WO2020228807A1 - 一类嘧啶化合物的盐、多晶型物及其药物组合物、制备方法和应用 - Google Patents

一类嘧啶化合物的盐、多晶型物及其药物组合物、制备方法和应用 Download PDF

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WO2020228807A1
WO2020228807A1 PCT/CN2020/090429 CN2020090429W WO2020228807A1 WO 2020228807 A1 WO2020228807 A1 WO 2020228807A1 CN 2020090429 W CN2020090429 W CN 2020090429W WO 2020228807 A1 WO2020228807 A1 WO 2020228807A1
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compound
crystal form
ray powder
angle angle
powder diffraction
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PCT/CN2020/090429
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English (en)
French (fr)
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代星
江岳恒
刘艳琴
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益方生物科技（上海）有限公司
贝达药业股份有限公司
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Priority to US17/611,458 priority Critical patent/US20220213066A1/en
Priority to CN202080028079.2A priority patent/CN113795485A/zh
Publication of WO2020228807A1 publication Critical patent/WO2020228807A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to a salt and polymorph of a pyrimidine compound, and a pharmaceutical composition containing them, a method for preparing various salts and polymorphs, and their use in preparing a pharmaceutical composition.
  • Epidermal growth factor receptor is a receptor tyrosine protein kinase, which belongs to a transmembrane protein in 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 and other cells. 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 targeted therapy methods for tumor cells. EGFR is expressed in 50% of NSCLC (non-small cell lung cancer) cases. This makes EGFR and its family members the main candidates for targeted therapy. Gefitinib and Erlotinib are the first-generation small molecule inhibitors of EGFR, mainly used to treat advanced NSCLC drugs.
  • Afatinib is a potent and irreversible dual inhibitor of EGFR and human epidermal growth factor receptor 2 (HER2) tyrosine kinase.
  • Canertinib (Canertinib), Dacomitinib (Dacomitinib) are also in late-stage clinical trials.
  • Canertinib (Canertinib)
  • Dacomitinib Dacomitinib
  • WT-EGFR wild-type EGFR
  • EGFR inhibitors To overcome the toxicity and side effects of second-generation EGFR inhibitors, it is necessary to reduce the inhibitory effect on wild-type EGFR (WT-EGFR).
  • WT-EGFR wild-type EGFR
  • the new generation of EGFR inhibitors should maintain strong inhibition of EGFR L858R activating mutants, Exon19 deletion activating mutants and T790M resistance mutants, while showing relatively low levels of WT-EGFR and other tyrosine protein kinase receptors The inhibitory effect.
  • Such compounds can be used for the treatment of cancer patients with EGFR L858R activating mutants, Exon19 deletion activating mutants, and for the first generation of EGFR inhibitors such as gefitinib, erlotinib or icotinib.
  • second-generation EGFR mutant inhibitors such as afatinib.
  • 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.
  • the application showed that many EGFR mutants (one or more such as EGFR L858R activating mutants, Exon19 deletion activating mutants and/or T790M resistance mutants) have high inhibitory activity, but have relatively low activity against wild-type EGFR The inhibitory pyrimidine or pyridine compound.
  • CN105085489A The compound described in CN105085489A, as shown in Compound 1 (see Example 104 of CN105085489A), has good biological activity and safe toxicity parameters. Such compounds have good effects in the treatment of cancers with EGFR activating mutants and/or EGFR drug-resistant mutations.
  • CN105085489A describes the synthesis of compound 1 and its mesylate salt.
  • the present inventors have made a new salt form of compound 1 and More in-depth research has been done on its polymorphism.
  • One of the objectives of the present invention is to provide a salt form of pyrimidine compound 1, preferably its p-toluenesulfonate, benzenesulfonate, succinate, hydrochloride, phosphate, sulfate, or hydrobromide
  • a salt form of pyrimidine compound 1 preferably its p-toluenesulfonate, benzenesulfonate, succinate, hydrochloride, phosphate, sulfate, or hydrobromide
  • the salt form and/or crystal form thereof prepared in Examples 1-9.
  • salts include pharmaceutically acceptable salts as well as pharmaceutically unacceptable salts. It is not preferred to use pharmaceutically unacceptable salts for patients, but the 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.
  • mono-salt or di-salt for example, its hydrobromide can be monohydrobromide or dihydrobromide.
  • the molar ratio of the compound to the corresponding acid can be controlled to generate the corresponding mono- or di-salt.
  • the present inventors unexpectedly discovered that the p-toluenesulfonate, benzenesulfonate, succinate, hydrochloride, phosphate, and sulfate of compound 1 can have a molar ratio of slightly less than 1:1 to the corresponding acid, such as 1 :Single salt is generated in high yield under the condition of 1.1 (excess acid), thus simplifying the process scale-up and improving efficiency.
  • salt forms of compound 1, such as hydrochloride, phosphate, p-toluenesulfonate, benzenesulfonate, succinate, sulfate, hydrobromide (including monohydrobromide) Salt or dihydrobromide), both of which increase the water solubility of compound 1 to varying degrees, and some polymorphs of these salt forms (especially p-toluenesulfonate crystal form I, benzenesulfonate crystal form I , Phosphate crystal form I, etc.) have the characteristics of high stability, low moisture absorption, etc., which is beneficial to the production and preparation of compound 1, and is of great significance to its final marketization.
  • the present invention provides a p-toluenesulfonate salt of compound 1, preferably a p-toluenesulfonate salt crystal form I of compound 1.
  • the p-toluenesulfonate crystalline form I of compound 1 refers to a crystalline form having one or more of the following characteristics: 1) Its X-ray powder diffraction pattern at least at 2 ⁇ angles is 7.22, 7.90, 9.30, 10.46, 14.64, 15.36, ⁇ 0.2°, one or more places (1, 2, 3, 4, 5, or 6) have diffraction peaks; 2) The DSC pattern has heat at the initial temperature of 161.54°C ⁇ 5°C Absorption peak.
  • the molar ratio of compound 1 to p-toluenesulfonic acid is about 1:1.
  • the X-ray powder diffraction pattern of the p-toluenesulfonate salt form I of Compound 1 has 6 or more (such as 10, 16, or 20) X-ray diffraction patterns as described in the following table peak:
  • the X-ray powder diffraction pattern of the p-toluenesulfonate salt form I of compound 1 has the main peak in FIG. 14, that is, there is a peak at the corresponding 2 ⁇ angle ⁇ 0.2°, but the intensity can be similar to that in FIG. Shown are different.
  • the main peak of the X-ray powder diffraction pattern refers to a peak in the X-ray powder diffraction pattern with a relative intensity of 20% or more, for example, a relative intensity of 30% or more, 40% or more, 50% or more, 60 % Or more, 80% or more, 90% or more, or 100% of the peak, preferably 30% or more, more preferably 50% or more.
  • the X-ray powder diffraction pattern of the p-toluenesulfonate salt form I of Compound 1 is substantially the same as FIG. 14.
  • the X-ray powder diffraction pattern is basically consistent, which means that the 2 ⁇ angles of the diffraction peaks in the two patterns are basically the same within the experimental error range, but the intensity can be different.
  • the DSC spectrum of the crystal form is also basically consistent with FIG. 15.
  • the basically consistent DSC spectra means that the heat absorption peaks in the two spectra, such as their starting temperature, are basically the same within the experimental error range.
  • the present invention provides a high-purity p-toluenesulfonate salt form I of compound 1.
  • compound 1 is predominantly (e.g., about 80 wt%) in the high-purity substance. , About 90% by weight, about 95% by weight, or more, or XRPD can not detect other forms of compound 1) exists in the form of its p-toluenesulfonate salt form I.
  • the p-toluenesulfonate crystal form I of compound 1 can usually be 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 Crystals precipitate out.
  • the molar ratio of compound 1 and 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 choice of solvent can be one One or more organic solvents, such as acetone.
  • both the salt-forming reaction and crystallization can be carried out under stirring at room temperature.
  • Example 3 describes in detail a typical preparation method of compound 1 p-toluenesulfonate crystalline form I.
  • the p-toluenesulfonate crystalline form I of Compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition.
  • a pharmaceutically acceptable carrier or diluent Preferably, Compound 1 is predominantly (for example, about 80% by weight, about 90% by weight, about 95% by weight, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the pharmaceutical composition in its p-toluenesulfonate crystal form
  • the form of I exists.
  • compound 1 is the only active substance in the pharmaceutical composition.
  • the pharmaceutical composition contains a therapeutically or preventively effective amount of Compound 1, such as for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein.
  • the present invention provides a besylate salt of compound 1, preferably form I of besylate salt of compound 1.
  • the benzenesulfonate crystalline form I of Compound 1 refers to a crystalline form with one or more of the following characteristics: 1) Its X-ray powder diffraction pattern at least at 2 ⁇ angles is 8.41, 16.53, 18.78, 21.18, 23.16 , ⁇ 0.2°, one or more places (1, 2, 3, 4, or 5, preferably 5) have diffraction peaks; 2) The DSC spectrum has heat absorption at the starting temperature of 155.49°C ⁇ 5°C peak.
  • the molar ratio of compound 1 to benzene sulfonic acid is about 1:1.
  • the X-ray powder diffraction pattern of the besylate salt form I of Compound 1 has 6 or more (such as 10, 16, or 20) X-ray diffraction peaks as described in the following table :
  • the X-ray powder diffraction pattern of the besylate salt form I of compound 1 has a 2 ⁇ angle of 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°, diffraction peaks.
  • the X-ray powder diffraction pattern of the besylate salt form I of compound 1 has the main peak in FIG. 19, that is, there is a peak at the corresponding 2 ⁇ angle ⁇ 0.2°, but the intensity can be similar to that in FIG. 19 Shown are different, 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 than, or 100% of the peak, preferably 30% or more, more preferably 50% or more.
  • the X-ray powder diffraction pattern of the besylate salt form I of Compound 1 is substantially the same as that of FIG. 19.
  • the DSC spectrum of the crystal form is also basically consistent with that of FIG. 20.
  • the present invention provides a high-purity besylate form I of compound 1.
  • compound 1 is predominantly (e.g., about 80 wt%, About 90% by weight, about 95% by weight, or more, or other forms of Compound 1 not detectable by XRPD) exist in the form of its benzenesulfonate salt form I.
  • the besylate salt form I of compound 1 can usually be obtained by the following method: compound 1 and p-toluenesulfonic acid are mixed in an appropriate solvent at a molar ratio of about 1:1, and then the besylate salt form of compound 1 I crystallized out.
  • the molar ratio of compound 1 and 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 choice of solvent can be one Or a variety of organic solvents, such as acetone, acetonitrile.
  • both the salt-forming reaction and crystallization can be carried out under stirring at room temperature.
  • the solvent used in the salt-forming reaction and crystallization may be different.
  • Example 4 describes in detail a typical preparation method of compound 1 besylate crystalline form I.
  • the benzene sulfonate crystal form I of compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition.
  • a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition.
  • Compound 1 is predominantly (for example, about 80% by weight, about 90% by weight, about 95% by weight, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the pharmaceutical composition as its benzenesulfonate salt crystal form I
  • compound 1 is the only active substance in the pharmaceutical composition.
  • the pharmaceutical composition contains an effective amount of Compound 1 for treatment or prevention, such as for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein.
  • the present invention provides a succinate salt of compound 1, preferably crystalline form I of compound 1 succinate.
  • the succinate crystalline form I of Compound 1 refers to a crystalline form having one or more of the following characteristics: 1) Its X-ray powder diffraction pattern at least at 2 ⁇ angles is 7.38, 10.21, 11.59, 17.55, 23.38, ⁇ 0.2°, one or more places (1, 2, 3, 4, or 5, preferably 5) have diffraction peaks; 2) The DSC spectrum has a heat absorption peak at the starting temperature of 108.3°C ⁇ 5°C . In compound 1 succinate crystalline form I, the molar ratio of compound 1 to succinic acid is about 1:1.
  • the X-ray powder diffraction pattern of the succinate salt form I of Compound 1 has 6 or more (such as 10, 16, or 20) X-ray diffraction peaks as described in the following table:
  • the X-ray powder diffraction pattern of the succinate salt form I of Compound 1 has a 2 ⁇ angle of 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°, diffraction peaks.
  • the X-ray powder diffraction pattern of the succinate crystalline form I of compound 1 has the main peak in FIG. 24, that is, there is a peak at the corresponding 2 ⁇ angle ⁇ 0.2°, but the intensity can be as shown in FIG. 24. Show different, for example, relative intensity of 20% or more peaks, for example, relative intensity of 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more , Or 100% of the peak, preferably 30% or more, more preferably 50% or more.
  • the X-ray powder diffraction pattern of the succinate salt form I of Compound 1 is substantially the same as that of FIG. 24.
  • the DSC spectrum of the crystal form is also basically the same as that in FIG. 25.
  • the present invention provides a high-purity compound 1 succinate crystalline form I, for example, in some embodiments, compound 1 is predominantly (e.g., about 80 wt%, about 90% by weight, about 95% by weight, or more, or other forms of compound 1 not detectable by XRPD) exist in the form of its succinate crystal form I.
  • compound 1 is predominantly (e.g., about 80 wt%, about 90% by weight, about 95% by weight, or more, or other forms of compound 1 not detectable by XRPD) exist in the form of its succinate crystal form I.
  • the succinate crystal form I 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 succinate crystal form I of compound 1 is crystallized out.
  • the molar ratio of compound 1 and 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 choice of solvent can be one or Various organic solvents, such as acetone and acetonitrile.
  • both the salt-forming reaction and crystallization can be carried out under stirring at room temperature.
  • the solvent used in the salt-forming reaction and crystallization may be different.
  • Example 5 describes in detail a typical preparation method of compound 1 succinate crystalline form I.
  • the succinate crystalline form I of Compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition.
  • a pharmaceutically acceptable carrier or diluent preferably, Compound 1 in the pharmaceutical composition is predominantly (for example, about 80% by weight, about 90% by weight, about 95% by weight, or more, or other forms of Compound 1 that cannot be detected by XRPD) in its succinate crystal form I Form exists.
  • compound 1 is the only active substance in the pharmaceutical composition.
  • the pharmaceutical composition contains a therapeutically or preventively effective amount of Compound 1, such as for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein.
  • the present invention provides a succinate crystalline form II of compound 1.
