Novel pharmaceutical salts and polymorphic forms of ERBB and BTK inhibitors

Abstract

Disclosed herein are novel pharmaceutical salts and polymorphic forms of (R)-N-(5-((4-((5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (Compound I) having inhibitory activity against ErbB (e.g., EGFR or Her2) and / or BTK, particularly mutant forms of ErbB and / or BTK. Further disclosed herein are processes for the preparation of pharmaceutical salts and polymorphic forms of Compound I, and the use of such pharmaceutical salts and polymorphic forms of Compound I in the inhibition of ErbB or BTK.

Description

[Technical field]

[0001]

[0001]

[0002] The present disclosure relates to novel pharmaceutical salts of ((R)—N-(5-((4-((5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (hereinafter referred to as “Compound I” and having the structure shown below):

[0002] [ka]

[0003] The present invention relates to crystalline polymorphs of Compound I or pharmaceutical salts, compositions containing same, processes for their preparation and uses. [Background technology]

[0004]

[0003]

[0004] ErbB family receptor tyrosine kinases act to transmit signals from the outside of the cell to the inside by activating secondary messaging effectors through phosphorylation events at their tyrosine phosphorylated residues. These signals regulate a variety of cellular processes including proliferation, carbohydrate utilization, protein synthesis, angiogenesis, cell growth, and cell survival. Deregulation of ErbB family signaling modulates proliferation, invasion, metastasis, angiogenesis, and tumor cell survival and may be associated with many human cancers such as lung cancer, head and neck cancer, and breast cancer. Various ErbB receptors such as EGFR and HER2 have been demonstrated to be associated with disorders such as cancer. Various mutations of EGFR and HER2 have also been demonstrated to be associated with certain cancer types or non-responsiveness / resistance of WT EGFR or HER2 to existing drugs.

[0005] Bruton's tyrosine kinase (BTK) is a member of the SRC-related family of cytoplasmic tyrosine kinases, which is mainly expressed in B cells and distributed in lymphoid, hematopoietic and blood systems. BTK plays a key role in the B cell receptor signaling pathway in B cells, which is necessary for B cell development, activation and survival. Therefore, BTK inhibitors have been developed to treat B cell malignancies that depend on BCR signaling, such as chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL). BTK has also been suggested to be involved in promoting Toll-like receptor signaling, which regulates macrophage activation and the production of proinflammatory cytokines. Several studies have demonstrated crosstalk between the BTK signaling pathway and the TLR signaling pathway, which mediates the transactivation of downstream cascades. In addition, BTK has been found to play an important role in regulating immunity. BTK has become an attractive target in the treatment of B cell malignancies, inflammation, and autoimmune diseases.

[0006]

[0006] Polymorphs are different crystalline forms of the same compound. Different polymorphs may have different crystal structures due to different packing of molecules in the lattice. This leads to different crystal symmetries and / or unit cell parameters, which directly affect physical properties such as X-ray diffraction characteristics of the crystal or powder. For example, different polymorphs generally diffract at different sets of angles, giving different intensity values. Thus, X-ray powder diffraction can be used to identify different polymorphs, or solid forms containing multiple polymorphs, in a reproducible and reliable manner.

[0007]

[0007] Crystalline polymorphic forms are of interest to the pharmaceutical industry, and especially to those involved in developing suitable dosage forms. Different crystalline forms of a drug substance may have different physical properties, such as melting point, solubility, dissolution rate, optical and mechanical properties, vapor pressure, hygroscopicity, particle shape, density, and flowability. These properties may directly affect the ability to process and / or manufacture the compound as a pharmaceutical product. Different crystalline forms may also exhibit different stability and bioavailability. For example, if the polymorphic form is not kept constant during clinical or stability studies, the exact dosage form used or studied may not be comparable between lots. Thus, the most stable crystalline form of a drug is often selected during drug development based on its minimal possibility of conversion to another crystalline form and its greater chemical stability. It is also desirable to have a process to produce the compound with the selected polymorphic form in high purity if the compound is to be used in clinical studies or commercial products, since impurities present may cause undesirable toxic effects. Certain polymorphic forms are suitable for inclusion in pharmaceutical formulations because they may have improved thermodynamic stability or may be more easily manufactured in large quantities with high purity.Certain polymorphic forms may exhibit other advantageous physical properties, such as lack of hygroscopic tendency due to different lattice energies, improved solubility, and improved dissolution rate.To ensure the quality, safety, and efficacy of pharmaceutical products, it is important to select a crystal form that is stable, reproducibly manufactured, and has favorable physicochemical properties.

[0008]

[0008] In WO2019149164A1 (the disclosure of which is incorporated herein in its entirety), we described various ErbB / BTK selective inhibitors, including (R)-N-(5-((4-((5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (Compound I), which has been demonstrated to be a potent ErbB / BTK selective inhibitor. For further development of pharmaceutical compositions or dosage forms, it is of interest to identify the crystalline polymorphic forms of this compound or its pharmaceutical salts.

[0009]

[0009] Methods for the synthesis of compound I known in the art are not suitable for large-scale, especially commercial-scale, production of compound I. There is a need for improved processes that can be operated on a large scale and provide one or more advantages over known methods, such as improved compound purity, improved compound isolation, increased yields, reduced costs, and improved compliance with regulatory requirements for pharmaceutical starting materials, intermediates, and products. Summary of the Invention

[0010]

[0010] [Means for solving the problem]

[0011] In one aspect, the present disclosure provides novel pharmaceutical salts of Compound I.

[0012] In some embodiments, the pharmaceutical salt of compound I provided herein is selected from the following: hydrochloride, methanesulfonate, sulfate, phosphate, maleate, fumarate, citrate, succinate, L-malate, L-(+)-tartrate, and hydrochloride of compound I. In certain embodiments, the pharmaceutical salt of compound I is hydrochloride, L-(+)-tartrate, fumarate, sulfate, and maleate of compound I. In certain embodiments, the pharmaceutical salt of compound I is in amorphous form. In certain embodiments, the pharmaceutical salt of compound I is in crystalline form. In certain embodiments, the pharmaceutical salt of compound I is in crystalline form of compound I hydrochloride, L-(+)-tartrate, fumarate, sulfate, and maleate.

[0012]

[0013] In another aspect, the present disclosure also provides a crystalline form of Compound I, or a pharma- ceutically acceptable salt thereof.

[0014] In some embodiments, the crystalline form is Form A of compound I, Form B of compound I, a crystalline form of the hydrochloride, L-(+)-tartrate, fumarate, sulfate, or maleate salt of compound I.

[0013]

[0015] In another aspect, the disclosure provides pharmaceutical compositions comprising one or more pharmaceutical salts or crystalline forms of Compound I, each disclosed herein.

[0016] In another aspect, the disclosure provides a method of treating an ErbB-related or BTK-related disease in a subject, comprising administering to a subject in need of treatment for an ErbB-related or BTK-related disease a therapeutically effective amount of a pharmaceutical salt or crystalline form of Compound I, or a pharmaceutical composition provided herein.

[0014]

[0017] In yet another aspect, the disclosure provides the use of a pharmaceutical salt or crystalline form of Compound I, or a pharmaceutical composition provided herein, in inhibiting ErbB or BTK, or in the manufacture of a medicament for inhibiting ErbB or BTK.

[0015]

[0018] In a further aspect, the present disclosure also provides processes for the preparation of pharmaceutical salts or crystalline forms of Compound I.

[0019] In a further aspect, the present disclosure also provides a process for preparing Compound I in high yield on a tens of kilograms scale. [Brief description of the drawings]

[0016]

[0020] [Figure 1]

[0021] 1 is XRPD data for crystalline Form A of Compound I free base. [Diagram 2]

[0022] 1 is DSC data for crystalline Form A of Compound I free base. [Diagram 3]

[0023] 1 is TGA data for crystalline Form A of Compound I free base. [Figure 4]

[0024] 1 is DVS data for crystalline Form A of Compound I free base. [Diagram 5]

[0025] 1 is XRPD data for crystalline form B of Compound I free base. [Figure 6]

[0026] 1 is DSC data for crystalline form B of Compound I free base. [Figure 7]

[0027] 1 is TGA data for crystalline form B of Compound I free base. [Figure 8]

[0028] 1 is DVS data for crystalline form B of Compound I free base. [Figure 9]

[0029] 1 shows XRPD data of the (+)-L-tartrate salt of compound I (Pattern I). [Figure 10]

[0030] 1 is XRPD data of the fumarate salt of Compound I. [Figure 11]

[0031] 1 is XRPD data of the sulfate salt of Compound I. [Figure 12]

[0032] 1 is XRPD data of the maleate salt of Compound I. [Figure 13]

[0033] 1 is XRPD data of the hydrochloride salt of Compound I. [Figure 14]

[0034] 1 shows XRPD data of the (+)-L-tartrate salt of Compound I (Pattern II). [Figure 15]

[0035] 1 is a TGA / DSC overlay data of the (+)-L-tartrate salt of Compound I (Pattern I, prepared in acetone). [Figure 16]

[0036] 1 is a TGA / DSC overlay data of the (+)-L-tartrate salt of Compound I (Pattern II, prepared in ethanol). [Figure 17]

[0037] 1 is a TGA / DSC overlay data of the fumarate salt of Compound I (prepared in ethanol). [Figure 18]

[0038] 1 is a TGA / DSC overlay data of the sulfate salt of Compound I. [Figure 19]

[0039] 1 is a TGA / DSC overlay data of Compound I maleate salt. [Figure 20]

[0040] 1 is a TGA / DSC overlay data of the hydrochloride salt of Compound I. [Figure 21]

[0041] 1 is DVS data of the crystalline form of Compound I-(+)-L-tartrate salt (Pattern II). [Figure 22]

[0042] 1 is DVS data for the crystalline form of Compound I-Fumarate salt. [Diagram 23]

[0043] 1 is DVS data for the crystalline form of Compound I-hydrochloride salt. [Figure 24]

[0044] 1 is an XRPD profile of Compound I-Form B before and after jet milling. [Diagram 25]

[0045] 1 is an XRPD profile of Compound I-Form B before and after grinding. [Figure 26]

[0046] 1 is a DSC profile of Compound I-Form B before and after jet milling. [Figure 27]

[0047] 1 is an XRPD profile of Compound I-Form B after storage at 2-8° C. for 20 days. [Figure 28]

[0048] 1 is a DSC profile of Compound I-Form B after storage at 2-8° C. for 20 days. [Figure 29]

[0049] 1H NMR to determine compound I-fumarate ratio (1:1). [Diagram 30]

[0050] 1H NMR to determine compound I-maleate ratio (1:1). [Diagram 31]

[0051] 1H NMR to determine compound I-tartrate (Pattern I) ratio (1:1). [Diagram 32]

[0052] 1H NMR to determine compound I-tartrate (Pattern II) ratio (1:1). [Diagram 33]

[0053] Single crystal X-ray diffraction ORTEP of compound I. [Diagram 34]

[0054] 1 is the dissolution profile of a 200 mg tablet of Compound I at pH 1.2. [Diagram 35]

[0055] 1 is the dissolution profile of a 200 mg tablet of Compound I at pH 4.5. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017]

[0056]

[0057] Before discussing in further detail, the following terms are defined:

[0058] definition

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the following terms are intended to have the following meanings:

[0018]

[0060] As used in the specification and claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a compound" includes both a single compound and a plurality of different compounds.

[0019]

[0061] The term "about" as used herein is intended to indicate that the quoted value should not be interpreted as absolute, but should also take into account the measurement error, batch-to-batch variation, and / or instrument-to-instrument variation as described above. Unless a measurement error or range of variation is specified in this application (e.g., for the diffraction angle 2θ in XRPD, the measurement error is ±0.2°, the measurement error of the endotherm of polymorph melting is ±0.01-10°C, the measurement error of the endotherm of polymorph dehydration / desolvation in DSC is ±0.01-20°C, and the measurement error in TGA is ±5-20°C), the term "about" when used before a numerical designation such as, for example, temperature, time, amount, and concentration, including ranges, indicates an approximation that may vary by as much as ±10%, ±5%, or ±1%.

[0020]

[0062] As used herein, "inhibitor" refers to a compound or agent that has the ability to inhibit the biological function of a target protein or polypeptide, such as by inhibiting the activity or expression of the target protein or polypeptide. Thus, the term "inhibitor" is defined in the context of the biological role of the target protein or polypeptide. Some inhibitors herein specifically interact with (e.g., bind to) the target, but compounds that inhibit the biological activity of a target protein or polypeptide by interacting with other members of the signal transduction pathway of the target protein or polypeptide are also specifically included within this definition. Non-limiting examples of biological activities inhibited by inhibitors include those associated with the development, growth, or spread of tumors, or undesirable immune responses manifested in autoimmune diseases. As used herein, "selective inhibition" or "selectively inhibiting" as applied to biologically active agents refers to the ability of an agent to selectively reduce target signaling activity relative to off-target signaling activity through direct or indirect interaction with the target. For example, a compound that selectively inhibits mutant EGFR / Her2 over wild-type EGFR / Her2 has at least about 2x activity against mutant EGFR / Her2 compared to the compound's activity against the wild-type EGFR / Her2 isoform (e.g., at least about 3x, about 5x, about 10x, about 20x, about 50x, or about 100x).

[0021]

[0063] As used herein, the term "pharmacologically acceptable" refers to those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response, or other problems or complications, consistent with a reasonable benefit / risk ratio. In some embodiments, pharma- ceutically acceptable compounds, materials, compositions and / or dosage forms refer to those that have been approved by a regulatory agency (such as the U.S. Food and Drug Administration, the China Food and Drug Administration, or the European Medicines Agency) for use in animals, more specifically in humans, or that are listed in a generally recognized pharmacopoeia (such as the United States Pharmacopoeia, the Chinese Pharmacopoeia, the European Pharmacopoeia, etc.).

[0022]

[0064] As used herein, "pharmaceutical acceptable salts" or "pharmaceutical salts" refers to derivatives of the disclosed compounds, in which the parent compound is modified by converting an existing acidic (e.g., carboxyl, etc.) or basic (e.g., amine, alkali, etc.) moiety into its salt form. In many cases, the disclosed compounds can form acid addition and / or base salts due to the presence of amino, alkali and / or carboxyl groups or groups similar thereto. "Pharmaceutically acceptable salts" typically include acid addition or base salts that retain the biological effectiveness and properties of the parent compound, which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharma- ceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or organic acids such as acetic, propionic, glycolic, pyruvic, oxalic, lactic, trifluoroacetic, benzoic, cinnamic, mandelic, ethanesulfonic, p-toluenesulfonic, salicylic, malonic, fumaric, citric, malic, maleic, tartaric, succinic, or methanesulfonic acid, or by using other methods used in the art, such as ion exchange.Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfonate. , lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. In some embodiments, organic acids from which salts can be derived include, for example, methanesulfonic acid, maleic acid, fumaric acid, citric acid, succinic acid, L-malic acid, L-(+)-tartaric acid, etc. In certain embodiments, the pharma- ceutically acceptable salts are hydrochloride, methanesulfonate, sulfate, phosphate, maleate, fumarate, citrate, succinate, L-malate, and L-(+)-tartrate.

[0023]

[0065] As used herein, the terms "polymorphic form", "polymorph" or "crystalline form" refer to a solid in which the constituent atoms, molecules, or ions are packed into a regularly arranged, repeating three-dimensional pattern having a highly regular chemical structure. In particular, a compound or a salt thereof may be produced in one or more crystalline forms. Different crystalline forms can be identified by XRPD patterns (e.g., the positions and / or intensities of X-ray diffraction peaks at various diffraction angles (2θ)), the onset of the melting point (and the onset of dehydration for hydrated forms) as indicated by endotherms in differential scanning calorimetry (DSC) thermograms, thermogravimetric analysis (TGA), solid-phase 1It can be characterized by H nuclear magnetic resonance (NMR) spectroscopy, aqueous solubility, high intensity light conditions, physical and chemical storage stability, and other measurements known in the art.

[0024]

[0066] "XRPD pattern" refers to an experimentally observed diffractogram or parameters derived therefrom, shown as an xy graph with peak positions expressed as diffraction angle (2θ) on the x-axis and peak intensity on the y-axis. Peaks within this pattern can be used to characterize crystalline solid forms.

[0025]

[0067] The term "peak position" as used herein refers to the position of the X-ray reflection measured and observed in powder X-ray diffraction experiments. The position of the peak is directly related to the dimensions of the unit cell. The peaks identified by their respective peak positions are extracted from the diffraction patterns of the various polymorphic forms of Compound I disclosed herein.

[0026]

[0068] The term "peak intensity" refers to the relative signal intensities within a given X-ray powder diffraction pattern. Factors that can affect the relative peak intensities are the thickness of the sample and the preferred orientation (i.e., the crystalline grains are not randomly distributed).

[0027]

[0069] As with any data measurement, there is variability in XRPD data. Peak intensities are particularly sensitive to sample preparation (e.g. particle size, water content, solvent content, and preferred orientation effects affect sensitivity), so samples of the same material prepared under different conditions may produce slightly different patterns; this variability is usually larger than the variability in diffraction angle, so data are often expressed only in terms of the diffraction angle of the peaks, rather than including their intensity. Variability in diffraction angle may also be sensitive to sample preparation. Other sources of variability arise from instrument parameters and processing of raw X-ray data: different X-ray machines operate using different parameters, which can lead to slightly different XRPD patterns from the same solid form, and similarly, different software packages process X-ray data differently, which also leads to variability. These and other sources of variability are known to those skilled in the pharmaceutical arts. Due to these sources of variability, the measurement error in XRPD diffraction angles is approximately 2θ (±0.2°) and must be taken into consideration when examining the XRPD patterns in the figures and when reading the data contained in the Tables included herein.

