                 39.608 
                 5.8 
               
               
                 17.821 
                 19.3 
                 25.349 
                 11.8 
                   
                   
               
               
                 18.131 
                 30.1 
                 25.942 
                 17.4 
               
               
                   
               
            
           
         
       
     
     Example 7. Crystalline Form I of Sulfate 
     1 (29.80 mg, 1.0 eq) was dissolved in ethyl acetate (33 v), and sulfuric acid (1.0 eq, 0.1 M in methanol) was added under stirring at 35° C. A solid precipitated out immediately. After the suspension was cooled to room temperature, and stirred overnight, a solid was collected by filtration and dried in vacuum at 50° C. for about 4 hours to obtain a crystalline form I of sulfate, which sample, a light yellow solid, was characterized by XRPD, DSC, TGA, DVS and  1 H-NMR, respectively. 
     The crystalline form I of sulfate is a crystal with good crystallinity (Table 7 and  FIG. 32 ). There are two overlapping endothermic peaks at 263° C. and 265° C. ( FIG. 33 ), which may be results of crystalline transformations of the sample during the heating process. The sample is hygroscopic and gains about 3.31% in weight under 80% relative humidity ( FIG. 35 ). The sample has a weight loss of 0.2% between room temperature and 90° C. as shown in TGA; the sample had about 0.3% residual ethyl acetate as shown in  1 H-NMR ( FIG. 33  and  FIG. 34 ). The sample may be an anhydrous crystal. The crystalline form of the sample does not change after the DVS test ( FIG. 36 ). 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 List of XRPD diffraction peaks of crystalline form I of sulfate 
               
            
           
           
               
               
               
               
               
               
            
               
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
               
               
                 2θ/° 
                 % 
                 2θ/° 
                 % 
                 2θ/° 
                 % 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 9.039 
                 43.4 
                 20.141 
                 29.4 
                 27.196 
                 40.3 
               
               
                 9.49 
                 14.7 
                 20.411 
                 34.9 
                 28.534 
                 38.8 
               
               
                 10.275 
                 100 
                 20.635 
                 63.3 
                 30.647 
                 8.4 
               
               
                 11.809 
                 17.6 
                 21.261 
                 8.4 
                 31.141 
                 20.7 
               
               
                 14.239 
                 9.5 
                 21.943 
                 7.5 
                 32.097 
                 5.6 
               
               
                 15.432 
                 5.1 
                 22.45 
                 10.3 
                 33.216 
                 5 
               
               
                 18.342 
                 69.1 
                 22.792 
                 16.3 
                   
                   
               
               
                 19.085 
                 12.6 
                 24.479 
                 20.4 
               
               
                   
               
            
           
         
       
     
     Example 8. Crystalline Form I of Monohydrobromide 
     1 (32.0 mg, 1.0 eq) was dissolved in acetone (22 v), hydrobromic acid (1.1 eq) was added under stirring at room temperature. After the reaction solution was stirred for 5 minutes, a solid precipitated out. The suspension was stirred for about 2 hours, and a solid was collected by filtration and dried overnight at 50° C. under vacuum to obtain a crystalline form I of monohydrobromide, which sample, an orange-yellow solid, was characterized by XRPD, DSC, TGA and  1 H-NMR, respectively. 
     The crystalline form I of monohydrobromide is a crystal with relatively poor crystallinity (Table 8 and  FIG. 37 ). There are two overlapping endothermic peaks at 243° C. and 249° C. ( FIG. 38 ), which may be results of crystalline transformations of the sample during the heating process. The sample has a 1.1% weight loss between 107 and 219° C. as shown in TGA, and the sample has about 1.2% residual acetone as shown in  1 H-NMR ( FIG. 38  and  FIG. 39 ). The sample is an anhydrous crystal. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 List of XRPD diffraction peaks of crystalline form I of 
               
               
                 monohydrobromide 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
               
               
                   
                 2θ/° 
                 % 
                 2θ/° 
                 % 
                 2θ/° 
                 % 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 3.67 
                 49.7 
                 17.703 
                 11.8 
                 28.981 
                 12 
               