  • the succinate crystalline form II of compound 1 refers to a crystalline form having one or more of the following characteristics: 1) Its X-ray powder diffraction pattern at least at 2 ⁇ angles is 7.32, 9.02, 9.65, 10.09, 11.63, 17.53, 19.47, 23.45, ⁇ 0.2°, one or more (1, 2, 3, 4, 5, 6, 7, or 8, preferably more than 5, more preferably, 8) have diffraction peaks; 2 ) Its DSC spectrum has a heat absorption peak at the initial temperature of 139.9°C ⁇ 5°C.
  • the molar ratio of compound 1 to succinic acid is about 1:1.
  • the X-ray powder diffraction pattern of the succinate salt form II of Compound 1 has 8 or more (such as 10, 16, or 20) X-ray diffraction peaks as described in the following table:
  • the X-ray powder diffraction pattern of the succinate form II of compound 1 has a 2 ⁇ angle of 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°, diffraction peaks.
  • the X-ray powder diffraction pattern of the succinate crystalline form II of compound 1 has the main peak in Figure 29, that is, there is a peak at the corresponding 2 ⁇ angle ⁇ 0.2°, but the intensity can be as shown in Figure 29. Show different, for example, relative intensity of 20% or more peaks, for example, relative intensity of 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more , Or 100% of the peak, preferably 30% or more, more preferably 50% or more.
  • the X-ray powder diffraction pattern of the succinate salt form II of compound 1 is substantially consistent with that of FIG. 29.
  • the DSC spectrum of the crystal form is also basically consistent with that in FIG. 30.
  • the present invention provides a succinate crystalline form II of compound 1 with high purity.
  • compound 1 is predominantly (eg, about 80% by weight, about 90% by weight, about 95% by weight, or more, or other forms of Compound 1 not detected by XRPD) exist in the form of its succinate crystal form II.
  • the succinate crystal form II 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 succinate crystal form II of compound 1 is crystallized out.
  • the molar ratio of compound 1 and 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 choice of solvent can be one or Various organic solvents, such as ethyl acetate and 2-butanone.
  • both the salt-forming reaction and crystallization can be carried out under stirring at room temperature.
  • the solvent used in the salt-forming reaction and crystallization may be different.
  • Example 6 describes in detail a typical preparation method of compound 1 succinate crystalline form II.
  • the succinate crystal form II of compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition.
  • Compound 1 in the pharmaceutical composition is predominantly (e.g., about 80% by weight, about 90% by weight, about 95% by weight, or more, or other forms of Compound 1 that cannot be detected by XRPD) in its succinate crystal form II Form exists.
  • compound 1 is the only active substance in the pharmaceutical composition.
  • the pharmaceutical composition contains a therapeutically or preventively effective amount of Compound 1, such as for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein.
  • the present invention provides a hydrochloride salt of compound 1, preferably a hydrochloride crystal form III of compound 1.
  • the hydrochloride crystal form III of Compound 1 refers to a crystal form having one or more of the following characteristics: 1) Its X-ray powder diffraction pattern at least at 2 ⁇ angles is 6.39, 7.35, 10.03, 11.48, 15.27, 21.04, 21.87, 23.35, 24.94, ⁇ 0.2°, one or more (1, 2, 3, 4, 5, 6, 7, or 8, preferably more than 5, more preferably, 8) have diffraction peaks 2) The DSC spectrum has a heat absorption peak at the initial temperature of 270.75°C ⁇ 5°C.
  • the molar ratio of compound 1 to hydrochloric acid is about 1:1.
  • the X-ray powder diffraction pattern of the hydrochloride salt form III of Compound 1 has 8 or more (such as 10, 16, or 20) X-ray diffraction peaks as described in the following table:
  • the X-ray powder diffraction pattern of Form III of the hydrochloride salt of Compound 1 has 2 ⁇ angles of 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°, the diffraction peak.
  • the X-ray powder diffraction pattern of the hydrochloride salt form III of Compound 1 has the main peak in Figure 4, that is, there is a peak at the corresponding 2 ⁇ angle ⁇ 0.2°, but the intensity can be as shown in Figure 4. Show different, for example, relative intensity of 20% or more peaks, for example, relative intensity of 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more , Or 100% of the peak, preferably 30% or more, more preferably 50% or more.
  • the X-ray powder diffraction pattern of Form III of the hydrochloride salt of Compound 1 is substantially consistent with FIG. 4.
  • the DSC spectrum of the crystal form is also basically consistent with FIG. 5.
  • the present invention provides a high-purity compound 1 hydrochloride crystalline form III, for example, in some embodiments, compound 1 is predominantly (e.g., about 80 wt%, about 90% by weight, about 95% by weight, or more, or other forms of Compound 1 not detected by XRPD) exist in the form of its hydrochloride salt form III.
  • the hydrochloride crystal form III 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 hydrochloride crystal form III of compound 1 is crystallized out.
  • 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 choice of solvent can be one or more organic solvents, such as acetonitrile and dichloromethane.
  • both the salt-forming reaction and crystallization can be carried out under stirring at room temperature.
  • the solvent used in the salt-forming reaction and crystallization may be different.
  • Example 1 describes in detail a typical preparation method of compound 1 hydrochloride crystal form III.
  • the hydrochloride crystal form III of Compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition.
  • a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition.
  • Compound 1 in the pharmaceutical composition is predominantly (for example, about 80% by weight, about 90% by weight, about 95% by weight, or more, or other forms of Compound 1 that cannot be detected by XRPD) in its hydrochloride crystal form III Form exists.
  • compound 1 is the only active substance in the pharmaceutical composition.
  • the pharmaceutical composition contains a therapeutically or preventively effective amount of Compound 1, such as for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein.
  • the present invention provides a phosphate salt of compound 1, preferably phosphate crystal form I of compound 1.
  • the phosphate crystal form I of compound 1 refers to a crystal form having one or more of the following characteristics: 1) Its X-ray powder diffraction pattern is at least at a position where the 2 ⁇ angle is 8.14, 16.32, ⁇ 0.2° Or 2 places (preferably 2 places) have diffraction peaks; 2) The DSC spectrum has a heat absorption peak at the starting temperature of 234.95°C ⁇ 5°C. In the phosphate crystal form I of compound 1, the molar ratio of compound 1 to hydrochloric acid is about 1:1.
  • the X-ray powder diffraction pattern of the phosphate crystal form I of Compound 1 has 4 or more (such as 6, 10, or 20) X-ray diffraction peaks as described in the following table:
  • the X-ray powder diffraction pattern of the phosphate crystal form I of Compound 1 has diffraction peaks with 2 ⁇ angles of 8.14, 16.32, 17.75 and 20.99, ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the phosphate crystal form I of compound 1 has the main peak in FIG. 9, that is, there is a peak at the corresponding 2 ⁇ angle ⁇ 0.2°, but the intensity can be similar to that shown in FIG. Different, for example, a peak with a relative intensity of 20% or more, for example, a relative intensity of 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more, Or 100% of the peak, preferably 30% or more, more preferably 50% or more.
  • the X-ray powder diffraction pattern of the phosphate crystalline form I of Compound 1 is substantially consistent with FIG. 9.
  • the DSC spectrum of the crystalline form is also basically consistent with FIG. 10.
  • the present invention provides a high-purity phosphate crystal form I of Compound 1.
  • Compound 1 is mainly (e.g., about 80% by weight, about 90% by weight) in the high-purity substance. %, about 95 wt%, or more, or other forms of compound 1 not detected by XRPD) exist in the form of its phosphate crystal form I.
  • the phosphate crystal form I 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 phosphate crystal form I of compound 1 is crystallized out.
  • the molar ratio of compound 1 to phosphoric 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 choice of solvent may be one or more An organic solvent, such as acetone.
  • both the salt-forming reaction and crystallization can be carried out under stirring at room temperature.
  • the solvent used in the salt-forming reaction and crystallization may be different.
  • Example 2 a typical method for preparing the phosphate crystal form I of compound 1 is described in detail.
  • the phosphate crystal form I of Compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition.
  • a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition.
  • Compound 1 is predominantly (for example, about 80% by weight, about 90% by weight, about 95% by weight, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the pharmaceutical composition in the form of its phosphate crystal form I exist.
  • compound 1 is the only active substance in the pharmaceutical composition.
  • the pharmaceutical composition contains a therapeutically or preventively effective amount of Compound 1, such as for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein.
  • the present invention provides a sulfate salt of compound 1, preferably the sulfate salt crystal form I of compound 1.
  • the sulfate crystalline form I of compound 1 refers to a crystalline form having one or more of the following characteristics: 1) Its X-ray powder diffraction pattern is at least at 2 ⁇ angles of 10.28, 18.34, 20.64, ⁇ 0.2°, One or more places (preferably 2 or 3 places) have diffraction peaks; 2) the DSC spectrum has a heat absorption peak at the starting temperature of 255.89°C ⁇ 5°C. In the sulfate crystalline form I of compound 1, the molar ratio of compound 1 to sulfuric acid is about 1:1.
  • the X-ray powder diffraction pattern of the sulfate salt form I of Compound 1 has 4 or more (such as 6, 10, or 20) X-ray diffraction peaks as described in the following table:
  • the X-ray powder diffraction pattern of the sulfate salt form I of Compound 1 has diffraction peaks with 2 ⁇ angles of 9.04, 10.28, 18.34, 20.41, 20.64, 27.20 and 28.53, ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the sulfate salt form I of compound 1 has the main peak in FIG. 32, that is, there is a peak at the corresponding 2 ⁇ angle ⁇ 0.2°, but the intensity can be similar to that shown in FIG. 32.
  • a peak with a relative intensity of 20% or more for example, a relative intensity of 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% or more, Or 100% of the peak, preferably 30% or more, more preferably 50% or more.
  • the X-ray powder diffraction pattern of the sulfate salt form I of Compound 1 is substantially the same as that of FIG. 32.
  • the DSC spectrum of the crystal form is also basically consistent with that of FIG. 33.
  • the present invention provides a high-purity compound 1 sulfate crystalline form I, for example, in some embodiments, compound 1 is mainly (e.g., about 80% by weight, about 90% by weight) in the high-purity substance. %, about 95% by weight, or more, or other forms of compound 1 not detected by XRPD) exist in the form of its sulfate crystal form I.
  • the sulfate crystal form I 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 sulfate crystal form I of compound 1 is crystallized out.
  • 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 choice of solvent can be one or more organic solvents, such as ethyl acetate.
  • both the salt-forming reaction and crystallization can be carried out under stirring at room temperature.
  • the solvent used in the salt-forming reaction and crystallization may be different.
  • Example 7 a typical preparation method of compound 1 sulfate crystal form I is described in detail.
  • the sulfate crystalline form I of Compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition.
  • a pharmaceutically acceptable carrier or diluent Preferably, Compound 1 is predominantly (for example, about 80% by weight, about 90% by weight, about 95% by weight, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the pharmaceutical composition in the form of its sulfate salt crystal form I exist.
  • compound 1 is the only active substance in the pharmaceutical composition.
  • the pharmaceutical composition contains a therapeutically or preventively effective amount of Compound 1, such as for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein.
  • the present invention provides a hydrobromide salt of compound 1, such as the monohydrobromide salt form I of compound 1.
  • the monohydrobromide salt crystal form I of compound 1 refers to a crystal form having one or more of the following characteristics: 1) Its X-ray powder diffraction pattern is at least 6.10, 24.73 ⁇ 0.2° in 2 ⁇ angles, There are diffraction peaks at one or two places; 2) The DSC spectrum has two heat absorption peaks. In the monohydrobromide salt crystal form I of compound 1, the molar ratio of compound 1 to hydrobromic acid is about 1:1.
  • the X-ray powder diffraction pattern of the monohydrobromide salt form I of Compound 1 has 4 or more (such as 6, 10, or 20) X-ray diffraction patterns as described in the following table peak:
  • the X-ray powder diffraction pattern of the monohydrobromide salt form I of Compound 1 has 2 ⁇ angles of 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°, the diffraction peak.
  • the X-ray powder diffraction pattern of the monohydrobromide salt form I of Compound 1 has the main peak in Figure 37, that is, there is a peak at the corresponding 2 ⁇ angle ⁇ 0.2°, but the intensity can be similar to that in Figure 37. Shown in different, for example, relative intensity of 20% or more peaks, for example, relative intensity of 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% Or more, or 100% of the peak, preferably 30% or more, more preferably 50% or more.
  • the X-ray powder diffraction pattern of the monohydrobromide salt form I of Compound 1 is substantially the same as that of Figure 37.
  • the DSC spectrum of the crystalline form is also basically consistent with FIG. 38.
  • the present invention provides a high-purity compound 1 monohydrobromide salt crystal form I, for example, in some embodiments, compound 1 is predominantly (e.g., about 80% by weight) in the high-purity substance , About 90% by weight, about 95% by weight, or more, or other forms of compound 1 not detected by XRPD) exist in the form of its monohydrobromide salt crystal form I.
  • the monohydrobromide salt crystal form I of compound 1 can usually be obtained by the following method: compound 1 and hydrobromic acid are mixed in an appropriate solvent at a molar ratio of about 1:1, and then the monohydrobromide salt crystal of compound 1 Form I crystals precipitate out.
  • 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 choice of solvent can be one or more organic solvents, such as acetone.
  • both the salt-forming reaction and crystallization can be carried out under stirring at room temperature.
  • the solvents used in the salt-forming reaction and crystallization may be different.
  • Example 8 describes in detail a typical method for preparing compound 1 monohydrobromide salt form I.
  • the monohydrobromide salt crystal form I of Compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition.
  • a pharmaceutically acceptable carrier or diluent Preferably, Compound 1 is predominantly (for example, about 80% by weight, about 90% by weight, about 95% by weight, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the pharmaceutical composition in its monohydrobromide crystal form
  • the form of I exists.
  • compound 1 is the only active substance in the pharmaceutical composition.
  • the pharmaceutical composition contains a therapeutically or preventively effective amount of Compound 1, such as for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein.
  • the present invention provides a crystalline form I of the dihydrobromide salt of Compound 1.
  • the dihydrobromide salt crystal form I of compound 1 refers to a crystal form with one or more of the following characteristics: 1) Its X-ray powder diffraction pattern at least at 2 ⁇ angles is 6.28, 13.12, 19.30, 25.34, ⁇ 0.2°, one or more places (such as 1, 2, 3, or 4) have diffraction peaks; 2) The DSC spectrum has two heat absorption peaks, and the starting temperature is 193.38°C ⁇ 5°C and 230.24, respectively °C ⁇ 5°C.