[0028]

[0070] DSC measures the difference in thermal energy between a solid sample and a suitable reference as the temperature is increased. DSC thermograms are typically characterized by endotherms (indicating the uptake of energy) and also exotherms (indicating the release of energy) as the sample is heated. Those skilled in the art will also understand that the values ​​or range of values ​​observed in the DSC thermogram of a particular compound will show variation between batches of different purity. Depending on the heating rate (i.e., scan rate) at which the DSC analysis is performed, the method of defining and determining the DSC onset temperature, the calibration standards used, the calibration of the instrument, and the relative humidity (RH), as well as the chemical purity of the sample, the endotherms exhibited by the compounds of the present disclosure may vary (for crystalline polymorphic melting, the endotherms are ±0.01-10°C, and for polymorphic dehydration / desolvation, the endotherms are ±0.01-20°C), and the extent of such variation should be considered when considering the DSC data contained herein. To further clarify, although one compound prepared in different batches may show variation in its DSC thermogram, these DSC thermograms with variation should still be considered "substantially similar" to one another. For any given example, the endotherm observed may also vary from instrument to instrument; however, if the instruments are similarly calibrated, they will generally fall within the ranges defined herein. Furthermore, it will be appreciated that removal of residual solvent in the prepared compound may also cause changes in the DSC onset and peak temperatures.

[0029]

[0071] TGA is a test procedure that records the change in weight of a test specimen as it is heated in air or in a controlled atmosphere such as nitrogen. Thermogravimetric curves (thermograms) provide information about the solvent and moisture content, as well as the thermal stability of the material. TGA thermograms exhibit similar variability as DSC (measurement error of approximately ±5-20°C), so those skilled in the art will recognize that measurement error should be taken into account when judging the substantial identity of TGA thermograms.

[0030]

[0072] It should be understood that the "compounds" of the present disclosure can exist in solvated and unsolvated forms, e.g., hydrated forms, solid forms, etc., and the present disclosure is intended to encompass all such solvated and unsolvated forms. It should be further understood that the "compounds" of the present disclosure can exist in the form of pharma- ceutically acceptable salts or esters.

[0031]

[0073] Unless otherwise specified, "ErbB" or "wild type ErbB" refers to a normal ErbB family member. In one aspect, the present disclosure provides inhibitory compounds of ErbB family kinases (e.g., EGFR, Her2, Her3 and / or Her4). In some embodiments, the compounds of the present disclosure can inhibit both wild type (WT) and mutant forms of ErbB family kinases. In some embodiments, the compounds of the present disclosure are selective inhibitors of at least one mutant of ErbB family kinase compared to the corresponding WT ErbB family kinase.

[0032]

[0074] As used herein, the term "mutation" refers to any alteration to a target protein, and "mutant" or "mutated form" refers to a protein containing said mutation. Examples of ErbB mutations include EGFR D761_E762insEAFQ, EGFR A763_Y764insHH, EGFR M766_A767instAI, EGFR A767_V769dupASV, EGFR A767_S768insTLA, EGFR S768_D770 dupSVD, EGFR S768_V769insVAS, EGFR S768_V769insAWT, EGFR V769_D770insASV, EGFR V769_D770insGV, EGFR V769_D770insCV, EGFR V769_D770insDNV, EGFR V769_D770insGSV, EGFR V769_D770insGVV, EGFR V769_D770insMASVD, EGFR D770_N771insSVD, EGFR D770_N771insNPG, EGFR D770_N771insAPW, EGFR D770_N771insD, EGFR D770_N771insDG, EGFR D770_N771insG, EGFR D770_N771insGL, EGFR D770_N771insN, EGFR D770_N771insNPH, EGFR D770_N771insSVP, EGFR D770_N771insSVQ, EGFR D770_N771insMATP, EGFR delD770insGY, EGFR N771_P772insH, EGFR N771_P772insN, EGFR N771_H773dupNPH, EGFR delN771insGY, EGFR delN771insGF, EGFR P772_H773insPR, EGFR P772_H773insYNP, EGFR P772_H773insX, EGFR P772_H773insDPH, EGFR P772_H773insDNP, EGFR P772_H773insQV, EGFR P772_H773insTPH, EGFR P772_H773insN, EGFR P772_H773insV, EGFR H773_V774insNPH, EGFR H773_V774insH, EGFRH773_V774insPH, EGFR H773_V774insGNPH, EGFR H773_V774dupHV, EGFR H773_V774insG, EGFR H773_V774insGH, EGFR V774_C775insHV, EGFR exon 19 deletion, EGFR L858R, EGFR T790M, EGFR L858R / T790M, EGFR exon 19 deletion / T790M, EGFR S768I, EGFR G719S, EGFR G719A, EGFR G719C, EGFR E709A / G719S, EGFR E709A / G719A, EGFR E709A / G719C, EGFR L861Q, and others in Her2; A775_G776insYVMA, Her2 delG776insVC, Her2 V777_G778insCG, Her2 P780_Y781insGSP, etc. In some embodiments, the compounds of the present disclosure are selective inhibitors of at least one mutation of EGFR compared to WT EGFR. In some embodiments, the compounds of the present disclosure are selective inhibitors of at least one mutation of Her2 compared to WT Her2. In some embodiments, the at least one mutation of EGFR is a point mutation (e.g., L858R, T790M). In some embodiments, the at least one mutation of EGFR is a deletion mutation (e.g., delE746-A750). In some embodiments, the at least one mutation of EGFR is an insertion mutation (e.g., EGFR exon20V769_D770insASV, exon20H773_V774insNPH). In some embodiments, at least one mutation in EGFR is an activating mutation (e.g., L858R, G719S, or delE746-A750). In some embodiments, at least one mutation in EGFR is a drug resistance mutation (e.g., exon 20_T790M). In some embodiments, at least one mutation in EGFR is T790M. In some embodiments, provided compounds selectively inhibit T790M / L858R co-mutation and are sparing with respect to WT EGFR inhibition.

[0033]

[0075] As used herein, the term "selectively inhibit" as used relative to inhibition of WT EGFR / Her2 means that a provided compound is a more potent inhibitor of at least one mutation in EGFR / Her2 (i.e., at least one point mutation, at least one deletion mutation, at least one insertion mutation, at least one activating mutation, at least one resistance mutation, or a combination of at least one deletion mutation and at least one point mutation) in at least one assay (e.g., a biochemical or cellular assay) described herein. In some embodiments, the term "selectively inhibit" when used in comparison to WT EGFR / Her2 inhibition means that the provided compounds are at least 100-fold, at least 50-fold, at least 45-fold, at least 40-fold, at least 35-fold, at least 30-fold, at least 25-fold, at least 20-fold, at least 15-fold, at least 10-fold, at least 5-fold, at least 4-fold, at least 3-fold, at least 2-fold, at least 1.5-fold, or at least 1.25-fold more potent as inhibitors of at least one mutation of EGFR / Her2 as defined and described herein as compared to WT EGFR / Her2. In some embodiments, the term "selectively inhibits", when used in comparison to WT EGFR / Her2 inhibition, means that the provided compounds are up to 1500-fold, up to 1200-fold, up to 1000-fold, up to 800-fold, up to 600-fold, up to 400-fold, up to 200-fold, up to 100-fold, up to 50-fold, up to 10-fold more potent as inhibitors of at least one mutation of EGFR / Her2 as defined and described herein, as compared to WT EGFR / Her2. As used herein, the term "sparing with respect to WT EGFR / Her2" means that said selective inhibitor of at least one mutation of EGFR / Her2 as defined and described above and herein is unable to inhibit WT EGFR / Her2 within the upper limit of detection in at least one assay (e.g., biochemical or cellular, as detailed in the Examples) described herein.In some embodiments, the term "sparing with respect to WT EGFR / Her2" refers to a compound provided having an IC of at least 10 μM, at least 9 μM, at least 8 μM, at least 7 μM, at least 6 μM, at least 5 μM, at least 3 μM, at least 2 μM, or at least 1 μM. 50 In some embodiments, the compounds of the present disclosure have an IC of 0.1-1000 nM, preferably 0.1-600 nM, 1-600 nM, 0.1-500 nM, 1-500 nM, 0.1-400 nM, 1-400 nM, 0.1-300 nM, 1-300 nM, 0.1-200 nM, 1-200 nM, 0.1-100 nM, 1-100 nM, 0.1-80 nM, 0.1-50 nM, 0.1-40 nM, 0.1-30 nM, 0.1-20 nM, 0.1-10 nM, or 0.1-5 nM, more preferably 0.1-20 nM, 0.1-10 nM, or 0.1-5 nM. 50 In some embodiments, compounds of the present disclosure inhibit phosphorylation of WT EGFR / Her2 and / or mutant EGFR / Her2 with a GI of 1-1000 nM, preferably 1-800 nM, 1-600 nM, 1-500 nM, 1-400 nM, 1-300 nM, 1-300 nM, 1-200 nM, 1-100 nM, 1-80 nM, 1-60 nM, 1-40 nM, 1-20 nM, or 1-10 nM, more preferably 1-300 nM, 1-200 nM, 1-100 nM, 1-80 nM, 1-60 nM, 1-40 nM, 1-20 nM, or 1-10 nM. 50 In some embodiments, compounds of the disclosure have a GI of 1-1000 nM, greater than 1000 nM, greater than 2000 nM, or greater than 3000 nM, preferably 1-800 nM, 1-600 nM, 1-500 nM, 1-400 nM, 1-300 nM, 1-300 nM, 1-200 nM, 1-100 nM, 1-80 nM, 1-60 nM, 1-40 nM, 1-20 nM, or 1-10 nM, more preferably 1-300 nM, 1-200 nM, 1-100 nM, 1-80 nM, 1-60 nM, 1-40 nM, 1-20 nM, or 1-10 nM, 50In some embodiments, the compound inhibits proliferation of BTK-bearing cells at IC values ​​against EGFR / Her2 mutants. 50 and / or G.I. 50 is the IC of a compound against wild-type EGFR / Her2 50 and / or G.I. 50 at least 2-fold, 3-fold, 4-fold, 5-fold, and preferably 10-fold, 20-fold, 30-fold, 50-fold, or 100-fold higher than

[0034]

[0076] The term "pharmaceutical composition" refers to a mixture of one or more physiologically / pharmaceutical acceptable salts of Compound I, or polymorphs of Compound I or its salts, as described herein, with other chemical components, such as physiologically / pharmaceutical acceptable diluents, excipients or carriers. The purpose of a pharmaceutical composition is to facilitate administration of a compound to a subject.

[0035]

[0077] As used herein, the term "sustained release form" refers to the release of an active agent from a pharmaceutical composition such that it becomes available for bioabsorption over an extended period of time (sustained release) or at a specific location (controlled release) in a subject, primarily in the gastrointestinal tract of the subject.

[0036]

[0078] The term "pharmaceutically acceptable carrier" as used herein refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a compound provided herein from one location, bodily fluid, tissue, organ (internal or external), or part of the body to another location, bodily fluid, tissue, organ, or part of the body. A pharmaceutically acceptable carrier can be a vehicle, diluent, excipient, or other material that can be used to contact the tissue of an animal without undue toxicity or adverse effects.Non-limiting examples of pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as polyethylene glycol, propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate. ; colorants; release agents; coating agents; sweeteners, flavors, and fragrances; preservatives; antioxidants; ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate; surfactants used in pharmaceutical dosage forms such as Tween or other similar polymeric delivery matrices; serum proteins such as human serum albumin; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; salts or electrolytes such as water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulosic materials; polyacrylates; waxes; and polyethylene-polyoxypropylene-block polymers. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrin, or other solubilizing derivatives, can also be used to enhance delivery of the compounds described herein.Pharmaceutically acceptable carriers that can be used in this disclosure include those generally known in the art, such as those disclosed in "Remington Pharmaceutical Sciences" Mack Pub. Co., New Jersey (1991), incorporated herein by reference.

[0037]

[0079] As used herein, "administration" of the disclosed compounds includes delivery of a compound described herein, or a prodrug or other pharma- ceutically acceptable derivative thereof, to a subject using any suitable formulation or route of administration, as discussed herein.

[0038]

[0080] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition described herein sufficient to prevent, treat, alleviate and / or ameliorate the symptoms and / or underlying causes of any disorder or disease in a subject, or an amount of an agent sufficient to produce a desired effect on a target cell, such as a reduction in cell migration. In one embodiment, a "therapeutically effective amount" is an amount sufficient to reduce or eliminate the symptoms of a disease. In another embodiment, a therapeutically effective amount is an amount sufficient to overcome the disease itself. In certain embodiments, a "therapeutically effective amount" is an amount effective to kill or inhibit the growth or spread of detectable cancer cells, reduce the size or number of tumors; or other measures of the level, stage, progression or severity of a cancer. The therapeutically effective amount varies depending on the subject and the condition being treated, the weight and age of the subject, the severity of the condition, the particular composition or excipient selected, the dosing regimen to be followed, the timing of administration, the mode of administration, etc., all of which can be readily determined by one of ordinary skill in the art. The complete therapeutic effect does not necessarily occur with the administration of a single dose, but may occur only after the administration of a series of doses. The specific dose will vary depending on, for example, the particular compound selected, the species of the subject and its age / pre-existing health condition or risk of health condition, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other drugs, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered. Thus, a therapeutically effective amount can be administered in one or more administrations. For example, but not limited to, in the context of treating cancer, a therapeutically effective amount of an agent refers to the amount of the agent that relieves, improves, palliates, or eliminates one or more symptoms of cancer in a patient.

[0039]

[0081] As used herein, the term "BTK-associated disease" or "BTK-associated disease" refers to a disease whose onset or progression, or both, is associated with genomic alterations or mutations, expression or activity of BTK.

[0040]

[0082] As used herein, the term "ErbB-associated disease" or "ErbB-associated disease" refers to a disease whose onset or progression or both are associated with genomic alterations or mutations, expression or activity of ErbB (including EGFR and Her2). Examples of "ErbB-associated disease" include "EGFR-associated disease" or "Her2-associated disease". The term "EGFR-associated disease" or "EGFR-associated disease" or "Her2-associated disease" or "Her2-associated disease" refers to a disease whose onset or progression or both are associated with genomic alterations or mutations, expression or activity of EGFR or Her2, as the case may be. Examples include, but are not limited to, immune-associated diseases, proliferative diseases, cancer, and other diseases.

[0041]

[0083] As used herein, the terms "treat", "treatment", and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered even in the absence of symptoms. For example, treatment may be administered to susceptible individuals (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors) prior to the onset of symptoms. Treatment may be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0042]

[0084] As used herein, "anti-cancer agent", "anti-tumor agent" or "chemotherapeutic agent" refers to any agent useful in the treatment of a neoplastic condition. One class of anti-cancer agents includes chemotherapeutic agents. "Chemotherapy" refers to the administration of one or more chemotherapeutic agents and / or other agents to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation, or in the form of a suppository.

[0043]

[0085] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)), and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, e.g., commercially relevant mammals such as cows, pigs, horses, sheep, goats, rabbits, hamsters, mice, cats, and / or dogs; and / or birds, e.g., commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys.

[0044]

[0086] Compound I

[0087] The compound ((R)-N-(5-((4-((5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (Compound I), described in WO2019149164A1, is a potent ErbB inhibitor and BTK inhibitor, and has the following structure:

[0045] [ka]

[0046] has.

[0088] Provided herein are novel pharmaceutical salts of Compound I, crystalline polymorphs of Compound I, or pharmaceutical salts of the disclosure, compositions thereof, methods for their preparation, and uses thereof, such as inhibiting ErbB or BTK, treating an ErbB-related or BTK-related disorder in a subject.

[0047]

[0089] Pharmaceutical Salts of Compound I

[0090] In one aspect, the present disclosure provides novel pharmaceutical salts of Compound I.

[0091] In some embodiments, the pharmaceutical salt of Compound I provided herein is selected from the following: hydrochloride, methanesulfonate, sulfate, phosphate, maleate, fumarate, citrate, succinate, L-malate, L-(+)-tartrate, and hydrochloride salts of Compound I.

[0048]

[0092] In some embodiments, the pharmaceutical salt of Compound I is a compound having the structure of Formula (I):

[0049] [ka]

[0050] (wherein n=1 or 2; X is hydrochloric acid, L-(+)-tartaric acid, fumaric acid, sulfuric acid, or maleic acid.

[0093] In certain embodiments, the pharmaceutical salt of compound I is a hydrochloride, L-(+)-tartrate, fumarate, sulfate, and maleate salt of compound I in crystalline form. In certain embodiments, the pharmaceutical salt of compound I is a monosalt. In certain embodiments, the pharmaceutical salt of compound I is an amorphous form. In certain embodiments, the pharmaceutical salt of compound I is a crystalline form. In certain embodiments, the pharmaceutical salt of compound I is a hydrochloride, L-(+)-tartrate, fumarate, sulfate, and maleate salt of compound I in crystalline form.

[0051]

[0094] Characterization of crystal morphology

[0095] In one aspect, the present disclosure provides several polymorphic crystalline forms of Compound I, or a pharma- ceutically acceptable salt thereof.

[0052]

[0096] Crystalline forms of compound I or its salts

[0097] In one aspect, the disclosure provides a crystalline form of Compound I, particularly the free base Form A or Form B of Compound I. In another aspect, the disclosure provides a crystalline form of a pharma- ceutically acceptable salt of Compound I, particularly a crystalline form of the hydrochloride salt of Compound I, a crystalline form of the L-(+)-tartrate salt of Compound I, a crystalline form of the fumarate salt of Compound I, a crystalline form of the sulfate salt of Compound I, or a crystalline form of the maleate salt of Compound I.

[0053]

[0098] 1. Free Form A

[0099] In some embodiments, a crystalline form of Compound I (free base) is disclosed that is Form A of Compound I.

[0054]

[0100] In some embodiments, Form A of Compound I has an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.62±0.20, 12.48±0.20, 17.34±0.20, and 20.04±0.20 degrees diffraction angles (2θ).

[0055]

[0101] In some embodiments, Form A of Compound I has an XRPD pattern further comprising at least one, two, three or more peaks at selected from the following: 10.68±0.20, 11.11±0.20, 16.02±0.20, 20.79±0.20, 23.71±0.20, and 24.64±0.20 degrees 2θ.