               
                   
                 6.104 
                 100 
                 19.27 
                 23 
                 29.532 
                 15.8 
               
               
                   
                 10.262 
                 18.7 
                 20.057 
                 21.1 
                 30.584 
                 18.7 
               
               
                   
                 12.251 
                 24.6 
                 21.916 
                 26.2 
                 31.816 
                 17.4 
               
               
                   
                 13.07 
                 20.9 
                 23.634 
                 16.8 
                 31.923 
                 15 
               
               
                   
                 14.58 
                 24.9 
                 24.73 
                 39 
                 37.951 
                 13.6 
               
               
                   
                 15.651 
                 23.3 
                 26.032 
                 28.9 
                 39.358 
                 13.4 
               
               
                   
                 16.739 
                 24.6 
                 26.437 
                 32.6 
               
               
                   
                   
               
            
           
         
       
     
     Example 9. Crystalline Form I of Dihydrobromide 
     1 (31.96 mg, 1.0 eq) was dissolved in acetone (38 v), hydrobromic acid (2.0 eq) was added under stirring at 50° C. The reaction solution was still clear after stirring for 2 hours. The solvent was removed by rotary evaporation and the resulting viscous substance was suspended in acetonitrile (45 v) at room temperature and slurried overnight. A solid was collected by filtration and dried under vacuum at 50° C. for about 4 hours to obtain a crystalline form I of dihydrobromide, which sample, an orange-yellow solid, was characterized by XRPD, DSC, TGA and  1 H-NMR, respectively. 
     The salt form I of dihydrobromide is a crystal with good crystallinity (Table 9 and  FIG. 40 ). There are two overlapping endothermic peaks at 210° C. and 242° C. ( FIG. 41 ), which may be results of crystalline transformations of the sample during the heating process; in addition, there is a broad endothermic peak at 25-40° C., which may be result of the loss of solvent or water, and this part of solvent or water is easily lost. TGA shows three weight losses ( FIG. 41 ). The first weight loss may be result of solvent loss. The sample has about 0.9% residual acetonitrile as shown in  1 H-NMR ( FIG. 42 ); and the last two weight losses may be caused by decomposition. The sample may be an anhydrous crystal. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 List of XRPD diffraction peaks of crystalline form I of 
               
               
                 dihydrobromide 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
                 Angle 
                 Intensity 
               
               
                   
                 2θ/° 
                 % 
                 2θ/° 
                 % 
                 2θ/° 
                 % 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 6.276 
                 79.5 
                 18.953 
                 39.5 
                 28.58 
                 25.5 
               
               
                   
                 7.329 
                 17.4 
                 19.305 
                 57.3 
                 29.384 
                 36.4 
               
               
                   
                 7.771 
                 16.1 
                 19.605 
                 20.3 
                 30.618 
                 23.4 
               
               
                   
                 9.38 
                 14.7 
                 20.387 
                 15.6 
                 31.164 
                 21.4 
               
               
                   
                 9.69 
                 13.3 
                 20.662 
                 19 
                 31.832 
                 29.2 
               
               
                   
                 10.493 
                 14.5 
                 21.148 
                 27.2 
                 32.348 
                 20 
               
               
                   
                 11.591 
                 17.1 
                 21.954 
                 46.8 
                 33.126 
                 17.3 
               
               
                   
                 12.071 
                 25.3 
                 22.87 
                 21.4 
                 33.849 
                 28.4 
               
               
                   
                 12.603 
                 17.6 
                 23.626 
                 37.1 
                 34.543 
                 16.4 
               
               
                   
                 13.122 
                 50.1 
                 24.148 
                 28.4 
                 35.211 
                 16.8 
               
               
                   
                 14.575 
                 28.5 
                 25.341 
                 100 
                 36.629 
                 15.9 
               
               
                   
                 16.777 
                 32.1 
                 25.61 
                 43.6 
                 38.6 
                 26.8 
               
               
                   
                 17.067 
                 19.5 
                 26.424 
                 40.5 
                 39.414 
                 23.6 
               
               
                   
                 18.236 
                 17.9 
                 27.78 
                 29.1