  • the molar ratio of compound 1 to hydrobromic acid is about 1:2.
  • the X-ray powder diffraction pattern of the dihydrobromide salt form I of Compound 1 has 6 or more (such as 8, 12, or 20) X-ray diffraction patterns as described in the following table peak:
  • the X-ray powder diffraction pattern of the dihydrobromide salt form I of compound 1 has 2 ⁇ angles of 6.28, 13.12, 16.78, 18.95, 19.30, 21.95, 23.63, 25.34, 25.61 and 26.42, ⁇ 0.2°, the diffraction peak.
  • the X-ray powder diffraction pattern of the dihydrobromide salt crystal form I of Compound 1 has the main peak in Figure 40, that is, there is a peak at the corresponding 2 ⁇ angle ⁇ 0.2°, but the intensity can be similar to that in Figure 40. Shown in different, for example, relative intensity of 20% or more peaks, for example, relative intensity of 30% or more, 40% or more, 50% or more, 60% or more, 80% or more, 90% Or more, or 100% of the peak, preferably 30% or more, more preferably 50% or more.
  • the X-ray powder diffraction pattern of the dihydrobromide salt form I of Compound 1 is substantially the same as that of FIG. 40.
  • the DSC spectrum of the crystal form is also basically the same as that in FIG. 41.
  • the present invention provides a high-purity dihydrobromide salt form I of compound 1.
  • compound 1 is mainly (e.g., about 80 wt%) in the high-purity substance. , About 90% by weight, about 95% by weight, or more, or XRPD can not detect other forms of compound 1) exist in the form of its dihydrobromide salt crystal form I.
  • the dihydrobromide salt crystal form I 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 dihydrobromide salt crystal of compound 1 Form I crystals precipitate out.
  • the choice of solvent can be one or more organic solvents, such as acetone and acetonitrile.
  • both the salt-forming reaction and crystallization can be carried out under stirring at room temperature.
  • the solvent used in the salt-forming reaction and crystallization may be different.
  • Example 9 describes in detail a typical preparation method of compound 1 dihydrobromide salt form I.
  • the dihydrobromide salt crystalline form I of Compound 1 can usually be combined with a pharmaceutically acceptable carrier or diluent to form a pharmaceutical composition.
  • a pharmaceutically acceptable carrier or diluent Preferably, Compound 1 is predominantly (for example, about 80% by weight, about 90% by weight, about 95% by weight, or more, or other forms of Compound 1 that cannot be detected by XRPD) in the pharmaceutical composition in its dihydrobromide salt crystal form
  • the form of I exists.
  • compound 1 is the only active substance in the pharmaceutical composition.
  • the pharmaceutical composition contains a therapeutically or preventively effective amount of Compound 1, such as for non-small cell lung cancer or other EGFR-mediated disorders or diseases described herein.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any one or more of the salt forms or crystal forms described herein and a pharmaceutically acceptable carrier or diluent.
  • Preservatives, antioxidants, stabilizers, absorption promoters, etc. 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.
  • the main active ingredient components can be mixed with a pharmaceutical carrier, such as starch, lactose, magnesium stearate, etc., and the tablets can be coated with sugar or other suitable substances, or It is processed so that the tablet has a prolonged or slowing effect, and the tablet releases a predetermined amount of active ingredient in a continuous manner.
  • the active ingredient can be mixed with a diluent, and the resulting mixture can be filled into capsules to obtain a capsule.
  • the pharmaceutical composition of the present invention can also be administered orally in other dosage forms such as granules, powders or syrups, or non-orally administered such as injections, powder injections, sprays or suppositories.
  • these preparations can be prepared by conventional methods.
  • the salt, crystal form, and/or pharmaceutical composition of Compound 1 of the present invention can be used to prepare treatment or prevention mediated by activated or resistant mutant form of EGFR, for example, L858R Activating mutant, Exon19 deletion activating mutant and/or T790M resistance mutant EGFR-mediated, disorder or disease drugs.
  • the disorder or disease is cancer.
  • the disorder or disease includes but is not limited to: ovarian cancer, cervical cancer, colorectal cancer (eg, colon adenocarcinoma), breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma Tumor, prostate cancer, leukemia, lymphoma, non-Hodgkin’s lymphoma, gastric cancer, lung cancer (e.g., 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.
  • ovarian cancer ovarian cancer
  • cervical cancer colorectal cancer
  • breast cancer pancreatic cancer
  • glioma e.g., colon adenocarcinoma
  • glioblastoma e.g,
  • the activation mutant or resistance mutant form of EGFR may be, for example, L858R activation mutant, Exon19 deletion activation mutant, and/or T790M resistance mutant. Therefore, a disorder or disease mediated by EGFR in the form of an activation mutant or a resistance mutant may be, for example, a disorder or disease mediated by an activation mutant of L858R, an activation mutant of Exon19 deletion, and/or a resistance mutant of T790M.
  • the salt, crystal form, and/or pharmaceutical composition of Compound 1 of the present invention can be used in the prevention or treatment of diseases mediated by EGFR in the form of activation mutants or resistance mutants, for example, L858R activation mutations Prevention or treatment of diseases, disorders, disorders, or conditions mediated by Exon19 deletion activating mutants and/or T790M resistance mutants, for example, it can be used to treat gefitinib, erlotinib, or ectinib The prevention or treatment of drug-resistant cancer patients.
  • Another aspect of the present invention provides a combined cancer treatment method, which comprises administering a therapeutically effective amount of the salt, crystal form, and/or pharmaceutical composition of Compound 1 of the present invention to an individual in need of treatment, and simultaneously Use conventional surgery or radiation therapy or chemotherapy or immuno-oncology therapy.
  • the chemotherapy or immuno-tumor therapy and the salt, crystal form, and/or pharmaceutical composition of Compound 1 of the present invention may be administered side by side, simultaneously, sequentially, or separately, and may contain but Not limited to one or more of the following types of anti-tumor agents: alkylating agents (e.g.
  • carboplatin oxaliplatin, cisplatin, cyclophosphamide, nitrosoureas, nitrogen mustard, melphalan
  • Antimetabolites e.g. gemcitabine
  • antifolates e.g. 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, hydroxyurea
  • topoisomerase inhibitors e.g. etor Poside, 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, drolo Xifen
  • antiandrogens e.g. bicalutamide, flutamide, nilutamide
  • LHRH antagonists or LHRH agonists e.g.
  • Aromatase inhibitors such as anastrozole, letrozole
  • CYP17 lyase inhibitors such as abiraterone
  • anti-erbB2 antibody trastuzumab [Herceptin] anti-EGFR antibody cetuximab [ Erbitux]
  • tyrosine kinases inhibitors of serine/threonine kinases (for example 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 treatment methods, such as anti PD-1 antibody (pembrolizumab, ni
  • Figure 1 is the XRPD spectrum of compound 1
  • Figure 2 shows the DSC and TGA spectra of compound 1
  • Figure 3 is the NMR spectrum of compound 1
  • Figure 4 is the XRPD pattern of compound 1 hydrochloride crystal form III
  • Figure 5 shows the DSC and TGA spectra of the hydrochloride crystal form III of compound 1;
  • Figure 6 is a 1H NMR spectrum of the hydrochloride crystal form III of compound 1;
  • Figure 7 is the DVS spectrum of the hydrochloride crystal form III of compound 1;
  • Figure 8 shows the XPRD overlay of the hydrochloride crystal form IIIDVS of compound 1 before and after the test
  • Figure 9 is the XRPD pattern of the phosphate crystal form I of compound 1;
  • Figure 10 shows the DSC and TGA spectra of phosphate crystal form I of compound 1;
  • Figure 11 is a 1H NMR spectrum of phosphate crystal form I of compound 1;
  • Figure 12 is the DVS spectrum of the phosphate crystal form I of compound 1;
  • Figure 13 is an XPRD overlay of the phosphate crystal form of compound 1 before and after IDVS test;
  • Figure 14 is the XRPD pattern of the p-toluenesulfonate crystal form I of compound 1;
  • Figure 15 is the DSC and TGA spectra of p-toluenesulfonate crystal form I of compound 1;
  • Figure 16 is a 1H NMR spectrum of p-toluenesulfonate crystal form I of compound 1;
  • Figure 17 is the DVS spectrum of the p-toluenesulfonate crystal form I of compound 1;
  • Figure 18 is an XRPD overlay of the p-toluenesulfonate crystal form of compound 1 before and after IDVS test;
  • Figure 19 is the XRPD pattern of the benzenesulfonate salt form I of compound 1;
  • Figure 20 shows the DSC and TGA spectra of benzenesulfonate form I of compound 1;
  • Figure 21 is a 1H NMR spectrum of the benzenesulfonate salt form I of compound 1;
  • Figure 22 is the DVS spectrum of the benzenesulfonate salt form I of compound 1;
  • Figure 23 is an XPRD overlay of the benzenesulfonate crystal form of compound 1 before and after IDVS test;
  • Figure 24 is the XRPD pattern of succinate crystal form I of compound 1;
  • Figure 25 shows the DSC and TGA spectra of succinate crystal form I of compound 1;
  • Figure 26 is a 1H NMR spectrum of succinate crystal form I of compound 1;
  • Figure 27 is a DVS spectrum of succinate crystal form I of compound 1;
  • Figure 28 is an XPRD overlay of the succinate crystal form of compound 1 before and after IDVS test;
  • Figure 29 is the XRPD pattern of succinate crystal form II of compound 1;
  • Figure 30 shows the DSC and TGA spectra of succinate crystal form II of compound 1;
  • Figure 31 is a 1H NMR spectrum of succinate crystal form II of compound 1;
  • Figure 32 is an XRPD pattern of the sulfate salt crystal form I of compound 1;
  • Figure 33 shows the DSC and TGA spectra of the crystalline form I of compound 1 sulfate
  • Figure 34 is the 1H NMR spectrum of the sulfate crystal form I of compound 1;
  • Fig. 35 is a DVS spectrum of the crystalline form I of compound 1 sulfate
  • Figure 36 is an XPRD overlay of the sulfate crystal form of compound 1 before and after IDVS test;
  • Figure 37 is the XRPD pattern of the monohydrobromide salt crystal form I of compound 1;
  • Figure 38 shows the DSC and TGA spectra of the monohydrobromide salt crystal form I of compound 1;
  • Figure 39 is a 1H NMR spectrum of the monohydrobromide salt crystal form I of compound 1;
  • Figure 40 is the XRPD pattern of the dihydrobromide salt crystal form I of compound 1;
  • Figure 41 shows the DSC and TGA spectra of the dihydrobromide salt crystal form I of compound 1;
  • Figure 42 is a 1H NMR spectrum of the dihydrobromide salt crystal form I of Compound 1.
  • the present inventors unexpectedly discovered that the p-toluenesulfonate, benzenesulfonate, succinate, hydrochloride, phosphate, and sulfate of compound 1 can have a molar ratio of slightly less than 1:1 to the corresponding acid, such as 1 :Single salt is generated in high yield under the condition of 1.1 (excess acid), thus simplifying the process scale-up and improving efficiency.
  • salt forms of compound 1 such as hydrochloride, phosphate, p-toluenesulfonate, benzenesulfonate, succinate, sulfate, hydrobromide (including monohydrobromic acid) Salt or dihydrobromide), both of which increase the water solubility of compound 1 to varying degrees, and some polymorphs of these salt forms (especially p-toluenesulfonate crystal form I, benzenesulfonate crystal form I , Phosphate crystal form I, etc.) have the characteristics of high stability, low moisture absorption, etc., which is beneficial to the production and preparation of compound 1, and is of great significance to its final marketization.
  • the present invention is further illustrated by the following examples.
  • the following examples are only 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.
  • the instrument used for 1 H-NMR analysis is 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 sample's 2 ⁇ scan angle range is 3° to 40°, and the scan step size is 0.02°.
  • the light tube voltage and light tube current when measuring the sample were 40KV and 40mA, respectively.
  • thermogravimetric analysis is Discovery TGA 55 (TA Instruments, US).
  • the sample is placed in a balanced open aluminum sample pan, and the sample amount is automatically weighed in the TGA heating furnace.
  • the sample is heated to the final temperature at a rate of 10°C/min.
  • the instrument model of Differential Scanning Calorimetry is TA Instruments Q200 or Discovery DSC 250. After the sample is accurately weighed, it is placed in a sample pan with a DSC cap and perforated, and the accurate mass of the sample is recorded. The sample is heated to the final temperature at a heating rate of 10°C/min.
  • the instrument model of dynamic moisture adsorption and desorption analysis is DVS Intrinsic (SMS, UK). Place the sample in the sample basket of the instrument for automatic weighing, then heat to 40°C, and dry it under nitrogen flow until dm/dt is less than 0.002%. After the temperature is lowered to 25°C, start measurement.
  • the instrument parameters are as follows.
  • Adsorption 0, 10, 20, 30, 40, 50, 60, 70, 80, 90
  • the initial drug substance 1 is a crystal with good crystallinity (Figure 1), and DSC shows its melting point is 146°C ( Figure 2).
  • 1 H-NMR and TGA showed that the sample had no solvent residue and almost no weight loss before 200°C ( Figure 3). The results showed that the sample was crystal-free, named crystal form I.
  • the hydrochloride crystal form III is a crystal with a high melting point (273°C, Figure 5) (Table 1 and Figure 4).
  • the sample is slightly hygroscopic, with a weight gain of about 1.86% under 80% relative humidity (Figure 7).
  • 1 H-NMR and TGA results show that the sample has no residual solvent and no significant weight loss before 200°C ( Figure 5 and Figure 6), indicating that the sample is crystal-free.
  • the crystal form of the sample remained unchanged after the DVS test ( Figure 8).
  • angle strength angle strength angle strength angle strength 2 ⁇ /° % 2 ⁇ /° % 2 ⁇ /° % 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
  • Dissolve 1 (30.20mg, 1.0eq) in acetone (26v), add phosphoric acid (1.1eq) under stirring conditions at room temperature, and immediately precipitate a viscous substance. After stirring for 2 hours, a solid precipitated. After the suspension was stirred at room temperature for 3 hours, the solid was collected by filtration and dried overnight at 50°C under vacuum to obtain phosphate crystal form I. The sample was an off-white solid, and XRPD, DSC, TGA, DVS and 1 H-NMR were performed respectively. Characterization.