[0056]

[0102] In some embodiments, Form A of Compound I has an XRPD pattern including peaks at 10.68±0.20, 11.11±0.20, 11.62±0.20, 12.48±0.20, 16.02±0.20, 17.34±0.20, 20.04±0.20, 20.79±0.20, 23.71±0.20, and 24.64±0.20 degrees 2θ.

[0057]

[0103] In some embodiments, Form A of Compound I has an XRPD pattern further comprising at least one, two, three or more peaks at angles 2θ selected from the following: 5.95±0.20, 14.96±0.20, 22.01±0.20, and 27.60±0.20 degrees 2θ.

[0058]

[0104] In some embodiments, Form A of Compound I has an XRPD pattern including peaks at 5.95±0.20, 10.68±0.20, 11.11±0.20, 11.62±0.20, 12.48±0.20, 14.96±0.20, 16.02±0.20, 17.34±0.20, 20.04±0.20, 20.79±0.20, 22.01±0.20, 23.71±0.20, 24.64±0.20, and 27.60±0.20 degrees 2θ.

[0059]

[0105] In some embodiments, Form A of Compound I has an XRPD pattern substantially as shown in Table 7.

[0106] In some embodiments, Form A of Compound I has an XRPD pattern substantially as shown in FIG.

[0060]

[0107] In some embodiments, Form A of Compound I has a DSC thermogram comprising an onset of desolvation at about 178.6°C and an endotherm with a peak at about 179.6°C.

[0108] In some embodiments, Form A of Compound I has a DSC thermogram substantially similar to that in FIG.

[0061]

[0109] In some embodiments, Form A of Compound I has a TGA thermogram that exhibits a mass loss of about 0.23% upon heating from about 38°C to about 160°C.

[0110] In some embodiments, Form A of Compound I has a TGA thermogram substantially similar to that in FIG.

[0062]

[0111] In some embodiments, Form A of Compound I has a DVS vapor sorption gram substantially similar to that in FIG.

[0112] 2. Free form B

[0113] In some embodiments, a crystalline form of Compound I (free base) is disclosed that is Form B of Compound I.

[0063]

[0114] In some embodiments, Form B of Compound I has an XRPD pattern comprising peaks at 9.39±0.20, 18.86±0.20, 19.50±0.20, and 20.06±0.20 degrees 2θ.

[0064]

[0115] In some embodiments, Form B of Compound I has an XRPD pattern further comprising at least one, two, three or more peaks at selected from the following: 10.59±0.20, 18.16±0.20, 18.56±0.20, 26.30±0.20, 33.71±0.20, and 34.81±0.20 degrees 2θ.

[0065]

[0116] In some embodiments, Form B of Compound I has an XRPD pattern including peaks at 9.39±0.20, 10.59±0.20, 18.16±0.20, 18.56±0.20, 18.86±0.20, 19.50±0.20, 20.06±0.20, 26.30±0.20, 33.71±0.20, and 34.81±0.20 degrees 2θ.

[0066]

[0117] In some embodiments, Form B of Compound I has an XRPD pattern further comprising at least one, two, three or more peaks at angles 2θ selected from the following: 22.07±0.20, 22.91±0.20, 23.68±0.20, and 24.00±0.20 degrees 2θ.

[0067]

[0118] In some embodiments, Form B of Compound I has an XRPD pattern including peaks at 9.39±0.20, 10.59±0.20, 18.16±0.20, 18.56±0.20, 18.86±0.20, 19.50±0.20, 20.06±0.20, 22.07±0.20, 22.91±0.20, 23.68±0.20, 24.00±0.20, 26.30±0.20, 33.71±0.20, and 34.81±0.20 degrees 2θ.

[0068]

[0119] In some embodiments, Form B of Compound I has an XRPD pattern substantially as shown in Table 8.

[0120] In some embodiments, Form B of Compound I has an XRPD pattern substantially as shown in FIG.

[0069]

[0121] In some embodiments, Form B of Compound I has a DSC thermogram comprising an onset of desolvation at about 194.8°C and an endotherm with a peak at about 196.7°C.

[0122] In some embodiments, Form B of Compound I has a DSC thermogram substantially similar to that in FIG.

[0070]

[0123] In some embodiments, Form B of Compound I has a TGA thermogram that exhibits less than 0.17% mass loss upon heating from about 38°C to about 178°C.

[0124] In some embodiments, Form B of Compound I has a TGA thermogram substantially similar to that in FIG.

[0071]

[0125] In some embodiments, Form B of Compound I has a DVS vapor sorption gram substantially similar to that in FIG.

[0126] 3. Crystalline Form of Compound I Hydrochloride

[0127] In some embodiments, a crystalline form of a pharma- ceutically acceptable salt of Compound I is disclosed, which is a crystalline form of Compound I hydrochloride.

[0072]

[0128] In some embodiments, the crystalline form of Compound I hydrochloride salt has an XRPD pattern comprising peaks at 9.35±0.20, 17.21±0.20, 18.21±0.20, 19.79±0.20, and 21.17±0.20 degrees 2θ.

[0073]

[0129] In some embodiments, the crystalline form of Compound I hydrochloride salt has an XRPD pattern further comprising at least one, two, three or more peaks at angles 2θ selected from the following: 9.05±0.20, 19.54±0.20, 21.17±0.20, 21.51±0.20, 26.24±0.20, and 30.64±0.20 degrees 2θ.

[0074]

[0130] In some embodiments, the crystalline form of Compound I hydrochloride salt has an XRPD pattern comprising peaks at 9.05±0.20, 9.35±0.20, 17.21±0.20, 18.21±0.20, 19.54±0.20, 19.79±0.20, 21.17±0.20, 21.51±0.20, 26.24±0.20, and 30.64±0.20 degrees 2θ.

[0075]

[0131] In some embodiments, the crystalline form of Compound I hydrochloride salt has an XRPD pattern further comprising at least one, two, three or more peaks at angles 2θ selected from the following: 7.30±0.20, 14.85±0.20, 20.91±0.20, 23.25±0.20, and 27.43±0.20 degrees 2θ.

[0076]

[0132] In some embodiments, the crystalline form of Compound I hydrochloride salt has an XRPD pattern including peaks at 7.30±0.20, 9.05±0.20, 9.35±0.20, 14.85±0.20, 17.21±0.20, 18.21±0.20, 19.54±0.20, 19.79±0.20, 20.91±0.20, 21.17±0.20, 21.51±0.20, 23.25±0.20, 26.24±0.20, 27.43±0.20, and 30.64±0.20 degrees 2θ.

[0077]

[0133] In some embodiments, the crystalline form of Compound I hydrochloride has an XRPD pattern substantially as shown in Table 16.

[0134] In some embodiments, the crystalline form of Compound I hydrochloride has an XRPD pattern substantially as shown in FIG.

[0078]

[0135] In some embodiments, the crystalline form of Compound I hydrochloride salt has a DSC thermogram comprising an onset of desolvation at about 207.8°C and an endotherm with a peak at about 212.1°C.

[0079]

[0136] In some embodiments, the crystalline form of Compound I hydrochloride salt has a TGA thermogram that exhibits a mass loss of about 0.76% upon heating to about 175°C.

[0137] In some embodiments, the crystalline form of Compound I hydrochloride salt has a TGA / DSC thermogram substantially similar to that in FIG.

[0080]

[0138] In some embodiments, the crystalline form of Compound I hydrochloride salt has a DVS vapor sorption gram substantially similar to that in FIG.

[0140] 4. Crystal form of compound I L-(+)-tartrate salt pattern I

[0141] In some embodiments, a crystalline form of a pharma- ceutically acceptable salt of Compound I is disclosed, which is a crystalline form of Compound I L-(+)-tartrate salt Pattern I.

[0081]

[0142] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern I has an XRPD pattern comprising peaks at 5.34±0.20, 5.38±0.20, 10.50±0.20, 10.92±0.20, and 16.37±0.20 degrees 2θ.

[0082]

[0143] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern I has an XRPD pattern further comprising at least one, two, three or more peaks at degrees 2θ selected from the following: 11.84±0.20, 15.05±0.20, 17.86±0.20, 18.52±0.20, and 18.99±0.20 degrees 2θ.

[0083]

[0144] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern I has an XRPD pattern including peaks at 5.34±0.20, 5.38±0.20, 10.50±0.20, 10.92±0.20, 11.84±0.20, 15.05±0.20, 16.37±0.20, 17.86±0.20, 18.52±0.20, and 18.99±0.20 degrees 2θ.

[0084]

[0145] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern I has an XRPD pattern further comprising at least one, two, three or more peaks at angles 2θ selected from the following: 7.29±0.20, 14.40±0.20, 22.02±0.20, and 23.96±0.20 degrees 2θ.

[0085]

[0146] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern I has an XRPD pattern including peaks at 5.34±0.20, 5.38±0.20, 7.29±0.20, 10.50±0.20, 10.92±0.20, 11.84±0.20, 14.40±0.20, 15.05±0.20, 16.37±0.20, 17.86±0.20, 18.52±0.20, 18.99±0.20, 22.02±0.20, and 23.96±0.20 degrees 2θ.

[0086]

[0147] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern I has an XRPD pattern substantially as shown in Table 17.

[0148] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern I has an XRPD pattern substantially as shown in FIG.

[0087]

[0149] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern I has a DSC thermogram comprising an onset of desolvation at about 207.8°C and an endotherm with a peak at about 212.1°C.

[0088]

[0150] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern I has a TGA thermogram that exhibits a mass loss of about 0.76% upon heating to about 175°C.

[0089]

[0151] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern I has a TGA thermogram substantially similar to that in FIG.

[0152] 5. Crystal form of compound I L-(+)-tartrate salt pattern II

[0153] In some embodiments, a crystalline form of a pharma- ceutically acceptable salt of Compound I is disclosed, which is the crystalline form of Compound I L-(+)-tartrate salt Pattern II.

[0090]

[0154] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern II has an XRPD pattern comprising peaks at 10.02±0.20, 18.03±0.20, 19.89±0.20, 21.15±0.20, and 21.26±0.20 degrees 2θ.

[0091]

[0155] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern II has an XRPD pattern further comprising at least one, two, three or more peaks at angles selected from the following: 12.70±0.20, 13.76±0.20, 16.80±0.20, 20.92±0.20, and 22.82±0.20 degrees 2θ.

[0092]

[0156] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern II has an XRPD pattern including peaks at 10.02±0.20, 12.70±0.20, 13.76±0.20, 16.80±0.20, 18.03±0.20, 19.89±0.20, 20.92±0.20, 21.15±0.20, 21.26±0.20, and 22.82±0.20 degrees 2θ.

[0093]

[0157] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern II has an XRPD pattern further comprising at least one, two, three or more peaks at selected from the following: 7.95±0.20, 15.91±0.20, 23.44±0.20, 25.55±0.20, and 29.99±0.20 degrees 2θ.

[0094]

[0158] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern II has an XRPD pattern including peaks at 7.95±0.20, 10.02±0.20, 12.70±0.20, 13.76±0.20, 15.91±0.20, 16.80±0.20, 18.03±0.20, 19.89±0.20, 20.92±0.20, 21.15±0.20, 21.26±0.20, 22.82±0.20, 23.44±0.20, 25.55±0.20, and 29.99±0.20 degrees 2θ.

[0095]

[0159] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern II has an XRPD pattern substantially as shown in Table 21.

[0160] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern II has an XRPD pattern substantially as shown in FIG.

[0096]

[0161] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern II has a DSC thermogram comprising an onset of desolvation at about 137.2°C and an endotherm with a peak at about 140.4°C.

[0097]

[0162] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern II has a TGA thermogram that exhibits a mass loss of about 3.59% upon heating to about 100°C.

[0098]

[0163] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern II has a TGA / DSC thermogram substantially similar to FIG.

[0164] In some embodiments, the crystalline form of Compound I L-(+)-tartrate salt Pattern II has a DVS vapor sorption gram substantially similar to that in FIG.

[0099]

[0165] 6. Crystalline Form of Compound I Fumarate

[0166] In some embodiments, a crystalline form of a pharma- ceutically acceptable salt of Compound I is disclosed, which is a crystalline form of Compound I fumarate salt.

[0100]

[0167] In some embodiments, the crystalline form of Compound I fumarate salt has an XRPD pattern comprising peaks at 11.92±0.20, 13.71±0.20, 19.54±0.20, 20.15±0.20, and 24.21±0.20 degrees 2θ.

[0101]

[0168] In some embodiments, the crystalline form of Compound I fumarate salt has an XRPD pattern further comprising at least one, two, three or more peaks at angles 2θ selected from the following: 13.08±0.20, 15.79±0.20, 18.86±0.20, 20.63±0.20, and 22.14±0.20 degrees 2θ.

[0102]

[0169] In some embodiments, the crystalline form of Compound I fumarate salt has an XRPD pattern comprising peaks at 11.92±0.20, 13.08±0.20, 13.71±0.20, 15.79±0.20, 19.54±0.20, 20.15±0.20, 18.86±0.20, 20.63±0.20, 22.14±0.20, and 24.21±0.20 degrees 2θ.

[0103]

[0170] In some embodiments, the crystalline form of Compound I fumarate salt has an XRPD pattern further comprising at least one, two, three or more peaks at angles 2θ selected from the following: 11.63±0.20, 12.33±0.20, 17.23±0.20, 18.52±0.20, and 23.79±0.20 degrees 2θ.

[0104]

[0171] In some embodiments, the crystalline form of Compound I fumarate salt has an XRPD pattern including peaks at 11.63±0.20, 11.92±0.20, 12.33±0.20, 13.08±0.20, 13.71±0.20, 15.79±0.20, 17.23±0.20, 18.52±0.20, 18.86±0.20, 19.54±0.20, 20.15±0.20, 20.63±0.20, 22.14±0.20, 23.79±0.20, and 24.21±0.20 degrees 2θ.

[0105]

[0172] In some embodiments, the crystalline form of Compound I fumarate salt has an XRPD pattern substantially as shown in Table 18.

[0173] In some embodiments, the crystalline form of Compound I fumarate salt has an XRPD pattern substantially as shown in FIG.

[0106]

[0174] In some embodiments, the crystalline form of Compound I fumarate salt has a DSC thermogram comprising an onset of desolvation at about 48.9°C and an endotherm with a peak at about 68.3°C.

[0107]

[0175] In some embodiments, the crystalline form of Compound I fumarate salt has a DSC thermogram that further comprises an onset of desolvation at about 132.79°C and a subsequent endotherm having a peak at about 141.78°C.

[0108]

[0176] In some embodiments, the crystalline form of Compound I fumarate salt has a TGA thermogram that exhibits a mass loss of about 2.86% upon heating to about 55°C.

[0177] In some embodiments, the crystalline form of Compound I fumarate salt has a TGA thermogram that exhibits a mass loss of about 2.42% upon heating from about 55°C to about 140°C.

[0109]

[0178] In some embodiments, the crystalline form of Compound I fumarate salt has a TGA / DSC thermogram substantially similar to that in FIG.

[0179] In some embodiments, the crystalline form of Compound I fumarate salt has a DVS vapor sorption gram substantially similar to that in FIG.

[0110]

[0180] 7. Crystalline form of compound I sulfate

[0181] In some embodiments, a crystalline form of a pharma- ceutically acceptable salt of Compound I is disclosed, which is a crystalline form of Compound I sulfate.

[0111]

[0182] In some embodiments, the crystalline form of Compound I sulfate salt has an XRPD pattern comprising peaks at 6.00±0.20, 12.16±0.20, 17.37±0.20, 18.19±0.20, and 20.51±0.20 degrees 2θ.

[0112]

[0183] In some embodiments, the crystalline form of Compound I sulfate salt has an XRPD pattern further comprising at least one, two, three or more peaks at angles 2θ selected from the following: 7.54±0.20, 17.16±0.20, 19.52±0.20, and 22.65±0.20 degrees 2θ.

[0113]

[0184] In some embodiments, the crystalline form of Compound I sulfate salt has an XRPD pattern comprising peaks at 6.00±0.20, 7.54±0.20, 12.16±0.20, 17.16±0.20, 17.37±0.20, 18.19±0.20, 19.52±0.20, 20.51±0.20, and 22.65±0.20 degrees 2θ.

[0114]

[0185] In some embodiments, the crystalline form of Compound I sulfate salt has an XRPD pattern further comprising at least one, two, three or more peaks at angles 2θ selected from the following: 14.90±0.20, 22.02±0.20, 24.86±0.20, and 25.73±0.20 degrees 2θ.

[0115]

[0186] In some embodiments, the crystalline form of Compound I sulfate salt has an XRPD pattern comprising peaks at 6.00±0.20, 7.54±0.20, 12.16±0.20, 14.90±0.20, 17.16±0.20, 17.37±0.20, 18.19±0.20, 19.52±0.20, 20.51±0.20, 22.02±0.20, 22.65±0.20, 24.86±0.20, and 25.73±0.20 degrees 2θ.

[0116]

[0187] In some embodiments, the crystalline form of Compound I sulfate salt has an XRPD pattern substantially as shown in Table 19.

[0188] In some embodiments, the crystalline form of Compound I sulfate salt has an XRPD pattern substantially as shown in FIG.

[0117]

[0189] In some embodiments, the crystalline form of Compound I sulfate salt has a DSC thermogram comprising an onset of desolvation at about 181.2°C and an endotherm with a peak at about 195.9°C.

[0118]

[0190] In some embodiments, the crystalline form of Compound I sulfate salt has a DSC thermogram further comprising an onset of post-desolvation at about 210.6°C and an endotherm having a peak at about 226.0°C.

[0119]

[0191] In some embodiments, the crystalline form of Compound I sulfate salt has a TGA thermogram that exhibits a mass loss of about 4.85% upon heating to about 120°C.

[0192] In some embodiments, the crystalline form of Compound I sulfate salt has a TGA thermogram substantially similar to that in FIG.

[0120]

[0193] 8. Crystalline Form of Compound I Maleate

[0194] In some embodiments, a crystalline form of a pharma- ceutically acceptable salt of Compound I is disclosed, which is a crystalline form of Compound I maleate.