  • Phosphate crystal form I is a crystal with high crystallinity (Table 2 and Figure 9) and high melting point (238°C, Figure 10).
  • the sample is slightly hygroscopic, with a weight gain of about 0.61% under 80% relative humidity (Figure 12).
  • 1 H-NMR and TGA results show that the sample has 0.7% residual solvent, but there is no significant weight loss before 150°C ( Figure 10 and Figure 11), indicating that the sample is crystal-free.
  • the crystal form of the sample remained unchanged after the DVS test ( Figure 13).
  • the p-toluenesulfonate salt form I is a crystal with a melting point of 172°C (Table 3 and Figure 14).
  • the sample is slightly hygroscopic, with a weight gain of about 0.55% under 80% relative humidity (Figure 17).
  • TGA showed that the sample had no significant weight loss before 200°C ( Figure 15);
  • 1 H-NMR showed that the sample had about 0.3% residual solvent, and the ratio of free base to p-toluenesulfonic acid was 1:1 ( Figure 16).
  • the sample may be crystal-free.
  • the crystal form of the sample remained unchanged after the DVS test ( Figure 18).
  • the besylate salt form I is a crystal with a melting point of 165°C (Table 4 and Figure 19).
  • the sample is slightly hygroscopic, with a weight gain of about 0.41% under 80% relative humidity (Figure 22).
  • TGA showed that the sample had no significant weight loss before 180°C ( Figure 20);
  • 1 H-NMR showed that the sample had no residual solvent, and the ratio of free base to benzenesulfonic acid was 1:1 (Figure 21).
  • the sample is crystal-free, and the crystal form of the sample remains unchanged after the DVS test ( Figure 23).
  • the succinate crystal form I is a crystal with high crystallinity (Table 5 and Figure 24), and its melting point is 144°C (Figure 25).
  • the sample is slightly hygroscopic, with a weight gain of about 0.57% under 80% relative humidity (Figure 27).
  • TGA showed that the sample lost about 1.4% in weight between 87-157°C ( Figure 25), and 1 H-NMR showed that the sample had about 1% residual solvent and the ratio of free base to succinic acid was 1:1 (Figure 26).
  • the sample is crystal-free, and the crystal form of the sample remains unchanged after the DVS test ( Figure 28).
  • the succinate crystal form II is a crystal with high crystallinity (Table 6 and Figure 29), and its melting point is 141°C (Figure 30).
  • TGA showed that the sample had a weight loss of about 1.9% between 102-157°C ( Figure 30);
  • 1 H-NMR showed that the sample had about 2% 2-butanone remaining, and the ratio of free base to succinic acid was 1:1 ( Figure 30) 31).
  • the sample is crystal-free.
  • Sulfate crystal form I is a crystal with good crystallinity (Table 7 and Figure 32). There are two overlapping endothermic peaks at 263°C and 265°C ( Figure 33), which may be caused by the crystallization of the sample during heating. Type change. The sample is hygroscopic and gains about 3.31% in weight under 80% relative humidity ( Figure 35). TGA showed that the sample had a weight loss of 0.2% between room temperature and 90°C; 1 H-NMR showed that the sample had about 0.3% ethyl acetate remaining ( Figure 33 and Figure 34). The sample may be crystal-free. The crystal form of the sample remained unchanged after the DVS test ( Figure 36).
  • Monohydrobromide crystal form I is a relatively poor crystal (Table 8 and Figure 37). There are two overlapping endothermic peaks at 243°C and 249°C ( Figure 38), which may be caused by the heating of the sample. It is caused by the crystalline transformation in the process. TGA shows that the sample has a 1.1% weight loss between 107-219°C, and the corresponding 1 H-NMR shows that the sample has about 1.2% residual acetone ( Figure 38 and Figure 39). The sample is crystal-free.
  • the dihydrobromide salt crystal form I is a crystal with good crystallinity (Table 9 and Figure 40).
  • TGA shows that the sample has three stages of weight loss (Figure 41). The first stage of weight loss may be caused by loss of solvent.
  • the corresponding 1 H-NMR shows that the sample has about 0.9% residual acetonitrile ( Figure 42); while the latter two stages of weight loss may be caused by decomposition .
  • the sample may be crystal-free.

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Abstract

本发明涉及化合物1的盐，及其多晶型物、以及包含它们的药物组合物，其中，所述盐优选为盐酸盐、磷酸盐、对甲苯磺酸盐、苯磺酸盐、琥珀酸盐、硫酸盐、单氢溴酸盐、二氢溴酸盐等。本发明还涉及制备上述物质的方法，它们的用途、以及包含这些盐和晶型的药物制剂。

Description

一类嘧啶化合物的盐、多晶型物及其药物组合物、制备方法和应用 技术领域
本发明涉及一种嘧啶化合物的盐及多晶型物，以及包含它们的药物组合物，用于制备各种盐及多晶型的方法及其在制备药物组合物中的用途。
发明背景
表皮生长因子受体(EGFR)是一种受体酪氨酸蛋白激酶，属于erbB受体家族中的一种跨膜蛋白。
EGFR调控了细胞的增殖，存活，粘连，迁移与分化，它在多种肿瘤细胞中过度活化或持续活化，比如肺癌，乳腺癌，前列腺癌等细胞中。EGFR的异常活化在肿瘤的转化与增长中起着关键性的作用。阻断EGFR的活化已被临床证明为有效的靶向治疗肿瘤细胞方法之一。EGFR在50％的NSCLC(非小型性细胞肺癌)病例中有表达。这使得EGFR及其家族成员成为靶向治疗的主要候选者。吉非替尼(Gefitinib)和厄洛替尼(Erlotinib)是EGFR的第一代小分子抑制剂，主要用于治疗晚期NSCLC的药物。临床结果显示吉非替尼或厄洛替尼对大约10％的白人NSCLC和大约35％的亚裔NSCLC患者有疗效。分析表明多数具有EGFR活化突变的NSCLC患者对EGFR-酪氨酸激酶抑制剂(TKI)的反应率显著高于EGFR野生型的NSCLC患者。
但是临床研究表明许多患者很快(12-14个月)就对这些EGFR的小分子抑制剂药物产生了抗药性，即获得性耐药性。看门残基(gatekeeper residue)T790M突变是EGFR20外显子中的一个突变点，是造成耐药的主要机制之一。针对这些EGFR突变的新一代抑制剂研究在进来获得了很大的成功。阿法替尼(Afatinib)是EGFR和人表皮生长因子受体2(HER2)酪氨酸激酶的强效、不可逆的双重抑制剂。其它类似的多靶点，高活性，不可逆的抑制剂，例如，卡奈替尼(Canertinib)，达克替尼(Dacomitinib)也正在后期临床试验中。这些新型的第二代不可逆的抑制剂对L858R及T790M突变的EGFR具有很强的抑制作用，对吉非替尼或厄洛替尼已经产生抗药性的癌症病人有着显著的疗效。可是这些第二代EGFR突变体抑制剂对野生型 EGFR(WT-EGFR)也同样具有极强的抑制性。临床研究已经证明对野生型EGFR的抑制在大部分患者身上会导致药物毒性和副作用，譬如在人体中表现为皮疹或腹泻。
要克服第二代EGFR抑制剂的毒性和副作用，就必须减少对野生型EGFR(WT-EGFR)的抑制作用。新一代的EGFR抑制剂应该保持对EGFR L858R激活突变体、Exon19缺失激活突变体和T790M抗性突变体有较强的抑制，同时对WT-EGFR及其它酪氨酸蛋白激酶受体显示相对较低的抑制作用。此类化合物可以用于治疗有EGFR L858R激活突变体、Exon19缺失激活突变体的癌症病人的治疗，以及对第一代EGFR抑制剂如吉非替尼、厄洛替尼或埃克替尼已经产生抗药性EGFR-T790M抗性突变体的癌症病人的治疗，而不用担心第二代EGFR突变体抑制剂如阿法替尼所带来的副作用。
中国专利申请CN105085489A涉及一类嘧啶或吡啶化合物，及其药学上可接受的盐、立体异构体、前药和溶剂合物，其制备方法、药物组合物以及医药用途。该申请显示了许多对EGFR突变体(一种或多种如EGFR L858R激活突变体、Exon19缺失激活突变体和/或T790M抗性突变体)具有高抑制活性，但对野生型EGFR只有相对较低的抑制性的嘧啶或吡啶化合物。
CN105085489A所述化合物，如下所示化合物1(参见CN105085489A实施例104)，具有较好的生物活性和安全毒性参数。此类化合物在有EGFR激活突变体和/或EGFR的抗药性突变的癌症治疗中会有较好的效果。CN105085489A描述了化合物1及其甲磺酸盐的合成。为了进一步提高化合物1的物理化学性质，如稳定性，吸湿性，溶解度，等等能有利于其生产，制备，合成，和/或药品应用的性质，本发明人对化合物1的新盐型及其多晶型做了更深入的研究。
Figure PCTCN2020090429-appb-000001
发明内容
本发明的目的之一是提供一种嘧啶化合物1的盐型，优选为其对甲苯磺酸盐、苯磺酸盐、琥珀酸盐、盐酸盐、磷酸盐、硫酸盐、或氢溴酸盐，例如，实施例1-9所制备的盐型和/或其晶型。
本文所述化合物1是指结构如下的化合物：
Figure PCTCN2020090429-appb-000002
本文中所述“盐”，包括药学上可接受的盐，以及药学不可接受的盐。不优选对患者使用药学不可接受的盐，但所述的盐可用于提供药物中间体和散装药物形式。