[0121]

[0195] In some embodiments, the crystalline form of Compound I maleate has an XRPD pattern comprising peaks at 11.94±0.20, 15.64±0.20, 16.10±0.20, 20.98±0.20, and 22.65±0.20 degrees 2θ.

[0122]

[0196] In some embodiments, the crystalline form of Compound I maleate has an XRPD pattern further comprising at least one, two, three or more peaks at angles 2θ selected from the following: 4.90±0.20, 7.45±0.20, 24.27±0.20, and 25.67±0.20 degrees 2θ.

[0123]

[0197] In some embodiments, the crystalline form of Compound I maleate has an XRPD pattern comprising peaks at 4.90±0.20, 7.45±0.20, 11.94±0.20, 15.64±0.20, 16.10±0.20, 20.98±0.20, 22.65±0.20, 24.27±0.20, and 25.67±0.20 degrees 2θ.

[0124]

[0198] In some embodiments, the crystalline form of Compound I maleate has an XRPD pattern further comprising at least one, two, three or more peaks at angles 2θ selected from the following: 9.57±0.20, 12.74±0.20, 13.19±0.20, and 18.46±0.20 degrees 2θ.

[0125]

[0199] In some embodiments, the crystalline form of Compound I maleate has an XRPD pattern comprising peaks at 4.90±0.20, 7.45±0.20, 9.57±0.20, 11.94±0.20, 12.74±0.20, 13.19±0.20, 15.64±0.20, 16.10±0.20, 18.46±0.20, 20.98±0.20, 22.65±0.20, 24.27±0.20, and 25.67±0.20 degrees 2θ.

[0126]

[0200] In some embodiments, the crystalline form of Compound I maleate has an XRPD pattern substantially as shown in Table 20.

[0201] In some embodiments, the crystalline form of Compound I maleate has an XRPD pattern substantially as shown in FIG.

[0127]

[0202] In some embodiments, the crystalline form of Compound I maleate has a DSC thermogram comprising an onset of desolvation at about 64.6°C and an endotherm with a peak at about 75.7°C.

[0128]

[0203] In some embodiments, the crystalline form of Compound I maleate has a DSC thermogram further comprising an onset of post-desolvation at about 137.3°C and an endotherm having a peak at about 140.4°C.

[0129]

[0204] In some embodiments, the crystalline form of Compound I maleate salt has a TGA thermogram that exhibits a mass loss of about 3.59% upon heating to about 100°C.

[0205] In some embodiments, the crystalline form of Compound I maleate has a TGA thermogram substantially similar to that in FIG.

[0130]

[0206] When crystalline forms are referred to herein, the degree of crystallinity is advantageously greater than about 60%, more advantageously greater than about 80%, more advantageously greater than about 90%, and more advantageously greater than about 95%. Most advantageously, the degree of crystallinity is greater than about 98%.

[0131]

[0207] In some embodiments, the polymorphic forms of the present disclosure are preferably substantially pure, meaning that each polymorphic form contains no more than 10% by weight, preferably no more than 5% by weight, preferably no more than 1% by weight of any one apparent impurity, including other polymorphic forms of the compound. In certain embodiments, the "substantially pure" polymorphic forms of the present disclosure have a purity of greater than 90%, greater than 95%, greater than 98%, or even greater than 99%.

[0132]

[0208] In some embodiments, the polymorphic forms of the present disclosure may exist together in a mixture.The mixture of the polymorphic forms of the present disclosure will have the characteristic XRPD peaks of each of the polymorphic forms present in the mixture.For example, the mixture of two polymorphic forms will have an XRPD pattern that is the convolution of the X-ray powder diffraction patterns corresponding to the substantially pure polymorphic forms.

[0133]

[0209] Process for preparation

[0210] Further provided herein are pharma- ceutically acceptable salts as well as polymorphic forms of Compound I, and processes for the preparation of the pharma- ceutically acceptable salts thereof.

[0134]

[0211] The pharmaceutical salt and polymorphic forms of the present disclosure can be prepared by methods known in the art.In some embodiments, the crystals of the pharmaceutically acceptable salt of compound I are prepared by dissolving compound I in acetone or ethanol solution, adding corresponding acid to acetone or ethanol solution, allowing the solution to stand and crystallize, and isolating the crystals of the pharmaceutically acceptable salt of compound I, and the pharmaceutically acceptable salt is selected from hydrochloride, L-(+)-tartrate, fumarate, sulfate, and maleate.However, these are in no way limiting the preparation method of the pharmaceutical salt and polymorphic forms of the present disclosure.

[0135]

[0212] Further provided herein is a process for preparing Compound I on a tens of kilograms scale with high product yields.

[0213] The process for preparing Compound I on a tens of kilograms scale is summarized in the following scheme:

[0136] [ka]

[0137]

[0214] The improved process summarized in the scheme above has been shown to be suitable for producing compound I in high yield on a tens of kilograms scale. In particular: (i) It is not necessary to isolate the compound of formula (7) in the process. (ii) a compound of formula (9) is selected and used to prepare a compound of formula (3), thereby significantly increasing the yield of the compound of formula (3); in some embodiments, the yield of the compound of formula (3) is increased by 29% compared to the method disclosed in WO2019149164A1; and (iii) The process employs a specific synthetic route from a compound having the structure of formula (6) to compound I, which significantly increases the product yield of compound I. In some embodiments, the yield of compound I is increased by 74% compared to the method disclosed in WO2019149164A1.

[0138]

[0215] In some embodiments, the process for preparing compound I comprises the steps of: (i) reacting an acrylamide reagent with a compound of formula (7):

[0139] [ka]

[0140] contacting the and (ii) adding a base reagent to the mixture obtained in step (i) to form compound I. In some embodiments, the acrylamide reagent is selected from the group consisting of acryloyl chloride, acrylic acid, 3-chloropropionic acid, and 3-chloropropionyl chloride. In some embodiments, the acrylamide reagent is 3-chloropropionyl chloride. In some embodiments, the base reagent is selected from the group consisting of N,N,-diisopropylethylamine, triethylamine, pyridine, DBU, K2CO3, KOH, KHCO3, LiOH, NaOH, Na2CO3, NaHCO3. In some embodiments, the base reagent is NaOH.

[0141]

[0216] In some embodiments, the process for preparing compound I includes (iii) reacting a compound of formula (6):

[0142] [ka]

[0143] In some embodiments, the organic solvent is tetrahydrofuran. In some embodiments, the compound of formula (7) obtained in step (iii) is not isolated and is used directly in step (i).

[0144]

[0217] In some embodiments, the process for preparing compound I includes (iv) reacting a compound of formula (5):

[0145] [ka]

[0146] with a compound of formula (10) or formula (11):

[0147] [ka]

[0148] In some embodiments, the base is KCO and / or N,N-diisopropylethylamine and the organic solvent is acetonitrile to prepare a compound of formula (6).

[0149]

[0218] In some embodiments, the process for preparing compound I includes (v) reacting a compound of formula (3)

[0150] [ka]

[0151] in the presence of an organic solvent and an organic acid to obtain a compound of formula (4):

[0152] [ka]

[0153] In some embodiments, the organic solvent is isopropanol and the organic acid is trifluoroacetic acid to prepare a compound of formula (5).

[0154]

[0219] In some embodiments, the process for preparing compound I comprises (vi) reacting a compound of formula (1) or a salt of a compound of formula (1) in the presence of an organic solvent and an organic base:

[0155] [ka]

[0156] with a compound of formula (8):

[0157] [ka]

[0158] preparing a compound of formula (3) by contacting (vii) crystallizing the mixture obtained in step (vi) by addition of aqueous NH4Cl. In some embodiments, the salt of the compound of formula (1) is selected from the group consisting of hydrochloride, methanesulfonate, sulfate, phosphate, maleate, fumarate, citrate, succinate, L-malate, and L-(+)-tartrate salts of the compound of formula (1). In some embodiments, the organic solvent is isopropanol and the organic base is N,N,-diisopropylethylamine.

[0159]

[0220] Further provided herein is a process for producing a compound of formula (1) or a salt of a compound of formula (1) in the presence of an organic solvent and an organic base:

[0160] [ka]

[0161] with a compound of formula (8):

[0162] [ka]

[0163] contacting the (ii) crystallizing the mixture obtained in step (i) by addition of aqueous NH4Cl. In some embodiments, the salt of the compound of formula (1) is selected from the group consisting of hydrochloride, methanesulfonate, sulfate, phosphate, maleate, fumarate, citrate, succinate, L-malate, and L-(+)-tartrate salts of the compound of formula (1). In some embodiments, the organic solvent is isopropanol and the organic base is N,N,-diisopropylethylamine.

[0164]

[0221] Further provided herein is a recrystallization process for preparing Form B of compound I, comprising dissolving compound I in an acetone / HO solution, adding Form B crystal seeds to the solution, and allowing the solution to crystallize to isolate Form B of compound I.

[0165]

[0222] Pharmaceutical Compositions

[0223] In one aspect, the present disclosure also provides a pharmaceutical composition comprising one or more crystalline polymorphic forms as described above and a pharma- ceutically acceptable carrier.

[0166]

[0224] The pharmaceutically acceptable carrier is a conventional pharmaceutical carrier in the art, which can be prepared by a method well known in the pharmaceutical field.In some embodiments, the compound of the present disclosure can be mixed with a pharmaceutically acceptable carrier for preparing a pharmaceutical composition.

[0167]

[0225] Some examples of materials which can function as pharma- ceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) (11) glycols, such as propylene glycol; (12) esters, such as ethyl oleate, ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) alcohols, such as ethyl alcohol and propane alcohol; (20) phosphate buffers; and (21) other non-toxic compatible substances used in pharmaceutical formulations, such as acetone.

[0168]

[0226] Pharmaceutical compositions may contain pharma- ceutically acceptable auxiliary substances required to approximate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, and the like, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like.

[0169]

[0227] The form of the pharmaceutical composition will depend on several criteria, including, but not limited to, the route of administration, the extent of the disease, or the dosage to be administered.

[0228] The pharmaceutical composition can be formulated for oral, nasal, rectal, transdermal, intravenous or intramuscular administration. According to the desired route of administration, the pharmaceutical composition can be formulated in the form of tablets, capsules, pills, dragees, powders, granules, sachets, cachets, lozenges, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), sprays, ointments, pastes, creams, lotions, gels, patches, inhalants or suppositories.

[0170]

[0229] The pharmaceutical composition may be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by using procedures known in the art. In some embodiments, the pharmaceutical composition is formulated in sustained release form. In some embodiments, the extended period can be about 1 hour to 24 hours, 2 hours to 12 hours, 3 hours to 8 hours, 4 hours to 6 hours, 1 day to 2 days, or more. In certain embodiments, the extended period is at least about 4 hours, at least about 8 hours, at least about 12 hours, or at least about 24 hours. The pharmaceutical composition may be formulated in the form of a tablet. For example, the release rate of the active agent may be controlled not only by dissolution of the active agent from a tablet or pill in gastrointestinal fluids and subsequent pH-independent diffusion, but also by the physical processes of tablet disintegration and erosion. In some embodiments, polymeric materials such as those disclosed in "Medical Applications of Controlled Release", Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); "Controlled Drug Bioavailability", Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J Macromol. Sci. Rev. Macromol Chem. 23:61 can be used for sustained release; see also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105. The above references are incorporated herein by reference in their entirety.

[0171]

[0230] In certain embodiments, the pharmaceutical composition comprises from about 0.0001 mg to about 5000 mg of a compound of the present disclosure (e.g., 0.0001 mg to about 10 mg, from about 0.001 mg to about 10 mg, from about 0.01 mg to about 10 mg, from about 0.1 mg to about 10 mg, from about 1 mg to about 10 mg, from about 5 mg to about 10 mg, from about 5 mg to about 20 mg, from about 5 mg to about 30 mg, from about 5 mg to about 40 mg, from about 5 mg to about 50 mg, from about 10 mg to about 100 mg, from about 20 mg to about 100 mg, from about 30 mg to about 100 mg, from about 40 mg to about 100 mg, from about 50 mg to about 100 mg, from about 50 mg to about 200 mg, from about 50 mg to about 300 mg, about 50mg to about 400mg, about 50mg to about 500mg, about 100mg to about 200mg, about 100mg to about 300mg, about 100mg to about 400mg, about 100mg to about 500mg, about 200mg to about 500mg, about 300mg to about 500mg, about 400mg to about 500mg, about 500mg to about 1000mg, about 600mg to about 1000mg, about 700mg to about 1000mg, about 800mg to about 1000mg, about 900mg to about 1000mg, about 1000mg to about 2000mg, about 2000mg to about 3000mg, about 3000mg to about 4000mg, or about 4000mg to about 5000mg). A suitable daily dose per subject can be from about 5 mg to about 500 mg, preferably from about 5 mg to about 50 mg, from about 50 mg to about 100 mg, or from about 50 mg to about 500 mg.

[0172]

[0231] In certain embodiments, the pharmaceutical composition is administered in an amount of about 0.0001 mg to about 10 mg, about 0.001 mg to about 10 mg, about 0.01 mg to about 10 mg, about 0.1 mg to about 10 mg, about 1 mg to about 10 mg, about 5 mg to about 10 mg, about 5 mg to about 20 mg, about 5 mg to about 30 mg, about 5 mg to about 40 mg, about 5 mg to about 50 mg, about 10 mg to about 100 mg, about 20 mg to about 100 mg, about 30 mg to about 100 mg, about 40 mg to about 100 mg, about 50 mg to about 100 mg, about 50 mg to about 200 mg, about 50 mg to about 300 mg, about 50 mg to about 400 mg, about 50 mg to about 500 mg, or about 1 The compound of the present disclosure can be formulated in a unit dosage form containing about 00 mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about 400 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg, about 300 mg to about 500 mg, about 400 mg to about 500 mg, about 500 mg to about 1000 mg, about 600 mg to about 1000 mg, about 700 mg to about 1000 mg, about 800 mg to about 1000 mg, about 900 mg to about 1000 mg, about 1000 mg to about 2000 mg, about 2000 mg to about 3000 mg, about 3000 mg to about 4000 mg, or about 4000 mg to about 5000 mg. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.

[0173]

[0232] In some embodiments, the pharmaceutical composition comprises one or more pharmaceutical salts and / or polymorphs of the present disclosure as a first active ingredient and further comprises a second active ingredient, which can be an anti-cancer agent known in the art, such as a cell signaling inhibitor, a cell signaling inhibitor, an alkylating agent, a topoisomerase inhibitor, an immunotherapeutic agent, a mitotic inhibitor, an antihormonal agent, a chemotherapeutic agent, an EGFR inhibitor, a CTLA-4 inhibitor, a MEK inhibitor, a PD-L1 inhibitor, an OX40 agonist, and the like. Representative examples of anti-cancer drugs for treating cancer or tumors include sorafenib, sunitinib, dasatinib, vorinostat, temsirolimus, everolimus, pazopanib, trastuzumab, ado-trastuzumab, emtansine, pertuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, panitumumab, tremelimumab, pembrolizumab, nivolumab, ipilimumab, atezolizumab, avelumab, durvalumab, crizotinib, ruxolitinib ...trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, trastuzumab, These may include, but are not limited to, clitaxel, vincristine, vinblastine, cisplatin, carboplatin, gemcitabine, tamoxifen, raloxifene, cyclophosphamide, clomadulin, carmustine, methotrexate, fluorouracil, actinomycin, doxorubicin, epirubicin, anthracyclines, bleomycin, mitomycin-C, irinotecan, topotecan, teniposide, interleukins, interferons, etc. In some embodiments, the second active agent is one or more of bevacizumab, pembrolizumab, nivolumab, ipilimumab, atezolizumab, avelumab, durvalumab, crizotinib.

[0174]

[0233] Uses and Methods for Treatment

[0234] In one aspect, the crystalline forms, pharmaceutical salts, or pharmaceutical compositions provided herein are for use as a medicament for inhibiting ErbB (e.g., EGFR, Her2, Her3, or Her4) or BTK. In another aspect, the present disclosure provides for the use of the crystalline forms, pharmaceutical salts, or pharmaceutical compositions of the present disclosure in the manufacture of a medicament for treating a disease associated with ErbB or BTK.

[0175]

[0235] In one aspect, the disclosure provides methods of inhibiting ErbB or BTK by using one or more of the crystalline forms, pharmaceutical salts, or pharmaceutical compositions provided herein.

[0176]

[0236] In another aspect, the present disclosure also provides methods of inhibiting ErbB or BTK by using one or more of the crystalline forms, pharmaceutical salts, or pharmaceutical compositions provided herein.

[0177]

[0237] In yet another aspect, the disclosure provides a method of treating an ErbB (e.g., including EGFR or Her2, particularly ErbB mutants), related disease, or BTK-related disease in a subject, comprising administering to the subject an effective amount of one or more crystalline forms, pharmaceutical salts, or pharmaceutical compositions provided herein.

[0178]

[0238] In some embodiments, the subject is a warm-blooded animal, such as a human.

[0239] In some embodiments, the ErbB-related disease or BTK-related disease is cancer, an autoimmune disease, or inflammation. In some embodiments, the ErbB-related disease is cancer. In certain embodiments, the ErbB-related disease is a disease associated with mutant ErbB. In some embodiments, the mutant ErbB is mutant EGFR. In some embodiments, the mutant ErbB is mutant Her2. In certain embodiments, the ErbB-related disease is a disease associated with mutant ErbB, including cancer. In some embodiments, the BTK-related disease is cancer or an autoimmune disease.