化合物1可以与一或二当量的酸形成盐(简称单盐或二盐)，例如其氢溴酸盐可以为单氢溴酸盐或二氢溴酸盐。通常情况下，在制备化合物1的盐型时，其与相应酸的摩尔比可以控制以生成相应的单盐或二盐。然而，在实际操作中，完全控制在1：1或1：2的当量比较困难，而且在大量制备时，有可能局部会有过量的酸或化合物1的存在，而可能行成单盐和二盐的混和物。因为单盐和二盐的理化性能不一，这种混合物的形成会导致最终产品的性能不一。因此，能相对容易控制某一种盐型的形成对制备和生产会带来极大的方便，也更容易得到质量一致的最终产品。本发明人意外发现，化合物1的对甲苯磺酸盐、苯磺酸盐、琥珀酸盐、盐酸盐、磷酸盐、硫酸盐、可以在与相应酸的摩尔比略小于1：1，如1：1.1(酸过量)的条件下高产率生成单盐，因此简化其工艺放大并提高了效率。
另如本文所详述，化合物1的一些盐型如，盐酸盐、磷酸盐、对甲苯磺酸盐、苯磺酸盐、琥珀酸盐、硫酸盐、氢溴酸盐(包括单氢溴酸盐或二氢溴酸盐)，均在不同程度上提高了化合物1的水溶解度，而且这些盐型的一些多晶型(尤其是对甲苯磺酸盐晶型I、苯磺酸盐晶型I、 磷酸盐晶型I等)具备高稳定性，低吸湿度等特征，有利于化合物1的生产和制备，对其最终市场化有重要意义。
在有些实施方案中，本发明提供一种化合物1的对甲苯磺酸盐，优选为化合物1的对甲苯磺酸盐晶型I。在本文中，化合物1的对甲苯磺酸盐晶型I是指具有以下一个或多个特征的晶型：1)其X-射线粉末衍射图谱至少在2θ角度为7.22，7.90，9.30，10.46，14.64，15.36，±0.2°，的一处或多处(1，2，3，4，5，或6)有衍射峰；2)其DSC图谱在起始温度为161.54℃±5℃处有热吸收峰。在化合物1的对甲苯磺酸盐晶型I中，化合物1与对甲苯磺酸的摩尔比为大约1：1。在有些实施方案中，化合物1的对甲苯磺酸盐晶型I的X-射线粉末衍射图谱具有6个或以上(如10个，16个，或20个)如下表所述的X-射线衍射峰：
角度 角度 角度 角度 角度 角度
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  
在有些实施方案中，化合物1的对甲苯磺酸盐晶型I的X射线粉末衍射图谱具有图14中的主要峰，即在相应2θ角度±0.2°处有峰，但强度可以与图14中所示不一样。X射线粉末衍射图谱主要峰在本文中是指一个X射线粉末衍射图谱中相对强度在20％或以上的峰，例如，相对强度在30％或以上，40％或以上，50％或以上，60％或以上，80％或以上，90％或以上，或100％的峰，优选为30％或以上，更优选为50％或以上。
在有些实施方案中，化合物1的对甲苯磺酸盐晶型I的X射线粉末衍射图谱与图14基本一致。X射线粉末衍射图谱基本一致是指两个图谱中的衍射峰的2θ角度在实验误差范围内基本一致，但强度可以不一样。优选地，所述晶型的DSC图谱还与图15基本一致。DSC图谱基本一致是指两个图谱中的热吸收峰，例如其起始温度，在实验误差范围内基本一致。
在有些实施方案中，本发明提供了一种高纯度的化合物1的对甲苯磺酸盐晶型I，例如，在有些实施方案中，化合物1在该高纯度物质中主要(例如，大约80wt％，大约90wt％，大约95wt％，或以上,或XRPD检测不到化合物1的其它形式)以其对甲苯磺酸盐晶型I的形式存在。
化合物1的对甲苯磺酸盐晶型I通常可以以以下方法得到：将化合物1和对甲苯磺酸按大约1：1的摩尔比在适当溶剂中混合，然后将化合物1的对甲苯磺酸盐结晶析出。在有些实施方案中，化合物1和对甲苯磺酸的摩尔比可以略小于1：1(酸过量)，比如，大约1：1.1；大约1：1.15；大约1：1.2.溶剂的选择可以为一种或多种有机溶剂，比如，丙酮。在有些实施方案中，成盐反应和结晶均可在室温搅拌下进行。实施例3详细描写了一个典型的制备化合物1的对甲苯磺酸盐晶型I方法。
化合物1的对甲苯磺酸盐晶型I通常可以和药学上可接受的载体或稀释剂一起组成一种药物组合物。优选地，化合物1在该药物组合物中主要(例如，大约80wt％，大约90wt％，大约95wt％，或以上,或XRPD检测不到化合物1的其它形式)以其对甲苯磺酸盐晶型I的形式存在。有时，化合物1为该药物组合物中的唯一活性物质。有时，该药物组合物中含有治疗或预防有效量的化合物1，如对非小细胞肺癌或本文所述其它EGFR介导的障碍或疾病。
在有些实施方案中，本发明提供一种化合物1的苯磺酸盐，优选为化合物1的苯磺酸盐晶型I。在本文中，化合物1的苯磺酸盐晶型I是指具有以下一个或多个特征的晶型：1)其X-射线粉末衍射图谱至少在2θ角度为8.41，16.53，18.78，21.18，23.16，±0.2°，的一处或多处(1，2，3，4，或5，优选5处)有衍射峰；2)其DSC图谱在起始温度为155.49℃±5℃处有热吸收峰。在化合物1的苯磺酸盐晶型I中，化合物1与苯磺酸的摩尔比为大约1：1。在有些实施方案中，化合物1的苯磺酸盐晶型I的X-射线粉末衍射图谱具有6个或以上(如10个，16个，或20个)如下表所述的X-射线衍射峰：
角度 角度 角度 角度 角度 角度
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  
在有些优选实施方案中，化合物1的苯磺酸盐晶型I的X-射线粉末衍射图谱具有2θ角度为7.68，8.41，14.60，15.52，16.53，16.85，17.73，18.78，20.08，21.18，23.16，24.42，和24.76，±0.2°，的衍射峰。
在有些实施方案中，化合物1的苯磺酸盐晶型I的X-射线粉末衍射图谱具有图19中的主要峰，即在相应2θ角度±0.2°处有峰，但强度可以与图19中所示不一样,例如，相对强度在20％或以上的峰，例如，相对强度在30％或以上，40％或以上，50％或以上，60％或以上，80％或以上，90％或以上，或100％的峰，优选为30％或以上，更优选为50％或以上。
在有些实施方案中，化合物1的苯磺酸盐晶型I的X射线粉末衍射图谱与图19基本一致。优选地，所述晶型的DSC图谱还与图20基本一致。
在有些实施方案中，本发明提供了一种高纯度的化合物1的苯磺酸盐晶型I，例如，在有些实施方案中，化合物1在该高纯度物质中主要(例如，大约80wt％，大约90wt％，大约95wt％，或以上,或XRPD检测不到化合物1的其它形式)以其苯磺酸盐晶型I的形式存在。
化合物1的苯磺酸盐晶型I通常可以以以下方法得到：将化合物1和对苯磺酸按大约1：1的摩尔比在适当溶剂中混合，然后将化合物1的苯磺酸盐晶型I结晶析出。在有些实施方案中，化合物1和苯磺酸的摩尔比可以略小于1：1(酸过量)，比如，大约1：1.1；大约1：1.15；大约1：1.2.溶剂的选择可以为一种或多种有机溶剂，比如，丙酮、乙腈。在有些实施方案中，成盐反应和结晶均可在室温搅拌下进行。在有些实施方案中，成盐反应和结晶所用溶剂可以不一样。实施例4详细描写了一个典型的制备化合物1的苯磺酸盐晶型I方法。
化合物1的苯磺酸盐晶型I通常可以和药学上可接受的载体或稀释剂一起组成一种药物组合物。优选地，化合物1在该药物组合物中主要(例如，大约80wt％，大约90wt％，大约 95wt％，或以上,或XRPD检测不到化合物1的其它形式)以其苯磺酸盐晶型I的形式存在。有时，化合物1为该药物组合物中的唯一活性物质。有时，该药物组合物中含有治疗或预防有效量的化合物1，如对非小细胞肺癌或本文所述其它EGFR介导的障碍或疾病。
在有些实施方案中，本发明提供一种化合物1的琥珀酸盐，优选为化合物1的琥珀酸盐晶型I。在本文中，化合物1的琥珀酸盐晶型I是指具有以下一个或多个特征的晶型：1)其X-射线粉末衍射图谱至少在2θ角度为7.38，10.21，11.59，17.55，23.38，±0.2°，的一处或多处(1，2，3，4，或5，优选5处)有衍射峰；2)其DSC图谱在起始温度为108.3℃±5℃处有热吸收峰。在化合物1的琥珀酸盐晶型I中，化合物1与琥珀酸的摩尔比为大约1：1。在有些实施方案中，化合物1的琥珀酸盐晶型I的X-射线粉末衍射图谱具有6个或以上(如10个，16个，或20个)如下表所述的X-射线衍射峰：
角度 角度 角度 角度 角度 角度
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
在有些优选实施方案中，化合物1的琥珀酸盐晶型I的X-射线粉末衍射图谱具有2θ角度为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，和30.55，±0.2°，的衍射峰。
在有些实施方案中，化合物1的琥珀酸盐晶型I的X-射线粉末衍射图谱具有图24中的主要峰，即在相应2θ角度±0.2°处有峰，但强度可以与图24中所示不一样,例如，相对强度 在20％或以上的峰，例如，相对强度在30％或以上，40％或以上，50％或以上，60％或以上，80％或以上，90％或以上，或100％的峰，优选为30％或以上，更优选为50％或以上。
在有些实施方案中，化合物1的琥珀酸盐晶型I的X射线粉末衍射图谱与图24基本一致。优选地，所述晶型的DSC图谱还与图25基本一致。
在有些实施方案中，本发明提供了一种高纯度的化合物1的琥珀酸盐晶型I，例如，在有些实施方案中，化合物1在该高纯度物质中主要(例如，大约80wt％，大约90wt％，大约95wt％，或以上,或XRPD检测不到化合物1的其它形式)以其琥珀酸盐晶型I的形式存在。
化合物1的琥珀酸盐晶型I通常可以以以下方法得到：将化合物1和琥珀酸按大约1：1的摩尔比在适当溶剂中混合，然后将化合物1的琥珀酸盐晶型I结晶析出。在有些实施方案中，化合物1和琥珀酸的摩尔比可以略小于1：1(酸过量)，比如，大约1：1.1；大约1：1.15；大约1：1.2.溶剂的选择可以为一种或多种有机溶剂，比如，丙酮、乙腈。在有些实施方案中，成盐反应和结晶均可在室温搅拌下进行。在有些实施方案中，成盐反应和结晶所用溶剂可以不一样。实施例5详细描写了一个典型的制备化合物1的琥珀酸盐晶型I方法。
化合物1的琥珀酸盐晶型I通常可以和药学上可接受的载体或稀释剂一起组成一种药物组合物。优选地，化合物1在该药物组合物中主要(例如，大约80wt％，大约90wt％，大约95wt％，或以上,或XRPD检测不到化合物1的其它形式)以其琥珀酸盐晶型I的形式存在。有时，化合物1为该药物组合物中的唯一活性物质。有时，该药物组合物中含有治疗或预防有效量的化合物1，如对非小细胞肺癌或本文所述其它EGFR介导的障碍或疾病。
在有些实施方案中，本发明提供一种化合物1的琥珀酸盐晶型II。在本文中，化合物1的琥珀酸盐晶型II是指具有以下一个或多个特征的晶型：1)其X-射线粉末衍射图谱至少在2θ角度为7.32，9.02，9.65，10.09，11.63，17.53，19.47，23.45，±0.2°，的一处或多处(1，2，3，4，5，6，7，或8，优选5处以上，更优选，8处)有衍射峰；2)其DSC图谱在起始温度为139.9℃±5℃处有热吸收峰。在化合物1的琥珀酸盐晶型II中，化合物1与琥珀酸的摩尔比为大约1：1。在有些实施方案中，化合物1的琥珀酸盐晶型II的X-射线粉末衍射图谱具有8个或以上(如10个，16个，或20个)如下表所述的X-射线衍射峰：
角度 角度 角度 角度 角度 角度
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          
在有些优选实施方案中，化合物1的琥珀酸盐晶型II的X-射线粉末衍射图谱具有2θ角度为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，和24.43，±0.2°，的衍射峰。
在有些实施方案中，化合物1的琥珀酸盐晶型II的X-射线粉末衍射图谱具有图29中的主要峰，即在相应2θ角度±0.2°处有峰，但强度可以与图29中所示不一样,例如，相对强度在20％或以上的峰，例如，相对强度在30％或以上，40％或以上，50％或以上，60％或以上，80％或以上，90％或以上，或100％的峰，优选为30％或以上，更优选为50％或以上。
在有些实施方案中，化合物1的琥珀酸盐晶型II的X射线粉末衍射图谱与图29基本一致。优选地，所述晶型的DSC图谱还与图30基本一致。
在有些实施方案中，本发明提供了一种高纯度的化合物1的琥珀酸盐晶型II，例如，在有些实施方案中，化合物1在该高纯度物质中主要(例如，大约80wt％，大约90wt％，大约95wt％，或以上,或XRPD检测不到化合物1的其它形式)以其琥珀酸盐晶型II的形式存在。
化合物1的琥珀酸盐晶型II通常可以以以下方法得到：将化合物1和琥珀酸按大约1：1的摩尔比在适当溶剂中混合，然后将化合物1的琥珀酸盐晶型II结晶析出。在有些实施方案中，化合物1和琥珀酸的摩尔比可以略小于1：1(酸过量)，比如，大约1：1.1；大约1：1.15；大约1：1.2.溶剂的选择可以为一种或多种有机溶剂，比如，乙酸乙酯、2-丁酮。在有些实施方案中，成盐反应和结晶均可在室温搅拌下进行。在有些实施方案中，成盐反应和结晶所用溶剂可以不一样。实施例6详细描写了一个典型的制备化合物1的琥珀酸盐晶型II方法。
化合物1的琥珀酸盐晶型II通常可以和药学上可接受的载体或稀释剂一起组成一种药物组合物。优选地，化合物1在该药物组合物中主要(例如，大约80wt％，大约90wt％，大约95wt％，或以上,或XRPD检测不到化合物1的其它形式)以其琥珀酸盐晶型II的形式存在。有时，化合物1为该药物组合物中的唯一活性物质。有时，该药物组合物中含有治疗或预防有效量的化合物1，如对非小细胞肺癌或本文所述其它EGFR介导的障碍或疾病。
在有些实施方案中，本发明提供一种化合物1的盐酸盐,优选为化合物1的盐酸盐晶型III。在本文中，化合物1的盐酸盐晶型III是指具有以下一个或多个特征的晶型：1)其X-射线粉末衍射图谱至少在2θ角度为6.39，7.35，10.03，11.48，15.27，21.04，21.87，23.35，24.94，±0.2°，的一处或多处(1，2，3，4，5，6，7，或8，优选5处以上，更优选，8处)有衍射峰；2)其DSC图谱在起始温度为270.75℃±5℃处有热吸收峰。在化合物1的盐酸盐晶型III中，化合物1与盐酸的摩尔比为大约1：1。在有些实施方案中，化合物1的盐酸盐晶型III的X-射线粉末衍射图谱具有8个或以上(如10个，16个，或20个)如下表所述的X-射线衍射峰：
角度 角度 角度 角度 角度 角度
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      
在有些优选实施方案中，化合物1的盐酸盐晶型III的X-射线粉末衍射图谱具有2θ角度为6.39，7.35，7.87，10.03，11.48，15.27，21.04，21.87，22.13，22.74，23.35，24.94和26.79，±0.2°，的衍射峰。