[0179]

[0240] In some embodiments, the cancer includes, but is not limited to, leukemia, glioblastoma, melanoma, chondrosarcoma, cholangiocarcinoma, osteosarcoma, lymphoma, lung cancer, adenoma, myeloma, hepatocellular carcinoma, adrenocortical carcinoma, pancreatic cancer, breast cancer, bladder cancer, prostate cancer, liver cancer, gastric cancer, colon cancer, colorectal cancer, ovarian cancer, cervical cancer, brain cancer, esophageal cancer, bone cancer, testicular cancer, skin cancer, kidney cancer, mesothelioma, neuroblastoma, thyroid cancer, head and neck cancer, esophageal cancer, eye cancer, prostate cancer, nasopharyngeal cancer, or oral cancer. In some embodiments, the cancer is lung cancer, breast cancer, ovarian cancer, bladder cancer, or neuroblastoma. In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, adenocarcinoma, squamous cell lung cancer, and large cell lung cancer). In some embodiments, the cancer is lymphoma or leukemia. In some embodiments, the cancer is metastatic lung cancer. In some embodiments, the cancer is a cancer with one or more ErbB mutations (e.g., EGFR or Her2 point mutations, deletion mutations, insertion mutations, activating mutations, or drug resistance mutations). In some embodiments, the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or Sjogren's syndrome.

[0180]

[0241] In some embodiments, the ErbB is EGFR or Her2, preferably mutant EGFR or mutant Her2. In some embodiments, the mutant EGFR is EGFR D761_E762insEAFQ, EGFR A763_Y764insHH, EGFR M766_A767instAI, EGFR A767_V769dupASV, EGFR A767_S768insTLA, EGFR S768_D770 dupSVD, EGFR S768_V769insVAS, EGFR S768_V769insAWT, EGFR V769_D770insASV, EGFR V769_D770insGV, EGFR V769_D770insCV, EGFR V769_D770insDNV, EGFR V769_D770insGSV, EGFR V769_D770insGVV, EGFR V769_D770insMASVD, EGFR D770_N771insSVD, EGFR D770_N771insNPG, EGFR D770_N771insAPW, EGFR D770_N771insD, EGFR D770_N771insDG, EGFR D770_N771insG, EGFR D770_N771insGL, EGFR D770_N771insN, EGFR D770_N771insNPH, EGFR D770_N771insSVP, EGFR D770_N771insSVQ, EGFR D770_N771insMATP, EGFR delD770insGY, EGFR N771_P772insH, EGFR N771_P772insN, EGFR N771_H773dupNPH, EGFR delN771insGY, EGFR delN771insGF, EGFR P772_H773insPR, EGFR P772_H773insYNP, EGFR P772_H773insX, EGFR P772_H773insDPH, EGFR P772_H773insDNP, EGFR P772_H773insQV, EGFR P772_H773insTPH, EGFR P772_H773insN, EGFR P772_H773insV, EGFR H773_V774insNPH, EGFR H773_V774insH, EGFR H773_V774insPH, EGFRH773_V774insGNPH, EGFR H773_V774dupHV, EGFR H773_V774insG, EGFR H773_V774insGH, EGFR V774_C775insHV, EGFR exon 19 deletion, EGFR L858R, EGFR T790M, EGFR L858R / T790M, EGFR exon 19 deletion / T790M, EGFR S768I, EGFR G719S, EGFR G719A, EGFR G719C, EGFR E709A / G719S, EGFR E709A / G719A, EGFR E709A / G719C, and EGFR L861Q. In some embodiments, the mutant Her2 is selected from the group consisting of Her2 A775_G776insYVMA, Her2 delG776insVC, Her2 V777_G778insCG, and Her2 P780_Y781insGSP.

[0181]

[0242] The crystal form, pharmaceutical salt, or pharmaceutical composition of the present disclosure can be used for the prevention or treatment of any onset or progression of a disease or condition associated with ErbB / BTK (expression or activity) in a mammal, particularly a human. In some embodiments, the crystal form, pharmaceutical salt, or pharmaceutical composition of the present disclosure can be used for the prevention or treatment of any onset or progression of a disease or condition associated with mutant ErbB in a mammal, particularly a human. In this context, the present disclosure also provides a method for screening a patient suitable for treatment with the compound or pharmaceutical composition of the present disclosure alone or in combination with other components (e.g., a second active component, e.g., an anti-cancer agent). The method includes sequencing a tumor sample from the patient and detecting the accumulation of ErbB (e.g., EGFR or Her2) or BTK in the patient, or detecting the mutation status of ErbB (e.g., EGFR or Her2) or BTK in the patient.

[0182]

[0243] In some embodiments, one or more crystalline forms, pharmaceutical salts, or pharmaceutical compositions provided herein are administered via parenteral or non-parenteral routes. In some embodiments, one or more crystalline forms, pharmaceutical salts, or pharmaceutical compositions provided herein are administered orally, enterally, bucally, nasally, intranasally, transmucosally, epidermally, transdermally, dermal, ophthalmic, pulmonary, sublingually, rectally, vaginally, topically, subcutaneously, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intracardially, intradermally, intraperitoneally, transtracheally, subcuticularly, intraarticularly, subcapsularly, subarachnoidally, intraspinally, or intrasternally.

[0183]

[0244] The crystalline forms or pharmaceutical salts provided herein can be administered in pure form or in the form of pharmaceutical compositions of the present disclosure. In some embodiments, one or more crystalline forms, pharmaceutical salts, or pharmaceutical compositions provided herein are used in combination with a second active ingredient, preferably an anti-cancer drug. In some embodiments, the crystalline forms, pharmaceutical salts, or pharmaceutical compositions provided herein can be administered to a subject in need thereof in combination with a second active ingredient (e.g., one or more anti-cancer drugs known in the art), either simultaneously or sequentially. In some embodiments, administration is performed once a day, twice a day, three times a day, or once every two days, once every three days, once every four days, once every five days, once every six days, or once a week.

[0184]

[0245] In some embodiments, one or more crystalline forms, pharmaceutical salts, or pharmaceutical compositions provided herein are administered orally. For oral administration, any dose that achieves the desired purpose is appropriate. In some embodiments, a suitable daily dosage is about 0.001-5000 mg, preferably between 0.1 mg-5 g, more preferably between 5 mg-1 g, more preferably between 10 mg-500 mg, and administration is once a day, twice a day, three times a day, daily, or 3-5 days a week. In some embodiments, the dosage of one or more compounds provided herein, their pharma- ceutically acceptable salts, esters, hydrates, solvates or stereoisomers, or pharmaceutical compositions is in the range of about 0.0001 mg, preferably 0.001 mg, 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 200 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 2000 mg, 3000 mg, 4000 mg, or up to about 5000 mg per day. EXAMPLES

[0185]

[0246]

[0247] The following abbreviations have the definitions set forth below:

[0186] [Table 1-1]

[0187] [Table 1-2]

[0188]

[0248] For clarity, the following table summarizes the compound identifiers, chemical names, and structures used interchangeably throughout this application for each compound discussed.

[0189] [Table 2-1]

[0190] [Table 2-2]

[0191] Example 1

[0249] Analysis method

[0250] 1 H NMR analysis

[0251] 1 H NMR was performed using a Bruker AVANCE III, Bruker Ultrashield 400, or Bruker Advance 300 equipped with an autosampler (B-ACS120).

[0192]

[0252] X-ray powder diffraction (XRPD)

[0253] Solid samples were examined using a D8 advance or D2 X-ray diffractometer (Bruker). The system was equipped with a LynxEye detector. Samples were scanned from 3 to 40° 2θ with a 0.02° 2θ step. Tube voltage and current were 40 KV and 40 mA (D8 ADVANCE), 30 KV and 10 mA, respectively.

[0193]

[0254] Polarized Light Microscopy (PLM)

[0255] PLM analysis was performed using a polarizing microscope ECLIPSE LV100POL (Nikon, JP). The sample was placed on a slide glass, cedar oil was dispersed, and observed at a suitable magnification.

[0194]

[0256] Thermogravimetric analysis (TGA)

[0257] TGA was performed on a TGA Q5000IR, Q500, Discovery TGA55 (TA Instruments, US) or a Mettler Toledo TGA2. Samples were placed in tarred aluminum open pans, automatically weighed, and inserted into the TGA furnace. Samples were heated at 10° C. / min to the final temperature.

[0195]

[0258] Differential Scanning Calorimetry (DSC)

[0259] DSC analysis was performed using a DSC Q2000, Q200, Discovery DSC250 (TA Instruments, US) or Mettler Toledo DSC3+. A weighed sample was placed in the DSC pinhole pan and the weight was accurately recorded. The sample was heated at 10° C. / min to the final temperature.

[0196]

[0260] Dynamic Moisture Sorption Analysis (DVS)

[0261] DVS was determined using DVS Advantage-1 or Intrinsic (SMS, UK). Samples were tested at target RH of 10-90% for the entire cycle in step mode. Analysis was performed in 10% RH increments. Equilibration: 60 min RH (%) Measurement points: First cycle: 0, 10, 20, 30, 40, 50, 60, 70, 80, 90. Second cycle: 90, 80, 70, 60, 50, 40, 30, 20, 10, 0.

[0197] Example 2

[0262] Procedure for the preparation of (R)-N-(5-((4-((5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (Compound I free base)

[0198] [ka]

[0199]

[0263] Procedure for the preparation of compound (2)

[0264] To a solution of methyl 2-amino-4-chloro-5-fluorobenzoate (1) (12.0 g, 58.9 mmol) in THF (200 mL) was added CH3MgBr (99 mL, 3 M in ether, 294.7 mmol) at 0-5 °C. The mixture was stirred at 12-17 °C for 1.5 h. The reaction mixture was quenched by addition of aqueous NH4Cl (100 mL) and then extracted with EtOAc (3 × 100 mL). The organic layer was washed with brine (3 × 100 mL) and concentrated under reduced pressure to give compound (2) (11.5 g, 96%) as a pale yellow oil.

[0200]

[0265] LCMS: 10-80CD_7MIN_220&254 Chromatography (XBrige Shield RP18 2.1×50mm) t =3.283min, MS(ESI)m / z 186.1 [M-OH] + .

[0201]

[0266] 1 H NMR (CDCl3, 400MHz): δ (ppm) 6.90 (d, J=10.8 Hz, 1H), 6.62 (d, J=6.8 Hz, 1H), 1.63 (s, 6H).

[0267] 13 C NMR (d6-DMSO, 101 MHz) δ (ppm) 149.7, 147.4, 144.3, 131.3, 131.2, 116.9, 116.7, 115.7, 113.6, 113.4, 71.6, 28.7.

[0268] Procedure for the preparation of compound (3)

[0269] To a solution of compound (2) (11.5 g, 56.5 mmol) and DIEA (14.6 g, 112.9 mmol) in isopropanol (200 mL) was added 2,4-dichloropyrimidine (10.1 g, 67.8 mmol). The resulting yellow mixture was heated at 90 °C for 60 h. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (30-43% EtOAc in petroleum ether) to give compound (3) (12.0 g, 67%) as a white solid.

[0202]

[0270] LCMS: 5-95AB_220&254.lcm chromatography (Xtimate C18 2.1×30mm) R =0.850 min, MS(ESI) m / z=315.9[M+H] + .

[0203]

[0271] 1 H NMR (CDCl3, 400MHz): δ (ppm) 9.17 (br s, 1H), 8.15 (d, J=5.6 Hz, 1H), 7.95 (d, J=6.8 Hz, 1H), 7.12 (d, J=10.0 Hz, 1H), 6.58 (d, J=6.0 Hz, 1H), 2.35 (s, 1H), 1.65 (s, 6H).

[0272] 13 C NMR (d6-DMSO, 101 MHz) δ (ppm) 161.9, 159.4, 157.8, 155.2, 152.8, 142.7, 132.8, 132.7, 126.6, 117.4, 117.2, 114.6, 114.4, 105.3, 71.7, 29.7.

[0273] Procedure for the preparation of compound (5)

[0274] nTo a solution of compound (3) (12.0 g, 38.0 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (4) (7.44 g, 40.0 mmol) in BuOH (160 mL) was added TFA (16 mL). The resulting orange mixture was heated at 50° C. for 15 h. The reaction mixture turned from orange to pale yellow, a solid precipitated, another 300 mg of 4-fluoro-2-methoxy-5-nitroaniline was added, and the reaction mixture was heated at 50° C. for another 4 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc / petroleum ether=1 / 1 (25 mL×3) and EtOAc (25 mL×3), then dried in vacuum to give compound (5) (15.2 g, 86%) as a grey solid.

[0204]

[0275] LCMS: 5-95AB_220&254.lcm chromatography (Xtimate C18 2.1×30mm) R =0.776 min, MS(ESI) m / z=466.0[M+H] + .

[0205]

[0276] 1 H NMR (CDCl3, 400MHz) δ (ppm) 8.52 (d, J=8.0 Hz, 1H), 7.96 (d, J=6.8 Hz, 1H), 7.84 (d, J=7.2 Hz, 1H), 7.32 (d, J=10.8 Hz, 1H), 7.20 (d, J=12.8 Hz, 1H), 6.47 (d, J=6.8 Hz, 1H), 4.00 (s, 3H), 1.59 (s, 6H).

[0277] 13 C NMR (d6-DMSO, 101 MHz) δ (ppm) 161.6, 156.2, 153.7, 152.6, 143.9, 143.5, 131.0, 128.6, 128.1, 121.9, 117.3, 117.1, 114.6, 114.4, 102.1, 101.9, 100.0, 71.5, 57.5, 29.9.

[0278] Procedure for the preparation of compound (6)

[0279] To a solution of compound (5) (5.0 g, 10.7 mmol) and K2CO3 (5.9 g, 42.9 mmol) in DMSO (50 mL) was added (R)-N,N-dimethylpyrrolidin-3-amine (2.6 g, HCl salt, 14.0 mmol). The resulting mixture was stirred at 50 °C for 12 h, during which the color changed from light yellow to dark yellow. The reaction mixture was poured into ice water (500 mL) with stirring, and a yellow solid precipitated. The precipitated solid was collected by filtration, then dissolved in CHCl (500 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound (6) (5.6 g, 93%) as a yellow solid.

[0206]

[0280] LCMS: 5-95AB_220&254.lcm chromatography (MKRP-18e25~2mm) t =0.676 min, MS(ESI) m / z=560.1[M+H] + .

[0207]

[0281] 1 H NMR (CDCl3, 400MHz) δ (ppm) 9.00 (s, 1H), 8.91 (s, 1H), 8.09 (d, J=5.8 Hz, 1H), 7.93 (d, J=7.0 Hz, 1H), 7.19 (s, 1H), 7.11 (d, J=10.5 Hz, 1H), 6.31 (s, 1H), 6.18 (d, J=5.8 Hz, 1H), 5.31 (s, 1H), 3.94 (s, 3H), 3.55 (td, J=10.1, 6.4 Hz, 1H), 3.31-3.39 (m, 1H), 3.10-3.22 (m, 2H), 2.81 (br s, 1H), 2.30 (s, 6H), 2.15-2.25 (m, 1H), 1.83-1.98 (m, 1H), 1.67 (s, 6H).

[0282] 13C NMR (d6-DMSO, 101 MHz) δ (ppm) 159.0, 158.9, 155.7, 154.9, 152.5, 150.1, 140.4, 137.7, 133.7, 127.4, 122.8, 119.8, 117.6, 116.0, 115.8, 112.9, 112.7, 97.0, 96.5, 71.0, 63.7, 55.0, 48.4, 42.8, 28.5.

[0283] Procedure for the preparation of compound (7) To a solution of compound (6) (5.6 g, 10.0 mmol) in EtOAc (100 mL) and THF (50 mL) was added Pd / C (1.2 g). The resulting mixture was purged and degassed with H2 three times, then stirred under H2 (hydrogen balloon, 15 Psi) at 11-18 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound (7) (5.0 g, 94%) as a pale yellow solid.

[0208]

[0285] LCMS: 5-95AB_1.5min_220&254 Chromatography (MK RP18e25~2mm) R t =0.660 min, MS(ESI) m / z=530.1[M+H] + .

[0209]

[0286] 1 H NMR (CDCl3, 400MHz) δ (ppm) 8.80 (s, 1H), 8.15 (d, J=7.3 Hz, 1H), 8.04 (d, J=5.5 Hz, 1H), 7.87 (s, 1H), 7.43 (s, 1H), 7.09 (d, J=10.5 Hz, 1H), 6.67 (s, 1H), 6.06 (d, J=5.5 Hz, 1H), 3.82 (s, 3H), 3.24 - 3.13 (m, 2H), 3.07 - 2.96 (m, 2H), 2.91 - 2.83 (m, 1H), 2.28 (s, 6H), 2.18 - 2.08 (m, 1H), 1.90 - 1.85 (m, 1H), 1.66 (s, 6H).

[0287] 13 C NMR (d6-DMSO, 101 MHz) δ (ppm) 160.1, 156.8, 153.7, 151.3, 142.3, 139.1, 135.4, 134.9, 131.4, 124.2, 123.9, 117.2, 117.0, 114.1, 113.9, 110.0, 103.5, 97.5, 72.1, 64.9, 56.3, 54.5, 49.8, 29.6, 28.6.

[0288] Procedure for the preparation of compound I

[0289] Step 1: To a solution of compound (7) (5.0 g, 9.43 mmol) in CHCl (150 mL) was added 3-chloropropanoyl chloride (1.3 g, 10.37 mmol) in an ice-water bath. The resulting mixture was stirred at 0-5 °C for 30 min (almost no undissolved oil precipitated). The reaction mixture was poured into saturated NaHCO (50 mL), stirred at 12-17 °C for 2 h, and extracted with CHCl (150 mL × 2). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give a crude residue, which was purified by column chromatography on silica gel (3% MeOH in CHCl) to give a pale yellow solid (3.4 g, 58% yield).

[0210]

[0290] LCMS: 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1×30mm) t =1.547min, MS(ESI) m / z=620.0[M+H] + .

[0211]

[0291] 1H NMR (CDCl3, 400MHz) δ (ppm) 9.58 (s, 1H), 9.31 (s, 1H), 8.56 (br s, 1H), 8.10 (d, J=5.8 Hz, 1H), 7.62 - 7.45 (m, 2H), 7.15 (d, J=10.5 Hz, 1H), 6.76 (s, 1H), 6.34 (d, J=5.8 Hz, 1H), 3.90 (t, J=6.3 Hz, 2H), 3.86 (s, 3H), 3.16 - 3.03 (m, 4H), 2.90 (br s, 3H), 2.32 (br s, 6H), 2.19 (br dd, J=6.3, 12.3 Hz, 1H), 1.98 (br s, 1H), 1.75 - 1.68 (m, 6H).

[0292] Step 2: To a solution of the yellow solid from step 1 (3.4 g, 5.48 mmol) in CH3CN (70 mL) was added TEA (2.2 g, 21.92 mmol). The resulting mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove approximately 35 mL of CH3CN and then poured into 500 mL of H2O and stirred for an additional 30 min. The mixture was filtered, the filter cake was collected and then lyophilized to give the title product Compound I (2.64 g, 82%) as a white solid.

[0212]

[0293] LCMS: 10-80AB_4min_220&254 Chromatography (Xtimate C18 2.1×30mm) t =1.471 min, MS(ESI) m / z=584.0[M+H] + .

[0213]

[0294] 1H NMR (CDCl3, 400MHz) δ (ppm) 9.67 (s, 1H), 9.44 (s, 1H), 8.55 (br s, 1H), 8.10 (d, J=6.0 Hz, 1H), 7.52 (br d, J=7.0 Hz, 1H), 7.48 (s, 1H), 7.15 (d, J=10.8 Hz, 1H), 6.76 (s, 1H), 6.42 - 6.28 (m, 3H), 5.82 - 5.75 (m, 1H), 5.66 (br s, 1H), 3.86 (s, 3H), 3.14 - 3.02 (m, 4H), 2.96 - 2.86 (m, 1H), 2.30 (s, 6H), 2.23 - 2.12 (m, 1H), 2.00 - 1.90 (m, 1H), 1.73 (s, 6H).

[0295] 13 C NMR (d6-DMSO, 101 MHz) δ (ppm) 163.5, 160.5, 159.9, 156.8, 153.5, 151.1, 149.9, 141.5, 138.5, 135.0, 132.0, 125.7, 123.7, 123.4, 119.9, 117.9, 117.2, 117.0, 114.0, 113.8, 99.5, 97.5, 72.2, 65.2, 55.6, 49.3, 43.9, 29.6. Example 3

[0296] Scale-up of the manufacturing process for (R)-N-(5-((4-((5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (Compound I free base)

[0297] Procedure for the preparation of compound (3)

[0214] [ka]

[0215]

[0298] Isopropanol (249.5 kg), DIPEA (118.6 kg) and compound (8) (78.1 kg) were charged into the reactor. Compound (9) (62.8 kg) was finally charged under N2 protection. The mixture was adjusted to 78°C (75-82°C) and stirred for 18 hours until the reaction was deemed complete. The reaction mixture was adjusted to 25°C and charged with 15 wt% NH4Cl aqueous solution (1093 kg) dropwise. The resulting mixture was stirred at 25°C for 3 hours and filtered. The cake was washed with purified water (95.0 kg x 2), and then the wet cake was slurried in IPA (252.2 kg) at 60°C for 4 hours. The slurry mixture was adjusted to 15°C and stirred for 3 hours. The slurry mixture was then filtered and the wet cake was washed with IPA (100 kg). The wet cake was dried at 45° C. for 20 hours to give 67.06 kg of compound (3) in 79.2% isolated yield with an assay of 99.4% HPLC purity. 1 H NMR (DMSO-d6, 400MHz), 1.47 (6H, s), 6.03 (1H, s), 6.74~6.76 (1H, d), 7.45~7.48 (1H, d), 7.90-7.92 (1H, d), 8.16~8.18 (1H, d), 9.87 (1H,s).

[0299] Procedure for the preparation of compound (5)

[0216] [ka]

[0217]

[0300] THF (189 kg), compound (3) (62.9 kg) and compound (4) (39.1 kg) were charged to a reactor, stirred at 25°C, and TFA (10.8 kg) was charged dropwise over 2 hours. The reaction was adjusted to 50-60°C and stirred for 24-28 hours until the reaction was deemed complete. The reaction was adjusted to 20-30°C, stirred for 2-4 hours, and then filtered. The wet cake was washed with IPA (154 kg) and dried at 45°C for 27 hours. 94.22 kg of compound (5) was obtained with an assay of 99.3% HPLC purity and 93.4% isolated yield. 1H NMR (DMSO-d6, 400MHz), 1.47 (6H, s), 3.95 (3H, s), 6.66~6.68 (1H, d), 7.38~7.41 (1H, d), 7.46·7.49 (1H, d), 7.67~7.69 (1H, d), 8.12~8.13 (1H, d), 8.37~8.39 (1H, d), 10.16 (1H, s), 10.80 (1H, s).

[0301] Procedure for the preparation of compound (6)

[0218] [ka]

[0219]

[0302] Acetonitrile (328 kg), K2CO3 (50.4 kg), compound (11) (44.8 kg) and DIPEA (140 kg) were charged to the reactor at 15-25 °C, and compound (5) (82.0 kg after assay correction) was charged to the reactor. The reaction system was adjusted to 75-82 °C and stirred for 20-30 h until the reaction was deemed complete. The reaction mixture was adjusted to 35-45 °C. Purified water (492 kg) was added dropwise to the reaction mixture and stirred for 4-6 h. The reaction mixture was adjusted to 15-25 °C, stirred for 3-5 h, and filtered. The wet cake was washed with ACN / H2O (148 kg) and H2O (164 kg). H2O (576 kg) was charged to the reactor, followed by the wet cake. The mixture was stirred at 15-25 °C for 4 h and filtered. The wet cake was washed with HO (164 kg) and ACN (148 kg). The wet cake was dried at 45° C. for 20 h. 88.91 kg of compound (6) was obtained with an isolated yield of 89.2% and an assay of 99.8% HPLC purity. 1H NMR (DMSO-d6, 400MHz), 1.65 (6H,s), 1.72~1.82 (1H, m), 2.07~2.19 (1H,m), 2.32~2.50 (6H,m), 2.66~2.75 (1H,m), 3.06~3.15 (2H,m), 3.19~3.23 (1H,m), 3.32~3.46 (1H,m), 3.88 (1H,s), 6.12~6.13 (1H,d), 6.17 (1H,s), 6.50 (1H,s), 7.29~7.32 (1,d), 7.93(1H,s), 7.99~8.00 (1H,s), 8.08~8.10 (1H,d), 8.18 (1H,s), 9.62 (1H,s).

[0303] Procedure for the preparation of compound I

[0220] [ka]

[0221]

[0304] Compound (6) (86.0 kg) and THF (855.4 kg) containing 5% Pt / C (3.3 kg, dry) were charged into the reactor. The hydrogen pressure of the reaction system was adjusted to 0.550-0.688 MPa (0.5-0.7 MPa), and the temperature of the reaction system was adjusted to 50 °C (45-55 °C). The reaction system was stirred for 24 h (20-30 h) until the reaction was deemed complete. The temperature was adjusted to -10 °C (-15-0 °C). The solution of compound (7) was filtered and transferred to another reactor. The cake was rinsed with THF (386 kg).

[0222]

[0305] Purified water (176 kg) was charged to the reactor and 3-chloropropionyl chloride (20.2 kg) in THF (416 kg) was charged dropwise at -15 to 0 °C over 2 hours. The mixture was stirred at -15 to 0 °C for 3 hours (2 to 4 hours) until the reaction was deemed complete. The temperature was adjusted to 20 °C (15 to 25 °C) and 3.5 wt% sodium hydroxide solution (709 kg) was charged dropwise at 20 °C (15 to 25 °C) and stirred for 4 hours (3 to 6 hours) until the reaction was deemed complete. The resulting mixture was held for 1 hour and the aqueous layer was separated. The organic phase was washed twice with 20% aqueous NaCl solution (592 kg). The organic solution was filtered through silica gel (235 kg) and the silica gel pad was washed with THF (2695 kg). The solution was concentrated to 340-350 L and exchanged with acetone (1008 kg) a total of two times. Acetone (448 kg) was charged to the system and an IPC sample was taken to control the residual THF at ≦5.0%.

[0223]

[0306] Purified water (95 kg) was charged into the reactor, the temperature was adjusted to 56 °C (52-59 °C), and the reaction system was stirred for 2 h to give a clear solution. Purified water (103 kg) was charged over 3 h and the solution was cooled to 40-44 °C. Seed crystals (68 g) were charged into the solution and stirred for 14-18 h. Purified water (1118 kg) was charged dropwise at a constant flow rate at 40-44 °C. The mixture was stirred at 40-44 °C for 2-6 h, adjusted to 15-25 °C in 4 h, stirred for 4 h (2-6 h), then filtered and dried to give 76.71 kg of solid compound I with an assay of 98.9% and an HPLC purity of 99.63% in 84.5% yield. 1H NMR (DMSO-d6, 400MHz), 1.49 (6H,s), 1.70~1.71 (1H,m), 2.08 (1H,m), 2.15 (6H,s), 2.64~2.68 (1H,m), 3.14~3.19 (3H,m), 3.32~3.34 (1H,m), 3.78 (3H,s), 5.65~5.68 (1H,m), 6.04~6.06 (1H,d), 6.13~6.18 (2H,m), 6.45~6.52 (2H,m), 7.27~7.30 (1H,d), 7.59 (1H,s), 7.81 (1H, s), 7.94~7.96 (1H, d), 8.13~8.15 (1H,d), 9.24 (1H,s), 9.57 (1H,s).

[0307] Recrystallization of Compound I

[0308] Crude Compound I (56.3 kg) and acetone / purified water (743.2 kg, 9 / 1 (v / v)) were added to the reactor. The reactor was heated to 48°C-55°C to obtain a clear solution, and purified water (190 kg) was added to the reactor in 1-3 hours. The temperature was adjusted to 38°C-42°C. Seed crystals (0.3 kg) were charged at 38°C-42°C and stirred for 16 hours. Purified water (997 kg) was charged dropwise to the reactor at 38°C-42°C in 6-8 hours and stirred for 4 hours. The reaction was adjusted to 20-25°C in 3 hours and stirred for 4 hours. The reaction was then filtered and washed twice with acetone / purified water (103 kg, 2v / 3v). The wet cake was dried at 45°C for 20 hours. 54.58 kg of Compound I was obtained with an assay of 99.8% and an HPLC purity of 99.83% with an isolated yield of 96.7%. 1H NMR (DMSO-d6, 400MHz), 1.50 (6H,s), 1.71 (1H, m), 2.07 (1H, m), 2.15 (6H, s), 2.66 (1H, m), 3.14 (1H), 3.19 (2H), 3.38 (1H, m), 3.79 (3H,s), 5.67 (1H, dd, J=10.0,2.0Hz), 6.06 (1H, d, J=5.6Hz), 6.15 (1H), 6.20 (1H), 6.50 (1H), 6.52 (1H), 7.29 (1H, d, J=10.8Hz), 7.61 (1H, s), 7.85 (1H, s), 7.96 (1H, d, J=5.6Hz), 8.16 (1H,d, J=7.6Hz), 9.27 (1H, s), 9.60(1H,s).

[0309] The single crystal X-ray diffraction ORTEP of compound I is shown in FIG.

[0224] Example 4

[0310] Preparation of single crystals of compound I

[0311] Compound I (6 mg) was added to 1.5 mL of MeOH in a 3 mL glass vial to obtain an unsaturated solution, which was then slowly evaporated at room temperature for 3 days to obtain single crystals suitable for X-ray diffraction.

[0225]

[0312] Crystal data

[0226] [Table 3]

[0227]

[0313] Data collection

[0228] [Table 4]

[0229]

[0314] Precision

[0230] [Table 5]

[0231]

[0315] Interconversion study of Form A and Form B

[0316] Competitive slurry experiments were performed to evaluate the relative stability of Form A and Form B. Interconversion studies were performed at room temperature and 50° C. using the single and binary solvents listed in Table 1 below. Approximately 80 mg (100 mg at 50° C.) of Form A and Form B (1:1, w / w) were weighed into sample vials (8 mL) and then 3 mL (2 mL at 50° C.) of solvent was added to each vial. The resulting suspensions were kept stirring at room temperature and 50° C. for 7 days and then filtered at the specified times. The wet and dried solids were analyzed by XRPD (dried in a vacuum oven at 45° C.).

[0232] [Table 6]

[0233]

[0318] The results are summarized in Tables 2 and 3. Form B predominated in the tested solvent systems, with water activities less than 0.15 at room temperature (24-27 °C). In all tested solvent systems, except pure water, form B was more stable than form A at 50 °C. Pure forms A and B were stable during the drying process (50 °C, vacuum) for at least 2 days. In the case of mixtures of forms A and B, form A was converted to form B during the drying process.

[0234] [Table 7]

[0235] [Table 8]

[0236]

[0321] Water activity studies of Form A and Form B

[0322] To study the effect of water on the stability of Form A and Form B, slurry experiments in systems with different water activities were conducted. The results are listed in Tables 5 and 6. Form A or Form B was separately suspended in different water activity systems (Table 4). Approximately 20 mg of Form A or Form B was suspended in 3 mL of acetone and water mixture at room temperature for 7 days. The remaining solid was filtered and dried in a vacuum oven at 45°C for 8-24 hours. The dried solid was characterized by XRPD.

[0237] [Table 9]

[0238] [Table 10]

[0239] [Table 11]

[0240]

[0326] Storage stability of Form B

[0327] The XRPD (Figure 27) and DSC profile (Figure 28) showed that no morphological changes were observed for Form B after storage at 2-8°C for at least 20 days.

[0241]

[0328] Milling studies of Form B

[0329] Grinding and jet milling were performed. Approximately 10 mg of Form B was added to a mortar and ground with a pestle for 1 minute and 2 minutes. Jet milling of Form B was performed on a 500 mg scale. Samples before and after grinding and milling were analyzed by XRPD.

[0242]

[0330] Equipment: Jet mill (equipment number: PPD-OAJ-1)

[0331] Feeding speed: manual

[0332] Supply pressure: 0.3 to 0.6 MPa

[0333] Milling 1 pressure: 0.4~0.8MPa

[0334] Milling 2 pressure: 0.4~0.8MPa

[0335] Grinding and jet milling were performed to test the physical stability of Form B in the milling process. As shown in the XRPD results of the solids obtained after milling (Figure 25), jet milling (Figure 24), and the DSC profile after jet milling (Figure 26), the crystallinity decreased after milling, but the crystalline morphology of Form B remained unchanged after milling and grinding.

[0243]

[0336] Preparation of polymorphic forms

[0337] Procedure for the preparation of crystalline form A of free base compound I

[0338] Compound I free base crude (30 g) was dissolved in ethanol (210 mL), isopropanol (60 mL) and water (13 mL) at 70-75 °C to obtain a clear solution. The temperature was adjusted to 60-65 °C, then Compound I-Form A crystal seed (0.06 g, 0.2% w / w) was added and stirred at 60-65 °C for at least 1 h. The mixture was cooled to 50-55 °C, stirred for 2-3 h, then cooled to 10-20 °C and filtered. The wet cake was washed with a mixture of ethanol / isopropanol. The wet cake was dried at 40-50 °C for at least 24 h to obtain crystalline Compound I-Form A (13.6 g, 45% yield).

[0244]

[0339] XRPD data for crystalline Form A of free base Compound I is shown in FIG.

[0245] [Table 12]

[0246]

[0341] The DSC data for crystalline form A of free base Compound I is shown in Figure 2. The DSC profile of crystalline form A of free base Compound I exhibits an endothermic transition with an onset temperature of about 178.63°C, a peak temperature of about 179.64°C and an associated enthalpy of 104.20 J / g.

[0247]

[0342] The TGA data for crystalline Form A of free base Compound I is shown in Figure 3. The TGA profile of Compound I-maleate salt shows a weight loss of about 0.232% before the temperature reaches 160.00°C.

[0248]

[0343] The DVS data for crystalline Form A of free base Compound I is shown in FIG.

[0344] Procedure for the preparation of crystalline form B of free base compound I

[0345] Method 1

[0346] Compound I-Form A (4 g) and ethanol (40 mL) were charged into the reactor and kept stirring. The mixture was heated to 70° C. and stirred until the solids were completely dissolved. The solution was cooled to 60° C. at a rate of 0.1° C. / min. Seed crystals of Compound I-Form B (0.02 g, 0.5% w / w) were added to the solution. For seed growth, the solution was kept at 60° C. for 70-80 min. The suspension was cooled to 5° C. at 0.1° C. / min and kept at 5° C. overnight. The suspension was filtered and the filter cake was dried in an oven (50° C., vacuum) for 5 h to obtain crystalline Compound I-Form B (yield about 80%).

[0249]

[0347] Method 2.

[0348] Crude API (15 kg) was dissolved in acetone / purified water (258 L, 9 / 1, v / v) at 48-55 °C to give a clear solution. Water (51 L) was added at 48-55 °C. The mixture was adjusted to 38-42 °C within 1 h. Compound I-form B crystal seed (0.08 kg, 0.005, w / w) was charged at 38-42 °C and stirred for at least 14 h. Water (268 L) was charged dropwise at 38-42 °C and stirred for at least 2 h. The mixture was cooled to 20-25 °C and stirred for at least 2 h. The mixture was filtered and the cake was washed with a mixture of acetone / purified water. The wet cake was dried at 45-50 °C for at least 16 h to give crystalline Compound I-form B (14.1 kg, 94% yield).

[0250]

[0349] XRPD data for crystalline Form B of free base Compound I is shown in FIG.

[0251] [Table 13]

[0252]

[0351] The DSC data for crystalline form B of free base Compound I is shown in Figure 6. The DSC profile of crystalline form A of free base Compound I exhibits an endothermic transition with an onset temperature of about 194.84°C, a peak temperature of about 195.74°C and an associated enthalpy of 111.60 J / g.

[0253]

[0352] The TGA data for crystalline form B of free base Compound I is shown in Figure 7. The TGA profile of Compound I-maleate salt shows a weight loss of about 0.166% before the temperature reaches 177.60°C.

[0254]

[0353] The DVS data for crystalline form B of free base Compound I is shown in FIG.