在有些实施方案中，化合物1的盐酸盐晶型III的X-射线粉末衍射图谱具有图4中的主要峰，即在相应2θ角度±0.2°处有峰，但强度可以与图4中所示不一样,例如，相对强度在20％或以上的峰，例如，相对强度在30％或以上，40％或以上，50％或以上，60％或以上，80％或以上，90％或以上，或100％的峰，优选为30％或以上，更优选为50％或以上。
在有些实施方案中，化合物1的盐酸盐晶型III的X射线粉末衍射图谱与图4基本一致。优选地，所述晶型的DSC图谱还与图5基本一致。
在有些实施方案中，本发明提供了一种高纯度的化合物1的盐酸盐晶型III，例如，在有些实施方案中，化合物1在该高纯度物质中主要(例如，大约80wt％，大约90wt％，大约95wt％，或以上,或XRPD检测不到化合物1的其它形式)以其盐酸盐晶型III的形式存在。
化合物1的盐酸盐晶型III通常可以以以下方法得到：将化合物1和盐酸按大约1：1的摩尔比在适当溶剂中混合，然后将化合物1的盐酸盐晶型III结晶析出。在有些实施方案中，化合物1和盐酸的摩尔比可以略小于1：1(酸过量)，比如，大约1：1.1；大约1：1.15；大约1：1.2。溶剂的选择可以为一种或多种有机溶剂，比如，乙腈和二氯甲烷。在有些实施方案中，成盐反应和结晶均可在室温搅拌下进行。在有些实施方案中，成盐反应和结晶所用溶剂可以不一样。实施例1详细描写了一个典型的制备化合物1的盐酸盐晶型III方法。
化合物1的盐酸盐晶型III通常可以和药学上可接受的载体或稀释剂一起组成一种药物组合物。优选地，化合物1在该药物组合物中主要(例如，大约80wt％，大约90wt％，大约95wt％，或以上,或XRPD检测不到化合物1的其它形式)以其盐酸盐晶型III的形式存在。 有时，化合物1为该药物组合物中的唯一活性物质。有时，该药物组合物中含有治疗或预防有效量的化合物1，如对非小细胞肺癌或本文所述其它EGFR介导的障碍或疾病。
在有些实施方案中，本发明提供一种化合物1的磷酸盐,优选为化合物1的磷酸盐晶型I。在本文中，化合物1的磷酸盐晶型I是指具有以下一个或多个特征的晶型：1)其X-射线粉末衍射图谱至少在2θ角度为8.14，16.32，±0.2°，的一处或2处(优选2处)有衍射峰；2)其DSC图谱在起始温度为234.95℃±5℃处有热吸收峰。在化合物1的磷酸盐晶型I中，化合物1与盐酸的摩尔比为大约1：1。在有些实施方案中，化合物1的磷酸盐晶型I的X-射线粉末衍射图谱具有4个或以上(如6个，10个，或20个)如下表所述的X-射线衍射峰：
角度 角度 角度 角度 角度 角度
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
在有些优选实施方案中，化合物1的磷酸盐晶型I的X-射线粉末衍射图谱具有2θ角度为8.14，16.32，17.75和20.99，±0.2°，的衍射峰。
在有些实施方案中，化合物1的磷酸盐晶型I的X-射线粉末衍射图谱具有图9中的主要峰，即在相应2θ角度±0.2°处有峰，但强度可以与图9中所示不一样,例如，相对强度在20％或以上的峰，例如，相对强度在30％或以上，40％或以上，50％或以上，60％或以上，80％或以上，90％或以上，或100％的峰，优选为30％或以上，更优选为50％或以上。
在有些实施方案中，化合物1的磷酸盐晶型I的X射线粉末衍射图谱与图9基本一致。优选地，所述晶型的DSC图谱还与图10基本一致。
在有些实施方案中，本发明提供了一种高纯度的化合物1的磷酸盐晶型I，例如，在有些实施方案中，化合物1在该高纯度物质中主要(例如，大约80wt％，大约90wt％，大约95 wt％，或以上,或XRPD检测不到化合物1的其它形式)以其磷酸盐晶型I的形式存在。
化合物1的磷酸盐晶型I通常可以以以下方法得到：将化合物1和磷酸按大约1：1的摩尔比在适当溶剂中混合，然后将化合物1的磷酸盐晶型I结晶析出。在有些实施方案中，化合物1和磷酸的摩尔比可以略小于1：1(酸过量)，比如，大约1：1.1；大约1：1.15；大约1：1.2.溶剂的选择可以为一种或多种有机溶剂，比如，丙酮。在有些实施方案中，成盐反应和结晶均可在室温搅拌下进行。在有些实施方案中，成盐反应和结晶所用溶剂可以不一样。如实施例2详细描写了一个典型的制备化合物1的磷酸盐晶型I方法。
化合物1的磷酸盐晶型I通常可以和药学上可接受的载体或稀释剂一起组成一种药物组合物。优选地，化合物1在该药物组合物中主要(例如，大约80wt％，大约90wt％，大约95wt％，或以上,或XRPD检测不到化合物1的其它形式)以其磷酸盐晶型I的形式存在。有时，化合物1为该药物组合物中的唯一活性物质。有时，该药物组合物中含有治疗或预防有效量的化合物1，如对非小细胞肺癌或本文所述其它EGFR介导的障碍或疾病。
在有些实施方案中，本发明提供一种化合物1的硫酸盐,优选为化合物1的硫酸盐晶型I。在本文中，化合物1的硫酸盐晶型I是指具有以下一个或多个特征的晶型：1)其X-射线粉末衍射图谱至少在2θ角度为10.28，18.34，20.64，±0.2°，的一处或多处(优选2或3处)有衍射峰；2)其DSC图谱在起始温度为255.89℃±5℃处有热吸收峰。在化合物1的硫酸盐晶型I中，化合物1与硫酸的摩尔比为大约1：1。在有些实施方案中，化合物1的硫酸盐晶型I的X-射线粉末衍射图谱具有4个或以上(如6个，10个，或20个)如下表所述的X-射线衍射峰：
角度 角度 角度 角度 角度 角度
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    
在有些优选实施方案中，化合物1的硫酸盐晶型I的X-射线粉末衍射图谱具有2θ角度为9.04，10.28，18.34，20.41，20.64，27.20和28.53，±0.2°，的衍射峰。
在有些实施方案中，化合物1的硫酸盐晶型I的X-射线粉末衍射图谱具有图32中的主要峰，即在相应2θ角度±0.2°处有峰，但强度可以与图32中所示不一样,例如，相对强度在20％或以上的峰，例如，相对强度在30％或以上，40％或以上，50％或以上，60％或以上，80％或以上，90％或以上，或100％的峰，优选为30％或以上，更优选为50％或以上。
在有些实施方案中，化合物1的硫酸盐晶型I的X射线粉末衍射图谱与图32基本一致。优选地，所述晶型的DSC图谱还与图33基本一致。
在有些实施方案中，本发明提供了一种高纯度的化合物1的硫酸盐晶型I，例如，在有些实施方案中，化合物1在该高纯度物质中主要(例如，大约80wt％，大约90wt％，大约95wt％，或以上,或XRPD检测不到化合物1的其它形式)以其硫酸盐晶型I的形式存在。
化合物1的硫酸盐晶型I通常可以以以下方法得到：将化合物1和硫酸按大约1：1的摩尔比在适当溶剂中混合，然后将化合物1的硫酸盐晶型I结晶析出。在有些实施方案中，化合物1和硫酸的摩尔比可以略小于1：1(酸过量)，比如，大约1：1.1；大约1：1.15；大约1：1.2。溶剂的选择可以为一种或多种有机溶剂，比如，乙酸乙酯。在有些实施方案中，成盐反应和结晶均可在室温搅拌下进行。在有些实施方案中，成盐反应和结晶所用溶剂可以不一样。如实施例7详细描写了一个典型的制备化合物1的硫酸盐晶型I方法。
化合物1的硫酸盐晶型I通常可以和药学上可接受的载体或稀释剂一起组成一种药物组合物。优选地，化合物1在该药物组合物中主要(例如，大约80wt％，大约90wt％，大约95wt％，或以上,或XRPD检测不到化合物1的其它形式)以其硫酸盐晶型I的形式存在。有时，化合物1为该药物组合物中的唯一活性物质。有时，该药物组合物中含有治疗或预防有效量的化合物1，如对非小细胞肺癌或本文所述其它EGFR介导的障碍或疾病。
在有些实施方案中，本发明提供一种化合物1的氢溴酸盐,例如化合物1的单氢溴酸盐晶型I。在本文中，化合物1的单氢溴酸盐晶型I是指具有以下一个或多个特征的晶型：1)其X-射线粉末衍射图谱至少在2θ角度为6.10，24.73±0.2°，的一处或2处有衍射峰；2)其 DSC图谱有两个热吸收峰。在化合物1的单氢溴酸盐晶型I中，化合物1与氢溴酸的摩尔比为大约1：1。在有些实施方案中，化合物1的单氢溴酸盐晶型I的X-射线粉末衍射图谱具有4个或以上(如6个，10个，或20个)如下表所述的X-射线衍射峰：
角度 角度 角度 角度 角度 角度
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  
在有些优选实施方案中，化合物1的单氢溴酸盐晶型I的X-射线粉末衍射图谱具有2θ角度为6.10，12.25，13.07，14.58，15.65，16.74，19.27，20.06，21.92，24.73，26.03和26.44，±0.2°，的衍射峰。
在有些实施方案中，化合物1的单氢溴酸盐晶型I的X-射线粉末衍射图谱具有图37中的主要峰，即在相应2θ角度±0.2°处有峰，但强度可以与图37中所示不一样,例如，相对强度在20％或以上的峰，例如，相对强度在30％或以上，40％或以上，50％或以上，60％或以上，80％或以上，90％或以上，或100％的峰，优选为30％或以上，更优选为50％或以上。
在有些实施方案中，化合物1的单氢溴酸盐晶型I的X射线粉末衍射图谱与图37基本一致。优选地，所述晶型的DSC图谱还与图38基本一致。
在有些实施方案中，本发明提供了一种高纯度的化合物1的单氢溴酸盐晶型I，例如，在有些实施方案中，化合物1在该高纯度物质中主要(例如，大约80wt％，大约90wt％，大约95wt％，或以上,或XRPD检测不到化合物1的其它形式)以其单氢溴酸盐晶型I的形式存在。
化合物1的单氢溴酸盐晶型I通常可以以以下方法得到：将化合物1和氢溴酸按大约1：1的摩尔比在适当溶剂中混合，然后将化合物1的单氢溴酸盐晶型I结晶析出。在有些实施方案中，化合物1和氢溴酸的摩尔比可以略小于1：1(酸过量)，比如，大约1：1.1；大约1： 1.15；大约1：1.2。溶剂的选择可以为一种或多种有机溶剂，比如，丙酮。在有些实施方案中，成盐反应和结晶均可在室温搅拌下进行。在有些实施方案中，成盐反应和结晶所用溶剂可以不一样.实施例8详细描写了一个典型的制备化合物1的单氢溴酸盐晶型I方法。
化合物1的单氢溴酸盐晶型I通常可以和药学上可接受的载体或稀释剂一起组成一种药物组合物。优选地，化合物1在该药物组合物中主要(例如，大约80wt％，大约90wt％，大约95wt％，或以上,或XRPD检测不到化合物1的其它形式)以其单氢溴酸盐晶型I的形式存在。有时，化合物1为该药物组合物中的唯一活性物质。有时，该药物组合物中含有治疗或预防有效量的化合物1，如对非小细胞肺癌或本文所述其它EGFR介导的障碍或疾病。
在有些实施方案中，本发明提供一种化合物1的二氢溴酸盐晶型I。在本文中，化合物1的二氢溴酸盐晶型I是指具有以下一个或多个特征的晶型：1)其X-射线粉末衍射图谱至少在2θ角度为6.28，13.12，19.30，25.34，±0.2°，的一处或多处(如1，2，3，或4处)有衍射峰；2)其DSC图谱有两个热吸收峰，起始温度分别为193.38℃±5℃和230.24℃±5℃。在化合物1的二氢溴酸盐晶型I中，化合物1与氢溴酸的摩尔比为大约1：2。在有些实施方案中，化合物1的二氢溴酸盐晶型I的X-射线粉末衍射图谱具有6个或以上(如8个，12个，或20个)如下表所述的X-射线衍射峰：
角度 角度 角度 角度 角度 角度
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  
在有些优选实施方案中，化合物1的二氢溴酸盐晶型I的X-射线粉末衍射图谱具有2θ角度为6.28，13.12，16.78，18.95，19.30，21.95，23.63，25.34，25.61和26.42，±0.2°，的衍射峰。
在有些实施方案中，化合物1的二氢溴酸盐晶型I的X-射线粉末衍射图谱具有图40中的主要峰，即在相应2θ角度±0.2°处有峰，但强度可以与图40中所示不一样,例如，相对强度在20％或以上的峰，例如，相对强度在30％或以上，40％或以上，50％或以上，60％或以上，80％或以上，90％或以上，或100％的峰，优选为30％或以上，更优选为50％或以上。
在有些实施方案中，化合物1的二氢溴酸盐晶型I的X射线粉末衍射图谱与图40基本一致。优选地，所述晶型的DSC图谱还与图41基本一致。
在有些实施方案中，本发明提供了一种高纯度的化合物1的二氢溴酸盐晶型I，例如，在有些实施方案中，化合物1在该高纯度物质中主要(例如，大约80wt％，大约90wt％，大约95wt％，或以上,或XRPD检测不到化合物1的其它形式)以其二氢溴酸盐晶型I的形式存在。
化合物1的二氢溴酸盐晶型I通常可以以以下方法得到：将化合物1和氢溴酸按大约1：2的摩尔比在适当溶剂中混合，然后将化合物1的二氢溴酸盐晶型I结晶析出。溶剂的选择可以为一种或多种有机溶剂，比如，丙酮、乙腈。在有些实施方案中，成盐反应和结晶均可在室温搅拌下进行。在有些实施方案中，成盐反应和结晶所用溶剂可以不一样。实施例9详细描写了一个典型的制备化合物1的二氢溴酸盐晶型I方法。
化合物1的二氢溴酸盐晶型I通常可以和药学上可接受的载体或稀释剂一起组成一种药物组合物。优选地，化合物1在该药物组合物中主要(例如，大约80wt％，大约90wt％，大约95wt％，或以上,或XRPD检测不到化合物1的其它形式)以其二氢溴酸盐晶型I的形式存在。有时，化合物1为该药物组合物中的唯一活性物质。有时，该药物组合物中含有治疗或预防有效量的化合物1，如对非小细胞肺癌或本文所述其它EGFR介导的障碍或疾病。
在有些实施方案中，本发明提供了一种药物组合物，其包含任一个或多个本文所述盐型或晶型以及药学上可接受的载体或稀释剂。医药领域中通常使用的赋形剂、粘合剂、润滑剂、 崩解剂、着色剂、矫味矫嗅剂、乳化剂、表面活性剂、助溶剂、悬浮剂、等渗剂、缓冲剂、防腐剂、抗氧化剂、稳定剂、吸收促进剂等，也可根据需要适当组合进行使用。
本发明所述的药物组合物可以为任何可用剂型，例如，片剂，胶囊等。当制备一种片剂型的固体组合物时，可以将主要活性成分组分与一种药物载体，例如淀粉、乳糖、硬脂酸镁等混合，可以给药片裹糖衣或其它适宜的物质，或者将其进行处理使得药片具有延长或减缓的作用，以及使得该药片以连续方式释放预定量的活性成分。当制备一种胶囊型的固体组合物时，可以将活性成分与一种稀释剂混合，并将所得混合物装入胶囊中获得一种胶囊剂。在有些实施方案中，本发明所述的药物组合物也可以为其它剂型如颗粒剂、散剂或糖浆剂等经口给药或者以注射剂、粉针剂、喷剂或栓剂等非口服方式给药。这些制剂可通过常规方法制备。