[0354] Physical properties of Form A and Form B

[0255] [Table 14]

[0256] [Table 15]

[0257] [Table 16]

[0258]

[0358] In vitro cell-based assays for Form A and Form B

[0259] [Table 17]

[0260]

[0360] PK studies of Forms A and B in rats and dogs

[0261] [Table 18]

[0262] [Table 19]

[0263] Example 5

[0363] Preparation of pharmaceutical salts and screening of salts of compound I

[0364] General procedure for the preparation of compound I using different acids

[0365] 50 mg of compound I was weighed into a 2 mL vial, and then 900 μL of acetone was added to the vial. The counter ion acid (1.1 equivalents) diluted (×10) with acetone was added to the vial. The vial was placed on a thermomixer and heated to 50° C. for 18 hours, and then the vial was cooled to 25° C. After holding at 25° C. for 1 hour, the solid in suspension was isolated by centrifugation and dried in a vacuum oven at 30° C. for 3 hours. The dried solid was characterized by XRPD. The dried solid obtained above was subjected to reslurry in isopropanol at 25° C. for 72 hours. The solid in suspension was isolated by centrifugation and dried in a vacuum oven at 30° C. overnight. The dried solid was again characterized by XRPD, TGA, and DSC.

[0264] [Table 20]

[0265]

[0367] 5.1: Preparation of (R)-N-(5-((4-((5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide hydrochloride (Compound I-hydrochloride)

[0368] Hydrochloride salt (prepared in acetone solution)

[0369] 1800 mg of compound I was suspended in 20.0 mL of acetone at 60° C. Hold at 60° C. for 1 hour. 1.1 equivalents of hydrochloric acid in acetone (6.76 mL, 0.5 mol / L) was added dropwise to the suspension. The suspension was held at 60° C. for 3 hours. The suspension was then cooled to 25° C. and held at 25° C. for 20 hours. The suspension was filtered through a funnel and the wet cake was washed with 0.5 mL of acetone. The wet solid was dried in a vacuum oven at 30° C. for 72 hours. A dry off-white solid (1623.3 mg, 83.4% yield) was obtained. The dried solid was characterized by XRPD, TGA, DSC, and DVS. The salt ratio of the hydrochloride salt to compound I was determined by IC testing. The measured chloride content was 5.78% compared to the theoretical chloride content of 5.72% at a 1:1 salt ratio.

[0266]

[0370] XRPD data for the crystalline form of Compound I-hydrochloride salt is shown in FIG.

[0267] [Table 21]

[0268]

[0372] The TGA data for the crystalline form of Compound I-hydrochloride is shown in Figure 20. The TGA profile of Compound I-hydrochloride shows a weight loss of about 0.759% before the temperature reaches 175°C.

[0269]

[0373] The DSC data for the crystalline form of Compound I-hydrochloride is shown in Figure 20. The DSC profile for the crystalline form of Compound I-hydrochloride shows an endothermic transition with an onset temperature of about 207.77°C, a peak temperature of about 212.14°C, and an associated enthalpy of 75.60 J / g.

[0270]

[0374] The DVS data for the crystalline form of Compound I-hydrochloride salt is shown in FIG.

[0375] 5.2: Preparation of (R)-N-(5-((4-((5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide L-(+)-tartrate (compound IL-(+)-tartrate, pattern I)

[0376] 50mg of compound I was weighed into a 2mL vial, then 900μL of acetone was added to the vial. L-(+)-tartaric acid (1.1 equivalents) diluted with acetone (×10) was added to the vial. The vial was placed on a thermomixer and heated to 50°C for 18 hours, then the vial was cooled to 25°C. After holding at 25°C for 1 hour, the solid in suspension was isolated by centrifugation and dried in a vacuum oven at 30°C for 3 hours. The dried solid was characterized by XRPD. The dried solid obtained above was subjected to reslurry in isopropanol at 25°C for 72 hours. The solid in suspension was isolated by centrifugation and dried in a vacuum oven at 30°C overnight. The dried solid was again characterized by XRPD, TGA, and DSC.

[0271]

[0377] The crystalline form of compound IL-(+)-tartrate (Pattern I) 1 H-NMR data is shown in Figure 31.

[0378] XRPD data for the crystalline form of compound IL-(+)-tartrate (Pattern I) is shown in FIG.

[0272] [Table 22]

[0273]

[0380] The TGA data of the crystalline form of compound IL-(+)-tartrate (Pattern I) is shown in Figure 15. The TGA profile of compound IL-(+)-tartrate (Pattern I) shows a weight loss of about 2.52% before the temperature reaches 100°C.

[0274]

[0381] The DSC data for the crystalline form of compound IL-(+)-tartrate (Pattern I) is shown in FIG.

[0382] The DSC profile of the crystalline form of the (+)-L-tartrate salt of Compound I (Pattern I, prepared in acetone) shows a first endothermic transition with an onset temperature of about 36.91° C., a peak temperature of about 56.29° C., and an associated enthalpy of 44.43 J / g, and a second endothermic transition with an onset temperature of about 136.73° C., a peak temperature of about 140.18° C., and an associated enthalpy of 19.53 J / g.

[0275]

[0383] 5.3: Preparation of (R)-N-(5-((4-((5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide fumarate (Compound I-Fumarate)

[0384] Fumarate salt (prepared in acetone solution)

[0385] 1800 mg of compound I was suspended in 25.0 mL of acetone at 60° C. and kept at 60° C. for 1 hour. Fumaric acid solid (392.3 mg, 1.1 eq.) was added to the suspension. The suspension was kept at 60° C. for 3 hours. The suspension was then cooled to 25° C. and kept at 25° C. for 20 hours. About 5 mg of seed crystals was added to the solution. The solution was kept at 25° C. for 42 hours. The suspension was filtered through a funnel and the wet cake was washed with 0.5 mL of acetone. The wet solid was dried in a vacuum oven at 30° C. for 72 hours. A dry light yellow solid (1588.8 mg, 71.7% yield) was obtained. The dried solid was characterized by XRPD, TGA, DSC, and DVS.

[0276]

[0386] Fumarate salt (prepared in ethanol solution)

[0387] 300 mg of compound I was suspended in 5.0 mL of acetone at 60° C. The suspension was kept at 60° C. for 1 hour. 1.1 equivalents of fumaric acid in ethanol (1.7 mL, 0.33 mol / L) was added dropwise to the suspension. The suspension was kept at 60° C. for 3 hours. The suspension was then cooled to 25° C. and kept at 25° C. for 20 hours. The suspension was filtered through a funnel and the wet cake was washed with 0.5 mL of ethanol. The wet solid was dried in a vacuum oven at 30° C. for 72 hours. A dry off-white solid (284.7 mg, 76.2% yield) was obtained as a solid. 1 Salt ratio = 1.0:1.0 (Compound I:fumaric acid) as determined by H-NMR. The dried solid was characterized by XRPD, TGA, DSC, and DVS.

[0277]

[0388] Crystalline form of compound I-fumarate salt 1 H-NMR data is shown in Figure 29.

[0389] XRPD data for the crystals of Compound I-fumaric acid salt is shown in FIG.

[0278] [Table 23]

[0279]

[0391] The TGA data for the crystalline form of Compound I-Fumarate is shown in Figure 17. The TGA profile of Compound I-Fumarate shows a weight loss of about 2.857% before the temperature reaches 55°C, and an additional weight loss of about 2.424% between the temperature range of 55-140°C.

[0280]

[0392] DSC data for the crystalline form of Compound I-Fumarate Salt is shown in Figure 17. The DSC profile for the crystalline form of Compound I-Fumarate Salt shows an endothermic transition with an onset temperature of about 48.86°C, a peak temperature of about 68.34°C, and an associated enthalpy of 28.63 J / g, and a subsequent endothermic transition with an onset temperature of about 132.79°C, a peak temperature of about 141.78°C, and an associated enthalpy of 27.78 J / g.

[0281]

[0393] The DVS data for the crystalline form of Compound I-Fumarate Salt is shown in FIG.

[0394] 5.4: Preparation of (R)-N-(5-((4-((5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide sulfate (Compound I-Sulfate)

[0395] 50mg of compound I was weighed into a 2mL vial, then 900μL of acetone was added to the vial. Sulfuric acid (1.1 equivalents) diluted with acetone (×10) was added to the vial. The vial was placed on a thermomixer and heated to 50℃ for 18 hours, then the vial was cooled to 25℃. After holding at 25℃ for 1 hour, the solid in suspension was isolated by centrifugation and dried in a vacuum oven at 30℃ for 3 hours. The dried solid was characterized by XRPD. The dried solid obtained above was subjected to reslurry in isopropanol at 25℃ for 72 hours. The solid in suspension was isolated by centrifugation and dried in a vacuum oven at 30℃ overnight. The dried solid was characterized again by XRPD, TGA, and DSC.

[0282]

[0396] XRPD data for the crystalline form of Compound I-sulfate salt is shown in FIG.

[0283] [Table 24]

[0284]

[0398] The TGA data for the crystalline form of Compound I-sulfate is shown in Figure 18. The TGA profile of Compound I-sulfate shows a weight loss of about 4.85% before the temperature reaches 120°C.

[0285]

[0399] DSC data for the crystalline form of Compound I-sulfate is shown in Figure 18. The DSC profile for the crystalline form of Compound I-sulfate shows an endothermic transition with an onset temperature of about 181.24°C, a peak temperature of about 195.93°C, and an associated enthalpy of 11.87 J / g, and a subsequent endothermic transition with an onset temperature of about 210.59°C, a peak temperature of about 226.02°C, and an associated enthalpy of 26.76 J / g.

[0286]

[0400] 5.5: Preparation of (R)-N-(5-((4-((5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide maleate (Compound I-Maleate)

[0401] 50mg of compound I was weighed into a 2mL vial, then 900μL of acetone was added to the vial. Maleic acid (1.1 equivalents) diluted with acetone (×10) was added to the vial. The vial was placed on a thermomixer and heated to 50°C for 18 hours, then the vial was cooled to 25°C. After holding at 25°C for 1 hour, the solid in suspension was isolated by centrifugation and dried in a vacuum oven at 30°C for 3 hours. The dried solid was characterized by XRPD. The dried solid obtained above was subjected to reslurry in isopropanol at 25°C for 72 hours. The solid in suspension was isolated by centrifugation and dried in a vacuum oven at 30°C overnight. The dried solid was again characterized by XRPD, TGA, and DSC.

[0287]

[0402] The crystalline form of compound I-maleate 1 H-NMR data is shown in Figure 30.

[0403] XRPD data for the crystalline form of Compound I-Maleate Salt is shown in FIG.

[0288] [Table 25]

[0289]

[0405] The TGA data for the crystalline form of Compound I-maleate is shown in Figure 19. The TGA profile of Compound I-maleate shows a weight loss of about 5.25% before the temperature reaches 100°C.

[0290]

[0406] The DSC data for the crystalline form of Compound I-maleate salt is shown in FIG.

[0407] 5.6: Preparation of (R)-N-(5-((4-((5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide tartrate (Compound I-(+)-L-tartrate, Pattern II)

[0408] L-(+)-Tartrate (Pattern II, prepared in ethanol solution)

[0409] 300 mg of compound I was suspended in 5.0 mL of acetone at 60° C. The suspension was kept at 60° C. for 1 hour. 1.1 equivalents of L-(+)-tartaric acid in ethanol (1.10 mL, 0.5 mol / L) was added dropwise to the suspension. The suspension was kept at 60° C. for 3 hours. The suspension was then cooled to 25° C. and kept at 25° C. for 20 hours. The suspension was filtered through a funnel and the wet cake was washed with 0.5 mL of ethanol. The wet solid was dried in a vacuum oven at 30° C. for 72 hours. A dry off-white solid (303.0 mg, 78.0% yield) was obtained. 1 Salt ratio determined by H-NMR = 1.0:1.0 (compound I:L-(+)-tartrate salt). The dried solid was characterized by XRPD, TGA, DSC, and DVS.

[0291]

[0410] The crystalline form of compound IL-(+)-tartrate (Pattern II) 1 H-NMR data is shown in Figure 32.

[0411] The XRPD data for the crystalline form of compound IL-(+)-tartrate (Pattern II) is shown in FIG.

[0292] [Table 26]

[0293]

[0413] The TGA data of the crystalline form of compound IL-(+)-tartrate (Pattern II) is shown in Figure 16. The TGA profile of compound IL-(+)-tartrate (Pattern II) shows a weight loss of about 3.587% before the temperature reaches 100°C.

[0294]

[0414] DSC data for the crystalline form of compound IL-(+)-tartrate (Pattern II) is shown in Figure 16. The DSC profile for the crystalline form of compound IL-(+)-tartrate (Pattern II) shows an endothermic transition with an onset temperature of about 64.62°C, a peak temperature of about 75.67°C, and an associated enthalpy of 34.23 J / g, and a subsequent endothermic transition with an onset temperature of about 137.25°C, a peak temperature of about 140.39°C, and an associated enthalpy of 17.53 J / g.

[0295]

[0415] Solubility and pH values ​​of different Compound I salts in biorelevant media

[0296] [Table 27]

[0297] Example 6

[0416] Dissolution of Compound I, Free Base, Form B, Tablet (200 mg)

[0417] Compound I (free base, Form B) tablets were milled under the milling conditions (D50=0.8 μm and D 90 = 3.3 μm) and non-milling conditions (D 50 = 34.1 μm and D 90 = 117.0 μm). The dissolution profiles at different pH (1.2 and 4.5) are summarized in Figures 34 and 35. At pH 1.2, over 85% of Compound I was released in 15 minutes. It can be seen that the polymorphs of the present disclosure exhibit enhanced dissolution rates.

[0298]

[0418] The tablets were manufactured according to the following manufacturing process.

[0419] The formulation included diluents, binders, disintegrants, lubricants, glidants and coating materials. The preferred excipients were microcrystalline cellulose lactose, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silicon dioxide and magnesium stearate. The coating material was Opadry®. The content of microcrystalline cellulose was 10%-70%, preferably 20%-38%; the content of lactose monohydrate was 15%-75%, preferably 25%-40%; the content of croscarmellose sodium was 1%-18%, preferably 2%-10%; the content of hydroxypropyl cellulose was 1%-15%, preferably 2%-8%; the content of magnesium stearate and colloidal silicon dioxide was 0.25%-5%, preferably 0.5%-3%; the coating weight gain was 1.5%-8%, preferably 2%-5%.

[0299]

[0420] Tablet manufacturing

[0421] The formula weights of Compound I (free base, Form B), lactose monohydrate, colloidal silicon dioxide, microcrystalline cellulose, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose and magnesium stearate were weighed out. Hydroxypropyl cellulose, microcrystalline cellulose and colloidal silicon dioxide were screened together. Compound I, lactose monohydrate, croscarmellose sodium, microcrystalline cellulose and magnesium stearate were screened. The screened excipients, except for the granular outer phase (microcrystalline cellulose, croscarmellose sodium and magnesium stearate), were charged into a high shear wet granulation bowl and blended. Purified water was sprayed onto the blended powder. Additional purified water was sprayed as needed. The wet material continued to granulate after spraying. The wet material was filled through a screen. The above materials were filled into a fluid bed and dried, and the drying process was monitored by loss on drying. The dried granules were filled through a screen. The milled granules, additional croscarmellose sodium and microcrystalline cellulose were charged to a bin blender and blended. The magnesium stearate was then charged to the bin blender. The lubricated mixture was compressed into tablets.

[0300]

[0422] Tablet Coating

[0423] A 12% (w / w) Opadry® suspension was prepared. Core tablets were preheated until the exhaust temperature reached approximately 40-50°C, after which coating was initiated. The coating solution was sprayed until the coating weight gain reached the target range. After spraying was complete, heating was discontinued and the coated tablets were dried and removed.

[0301] [Table 28]

Claims

1. A crystalline form of (R)—N-(5-((4-((5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide (Compound I) or a pharmaceutically acceptable salt thereof.

2. 2. The crystalline form of claim 1, which is Form A of Compound I.

3. (a) having an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles (2θ) of 11.62±0.20, 12.48±0.20, 17.34±0.20, and 20.04±0.20 degrees; (b) an X-ray powder diffraction (XRPD) pattern containing peaks at diffraction angles (2θ) of 11.62±0.20, 12.48±0.20, 17.34±0.20, and 20.04±0.20 degrees; and having an XRPD pattern comprising at least one, two, three or more peaks at angles selected from the following: 10.68±0.20, 11.11±0.20, 16.02±0.20, 20.79±0.20, 23.71±0.20, and 24.64±0.20 degrees 2θ; (c) having an XRPD pattern comprising peaks at 10.68±0.20, 11.11±0.20, 11.62±0.20, 12.48±0.20, 16.02±0.20, 17.34±0.20, 20.04±0.20, 20.79±0.20, 23.71±0.20, and 24.64±0.20 degrees 2θ; (d) having an XRPD pattern comprising peaks at 5.95±0.20, 10.68±0.20, 11.11±0.20, 11.62±0.20, 12.48±0.20, 14.96±0.20, 16.02±0.20, 17.34±0.20, 20.04±0.20, 20.79±0.20, 22.01±0.20, 23.71±0.20, 24.64±0.20, and 27.60±0.20 degrees 2θ; (e) having an XRPD pattern substantially as shown in Table 7. (f) having an XRPD pattern substantially as shown in Figure 1; (g) has a DSC thermogram comprising an endotherm with an onset of desolvation at about 178.6°C and a peak at about 179.6°C. (h) has a TGA thermogram that exhibits a mass loss of about 0.23% upon heating from about 38°C to about 160°C; (i) having a TGA thermogram substantially similar to that in Figure 3; (j) has a DSC thermogram substantially similar to Figure 2; or (k) having a DVS vapor sorption gram substantially similar to that in Figure 4; The crystalline form of claim 2.

4. 2. The crystalline form of claim 1, which is Form B of Compound I.

5. (a) having an XRPD pattern comprising peaks at 9.39±0.20, 18.86±0.20, 19.50±0.20, and 20.06±0.20 degrees 2θ; (b) an XRPD pattern comprising peaks at 9.39±0.20, 18.86±0.20, 19.50±0.20, and 20.06±0.20 degrees 2θ; and having an XRPD pattern comprising at least one, two, three or more peaks at angles selected from the following: 10.59±0.20, 18.16±0.20, 18.56±0.20, 26.30±0.20, 33.71±0.20, and 34.81±0.20 degrees 2θ; (c) having an XRPD pattern comprising peaks at 9.39±0.20, 10.59±0.20, 18.16±0.20, 18.56±0.20, 18.86±0.20, 19.50±0.20, 20.06±0.20, 26.30±0.20, 33.71±0.20, and 34.81±0.20 degrees 2θ; (d) having an XRPD pattern comprising peaks at 9.39±0.20, 10.59±0.20, 18.16±0.20, 18.56±0.20, 18.86±0.20, 19.50±0.20, 20.06±0.20, 22.07±0.20, 22.91±0.20, 23.68±0.20, 24.00±0.20, 26.30±0.20, 33.71±0.20, and 34.81±0.20 degrees 2θ; (e) having an XRPD pattern substantially as shown in Table 8. (f) having an XRPD pattern substantially as shown in Figure 5; (g) has a DSC thermogram comprising an endotherm with an onset of desolvation at about 194.8°C and a peak at about 195.7°C. (h) has a TGA thermogram that exhibits less than 0.17% mass loss upon heating from about 38°C to about 178°C; (i) having a TGA thermogram substantially similar to that in Figure 7; (j) has a DSC thermogram substantially similar to Figure 6; or (k) having a DVS vapor sorption gram substantially similar to that in FIG. 8; The crystalline form of claim 4.

6. 2. The crystalline form of claim 1, which is a crystalline form of a pharmaceutically acceptable salt of Compound I, optionally wherein the pharmaceutically acceptable salt is selected from hydrochloride, L-(+)-tartrate, fumarate, sulfate, and maleate salts.

7. 2. The crystalline form of claim 1, which is a crystalline form of the hydrochloride salt of Compound I.

8. (a) having an XRPD pattern comprising peaks at 9.35±0.20, 17.21±0.20, 18.21±0.20, 19.79±0.20, and 21.17±0.20 degrees 2θ; (b) an XRPD pattern comprising peaks at 9.35±0.20, 17.21±0.20, 18.21±0.20, 19.79±0.20, and 21.17±0.20 degrees 2θ; and having an XRPD pattern comprising at least one, two, three or more peaks at angles selected from the following: 9.05±0.20, 19.54±0.20, 21.17±0.20, 21.51±0.20, 26.24±0.20, and 30.64±0.20 degrees 2θ; (c) having an XRPD pattern comprising peaks at 9.05±0.20, 9.35±0.20, 17.21±0.20, 18.21±0.20, 19.54±0.20, 19.79±0.20, 21.17±0.20, 21.51±0.20, 26.24±0.20, and 30.64±0.20 degrees 2θ; (d) having an XRPD pattern comprising peaks at 7.30±0.20, 9.05±0.20, 9.35±0.20, 14.85±0.20, 17.21±0.20, 18.21±0.20, 19.54±0.20, 19.79±0.20, 20.91±0.20, 21.17±0.20, 21.51±0.20, 23.25±0.20, 26.24±0.20, 27.43±0.20, and 30.64±0.20 degrees 2θ; (e) having an XRPD pattern substantially as shown in Table 16. (f) having an XRPD pattern substantially as shown in Figure 13; (g) has a DSC thermogram comprising an onset of desolvation at about 207.8°C and an endotherm with a peak at about 212.1°C; (h) has a TGA thermogram that exhibits a mass loss of about 0.76% when heated to about 175°C; (i) has a TGA / DSC thermogram substantially similar to Figure 20; or (j) having a DVS vapor sorption gram substantially similar to that in FIG. 23; The crystalline form of claim 7.

9. 2. The crystalline form of claim 1, which is a crystalline form of Compound I L-(+)-tartrate salt.

10. 10. The crystalline form of claim 9, which is Compound I L-(+)-tartrate Pattern I crystalline form.

11. (a) having an XRPD pattern comprising peaks at 5.34±0.20, 5.38±0.20, 10.50±0.20, 10.92±0.20, and 16.37±0.20 degrees 2θ; (b) an XRPD pattern comprising peaks at 5.34±0.20, 5.38±0.20, 10.50±0.20, 10.92±0.20, and 16.37±0.20 degrees 2θ; and having an XRPD pattern comprising at least one, two, three or more peaks at angles selected from the following: 11.84±0.20, 15.05±0.20, 17.86±0.20, 18.52±0.20, and 18.99±0.20 degrees 2θ; (c) having an XRPD pattern comprising peaks at 5.34±0.20, 5.38±0.20, 10.50±0.20, 10.92±0.20, 11.84±0.20, 15.05±0.20, 16.37±0.20, 17.86±0.20, 18.52±0.20, and 18.99±0.20 degrees 2θ; (d) having an XRPD pattern comprising peaks at 5.34±0.20, 5.38±0.20, 7.29±0.20, 10.50±0.20, 10.92±0.20, 11.84±0.20, 14.40±0.20, 15.05±0.20, 16.37±0.20, 17.86±0.20, 18.52±0.20, 18.99±0.20, 22.02±0.20, and 23.96±0.20 degrees 2θ; (e) having an XRPD pattern substantially as shown in Table 17. (f) having an XRPD pattern substantially as shown in Figure 9; (g) has a DSC thermogram comprising an onset of desolvation at about 207.8°C and an endotherm with a peak at about 212.1°C; (h) has a TGA thermogram that exhibits a mass loss of about 0.76% when heated to about 175°C; or (i) has a TGA / DSC thermogram substantially similar to Figure 15; The crystalline form of claim 10.

12. 10. The crystalline form of claim 9, which is Compound I L-(+)-tartrate Pattern II.

13. (a) having an XRPD pattern comprising peaks at 10.02±0.20, 18.03±0.20, 19.89±0.20, 21.15±0.20, and 21.26±0.20 degrees 2θ; (b) an XRPD pattern comprising peaks at 10.02±0.20, 18.03±0.20, 19.89±0.20, 21.15±0.20, and 21.26±0.20 degrees 2θ; and having an XRPD pattern comprising at least one, two, three or more peaks at angles selected from the following: 12.70±0.20, 13.76±0.20, 16.80±0.20, 20.92±0.20, and 22.82±0.20 degrees 2θ; (c) having an XRPD pattern comprising peaks at 10.02±0.20, 12.70±0.20, 13.76±0.20, 16.80±0.20, 18.03±0.20, 19.89±0.20, 20.92±0.20, 21.15±0.20, 21.26±0.20, and 22.82±0.20 degrees 2θ; (d) having an XRPD pattern comprising peaks at 7.95±0.20, 10.02±0.20, 12.70±0.20, 13.76±0.20, 15.91±0.20, 16.80±0.20, 18.03±0.20, 19.89±0.20, 20.92±0.20, 21.15±0.20, 21.26±0.20, 22.82±0.20, 23.44±0.20, 25.55±0.20, and 29.99±0.20 degrees 2θ; (e) having an XRPD pattern substantially as shown in Table 21. (f) having an XRPD pattern substantially as shown in Figure 14; (g) has a DSC thermogram comprising an onset of desolvation at about 137.2°C and an endotherm with a peak at about 140.4°C. (h) has a TGA thermogram that exhibits a mass loss of about 3.59% when heated to about 100°C; (i) has a TGA / DSC thermogram substantially similar to Figure 16; or (j) having a DVS vapor sorption gram substantially similar to that in FIG. 21; 13. The crystalline form of claim 12.

14. 2. The crystalline form of claim 1, which is a crystalline form of Compound I fumarate.

15. (a) having an XRPD pattern comprising peaks at 11.92±0.20, 13.71±0.20, 19.54±0.20, 20.15±0.20, and 24.21±0.20 degrees 2θ; (b) an XRPD pattern comprising peaks at 11.92±0.20, 13.71±0.20, 19.54±0.20, 20.15±0.20, and 24.21±0.20 degrees 2θ; and having an XRPD pattern comprising at least one, two, three or more peaks at angles selected from the following: 13.08±0.20, 15.79±0.20, 18.86±0.20, 20.63±0.20, and 22.14±0.20 degrees 2θ; (c) having an XRPD pattern comprising peaks at 11.92±0.20, 13.08±0.20, 13.71±0.20, 15.79±0.20, 19.54±0.20, 20.15±0.20, 18.86±0.20, 20.63±0.20, 22.14±0.20, and 24.21±0.20 degrees 2θ; (d) having an XRPD pattern comprising peaks at 11.63±0.20, 11.92±0.20, 12.33±0.20, 13.08±0.20, 13.71±0.20, 15.79±0.20, 17.23±0.20, 18.52±0.20, 18.86±0.20, 19.54±0.20, 20.15±0.20, 20.63±0.20, 22.14±0.20, 23.79±0.20, and 24.21±0.20 degrees 2θ; (e) having an XRPD pattern substantially as shown in Table 18. (f) having an XRPD pattern substantially as shown in Figure 10; (g) has a DSC thermogram comprising an endotherm with an onset of desolvation at about 48.9°C and a peak at about 68.3°C. (h) has a DSC thermogram further comprising an onset of desolvation at about 132.79°C and a subsequent endotherm having a peak at about 141.78°C; (i) has a TGA thermogram that exhibits a mass loss of about 2.86% when heated to about 55°C; (j) has a TGA thermogram that exhibits a mass loss of about 2.42% upon heating from about 55°C to about 140°C; (k) has a TGA / DSC thermogram substantially similar to Figure 17; or (l) having a DVS vapor sorption gram substantially similar to that in FIG. 22; 15. The crystalline form of claim 14.

16. 10. The crystalline form of claim 1, which is a crystalline form of Compound I sulfate.

17. (a) having an XRPD pattern comprising peaks at 6.00±0.20, 12.16±0.20, 17.37±0.20, 18.19±0.20, and 20.51±0.20 degrees 2θ; (b) an XRPD pattern comprising peaks at 6.00±0.20, 12.16±0.20, 17.37±0.20, 18.19±0.20, and 20.51±0.20 degrees 2θ; and having an XRPD pattern comprising at least one, two, three or more peaks at angles 2θ selected from the following: 7.54±0.20, 17.16±0.20, 19.52±0.20, and 22.65±0.20 degrees 2θ; (c) having an XRPD pattern comprising peaks at 6.00±0.20, 7.54±0.20, 12.16±0.20, 17.16±0.20, 17.37±0.20, 18.19±0.20, 19.52±0.20, 20.51±0.20, and 22.65±0.20 degrees 2θ; (d) having an XRPD pattern comprising peaks at 6.00±0.20, 7.54±0.20, 12.16±0.20, 14.90±0.20, 17.16±0.20, 17.37±0.20, 18.19±0.20, 19.52±0.20, 20.51±0.20, 22.02±0.20, 22.65±0.20, 24.86±0.20, and 25.73±0.20 degrees 2θ; (e) having an XRPD pattern substantially as shown in Table 19. (f) having an XRPD pattern substantially as shown in Figure 11; (g) has a DSC thermogram comprising an endotherm with an onset of desolvation at about 181.2°C and a peak at about 195.9°C. (h) has a DSC thermogram further comprising an endotherm with a later onset of desolvation at about 210.6°C and a peak at about 226.0°C; (i) has a TGA thermogram that exhibits a mass loss of about 4.85% when heated to about 120°C; or (j) having a TGA / DSC thermogram substantially similar to Figure 18; 17. The crystalline form of claim 16.

18. 2. The crystalline form of claim 1, which is a crystalline form of Compound I maleate.

19. (a) having an XRPD pattern comprising peaks at 11.94±0.20, 15.64±0.20, 16.10±0.20, 20.98±0.20, and 22.65±0.20 degrees 2θ; (b) an XRPD pattern comprising peaks at 11.94±0.20, 15.64±0.20, 16.10±0.20, 20.98±0.20, and 22.65±0.20 degrees 2θ; and having an XRPD pattern comprising at least one, two, three or more peaks at angles 2θ selected from the following: 4.90±0.20, 7.45±0.20, 24.27±0.20, and 25.67±0.20 degrees 2θ; (c) having an XRPD pattern comprising peaks at 4.90±0.20, 7.45±0.20, 11.94±0.20, 15.64±0.20, 16.10±0.20, 20.98±0.20, 22.65±0.20, 24.27±0.20, and 25.67±0.20 degrees 2θ; (d) having an XRPD pattern comprising peaks at 4.90±0.20, 7.45±0.20, 9.57±0.20, 11.94±0.20, 12.74±0.20, 13.19±0.20, 15.64±0.20, 16.10±0.20, 18.46±0.20, 20.98±0.20, 22.65±0.20, 24.27±0.20 degrees 2θ, and 25.67±0.20 degrees 2θ; (e) having an XRPD pattern substantially as shown in Table 20. (f) having an XRPD pattern substantially as shown in Figure 12; (g) has a DSC thermogram comprising an endotherm with an onset of desolvation at about 64.6°C and a peak at about 75.7°C. (h) has a DSC thermogram further comprising an endotherm with a later onset of desolvation at about 137.3°C and a peak at about 140.4°C; (i) has a TGA thermogram that exhibits a mass loss of about 3.59% when heated to about 100°C; or (j) has a TGA / DSC thermogram substantially similar to Figure 19; 19. The crystalline form of claim 18.

20. 20. The crystalline form of any one of claims 1 to 19, which is a substantially pure polymorph.

21. Compounds of formula (I): 【Chemical 1】 (In the formula, n=1 or 2; X is hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, L-(+)-tartaric acid, fumaric acid, citric acid, succinic acid, L-malic acid or maleic acid).

22. 21. A pharmaceutical composition comprising one or more crystalline forms of any one of claims 1 to 20 and a pharmaceutically acceptable carrier.

23. 23. The crystalline form of any one of claims 1 to 20, the compound of claim 21, or the pharmaceutical composition of claim 22, for use as a medicament for inhibiting ErbB or BTK.

24. 22. A pharmaceutical composition for inhibiting ErbB or BTK, comprising one or more crystalline forms of any one of claims 1 to 20, a compound of claim 21.

25. 22. A pharmaceutical composition for treating an ErbB-related or BTK-related disease in a subject, comprising one or more crystalline forms of any one of claims 1 to 20, or a compound of claim 21.

26. 26. The pharmaceutical composition of claim 25, wherein the ErbB-related disease is cancer.

27. 26. The pharmaceutical composition of claim 25, wherein the BTK-associated disease is cancer or an autoimmune disease.

28. 28. The pharmaceutical composition of claim 27, wherein the cancer is lymphoma or leukemia.

29. 29. The pharmaceutical composition of claim 28, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or Sjogren's syndrome.

30. 26. The pharmaceutical composition of claim 25, wherein the subject is a warm-blooded animal such as a human.

31. 31. The pharmaceutical composition of any one of claims 25 to 30, wherein the ErbB is EGFR or Her2, preferably mutant EGFR or mutant Her2.

32. The mutant EGFRs are EGFR D761_E762insEAFQ, EGFR A763_Y764insHH, EGFR M766_A767instAI, EGFR A767_V769dupASV, EGFR A767_S768insTLA, EGFR S768_D770 dupSVD, EGFR S768_V769insVAS, EGFR S768_V769insAWT, EGFR V769_D770insASV, EGFR V769_D770insGV, EGFR V769_D770insCV, EGFR V769_D770insDNV, EGFR V769_D770insGSV, EGFR V769_D770insGVV, EGFR V769_D770insMASVD, EGFR D770_N771insSVD, EGFR D770_N771insNPG, EGFR D770_N771insAPW, EGFR D770_N771insD, EGFR D770_N771insDG, EGFR D770_N771insG, EGFR D770_N771insGL, EGFR D770_N771insN, EGFR D770_N771insNPH, EGFR D770_N771insSVP, EGFR D770_N771insSVQ, EGFR D770_N771insMATP, EGFR delD770insGY, EGFR N771_P772insH, EGFR N771_P772insN, EGFR N771_H773dupNPH, EGFR delN771insGY, EGFR delN771insGF, EGFR P772_H773insPR, EGFR P772_H773insYN, EGFR P772_H773insX, EGFR P772_H773insDPH, EGFR P772_H773insDNP, EGFR P772_H773insQV, EGFR P772_H773insTPH, EGFR P772_H773insN, EGFR P772_H7732. The pharmaceutical composition of claim 31 , wherein the EGFR exon 19 deletion is selected from EGFR H773_V774insGH, EGFR V774_C775insHV, EGFR exon 19 deletion, EGFR L858R, EGFR T790M, EGFR L858R / T790M, EGFR exon 19 deletion / T790M, EGFR S768I, EGFR G719S, EGFR G719A, EGFR G719C, EGFR E709A / G719S, EGFR E709A / G719A, EGFR E709A / G719C, and EGFR L861Q.

33. 32. The pharmaceutical composition of claim 31, wherein the mutant Her2 is selected from the group consisting of Her2 A775_G776insYVMA, Her2 delG776insVC, Her2 V777_G778insCG, and Her2 P780_Y781insGSP.

34. 22. A compound of formula (I) according to claim 21, or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof, in combination with a second therapeutic agent, preferably an anti-tumor agent.

35. 22. A crystalline form according to any one of claims 1 to 20, or a compound according to claim 21, in combination with a second therapeutic agent, preferably an antitumor agent.

36. 23. The pharmaceutical composition of claim 22, further comprising a second active ingredient.

37. 1. A process for producing crystals of a pharmaceutically acceptable salt of Compound I, comprising dissolving Compound I in an acetone or ethanol solution, adding a corresponding acid to the acetone or ethanol solution, allowing the solution to crystallize, and isolating crystals of a pharmaceutically acceptable salt of Compound I, wherein the pharmaceutically acceptable salt is selected from hydrochloride, L-(+)-tartrate, fumarate, sulfate, and maleate.

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