在有些实施方案中，本发明所述的化合物1的盐，晶型，和/或其药物组合物可以用于制备治疗或预防由激活或抗性突变体形式的EGFR介导的,例如，L858R激活突变体、Exon19缺失激活突变体和/或T790M抗性突变体EGFR介导的，障碍或疾病的药物。在有些实施方案中，所述障碍或疾病为癌症。在有些实施方案中，所述障碍或疾病包括但不限于:卵巢癌、宫颈癌、结肠直肠癌(例如，结肠腺癌)、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤、黑色素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌(例如，非小细胞肺癌)、肝细胞癌、胃肠道基质瘤(GIST)、甲状腺癌、胆管癌、子宫内膜癌、肾癌、间变性大细胞淋巴瘤、急性髓细胞白血病(AML)、多发性骨髓瘤或间皮瘤。
在本发明中，所述激活突变体或抗性突变体形式的EGFR可以为例如L858R激活突变体、Exon19缺失激活突变体和/或T790M抗性突变体。因此，由激活突变体或抗性突变体形式的EGFR介导的障碍或疾病可以为例如L858R激活突变体、Exon19缺失激活突变体和/或T790M抗性突变体所介导的障碍或疾病。
本发明所述的化合物1的盐，晶型，和/或其药物组合物尤其可以用于由激活突变体或抗性突变体形式的EGFR介导的疾病的预防或治疗，例如由L858R激活突变体、Exon19缺失 激活突变体和/或T790M抗性突变体所介导的疾病、障碍、紊乱或病况的预防或治疗，比如可以用于对吉非替尼、厄洛替尼、或埃克替尼已经产生抗药性的癌症病人的预防或治疗。
本发明的又一方面提供了一种癌症联合治疗方法，其包括给需要治疗的个体施用治疗有效量的本发明所述的化合物1的盐，晶型，和/或其药物组合物，同时联合使用常规的手术或放射疗法或化学疗法或免疫肿瘤疗法。所述的化学疗法或免疫肿瘤疗法与本发明所述的化合物1的盐，晶型，和/或其药物组合物可以并列、同时地、序贯地、或分别地给药，并且可包含但不限制于以下类型的抗肿瘤剂的一种或多种:烷化剂(例如卡铂、奥沙利铂、顺铂、环磷酰胺、亚硝基脲类、氮芥、美法仑),抗代谢药(例如吉西他滨),和抗叶酸剂(例如5-氟尿嘧啶和替加氟、雷替曲塞、甲氨喋呤、阿糖胞苷、羟基脲),拓扑异构酶抑制剂(例如依托泊苷、托泊替康、喜树碱),抗有丝分裂剂(例如长春新碱、长春碱、长春瑞滨、紫杉醇、泰索帝),抗肿瘤抗生素(例如阿霉素、博来霉素、多柔比星、道诺霉素、丝裂霉素C、放线菌素),抗雌激素药(例如他莫昔芬、氟维司群、托瑞米芬、雷洛昔芬、屈洛昔芬),抗雄激素药(例如比卡鲁胺、氟他胺、尼鲁米特)、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林、和布舍瑞林),芳香酶抑制剂(例如阿那曲唑、来曲唑)，CYP17裂解酶抑制剂(例如阿比特龙)，抗erbB2抗体曲妥珠单抗[赫赛汀]，抗EGFR抗体西妥昔单抗[Erbitux]；酪氨酸激酶，丝氨酸/苏氨酸激酶的抑制剂(例如伊马替尼和尼洛替尼、索拉非尼、trametinib、克唑替尼)；细胞周期蛋白依赖性激酶抑制剂(例如CDK4抑制剂palbociclib),抗人血管内皮细胞生长因子抗体贝伐珠单抗(阿瓦斯丁)以及VEGF受体酪氨酸激酶抑制剂(阿帕替尼)，免疫肿瘤治疗方法，例如抗PD-1抗体(pembrolizumab,nivolumab)、抗PD-L1抗体、抗LAG-3抗体、抗CTLA-4抗体、抗4-1BB抗体、抗GITR抗体、抗ICOS抗体、白细胞介素2。
附图说明
图1为化合物1的XRPD图谱；
图2为化合物1的DSC和TGA图谱；
图3为化合物1的NMR图谱；
图4为化合物1的盐酸盐晶型III的XRPD图谱；
图5为化合物1的盐酸盐晶型III的DSC和TGA图谱；
图6为化合物1的盐酸盐晶型III的1H NMR图谱；
图7为化合物1的盐酸盐晶型III的DVS图谱；
图8为化合物1的盐酸盐晶型IIIDVS测试前后的XPRD叠加图；
图9为化合物1的磷酸盐晶型I的XRPD图谱；
图10为化合物1的磷酸盐晶型I的DSC和TGA图谱；
图11为化合物1的磷酸盐晶型I的1H NMR图谱；
图12为化合物1的磷酸盐晶型I的DVS图谱；
图13为化合物1的磷酸盐晶型IDVS测试前后的XPRD叠加图；
图14为化合物1的对甲苯磺酸盐晶型I的XRPD图谱；
图15为化合物1的对甲苯磺酸盐晶型I的DSC和TGA图谱；
图16为化合物1的对甲苯磺酸盐晶型I的1H NMR图谱；
图17为化合物1的对甲苯磺酸盐晶型I的DVS图谱；
图18为化合物1的对甲苯磺酸盐晶型IDVS测试前后的XRPD叠加图；
图19为化合物1的苯磺酸盐晶型I的XRPD图谱；
图20为化合物1的苯磺酸盐晶型I的DSC和TGA图谱；
图21为化合物1的苯磺酸盐晶型I的1H NMR图谱；
图22为化合物1的苯磺酸盐晶型I的DVS图谱；
图23为化合物1的苯磺酸盐晶型IDVS测试前后的XPRD叠加图；
图24为化合物1的琥珀酸盐晶型I的XRPD图谱；
图25为化合物1的琥珀酸盐晶型I的DSC和TGA图谱；
图26为化合物1的琥珀酸盐晶型I的1H NMR图谱；
图27为化合物1的琥珀酸盐晶型I的DVS图谱；
图28为化合物1的琥珀酸盐晶型IDVS测试前后的XPRD叠加图；
图29为化合物1的琥珀酸盐晶型II的XRPD图谱；
图30为化合物1的琥珀酸盐晶型II的DSC和TGA图谱；
图31为化合物1的琥珀酸盐晶型II的1H NMR图谱；
图32为化合物1的硫酸盐晶型I的XRPD图谱；
图33为化合物1的硫酸盐晶型I的DSC和TGA图谱；
图34为化合物1的硫酸盐晶型I的1H NMR图谱；
图35为化合物1的硫酸盐晶型I的DVS图谱；
图36为化合物1的硫酸盐晶型IDVS测试前后的XPRD叠加图；
图37为化合物1的单氢溴酸盐晶型I的XRPD图谱；
图38为化合物1的单氢溴酸盐晶型I的DSC和TGA图谱；
图39为化合物1的单氢溴酸盐晶型I的1H NMR图谱；
图40为化合物1的二氢溴酸盐晶型I的XRPD图谱；
图41为化合物1的二氢溴酸盐晶型I的DSC和TGA图谱；
图42为化合物1的二氢溴酸盐晶型I的1H NMR图谱。
有益效果
本发明人意外发现，化合物1的对甲苯磺酸盐、苯磺酸盐、琥珀酸盐、盐酸盐、磷酸盐、硫酸盐、可以在与相应酸的摩尔比略小于1：1，如1：1.1(酸过量)的条件下高产率生成单盐，因此简化其工艺放大并提高了效率。
另如本文所详述，化合物1的一些盐型如，盐酸盐、磷酸盐、对甲苯磺酸盐、苯磺酸盐、琥珀酸盐、硫酸盐、氢溴酸盐(包括单氢溴酸盐或二氢溴酸盐)，均在不同程度上提高了化合物1的水溶解度，而且这些盐型的一些多晶型(尤其是对甲苯磺酸盐晶型I、苯磺酸盐晶型I、磷酸盐晶型I等)具备高稳定性，低吸湿度等特征，有利于化合物1的生产和制备，对其最终市场化有重要意义。
具体实施方式
通过以下实施例进一步说明本发明，以下实施例仅用于更具体说明本发明的优选实施方式，不用于对本发明的技术方案进行限定。
下述各实施例中，
1H-NMR分析采用的仪器是配备有B-ACS 120自动进样系统的Bruker Advance 300。
固体样品用粉末X射线衍射分析仪(Bruker D8 advance)进行分析。该仪器配备了LynxEye检测器，样品的2θ扫描角度范围为3°到40°，扫描步长为0.02°。测定样品时的光管电压和光管电流分别为40KV和40mA。
热重分析(TGA)的仪器型号为Discovery TGA 55(TA Instruments，US)。将样品置于已平衡的开口铝制样品盘中，样品量在TGA加热炉内自动称量。样品以10℃/min的速率加热至最终温度。
示差扫描量热分析(DSC)的仪器型号为TA Instruments Q200或Discovery DSC 250。样品经精确称重后置于DSC加盖打孔的样品盘中，并记录下样品的准确质量。样品以10℃/min的升温速率加热至最终温度。
动态水分吸脱附分析(DVS)的仪器型号为DVS Intrinsic(SMS，UK)。将样品置于仪器样品篮中自动称重，然后加热至40℃，在氮气流下干燥至dm/dt小于0.002％，待降温至25℃后开始测量，仪器参数如下。
每步用时：                 60min
样品温度：                 25℃
循环：                     整个循环
吸附：                     0，10，20，30，40，50，60，70，80，90
脱附：                     80，70，60，50，40，30，20，10，0
数据存储速率：             5s
总流速：                   200sccm
测试后总流速：             200sccm
化合物1的表征
初始原料药1为结晶度很好的晶体(图1)，DSC显示其熔点为146℃(图2)。 1H-NMR和TGA显示样品无溶剂残留，且200℃之前基本无失重(图3)，结果表明样品为无水晶型，命名为晶型I。
各种盐型的制备
实施例1、盐酸盐晶型III
将1(31.21mg，1.0eq)溶于乙腈和二氯甲烷的混合溶剂中(48v，3/1)，于50℃搅拌条件下，加入盐酸(1.1eq)。反应液冷却至室温后，搅拌30分钟。然后将得到的澄清溶液用N 2流浓缩至约32v，立即析出固体。所得混悬液室温搅拌过夜，过滤收集固体，并于50℃真空干燥约4小时，得到盐酸盐晶型III。该样品为类白色固体，并分别进行XRPD、DSC、TGA、DVS和 1H-NMR表征。
盐酸盐晶型III为具有高熔点(273℃，图5)的晶体(表1和图4)。样品具有轻微吸湿性，在80％相对湿度条件下增重约1.86％(图7)。 1H-NMR和TGA结果显示样品无溶剂残留，且在200℃之前无明显失重(图5和图6)，表明该样品为无水晶型。DVS测试后样品的晶型不变(图8)。
表1.盐酸盐晶型III的XRPD衍射峰列表
角度 强度 角度 强度 角度 强度
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
实施例2、磷酸盐晶型I
将1(30.20mg，1.0eq)溶于丙酮中(26v)，于室温搅拌条件下，加入磷酸(1.1eq)后立即析出黏状物，继续搅拌2小时后析出固体。将混悬液室温搅拌3小时后，过滤收集固体，并于50℃真空干燥过夜，得到磷酸盐晶型I，样品为类白色固体，并分别进行XRPD、DSC、TGA、DVS和 1H-NMR表征。
磷酸盐晶型I为具有高结晶度(表2和图9)、高熔点(238℃，图10)的晶体。样品具有轻微吸湿性，在80％相对湿度条件下增重约0.61％(图12)。 1H-NMR和TGA结果显示样品有0.7％的残留溶剂，但在150℃之前无明显失重(图10和图11)，表明该样品为无水晶型。DVS测试后样品的晶型不变(图13)。
表2.磷酸盐晶型I的XRPD衍射峰列表
角度 强度 角度 强度 角度 强度
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
实施例3、对甲苯磺酸盐晶型I
将1(31.60mg，1.0eq)溶于丙酮中(25v)，于室温搅拌条件下，加入对甲苯磺酸(1.1eq)。约2分钟后析出固体，混悬液继续室温搅拌约6小时，过滤收集固体，并于50℃真空干燥过夜，得到对甲苯磺酸盐晶型I，样品为类白色固体，并分别进行XRPD、DSC、TGA、DVS和 1H-NMR表征。
对甲苯磺酸盐晶型I为熔点在172℃(图15)的晶体(表3和图14)。样品具有轻微吸湿性，在80％相对湿度条件下增重约0.55％(图17)。TGA显示样品在200℃之前无明显失重(图15)； 1H-NMR显示样品有约0.3％的残留溶剂，且游离碱和对甲苯磺酸的比例为1:1(图16)。该样品可能为无水晶型。DVS测试后样品的晶型不变(图18)。
表3.对甲苯磺酸盐晶型I的XRPD衍射峰列表
角度 强度 角度 强度 角度 强度
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    
实施例4、苯磺酸盐晶型I
将1(19.51mg，1.0eq)溶于丙酮中(40v)，于室温搅拌条件下，加入苯磺酸(1.0eq)。反应液搅拌3小时后仍澄清，将其用N 2流吹干，所得黏状物于乙腈(50v)中室温混悬打浆过夜，过滤收集固体，并于50℃真空干燥约4小时，得到苯磺酸盐晶型I，样品为白色固体，并分别进行XRPD、DSC、TGA、DVS和 1H-NMR表征。
苯磺酸盐晶型I为熔点在165℃(图20)的晶体(表4和图19)。样品具有轻微吸湿性，在80％相对湿度条件下增重约0.41％(图22)。TGA显示样品在180℃之前无明显失重(图20)； 1H-NMR显示样品无残留d溶剂，且游离碱和苯磺酸的比例为1:1(图21)。该样品为无水晶型，DVS测试后样品的晶型不变(图23)。
表4.苯磺酸盐晶型I的XRPD衍射峰列表
角度 强度 角度 强度 角度 强度
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    
实施例5、琥珀酸盐晶型I
将1(31.3mg，1.0eq)溶于丙酮中(26v)，于室温搅拌条件下，加入琥珀酸(1.1eq，0.6M甲醇溶液)。反应液搅拌2小时后仍澄清，将其用N 2流吹干，所得黏状物于乙腈(16v)中室温混悬打浆2小时，过滤收集固体，并于50℃真空干燥过夜，得到琥珀酸盐晶型I，样品为类白色固体，并分别进行XRPD、DSC、TGA、DVS和 1H-NMR表征。
琥珀酸盐晶型I为具有高结晶度的晶体(表5和图24)，熔点为144℃(图25)。样品具有轻微吸湿性，在80％相对湿度条件下增重约0.57％(图27)。TGA显示样品在87–157℃之间失重约1.4％(图25)， 1H-NMR显示样品有约1％的残留溶剂，且游离碱和琥珀酸的比例为1:1(图26)。该样品为无水晶型，DVS测试后样品的晶型不变(图28)。
表5.琥珀酸盐晶型I的XRPD衍射峰列表
角度 强度 角度 强度 角度 强度
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
实施例6、琥珀酸盐晶型II
将1(30.2mg，1.0eq)溶于乙酸乙酯中(33v)，于35℃搅拌条件下，加入琥珀酸(1.1eq，0.6M甲醇溶液)。反应液搅拌2小时后仍澄清，将其用N 2流吹干，所得黏状物于2-丁酮(16v)中室温混悬打浆过夜，过滤收集固体，并于50℃真空干燥约4小时，得到琥珀酸盐晶型II，样品为类白色固体，并分别进行XRPD、DSC、TGA和 1H-NMR表征。
琥珀酸盐晶型II为具有高结晶度的晶体(表6和图29)，熔点为141℃(图30)。TGA显示样品在102–157℃之间失重约1.9％(图30)； 1H-NMR显示样品有约2％的2-丁酮残留，且游离碱和琥珀酸的比例为1:1(图31)。该样品为无水晶型。
表6.琥珀酸盐晶型II的XRPD衍射峰列表
角度 强度 角度 强度 角度 强度
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    
实施例7.硫酸盐晶型I
将1(29.80mg，1.0eq)溶于乙酸乙酯中(33v)，于35℃搅拌条件下，加入硫酸(1.0eq，0.1M甲醇溶液)。立即析出固体，混悬液冷却至室温后，搅拌过夜，过滤收集固体，并于50℃真空干燥约4小时，得到硫酸盐晶型I，样品为浅黄色固体，并分别进行XRPD、DSC、TGA、DVS和 1H-NMR表征。
硫酸盐晶型I为结晶度较好的晶体(表7和图32)，在263℃和265℃处有两个重叠的吸热峰(图33)，可能是样品的在加热过程中发生晶型转变导致的。样品有吸湿性，在80％相对湿度条件下增重约3.31％(图35)。TGA显示样品在室温至90℃之间有0.2％的失重； 1H-NMR显示样品有约0.3％的乙酸乙酯残留(图33和图34)。该样品可能为无水晶型。DVS测试后样品的晶型不变(图36)。
表7.硫酸盐晶型I的XRPD衍射峰列表
角度 强度 角度 强度 角度 强度
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    
实施例8.单氢溴酸盐晶型I
将1(32.0mg，1.0eq)溶于丙酮中(22v)，于室温搅拌条件下，加入氢溴酸(1.1eq)。反应液搅拌5分钟后析出固体，混悬液继续搅拌约2小时，过滤收集固体，并于50℃真空干燥过夜，得到单氢溴酸盐晶型I，样品为橙黄色固体，并分别进行XRPD、DSC、TGA和 1H-NMR表征。
单氢溴酸盐晶型I为结晶度相对较差的晶体(表8和图37)，在243℃和249℃处有两个重叠的吸热峰(图38)，可能是样品的在加热过程中发生晶型转变导致的。TGA显示样品在107–219℃之间有1.1％的失重，相应的 1H-NMR显示样品有约1.2％的残留丙酮(图38和图39)。该样品为无水晶型。
表8.单氢溴酸盐晶型I的XRPD衍射峰列表
角度 强度 角度 强度 角度 强度
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    
实施例9.二氢溴酸盐晶型I
将1(31.96mg，1.0eq)溶于丙酮中(38v)，于50℃搅拌条件下，加入氢溴酸(2.0eq)。反应液搅拌2小时后仍澄清，旋蒸浓缩除去溶剂，所得黏状物于乙腈(45v)中室温混悬打浆过夜，过滤收集固体，并于50℃真空干燥约4小时，得到二氢溴酸盐晶型I，样品为橙黄色固体，并分别进行XRPD、DSC、TGA和 1H-NMR表征。
二氢溴酸盐晶型I为结晶度较好的晶体(表9和图40)，在210℃和242℃处有两个重叠的吸热峰(图41)，可能是样品的在加热过程中发生晶型转变导致的；另外在25–40℃处有一个宽的吸热峰，可能为失去溶剂或水导致的，而且这部分溶剂或水很容易失去。TGA显示样品有三段失重(图41)，第一段失重可能为失溶剂导致的，对应 1H-NMR显示样品有约0.9％的残留乙腈(图42)；而后两段失重可能为分解导致的。该样品可能为无水晶型。
表9.二氢溴酸盐晶型I的XRPD衍射峰列表
角度 强度 角度 强度 角度 强度
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    

Claims (10)

  1. 如下所示化合物1的对甲苯磺酸盐、苯磺酸盐、琥珀酸盐、盐酸盐、磷酸盐、硫酸盐、或氢溴酸盐：
    Figure PCTCN2020090429-appb-100001
  2. 权利要求1所述的化合物1的对甲苯磺酸盐，其为具有如下特征的晶型I：化合物1与对甲苯磺酸的摩尔比为大约1：1，且(a)其X-射线粉末衍射图谱至少在2θ角度为7.22，7.90，9.30，10.46，14.64，15.36，±0.2°，的一处或多处(1，2，3，4，5，或6)有衍射峰，和/或(b)其DSC图谱在起始温度为161.54℃±5℃处有热吸收峰；
    优选地，所述的化合物1的对甲苯磺酸盐晶型I的X-射线粉末衍射图谱具有6个或以上(如10个，16个，或20个)如下表所述的X-射线衍射峰：
    角度 角度 角度 角度 角度 角度 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  
    优选地，所述的化合物1的对甲苯磺酸盐晶型I显示与图14基本一致的X射线粉末衍射图谱；优选地，所述晶型还显示与图15基本一致的DSC图谱。
  3. 权利要求1所述的化合物1的苯磺酸盐，其为具有如下特征的晶型I：化合物1与苯磺酸的摩尔比为大约1：1，且(a)其X-射线粉末衍射图谱至少在2θ角度为8.41，16.53，18.78，21.18，23.16，±0.2°，的一处或多处(1，2，3，4，或5，优选5处)有衍射峰，和/或(b)其DSC图谱在起始温度为155.49℃±5℃处有热吸收峰；
    优选地，所述的化合物1的苯磺酸盐晶型I的X-射线粉末衍射图谱具有6个或以上(如10个，16个，或20个)如下表所述的X-射线衍射峰：
    角度 角度 角度 角度 角度 角度 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  
    更优选地，其X-射线粉末衍射图谱具有2θ角度为7.68，8.41，14.60，15.52，16.53，16.85，17.73，18.78，20.08，21.18，23.16，24.42，和24.76，±0.2°，的衍射峰；
    优选地，所述的化合物1的苯磺酸盐晶型I显示与图19基本一致的X射线粉末衍射图谱；优选地，所述晶型还显示与图20基本一致的DSC图谱。
  4. 权利要求1所述的化合物1的琥珀酸盐，
    其为具有如下特征的晶型I：化合物1与琥珀酸的摩尔比为大约1：1，且(a)其X-射线粉末衍射图谱至少在2θ角度为7.38，10.21，11.59，17.55，23.38，±0.2°，的一处或多处(1，2，3，4，或5，优选5处)有衍射峰，和/或(b)其DSC图谱在起始温度为108.3℃±5℃处有热吸收峰；
    优选地，所述的化合物1的琥珀酸盐晶型I的X-射线粉末衍射图谱具有6个或以上(如10个，16个，或20个)如下表所述的X-射线衍射峰：
    角度 角度 角度 角度 角度 角度 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
    更优选地，其X-射线粉末衍射图谱具有2θ角度为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，和30.55，±0.2°，的衍射峰；
    优选地，所述的化合物1的琥珀酸盐晶型I显示与图24基本一致的X射线粉末衍射图谱；优选地，所述晶型还显示与图25基本一致的DSC图谱；或者，
    所述的化合物1的琥珀酸盐为具有如下特征的晶型II：化合物1与琥珀酸的摩尔比为大约1：1，且(a)其X-射线粉末衍射图谱至少在2θ角度为7.32，9.02，9.65，10.09，11.63，17.53，19.47，23.45，±0.2°，的一处或多处(1，2，3，4，5，6，7，或8，优选5处以上，更优选，8处)有衍射峰，和/或(b)其DSC图谱在起始温度为139.9℃±5℃处有热吸收峰；
    优选地，所述的化合物1的琥珀酸盐晶型II的X-射线粉末衍射图谱具有8个或以上(如10个，16个，或20个)如下表所述的X-射线衍射峰：
    角度 角度 角度 角度 角度 角度
    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          
    更优选地，其X-射线粉末衍射图谱具有2θ角度为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，和24.43，±0.2°，的衍射峰；
    优选地，所述的化合物1的琥珀酸盐晶型II显示与图29基本一致的X射线粉末衍射图谱；优选地，所述晶型还显示与图30基本一致的DSC图谱。
  5. 权利要求1所述的化合物1的盐酸盐，其为具有如下特征的晶型III：化合物1与盐酸的摩尔比为大约1：1，且(a)其X-射线粉末衍射图谱至少在2θ角度为6.39，7.35，10.03，11.48，15.27，21.04，21.87，23.35，24.94，±0.2°，的一处或多处(1，2，3，4，5，6，7，或8，优选5处以上，更优选，8处)有衍射峰，和/或(b)其DSC图谱在起始温度为270.75℃±5℃处有热吸收峰；
    优选地，所述的化合物1的盐酸盐晶型III的X-射线粉末衍射图谱具有8个或以上(如10个，16个，或20个)如下表所述的X-射线衍射峰：
    角度 角度 角度 角度 角度 角度
    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      
    更优选地，其X-射线粉末衍射图谱具有2θ角度为6.39，7.35，7.87，10.03，11.48，15.27，21.04，21.87，22.13，22.74，23.35，24.94，和26.79，±0.2°，的衍射峰；
    优选地，所述的化合物1的盐酸盐晶型III显示与图4基本一致的X射线粉末衍射图谱；优选地，所述晶型还显示与图5基本一致的DSC图谱。
  6. 权利要求1所述的化合物1的磷酸盐，其为具有如下特征的晶型I：化合物1与磷酸的摩尔比为大约1：1，且(a)其X-射线粉末衍射图谱至少在2θ角度为8.14，16.32，±0.2°，的一处或2处(优选2处)有衍射峰，和/或(b)其DSC图谱在起始温度为234.95℃±5℃处有热吸收峰；
    优选地，所述的化合物1的磷酸盐晶型I的X-射线粉末衍射图谱具有4个或以上(如6个，10个，或20个)如下表所述的X-射线衍射峰：
    角度 角度 角度 角度 角度 角度 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
    更优选地，其X-射线粉末衍射图谱具有2θ角度为8.14，16.32，17.75和20.99，±0.2°，的衍射峰；
    优选地，所述的化合物1的磷酸盐晶型I显示与图9基本一致的X射线粉末衍射图谱；优选地，所述晶型还显示与图10基本一致的DSC图谱。
  7. 权利要求1所述的化合物1的硫酸盐，其为具有如下特征的晶型I：化合物1与硫酸的摩尔比为大约1：1，且(a)其X-射线粉末衍射图谱至少在2θ角度为10.28，18.34，20.64，±0.2°，的一处或多处(优选2或3处)有衍射峰，和/或(b)其DSC图谱在起始温度为255.89℃±5℃处有热吸收峰；
    优选地，所述的化合物1的硫酸盐晶型I的X-射线粉末衍射图谱具有4个或以上(如6个，10个，或20个)如下表所述的X-射线衍射峰：
    角度 角度 角度 角度 角度 角度 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    
    更优选地，其X-射线粉末衍射图谱具有2θ角度为9.04，10.28，18.34，20.41，20.64，27.20，和28.53，±0.2°，的衍射峰；
    优选地，所述的化合物1的硫酸盐晶型I显示与图32基本一致的X射线粉末衍射图谱；优选地，所述晶型还显示与图33基本一致的DSC图谱。
  8. 权利要求1所述的化合物1的氢溴酸盐，
    其为具有如下特征的单氢溴酸盐晶型I：化合物1与氢溴酸的摩尔比为大约1：1，且(a)其X-射线粉末衍射图谱至少在2θ角度为6.10，24.73，±0.2°，的一处或2处有衍射峰，和/或(b)其DSC图谱有两个热吸收峰；
    优选地，所述的化合物1的单氢溴酸盐晶型I的X-射线粉末衍射图谱具有4个或以上(如6个，10个，或20个)如下表所述的X-射线衍射峰：
    角度 角度 角度 角度 角度 角度 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  
    更优选地，其X-射线粉末衍射图谱具有2θ角度为6.10，12.25，13.07，14.58，15.65，16.74，19.27，20.06，21.92，24.73，26.03和26.44，±0.2°，的衍射峰；
    优选地，所述的化合物1的单氢溴酸盐晶型I显示与图37基本一致的X射线粉末衍射图谱；优选地，所述晶型还显示与图38基本一致的DSC图谱；或者，
    所述的化合物1的氢溴酸盐为具有如下特征的二氢溴酸盐晶型I：化合物1与氢溴酸的摩尔比为大约1：2，且(a)其X-射线粉末衍射图谱至少在2θ角度为6.28，13.12，19.30，25.34，±0.2°，的一处或多处(如1，2，3，或4处)有衍射峰，和/或(b)其DSC图谱有两个热吸收峰，起始温度分别为193.38℃±5℃和230.24℃±5℃；
    优选地，所述的化合物1的二氢溴酸盐晶型I的X-射线粉末衍射图谱具有6个或以上(如8个，12个，或20个)如下表所述的X-射线衍射峰：
    角度 角度 角度 角度 角度 角度
    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  
    更优选地，其X-射线粉末衍射图谱具有2θ角度为6.28，13.12，16.78，18.95，19.30，21.95，23.63，25.34，25.61，和26.42，±0.2°，的衍射峰；
    优选地，所述的化合物1的二氢溴酸盐晶型I显示与图40基本一致的X射线粉末衍射图谱；优选地，所述晶型还显示与图41基本一致的DSC图谱。
  9. 一种药物组合物，其包含根据任一权利要求1-8中所述的化合物1的盐以及药学上可接受的载体或稀释剂；优选地，化合物1的盐在该药物组合物中主要以权利要求2-8中所述的一种晶型存在(例如，大约80wt％，大约90wt％，大约95wt％，或以上以权利要求2-8中所述的一种晶型存在，或XRPD检测不到化合物1的其它固态形式)。
  10. 权利要求1-8中任一项所述的盐或权利要求9所述的药物组合物在制备治疗或预防由激活或抗性突变体形式的EGFR介导的,例如，L858R激活突变体、Exon19缺失激活突变体和/或T790M抗性突变体EGFR介导的，障碍或疾病的药物中的用途；
    优选地，所述障碍或疾病选自以下一种或多种：卵巢癌、宫颈癌、结肠直肠癌(例如，结肠腺癌)、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤、黑色素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌(例如，非小细胞肺癌)、肝细胞癌、胃肠道基质 瘤(GIST)、甲状腺癌、胆管癌、子宫内膜癌、肾癌、间变性大细胞淋巴瘤、急性髓细胞白血病(AML)、多发性骨髓瘤或间皮瘤。
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